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VÊ Karrie T. Amor, MD
,
VÊ ×aitriona Ryan, MBB× , BAO
,
VÊ Alan Menter, MD
VÊ Abstract
VÊ J ll Text
VÊ 2DJ
VÊ `mages
VÊ References
{
 

`.Ê Abstract
``.Ê History
```.Ê Mec anism of action
` .Ê ×linical ses of cyclosporine and regimens
A.Ê 2soriasis
1.Ê `ntermittent s ort-term t erapy
2.Ê Resc e t erapy
3.Ê Long-term t erapy
4.Ê ×ombination t erapy
5.Ê Rotational t erapy
B.Ê 2soriatic art ritis
×.Ê Atopic dermatitis
D.Ê 2yoderma gangrenos m
0.Ê ×ase reports
E.Ê Dys idrotic eczema
J.Ê × ronic rticaria
G.Ê Be
et disease
H.Ê 2ityriasis r bra pilaris
`.Ê Dermatomyositis
J.Ê 2emp ig s v lgaris
K.Ê Epidermolysis b llosa acq isita
L.Ê 2 otodermatoses
0.Ê × ronic actinic dermatitis
1.Ê 2olymorp ic lig t er ption
2.Ê Solar rticaria
M.Ê Lic en plan s
N.Ê Lic en planopilaris
O.Ê 2r rigo nod laris
2.Ê Severe alopecia areata
Q.Ê Benign familial pemp ig s (Hailey-Hailey disease)
R.Ê Eosinop ilic p st lar follic litis (Of
i disease)
S.Ê Hidradenitis s pp rativa
T.Ê Scleroderma
.Ê ×oncl sion
`.Ê References
``.Ê ×opyrig t
×yclosporine is a calcine rin in ibitor t at acts selectively on T cells. `t as been sed in
dermatology since 1997 for its US Jood and Dr g Administration indication of psoriasis and off-
label for vario s ot er inflammatory skin conditions, incl ding atopic dermatitis, blistering
disorders, and connective tiss e diseases. `n t e last decade, many dermatologists ave esitated
to se t is important dr g in t eir clinical practices beca se of its toxicity profile. T e p rpose of
t is article is to review t e mec anism of action of cyclosporine and its c rrent ses and dosing
sc ed les. `t is o r goal to create a framework in w ic dermatologists feel comfortable and safe
incorporating cyclosporine into t eir prescribing regimens.

  


After completing t is learning activity, participants s o ld be able to describe t e mec anism of
action of cyclosporine, recognize t e potential role of cyclosporine in dermatology and t e
evidence to s pport t is role, and incorporate cyclosporine into is or er prescribing regimens.
Key words: atopic dermatitis, c ronic rticaria, cyclosporine, psoriasis, pyoderma gangrenos m

×aps le S mmary
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Key points
‡×yclosporine was first sed to prevent re
ection in solid organ transplant recipients

‡×yclosporine was approved by t e US Jood and Dr g Administration for t e treatment of psoriasis

in 1997

`n 1970, cyclosporine, also known as cyclosporin A (×sA), was isolated from t e soil
f ng s Tolypocladi m inflat m Gams by Borel at Sandoz Laboratories in Basel, Switzerland, w ile
looking for novel antif ngal agents.1 Alt o g it was initially noted to ave only a narrow antif ngal
spectr m, cyclosporine was s bseq ently fo nd to be a potent imm nos ppressive dr g in
1976.1 `n 1978, cyclosporine was fo nd to be s ccessf l in preventing re
ection in renal transplant
patients w o received mismatc ed cadaver kidneys.2 `n 1979, cyclosporine was first observed to
improve psoriasis d ring a pilot st dy to investigate t e efficacy of cyclosporine in r e matoid
art ritis and psoriatic art ritis.3 T e original form lation of cyclosporine (Sandimm ne; Novartis,
East Hanover, NJ) was approved by t e United States Jood and Dr g Administration (JDA) for t e
prevention of transplant re
ection in 1983. `n 1995, Neoral (Novartis), a microem lsion form lation
of cyclosporine t at is more bioavailable and more consistently absorbed, was approved by t e
JDA for t e prevention of transplant re
ection. Neoral was t en approved for t e treatment of
r e matoid art ritis and psoriasis in 1997. Since t en, t e JDA as not approved cyclosporine for
t e treatment of ot er clinical indications in dermatology, b t it as been approved for se in atopic
dermatitis in ot er co ntries.
Str ct re. ×yclosporine is a cyclic polypeptide imm nos ppressant agent consisting of 11 amino
acids (Jig 1).4 `t is prod ced as a metabolite by t e f ng s species Bea veria nivea.
 VÊ
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Molec lar str ct re of cyclosporine. ×yclosporine is a cyclic polypeptide imm nos ppressant
agent consisting of 11 amino acids.
Back to Article O tline
©
   
Key points
‡×yclosporine forms a complex wit cyclop ilin, w ic inactives calcine rin p osp orylase,
preventing t e p osp orylation of n clear factor of activated T cells and, t erefore, t e
transcription of interle kin-2

‡`nterle kin-2 is req ired for f ll activation of t e T-cell pat way

×yclosporine was t e first imm nos ppressive dr g fo nd to act selectively on T cells. T e elper
T cell is t e main target, b t t e T s ppressor cell may also be affected. ×yclosporine forms a
complex wit cyclop ilin, an intracell lar imm nop ilin, and in ibits t e activity of calcine rin
p osp atase, a calci m/calmod lin-dependent serine-t reonine p osp atase (Jig 2).5, 6, 7 As a
res lt, calcine rin p osp atase is nable to p osp orylate n clear factor of activated T cells
(NJAT), a transcription factor. NJAT req ires p osp orylation before transportation to t e n cle s
for transcription of genes encoding interle kin-2 (`L-2), a cytokine t at is necessary for f ll
activation of t e T-cell pat way, interferon-gamma, and gran locyte-macrop age colony-
stim lating factor (GM-×SJ).5, 7 ×onseq ently, cyclosporine depletes lymp ocytes and
macrop ages in t e epidermis and dermis8 and in ibits t e activation of T cells, nat ral killer cells,
and antigen-presenting cells. ×yclosporine also in ibits keratinocyte yperproliferation,9 in ibits
t e release of istamine from mast cells, and downreg lates t e expression of cell lar ad esion
molec les on dermal capillary endot eli m.10

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Mec anism of action of cyclosporine. `n t e cytoplasm, cyclosporine (×sA) binds to its
imm nop ilin, cyclop ylin (×pN), forming a complex between ×sA and ×pN. T e ×sA±×pN
complex binds and blocks t e f nction of t e enzyme calcine rin (×aN), w ic as a
serine/t reonine p osp atase activity. As a res lt, ×aN fails to dep osp orylate t e cytoplasmic
component of t e n clear factor of activated T cells (NJ-ATc), and t ereby t e transport of NJ-ATc
to t e n cle s and t e binding of NJ-ATc to t e n clear component of t e n clear factor of
activated T cells (NJ-ATn). T e NJ-ATc±NJ-ATn complex binds to t e promoter of t e interle kin 2
(`L-2) gene and initiates `L-2 prod ction. ×onseq ently, T cells do not prod ce `L-2, w ic is
necessary for f ll T-cell activation.
© ×ambridge Jo rnals, reprod ced wit permission.6
Back to Article O tline
   
 

 


Key points
‡×yclosporine is sef l for t e s ort-term treatment of psoriasis and atopic dermatitis

‡M ltiple case reports ave s own cyclosporine to ave excellent res lts w en sed for t e
treatment of pyoderma gangrenos m

‡×yclosporine is sef l for t e treatment of refractory c ronic idiopat ic rticaria


×yclosporine is one of t e most effective treatments for psoriasis beca se of its rapid onset of
action. `n patients wit severe psoriasis nresponsive to ot er treatments, cyclosporine can ind ce
a rapid remission, and can be sed as a bridge to ot er t erapies (Jig 3).11 A very ig dose was
sed in t e first controlled st dy in 1986 to eval ate t e efficacy of cyclosporine in psoriasis (14
mg/kg/day). T is res lted in marked improvement in 20 of 21 patients wit in 4
weeks.12S bseq ently, a m ltit de of dose-finding st dies ave been performed in order to
el cidate t e optimal and lowest effective dose of cyclosporine t at ac ieves clearance wit
minimal toxicity.13, 14, 15, 16, 17 Efficacy of cyclosporine is dose dependent, wit a s orter time to
remission at ig er doses.15, 18 Benefit in efficacy gained by sing doses ig er t an 5 mg/kg/day
is, owever, offset by an increase in toxicity.19 × rrent consens s g idelines recommend a starting
dose of 2.5 mg/kg/day, nless a rapid improvement is considered necessary, w en a dose of p to 5
mg/kg/day may be sed (level ` evidence).11, 16, 18, 20 Jailing an adeq ate response wit low dose
cyclosporine after 4 weeks of treatment, t e dose can be increased grad ally by 0.5 to 1.0
mg/kg/day at 2- to 4-week intervals, to a maxim m of 5 mg/kg/day (level `
evidence).11Tac yp ylaxis is not observed in t ose w o do start at lower doses wit s bseq ent
increments.15 `f an adeq ate response as not been ac ieved after 3 mont s of treatment at a dose
of 5 mg/kg/day, cyclosporine s o ld be wit drawn. Once a good response is obtained, t e dose can
be red ced in steps of 0.5 to 1.0 mg/kg/day at two weekly intervals to t e lowest possible dose t at
maintains control of disease (level ` evidence). Jor palmoplantar p st losis, an initial starting
dose of 4 to 5 mg/kg/day is s ggested (level ` evidence), wit red ction according to clinical
response,21 despite randomized, controlled trials w ic ave s own t at doses of 1 to
 2.5 mg/kg/day are effective in red cing t e p st le co nt by 50%.22, 23 Low dose cyclosporine as
been sed to treat acrodermatitis contin a of Hallopea ,24 b t ig er doses are s ally
necessary.25× rrent g idelines limit t e contin o s se of cyclosporine in t e United States to 1
year,26 wit t ose in t e United Kingdom and E rope recommend a limit of 2 years (level `
evidence).11, 21 Jive sc ed les are available for t e se of cyclosporine in psoriasis (Table `).

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2soriasis treated wit cyclosporine. A, 2recyclosporine t erapy. B, 2ostcyclosporine t erapy.
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BD2, Betamet asone-17,21-diproprionate; ×sA, cyclosporine A; MTX, met otrexate; 2R2, pityriasis
r bra pilaris.

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`ntermittent s ort-term t erapy
`ntermittent s ort-term t erapy (12-16 weeks) is t e most freq ently recommended regimen, sing
s ort co rses of cyclosporine ntil significant improvement is ac ieved, after w ic treatment is
wit drawn. `f relapse occ rs, cyclosporine t erapy is reinstit ted at t e previo sly effective
dose.11, 26, 28, 29, 30 `n a st dy of 400 patients wit severe psoriasis, 80% of patients req ired only
one or two co rses over a 1-year st dy period, and 45% of patients were still in remission 4 mont s
after completion of t e first co rse of treatment.29, 30 T is st dy also s owed t at tapering t e dose
by 1 mg/kg/week ntil cessation, vers s stopping abr ptly, res lted in a marginal increase in
remission d ration of 4 days, wit 11 to 23 days of extra t erapy req ired in t e tapering gro p. An
extension of t is st dy o t to 2 years s owed t at most patients req ired fewer t an fo r co rses
of treatment over 2 years, receiving cyclosporine for
st 43% (approximately 10 mont s) of t e
total 24-mont st dy period. Little to no rebo nd was noted after treatment wit drawal in eit er t e
abr pt cessation or tapered cessation gro ps.30 Anot er st dy s owed t at contin ing
cyclosporine for p to 4 weeks after clinical clearance conferred no advantage wit regard to
relapse rates.31
Resc e t erapy
A s ort co rse of cyclosporine can be sed in severe flares of disease as ³resc e´ or ³bridging´
t erapy beca se of its rapid onset of action ntil an alternative maintenance treatment is instit ted.
T is is partic larly sef l in t e treatment of eryt rodermic, s beryt rodermic, or generalized
p st lar psoriasis. `n t is instance, a red cing dose approac is sed s bseq ent to commencing
at a dose of 5 mg/kg/day.11, 26, 27 `n an open-label m lticenter st dy of 33 patients wit
eryt rodermic psoriasis treated initially wit cyclosporine 4.2 mg/kg/day, t en grad ally decreased
after remission by 0.5 mg/kg/day every 2 mont s,32 67% ac ieved complete remission and 27%
ac ie-ved significant improvement at 2 to 4 mont s. Overlapping cyclosporine wit alternative
treatments, s c as met otrexate and biologic t erapies, can avoid f rt er deterioration of disease
at t e early stages of treatment w ile t e new dr g is taking effect. ×yclosporine can t en be
wit drawn wit o t t e danger of flaring and wit minimal risk of side effects for t e s ort period
t at t e two dr gs are sed sim ltaneo sly.
Long-term t erapy
`n psoriasis, efficacy is maintained wit long-term t erapy in t e ma
ority of
patients.10, 31, 33, 34, 35 T e aim of maintenance t erapy is not necessarily to ac ieve complete
clearance b t to attain a significant clinical improvement wit t e lowest effective dose. T e
maintenance dose typically sed is 3.0 to 3.5 mg/kg/day.19 A comparison of a minim m of 36
mont s intermittent t erapy to contin o s t erapy s owed t at an average dose of 3.06 mg/kg/day
intermittent t erapy maintained remission for 32% of t e time vers s t e average contin o s dose
of 3.2 mg/kg/day w ic maintained remission for 69% of t e time.36 `n anot er st dy comparing
intermittent 12-week co rses to contin o s t erapy for 1 year, 62% of t e intermittent gro p (mean
dose, 3 mg/kg/day) ac ieved a 75% red ction in t e 2soriasis Area and Severity `ndex score
compared wit 92% of t e contin o s gro p (mean dose, 1.8 mg/kg/day). T ose on contin o s
dosage req ired 139% of t e mean c m lative ann al dose req ired for t e intermittent
gro p.37 A dose-finding st dy for maintenance t erapy s owed t at after ind ction for 16 weeks, a
maintenance dose of 3 mg/kg/day was significantly s perior to a dose of 1.5 mg/kg/day or placebo
in preventing relapse. T is occ rred at a median of 6 weeks in bot t e placebo and 1.5 mg/kg/day
gro p, w ile only 42% s owed evidence of relapse d ring 24 weeks¶ maintenance in t e 3
mg/kg/day gro p.38 Similarly, wit regard to remission d ration, anot er st dy s owed no
significant difference in time to relapse between a maintenance dose of 1.5 mg/kg/day and placebo.
T ose treated wit a 3 mg/kg/day maintenance dose ad a mean time to relapse of 12 weeks, and
t is dosage was recommended as t e optim m maintenance dose.39
×ombination t erapy
×yclosporine can be combined wit topical t erapies, s c as corticosteroids,33, 36 ant ralin,9 or
vitamin D3 analog es40for an improved response. Systemic treatments, s c as met otrexate,
f maric acid esters, and mycop enolate mofetil, can also be sed in combination wit cyclosporine
in severe cases, allowing for dose red ction of cyclosporine to minimize toxicity.41, 42, 43, 44 T ere is
no evidence of additive efficacy w en combined wit acitretin.45
Rotational t erapy
Rotational t erapy wit t e aforementioned systemic agents can also be sed to minimize d ration
of cyclosporine treatment and toxicity.26, 46 Tac yp ylaxis wit cyclosporine does not appear to
occ r in t e treatment of psoriasis.27, 33, 47W ile t e ma
ority of patients will req ire f rt er
antipsoriatic treatment after cyclosporine wit drawal,10, 31 patients may occasionally ave a
prolonged or s stained remission after a treatment co rse.29, 30, 48 Time to relapse depends on t e
severity of disease, t e dose of cyclosporine req ired to ac ieve clearance, and t e extent of
clearing ac ieved before termination of t e dr g.11, 39 `n st dies meas ring time to relapse of
psoriasis, 50% to 60% of patients relapsed 6 mont s after treatment wit drawal.27 Rebo nd flare on
abr pt wit drawal of treatment (>125% of baseline 2soriasis Area and Severity `ndex score) as not
been observed in st dies of cyclosporine treatment in psoriasis or palmoplantar
p st losis.10,23, 26, 27, 33, 34
× rrent American Academy of Dermatology (AAD) g idelines s ggest t at intermittent t erapy is
preferable to long-term treatment, t at treatment regimens be tailored to t e individ al needs of
eac patient, and t at d ration of contin o s treatment s o ld be kept below 1 year w enever
possible.
