Off-label uses of biologics in dermatology: Interferon and intravenous immunoglobulin (Part 1 of 2)

EBLUEPRINTS

Off-label uses of biologics in dermatology: Interferon and intravenous immunoglobulin (Part 1 of 2) David I. Smith, MD,a Pooja M. Swamy, MD,a and Michael P. Heffernan, MDb St. Louis, Missouri and Dayton, Ohio The introduction of a number of biologic therapies into the market has revolutionized the practice of dermatology. These therapies include interferons, intravenous immunoglobulin, infliximab, adalimumab, etanercept, efalizumab, alefacept, and rituximab. Most dermatologists are familiar with the Food and Drug Administrationeapproved indications of these medications. However, numerous off-label uses have evolved. As part 1 of a 2-part series, this article will review the literature regarding the off-label uses of the interferons and intravenous immunoglobulin in dermatology. ( J Am Acad Dermatol 2007;56:e1-54.)

INTERFERON Introduction The interferons are a family of cytokines composed of 3 main speciesealfa, beta, and gammae which are mainly derived from leukocytes, fibroblasts, and immune cells, respectively. The 3 species are divided into two subclasses: the type I subclass (interferon alfa-2a, interferon alfa-2b, and interferon beta) and the type II subclass (interferon gamma).1 The Food and Drug Administration (FDA)-approved indications for interferon are listed in Table I. All 3 species of interferons have similar antiviral and antiproliferative effects but differ in their immunemodulating properties. It is through these mechanisms of action that interferon has been used to treat numerous dermatologic diseases (Table II). Common side effects of interferon alfa include flu-like symptoms (fever, myalgia, arthralgias, fatigue, chills), anorexia, headaches, nausea, vomiting, diarrhea, sleep disturbances, hair thinning, injectionsite reactions, hypothyroidism and hyperthyroidism, and hyperglycemia. Other side effects include reversible bone-marrow suppression; transient hepatic enzyme elevations, which typically normalize 2 to 5 days after initiation of therapy; neurologic symptoms (paresthesia, motor weakness, dizziness, confusion, dysarthria, short-term memory loss); psychiatric

From Washington University, St. Louisa and Wright State University School of Medicine, Dayton.b Funding sources: None. Conflicts of interest: None identified. Reprint requests: Michael P. Heffernan, MD, Wright State University School of Medicine, Dayton, OH 45408-1445. E-mail: [email protected]. Published online November 10, 2006. 0190-9622/$32.00 ª 2007 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2006.06.016

Abbreviations used: AASV: antineutrophil cytoplasmic antibodye associated systemic vasculitis AD: atopic dermatitis Ag: antigen AK: actinic keratosis BCC: basal cell carcinoma BP: bullous pemphigoid CP: cicatricial pemphigoid CR: complete response DLE: discoid lupus erythematosus DM: dermatomyositis dsg: desmoglein FDA: Food and Drug Administration Ig: immunoglobulin ISA: immunosuppressive agent IV: intravenous IVIG: intravenous immunoglobulin LE: lupus erythematosus MMP: mucous membrane pemphigoid PF: pemphigus foliaceus PM: polymyositis PR: partial response PUVA: psoralen plus UVA PV: pemphigus vulgaris SCC: squamous cell carcinoma SCLE: subacute cutaneous lupus erythematosus SJS: Stevens-Johnson syndrome SQ: subcutaneous TEN: toxic epidermal necrolysis

complications, such as depression or suicidal behavior; sarcoidosis; pulmonary infiltrates (pneumonitis or pneumonia); renal insufficiency or failure; nephritic syndrome; pancreatitis; severe or fatal gastric hemorrhage; and rarely autoimmune diseases (immune thrombocytopenia, hemolytic anemia, hypothyroidism, diabetes mellitus, vasculitis, rheumatoid arthritis, lupus erythematosus (LE), and psoriasis), retinal hemorrhages, cotton-wool spots, or retinal artery or vein obstruction.2,3 Side effects of interferon beta are similar and include flu-like symptoms, headache, rigors, chest e1

e2 Smith, Swamy, and Heffernan

J AM ACAD DERMATOL JANUARY 2007

Table I. Interferon overview Interferon class

Alfa

Cell derived

Leukocytes

Human lymphoblastoid Beta

Fibroblasts, epithelial cells

Gamma

T lymphocytes, natural killer cells

Type

Product name

Interferon alfa-2a

Roferon A

Interferon alfa-2b

Intron A

Interferon alfa-n3 Interferon alfa-n1

Alferon N Wellferon

Interferon beta-1a

Rebif, Avonex

Interferon beta-1b Interferon gamma-1b

Betaseron Actimmune

FDA indication

Chronic hepatitis C, hairy cell leukemia, AIDS-related Kaposi’s sarcoma, Ph-positive CML Chronic hepatitis C and B, hairy cell leukemia, AIDS-related Kaposi’s sarcoma, malignant melanoma, follicular lymphoma, condyloma acuminata Condyloma acuminata Chronic hepatitis C and B, hairy cell leukemia, juvenile laryngeal papillomatosis, condylomata acuminata Relapsing forms of multiple sclerosis Relapsing forms of multiple sclerosis Chronic granulomatous disease and severe malignant osteopetrosis

CML, Chronic myelogenous leukemia; FDA, Food and Drug Administration.

pain, back pain, psychiatric disorders (depression, anxiety), asthenia, injection-site reactions/necrosis, elevation of liver enzymes, hematologic abnormalities (anemia, leukopenia, thrombocytopenia), thyroid abnormalities, abdominal pain, seizures, allergic reactions, and cardiac abnormalities (hypertension, palpitations, tachycardia). The side effects of interferon gamma include flulike symptoms, headaches, injection-site reactions, nausea, vomiting, hepatic enzyme abnormalities, granulocytopenia, thrombocytopenia, and increased serum triglycerides.4 Actinic keratoses Actinic keratosis (AK) is a premalignant cutaneous lesion of keratinocyte origin that has the potential to progress to squamous cell carcinoma (SCC) if not treated. Edwards et al5 demonstrated in a twophase study the effectiveness of intralesional interferon alfa-2b in the treatment of AKs. In phase I, 11 of 12 lesions cleared after 9 injections of interferon alfa-2b (0.5 3 106 U/injection) compared with none of 12 AKs injected with placebo. Smaller doses of interferon alfa-2b (0.1 and 0.01 3 106 U/injection) produced clearing of 42% and 58% of lesions, respectively. The second phase, which was designed to investigate the optimum schedule for treatment with interferon, showed that a minimum of 6 injections of interferon alfa-2b (0.5 3 106 U/injection) was necessary to clear 14 of 15 AKs. Although effective, the inconvenience of multiple injections, the adverse side effects, and the high cost of intralesional interferon alfa make this form of

Table II. Off-label dermatologic uses of interferon Actinic keratosis Squamous cell carcinoma Basal cell carcinoma Cutaneous T-cell lymphoma Angiosarcoma Hemangioma Tufted angioma Mastocytosis Keloids Herpes simplex virus Varicella zoster virus

Hansen’s disease Leishmaniasis Lupus erythematosus Scleroderma Behc¸et’s disease Alopecia areata Atopic dermatitis Lichen planus Chronic urticaria Urticarial vasculitis

therapy impractical. In a separate trial, Edwards et al6 were unable to show a statistically significant clearance effect of topical interferon alfa-2b gel (30 million IU/g applied 4 times/d for 4 weeks) versus placebo. Squamous cell carcinoma Interferon alfa has been evaluated in several small, open-label, prospective studies as a treatment for localized, recurrent, and metastatic SCC.3,7-13 A summary of these studies can be found in Table III. Interferon therapy, which produces excellent cosmetic results through minimal invasiveness and scarring, should be considered an effective alternative therapy for SCCs. The cure rate for early stage SCC with intralesional interferon alfa in one openlabel study involving 36 SCCs was 88%.7 Systemic interferon alfa has produced 34% to 68% overall response rates in advanced SCC depending on the adjunctive therapy used.10-13 Because of the high

Study type 7

Open-label, prospective

Kim3

Retrospective review

Toma10

Open-label, phase II trial

Lippman11

Open-label, phase II trial

Shin12

Olieman13

36 (28 Invasive and 8 in situ)

Treatment type

Dose 6

Schedule

Results

Interferon alfa-2b intralesional

1.5 3 10 U

3 3 /wk for 3 wk

88.2% Complete response, 93.9% had very good or excellent cosmetic results

3

Interferon alfa-2b intralesional

1-2.5 3 106 U (total dosage of 9-30 3 106 U)

3-5 wk

100% Complete response, no recurrences during mean follow-up period of 33 mo

35

(1) Interferon alfa-2a plus (2) isotretinoin

(1) 6 3 106 U, (2) 0.6-1 mg/kg

qd for 3 mo

41% Overall response (5 complete and 8 partial)

32 (Recalcitrant, difficult, or metastatic)

(1) Interferon alfa-2a SQ plus (2) isotretinoin

(1) 3 3 106 U (2) 1 mg/kg

qd at least 2 mo

68% Overall response, 25% complete response (advanced local disease response rate 93% vs regional disease response rate 67% vs distant metastases response rate 25%)

Open-label, phase II trial

39 (Advanced SCC)

(1) Interferon alfa SQ plus (2) isotretinoin plus (3) cisplatin IV injection

(1) 5 3 106 U/m2, (2) 1 mg/kg, (3) 20 mg/m2

3 3 /wk qd 1 3 /wk

34% Overall response, 17% complete response, 17% partial response (67% response rate for locally advanced vs 25% response rate for regional mestastasis vs 9% response rate for distant metastasis)

Multicenter, phase II

12 (Locally advanced SCC of extremities including primary, recurrent, or metastatic)

HILP with (1) interferon gamma plus (2) TNF-alpha plus (3) melphalan

Perfusion technique with (1) 0.2 mg (also given SQ qd for 2 d before HILP), (2) 3 (arm)-4 (leg) mg, (3) 10 (limb volume, leg)-13 (limb volume, arm) mg/L

N/A

67% Complete response, 25% partial response, 8% no change Follow-up: 75% achieved limb salvage, 25% had local recurrences, 8% regional lymph node metastases, 0% distant metastases

HILP, Hyperthermic isolated limb perfusion; IV, intravenous; N/A, not available; qd, once daily; SCC, squamous cell carcinoma; SQ, subcutaneous; TNF, tumor necrosis factor.

Smith, Swamy, and Heffernan e3

Edwards

No. of cases

J AM ACAD DERMATOL

Author

VOLUME 56, NUMBER 1

Table III. Squamous cell carcinoma

e4 Smith, Swamy, and Heffernan

J AM ACAD DERMATOL JANUARY 2007

cost and inconvenience of interferon, it should be mainly considered in patients with poor wound healing or poor circulation, with poor hemostasis, and who could be left with deformities or decreased function caused by operation.3 Basal cell carcinoma Interferon has been extensively studied in the treatment of basal cell carcinoma (BCC). A summary of the literature can be found in Table IV.3,14-25 In large prospective, controlled and uncontrolled clinical trials of noduloulcerative and superficial BCCs, intralesional interferon alfa-2b results in a cure rate of 67% to 86%.15,16 A sustained release preparation requiring once weekly injections is equally as effective.19 Interferon alfa-2b is much less effective in the treatment of morpheaform and recurrent BCCs, but can be used as an adjunct to operation by reducing the tumor burden.17 Intralesional interferon beta-1a produces a cure rate of 67% in nonmorpheaform BCCs.18 When an alternative to conventional therapies is required for BCCs, interferon should be considered an effective form of treatment with minimal invasiveness and scarring. As with SCCs, interferon should be considered in patients with poor wound healing from systemic disease or poor circulation, with poor hemostasis, and who could be left with deformities or decreased function caused by operation.3 However, interferon can be costly and timeconsuming. Because of its expense, interferon should be aimed at those who may require extensive home nursing or hospitalization with conventional methods and benefit from a better cosmetic result in problematic areas.25 Cutaneous T-cell lymphoma Cutaneous T-cell lymphoma is a malignancy of skin-homing T cells. Treatments include topical steroids, topical nitrogen mustard, psoralen plus UVA (PUVA), extracorporeal photopheresis, retinoids, and chemotherapy. Interferon has been shown to be an effective treatment option in several controlled and uncontrolled prospective trials and case series (Table V).26-40 Bunn and Norris27 reviewed 9 trials evaluating the effects of interferon on cutaneous T-cell lymphoma. They found that in a total of 126 patients, the overall response rate was 56% with a complete response (CR) rate of 17%. This response rate was similar to that achieved with combined chemotherapy but with less serious and more reversible side effects. The overall response rate to interferon alfa was 60% versus 31% with interferon gamma. However, only one interferon gamma study was evaluated. Patients with lower stage disease and who had not been

previously treated with chemotherapy had a higher overall response rate of 69% compared with 57% for those with advanced stage disease and previously treated with chemotherapy. Even though interferon alfa produces a high response rate, only a few achieved a CR with monotherapy and rarely did a patient attain long-term disease-free survival with interferon treatment. Combining treatment of interferon with retinoids30,31 or PUVA32 appears to increase the CR rate and lengthen the duration of remission. PUVA was more effective than acitretin when combined with interferon alfa-2a in one comparative study.32 Combination treatment with interferon alfa and PUVA in stage I to II mycosis fungoides resulted in a complete remission rate of 70% to 84% in the 3 largest clinical trials.32-34 Data on remission rates for higher stage disease are scantier, but CRs have been attained.33,35 Studies comparing interferon alfa and PUVA with PUVA alone have not been performed. Data evaluating interferon alfa in combination with extracorporeal photopheresis are limited and no strong conclusions can be drawn.39,40 Angiosarcoma Angiosarcomas are malignant vascular tumors that occur in 3 types: tumors associated with chronic lymphedema, tumors after irradiation, and tumors arising on the head in the elderly. Treatments include surgical excision and radiotherapy, which are associated with high rates of recurrence. Monotherapy with interferon alfa has been unsuccessful in the treatment of 3 patients with angiosarcoma.41,42 The combination of interferon alfa-2a with other agents has been more successful. A case of recurrent angiosarcoma of the face and scalp after electron beam therapy was treated with subcutaneous (SQ) interferon alfa-2a (6 3 106 IU/d) and oral 13cis-retinoic acid (1 mg/kg/d) for 6 months.43 This combination treatment produced stabilization of disease with histopathologic clearance of lesions. No relapse or progression was detected 20 months after initiation of therapy. The combination of intravenous (IV) doxorubicin (20 mg/m2 in 2-week cycles) and SQ interferon alfa-2a (4.5 3 106 IU 3 times/wk) resulted in a partial response (PR) in all metastatic sites of a patient with relapsing scalp angiosarcoma after operation and electron beam therapy.44 However, disease progression occurred after 17 months. Hemangiomas Hemangiomas are benign tumors of the vascular endothelium that mainly occur in the first few weeks of life and then undergo a rapid growth phase during the first year followed by regression. Interferon

Greenway

Study type 14

Cornell15

Open-label, prospective Randomized, multicenter, placebocontrolled

Chimenti16

Open-label, prospective

Buechner20

Open-label, prospective N/A

Healsmith21

No. of cases

8

4 11

4

Dogan22

Open-label, prospective Open-label, prospective

13

Retrospective review

11

Kowalzick18 Open-label, phase III, multicenter

139

Edwards19

Open-label, prospective

15

65

N/A Various

Nodular, infiltrating, recurrent Noduloulcerative and superficial Primary morpheaform and recurrent on face Recurrent or aggressive BCC of eyelids (adjunct in lesions with positive margins after resection) Solid and others

Nodular or superficial

BCC, Basal cell carcinoma; N/A, not available; SQ, subcutaneous.

Treatment type

Alfa-2 intralesional Alfa-2b intralesional

Dose

Schedule 6

1.5 3 10 U 1.5 3 106 U

Alfa-2b intralesional and perilesional Alfa-2b intralesional Alfa-2b intralesional

1.5-3 3 106 U

Alfa-2b intralesional

1-1.5 3 106 U

Alfa-2a intralesional Alfa-2b intralesional

3-4.5 3 106 U

Alfa-2b (SQ to affected area)

Beta-1a intralesional

Sustained-release protamine zinc chelate interferon alfa-2b formulation intralesional

1.5 3 106 U 1.5 3 106 U

1.5 3 106 U

3 3 106 U

3 3 /wk for 3 wk 3 3 /wk for 3 wk

3 3 /wk for 4-8 wk

100% Complete response 86% Complete response with interferon, 29% complete response with placebo, 81% of patients treated with interferon remained tumor free 1 year after starting treatment 67.1% Complete response, 23.6% partial response, 9.3% no response

3 3 /wk for 2 wk 9 injections

100% Complete response

3 3 /wk for 2 wk

10/11 No residual tumor

6/11 Complete response, 3/11 tumor size reduced, follow-up 12-26 mo no recurrence 8-9 injections 100% Complete response, over 3-3.5 wk no recurrences during mean follow-up period of 33 mo 3 3 /wk 84.6% Complete response for 4 wk 3 3 /wk 27% No residual tumor, for 3 wk 33% had .75 reduction in size, 40% no response

1 3 106 U 3 3 /wk for 3 wk

10 3 106 U

Results

Single injection (33 patients) or 1/wk for 3 wk (32 patients)

66.9% Complete response (relapse rate of only 4.5% with median follow-up of 2 years), good or very good cosmetic result in 83% 80% Cured with 3 injections, 52% cured with 1 injection, excellent or very good cosmetic results rated by patients (73%) or investigators (64%)

Smith, Swamy, and Heffernan e5

Retrospective review

Fenton24

Superficial or nodular Noduloulcerative or superficial

172 (130 Interferon and 42 placebo; 7 patients excluded from interferon group) 140 Noduloulcerative or superficial

Kim3

Stenquist17

BCC type

J AM ACAD DERMATOL

Author

VOLUME 56, NUMBER 1

Table IV. Basal cell carcinoma

Author

Study type 26

No. of cases

Treatment type

Dose 6

Schedule

Results

Interferon alfa-2b intralesional

1 3 10 U

3 3 /wk for 4 wk

10/12 Plaques showed complete clinical regression with interferon, 1/12 plaques showed complete clinical regression with placebo

Vonderheid26 (patients selected from previous study)

Open-label, prospective

5

Interferon alfa-2b IM

5 3 106 U

3 3 /wk for 4-16 wk

No clinically significant improvement

Bunn27

Review of 9 trials

Interferon alfa (8 studies) or interferon gamma (1 study)

3-50 3 106 U or 0.25-0.5 mg/m2

Various schedules qd

56% Overall response, 17% CR (overall response rate to interferon alfa was 60% vs 31% with interferon gamma)

McGinnis28

Case reports

(1) Interferon alfa-2b SQ plus (2) oral bexarotene

(1) 1.2-4 3 106 U, (2) 150 mg

(1) 3 3 /wk, (2) qd

Rapid clearing of skin disease in all 3 patients

Zachariae29

Open-label, prospective

11 (Stage II [5], stage IV [6])

(1) Interferon alfa-2a SQ alone (4 patients) or in combination with (2) oral etretinate (7 patients)

(1) 3-36 3 106 U, (2) 0.7 mg/kg

(1) Qd for 3 mo then 3 3 /wk for 12 mo, (2) qd

Stage II: CR in 1/5, PR in 3/5 Stage IV: CR in 0/6, PR in 3/6, not evaluable in 2/6

Aviles30

Open-label, prospective

12 (Stage IV)

(1) Interferon alfa-2a plus (2) oral etretinate

(1) 9 3 106 U, (2) 0.8 mg/kg

(1) 3 3 /wk for 1 y (increased to daily if no response or \50% of response after 6 mo), (2) qd for 1 y (discontinued after 6 mo if CR achieved)

83% CR (56% remained in complete remission after median follow-up of 3 y)

126 (110 Interferon alfa and 16 interferon gamma) 3

JANUARY 2007

6

J AM ACAD DERMATOL

Randomized, double-blind, placebocontrolled

Vonderheid

e6 Smith, Swamy, and Heffernan

Table V. Cutaneous T-cell lymphoma

Interferon alfa-2a plus etretinate

(1) 6-9 3 106 U, (2) 0.5 mg/kg

Interferon daily for 3 mo as monotherapy then in responders continued interferon 3 3 /wk alone (19 patients) or in nonresponders interferon 3 3 /wk combined with etretinate daily (26 patients) for total of 12 mo of treatment

62.2% Complete or partial remissions (17 patients monotherapy and 11 patients combination treatment), 20/25 MF stage I and II responded (12 monotherapy and 8 combination treatment), 8/20 stage IV or SS responded (5 monotherapy and 3 combination treatment)

Roenigk35

Open-label, phase I trial

15 (Stages Ib-IVb)

Interferon alfa-2a IM plus PUVA

6-30 3 106 U (maximum dose tolerated was 18 3 106 U)

3 3 /wk for 2 y

93.3% Overall response, 80% CR, 13.3% PR

Otte36

Open-label, prospective

11 (Stages Ib-IV)

Interferon alfa-2a SQ plus PUVA

9 3 106 U (and then maintained at 1.5 or 3 3 106 U 2-3 3 /wk)

3 3 /wk for 48 d

45% CR, 55% PR

Interferon alfa-2a SQ plus photochemotherapy

Maximum dose of 9 3 106 U

Once complete or partial remission was achieved, patients were continued on interferon 3-9 3 106 U/wk

10/13 CR, 3/13 PR (10-40 mo follow-up, 4 patients progressed and 4 patients developed local recurrence, remission was achieved in patients with local recurrence by repeating initial treatment schedule)

Interferon alfa-2a IM or SQ plus PUVA

6-30 3 106 U/m2 (maximum tolerated dose of 12 3 106 U/m2)

3 3 /wk

62% CR, 28% PR (3 nonresponders had largecell phenotype CTCL) (29 of 39 patients alive and median survival duration of 62 mo with range of 1-66)

Stadler

Kuzel38

37

Open-label, prospective

Open-label, phase I and II

16

39 (Stage Ib [14], IIa [5], IIb [6], III [8], IVa [5], IVb [1])

Continued

Smith, Swamy, and Heffernan e7

45 (Stage Ia [4], Ib [8], IIa [5], IIb [8], IVb [7], and 13 with SS)

J AM ACAD DERMATOL

Open-label, prospective, multicenter

VOLUME 56, NUMBER 1

Dreno31

Author

Study type

No. of cases

Treatment type

Dose 6

Schedule

e8 Smith, Swamy, and Heffernan

Table V. Cont’d Results

Open-label, phase II trial

63 (Stage Ia [6], Ib [37], IIa [3], IIb [3], III [12], IVa [2])

Interferon alfa-2a SQ plus PUVA

3-12 3 10 U

3 3 /wk

74.6% CR, 6% PR (5-y overall survival of 91% and 5-y disease-free survival of 75%)

Stadler32

Prospective, randomized multicenter clinical trial

82 (Stage I and II)

Interferon alfa-2a SQ plus PUVA (40 patients) vs interferon alfa-2a plus acitretin (42 patients)

9 3 106 U SQ plus PUVA vs interferon 9 3 106 U SQ plus acitretin 25 mg then 50 mg

Interferon 3 3 /wk plus PUVA vs interferon 3 3 /wk plus acitretin 25 mg qd for first wk then 50 mg qd

70% Complete remission 38.1% Complete remission

Rupoli34

Open-label, prospective, multicenter

89 (Stage Ia to IIa)

Interferon alfa-2b SQ plus PUVA

6-18 3 106 U SQ

1 3 /wk

84% Complete remission, 98% overall response rate

Wollina39

Open-label, prospective trial

14 (Stage IIa and IIb)

Interferon alfa-2a SQ plus extracorporeal photochemotherapy (oral 8-methoxypsoralen)

Maximum tolerable dose up to 18 3 106 U

3 3 /wk 2 3 /mo for 6 mo

28.6% CR, 21.4% PR (stage IIa response rate of 60% vs stage IIb response rate of 25%), total response rate of 46.2% in 13 patients after 1-y follow-up (5 of 9 with stage IIa and 1 of 4 with stage IIb responded)

Gottlieb40

Retrospective review

41 (Mainly stage III and IV with presence of circulating malignant T cells)

Interferon alfa SQ plus extracorporeal photochemotherapy

1.5-5 3 106 U

3-5 3 /wk

Combination of interferon alfa and photopheresis may produce higher response rates than photopheresis alone

JANUARY 2007

CR, Complete response; CTCL, cutaneous T-cell lymphoma; IM, intramuscular; PR, partial response; PUVA, psoralen-UVA; qd, once daily; SQ, subcutaneous; SS, Se´zary syndrome.

