The use of cyclosporine in dermatology: Part IKarrie T.   Amor , MD

, 

Caitriona   Ryan , MBBCh, BAO

, 

Alan   Menter , MD

Abstract Full Text PDF Images References

Article OutlineI. Abstract

II. History III. Mechanism of action IV. Clinical uses of cyclosporine and regimens

A. Psoriasis

1. Intermittent short-term therapy

2. Rescue therapy

3. Long-term therapy

4. Combination therapy

5. Rotational therapy

B. Psoriatic arthritis

C. Atopic dermatitis

D. Pyoderma gangrenosum

1. Case reports

E. Dyshidrotic eczema

F. Chronic urticaria

G. Behçet disease

H. Pityriasis rubra pilaris

I. Dermatomyositis

J. Pemphigus vulgaris

K. Epidermolysis bullosa acquisita

L. Photodermatoses

1. Chronic actinic dermatitis

2. Polymorphic light eruption

3. Solar urticaria

M. Lichen planus

N. Lichen planopilaris

O. Prurigo nodularis

P. Severe alopecia areata

Q. Benign familial pemphigus (Hailey-Hailey disease)

R. Eosinophilic pustular folliculitis (Ofuji disease)

S. Hidradenitis suppurativa

T. Scleroderma

V. Conclusion VI. References

VII. Copyright

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.

Learning objectivesAfter 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 Capsule Summary

Back to Article OutlineHistory Key points•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 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 study to investigate the efficacy of cyclosporine in rheumatoid arthritis and psoriatic arthritis.3 The original formulation of cyclosporine (Sandimmune; Novartis, East Hanover, NJ) was approved by the United States Food and Drug Administration (FDA) for the prevention of transplant rejection in 1983. In 1995, Neoral (Novartis), a microemulsion formulation of cyclosporine that is more bioavailable and more consistently absorbed, was approved by the FDA for the prevention of transplant rejection. Neoral was then approved for the treatment of rheumatoid arthritis and psoriasis in 1997. Since then, the FDA has not approved cyclosporine for the treatment of other clinical indications in dermatology, but it has been approved for use in atopic dermatitis in other countries.

Structure. Cyclosporine is a cyclic polypeptide immunosuppressant agent consisting of 11 amino acids (Fig 1).4 It is produced as a metabolite by the fungus species Beauveria nivea.

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

Back to Article OutlineMechanism of action Key points•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, 6, 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, interferon-gamma, and granulocyte-macrophage colony-stimulating factor (GM-CSF).5, 7 Consequently, cyclosporine depletes lymphocytes and macrophages in the epidermis and dermis8 and inhibits the activation of T cells, natural killer cells, and antigen-presenting cells. Cyclosporine also inhibits keratinocyte hyperproliferation,9 inhibits the release of histamine from mast cells, and downregulates the expression of cellular adhesion molecules on dermal capillary endothelium.10

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Download to PowerPoint 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 CsA–CpN 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-ATc–NF-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.

© Cambridge Journals, reproduced with permission.6

Back to Article OutlineClinical uses of cyclosporine and regimens Key points•Cyclosporine is useful for the short-term treatment of psoriasis and atopic dermatitis

•Multiple case reports have shown cyclosporine to have excellent results when used for the treatment of pyoderma gangrenosum

•Cyclosporine is useful for the treatment of refractory chronic idiopathic urticaria

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.12Subsequently, a multitude of dose-finding studies have been performed in order to elucidate the optimal and lowest effective dose of cyclosporine that achieves clearance with minimal toxicity.13, 14, 15, 16, 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 mg/kg/day at 2- to 4-week intervals, to a maximum of 5 mg/kg/day (level IV evidence).11Tachyphylaxis 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 IV evidence). 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.25Current 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 IV evidence).11, 21 Five schedules are available for the use of cyclosporine in psoriasis (Table I).

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Psoriasis treated with cyclosporine. A, Precyclosporine therapy. B, Postcyclosporine therapy.Table I. Cyclosporine therapy for dermatologic diseases

Disease CsA dose

Duration of treatment

Response

Time to relapse after discontinued

Other drugs

Comments

Reference(s)

Psoriasis 12-16 wks, 12 mos maximum

Excellent

Average 111 days; however, 30% had no relapse

11, 12, 13, 14,15, 16, 17, 18,19,2,23, 24, 25, 26

Disease CsA dose

Duration of treatment

Response

Time to relapse after discontinued

Other drugs

Comments

Reference(s)

6 mos after CsA discontinued

A. Intermittent short-term therapy

2.5-5 mg/kg/day for 12-16 wks, course repeated when relapse occurs

11, 26, 27, 28,29, 30, 31

B. Rescue therapy

5 mg/kg/day for 12-16 wks for flaring of disease

11, 26, 27, 32

C. Long term therapy

<5 mg/kg/day for up to 1 y; reducing dose to lowest effective

10, 19, 31, 32,33, 34, 35, 36,37,

D. Combinat

Corticosteroids,

9, 33, 36, 40,41, 42, 43, 44

Disease CsA dose

Duration of treatment

Response

Time to relapse after discontinued

Other drugs

Comments

Reference(s)

ion therapy

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

E. Rotational therapy

Can minimize CsA toxicity

26, 46

Psoriatic arthritis

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

6-12 mos

Very good

MTX 15 mg/wk, occasionally

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

49, 50, 51, 52,53, 54

Disease CsA dose

Duration of treatment

Response

Time to relapse after discontinued

Other drugs

Comments

Reference(s)

response

Atopic dermatitis

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

12-16 wks, 12 mos max

Excellent

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

Used for short treatment of severe, atopic dermatitis that cannot be controlled with topical therapy. Approved for this indication in Europe and the UK

21, 55, 56, 57,58, 59, 60, 61,62,5,66, 67, 68, 69,70, 71, 72

Pyoderma gangrenosum

5 mg/kg/day

>6 mos Excellent

Methylprednisolone (0.5-1 mg/kg/day, or pulse treatment 1 g/day for 1-5 days) usually given concurrently

21, 73, 74, 75,76, 77, 78

Dyshidrotic eczema

2.5-3 mg/kg/day

6 wks, up to 16 wks

Equivalent

77% of patients continued

CsA equivalent to

79, 80, 81

Disease CsA dose

Duration of treatment

Response

Time to relapse after discontinued

Other drugs

Comments

Reference(s)

to have a 54% improvement at 1 y

BDP cream

Chronic urticaria

4 mg/kg/day

12-16 wks

Very good

33% at 3-6 mos, relapse less severe

Cetirizine 10 mg/day, occasionally concurrently

Used to treat chronic urticaria as a steroid sparing agent or in cases refractory to corticosteroids

83, 84, 85, 86,87, 88, 89, 90,91,

Behçet disease

5 mg/kg/day

>6 mos Very good

Prednisone, occasionally

Used for refractory eye disease, topical steroid–resistant mucocutaneous disease, and arthritis. Poor prevention of neurologic involvement

94, 95, 96, 97,98, 99, 100,101, 1023,104

Disease CsA dose

Duration of treatment

Response

Time to relapse after discontinued

Other drugs

Comments

Reference(s)

Pityriasis rubra pilaris

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

>8 mos Mixed

Used in erythrodermic classic adult and erythrodermic juvenile PRP

103, 104, 105,106, 107, 108,1091,112, 113

Dermatomyositis

1-1.8 mg/kg/day, >200 mg/day

Very good

Prednisone 40 mg/day

Used in cases not responsive to prednisone combined with MTX or azathioprine. Effective for lung and esophageal involvement

106, 107, 108,109, 110, 111,112

Pemphigus vulgaris

1-3 mg/kg/day

8 mos ± 11.8 mos

Good, but better treatment options available

43% free of relapse after combination therapy with cyclosporine and prednisone 5 y after

Prednisone, usually given concurrently

Used as a steroid sparing agent

114, 115, 116,117, 118, 119,120

Disease CsA dose

Duration of treatment

Response

Time to relapse after discontinued

Other drugs

Comments

Reference(s)

discontinuation of therapy

Epidermolysis bullosa acquisita

4-5 mg/kg/day

1-24 mos

Good, but better treatment options available

Prednisone, usually given concurrently

Used as a steroid sparing agent

122, 123, 124

Photodermatoses

A. Chronic actinic dermatitis

4-4.5 mg/kg/day

Good 125, 126

B. Polymorphic light eruption

3-4 mg/kg/day

May be given 1 wk before sun exposure, and discontinued upon return

Good 127, 128

C. Solar urticaria

4.5 mg/kg/day

Short courses during summer

Flares once cyclosporine discontin

129

Disease CsA dose

Duration of treatment

Response

Time to relapse after discontinued

Other drugs

Comments

Reference(s)

months ued

Lichen planus

3-4.5 mg/kg/day

2-3 mos

Good Prednisone, occasionally topical steroids

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

130, 131, 132,133, 134, 135,136

Lichen planopilaris

3-5 mg/kg/day

3-5 mos

Good Symptom free, stable disease at 12 mos postcyclosporine

CsA may be effective in the initial phases before severe follicular damage

139, 140, 141

Disease CsA dose

Duration of treatment

Response

Time to relapse after discontinued

Other drugs

Comments

Reference(s)

occurs

Prurigo nodularis

3.5-4 mg/kg/day

6-9 mos

Good 142, 143

Severe alopecia areata

5 mg/kg/day

2-12 mos

Mixed

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

Methylprednisolone (pulse and daily dosing), prednisone

Eight case reports of patients who developed alopecia areata while on CsA for solid organ transplant, and atopic dermatitis

26, 144, 145,146, 147, 148,149,1,152

Benign familial pemphigus (Hailey-Hailey)

1.2-3.4 mg/kg/day

6-8 mos

Good Acitretin 10 mg/day, occasionally

153, 154

Eosinophilic pustular folliculitis

100-150 mg/day

2-12 wks

Good 155, 156

Hidradenitis suppurati

4-4.5 mg/kg/day

Good Prednisolone, broad spectrum

157, 158

Disease CsA dose

Duration of treatment

Response

Time to relapse after discontinued

Other drugs

Comments

Reference(s)

va antibiotics

Scleroderma

May potentially worsen hypertension or renal disease associated with systemic sclerosis

159, 160, 161

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.