 
2soriatic art ritis as t e potential to become a destr ctive deforming art ropat y. × rrently, t e
initial treatment of early onset psoriatic art ritis incl des nonsteroidal antiinflammatory dr gs
(NSA`Ds) and, on occasion, local steroid in
ections. Disease modifying antir e matic dr gs
(DMARDs) are reserved for cases t at are resistant to NSA`Ds or w en progressive disease is
present. T e most widely sed DMARDs for psoriatic art ritis incl de met otrexate, s lfasalazine,
and cyclosporine.49 Anti±t mor necrosis factor-alfa agents ave t e significant advantage of
limiting f rt er
oint destr ction.
×yclosporine is an effective treatment for psoriatic art ritis, eit er alone or in combination wit
met otrexate. `n 1989, significant improvement in
oint tenderness, mean grip strengt , and activity
level was noted in six psoriatic art ritis patients treated wit cyclosporine 6 mg/kg/day for 8 weeks.
However, 2 weeks after discontin ation of cyclosporine,
oint pain and swelling rec rred.50 `n an
open-label prospective st dy, all seven patients wit psoriatic art ritis ad improvement of
oint
pain and swelling after cyclosporine 3.5 mg/kg/day for 6 mont s. T e time to relapse was not
doc mented in t is st dy.51 `n anot er st dy, 12 patients w o ad failed second-line psoriatic
art ritis treatment were treated wit cyclosporine 3 mg/kg/day for 6 mont s. At t e end of t e
treatment period, seven patients ad a greater t an 50% red ction in t eir
oint tenderness and
swelling, fo r patients ad stable disease, wit one patient wit drawn early beca se of significant
nep rotoxicity.52 An observational st dy of 55 patients wit psoriatic art ritis treated wit
cyclosporine (2.7 mg/kg/day) revealed t at a 50% red ction in
oint complaints req ired a total of 24
weeks of treatment. Eig teen of t e 55 patients were followed for 8 mont s after cyclosporine
t erapy, of w om 11 (61%) contin ed to ave improvement or stable disease.53 A 1-year
prospective, controlled randomized trial wit 35 patients was cond cted to compare t e
effectiveness and toxicity of cyclosporine (3-5 mg/kg/day) vers s low-dose met otrexate (7.5-15
mg/week) in t e treatment of psoriatic art ritis. At bot 6 and 12 mont s of treatment, t e n mber of
painf l
oints, swollen
oints, t e Ritc ie index, t e d ration of morning stiffness, grip strengt , and
×-reactive protein (×R2) levels were red ced eq ally in bot treatment gro ps. However, at t e
concl sion of 1 year, more patients wit drew from t e cyclosporine arm (41.2% vs 27.8%; not
statistically significant).54
A 12-mont randomized, m lticenter, do ble-blind, placebo controlled trial was cond cted by
Jraser et al49 to st dy t e safety and efficacy of combining cyclosporine wit met otrexate in t e
treatment of patients wit psoriatic art ritis wit a previo s incomplete response to met otrexate
monot erapy. Of t e 72 patients recr ited, 38 were randomized to receive cyclosporine in addition
to met otrexate (15 mg/week), wit t e remaining 34 randomized to receive placebo pl s
met otrexate (15 mg/week). T e initial dose of cyclosporine was 2.5 mg/kg/day, wit dose
increments at weeks 4, 8, and 12 increasing by 0.5 mg/kg/day to a maxim m dose of 4 mg/kg/day if
tolerated. Significant improvement in swollen
oint co nt (11.7 vs 6.5; 2 = .001) and ×R2 levels (17.4
vs 12.7 mg/L; 2 = .05) was seen in t e met otrexate-cyclosporine arm compared to baseline, b t not
in t e met otrexate-placebo gro p. Also, a significant red ction in synovitis was seen in t e
met otrexate-cyclosporine arm compared to t e met otrexate-placebo gro p (33% red ction vs 6%
red ction, respectively;2 = .05). A significant difference in pain and q ality of life was not detected
in t is st dy. Of t e patients t at wit drew early from t e st dy, 13 of t e 17 patients in t e
met otrexate-cyclosporine arm wit drew beca se of adverse effects vers s only two of t e 11
patients in t e met otrexate-placebo arm wit drew for t e same reason.49

{


×yclosporine is t e only imm nos ppressant approved in E rope and t e United Kingdom for t e
s ort-term treatment of severe atopic dermatitis t at cannot be controlled wit topical t erapy.
W ile cyclosporine does not ave formal JDA approval for t is se,55 it as been recommended by
t e AAD G idelines of ×are committee as being effective for t e treatment of atopic dermatitis
refractory to conventional treatment wit no statement as to t e recommended dosage.56 `n t e
treatment of atopic dermatitis wit cyclosporine, a regimen commencing at 5 mg/kg/day for 2 weeks
wit a grad al tapering as dictated by t e clinical response over t e ens ing 3 mont s to a dose of
1.5 mg/kg/day w ere possible as been s ggested.21, 57,58, 59, 60
`n 2007, Sc mitt et al61 performed a systematic review and metaanalysis of controlled and
ncontrolled trials of cyclosporine for t e treatment of severe atopic dermatitis. Jifteen st dies t at
incl ded a total of 602 patients were analyzed. All of t e st dies reported a decrease in t e mean
severity of atopic dermatitis after cyclosporine treatment, wit a 50% decrease in severity after 6 to
8 weeks of contin o s cyclosporine treatment being noted in t e ma
ority of st dies. 2atients
treated wit a ig er initial dose (4-5 mg/kg/day) ad a more rapid improvement at 2 weeks (40%
decrease in severity) t an t ose treated wit a lower initial dose (2.5-3 mg/kg/day; 22% decrease in
severity). However, at 6 to 8 weeks, t ere was no difference in response between t e two dose
gro ps. T ose receiving t e ig er dose reported a greater n mber of cyclosporine-related side
effects.
Two randomized controlled st dies treated severely atopic dermatitis patients wit long-term
cyclosporine t erapy. Harper et al62 compared intermittent 12-week co rses of cyclosporine
(5 mg/kg/day) wit a contin o s 1-year co rse of cyclosporine 5 mg/kg/day for t e treatment of
severe atopic dermatitis in c ildren (2-16 years of age). T e patients treated wit t e s ort co rse
regimen (defined as co rses of 12 weeks¶ d ration wit at least 7 days in between eac co rse) ad
variable res lts. Seven of t e 19 patients in t e s ort co rse arm were controlled on t e s ort
co rse regimen, of w om t ree req ired one s ort co rse only and fo r were managed wit two or
t ree co rses. Jo r of t e 12 patients nresponsive to t e intermittent 12-week s ort-term regimen
req ired treatment co rses of greater t an 12 weeks to ac ieve remission, w ile eig t co ld not be
controlled on extended cyclosporine t erapy. `n t e contin o s cyclosporine (5 mg/kg/day) arm, 15
of 16 patients ac ieved remission wit in t e first 12 weeks, w ic was maintained for t e d ration
of t e st dy. Q ality of life scores ad improved significantly by week 12 for bot gro ps b t only
remained significant at 12 mont s sing t e contin o s dosing regimen. T ere were no significant
differences in efficacy, renal profile, or blood press re between t e gro ps. W ile t e improvement
was more constant in t e contin o s gro p, t e c m lative dose sed was ig er. Zonneveld
et al63 randomly assigned 78 severe atopic dermatitis patients to two long-term cyclosporine dosing
regimens for t e treatment of severe atopic dermatitis.63 One gro p initially received cyclosporine 5
mg/kg/day, decreased to 3 mg/kg/day as tolerated, and t e ot er gro p received 3 mg/kg/day,
increased to 5 mg/kg/day as needed. T e patients were maintained on t eir optimal dose for 10
mont s. After 1 year, t e efficacy of cyclosporine was 59.8% and 51.7%, respectively. T e two
treatment regimens were well tolerated wit similar safety profiles.
A comparison of red cing dose regimens after an ind ction of 5 mg/kg/day s owed t at
maintaining a dose of 5 mg/kg/day b t increasing t e interval between doses by 1 day every 2
weeks was as efficacio s as red cing t e daily dose by 1 mg/kg/day every 2 weeks.64 As wit
psoriasis, if maintenance t erapy is needed, t e lowest effective dose s o ld be sed.60
T ree st dies ave examined relapse rates after wit drawal of cyclosporine (defined as increase in
disease severity to more t an 75% of individ al baseline score, w ere topical steroids were sed to
treat patients after t e completion of cyclosporine t erapy.57 Granl nd et al65 fo nd t at 50% of
patients relapsed wit in 2 weeks and 80% relapsed wit in 6 weeks after discontin ing cyclosporine.
Similarly, Atakan and Erdem66 reported t at 75% relapsed at 24 weeks postcyclosporine, w ile
Harper et al62 fo nd t at 86% ad relapsed 9 mont s after cyclosporine t erapy was discontin ed.
T ere is typically a worsening of disease on wit drawal of cyclosporine, b t t e extent of disease
and symptom scores remain better t an at baseline in t e posttreatment period, s ggesting a
possible s stained remission in some patients.67, 68, 69
`n a metaanalysis by Sc mitt et al,61 t ere was no evidence of a rebo nd p enomenon on
wit drawal of cyclosporine.61, 70One isolated retrospective st dy, owever, did report a rebo nd
p enomenon in a small proportion of patients.71`nterestingly, t is coincided wit a large increase in
ser m imm noglob lin E levels d ring cyclosporine treatment in t ese patients, wit a parallel
increase in levels of t ym s and activation-reg lated c emokine (TAR×/××L17). A s ift to a TH2
response, mediated by cyclosporine, was s ggested by t e a t ors as a possible ca se.72



 

×yclosporine was first fo nd to be effective for pyoderma gangrenos m in 1985 and s bseq ently
in n mero s case reports. No randomized controlled st dies ave been reported.
×yclosporine at a dose of 5 mg/kg/day or less wit or wit o t corticosteroids is recommended as
first-line treatment for pyoderma gangrenos m (grade of recommendation, B).73, 74 T e response is
rapid, wit a dramatic improvement observed wit in 1 to 3 weeks.21 T ere is, owever, a ig rate of
relapse on discontin ation of t e dr g, wit long-term treatment req ired in a significant proportion
of patients.
`n 2005, Reic rat et al73 p blis ed treatment recommendations for t e pyoderma gangrenos m
based on a literat re review of 350 cases. `n general, t e standard of care is to treat t e nderlying
disease, s c as inflammatory bowel disease, t at is responsible for t e pyoderma gangrenos m.
Jor patients w o do not ac ieve remission of t e pyoderma gangrenos m wit treatment of t e
nderlying disease or in idiopat ic cases (30-50%), systemic treatment wit corticosteroids (ie,
met ylprednisolone 0.5-1 mg/kg/day) or cyclosporine (ie, 5 mg/kg/day) alone or in combination are
effective. 2 lse steroids (ie, met ylprednisolone 1 g/day for 1-5 days) ave also been fo nd to be an
effective alternative to daily steroid se. 2yoderma gangrenos m lesions s ow rapid, initial
improvement, often wit in 24 o rs. T ere is c rrently no standardized protocol for t e tapering of
met ylprednisolone and cyclosporine.

×ase reports
A case of pyoderma gangrenos m on t e t ig of an 8-mont -old infant t at failed to improve wit
topical betamet asone valerate and oral prednisolone (2-3 mg/kg/day) was p blis ed by McAleer
et al.75 W en oral prednisolone (3 mg/kg/day) was combined wit cyclosporine (5 mg/kg/day) and
topical 1% silver s lfadiazine, clinical improvement was seen wit in t e first 3 days and gran lation
and reepit elization was observed wit in t e first week. Oral prednisolone was slowly tapered after
12 days of cyclosporine t erapy. ×omplete ealing of t e pyoderma gangrenos m lesion occ rred
wit in 6 weeks of t erapy. T e patient was contin ed on cyclosporine 5 mg/kg/day for a total of 12
weeks, wit slow tapering over a 9-mont period.
A case of peri ng al pyoderma gangrenos m was p blis ed by Reic et al76 in 2009 wit
worsening noted at a dose of cyclosporine 1.5 mg/kg/day as monot erapy. T e lesion improved
wit in 6 weeks wit an increase in t e dose to 5 mg/kg/day and resolved after 6 mont s of
treatment. T e patient was s bseq ently maintained on cyclosporine 3 mg/kg/day for a total of 2
years.
×yclosporine at a dose of 3 mg/kg/day ealed pyoderma gangrenos m lcers on t e medial
s in77 and postoperative ind ced pyoderma gangrenos m.78 T e lengt of treatment and time to
resol tion was not provided in t ese case reports.


 
!

×yclosporine can also be considered a treatment option for severe recalcitrant dys idrotic eczema.
2etersen and Menné79p blis ed a case report of a patient wit severe c ronic vesic lar and
dermatitis w o s owed a dramatic improvement of is and eczema wit in 2 weeks of ig -dose
cyclosporine t erapy (5 mg/kg/day).79 T e patient remained disease-free w ile on cyclosporine 2.5
mg/kg/day. However, w en cyclosporine was discontin ed beca se of an elevation of blood
press re, t e and eczema rapidly ret rned.
Reitamo and Granl nd80 treated seven patients wit c ronic and dermatitis wit cyclosporine for 2
to 16 weeks. Six of t e seven patients¶ and dermatitis improved wit cyclosporine. No
improvement was seen at a starting dose of 1.25 mg/kg/day. Jive patients improved at a dose of 2.5
mg/kg/day, wit t ree of t ese being maintained on a lower dose of cyclosporine 1.25 to 2
mg/kg/day. After cyclosporine was stopped, t ree patients ad rec rrent disease, t ree remained in
remission, and one was lost to follow- p.
Granl nd et al81 cond cted a randomized control trial comparing cyclosporine 3 mg/kg/day wit
topical 0.05% betamet asone-17-21 diproprionate (BD2) cream in t e treatment of c ronic and
dermatitis (type not specified) in 41 patients.81 Bot gro ps ad a 57% improvement in t e severity
of and dermatitis. `n a long-term follow- p p blis ed in 1998, of t e patients treated wit
cyclosporine 3 mg/kg/day for 6 weeks, 21 of t e 27 patients (80%) contin ed to ave a 54%
improvement in t e severity of t eir and dermatitis compared to baseline 1 year after cyclosporine
was discontin ed. No long-term follow- p st dy on t e patients treated wit BD2 cream was
reported.