J AM ACAD DERMATOL

ChiarionSileni33

Study type

No. of patients

Treatment type

Dose

Interferon alfa-2a SQ

3 3 10 U/m

Qd for mean duration of 10.2 mo

42% Complete, 16% substantial, and 26% intermediate reduction in size

Ezekowitz46

Open-label, prospective (life- or visionthreatening hemangiomas)

20 (Neonates and infants)

Interferon alfa-2a SQ

3 3 106 U/m2

Qd for mean of 7.8 mo

18 Had $ 50% regression in their hemangiomas

Tryfonas47

N/A (lifethreatening hemangiomas)

10 (4 h-6.5 y)

Interferon alfa-2a SQ

3 3 106 U/m2 (increased daily from 1 to 3 3 106 U/m2 over first wk)

Every second day for mean of 10 mo

Total or almost total regression in 5 patients, partial regression in rest, no recurrences after mean follow-up of 8 mo

Ricketts48

Case reports

4 Infants and 1 child

Interferon alfa-2a SQ

Initially 1 3 106 U/m2 then sustained at 3 3 106 U/m2

Qd for 5-11 mo

3 Total or near total regression, 1 partial (50%) regression, 1 stabilization of disease

Bauman49

Open-label, prospective (organ-interfering or life-threatening)

10 (Median age of 4.5 mo)

Interferon alfa-2a SQ

3 3 106 U/m2

$ 3 mo

[50% Regression in 6 patients, 25%-50% regression in 2, \25% regression in 1 whose lesion had features suggestive of vascular malformation

Garmendia50

Open-label, prospective (organ-interfering or life-threatening)

Interferon alfa-2b SQ

3 3 106 U/m2

Qd for 6 mo

71.1% Regression in lesions including 68% \ age 1 y Continued

Smith, Swamy, and Heffernan e9

19 (Mean age 9.6 mo)

39

2

Results

Open-label, prospective trial (lifethreatening or massive hemangiomas)

Greinwald

6

Schedule

45

J AM ACAD DERMATOL

Author

VOLUME 56, NUMBER 1

Table VI. Hemangiomas

Author

Study type 51

No. of patients

Treatment type

Dose 6

Open-label, prospective (head and neck hemangiomas)

14 Infants and 1 adult (5 wk-24 y)

Interferon alfa-2b SQ*

3 3 10 IU/m

Tamayo54

Open-label, prospective (organ-interfering or life-threatening)

7 Infants

Interferon alfa-2b SQ

Chang53

Retrospective case reports (complicated hemangiomas)

4 Children

TeillacHamel55

Retrospective case series

Hastings52

Rampini56

Soumekh

Schedule 2

Results

80% Beneficial response, successful surgical resection in 3 patients with minimal response

3 3 106 U/m2

Qd during first mo and subsequently every 48-72 h for 3-12 mo

Considerable reduction of volume of hemangiomas and remission of complications in all 7 patients

Interferon alfa-2b (some also received corticosteroid treatment)

3 3 106 U/m2

Qd for 2-9 mo

3 Patients achieved involution of lesion, 1 developed mild gross motor delay that improved with cessation of treatment

4

Interferon alfa-2b SQ

3 3 106 U/m2

Qd for 15 d then 3 3 /wk for total of at least 2-3 mo

No response

Open-label, prospective (life- or organthreatening hemangiomas)

40 (2-36 mo)

Interferon alfa-2b SQ

3 3 106 U/m2

Qd for 3 mo then tapered or retreated according to response

Reduced orbital lesion volume by average of 82% in all patients, eye opening seen at average of 6 wk of treatment

N/A (complex cutaneous hemangiomas)

8 (2-11 mo)

Interferon alfa-2b SQ

1 3 106 U/m2 then 2 3 106 U/m2

3 3 /wk for first wk 3 3 /wk until end of treatment (mean of 8 mo)

$ 50% Regression in all 8 patients, just as effective as higher doses of interferon alfa, reduces cost of treatment by 60% JANUARY 2007

J AM ACAD DERMATOL

Qd for 6 mo then 3 3 /wk for additional 6 mo

N/A, Not available; qd, once daily; SQ, subcutaneous. *If platelet count \ 20,000/mm3 or bleeding disorder, interferon given twice/d at 3 3 106 IU/m2/dose intravenously; once normalized, once/d SQ resumed.

e10 Smith, Swamy, and Heffernan

Table VI. Cont’d

J AM ACAD DERMATOL

Smith, Swamy, and Heffernan e11

VOLUME 56, NUMBER 1

alfa-2a and -2b have been successfully used to treat hemangiomas in several open-label, prospective trials and case series (Table VI).45-56 However, because of the natural history of hemangiomas and their tendency to involute, it is difficult to determine how effective interferon alfa is without placebo-controlled trials. Treatment necessitates daily or every other day intralesional injections for at least 3 months and often longer, which is expensive and time-consuming. Moreover, in infants younger than 1 year, interferon alfa has the potential to produce permanent spastic diplegia or other forms of motor developmental disturbance.57,58 The use of interferon alfa should, therefore, be limited to function-impairing or life-threatening hemangiomas. To this end, Hastings et al52 have reduced lesion size by 82% in 15 patients with orbital hemangiomas by using SQ interferon alfa-2b (3 3 106 U/m2/d for 3 months). Similarly, Ezekowitz et al46 noted regression of 50% or more in life- or vision-threatening hemangiomas that were resistant to corticosteroids in 18 of the 20 patients with interferon alfa-2a. Greinwald et al45 had similar results. Likewise, Garmendia et al50 noted regression in 71% of lifethreatening or impairing hemangiomas in 39 children with interferon alfa-2b. Importantly, Garmendia et al50 noted regression in 68% of hemangiomas in infants younger than 1 year (n = 19) when spontaneous involution is rare. In conclusion, interferon alfa should be considered a viable treatment option for children with function-impairing or life-threatening hemangiomas. Tufted angioma Tufted angiomas are rare benign vascular neoplasms that occur most often in children and do not normally involute. There have been 3 case studies reporting the successful use of interferon alfa in the treatment of tufted angiomas59-61 and one case report showing no benefit.62 Mastocytosis Mastocytosis occurs in several forms: solitary mastocytomas, urticaria pigmentosa, diffuse cutaneous mastocytosis, telangiectasia macularis eruptiva perstans, and systemic mastocytosis. In a prospective, multicenter, phase II trial, 20 adults with systemic mastocytosis were treated for 6 months with daily SQ interferon alfa-2b (1-5 3 106 U/m2). PR and minor response, which mainly concerned vascular congestion and skin lesions, were observed in 65% of patients. Bone-marrow infiltration remained unchanged in the 12 affected patients.63 In a phase I study, 6 patients with systemic mastocytosis were treated with daily SQ interferon alfa-2b (0.5-3 3 106

U). In two patients, ascites resolved and two other patients reported improved energy levels and had decreased size of lymph nodes. Bone-marrow mastocytosis decreased by 5% to 10% after 12 months of therapy.64 Kolde et al65 treated 6 patients with urticaria pigmentosa with SQ injections of interferon alfa-2a (5 3 106 U 3-5 times/wk). Interferon therapy resulted in marked improvement in cutaneous symptoms and reduction of bone-marrow infiltration, but no change in skin lesions or reduction in the degree of mast cell infiltration of the skin. Other case reports have documented a beneficial effect of interferon alfa-2a and -2b in the treatment of mastocytosis.66-69 Keloids and hypertrophic scars Interferon alfa and gamma have been studied as treatments for keloids and hypertrophic scars because of their antiproliferative properties. Interferon gamma suppresses the synthesis of collagen in vitro and in vivo.70,71 Interferon alfa-2b causes keloidal fibroblasts to produce normal or subnormal amounts of collagen and glycosaminoglycans, normalizes levels of collagenase activity, and induces apoptosis in myofibroblasts.72,73 Interferon alfa-2b and interferon gamma have both been shown to antagonize the production of a fibrogenic cytokine, transforming growth factor-beta, in vitro and in vivo in hypertrophic scars.74 Both interferon gamma and interferon alfa-2b have been evaluated as potential monotherapy or adjuvant treatments for keloids and hypertrophic scars (Table VII).72,75-83 Three small prospective studies involving 23 participants have shown intralesional interferon gamma to be beneficial in the reduction of hypertrophic scar and keloid size.75-77 One small study did not find interferon gamma to be helpful in preventing recurrence of keloids after surgical excision.78 However, the dose of interferon gamma used in this study was low. The use of interferon alfa-2b as monotherapy for keloidal scars was unsuccessful in two prospective studies involving 18 evaluable participants.79,80 However, Tredget et al81 obtained positive results in 7 of 9 patients they treated with hypertrophic scars. Interferon alfa-2b was much less effective at preventing recurrence of keloids after surgical excision in one randomized, controlled study in comparison with intralesional Kenalog.82 In conclusion, interferon gamma may be beneficial in the treatment of keloids and hypertrophic scars, but the number of patients studied is small. Interferon alfa appears less effective in the treatment of keloids and hypertrophic scars.

Author

Study type 75

No. of cases

Treatment type

Dose

Schedule

Results

Interferon gamma intralesional

0.01 or 0.1 mg

3 3 /wk for 3 wk

Average reduction in height of keloids: 30.4% with interferon, 1.1% with placebo

Larrabee76

Open-label, prospective (keloids and hypertrophic scars)

10

Interferon gamma intralesional

Up to 0.05 mg

1 3 /wk for 10 wk

Reduction in linear dimensions (5/10 scars decreased by at least 50%) and flattening out of keloidal and hypertrophic scars

Pittet77

Open-label, prospective (hypertrophic scars)

7

Interferon gamma intralesional

6 3 106 U

2 3 /wk for 4 wk

6 Of 7 patients reported complete relief of symptoms and 1 reported very substantial improvement, decreased symptoms and size of lesions, at wk 16, 2 patients reported minimal reappearance of symptoms

Broker78

Double-blind, placebo-controlled trial (keloids after surgical excision)

Interferon gamma intralesional

10 g

10 Weekly injections

Did not prevent recurrence of keloids

al-Khawajah79

Placebo-controlled, prospective (keloids)

22

Interferon alfa-2b intralesional

0.5 3 106 U/cm2

Twice/wk for 3 wk

Insignificant reductions in height in 13 of 22 evaluable patients

Wong80

Open-label, prospective (keloids)

5

Interferon alfa-2b intralesional

0.6-3 3 106 U/mL

Once/3 d or weekly; tapered to once/2 wk in 3 patients

Ineffective

7/9 Evaluable

JANUARY 2007

6

J AM ACAD DERMATOL

Placebo-controlled trial (keloids)

Granstein

e12 Smith, Swamy, and Heffernan

Table VII. Keloids and hypertrophic scars

Tredget81

Open-label, prospective (hypertrophic scarring after thermal burn)

9

Davison82

Randomized, comparator

Berman83

Retrospective review (keloids after surgical excision)

Conejo-Mir84

Open-label, prospective

SQ, Subcutaneous; TAC, triamcinolone.

Interferon alfa-2b intralesional Interferon alfa-2b SQ

1.5 3 106 U

2 Injections

41% Reduction in area of keloid

2 3 106 IU

3 3 /wk for 24 wk

7 Of 9 patients had significant improvement in scar assessment and 3 of 9 patients had significant reductions in scar volume, no recurrence in all patients

13 Treated with interferon after surgical excision, 26 treated with triamcinolone acetonide

(1) Interferon alfa-2b intralesional or (2) TAC

(1) 1 3 106 U/linear cm or (2) 10 mg/ linear cm

Repeated in 1 wk

7/13 (54%) Of interferontreated lesions recurred, 4/26 (15%) of TAC-treated lesions recurred

16 Treated with interferon after surgical excision, 65 treated with triamcinolone acetonide after surgical excision, 43 without postoperative injections

(1) Interferon alfa-2b intralesional or (2) TAC

(1) 1 3 106 U in 0.1 mL/linear cm/treatment (12/16 sites were also treated with 5 3 106 U after 1 wk) or (2) 10-40 mg/mL/ treatment

On same day of excision on same day of excision and 7 d postoperation in 61/65

Only 18.7% (3/16) of interferontreated lesions recurred (P = .025), 51.1% (22/43) of lesions excised without postoperative injections recurred, 58.5% (38/65) TAC-treated lesions recurred

Interferon alfa-2b sublesional and perilesional after carbon dioxide laser ablation

3 3 106 IU

3 3 /wk for 3 wk

After 3-y follow-up, 66% of 30 keloids did not recur

30

Smith, Swamy, and Heffernan e13

1

J AM ACAD DERMATOL

Case report (keloid)

VOLUME 56, NUMBER 1

Berman72

e14 Smith, Swamy, and Heffernan

J AM ACAD DERMATOL JANUARY 2007

Warts Warts are common, benign proliferations produced in the epidermis by infection with the human papillomavirus. Recombinant interferon alfa and beta, human leukocyte interferon, and lymphoblastoid interferon have all shown efficacy in the treatment of warts as summarized in Table VIII.85-96 Most studies have involved small sample sizes. In the only double-blind, placebo-controlled study, which involved 64 patients treated with intralesional interferon beta, 81% of interferon-treated extremities had either a significant improvement (10 patients) or a cure (42 patients) versus only a 17% response rate (4 patients with a significant improvement and 7 patients with a cure) in placebo-treated extremities.85 An average of 5.9 injections with interferon beta was needed to produce a cure. Interferon has also been used to treat epidermodysplasia verruciformis. Intralesional interferon alfa or beta has been partially effective in patients with epidermodysplasia verruciformis but the treatment has been difficult to tolerate based on the number of lesions patients possess.97,98 Results from systemic treatment have been mixed and relapse is common after discontinuation.97-99 Herpes simples virus Herpes simplex virus types 1 and 2 cause herpes labialis, genital herpes, and more severe infections. Because of its antiviral properties, interferon has been studied as a treatment option for herpes simplex virus infections (Table IX).100-123 Interferon has been most studied in genital herpes where large, randomized, placebo-controlled clinical trials have been performed to evaluate the effectiveness of topical and systemic interferon alfa. For the treatment of primary infection, two randomized, double-blind, placebo-controlled studies have been performed using systemic interferon alfa, but the results were mixed.100,101 In regard to recurrent episodes, two double-blind, placebo-controlled studies and one open-label study involving 273 patients have validated that SQ interferon alfa-2a is effective in shortening the healing time and reducing of the duration of viral shedding.102-104 As little as a single dose of SQ interferon alfa-2a (6 3 106 U) can be effective. Repeated treatments can prevent further recurrences.102 Kuhls et al104 and Pazin101 suggest that the effects of systemic interferon alfa are similar to or less than acyclovir. Indeed, a controlled trial in 105 patients comparing topical acyclovir with intramuscular interferon alfa-2a found a trend toward superiority of acyclovir in all categories evaluated (time to crusting, healing, negative culture, and cessation of pain).105

Topical interferon alfa, in gel, cream, and ointment formulations at various concentrations and dosing schedules, has also been studied in a number of large, double-blind, placebo-controlled trials for the treatment of genital herpes.107-115 With the exception of one study,115 topical interferon alfa has been shown to be more effective than placebo in the treatment of primary107-109 and recurrent110-114 genital herpes. Interferon beta cream has also been shown to be effective in preventing recurrences of genital herpes in placebo-controlled studies.116,117 Other studies of interferon in the treatment of herpes labialis and other forms of herpes, such as herpes keratitis and severe systemic infections, have been limited to case reports and case series.118-121 Interferon may also be effective as prophylaxis against herpes labialis after surgical procedures.122 In summary, systemic interferon alfa is effective for the reduction of symptoms, healing time, and duration of viral shedding in recurrent genital herpes and other forms of herpes, but with more tolerable, less expensive, antiherpetic therapies available such as acyclovir, systemic interferon alfa is considered a second-line therapy. Topical interferon alfa may be useful for infrequent recurrences,110 active episodes,114 or as an adjunct to reduce acyclovir-resistant strains of herpes simplex virus.112 In addition, there may be a role for topical interferon alfa as an alternative to acyclovir for patients whose recurrence frequency rate does not warrant chronic oral acyclovir suppression114 or for patients who do not want to take oral acyclovir.112 Varicella zoster virus Varicella zoster virus, a member of the human herpesvirus family, presents itself in two forms. The primary infection is referred to as varicella or chickenpox whereas the recurrent infection, which is a result of latent varicella zoster virus replication, is referred to as herpes zoster or shingles. A number of case series and clinical trials have evaluated interferon in the treatment of herpes zoster (Table X).122,124-134 Early placebo-controlled studies with systemic human leukocyte interferon in 254 patients with herpes zoster demonstrated a positive effect of interferon in shortening the duration of pain,124,125 enhancing healing,124,125 limiting cutaneous126-128 and visceral126 dissemination, and reducing the severity of postherpetic neuralgia.126,127 Of those treated, 161 were immunosuppressed patients with cancer. More recent studies using interferon alfa-2a have achieved similar results. In a randomized, controlled study comparing interferon alfa (10 3 106 U/d SQ) with acyclovir (5 mg/kg IV 3 times/d), Duschet et al130 found interferon alfa-2a to be as effective as acyclovir

Study type 89

No. of cases

Double-blind, placebo-controlled

8 (4 Interferon, 4 placebo)

Pazin90

Case report

Niimura85

Double-blind, placebo-controlled trial

64

Beissert91

Case report (disseminated, recurrent for 13 y)

Niimura86

Open-label, prospective (verruca plana)

Schoenfeld92

Case report (resistant verruca plana on face)

Dose

Schedule 5

Results

Interferon alfa-2 intralesional

0.1 mL of 10 U into single wart

3 3 /wk for 3 wk

Improvement in 86.1% with interferon vs 38.0% with placebo

Interferon alfa Intralesional

1.2 3 106 U

2 3 /wk for 15.5 wk

Progressive disappearance of common warts

Interferon beta intralesional

0.1 3 106 U

Maximum of 10 weekly injections (interferon in 1 extremity and placebo in matching extremity)

With interferon 81% of patients had either cure (42) or significant improvement (10), with placebo 17% had either cure (7) or significant improvement (4); average of 5.9 injections needed to produce cure, significant difference after 5 injections (P \ .001)

1

Interferon beta SQ

Starting at 1 3 106 U, titrating up to 9 3 106 U

Every other day, 3 3 /wk for 6 wk

Complete remission with sustained remission 3 mo after therapy

45

Interferon beta SQ

0.3 3 106 U

1 3 /wk for [3 mo

Overall response rate of 54% (17 complete response, 3 partial response, 17 no response, 8 dropouts)

Interferon beta topical (Frone cream)

1 3 105 U/mL

3 3 /d for 23 d

Complete resolution with no recurrence for at least 2 y

1

1

Continued

Smith, Swamy, and Heffernan e15

Berman

Treatment type

J AM ACAD DERMATOL

Author

VOLUME 56, NUMBER 1

Table VIII. Verrucae vulgaris

Author

Study type

No. of cases

Treatment type

Dose

Schedule

Results

9

Natural human leukocyte interferon alfa intralesional

1 3 104 U/mL (n = 3) and 1 3 106 U/mL (n = 6)

Single dose/wart

Complete response achieved in 7 by 12 wk

Brodell87

Open-label, prospective (palmar and plantar warts)

22

Interferon alfa-n3 intralesional (administered with needleless injector)*

0.1 mL/injection (large warts required [1 injection)

2 3 /wk for minimum of 8 wk or until clear

73% Showed complete clearing of lesons in mean of 11 wk, 81% remained clear at follow-up of 9.5 mo

Naples94

Case reports (palmar and plantar warts)

2

Interferon alfa-n3 intralesional (needleless injector)*

0.5 3 106 U

Biweekly

Complete resolution of lesions

Gibson95

Open-label, prospective (resistant common and plantar warts)

7

Human lymphoblastoid interferon alfa intralesional

0.5-1 3 106 U

2 3 /wk for 6 wk

4 Complete and 2 partial clearance of lesions

Gibson96

Open-label, prospective (resistant common and plantar warts)

39

Human lymphoblastoid interferon alfa: (1) intralesional; (2) IM into hip region; and (3) needleless injectory into or immediately adjacent to lesions (some warts needed prior preparation)

(1) 1.1-5.8 3 106 U, (2) low dose 5.6 3 106 U or high dose 14 3 106 U then 10.64 3 106 U, (3) dose dependent on site, size, and No. of warts

(1) 1 3 /wk for 12 wk, (2) low dose/wk in 2 divided doses for 6 wk or high dose/wk in 5 divided doses for 2 wk and highest dose/wk in 2 divided doses for another $ 2 wk, (3) once-twice/wk for 6-12 wk

Intralesional route most favorable because of acceptable therapeutic ratio, quick application of procedure, and no prior prepsration of lesion needed, 11/12 IL cases attained complete clearance, only 5/16 IM cases had encouraging results, results for dermojet somewhere between IL and IM

JANUARY 2007

Open-label, prospective (recurrent, persistent, common warts)

J AM ACAD DERMATOL

Pueyo93

IL, Intralesional; IM, intramuscular; SQ, subcutaneous. *Dermo-Jet, Robbins Instruments, Inc, Chatham, NJ. y Pan-Jet, Shuco International London Ltd, London.

e16 Smith, Swamy, and Heffernan

Table VIII. Cont’d

Study type

No. of cases

Treatment type

Dose

Schedule

Results

Genital herpes

Randomized, double-blind (first episodes of infection)

31 (18 Women and 13 men, 16 interferon and 15 placebo)

Interferon alfa-2 SQ

5 3 106 U followed by 1 3 106 U

Qd for 5 d 3 3 /wk for 3 mo

Pazin101

Double-blind, placebocontrolled trial (first episodes in women)

64 (34 Interferon, 30 placebo)

Interferon alfa IM (given within 3 d of onset of lesions)

5 3 104 U/kg (approximately 3 3 106 U/d)

12 doses over 14 d

Cardamakis102

Open-label, prospective (recurrent herpes)

97

Interferon alfa-2a SQ

3 3 106 U

3 3 /wk for 4 wk then repeated after 3 and 6 mo

Lassus103

Double-blind, placebocontrolled (recurrent herpes)

Interferon alfa-2a SQ (given within 24 h after first signs of recurrence)

6 or 18 3 106 U

Either as single dose followed by 2 doses of placebo or 3 consecutive doses

100 (20 Patients in each group)

No effect on first episode; in men, significant reduction of healing time and duration of viral shedding in recurrences were observed during administration of interferon treatment whereas same trends were observed 6 mo after maintenance therapy but were not significant; in women, same trends were also seen during administration of interferon treatment but they were not significant and were not observed after maintenance therapy Interferon produced quicker healing of initial episodes and significant reductions in duration of virus shedding; interferon had no significant effect on pain; interferon produced no effect on subsequent recurrences in 1-y follow-up Prevented recurrence in 51 patients (20 male and 31 female); significant responses included shortened healing time (2.5 vs 8.5 d), decreased duration of pain, itching, and burning, and reduced No. of recurrences (2.64 vs 7.46) during study period Recommended optimal regimen: single dose of 6 3 106 U; no dose-response relationship; interferon significantly reduced duration of recurrent episode by about 50%; reduction of [50% in healing time in 81% with interferon vs 10% with placebo; interferon did not prevent or prolong interval between recurrences and did not shorten duration of subsequent recurrence Continued

Smith, Swamy, and Heffernan e17

Mendelson100

J AM ACAD DERMATOL

Author

VOLUME 56, NUMBER 1

Table IX. Herpes simplex virus

Author

Study type

No. of cases

Treatment type

Dose

Schedule

e18 Smith, Swamy, and Heffernan

Table IX. Cont’d Results

Genital herpes

Double-blind, placebo-controlled (recurrent herpes)

76 (14 Low dose, 20 high dose, 34 placebo)

Interferon alfa-2a SQ

1 or 3 3 106 U

3 3 /wk for 12 wk

Levin105

Double-blind, placebo-controlled trial (first episode and recurrent herpes)

105 (53 Interferon, 52 acyclovir)

(1) Interferon alfa-2a IM vs (2) topical acyclovir ointment

(1) 9 3 106 U (2) vs 5% ointment

(1) Qd for 5 d Although not significant, topical acyclovir superior to interferon during 9-d alfa-2a in all categories evaluated treatment (time to crusting, healing, negative period vs (2) culture, and cessation of pain); applied significant side effects (anorexia, every 4 h nausea, fatigue, fevers, chills, while awake headaches, leukopenia) with for 7 d interferon alfa-2a; interferon alfa-2a had no affect on recurrence rate; recurrence rates of acyclovir group were similar to reports of previous untreated patients

Eron106

Double-blind, placebo-controlled trial (frequent recurrent herpes)

37 (20 Interferon, 17 placebo)

Interferon alfa-2b SQ

3 3 106 U

3 3 /wk for 12 wk

Minimal effects on suppression of recurrences and moderate toxicity (chills, fever, fatigue, and leukopenia) with interferon alfa

Syed107

Placebo-controlled, double-blind (first episodes of herpes in Asian male patients)

60 Male patients (30 in each group)

Interferon alfa in hydrophilic cream

2 3 106 U/g

3 3 /d for 5 d

Interferon produced significant reductions in mean duration of healing and in local and systemic symptoms in male patients; 80% cured in interferon group vs 17% in placebo group; after 22 mo, 17% of cured patients showed recurrence

Syed108

Placebo-controlled, double-blind (first episodes of herpes in Asian female patients)

60 Male patients (30 in each group)

Interferon alfa in hydrophilic cream

2 3 106 U/g

3 3 /d for 5 d

Interferon resulted in significantly shorter mean duration of viral shedding and healing of lesions in female patients; 83.3% cured in interferon group vs 17% in placebo group After 22 mo, 10% of cured patients showed recurrence

Low dose not effective; higher dose produced shorter period of viral shedding, fewer outbreaks during study, less itching, and faster healing time

JANUARY 2007

J AM ACAD DERMATOL

Kuhls104

2 3 106 U/g

3 3 /d for 5 d

Shupack111

Double-blind, placebo-controlled clinical trial (recurrent herpes)

98 (41 Low-dose interferon, 25 high-dose interferon, 31 placebo)

Interferon alfa gel (applied during prodromal phase or at first sign of recurrence)

104 or 106 IU/g in 1% nonoxynol 9 base

3 3 /d for 7 d

Lebwohl110 Randomized, double-blind, placebo-controlled clinical trial (recurrent herpes)

387 (237 Interferon, 150 placebo)

Interferon alfa-2 gel

6 3 106 U/g

4 3 /d for 4 d

Shupack112

Double-blind, placebo-controlled trial (recurrent herpes)

105 U/g

4 3 /d until resolution or up to maximum of 7 d

FriedmanKien113

Double-blind, placebo-controlled (recurrent herpes)

Interferon alfa in 40 (20 Completed hydrophilic ointment therapy with base combined with 12 medicated and 5% dimethyl sulfoxide 8 placebo) (applied at onset of first prodromal symptoms) Interferon alfa with 128 (37 Low-dose 1% nonoxynol interferon, 9 in cream base 46 high-dose interferon, 45 placebo)

104 or 106 U/g

3 3 /d for 5 d

Sacks114

Randomized, double-blind, placebo-controlled (recurrent herpes)

103 or 106 U/g

3 3 /d for 5 d

188 (Only 99 assessable; 34 low-dose interferon, 35 high-dose interferon, 30 placebo)

Interferon alfa combined with 0.1% (low dose) or 1% (high dose) nonoxynol 9 in 3.5% methylcellulose gel

Interferon cream produced significantly shorter mean duration of lesions than gel and placebo; cure rates of 80% with interferon cream, 55% with interferon gel, and 20% with placebo; at 24-mo follow-up, 4 of cured patients had relapse after 18 mo High dose significantly more effective in reducing duration of viral shedding, pain, burning, and itching; no difference between groups in regard to time to crusting or healing Interferon produced 26% reduction in duration of viral shedding; in men, interferon produced significant reductions in time to crusting, duration of pain, and itching (these were not significant for women) Interferon resulted in significantly more rapid cessation of viral shedding and more rapid healing

End of new lesion formation and less frequent scabbing of lesions was statistically superior in low vs high dose and placebo; faster healing of lesions was statistically superior in low vs high dose No significant effect on time to crusting or time to healing; high dose statistically reduced virus shedding and lesion symptoms

Continued

Smith, Swamy, and Heffernan e19

Interferon alfa in hydrophilic cream vs gel vs placebo

J AM ACAD DERMATOL

60 (20 In each Double-blind, group) placebo-controlled, comparative (first episodes of herpes in male patients)

VOLUME 56, NUMBER 1

Syed109

Author

Study type

No. of cases

Treatment type

Dose

Schedule

e20 Smith, Swamy, and Heffernan

Table IX. Cont’d Results

Genital herpes

Ophir116

Randomized, double-blind, placebo-controlled trial (recurrent herpes)

Eron115

Double-blind, placebo-controlled trial (recurrent herpes)

Glezerman117

35 (22 Interferon, 13 placebo)

Interferon beta cream (Frone)

105 U/g (0.2 g/ application)

30 or 10 3 Topical interferon 94 (18 High-dose 106 U/ml alfa-2a (aqueous interferon, solutions) 22 low-dose interferon, 19 placebo) 105 U/g Topical interferon 25 (Interferon with Double-blind, beta gel (applied labial herpes [7] or placebo-controlled locally during recurrent genital trial (herpes of lips eruptions) herpes [5] and [n = 14] or genitals placebo with labial [n = 11]) herpes [7] or genital herpes [6])

6 3 /d for 5 d until lesions disappeared or crusted; resumed at first sensation of itching for any recurrent eruption that occurred over 6-mo trial 6 3 /d for 5 d

Topical episodic treatment with interferon beta significantly decreased average recurrences/y from 11 to 2.2 and produced overall response of 77.3%; 36.4% complete responders (more complete responders in women, 46.1% vs 22.2%) Not effective for duration of virus shedding, time to crusting, or time to healing

4 3 /d

Interferon reduced mean No. of recurrences (P \ .007), duration of eruptions (P \ .007), and symptoms and severity of disease after 2-y follow-up; no side effects observed; interferon beta reduced frequency of labial herpes 4- to 1-fold and genital herpes 3- to 1-fold

Qd (dose divided between morning and evening injections) for 5 d starting on day before operation

5 of 19 Patients treated with interferon developed herpes labialis vs 10 of 18 in placebo group; interferon produced statistically significant reductions in lesions, oropharyngeal virus shedding, and duration of shedding

3 Doses (morning and evening on day before operation and morning of operation), 7 doses (evening after operation then 2 3 /d for 3 d

Presurgical treatment with interferon alone may actually precipitate and accentuate HSV infection in comparison with concurrent controls (P \ .05) whereas postsurgical treatment alone had no affect

Other forms of HSV

Pazin122

Interferon alfa IM

7 3 104 U/kg

Interferon alfa 3.5 3 104 IM presurgical or U/kg postsurgical

JANUARY 2007

J AM ACAD DERMATOL

Ho123

Double-blind, placebo- 42 (19 Interferon, 18 placebo) controlled trial (patients with herpes labialis undergoing microneurosurgical procedures on trigeminal-nerve root) 55 (11 Presurgical Placebo-controlled interferon, 23 post trial (patients with surgical interferon, herpes labialis 21 placebo) undergoing microvascular decompression for trigeminal neuralgia)

1

(1) 3 3 106 U (1) Interferon alfa IM and minimal and (2) 20 mg doses of 2 3 /d (2) cytarabine hydrochloride SQ

Levin120

Open-label, prospective

Interferon 4 (Subset involving alfa IM immunosuppression with spreading HSV) 1 (infant with herpes simplex acute fulminant hepatitis)

Isacsohn121

Placebo-controlled trial

13 HSV dermatitis, 12 herpes labialis, 5 placebo with HSV dermatitis

Human fibroblast interferon cream

3 3 106 U Infant received 105 U/kg

Rapid complete healing of skin lesions with remission of leukemia

Qd for 4 d Qd

Subset of 4 achieved dramatic recovery with interferon, which dramatically decreased pain within several hours of first injection, halted spread of infection within 24 h, and began drying eruption within 1-2 d; infant was critically ill when treatment began and died on d 5

N/A

Study too small for statistically significant results; interferon shortened course of disease without any side effects in adults and children; 5/6 patients with labial herpes who served as their own controls in second phase, which evaluated interferon effects on recurrences, did not develop vesicles and adenopathy

Continued

Smith, Swamy, and Heffernan e21

HSV dermatitis 105 U/mL labial herpes: first phase, 105 U/mL; second phase (applied during occurrence of premonitory local symptoms) 5 3 105U/mL on buccal mucosa and 105 U/mL externally on peribuccal area

12 Daily injections during 15-d treatment period

J AM ACAD DERMATOL

Case report (AML and extensive progressive cutaneous HSV infection)

VOLUME 56, NUMBER 1

Shalev118

Author

Study type

No. of cases

Treatment type

Dose

Schedule

e22 Smith, Swamy, and Heffernan

Table IX. Cont’d Results

Other forms of HSV

Giani119

Case report (HIV-infected man with destructive mucocutaneous phagedenic HSV infection who was acyclovir resistant and foscarnet intolerant)

1

Lymphoblastoid interferon lymphoblastoid interferon topically and UV rays

3 3 106 U and 1.5 3 106 U

Alternate days Qd

Achieved partial response

Glezerman117

Double-blind, placebo-controlled trial (herpes of lips [n = 14] or genitals [n = 11])

25 (Interferon with labial herpes [7] or recurrent genital herpes [5] and placebo with labial herpes [7] or genital herpes [6])

Topical interferon beta gel (applied locally during eruptions)

105 U/g

4 3 /d

Interferon reduced mean No. of recurrences (P \ .007), duration of eruptions (P \ .007), and symptoms and severity of disease after 2-y follow-up; no side effects observed; interferon beta reduced frequency of labial herpes 4- to 1-fold and genital herpes 3- to 1-fold

AML, Acute myelogenous leukemia; HSV, herpes simplex virus; IM, intramuscular; N/A, not available; qd, once daily; SQ, subcutaneous.