†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.

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, 29, 30 In a study of 400 patients with severe psoriasis, 80% of patients 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 24-month 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% achie-ved 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, 34, 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 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 analogues40for 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, 42, 43, 44 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, 47While 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 Anti–tumor 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 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, double-blind, 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 methotrexate-placebo 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 ensuing 3 months to a dose of 1.5 mg/kg/day where possible has been suggested.21, 57,58, 59, 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 (2.5-3 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, 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, 70One isolated retrospective study, however, did report a rebound phenomenon in a small proportion of patients.71Interestingly, 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 first-line 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 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 9-month 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 Menné79published a case report of a patient with severe chronic vesicular hand dermatitis 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.85Long-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, 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 long-lasting 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 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

Behçet disease Cyclosporine as monotherapy is an effective treatment for a number of the clinical manifestations of Behçet disease, being particularly useful in refractory eye disease, mucocutaneous disease, and arthritis, in addition to being valuable as a steroid-sparing 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 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 nodosum–like 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 Behçet disease.99 Fifty-two patients (104 eyes) with ocular Behçet 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 Behçet 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 nodosa–like skin lesions, a rare cutaneous manifestation in Behçet 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 Behçet 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 Behçet 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 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-year-old 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 post–cyclosporine therapy, no recurrence of PRP had occurred.

Dermatomyositis Dermatomyositis is traditionally treated with high-dose 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.108Cyclosporine 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 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,114immunosuppressants such as azathioprine, cyclophosphamide, methotrexate, dapsone, and cyclosporine were used as steroid-sparing 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, 117, 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 ± 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 ± 10.5 months, with the 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 high-dose corticosteroids and corticosteroid steroid–sparing 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 (30-100 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 steroid-sparing 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

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 beta-carotene 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 follow-up 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 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, 131, 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.135However, 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 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 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 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

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 long-term 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.Back to Article OutlineConclusion 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 Behçet 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.

Back to Article Outline

The use of cyclosporine in dermatology: Part II Caitriona   Ryan , MBBCh, BAO

, 

Karrie T.   Amor , MD, 

Alan   Menter , MD Abstract Full Text

PDF Images References Article Outline

I. Abstract II. Pharmacokinetics

A. Absorption 1. Original and microemulsion formulations

B. Distribution C. Metabolism and elimination D. Body weight issues E. Ethnic variation F. Localized administration   of   cyclosporine

III. Contraindications IV. Drug interactions V. Adverse effects

A. Renal dysfunction 1. Vascular dysfunction 2. Tubular dysfunction

B. Chronic nephrotoxicity 1. Vasculopathy 2. Tubulopathy

C. Recommendations D. Hypertension E. Recommendations F. Malignancy potential G. Neurologic side effects H. Gastrointestinal side effects I. Gingival hyperplasia J. Cutaneous side effects K. Infections L. Other side effects M. Hyperlipidemia N. Recommendations O. Other laboratory abnormalities

VI. Monitoring A. Screening and history B. Baseline laboratory investigations C. Regular follow-up investigations D. Annual investigations E. Cyclosporine   serum concentrations F. Vaccinations

VII. Pregnancy A. Lactation

VIII. Pediatric   use A. Discussion and our personal 25-year experience   of   cyclosporine   usage

IX. Conclusion X. Acknowledgment XI. References

XII. Copyright Cyclosporine is highly effective in the treatment of a multitude of dermatoses. Concern over its side effect profile has limited its use in dermatology. Adverse effects are, for the most part, dose dependent and related to duration of therapy. Using the recommended monitoring protocols results in a significant decrease in the incidence of cyclosporine-related toxicities. This article provides a comprehensive review of the pharmacokinetics of cyclosporine, potential drug interactions, adverse effects, and recommendations for monitoring in patients treated with cyclosporine. The use of cyclosporine in pregnancy and in the pediatric population is also addressed.

Learning objectivesAfter completing this learning activity, participants should be familiar with the monitoring guidelines of cyclosporine, its contraindications, its possible drug interactions, its adverse effect profile, and its use in pregnancy and the childhood and adolescent populations.

Key words: atopic dermatitis, calcineurin inhibitors, cyclosporine, drug interactions, pharmacokinetics, psoriasis 

Capsule Summary

Back to Article OutlinePharmacokinetics Key points•The specific brand of cyclosporine should be specified at each visit because of differences in bioavailability between the original and microemulsion formulations of cyclosporine (level IB evidencea)

•A higher serum concentration of cyclosporine results when the drug is administered before rather than after meals

•Ideal body weight rather than actual body weight should be used to calculate the required dose (Level IIB evidence)

Absorption Cyclosporine is a lipophilic molecule that is poorly absorbed when administered orally, with wide variations in inter- and intrapatient bioavailability, ranging from 1% and 89%.1, 2 Bile salts are required to facilitate absorption,3 which occurs within

approximately 30 minutes, while peak serum concentration (cmax) occurs 2 to 4 hours after the dose.2, 4, 5

Original and microemulsion formulations 

Because of the variability in absorption of the original formulation of cyclosporine (Sandimmune; Novartis, East Hanover, NJ), a more hydrophilic microemulsion (Neoral; Novartis) was developed that allowed greater bioavailability and less intraindividual fluctuation in serum concentration of the drug.6, 7 A randomized, double-blind study comparing the two formulations showed a more rapid response, higher remission rates in the first 8 weeks, and a 10% lower dose to maintain efficacy with the microemulsion.8 These preparations of cyclosporine are not bioequivalent. Most patients who have normal absorption of the original formulation have equivalent absorption of the microemulsion, while a small subset of patients who absorb the original formulation poorly have an increased absorption of the microemulsion compared to the original, leading to an increased serum cyclosporine concentration. When converting patients from the original cyclosporine formulation to the microemulsion formulation, a 1:1 mg:mg dose conversion is used in order to maintain steady-state trough concentration in the target therapeutic range.1, 6 Particular caution should be exercised in those changing from high doses of the original formulation to the microemulsion, with blood pressure and serum creatinine being monitored more closely in the subsequent weeks. When used in organ transplantation, serial serum trough cyclosporine concentrations are routinely measured after changes in formulation because of the narrow therapeutic window between prevention of graft rejection and drug toxicity. This is not necessary in the dermatology setting, because the incidence of adverse events following changes in formulations is relatively low.6

Currently, there is significant variability in the pharmacokinetics of newer generic forms of the microemulsion formulation ofcyclosporine.9, 10 Different brands should not be used interchangeably without strict supervision. It is recommended that the brand be specified with each prescription at each visit, to avoid alterations in cyclosporine concentration resulting in a lower efficacy or increased toxicity of the drug.The dose of cyclosporine should be divided into a twice daily dose, and optimally should be taken at the same time each day to minimize intraindividual variation in serum concentration.11 Cyclosporine emulsion is available in capsule form (in 25- or 100-mg capsules) or as a bioequivalent solution (100 mg/5 mL).12 The oral solution should be drawn up with the syringe provided and mixed with orange or apple juice or milk.13

Distribution Cyclosporine is widely distributed in the body because of its lipophilic nature. Once absorbed, cyclosporine binds to erythrocytes, leukocytes, and lipoproteins. In plasma, cyclosporine is almost exclusively bound to lipoproteins (>90%), and there is transfer of cyclosporine between different lipoprotein classes and from albumin to lipoproteins.14 Becausecyclosporine is highly lipophilic, a high dietary fat intake can affect serum concentrations related to increased serum lipid levels. One study showed that high dietary fat intake can increase the total body clearance of cyclosporine without

changing the elimination rate constant.15 A higher serum concentration of cyclosporine is produced when the drug is administered before rather than after meals.2, 16 This also translates into higher clinical efficacy of the drug, highlighting the importance oftaking cyclosporine consistently before or after meals where possible.17 Cyclosporine has been reported to have a first-pass effect of 27% in the liver.5 The biphasic distribution of cyclosporine is thought to be caused by the enterohepatic recirculation of cyclosporine from the bile to the small intestine.2

Metabolism and elimination The oral bioavailability and the systemic clearance of cyclosporine is controlled by the cytochrome P450 isoenzymes 3A4 (CYP3A4) and 3A5 (CYP3A5) in the liver and small intestine, and by the efflux p-glycoprotein pump (PGP), a transmembrane transporter, which is expressed in the gastrointestinal tract and liver and encoded for by the multidrug resistance-1 gene (MDR1, also known as adenosine triphosphate–binding cassette B1 [ABCB1]).18, 19, 20, 21, 22, 23, 24, 25 Many single-nucleotide polymorphisms in the genes encoding CYP3A4, CYP3A5, and PGP have been identified and are thought, in part, to account for the variability in pharmacokinetics of cyclosporine. Much of our knowledge on the effects of genetic polymorphisms on variability in pharmacokinetics of cyclosporine comes from transplantation research, but much of the published data to date has shown conflicting or nonsignificant results.18, 19, 20, 21, 22, 23, 24, 25

Cyclosporine elimination follows first-order kinetics with a constant fraction of drug eliminated per unit time.2 Metabolites ofcyclosporine are excreted primarily in the bile. Only 6% of the dose is excreted by the urine, mainly as cyclosporinemetabolites with 0.1% of the dose excreted unchanged in urine.2 The half-life of cyclosporine in serum is between 6 and 24 hours.2, 5 The pharmacokinetics of cyclosporine are altered in children, with clearance rates of up to four times that of adults over 40 years of age, resulting in lower blood concentrations for the same dose.26, 27 Because the clearance of cyclosporineafter intravenous administration does not appear to be related to age,28 it has been proposed that the decreased bioavailability is related to shorter bowel length rather than to metabolic differences.29

Body weight issues Cyclosporine is dosed on a weight per weight basis. Although highly lipophilic, observations suggest that distribution of the drug is limited primarily to lean body mass in obese patients and can lead to increased toxicity if patients are dosed according to their actual body weight.30, 31 One study showed no significant differences in bioavailability, elimination half-life, clearance, or steady-state volume of distribution of cyclosporine when these calculations were normalized by ideal body weight. Following dosage based on actual body weight, obese transplant recipients had a mean serum trough level almost double that of nonobese recipients.32 Trough levels of cyclosporine have also been shown to increase with the obesity index, with a resulting increase in nephrotoxicity.33 While ideal body weight rather than actual body weight should be used to calculate the required dose, some guidelines recommend dosing obese patients according to their actual body weight.11Body weight–independent dosage regimens for both psoriasis and atopic

dermatitis have, in fact, been shown to be equally effective and safe as weight-orientated dosage regimens.34, 35 In the clinical setting, however, it is generally the lowest effective dose to achieve disease control that guides the maintenance dose.

