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Effectiveness of Intravenous Immunoglobulin Therapy for Skin Disease Other Than Toxic Epidermal Necrolysis: A Retrospective Review of Mayo Clinic Experience
ORIGINAL ARTICLE
INTRAVENOUS IMMUNOGLOBULIN THERAPY AND SKIN DISEASE
Effectiveness of Intravenous Immunoglobulin Therapy for Skin Disease Other Than Toxic Epidermal Necrolysis: A Retrospective Review of Mayo Clinic Experience DAVID A. WETTER, MD; MARK DENIS P. DAVIS, MD; JAMES A. YIANNIAS, MD; LAWRENCE E. GIBSON, MD; MARK V. DAHL, MD; ROKEA A. EL-AZHARY, MD; ALISON J. BRUCE, MBCHB; DONALD P. LOOKINGBILL, MD; IFTIKHAR AHMED, MD; ARNOLD L. SCHROETER, MD; AND MARK R. PITTELKOW, MD OBJECTIVE: To examine retrospectively the use and effectiveness of intravenous immunoglobulin (IVIg) treatment of various skin diseases, primarily immunobullous disease. PATIENTS AND METHODS: We identified patients who had received IVIg therapy for skin disease between 1996 and 2003 at the Mayo Clinic in Rochester, Minn, Scottsdale, Ariz, and Jacksonville, Fla, and retrospectively reviewed their medical records. RESULTS: Eighteen patients were treated with IVIg for various skin diseases: immunobullous disease in 11 adults (pemphigus vulgaris [7 patients], bullous pemphigoid [3], and cicatricial pemphigoid [1]); dermatomyositis (2); mixed connective tissue disease (1); chronic urticaria (1); scleromyxedema (1); leukocytoclastic vasculitis (1); and linear IgA bullous disease (1). Responses of patients by type of disease were as follows: pemphigus vulgaris, 1 partial response (PR) and 6 no response (NR); bullous pemphigoid, 1 complete response (CR) and 2 NR; cicatricial pemphigoid, 1 NR; dermatomyositis, 1 CR and 1 PR; mixed connective tissue disease, 1 CR; chronic urticaria, 1 CR; scleromyxedema, 1 CR; leukocytoclastic vasculitis, 1 PR; and linear IgA bullous disease, 1 CR. Six patients (33%) experienced CR, 3 (17%) had PR, and 9 (50%) had NR to IVIg therapy. All 9 nonresponders were adult patients with immunobullous disease. CONCLUSION: Although this was a retrospective study of a small cohort of a mixture of patients, the findings emphasize that our experience with IVIg treatment for skin disease, particularly immunobullous disease, is less favorable than that reported previously. Further studies are needed to verify the efficacy of IVIg for skin disease.
Mayo Clin Proc. 2005;80(1):41-47 CR = complete response; IVIg = intravenous immunoglobulin; NR = no ≈50 = 50% response; PR>50 = PR response; PR = partial response; PR≈ greater than 50%; PR<50 = PR less than 50%
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ecent studies have reported intravenous immunoglobulin (IVIg) as effective treatment of various skin diseases, particularly immunobullous disease refractory to conventional therapies.1-14 In patients with long-standing skin disease, IVIg therapy has been reported to induce clinical remission and to allow discontinuation of concomitant glucocorticosteroid and immunosuppressive agents.4,15-17 According to recently published guidelines for use of IVIg in patients with autoimmune mucocutaneous blistering diseases, IVIg therapy is indicated if conventional therapy fails, if patients experience serious adverse effects from conventional therapy, if conventional Mayo Clin Proc.
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therapy is contraindicated, or if patients have progressive disease.18 The guidelines suggest that a dosage of 2 g/kg every 3 to 4 weeks is most likely to produce beneficial results. Our observational experience with IVIg has been less favorable than that published previously. The aim of our study was to examine retrospectively the use and effectiveness of IVIg treatment of skin disease at the Mayo Clinic. Because multiple well-designed studies of the effectiveness of IVIg for management of toxic epidermal necrolysis have been reported, we excluded patients with this disease from our study and concentrated on patients for whom IVIg was prescribed for other skin diseases. PATIENTS AND METHODS Patients who received IVIg treatment of skin disease between 1996 and 2003 at the Mayo Clinic in Rochester, Minn, Scottsdale, Ariz, and Jacksonville, Fla, were identified from the Mayo Clinic Central Pharmacy database. Patients who had been treated by the Department of Dermatology and who had consented to their medical records being used for research (per Minnesota law) were included in the study. Patients treated with IVIg for toxic epidermal necrolysis were not included in the study. This study was approved by the Mayo Foundation Institutional Review Board. Medical charts were examined retrospectively for the following information: demographics, diagnosis, disease duration and severity before IVIg treatment, previous systemic therapies, IVIg administration protocol, type of IVIg used, duration of IVIg treatment, concomitant therapy, reFrom the Department of Internal Medicine (D.A.W.) and Department of Dermatology (M.D.P.D., L.E.G., R.A.e.-A., A.J.B., I.A., A.L.S., M.R.P.), Mayo Clinic College of Medicine, Rochester, Minn; Department of Dermatology, Mayo Clinic College of Medicine, Scottsdale, Ariz (J.A.Y., M.V.D.); and Department of Dermatology, Mayo Clinic College of Medicine, Jacksonville, Fla (D.P.L.). Address reprint requests and correspondence to Mark Denis P. Davis, MD, Department of Dermatology, Mayo Clinic College of Medicine, 200 First St SW, Rochester, MN 55905 (e-mail: [email protected]). © 2005 Mayo Foundation for Medical Education and Research
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INTRAVENOUS IMMUNOGLOBULIN THERAPY AND SKIN DISEASE
TABLE 1. Patient Characteristics*
RESULTS
Patient No./ sex
Age at disease onset (y)
Disease
Disease duration before IVIg treatment (mo)
1/M 2/F 3/M 4/M 5/M 6/F 7/M 8/F 9/F 10/M 11/M 12/F 13/F 14/M 15/F 16/F 17/M 18/M
33 75 40 49 54 47 47 69 71 71 42 40 65 27 25 49 60 1 wk
PV PV PV PV PV PV PV BP BP BP CP D D MCTD CU S LV LABD
15 26 5 15 24 12 21 40 84 61 122 72 10 6 41 57 2 1 wk
*BP = bullous pemphigoid; CP = cicatricial pemphigoid; CU = chronic urticaria; D = dermatomyositis; IVIg = intravenous immunoglobulin; LABD = linear IgA bullous disease; LV = leukocytoclastic vasculitis; MCTD = mixed connective tissue disease; PV = pemphigus vulgaris; S = scleromyxedema.