JANUARY 2007

J AM ACAD DERMATOL

Study type

No. of cases

Treatment type

Dose

1 3 10 U 37 (3 Disseminated Exogenous form, 25 localized human form, 9 control) leukocyte interferon IM

Emodi125

Placebocontrolled, prospective

62 (36 Localized or disseminated disease and 26 control)

1 3 106 U Exogenous human (30 patients) leukocyte 3 3 106 U interferon IM (6 patients)

Merigan126 3 Placebocontrolled, randomized, doubleblind trials

90 Zoster and cancer (45 interferon, 45 placebo)

Human leukocyte interferon

Merigan127 Placebocontrolled, randomized, doubleblind trial

21 Zoster and cancer (11 interferon, 10 placebo)

Human leukocyte interferon

Arvin128

44 Children with zoster and cancer (23 interferon, 21 placebo)

Human First phase, 4.2 3 104 First phase, divided into leukocyte 2 doses/d until no new to 2.5 3 105 U/kg/d; interferon IM vesicles had appeared for 24 h; second phase, 3.5 3 second phase, divided into 105 U/kg/d followed 2 doses/d for 48 h; third phase, by 1.75 3 105 U/kg/d divided into 2 doses/d for 72 h

Two-phase, randomized, doubleblind, placebocontrolled trial

Results

Qd for 5-8 d

Shortened duration of pain and enhanced development of crust formation in comparison with control group

Single daily dose

Achieved shorter duration of pain, enhanced development of crust formation, and accelerated viral clearance from lesions in comparison with control group

First trial, 4.2 3 104 U/kg; second trial, 1.7 3 105 U/kg; third trial, 2.55 3 105 U/kg

First and second trials, first dose followed by half that dose every 12 h until d 8 after rash onset (if cutaneous dissemination present, interferon continued until no new lesions appeared); third trial, every 12 h for 4 doses then half that dose every 12 h until d 7 of rash

Total treatment for all trials ranged from 5-7 d; higher doses in second and third trial significantly limited cutaneous dissemination, limited progression within primary dermatome, and reduced severity of postherpetic neuralgia; third trial had no dissemination of disease; interferon-treated patients had 6 times less frequent visceral complications and trend toward less acute pain than control group

2.55 3 105 U/kg IM

Every 12 h

48 h of interferon treatment during early phase of infection had no effect on acute pain or disease progression within primary dermatome but had modest significant effects on diminishing distal cutaneous spread and reducing severity and duration of postherpetic neuralgia First phase, 81% with interferon produced no new lesions for 24 h by d 7 vs only 56% with placebo; second phase, 92% with interferon developed no new lesions for 24 h by d 6 vs only 45% with placebo Continued

Smith, Swamy, and Heffernan e23

Placebocontrolled, prospective

Emodi

6

Schedule

124

J AM ACAD DERMATOL

Author

VOLUME 56, NUMBER 1

Table X. Herpes zoster

Author

Study type 129

No. of cases

Treatment type

Dose

Schedule 6

Results

48 Evaluable with zoster and cancer (24 low dose and 24 placebo)

Interferon alfa-2a IM

36 or 68 3 10 U

Qd for 7 d

Significantly effective in reducing dissemination of herpes zoster in immunosuppression with cancer (P \ .003) but was associated with more common or severe side effects; higher dose discontinued before end of study because of frequent adverse side effects

Duschet130

Randomized, comparator

127 (64 Interferon and 63 acyclovir)

(1) Interferon alfa SQ vs (2) acyclovir IV

(1) 10 3 106 U vs (2) 5 mg/kg

(1) Qd vs (2) 3 3 /d

No statistical difference between 2 drugs in acceleration of cutaneous lesion healing, inhibition of cutaneous and visceral dissemination, and reduction of pain; neither drug able to prevent herpes zoster neuralgia; more frequent minor side effects with interferon alfa

Naoum131

Open-label, placebocontrolled, comparator

84

Interferon alfa-2a

3 3 106 U SQ (n = 53) or 6 3 106 U SQ (n = 12) or 3 3 106 U intralesional (n = 12) or placebo (n = 7)

3 3 /wk for total of 6 sessions

Highest dosage produced reduction in period to re-epithelialization in comparison with other groups but no treatment groups affected postherpetic pain

Miyoshi132

N/A

8

Topical interferon alfa gel ointment (10,000 U/g)

5g

Applied to affected area every day by puncturing each vesicle

7/8 Responded; elimination of vesicles and redness were observed 4 d after start of therapy without any side effects; pain was not affected JANUARY 2007

IM, Intramuscular; IV, intravenous; N/A, not available; qd, once daily; SQ, subcutaneous.

J AM ACAD DERMATOL

Randomized, double-blind, placebocontrolled trial

Winston

e24 Smith, Swamy, and Heffernan

Table X. Cont’d

J AM ACAD DERMATOL

Smith, Swamy, and Heffernan e25

VOLUME 56, NUMBER 1

in the acceleration of healing of cutaneous lesions, inhibition of cutaneous and visceral dissemination, and reduction of pain. Neither drug was able to prevent herpes zoster neuralgia. Lower doses of interferon alfa-2a (eg, 3 3 106 U 3 times/wk) do not appear to be as effective.131 Topical interferon alfa, interferon alfa-2b, and interferon gamma have been effective in case reports and small case series.122,132-134 In summary, large, randomized, placebo-controlled studies evaluating the effectiveness of interferons in the treatment of herpes zoster have attained marginal to strong results, but given the availability of equally effective, less-expensive, better-tolerated treatments that are easier to administer, such as acyclovir, the interferons should be considered a second-line therapy for herpes zoster. Hansen’s disease Hansen’s disease, which is caused by Mycobacterium leprae, most commonly affects the skin and peripheral nerves. There are 4 types of leprosy: lepromatous, tuberculoid, indeterminate, and dimorphous. Failure to eliminate the mycobacterium is thought to be a result of inadequate activation of macrophages. Interferon gamma has been evaluated as a possible treatment for leprosy because of its ability to activate macrophages. In the only randomized, controlled study, Barral-Netto et al135 treated 10 patients with multibacillary leprosy with intramuscular interferon gamma (2 3 106 U for 10 days, followed by 10 3 106 U for 10 days) plus multidrug therapy and 10 patients with multidrug therapy alone. Interferon gamma failed to change the clinical course of these patients. In several uncontrolled studies, treatment with intralesional interferon gamma appears to induce delayed type hypersensitivity and epithelioid cell transformation at the site of injection and decreases the bacterial counts in the skin lesions, thereby shifting the disease toward the tuberculoid form.136-138 A large study involving 22 patients, however, failed to achieve this effect.139 Furthermore, interferon gamma may induce erythema nodosum leprosum.138-140 Therefore, interferon gamma does not appear to be a useful adjunct in the treatment of leprosy. Leishmaniasis Leishmaniasis is a parasitic infection transmitted by phlebotomine sandflies. Leishmania species produce species-specific disease, which ranges from cutaneous ulcers to mucocutaneous infection to systemic disease. First-line treatment is parenteral pentavalent antimonials. Second-line treatments include pentamidine and amphotericin B. Interferon gamma

has been studied as a treatment for Leishmaniasis because of its ability to activate macrophages. In a placebo-controlled study, Harms et al141 treated patients with L braziliensis guyanensis and L tropica with perilesional interferon gamma. Three weeks after interferon gamma treatment, 12/13 lesions caused by L braziliensis guyanensis had become smaller compared with 6/13 control lesions; only 4 treated lesions were free of parasites. Of 13 L tropica lesions treated with interferon gamma, 9 resolved completely within 4 to 8 weeks of treatment. The main side effect was an acute inflammatory reaction around interferon gammaetreated L tropica lesions. In another controlled study, Harms et al142 treated 20 patients with 38 lesions caused by L tropica with 1 to 3 mL of meglumine antimoniate and 20 patients with 37 lesions with 25 g of interferon gamma intradermally once weekly for 5 consecutive weeks. Although all lesions treated with Glucantime were free of parasites after the third injection, only 69% of those treated with interferon gamma were parasitologically cured by week 10. Within 10 weeks, lesions treated with Glucantime healed completely in 29/38 cases and partially in 9/38 cases, whereas 1/37 and 13/37 lesions treated with interferon gamma healed completely and partially, respectively. Falcoff et al143 treated 13 patients with antimonyresistant cutaneous or mucocutaneous leishmaniasis with intramuscular interferon gamma (2 3 106 U/m2/d for 30-60 days) and pentavalent antimonial compounds. Of 13 patients, 11 achieved full resolution of lesions. The successful use of interferon gamma in 8 patients lends further support to the use of systemic interferon gamma as an adjunctive treatment for leishmaniasis.144-148 However, in 4 cases, patients relapsed 2 to 3 months after treatment.147,148 Discoid LE and subacute cutaneous LE Discoid LE (DLE) and subacute cutaneous LE (SCLE) are autoimmune inflammatory disorders of the skin. Interferon alfa has been studied as a treatment option for these diseases because of its immunomodulatory effects, which include enhancement of suppressor and cytotoxic T cells and inhibition of helper T-cell function.149 In the largest case series, Thivolet et al150 treated 6 patients with DLE and 4 patients with SCLE with interferon alfa-2a (18-120 3 106 U once/wk for 4-13 weeks). Of 6 patients with DLE, 5 improved with a mean dose of 35 3 106 U once/wk and 3 of 4 patients with SCLE improved with a mean dose of 80 3 106 U once/wk. Patients relapsed once treatments were discontinued. Martinez et al149,151 have successfully treated two patients with localized DLE with intralesional interferon alfa-2b and one patient with intralesional interferon alfa-2a. Caution should

e26 Smith, Swamy, and Heffernan

J AM ACAD DERMATOL JANUARY 2007

be used, however, as interferon has been associated with flares of lupus in animal models and in a patient being treated for rheumatoid arthritis.152 Scleroderma Scleroderma is a fibrotic disease that can be localized (morphea) or generalized with visceral involvement (progressive systemic sclerosis). Interferon gamma has been studied in scleroderma because of its ability to inhibit fibroblast proliferation and collagen production in addition to its immunomodulatory properties. However, interferon gamma also has been shown to increase the production of glycosaminoglycans and fibronectin in vitro, which are two proteins that are elevated in scleroderma.153 Interferon alfa inhibits collagen synthesis and fibroblast proliferation to a lesser degree than interferon gamma, but does not increase the two matrix proteins.154,155 Several controlled and uncontrolled studies have investigated systemic interferon gamma in the treatment of systemic sclerosis with mixed results (Table XI).154-164 Four open-label studies involving 58 patients demonstrated improvements in skin scores with interferon gamma at various doses and dosing schedules.156-159 Higher doses achieved better results.157,159 However, two controlled studies involving 68 patients have failed to achieve statistically significant improvements.161,163 Moreover, there were high drop-out rates in most studies as a result of adverse events including induction of renal crisis in several patients. Systemic interferon alfa was found to be mostly ineffective in the treatment of scleroderma and may actually be deleterious.154,155 Behc¸et’s disease Behc¸et’s disease is a chronic, relapsing multisystem vasculitis characterized by recurrent aphthous ulcers, genital ulcers, and uveitis. This disease can also involve the gastrointestinal, pulmonary, cardiovascular, renal, urologic, musculoskeletal, and central nervous systems. Interferon alfa has been shown to effectively treat Behc¸et’s disease in one randomized, placebo-controlled, double-blind study,165 several prospective, open-label studies,166-174 and one retrospective study175 (Table XII). Topical interferon alfa does not appear to be effective in the treatment of oral disease.176 Kotter et al177 reviewed the literature in 2004. A total of 338 patients have been treated with interferon alfa-2a (n = 264) or interferon alfa-2b (n = 74). They report overall response rates for mucocutaneous symptoms as 86% (mostly partial), for uveitis as 94%, and for arthritis as 96%. Response is dose dependent with a 56% long-term remission rate after cessation of treatment. In an earlier review of 144 patients who received interferon alfa, Zouboulis

and Orfanos178 reported similar results. Both reported interferon alfa-2a to be more effective than 2b. Zouboulis and Orfanos178 recommended a 3-month high-dose regimen (9 3 106 U 3 times/wk) followed by a low maintenance dose (3 3 106 U 3 times/wk). Continuous treatment with interferon alfa should be limited in the majority of patients to 6 months because of side effects such as the induction of binding or neutralizing antibodies, epidermal autoantibodies, autoimmune disease, myopathy, and psychosis. Patients treated for longer than 6 months should have close clinical follow-up. Alopecia areata Alopecia areata results in nonscarring hair loss that can present as small patches of hair loss, total loss of scalp hair (alopecia totalis), or total loss of body hair (alopecia universalis). Magee et al179 treated 11 patients with intralesional interferon alfa2 (1.5 3 106 U 3 times/wk for 3 weeks), but was unable to produce a clinically significant response in these patients with alopecia areata. Indeed, there have been a number of reports of alopecia areata developing during treatment with interferon alfa.180-182 Therefore, interferon alfa does not appear to be an effective form of treatment for alopecia areata and may in fact produce this disease state. Atopic dermatitis Atopic dermatitis (AD) is a prototypical type 2 helper T-lymphocyte disease characterized by immunologic abnormalities including evidence for reduced interferon-gamma production.183 A number of clinical trials have been performed as reviewed by Chang and Stevens183 and presented in Table XIII.184-191 Two randomized, placebo-controlled trials involving 134 patients with AD who were treated with interferon gamma have been performed.184,185 Both trials demonstrated statistically significant improvement in the treatment groups. Improvements were maintained for up to 2 years in one study.184,186 Additional uncontrolled studies support these findings.187-192 These studies support the use of interferon gamma in patients with severe AD who have failed conventional treatment options. Interferon alfa has been less well studied. Noh and Lee192 found interferon alfa to be effective in the treatment of 11 of 13 patients with AD of Besnier’s prurigo pattern who did not respond to interferon gamma or thymopentin. Torrelo et al193 noted improvement in 5 of 13 patients they treated and Kimata et al194 noted significant improvement in 3 children. However, both Paukkonen et al195 and Jullien et al196 failed to see significant improvement in the 16 patients they treated with interferon alfa.

Treatment type

Dose

Schedule

Results

Open-label, prospective (stable or worsening systemic sclerosis)

10

Interferon gamma IM

10 g, then 25 g, then 50 g, then 100 g

Qd for 10 d for first 3 doses, then qd for 5 mo

9 of 10 Patients had significant improvements in total skin score, maximum oral opening, grip strength, range of motion of wrists and elbow, functional index, creatinine clearance, and dysphagia

Freundlich157

Phase I/II, open-label trial (rapidly progressive early diffuse cutaneous systemic sclerosis)

18

Interferon gamma IM

0.1 or 0.5 mg/m2

3 3 /wk for 18 wk

Statistically significant beneficial effects on skin thickness and total body surface area, high-dose group achieved greater benefits (mean of 33% change in skin thickness and mean of 48.4% change in area score)

Hein158

Open-label, prospective (systemic sclerosis)

14

Interferon gamma SQ

50 g

3 3 /wk for12 mo

Significant improvement in total skin score and significant increase in PaO2 on blood gas analysis; no significant change for dysphagia, Raynaud’s phenomenon, or cardiac involvement

Vlachoyiannopoulos159

Open phase I/II trial (systemic sclerosis)

16

Interferon gamma

60 or 150 g/m2

3 3 /wk for 8 mo

High-dose group achieved higher significant decrease in mean skin thickness score with decrease in thickness more evident in trunk, face, and upper aspect of arms

Polisson160

Multicenter, open-label, prospective (14 diffuse and 6 limited systemic sclerosis)

20

Interferon gamma IM

0.01 mg/m2 then 0.1 mg/m2

Qd for 1 wk, then qd for 17 wk

9 of 20 Patients achieved 20% reduction in skin score with 1 patient achieving almost total remission of all skin abnormalities whereas 8 did not achieve appreciable reductions

Grassegger161

Randomized controlled multicenter trial (types 1 and 2 scleroderma)

44 (27 Interferon, 17 control)

Interferon gamma SQ

100 g

3 3 /wk for 12 mo

Mild beneficial effects on disease-associated subjective symptoms and skin sclerosis in types 1 and 2 scleroderma Continued

Smith, Swamy, and Heffernan e27

No. of cases

Kahan

Study type 156

J AM ACAD DERMATOL

Author

VOLUME 56, NUMBER 1

Table XI. Scleroderma

Author

No. of cases

Hunzelmann

Open-label, prospective (diffuse or limited form of systemic sclerosis and progressive disease)

32

Interferon gamma SQ

Hunzelmann163

Randomized, double-blind, placebo-controlled, multicenter (localized scleroderma with progressive disease)

24

Interferon gamma 100 g SQ in periphery of 1 defined lesion

Arnaudova164

Open-label, prospective (progressive systemic sclerosis and localized scleroderma)

5

Interferon gammae containing gel (Virogel G5)

1 3 105 U g/gel Applied gel to affected areas 1-2 3 /d for 1-2 mo

Improvements in subjective skin softening and objective skin fold, greater subjective improvement was achieved with gel applied twice/d

Stevens154

Multicenter, open-label, prospective (diffuse cutaneous systemic sclerosis)

19

Interferon alfa IM or SQ

3 3 106 U increased to 6 3 106 U in 1 mo then increased to 9 3 106 U at 2 mo

3 3 /wk for 6 mo

10 of 14 Patients had statistically insignificant favorable outcome (improvement or stabilization) in their mean skin score, majority had statistically insignificant favorable outcome for grip strength and finger contractures, no significant effect on respiratory function or visceral involvement

Black155

Randomized, double-blind, placebo-controlled trial (early diffuse scleroderma)

13.5 3 106 U

Per wk in divided doses for 12 mo

Ineffective in reducing severity of skin involvement and may actually be deleterious

35 (19 Interferon, Interferon 16 placebo) alfa SQ

Dose

50 g

Schedule

3 3 /wk for 1 y

Results

Stabilization of skin score and lack of worsening of visceral involvement in 20 patients with diffuse or limited systemic scleroderma with progressive disease

Interferon ineffective in diminishing 5 Consecutive d size or fibrosis of lesions, but did during first 2 wk reduce No. of new lesions (P = .07) and once/wk for another 4 wk

JANUARY 2007

IM, Intramuscular; qd, once daily; SQ, subcutaneous.

Treatment type

J AM ACAD DERMATOL

Study type 162

e28 Smith, Swamy, and Heffernan

Table XI. Cont’d

Study type

No. of cases

Treatment type

Dose

Results

10

Interferon alfa-2a SQ

3 3 10 U SQ then titrated based on disease course (average 1.5 3 106 U)

Qd for 6 mo

7/10 Had reductions in No. of oral and genital ulcers, cutaneous lesions, articular symptoms, pain scores, and prednisone dose

Azizlerli167

Open-label, prospective

18

Interferon alfa-2a SQ

3 3 106 IU then 6 3 106 IU then 9 3 106 IU

3 3 /wk for 1 wk then 3 3 /wk for second wk then 3 3 /wk thereafter for total of 12 wk

50% Achieved good results, 39% achieved very good results, 1-y follow-up; 7 patients remained in remission; treatment may be more beneficial for genital ulcers and erythema nodosum in comparison with aphthous ulcers

C¸algu¨neri168

Open-label, prospective

29

Interferon alfa SQ

5 3 106 U then tapered to 3 3 106 U followed by gradual increases in dose intervals (1 patient 10 3 106 U because of lack of response)

3 3 /wk for 6-9 mo then 3 3 /wk for mean duration of 22.2 mo

96% Overall response rate, 94% uveitis, 100% arthritis; remission in all 4 patients with neurologic disease and in all 10 with vascular disease

Alpsoy165

Randomized, placebocontrolled, double-blind

50 (23 Interferon, 21 placebo)

Interferon alfa-2a SQ

6 3 106 IU

3 3 /wk for 3 mo

15 of 23 Patients treated with interferon responded (2 complete and 13 partial); significantly reduced duration and pain of oral ulcers, frequency of genital ulcers and papulopustular lesions

Boyvat175

Retrospective

20

Interferon alfa-2a SQ

9 3 106 IU

3 3 /wk for 3 mo

6 Complete and 9 partial remission, 56% of complete or partial remissions had long-term remissions ranging from 36-48 mo

Alpsoy169

Open-label, prospective

14

Interferon alfa-2a SQ

3 3 106 U gradually increased to 12 3 106 U (half continued on 9 3 106 U once/mo)

3 3 /wk for 2 mo

All symptom-free by end of 2-mo treatment period but some had mild, short-term attacks of oral and genital ulcerations; significantly decreased frequency and remission duration of oral and genital ulcers and pustular vasculitis (P \ .05) Continued

Smith, Swamy, and Heffernan e29

Open-label, prospective

O’Duffy

6

Schedule

166

J AM ACAD DERMATOL

Author

VOLUME 56, NUMBER 1

Table XII. Behc¸et’s disease

Author 170

Study type

No. of cases

Treatment type

Dose 6

Schedule

e30 Smith, Swamy, and Heffernan

Table XII. Cont’d Results

Open-label, prospective

22

Interferon alfa SQ

3 3 10 U

2/wk for 3 mo

18 Patients had manifest clinical improvement and 2 had partial responses

Georgiou171

Open-label, prospective

12

Interferon alfa-2a SQ

6 3 106 IU

3 3 /wk for 2 mo

9 Complete and 2 partial remission, 1-y follow-up, 5 of 9 complete responders had no episodes of Behc¸et’s observed

Kotter172

Open-label, prospective

7

Interferon alfa-2a (2 patients also received low-dose steroids)

6 3 106 IU then 3 3 106 IU then 3 3 106 IU (1 patient with Kaposi’s sarcoma started at 18 3 106 IU/d)

Qd for 4-8 wk then qd for 3-4 mo then every other day for total mean of 23.6 mo

100% Complete remission of ocular vasculitis/panuveitis

Kotter173

Open-label, prospective

50

Interferon alfa-2a SQ

6 3 106 U

Qd for at least 14 d followed by dose adjustments

Response rate of 92% for ocular symptoms; remission in erythema nodosum, papulopustular lesioins, genital ulcers, arthritis, and gastrointestinal symptoms in all patients; complete remission of aphthous ulcers in only 36%

Hamuryudan174

Open-label, prospective

20

Interferon alfa-2b

5 3 106 U

3 3 /wk for 6 wk followed by once/wk for 10 wk

Significant reduction in No. and duration of arthritis attacks (P \ .05) and ESR (P \ .001); nonsignificant reduction in mucocutaneous lesions

JANUARY 2007

J AM ACAD DERMATOL

Kosar

144

Interferon alfa systemic

9 3 106 U followed by low maintenance dose of 3 3 106 U

3 3 /wk for 3 mo then 3 3 /wk (from 2-4 mo to intermittent cycles to long-term treatment)

Overall response rate of 74% with mucocutaneous manifestations, 95% with uveitis, 93% with arthropathy/ arthritis; mucocutaneous (47% vs 7%) and ocular (67% vs 8%) manifestations more effectively treated with interferon alfa-2a than -2b

Kotter177

Analytical review (32 original reports and 4 abstracts)

338

Systemic interferon alfa interferon alfa-2a (n = 264) interferon alfa-2b (n = 74)

Varied

Varied

Overall response rates: 86% mucocutaneous symptoms (mostly partial remissions), 94% uveitis, 96% arthritis; higher dose more effective than lower-dose regimens with 56% long-term remission rate after cessation of treatment; interferon alfa-2a had more complete remissions than -2b but also had more patients in its study group

Hamuryudan176

Randomized, double-blind, placebocontrolled trial

63 (31 Interferon and 32 placebo)

Topical interferon alfa-2c hydrogel

1 3 105 U/g

Applied thin layer 3 3 /d for 24 wk

Dose ineffective in treatment of oral ulcers

Smith, Swamy, and Heffernan e31

ESR, Erythrocyte sedimentation rate; qd, once daily; SQ, subcutaneous.