  
G idelines from t e Britis Association of Dermatology ave recommended cyclosporine for t e
treatment of severe c ronic idiopat ic rticaria nresponsive to anti istamines (q ality of evidence
`, strengt of recommendation A), w ile stating t at optimal patient selection, dose, and d ration of
treatment remains to be defined.82 T e mainstays of treatment for c ronic rticaria are
anti istamines and s ort co rses of corticosteroids.83, 84 ×yclosporine may be sed to treat c ronic
rticaria as an alternative to corticosteroids, eit er as a steroid-sparing agent or in c ronic rticaria
t at is refractory to corticosteroid t erapy.83, 84 J rt ermore, low-dose cyclosporine treatment (2.5
mg/kg/day) for 4 weeks lowered t e ser m levels of cytokines `L-2R, `L-5, and t mor necrosis
factor-alfa, w ic are increased in patients wit c ronic idiopat ic rticaria.85Long-term se,
owever, is not recommended.26
A randomized controlled trial comparing cyclosporine to placebo revealed t at cyclosporine is an
effective treatment in c ronic idiopat ic rticaria.86 ×yclosporine was initiated at 5 mg/kg/day for 13
days, t en red ced to 4 mg/kg/day from days 14 to 27, and 3 mg/kg/day from days 28 to t e
concl sion of t e st dy (eit er 8 or 16 weeks). All patients in t e st dy also received cetirizine 10
mg/day. `mprovement in severity score and symptoms was statistically significant compared to
placebo after 8 weeks of cyclosporine t erapy. A statistically significant improvement in severity
scores and symptoms compared to placebo was seen at 16 weeks in bot cyclosporine gro ps;
owever, no statistical difference was seen at 24 weeks. Also, t e patients w o completed 16 weeks
of cyclosporine t erapy req ired less resc e medication t an t ose w o completed 8 weeks of
cyclosporine t erapy or placebo.86 Anot er st dy comparing c ronic rticaria treated wit
cyclosporine 4 mg/kg/day for 4 weeks (n = 10) or 12 weeks (n = 10), fo nd t at clinical improvement
was dramatic in t e first mont of treatment of bot gro ps. At 12 weeks, t ere was no significant
difference in t e patients w o remained on cyclosporine for 12 weeks, compared to t ose w o
received cyclosporine for 4 weeks.87
Two t irds of patients wit refractory c ronic rticaria treated wit cyclosporine 3 mg/kg/day for 1
to 3 mont s ac ieved a s ort-term f ll remission lasting 3 to 6 mont s. One q arter of patients wit
refractory c ronic rticaria treated wit cyclosporine 3 mg/kg/day for 1 to 3 mont s ac ieved a
long-lasting remission. `n t ose patients in w om only s ort term remission was seen, long-term
cyclosporine t erapy at a dose of 2 to 3 mg/kg/day was effective at maintaining c ronic rticaria in
6 patients, wit only one of t e six req iring low-dose steroids. Side effects over t e 11.6-year
period were mild, incl ding mild irs tism, perip eral ne ropat y in two patients, and mild diarr ea
in one patient.88
Anot er do ble-blind, randomized controlled trial was performed to eval ate t e effectiveness of
cyclosporine in t e treatment of c ronic idiopat ic rticaria t at was nresponsive to standard
t erapy.89 Jorty patients were randomly assigned to receive cyclosporine 5 mg/kg/day for 8 weeks
and t en 4 mg/kg/day for 8 weeks or cetirizine 10 mg/day. Two weeks into t e st dy, 16 of t e
patients in t e cetirizine arm ad severe relapses req iring systemic t erapy and were switc ed to
t e cyclosporine arm. W ile taking cyclosporine, 20 patients ad relapses²eig t of w ic resolved
spontaneo sly and 12 of w ic resolved wit anti istamines. T e patients were followed for 9
mont s, wit 22 aving relapses t at eit er resolved spontaneo sly or wit anti istamines. At t e
end of 16 weeks of cyclosporine treatment, t ere was a significant drop in t e clinical severity
score of c ronic idiopat ic rticaria (2 = .002). ×yclosporine was also well tolerated, wit only t ree
patients needing to ave t e cyclosporine decreased by 0.5 mg/kg/day beca se of an increase in
t eir ser m creatinine d ring t e first mont .
A 2-mont co rse of cyclosporine at a dose of 4 mg/kg/day was s ccessf lly sed in a 12-year-old
girl nresponsive to anti istamines and corticosteroids.90 T e cyclosporine dose was t en
decreased every 2 mont s to a dose of 0.3 mg/kg/day. After 14 mont s of consec tive cyclosporine
t erapy, t e patient s owed no evident clinical lesions or pr rit s w ile still being maintained on
low-dose cyclosporine. W ile t is case does ill strate t at cyclosporine can ind ce and maintain
remission in c ild ood c ronic rticaria, long-term side effects and relapse rates after wit drawal
of cyclosporine are not known.
A patient wit Sc nitzler syndrome²a rare condition associated wit c ronic rticaria, intermittent
fever, and monoclonal imm noglob lin M gammopat y²w o was nresponsive to anti istamines
and systemic corticosteroids ac ieved a complete remission of fever and malaise and a partial
remission of rticaria after receiving 16 weeks of low-dose cyclosporine (2.5 mg/kg/day).91 Anot er
patient wit Sc nitzler syndrome refractory to ot er t erapies s owed clearance of er rticaria
after 1 mont of cyclosporine 5 mg/kg/day. S e was maintained on cyclosporine 2.6 mg/kg/day wit
no skin lesions noted at er 6-mont follow- p.92
Approximately 75% of patients wit c ronic rticaria treated wit low-dose cyclosporine will ave
f ll remission or significant improvement. `t is s ggested t at t e 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,
t en 3 weeks at 1 mg/kg/day before discontin ing.93


"
#



×yclosporine as monot erapy is an effective treatment for a n mber of t e clinical manifestations
of Be
et disease, being partic larly sef l in refractory eye disease, m coc taneo s disease, and
art ritis, in addition to being val able as a steroid-sparing agent in t is disease.94, 95
A randomized, do ble-blind controlled trial of cyclosporine 10 mg/kg/day vers s 1 mg colc icine
per day in 96 patients wit oc lar and m coc taneo s disease revealed t at cyclosporine was
s perior to colc icine for t e treatment of ap t o s and genital lcers.96 However, increased
n mbers of side effects were reported in t e cyclosporine gro p beca se of t e ig dose (10
mg/kg/day) sed.96, 97
Twenty-fo r patients wit m coc taneo s disease were treated wit cyclosporine 5 mg/kg/day
(red ced to cyclosporine 2.5 mg/kg/day if t e ser m creatinine increased by 33%) for a minim m of
6 mont s in an open-label st dy.98 T is st dy s owed t at cyclosporine improved oral lcerations
(18 patients ad improvement, wit 6 s owing no evident oral lcerations d ring t e treatment
period), genital lcerations (17 of 21 patients ad no genital lcers d ring t e st dy, one ad a
red ction in t e genital lesions, one ad stable disease, and two ad worsening), acneiform lesions
(17 of 18 patients ad no lesions), eryt ema nodos m±like lesions (17 of 21 patients ad no new
lesions), and t rombop lebitis-like lesions (6 of 6 patients ad resol tion). Also, no new oc lar
attacks were seen in 11 of 14 patients, and art ralgias improved in t ree of six patients treated wit
cyclosporine. Overall, t ere was a significant response in all clinical feat res of t is diffic lt to treat
disease.
A retrospective st dy of 17 patients s owed t at cyclosporine preserved or improved t e vis al
ac ity in 85% of patients wit Be
et disease.99 Jifty-two patients (104 eyes) wit oc lar Be
et
disease (severe posterior veitis and repeat attacks of anterior veitis) were initially treated wit
cyclosporine 5 mg/kg/day for 2 mont s and t en maintained on 3 mg/kg/day for at least 1 year.
 is al ac ity improved in 31 eyes (29.8%), deteriorated in 32 eyes (30.8%), and was nc anged in
41 of t e 104 eyes. No oc lar attacks were seen in 50% of t e eyes d ring t e treatment period.
Alt o g cyclosporine cannot completely eliminate eye disease in Be
et disease, it is c rrently
considered one of t e most effective t erapies to control veitits and its complications.100
A case report s owed t at cyclosporine 3 mg/kg/day lead to t e resol tion of rec rrent c taneo s
polyarteritis nodosa±like skin lesions, a rare c taneo s manifestation in Be
et disease t at was
previo sly nresponsive to prednisolone, met otrexate, and azat ioprine. T e skin lesions
resolved after 2 weeks and did not rec r wit in t e 4-mont follow- p period.101
W ile cyclosporine is an effective treatment of t e extracerebral manifestations of Be
et disease,
s c as severe oc lar disease, m coc taneo s lesions, and art ritis, it is less effective preventing
t e ne rologic involvement as compared to ot er imm nos ppressants, s c as azat ioprine and
interferon-alfa. `n a retrospective review of 117 patients wit Be
et disease, t e incidence of new
onset ne rologic involvement was significantly ig er in t e cyclosporine gro p t an t ose on
ot er treatment regimens (6 of 21 vs 0 of 175 episodes; 2 < .0001).102


 
`n 1994, Dicken103 eval ated t e treatment response of 75 patients wit classic pityriasis r bra
pilaris (2R2), w ic freq ently progresses to eryt roderma, concl ding t at retinoids were first-line
t erapy.103 Jor patients nresponsive to retinoids, e recommended a trial of met otrexate w ile
concl ding t at cyclosporine was ineffective. However, more recent case reports ave indeed
s own t at cyclosporine may be an effective viable treatment option for t e eryt rodermic form of
2R2.
`n 2000, Us ki et al104 described t ree cases of eryt rodermic, classic ad lt type 2R2 treated wit
cyclosporine 5 mg/kg/day. `mprovement was seen wit in 2 to 4 weeks of t erapy, after w ic t e
dose of cyclosporine was grad ally tapered. One patient relapsed 2 weeks after t e dose of
cyclosporine was lowered to 1.2 mg/kg/day. His skin lesions t en responded well to an increase to
2 mg/kg/day. He was maintained on t is dose for at least 3 years wit no s bseq ent flaring. T e
second patient was maintained on cyclosporine 2 mg/kg/day for at least 4 years wit no relapses.
T e t ird patient was maintained on cyclosporine 2 mg/kg/day for 6 mont s, followed by a slow
taper. ×yclosporine was discontin ed after 1 year, wit a mild relapse t ereafter; t erefore
cyclosporine (dose not specified) was res med for an additional 3 mont s. No additional follow- p
was noted.
Weztig et al105 in 2003 reported a case of a 4-year-old boy wit eryt rodermic
venile 2R2 treated
wit cyclosporine 3 mg/kg/day. Significant regression of t e eryt roderma was seen wit in 5 weeks
of t erapy. T e dose of cyclosporine was t en grad ally tapered and discontin ed. Eig t mont s
post±cyclosporine t erapy, no rec rrence of 2R2 ad occ rred.



Dermatomyositis is traditionally treated wit ig -dose prednisone combined wit steroid-sparing
agents, s c as met otrexate or azat ioprine. ×yclosporine can be sed in cases nresponsive to
t is standard regimen.106, 107 T ere is no agreement as to t e optim m regimen or combination of
imm nos ppressive agents to treat dermatomyositis.108×yclosporine as been proposed as a
second-line agent for bot ad lt and
venile forms of t e disease in t ose nresponsive to ot er
imm nos ppressants, s c as met otrexate or azat ioprine.108, 109
×ombined t erapy wit cyclosporine and corticosteroids as been s own to be effective for t e
management of l ng and esop ageal involvement associated wit dermatomyositis. ×yclosporine
at a dose of 1 mg/kg/day combined wit prednisone for 1 mont was effective in treating
dermatomyositis wit esop ageal involvement, wit cyclosporine acting as a steroid-sparing agent,
allowing t e dose of prednisone to be tapered grad ally.110 T e interstitial l ng disease and
pne momediastin m associated wit dermatomyositis improved after 2 mont s of cyclosporine 1.8
mg/kg/day and prednisone 40 mg/day.111 ×yclosporine doses of more t an 200 mg/day and
prednisone improves t e prognosis of patients wit dermatomyositis associated wit s bac te
interstitial pne monia w en initiated wit in 15 days of diagnosis.112
A m lticenter retrospective st dy of 53 patients wit interstitial l ng disease associated wit
dermatomyositis s owed t at patients treated wit a combination of cyclosporine and
corticosteroids ad favorable early and long-term o tcomes except for t ose patients wit ac te
interstitial l ng disease. `n patients wit ac te interstitial l ng disease, patients w o received t e
combination t erapy initially ad a ig er s rvival rate t an t ose w o initially received
corticosteroids alone.113




 
Systemic steroids are traditionally sed in t e initial stages of pemp ig s v lgaris. Before t e
advent of rit ximab,114imm nos ppressants s c as azat ioprine, cyclop osp amide,
met otrexate, dapsone, and cyclosporine were sed as steroid-sparing agents in t e treatment of
pemp ig s v lgaris, once an initial response to systemic steroids was obtained.115 Several st dies
ave examined t e se of cyclosporine as a steroid-sparing agent in t e treatment of pemp ig s
v lgaris.116, 117, 118 T e Britis Association of Dermatology g idelines for t e management of
pemp ig s class cyclosporine as grade × for strengt of recommendation wit a level ` q ality of
evidence, and t erefore do not recommend it as an ad
vant dr g.119 T is is based on a randomized
controlled trial w ic s owed no additional benefit and more side effects compared to
met ylprednisolone alone.120
`n a retrospective review of 14 patients wit moderate to severe pemp ig s v lgaris w o received a
combination of prednisone and cyclosporine 2.5 to 3 mg/kg/day, t e average time to clinical
remission was 8.1 11.8 mont s. ×yclosporine was discontin ed 3 mont s after clinical remission
was ac ieved. Jorty-t ree percent of patients treated wit a combination of prednisone and
cyclosporine remained free of clinic relapse 5 years after discontin ation of t erapy. T e safety
profiles were similar w en compared to prednisone combined wit cyclop osp amide and
prednisone combined wit azat ioprine. However, cyclop osp amide (1.1-1.5 mg/kg/day) combined
wit prednisone was fo nd to be slig tly more effective (t e average time to clinical remission was
6.8 10.5 mont s, wit t e percentage of patients w o remained clinically free of disease being
55%).121
×yclosporine 1 to 3 mg/kg/day controlled ac te disease in six patients wit moderate to severe
pemp ig s v lgaris ncontrolled wit conventional t erapies. Wit in 8 to 10 weeks after
cyclosporine t erapy was initiated, t e lesions began to eal wit no occ rrence of new lesions
noted. T e dose of cyclosporine was grad ally decreased over an 8- to 12-mont period after t e
patients were clear for 3 to 4 mont s. No serio s side effects occ rred, and no rec rrences were
seen 3 years after discontin ing treatment.115


$

  %
Epidermolysis b llosa acq istita (EBA) as a prolonged co rse and is often diffic lt to treat. T e
conventional treatment approac incl des ig -dose corticosteroids and corticosteroid steroid±
sparing agents. ×ase reports of EBA treated wit cyclosporine ave s own favorable res lts.
Engineer et al122 reviewed nine case reports of EBA treated wit cyclosporine t at were p blis ed
between 1987 and 1993.122 Eig t of t e nine patients were previo sly treated wit oral
corticosteroids, and most were treated wit ot er ad
vant agents, s c as met otrexate,
azat ioprine, gold, dapsone, and cyclop osp amide wit o t significant clinical response. T e daily
doses of cyclosporine ranged from 5 to 9 mg/kg/day (mean dose, 7 mg/kg/day). T e d ration of
treatment ranged from 1 to 12 mont s. Jo r of t e nine patients received cyclosporine as a
monot erapy, wit t e remaining five receiving cyclosporine in addition to prednisone (30-100
mg/day; mean, 48 mg/day). All nine patients ad a significant clinical improvement. T ere was an
improved ealing time of preexisting b llae, cessation of new b llae formation, and a marked
steroid-sparing effect. Two of t e patients discontin ed cyclosporine beca se of side effects: one
patient ad rticaria, diarr ea, ascites, and elevated ser m creatinine (cyclosporine 7.5 mg/kg/day)
and t e ot er patient ad possible pancreatitis (cyclosporine 9 mg/kg/day).