sponse to treatment, adverse effects from IVIg treatment, evidence of disease worsening after discontinuation of IVIg therapy (“rebound effects”), and follow-up after cessation of IVIg therapy. SPECIFIC IVIG PREPARATIONS The following preparations of IVIg were used: Venoglobulin (Alpha Therapeutic Corp, Los Angeles, Calif), 13 patients; Gamimune (Bayer, West Haven, Conn), 2 patients; Gammagard (Baxter, Deerfield, Ill), 1 patient; Carimune (ZLB, Glendale, Calif), 1 patient; and GammarP I.V. (Aventis, King of Prussia, Pa), 1 patient. GRADING OF RESPONSE TO TREATMENT Patient response to IVIg was graded as complete response (CR), partial response (PR), or no response (NR). Total resolution of old lesions and lack of new lesions indicated CR. Persistence of old lesions and development of new ones indicated NR. The presence of active lesions with healing of some lesions indicated PR, assessed as greater than 50% (PR>50), less than 50% (PR<50), or equal to 50% (PR≈50) by the attending physician. Indices of treatment efficacy included comparison of symptoms, signs, and pertinent laboratory tests (such as antibody levels in autoimmune disease) before and after therapy. Many patients were receiving concomitant immunosuppressive treatment. Overall dosages of and fluctuations in concomitant therapies were documented. 42
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DEMOGRAPHICS Eighteen patients (10 males, 8 females) were studied (Table 1). Age at disease onset ranged from 1 week to 75 years, with a mean (SD) age of 48 (19) years. Nine skin diseases were represented in the patient group: 3 types of immunobullous disease in adults (pemphigus vulgaris [7 patients], bullous pemphigoid [3], and cicatricial pemphigoid [1]), dermatomyositis (2), mixed connective tissue disease (1), chronic urticaria (1), scleromyxedema (1), leukocytoclastic vasculitis (1), and linear IgA bullous disease (1). Skin biopsy specimens confirmed the diagnoses in 17 of 18 patients (94%). In general, patients had severe disease unresponsive to high doses of glucocorticosteroids and immunosuppressive agents. Many patients experienced adverse effects from conventional therapies. The median duration of systemic treatment before initiation of IVIg therapy was 17 months (range, 0110 months). IVIG THERAPY Data about specific IVIg regimens, preparations of IVIg used, and durations of treatment are shown in Table 2. Median duration of IVIg treatment was 6.5 months (range, 1-14 months), and median duration of concomitant prednisone therapy was 4 months (range, 0-13 months). Fourteen patients (78%) received an IVIg dosage of 2 g/kg per monthly cycle; others received dosages ranging from 0.4 g/ kg per month to 2 g/kg every 2 weeks. Most patients were treated concomitantly with immunosuppressive agents or glucocorticosteroids (Table 3). Overall Response to IVIg Treatment. Nine (50%) of the 18 patients had NR, 6 (33%) had CR, and 3 (17%) had PR (1 PR>50, 1 PR≈50, 1 PR<50). Response of Adult Patients With Immunobullous Disease. Eleven patients had immunobullous disease: pemphigus vulgaris in 7, bullous pemphigoid in 3, and cicatricial pemphigoid in 1. Individual responses to IVIg treatment are shown in Table 4, and previous and concomitant therapies are listed in Table 3. Nine (82%) of the 11 adult patients with immunobullous disease had NR. One patient with bullous pemphigoid experienced CR, and 1 patient with pemphigus vulgaris exhibited PR of 80% as evidenced by improvement in his skin. All 11 patients had severe disease refractory to conventional therapies (Table 3). Median duration of systemic treatment before IVIg was 22 months (range, 5-110 months). Median duration of IVIg therapy was 7 months (range, 1-11 months) at a typical dosage of 2 g/kg per monthly cycle. During IVIg therapy, all 11 patients received either prednisone or prednisolone and 1 or more
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INTRAVENOUS IMMUNOGLOBULIN THERAPY AND SKIN DISEASE
additional therapies. The conditions of 7 patients (64%) worsened, and they required increasing doses of concomitant therapies in an attempt to control their disease; 3 of the remaining 4 patients required either ongoing prednisone or prednisolone and another agent throughout therapy. Glucocorticosteroid doses were unable to be tapered in 9 patients (82%). Median duration of concomitant prednisone therapy was 6 months (range, 1-11 months). Median number of treatment cycles in nonresponders was 7 (range, 5-17 cycles) over a median duration of 7 months (range, 511 months). Six of the 7 patients with pemphigus vulgaris had biopsyproven disease; patient 2 had inconclusive histology and direct immunofluorescence tests, but the clinical presentation and high titers of antiepithelial antibodies in the serum corroborated the diagnosis. Before IVIg therapy, these patients had nonhealing bullae and erosions. Mouth ulcers were the predominant manifestation in 3 patients. Patients averaged 6.9 months of IVIg treatment (range, 1-11 months) without clinical benefit. Disease worsened in all but 1 patient when concomitant doses of prednisone were reduced. Doses of other immunosuppressive agents were increased during therapy; agents were discontinued and alternatives introduced in attempts to control the disease process. Nonresponders averaged 22 mg/d of prednisone while receiving IVIg (range, 3-52 mg/d). The patient who responded to IVIg treatment experienced 80% improvement 1 week after initiation of therapy but died several weeks later due to unexplained pneumonitis. Two of the 3 patients with bullous pemphigoid had NR, and 1 patient exhibited CR. Patients primarily experienced oral disease before initiation of IVIg therapy. Nonresponders averaged 4 mg/d of prednisone while receiving IVIg and experienced flaring of the disease, which was unresponsive to modifications of concomitant therapies. The 1 patient who had CR had no active lesions after 4 cycles of therapy; this patient stopped taking azathioprine after 3 months because of leukopenia. One patient with NR discontinued use of cyclophosphamide after 5 cycles of IVIg because of leukopenia. The patient with cicatricial pemphigoid presented with severe oral and ocular disease that had not responded to systemic therapy. After 10 months of IVIg therapy, the patient experienced no oral or ocular improvement. Concomitant therapies were added and doses increased, all without benefit. Response of Neonate With Immunobullous Disease. The neonate with linear IgA bullous disease was 1 week old at disease onset and experienced CR. The disease initially involved the airway, mouth, and buttocks and required 4 months of hospitalization. Prednisone and dapMayo Clin Proc.
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TABLE 2. Details of IVIg Treatment* Patient No./ disease/ response
Preparation of IVIg
1/PV/NR 2/PV/NR 3/PV/PR>50 4/PV/NR 5/PV/NR 6/PV/NR 7/PV/NR 8/BP/CR 9/BP/NR 10/BP/NR 11/CP/NR
Gammagard Venoglobulin Venoglobulin Gammar-P I.V. Venoglobulin Venoglobulin Gamimune Venoglobulin Venoglobulin Carimune Venoglobulin
12/D/PR<50 13/D/CR 14/MCTD/CR
Venoglobulin Gamimune Venoglobulin
15/CU/CR 16/S/CR 17/LV/PR≈50
Venoglobulin Venoglobulin Venoglobulin
18/LABD/CR
Venoglobulin
IVIg regimen (g/kg) (cycle)† 2 (4) 2 (3) 2 (3) 2 (3) 2 (3) 2 (3) 2 (3) 2 (3) 2 (3) 2 (3) 2 (3 d every 2-3 wk) 2 (2) 2 (5) 0.5 (weekly) 2 (5) 2 (4) 0.4 (monthly) 1 (every 2-4 wk)
Duration of IVIg treatment (mo) 8 7 1 6 9 11 6 9 5 7 10 2 1 5 wk 1 7 6 14
*BP = bullous pemphigoid; CP = cicatricial pemphigoid; CR = complete response; CU = chronic urticaria; D = dermatomyositis; IVIg = intravenous immunoglobulin; LABD = linear IgA bullous disease; LV = leukocytoclastic vasculitis; MCTD = mixed connective tissue disease; NR = no response; PR≈50 = 50% response; PR>50 = partial response greater than 50%; PR<50 = partial response less than 50%; PV = pemphigus vulgaris; S = scleromyxedema. †The cycle is defined as the number of days each month, unless indicated otherwise.