J AM ACAD DERMATOL

Review of 22 reports

VOLUME 56, NUMBER 1

Zouboulis178

Author

Boguniewicz

Reinhold190

Musial189

Hanifin184

Schneider188

Study type 191

Short-term, open-label, phase I trial

Short-term, open-label, prospective Short-term, open-label, prospective Randomized, placebocontrolled, double-blind, multicenter Long-term, open-label

No. of cases

Part I, 14; part II, 8

Interferon gamma

Part I 0.01, 0.05, and 0.1 mg/m2 SQ Part II 0.05 mg/m2 SQ

14

2 3 106 U SQ

10

0.05 mg/m2 SQ

Schedule

Qd at 3 successive dose levels for 5 d with 2 d off between each dose level qd for 6 wk (9 patients received 3 3 /wk maintenance treatment for up to 14 mo) 5 d for 1 wk then 3 3 /wk for 3 wk then 2 3 /wk for 2 wk 3 Consecutive d for 4 wk

83 (40 Interferon and 43 placebo)

50 g/m2 SQ

12 wk

15

50 g/m2 SQ

Qd or qod for minimum 22 mo

24 (from Hanifin et al184)

50 g/m2 SQ

Qd for 24 mo

Jang185

Randomized, placebocontrolled, dose-finding

20, 21, 100

0.5 3 106 U/m2, 1.5 3 106 U/m2, placebo SQ

3 3 /wk for 12 wk

Noh187

Open-label, prospective

2 3 106 U/m2 SQ

Given for 5 d during 1 wk then 3 3 /wk for 3 wk then 2 3 /wk for 2 wk

68

BSA, Body surface area; qd, once daily; qod, once every other day; SQ, subcutaneous.

Clinical severity score significantly improved (P \ .04 and 01, respectively) (erythema and pruritus most reduced)

Pruritus, inflammation, and extent of disease significantly improved by 3 wk (P \ .05) Severity score significantly improved by 11 d (P \ .05) Erythema, excoriations or erosions, eosinophilia, conjunctivitis; 45% with interferon and 21% with placebo had [50% improvement in physicians’ overall response evaluations (P = .016) Mean total BSA decreased from 61.6% to 18.5% and mean total clinical severity score decreased from 11.4 to 6.3 at 24 mo (P \ .001) Erythema, edema, pruritus, excoriations, dryness, lichenification, total BSA involvement, total clinical severity, allergic conjunctivitis, allergic rhinitis improved (P \ .05) Interferon-treated groups had significant improvement in erythema, edema, excoriation, scale, lichenification, pigmentation, pruritus, loss of sleep, total BSA, and total clinical severity compared with placebo (P \ .05) 33.8% Improved over 20% in clinical severity with 4 patients showing complete remission, 44.1% improved # 20% in clinical severity

JANUARY 2007

Long-term, open-label

Area of significant improvement

J AM ACAD DERMATOL

Stevens186

e32 Smith, Swamy, and Heffernan

Table XIII. Atopic dermatitis

Smith, Swamy, and Heffernan e33

J AM ACAD DERMATOL VOLUME 56, NUMBER 1

Lichen planus Lichen planus is a papulosquamous disease that manifests on the skin as pruritic, flat-topped violaceous papules and as erosions on the oral mucosa. Lichen planus associated with viral hepatitis cleared with interferon alfa (3-6 3 106 U 3 times/wk) in 3 patients.197,198 Three patients with generalized lichen planus, who did not have hepatitis, cleared with SQ interferon alfa-2b (3-10 3 106 U every other day). This improvement was followed by a stepwise dosage reduction.199 Even with the successful treatment of lichen planus with interferon alfa, caution should be observed in regard to its use. There have been a number of reports that have observed the induction or worsening of lichen planus during interferon alfa treatment for diseases such as hepatitis and melanoma.200-203 Chronic urticaria Chronic urticaria represents a wide range of diseases such as idiopathic urticaria, physical urticaria, and urticaria secondary to medical conditions. Treatment of chronic urticaria with interferon has resulted in only transient improvement.66,204 Czarnetzki et al66 treated 9 patients with SQ interferon alfa-2a (3 3 106 U 3 times/wk for 8 weeks). Only one patient with urticarial vasculitis responded. In another study, Torrelo et al204 treated 8 patients with idiopathic chronic urticaria unresponsive to other treatments with intramuscular interferon alfa-2a (3 3 106 U 3 times/wk for at least 2 weeks). Half of the patients showed a good response, but the response was transient. Urticarial vasculitis Urticarial vasculitis is a form of leukocytoclastic vasculitis that presents as raised erythematous wheals or plaques. The 4 main causes are idiopathic, viral, drug-induced, and autoimmune. Hamid et al205 treated two patients with urticarial vasculitis secondary to hepatitis C virus infection with SQ interferon alfa-2b (3 3 106 U 3 times/wk). Both patients improved, but relapsed on discontinuation of the interferon. In another report, a patient with refractory urticarial vasculitis and angioedema responded to SQ interferon alfa-2a (3 3 106 U every other day). The angioedema recurred after cessation of treatment, but resolved with retreatment.206 Interferon alfa may have a role as an alternative treatment for urticarial vasculitis but maintenance therapy may be required to prevent relapse.

donors.207 The purified immunoglobulin is stabilized with glucose, maltose, sucrose, mannitol, sorbitol, glycine, or albumin. IVIG is made up of more than 90% immunoglobulin (Ig)G and small amounts of IgM and IgA. The total amount of immunoglobulins that are infused with a 2-g/kg dose is enormous; serum IgG will increase approximately 5-fold.208 A list of IVIG products that are available in the United States is provided in Table XIV. FDA-approved indications for IVIG include hypogammaglobulinemia, chronic lymphocytic leukemia, HIV in children, allogeneic bone-marrow transplantation, idiopathic thrombocytopenic purpura, and Kawasaki syndrome. The off-label use of IVIG in dermatology is expanding to include treatment of a variety of conditions including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), autoimmune blistering disorders, dermatomyositis (DM), LE and other collagen vascular disorders, vasculitis, and AD (Table XV). No large, multicenter, randomized controlled studies have been performed to support these off-label uses of IVIG. A review of the literature regarding the off-label use of IVIG in dermatologic conditions will be presented here. References were obtained by searching PUBMED using the search words ‘‘intravenous immunoglobulin’’ or ‘‘intravenous gammaglobulin’’ and ‘‘skin’’ or ‘‘cutaneous.’’ The mechanism of action of IVIG is not fully understood and likely differs depending on the disease. In the dermatologic diseases presented in this review article, a combination of mechanisms is likely. Proposed mechanisms include: d

d

d

d d

d

IV IMMUNOGLOBULIN Introduction IV immunoglobulin (IVIG) is composed of human plasma derived from pools of 1000 to 15,000

d d

Lowering the levels of deleterious autoantibodies through idiotypic antibodies contained in IVIG.209,210 Accelerating the catabolism of pathogenic IgG by saturating FcRn receptors with exogenous IgG.211,212 Inhibiting the pathogenic activation of T lymphocytes by antibodies to CD4 and other T-cell receptors.213,214 Inhibiting complement-mediated damage.215 Interfering with the production, release, and function of inflammatory cytokines including interleukins 2, 3, 4, 5, 6, and 10, tumor necrosis factor-alpha, and granulocyte-macrophage colony-stimulating factor.216-220 Inhibiting the differentiation and maturation of dendritic cells, thereby reducing the activation of harmful T cells.221 Increasing sensitivity to corticosteroids.222 Inhibition of thromboxane A2 and endothelin, and increased prostacyclin secretion.223

e34 Smith, Swamy, and Heffernan

J AM ACAD DERMATOL JANUARY 2007

Table XIV. Overview of intravenous immunoglobulin products

Product

Gamunex

Manufacturer

Bayer

Gamimune N Bayer

Gammagard Baxter

Polygam S/D Baxter

Iveegam EN Baxter

Carimune NF ZLB Bioplasma

Viral inactivation

Concentration, %

Recommended infusion rate, mL/kg/h

Cold alcohol fractionation, caprylate filtration, ionexchange chromatography, pH 4.0-4.5 Cohn-Oncley, solvent/detergent, pH 4.0-4.5 Cohn-Oncley, ultrafiltration, ion-exchange chromatography, solvent/detergent Cohn-Oncley, ultrafiltration, ion-exchange chromatography, solvent/detergent Cold ethanol, polyethylene glycol, trypsin Cold alcohol fractionation, nanofiltration, pepsin, pH 4.0

10

0.6-4.8

258

None

4.0-4.5

10

0.6-4.8

274

None

4.0-4.5

5

0.5-4

636

2% Glucose

6.8

5

0.5-4

636

2% Glucose

6.8

[240

5% Glucose

6.4-7.2

Gammar PIV Aventis Behring

Cold alcohol fractionation, pasteurization Flebogamma Instituto Cold alcohol Grifols fractionation, polyethylene glycol, ion-exchange chromatography Octagam Octapharma Cohn-Oncely, ultrafiltration, chromatography, solvent/detergent, pH 4

5

3-12

5

1-2 (mL/min)

Osmolality, mOsm/kg

Sugar content

Varies by In sterile water: 1.67 g Sucrose/1 g concentration 3%, 192; 6%, protein 384; 9%, 576; 12%, 768 In NS: 3%, 498; 6%, 690; 9%, 882; 12%, 1074 In D5: 3%, 444; 6%, 636; 9%, 828; 12%, 1020 0.6-3.6 309 5% Sucrose

pH

6.6

6.8

5

0.5-5

240-350

None

5-6

5

0.6-4.2

310-380

10% Maltose

N/A

D5, 5% Dextrose; N/A, not available; NS, normal saline.

IVIG is relatively safe, particularly in comparison with alternative immunosuppressive treatments, but the practitioner should be aware of potential adverse reactions. Infusion-related side effects occur in less than 10% of patients and are generally mild and

self-limiting.208 These side effects include headache, myalgias, flushing, fever, chills, fatigue, nausea or vomiting, low backache, chest discomfort, hypotension and hypertension, tachycardia, and skin eruptions.

Smith, Swamy, and Heffernan e35

J AM ACAD DERMATOL VOLUME 56, NUMBER 1

Table XV. Off-label dermatologic uses of intravenous immunoglobulin Autoimmune bullous diseases: Pemphigus vulgaris Pemphigus foliaceus Bullous pemphigoid Mucous membrane pemphigoid Epidermolysis bullosa aquisita Linear IgA Pemphigoid gestationis Toxic epidermal necrolysis Connective tissue diseases: Dermatomyositis Lupus erythematosus Scleroderma Mixed connective tissue disease Vasculitis: Livedoid vasculitis ANCA-associated vasculitis Polyarteritis nodosa ANCA-negative vasculitis Leukocytoclastic vasculitis Behc¸et’s disease

Urticaria: Delayed pressure urticaria Solar urticaria Chronic idiopathic urticaria Autoimmune urticaria Angioedema and hypereosinophilia Atopic dermatitis Scleromyxedema Pretibial myxedema Nephrogenic fibrosing dermopathy Psoriasis and psoriatic arthritis Pyoderma gangrenosum Kaposi’s sarcoma Anticonvulsant syndrome Polymorphous light eruption

ANCA, Antineutrophil cytoplasmic antibody; Ig, immunoglobulin.

Premedication with acetominophen, nonsteroidal anti-inflammatory agents, antihistamines, or lowdose IV corticosteroids may help avoid infusionrelated rigors, headaches, and other adverse events. Myalgias, chills, and chest discomfort may occur during the first hour and respond to halting the infusion for 30 minutes and then resuming at a slower rate. Postinfusion fatigue, fever, or nausea may occur and last for 24 hours. Skin eruptions include eczematous reactions, urticaria, lichenoid reactions, pruritus of the palms, and petechiae.208,224 Cardiovascular side effects can be managed with diuretics or by spreading the infusion over a greater number of days. Generally, IVIG is given at a dose of 2 g/kg over 3 to 5 days, but can be given over 2 days in younger patients with normal renal and cardiovascular function.208 The rate of infusion varies between products as described in Table XIV. More serious, but rare, adverse events include thromboembolic events, hemolytic anemia,225 transfusion-related acute lung injury, aseptic meningitis,226,227 anaphylaxis, and renal tubular necrosis. Thromboembolic events are likely the result of increased serum viscosity. Caution should be used in patients with risk factors for thromboembolism, such as patients with a history of thromboembolism, immobilized patients, and patients with hyperviscosity syndromes. The FDA has identified high infusion rates and high doses as potential risk factors for thromboembolism in patients at risk.227 Hemolytic anemia may result from blood group antibodies.

Neutropenia is common, transient (lasting 2-14 days), and usually benign.228-230 Niebanck et al230 hypothesize that this may be a result of antineutrophil antibodies contained in IVIG or from induction of neutrophil apoptosis. Transfusion-related acute lung injury is characterized by severe respiratory distress occurring 1 to 6 hours after the infusion. Severe anaphylactic reactions may occur in patients with IgA deficiency. Aseptic meningitis occurs in 11% of patients receiving IVIG, particularly patients with a history of migraines.231 It usually presents with headache, meningismus, and photophobia. Acute tubular necrosis is usually reversible; it occurs most often in individuals with pre-existing renal disease, diabetes mellitus, and in the elderly.232 Acute tubular necrosis has been associated with IVIG products containing high concentrations of sucrose.208 As with all blood products, there is a risk of transmission of viruses and prions. IVIG is screened for hepatitis B and C, HIV, and syphilis, and donors are carefully selected. Additional methods to remove viruses include physical inactivation with heat and chemical inactivation with solvents, detergents, low pH, and caprylate. Caprylate and nanofiltration may also remove prions.233 Transmission of hepatitis B virus and HIV has not been reported.231 Transmission of hepatitis C virus has been reported and was likely a result of inadequate viral inactivation steps.234 The introduction of improved viral inactivation techniques, such as incubation at pH4 and solventdetergent treatment, should minimize this risk.234

e36 Smith, Swamy, and Heffernan

J AM ACAD DERMATOL JANUARY 2007

In addition, there remains the risk of transmission of currently unidentified infectious agents. Autoimmune bullous diseases Pemphigus vulgaris. Pemphigus vulgaris (PV) is an autoimmune blistering disorder of the skin and mucous membranes that is characterized by autoantibodies directed against desmoglein (dsg) 1 and dsg 3. IVIG lowers antibody titers to dsg 1 and dsg 3, often making them undetectable.235-240 IVIG has been shown to be effective in the treatment of PV in numerous studies as summarized in Table XVI. In the two largest studies, which are from one institution, 42 patients were treated with IVIG (2 g/kg every 4 weeks) until control was achieved, as defined by healing of old lesions and no new lesions.236,238 The interval between IVIG treatments was then gradually increased to every 16 weeks. Prednisone and immunosuppressive agent (ISA) were tapered off during this time in all patients; IVIG was used as monotherapy thereafter. Treatment with IVIG led to a clinical remission in all patients. In the study by Ahmed,238 control was achieved after a mean of 4.5 months, prednisone was tapered off after a mean of 4.8 months, and ISAs were tapered off after a mean of 2.9 months. Both studies were prospective, but uncontrolled. There have been an additional two case series and 6 case reports of the successful treatment of 23 patients with PV with IVIG.239,241-247 However, 9 case reports of treatment failures from other institutions have been reported.248-251 In one case, the patient only received one cycle of IVIG.250 Pemphigus foliaceus. Pemphigus foliaceus (PF) is an autoimmune blistering disorder characterized by autoantibodies to dsg 1. There are 3 published case series252-254 and two case reports255,256 reporting the successful use of IVIG in the treatment of PF. IVIG lowers antibody titers to dsg 1, often making them undetectable.252 Sami et al252 conducted a prospective study of 8 patients with severe (body surface area [ 30%) steroid-resistant PF. Patients were treated with IVIG (2 g/kg every 4 weeks) until they were completely healed. The interval between IVIG treatments was then gradually lengthened to every 16 weeks. All patients attained clinical control after a mean of 4 months. Prednisone was tapered off in a mean of 2.9 months; IVIG was used as monotherapy thereafter. Ahmed and Sami253 reported 11 patients with PF who were treated with IVIG (2 g/kg every 4 weeks) until they were completely healed. The interval between IVIG treatments was then gradually lengthened to every 16 weeks. All patients cleared after an average of 5.3 months of therapy. Prednisone was

tapered off in a mean of 4.5 months and other ISAs after a mean of 2.6 months; IVIG was used as monotherapy thereafter. All 11 patients maintained remission after discontinuation of IVIG for a mean follow-up time of 18.6 months. Bullous pemphigoid. Bullous pemphigoid (BP) is a subepidermal autoimmune blistering disorder characterized by autoantibodies against BP antigen (Ag) 1 and 2. There are two published case series256-258 and 3 case reports (n = 5)241,245,251 reporting the successful use of IVIG in the treatment of BP. There have been two reported treatment failures.251 IVIG lowers autoantibody titers to both BP Ag 1 and 2.258 In the only prospective study, Ahmed et al257 treated 15 patients with BP with IVIG (2 g/kg every 4 weeks). The interval between IVIG treatments was then gradually lengthened to every 16 weeks after patients cleared. All 15 patients cleared after a mean of 2.9 months and were able to discontinue prednisone after mean of 3.3 months. IVIG was used as monotherapy thereafter. All 15 patients achieved sustained remission with a mean duration of follow-up off IVIG of 22.9 months. Mucous membrane pemphigoid. Mucous membrane pemphigoid (MMP), also referred to as cicatricial pemphigoid (CP), is a heterogenous group of autoimmune subepithelial blistering disorders that primarily affects mucosal surfaces and, occasionally, the skin. Autoantibodies to beta4-integrin, alpha6integrin, BP Ag 1, BP Ag 2, and laminin 5 have been detected. IVIG has been shown to lower titers of beta4-integrin and alpha6-integrin in patients with MMP.259,260 IVIG has been shown to be effective in the treatment of MMP in several prospective studies from one institution (Table XVII).259-265 There have been two additional case reports of treatment successes and one treatment failure from other institutions.251,266,267 The studies from the single institution referenced in Table XVII involved patients with oral and/or ocular MMP. Patients were initially treated with corticosteroids and other ISAs, which were tapered off in all cases. Remission was generally attained in 4 to 5 months and treatment with IVIG led to prolonged remissions that persisted after treatment with IVIG was discontinued. One study of 16 patients with stage 2 ocular MMP compared IVIG with standard treatment with corticosteroids and ISAs.264 Randomization was based on whether insurance would pay for IVIG. Eight patients (group A) were treated with IVIG (2 g/kg every 2-4 weeks) until control was achieved. The interval between IVIG treatments was then gradually lengthened to every 16 weeks and corticosteroids and other ISAs were tapered off. The other 8 patients (group B) were treated with

Smith, Swamy, and Heffernan e37

J AM ACAD DERMATOL VOLUME 56, NUMBER 1

Table XVI. Pemphigus vulgaris Author 235

Herzog Sami236

Sami237 Ahmed238 Bystryn239 Harman241 Wetter251

Study type

No. of cases

N/A Open-label, prospective Retrospective Open-label, prospective N/A Retrospective Retrospective

4 21y

IVIG dose, g/kg

2 2

15 21

1-2 2

6 7 7

2 2 2

Schedule

Age, y (range)

No. improved

Q 4 wk Q 4 wk

57 (38-74) 53 (31-73)*

4 21

Q 3-4 wk Q 4 wk, then taper 1-3 Cycles 1 Cycle 7 (1-11) Cycles

58 (30-82)* 56 (23-83)*

15 21

66 (57-70) 53 (39-67) 49 (33-75)

6 7 1

IVIG, Intravenous immunoglobulin; N/A, not available; Q, every. *Age at onset of disease. y 11 Previously reported.

Table XVII. Mucous membrane pemphigoid Author

Yeh259 Sami262 Sami263 Letko264 Sami260 Ahmed265

Study type

Prospective N/A Prospective Prospective, comparator Prospective Retrospective, comparator

No. of cases

Area of involvement

Dose of IVIG, g/kg

Schedule

13 15 10 8

Mixed Mixed Ocular Ocular

2-3 1-2 2-3 2

Q 2-6 wk, then taper Q 4 wk, then taper Q 2 wk, then taper Q 2-4 wk, then taper

59 66 65 62.7

(29-81) (56-71) (50-75) (52-70)

13 15 10 8

Oral Oral

1-2 1-2

Q 4 wk, then taper Q 4 wk, then taper

55.5 (36-64) 58 (44-66)

7 8

7 8

Age, y (range)

No. improved

IVIG, Intravenous immunoglobulin; N/A, not available; Q, every.

corticosteroids and other ISAs. The median time to remission for groups A and B was 4 and 8.5 months, respectively. There were no recurrences for group A, whereas 5 of 8 patients in group B experienced a recurrence. No patients in group A experienced progression, whereas 4 of 8 patients in group B progressed to stage 3. Epidermolysis bullosa acquisita. Epidermolysis bullosa acquisita is a rare acquired bullous disease of the skin and mucous membrane characterized by autoantibodies against type VII collagen. There have been 9 patients with epidermolysis bullosa aquisita who have been treated with IVIG reported in the literature.241,268-274 IVIG was given as monotherapy in 5 cases and in conjunction with corticosteroids or other immunosuppressives in the others. The dose used ranged from 1 to 2 g/kg. Treatment was successful in 8 of these cases with resultant decrease in formation of new blister formation and healing of old lesions. Linear IgA. Linear IgA bullous dermatosis is an acquired subepidermal blistering disorder caused by IgA antibodies against a variety of dermoepidermal Ags. There have been 7 patients with linear IgA bullous dermatosis who have been successfully treated with IVIG.251,275-280

Pemphigoid gestationis. There has been one case report of a 17-year-old girl with pemphigoid gestationis that persisted 1.5 years after delivery.241 This patient had a diffuse bullous eruption and the authors were unable to reduce her prednisone below 40 mg. She received one cycle of IVIG (2 g/kg) with prednisone (20 mg), which led to a remission and a marked reduction in antibasement membrane zone IgG and C3. Her disease returned 5 weeks later at which time she received a second course of IVIG with concomitant cyclosporine (100 mg/d). She again responded and her disease remains quiescent on 10 mg/d of prednisone. Summary. In summary, 64 patients with PV have been successfully treated with IVIG, of whom 46 were treated at a single institution.236-238 In all, 28 patients with PF have been successfully treated with IVIG, of whom 26 were treated at a single institution.252-254 There are reports of 38 patients with BP who have been successfully treated with IVIG in the literature. Of these patients, 25 were treated at a single institution.257,258 In all, 63 patients with CP have been successfully treated with IVIG, of whom 61 were treated at a single institution.260-265 Additional case reports suggest that IVIG may be beneficial in other bullous diseases including linear IgA,

e38 Smith, Swamy, and Heffernan

J AM ACAD DERMATOL JANUARY 2007

epidermolysis bullosa aquisita, and pemphigoid gestationis. It should be kept in mind that there is likely selection bias toward reporting favorable results. Large, multicenter, randomized, controlled studies of IVIG for the treatment of autoimmune bullous diseases have not been performed. Nevertheless, the results of the studies presented here suggest that IVIG can be considered as a viable treatment option for patients with PV, PF, BP, and CP who are resistant to conventional therapy, have experienced complications as a result of conventional therapy, or for whom conventional therapy is contraindicated. In most cases, patients were treated in conjunction with corticosteroids or other ISAs, which could often be tapered or discontinued. Maintenance infusions are generally required to maintain remission, although the interval between treatments can be lengthened to 16 weeks. Some patients have maintained prolonged remissions after treatment with IVIG. A consensus statement on the use of IVIG in the treatment of autoimmune mucocutaneous blistering diseases has recently been published.227 The authors recommend a starting dose of 2 g/kg every 3 to 4 weeks until control can be achieved. Thereafter, the interval between treatments can be lengthened in 2-week intervals to 16 weeks. For patients with aggressive ocular CP it appears that more frequent IVIG treatments every 2 weeks are required to gain control. Because the vast majority of the literature on the use of IVIG for autoimmune bullous diseases was generated at a single institution, additional reports of large case series by other authors are encouraged. Indeed, a retrospective series published by the Mayo Clinic failed to obtain such strikingly positive results.251 Toxic epidermal necrolysis SJS and TEN are rare, acute, life-threatening mucocutaneous diseases characterized by widespread sloughing of the epidermis and frequently the mucous membranes. Mortality is high and increases with more extensive skin detachment. The average mortality of TEN in large series range between 25% and 35%.281-284 The mortality of SJS is only about 1%.282 Current treatment options are limited to supportive care in intensive care/burn departments. Treatment with corticosteroids and other immunosuppressives is controversial and may result in higher incidences of complications secondary to sepsis. The mechanism of action of IVIG in the treatment of TEN is unknown, but may partially be explained by the observation of Viard et al285 that antibodies present in IVIG block Fas-mediated keratinocyte apoptosis in vitro. Because of the low prevalence of

TEN, randomized controlled studies have not been performed. The evidence for and against IVIG in the treatment of SJS and TEN consists of two open-label, prospective studies and a number of retrospective case series and case reports.285-312 In addition, there has been one report of the successful use of IVIG (2.4 g/kg given over 3 days) as prophylaxis for a patient with recurrent episodes of SJS from IV contrast.313 Particularly in regard to case reports, it should be kept in mind that there is likely a selection bias toward reporting favorable results. A summary of the case series can be found in Table XVIII, although caution should be used because comparison across studies is difficult as a result of differences in severity of disease, patient characteristics, efficacy variables, and outcome measures. Of the 11 studies, 8 concluded that IVIG was beneficial in the treatment of TEN, although in only one of the studies using a comparator group was a statistically significant result achieved.288 Shortt et al289 concluded that IVIG was not beneficial in their retrospective series, because although patients receiving IVIG experienced a lower mortality compared with historic control subjects, the difference was not statistically significant. There was also a trend toward less progression of skin sloughing in the IVIG-treated group compared with historic control subjects. A prospective, open-label study by Bachot et al287 and a retrospective study by Brown et al295 also did not find IVIG to be beneficial in the treatment of TEN. The study by Bachot et al287 included patients with SJS. The study by Brown et al285 was confounded by the fact that 67% of the patients treated with IVIG also received concomitant corticosteroids. Brown et al285 also used lower doses of IVIG than most other studies (mean dose 1.6 g/kg). This is important, because Prins et al286 found a higher mortality with lower doses (mean 2.7 g/kg in survivors vs a mean of 2 g/kg in those who died) in their retrospective review. Moreover, the days from onset of symptoms to treatment was 9.2 in the IVIG group versus 5.6 in the historic control group, although this difference was not statistically significant. Again, Prins et al286 found a higher mortality when treatment was delayed (6.8 days in survivors vs 10.2 days in those who died). Because several studies did not include a comparator group, a compilation of mortality benefit from IVIG across studies is not possible. Because of the lack of controlled, prospective, multicenter trials, strong conclusions regarding the effectiveness of IVIG in the treatment of TEN cannot be reached. Moreover, because IVIG is a biologic substance, there is variation in the final product between manufacturers and batch-to-batch that

Smith, Swamy, and Heffernan e39

J AM ACAD DERMATOL VOLUME 56, NUMBER 1

Table XVIII. Toxic epidermal necrolysis and Stevens-Johnson syndrome

Author

Viard285 Prins286 Bachot287 Trent288 Shortt289 Stella290 Campione291 Tristani-Firouzi292 Kim293 Al-Mutairi294 Brown295

Study type

Multicenter retrospective Multicenter retrospectivey Prospective, open-label Retrospective Retrospective Unknown Unknown Retrospective Retrospective Prospective, open-label Retrospective

No. of cases

Average age, y

Mean BSA at initiation of IVIG, %

Mean dose, g/kg

Time to Time onset interruption of SJS/TEN to of Mortality, treatment, d progression, d %

Comparator mortality *

10

39

29

2.5

3.6

1.5

0

N/A

48

43

45

2.7

7

2.3

12

25-30

34

47

19

2

4.3

N/A

32

24

16 16 9 10 8 14 12

43 53 54 49 8.1 N/A 27

43 65 16 44 67 [30 57.5

4 2.8 2.8 2 2.4 1.6-2 3.6

3.5 N/A 6 \3 3.2 N/A N/A

3.75 N/A 4.8 N/A 2.1 N/A 2.8

6 25 11 10 0 7.2 0

36z 38 N/A 35 0 16.8 N/A

24

47

45

1.6

9.2

N/A

42

29

BSA, Body surface area; IVIG, intravenous immunoglobulin; N/A, not available; SCORTEN, Severity of Illness Score for Toxic Epidermal Neurolysis; SJS, Stevens-Johnson syndrome; TEN, toxic epidermal necrolysis. *SCORTEN was used as comparator group by Bachot et al,287 Trent et al,288 Campione et al,291 and Kim et al.293 Shortt et al,289 Tristani-Firouzi et al,292 and Brown et al295 used cohort. Prins et al286 compared mortality to 2 previous studies of patients who did not receive IVIG but who had similar ages and BSA characteristics.281,282 y Study by Prins et al286 included 8 cases published by Viard et al,285 9 cases published by Trent et al,288 and at least 4 cases published by Campione et al.291 z Statistically significant results.

could affect results.314 For example, if interruption of Fas-mediated cell death by antibodies in IVIG is the mechanism of its action in TEN, then batches that are lacking these antibodies will not be successful. This could explain the difference in results attained by Prins et al286 and Trent et al,288 who used multiple brands of IVIG and attained positive results, with Bachot et al287 and Shortt et al,289 who used one brand (Tegeline and Gamimune N, respectively) and did not attain positive results. The brand used in the study by Brown et al295 was not stated. Furthermore, Tegeline contains sucrose, which may be nephrotoxic. Bachot et al287 noted that mortality in their patients treated with IVIG mostly occurred in elderly patients with pre-existing renal dysfunction. Although randomized, controlled, multicenter studies are lacking, the results from the majority of case series supports the use of IVIG in the treatment of TEN and TEN/SJS overlap. Prins et al286 recommend a dose of 3 g/kg given over 3 days. However, in the absence of randomized, controlled trials, treatment with IVIG cannot be considered the standard of care. Because of the low mortality associated with SJS and the unestablished efficacy of IVIG in the treatment of TEN or SJS, the use of IVIG in the treatment of SJS is not warranted.