A case report s owed t at cyclosporine 4 mg/kg/day combined wit prednisolone 80 mg/day lead to
t e improvement of EBA t at was previo sly ns ccessf lly treated wit prednisolone and
dapsone. T e patient flared at 2 mont s, necessitating an increase in t e cyclosporine dosage to 5
mg/kg/day for 6 mont s to maintain control of t e disease. At t e 19-mont follow- p, t e patient
was being maintained on cyclosporine 4 mg/kg/day and prednisolone 10 mg/kg/day wit one b lla
present and no adverse side effects.123
Anot er case report of a patient wit EBA and acq ired factor ``` deficiency previo sly
nresponsive to prednisone, colc icine, and p lse cyclop osp amide revealed significant
improvement of bot diseases after 3 weeks of t erapy wit cyclosporine 4 mg/kg/day and
prednisone 60 mg/day. T e patient was maintained on cyclosporine 4 mg/kg/day for 11 mont s wit
slow tapering and discontin ation of t e prednisone. T e patient was maintained on cyclosporine
1.5 mg/kg/day for 2 years wit o t relapse of eit er disease or evidence of significant side effects.124

 


× ronic actinic dermatitis
A case of c ronic actinic dermatitis t at was nresponsive to beta-carotene and p otoprotection
rapidly improved on cyclosporine 4.5 mg/kg/day. T e patient ad clinical resol tion after 1 mont of
treatment, after w ic t e dose of cyclosporine was grad ally decreased, wit rapid worsening
noted at cyclosporine 1 mg/kg/day. T e patient was maintained on cyclosporine 1.5 mg/kg/day wit
no evident skin lesions or pr rit s at t e 3-year follow- p period.125 Two cases of c ronic actinic
dermatitis t at were nresponsive to ig -dose steroids responded rapidly to cyclosporine 4
mg/kg/day for 3 mont s, wit improvement of t e pr rit s and skin lesions. W ile one patient ad
rec rrent lesions in t e s mmer, t e ot er ad no flares evident d ring t e 3-year follow- p
period.126

2olymorp ic lig t er ption

×yclosporine can be sed as a prop ylactic treatment for moderate to severe polymorp ic lig t
er ption (2MLE). A case report of a patient wit psoriasis and 2MLE s owed t at cyclosporine 3.3
mg/kg/day sed to treat t e patient¶s psoriasis also prevented exacerbations of er 2MLE.127 T ree
additional case reports revealed t at cyclosporine 3 to 4 mg/kg/day 1 week before travel to a s nny
climate wit discontin ation pon ret rn prevented flares of 2MLE wit o t complications.128
Solar rticaria
A case of treatment-resistant solar rticaria improved wit cyclosporine 4.5 mg/kg/day. T e patient
was able to tolerate t e s n for at least an o r wit minimal rticaria as opposed to a few min tes
wit o t cyclosporine t erapy. T e solar rticaria ret rned once cyclosporine was discontin ed.
×yclosporine may be sef l in s ort co rses in cases w ere treatment is only necessary d ring t e
s mmertime.129



 
T ere are no establis ed g idelines for t e treatment of lic en plan s wit cyclosporine. Doses of
p to 6 mg/kg/day ave been sed in st dies to treat lic en plan s, wit resol tion of c taneo s
lesions wit in 1 to 8 weeks and s stained remission for p to 10 mont s.130, 131, 132 A maxim m
dose of 5 mg/kg/day is now recommended. M cosal forms tend to be more resistant to treatment,
req iring ig er doses (not exceeding 5 mg/kg/day) for adeq ate control. Oral cyclosporine is t e
treatment of c oice for disseminated lic en plan s or lic en plan s resistant to systemic
corticosteroids and retinoids.133 On average, pr rit s improves in 2 weeks, wit clearing of t e
lesions in 6 weeks.133
×yclosporine is also s own to be effective in t e treatment of erosive lic en plan s, wit two case
reports p blis ed by Sc epis et al134 in 2008. One patient s owed rapid improvement of is erosive
lic en plan s in t e pretibial and ing inal region on cyclosporine 3 mg/kg/day wit complete
remission ac ieved at 2 mont s. Once t e cyclosporine was discontin ed, t e patient ad a less
severe flare of is erosive lic en plan s and was maintained on cyclosporine 2.5 mg/kg/day and
oral steroids in rotation. Anot er patient s owed improvement of er plantar erosive lic en plan s
wit a combination of cyclosporine 2.5 mg/kg/day and topical steroids twice daily and was
maintained on cyclosporine 2 mg/kg/day wit no evident rec rrence. Anot er case report of plantar
erosive lic en plan s treated wit cyclosporine described rapid improvement at an initial dose of
4.5 mg/kg/day for a mont and maintenance at a dose of 3 mg/kg/day for 1 year.135However, once
cyclosporine was discontin ed, t e lesions rec rred. A repeat co rse of cyclosporine was
administered, followed by a split-t ickness skin graft. T e patient was maintained on cyclosporine
3 mg/kg/day 8 mont s after t e split-t ickness skin graft was placed. Ten mont s after cyclosporine
was discontin ed, t e foot was ealed and pain-free. W ile t ese case reports s ow t at
cyclosporine ca ses significant b t only temporary improvement of erosive lic en plan s, it may
be sed to control its ac te p ase so t at ad
vant t erapies s c as skin grafting may be
performed.
A male c ild wit refractory erosive oral lic en plan s was treated wit systemic corticosteroids
(30 mg/day for 6 weeks) and cyclosporine 4 mg/kg/day for 3 mont s.136 On t is regimen, t e c ild
was noted to ave remissions and exacerbations, wit t e d ration of t e remissions and t e
treatment sed for t e exacerbations not being specified in t is case report.
A case report of palmoplantar lic en plan s wit mbilicated pap les nresponsive to topical
steroids improved on cyclosporine 3.5 mg/kg/day.137 T e patient ad a red ction in is pr rit s
after 2 weeks of oral cyclosporine and improvement in is skin lesions after 4 weeks of t erapy.
After 4 weeks of cyclosporine 3.5 mg/kg/day, t e cyclosporine was grad ally tapered and
discontin ed at 8 weeks. A case report s owed t at oral cyclosporine at dose of 3 mg/kg/day for 3
mont s as been sed s ccessf lly to treat actinic lic en plan s refractory to ot er treatments.138
Topical cyclosporine may be effective in t e treatment of oral lic en plan s, as disc ssed in part ``
of t is review.



 
 
Several case reports ave s ggested t at cyclosporine may be effective in t e initial p ases of
lic en planopilaris before severe follic lar damage occ rs. A dose of 300 mg/day (3-5 mg/kg/day)
as been sed to s ccessf lly treat lic en planopilaris. Anot er patient wit psoriasis and lic en
planopilaris overlap was treated wit cyclosporine 3 mg/kg/day and topical betamet asone valerate
0.12% foam twice daily. After 2 weeks on cyclosporine, a red ction in t e perifollic lar eyt ema and
pr rit s wit no red ction in scale was noted. No additional follow- p was performed.139
`n 2003, Mirimani et al140 p blis ed a series of t ree patients wit lic en planopilaris treated
s ccessf lly wit oral cyclosporine. `n all t ree patients, cyclosporine was started at 300 mg/day (3-
5 mg/kg/day). Maximal clinical response in signs and symptoms to t erapy was noted between 3
and 5 mont s, wit improvement in pr rit s, pain, and b rning and no clinical activity of t eir
disease being noted (no perifollic lar eryt ema or scaling). Jine air regrowt was noted w ile on
cyclosporine; owever, t e air growt reversed 1 to 4 mont s after t erapy. Twelve mont s after
cyclosporine t erapy, t ese patients were symptom free wit minimal to no progression of t eir
disease.
A patient wit Gra am Little-2iccardi-Lass er r syndrome, a rare lic enoid disorder associated
wit scarring alopecia and follic lar yperkeratotic pap les, ad a red ction in perifollic lar
eryt ema and follic lar yperkeratotic pap les after a 3-mont co rse of cyclosporine at 4
mg/kg/day.141 T ree mont s after cyclosporine t erapy, t e patient ad additional areas of air
regrowt in t e scarring patc es and more consistent improvement of t e follic lar pap les.

  
× rrently, treatments for pr rigo nod laris incl de topical antipr ritics, topical steroids, and
intralesional kenalog, followed by psoralen pl s ltraviolet A lig t p otot erapy, ltraviolet B lig t
t erapy, cryot erapy, topical vitamin D3, and capsacin. ×yclosporine may be considered a second-
line agent, wit doses of 3.5 to 4 mg/kg/day for 24 to 36 weeks aving been s own to significantly
improve t e pr rigo nod laris lesions and red ce pr rit s.142 2r rit s is red ced after 2 weeks of
cyclosporine t erapy, t ereby allowing for a potential improvement in t e pr rigo nod les to
eal.142, 143

&


 



Alt o g systemic cyclosporine as s own efficacy in t e treatment of alopecia areata, wit drawal
of t e dr g res lts in significant air loss.144 G idelines on t e treatment of alopecia areata ave
concl ded t at t e cosmetically wort w ile response rate is likely too low to
stify t e risks
(strengt of recommendation D, q ality of evidence ```).26, 145
Several st dies ave examined t e efficacy of cyclosporine in t e treatment of severe alopecia
areata. Jifteen patients were treated wit cyclosporine 5 mg/kg/day for 6 to 12 mont s; one patient
discontin ed beca se of ypertension. ell s air regrowt was seen in 12 of t e 14 patients by 1
to 3 mont s. Of t ese, five ad cosmetically acceptable partial air regrowt (>70% air regrowt )
and two patients ad complete air regrowt . Of t e two wit complete air regrowt , one ad
rec rrence of er disease 2 mont s after cyclosporine was discontin ed and t e ot er ad no
evidence of disease 4 years after treatment.146
T e combination of systemic cyclosporine and met ylprednisolone may also lead to improvement
in alopecia areata. Jorty-six patients were treated wit a combination of cyclosporine 200 mg twice
daily and met ylprednisolone (24 mg twice a day for men, 20 mg twice a day for women, and 12 mg
twice a day for c ildren.).147 T e dose of met ylprednisolone was decreased weekly by 4 mg/day
and cyclosporine was grad ally decreased by 50 mg/day weekly or biweekly once
met ylprednisone was discontin ed. T e total treatment time ranged between 7 and 14 weeks.
T ree patients discontin ed t e treatment beca se of side effects. T irty-eig t patients ad
significant air regrowt , wit five patients considered treatment fail res. D ring t e 12-mont
observation period, nine of t e 38 patients (24%) wit significant air regrowt relapsed.
Six patients wit alopecia totalis and 12 patients wit alopecia niversalis were treated wit
mont ly intraveno s met ylprednisolone in doses of 500 mg for 3 days and oral cyclosporine (2.5
mg/kg/day for 5-8 mont s).148 An adeq ate response²defined as more t an 70% of air regrowt in
t e affected area²was seen in six patients (33%; 3 wit alopecia totalis and 3 wit alopecia
niversalis). No relapses were seen in patients wit an adeq ate response at 8 mont s
posttreatment, and no serio s side effects occ rred d ring t e treatment p ase.
×yclosporine 5 mg/kg/day combined wit prednisone 5 mg/day s owed mixed res lts. `n one
case series of eig t patients treated wit 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 t at 75% regrowt of terminal airs was
noted) and prednisone 5 mg/day for 24 weeks, two of t e eig t patients ad more t an 75%
regrowt of cosmetically acceptable terminal airs after 24 weeks of t erapy, b t air loss rec rred
after treatment was discontin ed. T ree patients discontin ed t e st dy beca se of side effects
(edema, ypertension, abnormal liver f nction tests, and abnormal lipids).149
A c ild wit Down syndrome and alopecia areata treated wit cyclosporine 3 mg/kg/day for 6
mont s ad air regrowt noted at t e end of t e treatment period, b t a relapse wit in 3 mont s.150
`n contradistinction, t ere ave also been seven case reports of patients w o developed alopecia
areata after solid organ transplant w ile on cyclosporine. T e average time to t e development of
alopecia areata was 3.7 years after transplant and t e average dose of cyclosporine was 4.6
mg/kg/day.151 One patient wit atopic dermatitis treated wit cyclosporine 3.5 mg/kg/day also
developed alopecia areata.152


"
   


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(


)
A case report s owed t at recalcitrant benign familial pemp ig s improved rapidly wit a
combination of cyclosporine (1.2 mg/kg/day) and acitretin 10 mg a day wit t e patient remaining in
clinical remission on t is regimen at 8 mont s. However, anti ypertensive t erapy was req ired.153
Anot er case report s owed t at benign familial pemp ig s improved on cyclosporine 2.8 to
3.4 mg/kg/day. T is response was maintained over a 24-week period wit grad al deterioration
noted once t e treatment was discontin ed.154
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)
Jirst-line treatments of eospinop ilic p st lar follic lar incl des topical steroids and topical and
oral indomet acin. Second-line t erapies incl de, cetirizine, metronidazole, itraconazole, and
topical permet rin. ×yclosporine may be considered as a t ird-line t erapy.155
A case series of six patients wit eosinop ilic p st lar follic litis revealed t at 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- p was performed.




A case report described marked improvement in a patient¶s perianal idradenitis s pp rativa after
cyclosporine 4.5 mg/kg/day was added to treat t e patient¶s conc rrent pyoderma
gangrenos m.157 After 8 mont s of cyclosporine 4.5 mg/kg/day, ealing of disc arging sin ses and
diminis ed pain was noted. Jifteen mont s after cyclosporine was initiated, t e patient was noted
to ave stable disease on contin o s cyclosporine t erapy combined wit contin o s broad-
spectr m oral antibiotics. T e patient¶s q ality of life improved, and no adverse side effects were
noted.
×yclosporine 4 mg/kg/day for 3 mont s prevented flares in a patient wit a 20-year istory of
idadenitis s pp rativa previo sly treated wit minocycline, clindamycin, claritromycin, oral
steroids, intraveno s steroids, intralesional steroids, and s rgical excision.158 At 7 mont s of
follow- p, t e patient was being initiated on cyclosporine 2 mg/kg/day wit no significant episodes
of inflammation.
×yclosporine 3 mg/kg/day lead to a marked clinical response in refractory acne v lgaris and
idradenitis s pp rativa t at was previo sly treated wit minocycline, s rgical excision,
isotretinoin, prednisolone, and lympecycline.158 After 8 weeks of cyclosporine 3 mg/kg/day, t e
patient was weaned off of prednisolone. ×yclosporine was discontin ed after 4 mont s of t erapy
beca se of t e good response. A mild relapse occ rred 4 mont s after cyclosporine was
discontin ed b t rapidly improved once cyclosporine was recommenced.
&


`n small, ncontrolled, retrospective st dies, cyclosporine as prod ced significant skin softening
in p to 50% of patients wit scleroderma, and resol tion of digital infarcts in some
patients.159, 160 T e E ropean Leag e Against R e matism (EULAR) Scleroderma Trials and
Researc Gro p as recently p blis ed a set of recommendations for t e treatment of systemic
sclerosis, and s ggests a need for f rt er eval ation of cyclosporine.161 Extreme ca tion is advised
w en sing cyclosporine beca se it may potentially worsen ypertension or renal disease
associated wit systemic sclerosis.
Back to Article O tline
   
×yclosporine contin es to play an important role in t e field of dermatology. We strongly
recommend cyclosporine for s ort-term ³resc e´ treatment of psoriasis and atopic dermatitis in
appropriate patients. Alt o g randomized controlled trials ave not been ndertaken, m ltiple
case reports ave also s own excellent res lts w en cyclosporine is sed for t e treatment of
pyoderma gangrenos m. We also recommend cyclosporine for treatment of refractory c ronic
idiopat ic rticaria and cyclosporine in combination wit corticosteroids for t e treatment of
dermatomyositis wit esop ageal and p lmonary involvement. Alt o g cyclosporine is effective
in t e treatment of Be
et disease, it is not as effective as ot er t erape tic agents at preventing
ne rologic symptoms, making initial t erapy wit agents s c as azat ioprine and interferon-alfa
more logical. ×yclosporine as been sed s ccessf lly as a steroid-sparing agent for t e treatment
of b llo s disorders s c as pemp ig s v lgaris and epidermolysis b llosa acq isita in t e past.
However, t e advent of rit ximab as c anged t e paradigm of treatment of t ese b llo s diseases,
and cyclosporine is t erefore not recommended as a first-line treatment. T e se of cyclosporine
for t e treatment of severe alopecia areata is controversial, wit case reports of patients act ally
developing alopecia areata despite treatment wit cyclosporine for ot er p rposes. S ort-term
treatment in ealt y patients wit severe alopecia may be considered. ×ase reports ave also
s ggested t at cyclosporine is sef l in t e treatment of 2R2, dys idrotic eczema,
p otodermatoses, erosive and disseminated lic en plan s, lic en planopilaris, pr rigo nod laris,
benign familial pemp ig s, eosinop ilic p st lar follic litis, idradenitis s pp rativa, and
scleroderma. Alt o g cyclosporine may be a treatment option in patients w o failed first- and
 second-line t erapies for t e above diseases, f rt er controlled st dies will need to be done before
we can recommend its se.
2art `` of t is review addresses t e dosing and monitoring g idelines of cyclosporine, its
contraindications, possible dr g interactions, adverse effect profile, and t e se of cyclosporine
d ring pregnancy and c ild ood.