Ethnic variation Studies of transplant recipients have shown significant differences in bioavailability of cyclosporine between different ethnic populations. African Americans have decreased absorption and markedly lower bioavailability of cyclosporine compared to whites.36, 37 This is most likely caused by significant ethnic variation in the frequency of polymorphisms in MDR1 and the genes encoding the CYP3A enzymes.38, 39

Localized administration of cyclosporine Placebo controlled studies of topical preparations of cyclosporine have shown it to be ineffective in the treatment of psoriasis and alopecia areata.40, 41 A double-blind randomized controlled trial of topical cyclosporine rinse 500 mg/5 mL three times a day for 8 weeks for oral lichen planus, however, showed a marked improvement in all patients compared to placebo,42 a finding supported by other studies.43, 44 This success is most likely related to a significantly higher local absorption ofcyclosporine in mucosa compared to skin, with cyclosporine levels measured in the oral mucosa being comparable to those found in lesional skin of patients treated with high-dose systemic cyclosporine. Two double-blind trials of intralesional injections of cyclosporine for psoriasis also showed a significant improvement in all patients compared to controls—again, most likely because of the higher local concentration achieved by intralesional versus topical administration.45, 46 Clearanceof pyoderma gangrenosum with intralesional cyclosporine has also been reported.47 Unfortunately, the intralesional formulation of the drug is not commercially available because of unacceptable pain at the injection site.Back to Article OutlineContraindications Key points•Cyclosporine is contraindicated in uncontrolled hypertension, renal disease, serious infections, and in those with a previous history of malignancy, excluding basal cell carcinoma (level IV evidence)

•Cyclosporine should be avoided in those with a high cumulative dose of previous psoralen and ultraviolet A light phototherapy (level III evidence)

Cyclosporine is contraindicated in uncontrolled hypertension, significant renal impairment, serious infections, and in those with a current or previous history of malignancy (except basal cell carcinoma).11, 48, 49, 50, 51 Skin infections in

atopic eczema are not an absolute contraindication, but appropriate antibiotic therapy should be instituted before commencingcyclosporine.51 Caution and careful clinical judgment should also be used in pregnancy, lactation, epilepsy, severe hepatic dysfunction, primary or secondary immunodeficiency disorders, diabetes, obesity, premalignant conditions, advancing age (>65 years), a tendency to drug or alcohol abuse, and the inability to attend for regular monitoring. In those patients with a high cumulative dose of previous psoralen plus ultraviolet A light (PUVA) phototherapy, severe actinic damage or who have been treated with radiotherapy, cyclosporine may increase cutaneous carcinogenicity and should be avoided whenever possible.11

Back to Article Outline

Drug interactions Key points•Cyclosporine is metabolized by the cytochrome P450 system and interacts with drugs that inhibit or stimulate this system

•Nephrotoxic drugs should be avoided

•A full drug history should be taken at every patient visit

Cyclosporine is almost entirely metabolized in the liver by the cytochrome P450 IIIA system. Drugs that inhibit or stimulate the cytochrome P450 system increase or decrease cyclosporine levels respectively (Table I). In particular, caution must be exercised with the use of erythromycin to treat infected eczema, because it can increase cyclosporine toxicity.51 Grapefruit juice also inhibits the metabolism of cyclosporine by inhibiting cytochrome P450 enzymes in the intestinal wall, and should be avoided during cyclosporine treatment, especially when using the oral suspension in the pediatric population. Heavy alcohol intake can also increase cyclosporine levels.52 Nephrotoxic drugs, such as nonsteroidal antiinflammatory drugs (NSAIDs), aminoglycosides, ciprofloxacin, clotrimazole, and fibrates can impair renal function during cyclosporine treatment and should be avoided if possible. Treatment with NSAIDs for psoriatic arthritis can potentiate nephrotoxicity caused bycyclosporine.53 Cyclosporine can delay the metabolism of multiple agents, including digoxin, simvastatin, prednisolone, diclofenac, and methotrexate, leading to increased concentration and toxicity of these drugs (Table II).Table I. Drug interactions with cyclosporine

Drugs that inhibit the cytochrome P450 system, leading to a higher concentration of cyclosporine

Calcium channel blockers (diltiazem, nicardipine, verapamil, and mibefradil)

Antifungals (fluconazole, itraconazole, ketoconazole, and voriconazole)

Macrolide antibiotics (erythromycin, clarithromycin, and josamycin)

Doxycycline

Gentamicin and tobramycin

Ticarcillin

Ciprofloxacin

Oral contraceptives and androgen steroids

Allopurinol

Bromocriptine

Amiodarone

Ranitidine and cimetidine

Metoclopramide

Methylprednisolone

Protease inhibitors

Statins (especially atorvostatin and simvastatin)

Danazol

Thiazide diuretics

Furosemide

Warfarin

Grapefruit juice

Drugs that stimulate the cytochrome P450 system, leading to a lowercyclosporine level

Anticonvulsants (carbamazepine, phenobarbitone, phenytoin, and valproate)

Rifampicin

Rifabutin

Isoniazid

Octreotide

Orlistat

Terbenafine

Sulfinpyrazone

Probucol

Troglitazone

Ticlopidine

Metamizole

Selective serotonin reuptake inhibitors

(sertraline)

Nafcillin

St John's Wort (Hypericum perforatum)

Drugs that impair renal function during cyclosporine treatment

Nonsteroidal antiinflammatory drugs

Aminoglycosides (gentamycin and tobramycin)

Vancomycin

Ciprofloxacin

Trimethoprim with sulfamethoxazole

Clotrimazole and ketoconazole

Fibrates

Amphotericin B

Acyclovir

Melphalan

Methotrexate

Colcichine

Cimetidine and ranitidine

Drugs where cyclosporine affects metabolism, causing increased levels

Digoxin

Statins (simvastatin, lovastatin, atorvostatin, and pravastatin)

Prednisolone

Diclofenac

Methotrexate

Colchicine

Drugs for erectile dysfunction (sildenafil, tadalafil, and vardenafil)

Benzodiazepines

Treatments where cyclosporine increases carcinogenicity High cumulative doses of ultraviolet light irradiationRadiotherapy

Table II. Adverse events in studies of cyclosporine use (n > 50 patients) in psoriasis and atopic dermatitis

Study, study type, dose (mg/kg/day)

No. ofpatients/duration

AE requiring discontinuation

Renal dysfunction

Hypertension

GI side effects

Headache

Tremor

Psoriasis short-term therapy

Ellis et al,164 RCT

85/16 wks 5% overall NA NA

3 mg/kg/d 28% 20% 4%

5 mg/kg/d 55% 30% 25%

7.5 mg/kg/d 47% 53% 7%

Ho 400/<12 wk IT, for 4% 30% 12% 11% GS 5% NA

Study, study type, dose (mg/kg/day)

No. ofpatients/duration

AE requiring discontinuation

Renal dysfunction

Hypertension

GI side effects

Headache

Tremor

et al,76randomized PO, 2.5-5 mg/kg/d

1 y

Ho et al,77 PO, 2.5-5 mg/kg/d

76/<12 wk IT, for 2 y

7% 24% 24% 36% N 49% NA

Faerber et al,78 MA

597/<12 wk IT 4.1%

1.25 mg/kg/d

— 5% 3% GS 1.9% NA

2.5 mg/kg/d

1% 14% 8% GS 3.8% NA

5 mg/kg/d 8% 9% 7% GS 2.3% NA

Koo et al,8 RNCT, 2.5-5 mg/kg/d

152 MF/24 wks 9% 20% 17% D/N 26% 26%

157 OF/24 wks 5% 15% 30% D/N 22% 22%

Krupp et al,116 MA, 1.25-5 mg/kg/d

631/12 wks to 16 mos

5.9% NA NA 3.8% N, 1.1% V, 2.3% AP, 2% D,

6.3% 1.1%

Study, study type, dose (mg/kg/day)