Connective tissue disease Dermatomyositis. DM is a pathogenetically heterogenous disease characterized by muscle inflammation and weakness, and cutaneous manifestations. Muscle involvement without skin manifestations is called polymyositis (PM). Subsets of patients may have an underlying malignancy, autoantibodies and/or additional autoimmune diseases, or no humoral autoimmunity. IVIG has been used to treat both DM and PM. A summary of case series in which IVIG has been used to treat DM can be found in Table XIX.315-325 Evidence strongly suggests that IVIG is effective in improving muscle weakness. Of 133 patients with DM or PM, 103 had improvement in muscle strength in 11 case series,315-325 including 11 of 12 patients in a randomized, placebo-controlled, crossover trial.316 However, caution should be used because comparison across studies is difficult as a result of differences in severity of disease, efficacy variables, and outcome measures. Moreover, most patients in these reports were on various combinations of corticosteroids and other immunosuppressives. The effectiveness of IVIG on cutaneous manifestations of DM is less clear. Reports on the treatment of DM with IVIG have been exclusively in neurologic and rheumatologic journals, often with little to no

e40 Smith, Swamy, and Heffernan

J AM ACAD DERMATOL JANUARY 2007

Table XIX. Dermatomyositis Author

Cherin315 Dalakas316

Mastaglia317 De Vita318 Gottfried319 Danieli320 Lang321 Barron322

Sansome323 Tsai324 Al-Mayouf325

Study type

Prospective, open-label Randomized, placebocontrolled, crossover Prospective, open-label Retrospective Retrospective Retrospective Prospective, open-label Retrospective

Prospective, open-label Retrospective Retrospective

No. of cases

Average age, y

20*

43 (24-83)

2.0 mo

15/20

N/A

15

36

2.0 mo

11/12y

8/?z

5

54 (35-78)

2.0 mo

3/5

N/A

6 19 20§ 5

41 (14-59) 31-84 22-66 2.5-15

2.0 mo 2.0 mo 1.0 mo N/A

3/6 7/19 20/20 5/5

N/A 7/19 N/A 5/5

1.6-2.0

12/12

6/6, Results not reported in 6 patients N/A

12

2-17

9

10.6 (8.5-11.9)

7 18

5.8 (2-10.2)

Mean dose, g/kg

2.0 q 5.5 wk N/A 2.0 q 2 wk, then monthly

Muscular improvement

9/9 6/7 12/18

Cutaneous improvement

N/A 12/18

N/A, Not available; q, every. *Fourteen patients had polymyositis. y Three patients did not receive intravenous immunoglobulin. z No. of patients with rash not stated. § Eight patients had polymyositis.

attention paid to the cutaneous response to IVIG. However, in those reports that did discuss the cutaneous response, a resolution of the rash usually correlated with an improvement in muscle strength. Most patients tend to relapse after IVIG is discontinued. The mechanism of action of IVIG in the treatment of DM has been elucidated in several studies. Basta and Dalakas326 examined sera and muscle biopsy specimens in 13 patients from their double-blind, placebo-controlled crossover study316 and concluded that IVIG exerts its beneficial effects by intercepting the assembly and deposition of membrane attack complex on the endomysial capillaries through the formation of complexes between the infused immunoglobulins and C3b. Dalakas et al316 have demonstrated that IVIG leads to a decrease in major histocompatibility complex-1 and intracellular adhesion molecule-1 in muscle suggesting that IVIG binds Fc receptors on macrophages, leading to decreased production of pathologic cytokines. Systemic LE. Goodfield et al327 describe 10 patients with cutaneous LE who were treated with IVIG (1 g/kg for two cycles followed by 400 mg/kg/mo until disease resolution or for 6 months). Five

patients had complete or near complete clearing of their skin disease, two had partial but helpful improvement, and 3 had limited responses. Levy et al328 reported a case series of 20 patients with various manifestations of systemic LE who were treated with IVIG (2 g/kg). The 4 patients with cutaneous manifestations (vasculitis, urticaria and butterfly rash, ulcers, and discoid lupus) experienced resolution or marked improvement. Schroeder et al329 treated 12 patients with systemic LE with IVIG (120 g over 4 days for two cycles) in an uncontrolled study. Five patients had facial erythema, of which 3 experienced partial remissions. Two of 4 patients with Raynaud’s phenomenon showed marked improvement. Francioni et al330 treated 12 patients with systemic LE with IVIG (2 g/kg once/mo for 6-24 cycles) in an uncontrolled study. The authors report that the majority of patients with rash, vasculitis, and cutaneous and buccal mucosa ulcerations experienced regression; specifics were not provided. Genereau et al331 described one patient with cutaneous lupus who was successfully treated with IVIG (2 g/kg). Krueter et al332 described one patient with severe, recalcitrant SCLE who nearly cleared after IVIG (3 g/kg). However, the patient

J AM ACAD DERMATOL

Smith, Swamy, and Heffernan e41

VOLUME 56, NUMBER 1

later progressed to sytemic LE and died. In contrast, two patients with SCLE described by De Pita et al333 did not respond to IVIG therapy. Scleroderma. There is one open-label study reporting the successful use of IVIG in the treatment of scleroderma.334 Fifteen patients were treated with IVIG (2 g/kg once/mo for 3-6 cycles). The authors report a mean decrease in Rodnan skin score of 35% (P \.001) and a statistically significant improvement on the results of the Health Assessment Questionnaire. The same authors previously reported 3 patients with scleroderma who responded to IVIG.335 Mixed connective tissue disease. Ulmer et al336 described a patient with mixed connective tissue disease manifested by macular erythema and acral cyanosis, and other systemic manifestations. The patient responded after two monthly cycles of IVIG (2 g/kg), cleared after 16 weeks, and has maintained remission with IVIG cycles every 6 weeks. Wetter et al251 described a patient with widespread ulcerations, Raynaud’s phenomenon, and mysositis who experienced complete healing of his ulcerations within 3 weeks of treatment with two cycles of IVIG (2 g/kg), prednisone, and mycophenolate mofetil. The patient had previously failed 6 months of treatment with prednisone and mycophenolate mofetil. Vasculitis Livedoid vasculitis. Krueter et al337 reported an open-label, prospective trial of IVIG in the treatment of 9 patients with livedoid vasculitis. IVIG (1-1.5 g/kg once/mo for a mean of 7.6 cycles) resulted in improvement of skin lesions and pain, and a significant decrease in the clinical score (P \ .001). Case reports of an additional 6 patients with lividoid vasculitis who were successfully treated with IVIG have been reported.338-341 Antineutrophil cytoplasmic antibodye associated vasculitis. Jayne et al342-344 have shown that IVIG is effective in treating antineutrophil cytoplasmic antibodyeassociated systemic vasculitis (AASV), but do not specifically remark on the response of skin manifestations. Richter et al345 reported a clinically significant benefit of IVIG in the treatment of 6 of 15 patients with AASV who were poor responders to conventional therapy. Three patients had skin manifestations, of which two improved. Ito-Ihara et al346 successfully treated 12 patients with rapidly progressive glomerulonephritis from AASV with IVIG. One patient had cutaneous involvement, but the response to treatment was not provided. Additional small case reports support the use of IVIG in the treatment of AASV341,347,348 including one additional case of a patient with palpable purpura.341

Cutaneous polyarteritis nodosa. There are 5 case studies reporting the successful use of IVIG in the treatment of cutaneous polyarteritis nodosa,349-353 although improvement could not be maintained in two patients.349,353 In addition, 3 patients with parvovirus B19eassociated cutaneous polyarteritis nodosa who were successfully treated with IVIG have been described.354,355 Antineutrophil cytoplasmic antibodye negative, nonleucocytoclastic vasculitis. Altmeyer et al356 treated 7 patients with recurrent necrotizing antineutrophil cytoplasmic antibodyenegative nonleucocytoclastic vasculitis with IVIG. Complete clearance of disease was observed in 5 of 7 patients within 6 months while receiving IVIG (0.5 g/kg every 4 weeks for 1 year). Two of the 5 responders healed completely and therapy could be stopped after 6 months. Leukocytoclastic vasculitis. Two cases of leukocytoclastic vasculitis successfully treated with IVIG have been reported in the literature.357,358 Ong and Benson357 successfully treated a patient with recalcitrant leukocytoclastic vasculitis with IVIG (2 g/kg for 9 cycles). IVIG resulted in complete healing of the patient’s ulcer and enabled discontinuation of prednisone, cyclosporine, and azathioprine. Sais et al358 successfully treated a patient with common variable immunodeficiency and leukocytoclastic vasculitis manifested by confluent palpable purpura with IVIG (300 mg/kg every 3 weeks). The purpura resolved in 10 days. Wetter et al251 noted a PR in one patient. Behc¸et’s disease. Seider et al359 reported the successful use of IVIG in the treatment of ocular Behc¸et’s disease in 4 patients resistant to corticosteroids and cyclosporine. Patients were treated with IVIG (0.4 g/kg/d) for 5 days, followed by 3 infusions over that month. Infusions were then repeated every 3 weeks for 3 cycles, followed by infusions every 6 weeks for 1 year. All 4 patients responded to treatment. Urticaria Delayed pressure urticaria. Dawn et al360 reported 8 patients with delayed pressure urticaria who were treated with IVIG (2 g/kg). Of the 8, 5 remitted or improved after 3 or fewer infusions. Solar urticaria Two patients with solar urticaria successfully treated with IVIG have been reported in the literature.361,362 Darras et al361 successfully treated a patient with IVIG (2.5 g/kg) in conjunction with PUVA. PUVA therapy alone resulted only in a PR. Puech-Plottova et al362 treated a patient with severe solar urticaria with IVIG. The minimal urticarial dose to UVA was

e42 Smith, Swamy, and Heffernan

J AM ACAD DERMATOL JANUARY 2007

increased from 0.025 to 27 J/cm2. One year after treatment, the solar urticaria completely resolved. Chronic idiopathic urticaria Kroiss et al363 treated a 63-year-old woman with chronic idiopathic urticaria with IVIG (200 mg/kg) with maintenance infusions every 4 weeks. Treatment resulted in a decrease of her urticaria score from 8 to 1. Wetter et al251 treated one patient with urticaria resistant to multiple immunosuppressives and antihistamines. The patient responded within 1 day to one infusion with IVIG (2 g/kg) and remained 95% improved during the next 3 months. Autoimmune urticaria O’Donnell et al364 treated 10 patients with autoimmune chronic urticaria from histamine-releasing autoantibodies with one cycle of IVIG (2 g/kg). Clinical benefit was noted in 9 of 10 patients: 3 patients experienced prolonged complete remissions (3-year follow-up), two had temporary CRs, and symptoms in 4 patients improved subsequent to treatment. There was significant improvement in the urticaria activity scores and visual analog scores at 2 (P \.01) and 6 (P \.01) weeks post-IVIG compared with the baseline values. Asero365 treated 3 patients with autoimmune chronic urticaria with one infusion of IVIG (2 g/kg). One patient experienced a 3-week remission. The other two patients had no or a minimal response to IVIG. Klote et al366 successfully treated one patient with IVIG with remission of disease within 48 hours. However, the patient’s disease recurred and only partially responded to a second treatment. Angioedema with hypereosinophilia Orson367 treated a 54-year-old man with angioedema and hypereosinophilia with prednisone (40 mg/d) and IVIG (400 mg/kg every 3 weeks). The patient had a marked decrease in symptoms and eosinophil count after 6 weeks and prednisone was tapered off in 6 months. Interestingly, when the brand of IVIG was changed from Panglobulin to Gamimune N, the patient’s illness recurred. Retreatment with Panglobulin led to remission once again. This case report enphasizes the biologic variability that may exist between brands of IVIG. Atopic dermatitis Forty patients with AD treated with IVIG have been reported in the literature.368-374 Additional studies conducted by Noh et al375,376 are not discussed as patients received very low doses of IVIG. Paul et al368 conducted the only controlled study. In this randomized, parallel-group, evaluator-blinded

trial of 10 patients with severe AD, patients were randomized to immediate or delayed (by 1 month) treatment with one infusion of IVIG (2 g/kg over 2 days). There was a statistically significant, but modest, decrease in the severity scoring index of AD of 22% at 60 days after IVIG infusion. Paul et al368 concluded that IVIG treatment was not associated with clinically significant improvement of AD signs and symptoms. Jolles et al369 conducted an open-label study of 6 patients with severe AD. The mean age was 36 years (range 18-53). Patients received IVIG (2 g/kg once/mo for 6 cycles) with a 3-month follow-up period. Of 6 patients, 4 had major improvements in skin scores and the overall reduction was significant (P = .035). Huang et al370 treated 5 infants with monthly infusions of IVIG (2 g/kg for 3 cycles) as monotherapy. The severity scoring index of AD was significantly reduced compared with a control group treated with topical corticosteroids. In addition, patients attained a prolonged remission of greater than 6 months. This finding was similar to another case series of IVIG for AD in children in which 4 children attained a remission of 6 months with IVIG monotherapy.371 An additional 15 patients with AD have been treated with IVIG.372-374 Six improved,372,374 whereas 9 had insignificant improvement or none at all.373 In summary, of 9 children treated with IVIG as monotherapy, all improved.370,371 In contrast, none of 13 adults treated with IVIG as monotherapy had significant improvement.368,374 However, 10 of 17 adult patients treated with IVIG as an adjunct to corticosteroids or other ISAs responded.369,372,374 The 7 patients who did not respond received lowdose corticosteroids. In conclusion, IVIG may be helpful as monotherapy for some patients with AD, particularly children. It appears that adults may need concomitant immunosuppression. The results of published case reports are mixed suggesting that larger, controlled studies are needed before the use of IVIG in the treatment of severe AD can be justified. Miscellaneous disorders Scleromyxedema. Thirteen patients with scleromyxedema have been successfully treated with IVIG251,377-383 including one patient with dementia.383 All patients received 2 g/kg every 4 to 6 weeks. Improvement was generally seen after 2 to 12 weeks and was sustained after several cycles. Pretibial myxedema and Graves’ ophthalmopathy. Antonelli et al384 reported 7 patients with Graves’ ophthalmopathy and pretibial myxedema who were treated with IVIG (2 g/kg every 3 weeks for 7-15 cycles). Both the ophthalmopathy

J AM ACAD DERMATOL

Smith, Swamy, and Heffernan e43

VOLUME 56, NUMBER 1

and pretibial myxedema improved in all 7 patients. This group later reported the result of a prospective, nonrandomized, evaluator-blinded, comparator trial of methylprednisolone to IVIG (2 g/kg every 3 weeks) in 65 patients with Graves’ ophthalmopathy.385 Improvement in soft-tissue involvement, diploplia, and proptosis was nearly identical between the two treatment groups. Kahaly et al386 obtained similar results in a randomized trial comparing IVIG (2 g/kg every 3 weeks for 6 cycles) with prednisolone (100-mg starting dose for 20 weeks). Neither report discusses the effect of IVIG on pretibial myxedema. Nephrogenic fibrosing dermopathy. Chung and Chung387 reported a patient with nephrogenic fibrosing dermopathy who was treated with monthly infusions of IVIG (2 g/kg). The patient had mild improvement after 1 month, but no further improvement with additional infusions. Psoriasis/psoriatic arthritis. Gurmin et al388 treated 3 patients with psoriasis and psoriatic arthritis with IVIG (2 g/kg). Treatment led to dramatic improvement in arthritis with a decrease in erythrocyte sedimentation rate and C-reactive protein after one infusion, although monthly maintenance therapy was required. One patient had severe psoriasis, which cleared after 3 infusions, and another had mild psoriasis, which cleared after one infusion. A third patient with severe psoriasis had minimal improvement, but only received one infusion of IVIG. Pyoderma gangrenosum. There have been 4 patients with pyoderma gangrenosum who have been successfully treated with IVIG.389-392 Gupta et al389 first reported a patient with pyoderma gangrenosum who experienced marked improvement within 2 weeks of IVIG (2 g/kg). After a second course, the ulcer completely healed. Dirschka et al390 treated a patient with pyoderma gangrenosum with monthly infusions of IVIG (2 g/kg), which resulted in complete healing after 4 months. Hagman et al391 described a patient with multiple ulcers who had objective improvement within 2 weeks of one infusion of IVIG (2 g/kg). A second infusion induced a dramatic clinical improvement of one ulcer and healing of the others. Dobson et al392 reported a patient with superficial granulomatous pyoderma who completely healed in 3 months. Kaposi’s sarcoma. Carmeli et al393 reported a 45-year-old man with PM who had developed Kaposi’s sarcoma from immunosuppressive therapy. Reduction in the dose of his immunosuppression did not lead to resolution of the sarcoma. IVIG (2 g/kg) was instituted to treat the PM. Within 2 weeks, the Kaposi’s sarcoma began to regress, and after 3 cycles, had nearly resolved.

Anticonvulsant syndrome. Mostella et al394 reported a patient with anticonvulsant hypersensitivity syndrome. The patient was treated with one infusion of 30 g of IVIG in conjunction with pulse methylprednisolone. These treatments resulted in rapid improvement of her illness, but it is not possible to discern whether the IVIG played a role. Polymorphous light eruption. Creamer et al395 report a 55-year-old woman with common variable hypogammaglobulinemia with coincident polymorphous light eruption. Treatment of her hypogammaglobulinemia with replacement IVIG (500 mg/kg every 4 weeks) led to complete resolution of her polymorphous light eruption. REFERENCES 1. De Andrea M, Ravera R, Gioia D, Gariglio M, Landolfo S. The interferon system: an overview. Eur J Paediatr Neurol 2002; 6(Suppl):A41-6; discussion A55-8. 2. Asadullah K, Sterry W, Trefzer U. Cytokines: interleukin and interferon therapy in dermatology. Clin Exp Dermatol 2002; 27:578-84. 3. Kim KH, Yavel RM, Gross VL, Brody N. Intralesional interferon alpha-2b in the treatment of basal cell carcinoma and squamous cell carcinoma: revisited. Dermatol Surg 2004; 30:116-20. 4. Mahrle G, Schulze HJ. Recombinant interferon-gamma (rIFNgamma) in dermatology. J Invest Dermatol 1990;95(Suppl): 132S-7S. 5. Edwards L, Levine N, Weidner M, Piepkorn M, Smiles K. Effect of intralesional alpha 2-interferon on actinic keratoses. Arch Dermatol 1986;122:779-82. 6. Edwards L, Levine N, Smiles KA. The effect of topical interferon alpha 2b on actinic keratoses. J Dermatol Surg Oncol 1990;16:446-9. 7. Edwards L, Berman B, Rapini RP, Whiting DA, Tyring S, Greenway HT Jr, et al. Treatment of cutaneous squamous cell carcinomas by intralesional interferon alfa-2b therapy. Arch Dermatol 1992;128:1486-9. 8. Grob JJ, Suzini F, Richard MA, Weiller M, Zarour H, Noe C, et al. Large keratoacanthomas treated with intralesional interferon alfa-2a. J Am Acad Dermatol 1993;29:237-41. 9. Wickramasinghe L, Hindson TC, Wacks H. Treatment of neoplastic skin lesions with intralesional interferon. J Am Acad Dermatol 1989;20:71-4. 10. Toma S, Palumbo R, Vincenti M, Aitini E, Paganini G, Pronzato P, et al. Efficacy of recombinant alpha-interferon 2a and 13cis-retinoic acid in the treatment of squamous cell carcinoma. Ann Oncol 1994;5:463-5. 11. Lippman SM, Parkinson DR, Itri LM, Weber RS, Schantz SP, Ota DM, et al. 13-cis-Retinoic acid and interferon alpha-2a: effective combination therapy for advanced squamous cell carcinoma of the skin. J Natl Cancer Inst 1992;84:235-41. 12. Shin DM, Glisson BS, Khuri FR, Clifford JL, Clayman G, Benner SE, et al. Phase II and biologic study of interferon alfa, retinoic acid, and cisplatin in advanced squamous skin cancer. J Clin Oncol 2002;20:364-70. 13. Olieman AF, Lienard D, Eggermont AM, Kroon BB, Lejeune FJ, Hoekstra HJ, et al. Hyperthermic isolated limb perfusion with tumor necrosis factor alpha, interferon gamma, and melphalan for locally advanced nonmelanoma skin tumors of the extremities: a multicenter study. Arch Surg 1999; 134:303-7.

e44 Smith, Swamy, and Heffernan

J AM ACAD DERMATOL JANUARY 2007

14. Greenway HT, Cornell RC, Tanner DJ, Peets E, Bordin GM, Nagi C. Treatment of basal cell carcinoma with intralesional interferon. J Am Acad Dermatol 1986;15:437-43. 15. Cornell RC, Greenway HT, Tucker SB, et al. Intralesional interferon therapy for basal cell carcinoma. J Am Acad Dermatol 1990;23:694-700. 16. Chimenti S, Peris K, Di Cristofaro S, Fargnoli MC, Torlone G. Use of recombinant interferon alfa-2b in the treatment of basal cell carcinoma. Dermatology 1995;190:214-7. 17. Stenquist B, Wennberg AM, Gisslen H, Larko O. Treatment of aggressive basal cell carcinoma with intralesional interferon: evaluation of efficacy by Mohs surgery. J Am Acad Dermatol 1992;27:65-9. 18. Kowalzick L, Rogozinski T, Wimheuer R, Pilz J, Manske U, Scholz A, et al. Intralesional recombinant interferon beta-1a in the treatment of basal cell carcinoma: results of an open-label multicentre study. Eur J Dermatol 2002;12:558-61. 19. Edwards L, Tucker SB, Perednia D, Smiles KA, Taylor EL, Tanner DJ, et al. The effect of an intralesional sustainedrelease formulation of interferon alfa-2b on basal cell carcinomas. Arch Dermatol 1990;126:1029-32. 20. Buechner SA. Intralesional interferon alfa-2b in the treatment of basal cell carcinoma: immunohistochemical study on cellular immune reaction leading to tumor regression. J Am Acad Dermatol 1991;24:731-4. 21. Healsmith MF, Berth-Jones J, Fletcher A, Graham-Brown RA. Treatment of basal cell carcinoma with intralesional interferon alpha-2b. J R Soc Med 1991;84:524-6. 22. Dogan B, Harmanyeri Y, Baloglu H, Oztek I. Intralesional alfa2a interferon therapy for basal cell carcinoma. Cancer Lett 1995;91:215-9. 23. Alpsoy E, Yilmaz E, Basaran E, Yazar S. Comparison of the effects of intralesional interferon alfa-2a, 2b and the combination of 2a and 2b in the treatment of basal cell carcinoma. J Dermatol 1996;23:394-6. 24. Fenton S, Kennedy S, Moriarty P. The role of interferon alpha 2b as an adjunctive treatment in the management of aggressive basal cell carcinoma of the eyelids. Acta Ophthalmol Scand 2002;80:674-5. 25. Shiell A. Consideration of the cost of interferon alfa-2b in the treatment of basal cell carcinoma. Australas J Dermatol 1994;35:71-5. 26. Vonderheid EC, Thompson R, Smiles KA, Lattanand A. Recombinant interferon alfa-2b in plaque-phase mycosis fungoides: intralesional and low-dose intramuscular therapy. Arch Dermatol 1987;123:757-63. 27. Bunn AP Jr, Norris DA. The therapeutic role of interferons and monoclonal antibodies in cutaneous T-cell lymphomas. J Invest Dermatol 1990;95(Suppl):209S-12S. 28. McGinnis KS, Junkins-Hopkins JM, Crawford G, Shapiro M, Rook AH, Vittorio CC. Low-dose oral bexarotene in combination with low-dose interferon alfa in the treatment of cutaneous T-cell lymphoma: clinical synergism and possible immunologic mechanisms. J Am Acad Dermatol 2004;50:375-9. 29. Zachariae H, Thestrup-Pedersen K. Interferon alpha and etretinate combination treatment of cutaneous T-cell lymphoma. J Invest Dermatol 1990;95(Suppl):206S-28S. 30. Aviles A, Guzman R, Garcia EL, Diaz-Maqueo JC. Biological modifiers (etretinate (changed from etetrinate) and alfa 2a) in the treatment of refractory cutaneous T-cell lymphoma. Cancer Biother Radiopharm 1996;11:21-4. 31. Dreno B, Claudy A, Meynadier J, Verret JL, Souteyrand P, Ortonne JP, et al. The treatment of 45 patients with cutaneous T-cell lymphoma with low doses of interferon-alpha 2a and etretinate. Br J Dermatol 1991;125:456-9.