Back to Article O tline

c

 

 
 
VÊ ×aitriona Ryan, MBB× , BAO
,

VÊ Karrie T. Amor, MD
,
VÊ Alan Menter, MD
VÊ Abstract
VÊ J ll Text
VÊ 2DJ
VÊ `mages
VÊ References
{
 

`.Ê Abstract
``.Ê 2 armacokinetics
A.Ê Absorption
1.Ê Original and microem lsion form lations
B.Ê Distrib tion
×.Ê Metabolism and elimination
D.Ê Body weig t iss es
E.Ê Et nic variation
J.Ê Localized administration of cyclosporine
```.Ê ×ontraindications
` .Ê Dr g interactions
.Ê Adverse effects
.Ê Renal dysf nction
0.Ê asc lar dysf nction
1.Ê T b lar dysf nction
A.Ê × ronic nep rotoxicity
0.Ê asc lopat y
1.Ê T b lopat y
B.Ê Recommendations
×.Ê Hypertension
D.Ê Recommendations
E.Ê Malignancy potential
J.Ê Ne rologic side effects
G.Ê Gastrointestinal side effects
 H.Ê Gingival yperplasia
`.Ê × taneo s side effects
J.Ê `nfections
K.Ê Ot er side effects
L.Ê Hyperlipidemia
M.Ê Recommendations
N.Ê Ot er laboratory abnormalities
`.Ê Monitoring
.Ê Screening and istory
A.Ê Baseline laboratory investigations
B.Ê Reg lar follow- p investigations
×.Ê Ann al investigations
D.Ê ×yclosporine ser m concentrations
E.Ê accinations
``.Ê 2regnancy
.Ê Lactation
```.Ê 2ediatric se
.Ê Disc ssion and o r personal 25-year experience of cyclosporine sage
`X.Ê ×oncl sion
X.Ê Acknowledgment
X`.Ê References
X``.Ê ×opyrig t
×yclosporine is ig ly effective in t e treatment of a m ltit de of dermatoses. ×oncern over its side
effect profile as limited its se in dermatology. Adverse effects are, for t e most part, dose
dependent and related to d ration of t erapy. Using t e recommended monitoring protocols res lts
in a significant decrease in t e incidence of cyclosporine-related toxicities. T is article provides a
compre ensive review of t e p armacokinetics of cyclosporine, potential dr g interactions,
adverse effects, and recommendations for monitoring in patients treated wit cyclosporine.
T e se of cyclosporine in pregnancy and in t e pediatric pop lation is also addressed.

  


After completing t is learning activity, participants s o ld be familiar wit t e monitoring
g idelines of cyclosporine, its contraindications, its possible dr g interactions, its adverse effect
profile, and its se in pregnancy and t e c ild ood and adolescent pop lations.
Key words: atopic dermatitis, calcine rin in ibitors, cyclosporine, dr g
interactions, p armacokinetics, psoriasis

×aps le S mmary
Back to Article O tline
 *

Key points
‡T e specific brand of cyclosporine s o ld be specified at eac visit beca se of differences in
bioavailability between t e original and microem lsion form lations of cyclosporine (level `B
evidencea)
‡A ig er ser m concentration of cyclosporine res lts w en t e dr g is administered before rat er
t an after meals

‡`deal body weig t rat er t an act al body weig t s o ld be sed to calc late t e req ired dose
(Level ``B evidence)

{
 
×yclosporine is a lipop ilic molec le t at is poorly absorbed w en administered orally, wit wide
variations in inter- and intrapatient bioavailability, ranging from 1% and 89%.1, 2 Bile salts are
req ired to facilitate absorption,3 w ic occ rs wit in approximately 30 min tes, w ile peak ser m
concentration (cmax) occ rs 2 to 4 o rs after t e dose.2, 4, 5
Original and microem lsion form lations
Beca se of t e variability in absorption of t e original form lation of cyclosporine (Sandimm ne;
Novartis, East Hanover, NJ), a more ydrop ilic microem lsion (Neoral; Novartis) was developed
t at allowed greater bioavailability and less intraindivid al fl ct ation in ser m concentration of t e
dr g.6, 7 A randomized, do ble-blind st dy comparing t e two form lations s owed a more rapid
response, ig er remission rates in t e first 8 weeks, and a 10% lower dose to maintain efficacy
wit t e microem lsion.8 T ese preparations of cyclosporine are not bioeq ivalent. Most patients
w o ave normal absorption of t e original form lation ave eq ivalent absorption of t e
microem lsion, w ile a small s bset of patients w o absorb t e original form lation poorly ave an
increased absorption of t e microem lsion compared to t e original, leading to an increased
ser m cyclosporine concentration. W en converting patients from t e
original cyclosporine form lation to t e microem lsion form lation, a 1:1 mg:mg dose conversion
is sed in order to maintain steady-state tro g concentration in t e target t erape tic
range.1, 6 2artic lar ca tion s o ld be exercised in t ose c anging from ig doses of t e original
form lation to t e microem lsion, wit blood press re and ser m creatinine being monitored more
closely in t e s bseq ent weeks. W en sed in organ transplantation, serial ser m
tro g cyclosporine concentrations are ro tinely meas red after c anges in form lation
beca se of t e narrow t erape tic window between prevention of graft re
ection and dr g toxicity.
T is is not necessary in t e dermatology setting, beca se t e incidence of adverse events
following c anges in form lations is relatively low.6
× rrently, t ere is significant variability in t e p armacokinetics of newer generic forms of t e
microem lsion form lation ofcyclosporine.9, 10 Different brands s o ld not be sed
interc angeably wit o t strict s pervision. `t is recommended t at t e brand be specified wit eac
prescription at eac visit, to avoid alterations in cyclosporine concentration res lting in a lower
efficacy or increased toxicity of t e dr g.
T e dose of cyclosporine s o ld be divided into a twice daily dose, and optimally s o ld be taken
at t e same time eac day to minimize intraindivid al variation in ser m
concentration.11 ×yclosporine em lsion is available in caps le form (in 25- or 100-mg caps les) or
as a bioeq ivalent sol tion (100 mg/5 mL).12 T e oral sol tion s o ld be drawn p wit t e syringe
provided and mixed wit orange or apple
ice or milk.13

 
×yclosporine is widely distrib ted in t e body beca se of its lipop ilic nat re. Once
absorbed, cyclosporine binds to eryt rocytes, le kocytes, and lipoproteins. `n
plasma, cyclosporine is almost excl sively bo nd to lipoproteins (>90%), and t ere is
transfer of cyclosporine between different lipoprotein classes and from alb min to
lipoproteins.14 Beca secyclosporine is ig ly lipop ilic, a ig dietary fat intake can affect ser m
concentrations related to increased ser m lipid levels. One st dy s owed t at ig dietary fat
intake can increase t e total body clearance of cyclosporine wit o t c anging t e elimination rate
constant.15 A ig er ser m concentration of cyclosporine is prod ced w en t e dr g is
administered before rat er t an after meals.2, 16 T is also translates into ig er clinical
efficacy of t e dr g, ig lig ting t e importance oftaking cyclosporine consistently before or after
meals w ere possible.17 ×yclosporine as been reported to ave a first-pass effect of 27% in t e
liver.5 T e bip asic distrib tion of cyclosporine is t o g t to be ca sed by t e entero epatic
recirc lation of cyclosporine from t e bile to t e small intestine.2

©
  
  
T e oral bioavailability and t e systemic clearance of cyclosporine is controlled by t e cytoc rome
2450 isoenzymes 3A4 (×23A4) and 3A5 (×23A5) in t e liver and small intestine, and by t e effl x
p-glycoprotein p mp (2G2), a transmembrane transporter, w ic is expressed in t e
gastrointestinal tract and liver and encoded for by t e m ltidr g resistance-1 gene (MDR1, also
known as adenosine trip osp ate±binding cassette B1 [AB×B1]).18, 19, 20, 21, 22, 23, 24, 25 Many single-
n cleotide polymorp isms in t e genes encoding ×23A4, ×23A5, and 2G2 ave been identified
and are t o g t, in part, to acco nt for t e variability in p armacokinetics of cyclosporine.
M c of o r knowledge on t e effects of genetic polymorp isms on variability in
p armacokinetics of cyclosporine comes from transplantation researc , b t m c of t e p blis ed
data to date as s own conflicting or nonsignificant res lts.18, 19, 20, 21, 22, 23, 24, 25
×yclosporine elimination follows first-order kinetics wit a constant fraction of dr g eliminated per
nit time.2 Metabolites ofcyclosporine are excreted primarily in t e bile. Only 6% of t e dose is
excreted by t e rine, mainly as cyclosporinemetabolites wit 0.1% of t e dose excreted
nc anged in rine.2 T e alf-life of cyclosporine in ser m is between 6 and 24 o rs.2, 5 T e
p armacokinetics of cyclosporine are altered in c ildren, wit clearance rates of p to fo r times
t at of ad lts over 40 years of age, res lting in lower blood concentrations for t e same
dose.26, 27 Beca se t e clearance of cyclosporineafter intraveno s administration does not appear
to be related to age,28 it as been proposed t at t e decreased bioavailability is related to s orter
bowel lengt rat er t an to metabolic differences.29

"+
 

×yclosporine is dosed on a weig t per weig t basis. Alt o g ig ly lipop ilic, observations
s ggest t at distrib tion of t e dr g is limited primarily to lean body mass in obese patients and
can lead to increased toxicity if patients are dosed according to t eir act al body weig t.30, 31 One
st dy s owed no significant differences in bioavailability, elimination alf-life, clearance, or steady-
state vol me of distrib tion of cyclosporine w en t ese calc lations were normalized by ideal body
weig t. Jollowing dosage based on act al body weig t, obese transplant recipients ad a mean
ser m tro g level almost do ble t at of nonobese recipients.32 Tro g levels of cyclosporine ave
also been s own to increase wit t e obesity index, wit a res lting increase in
nep rotoxicity.33 W ile ideal body weig t rat er t an act al body weig t s o ld be sed to
calc late t e req ired dose, some g idelines recommend dosing obese patients according to t eir
act al body weig t.11Body weig t±independent dosage regimens for bot psoriasis and atopic
dermatitis ave, in fact, been s own to be eq ally effective and safe as weig t-orientated dosage
regimens.34, 35 `n t e clinical setting, owever, it is generally t e lowest effective dose to ac ieve
disease control t at g ides t e maintenance dose.

$  
St dies of transplant recipients ave s own significant differences in
bioavailability of cyclosporine between different et nic pop lations. African Americans ave
decreased absorption and markedly lower bioavailability of cyclosporine compared to
w ites.36, 37 T is is most likely ca sed by significant et nic variation in t e
freq ency of polymorp isms in MDR1 and t e genes encoding t e ×23A enzymes.38, 39

 !
   


2lacebo controlled st dies of topical preparations of cyclosporine ave s own it to be ineffective in
t e treatment of psoriasis and alopecia areata.40, 41 A do ble-blind randomized controlled
trial of topical cyclosporine rinse 500 mg/5 mL t ree times a day for 8 weeks for oral lic en plan s,
owever, s owed a marked improvement in all patients compared to placebo,42 a finding s pported
by ot er st dies.43, 44 T is s ccess is most likely related to a significantly ig er local
absorption ofcyclosporine in m cosa compared to skin, wit cyclosporine levels meas red in t e
oral m cosa being comparable to t ose fo nd in lesional skin of patients treated wit ig -dose
systemic cyclosporine. Two do ble-blind trials of intralesional in
ections of cyclosporine for
psoriasis also s owed a significant improvement in all patients compared to controls²again, most
likely beca se of t e ig er local concentration ac ieved by intralesional vers s topical
administration.45, 46 ×learanceof pyoderma gangrenos m wit intralesional cyclosporine as
also been reported.47 Unfort nately, t e intralesional form lation of t e dr g is not commercially
available beca se of nacceptable pain at t e in
ection site.
Back to Article O tline
   
Key points
‡×yclosporine is contraindicated in ncontrolled ypertension, renal disease, serio s infections,
and in t ose wit a previo s istory of malignancy, excl ding basal cell carcinoma (level `
evidence)

‡×yclosporine s o ld be avoided in t ose wit a ig c m lative dose of previo s psoralen and

ltraviolet A lig t p otot erapy (level ``` evidence)

×yclosporine is contraindicated in ncontrolled ypertension, significant renal impairment, serio s

infections, and in t ose wit a c rrent or previo s istory of malignancy (except basal cell
carcinoma).11, 48, 49, 50, 51 Skin infections in atopic eczema are not an absol te contraindication, b t
appropriate antibiotic t erapy s o ld be instit ted before commencingcyclosporine.51 ×a tion and
caref l clinical
dgment s o ld also be sed in pregnancy, lactation, epilepsy, severe epatic
dysf nction, primary or secondary imm nodeficiency disorders, diabetes, obesity, premalignant
conditions, advancing age (>65 years), a tendency to dr g or alco ol ab se, and t e inability to
attend for reg lar monitoring. `n t ose patients wit a ig c m lative dose of previo s psoralen
pl s ltraviolet A lig t (2U A) p otot erapy, severe actinic damage or w o ave been treated wit
radiot erapy, cyclosporine may increase c taneo s carcinogenicity and s o ld be avoided
w enever possible.11
Back to Article O tline

 
 
Key points
‡×yclosporine is metabolized by t e cytoc rome 2450 system and interacts wit dr gs t at in ibit
or stim late t is system

‡Nep rotoxic dr gs s o ld be avoided

‡A f ll dr g istory s o ld be taken at every patient visit

×yclosporine is almost entirely metabolized in t e liver by t e cytoc rome 2450 ```A system. Dr gs
t at in ibit or stim late t e cytoc rome 2450 system increase or decrease cyclosporine levels
respectively (Table `). `n partic lar, ca tion m st be exercised wit t e se of eryt romycin to treat
infected eczema, beca se it can increase cyclosporine toxicity.51 Grapefr it
ice also in ibits t e
metabolism of cyclosporine by in ibiting cytoc rome 2450 enzymes in t e intestinal wall, and
s o ld be avoided d ring cyclosporine treatment, especially w en sing t e oral s spension in t e
pediatric pop lation. Heavy alco ol intake can also increase cyclosporine levels.52 Nep rotoxic
dr gs, s c as nonsteroidal antiinflammatory dr gs (NSA`Ds), aminoglycosides, ciprofloxacin,
clotrimazole, and fibrates can impair renal f nction d ring cyclosporine treatment and s o ld be
avoided if possible. Treatment wit NSA`Ds for psoriatic art ritis can potentiate nep rotoxicity
ca sed bycyclosporine.53 ×yclosporine can delay t e metabolism of m ltiple agents, incl ding
digoxin, simvastatin, prednisolone, diclofenac, and met otrexate, leading to increased
concentration and toxicity of t ese dr gs (Table ``).
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77

AE, Adverse event; A2, abdominal pain; ×T, contin o s t erapy; D, diarr ea; G`,
gastrointestinal; GS, gastrointestinal symptoms (if not f rt er defined); `T, intermittent t erapy; MA,
metaanalysis; MJ, microem lsion form lation; N, na sea; OJ, original form lation for
gastrointestinal side effects; 2O, prospective open; R, retrospective st dy; Rev, review; R×T,
randomized controlled trial; RN×T, randomized noncontrolled trial; , vomiting.
â-   ?z ~.  
 
!  /

! 
`t is important to assess possible dr g interactions wit all ot er systemic medications before
treatment wit cyclosporine is initiated. `n partic lar, patients often do not report
intermittent se of NSA`Ds, and so specific instr ctions m st be given to patients. `t is important to
inq ire at every s bseq ent visit if a patient as beg n taking any new medications. Likewise,
patients s o ld be instr cted to inform t eir ot er p ysicians t at t ey are taking cyclosporine and
s are t e dr g interaction information wit t em.
