The use of cyclosporine in dermatology

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 objectives
After completing this learning activity, participants should be able to describe the
mechanism of action of cyclosporine, recognize the potential role of cyclosporine in
dermatology and the evidence to support this role, and incorporate cyclosporine into his
or her prescribing regimens.

History
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.

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

Mechanism 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

 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.

•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
25
necessary. Current guidelines limit the continuous use of cyclosporine in the United
States to 1 year,26 with those in the United Kingdom and Europe recommend a limit of 2
years (level IV evidence).11, 21 Five schedules are available for the use of cyclosporine
in psoriasis (Table I).


 View Large Image
 Download to PowerPoint
 Fig 3.
Psoriasis treated with cyclosporine. A, Precyclosporine therapy. B, Postcyclosporine
therapy.
Table I. Cyclosporine therapy for dermatologic diseases

Disease CsA dose Duration of Response Time to Other drugs Commen

treatment relapse
after
discontinue
d

Psoriasis 12-16 wks, 12 Excellent Average

mos maximum 111 days;
however,
30% had no
relapse 6
mos after
CsA
discontinue
d

A. Intermittent 2.5-5
short-term mg/kg/day
therapy for 12-16
Disease CsA dose Duration of Response Time to Other drugs Commen
treatment relapse
after
discontinue
d

wks, course
repeated
when
relapse
occurs

B. Rescue 5 mg/kg/day
therapy for 12-16
wks for
flaring of
disease

C. Long term <5

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

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

E. Rotational Can mi
therapy CsA toxic

Psoriatic arthritis 3-4 6-12 mos Very good MTX 15 mg/wk, 50% red
mg/kg/day, occasionally in
max 5 complaint
mg/kg/day required 2
of
monother
CsA-MTX
Disease CsA dose Duration of Response Time to Other drugs Commen
treatment relapse
after
discontinue
d

combinati
therapy g
patients
partial
response

Atopic 2.5-3 12-16 wks, 12 Excellent 2 wks Used for

dermatitis mg/kg/day, mos max (50%), 6 treatment
max 5 wks (80%) severe,
mg/kg/day dermatitis
cannot
controlled
topical th
Approved
this ind
in Europ
the UK

Pyoderma 5 mg/kg/day >6 mos Excellent Methylprednisolon

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

Dyshidrotic 2.5-3 6 wks, up to 16 Equivalent 77% of CsA equ

eczema mg/kg/day wks patients to BDP cr
continued to
have a 54%
improveme
nt at 1 y

Chronic urticaria 4 mg/kg/day 12-16 wks Very good 33% at 3-6 Cetirizine 10 Used to
mos, relapse mg/day, chronic ur
less severe occasionally as a
concurrently sparing ag
in
refractory
corticoste

Behçet disease 5 mg/kg/day >6 mos Very good Prednisone, Used

Disease CsA dose Duration of Response Time to Other drugs Commen
treatment relapse
after
discontinue
d

occasionally refractory
disease,
steroid–re
mucocuta
disease,
arthritis.
prevention
neurologi
involvem

Pityriasis rubra 3-5 >8 mos Mixed Used

pilaris mg/kg/day, erythrode
maintenance classic
dose 2 and
mg/kg/day erythrode
juvenile P

Dermatomyositis 1-1.8 Very good Prednisone 40 Used in

mg/kg/day, mg/day not resp
>200 to pred
mg/day combined
MTX
azathiopri
Effective
lung
esophagea
involvem

Pemphigus 1-3 8 mos ± 11.8 Good, but 43% free of Prednisone, usually Used a
vulgaris mg/kg/day mos better relapse after given concurrently steroid s
treatment combination agent
options therapy with
available cyclosporin
e and
prednisone
5 y after
discontinuat
ion of
therapy

Epidermolysis 4-5 1-24 mos Good, but Prednisone, usually Used a

Disease CsA dose Duration of Response Time to Other drugs Commen
treatment relapse
after
discontinue
d

bullosa acquisita mg/kg/day better given concurrently steroid s

treatment agent
options
available

Photodermatoses

A. Chronic 4-4.5 Good

actinic mg/kg/day
dermatitis

B. 3-4 May be given 1 Good

Polymorphic mg/kg/day wk before sun
light eruption exposure, and
discontinued
upon return

C. Solar 4.5 Short courses Flares once

urticaria mg/kg/day during summer cyclosporin
months e
discontinue
d

Lichen planus 3-4.5 2-3 mos Good Prednisone, Used

mg/kg/day occasionally dissemina
topical steroids lichen p
erosive
planus,
lichen
resistant
systemic
corticoste
and ret
Topical
may
effective
treatment
oral
planus

Lichen 3-5 3-5 mos Good Symptom CsA ma

Disease CsA dose Duration of Response Time to Other drugs Commen
treatment relapse
after
discontinue
d

planopilaris mg/kg/day free, stable effective

disease at initial
12 mos before
postcyclosp follicular
orine damage o

Prurigo 3.5-4 6-9 mos Good

nodularis mg/kg/day

Severe alopecia 5 mg/kg/day 2-12 mos Mixed 33%-86% Methylprednisolon Eight

areata with >70% e (pulse and daily reports
hair dosing), prednisone patients
regrowth, developed
76% with alopecia
maintained while on
hair for solid
regrowth at transplant
12 mos atopic
follow-up dermatitis