32. Stadler R, Otte HG, Luger T, Henz BM, Kuhl P, Zwingers T, et al. Prospective randomized multicenter clinical trial on the use of interferon -2a plus acitretin versus interferon -2a plus PUVA in patients with cutaneous T-cell lymphoma stages I and II. Blood 1998;92:3578-81. 33. Chiarion-Sileni V, Bononi A, Fornasa CV, Soraru M, Alaibac M, Ferrazzi E, et al. Phase II trial of interferon-alpha-2a plus psolaren with ultraviolet light A in patients with cutaneous T-cell lymphoma. Cancer 2002;95:569-75. 34. Rupoli S, Goteri G, Pulini S, Filosa A, et al. Marche Regional Multicentric Study Group of Cutaneous Lymphomas. Longterm experience with low-dose interferon-alpha and PUVA in the management of early mycosis fungoides. Eur J Haematol 2005;75:136-45. 35. Roenigk HH Jr, Kuzel TM, Skoutelis AP, Springer E, Yu G, Caro W, et al. Photochemotherapy alone or combined with interferon alpha-2a in the treatment of cutaneous Tcell lymphoma. J Invest Dermatol 1990;95(Suppl):198S-205S. 36. Otte HG, Herges A, Stadler R. Combination therapy with interferon alfa 2a and PUVA in cutaneous T-cell lymphoma. Hautarzt 1992;43:695-9. 37. Stadler R, Otte HG. Combination of cutaneous T cell lymphoma with interferon alpha-2a and photochemotherapy. Recent Results Cancer Res 1995;139:391-401. 38. Kuzel TM, Roenigk HH Jr, Samuelson E, Herrmann JJ, Hurria A, Rademaker AW, et al. Effectiveness of interferon alfa-2a combined with phototherapy for mycosis fungoides and the Sezary syndrome. J Clin Oncol 1995;13:257-63. 39. Wollina U, Looks A, Meyer J, Knopf B, Koch HJ, Liebold K, et al. Treatment of stage II cutaneous T-cell lymphoma with interferon alfa-2a and extracorporeal photochemotherapy: a prospective controlled trial. J Am Acad Dermatol 2001; 44:253-60. 40. Gottlieb S, Wolfe J, Fox P, et al. Treatment of cutaneous T-cell lymphoma with extracorporeal photopheresis monotherapy and in combination with recombinant interferon alpha: a 10year experience at a single institution. J Am Acad Dermatol 1996;35:946-57. 41. Guillot B, Raison-Peyron N, Acevedo M, Meunier L, Dandurand M, Meynadier J. Angiosarcoma of the scalp and face: failure of an interferon alpha treatment. Eur J Dermatol 2000;10:300-2. 42. Krasagakis K, Hettmannsperger U, Tebbe B, Garbe C. Cutaneous metastatic angiosarcoma with a lethal outcome, following radiotherapy for a cervical carcinoma. Br J Dermatol 1995; 133:610-4. 43. Spieth K, Gille J, Kaufmann R. Therapeutic efficacy of interferon alfa-2a and 13-cis-retinoic acid in recurrent angiosarcoma of the head. Arch Dermatol 1999;135:1035-7. 44. Jackel A, Deichmann M, Waldmann V, Bock M, Naher H. Regression of metastatic angiosarcoma of the skin after systemic treatment with liposome-encapsulated doxorubicin and interferon-alpha. Br J Dermatol 1999;140: 1187-8. 45. Greinwald JH Jr, Burke DK, Bonthius DJ, Bauman NM, Smith RJ. An update on the treatment of hemangiomas in children with interferon alfa-2a. Arch Otolaryngol Head Neck Surg 1999;125:21-7. 46. Ezekowitz RA, Mulliken JB, Folkman J. Interferon alfa-2a therapy for life-threatening hemangiomas of infancy. N Engl J Med 1992;326:1456-63. 47. Tryfonas GI, Tsikopoulos G, Liasidou E, Gavopoulos S, Georgakis G, Badouraki M, et al. Conservative treatment of hemangiomas in infancy and childhood with interferonalpha 2a. Pediatr Surg Int 1998;13:590-3.

Smith, Swamy, and Heffernan e45

J AM ACAD DERMATOL VOLUME 56, NUMBER 1

48. Ricketts RR, Hatley RM, Corden BJ, Sabio H, Howell CG. Interferon-alpha-2a for the treatment of complex hemangiomas of infancy and childhood. Ann Surg 1994;219:605-14. 49. Bauman NM, Burke DK, Smith RJ. Treatment of massive or life-threatening hemangiomas with recombinant alpha(2a)interferon. Otolaryngol Head Neck Surg 1997;117:99-110. 50. Garmendia G, Miranda N, Borroso S, Longchong M, Martinez E, Ferrero J, et al. Regression of infancy hemangiomas with recombinant IFN-alpha 2b. J Interferon Cytokine Res 2001; 21:31-8. 51. Soumekh B, Adams GL, Shapiro RS. Treatment of head and neck hemangiomas with recombinant interferon alpha 2B. Ann Otol Rhinol Laryngol 1996;105:201-6. 52. Hastings MM, Milot J, Barsoum-Homsy M, Hershon L, Dubois J, Leclerc JM. Recombinant interferon alfa-2b in the treatment of vision-threatening capillary hemangiomas in childhood. J AAPOS 1997;1:226-30. 53. Chang E, Boyd A, Nelson CC, Crowley D, Law T, Keough KM, et al. Successful treatment of infantile hemangiomas with interferon-alpha-2b. J Pediatr Hematol Oncol 1997;19: 237-44. 54. Tamayo L, Ortiz DM, Orozco-Covarrubias L, et al. Therapeutic efficacy of interferon alfa-2b in infants with life-threatening giant hemangiomas. Arch Dermatol 1997;133:1567-71. 55. Teillac-Hamel D, De Prost Y, Bodemer C, Andry P, Enjolras O, Sebag G, et al. Serious childhood angiomas: unsuccessful alpha-2b interferon treatment: a report of four cases. Br J Dermatol 1993;129:473-6. 56. Rampini E, Rampini P, Occella C, Bleidl D. Interferon alpha 2b for treatment of complex cutaneous haemangiomas of infancy: a reduced dosage schedule. Br J Dermatol 2000;142:189. 57. Barlow C, Priebe CJ, Mulliken JB, et al. Spastic diplegia as a complication of interferon alfa-2a treatment of hemangiomas of infancy. J Pediatr 1998;132:527-30. 58. Michaud AP, Bauman NM, Burke DK, Manaligod JM, Smith RJ. Spastic diplegia and other motor disturbances in infants receiving interferon-alpha. Laryngoscope 2004;114:1231-6. 59. Suarez SM, Pensler JM, Paller AS. Response of deep tufted angioma to interferon alfa. J Am Acad Dermatol 1995;33:124-6. 60. Park KC, Ahn PS, Lee YS, Kim KH, Cho KH. Treatment of angioblastoma with recombinant interferon-alpha2. Pediatr Dermatol 1995;12:184-6. 61. Wollina U. Interferon for tufted angioma. Pediatr Dermatol 1999;16:338. 62. Robenzadeh A, Don PC, Weinberg JM. Treatment of tufted angioma with interferon alfa: role of bFGF. Pediatr Dermatol 1998;15:482. 63. Casassus P, Caillat-Vigneron N, Martin A, Simon J, Gallais V, Beaudry P, et al. Treatment of adult systemic mastocytosis with interferon-alpha: results of a multicenter phase II trial on 20 patients. Br J Haematol 2002;119:1090-7. 64. Butterfield JH. Response of severe systemic mastocytosis to interferon alpha. Br J Dermatol 1998;138:489-95. 65. Kolde G, Sunderkotter C, Luger TA. Treatment of urticaria pigmentosa using interferon alpha. Br J Dermatol 1995;133: 91-4. 66. Czarnetzki BM, Algermissen B, Jeep S, Haas N, Nurnberg W, Muller K, et al. Interferon treatment of patients with chronic urticaria and mastocytosis. J Am Acad Dermatol 1994;30: 500-1. 67. Hubner C, Wedding U, Strater J, Limberg B, Stremmel W. Clinical stable systemic mastocytosis with interferon alpha2b therapy. J Intern Med 1997;241:529-33. 68. Kluin-Nelemans HC, Jansen JH, Breukelman H, Wolthers BG, Kluin PM, Kroon HM, et al. Response to interferon alfa-2b in

69.

70.

71.

72.

73.

74.

75.

76.

77.

78.

79.

80.

81.

82.

83.

84.

85.

a patient with systemic mastocytosis. N Engl J Med 1992; 326:619-23. Petit A, Pulik M, Gaulier A, Lionnet F, Mahe A, Sigal M. Systemic mastocytosis associated with chronic myelomonocytic leukemia: clinical features and response to interferon alfa therapy. J Am Acad Dermatol 1995;32:850-3. Laato M, Heino J, Gerdin B, Kahari VM, Niinikoski J. Interferongamma-induced inhibition of wound healing in vivo and in vitro. Ann Chir Gynaecol 2001;90(Suppl):19-23. Granstein RD, Murphy GF, Margolis RJ, Byrne MH, Amento EP. Gamma-interferon inhibits collagen synthesis in vivo in the mouse. J Clin Invest 1987;79:1254-8. Berman B, Duncan MR. Short-term keloid treatment in vivo with human interferon alfa-2b results in a selective and persistent normalization of keloidal fibroblast collagen, glycosaminoglycan, and collagenase production in vitro. J Am Acad Dermatol 1989;21:694-702. Nedelec B, Shankowsky H, Scott PG, Ghahary A, Tredget EE. Myofibroblasts and apoptosis in human hypertrophic scars: the effect of interferon-alpha2b. Surgery 2001;130: 798-808. Tredget EE, Shankowsky HA, Pannu R, Nedelec B, Iwashina T, Ghahary A, et al. Transforming growth factor-beta in thermally injured patients with hypertrophic scars: effects of interferon alpha-2b. Plast Reconstr Surg 1998;102:1317-28. Granstein RD, Rook A, Flotte TJ, Haas A, Gallo RL, Jaffe HS, et al. A controlled trial of intralesional recombinant interferongamma in the treatment of keloidal scarring: clinical and histologic findings. Arch Dermatol 1990;126:1295-302. Larrabee WF Jr, East CA, Jaffe HS, Stephenson C, Peterson KE. Intralesional interferon gamma treatment for keloids and hypertrophic scars. Arch Otolaryngol Head Neck Surg 1990; 116:1159-62. Pittet B, Rubbia-Brandt L, Desmouliere A, Sappino AP, Roggero P, Guerret S, et al. Effect of gamma-interferon on the clinical and biologic evolution of hypertrophic scars and Dupuytren’s disease: an open pilot study. Plast Reconstr Surg 1994;93:1224-35. Broker BJ, Rosen D, Amsberry J, Schmidt R, Sailor L, Pribitkin EA, et al. Keloid excision and recurrence prophylaxis via intradermal interferon-gamma injections: a pilot study. Laryngoscope 1996;106:1497-501. al-Khawajah MM. Failure of interferon-alpha 2b in the treatment of mature keloids. Int J Dermatol 1996;35: 515-7. Wong TW, Chiu HC, Yip KM. Intralesional interferon alfa-2b has no effect in the treatment of keloids. Br J Dermatol 1994; 130:683-5. Tredget EE, Wang R, Shen Q, Scott PG, Ghahary A. Transforming growth factor-beta mRNA and protein in hypertrophic scar tissues and fibroblasts: antagonism by IFN-alpha and IFN-gamma in vitro and in vivo. J Interferon Cytokine Res 2000;20:143-51. Davison SP, Mess S, Kauffman LC, Al-Attar A. Ineffective treatment of keloids with interferon alpha-2b. Plast Reconstr Surg 2006;117:247-52. Berman B, Flores F. Recurrence rates of excised keloids treated with postoperative triamcinolone acetonide injections or interferon alfa-2b injections. J Am Acad Dermatol 1997;37:755-7. Conejo-Mir JS, Corbi R. Carbon dioxide laser ablation associated with interferon alfa-2b injections reduces the recurrence of keloids. J Am Acad Dermatol 1998;39:1039-40. Niimura M. Application of beta-interferon in virus-induced papillomas. J Invest Dermatol 1990;95(Suppl):149S-51S.

e46 Smith, Swamy, and Heffernan

J AM ACAD DERMATOL JANUARY 2007

86. Niimura M. Treatment of flat warts with human fibroblast interferon. Nishinihon J Dermatol 1983;45:59-64. 87. Brodell RT, Bredle DL. The treatment of palmar and plantar warts using natural alpha interferon and a needleless injector. Dermatol Surg 1995;21:213-8. 88. Gibson JR, Harvey SG, Kemmett D, Salisbury J, Marks P. Treatment of common and plantar viral warts with human lymphoblastoid interferon-alphaepilot studies with intralesional, intramuscular and dermojet injections. Br J Dermatol 1986;115(Suppl):76-9. 89. Berman B, Davis-Reed L, Silverstein L, Jaliman D, France D, Lebwohl M. Treatment of verrucae vulgaris with alpha 2 interferon. J Infect Dis 1986;154:328-30. 90. Pazin GJ, Ho M, Haverkos HW, Armstrong JA, Breinig MC, Wechsler HL, et al. Effects of interferon-alpha on human warts. J Interferon Res 1982;2:235-43. 91. Beissert S, Koch U, Sunderkotter C, Luger TA, Schwarz T. Successful treatment of disseminated verrucae vulgares with interferon-beta. J Am Acad Dermatol 1993;29:1041-2. 92. Schoenfeld A, Ovadia J, Stein L, Levavi H, Nitke S, Doerner T, et al. Treatment of flat facial warts with interferon-beta cream. J Dermatol Surg Oncol 1987;13:299-301. 93. Pueyo S, Criscuolo M, Davidovich C, Zorzopulos J, Pesce A, Diaz A. Treatment of recurrent common warts with one low dose of intralesional natural human leukocyte interferon alpha. J Biol Regul Homeost Agents 1990;4:47-50. 94. Naples SP, Brodell RT. Verruca vulgaris: treatment with natural interferon alfa using a needleless injector. Arch Dermatol 1993;129:698-700. 95. Gibson JR. Intralesional human lymphoblastoid interferon alpha for the treatment of cutaneous, nongenital viral warts. Arch Dermatol 1986;122:1098-9. 96. Gibson JR, Harvey SG. Interferon in the treatment of persistent viral warts. Dermatologica 1984;169:47-8. 97. Niimura M. Intralesional human fibroblast interferon in patients with epidermodysplasia verruciformis. In: Kono R, Nakajima A, editors. Herpes virus and virus chemotherapy. New York: Excerpta Medica; 1985. p. 313. 98. Androphy EJ, Dvoretzky I, Maluish AE, Wallace HJ, Lowy DR. Response of warts in epidermodysplasia verruciformis to treatment with systemic and intralesional alpha interferon. J Am Acad Dermatol 1984;11:197-202. 99. Anadolu R, Oskay T, Erdem C, Boyvat A, Terzi E, Gu¨rgey E. Treatment of epidermodysplasia verruciformis with a combination of acitretin and interferon alfa-2a. J Am Acad Dermatol 2001;45:296-9. 100. Mendelson J, Clecner BY, Eiley S. Effect of recombinant interferon alpha 2 on clinical course of first episode genital herpes infection and subsequent recurrences. Genitourin Med 1986;62:97-101. 101. Pazin GJ, Harger JH, Armstrong JA, Breinig MK, Caplan RJ, Cantell K, et al. Leukocyte interferon for treating first episodes of genital herpes in women. J Infect Dis 1987;156:891-8. 102. Cardamakis E, Relakis K, Kotoulas IG, Michopoulos J, Metallinos K, Mantouvalos H, et al. Treatment of recurrent genital herpes with interferon alpha-2alpha. Gynecol Obstet Invest 1998; 46:54-7. 103. Lassus A, Bergelin I, Paloranta A, Rinne E, Eskelinen A, Saila K. Efficacy of interferon and placebo in the treatment of recurrent genital herpes: a double-blind trial. Sex Transm Dis 1987;14:185-90. 104. Kuhls TL, Sacher J, Pineda E, Santomauro D, Wiesmeier E, Growdon WA, et al. Suppression of recurrent genital herpes simplex virus infection with recombinant alpha 2 interferon. J Infect Dis 1986;154:437-42.

105. Levin MJ, Judson FN, Eron L, Bryson YJ, Corey L, Murray M, et al. Comparison of intramuscular recombinant alpha interferon (rIFN-2A) with topical acyclovir for the treatment of first-episode herpes genitalis and prevention of recurrences. Antimicrob Agents Chemother 1989;33:649-52. 106. Eron LJ, Harvey L, Toy C, Santomauro D. Interferon in the prevention of genital herpes recurrence. Antimicrob Agents Chemother 1986;30:608-10. 107. Syed TA, Cheema KM, Kahlon BM, Kahlon RC, Khayyami M, Kahlon AM, et al. Human leukocyte interferon-alpha in cream for the treatment of genital herpes in Asian males: a placebocontrolled, double-blind study. Dermatology 1995;191:32-5. 108. Syed TA, Lundin S, Cheema KM, Kahlon RC, Khayyami M, Ahmad SA, et al. Human leukocyte interferon-alpha in cream for the management of genital herpes in Asian women: a placebo-controlled, double-blind study. J Mol Med 1995; 73:141-4. 109. Syed TA, Ahmadpour OA, Ahmad SA, Ahmad SH. Human leukocyte interferon-alpha in a hydrophilic cream versus in a gel for the treatment of genital herpes in males: a placebocontrolled, double-blind, comparative study. J Dermatol 1997;24:564-8. 110. Lebwohl M, Sacks S, Conant M, Connor J, Douglas JM Jr, Eron L, et al. Recombinant alpha-2 interferon gel treatment of recurrent herpes genitalis. Antiviral Res 1992;17:235-43. 111. Shupack J, Stiller M, Knobler E, Ackerman C, Jondreau L, Kenny C. Topical alpha-interferon in recurrent genital herpes simplex infection: a double-blind, placebo-controlled clinical trial. Dermatologica 1990;181:134-8. 112. Shupack J, Stiller M, Davis I, Kenny C, Jondreau L. Topical alphainterferon ointment with dimethyl sulfoxide in the treatment of recurrent genital herpes simplex. Dermatology 1992;184: 40-4. 113. Friedman-Kien AE, Klein RJ, Glaser RD, Czelusniak SM. Treatment of recurrent genital herpes with topical alpha interferon gel combined with nonoxynol 9. J Am Acad Dermatol 1986;15:989-94. 114. Sacks SL, Varner TL, Davies KS, Rekart ML, Striver HG, Delong ER, et al. Randomized, double-blind, placebo-controlled, patient-initiated study of topical high- and low-dose interferon-alpha with nonoxynol-9 in the treatment of recurrent genital herpes. J Infect Dis 1990;161:692-8. 115. Eron LJ, Toy C, Salsitz B, Scheer RR, Wood DL, Nadler PI. Therapy of genital herpes with topically applied interferon. Antimicrob Agents Chemother 1987;31:1137-9. 116. Ophir J, Brenner S, Bali R, Kriss-Leventon S, Smetana Z, Revel M. Effect of topical interferon-beta on recurrence rates in genital herpes: a double-blind, placebo-controlled, randomized study. J Interferon Cytokine Res 1995;15:625-31. 117. Glezerman M, Lunenfeld E, Cohen V, Sarov I, Movshovitz M, Doerner T, et al. Placebo-controlled trial of topical interferon in labial and genital herpes. Lancet 1988;1:150-2. 118. Shalev Y, Berrebi A, Green L, Levin S, Frumkin A, Hurwitz N, et al. Progressive cutaneous herpes simplex infection in acute myeloblastic leukemia: successful treatment with interferon and cytarabine. Arch Dermatol 1984;120:922-6. 119. Giani G, Quirino T, Sacrini F, Carbone A, Vaccher E, Resta M, et al. Destructive mucocutaneous phagedenic herpes simplex virus infection in an HIV-infected patient who had a partial response to interferon and ultraviolet rays. Clin Infect Dis 1996;22:381-2. 120. Levin S, Hahn T, Rosenberg H, Bino T. Treatment of life-threatening viral infections with interferon alpha: pharmacokinetic studies in a clinical trial. Isr J Med Sci 1982;18:439-46.

Smith, Swamy, and Heffernan e47

J AM ACAD DERMATOL VOLUME 56, NUMBER 1

121. Isacsohn M, Berson B, Sternberg I, Morag A. Human fibroblast interferon in treatment of viral diseases of the skin and mucous membranes. Isr J Med Sci 1983;19:959-62. 122. Pazin GJ, Armstrong JA, Lam MT, Tarr GC, Jannetta PJ, Ho M. Prevention of reactivated herpes simplex infection by human leukocyte interferon after operation on the trigeminal root. N Engl J Med 1979;301:225-30. 123. Ho M, Pazin GJ, Armstron JA, Haverkos HS, et al. Paradoxical effects of interferon on reactivation of oral infection with herpes simplex virus after microvascular decompression for trigeminal neuralgia. J Infect Dis 1984;150:867-72. 124. Emodi G, Rufli T, Just M, Hernandez R. Human interferon therapy for herpes zoster in adults. Scand J Infect Dis 1975;7:1-5. 125. Emodi G, Rufli T. Antiviral action of interferon in man: use of interferon in varicella-zoster infections in man. Tex Rep Biol Med 1977;35:511-5. 126. Merigan TC, Rand KH, Pollard RB, Abdallah PS, Jordan GW, Fried RP. Human leukocyte interferon for the treatment of herpes zoster in patients with cancer. N Engl J Med 1978; 298:981-7. 127. Merigan TC, Gallagher JG, Pollard RB, Arvin AM. Short-course human leukocyte interferon in treatment of herpes zoster in patients with cancer. Antimicrob Agents Chemother 1981;19: 193-5. 128. Arvin AM, Kushner JH, Feldman S, Baehner RL, Hammond D, Merigan TC. Human leukocyte interferon for the treatment of varicella in children with cancer. N Engl J Med 1982;306: 761-5. 129. Winston DJ, Eron LJ, Ho M, Pazin G, Kessler H, Pottage JC Jr, et al. Recombinant interferon alpha-2a for treatment of herpes zoster in immunosuppressed patients with cancer. Am J Med 1988;85:147-51. 130. Duschet P, Schwarz T, Soyer P, Henk A, Hausmaninger H, Gschnait F. Treatment of herpes zoster: recombinant alpha interferon versus acyclovir. Int J Dermatol 1988;27:193-7. 131. Naoum C, Perissios A, Varnavas V, Lagos D. Treatment of herpes zoster with interferon alpha-2A. Int J Dermatol 1996; 35:749-50. 132. Miyoshi H, Hirotsuji N, Kino T, Katsu K. Interferon alpha gel for herpes zoster. Dermatology 1997;194:306. 133. Rossi S, Whitfeld M, Berger TG. The treatment of acyclovirresistant herpes zoster with trifluorothymidine and interferon alfa. Arch Dermatol 1995;131:24-6. 134. Usuki K, Kitamura K, Urabe A, Takaku F. Herpes zoster, postherpetic neuralgia, and interferon-gamma. Ann Intern Med 1988;108:643-4. 135. Barral-Netto M, Santos S, Santos I, Sohsten R, von Bittencourt AL, Carvalho EM, et al. Immunochemotherapy with interferon-g and multidrug therapy for multibacillary leprosy. Acta Trop 1999;72:185-201. 136. Nathan CF, Kaplan G, Levis WR, Nusrat A, Witmer MD, Sherwin SA, et al. Local and systemic effects of intradermal recombinant interferon-gamma in patients with lepromatous leprosy. N Engl J Med 1986;315:6-15. 137. Samuel NM, Grange JM, Samuel S, Lucas S, Owilli OM, Adalla S, et al. A study of the effects of intradermal administration of recombinant gamma interferon in lepromatous leprosy patients. Lepr Rev 1987;58:389-400. 138. Bottasso O, Besuschio S, Merlin V, Morini JC, Bernabo J, Falcoff R, et al. Lepromatous leprosy treated with recombinant interferon gamma: cutaneous histologic changes. Int J Dermatol 1992;31:813-7. 139. Mathur NK, Mittal A, Mathur D, Jain SK. Long-term follow up of lepromatous leprosy patients receiving intralesional

140.

141.

142.

143.

144.

145. 146.

147.

148.

149.

150.

151.

152.

153.

154.

