The use of cyclosporine in dermatology: Part I

CONTINUING

MEDICAL EDUCATION

The use of cyclosporine in dermatology: Part I Karrie T. Amor, MD,a Caitriona Ryan, MBBCh, BAO,b and Alan Menter, MDb Houston and Dallas, Texas Cyclosporine is a calcineurin inhibitor that acts selectively on T cells. It has been used in dermatology since 1997 for its US Food and Drug Administration indication of psoriasis and off-label for various other inflammatory skin conditions, including atopic dermatitis, blistering disorders, and connective tissue diseases. In the last decade, many dermatologists have hesitated to use this important drug in their clinical practices because of its toxicity profile. The purpose of this article is to review the mechanism of action of cyclosporine and its current uses and dosing schedules. It is our goal to create a framework in which dermatologists feel comfortable and safe incorporating cyclosporine into their prescribing regimens. ( J Am Acad Dermatol 2010;63:925-46.) Learning objectives: After completing this learning activity, participants should be able to describe the mechanism of action of cyclosporine, recognize the potential role of cyclosporine in dermatology and the evidence to support this role, and incorporate cyclosporine into his or her prescribing regimens. Key words: atopic dermatitis; chronic urticaria; cyclosporine; psoriasis; pyoderma gangrenosum.

HISTORY Key points d

d

Cyclosporine was first used to prevent rejection in solid organ transplant recipients Cyclosporine was approved by the US Food and Drug Administration for the treatment of psoriasis in 1997

In 1970, cyclosporine, also known as cyclosporin A (CsA), was isolated from the soil fungus

From the Departments of Dermatology at the University of Texas,a Houston, and Baylor University Medical Center,b Dallas. Bruce H. Thiers, MD, Editor, has disclosed the following financial relationships: Elsevier- Other/Honoraria, Galderma- Other/ Honoraria, Graceways Pharmaceuticals- Consultant/Honoraria. Dirk M. Elston, MD, Deputy Editor, has disclosed the following financial relationships: Intendis- Investigator/No Compensation. Robert T. Brodell, MD, JAAD CME Planner, has disclosed the following financial relationships: 3M/Graceway PharmaceuticalsSpeaker/Honoraria, Allergan- Speaker/Honoraria, Dermik/BenzaClin- Speaker/Honoraria, Dow Pharmaceutical Sciences- Consultant/ Honoraria, Galderma Laboratories, LP- Speaker/Honoraria, GlaxoSmithKline- Speaker/Honoraria, Graceway Pharmaceuticals, LLCSpeaker/Honoraria, Medicis- Advisory Board/Honoraria, Novaritis Pharmaceuticals- Speaker/Honoraria, Promius- Advisory Board/ Honoraria, Sanofi-Aventis- Speaker/Honoraria. Joseph C. English III, MD, JAAD CME Planner, has disclosed the following financial relationships: Centocor- Investigator/No compensation. James R. Treat, MD, JAAD CME Planner, has disclosed the following financial relationships: Pierre Fabre-Investigator/Grants. Hensin Tsao, MD, JAAD CME Planner, has disclosed the following financial relationships: Genentech- Consultant/Honoraria, Quest DiagnosticsConsultant/Honoraria, SciBASE-Consultant/Honoraria. Matthew Zirwas, MD, JAAD CME Planner, has disclosed the following financial relationships: Astellas Pharmaceuticals- Speaker/Honoraria, Coria Laboratories- Speaker/Honoraria, Consultant/Honoraria,

Tolypocladium inflatum Gams by Borel at Sandoz Laboratories in Basel, Switzerland, while looking for novel antifungal agents.1 Although it was initially noted to have only a narrow antifungal spectrum, cyclosporine was subsequently found to be a potent immunosuppressive drug in 1976.1 In 1978, cyclosporine was found to be successful in preventing rejection in renal transplant patients who received mismatched cadaver kidneys.2 In 1979, cyclosporine was first observed to improve psoriasis during a pilot

Onset Therapeutics-Consultant/Honoraria. Caitrona Ryan, MBBCh, BAO, Author, has disclosed the following financial relationships: Abbott-Other/Grant, Galderma- Advisory Board/Honoraria. Alan Menter, MD, Author, has disclosed the following financial relationships: Abbott- Advisory Board/Grant, Consultant/Honoraria, Investigator/Honoraria, Speaker/Honoraria, Amgen-Speaker/Honoraria, Advisory Board/Grant, Astellas- Consultant/Grant, Advisory Board/Honoraria, Celgene-Investigator/Grant, Centocor- Advisory Board/Honoraria, Consultant/Grant, Eli Lilly- Investigator/Grant, Galderma-Advisory Board/Honoraria, Speaker/Honoraria, Genentech- Advisory Board/Grant, Novartis- Investigator/Grant, Novo Nordisk- Investigator/Grant, Pfizer- Investigator/Grant, Promius-Investigator/Grant, Stiefel-Investigator/Grant, SyntrixInvestigator/Grant, Warner Chilcott-Advisory Board/Honoraria, Wyeth-Advisory Board/Honoraria, Speaker/Honoraria, Investigator/Grant. All other authors, editors, planners, peer reviewers, and staff have no relevant financial relationships. Reprints not available from the authors. Correspondence to: Alan Menter, MD, Department of Dermatology, Baylor Research Institute, 3900 Junius St, Ste 145, Dallas, TX 75246. E-mail: [email protected]. 0190-9622/$36.00 ª 2010 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2010.02.063

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study to investigate the efficacy of cyclosporine in stimulating factor (GM-CSF).5,7 Consequently, cyclo3 rheumatoid arthritis and psoriatic arthritis. The sporine depletes lymphocytes and macrophages in the epidermis and dermis8 and inhibits the activation original formulation of cyclosporine (Sandimmune; of T cells, natural killer cells, and antigen-presenting Novartis, East Hanover, NJ) was approved by the cells. Cyclosporine also inhibits keratinocyte hyperUnited States Food and Drug Administration (FDA) proliferation,9 inhibits the release of histamine from for the prevention of transplant rejection in 1983. In mast cells, and downregulates the expression of 1995, Neoral (Novartis), a microemulsion formulacellular adhesion molecules tion of cyclosporine that is on dermal capillary more bioavailable and more CAPSULE SUMMARY endothelium.10 consistently absorbed, was approved by the FDA for Cyclosporine is a calcineurin inhibitor the prevention of transplant CLINICAL USES OF that acts selectively on T cells. rejection. Neoral was then CYCLOSPORINE AND Cyclosporine is a highly effective approved for the treatment REGIMENS treatment because of its rapid onset. of rheumatoid arthritis and Key points psoriasis in 1997. Since d Cyclosporine is useful Cyclosporine is approved by the US Food then, the FDA has not apfor the short-term treatand Drug Administration for the proved cyclosporine for the ment of psoriasis and treatment of psoriasis. treatment of other clinical atopic dermatitis Cyclosporine has also been used to indications in dermatology, d Multiple case reports successfully treat several other but it has been approved for have shown cyclospordermatologic conditions, including use in atopic dermatitis in ine to have excellent reatopic dermatitis, pyoderma other countries. sults when used for the gangrenosum, and refractory chronic Structure. Cyclosporine treatment of pyoderma idiopathic urticaria. is a cyclic polypeptide gangrenosum immunosuppressant agent d Cyclosporine is useful consisting of 11 amino acids (Fig 1).4 It is produced for the treatment of refractory chronic idioas a metabolite by the fungus species Beauveria pathic urticaria nivea. d

d

d

d

MECHANISM OF ACTION Key points d

d

Cyclosporine forms a complex with cyclophilin, which inactives calcineurin phosphorylase, preventing the phosphorylation of nuclear factor of activated T cells and, therefore, the transcription of interleukin-2 Interleukin-2 is required for full activation of the T-cell pathway

Cyclosporine was the first immunosuppressive drug found to act selectively on T cells. The helper T cell is the main target, but the T suppressor cell may also be affected. Cyclosporine forms a complex with cyclophilin, an intracellular immunophilin, and inhibits the activity of calcineurin phosphatase, a calcium/calmodulin-dependent serine-threonine phosphatase (Fig 2).5-7 As a result, calcineurin phosphatase is unable to phosphorylate nuclear factor of activated T cells (NFAT), a transcription factor. NFAT requires phosphorylation before transportation to the nucleus for transcription of genes encoding interleukin-2 (IL-2), a cytokine that is necessary for full activation of the T-cell pathway, interferongamma, and granulocyte-macrophage colony-