No. ofpatients/duration

AE requiring discontinuation

Renal dysfunction

Hypertension

GI side effects

Headache

Tremor

1.1% GS

Psoriasis long-term therapy

Christophers et al,55 RCT

217/12-36 wks

1.25 mg/kg/d

1.8% 1% 11% 3.7% GS 0% 1.8%

2.5 mg/kg/d

3.2% 5% 21% 4.4% GS 0.5% 0.5%

5 mg/kg/d 1.6% 13% 26% 5% GS 5% 1.7%

Mrowietz et al,57 RCT, 2.5mg/kg/d and 5 mg/kg/d (extension ofabove study

88/6-30 mos 6% 5% 8% 22% GS 3% 2%

Shupack et al,86 RCT

181/40 wks

5 mg/kg induction for 16wks

7% 42.5% 8.8% 12% N 30% NA

Study, study type, dose (mg/kg/day)

No. ofpatients/duration

AE requiring discontinuation

Renal dysfunction

Hypertension

GI side effects

Headache

Tremor

1.5/3 mg/kg/d or placebo for 24 wks

11% 17% of 3 mg/kg, 10%of placebo

Laburte et al,68 RNCT

251/21 mos 18%

2.5 mg/kg/d

45.2% 27.4% 11.3% N 12.9% 8.1%

5 mg/kg/d 55% 10.6% 13.5% N 15.3% 14.2%

Grossman et al,88 R, 2.5-5 mg/kg/d

122/3-76 mos 4% 43% 24% 6% 11% 2%

Atopic dermatitis short-term therapy

Berth-Jones et al,197 PO, 2.5 mg/kg/d for 8 wks, then 2-4 mg/kg/d

100/48 wks 14% 45% 5% 66% 26% 9%

Czech et al,35RNCT, 150 mg/d vs 300 mg/d,

106/8-12 wks 3% 6% NA 13% GS NA NA

Study, study type, dose (mg/kg/day)

No. ofpatients/duration

AE requiring discontinuation

Renal dysfunction

Hypertension

GI side effects

Headache

Tremor

reducing

Schmitt et al,95 MA∗ 602/6 wks-12 mos Adults,

1.6%/mo; children, 0.8%/mo∗

Adult, 3.2%/mo; children, 2.5%/mo∗

Adults, 1.6%/mo; children 0%/mo∗

Adults GS, 18.1%/mo; children GS, 17.5%/mo∗

Adults, 5.8%/mo; children, 9.1%/mo∗

NA

Atopic dermatitis long-term therapy

Hijnen et al,198 R, 2.5-5 mg/kg/d

73/>6 mos (mean, 1.3 y)

16% 10% 15% 5% N 7% 1%

AE, Adverse event; AP, abdominal pain; CT, continuous therapy; D, diarrhea; GI, gastrointestinal; GS, gastrointestinal symptoms (if not further defined); IT, intermittent therapy; MA, metaanalysis; MF, microemulsion formulation; N, nausea; OF, original formulation for gastrointestinal side effects; PO, prospective open; R, retrospective study; Rev, review; RCT, randomized controlled trial; RNCT, randomized noncontrolled trial; V, vomiting.∗In the metaanalysis by Schmitt et al,95 adverse events were calculated as % of patients/month of treatment

It is important to assess possible drug interactions with all other systemic medications before treatment with cyclosporine is initiated. In particular, patients often do not report intermittent use of NSAIDs, and so specific instructions must be given to patients. It is important to inquire at every subsequent visit if a patient has begun taking any new medications. Likewise, patients should be instructed to inform their other physicians that they are taking cyclosporine and share the drug interaction information with them.

Back to Article OutlineAdverse effects Key points

•A maximum dose of 5 mg/kg should be used for up to 1 year only (level IV evidence)

•Acute renal deterioration is typically reversible on withdrawal of cyclosporine treatment, while chronic impairment may be irreversible

•If serum creatinine increases 30% over the patient's baseline value on two consecutive readings 2 weeks apart, the dose should be reduced (level IV evidence)

•When hypertension develops, the dose should be reduced by 25% to 50% or antihypertensive therapy introduced (level IV evidence); calcium channel blockers of the dihydropyridine class are the antihypertensives of choice (level IIB evidence)

•Tetracyclines should not be used to treat cyclosporine-induced acne because there is a risk of pseudotumor cerebi (level III evidence)

Statin therapy should be used with caution in the treatment of cyclosporine-induced hyperlipidemia because of the rare occurrence of rhabdomyolysis (level III evidence). The concern over the side effect profile of cyclosporine has largely limited its use in dermatology. For the most part, these side effects are dose dependent, related to the duration of therapy, and reversible on discontinuation, although structural renal abnormalities may be persistent.31, 54, 55, 56, 57 Adherence to current guidelines on the appropriate dosage and monitoring of cyclosporine will considerably decrease the risk of side effects.11, 48, 49, 50, 51 A summary of the frequency of adverse events reported in the largest studies (n >50 patients) ofcyclosporine in the treatment of psoriasis and atopic dermatitis is represented in Table II (long-term observational and retrospective studies are included because these add important information for assessing the frequency of side effects). While the mechanisms involved in many cyclosporine-induced side effects remain poorly understood, it has been suggested that mitochondrial dysfunction and the inhibition of immunophilins—especially those involved in mitochondrial ion channel regulation—may play an important role.58, 59

Renal dysfunction Cyclosporine-induced renal dysfunction is the predominant cause for dermatologist-driven concern, and therefore the lack ofembrace of its use by a substantial percentage of the dermatology community. Most persistent renal dysfunction, however, is related to prolonged therapy (ie, longer than 2 years) or doses of greater than 5 mg/kd/day, both of which may result in structural renal changes.31, 60, 61, 62, 63, 64, 65, 66, 67, 68 Renal dysfunction can be

functional or structural. Functional impairment, which may begin soon after commencing treatment, can be subdivided into vascular dysfunction and tubular dysfunction.31, 61, 64, 69

Vascular dysfunction 

Vascular dysfunction is caused by vasoconstriction of the afferent glomerular arterioles, leading to increased vascular resistance. This results in a decrease in renal glomerular filtration rate (GFR) and renal blood flow with decreased clearanceof creatinine.

Tubular dysfunction 

Tubular dysfunction is characterized by decreased magnesium reabsorption, decreased uric acid excretion, decreased potassium and hydrogen ion secretion, and distal tubular acidosis. Hypomagnesemia, decreased bicarbonate concentration, hyperuricemia, and hyperkalemia may result.69 There is no loss of urinary concentrating power as is the case with other nephrotoxins.69

Endothelin-1 has been implicated in the vascular dysfunction caused by cyclosporine.70 Patients with psoriasis have higher levels of plasma endothelin, with the highest values occurring in those treated with cyclosporine.71 Both endothelin andcyclosporine mediate vasoconstriction, which may potentiate the nephrotoxic effects of cyclosporine in psoriasis patients.Cyclosporine has also been proposed to cause endothelial dysfunction by increasing production of superoxide,72decreasing production of nitric oxide in endothelial cells,73 upregulating angiotensin II receptors, and increasing the concentration of calcium in smooth muscle cells to cause increased sensitivity to vasoconstrictive stimuli.58, 74

Acute deterioration related to functional changes is typically reversible on withdrawal of cyclosporine treatment.64 In studiesof intermittent short-term therapy in psoriasis (12-16 weeks), renal dysfunction was typically transient. Between 4% and 27%of patients had increases in serum creatinine levels, which returned to normal within 4 weeks75, 76, 77, 78 (Table II). A pooled analysis of 10 studies assessing 563 psoriasis patients treated with cyclosporine showed an increase in creatinine of 50% above baseline in 4% and 13% of those taking 2.5 and 5 mg/kg/day, respectively, in the first 12 weeks.79Intermittent therapy is thought to allow normalization of renal function between courses, thereby minimizing renal toxicity.66

Chronic nephrotoxicity Chronic nephrotoxicity causes an obliterative microvascular renal injury (vasculopathy) and a tubulopathy.

Vasculopathy 

Vasculopathy comprises glomerular or arteriolar thrombi, arteriolopathy, and interstitial fibrosis with tubular atrophy.80Thrombi are composed of fibrin or platelets lodged in glomeruli or blood vessels. The arteriolopathy affects vessels in the peripheral vascular tree with up to two layers of smooth muscle. It is characterized by nodular protein deposits in the media consisting of immunoglobulin M and complement (C3 and C1q) which replace necrotic myocytes in the arteriolar wall in a pearl necklace or clover leaf pattern to narrow or occlude the vascular lumen.81 Mucoid thickening of the intimal wall can also occur. This leads to arteriolar hyalinosis, interstitial fibrosis (striped form), tubular atrophy, and glomerular sclerosis (Fig 1). Tubular interstitial fibrosis is associated with an increase in transforming growth factor-beta (TGF-β).58 There may also be an increase in serum factor VIII and antithrombin III in those with cyclosporine-induced vasculopathy.82

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Fig 1. 

Cyclosporine-induced chronic nephropathy. Note the interstitial fibrosis (arrow) with adjacent tubular atrophy. (Periodic acid–

Schiff stain; original magnification, ×10.)