155.

recombinant gamma-interferon. Int J Lepr Other Mycobact Dis 1992;60:98-100. Sampaio EE, Moreira AL, Sarno EN, Malta AM, Kaplan G. Prolonged treatment with recombinant interferon gamma induces erythema nodosum leprosum in lepromatous leprosy patients. J Exp Med 1992;175:1729-37. Harms G, Zwingenberger K, Cehade AK, Talhari S, Racz P, Mouakeh A, et al. Effects of intradermal gamma-interferon in cutaneous leishmaniasis. Lancet 1989;1:1287-92. Harms G, Chehade AK, Douba M, Roepke M, Mouakeh A, Rosenkaimer F, et al. A randomized trial comparing a pentavalent antimonial drug and recombinant interferongamma in the local treatment of cutaneous leishmaniasis. Trans R Soc Trop Med Hyg 1991;85:214-6. Falcoff E, Taranto NJ, Remondegui CE, Dedet JP, Canini LM, Ripoll CM, et al. Clinical healing of antimony-resistant cutaneous or mucocutaneous leishmaniasis following the combined administration of interferon-gamma and pentavalent antimonial compounds. Trans R Soc Trop Med Hyg 1994;88: 95-7. Kolde G, Luger T, Sorg C, Sunderkotter C. Successful treatment of cutaneous leishmaniasis using systemic interferon-gamma. Dermatology 1996;192:56-60. Kurkcuoglu N, Tandogdu R. Interferon gamma therapy for cutaneous leishmaniasis. Arch Dermatol 1990;126:831-2. Bottasso O, Cabrini J, Falcoff R. Successful treatment of an antimony-resistant American mucocutaneous leishmaniasis: a case report. Arch Dermatol 1992;128:996-7. Becker I, Volkow P, Velasco-Castrejon O, Salaiza-Suazo N, Berzunza-Cruz M, Dominguez JS, et al. The efficacy of pentamidine combined with allopurinol and immunotherapy for the treatment of patients with diffuse cutaneous leishmaniasis. Parasitol Res 1999;85:165-70. Salaiza-Suazo N, Volkow P, Tamayo R, Moll H, Gillitzer R, Perez-Torres A, et al. Treatment of two patients with diffuse cutaneous leishmaniasis caused by Leishmania mexicana modifies the immunohistological profile but not the disease outcome. Trop Med Int Health 1999;4:801-11. Martinez J, de Misa RF, Boixeda P, Arrazola JM, Ledo A. Longterm results of intralesional interferon alpha-2B in discoid lupus erythematosus. J Dermatol 1993;20:444-6. Thivolet J, Nicolas JF, Kanitakis J, Lyonnet S, Chouvet B. Recombinant interferon alpha 2a is effective in the treatment of discoid and subacute cutaneous lupus erythematosus. Br J Dermatol 1990;122:405-9. Martinez J, de Misa RF, Torrelo A, Ledo A. Low-dose intralesional interferon alfa for discoid lupus erythematosus. J Am Acad Dermatol 1992;26:494-6. Machold KP, Smolen JS. Interferon-gamma induced exacerbation of systemic lupus erythematosus. J Rheumatol 1990; 17:831-2. Varga J, Olsen A, Herhal J, Constantine G, Rosenbloom J, Jimenez SA. Interferon-gamma reverses the stimulation of collagen but not fibronectin gene expression by transforming growth factor beta in normal human fibroblasts. Eur J Clin Invest 1990;20:487-93. Stevens W, Vancheeswaran R, Black CM. Alpha interferon-2a (Roferon-A) in the treatment of diffuse cutaneous systemic sclerosis: a pilot study. UK Systemic Sclerosis Study Group. Br J Rheumatol 1992;31:683-9. Black CM, Silman AJ, Herrick AI, Denton CP, Wilson H, Newman J, et al. Interferon-alpha does not improve outcome at one year in patients with diffuse cutaneous scleroderma: results of a randomized, double-blind, placebo-controlled trial. Arthritis Rheum 1999;42:299-305.

e48 Smith, Swamy, and Heffernan

J AM ACAD DERMATOL JANUARY 2007

156. Kahan A, Amor B, Menkes CJ, Strauch G. Recombinant interferon-gamma in the treatment of systemic sclerosis. Am J Med 1989;87:273-7. 157. Freundlich B, Jimenez SA, Steen VD, Medsger TA Jr, Szkolnicki M, Jaffe HS. Treatment of systemic sclerosis with recombinant interferon-gamma: a phase I/II clinical trial. Arthritis Rheum 1992;35:1134-42. 158. Hein R, Behr J, Hundgen M, Hunzelmann N, Meurer M, Braun-Falco O, et al. Treatment of systemic sclerosis with gamma-interferon. Br J Dermatol 1992;126:496-501. 159. Vlachoyiannopoulos PG, Tsifetaki N, Dimitriou I, Galaris D, Papiris SA, Moutsopoulos HM. Safety and efficacy of recombinant gamma interferon in the treatment of systemic sclerosis. Ann Rheum Dis 1996;55:761-8. 160. Polisson RP, Gilkeson GS, Pyun EH, Pisetsky DS, Smith EA, Simon LS. A multicenter trial of recombinant human interferon gamma in patients with systemic sclerosis: effects on cutaneous fibrosis and interleukin 2 receptor levels. J Rheumatol 1996;23:654-8. 161. Grassegger A, Schuler G, Hessenberger G, Walder-Hantich B, Jabkowski J, Macheiner W, et al. Interferon-gamma in the treatment of systemic sclerosis: a randomized controlled multicenter trial. Br J Dermatol 1998;139:639-48. 162. Hunzelmann N, Anders S, Fierlbeck G, Hein R, Herrmann K, Albrecht M, et al. Systemic scleroderma: multicenter trial of 1 year of treatment with recombinant interferon gamma. Arch Dermatol 1997;133:609-13. 163. Hunzelmann N, Anders S, Fierlbeck G, Hein R, Herrmann K, Albrecht M, et al. Double-blind, placebo-controlled study of intralesional interferon gamma for the treatment of localized scleroderma. J Am Acad Dermatol 1997;36:433-5. 164. Arnaudova P, Rashkov R, Tsanev R. Application of interferon-gamma containing gel for local treatment of skin ulcers in autoimmune vasculitides and skin changes in progressive systemic sclerosis. J Rheumatol 1993;20: 1445-6. 165. Alpsoy E, Durusoy C, Yilmaz E, Ozgurel Y, Ermis O, Yazar S, et al. Interferon alfa-2a in the treatment of Behc¸et disease: a randomized placebo-controlled and double-blind study. Arch Dermatol 2002;138:467-71. 166. O’Duffy JD, Calamia K, Cohen S, Goronzy JJ, Herman D, Jorizzo J, et al. Interferon-alpha treatment of Behc¸et’s disease. J Rheumatol 1998;25:1938-44. 167. Azizlerli G, Sarica R, Kose A, Ovul C, Kavala M, Kayabali M, et al. Interferon alfa-2a in the treatment of Behc¸et’s disease. Dermatology 1996;192:239-41. 168. C¸algu¨neri M, O¨zte`rk MA, Ertenli I, Kiraz S, Apras S, O¨zbalkan Z. Effects of interferon {alpha} treatment on the clinical course of refractory Behc¸et’s disease: an open study. Ann Rheum Dis 2003;62:492-3. 169. Alpsoy E, Yilmaz E, Basaran E. Interferon therapy for Behc¸et’s disease. J Am Acad Dermatol 1994;31:617-9. 170. Kosar A, Haznedaroglu S, Karaaslan Y, Buyukasik Y, Haznedaroglu IC, Ozath D, et al. Effects of interferon-alpha 2a treatment on serum levels of tumor necrosis factoralpha, tumor necrosis factor-alpha 2 receptor, interleukin-2, interleukin-2 receptor, and E-selectin in Behc¸et’s disease. Rheumatol Int 1999;19:11-4. 171. Georgiou S, Monastirli A, Pasmatzi E, Gartaganis S, Goerz G, Tsambaos D. Efficacy and safety of systemic recombinant interferon-alpha in Behc¸et’s disease. Intern Med 1998;243: 367-72. 172. Kotter I, Eckstein AK, Stubiger N, Zierhut M. Treatment of ocular symptoms of Behc¸et’s disease with interferon alpha 2a: a pilot study. Br J Ophthalmol 1998;82:488-94.

173. Kotter I, Vonthein R, Zierhut M, Eckstein AK, Ness T, Gunaydin I, et al. Differential efficacy of human recombinant interferonalpha2a on ocular and extraocular manifestations of Behc¸et disease: results of an open 4-center trial. Semin Arthritis Rheum 2004;33:311-9. 174. Hamuryudan V, Moral F, Yurdakul S, Mat C, Tuzun Y, Ozyazgan Y, et al. Systemic interferon alpha 2b treatment in Behc¸et’s syndrome. J Rheumatol 1994;21:1098-100. 175. Boyvat A, Sisman-Solak C, Gurler A. Long-term effects of interferon alpha 2A treatment in Behc¸et’s disease. Dermatology 2000;201:40-3. 176. Hamuryudan V, Yurdakul S, Rosenkaimer F, Yazici H. Inefficacy of topical alpha interferon in the treatment of oral ulcers of Behc¸et’s syndrome: a randomized, double blind trial. Br J Rheumatol 1991;30:395-6. 177. Kotter I, Gunaydin I, Zierhut M, Stubiger N. The use of interferon alpha in Behc¸et disease: review of the literature. Semin Arthritis Rheum 2004;33:320-35. 178. Zouboulis CC, Orfanos CE. Treatment of AdamantiadesBehc¸et disease with systemic interferon alfa. Arch Dermatol 1998;134:1010-6. 179. Magee KL, Hsu SM, Tucker SB. Trial of intralesional interferon alfa in the treatment of alopecia areata. Arch Dermatol 1990;126:760-2. 180. Agesta N, Zabala R, Diaz-Perez JL. Alopecia areata during interferon alpha-2b/ribavirin therapy. Dermatology 2002;205: 300-1. 181. Kernland KH, Hunziker T. Alopecia areata induced by interferon alpha? Dermatology 1999;198:418-9. 182. Lang AM, Norland AM, Schuneman RL, Tope WD. Localized interferon alfa-2b-induced alopecia. Arch Dermatol 1999; 135:1126-8. 183. Chang TT, Stevens SR. Atopic dermatitis: the role of recombinant interferon-gamma therapy. Am J Clin Dermatol 2002; 3:175-83. 184. Hanifin JM, Schneider LC, Leung DY, Ellis CN, Jaffe HS, Izu AE, et al. Recombinant interferon gamma therapy for atopic dermatitis. J Am Acad Dermatol 1993;28:189-97. 185. Jang IG, Yang JK, Lee HJ, Yi JY, Kim HO, Kim CW, et al. Clinical improvement and immunohistochemical findings in severe atopic dermatitis treated with interferon gamma. J Am Acad Dermatol 2000;42:1033-40. 186. Stevens SR, Hanifin JM, Hamilton T, Tofte SJ, Cooper KD. Long-term effectiveness and safety of recombinant human interferon gamma therapy for atopic dermatitis despite unchanged serum IgE levels. Arch Dermatol 1998;134: 799-804. 187. Noh GW, Lee KY. Blood eosinophils and serum IgE as predictors for prognosis of interferon-gamma therapy in atopic dermatitis. Allergy 1998;53:1202-7. 188. Schneider LC, Baz Z, Zarcone C, Zurakowski D. Long-term therapy with recombinant interferon-gamma (rIFN-gamma) for atopic dermatitis. Ann Allergy Asthma Immunol 1998; 80:263-8. 189. Musial J, Milewski M, Undas A, Kopinski P, Duplaga M, Szczeklik A. Interferon-gamma in the treatment of atopic dermatitis: influence on T-cell activation. Allergy 1995;50: 520-3. 190. Reinhold U, Kukel S, Brzoska J, Kreysel HW. Systemic interferon gamma treatment in severe atopic dermatitis. J Am Acad Dermatol 1993;29:58-63. 191. Boguniewicz M, Jaffe HS, Izu A, Sullivan MJ, York D, Geha RS, et al. Recombinant gamma interferon in treatment of patients with atopic dermatitis and elevated IgE levels. Am J Med 1990;88:365-70.

J AM ACAD DERMATOL

Smith, Swamy, and Heffernan e49

VOLUME 56, NUMBER 1

192. Noh G, Lee KY. Successful interferon alpha therapy in atopic dermatitis of Besnier’s prurigo pattern with normal serum IgE and blood eosinophil fraction: randomized case-controlled study. Cytokine 2001;13:124-8. 193. Torrelo A, Harto A, Sendagorta E, Czarnetzki BM, Ledo A. Interferon-alpha therapy in atopic dermatitis. Acta Derm Venereol 1992;72:370-2. 194. Kimata H, Akiyama Y, Kubota M, Furusho K. Interferon-alpha treatment for severe atopic dermatitis. Allergy 1995;50:837-40. 195. Paukkonen K, Fraki J, Horsmanheimo M. Interferon-alpha treatment decreases the number of blood eosinophils in patients with severe atopic dermatitis. Acta Derm Venereol 1993;73:141-2. 196. Jullien D, Nicolas JF, Frappaz A, Thivolet J. Alpha interferon treatment in atopic dermatitis. Acta Derm Venereol 1993;73: 130-2. 197. Doutre MS, Beylot C, Couzigou P, Long P, Royer P, Beylot J. Lichen planus and virus C hepatitis: disappearance of the lichen under interferon alfa therapy. Dermatology 1992; 184:229. 198. Lapidoth M, Arber N, Ben-Amitai D, Hagler J. Successful interferon treatment for lichen planus associated with chronic active hepatitis due to hepatitis C virus infection. Acta Derm Venereol 1997;77:171-2. 199. Hildebrand A, Kolde G, Luger TA, Schwarz T. Successful treatment of generalized lichen planus with recombinant interferon alfa-2b. J Am Acad Dermatol 1995;33:880-3. 200. Strumia R, Venturini D, Boccia S, Gamberini S, Gullini S. UVA and interferon-alfa therapy in a patient with lichen planus and chronic hepatitis C. Int J Dermatol 1993;32:386. 201. Nunez M, Miralles ES, de las Heras ME, Ledo A. Appearance of oral erosive lichen planus during interferon alfa-2a therapy for chronic active hepatitis C. J Dermatol 1995;22:461-2. 202. Varela P, Areias J, Mota F, Canelhas A, Sanches M. Oral lichen planus induced by interferon-alpha-N1 in a patient with hepatitis C. Int J Dermatol 2000;39:239-40. 203. Herrera Saval A, Camacho Martinez F. Lichen planus induced by interferon-alpha-2B therapy in a patient with cutaneous malignant melanoma. Acta Derm Venereol 1999;79:395. 204. Torrelo A, Harto A, Ledo A. Interferon therapy for chronic urticaria. J Am Acad Dermatol 1995;32:684-5. 205. Hamid S, Cruz PD Jr, Lee WM. Urticarial vasculitis caused by hepatitis C virus infection: response to interferon alfa therapy. J Am Acad Dermatol 1998;39:278-80. 206. Matteson EL. Interferon alpha 2a therapy for urticarial vasculitis with angioedema apparently following hepatitis A infection. J Rheumatol 1996;23:382-4. 207. Jolles S. High-dose intravenous immunoglobulin (hdIVIg) in the treatment of autoimmune blistering disorders. Clin Exp Immunol 2002;129:385-9. 208. Dalakas MC. The use of intravenous immunoglobulin in the treatment of autoimmune neuromuscular diseases: evidence-based indications and safety profile. Pharmacol Ther 2004;102:177-93. 209. Rossi F, Kazatchkine MD. Antiidiotypes against autoantibodies in pooled normal human polyspecifinc IG. J Immunol 1989;143:4104-9. 210. Dwyer JM. Manipulating the immune system with immune globulin. N Engl J Med 1992;326:107-11. 211. Yu Z, Lennon VA. Mechanism of intravenous immune globulin therapy in antibody-mediated autoimmune diseases. N Engl J Med 1999;340:227-8. 212. Masson PL. Elimination of infectious antigens and increase of IgG catabolism as possible modes of action of IVIg. J Autoimmun 1993;6:683-9.

213. Hurez V, Kaveri SC, Mouhoub A, Dietrich G, Mani JC, Klatzmann D, et al. Anti-CD4 activity of normal human immunoglobulin G for therapeutic use (intravenous immunoglobulin, IVIg). Ther Immunol 1994;1:269-77. 214. Toyoda M, Zhang XM, Petrosian A, Wachs K, Moudgil A, Jordan SC. Inhibition of allospecific responses in the mixed lymphocyte reaction by pooled human gamma-globulin. Transpl Immunol 1994;2:337-41. 215. Basta M, Fries LF, Frank MM. High doses of intravenous immunoglobulin do not affect the recognition phase of the classical complement pathway. Blood 1991;78:700-2. 216. Toyoda M, Zhang X, Petrosian A, Galera OA, Wang SJ, Jordan SC. Modulation of immunoglobulin production and cytokine mRNA expression in peripheral blood mononuclear cells by intravenous immunoglobulin. J Clin Immunol 1994;14:178-89. 217. Abe Y, Aesushi H, Masazumi M, Kimura S. Anticytokine nature of natural human immunoglobulin: one possible mechanism of the clinical effect of intravenous immunoglobulin therapy. Immunol Rev 1994;129:5-19. 218. Andersson UG, Bjork L, Skansen-Saphir U, Andersson JP. Down-regulation of cytokine production and interleukin-2 receptor expression by pooled human IgG. Immunology 1993;79:211-6. 219. Amran A, Renz H, Lack G, Bradley K, Gelfand EW. Suppression of cytokine-dependent human T-cell proliferation by intravenous immunoglobulin. Clin Immunol Immunopathol 1994; 73:180-6. 220. Ross C, Svenson M, Hansen MB, Vejlsgaard GL, Bendtzen K. High avidity IFN-neutralizing antibodies in pharmacologically prepared IgG (intravenous immunoglobulin). Eur J Immunol 1995;95:1974-8. 221. Bayry J, Lacroix-Desmazes S, Carbonneil C, Misra N, Donkova V, Pashov A, et al. Inhibition of maturation and function of dendritic cells by intravenous immunoglobulin. Blood 2003; 101:758-65. 222. Kazatchkine MD, Kaveri SV. Immunomodulation of autoimmune and inflammatory diseases with intravenous immune globulin. N Engl J Med 2001;345:747-55. 223. Oravec S, Ronda N, Carayon A, Milliez J, Kazatchkine MD, Hornych A. Normal human polyspecific immunoglobulin G (intravenous immunoglobulin) modulates endothelial cell function in vitro. Nephrol Dial Transplant 1995;10:796-800. 224. Vecchietti G, Kerl K, Prins C, Kaya G, Saurat JH, French LE. Severe eczematous skin reaction after high-dose intravenous immunoglobulin infusion. report of 4 cases and review of the literature. Arch Dermatol 2006;142:213-7. 225. Wilson JR, Bhoopalam H, Fisher M. Hemolytic anemia associated with intravenous immunoglobulin. Muscle Nerve 1997;20:1142-5. 226. Jolles S, Hill H. Management of aseptic meningitis secondary to intravenous immunoglobulin. BMJ 1998;316:936. 227. Ahmed AR, Dahl MV. Consensus statement on the use of intravenous immunoglobulin therapy in the treatment of autoimmune mucocutaneous blistering diseases. Arch Dermatol 2003;139:1051-9. 228. Matsuda M, Hosoda W, Sekijima Y, Hoshi K, Hashimoto T, Itoh S, et al. Neutropenia as a complication of high-dose intravenous immunoglobulin therapy in adult patients with neuroimmunologic disorders. Clin Neuropharmacol 2003;26: 306-11. 229. Berkovitch M, Dolinski G, Tauber T, Aladjem M, Kaplinsky C. Neutropenia as a complication of intravenous immunoglobulin (IVIG) therapy in children with immune thrombocytopenic purpura: common and non-alarming. Int J Immunopharmacol 1999;21:411-5.

e50 Smith, Swamy, and Heffernan

J AM ACAD DERMATOL JANUARY 2007

230. Niebanck AE, Kwiatkowski JL, Raffini LJ. Neutropenia following IVIG therapy in pediatric patients with immune-mediated thrombocytopenia. J Pediatr Hematol Oncol 2005;27:145-7. 231. Dahl MV, Bridges AG. Intravenous immune globulin: fighting antibodies with antibodies. J Am Acad Dermatol 2001;45: 775-83. 232. Sati HI, Ahya R, Watson HG. Incidence and associations of acute renal failure complicating high-dose intravenous immunoglobulin therapy. Br J Haematol 2001;113:556-7. 233. Roifman CM, Schroeder H, Berger M, Sorensen R, Ballow M, Buckley RH, et al. Comparison of the efficacy of IGIV-C, 10% (caprylate/chromatography) and IGIV-SD, 10% as replacement therapy in primary immune deficiency: a randomized double-blind trial. Int Immunopharmacol 2003;3:1325-33. 234. Yap PL. The viral safety of intravenous immune globulin. Clin Exp Immunol 1996;104(Suppl):35-42. 235. Herzog S, Schmidt E, Goebeler M, Brocker EB, Zillikens D. Serum levels of autoantibodies to desmoglein 3 in patients with therapy-resistant pemphigus vulgaris successfully treated with adjuvant intravenous immunoglobulins. Acta Derm Venereol 2004;84:48-52. 236. Sami N, Bhol KC, Ahmed RA. Influence of intravenous immunoglobulin therapy on autoantibody titers to desmoglein 3 and desmoglein 1 in pemphigus vulgaris. Eur J Dermatol 2003;13:377-81. 237. Sami N, Qureshi A, Ruocco E, Ahmed AR. Corticosteroidsparing effect of intravenous immunoglobulin therapy in patients with pemphigus vulgaris. Arch Dermatol 2002; 138:1158-62. 238. Ahmed AR. Intravenous immunoglobulin therapy in the treatment of patients with pemphigus vulgaris unresponsive to conventional immunosuppressive treatment. J Am Acad Dermatol 2001;45:679-90. 239. Bystryn JC, Jiao D, Natow S. Treatment of pemphigus with intravenous immunoglobulin. J Am Acad Dermatol 2002;47: 358-63. 240. Sami N, Bhol KC, Beutner EH, Plankett RW, Leiferman KM, Ahmed AR. Diagnostic features of pemphigus vulgaris in patients with bullous pemphigoid: molecular analysis of autoantibody profile. Dermatology 2002;204:108-17. 241. Harman KE, Black MM. High-dose intravenous immune globulin for the treatment of autoimmune blistering diseases: an evaluation of its use in 14 cases. Br J Dermatol 1999;140:865-74. 242. Sibaud V, Beylot-Barry M, Doutre MS, Beylot C. Successful treatment of corticoid-resistant pemphigus with high-dose intravenous immunoglobulins [French]. Ann Dermatol Venereol 2000;127:408-10. 243. Colonna L, Cianchini G, Frezzolini A, De Pita O, Di Lella G, Puddu P. Intravenous immunoglobulins for pemphigus vulgaris: adjuvant or first choice therapy. Br J Dermatol 1998; 138:1102-3. 244. Wever S, Zillikenz D, Broker EB. Successful treatment of pemphigus vulgaris by pulsed intravenous immunoglobulin therapy. Br J Dermatol 1996;135:862-3. 245. Beckers RC, Brand A, Vermeer BJ, Boom BW. Adjuvant highdose intravenous gammaglobulin in the treatment of pemphigus and bullous pemphigoid: experience in six patients. Br J Dermatol 1995;133:289-93. 246. Humbert P, Derancourt C, Aubin F, Agache P. Effects of intravenous gammaglobulin in pemphigus [letter]. J Am Acad Dermatol 1990;22:326. 247. Bewley AP, Keefe M. Successful treatment of pemphigus vulgaris by pulsed intravenous immunoglobulin therapy. Br J Dermatol 1996;135:128-9.

248. Jolles S, Hughes J, Rustin M. Therapeutic failure of high-dose intravenous immunoglobulin in pemphigus vulgaris. J Am Acad Dermatol 1999;40:499-500. 249. Messer G, Sizmann N, Feucht H, Meurer M. High-dose intravenous immunoglobulins for immediate control of severe pemphigus vulgaris. Br J Dermatol 1995;133:1014-6. 250. Tappeiner G, Steiner A. High-dosage intravenous gamma globulin: therapeutic failure in pemphigus and pemphigoid [see comments]. J Am Acad Dermatol 1989;20:684-5. 251. Wetter DA, Davis MD, Yiannias JA, Gibson LE, Dahl MV, el-Azhary RA, et al. Effectiveness of intravenous immunoglobulin therapy for skin disease other than toxic epidermal necrolysis: a retrospective review of Mayo Clinic experience. Mayo Clin Proc 2005;80:41-7. 252. Sami N, Bhol KC, Ahmed AR. Influence of IVIg therapy on autoantibody titers to desmoglein 1 in patients with pemphigus foliaceus. Clin Immunol 2002;105:192-8. 253. Ahmed AR, Sami N. Intravenous immunoglobulin therapy for patients with pemphigus foliaceus unresponsive to conventional therapy. J Am Acad Dermatol 2002;46:42-9. 254. Sami N, Qureshi A, Ahmed AR. Steroid sparing effect of intravenous immunoglobulin therapy in patients with pemphigus foliaceus. Eur J Dermatol 2002;12:174-8. 255. Toth GG, Jonkman MF. Successful treatment of recalcitrant penicillamine-induced pemphigus foliaceus by low-dose intravenous immunoglobulins. Br J Dermatol 1999;141:583-5. 256. Godard W, Roujeau JC, Guillot B, Andre C, Rifle G. Bullous pemphigoid and intravenous gammaglobulin. Ann Intern Med 1985;103:964-5. 257. Ahmed AR. Intravenous immunoglobulin therapy for patients with bullous pemphigoid unresponsive to conventional immunosuppressive treatment. J Am Acad Dermatol 2001;45:825-35. 258. Sami N, Ali S, Bhol KC, Ahmed AR. Influence of intravenous immunoglobulin therapy on autoantibody titers to BP Ag1 and BP Ag2 in patients with bullous pemphigoid. J Eur Acad Dermatol Venereol 2003;17:641-5. 259. Yeh SW, Usman AQ, Ahmed AR. Profile of autoantibody to basement membrane zone proteins in patients with mucous membrane pemphigoid: long-term follow up and influence of therapy. Clin Immunol 2004;112:268-72. 260. Sami N, Bhol KC, Ahmed AR. Treatment of oral pemphigoid with intravenous immunoglobulin as monotherapy. Longterm follow-up: influence of treatment on antibody titers to human alpha6 integrin. Clin Exp Immunol 2002;129:533-40. 261. Kumari S, Bhol KC, Rehman F, Foster CS, Ahmed AR. Interleukin 1 components in cicatricial pemphigoid: role in intravenous immunoglobulin therapy. Cytokine 2001;14:218-24. 262. Sami N, Bhol KC, Razzaque Ahmed A. Intravenous immunoglobulin therapy in patients with multiple mucosal involvement in mucous membrane pemphigoid. Clin Immunol 2002;102: 59-67. 263. Sami N, Letko E, Androudi S, Daoud Y, Foster CS, Ahmed AR. Intravenous immunoglobulin therapy in patients with ocularcicatricial pemphigoid: a long-term follow-up. Ophthalmology 2004;111:1380-2. 264. Letko E, Miserocchi E, Daoud YJ, Christen W, Foster CS, Ahmed AR. A nonrandomized comparison of the clinical outcome of ocular involvement in patients with mucous membrane (cicatricial) pemphigoid between conventional immunosuppressive and intravenous immunoglobulin therapies. Clin Immunol 2004;111:303-10. 265. Ahmed AR, Colon JE. Comparison between intravenous immunoglobulin and conventional immunosuppressive therapy regimens in patients with severe oral pemphigoid:

Smith, Swamy, and Heffernan e51

J AM ACAD DERMATOL VOLUME 56, NUMBER 1

266.

267.

268.

269.

270.

271.

272.

273.

274.

275.

276.

277.

278.

279.

280.

281.