Psoriasis Cyclosporine is one of the most effective treatments for psoriasis because of its rapid onset of action. In patients with severe psoriasis unresponsive to other treatments, cyclosporine can induce a rapid remission, and can be used as a bridge to other therapies (Fig 3).11 A very high dose was used in the first controlled study in 1986 to evaluate the efficacy of cyclosporine in psoriasis (14 mg/kg/day). This resulted in marked improvement in 20 of 21 patients within 4 weeks.12 Subsequently, a multitude of dosefinding studies have been performed in order to elucidate the optimal and lowest effective dose of cyclosporine that achieves clearance with minimal toxicity.13-17 Efficacy of cyclosporine is dose dependent, with a shorter time to remission at higher doses.15,18 Benefit in efficacy gained by using doses higher than 5 mg/kg/day is, however, offset by an increase in toxicity.19 Current consensus guidelines recommend a starting dose of 2.5 mg/kg/day, unless a rapid improvement is considered necessary, when a dose of up to 5 mg/kg/day may be used (level IV evidence).11,16,18,20 Failing an adequate response with low dose cyclosporine after 4 weeks of treatment, the dose can be increased gradually by 0.5 to 1.0

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Fig 1. Molecular structure of cyclosporine. Cyclosporine is a cyclic polypeptide immunosuppressant agent consisting of 11 amino acids.

mg/kg/day at 2- to 4-week intervals, to a maximum of 5 mg/kg/day (level IV evidence).11 Tachyphylaxis is not observed in those who do start at lower doses with subsequent increments.15 If an adequate response has not been achieved after 3 months of treatment at a dose of 5 mg/kg/day, cyclosporine should be withdrawn. Once a good response is obtained, the dose can be reduced in steps of 0.5 to 1.0 mg/kg/day at two weekly intervals to the lowest possible dose that maintains control of disease (level IVevidence). For palmoplantar pustulosis, an initial starting dose of 4 to 5 mg/kg/day is suggested (level IV evidence), with reduction according to clinical response,21 despite randomized, controlled trials which have shown that doses of 1 to 2.5 mg/kg/day are effective in reducing the pustule count by 50%.22,23 Low dose cyclosporine has been used to treat acrodermatitis continua of Hallopeau,24 but higher doses are usually necessary.25 Current guidelines limit the continuous use of cyclosporine in the United States to 1 year,26 with those in the United Kingdom and Europe recommend a limit of 2 years (level IVevidence).11,21 Five schedules are available for the use of cyclosporine in psoriasis (Table I). Intermittent short-term therapy. Intermittent short-term therapy (12-16 weeks) is the most frequently recommended regimen, using short courses of cyclosporine until significant improvement is achieved, after which treatment is withdrawn. If relapse occurs, cyclosporine therapy is reinstituted at the previously effective dose.11,26,28-30 In a study of 400 patients with severe psoriasis, 80% of patients

Amor, Ryan, and Menter 927

required only one or two courses over a 1-year study period, and 45% of patients were still in remission 4 months after completion of the first course of treatment.29,30 This study also showed that tapering the dose by 1 mg/kg/week until cessation, versus stopping abruptly, resulted in a marginal increase in remission duration of 4 days, with 11 to 23 days of extra therapy required in the tapering group. An extension of this study out to 2 years showed that most patients required fewer than four courses of treatment over 2 years, receiving cyclosporine for just 43% (approximately 10 months) of the total 24month study period. Little to no rebound was noted after treatment withdrawal in either the abrupt cessation or tapered cessation groups.30 Another study showed that continuing cyclosporine for up to 4 weeks after clinical clearance conferred no advantage with regard to relapse rates.31 Rescue therapy. A short course of cyclosporine can be used in severe flares of disease as ‘‘rescue’’ or ‘‘bridging’’ therapy because of its rapid onset of action until an alternative maintenance treatment is instituted. This is particularly useful in the treatment of erythrodermic, suberythrodermic, or generalized pustular psoriasis. In this instance, a reducing dose approach is used subsequent to commencing at a dose of 5 mg/kg/day.11,26,27 In an open-label multicenter study of 33 patients with erythrodermic psoriasis treated initially with cyclosporine 4.2 mg/kg/day, then gradually decreased after remission by 0.5 mg/kg/day every 2 months,32 67% achieved complete remission and 27% achieved significant improvement at 2 to 4 months. Overlapping cyclosporine with alternative treatments, such as methotrexate and biologic therapies, can avoid further deterioration of disease at the early stages of treatment while the new drug is taking effect. Cyclosporine can then be withdrawn without the danger of flaring and with minimal risk of side effects for the short period that the two drugs are used simultaneously. Long-term therapy. In psoriasis, efficacy is maintained with long-term therapy in the majority of patients.10,31,33-35 The aim of maintenance therapy is not necessarily to achieve complete clearance but to attain a significant clinical improvement with the lowest effective dose. The maintenance dose typically used is 3.0 to 3.5 mg/kg/day.19 A comparison of a minimum of 36 months intermittent therapy to continuous therapy showed that an average dose of 3.06 mg/kg/day intermittent therapy maintained remission for 32% of the time versus the average continuous dose of 3.2 mg/kg/day which maintained remission for 69% of the time.36 In another study comparing intermittent 12-week courses to

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Fig 2. Mechanism of action of cyclosporine. In the cytoplasm, cyclosporine (CsA) binds to its immunophilin, cyclophylin (CpN), forming a complex between CsA and CpN. The CsAeCpN complex binds and blocks the function of the enzyme calcineurin (CaN), which has a serine/threonine phosphatase activity. As a result, CaN fails to dephosphorylate the cytoplasmic component of the nuclear factor of activated T cells (NF-ATc), and thereby the transport of NF-ATc to the nucleus and the binding of NF-ATc to the nuclear component of the nuclear factor of activated T cells (NF-ATn). The NF-ATceNF-ATn complex binds to the promoter of the interleukin 2 (IL-2) gene and initiates IL-2 production. Consequently, T cells do not produce IL-2, which is necessary for full T-cell activation. ª Cambridge Journals, reproduced with permission.6

continuous therapy for 1 year, 62% of the intermittent group (mean dose, 3 mg/kg/day) achieved a 75% reduction in the Psoriasis Area and Severity Index score compared with 92% of the continuous group (mean dose, 1.8 mg/kg/day). Those on continuous dosage required 139% of the mean cumulative annual dose required for the intermittent group.37 A dose-finding study for maintenance therapy showed that after induction for 16 weeks, a maintenance dose of 3 mg/kg/day was significantly superior to a dose of 1.5 mg/kg/day or placebo in preventing relapse. This occurred at a median of 6 weeks in both the placebo and 1.5 mg/kg/day group, while only 42% showed evidence of relapse during 24 weeks’ maintenance in the 3 mg/kg/day group.38

Similarly, with regard to remission duration, another study showed no significant difference in time to relapse between a maintenance dose of 1.5 mg/kg/day and placebo. Those treated with a 3 mg/kg/day maintenance dose had a mean time to relapse of 12 weeks, and this dosage was recommended as the optimum maintenance dose.39 Combination therapy. Cyclosporine can be combined with topical therapies, such as corticosteroids,33,36 anthralin,9 or vitamin D3 analogues40 for an improved response. Systemic treatments, such as methotrexate, fumaric acid esters, and mycophenolate mofetil, can also be used in combination with cyclosporine in severe cases, allowing for dose reduction of cyclosporine to minimize toxicity.41-44

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Fig 3. Psoriasis treated with cyclosporine. A, Precyclosporine therapy. B, Postcyclosporine therapy.