sone were administered, and IVIg was initiated 1 week later. After 5 cycles of IVIg over 31/2 months, the disease remitted completely. Remission has been maintained for 101/2 months with monthly IVIg treatments. Dapsone was discontinued initially after 2 weeks of therapy because of anemia but was restarted and used throughout the last 5 months of IVIg therapy. Prednisolone has been used concomitantly for 13 months. Response of Patients With Nonimmunobullous Disease. Patients’ responses to IVIg treatment and previous and concomitant therapies are shown in Tables 3 and 4. One of 2 patients with dermatomyositis was treated with IVIg and had CR; the other patient had PR<50. Both patients presented with the characteristic cutaneous findings and weakness of dermatomyositis. The patient who responded completely to IVIg did so after only 1 treatment cycle, evidenced by cutaneous improvement and decreasing creatine kinase levels. One month before this patient received IVIg, azathioprine had been added, and the prednisone dosage had been increased. The patient’s disease is adequately controlled with these 2 medications 28 months
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INTRAVENOUS IMMUNOGLOBULIN THERAPY AND SKIN DISEASE
TABLE 3. Systemic Treatments Before and During IVIg Treatment* Patient No./ disease/ response
Previous systemic treatment (maximum dosage)
Concomitant systemic treatment (maximum dosage)
1/PV/NR
Prednisone (150 mg/d, 14 mo); mycophenolate mofetil (3 g/d, 14 mo); cyclophosphamide (50 mg/d, 8 mo); azathioprine (150 g/d, 5 mo); plasmapheresis
Prednisone (20 mg/d, 8 mo); mycophenolate mofetil (3 g/d, 8 mo); azathioprine (200 mg/d, 8 mo); cyclophosphamide (50 mg/d) and cyclosporine (both added after 8 mo)
2/PV/NR
Prednisone (40 mg/d, 23 mo); azathioprine (50 mg/d, 3 mo); niacinamide (2 g/d, 3 mo); mycophenolate mofetil (3 g/d, 20 mo)
Prednisone (5 mg/d, 7 mo); mycophenolate mofetil (3 g/d, 7 mo)
3/PV/PR>50
Prednisolone (140 mg/d, 5 mo); azathioprine (200 mg/d, 5 mo)
Prednisolone (140 mg/d, 1 mo); azathioprine (150 mg/d, 1 mo)
4/PV/NR
Prednisone (60 mg/d, 6 mo); dapsone (100 mg/d, 6 mo); minocycline (200 mg/d, 6 mo); methotrexate
5/PV/NR
Prednisone (40 mg/d, 20 mo); mycophenolate mofetil (3 g/d, 5 mo); azathioprine (200 mg/d, 15 mo); niacinamide (2 g/d, 16 mo)
6/PV/NR
Prednisone (40 mg/d, 9 mo); methylprednisolone tapers
Prednisone (30 mg/d, 11 mo); methotrexate (15 mg/wk, 9 mo)
7/PV/NR
Prednisone (120 mg/d, 19 mo); mycophenolate mofetil (3 g/d, 16 mo); doxycycline (200 mg/d); azathioprine (150 mg/d, 1 mo)
Prednisone (60 mg/d, 6 mo); azathioprine (150 mg/d, 4 mo); cyclophosphamide (200 mg/d, 2 mo); valacyclovir (1000 mg/d, 5 mo)
8/BP/CR
Prednisone (30 mg/d, 37 mo); niacinamide (2 g/d, 24 mo); tetracycline (1.5 g/d, 7 mo); mycophenolate mofetil (3 g/d, 10 mo); azathioprine (150 mg/d, 20 mo)
Prednisone (2 mg/d, 3 mo); azathioprine (150 mg/d, 3 mo, stopped due to leukopenia); niacinamide (1 g/d, 9 mo); hydroco rtisone (50 mg/IVIg infusion, 5 mo, due to nausea, headache)
9/BP/NR
Prednisone (30 mg/d, 72 mo); niacinamide (2 g/d, 72 mo); dapsone (125 mg/d, 36 mo); mycophenolate mofetil (3 g/d, 12 mo); azathioprine (125 mg/d, 16 mo); tetracycline/minocycline/doxycycline
Prednisone (5 mg/d, 5 mo); azathioprine (125 mg/d, 5 mo); doxycycline (100 mg/d, 5 mo); niacinamide (1 g/d, 1 mo, stopped due to LFTs)
Prednisone (20 mg/d, 6 mo); azathioprine (150 mg/d, 6 mo); minocycline (200 mg/d, 2 mo) Prednisone (40 mg/d, 9 mo); azathioprine (200 mg/d, 7 mo); cyclophosphamide (150 mg/d, 1.5 mo); niacin (2 g/d, 8 mo)
10/BP/NR
Dapsone (200 mg/d, 30 mo); prednisone (60 mg/d, 36 mo); niacin (2 g/d, 36 mo); mycophenolate mofetil (3 g/d, 7 mo); azathioprine (150 mg/d, 18 mo); cyclophosphamide (100 mg/d, 7 mo); minocycline/doxycycline
Prednisone (6 mg/d, 7 mo); cyclophosphamide (100 mg/d, 5 mo, stopped due to leukopenia); niacin (2 g/d, 7 mo); doxycycline (200 mg/d, added after 7 mo)
11/CP/NR
Prednisone (60 mg/d, many years); cyclophosphamide (200 mg/d, 4 mo); dapsone (100 mg/d, many years); mycophenolate mofetil (2 g/d, 1.5 mo)
Methylprednisolone with IVIg (2.5 mo, 6 cycles); mycophenolate mofetil (3 g/d, 5 mo); cyclophosphamide (150 mg/d, 5 mo)
12/D/PR<50
Prednisone (60 mg/d, 60 mo); hydroxychloroquine sulfate (400 mg/d, 24 mo); methotrexate (6 mo); azathioprine (25 mg/d, 5 mo); cyclosporine (450 mg/d, 3 mo); mycophenolate mofetil (3 g/d, 6 mo)
Prednisone (20 mg/d, 2 mo); mycophenolate mofetil (2 g/d, 2 mo)
13/D/CR
Prednisone (60 mg/d, 8 mo); hydroxychloroquine sulfate (400 mg/d, 1 mo); azathioprine (150 mg/d, 1 mo)
Prednisone (60 mg/d, 1 mo); azathioprine (150 mg/d, 1 mo)
14/MCTD/CR
Prednisone (50 mg/d, 5 mo); mycophenolate mofetil (2 g/d); methylprednisolone (1 g/d, 3 d)
15/CU/CR
Prednisone (60 mg/d, many courses); antihistamines (6 different types); cyclosporine (75 mg/d, 2 mo); colchicine (1.2 mg/d, 3 mo); sulfasalazine (3 g/d, 1.5 mo)
None
16/S/CR
Methylprednisolone; dexamethasone (12 mg/wk, 2 mo); isotretinoin (80 mg/d); PUVA (2 mo); hydroxychloroquine sulfate (400 mg/d, mo); thalidomide (200 mg/d, 4 mo); SCT
None
17/LV/PR≈50
None
18/LABD/CR
Prednisone (1 wk); dapsone (1 wk)
Prednisone (40 mg/d, 1.25 mo); mycophenolate mofetil (2 g/d, 1.25 mo)
Prednisone (20 mg/d, 1 mo); azathioprine (100 mg/d, 6 mo) Prednisolone (5 mg/d, 13 mo); dapsone (10 mg/d, 5.5 mo)
*BP = bullous pemphigoid; CP = cicatricial pemphigoid; CR = complete response; CU = chronic urticaria; D = dermatomyositis; IVI g = intravenous immunoglobulin; LABD = linear IgA bullous disease; LFTs = liver function tests; LV = leukocytoclastic vasculitis; MCTD = mixed connective tissue disease; NR = no response; PR≈50 = 50% response; PR>50 = partial response greater than 50%; PR<50 = partial response less than 50%; PUVA = psoralen + ultraviolet A radiation; PV = pemphigus vulgaris; S = scleromyxedema; SCT = stem cell transplantation.
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INTRAVENOUS IMMUNOGLOBULIN THERAPY AND SKIN DISEASE
TABLE 4. Patient Responses to IVIg Treatment* Response to IVIg
Time for effective response (No. of cycles)
Maintenance IVIg, mo (No. of cycles)
1/PV 2/PV 3/PV 4/PV
NR NR PR>50 NR
NA NA 1 wk (1) NA
None None None None
5/PV
NR
NA
None
6/PV
NR
NA
None
7/PV
NR
NA
None
8/BP
CR
31/2 mo (4)
51/2 mo (5)
9/BP
NR
NA
None
10/BP 11/CP 12/D
NR NR PR<50
NA NA 2 mo (2)
13/D
CR
1 mo (1)
None None Remains on IVIg at time of study None
14/MCTD
CR
3 wk (3)
2 wk (2)
15/CU 16/S 17/LV 18/LABD
CR CR PR≈50 CR
1 d (0.2) 5 mo (5) 2 mo (2) 31/2 mo (5)
None 2 mo 4 mo 10 1/2 mo
Patient No./ disease
Follow-up after discontinuing IVIg (outcome)
Adverse effects from IVIg
No follow-up available None IVIg stopped at time of study Nausea, fever, flushing 1 mo (died of pneumonitis 1 mo after IVIg cycle) Not known 5 mo (gradually improved with prednisone, pulse None cyclophosphamide, and pulse dexamethasone) 7 mo (began to improve with cyclophosphamide Achiness, fatigue and prednisone) 5 mo (moderately improved with prednisone None and methotrexate) 4 mo (moderately improved with None cyclophosphamide and prednisone) Taking IVIg at time of study Fever, headache, nausea, myalgias 4 mo (mildly improved with prednisone and None cyclophosphamide) Taking IVIg at time of study None IVIg stopped at time of study Hypertensive episode Taking IVIg at time of study None 28 mo (controlled with prednisone and azathioprine) 3 mo (controlled with prednisone taper and mycophenolate mofetil) 3 1/2 mo (95% resolution) Taking IVIg at time of study No follow-up available Taking IVIg at time of study
None Severe flulike illness (IVIg discontinued) Severe headache None None None
*BP = bullous pemphigoid; CP = cicatricial pemphigoid; CR = complete response; CU = chronic urticaria; D = dermatomyositis; IVI g = intravenous immunoglobulin; LABD = linear IgA bullous disease; LV = leukocytoclastic vasculitis; MCTD = mixed connective tissue disease; NA = not applicable; NR = no response; PR≈50 = 50% response; PR>50 = partial response greater than 50%; PR<50 = partial response less than 50%; PV = pemphigus vulgaris; S = scleromyxedema.
later. The other patient had responded only minimally after 2 monthly cycles of IVIg and concomitant therapy with prednisone and mycophenolate mofetil and was still receiving IVIg at the time of data analysis. The patient with mixed connective tissue disease had CR. The patient had widespread ulcerations, Raynaud phenomenon, and myositis that did not respond after 6 months of systemic therapy. He received prednisone and mycophenolate mofetil in addition to IVIg. After 3 weeks of therapy, the ulcerations were completely healed and painless and remained healed while the patient received concomitant therapies 3 months after IVIg was discontinued because of adverse effects. The patient with chronic urticaria had CR. She had 80% to 90% skin involvement at times and had received systemic therapies for 41 months with no benefit. She received 1 cycle of IVIg and responded within 1 day of the first infusion. This patient showed 95% improvement over 3 months after discontinuation of IVIg without concomitant therapies. The patient with scleromyxedema had CR. Fifteen months of various systemic treatments had failed to help her, but her skin had almost returned to normal after 5 Mayo Clin Proc.