Benign familial 1.2-3.4 6-8 mos Good Acitretin 10

pemphigus mg/kg/day mg/day,
(Hailey-Hailey) occasionally

Eosinophilic 100-150 2-12 wks Good

pustular mg/day
folliculitis

Hidradenitis 4-4.5 Good Prednisolone,

suppurativa mg/kg/day broad spectrum
antibiotics

Scleroderma May pote

worsen
hypertens
renal d
associated
systemic
sclerosis
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
33 36 9 40
corticosteroids, , anthralin, or vitamin D3 analogues for an improved response.
Systemic treatments, such as methotrexate, fumaric acid esters, and mycophenolate
mofetil, can also be used in combination with cyclosporine in severe cases, allowing for
dose reduction of cyclosporine to minimize toxicity.41, 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 Outline
Conclusion
Cyclosporine continues to play an important role in the field of dermatology. We strongly
recommend cyclosporine for short-term “rescue” treatment of psoriasis and atopic
dermatitis in appropriate patients. Although randomized controlled trials have not been
undertaken, multiple case reports have also shown excellent results when cyclosporine
is used for the treatment of pyoderma gangrenosum. We also recommend cyclosporine
for treatment of refractory chronic idiopathic urticaria and cyclosporine in combination
with corticosteroids for the treatment of dermatomyositis with esophageal and
pulmonary involvement. Although cyclosporine is effective in the treatment of 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
. Renal dysfunction
0. Vascular dysfunction
1. Tubular dysfunction
A. Chronic nephrotoxicity
0. Vasculopathy
1. Tubulopathy
B. Recommendations
C. Hypertension
D. Recommendations
E. Malignancy potential
F. Neurologic side effects
 G. Gastrointestinal side effects
H. Gingival hyperplasia
I. Cutaneous side effects
J. Infections
K. Other side effects
L. Hyperlipidemia
M. Recommendations
N. Other laboratory abnormalities
VI. Monitoring
. Screening and history
A. Baseline laboratory investigations
B. Regular follow-up investigations
C. Annual investigations
D. Cyclosporine serum concentrations
E. Vaccinations
VII.Pregnancy
. Lactation
VIII. Pediatric use
. 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 objectives
After 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 Outline
Pharmacokinetics
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
45 46
administration. , 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 Outline
Contraindications
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
irradiation
Radiotherapy

Table II. Adverse events in studies of cyclosporine use (n > 50 patients) in psoriasis and
atopic dermatitis
Study, study type, No. ofpatients/duration AE requiring Renal Hypertension GI side
dose (mg/kg/day) discontinuation dysfunction effects

Psoriasis short-term therapy

Ellis et al,164 RCT 85/16 wks 5% overall NA NA

3 mg/kg/d 28%

5 mg/kg/d 55%

7.5 mg/kg/d 47%

Ho 400/<12 wk IT, for 1 y 4% 30% 12% 11% GS

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

Ho et al,77 PO, 76/<12 wk IT, for 2 y 7% 24% 24% 36% N

2.5-5 mg/kg/d

Faerber 597/<12 wk IT 4.1%

et al,78 MA

1.25 mg/kg/d — 5% 3% GS

2.5 mg/kg/d 1% 14% 8% GS

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

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

8
et al, RNCT, 2.5-5
mg/kg/d
Study, study type, No. ofpatients/duration AE requiring Renal Hypertension GI side
dose (mg/kg/day) discontinuation dysfunction effects

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

Krupp 631/12 wks to 16 mos 5.9% NA NA 3.8% N,

116
et al, MA, 1.25-5 1.1% V,
mg/kg/d 2.3% AP,
2% D, 1.1%
GS

Psoriasis long-term therapy

Christophers 217/12-36 wks

et al,55 RCT

1.25 mg/kg/d 1.8% 1% 11% 3.7% GS

2.5 mg/kg/d 3.2% 5% 21% 4.4% GS

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

Mrowietz 88/6-30 mos 6% 5% 8% 22% GS

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

Shupack 181/40 wks

et al,86 RCT

5 mg/kg 7% 42.5% 8.8% 12% N

induction for
Study, study type, No. ofpatients/duration AE requiring Renal Hypertension GI side
dose (mg/kg/day) discontinuation dysfunction effects

16wks

1.5/3 11% 17% of 3

mg/kg/d or mg/kg,
placebo for 24 wks 10%of placebo

Laburte 251/21 mos 18%

et al,68 RNCT

2.5 mg/kg/d 45.2% 27.4% 11.3% N

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

Grossman 122/3-76 mos 4% 43% 24% 6%

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

Atopic dermatitis short-term therapy

Berth-Jones 100/48 wks 14% 45% 5% 66%

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

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

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

Schmitt 602/6 wks-12 mos Adults, Adult, Adults, Adults GS,

et al,95 MA∗ 1.6%/mo; 3.2%/mo; 1.6%/mo; 18.1%/mo;
children, children, children children
Study, study type, No. ofpatients/duration AE requiring Renal Hypertension GI side
dose (mg/kg/day) discontinuation dysfunction effects

0.8%/mo∗ 2.5%/mo∗ 0%/mo∗ GS,

17.5%/mo∗

Atopic dermatitis long-term therapy

Hijnen 73/>6 mos (mean, 1.3 y) 16% 10% 15% 5% N

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

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 Outline
Adverse 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 IV
malignancy; full medication history, which should be repeated at every subsequent visit

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

Physical Actinic damage/cutaneous malignancies; herpes simplex; viral warts

examination

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

count

Potassium Baseline, then monthly

Bilirubin, liver Baseline, then monthly

enzymes

Fasting lipid profile Baseline, then monthly

Uric acid Baseline, then monthly

Investigation Details Level ofevidence

Magnesium Baseline, then monthly

Urinalysis Baseline, then monthly

Tuberculin test Baseline

Glomerular filtration After 1 y of continuous therapy

rate

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
Back to Article Outline
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.
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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.
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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.