There is no evidence of additive efficacy when combined with acitretin.45 Rotational therapy. Rotational therapy with the aforementioned systemic agents can also be used to minimize duration of cyclosporine treatment and toxicity.26,46 Tachyphylaxis with cyclosporine does not appear to occur in the treatment of psoriasis.27,33,47 While the majority of patients will require further antipsoriatic treatment after cyclosporine withdrawal,10,31 patients may occasionally have a prolonged or sustained remission after a treatment course.29,30,48 Time to relapse depends on the severity of disease, the dose of cyclosporine required to achieve clearance, and the extent of clearing achieved before termination of the drug.11,39 In studies measuring time to relapse of psoriasis, 50% to 60% of patients relapsed 6 months after treatment withdrawal.27 Rebound flare on abrupt withdrawal of treatment ([125% of baseline Psoriasis Area and Severity Index score) has not been observed in studies of cyclosporine treatment in psoriasis or palmoplantar pustulosis.10,23,26,27,33,34 Current American Academy of Dermatology (AAD) guidelines suggest that intermittent therapy is preferable to long-term treatment, that treatment regimens be tailored to the individual needs of each patient, and that duration of continuous treatment should be kept below 1 year whenever possible. Psoriatic arthritis Psoriatic arthritis has the potential to become a destructive deforming arthropathy. Currently, the initial treatment of early onset psoriatic arthritis includes nonsteroidal antiinflammatory drugs (NSAIDs) and, on occasion, local steroid injections. Disease modifying antirheumatic drugs (DMARDs)

are reserved for cases that are resistant to NSAIDs or when progressive disease is present. The most widely used DMARDs for psoriatic arthritis include methotrexate, sulfasalazine, and cyclosporine.49 Antietumor necrosis factor-alfa agents have the significant advantage of limiting further joint destruction. Cyclosporine is an effective treatment for psoriatic arthritis, either alone or in combination with methotrexate. In 1989, significant improvement in joint tenderness, mean grip strength, and activity level was noted in six psoriatic arthritis patients treated with cyclosporine 6 mg/kg/day for 8 weeks. However, 2 weeks after discontinuation of cyclosporine, joint pain and swelling recurred.50 In an open-label prospective study, all seven patients with psoriatic arthritis had improvement of joint pain and swelling after cyclosporine 3.5 mg/kg/day for 6 months. The time to relapse was not documented in this study.51 In another study, 12 patients who had failed second-line psoriatic arthritis treatment were treated with cyclosporine 3 mg/kg/day for 6 months. At the end of the treatment period, seven patients had a greater than 50% reduction in their joint tenderness and swelling, four patients had stable disease, with one patient withdrawn early because of significant nephrotoxicity.52 An observational study of 55 patients with psoriatic arthritis treated with cyclosporine (2.7 mg/kg/day) revealed that a 50% reduction in joint complaints required a total of 24 weeks of treatment. Eighteen of the 55 patients were followed for 8 months after cyclosporine therapy, of whom 11 (61%) continued to have improvement or stable disease.53 A 1-year prospective, controlled randomized trial with 35 patients was conducted to compare the effectiveness and toxicity of

Disease

CsA dose

Psoriasis

A. Intermittent short-term therapy

B. Rescue therapy C. Long term therapy

Duration of treatment

12-16 wks, 12 mos maximum

Response

Excellent

Other drugs

Comments

Average 111 days; however, 30% had no relapse 6 mos after CsA discontinued

IB

A

IB

A

11,26-31

11,26,27,32

10,19,31-39

9,33,36,40-44

Corticosteroids, anthralin, or vitamin D3 analogues for an improved response. MTX, fumaric acid esters, and mycophenolate mofetil in severe cases

6-12 mos

Very good

MTX 15 mg/wk, occasionally

26,46 49-54

DECEMBER 2010

Can minimize CsA toxicity 50% reduction in joint complaints required 24 wks of CsA monotherapy, CsA-MTX combination therapy given to patients with partial MTX response

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3-4 mg/kg/day, max 5 mg/kg/day

Level of Clinical Reference(s) evidence* recommendationy

11-26

2.5-5 mg/kg/day for 12-16 wks, course repeated when relapse occurs 5 mg/kg/day for 12-16 wks for flaring of disease \5 mg/kg/day for up to 1 y; reducing dose to lowest effective

D. Combination therapy

E. Rotational therapy Psoriatic arthritis

Time to relapse after discontinued

930 Amor, Ryan, and Menter

Table I. Cyclosporine therapy for dermatologic diseases

Excellent

Pyoderma 5 mg/kg/day gangrenosum

[6 mos

Excellent

Dyshidrotic eczema

2.5-3 mg/kg/day

6 wks, up to 16 wks

Equivalent

Chronic urticaria

4 mg/kg/day

12-16 wks

Very good

Behc¸et disease

5 mg/kg/day

[6 mos

Very good

Pityriasis rubra pilaris

3-5 mg/kg/day, maintenance dose 2 mg/kg/day

[8 mos

Mixed

2 wks (50%), 6 wks (80%)

77% of patients continued to have a 54% improvement at 1 y 33% at 3-6 mos, relapse less severe

Used for short treatment of severe, atopic dermatitis that cannot be controlled with topical therapy. Approved for this indication in Europe and the UK Methylprednisolone (0.5-1 mg/kg/day, or pulse treatment 1 g/day for 1-5 days) usually given concurrently CsA equivalent to BDP cream

Cetirizine 10 mg/day, occasionally concurrently Prednisone, occasionally

Used to treat chronic urticaria as a steroid sparing agent or in cases refractory to corticosteroids Used for refractory eye disease, topical steroideresistant mucocutaneous disease, and arthritis. Poor prevention of neurologic involvement Used in erythrodermic classic adult and erythrodermic juvenile PRP

21,55-72

IA

A

21,73-78

IIB

A

79-81

IB

C

82-93

IB

B

94-102

IIA

B

103-113

III

C

Continued

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12-16 wks, 12 mos max

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2.5-3 mg/kg/day, max 5 mg/kg/day

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Atopic dermatitis

Disease

CsA dose

Duration of treatment

Dermatomyositis 1-1.8 mg/kg/day, [200 mg/day

Response

Time to relapse after discontinued

Very good

Other drugs

Level of Clinical Reference(s) evidence* recommendationy

Used in cases not responsive to prednisone combined with MTX or azathioprine. Effective for lung and esophageal involvement Used as a steroid sparing agent

106-113

III

B

114-121

III

D

Used as a steroid sparing agent

122-124

III

D

Good

125, 126

III

C

May be given Good 1 wk before sun exposure, and discontinued upon return Short courses during summer months

127, 128

III

C

129

III

C

Pemphigus vulgaris

1-3 mg/kg/day

8 mos 6 11.8 mos

Good, but better treatment options available

Epidermolysis bullosa acquisita

4-5 mg/kg/day

1-24 mos

Good, but better treatment options available

Prednisone 40 mg/day

Comments

43% free of Prednisone, relapse after usually combination given therapy with concurrently cyclosporine and prednisone 5 y after discontinuation of therapy Prednisone, usually given concurrently

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Table I. Cont’d

Photodermatoses

A. Chronic 4-4.5 mg/kg/day actinic dermatitis B. Polymor- 3-4 mg/kg/day phic light eruption

C. Solar urticaria

4.5 mg/kg/day

Flares once cyclosporine discontinued

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2-3 mos

Good

Lichen planopilaris

3-5 mg/kg/day

3-5 mos

Good

6-9 mos

Good

2-12 mos

Mixed

6-8 mos

Good

2-12 wks

Good

Prurigo 3.5-4 mg/kg/day nodularis Severe alopecia 5 mg/kg/day areata

Scleroderma

Good

Symptom free, stable disease at 12 mos postcyclosporine

33%-86% with [70% hair regrowth, 76% with maintained hair regrowth at 12 mos follow-up

Used for disseminated lichen planus, erosive lichen planus, and lichen planus resistant to systemic corticosteroids and retinoids. Topical CsA may be effective in the treatment of oral lichen planus CsA may be effective in the initial phases before severe follicular damage occurs

Methylprednisolone Eight case reports (pulse and daily of patients dosing), who developed prednisone alopecia areata while on CsA for solid organ transplant, and atopic dermatitis Acitretin 10 mg/day, occasionally

Prednisolone, broad spectrum antibiotics May potentially worsen hypertension or renal disease associated with systemic sclerosis

130-138

III

C

139-141

III

C

142, 143

III

C

26, 144-152

III

C

153, 154

III

C

155, 156

III

C

157, 158

III

C

159-161

III

D

BDP, Betamethasone-17,21-diproprionate; CsA, cyclosporine A; MTX, methotrexate; PRP, pityriasis rubra pilaris. *Level of evidence: Level IA evidence includes evidence from meta-analysis of randomized controlled trials; Level IB evidence includes evidence from at least one randomized controlled trial; Level IIA evidence includes evidence from at least one controlled study without randomization; Level IIB evidence includes evidence from at least one other type of experimental study; Level III evidence includes evidence from nonexperimental descriptive studies, such as comparative studies, correlation studies, and case-control studies; Level IV evidence includes evidence from expert committee reports or opinions or clinical experience of respected authorities, or both. y Clinical Recommendations: A. Recommendation based on consistent and good-quality patient-oriented evidence. B. Recommendation based on inconsistent or limited-quality patient-oriented evidence. C. Recommendation based on consensus, opinion, or case studies. D. Do not recommend, other treatment options are more effective.