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cycles of IVIg and remained so after 7 cycles. No concomitant therapies were given during IVIg treatment. The patient with leukocytoclastic vasculitis had PR≈50. He had multiple small, infected lower extremity ulcers and had received no systemic therapy before initiation of IVIg. The patient received 6 cycles of IVIg, and prednisone and azathioprine therapy was initiated. Prednisone was discontinued after 1 month, and no new lesions developed after 2 monthly IVIg cycles, although an ulcer swab showed methicillin-resistant Staphylococcus aureus. After 6 cycles of IVIg, the patient still had several skin ulcers. Adverse Effects of IVIg. Eleven (61%) of the 18 patients had no adverse effects attributable to IVIg (Table 4). However, 3 patients experienced nausea, fever, flushing, headache, and myalgias. One patient developed transient hypertension after an infusion. The patient with chronic urticaria developed a severe headache after her first infusion. The patient with mixed connective tissue disease developed a severe flulike illness that necessitated discontinuation of IVIg after 5 weeks. As mentioned previously, 1 patient died of pneumonitis 1 month after initiation of IVIg; whether this was related to IVIg or to infectious or autoimmune factors is unknown.
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IVIg Preparations Used. Of the 9 nonresponders, 5 received Venoglobulin, and the other 4 received Gamimune, Carimune, Gammar-P I.V., and Gammagard, respectively. Of the 6 who had CR, 5 received Venoglobulin and 1 received Gamimune. The 3 who had PR all received Venoglobulin. The totals for each preparation were as follows: Venoglobulin—5 CR, 3 PR, and 5 NR; Gamimune— 1 CR and 1 NR; Gammagard—1 NR; Carimune—1 NR; and Gammar-P I.V.—1 NR. Rebound Effect. In 9 of the 18 patients, information could not be ascertained about a possible rebound effect (flaring of clinical disease after cessation of IVIg therapy) because IVIg therapy was ongoing or the patient died. None of the remaining 9 patients experienced a rebound effect after discontinuing IVIg therapy. DISCUSSION We recognize and acknowledge the shortcomings of the present study: it is retrospective, the cohort studied is small, the diseases are heterogeneous with small numbers of patients in each group, and IVIg was used infrequently as monotherapy. Also, we recognize the limitations of measuring response to treatment by a global assessment of severity. Nonetheless, we have been struck by the contrast in our experience compared with that of other recent reports. In this study, IVIg was effective in only half the patients with skin disease. In particular, IVIg was ineffective in most of our patients with immunobullous disease. All 9 nonresponding patients in our study had a form of immunobullous disease. The 11 adult patients with immunobullous disease met published criteria for use of IVIg in that they had longstanding disease unresponsive to glucocorticosteroid and immunosuppressive therapy or experienced adverse effects from conventional therapy.18 On average, they received 33 months of systemic therapy before initiation of IVIg therapy. Previous studies suggest that inadequate dosing and duration of treatment with IVIg may explain why some patients do not to respond to therapy.19,20 However, our patients received doses similar to responders in previous studies for similar periods. Of our patients with immunobullous disease, nonresponders received an average of 8.4 treatment cycles over an average of 7.7 months at an average dosage of 2 g/kg per cycle. This dosage and duration agree with those reported in previous studies to produce desirable results.3,20 Reportedly, IVIg allows a reduction in concomitant glucocorticosteroid therapy and can be used successfully as monotherapy.3,15-17 Our findings do not support this contention. Most of our patients with immunobullous disease 46
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continued to require substantial doses of prednisone and other immunosuppressive agents while receiving IVIg therapy. We were unable to taper glucocorticosteroid dosages in 9 of the 11 adult patients with immunobullous disease. In the 7 patients who had pemphigus vulgaris, the mean duration of IVIg treatment was 6.9 months; the mean duration of concomitant prednisone therapy was also 6.9 months. Given the array of skin diseases and small sample sizes in this analysis, it is difficult to generalize regarding the effectiveness of IVIg for the other diseases represented in this study. Of the 7 patients who did not have adult immunobullous disease, 5 had CR. However, only 2 of these 5 patients were treated with IVIg as monotherapy; the other 3 required concomitant prednisone or prednisolone along with an immunosuppressive agent for the duration of IVIg therapy. Two of these 3 patients continued to require these concomitant therapies after discontinuation of IVIg; the other patient continues to receive IVIg and has received concomitant prednisolone for 13 months. The brand of IVIg may affect therapeutic efficacy.18,21 The various manufacturers prepare their IVIg differently. Five different preparations were used in our study, with Venoglobulin used most often. No obvious differences were found among patients receiving different preparations (Table 2). Each brand had at least 1 nonresponder. Venoglobulin had an equal number of complete responders and nonresponders. CONCLUSION Our experience with use of IVIg to treat skin disease is less favorable than that published previously. We did not find IVIg therapy to be routinely effective against adult immunobullous disease, as has been reported previously. Further studies are needed to verify the efficacy of IVIg for various skin diseases and to determine the role of IVIg and coadministered treatments in inducing remissions. REFERENCES 1. Bystryn JC, Jiao D, Natow S. Treatment of pemphigus with intravenous immunoglobulin. J Am Acad Dermatol. 2002;47:358-363. 2. Ahmed AR, Sami N. Intravenous immunoglobulin therapy for patients with pemphigus foliaceus unresponsive to conventional therapy. J Am Acad Dermatol. 2002;46:42-49. 3. Ahmed AR. Intravenous immunoglobulin therapy in the treatment of patients with pemphigus vulgaris unresponsive to conventional immunosuppressive treatment. J Am Acad Dermatol. 2001;45:679-690. 4. 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. 5. Foster CS, Ahmed AR. Intravenous immunoglobulin therapy for ocular cicatricial pemphigoid: a preliminary study. Ophthalmology. 1999;106:21362143.
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6. Prins C, Kerdel FA, Padilla RS, 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. 7. 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. 8. O’Donnell BF, Barr RM, Black AK, et al. Intravenous immunoglobulin in autoimmune chronic urticaria. Br J Dermatol. 1998;138:101-106. 9. 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;147:554-557. 10. Al-Mayouf SM, Laxer RM, Schneider R, Silverman ED, Feldman BM. Intravenous immunoglobulin therapy for juvenile dermatomyositis: efficacy and safety. J Rheumatol. 2000;27:2498-2503. 11. Gedalia A, Correa H, Kaiser M, Sorensen R. Case report: steroid sparing effect of intravenous gamma globulin in a child with necrotizing vasculitis. Am J Med Sci. 1995;309:226-228. 12. 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;40:485-488. 13. Lister RK, Jolles S, Whittaker S, et al. Scleromyxedema: response to high-dose intravenous immunoglobulin (hdIVIg). J Am Acad Dermatol. 2000; 43:403-408.
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14. Ulmer A, Kotter I, Pfaff A, Fierlbeck G. Efficacy of pulsed intravenous immunoglobulin therapy in mixed connective tissue disease. J Am Acad Dermatol. 2002;46:123-127. 15. Sami N, Qureshi A, Ruocco E, Ahmed AR. Corticosteroid-sparing effect of intravenous immunoglobulin therapy in patients with pemphigus vulgaris. Arch Dermatol. 2002;138:1158-1162. 16. Sami N, Qureshi A, Ahmed AR. Steroid sparing effect of intravenous immunoglobulin therapy in patients with pemphigus foliaceus. Eur J Dermatol. 2002;12:174-178. 17. Ahmed AR. Intravenous immunoglobulin therapy for patients with bullous pemphigoid unresponsive to conventional immunosuppressive treatment. J Am Acad Dermatol. 2001;45:825-835. 18. Ahmed AR, Dahl MV. Consensus statement on the use of intravenous immunoglobulin therapy in the treatment of autoimmune mucocutaneous blistering diseases. Arch Dermatol. 2003;139:1051-1059. 19. Engineer L, Ahmed AR. Role of intravenous immunoglobulin in the treatment of bullous pemphigoid: analysis of current data. J Am Acad Dermatol. 2001;44:83-88. 20. Engineer L, Bhol KC, Ahmed AR. Analysis of current data on the use of intravenous immunoglobulins in management of pemphigus vulgaris. J Am Acad Dermatol. 2000;43:1049-1057. 21. Lemm G. Composition and properties of IVIg preparations that affect tolerability and therapeutic efficacy. Neurology. 2002;59(suppl 6):S28S32.