Tubulopathy 

Tubular structural changes include isometric vacuolization of the proximal tubule, occasional giant mitochondria in tubular epithelial cells, single cell necrosis, and microcalcification of Tamm–Horsfall protein in the distal tubule.69 These changes are now rare, with the usage of lower cyclosporine doses. While tubulopathic changes are reversible, vasculopathic changes are maintained in up to half of patients.69, 83

There have been many studies of the safety of long-term cyclosporine therapy in dermatology with regard to nephrotoxcity. A prospective study of renal structure and function in psoriatic patients treated with long-term cyclosporine (mean, 3.9 mg/kg/day) for up to 3 years compared 19 psoriatic patients to 38 age-matched transplant donors. Interstitial fibrosis and tubular atrophy were present in all biopsies after 1 year of therapy and became progressive with further treatment.84 These changes were more marked in hypertensive patients but were not strongly correlated to renal function. In a study of renal biopsy specimens obtained from 30 psoriasis patients treated with cyclosporine, no patient treated for 2 years or longer had a normal kidney biopsy specimen, and there was pronounced glomerular sclerosis after 4 years of continuous treatment.85A study of maintenance cyclosporine for 3.5 years in psoriasis patients showed a moderate degree of interstitial fibrosis and glomerular scarring in two of 14 patients after 2.5 years, with minimal to mild change in all of the remaining 12 patients.64One year later, there was progression of fibrosis in nine of the 12 patients still enrolled in the study. Similarly, 1 month after drug withdrawal, tubulointerstitial scarring and arteriolopathy was seen in 27% of renal biopsy specimens taken from 15 psoriatic patients who had received cyclosporine (<5 mg/kg/day) for 30 months.67 These patients had marked increases in serum creatinine levels of more than 90% above baseline, and conversely, those showing no increase in serum creatinine levels did not have structural renal changes in 86% of cases. There was no correlation, however, with dose or treatment duration. In a study evaluating eight patients treated with a mean dose of 3.3 mg/kg/day for 5 years, renal biopsy specimens revealed tubular atrophy and arterial hyalinosis in six patients (75%), with interstitial fibrosis and obliteration of glomeruli.62Again, the best predictor of permanent renal damage was a persistent increase in serum creatinine level 1 month after treatment withdrawal. These studies contrasted to an earlier study in which no relevant cyclosporine-related structural changes were seen in 14 psoriatic patients taking cyclosporine for a mean of 15 months compared with 16 psoriatic controls.66

Many studies of long-term cyclosporine treatment have attempted to quantify the optimum dosage and duration ofcyclosporine treatment to prevent chronic nephrotoxicity. A study of 192 patients treated with a mean dose of 8.2 mg/kg/day for 13 months for a variety of autoimmune conditions showed renal dysfunction to be dose-related and more common in older patients, and recommended a ceiling dosage of 5 mg/kg/day and a maximum increase in serum creatinine of 30% over baseline based on these results.65 A multicenter study of long-term maintenance therapy with cyclosporine for psoriasis, in which 88 patients were treated for up to 30 months with either 2.5 or 5 mg/kg/day57 followed by a posttreatment period of 3 months showed an increase in serum creatinine of 10% above baseline which occurred in 4.5% of patients. In this study, no

association was found between side effects and cyclosporine dose. In a study of 44 patients treated withcyclosporine used for up to 4 years, there was a persistent rise in serum creatinine in 14% of patients, with a mean reduction of 16% in GFR (9% of those treated with <3 mg/kg/day compared with 23% for those treated with >3 mg/kg/day).63GFR normalized in all cases with discontinuation of cyclosporine.63 In a follow-up study by the same group, renal function was again examined in the seven patients who had remained on cyclosporine for between 9.5 and 11 years.31 All seven patients showed a persistent increase in serum creatinine of greater than 30% over baseline, and four of these had increases of greater than 50%. Similarly, 17% of 181 patients taking 3 mg/kg/day for 6 months (after an induction period of 4 months with 5 mg/kg/day) had an increase in serum creatinine.86 An elevation of serum creatinine of 30% above baseline was reported in 46% of 250 patients treated for 21 months.68 A study of 28 patients reported renal dysfunction in 71% ofpatients treated with 3.5 mg/kg/day for a median of 55 months, which persisted after discontinuation of the drug in 35% ofpatients.87 Other risk factors for cyclosporine-induced nephropathy include preexisting or new-onset hypertension, renal conditions, other nephrotoxic medications, older age, and obesity.64, 65, 88

Recommendations If there is an elevation of serum creatinine of at least 30% over the patient's baseline value, recorded on two consecutive readings 2 weeks apart, the dose should be reduced by 1 mg/kg/day or by 25% to 50% for a minimum of 4 weeks, even if the value lies within the normal reference range (Fig 2; level IV evidence).11, 48, 49, 50, 51, 65, 89 If serum creatinine does not improve after 4 weeks therapy at the reduced dose, cyclosporine should be decreased by another 25% to 50%. If creatinine remains elevated at this stage, cyclosporine should be discontinued. Treatment should not be recommenced until the serum creatinine has returned to less than 10% above the patient's baseline value. If creatinine rises 30% over baseline again on reintroduction of cyclosporine, the drug should be permanently withdrawn. If serum creatinine lies outside the normal reference range but remains less than 30% above baseline for a given patient, there may be underlying preexisting renal impairment and caution should be exercised. Measurement of the GFR is recommended at least annually for those on long-term treatment,48, 49, 50 because secretion of creatinine in the renal tubules can increase in cyclosporine-induced nephropathy, making the interpretation of serum creatinine levels less reliable.90 Cyclosporine-induced nephropathy has been reported in patients with normal serum creatinine levels.91 As discussed in part I of this review, there is a discrepancy between guidelines from the United States and those from Europe with regard to recommended duration of continuous treatment to prevent chronic nephrotoxicity. In the United States, a maximum of 1 year of treatment is recommended by the American Academy of Dermatology, while guidelines published by the British Association of Dermatology and the European Association of Dermatology and Venereology recommend a ceiling of 2 years.11, 48, 49, 50, 51 In general, if cyclosporine is administered at a dose of 5 mg/kg/day or less and patients' serum creatinine levels are carefully monitored to ensure that they do not increase to more than 30% above baseline, renal side effects will be fully reversible after discontinuation of the drug.75, 79, 81

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Fig 2. 

Management of cyclosporine-induced renal dysfunction.

Hypertension 

There is a wide variety in the reported incidence of new-onset hypertension with cyclosporine treatment, ranging from 0% to 57% in different studies (Table II). Studies of short-course cyclosporine therapy show a low incidence of new-onset hypertension, ranging from 0% to 24%, which is typically reversible on dose reduction or with the use of antihypertensive medications.76 In studies of long-term treatment, hypertension is more frequent. In a study by Mrowietz et al,57 8% ofpatients had an elevated blood pressure as determined by an increase of at least 10% of either systolic or diastolic pressure, while 3.5% showed an increase in blood pressure in the posttreatment phase.57 In a pooled analysis of 10 studies, 10.6% of patients had new-onset hypertension that was not dose related (10% of those taking 2.5 mg/kg/day and 11.9% taking 5 mg/kg/day).79 The lack of relationship between dose of cyclosporine and frequency of hypertension has been shown in other randomized studies.55, 68, 92 This suggests that there is a subset of patients with increased individual sensitivity to cyclosporine who are susceptible to hypertension even at low doses. For this reason, it has been proposed thatcyclosporine-induced hypertension should be managed by antihypertensive therapy rather than dose reduction.79 Initiating or monitoring antihypertensive therapy may be another reason why dermatologists have been resistant to embracecyclosporine in their clinical practices. In another study of long-term therapy in 122 patients the median time to developmentof hypertension was 55 months.88 The onset of hypertension in this group was shown to be bimodal, with a peak during the first 9 months of therapy and again after 36 months. In the pooled analysis by Feutren et al,79 a significant increase in diastolic blood pressure was detected after 1 month of treatment compared to controls, but no further increase was seen between months 1 and 3. There was no significant difference between mean blood pressure at baseline and at 3 months posttreatment. Longer-term studies have shown the persistence of hypertension posttreatment in up to 35% of patients.87There appears to be a lower incidence of new-onset hypertension in studies of short-term cyclosporine treatment in adults with atopic dermatitis compared with studies of psoriasis (Table II). Although this may reflect a younger mean age in the cohort of patients recruited to atopic dermatitis studies, psoriasis patients may have a higher inherent risk of developing hypertension because of an increased incidence of obesity and the metabolic syndrome and therefore hypertension.93, 94 In a large systematic review and metaanalysis of 15 studies of cyclosporine in atopic dermatitis, seven studies showed no newly diagnosed hypertension, with five of these studies being in adults only.95 In the pooled analysis of adults alone, there was a 1.6% incidence per month of newly diagnosed hypertension.

Recommendations Earlier studies evaluating adverse effects of cyclosporine used thresholds of 160 mm Hg and 95 mm Hg to define systolic hypertension and diastolic hypertension, respectively. Subsequently, the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure have decreased the reference ranges used to define prehypertension (120-139/80-89 mm Hg) and hypertension (>140/90 mm Hg).96 Patients with psoriasis in particular are known to be at increased risk of cardiovascular morbidity and mortality94; it is important to monitor blood pressure regularly (eg, weekly self-monitoring) and institute appropriate management as soon as there is evidence of cyclosporine-induced hypertension.48,49, 50 The current guidelines recommend a dose reduction of 25% to 50% if possible or the introduction of antihypertensive therapy (Fig 3; level IV evidence).48, 49, 50 Because there appears to be no correlation between the onset of hypertension and cyclosporine dose, the introduction of antihypertensives in the first instance may be more appropriate. Calcium channels blockers of the dihydropyridine class, such as amlodipine or isradipine, are the antihypertensives of choice incyclosporine-mediated hypertension because of their vasodilating effect on the afferent arteriole, which may confer protection against nephropathy.97, 98, 99 Verapamil and diltiazem should be avoided because they interfere with serum cyclosporinelevels, while nifedipine can potentiate the gingival hypertrophy caused by cyclosporine. There have been reports ofangiotensin-converting enzyme inhibitors causing a decrease in GFR in cyclosporine-treated hypertensive patients, although other studies have shown perindopril to be equally effective as amlodipine in lowering blood pressure without affecting GFR or effective renal plasma flow.100, 101, 102 The use of thiazide diuretics may lead to increased nephrotoxicity.103 Potassium-sparing diuretics should also be avoided, because cyclosporine can increase serum potassium.

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Fig 3. 

Management of cyclosporine-induced hypertension.