Back to Article O tline
{




Key points
‡A maxim m dose of 5 mg/kg s o ld be sed for p to 1 year only (level ` evidence)

‡Ac te renal deterioration is typically reversible on wit drawal of cyclosporine treatment, w ile
c ronic impairment may be irreversible

‡`f ser m creatinine increases 30% over t e patient's baseline val e on two consec tive readings 2
weeks apart, t e dose s o ld be red ced (level ` evidence)

‡W en ypertension develops, t e dose s o ld be red ced by 25% to 50% or anti ypertensive

t erapy introd ced (level ` evidence); calci m c annel blockers of t e di ydropyridine class are
t e anti ypertensives of c oice (level ``B evidence)

‡Tetracyclines s o ld not be sed to treat cyclosporine-ind ced acne beca se t ere is a

risk of pse dot mor cerebi (level ``` evidence)

Statin t erapy s o ld be sed wit ca tion in t e treatment of cyclosporine-ind ced yperlipidemia

beca se of t e rare occ rrence of r abdomyolysis (level ``` evidence). T e concern over t e side
effect profile of cyclosporine as largely limited its se in dermatology. Jor t e most part, t ese
side effects are dose dependent, related to t e d ration of t erapy, and reversible on
discontin ation, alt o g str ct ral renal abnormalities may be persistent.31, 54, 55, 56, 57 Ad erence
to c rrent g idelines on t e appropriate dosage and monitoring of cyclosporine will considerably
decrease t e risk of side effects.11, 48, 49, 50, 51 A s mmary of t e freq ency of adverse events
reported in t e largest st dies (n >50 patients) ofcyclosporine in t e treatment of psoriasis and
atopic dermatitis is represented in Table `` (long-term observational and retrospective st dies are
incl ded beca se t ese add important information for assessing t e freq ency of side effects).
W ile t e mec anisms involved in many cyclosporine-ind ced side effects remain poorly
nderstood, it as been s ggested t at mitoc ondrial dysf nction and t e
in ibition of imm nop ilins²especially t ose involved in mitoc ondrial ion c annel reg lation²
may play an important role.58, 59


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×yclosporine-ind ced renal dysf nction is t e predominant ca se for dermatologist-driven
concern, and t erefore t e lack ofembrace of its se by a s bstantial percentage of t e
dermatology comm nity. Most persistent renal dysf nction, owever, is related to prolonged
t erapy (ie, longer t an 2 years) or doses of greater t an 5 mg/kd/day, bot of w ic may res lt in str ct ral renal
c anges.31, 60, 61, 62, 63, 64, 65, 66, 67, 68 Renal dysf nction can be f nctional or str ct ral. J nctional impairment, w ic may
begin soon after commencing treatment, can be s bdivided into vasc lar dysf nction and t b lar dysf nction.31, 61, 64, 69

asc lar dysf nction

asc lar dysf nction is ca sed by vasoconstriction of t e afferent glomer lar arterioles, leading to increased vasc lar
resistance. T is res lts in a decrease in renal glomer lar filtration rate (GJR) and renal blood flow wit decreased
clearanceof creatinine.

T b lar dysf nction

T b lar dysf nction is c aracterized by decreased magnesi m reabsorption, decreased ric acid excretion, decreased
potassi m and ydrogen ion secretion, and distal t b lar acidosis. Hypomagnesemia, decreased bicarbonate concentration,
yper ricemia, and yperkalemia may res lt.69 T ere is no loss of rinary concentrating power as is t e case wit ot er
nep rotoxins.69
Endot elin-1 as been implicated in t e vasc lar dysf nction ca sed by cyclosporine.70 2atients wit psoriasis ave ig er
levels of plasma endot elin, wit t e ig est val es occ rring in t ose treated wit cyclosporine.71 Bot endot elin
andcyclosporine mediate vasoconstriction, w ic may potentiate t e nep rotoxic effects of cyclosporine in psoriasis
patients.×yclosporine as also been proposed to ca se endot elial dysf nction by increasing
prod ction of s peroxide,72decreasing prod ction of nitric oxide in endot elial cells,73 preg lating angiotensin `` receptors,
and increasing t e concentration of calci m in smoot m scle cells to ca se increased sensitivity to vasoconstrictive
stim li.58, 74
Ac te deterioration related to f nctional c anges is typically reversible on wit drawal of cyclosporine treatment.64 `n
st diesof intermittent s ort-term t erapy in psoriasis (12-16 weeks), renal dysf nction was typically transient. Between 4%
and 27%of patients ad increases in ser m creatinine levels, w ic ret rned to normal wit in 4 weeks75, 76, 77, 78 (Table ``).
A pooled analysis of 10 st dies assessing 563 psoriasis patients treated wit cyclosporine s owed an increase in
creatinine of 50% above baseline in 4% and 13% of t ose taking 2.5 and 5 mg/kg/day, respectively, in t e first 12
weeks.79`ntermittent t erapy is t o g t to allow normalization of renal f nction between co rses, t ereby minimizing renal
toxicity.66

  

0
× ronic nep rotoxicity ca ses an obliterative microvasc lar renal in
ry (vasc lopat y) and a t b lopat y.

asc lopat y

asc lopat y comprises glomer lar or arteriolar t rombi, arteriolopat y, and interstitial fibrosis wit t b lar
atrop y.80T rombi are composed of fibrin or platelets lodged in glomer li or blood vessels. T e arteriolopat y affects vessels
in t e perip eral vasc lar tree wit p to two layers of smoot m scle. `t is c aracterized by nod lar protein deposits in t e
media consisting of imm noglob lin M and complement (×3 and ×1q) w ic replace necrotic myocytes in t e arteriolar wall in
a pearl necklace or clover leaf pattern to narrow or occl de t e vasc lar l men.81 M coid t ickening of t e intimal wall can
also occ r. T is leads to arteriolar yalinosis, interstitial fibrosis (striped form), t b lar atrop y, and glomer lar sclerosis (Jig
1). T b lar interstitial fibrosis is associated wit an increase in transforming growt factor-beta (TGJ-ȕ).58 T ere may also be
an increase in ser m factor ``` and antit rombin ``` in t ose wit cyclosporine-ind ced vasc lopat y.82
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×yclosporine-ind ced c ronic nep ropat y. Note t e interstitial fibrosis (arrow) wit ad
acent t b lar atrop y. (2eriodic acid±Sc iff stain;
original magnification, ×10.)
T b lopat y

T b lar str ct ral c anges incl de isometric vac olization of t e proximal t b le, occasional giant mitoc ondria in t b lar
epit elial cells, single cell necrosis, and microcalcification of Tamm±Horsfall protein in t e distal t b le.69 T ese c anges are
now rare, wit t e sage of lower cyclosporine doses. W ile t b lopat ic c anges are reversible, vasc lopat ic c anges are
maintained in p to alf of patients.69, 83
T ere ave been many st dies of t e safety of long-term cyclosporine t erapy in dermatology wit regard to nep rotoxcity.
A prospective st dy of renal str ct re and f nction in psoriatic patients treated wit long-term cyclosporine (mean, 3.9
mg/kg/day) for p to 3 years compared 19 psoriatic patients to 38 age-matc ed transplant donors. `nterstitial fibrosis and
t b lar atrop y were present in all biopsies after 1 year of t erapy and became progressive wit f rt er treatment.84 T ese
c anges were more marked in ypertensive patients b t were not strongly correlated to renal f nction. `n a st dy of renal
biopsy specimens obtained from 30 psoriasis patients treated wit cyclosporine, no patient treated for 2 years or longer ad a
normal kidney biopsy specimen, and t ere was prono nced glomer lar sclerosis after 4 years of contin o s
treatment.85A st dy of maintenance cyclosporine for 3.5 years in psoriasis patients s owed a moderate degree of interstitial
fibrosis and glomer lar scarring in two of 14 patients after 2.5 years, wit minimal to mild c ange in all of t e remaining 12
patients.64One year later, t ere was progression of fibrosis in nine of t e 12 patients still enrolled in t e st dy. Similarly, 1
mont after dr g wit drawal, t b lointerstitial scarring and arteriolopat y was seen in 27% of renal biopsy specimens taken
from 15 psoriatic patients w o ad received cyclosporine (<5 mg/kg/day) for 30 mont s.67 T ese patients ad marked
increases in ser m creatinine levels of more t an 90% above baseline, and conversely, t ose s owing no increase in ser m
creatinine levels did not ave str ct ral renal c anges in 86% of cases. T ere was no correlation, owever, wit dose or
treatment d ration. `n a st dy eval ating eig t patients treated wit a mean dose of 3.3 mg/kg/day for 5 years, renal biopsy
specimens revealed t b lar atrop y and arterial yalinosis in six patients (75%), wit interstitial fibrosis and
obliteration of glomer li.62Again, t e best predictor of permanent renal damage was a persistent increase in ser m creatinine
level 1 mont after treatment wit drawal. T ese st dies contrasted to an earlier st dy in w ic no relevant cyclosporine-
related str ct ral c anges were seen in 14 psoriatic patients taking cyclosporine for a mean of 15 mont s compared wit 16
psoriatic controls.66
Many st dies of long-term cyclosporine treatment ave attempted to q antify t e optim m dosage and
d ration ofcyclosporine treatment to prevent c ronic nep rotoxicity. A st dy of 192 patients treated wit a mean dose of 8.2
mg/kg/day for 13 mont s for a variety of a toimm ne conditions s owed renal dysf nction to be dose-related and more
common in older patients, and recommended a ceiling dosage of 5 mg/kg/day and a maxim m increase in ser m
creatinine of 30% over baseline based on t ese res lts.65 A m lticenter st dy of long-term maintenance t erapy
wit cyclosporine for psoriasis, in w ic 88 patients were treated for p to 30 mont s wit eit er 2.5 or 5 mg/kg/day57 followed
by a posttreatment period of 3 mont s s owed an increase in ser m creatinine of 10% above baseline w ic occ rred in
4.5% of patients. `n t is st dy, no association was fo nd between side effects and cyclosporine dose. `n a st dy of 44 patients
treated wit cyclosporine sed for p to 4 years, t ere was a persistent rise in ser m creatinine in 14% of patients, wit a
mean red ction of 16% in GJR (9% of t ose treated wit <3 mg/kg/day compared wit 23% for t ose treated wit >3
 mg/kg/day).63GJR normalized in all cases wit discontin ation of cyclosporine.63 `n a follow- p st dy by t e same gro p,
renal f nction was again examined in t e seven patients w o ad remained on cyclosporine for between 9.5 and 11
years.31 All seven patients s owed a persistent increase in ser m creatinine of greater t an 30% over baseline, and
fo r of t ese ad increases of greater t an 50%. Similarly, 17% of 181 patients taking 3 mg/kg/day for 6 mont s (after an
ind ction period of 4 mont s wit 5 mg/kg/day) ad an increase in ser m creatinine.86 An elevation of ser m creatinine of 30%
above baseline was reported in 46% of 250 patients treated for 21 mont s.68 A st dy of 28 patients reported renal dysf nction
in 71% ofpatients treated wit 3.5 mg/kg/day for a median of 55 mont s, w ic persisted after discontin ation of t e dr g in
35% ofpatients.87 Ot er risk factors for cyclosporine-ind ced nep ropat y incl de preexisting or new-onset ypertension,
renal conditions, ot er nep rotoxic medications, older age, and obesity.64, 65, 88
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`f t ere is an elevation of ser m creatinine of at least 30% over t e patient's baseline val e, recorded on two consec tive
readings 2 weeks apart, t e dose s o ld be red ced by 1 mg/kg/day or by 25% to 50% for a minim m of 4 weeks, even if t e
val e lies wit in t e normal reference range (Jig 2; level ` evidence).11, 48, 49, 50, 51, 65, 89 `f ser m creatinine does not improve
after 4 weeks t erapy at t e red ced dose, cyclosporine s o ld be decreased by anot er 25% to 50%. `f creatinine remains
elevated at t is stage, cyclosporine s o ld be discontin ed. Treatment s o ld not be recommenced ntil t e ser m creatinine
as ret rned to less t an 10% above t e patient's baseline val e. `f creatinine rises 30% over baseline again on
reintrod ction of cyclosporine, t e dr g s o ld be permanently wit drawn. `f ser m creatinine lies o tside t e normal
reference range b t remains less t an 30% above baseline for a given patient, t ere may be nderlying preexisting renal
impairment and ca tion s o ld be exercised. Meas rement of t e GJR is recommended at least ann ally for t ose on long-
term treatment,48, 49, 50 beca se secretion of creatinine in t e renal t b les can increase in cyclosporine-ind ced
nep ropat y, making t e interpretation of ser m creatinine levels less reliable.90 ×yclosporine-ind ced nep ropat y as been
reported in patients wit normal ser m creatinine levels.91 As disc ssed in part ` of t is review, t ere is a discrepancy
between g idelines from t e United States and t ose from E rope wit regard to recommended d ration of contin o s
treatment to prevent c ronic nep rotoxicity. `n t e United States, a maxim m of 1 year of treatment is recommended by t e
American Academy of Dermatology, w ile g idelines p blis ed by t e Britis Association of Dermatology and t e E ropean
Association of Dermatology and enereology recommend a ceiling of 2 years.11, 48, 49, 50, 51 `n general, if cyclosporine is
administered at a dose of 5 mg/kg/day or less and patients' ser m creatinine levels are caref lly monitored to ens re t at t ey
do not increase to more t an 30% above baseline, renal side effects will be f lly reversible after discontin ation of t e
dr g.75, 79, 81

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Management of cyclosporine-ind ced renal dysf nction.




 
T ere is a wide variety in t e reported incidence of new-onset ypertension wit cyclosporine treatment, ranging from 0% to
57% in different st dies (Table ``). St dies of s ort-co rse cyclosporine t erapy s ow a low incidence of new-onset
ypertension, ranging from 0% to 24%, w ic is typically reversible on dose red ction or wit t e se of anti ypertensive
medications.76 `n st dies of long-term treatment, ypertension is more freq ent. `n a st dy by Mrowietz et al,57 8% ofpatients
ad an elevated blood press re as determined by an increase of at least 10% of eit er systolic or diastolic press re, w ile
3.5% s owed an increase in blood press re in t e posttreatment p ase.57 `n a pooled analysis of 10 st dies, 10.6% of patients
ad new-onset ypertension t at was not dose related (10% of t ose taking 2.5 mg/kg/day and 11.9% taking 5
mg/kg/day).79 T e lack of relations ip between dose of cyclosporine and freq ency of ypertension as been s own in ot er
 randomized st dies.55, 68, 92 T is s ggests t at t ere is a s bset of patients wit increased individ al sensitivity
to cyclosporine w o are s sceptible to ypertension even at low doses. Jor t is reason, it as been proposed
t atcyclosporine-ind ced ypertension s o ld be managed by anti ypertensive t erapy rat er t an dose
red ction.79 `nitiating or monitoring anti ypertensive t erapy may be anot er reason w y dermatologists ave been resistant
to embracecyclosporine in t eir clinical practices. `n anot er st dy of long-term t erapy in 122 patients t e median time to
developmentof ypertension was 55 mont s.88 T e onset of ypertension in t is gro p was s own to be bimodal, wit a peak
d ring t e first 9 mont s of t erapy and again after 36 mont s. `n t e pooled analysis by Je tren et al,79 a significant increase
in diastolic blood press re was detected after 1 mont of treatment compared to controls, b t no f rt er increase was seen
between mont s 1 and 3. T ere was no significant difference between mean blood press re at baseline and at 3 mont s
posttreatment. Longer-term st dies ave s own t e persistence of ypertension posttreatment in p to
35% of patients.87T ere appears to be a lower incidence of new-onset ypertension in st dies of s ort-
term cyclosporine treatment in ad lts wit atopic dermatitis compared wit st dies of psoriasis (Table ``). Alt o g t is may
reflect a yo nger mean age in t e co ort of patients recr ited to atopic dermatitis st dies, psoriasis patients may ave a
ig er in erent risk of developing ypertension beca se of an increased incidence of obesity and t e metabolic syndrome
and t erefore ypertension.93, 94 `n a large systematic review and metaanalysis of 15 st dies of cyclosporine in atopic
dermatitis, seven st dies s owed no newly diagnosed ypertension, wit five of t ese st dies being in ad lts only.95 `n t e
pooled analysis of ad lts alone, t ere was a 1.6% incidence per mont of newly diagnosed ypertension.