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Effectiveness of Intravenous Immunoglobulin Therapy for Skin Disease Other Than Toxic Epidermal Necrolysis: A Retrospective Review of Mayo Clinic Experience DAVID A. WETTER, MD; MARK DENIS P. DAVIS, MD; JAMES A. YIANNIAS, MD; LAWRENCE E. GIBSON, MD; MARK V. DAHL, MD; ROKEA A. EL-AZHARY, MD; ALISON J. BRUCE, MBCHB; DONALD P. LOOKINGBILL, MD; IFTIKHAR AHMED, MD; ARNOLD L. SCHROETER, MD; AND MARK R. PITTELKOW, MD OBJECTIVE: To examine retrospectively the use and effectiveness of intravenous immunoglobulin (IVIg) treatment of various skin diseases, primarily immunobullous disease. PATIENTS AND METHODS: We identified patients who had received IVIg therapy for skin disease between 1996 and 2003 at the Mayo Clinic in Rochester, Minn, Scottsdale, Ariz, and Jacksonville, Fla, and retrospectively reviewed their medical records. RESULTS: Eighteen patients were treated with IVIg for various skin diseases: immunobullous disease in 11 adults (pemphigus vulgaris [7 patients], bullous pemphigoid [3], and cicatricial pemphigoid [1]); dermatomyositis (2); mixed connective tissue disease (1); chronic urticaria (1); scleromyxedema (1); leukocytoclastic vasculitis (1); and linear IgA bullous disease (1). Responses of patients by type of disease were as follows: pemphigus vulgaris, 1 partial response (PR) and 6 no response (NR); bullous pemphigoid, 1 complete response (CR) and 2 NR; cicatricial pemphigoid, 1 NR; dermatomyositis, 1 CR and 1 PR; mixed connective tissue disease, 1 CR; chronic urticaria, 1 CR; scleromyxedema, 1 CR; leukocytoclastic vasculitis, 1 PR; and linear IgA bullous disease, 1 CR. Six patients (33%) experienced CR, 3 (17%) had PR, and 9 (50%) had NR to IVIg therapy. All 9 nonresponders were adult patients with immunobullous disease. CONCLUSION: Although this was a retrospective study of a small cohort of a mixture of patients, the findings emphasize that our experience with IVIg treatment for skin disease, particularly immunobullous disease, is less favorable than that reported previously. Further studies are needed to verify the efficacy of IVIg for skin disease.
Mayo Clin Proc. 2005;80(1):41-47 CR = complete response; IVIg = intravenous immunoglobulin; NR = no ≈50 = 50% response; PR>50 = PR response; PR = partial response; PR≈ greater than 50%; PR<50 = PR less than 50%
R
ecent studies have reported intravenous immunoglobulin (IVIg) as effective treatment of various skin diseases, particularly immunobullous disease refractory to conventional therapies.1-14 In patients with long-standing skin disease, IVIg therapy has been reported to induce clinical remission and to allow discontinuation of concomitant glucocorticosteroid and immunosuppressive agents.4,15-17 According to recently published guidelines for use of IVIg in patients with autoimmune mucocutaneous blistering diseases, IVIg therapy is indicated if conventional therapy fails, if patients experience serious adverse effects from conventional therapy, if conventional Mayo Clin Proc.
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therapy is contraindicated, or if patients have progressive disease.18 The guidelines suggest that a dosage of 2 g/kg every 3 to 4 weeks is most likely to produce beneficial results. Our observational experience with IVIg has been less favorable than that published previously. The aim of our study was to examine retrospectively the use and effectiveness of IVIg treatment of skin disease at the Mayo Clinic. Because multiple well-designed studies of the effectiveness of IVIg for management of toxic epidermal necrolysis have been reported, we excluded patients with this disease from our study and concentrated on patients for whom IVIg was prescribed for other skin diseases. PATIENTS AND METHODS Patients who received IVIg treatment of skin disease between 1996 and 2003 at the Mayo Clinic in Rochester, Minn, Scottsdale, Ariz, and Jacksonville, Fla, were identified from the Mayo Clinic Central Pharmacy database. Patients who had been treated by the Department of Dermatology and who had consented to their medical records being used for research (per Minnesota law) were included in the study. Patients treated with IVIg for toxic epidermal necrolysis were not included in the study. This study was approved by the Mayo Foundation Institutional Review Board. Medical charts were examined retrospectively for the following information: demographics, diagnosis, disease duration and severity before IVIg treatment, previous systemic therapies, IVIg administration protocol, type of IVIg used, duration of IVIg treatment, concomitant therapy, reFrom the Department of Internal Medicine (D.A.W.) and Department of Dermatology (M.D.P.D., L.E.G., R.A.e.-A., A.J.B., I.A., A.L.S., M.R.P.), Mayo Clinic College of Medicine, Rochester, Minn; Department of Dermatology, Mayo Clinic College of Medicine, Scottsdale, Ariz (J.A.Y., M.V.D.); and Department of Dermatology, Mayo Clinic College of Medicine, Jacksonville, Fla (D.P.L.). Address reprint requests and correspondence to Mark Denis P. Davis, MD, Department of Dermatology, Mayo Clinic College of Medicine, 200 First St SW, Rochester, MN 55905 (e-mail: [email protected]). © 2005 Mayo Foundation for Medical Education and Research
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TABLE 1. Patient Characteristics*
RESULTS
Patient No./ sex
Age at disease onset (y)
Disease
Disease duration before IVIg treatment (mo)
1/M 2/F 3/M 4/M 5/M 6/F 7/M 8/F 9/F 10/M 11/M 12/F 13/F 14/M 15/F 16/F 17/M 18/M
33 75 40 49 54 47 47 69 71 71 42 40 65 27 25 49 60 1 wk
PV PV PV PV PV PV PV BP BP BP CP D D MCTD CU S LV LABD
15 26 5 15 24 12 21 40 84 61 122 72 10 6 41 57 2 1 wk
*BP = bullous pemphigoid; CP = cicatricial pemphigoid; CU = chronic urticaria; D = dermatomyositis; IVIg = intravenous immunoglobulin; LABD = linear IgA bullous disease; LV = leukocytoclastic vasculitis; MCTD = mixed connective tissue disease; PV = pemphigus vulgaris; S = scleromyxedema.