Malignancy potential The increased risk of malignancy associated with long-term cyclosporine use in transplant populations is well described.104, 105 In this population, however, multiple immunosuppressive agents are frequently used in concert, resulting in higher levels of immunosuppression. Experimental studies have shown that cyclosporine is not genotoxic but causes dose-dependent tumor promotion.106, 107 In skin tumor models, cyclosporine has been shown to enhance the induction ofskin tumors by ultraviolet irradiation.108 The increased risk of malignancy has been attributed to potent immunosuppression, but other direct effects have also been observed. Cyclosporine increases formation of reactive oxygen species which promotes transformation to malignancy.109 In mice studies, cyclosporine increases the synthesis of TGF-β, interleukin-6 (IL-6), and vascular epidermal growth factor (VEGF) in tumor cells, resulting in increased tumor growth, metastasis, and angiogenesis.110 Another study showed that cyclosporine induces invasiveness of nontransformed cells by a cell autonomous mechanism, which is blocked by monoclonal antibodies to TGF-β.111 Cyclosporine can also inhibit DNA repair by inducing apoptosis in activated T cells.110

In a study of 1252 psoriasis patients treated for a mean duration of 1.9 years with low-dose cyclosporine (2.7-3.1mg/kg), there was a six-fold increase in cutaneous squamous cell carcinomas (SCCs) after a 5-year follow-up period.112 The risk increased with longer duration of therapy (>2 years), with the increased incidence being seen solely in those with a previous history of PUVA treatment. Another nested cohort crossover study of 28 patients who had been treated with PUVA followed bycyclosporine showed a seven-fold increase in risk of SCC after treatment with cyclosporine compared to before first use ofthe drug.113 Six of the 842 psoriasis patients studied in the Sandoz Pharma study114 developed malignant or premalignant skin lesions, almost all of whom had been treated previously with PUVA, ultraviolet B light, or methotrexate. Another case report described eruptive keratoacanthomas and nodular basal cell carcinoma in psoriasis patients treated withcyclosporine.115 In view of this increased risk of cutaneous SCC, current guidelines suggest that narrowband ultraviolet B light should be used as a first-line agent when considering phototherapy, so that cyclosporine remains a future treatment option. If PUVA is used, the number of lifetime treatments should be limited to fewer than 200. Immunosuppression should not be used concurrently with phototherapy or directly before or after PUVA; immunosuppressants should be avoided in those with a high cumulative dose of PUVA or a previous history of SCC or melanoma.48, 49, 50

Studies in transplant recipients have shown an increased risk of lymphoma. There was no increase, however, in the occurrence of lymphomas in the 1252 psoriasis patients described by Paul et al.112 In the Sandoz Pharma study,114 three ofthe 842 psoriasis patients developed benign cutaneous lymphoproliferative disorders, another developed a B-cell lymphoma, and one a cutaneous T-cell lymphoma. The benign cutaneous lymphoproliferative disorders and B-cell lymphoma regressed rapidly on withdrawal of cyclosporine. There have been isolated case reports of the development of B- and T-cell lymphomas in psoriasis patients treated with cyclosporine.116, 117, 118, 119 It is important to note, however, that psoriasis causes a state of chronic overactivation of the immune system with a higher incidence of lymphoma and other malignancies than the normal population.120, 121 Cyclosporine has been shown to promote Epstein–Barr virus (EBV) transformation of human peripheral blood lymphocytes.122 One report described the development of EBV-associated lymphoproliferative disease after long-term cyclosporine use, with spontaneous regression on

stopping the drug, strongly suggesting causality.123 Other lymphoproliferative disorders, such as hairy cell leukemia and Waldenstrom macroglobulemia, have been reported.124

Although there have been multiple case reports of solid tumors in patients on cyclosporine therapy in the literature,125 there was no increase in the incidence of solid tumors in the psoriasis study by Paul et al.112 In the Sandoz Pharma study,114 fiveof the 842 patients (0.7%) developed solid organ tumors, which were considered unlikely to be cyclosporine related by the investigator or reporting physician. Remarkably, an immunoprotective effect against certain tumor types has been suggested by large case-control studies of patients suppressed with cyclosporine in combination with other immunosuppressive agents, with a decreased odds ratio of rectal and breast cancers.126, 127

Neurologic side effects The neurologic side effects of cyclosporine include headaches, tremor, seizures, psychosis, paraesthesias, and sleep disturbance. Headache occurs in up to half of patients, while parasthesias and tremor occur in up to 40% and 26% ofpatients, respectively (Table II). Paraesthesia and tremor often occur in the first weeks of treatment and improve without reduction of the dose, with hypomagnesemia suggested as a possible cause.115, 128

Pseudotumor cerebri has been reported in several pediatric patients taking cyclosporine.129, 130, 131 In particular, tetracyclines should not be used to treat cyclosporine-induced acne because this increases the possibility of developing this complication. Three young female patients in our department have developed pseudotumor cerebri as a result of this combination, one of whom required a ventriculoperitoneal shunt. The condition is rapidly reversible on withdrawal ofcyclosporine, so prompt diagnosis is necessary to prevent permanent visual deficits. Seizures have also rarely been reported, and those with a history of epilepsy should be warned that cyclosporine can lower the seizure threshold. The risk ofseizures is increased in those taking high doses of prednisone, prednisolone, or methlyprednisolone. Cyclosporine levels in those on antiepileptic therapy may also be lower than expected because of upregulation of the cytochrome P450 system (Table I). Cyclosporine has rarely been reported to cause a reversible posterior leukoencephalopathy, consisting ofheadache, hypertension, seizures, cortical blindness, and other visual abnormalities with characteristic magnetic resonance imaging changes.132 There have been four reports of cyclosporine-induced Parkinsonism.133

A study using a magnetic resonance spectroscopy–based metabonomic approach to evaluate the effect of cyclosporine on rat brain cell metabolism showed a significant decrease in high-energy phosphate metabolism and a reduction in intracellular concentrations of neurotransmitters, such as glutamate and N-acetyl-asparate (NAA) in rat brain cells.134

Gastrointestinal side effects The reported incidence of gastrointestinal side effects, such as nausea, vomiting, diarrhea, or flatulence, varies considerably (Table II). In the pooled analysis by Krupp et al,114 nausea, abdominal pain, diarrhea, vomiting, and gastrointestinal complaints were seen in 3.8%, 2.3%, 2%, 1.1%, and 1.1%, respectively. Hyperbilirubinemia also occurs in up to 30% ofpatients.50 This is generally dose related and, in the absence of other abnormalities of liver function, does not require further evaluation.49 It is believed to be a consequence of competitive inhibition of transport between bilirubin and cyclosporinerather than direct hepatotoxicity.86 An increase in transaminases occurs in up to 30% of patients.50 If serum bilirubin or transaminases rise to twice the normal value, a dose reduction of 25% is necessary.50 An increased incidence ofcholelithiasis has been reported in renal and cardiac transplant recipients treated with cyclosporine compared with those treated with alternative immunosuppressants.135

Gingival hyperplasia Gingival hyperplasia is caused by fibrous hyperplasia and has been reported in up to 30% of patients on cyclosporine, with a higher incidence reported in children (Fig 4).136, 137 The pathogenesis is uncertain but it is often associated with poor oral hygiene. Plaque control and the removal of local irritants have been shown to be of benefit.138 Genetic heterogeneity also seems to play an important role in its development.136 Complications include functional difficulties, disfigurement, and increased caries.136 Onset

tends to be during the first 3 to 6 months of treatment. Treatment with metronidazole resulted in complete resolution in one series of four patients.139

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Fig 4. 

Cyclosporine-induced gingival hyperplasia.

Cutaneous side effects A study examining cutaneous side effects of cyclosporine therapy in 67 renal transplant patients revealed hypertrichosis in 60%, epidermal cysts in 28%, keratosis pilaris in 21%, acne in 15%, folliculitis in 12%, and sebaceous hyperplasia in 10%.140 There is considerable variability in there reported incidence of hypertrichosis (Table II). Hypertrichosis was reported in 6.8% of patients in the study by Krupp et al,114 23% in that of Grossman et al88 and in 54% in a study by Griffiths et al.141This side effect is more cosmetically unacceptable for women with darker hair. The etiology is unknown with no evidence to suggest an alteration in endocrine status.115 Cyclosporine modulates protein kinase C expression and translocation in hair epithelial cells and promotes proliferation of these cells.142 Cyclosporine also prolongs human hair growth in vitro.143

Most other cutaneous side effects also affect the pilosebacous unit, with studies suggesting that the follicular epithelium is more sensitive to cyclosporine than the interfollicular epithelium.142 Acneiform eruptions or worsening of preexisting acne vulgaris are common with cyclosporine.144 As previously mentioned, tetracyclines should not be used to treat acne becauseof the increased risk of pseudotumor cerebri. In a study of intermittent therapy in 400 psoriasis patients, transient palmar and/or plantar pustular psoriasis occurred in 5 patients on withdrawal of cyclosporine but was not serious enough to warrant study discontinuation in any patient.76

Infections Despite its immunosuppressive effects, infectious side effects with cyclosporine are rare and seldom severe. In controlled studies, there was no difference in the frequency of infections between those taking cyclosporine compared with etretinate or placebo. If spontaneous recovery did not occur, treatment of the infection or withdrawal of the drug led to resolution.115A review of 2 decades of safety data of cyclosporine in dermatology patients suggested no increased risk of opportunistic infections or tuberculosis reactivation.125 Because cyclosporine has been reported to cause the reactivation of latent tuberculosis infection in higher doses used in transplant recipients, and because cyclosporine is an immunosuppressant, the National Psoriasis Foundation recommends screening for latent tuberculosis infection before initiation of cyclosporinetreatment (level of evidence IV).145, 146 Management of infection while taking cyclosporine depends on the pathogen and the severity of infection. Bacterial or fungal infections should be treated with appropriate antibiotic therapy as soon as they are detected. Commencement of cyclosporine should be delayed until the resolution of active herpes simplex in those with atopic dermatitis, and withdrawal should be considered if there is evidence of dissemination, to reduce the risk of eczema herpeticum.51