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Benign familial 1.2-3.4 mg/kg/day pemphigus (Hailey-Hailey) Eosinophilic 100-150 mg/day pustular folliculitis Hidradenitis 4-4.5 mg/kg/day suppurativa

Prednisone, occasionally topical steroids

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3-4.5 mg/kg/day

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Lichen planus

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cyclosporine (3-5 mg/kg/day) versus low-dose methotrexate (7.5-15 mg/week) in the treatment of psoriatic arthritis. At both 6 and 12 months of treatment, the number of painful joints, swollen joints, the Ritchie index, the duration of morning stiffness, grip strength, and C-reactive protein (CRP) levels were reduced equally in both treatment groups. However, at the conclusion of 1 year, more patients withdrew from the cyclosporine arm (41.2% vs 27.8%; not statistically significant).54 A 12-month randomized, multicenter, doubleblind, placebo controlled trial was conducted by Fraser et al49 to study the safety and efficacy of combining cyclosporine with methotrexate in the treatment of patients with psoriatic arthritis with a previous incomplete response to methotrexate monotherapy. Of the 72 patients recruited, 38 were randomized to receive cyclosporine in addition to methotrexate (15 mg/week), with the remaining 34 randomized to receive placebo plus methotrexate (15 mg/week). The initial dose of cyclosporine was 2.5 mg/kg/day, with dose increments at weeks 4, 8, and 12 increasing by 0.5 mg/kg/day to a maximum dose of 4 mg/kg/day if tolerated. Significant improvement in swollen joint count (11.7 vs 6.5; P = .001) and CRP levels (17.4 vs 12.7 mg/L; P = .05) was seen in the methotrexate-cyclosporine arm compared to baseline, but not in the methotrexateplacebo group. Also, a significant reduction in synovitis was seen in the methotrexate-cyclosporine arm compared to the methotrexate-placebo group (33% reduction vs 6% reduction, respectively; P = .05). A significant difference in pain and quality of life was not detected in this study. Of the patients that withdrew early from the study, 13 of the 17 patients in the methotrexate-cyclosporine arm withdrew because of adverse effects versus only two of the 11 patients in the methotrexate-placebo arm withdrew for the same reason.49

Atopic dermatitis Cyclosporine is the only immunosuppressant approved in Europe and the United Kingdom for the short-term treatment of severe atopic dermatitis that cannot be controlled with topical therapy. While cyclosporine does not have formal FDA approval for this use,55 it has been recommended by the AAD Guidelines of Care committee as being effective for the treatment of atopic dermatitis refractory to conventional treatment with no statement as to the recommended dosage.56 In the treatment of atopic dermatitis with cyclosporine, a regimen commencing at 5 mg/kg/day for 2 weeks with a gradual tapering as dictated by the clinical response over the

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ensuing 3 months to a dose of 1.5 mg/kg/day where possible has been suggested.21,57-60 In 2007, Schmitt et al61 performed a systematic review and metaanalysis of controlled and uncontrolled trials of cyclosporine for the treatment of severe atopic dermatitis. Fifteen studies that included a total of 602 patients were analyzed. All of the studies reported a decrease in the mean severity of atopic dermatitis after cyclosporine treatment, with a 50% decrease in severity after 6 to 8 weeks of continuous cyclosporine treatment being noted in the majority of studies. Patients treated with a higher initial dose (4-5 mg/kg/day) had a more rapid improvement at 2 weeks (40% decrease in severity) than those treated with a lower initial dose (2.53 mg/kg/day; 22% decrease in severity). However, at 6 to 8 weeks, there was no difference in response between the two dose groups. Those receiving the higher dose reported a greater number of cyclosporine-related side effects. Two randomized controlled studies treated severely atopic dermatitis patients with long-term cyclosporine therapy. Harper et al62 compared intermittent 12-week courses of cyclosporine (5 mg/kg/day) with a continuous 1-year course of cyclosporine 5 mg/kg/day for the treatment of severe atopic dermatitis in children (2-16 years of age). The patients treated with the short course regimen (defined as courses of 12 weeks’ duration with at least 7 days in between each course) had variable results. Seven of the 19 patients in the short course arm were controlled on the short course regimen, of whom three required one short course only and four were managed with two or three courses. Four of the 12 patients unresponsive to the intermittent 12-week short-term regimen required treatment courses of greater than 12 weeks to achieve remission, while eight could not be controlled on extended cyclosporine therapy. In the continuous cyclosporine (5 mg/kg/day) arm, 15 of 16 patients achieved remission within the first 12 weeks, which was maintained for the duration of the study. Quality of life scores had improved significantly by week 12 for both groups but only remained significant at 12 months using the continuous dosing regimen. There were no significant differences in efficacy, renal profile, or blood pressure between the groups. While the improvement was more constant in the continuous group, the cumulative dose used was higher. Zonneveld et al63 randomly assigned 78 severe atopic dermatitis patients to two long-term cyclosporine dosing regimens for the treatment of severe atopic dermatitis.63 One group initially received cyclosporine 5 mg/kg/day, decreased to 3 mg/kg/day as tolerated, and the other group received 3 mg/kg/day,

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increased to 5 mg/kg/day as needed. The patients were maintained on their optimal dose for 10 months. After 1 year, the efficacy of cyclosporine was 59.8% and 51.7%, respectively. The two treatment regimens were well tolerated with similar safety profiles. A comparison of reducing dose regimens after an induction of 5 mg/kg/day showed that maintaining a dose of 5 mg/kg/day but increasing the interval between doses by 1 day every 2 weeks was as efficacious as reducing the daily dose by 1 mg/kg/day every 2 weeks.64 As with psoriasis, if maintenance therapy is needed, the lowest effective dose should be used.60 Three studies have examined relapse rates after withdrawal of cyclosporine (defined as increase in disease severity to more than 75% of individual baseline score, where topical steroids were used to treat patients after the completion of cyclosporine therapy.57 Granlund et al65 found that 50% of patients relapsed within 2 weeks and 80% relapsed within 6 weeks after discontinuing cyclosporine. Similarly, Atakan and Erdem66 reported that 75% relapsed at 24 weeks postcyclosporine, while Harper et al62 found that 86% had relapsed 9 months after cyclosporine therapy was discontinued. There is typically a worsening of disease on withdrawal of cyclosporine, but the extent of disease and symptom scores remain better than at baseline in the posttreatment period, suggesting a possible sustained remission in some patients.67,68,69 In a metaanalysis by Schmitt et al,61 there was no evidence of a rebound phenomenon on withdrawal of cyclosporine.61,70 One isolated retrospective study, however, did report a rebound phenomenon in a small proportion of patients.71 Interestingly, this coincided with a large increase in serum immunoglobulin E levels during cyclosporine treatment in these patients, with a parallel increase in levels of thymus and activation-regulated chemokine (TARC/CCL17). A shift to a TH2 response, mediated by cyclosporine, was suggested by the authors as a possible cause.72

Pyoderma gangrenosum Cyclosporine was first found to be effective for pyoderma gangrenosum in 1985 and subsequently in numerous case reports. No randomized controlled studies have been reported. Cyclosporine at a dose of 5 mg/kg/day or less with or without corticosteroids is recommended as firstline treatment for pyoderma gangrenosum (grade of recommendation, B).73,74 The response is rapid, with a dramatic improvement observed within 1 to 3 weeks.21 There is, however, a high rate of relapse on