sponse to treatment, adverse effects from IVIg treatment, evidence of disease worsening after discontinuation of IVIg therapy (“rebound effects”), and follow-up after cessation of IVIg therapy. SPECIFIC IVIG PREPARATIONS The following preparations of IVIg were used: Venoglobulin (Alpha Therapeutic Corp, Los Angeles, Calif), 13 patients; Gamimune (Bayer, West Haven, Conn), 2 patients; Gammagard (Baxter, Deerfield, Ill), 1 patient; Carimune (ZLB, Glendale, Calif), 1 patient; and GammarP I.V. (Aventis, King of Prussia, Pa), 1 patient. GRADING OF RESPONSE TO TREATMENT Patient response to IVIg was graded as complete response (CR), partial response (PR), or no response (NR). Total resolution of old lesions and lack of new lesions indicated CR. Persistence of old lesions and development of new ones indicated NR. The presence of active lesions with healing of some lesions indicated PR, assessed as greater than 50% (PR>50), less than 50% (PR<50), or equal to 50% (PR≈50) by the attending physician. Indices of treatment efficacy included comparison of symptoms, signs, and pertinent laboratory tests (such as antibody levels in autoimmune disease) before and after therapy. Many patients were receiving concomitant immunosuppressive treatment. Overall dosages of and fluctuations in concomitant therapies were documented. 42
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DEMOGRAPHICS Eighteen patients (10 males, 8 females) were studied (Table 1). Age at disease onset ranged from 1 week to 75 years, with a mean (SD) age of 48 (19) years. Nine skin diseases were represented in the patient group: 3 types of immunobullous disease in adults (pemphigus vulgaris [7 patients], bullous pemphigoid [3], and cicatricial pemphigoid [1]), dermatomyositis (2), mixed connective tissue disease (1), chronic urticaria (1), scleromyxedema (1), leukocytoclastic vasculitis (1), and linear IgA bullous disease (1). Skin biopsy specimens confirmed the diagnoses in 17 of 18 patients (94%). In general, patients had severe disease unresponsive to high doses of glucocorticosteroids and immunosuppressive agents. Many patients experienced adverse effects from conventional therapies. The median duration of systemic treatment before initiation of IVIg therapy was 17 months (range, 0110 months). IVIG THERAPY Data about specific IVIg regimens, preparations of IVIg used, and durations of treatment are shown in Table 2. Median duration of IVIg treatment was 6.5 months (range, 1-14 months), and median duration of concomitant prednisone therapy was 4 months (range, 0-13 months). Fourteen patients (78%) received an IVIg dosage of 2 g/kg per monthly cycle; others received dosages ranging from 0.4 g/ kg per month to 2 g/kg every 2 weeks. Most patients were treated concomitantly with immunosuppressive agents or glucocorticosteroids (Table 3). Overall Response to IVIg Treatment. Nine (50%) of the 18 patients had NR, 6 (33%) had CR, and 3 (17%) had PR (1 PR>50, 1 PR≈50, 1 PR<50). Response of Adult Patients With Immunobullous Disease. Eleven patients had immunobullous disease: pemphigus vulgaris in 7, bullous pemphigoid in 3, and cicatricial pemphigoid in 1. Individual responses to IVIg treatment are shown in Table 4, and previous and concomitant therapies are listed in Table 3. Nine (82%) of the 11 adult patients with immunobullous disease had NR. One patient with bullous pemphigoid experienced CR, and 1 patient with pemphigus vulgaris exhibited PR of 80% as evidenced by improvement in his skin. All 11 patients had severe disease refractory to conventional therapies (Table 3). Median duration of systemic treatment before IVIg was 22 months (range, 5-110 months). Median duration of IVIg therapy was 7 months (range, 1-11 months) at a typical dosage of 2 g/kg per monthly cycle. During IVIg therapy, all 11 patients received either prednisone or prednisolone and 1 or more
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additional therapies. The conditions of 7 patients (64%) worsened, and they required increasing doses of concomitant therapies in an attempt to control their disease; 3 of the remaining 4 patients required either ongoing prednisone or prednisolone and another agent throughout therapy. Glucocorticosteroid doses were unable to be tapered in 9 patients (82%). Median duration of concomitant prednisone therapy was 6 months (range, 1-11 months). Median number of treatment cycles in nonresponders was 7 (range, 5-17 cycles) over a median duration of 7 months (range, 511 months). Six of the 7 patients with pemphigus vulgaris had biopsyproven disease; patient 2 had inconclusive histology and direct immunofluorescence tests, but the clinical presentation and high titers of antiepithelial antibodies in the serum corroborated the diagnosis. Before IVIg therapy, these patients had nonhealing bullae and erosions. Mouth ulcers were the predominant manifestation in 3 patients. Patients averaged 6.9 months of IVIg treatment (range, 1-11 months) without clinical benefit. Disease worsened in all but 1 patient when concomitant doses of prednisone were reduced. Doses of other immunosuppressive agents were increased during therapy; agents were discontinued and alternatives introduced in attempts to control the disease process. Nonresponders averaged 22 mg/d of prednisone while receiving IVIg (range, 3-52 mg/d). The patient who responded to IVIg treatment experienced 80% improvement 1 week after initiation of therapy but died several weeks later due to unexplained pneumonitis. Two of the 3 patients with bullous pemphigoid had NR, and 1 patient exhibited CR. Patients primarily experienced oral disease before initiation of IVIg therapy. Nonresponders averaged 4 mg/d of prednisone while receiving IVIg and experienced flaring of the disease, which was unresponsive to modifications of concomitant therapies. The 1 patient who had CR had no active lesions after 4 cycles of therapy; this patient stopped taking azathioprine after 3 months because of leukopenia. One patient with NR discontinued use of cyclophosphamide after 5 cycles of IVIg because of leukopenia. The patient with cicatricial pemphigoid presented with severe oral and ocular disease that had not responded to systemic therapy. After 10 months of IVIg therapy, the patient experienced no oral or ocular improvement. Concomitant therapies were added and doses increased, all without benefit. Response of Neonate With Immunobullous Disease. The neonate with linear IgA bullous disease was 1 week old at disease onset and experienced CR. The disease initially involved the airway, mouth, and buttocks and required 4 months of hospitalization. Prednisone and dapMayo Clin Proc.
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TABLE 2. Details of IVIg Treatment* Patient No./ disease/ response
Preparation of IVIg
1/PV/NR 2/PV/NR 3/PV/PR>50 4/PV/NR 5/PV/NR 6/PV/NR 7/PV/NR 8/BP/CR 9/BP/NR 10/BP/NR 11/CP/NR
Gammagard Venoglobulin Venoglobulin Gammar-P I.V. Venoglobulin Venoglobulin Gamimune Venoglobulin Venoglobulin Carimune Venoglobulin
12/D/PR<50 13/D/CR 14/MCTD/CR
Venoglobulin Gamimune Venoglobulin
15/CU/CR 16/S/CR 17/LV/PR≈50
Venoglobulin Venoglobulin Venoglobulin
18/LABD/CR
Venoglobulin
IVIg regimen (g/kg) (cycle)† 2 (4) 2 (3) 2 (3) 2 (3) 2 (3) 2 (3) 2 (3) 2 (3) 2 (3) 2 (3) 2 (3 d every 2-3 wk) 2 (2) 2 (5) 0.5 (weekly) 2 (5) 2 (4) 0.4 (monthly) 1 (every 2-4 wk)
Duration of IVIg treatment (mo) 8 7 1 6 9 11 6 9 5 7 10 2 1 5 wk 1 7 6 14
*BP = bullous pemphigoid; CP = cicatricial pemphigoid; CR = complete response; CU = chronic urticaria; D = dermatomyositis; IVIg = intravenous immunoglobulin; LABD = linear IgA bullous disease; LV = leukocytoclastic vasculitis; MCTD = mixed connective tissue disease; NR = no response; PR≈50 = 50% response; PR>50 = partial response greater than 50%; PR<50 = partial response less than 50%; PV = pemphigus vulgaris; S = scleromyxedema. †The cycle is defined as the number of days each month, unless indicated otherwise.
sone were administered, and IVIg was initiated 1 week later. After 5 cycles of IVIg over 31/2 months, the disease remitted completely. Remission has been maintained for 101/2 months with monthly IVIg treatments. Dapsone was discontinued initially after 2 weeks of therapy because of anemia but was restarted and used throughout the last 5 months of IVIg therapy. Prednisolone has been used concomitantly for 13 months. Response of Patients With Nonimmunobullous Disease. Patients’ responses to IVIg treatment and previous and concomitant therapies are shown in Tables 3 and 4. One of 2 patients with dermatomyositis was treated with IVIg and had CR; the other patient had PR<50. Both patients presented with the characteristic cutaneous findings and weakness of dermatomyositis. The patient who responded completely to IVIg did so after only 1 treatment cycle, evidenced by cutaneous improvement and decreasing creatine kinase levels. One month before this patient received IVIg, azathioprine had been added, and the prednisone dosage had been increased. The patient’s disease is adequately controlled with these 2 medications 28 months