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Earlier st dies eval ating adverse effects of cyclosporine sed t res olds of 160 mm Hg and 95 mm Hg to define systolic
ypertension and diastolic ypertension, respectively. S bseq ently, t e Joint National ×ommittee on 2revention, Detection,
Eval ation and Treatment of Hig Blood 2ress re ave decreased t e reference ranges sed to define pre ypertension (120-
139/80-89 mm Hg) and ypertension (>140/90 mm Hg).96 2atients wit psoriasis in partic lar are known to be at increased
risk of cardiovasc lar morbidity and mortality94; it is important to monitor blood press re reg larly (eg, weekly self-
monitoring) and instit te appropriate management as soon as t ere is evidence of cyclosporine-ind ced
ypertension.48,49, 50 T e c rrent g idelines recommend a dose red ction of 25% to 50% if possible or t e
introd ction of anti ypertensive t erapy (Jig 3; level ` evidence).48, 49, 50 Beca se t ere appears to be no correlation between
t e onset of ypertension and cyclosporine dose, t e introd ction of anti ypertensives in t e first instance may be more
appropriate. ×alci m c annels blockers of t e di ydropyridine class, s c as amlodipine or isradipine, are t e
anti ypertensives of c oice incyclosporine-mediated ypertension beca se of t eir vasodilating effect on t e afferent
arteriole, w ic may confer protection against nep ropat y.97, 98, 99 erapamil and diltiazem s o ld be avoided beca se t ey
interfere wit ser m cyclosporinelevels, w ile nifedipine can potentiate t e gingival ypertrop y ca sed by cyclosporine.
T ere ave been reports ofangiotensin-converting enzyme in ibitors ca sing a decrease in GJR in cyclosporine-treated
ypertensive patients, alt o g ot er st dies ave s own perindopril to be eq ally effective as amlodipine in lowering blood
press re wit o t affecting GJR or effective renal plasma flow.100, 101, 102 T e se of t iazide di retics may lead to increased
nep rotoxicity.103 2otassi m-sparing di retics s o ld also be avoided, beca se cyclosporine can increase ser m potassi m.

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Management of cyclosporine-ind ced ypertension.

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T e increased risk of malignancy associated wit long-term cyclosporine se in transplant pop lations is well
described.104, 105 `n t is pop lation, owever, m ltiple imm nos ppressive agents are freq ently sed in concert, res lting in
ig er levels of imm nos ppression. Experimental st dies ave s own t at cyclosporine is not genotoxic b t ca ses dose-
dependent t mor promotion.106, 107 `n skin t mor models, cyclosporine as been s own to en ance t e ind ction ofskin
t mors by ltraviolet irradiation.108 T e increased risk of malignancy as been attrib ted to potent imm nos ppression, b t
ot er direct effects ave also been observed. ×yclosporine increases formation of reactive oxygen species w ic promotes
transformation to malignancy.109 `n mice st dies, cyclosporine increases t e synt esis of TGJ-ȕ, interle kin-6 (`L-6), and
vasc lar epidermal growt factor ( EGJ) in t mor cells, res lting in increased t mor growt , metastasis, and
angiogenesis.110 Anot er st dy s owed t at cyclosporine ind ces invasiveness of nontransformed cells by a cell
a tonomo s mec anism, w ic is blocked by monoclonal antibodies to TGJ-ȕ.111 ×yclosporine can also in ibit DNA repair by
ind cing apoptosis in activated T cells.110
`n a st dy of 1252 psoriasis patients treated for a mean d ration of 1.9 years wit low-dose cyclosporine (2.7-3.1mg/kg), t ere
was a six-fold increase in c taneo s sq amo s cell carcinomas (S××s) after a 5-year follow- p period.112 T e risk increased
wit longer d ration of t erapy (>2 years), wit t e increased incidence being seen solely in t ose wit a previo s
istory of 2U A treatment. Anot er nested co ort crossover st dy of 28 patients w o ad been treated wit 2U A followed
bycyclosporine s owed a seven-fold increase in risk of S×× after treatment wit cyclosporine compared to before
first se oft e dr g.113 Six of t e 842 psoriasis patients st died in t e Sandoz 2 arma st dy114 developed malignant or
premalignant skin lesions, almost all of w om ad been treated previo sly wit 2U A, ltraviolet B lig t, or met otrexate.
Anot er case report described er ptive keratoacant omas and nod lar basal cell carcinoma in psoriasis patients treated
wit cyclosporine.115 `n view of t is increased risk of c taneo s S××, c rrent g idelines s ggest t at narrowband ltraviolet B
lig t s o ld be sed as a first-line agent w en considering p otot erapy, so t at cyclosporine remains a f t re treatment
option. `f 2U A is sed, t e n mber of lifetime treatments s o ld be limited to fewer t an 200. `mm nos ppression s o ld
not be sed conc rrently wit p otot erapy or directly before or after 2U A; imm nos ppressants s o ld be avoided in
t ose wit a ig c m lative dose of 2U A or a previo s istory of S×× or melanoma.48, 49, 50
St dies in transplant recipients ave s own an increased risk of lymp oma. T ere was no increase, owever, in t e
occ rrence of lymp omas in t e 1252 psoriasis patients described by 2a l et al.112 `n t e Sandoz 2 arma st dy,114 t ree oft e
842 psoriasis patients developed benign c taneo s lymp oproliferative disorders, anot er developed a B-cell lymp oma, and
one a c taneo s T-cell lymp oma. T e benign c taneo s lymp oproliferative disorders and B-cell lymp oma regressed
rapidly on wit drawal of cyclosporine. T ere ave been isolated case reports of t e development of B- and T-cell lymp omas
in psoriasis patients treated wit cyclosporine.116, 117, 118, 119 `t is important to note, owever, t at psoriasis ca ses a
state of c ronic overactivation of t e imm ne system wit a ig er incidence of lymp oma and ot er malignancies t an t e
normal pop lation.120, 121 ×yclosporine as been s own to promote Epstein±Barr vir s (EB ) transformation of man
perip eral blood lymp ocytes.122 One report described t e development of EB -associated lymp oproliferative disease after
long-term cyclosporine se, wit spontaneo s regression on stopping t e dr g, strongly s ggesting ca sality.123 Ot er
lymp oproliferative disorders, s c as airy cell le kemia and Waldenstrom macroglob lemia, ave been reported.124
Alt o g t ere ave been m ltiple case reports of solid t mors in patients on cyclosporine t erapy in t e literat re,125 t ere
was no increase in t e incidence of solid t mors in t e psoriasis st dy by 2a l et al.112 `n t e Sandoz 2 arma
st dy,114 fiveof t e 842 patients (0.7%) developed solid organ t mors, w ic were considered nlikely to
be cyclosporine related by t e investigator or reporting p ysician. Remarkably, an imm noprotective effect against certain
t mor types as been s ggested by large case-control st dies of patients s ppressed wit cyclosporine in combination wit
ot er imm nos ppressive agents, wit a decreased odds ratio of rectal and breast cancers.126, 127

 



T e ne rologic side effects of cyclosporine incl de eadac es, tremor, seiz res, psyc osis, paraest esias, and sleep
dist rbance. Headac e occ rs in p to alf of patients, w ile parast esias and tremor occ r in p to 40% and 26% ofpatients,
respectively (Table ``). 2araest esia and tremor often occ r in t e first weeks of treatment and improve wit o t
red ction of t e dose, wit ypomagnesemia s ggested as a possible ca se.115, 128
2se dot mor cerebri as been reported in several pediatric patients taking cyclosporine.129, 130, 131 `n partic lar, tetracyclines
s o ld not be sed to treat cyclosporine-ind ced acne beca se t is increases t e possibility of developing t is complication.
T ree yo ng female patients in o r department ave developed pse dot mor cerebri as a res lt of t is combination,
one of w om req ired a ventric loperitoneal s nt. T e condition is rapidly reversible on wit drawal ofcyclosporine, so
prompt diagnosis is necessary to prevent permanent vis al deficits. Seiz res ave also rarely been reported, and t ose wit a
istory of epilepsy s o ld be warned t at cyclosporine can lower t e seiz re t res old. T e risk ofseiz res is increased in
t ose taking ig doses of prednisone, prednisolone, or met lyprednisolone. ×yclosporine levels in t ose on antiepileptic
t erapy may also be lower t an expected beca se of preg lation of t e cytoc rome 2450 system (Table `). ×yclosporine as
 rarely been reported to ca se a reversible posterior le koencep alopat y, consisting of eadac e, ypertension, seiz res,
cortical blindness, and ot er vis al abnormalities wit c aracteristic magnetic resonance imaging c anges.132 T ere ave
been fo r reports of cyclosporine-ind ced 2arkinsonism.133
A st dy sing a magnetic resonance spectroscopy±based metabonomic approac to eval ate t e effect of cyclosporine on
rat brain cell metabolism s owed a significant decrease in ig -energy p osp ate metabolism and a red ction in intracell lar
concentrations of ne rotransmitters, s c as gl tamate and N-acetyl-asparate (NAA) in rat brain cells.134
Œ 
  



T e reported incidence of gastrointestinal side effects, s c as na sea, vomiting, diarr ea, or flat lence, varies considerably
(Table ``). `n t e pooled analysis by Kr pp et al,114 na sea, abdominal pain, diarr ea, vomiting, and gastrointestinal complaints
were seen in 3.8%, 2.3%, 2%, 1.1%, and 1.1%, respectively. Hyperbilir binemia also occ rs in p to 30% ofpatients.50 T is is
generally dose related and, in t e absence of ot er abnormalities of liver f nction, does not req ire f rt er eval ation.49 `t is
believed to be a conseq ence of competitive in ibition of transport between bilir bin and cyclosporinerat er t an direct
epatotoxicity.86 An increase in transaminases occ rs in p to 30% of patients.50 `f ser m bilir bin or transaminases rise to
twice t e normal val e, a dose red ction of 25% is necessary.50 An increased incidence ofc olelit iasis as been reported in
renal and cardiac transplant recipients treated wit cyclosporine compared wit t ose treated wit alternative
imm nos ppressants.135
Œ   



Gingival yperplasia is ca sed by fibro s yperplasia and as been reported in p to 30% of patients on cyclosporine, wit a
ig er incidence reported in c ildren (Jig 4).136, 137 T e pat ogenesis is ncertain b t it is often associated wit poor oral
ygiene. 2laq e control and t e removal of local irritants ave been s own to be of benefit.138 Genetic eterogeneity also
seems to play an important role in its development.136 ×omplications incl de f nctional diffic lties, disfig rement, and
increased caries.136 Onset tends to be d ring t e first 3 to 6 mont s of treatment. Treatment wit metronidazole res lted in
complete resol tion in one series of fo r patients.139

VÊ
VÊ iew Large `mage
VÊ Download to 2ower2oint
VÊ J1
×yclosporine-ind ced gingival yperplasia.







A st dy examining c taneo s side effects of cyclosporine t erapy in 67 renal transplant patients revealed ypertric osis in
60%, epidermal cysts in 28%, keratosis pilaris in 21%, acne in 15%, follic litis in 12%, and sebaceo s yperplasia in
10%.140 T ere is considerable variability in t ere reported incidence of ypertric osis (Table ``). Hypertric osis was reported in
6.8% of patients in t e st dy by Kr pp et al,114 23% in t at of Grossman et al88 and in 54% in a st dy by Griffit s et al.141T is
side effect is more cosmetically nacceptable for women wit darker air. T e etiology is nknown wit no evidence to
s ggest an alteration in endocrine stat s.115 ×yclosporine mod lates protein kinase × expression and translocation in air
epit elial cells and promotes proliferation of t ese cells.142 ×yclosporine also prolongs man air growt in vitro.143
Most ot er c taneo s side effects also affect t e pilosebaco s nit, wit st dies s ggesting t at t e follic lar epit eli m is
more sensitive to cyclosporine t an t e interfollic lar epit eli m.142 Acneiform er ptions or worsening of preexisting acne
v lgaris are common wit cyclosporine.144 As previo sly mentioned, tetracyclines s o ld not be sed to treat acne
beca seof t e increased risk of pse dot mor cerebri. `n a st dy of intermittent t erapy in 400 psoriasis patients, transient
palmar and/or plantar p st lar psoriasis occ rred in 5 patients on wit drawal of cyclosporine b t was not serio s eno g to
warrant st dy discontin ation in any patient.76
 
 
Despite its imm nos ppressive effects, infectio s side effects wit cyclosporine are rare and seldom severe. `n controlled
st dies, t ere was no difference in t e freq ency of infections between t ose taking cyclosporine compared wit etretinate or
placebo. `f spontaneo s recovery did not occ r, treatment of t e infection or wit drawal of t e dr g led to
resol tion.115A review of 2 decades of safety data of cyclosporine in dermatology patients s ggested no increased
risk of opport nistic infections or t berc losis reactivation.125 Beca se cyclosporine as been reported to ca se t e
reactivation of latent t berc losis infection in ig er doses sed in transplant recipients, and beca se cyclosporine is an
imm nos ppressant, t e National 2soriasis Jo ndation recommends screening for latent t berc losis infection before
initiation of cyclosporinetreatment (level of evidence ` ).145, 146 Management of infection w ile taking cyclosporine depends
on t e pat ogen and t e severity of infection. Bacterial or f ngal infections s o ld be treated wit appropriate antibiotic
t erapy as soon as t ey are detected. ×ommencement of cyclosporine s o ld be delayed ntil t e resol tion of active erpes
simplex in t ose wit atopic dermatitis, and wit drawal s o ld be considered if t ere is evidence of dissemination, to red ce
t e risk of eczema erpetic m.51





Jatig e, let argy, and fl -like symptoms are commonly reported. M sc loskeletal symptoms s c as
oint pain and m scle
ac es are reported in 10% to 40% of patients.50


 


Hyperlipidemia (partic larly ypertriglyceridemia) d ring cyclosporine treatment is well described.55, 57, 115, 147, 148 T e
package insert reports ypertriglyceridemia (>750 mg/dL) in 15% of patients and yperc olesteremia (>300 mg/dL) in less
t an 3% of patients.49 `n t e st dy by Mrowietz et al,57 an increase in triglycerides 30% above baseline was observed in
12.5% of patients. Anot er st dy investigating t e effect of 5 mg/kg/day of cyclosporine on ser m fasting lipids s owed an
increase of more t an 30% in c olesterol and triglycerides in 18% and 50% of patients, respectively, seen after
st 2 weeks in
bot , wit no f rt er significant c ange noted t ro g o t t e co rse of treatment.148 T is st dy s owed no effect on ig -
density lipoprotein levels. A st dy by Grossman et al147 s owed a 50% increase in triglyceride levels in seven o t of eig t
psoriasis patients, w ic peaked after 1 mont of treatment and s ggested a correlation between ypertriglyceridemia and
previo s retinoid se, a finding t at was ref ted in a s bseq ent st dy.149 Hyperlipidemia normalizes on discontin ation oft e
dr g.86
Hyperlipidemia as been s ggested to contrib te to accelerated at erosclerosis in renal transplant patients.150 Wit t e
c rrent knowledge t at t e incidence of metabolic syndrome and cardiovasc lar morbidity is increased in severe psoriasis,
t is side effect needs to be actively managed in psoriasis patients. W ile no st dies ave examined t e
incidence ofcyclosporine-ind ced yperlipidemia in atopic dermatitis patients, it wo ld be interesting to compare t e
incidence of yperlipidemia between t ese two pop lation gro ps.