Other side effects 

Fatigue, lethargy, and flu-like symptoms are commonly reported. Musculoskeletal symptoms such as joint pain and muscle aches are reported in 10% to 40% of patients.50

Hyperlipidemia Hyperlipidemia (particularly hypertriglyceridemia) during cyclosporine treatment is well described.55, 57, 115, 147, 148 The package insert reports hypertriglyceridemia (>750 mg/dL) in 15% of patients and hypercholesteremia (>300 mg/dL) in less than 3% of patients.49 In the study by Mrowietz et al,57 an increase in triglycerides 30% above baseline was observed in 12.5% of patients. Another study investigating the effect of 5 mg/kg/day of cyclosporine on serum fasting lipids showed an increase of more than 30% in cholesterol and triglycerides in 18% and 50% of patients, respectively, seen after just 2 weeks in both, with no further significant change noted throughout the course of treatment.148 This study showed no effect on high-density lipoprotein levels. A study by Grossman et al147 showed a 50% increase in triglyceride levels in seven out of eight psoriasis patients, which peaked after 1 month of treatment and suggested a correlation between hypertriglyceridemia and previous retinoid use, a finding that was refuted in a subsequent study.149 Hyperlipidemia normalizes on discontinuation ofthe drug.86

Hyperlipidemia has been suggested to contribute to accelerated atherosclerosis in renal transplant patients.150 With the current knowledge that the incidence of metabolic syndrome and cardiovascular morbidity is increased in severe psoriasis, this side effect needs to be actively managed in psoriasis patients. While no studies have examined the incidence ofcyclosporine-induced hyperlipidemia in atopic dermatitis patients, it would be interesting to compare the incidence ofhyperlipidemia between these two population groups.

Recommendations If hyperlipidemia develops and cyclosporine therapy is maintained, a lipid-lowering diet should be introduced (level IV evidence). If this is not successful, the dose of cyclosporine should be reduced or a lipid-lowering agent should be commenced. Because cyclosporine decreases the clearance of statins, rhabdomyolysis may occur in patients taking concomitant statin therapy.151 Vigilance is important in detecting this rare but potentially fatal drug interaction. Patients should be instructed to report symptoms such as muscle pain or weakness, dark-colored urine, or generalized malaise immediately, and serum creatinine phosphokinase should be monitored after commencement of the drug. There have also been reports of nephrotoxicty and renal failure when fibrates have been used with cyclosporine in transplant recipients.152

Other laboratory abnormalities One of the advantages of cyclosporine compared to other immunosuppressant therapies is the lack of myelosuppression relating to treatment. A slight normochromic, normocytic anemia, however, may be observed,115, 153 and microangiopathic hemolytic anemia and thrombocytopenia have also rarely been reported.49 Renal dysfunction can lead to hypomagnesemia, hyperuricemia, and hyperkalemia. One study showed hyperuricemia (2.6% of patients) and hypomagnesemia (8.8%) to be dose-related, while hyperkalemia (0.5%) was not related to dose or treatment duration.115 Hypomagnesemia has been reported in 5% to 15% of patients and should be treated with oral magnesium supplements (beginning at 200 mg magnesium daily and increased as needed), with adherence monitored.50 Studies in rats have shown that magnesium supplementation may prevent chronic cyclosporine nephropathy by adjusting nitric oxide synthase activity.154

Hyperuricemia should be treated with a low purine diet and sufficient fluid intake.50 Hyperkalemia in the setting of normal renal function can occur and is most likely caused by tubular dysfunction and secondary hypoaldosteronism.155 If fluid intake and a low potassium diet do not restore normal serum potassium levels, dose reduction is necessary.50 Increased levels ofserum alkaline phosphatase (ALP) have been reported in up to 8% of psoriasis patients undergoing treatment, generally in the setting of normal liver function tests.115 This is likely related to an increase in the bone isozyme of ALP, caused by changes in bone metabolism. Cyclosporine has been shown to cause mild osteoblastic proliferation and matrix mineralization activity, as reflected by increased serum alkaline phosphatase in renal transplant patients with normal parathyroid hormone levels.156

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Monitoring 

Key points•Blood pressure and blood urea nitrogen and serum creatinine levels should be measured at baseline, weeks 2, 4, 6, and 8, and then monthly thereafter

•Patients should be instructed regarding dental care commencing treatment and attend their dentist at 6-month intervals to monitor for gingival hypertrophy

•National malignancy screening programs should be adhered to

•Vaccination should take place before the initiation of treatment where possible

Screening and history Before beginning cyclosporine treatment, patients should be screened with a careful history, examination, and baseline laboratory investigations (Table III). In particular, a history of malignancy, renal dysfunction, hypertension, current infections, or a history of previous PUVA phototherapy should be elicited. A full medication list should be recorded, including over the counter preparations. The physical examination should include measurement of blood pressure at two time points and an assessment of the skin for actinic damage and skin cancers. Initiation of treatment should be deferred until active herpes simplex lesions have resolved, particularly in the atopic dermatitis population. If possible, viral warts should be treated before beginning a course of cyclosporine. Patients should be instructed regarding careful dental hygiene and to visit their dentist at 6-month intervals to monitor for gingival hypertrophy. The need for contraception should be discussed with womenof child-bearing age and a pregnancy test performed if indicated. Specifically, cyclosporine can reduce the efficacy ofprogesterone-containing contraceptives, so alternative birth control methods should be considered.50 Patients should also be counseled regarding the need for long-term sun protection in view of the higher incidence of skin cancer in those takingcyclosporine.Table III. Guidelines for pretreatment assessment and monitoring

Investigation Details Level ofevidence

Full history Previous infections: TB, hepatitis B/C; history of hypertension, kidney disease, liver disease, or malignancy; full medication history, which should be repeated at every subsequent visit

IV

Blood pressure Baseline (2 separate measurements, should be <140/90 mm Hg); taken again at weeks 2, 4, 6, and 8, then monthly

Physical examination

Actinic damage/cutaneous malignancies; herpes simplex; viral warts

Serum creatinine Baseline (mean of 2 separate fasting measurements; if discrepancy of >10%, repeat again);taken again

Investigation Details Level ofevidence

at weeks 2, 4, 6, and 8, then monthly

Blood urea nitrogen Baseline and at weeks 2, 4, 6, and 8, then monthly

Complete blood cell count

Baseline, then monthly

Potassium Baseline, then monthly

Bilirubin, liver enzymes

Baseline, then monthly

Fasting lipid profile Baseline, then monthly

Uric acid Baseline, then monthly

Magnesium Baseline, then monthly

Urinalysis Baseline, then monthly

Tuberculin test Baseline

Glomerular filtration rate

After 1 y of continuous therapy

Screening Programs Cervical, breast, and colon cancer screening as per national guidelines

Vaccinations Annual pneumococcal and influenza vaccinations

Baseline laboratory investigations Fasting serum creatinine should be measured in a standardized manner on at least two separate occasions (fasting >12 hours, in the morning, no preceding strenuous exercise), and repeated again if there is a discrepancy of more than 10 μmol/L between these measurements.11, 48, 49, 50 The average of these two values then serves as the baseline serum creatinine against which subsequent treatment values are compared. Baseline laboratory investigations should also include a complete blood count, blood urea nitrogen (BUN), potassium, bilirubin, liver enzymes, uric acid, magnesium, fasting lipids, and urinalysis for proteinuria.11

Regular follow-up investigations 

Blood pressure, BUN, and serum creatinine should be measured at weeks 2, 4, 6, and 8, and then monthly thereafter, with more frequent readings if there are abnormal measurements.11, 48, 49, 50 Measurements of the complete blood cell count, potassium, uric acid, fasting lipids, bilirubin, liver enzymes, and magnesium should be taken initially monthly and thereafter pending the course of therapy (2-month intervals, possibly). Patients should be weighed at every visit.

Annual investigations The GFR should be assessed annually for the small number of patients who are treated continuously for more than 1 year.48, 49, 50 There should be full compliance with national screening programs for cervical, breast, and prostate cancers.