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INTRAVENOUS IMMUNOGLOBULIN THERAPY AND SKIN DISEASE
TABLE 3. Systemic Treatments Before and During IVIg Treatment* Patient No./ disease/ response
Previous systemic treatment (maximum dosage)
Concomitant systemic treatment (maximum dosage)
1/PV/NR
Prednisone (150 mg/d, 14 mo); mycophenolate mofetil (3 g/d, 14 mo); cyclophosphamide (50 mg/d, 8 mo); azathioprine (150 g/d, 5 mo); plasmapheresis
Prednisone (20 mg/d, 8 mo); mycophenolate mofetil (3 g/d, 8 mo); azathioprine (200 mg/d, 8 mo); cyclophosphamide (50 mg/d) and cyclosporine (both added after 8 mo)
2/PV/NR
Prednisone (40 mg/d, 23 mo); azathioprine (50 mg/d, 3 mo); niacinamide (2 g/d, 3 mo); mycophenolate mofetil (3 g/d, 20 mo)
Prednisone (5 mg/d, 7 mo); mycophenolate mofetil (3 g/d, 7 mo)
3/PV/PR>50
Prednisolone (140 mg/d, 5 mo); azathioprine (200 mg/d, 5 mo)
Prednisolone (140 mg/d, 1 mo); azathioprine (150 mg/d, 1 mo)
4/PV/NR
Prednisone (60 mg/d, 6 mo); dapsone (100 mg/d, 6 mo); minocycline (200 mg/d, 6 mo); methotrexate
5/PV/NR
Prednisone (40 mg/d, 20 mo); mycophenolate mofetil (3 g/d, 5 mo); azathioprine (200 mg/d, 15 mo); niacinamide (2 g/d, 16 mo)
6/PV/NR
Prednisone (40 mg/d, 9 mo); methylprednisolone tapers
Prednisone (30 mg/d, 11 mo); methotrexate (15 mg/wk, 9 mo)
7/PV/NR
Prednisone (120 mg/d, 19 mo); mycophenolate mofetil (3 g/d, 16 mo); doxycycline (200 mg/d); azathioprine (150 mg/d, 1 mo)
Prednisone (60 mg/d, 6 mo); azathioprine (150 mg/d, 4 mo); cyclophosphamide (200 mg/d, 2 mo); valacyclovir (1000 mg/d, 5 mo)
8/BP/CR
Prednisone (30 mg/d, 37 mo); niacinamide (2 g/d, 24 mo); tetracycline (1.5 g/d, 7 mo); mycophenolate mofetil (3 g/d, 10 mo); azathioprine (150 mg/d, 20 mo)
Prednisone (2 mg/d, 3 mo); azathioprine (150 mg/d, 3 mo, stopped due to leukopenia); niacinamide (1 g/d, 9 mo); hydroco rtisone (50 mg/IVIg infusion, 5 mo, due to nausea, headache)
9/BP/NR
Prednisone (30 mg/d, 72 mo); niacinamide (2 g/d, 72 mo); dapsone (125 mg/d, 36 mo); mycophenolate mofetil (3 g/d, 12 mo); azathioprine (125 mg/d, 16 mo); tetracycline/minocycline/doxycycline
Prednisone (5 mg/d, 5 mo); azathioprine (125 mg/d, 5 mo); doxycycline (100 mg/d, 5 mo); niacinamide (1 g/d, 1 mo, stopped due to LFTs)
Prednisone (20 mg/d, 6 mo); azathioprine (150 mg/d, 6 mo); minocycline (200 mg/d, 2 mo) Prednisone (40 mg/d, 9 mo); azathioprine (200 mg/d, 7 mo); cyclophosphamide (150 mg/d, 1.5 mo); niacin (2 g/d, 8 mo)
10/BP/NR
Dapsone (200 mg/d, 30 mo); prednisone (60 mg/d, 36 mo); niacin (2 g/d, 36 mo); mycophenolate mofetil (3 g/d, 7 mo); azathioprine (150 mg/d, 18 mo); cyclophosphamide (100 mg/d, 7 mo); minocycline/doxycycline
Prednisone (6 mg/d, 7 mo); cyclophosphamide (100 mg/d, 5 mo, stopped due to leukopenia); niacin (2 g/d, 7 mo); doxycycline (200 mg/d, added after 7 mo)
11/CP/NR
Prednisone (60 mg/d, many years); cyclophosphamide (200 mg/d, 4 mo); dapsone (100 mg/d, many years); mycophenolate mofetil (2 g/d, 1.5 mo)
Methylprednisolone with IVIg (2.5 mo, 6 cycles); mycophenolate mofetil (3 g/d, 5 mo); cyclophosphamide (150 mg/d, 5 mo)
12/D/PR<50
Prednisone (60 mg/d, 60 mo); hydroxychloroquine sulfate (400 mg/d, 24 mo); methotrexate (6 mo); azathioprine (25 mg/d, 5 mo); cyclosporine (450 mg/d, 3 mo); mycophenolate mofetil (3 g/d, 6 mo)
Prednisone (20 mg/d, 2 mo); mycophenolate mofetil (2 g/d, 2 mo)
13/D/CR
Prednisone (60 mg/d, 8 mo); hydroxychloroquine sulfate (400 mg/d, 1 mo); azathioprine (150 mg/d, 1 mo)
Prednisone (60 mg/d, 1 mo); azathioprine (150 mg/d, 1 mo)
14/MCTD/CR
Prednisone (50 mg/d, 5 mo); mycophenolate mofetil (2 g/d); methylprednisolone (1 g/d, 3 d)
15/CU/CR
Prednisone (60 mg/d, many courses); antihistamines (6 different types); cyclosporine (75 mg/d, 2 mo); colchicine (1.2 mg/d, 3 mo); sulfasalazine (3 g/d, 1.5 mo)
None
16/S/CR
Methylprednisolone; dexamethasone (12 mg/wk, 2 mo); isotretinoin (80 mg/d); PUVA (2 mo); hydroxychloroquine sulfate (400 mg/d, mo); thalidomide (200 mg/d, 4 mo); SCT
None
17/LV/PR≈50
None
18/LABD/CR
Prednisone (1 wk); dapsone (1 wk)
Prednisone (40 mg/d, 1.25 mo); mycophenolate mofetil (2 g/d, 1.25 mo)
Prednisone (20 mg/d, 1 mo); azathioprine (100 mg/d, 6 mo) Prednisolone (5 mg/d, 13 mo); dapsone (10 mg/d, 5.5 mo)
*BP = bullous pemphigoid; CP = cicatricial pemphigoid; CR = complete response; CU = chronic urticaria; D = dermatomyositis; IVI g = intravenous immunoglobulin; LABD = linear IgA bullous disease; LFTs = liver function tests; LV = leukocytoclastic vasculitis; MCTD = mixed connective tissue disease; NR = no response; PR≈50 = 50% response; PR>50 = partial response greater than 50%; PR<50 = partial response less than 50%; PUVA = psoralen + ultraviolet A radiation; PV = pemphigus vulgaris; S = scleromyxedema; SCT = stem cell transplantation.
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TABLE 4. Patient Responses to IVIg Treatment* Response to IVIg
Time for effective response (No. of cycles)
Maintenance IVIg, mo (No. of cycles)
1/PV 2/PV 3/PV 4/PV
NR NR PR>50 NR
NA NA 1 wk (1) NA
None None None None
5/PV
NR
NA
None
6/PV
NR
NA
None
7/PV
NR
NA
None
8/BP
CR
31/2 mo (4)
51/2 mo (5)
9/BP
NR
NA
None
10/BP 11/CP 12/D
NR NR PR<50
NA NA 2 mo (2)
13/D
CR
1 mo (1)
None None Remains on IVIg at time of study None
14/MCTD
CR
3 wk (3)
2 wk (2)
15/CU 16/S 17/LV 18/LABD
CR CR PR≈50 CR
1 d (0.2) 5 mo (5) 2 mo (2) 31/2 mo (5)
None 2 mo 4 mo 10 1/2 mo
Patient No./ disease
Follow-up after discontinuing IVIg (outcome)
Adverse effects from IVIg
No follow-up available None IVIg stopped at time of study Nausea, fever, flushing 1 mo (died of pneumonitis 1 mo after IVIg cycle) Not known 5 mo (gradually improved with prednisone, pulse None cyclophosphamide, and pulse dexamethasone) 7 mo (began to improve with cyclophosphamide Achiness, fatigue and prednisone) 5 mo (moderately improved with prednisone None and methotrexate) 4 mo (moderately improved with None cyclophosphamide and prednisone) Taking IVIg at time of study Fever, headache, nausea, myalgias 4 mo (mildly improved with prednisone and None cyclophosphamide) Taking IVIg at time of study None IVIg stopped at time of study Hypertensive episode Taking IVIg at time of study None 28 mo (controlled with prednisone and azathioprine) 3 mo (controlled with prednisone taper and mycophenolate mofetil) 3 1/2 mo (95% resolution) Taking IVIg at time of study No follow-up available Taking IVIg at time of study
None Severe flulike illness (IVIg discontinued) Severe headache None None None
*BP = bullous pemphigoid; CP = cicatricial pemphigoid; CR = complete response; CU = chronic urticaria; D = dermatomyositis; IVI g = intravenous immunoglobulin; LABD = linear IgA bullous disease; LV = leukocytoclastic vasculitis; MCTD = mixed connective tissue disease; NA = not applicable; NR = no response; PR≈50 = 50% response; PR>50 = partial response greater than 50%; PR<50 = partial response less than 50%; PV = pemphigus vulgaris; S = scleromyxedema.
later. The other patient had responded only minimally after 2 monthly cycles of IVIg and concomitant therapy with prednisone and mycophenolate mofetil and was still receiving IVIg at the time of data analysis. The patient with mixed connective tissue disease had CR. The patient had widespread ulcerations, Raynaud phenomenon, and myositis that did not respond after 6 months of systemic therapy. He received prednisone and mycophenolate mofetil in addition to IVIg. After 3 weeks of therapy, the ulcerations were completely healed and painless and remained healed while the patient received concomitant therapies 3 months after IVIg was discontinued because of adverse effects. The patient with chronic urticaria had CR. She had 80% to 90% skin involvement at times and had received systemic therapies for 41 months with no benefit. She received 1 cycle of IVIg and responded within 1 day of the first infusion. This patient showed 95% improvement over 3 months after discontinuation of IVIg without concomitant therapies. The patient with scleromyxedema had CR. Fifteen months of various systemic treatments had failed to help her, but her skin had almost returned to normal after 5 Mayo Clin Proc.