282.

effects on disease progression in patients nonresponsive to dapsone therapy. Arch Dermatol 2001;137:1181-9. Leverkus M, Georgi M, Nie Z, Hashimoto T, Brocker EB, Zillikens D. Cicatricial pemphigoid with circulating IgA and IgG autoantibodies to the central portion of the BP180 ectodomain: beneficial effect of adjuvant therapy with highdose intravenous immunoglobulin. J Am Acad Dermatol 2002;46:116-22. Urcelay ML, McQueen A, Douglas WS. Cicatricial pemphigoid treated with intravenous immunoglobulin. Br J Dermatol 1997;137:477-8. Engineer L, Dow EC, Braverman IM, Ahmed AR. Epidermolysis bullosa acquisita and multiple myeloma. J Am Acad Dermatol 2002;47:943-6. Gourgiotou K, Exadaktylou D, Aroni K, Rallis E, Nicolaidou E, Paraskevakou H, et al. Epidermolysis bullosa acquisita: treatment with intravenous immunoglobulins. J Eur Acad Dermatol Venereol 2002;16:77-80. Jappe U, Zillikens D, Bonnekoh B, Gollnick H. Epidermolysis bullosa acquisita with ultraviolet radiationsensitivity. Br J Dermatol 2000;142:517-20. Kofler H, Wambacher-Gasser B, Topar G, Weinlich G, Schuler G, Hintner H, et al. Intravenous immunoglobulin treatment in therapy-resistant epidermolysis bullosa acquisita. J Am Acad Dermatol 1997;36:331-5. Mohr C, Sunderkotter C, Hildebrand A, Biel K, Rutter A, Rutter GH, et al. Successful treatment of epidermolysis bullosa acquisita using intravenous immunoglobulins. Br J Dermatol 1995;132:824-6. Caldwell JB, Yancey KB, Engler RJ, James WD. Epidermolysis bullosa acquisita: efficacy of high-dose intravenous immunoglobulins. J Am Acad Dermatol 1994;31:827-8. Meier F, Sonnichsen K, Schaumburg-Lever G, Dopfer R, Rassner G. Epidermolysis bullosa acquisita: efficacy of highdose intravenous immunoglobulins. J Am Acad Dermatol 1993;29:334-7. Cauza K, Hinterhuber G, Sterniczky B, Brugger K, Pieczkowski F, Karlhofer F, et al. Unusual clinical manifestation of linear IgA dermatosis: a report of two cases. J Am Acad Dermatol 2004;51(Suppl):S112-7. Gluth MB, Witman PM, Thompson DM. Upper aerodigestive tract complications in a neonate with linear IgA bullous dermatosis. Int J Pediatr Otorhinolaryngol 2004;68:965-70. Goebeler M, Seitz C, Rose C, Sitaru C, Jeschke R, Marx A, et al. Successful treatment of linear IgA disease with salazosulphapyridine and intravenous immunoglobulins. Br J Dermatol 2003;149:912-4. Letko E, Bhol K, Foster CS, Ahmed AR. Linear IgA bullous disease limited to the eye: a diagnostic dilemma; response to intravenous immunoglobulin therapy. Ophthalmology 2000; 107:1524-8. Kroiss MM, Vogt T, Landthaler M, Stolz W. High-dose intravenous immune globulin is also effective in linear IgA disease [erratum appears in Br J Dermatol 2000;142:1268]. Br J Dermatol 2000;142:582. Khan IU, Bhol KC, Ahmed AR. Linear IgA bullous dermatosis in a patient with chronic renal failure: response to intravenous immunoglobulin therapy. J Am Acad Dermatol 1999;40: 485-8. Revuz J, Penso D, Roujeau JC, Roujeau JC, Guillaume JC, Payne CR, et al. Toxic epidermal necrolysis: clinical findings and prognosis factors in 87 patients. Arch Dermatol 1987; 123:1160-5. Roujeau JC, Guillaume JC, Fabre JP, Penso D, Flechet ML, Girre JP. Toxic epidermal necrolysis (Lyell syndrome): incidence

283.

284.

285.

286.

287.

288.

289.

290.

291.

292.

293.

294.

295.

296.

297.

298.

and drug etiology in France, 1981-1985. Arch Dermatol 1990;126:37-42. Schopf E, Stuhmer A, Rzany B, Victor N, Zentgraf R, Kapp JF. Toxic epidermal necrolysis and Stevens-Johnson syndrome: an epidemiologic study from West Germany. Arch Dermatol 1991;127:839-42. Bastuji-Garin S, Zahedi M, Guillaume JC, Roujeau JC. Toxic epidermal necrolysis (Lyell syndrome) in 77 elderly patients. Age Ageing 1993;22:450-6. Viard I, Wehrli P, Bullani R, Schneider P, Holler N, Salomon D, et al. Inhibition of toxic epidermal necrolysis by blockade of CD95 with human intravenous immunoglobulin. Science 1998;282:490-3. Prins C, Kerdel FA, Padilla RS, Hunziker T, Chimenti S, Viard I, et al, TEN-IVIG Study Group. Treatment of toxic epidermal necrolysis with high-dose intravenous immunoglobulins: multicenter retrospective analysis of 48 consecutive cases. Arch Dermatol 2003;139:26-32. Bachot N, Revuz J, Roujeau JC. Intravenous immunoglobulin treatment for Stevens-Johnson syndrome and toxic epidermal necrolysis: a prospective noncomparative study showing no benefit on mortality or progression. Arch Dermatol 2003; 139:33-6. Trent JT, Kirsner RS, Romanelli P, Kerdel FA. Analysis of intravenous immunoglobulin for the treatment of toxic epidermal necrolysis using SCORTEN: the University of Miami experience. Arch Dermatol 2003;139:39-43. Shortt R, Gomez M, Mittman N, Cartotto R. Intravenous immunoglobulin does not improve outcome in toxic epidermal necrolysis. J Burn Care Rehabil 2004;25:246-55. Stella M, Cassano P, Bollero D, Clemente A, Giorio G. Toxic epidermal necrolysis treated with intravenous high-dose immunoglobulins: our experience. Dermatology 2001;203: 45-9. Campione E, Marulli GC, Carrozzo AM, Chimenti MS, Costanzo A, Bianchi L. High-dose intravenous immunoglobulin for severe drug reactions: efficacy in toxic epidermal necrolysis. Acta Derm Venereol 2003;83:430-2. Tristani-Firouzi P, Petersen MF, Saffle JR, Morris SE, Zone JJ. Treatment of toxic epidermal necrolysis with intravenous immunoglobulin in children. J Am Acad Dermatol 2002;47: 548-52. Kim KJ, Lee DP, Suh HS, Lee MW, Choi JH, Moon KC, et al. Toxic epidermal necrolysis: analysis of clinical course and SCORTEN-based comparison of mortality rate and treatment modalities in Korean patients. Acta Derm Venereol 2005;85: 497-502. Al-Mutairi N, Arun J, Osama NE, Amr Z, Mazen AS, Ibtesam elA, et al. Prospective, noncomparative open study from Kuwait of the role of intravenous immunoglobulin in the treatment of toxic epidermal necrolysis. Int J Dermatol 2004; 43:847-51. Brown KM, Siliver GM, Halerz M, Walaszek P, Sandroni A, Gamelli RL. Toxic epidermal necrolysis: does immunoglobulin make a difference? J Burn Care Rehabil 2004;25:81-8. Morici MV, Galen WK, Shetty AK, Lebouef RP, Gouri TP, Cowan GS, et al. Intravenous immunoglobulin therapy for children with Stevens-Johnson syndrome. J Rheumatol 2000; 27:2494-7. Metry DW, Jung P, Levy ML. Use of intravenous immunoglobulin in children with Stevens-Johnson syndrome and toxic epidermal necrolysis: seven cases and review of the literature. Pediatrics 2003;112:1430-6. Yip LW, Thong BY, Tan AW, Khin LW, Chng HH, Heng WJ. High-dose intravenous immunoglobulin in the treatment

e52 Smith, Swamy, and Heffernan

J AM ACAD DERMATOL JANUARY 2007

299.

300.

301.

302.

303.

304.

305.

306.

307.

308.

309.

310.

311.

312.

313.

314.

315.

316.

of toxic epidermal necrolysis: a study of ocular benefits. Eye 2005;19:846-53. Amato GM, Travia A, Ziino O. The use of intravenous highdose immunoglobulins (IVIG) in a case of Stevens-Johnson syndrome. Pediatr Med Chir 1992;14:555-6. Moudgil A, Porat S, Brunnel P, Jordan SC. Treatment of Stevens-Johnson syndrome with pooled human intravenous immuneglobulin. Clin Pediatr 1995;34:48-51. Sanwo M, Nwadiuko R, Beall G. Use of intravenous immunoglobulin in the treatment of severe cutaneous drug reactions in patients with AIDS. J Allergy Clin Immunol 1996;98:1112-5. Phan TG, Wong RC, Crotty K, Adelstein S. Toxic epidermal necrolysis in acquired immunodeficiency syndrome treated with intravenous gammaglobulin. Australas J Dermatol 1999; 40:153-7. Magina S, Lisboa C, Goncalves E, Conceicao F, Leal V, Mesquita-Guimaraes J. A case of toxic epidermal necrolysis treated with intravenous immunoglobin. Br J Dermatol 2000;142:191-2. Straussberg R, Harel L, Ben-Amitai D, Cohen D, Amir J. Carbamazepine-induced Stevens-Johnson syndrome treated with IV steroids and IVIG. Pediatr Neurol 2000;22:231-3. Brett AS, Philips D, Lynn AW. Intravenous immunoglobulin therapy for Stevens-Johnson syndrome. South Med J 2001;94:342-3. Samimi SS, Siegfried E. Stevens-Johnson syndrome developing in a girl with systemic lupus erythematosus on high-dose corticosteroid therapy. Pediatr Dermatol 2002;19:52-5. Simeone F, Rubio ER. Treatment of toxic epidermal necrolysis with intravenous immunoglobulin. J La State Med Soc 2003; 155:266-9. Sidwell RU, Swift S, Yan CL, Porter W, Thompson EM, Clark JA, et al. Treatment of toxic epidermal necrolysis with intravenous immunoglobulin. Int J Clin Pract 2003;57:643-5. Tan A, Tan HH, Lee CC, Ng SK. Treatment of toxic epidermal necrolysis in AIDS with intravenous immunoglobulins. Clin Exp Dermatol 2003;28:269-71. Mayorga C, Torres MJ, Corzo JL, Sanchez-Sabate E, Alvarez J, Vera A, et al. Improvement of toxic epidermal necrolysis after the early administration of a single high dose of intravenous immunoglobulin. Ann Allergy Asthma Immunol 2003;91: 86-91. Kalyoncu M, Cimsit G, Cakir M, Okten A. Toxic epidermal necrolysis treated with intravenous immunoglobulin and granulocyte colony-stimulating factor. Indian Pediatr 2004; 41:392-5. Arca E, Kose O, Erbil AH, Nisanci M, Akar A, Gur AR. A 2-yearold girl with Stevens-Johnson syndrome/toxic epidermal necrolysis treated with intravenous immunoglobulin. Pediatr Dermatol 2005;22:317-20. Hebert AA, Bogle MA. Intravenous immunoglobulin prophylaxis for recurrent Stevens-Johnson syndrome. J Am Acad Dermatol 2004;50:286-8. Wolff K, Tappeiner G. Treatment of toxic epidermal necrolysis: the uncertainty persists but the fog is dispersing. Arch Dermatol 2003;139:85-6. Cherin P, Herson S, Wechsler B, Piette JP, Bletry O, Coutellier A, et al. Efficacy of intravenous gammaglobulin therapy in chronic refractory PM and dermatomyositis: an open study with 20 patients. Am J Med 1991;91:162-7. Dalakas MC, Illa I, Dambrosia JM, Soueidan SA, Stein DP, Otero C, et al. A controlled trial of high-dose intravenous immune globulin infusions as treatment for dermatomyositis. N Engl J Med 1993;329:1993-2000.

317. Mastaglia FL, Phillips BA, Zilko PJ. Immunoglobulin therapy in inflammatory myopathies. J Neurol Neurosurg Psychiatry 1998;65:107-10. 318. De Vita S, Ferraccioli GF, Di Poi E, Bartoli E, Bombardieri S. High dose intravenous immunoglobulin therapy for rheumatic diseases: clinical relevance and personal experience. Clin Exp Rheumatol 1996;14(Suppl):S85-92. 319. Gottfried I, Seeber A, Anegg B, Rieger A, Stingl G, Volc-Platzer B. High dose intravenous immunoglobulin (IVIG) in dermatomyositis: clinical responses and effect on sIL-2R levels. Eur J Dermatol 2000;10:29-35. 320. Danieli MG, Malcangi G, Palmieri C, Logullo F, Salvi A, Piani M, et al. Cyclosporin A and intravenous immunoglobulin treatment in polymyositis/dermatomyositis. Ann Rheum Dis 2002;61:37-41. 321. Lang B, Laxer RM, Murphy G, Silverman ED, Roifman C. Treatment of dermatomyositis with intravenous gammaglobulin. Am J Med 1991;91:169-72. 322. Barron KS, Sher MR, Silverman ED. Intravenous immunoglobulin therapy: magic or black magic. J Rheumatol Suppl 1992;33:94-7. 323. Sansome A, Dubowitz V. Intravenous immunoglobulin in juvenile dermatomyositisefour year review of nine cases. Arch Dis Child 1995;72:25-8. 324. Tsai MJ, Lai CC, Lin SC, Chiang BL, Chou CC, Hsieh KH. Intravenous immunoglobulin therapy in juvenile dermatomyositis. Acta Paediatr 1997;38:111-5. 325. Al-Mayouf SM, Laxer RM, Schneider R, Silverman ED, Feldman BM. Intravenous immunoglobulin therapy for juvenile dermatomyositis: efficacy and safety. J Rheumatol 2000;27: 2498-503. 326. Basta M, Dalakas MC. High-dose intravenous immunoglobulin exerts its beneficial effect in patients with dermatomyositis by blocking endomysial deposition of activated complement fragments. J Clin Invest 1994;94:1729-35. 327. Goodfield M, Davison K, Bowden K. Intravenous immunoglobulin (IVIg) for therapy-resistant cutaneous lupus erythematosus (LE). J Dermatol Treat 2004;15:46-50. 328. Levy Y, Sherer Y, Ahmed A, Langevitz P, George J, Fabbrizzi F, et al. A study of 20 SLE patients with intravenous immunoglobulineclinical and serologic response. Lupus 1999;8:705-12. 329. Schroeder JO, Zeuner RA, Euler HH, Loffler H. High dose intravenous immunoglobulins in systemic lupus erythematosus: clinical and serological results of a pilot study. J Rheumatol 1996;23:71-5. 330. Francioni C, Galeazzi M, Fioravanti A, Gelli R, Megale F, Marcolongo R. Long-term i.v. Ig treatment in systemic lupus erythematosus. Clin Exp Rheumatol 1994;12:163-8. 331. Genereau T, Chosidow O, Danel C, Cherin P, Herson S. High-dose intravenous immunoglobulin in cutaneous lupus erythematosus. Arch Dermatol 1999;135:1124-5. 332. Krueter A, Hyun J, Altmeyer P, Gambichler T. Intravenous immunoglobulin for recalcitrant subacute cutaneous lupus erythematosus. Acta Derm Venereol 2005;85:545-7. 333. De Pita O, Bellucci AM, Ruffelli M, Girardelli CR, Puddu P. Intravenous immunoglobulin therapy is not able to efficiently control cutaneous manifestations in patients with lupus erythematosus. Lupus 1997;6:415-7. 334. Levy Y, Amital H, Langevitz P, Nacci F, Righi A, Confroti L, et al. Intravenous immunoglobulin modulates cutaneous involvement and reduces skin fibrosis in systemic sclerosis: an open-label study. Arthritis Rheum 2004;50:1005-7. 335. Amital H, Rewald E, Levy Y, Bar-Dayan Y, Manthorpe R, Engervall P, et al. Fibrosis regression induced by intravenous gammaglobulin treatment. Ann Rheum Dis 2003;62:175-7.

J AM ACAD DERMATOL

Smith, Swamy, and Heffernan e53

VOLUME 56, NUMBER 1

336. Ulmer A, Kotter I, Pfaff A, Fierlbeck G. Efficacy of pulsed intravenous immunoglobulin therapy in mixed connective tissue disease. J Am Acad Dermatol 2002;46:123-7. 337. Krueter A, Gambichler T, Breuckmann F, Bechara FG, Rotterdam S, Stucker M, et al. Pulsed intravenous immunoglobulin therapy in livedoid vasculitis: an open trial evaluating 9 consecutive patients. J Am Acad Dermatol 2004;51:574-9. 338. Schanz S, Ulmer A, Fierlbeck G. Intravenous immunoglobulin in livedo vasculitis: a new treatment option? J Am Acad Dermatol 2003;49:555-6. 339. Ravat FE, Evans AV, Russell-Jones R. Response of livedoid vasculitis to intravenous immunoglobulin. Br J Dermatol 2002;147:166-9. 340. Amital H, Levy Y, Shoenfeld Y. Use of intravenous immunoglobulin in livedo vasculitis. Clin Exp Rheumatol 2000;18: 404-6. 341. Levy Y, Sherer Y, George J, Langevitz P, Ahmed A, Bar-Dayan Y, et al. Serologic and clinical response to treatment of systemic vasculitis and associated autoimmune disease with intravenous immunoglobulin. Int Arch Allergy Immunol 1999;119:231-8. 342. Jayne DR, Chapel H, Adu D, Misbah S, O’Donoghue D, Scott D, et al. Intravenous immunoglobulin for ANCA-associated systemic vasculitis with persistent disease activity. QJM 2000; 93:433-9. 343. Jayne DR, Lockwood CM. Intravenous immunoglobulin as sole therapy for systemic vasculitis. Br J Rheumatol 1996; 35:1150-3. 344. Jayne DR, Esnault VL, Lockwood CM. ANCA anti-idiotype antibodies and the treatment of systemic vasculitis with intravenous immunoglobulin. J Autoimmun 1993;6:207-19. 345. Richter C, Schnabel A, Csernok E, De Groot K, Reinhold-Keller E, Gross WL. Treatment of anti-neutrophil cytoplasmic antibody (ANCA)-associated systemic vasculitis with high-dose intravenous immunoglobulin. Clin Exp Immunol 1995;101: 2-7. 346. Ito-Ihara T, Ono T, Nogaki F, Suyama K, Tanaka M, Yonemoto S, et al. Clinical efficacy of intravenous immunoglobulin for patients with MPO-ANCA-associated rapidly progressive glomerulonephritis. Nephron Clin Pract 2006; 102:c35-42. 347. Adlakha A, Rao K, Adlakha K, Ryu JH. A case of pediatric Wegener’s granulomatosis with recurrent venous thromboses treated with intravenous immunoglobulin and laryngotracheoplasty. Pediatr Pulmonol 1995;20:265-8. 348. Tuso P, Moudgil A, Hay J, Goodman D, Kamil E, Koyyana R, et al. Treatment of antineutrophil cytoplasmic autoantibodypositive systemic vasculitis and glomerulonephritis with pooled intravenous gammaglobulin. Am J Kidney Dis 1992; 20:504-8. 349. Kroiss M, Hohenleutner U, Gruss C, Glaessl A, Landthaler M, Stolz W. Transient and partial effect of high-dose intravenous immunoglobulin in polyarteritis nodosa. Dermatology 2001; 203:188-9. 350. Gedalia A, Sorensen R. Intravenous immunoglobulin in childhood cutaneous polyarteritis nodosa. Clin Exp Rheumatol 1998;16:767. 351. Uziel Y, Silverman ED. Intravenous immunoglobulin therapy in a child with cutaneous polyarteritis nodosa. Clin Exp Rheumatol 1998;16:187-9. 352. Machet L, Vincent O, Machet MC, Barruet K, Vaillant L, Lorette G. Cutaneous periarteritis nodosa resistant to combined corticosteroids and immunosuppressive agents. Efficacy of treatment with intravenous immunoglobulins [French]. Ann Dermatol Venereol 1995;122:769-72.

353. Asano Y, Ihn H, Maekawa T, Kadono T, Tamaki K. High-dose intravenous immunoglobulin infusion in polyarteritis nodosa: report on one case and review of the literature. Clin Rheumatol 2006;25:396-8. 354. Viguier M, Guillevin L, Laroche L. Treatment of parvovirus B19-associated polyarteritis nodosa with intravenous immune globulin. N Engl J Med 2001;344:1481-2. 355. Finkel TH, Torok TJ, Ferguson PJ, Durigon EL, Zaki SR, Leung DY, et al. Chronic parvovirus B19 infection and systemic necrotising vasculitis: opportunistic infection or aetiological agent? Lancet 1994;343:1255-8. 356. Altmeyer P, Seifarth D, Bacharach-Buhles M. High dosage intravenous immunoglobulin (IVIG) therapy in therapyrefractory ANCA-negative, necrotizing vasculitis [German]. Hautarzt 1999;50:853-8. 357. Ong CS, Benson EM. Successful treatment of chronic leucocytoclastic vasculitis and persistent ulceration with intravenous immunoglobulin. Br J Dermatol 2000;143:447-9. 358. Sais G, Vidaller A, Servitje O, Jucgla A, Peyri J. Leukocytoclastic vasculitis and common variable immunodeficiency: successful treatment with intravenous immune globulin. J Allergy Clin Immunol 1996;98:232-3. 359. Seider N, Beiran I, Scharf J, Miller B. Intravenous immunoglobulin therapy for resistant ocular Behc¸et’s disease. Br J Ophthalmol 2001;85:1287-8. 360. Dawn G, Urcelay M, Ah-Weng A, O’Neill SM, Douglas WS. Effect of high-dose intravenous immunoglobulin in delayed pressure urticaria. Br J Dermatol 2003;149:836-40. 361. Darras S, Segard M, Mortier L, Bonnevalle A, Thomas P. Treatment of solar urticaria by intravenous immunoglobulins and PUVA therapy [French]. Ann Dermatol Venereol 2004; 131:65-9. 362. Puech-Plottova I, Michel JL, Rouchouse B, Perrot JL, Dzviga C, Cambazard F. Solar urticaria: one case treated by intravenous immunoglobulin [French]. Ann Dermatol Venereol 2000;127:831-5. 363. Kroiss M, Vogt T, Landthaler M, Stolz W. The effectiveness of low-dose intravenous immunoglobulin in chronic urticaria. Acta Derm Venereol 2000;80:225. 364. O’Donnell BF, Barr RM, Black AK, Francis DM, Kermani F, Niimi N, et al. Intravenous immunoglobulin in autoimmune chronic urticaria. Br J Dermatol 1998;138:101-6. 365. Asero R. Are IVIG for chronic unremitting urticaria effective? Allergy 2000;55:1099-101. 366. Klote MM, Nelson MR, Engler RJ. Autoimmune urticaria response to high-dose intravenous immunoglobulin. Ann Allergy Asthma Immunol 2005;94:307-8. 367. Orson FM. Intravenous immunoglobulin therapy suppresses manifestations of the angioedema with hypereosinophilia syndrome. Am J Med Sci 2003;326:94-7. 368. Paul C, Lahfa M, Bachelez H, Chevret S, Dubertret L. A randomized controlled evaluator-blinded trial of intravenous immunoglobulin in adults with severe atopic dermatitis. Br J Dermatol 2002;147:518-22. 369. Jolles S, Sewell C, Webster D, Ryan A, Heelan B, Waite A, et al. Adjunctive high-dose intravenous immunoglobulin treatment for resistant atopic dermatitis: efficacy and effects on intracellular cytokine levels and CD4 counts. Acta Derm Venereol 2003;83:433-7. 370. Huang JL, Lee WY, Chen LC, Kuo ML, Hsieh KH. Changes of serum levels of interleukin-2, intercellular adhesion molecule-1, endothelial leukocyte adhesion molecule-1 and Th1 and Th2 cell in severe atopic dermatitis after intravenous immunoglobulin therapy. Ann Allergy Asthma Immunol 2000;84: 345-52.

e54 Smith, Swamy, and Heffernan

J AM ACAD DERMATOL JANUARY 2007

371. Kimata H. High dose gammaglobulin treatment for atopic dermatitis. Arch Dis Child 1994;70:335-6. 372. Jolles S, Hughes J, Rustin M. The treatment of atopic dermatitis with adjunctive high-dose intravenous immunoglobulin: a report of three patients and review of the literature. Br J Dermatol 2000;142:551-4. 373. Wakim M, Alazard M, Yajima A, Speights D, Saxon A, Stiehm ER. High dose intravenous immunoglobulin in atopic dermatitis and hyper-IgE syndrome. Ann Allergy Asthma Immunol 1998;81:153-8. 374. Gelfand EW, Landwehr LP, Esterl B, Mazer B. Intravenous immune globulin: an alternative therapy in steroid-dependent allergic diseases. Clin Exp Immunol 1996;104(Suppl):61-6. 375. Noh G, Lozano F. Intravenous immune globulin effects on serum-soluble CD5 levels in atopic dermatitis. Clin Exp Allergy 2001;31:1932-8. 376. Noh G, Lee K. Intravenous immune globulin (IVIG) therapy in streroid-resistant atopic dermatitis. J Korean Med Sci 1999; 14:63-8. 377. Kulczycki A, Nelson M, Eisen A, Heffernan M. Scleromyxoedema: treatment of cutaneous and systemic manifestations with high-dose intravenous immunoglobulin. Br J Dermatol 2003;149:1276-81. 378. Lister RK, Jolles S, Whittaker S, Black C, Forgacs I, Cramp M, et al. Scleromyxedema: response to high-dose intravenous immunoglobulin (hdIVIg). J Am Acad Dermatol 2000; 43:403-8. 379. Kumar N, Rodriguez M. Scleromyxedema in a patient with multiple sclerosis and monoclonal gammopathy on interferon beta-1a. Mult Scler 2004;10:85-6. 380. Karim A, Lawlor F, Black MM. Successful treatment of scleromyxoedema with high dose intravenous immunoglobulin. Clin Exp Dermatol 2004;29:317-8. 381. Righi A, Schiavon F, Jablonska S, Doria A, Blasczyk M, Rondinone R, et al. Intravenous immunoglobulins control scleromyxoedema. Ann Rheum Dis 2002;61:59-61. 382. Wojas-Pelc A, Blaszczyk M, Glinska M, Jablonska S. Tumorous variant of scleromyxedema: successful therapy with intravenous immunoglobulins. J Eur Acad Dermatol Venereol 2005; 19:462-5. 383. Shergill B, Orteu CH, McBride SR, Rustin MH. Dementia associated with scleromyxoedema reversed by high-dose intravenous immunoglobulin. Br J Dermatol 2005;153:650-2.

384. Antonelli A, Navarranne A, Palla R, Alberti B, Saracino A, Mestre C, et al. Pretibial myxedema and high-dose intravenous immunoglobulin treatment. Thyroid 1994;4:399-408. 385. Baschieri L, Antonelli A, Nardi S, Alberti B, Lepri A, Canapicchi R, et al. Intravenous immunoglobulin versus corticosteroid in treatment of Graves’ ophthalmopathy. Thyroid 1997;7: 579-85. 386. Kahaly G, Pitz S, Muller-Forell W, Hommel G. Randomized trial of intravenous immunoglobulins versus prednisolone in Graves’ ophthalmopathy. Clin Exp Immunol 1996;106: 197-202. 387. Chung HJ, Chung KY. Nephrogenic fibrosing dermopathy: response to high-dose intravenous immunoglobulin. Br J Dermatol 2004;150:596-7. 388. Gurmin V, Mediwake R, Fernando M, Whittaker S, Rustin MH, Beynon HL. Psoriasis: response to high-dose intravenous immunoglobulin in three patients. Br J Dermatol 2002;147: 554-7. 389. Gupta AK, Shear NH, Sauder DN. Efficacy of human intravenous immune globulin in pyoderma gangrenosum. J Am Acad Dermatol 1995;32:140-2. 390. Dirschka T, Kastner U, Behrens S, Altmeyer P. Successful treatment of pyoderma gangrenosum with intravenous human immunoglobulin. J Am Acad Dermatol 1998;39: 789-90. 391. Hagman JH, Carrozzo AM, Campione E, Romanelli P, Chimenti S. The use of high-dose immunoglobulin in the treatment of pyoderma gangrenosum. J Dermatol Treat 2001;12:19-22. 392. Dobson CM, Parslew RA, Evans S. Superficial granulomatous pyoderma treated with intravenous immunoglobulin. J Am Acad Dermatol 2003;48:456-60. 393. Carmeli Y, Mevorach D, Kaminski N, Raz E. Regression of Kaposi’s sarcoma after intravenous immunoglobulin treatment for polymyositis. Cancer 1994;73:2859-61. 394. Mostella J, Pieroni R, Jones R, Finch CK. Anticonvulsant hypersensitivity syndrome: treatment with corticosteroids and intravenous immunoglobulin. South Med J 2004;97: 319-21. 395. Creamer D, McGregor JM, Hawk JL. Polymorphic light eruption occurring in common variable hypogammaglobulinemia, and resolving with intravenous immunoglobulin therapy. Clin Exp Dermatol 1999;24:273-4.