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discontinuation of the drug, with long-term treatment required in a significant proportion of patients. In 2005, Reichrath et al73 published treatment recommendations for the pyoderma gangrenosum based on a literature review of 350 cases. In general, the standard of care is to treat the underlying disease, such as inflammatory bowel disease, that is responsible for the pyoderma gangrenosum. For patients who do not achieve remission of the pyoderma gangrenosum with treatment of the underlying disease or in idiopathic cases (30-50%), systemic treatment with corticosteroids (ie, methylprednisolone 0.5-1 mg/kg/day) or cyclosporine (ie, 5 mg/kg/day) alone or in combination are effective. Pulse steroids (ie, methylprednisolone 1 g/day for 1-5 days) have also been found to be an effective alternative to daily steroid use. Pyoderma gangrenosum lesions show rapid, initial improvement, often within 24 hours. There is currently no standardized protocol for the tapering of methylprednisolone and cyclosporine. Case reports. A case of pyoderma gangrenosum on the thigh of an 8-month-old infant that failed to improve with topical betamethasone valerate and oral prednisolone (2-3 mg/kg/day) was published by McAleer et al.75 When oral prednisolone (3 mg/kg/day) was combined with cyclosporine (5 mg/kg/day) and topical 1% silver sulfadiazine, clinical improvement was seen within the first 3 days and granulation and reepithelization was observed within the first week. Oral prednisolone was slowly tapered after 12 days of cyclosporine therapy. Complete healing of the pyoderma gangrenosum lesion occurred within 6 weeks of therapy. The patient was continued on cyclosporine 5 mg/kg/day for a total of 12 weeks, with slow tapering over a 9month period. A case of periungual pyoderma gangrenosum was published by Reich et al76 in 2009 with worsening noted at a dose of cyclosporine 1.5 mg/kg/day as monotherapy. The lesion improved within 6 weeks with an increase in the dose to 5 mg/kg/day and resolved after 6 months of treatment. The patient was subsequently maintained on cyclosporine 3 mg/kg/day for a total of 2 years. Cyclosporine at a dose of 3 mg/kg/day healed pyoderma gangrenosum ulcers on the medial shin77 and postoperative induced pyoderma gangrenosum.78 The length of treatment and time to resolution was not provided in these case reports. Dyshidrotic eczema Cyclosporine can also be considered a treatment option for severe recalcitrant dyshidrotic eczema. Petersen and Menne´79 published a case report of a patient with severe chronic vesicular hand dermatitis

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who showed a dramatic improvement of his hand eczema within 2 weeks of high-dose cyclosporine therapy (5 mg/kg/day).79 The patient remained disease-free while on cyclosporine 2.5 mg/kg/day. However, when cyclosporine was discontinued because of an elevation of blood pressure, the hand eczema rapidly returned. Reitamo and Granlund80 treated seven patients with chronic hand dermatitis with cyclosporine for 2 to 16 weeks. Six of the seven patients’ hand dermatitis improved with cyclosporine. No improvement was seen at a starting dose of 1.25 mg/kg/day. Five patients improved at a dose of 2.5 mg/kg/day, with three of these being maintained on a lower dose of cyclosporine 1.25 to 2 mg/kg/day. After cyclosporine was stopped, three patients had recurrent disease, three remained in remission, and one was lost to follow-up. Granlund et al81 conducted a randomized control trial comparing cyclosporine 3 mg/kg/day with topical 0.05% betamethasone-17-21 diproprionate (BDP) cream in the treatment of chronic hand dermatitis (type not specified) in 41 patients.81 Both groups had a 57% improvement in the severity of hand dermatitis. In a long-term follow-up published in 1998, of the patients treated with cyclosporine 3 mg/kg/day for 6 weeks, 21 of the 27 patients (80%) continued to have a 54% improvement in the severity of their hand dermatitis compared to baseline 1 year after cyclosporine was discontinued. No long-term follow-up study on the patients treated with BDP cream was reported. Chronic urticaria Guidelines from the British Association of Dermatology have recommended cyclosporine for the treatment of severe chronic idiopathic urticaria unresponsive to antihistamines (quality of evidence I, strength of recommendation A), while stating that optimal patient selection, dose, and duration of treatment remains to be defined.82 The mainstays of treatment for chronic urticaria are antihistamines and short courses of corticosteroids.83,84 Cyclosporine may be used to treat chronic urticaria as an alternative to corticosteroids, either as a steroid-sparing agent or in chronic urticaria that is refractory to corticosteroid therapy.83,84 Furthermore, low-dose cyclosporine treatment (2.5 mg/kg/day) for 4 weeks lowered the serum levels of cytokines IL-2R, IL-5, and tumor necrosis factor-alfa, which are increased in patients with chronic idiopathic urticaria.85 Long-term use, however, is not recommended.26 A randomized controlled trial comparing cyclosporine to placebo revealed that cyclosporine is an effective treatment in chronic idiopathic urticaria.86 Cyclosporine was initiated at 5 mg/kg/day for 13 days,

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then reduced to 4 mg/kg/day from days 14 to 27, and 3 mg/kg/day from days 28 to the conclusion of the study (either 8 or 16 weeks). All patients in the study also received cetirizine 10 mg/day. Improvement in severity score and symptoms was statistically significant compared to placebo after 8 weeks of cyclosporine therapy. A statistically significant improvement in severity scores and symptoms compared to placebo was seen at 16 weeks in both cyclosporine groups; however, no statistical difference was seen at 24 weeks. Also, the patients who completed 16 weeks of cyclosporine therapy required less rescue medication than those who completed 8 weeks of cyclosporine therapy or placebo.86 Another study comparing chronic urticaria treated with cyclosporine 4 mg/kg/day for 4 weeks (n = 10) or 12 weeks (n = 10), found that clinical improvement was dramatic in the first month of treatment of both groups. At 12 weeks, there was no significant difference in the patients who remained on cyclosporine for 12 weeks, compared to those who received cyclosporine for 4 weeks.87 Two thirds of patients with refractory chronic urticaria treated with cyclosporine 3 mg/kg/day for 1 to 3 months achieved a short-term full remission lasting 3 to 6 months. One quarter of patients with refractory chronic urticaria treated with cyclosporine 3 mg/kg/day for 1 to 3 months achieved a longlasting remission. In those patients in whom only short term remission was seen, long-term cyclosporine therapy at a dose of 2 to 3 mg/kg/day was effective at maintaining chronic urticaria in 6 patients, with only one of the six requiring low-dose steroids. Side effects over the 11.6-year period were mild, including mild hirsutism, peripheral neuropathy in two patients, and mild diarrhea in one patient.88 Another double-blind, randomized controlled trial was performed to evaluate the effectiveness of cyclosporine in the treatment of chronic idiopathic urticaria that was unresponsive to standard therapy.89 Forty patients were randomly assigned to receive cyclosporine 5 mg/kg/day for 8 weeks and then 4 mg/kg/day for 8 weeks or cetirizine 10 mg/day. Two weeks into the study, 16 of the patients in the cetirizine arm had severe relapses requiring systemic therapy and were switched to the cyclosporine arm. While taking cyclosporine, 20 patients had relapses—eight of which resolved spontaneously and 12 of which resolved with antihistamines. The patients were followed for 9 months, with 22 having relapses that either resolved spontaneously or with antihistamines. At the end of 16 weeks of cyclosporine treatment, there was a significant drop in the clinical severity score of chronic idiopathic urticaria (P = .002). Cyclosporine was also

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well tolerated, with only three patients needing to have the cyclosporine decreased by 0.5 mg/kg/day because of an increase in their serum creatinine during the first month. A 2-month course of cyclosporine at a dose of 4 mg/kg/day was successfully used in a 12-year-old girl unresponsive to antihistamines and corticosteroids.90 The cyclosporine dose was then decreased every 2 months to a dose of 0.3 mg/kg/day. After 14 months of consecutive cyclosporine therapy, the patient showed no evident clinical lesions or pruritus while still being maintained on low-dose cyclosporine. While this case does illustrate that cyclosporine can induce and maintain remission in childhood chronic urticaria, long-term side effects and relapse rates after withdrawal of cyclosporine are not known. A patient with Schnitzler syndrome—a rare condition associated with chronic urticaria, intermittent fever, and monoclonal immunoglobulin M gammopathy—who was unresponsive to antihistamines and systemic corticosteroids achieved a complete remission of fever and malaise and a partial remission of urticaria after receiving 16 weeks of low-dose cyclosporine (2.5 mg/kg/day).91 Another patient with Schnitzler syndrome refractory to other therapies showed clearance of her urticaria after 1 month of cyclosporine 5 mg/kg/day. She was maintained on cyclosporine 2.6 mg/kg/day with no skin lesions noted at her 6-month follow-up.92 Approximately 75% of patients with chronic urticaria treated with low-dose cyclosporine will have full remission or significant improvement. It is suggested that the most effective treatment is cyclosporine 3 mg/kg/day (given as two doses) for 6 weeks, followed by 3 weeks at 2 mg/kg/day, then 3 weeks at 1 mg/kg/day before discontinuing.93 Behc¸et disease Cyclosporine as monotherapy is an effective treatment for a number of the clinical manifestations of Behc¸et disease, being particularly useful in refractory eye disease, mucocutaneous disease, and arthritis, in addition to being valuable as a steroidsparing agent in this disease.94,95 A randomized, double-blind controlled trial of cyclosporine 10 mg/kg/day versus 1 mg colchicine per day in 96 patients with ocular and mucocutaneous disease revealed that cyclosporine was superior to colchicine for the treatment of aphthous and genital ulcers.96 However, increased numbers of side effects were reported in the cyclosporine group because of the high dose (10 mg/kg/day) used.96,97 Twenty-four patients with mucocutaneous disease were treated with cyclosporine 5 mg/kg/day (reduced to cyclosporine 2.5 mg/kg/day if the serum creatinine