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cycles of IVIg and remained so after 7 cycles. No concomitant therapies were given during IVIg treatment. The patient with leukocytoclastic vasculitis had PR≈50. He had multiple small, infected lower extremity ulcers and had received no systemic therapy before initiation of IVIg. The patient received 6 cycles of IVIg, and prednisone and azathioprine therapy was initiated. Prednisone was discontinued after 1 month, and no new lesions developed after 2 monthly IVIg cycles, although an ulcer swab showed methicillin-resistant Staphylococcus aureus. After 6 cycles of IVIg, the patient still had several skin ulcers. Adverse Effects of IVIg. Eleven (61%) of the 18 patients had no adverse effects attributable to IVIg (Table 4). However, 3 patients experienced nausea, fever, flushing, headache, and myalgias. One patient developed transient hypertension after an infusion. The patient with chronic urticaria developed a severe headache after her first infusion. The patient with mixed connective tissue disease developed a severe flulike illness that necessitated discontinuation of IVIg after 5 weeks. As mentioned previously, 1 patient died of pneumonitis 1 month after initiation of IVIg; whether this was related to IVIg or to infectious or autoimmune factors is unknown.
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IVIg Preparations Used. Of the 9 nonresponders, 5 received Venoglobulin, and the other 4 received Gamimune, Carimune, Gammar-P I.V., and Gammagard, respectively. Of the 6 who had CR, 5 received Venoglobulin and 1 received Gamimune. The 3 who had PR all received Venoglobulin. The totals for each preparation were as follows: Venoglobulin—5 CR, 3 PR, and 5 NR; Gamimune— 1 CR and 1 NR; Gammagard—1 NR; Carimune—1 NR; and Gammar-P I.V.—1 NR. Rebound Effect. In 9 of the 18 patients, information could not be ascertained about a possible rebound effect (flaring of clinical disease after cessation of IVIg therapy) because IVIg therapy was ongoing or the patient died. None of the remaining 9 patients experienced a rebound effect after discontinuing IVIg therapy. DISCUSSION We recognize and acknowledge the shortcomings of the present study: it is retrospective, the cohort studied is small, the diseases are heterogeneous with small numbers of patients in each group, and IVIg was used infrequently as monotherapy. Also, we recognize the limitations of measuring response to treatment by a global assessment of severity. Nonetheless, we have been struck by the contrast in our experience compared with that of other recent reports. In this study, IVIg was effective in only half the patients with skin disease. In particular, IVIg was ineffective in most of our patients with immunobullous disease. All 9 nonresponding patients in our study had a form of immunobullous disease. The 11 adult patients with immunobullous disease met published criteria for use of IVIg in that they had longstanding disease unresponsive to glucocorticosteroid and immunosuppressive therapy or experienced adverse effects from conventional therapy.18 On average, they received 33 months of systemic therapy before initiation of IVIg therapy. Previous studies suggest that inadequate dosing and duration of treatment with IVIg may explain why some patients do not to respond to therapy.19,20 However, our patients received doses similar to responders in previous studies for similar periods. Of our patients with immunobullous disease, nonresponders received an average of 8.4 treatment cycles over an average of 7.7 months at an average dosage of 2 g/kg per cycle. This dosage and duration agree with those reported in previous studies to produce desirable results.3,20 Reportedly, IVIg allows a reduction in concomitant glucocorticosteroid therapy and can be used successfully as monotherapy.3,15-17 Our findings do not support this contention. Most of our patients with immunobullous disease 46
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continued to require substantial doses of prednisone and other immunosuppressive agents while receiving IVIg therapy. We were unable to taper glucocorticosteroid dosages in 9 of the 11 adult patients with immunobullous disease. In the 7 patients who had pemphigus vulgaris, the mean duration of IVIg treatment was 6.9 months; the mean duration of concomitant prednisone therapy was also 6.9 months. Given the array of skin diseases and small sample sizes in this analysis, it is difficult to generalize regarding the effectiveness of IVIg for the other diseases represented in this study. Of the 7 patients who did not have adult immunobullous disease, 5 had CR. However, only 2 of these 5 patients were treated with IVIg as monotherapy; the other 3 required concomitant prednisone or prednisolone along with an immunosuppressive agent for the duration of IVIg therapy. Two of these 3 patients continued to require these concomitant therapies after discontinuation of IVIg; the other patient continues to receive IVIg and has received concomitant prednisolone for 13 months. The brand of IVIg may affect therapeutic efficacy.18,21 The various manufacturers prepare their IVIg differently. Five different preparations were used in our study, with Venoglobulin used most often. No obvious differences were found among patients receiving different preparations (Table 2). Each brand had at least 1 nonresponder. Venoglobulin had an equal number of complete responders and nonresponders. CONCLUSION Our experience with use of IVIg to treat skin disease is less favorable than that published previously. We did not find IVIg therapy to be routinely effective against adult immunobullous disease, as has been reported previously. Further studies are needed to verify the efficacy of IVIg for various skin diseases and to determine the role of IVIg and coadministered treatments in inducing remissions. REFERENCES 1. Bystryn JC, Jiao D, Natow S. Treatment of pemphigus with intravenous immunoglobulin. J Am Acad Dermatol. 2002;47:358-363. 2. Ahmed AR, Sami N. Intravenous immunoglobulin therapy for patients with pemphigus foliaceus unresponsive to conventional therapy. J Am Acad Dermatol. 2002;46:42-49. 3. Ahmed AR. Intravenous immunoglobulin therapy in the treatment of patients with pemphigus vulgaris unresponsive to conventional immunosuppressive treatment. J Am Acad Dermatol. 2001;45:679-690. 4. 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. 5. Foster CS, Ahmed AR. Intravenous immunoglobulin therapy for ocular cicatricial pemphigoid: a preliminary study. Ophthalmology. 1999;106:21362143.
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6. Prins C, Kerdel FA, Padilla RS, 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. 7. 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. 8. O’Donnell BF, Barr RM, Black AK, et al. Intravenous immunoglobulin in autoimmune chronic urticaria. Br J Dermatol. 1998;138:101-106. 9. 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;147:554-557. 10. Al-Mayouf SM, Laxer RM, Schneider R, Silverman ED, Feldman BM. Intravenous immunoglobulin therapy for juvenile dermatomyositis: efficacy and safety. J Rheumatol. 2000;27:2498-2503. 11. Gedalia A, Correa H, Kaiser M, Sorensen R. Case report: steroid sparing effect of intravenous gamma globulin in a child with necrotizing vasculitis. Am J Med Sci. 1995;309:226-228. 12. 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;40:485-488. 13. Lister RK, Jolles S, Whittaker S, et al. Scleromyxedema: response to high-dose intravenous immunoglobulin (hdIVIg). J Am Acad Dermatol. 2000; 43:403-408.
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14. Ulmer A, Kotter I, Pfaff A, Fierlbeck G. Efficacy of pulsed intravenous immunoglobulin therapy in mixed connective tissue disease. J Am Acad Dermatol. 2002;46:123-127. 15. Sami N, Qureshi A, Ruocco E, Ahmed AR. Corticosteroid-sparing effect of intravenous immunoglobulin therapy in patients with pemphigus vulgaris. Arch Dermatol. 2002;138:1158-1162. 16. Sami N, Qureshi A, Ahmed AR. Steroid sparing effect of intravenous immunoglobulin therapy in patients with pemphigus foliaceus. Eur J Dermatol. 2002;12:174-178. 17. Ahmed AR. Intravenous immunoglobulin therapy for patients with bullous pemphigoid unresponsive to conventional immunosuppressive treatment. J Am Acad Dermatol. 2001;45:825-835. 18. Ahmed AR, Dahl MV. Consensus statement on the use of intravenous immunoglobulin therapy in the treatment of autoimmune mucocutaneous blistering diseases. Arch Dermatol. 2003;139:1051-1059. 19. Engineer L, Ahmed AR. Role of intravenous immunoglobulin in the treatment of bullous pemphigoid: analysis of current data. J Am Acad Dermatol. 2001;44:83-88. 20. Engineer L, Bhol KC, Ahmed AR. Analysis of current data on the use of intravenous immunoglobulins in management of pemphigus vulgaris. J Am Acad Dermatol. 2000;43:1049-1057. 21. Lemm G. Composition and properties of IVIg preparations that affect tolerability and therapeutic efficacy. Neurology. 2002;59(suppl 6):S28S32.
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