Cyclosporine serum concentrations Cyclosporine serum concentrations are typically monitored in transplant patients to avoid toxicity caused by high concentrations and to minimize possible organ rejection caused by low concentrations. In practice, this has not been adopted or shown to be of benefit in monitoring efficacy or toxicity in dermatology patients.57, 157, 158 No difference was detected between mean cyclosporine trough levels measured using specific monoclonal or nonspecific polyclonal radioimmunoassay in relation to efficacy or renal dysfunction. It can be used, however, if there is a query regarding patient adherence to treatment or to detect cyclosporine levels above the recommended dosing range.159

Vaccinations Live vaccination is contraindicated while on cyclosporine.11 There have been numerous studies of immunologic response to inactivated vaccines in transplant recipients treated with cyclosporine. Pneumococcal vaccination with a 23-valent vaccine in transplant recipients treated with cyclosporine has been shown to be equally effective as in controls, while immune response to influenza vaccination is significantly reduced although not completely abolished.160, 161 It has been suggested that this differential response is related to T-cell independent antibody production against polysaccharide antigens in the pneumococcal vaccine.160 Immune response to hepatitis B vaccination is impaired.162 The response to standard diphtheria and tetanus booster vaccination in pediatric renal transplant recipients treated with cyclosporine is comparable to healthy children.163 Vaccination should take place before the initiation of treatment where possible, and although response may be suboptimal,11, 49 annual vaccination with pneumococcal and influenza vaccines is advocated.11 Delayed-type hypersensitivity reactions to skin-test antigens are reduced by cyclosporine, and so the interpretation of tuberculin skin testing is unreliable in those undergoing treatment.164, 165 As a result, Mantoux testing is recommended before initiation ofcyclosporine.11

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Pregnancy Key points•Cyclosporine crosses the placental blood barrier and is a category C drug in pregnancy

•Pregnancy registries show no increase in the risk of teratogenicity, although there were trends towards low birth weight and prematurity

•Cyclosporine is excreted in breast milk

Cyclosporine has been labeled as a category C drug by the FDA Pregnancy Labeling Task Force (animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well controlled

studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks). Cyclosporine has been shown to passively cross the placental blood barrier to achieve 10% to 50% of the maternal plasma concentration.166 The administration of 25 mg/kg of cyclosporine to female Lewis rats resulted in characteristic drug-induced pathologic changes in the mother and a high incidence of fetal mortality, while a dose of 10 mg/kg was not fetotoxic.167 Animal studies have not shown increased malformation rates, but in utero exposure to cyclosporine in rabbits induced a nephron reduction that led to systemic hypertension and progressive chronic renal insufficiency in adulthood.168

As controlled studies in humans cannot ethically be performed, we must look to pregnancy registries to evaluate the safety ofcyclosporine in pregnancy. The majority of our safety data comes from analyses of pregnancy outcomes in transplant recipients, which have concluded that there is no evidence of teratogenicity.50, 169, 170 A metaanalysis of 410 patients in 15 studies (6 with control groups) showed no statistically significant increase in the incidence of congenital malformations, preterm delivery or low birth weight associated with cyclosporine exposure during pregnancy, although there were definite trends towards low birth weight (prevalence, 43%) and prematurity (prevalence, 56%).169 A report on 629 pregnancies in patients treated with cyclosporine for transplantation collected by the Sandoz international database showed a higher incidence of prematurity and low birth weight, as would be expected with conventional immunosuppressive therapy, but the rates of fetal loss and malformation were within the normal range for the general population.170

A 12-year follow-up of 175 children exposed to cyclosporine in utero showed a 16% incidence of mental developmental delay.171 This was attributed to the high incidence of prematurity in the group. A study of seven children exposed tocyclosporine in utero showed a transient minimal effect on fetal immune development, with normal immunoglobulin and complement levels on serologic testing, and normal seroconversion in response to vaccination. The authors concluded that children exposed in utero are unlikely to be at risk of immunodeficiency or autoimmunity.172 Another study examined six infants born to female kidney transplant recipients who had received cyclosporine and methylprednisolone throughout their pregnancies.173 This showed a disturbance of the maturation and development of T cells, B cells, and natural killer cells, which was apparent up to 1 year of age. While there were no clinical signs of immunosuppression, the authors suggested that conventional vaccinations should be delayed in these infants. Despite the aforementioned study showing nephron reduction in rabbits exposed to cyclosporine, there appears to be no nephrotoxic effect in children exposed to cyclosporine in utero.174

Cyclosporine trough levels decrease with pregnancy because of the increased volume of distribution and increased metabolism.175 Because of the unique state of immunologic tolerance afforded by pregnancy, however, a significant proportion of dermatoses improve during pregnancy, making increases in cyclosporine dosages seldom necessary.

Lactation Mothers taking cyclosporine have been advised not to breastfeed because of concerns regarding immunosuppressive effects in the neonate (level IV evidence).11, 48, 49, 50, 176 Cyclosporine is excreted in breast milk, with a wide variation in the milk-to-maternal serum concentration ratio, depending on the time of sampling and maternal dose.177 To date, evidence on the safety of breastfeeding during cyclosporine therapy is limited to two small case series and two case reports. No adverse events related to maternal cyclosporine treatment during lactation have been observed in these reports, and cyclosporineconcentrations in the blood of the infants were undetectable with the exception of one infant.177, 178 While this is reassuring, evidence concerning the safety of breastfeeding is limited and still inconclusive.Back to Article Outline

Pediatric use Key points•There is decreased bioavailability of cyclosporine in children

•Children are less susceptible to cyclosporine-induced nephropathy than adults

Cyclosporine has been used in transplant recipients as young as 1 year of age with no serious adverse effects. The safety and efficacy of both intermittent and continuous cyclosporine therapy in children for the treatment of atopic dermatitis for up to a year at doses of up to 5 mg/kg/day has also been shown (Table II).179, 180, 181, 182 No randomized controlled trials have been performed for pediatric psoriasis, but cyclosporine is often used in the treatment of severe psoriasis in this age group.183 Children are less susceptible to cyclosporine-induced nephropathy than adults.65, 81, 95 This may be because ofdecreased sensitivity to cyclosporine, higher clearance, or decreased bioavailability of the drug. For a given reduction in renal function, however, the incidence of renal vasculopathy is the same. A metaanalysis of cyclosporine use in atopic dermatitis suggested that although the effectiveness was similar in adults and children, tolerability was better in children than in adults.95 In the pooled analysis, only 2.5% of children had an increase in creatinine of more than 30% per month oftreatment and no children developed hypertension.

Discussion and our personal 25-year experience of cyclosporine usage The Baylor University Medical Center (Dallas, TX) has large liver, renal, and bone marrow transplant units. We have been fortunate to have had a close working relationship with their physicians, resulting in our usage of cyclosporine for more than 25 years, particularly for severe psoriasis and atopic dermatitis of all age groups. With the advent of biologic therapies, ouruse of cyclosporine has changed significantly over the past seven years. Cyclosporine is now typically used as a “rescue” or “induction” therapy for periods of up to 6 months because of its rapid onset of action and considerable efficacy. A small subset of patients, particularly the pediatric population, is still treated with maintenance therapy for periods of up to 1 year. Intermittent therapy in psoriasis—with inevitable flares and disappointed, frustrated patients—has become a regimen of the past. In recent years, there have been significant therapeutic advances in psoriasis. Today, the majority of psoriasis patients can expect to achieve prolonged clearance or near-clearance of their disease with the currently available systemic or biologic agents. Similarly, there have been advances in the treatment of pyoderma gangrenosum with biologic agents. New, highly effective, biologic and nonbiologic immunomodulatory agents are in clinical development for the treatment of chronic idiopathic urticaria.184 Progress in the treatment of atopic dermatitis has been more limited, but systemic agents such as azathioprine, methotrexate, interferon-gamma, and mycophenolate mofetil are now more commonly used.There is now a greater appreciation of the importance of disease-related quality of life for dermatologic conditions and the importance of a psychosocial approach to management. Many dermatologic conditions, especially psoriasis and atopic dermatitis, can cause significant psychological and emotional stress for both patients and their families, especially in the younger population groups, with an increased prevalence of depression and poor self-esteem.185, 186, 187 Quality of life can be impaired to a similar extent as is seen in chronic diseases such as diabetes mellitus and coronary heart disease.188,189, 190 Quality of life instruments are increasingly being used to further inform clinical decision making, but a poor correlation has been seen in both psoriasis and atopic dermatitis between objective, clinician-determined clinical extent and subjective, patient-driven quality of life scores.190, 191, 192, 193, 194 What constitutes “significant disease” varies considerably among patients.195, 196 While some patients may be intolerant of even a minor amount of skin disease, others are unperturbed by what many clinicians may consider severe disease. To allow a patient to achieve clearance, raise their expectations, and then subject them to relapse, albeit to a lesser disease extent, in order to be treated with another course ofintermittent therapy may be highly distressing for patients. Having experienced remission, sometimes the first in many years, patients live in fear of return of their disease, and the prospect of relapse can cause significant and unnecessary anxiety. As a result, we personally do not recommend the use of repeated courses of “intermittent therapy” with cyclosporine for psoriasis, but rather its use as a rescue agent for significant flares of psoriasis with continuation of the previous drug or

initiation of another agent as the cyclosporine is tapered. In the treatment of atopic dermatitis, particularly in pediatric and adolescent patients, we will frequently recommend continuous rather than intermittent therapy for up to a year for a more consistent control of disease and resultant improvement in quality of life, especially in younger patients. Rotational therapy with azathioprine or methotrexate may also minimize toxicity while allowing a more stable disease course.Back to Article Outline

Conclusion In summary, since its advent in 1972, cyclosporine has played a very valuable role, not only in the treatment of many dermatoses but also in the expansion of our knowledge of the immunopathophysiology of many dermatologic conditions. Its serendipitous discovery in 1979 for psoriasis changed the entire field of psoriasis research from that of a hyperproliferative, keratinocyte-driven disorder to that of an “immune-driven” disease, paving the way for the subsequent biologic revolution in psoriasis. Because of its rapid onset of action and marked efficacy, cyclosporine is particularly useful in the treatment ofsignificant flares of cutaneous disease—especially psoriasis and atopic dermatitis—that are unresponsive to other therapies, and also as a bridging agent during the induction of other maintenance agents. With a growing armamentarium oftherapeutic alternatives, intermittent therapy should no longer be necessary and long-term treatment with cyclosporine is only advocated in exceptional cases. In these patients, combination or rotational therapy can be used to minimize cumulative dosage and long-term side effects. In general, however, treatment for more than 1 year should be avoided where possible. Side effects are dose dependent, related to the duration of therapy, and reversible on discontinuation once treatment guidelines are followed and careful monitoring is practiced. Cyclosporine is a drug in common use in our clinical practice and one we are very comfortable with, provided that the aforementioned guidelines are closely followed. It is a drug that should be an integral part of our therapeutic armamentarium and be considered for broader use by the dermatologic community.

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 We thank Drs Stacy Hinson and Nesrin A. Onur for their histopathologic image of chronic cyclosporine-induced nephropathy, and Cristina Martinez for her technical support.