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increased by 33%) for a minimum of 6 months in an open-label study.98 This study showed that cyclosporine improved oral ulcerations (18 patients had improvement, with 6 showing no evident oral ulcerations during the treatment period), genital ulcerations (17 of 21 patients had no genital ulcers during the study, one had a reduction in the genital lesions, one had stable disease, and two had worsening), acneiform lesions (17 of 18 patients had no lesions), erythema nodosumelike lesions (17 of 21 patients had no new lesions), and thrombophlebitis-like lesions (6 of 6 patients had resolution). Also, no new ocular attacks were seen in 11 of 14 patients, and arthralgias improved in three of six patients treated with cyclosporine. Overall, there was a significant response in all clinical features of this difficult to treat disease. A retrospective study of 17 patients showed that cyclosporine preserved or improved the visual acuity in 85% of patients with Behc¸et disease.99 Fifty-two patients (104 eyes) with ocular Behc¸et disease (severe posterior uveitis and repeat attacks of anterior uveitis) were initially treated with cyclosporine 5 mg/kg/day for 2 months and then maintained on 3 mg/kg/day for at least 1 year. Visual acuity improved in 31 eyes (29.8%), deteriorated in 32 eyes (30.8%), and was unchanged in 41 of the 104 eyes. No ocular attacks were seen in 50% of the eyes during the treatment period. Although cyclosporine cannot completely eliminate eye disease in Behc¸et disease, it is currently considered one of the most effective therapies to control uveitits and its complications.100 A case report showed that cyclosporine 3 mg/kg/day lead to the resolution of recurrent cutaneous polyarteritis nodosaelike skin lesions, a rare cutaneous manifestation in Behc¸et disease that was previously unresponsive to prednisolone, methotrexate, and azathioprine. The skin lesions resolved after 2 weeks and did not recur within the 4-month follow-up period.101 While cyclosporine is an effective treatment of the extracerebral manifestations of Behc¸et disease, such as severe ocular disease, mucocutaneous lesions, and arthritis, it is less effective preventing the neurologic involvement as compared to other immunosuppressants, such as azathioprine and interferon-alfa. In a retrospective review of 117 patients with Behc¸et disease, the incidence of new onset neurologic involvement was significantly higher in the cyclosporine group than those on other treatment regimens (6 of 21 vs 0 of 175 episodes; P \ .0001).102 Pityriasis rubra pilaris In 1994, Dicken103 evaluated the treatment response of 75 patients with classic pityriasis rubra

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pilaris (PRP), which frequently progresses to erythroderma, concluding that retinoids were first-line therapy.103 For patients unresponsive to retinoids, he recommended a trial of methotrexate while concluding that cyclosporine was ineffective. However, more recent case reports have indeed shown that cyclosporine may be an effective viable treatment option for the erythrodermic form of PRP. In 2000, Usuki et al104 described three cases of erythrodermic, classic adult type PRP treated with cyclosporine 5 mg/kg/day. Improvement was seen within 2 to 4 weeks of therapy, after which the dose of cyclosporine was gradually tapered. One patient relapsed 2 weeks after the dose of cyclosporine was lowered to 1.2 mg/kg/day. His skin lesions then responded well to an increase to 2 mg/kg/day. He was maintained on this dose for at least 3 years with no subsequent flaring. The second patient was maintained on cyclosporine 2 mg/kg/day for at least 4 years with no relapses. The third patient was maintained on cyclosporine 2 mg/kg/day for 6 months, followed by a slow taper. Cyclosporine was discontinued after 1 year, with a mild relapse thereafter; therefore cyclosporine (dose not specified) was resumed for an additional 3 months. No additional follow-up was noted. Weztig et al105 in 2003 reported a case of a 4-yearold boy with erythrodermic juvenile PRP treated with cyclosporine 3 mg/kg/day. Significant regression of the erythroderma was seen within 5 weeks of therapy. The dose of cyclosporine was then gradually tapered and discontinued. Eight months postecyclosporine therapy, no recurrence of PRP had occurred. Dermatomyositis Dermatomyositis is traditionally treated with highdose prednisone combined with steroid-sparing agents, such as methotrexate or azathioprine. Cyclosporine can be used in cases unresponsive to this standard regimen.106,107 There is no agreement as to the optimum regimen or combination of immunosuppressive agents to treat dermatomyositis.108 Cyclosporine has been proposed as a second-line agent for both adult and juvenile forms of the disease in those unresponsive to other immunosuppressants, such as methotrexate or azathioprine.108,109 Combined therapy with cyclosporine and corticosteroids has been shown to be effective for the management of lung and esophageal involvement associated with dermatomyositis. Cyclosporine at a dose of 1 mg/kg/day combined with prednisone for 1 month was effective in treating dermatomyositis with esophageal involvement, with cyclosporine acting as a steroid-sparing agent, allowing the dose

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of prednisone to be tapered gradually.110 The interstitial lung disease and pneumomediastinum associated with dermatomyositis improved after 2 months of cyclosporine 1.8 mg/kg/day and prednisone 40 mg/day.111 Cyclosporine doses of more than 200 mg/day and prednisone improves the prognosis of patients with dermatomyositis associated with subacute interstitial pneumonia when initiated within 15 days of diagnosis.112 A multicenter retrospective study of 53 patients with interstitial lung disease associated with dermatomyositis showed that patients treated with a combination of cyclosporine and corticosteroids had favorable early and long-term outcomes except for those patients with acute interstitial lung disease. In patients with acute interstitial lung disease, patients who received the combination therapy initially had a higher survival rate than those who initially received corticosteroids alone.113 Pemphigus vulgaris Systemic steroids are traditionally used in the initial stages of pemphigus vulgaris. Before the advent of rituximab,114 immunosuppressants such as azathioprine, cyclophosphamide, methotrexate, dapsone, and cyclosporine were used as steroidsparing agents in the treatment of pemphigus vulgaris, once an initial response to systemic steroids was obtained.115 Several studies have examined the use of cyclosporine as a steroid-sparing agent in the treatment of pemphigus vulgaris.116-118 The British Association of Dermatology guidelines for the management of pemphigus class cyclosporine as grade C for strength of recommendation with a level I quality of evidence, and therefore do not recommend it as an adjuvant drug.119 This is based on a randomized controlled trial which showed no additional benefit and more side effects compared to methylprednisolone alone.120 In a retrospective review of 14 patients with moderate to severe pemphigus vulgaris who received a combination of prednisone and cyclosporine 2.5 to 3 mg/kg/day, the average time to clinical remission was 8.1 6 11.8 months. Cyclosporine was discontinued 3 months after clinical remission was achieved. Forty-three percent of patients treated with a combination of prednisone and cyclosporine remained free of clinic relapse 5 years after discontinuation of therapy. The safety profiles were similar when compared to prednisone combined with cyclophosphamide and prednisone combined with azathioprine. However, cyclophosphamide (1.1-1.5 mg/kg/day) combined with prednisone was found to be slightly more effective (the average time to clinical remission was 6.8 6 10.5 months, with the

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percentage of patients who remained clinically free of disease being 55%).121 Cyclosporine 1 to 3 mg/kg/day controlled acute disease in six patients with moderate to severe pemphigus vulgaris uncontrolled with conventional therapies. Within 8 to 10 weeks after cyclosporine therapy was initiated, the lesions began to heal with no occurrence of new lesions noted. The dose of cyclosporine was gradually decreased over an 8- to 12-month period after the patients were clear for 3 to 4 months. No serious side effects occurred, and no recurrences were seen 3 years after discontinuing treatment.115 Epidermolysis bullosa acquisita Epidermolysis bullosa acquistita (EBA) has a prolonged course and is often difficult to treat. The conventional treatment approach includes highdose corticosteroids and corticosteroid steroidesparing agents. Case reports of EBA treated with cyclosporine have shown favorable results. Engineer et al122 reviewed nine case reports of EBA treated with cyclosporine that were published between 1987 and 1993.122 Eight of the nine patients were previously treated with oral corticosteroids, and most were treated with other adjuvant agents, such as methotrexate, azathioprine, gold, dapsone, and cyclophosphamide without significant clinical response. The daily doses of cyclosporine ranged from 5 to 9 mg/kg/day (mean dose, 7 mg/kg/day). The duration of treatment ranged from 1 to 12 months. Four of the nine patients received cyclosporine as a monotherapy, with the remaining five receiving cyclosporine in addition to prednisone (30100 mg/day; mean, 48 mg/day). All nine patients had a significant clinical improvement. There was an improved healing time of preexisting bullae, cessation of new bullae formation, and a marked steroidsparing effect. Two of the patients discontinued cyclosporine because of side effects: one patient had urticaria, diarrhea, ascites, and elevated serum creatinine (cyclosporine 7.5 mg/kg/day) and the other patient had possible pancreatitis (cyclosporine 9 mg/kg/day). A case report showed that cyclosporine 4 mg/kg/day combined with prednisolone 80 mg/day lead to the improvement of EBA that was previously unsuccessfully treated with prednisolone and dapsone. The patient flared at 2 months, necessitating an increase in the cyclosporine dosage to 5 mg/kg/day for 6 months to maintain control of the disease. At the 19-month follow-up, the patient was being maintained on cyclosporine 4 mg/kg/day and prednisolone 10 mg/kg/day with one bulla present and no adverse side effects.123

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Another case report of a patient with EBA and acquired factor VIII deficiency previously unresponsive to prednisone, colchicine, and pulse cyclophosphamide revealed significant improvement of both diseases after 3 weeks of therapy with cyclosporine 4 mg/kg/day and prednisone 60 mg/day. The patient was maintained on cyclosporine 4 mg/kg/day for 11 months with slow tapering and discontinuation of the prednisone. The patient was maintained on cyclosporine 1.5 mg/kg/day for 2 years without relapse of either disease or evidence of significant side effects.124 Photodermatoses Chronic actinic dermatitis. A case of chronic actinic dermatitis that was unresponsive to betacarotene and photoprotection rapidly improved on cyclosporine 4.5 mg/kg/day. The patient had clinical resolution after 1 month of treatment, after which the dose of cyclosporine was gradually decreased, with rapid worsening noted at cyclosporine 1 mg/kg/day. The patient was maintained on cyclosporine 1.5 mg/kg/day with no evident skin lesions or pruritus at the 3-year follow-up period.125 Two cases of chronic actinic dermatitis that were unresponsive to high-dose steroids responded rapidly to cyclosporine 4 mg/kg/day for 3 months, with improvement of the pruritus and skin lesions. While one patient had recurrent lesions in the summer, the other had no flares evident during the 3-year followup period.126 Polymorphic light eruption. Cyclosporine can be used as a prophylactic treatment for moderate to severe polymorphic light eruption (PMLE). A case report of a patient with psoriasis and PMLE showed that cyclosporine 3.3 mg/kg/day used to treat the patient’s psoriasis also prevented exacerbations of her PMLE.127 Three additional case reports revealed that cyclosporine 3 to 4 mg/kg/day 1 week before travel to a sunny climate with discontinuation upon return prevented flares of PMLE without complications.128 Solar urticaria. A case of treatment-resistant solar urticaria improved with cyclosporine 4.5 mg/kg/day. The patient was able to tolerate the sun for at least an hour with minimal urticaria as opposed to a few minutes without cyclosporine therapy. The solar urticaria returned once cyclosporine was discontinued. Cyclosporine may be useful in short courses in cases where treatment is only necessary during the summertime.129 Lichen planus There are no established guidelines for the treatment of lichen planus with cyclosporine. Doses of up

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to 6 mg/kg/day have been used in studies to treat lichen planus, with resolution of cutaneous lesions within 1 to 8 weeks and sustained remission for up to 10 months.130-132 A maximum dose of 5 mg/kg/day is now recommended. Mucosal forms tend to be more resistant to treatment, requiring higher doses (not exceeding 5 mg/kg/day) for adequate control. Oral cyclosporine is the treatment of choice for disseminated lichen planus or lichen planus resistant to systemic corticosteroids and retinoids.133 On average, pruritus improves in 2 weeks, with clearing of the lesions in 6 weeks.133 Cyclosporine is also shown to be effective in the treatment of erosive lichen planus, with two case reports published by Schepis et al134 in 2008. One patient showed rapid improvement of his erosive lichen planus in the pretibial and inguinal region on cyclosporine 3 mg/kg/day with complete remission achieved at 2 months. Once the cyclosporine was discontinued, the patient had a less severe flare of his erosive lichen planus and was maintained on cyclosporine 2.5 mg/kg/day and oral steroids in rotation. Another patient showed improvement of her plantar erosive lichen planus with a combination of cyclosporine 2.5 mg/kg/day and topical steroids twice daily and was maintained on cyclosporine 2 mg/kg/day with no evident recurrence. Another case report of plantar erosive lichen planus treated with cyclosporine described rapid improvement at an initial dose of 4.5 mg/kg/day for a month and maintenance at a dose of 3 mg/kg/day for 1 year.135 However, once cyclosporine was discontinued, the lesions recurred. A repeat course of cyclosporine was administered, followed by a split-thickness skin graft. The patient was maintained on cyclosporine 3 mg/kg/day 8 months after the split-thickness skin graft was placed. Ten months after cyclosporine was discontinued, the foot was healed and pain-free. While these case reports show that cyclosporine causes significant but only temporary improvement of erosive lichen planus, it may be used to control its acute phase so that adjuvant therapies such as skin grafting may be performed. A male child with refractory erosive oral lichen planus was treated with systemic corticosteroids (30 mg/day for 6 weeks) and cyclosporine 4 mg/kg/day for 3 months.136 On this regimen, the child was noted to have remissions and exacerbations, with the duration of the remissions and the treatment used for the exacerbations not being specified in this case report. A case report of palmoplantar lichen planus with umbilicated papules unresponsive to topical steroids improved on cyclosporine 3.5 mg/kg/day.137 The patient had a reduction in his pruritus after 2 weeks

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of oral cyclosporine and improvement in his skin lesions after 4 weeks of therapy. After 4 weeks of cyclosporine 3.5 mg/kg/day, the cyclosporine was gradually tapered and discontinued at 8 weeks. A case report showed that oral cyclosporine at dose of 3 mg/kg/day for 3 months has been used successfully to treat actinic lichen planus refractory to other treatments.138 Topical cyclosporine may be effective in the treatment of oral lichen planus, as discussed in part II of this review. Lichen planopilaris Several case reports have suggested that cyclosporine may be effective in the initial phases of lichen planopilaris before severe follicular damage occurs. A dose of 300 mg/day (3-5 mg/kg/day) has been used to successfully treat lichen planopilaris. Another patient with psoriasis and lichen planopilaris overlap was treated with cyclosporine 3 mg/kg/day and topical betamethasone valerate 0.12% foam twice daily. After 2 weeks on cyclosporine, a reduction in the perifollicular eythema and pruritus with no reduction in scale was noted. No additional follow-up was performed.139 In 2003, Mirimani et al140 published a series of three patients with lichen planopilaris treated successfully with oral cyclosporine. In all three patients, cyclosporine was started at 300 mg/day (3-5 mg/kg/day). Maximal clinical response in signs and symptoms to therapy was noted between 3 and 5 months, with improvement in pruritus, pain, and burning and no clinical activity of their disease being noted (no perifollicular erythema or scaling). Fine hair regrowth was noted while on cyclosporine; however, the hair growth reversed 1 to 4 months after therapy. Twelve months after cyclosporine therapy, these patients were symptom free with minimal to no progression of their disease. A patient with Graham Little-Piccardi-Lassuerur syndrome, a rare lichenoid disorder associated with scarring alopecia and follicular hyperkeratotic papules, had a reduction in perifollicular erythema and follicular hyperkeratotic papules after a 3-month course of cyclosporine at 4 mg/kg/day.141 Three months after cyclosporine therapy, the patient had additional areas of hair regrowth in the scarring patches and more consistent improvement of the follicular papules. Prurigo nodularis Currently, treatments for prurigo nodularis include topical antipruritics, topical steroids, and intralesional kenalog, followed by psoralen plus ultraviolet A light phototherapy, ultraviolet B light

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therapy, cryotherapy, topical vitamin D3, and capsacin. Cyclosporine may be considered a second-line agent, with doses of 3.5 to 4 mg/kg/day for 24 to 36 weeks having been shown to significantly improve the prurigo nodularis lesions and reduce pruritus.142 Pruritus is reduced after 2 weeks of cyclosporine therapy, thereby allowing for a potential improvement in the prurigo nodules to heal.142,143 Severe alopecia areata Although systemic cyclosporine has shown efficacy in the treatment of alopecia areata, withdrawal of the drug results in significant hair loss.144 Guidelines on the treatment of alopecia areata have concluded that the cosmetically worthwhile response rate is likely too low to justify the risks (strength of recommendation D, quality of evidence III).26,145 Several studies have examined the efficacy of cyclosporine in the treatment of severe alopecia areata. Fifteen patients were treated with cyclosporine 5 mg/kg/day for 6 to 12 months; one patient discontinued because of hypertension. Vellus hair regrowth was seen in 12 of the 14 patients by 1 to 3 months. Of these, five had cosmetically acceptable partial hair regrowth ([70% hair regrowth) and two patients had complete hair regrowth. Of the two with complete hair regrowth, one had recurrence of her disease 2 months after cyclosporine was discontinued and the other had no evidence of disease 4 years after treatment.146 The combination of systemic cyclosporine and methylprednisolone may also lead to improvement in alopecia areata. Forty-six patients were treated with a combination of cyclosporine 200 mg twice daily and methylprednisolone (24 mg twice a day for men, 20 mg twice a day for women, and 12 mg twice a day for children.).147 The dose of methylprednisolone was decreased weekly by 4 mg/day and cyclosporine was gradually decreased by 50 mg/day weekly or biweekly once methylprednisone was discontinued. The total treatment time ranged between 7 and 14 weeks. Three patients discontinued the treatment because of side effects. Thirty-eight patients had significant hair regrowth, with five patients considered treatment failures. During the 12-month observation period, nine of the 38 patients (24%) with significant hair regrowth relapsed. Six patients with alopecia totalis and 12 patients with alopecia universalis were treated with monthly intravenous methylprednisolone in doses of 500 mg for 3 days and oral cyclosporine (2.5 mg/kg/day for 5-8 months).148 An adequate response—defined as more than 70% of hair regrowth in the affected area—was seen in six patients (33%; 3 with alopecia

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totalis and 3 with alopecia universalis). No relapses were seen in patients with an adequate response at 8 months posttreatment, and no serious side effects occurred during the treatment phase. Cyclosporine 5 mg/kg/day combined with prednisone 5 mg/day showed mixed results. In one case series of eight patients treated with cyclosporine 5 mg/kg/day (decreased by 1 mg/kg/day after 10 weeks, and by 0.5 mg/kg/day every 6 weeks if more that 75% regrowth of terminal hairs was noted) and prednisone 5 mg/day for 24 weeks, two of the eight patients had more than 75% regrowth of cosmetically acceptable terminal hairs after 24 weeks of therapy, but hair loss recurred after treatment was discontinued. Three patients discontinued the study because of side effects (edema, hypertension, abnormal liver function tests, and abnormal lipids).149 A child with Down syndrome and alopecia areata treated with cyclosporine 3 mg/kg/day for 6 months had hair regrowth noted at the end of the treatment period, but a relapse within 3 months.150 In contradistinction, there have also been seven case reports of patients who developed alopecia areata after solid organ transplant while on cyclosporine. The average time to the development of alopecia areata was 3.7 years after transplant and the average dose of cyclosporine was 4.6 mg/kg/day.151 One patient with atopic dermatitis treated with cyclosporine 3.5 mg/kg/day also developed alopecia areata.152 Benign familial pemphigus (Hailey-Hailey disease) A case report showed that recalcitrant benign familial pemphigus improved rapidly with a combination of cyclosporine (1.2 mg/kg/day) and acitretin 10 mg a day with the patient remaining in clinical remission on this regimen at 8 months. However, antihypertensive therapy was required.153 Another case report showed that benign familial pemphigus improved on cyclosporine 2.8 to 3.4 mg/kg/day. This response was maintained over a 24-week period with gradual deterioration noted once the treatment was discontinued.154 Eosinophilic pustular folliculitis (Ofuji disease) First-line treatments of eospinophilic pustular follicular includes topical steroids and topical and oral indomethacin. Second-line therapies include, cetirizine, metronidazole, itraconazole, and topical permethrin. Cyclosporine may be considered as a third-line therapy.155

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A case series of six patients with eosinophilic pustular folliculitis revealed that cyclosporine in a dosage range of 100 to 150 mg daily for 2 to 12 weeks was effective in all six patients treated.156 No longterm follow-up was performed.

Hidradenitis suppurativa A case report described marked improvement in a patient’s perianal hidradenitis suppurativa after cyclosporine 4.5 mg/kg/day was added to treat the patient’s concurrent pyoderma gangrenosum.157 After 8 months of cyclosporine 4.5 mg/kg/day, healing of discharging sinuses and diminished pain was noted. Fifteen months after cyclosporine was initiated, the patient was noted to have stable disease on continuous cyclosporine therapy combined with continuous broad-spectrum oral antibiotics. The patient’s quality of life improved, and no adverse side effects were noted. Cyclosporine 4 mg/kg/day for 3 months prevented flares in a patient with a 20-year history of hidadenitis suppurativa previously treated with minocycline, clindamycin, claritromycin, oral steroids, intravenous steroids, intralesional steroids, and surgical excision.158 At 7 months of follow-up, the patient was being initiated on cyclosporine 2 mg/kg/day with no significant episodes of inflammation. Cyclosporine 3 mg/kg/day lead to a marked clinical response in refractory acne vulgaris and hidradenitis suppurativa that was previously treated with minocycline, surgical excision, isotretinoin, prednisolone, and lympecycline.158 After 8 weeks of cyclosporine 3 mg/kg/day, the patient was weaned off of prednisolone. Cyclosporine was discontinued after 4 months of therapy because of the good response. A mild relapse occurred 4 months after cyclosporine was discontinued but rapidly improved once cyclosporine was recommenced.

Scleroderma In small, uncontrolled, retrospective studies, cyclosporine has produced significant skin softening in up to 50% of patients with scleroderma, and resolution of digital infarcts in some patients.159,160 The European League Against Rheumatism (EULAR) Scleroderma Trials and Research Group has recently published a set of recommendations for the treatment of systemic sclerosis, and suggests a need for further evaluation of cyclosporine.161 Extreme caution is advised when using cyclosporine because it may potentially worsen hypertension or renal disease associated with systemic sclerosis.

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CONCLUSION Cyclosporine continues to play an important role in the field of dermatology. We strongly recommend cyclosporine for short-term ‘‘rescue’’ treatment of psoriasis and atopic dermatitis in appropriate patients. Although randomized controlled trials have not been undertaken, multiple case reports have also shown excellent results when cyclosporine is used for the treatment of pyoderma gangrenosum. We also recommend cyclosporine for treatment of refractory chronic idiopathic urticaria and cyclosporine in combination with corticosteroids for the treatment of dermatomyositis with esophageal and pulmonary involvement. Although cyclosporine is effective in the treatment of Behc¸et disease, it is not as effective as other therapeutic agents at preventing neurologic symptoms, making initial therapy with agents such as azathioprine and interferon-alfa more logical. Cyclosporine has been used successfully as a steroid-sparing agent for the treatment of bullous disorders such as pemphigus vulgaris and epidermolysis bullosa acquisita in the past. However, the advent of rituximab has changed the paradigm of treatment of these bullous diseases, and cyclosporine is therefore not recommended as a first-line treatment. The use of cyclosporine for the treatment of severe alopecia areata is controversial, with case reports of patients actually developing alopecia areata despite treatment with cyclosporine for other purposes. Short-term treatment in healthy patients with severe alopecia may be considered. Case reports have also suggested that cyclosporine is useful in the treatment of PRP, dyshidrotic eczema, photodermatoses, erosive and disseminated lichen planus, lichen planopilaris, prurigo nodularis, benign familial pemphigus, eosinophilic pustular folliculitis, hidradenitis suppurativa, and scleroderma. Although cyclosporine may be a treatment option in patients who failed first- and second-line therapies for the above diseases, further controlled studies will need to be done before we can recommend its use. Part II of this review addresses the dosing and monitoring guidelines of cyclosporine, its contraindications, possible drug interactions, adverse effect profile, and the use of cyclosporine during pregnancy and childhood. REFERENCES 1. Borel JF, Feuer C, Gubler HU. Biological effects of cyclosporine A: a new anti-lymphocyte agent. Agents Act 1976;6: 468-75. 2. Calne RY, White DJ, Thiru S, Evans DB, McMaster P, Dunn DC, et al. Cyclosporin A in patients receiving renal allografts from cadaver donors. Lancet 1978;2:1323-7. 3. Mueller W, Hermann B. Cyclosporin A for psoriasis. N Engl J Med 1979;301:555.

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