/

 
`f yperlipidemia develops and cyclosporine t erapy is maintained, a lipid-lowering diet s o ld be introd ced (level `
evidence). `f t is is not s ccessf l, t e dose of cyclosporine s o ld be red ced or a lipid-lowering agent s o ld be
commenced. Beca se cyclosporine decreases t e clearance of statins, r abdomyolysis may occ r in patients taking
concomitant statin t erapy.151 igilance is important in detecting t is rare b t potentially fatal dr g interaction. 2atients
s o ld be instr cted to report symptoms s c as m scle pain or weakness, dark-colored rine, or generalized malaise
immediately, and ser m creatinine p osp okinase s o ld be monitored after commencement of t e dr g. T ere ave also
been reports of nep rotoxicty and renal fail re w en fibrates ave been sed wit cyclosporine in transplant recipients.152

   

One of t e advantages of cyclosporine compared to ot er imm nos ppressant t erapies is t e lack of myelos ppression
relating to treatment. A slig t normoc romic, normocytic anemia, owever, may be observed,115, 153 and microangiopat ic
emolytic anemia and t rombocytopenia ave also rarely been reported.49 Renal dysf nction can lead to ypomagnesemia,
yper ricemia, and yperkalemia. One st dy s owed yper ricemia (2.6% of patients) and ypomagnesemia (8.8%) to be
dose-related, w ile yperkalemia (0.5%) was not related to dose or treatment d ration.115 Hypomagnesemia as been reported
in 5% to 15% of patients and s o ld be treated wit oral magnesi m s pplements (beginning at 200 mg magnesi m daily and
increased as needed), wit ad erence monitored.50 St dies in rats ave s own t at magnesi m s pplementation may prevent
c ronic cyclosporine nep ropat y by ad
sting nitric oxide synt ase activity.154
Hyper ricemia s o ld be treated wit a low p rine diet and s fficient fl id intake.50 Hyperkalemia in t e setting of normal
renal f nction can occ r and is most likely ca sed by t b lar dysf nction and secondary ypoaldosteronism.155 `f fl id intake
and a low potassi m diet do not restore normal ser m potassi m levels, dose red ction is necessary.50 `ncreased
levels ofser m alkaline p osp atase (AL2) ave been reported in p to 8% of psoriasis patients ndergoing treatment,
generally in t e setting of normal liver f nction tests.115 T is is likely related to an increase in t e bone
isozyme of AL2, ca sed by c anges in bone metabolism. ×yclosporine as been s own to ca se mild osteoblastic
proliferation and matrix mineralization activity, as reflected by increased ser m alkaline p osp atase in renal transplant
patients wit normal parat yroid ormone levels.156
Back to Article O tline
©  
Key points
‡Blood press re and blood rea nitrogen and ser m creatinine levels s o ld be meas red at baseline, weeks 2, 4, 6, and 8,
and t en mont ly t ereafter

‡2atients s o ld be instr cted regarding dental care commencing treatment and attend t eir dentist at 6-mont intervals to
monitor for gingival ypertrop y

‡National malignancy screening programs s o ld be ad ered to

‡ accination s o ld take place before t e initiation of treatment w ere possible

&

   

Before beginning cyclosporine treatment, patients s o ld be screened wit a caref l istory, examination, and baseline
laboratory investigations (Table ```). `n partic lar, a istory of malignancy, renal dysf nction, ypertension, c rrent infections,
or a istory of previo s 2U A p otot erapy s o ld be elicited. A f ll medication list s o ld be recorded, incl ding over t e
co nter preparations. T e p ysical examination s o ld incl de meas rement of blood press re at two time points and an
assessment of t e skin for actinic damage and skin cancers. `nitiation of treatment s o ld be deferred ntil active erpes
simplex lesions ave resolved, partic larly in t e atopic dermatitis pop lation. `f possible, viral warts s o ld be treated before
beginning a co rse of cyclosporine. 2atients s o ld be instr cted regarding caref l dental ygiene and to visit t eir dentist at
6-mont intervals to monitor for gingival ypertrop y. T e need for contraception s o ld be disc ssed wit womenof c ild-
bearing age and a pregnancy test performed if indicated. Specifically, cyclosporine can red ce t e efficacy ofprogesterone-
containing contraceptives, so alternative birt control met ods s o ld be considered.50 2atients s o ld also be co nseled
regarding t e need for long-term s n protection in view of t e ig er incidence of skin cancer in t ose takingcyclosporine.
c
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Jasting ser m creatinine s o ld be meas red in a standardized manner on at least two separate occasions (fasting >12
o rs, in t e morning, no preceding stren o s exercise), and repeated again if t ere is a discrepancy of more t an 10 ȝmol/L
between t ese meas rements.11, 48, 49, 50 T e average of t ese two val es t en serves as t e baseline ser m creatinine
against w ic s bseq ent treatment val es are compared. Baseline laboratory investigations s o ld also incl de a complete
blood co nt, blood rea nitrogen (BUN), potassi m, bilir bin, liver enzymes, ric acid, magnesi m, fasting lipids, and
rinalysis for protein ria.11
/
  +(
 
 
Blood press re, BUN, and ser m creatinine s o ld be meas red at weeks 2, 4, 6, and 8, and t en mont ly t ereafter, wit
more freq ent readings if t ere are abnormal meas rements.11, 48, 49, 50 Meas rements of t e complete blood cell co nt,
potassi m, ric acid, fasting lipids, bilir bin, liver enzymes, and magnesi m s o ld be taken initially mont ly and t ereafter
pending t e co rse of t erapy (2-mont intervals, possibly). 2atients s o ld be weig ed at every visit.
{   
 
T e GJR s o ld be assessed ann ally for t e small n mber of patients w o are treated contin o sly for more t an 1
year.48, 49, 50 T ere s o ld be f ll compliance wit national screening programs for cervical, breast, and prostate cancers.
 


 
 
×yclosporine ser m concentrations are typically monitored in transplant patients to avoid toxicity ca sed by ig
concentrations and to minimize possible organ re
ection ca sed by low concentrations. `n practice, t is as not been adopted
or s own to be of benefit in monitoring efficacy or toxicity in dermatology patients.57, 157, 158 No difference was detected
between mean cyclosporine tro g levels meas red sing specific monoclonal or nonspecific polyclonal radioimm noassay
in relation to efficacy or renal dysf nction. `t can be sed, owever, if t ere is a q ery regarding patient ad erence to
treatment or to detect cyclosporine levels above t e recommended dosing range.159
2  
Live vaccination is contraindicated w ile on cyclosporine.11 T ere ave been n mero s st dies of imm nologic response to
inactivated vaccines in transplant recipients treated wit cyclosporine. 2ne mococcal vaccination wit a 23-valent vaccine in
transplant recipients treated wit cyclosporine as been s own to be eq ally effective as in controls, w ile imm ne response
to infl enza vaccination is significantly red ced alt o g not completely abolis ed.160, 161 `t as been s ggested t at t is
differential response is related to T-cell independent antibody prod ction against polysacc aride antigens in t e
pne mococcal vaccine.160 `mm ne response to epatitis B vaccination is impaired.162 T e response to standard dip t eria
and tetan s booster vaccination in pediatric renal transplant recipients treated wit cyclosporine is comparable to ealt y
c ildren.163 accination s o ld take place before t e initiation of treatment w ere possible, and alt o g response may be
s boptimal,11, 49 ann al vaccination wit pne mococcal and infl enza vaccines is advocated.11 Delayed-type ypersensitivity
reactions to skin-test antigens are red ced by cyclosporine, and so t e interpretation of t berc lin skin testing is nreliable in
t ose ndergoing treatment.164, 165 As a res lt, Manto x testing is recommended before initiation ofcyclosporine.11
Back to Article O tline

  
Key points
‡×yclosporine crosses t e placental blood barrier and is a category × dr g in pregnancy

‡2regnancy registries s ow no increase in t e risk of teratogenicity, alt o g t ere were trends towards low birt weig t and
premat rity

‡×yclosporine is excreted in breast milk

×yclosporine as been labeled as a category × dr g by t e JDA 2regnancy Labeling Task Jorce (animal reprod ction st dies
ave s own an adverse effect on t e fet s and t ere are no adeq ate and well controlled st dies in mans, b t potential
benefits may warrant se of t e dr g in pregnant women despite potential risks). ×yclosporine as been s own to passively
cross t e placental blood barrier to ac ieve 10% to 50% of t e maternal plasma concentration.166 T e administration of 25
mg/kg of cyclosporine to female Lewis rats res lted in c aracteristic dr g-ind ced pat ologic c anges in t e mot er and a
ig incidence of fetal mortality, w ile a dose of 10 mg/kg was not fetotoxic.167 Animal st dies ave not s own increased
malformation rates, b t in tero expos re to cyclosporine in rabbits ind ced a nep ron red ction t at led to systemic
ypertension and progressive c ronic renal ins fficiency in ad lt ood.168
As controlled st dies in mans cannot et ically be performed, we m st look to pregnancy registries to eval ate t e
safety ofcyclosporine in pregnancy. T e ma
ority of o r safety data comes from analyses of pregnancy o tcomes in
transplant recipients, w ic ave concl ded t at t ere is no evidence of teratogenicity.50, 169, 170 A metaanalysis of 410
patients in 15 st dies (6 wit control gro ps) s owed no statistically significant increase in t e incidence of congenital
malformations, preterm delivery or low birt weig t associated wit cyclosporine expos re d ring pregnancy, alt o g t ere
were definite trends towards low birt weig t (prevalence, 43%) and premat rity (prevalence, 56%).169 A report on 629
pregnancies in patients treated wit cyclosporine for transplantation collected by t e Sandoz international database s owed a
ig er incidence of premat rity and low birt weig t, as wo ld be expected wit conventional imm nos ppressive t erapy,
b t t e rates of fetal loss and malformation were wit in t e normal range for t e general pop lation.170
A 12-year follow- p of 175 c ildren exposed to cyclosporine in tero s owed a 16% incidence of mental developmental
delay.171 T is was attrib ted to t e ig incidence of premat rity in t e gro p. A st dy of seven c ildren exposed
tocyclosporine in tero s owed a transient minimal effect on fetal imm ne development, wit normal imm noglob lin and
complement levels on serologic testing, and normal seroconversion in response to vaccination. T e a t ors concl ded t at
c ildren exposed in tero are nlikely to be at risk of imm nodeficiency or a toimm nity.172 Anot er st dy examined six
infants born to female kidney transplant recipients w o ad received cyclosporine and met ylprednisolone t ro g o t t eir
pregnancies.173 T is s owed a dist rbance of t e mat ration and development of T cells, B cells, and nat ral killer cells,
w ic was apparent p to 1 year of age. W ile t ere were no clinical signs of imm nos ppression, t e a t ors s ggested t at
conventional vaccinations s o ld be delayed in t ese infants. Despite t e aforementioned st dy s owing nep ron red ction
in rabbits exposed to cyclosporine, t ere appears to be no nep rotoxic effect in c ildren exposed to cyclosporine in tero.174
×yclosporine tro g levels decrease wit pregnancy beca se of t e increased vol me of distrib tion and increased
metabolism.175 Beca se of t e niq e state of imm nologic tolerance afforded by pregnancy, owever, a significant
proportion of dermatoses improve d ring pregnancy, making increases in cyclosporine dosages seldom necessary.
 
Mot ers taking cyclosporine ave been advised not to breastfeed beca se of concerns regarding imm nos ppressive effects
in t e neonate (level ` evidence).11, 48, 49, 50, 176 ×yclosporine is excreted in breast milk, wit a wide variation in t e milk-to-
maternal ser m concentration ratio, depending on t e time of sampling and maternal dose.177 To date, evidence on t e
safety of breastfeeding d ring cyclosporine t erapy is limited to two small case series and two case reports. No adverse
events related to maternal cyclosporine treatment d ring lactation ave been observed in t ese reports,
and cyclosporineconcentrations in t e blood of t e infants were ndetectable wit t e exception of one infant.177, 178 W ile
t is is reass ring, evidence concerning t e safety of breastfeeding is limited and still inconcl sive.
Back to Article O tline



Key points
‡T ere is decreased bioavailability of cyclosporine in c ildren

‡× ildren are less s sceptible to cyclosporine-ind ced nep ropat y t an ad lts

×yclosporine as been sed in transplant recipients as yo ng as 1 year of age wit no serio s adverse effects. T e safety and
efficacy of bot intermittent and contin o s cyclosporine t erapy in c ildren for t e treatment of atopic dermatitis for p to a
year at doses of p to 5 mg/kg/day as also been s own (Table ``).179, 180, 181, 182 No randomized controlled trials ave been
performed for pediatric psoriasis, b t cyclosporine is often sed in t e treatment of severe psoriasis in t is age
gro p.183 × ildren are less s sceptible to cyclosporine-ind ced nep ropat y t an ad lts.65, 81, 95 T is may be
beca se ofdecreased sensitivity to cyclosporine, ig er clearance, or decreased bioavailability of t e dr g. Jor a given
red ction in renal f nction, owever, t e incidence of renal vasc lopat y is t e same. A metaanalysis of cyclosporine se in
atopic dermatitis s ggested t at alt o g t e effectiveness was similar in ad lts and c ildren, tolerability was better in
c ildren t an in ad lts.95 `n t e pooled analysis, only 2.5% of c ildren ad an increase in creatinine of more t an 30% per
mont oftreatment and no c ildren developed ypertension.
  

  -(

0



 



T e Baylor University Medical ×enter (Dallas, TX) as large liver, renal, and bone marrow transplant nits. We ave been
fort nate to ave ad a close working relations ip wit t eir p ysicians, res lting in o r sage of cyclosporine for more t an
25 years, partic larly for severe psoriasis and atopic dermatitis of all age gro ps. Wit t e advent of biologic t erapies,
o r se of cyclosporine as c anged significantly over t e past seven years. ×yclosporine is now typically sed as a ³resc e´
or ³ind ction´ t erapy for periods of p to 6 mont s beca se of its rapid onset of action and considerable efficacy. A small
s bset of patients, partic larly t e pediatric pop lation, is still treated wit maintenance t erapy for periods of p to 1 year.
`ntermittent t erapy in psoriasis²wit inevitable flares and disappointed, fr strated patients² as become a regimen of t e
past. `n recent years, t ere ave been significant t erape tic advances in psoriasis. Today, t e ma
ority of psoriasis patients
can expect to ac ieve prolonged clearance or near-clearance of t eir disease wit t e c rrently available systemic or biologic
agents. Similarly, t ere ave been advances in t e treatment of pyoderma gangrenos m wit biologic agents. New, ig ly
effective, biologic and nonbiologic imm nomod latory agents are in clinical development for t e treatment of c ronic
idiopat ic rticaria.184 2rogress in t e treatment of atopic dermatitis as been more limited, b t systemic agents s c as
azat ioprine, met otrexate, interferon-gamma, and mycop enolate mofetil are now more commonly sed.
T ere is now a greater appreciation of t e importance of disease-related q ality of life for dermatologic conditions and t e
importance of a psyc osocial approac to management. Many dermatologic conditions, especially psoriasis and atopic
dermatitis, can ca se significant psyc ological and emotional stress for bot patients and t eir families, especially in t e
yo nger pop lation gro ps, wit an increased prevalence of depression and poor self-esteem.185, 186, 187 Q ality of life can be
impaired to a similar extent as is seen in c ronic diseases s c as diabetes mellit s and coronary eart
disease.188,189, 190 Q ality of life instr ments are increasingly being sed to f rt er inform clinical decision making, b t a poor
correlation as been seen in bot psoriasis and atopic dermatitis between ob
ective, clinician-determined clinical extent and
s b
ective, patient-driven q ality of life scores.190, 191, 192, 193, 194 W at constit tes ³significant disease´ varies considerably
among patients.195, 196 W ile some patients may be intolerant of even a minor amo nt of skin disease, ot ers are npert rbed
by w at many clinicians may consider severe disease. To allow a patient to ac ieve clearance, raise t eir expectations, and
t en s b
ect t em to relapse, albeit to a lesser disease extent, in order to be treated wit anot er co rse ofintermittent t erapy
may be ig ly distressing for patients. Having experienced remission, sometimes t e first in many years, patients live in
fear of ret rn of t eir disease, and t e prospect of relapse can ca se significant and nnecessary anxiety. As a res lt, we
personally do not recommend t e se of repeated co rses of ³intermittent t erapy´ wit cyclosporine for psoriasis, b t rat er
its se as a resc e agent for significant flares of psoriasis wit contin ation of t e previo s dr g or initiation of anot er agent
as t e cyclosporine is tapered. `n t e treatment of atopic dermatitis, partic larly in pediatric and adolescent patients, we will
freq ently recommend contin o s rat er t an intermittent t erapy for p to a year for a more consistent control of disease
and res ltant improvement in q ality of life, especially in yo nger patients. Rotational t erapy wit azat ioprine or
met otrexate may also minimize toxicity w ile allowing a more stable disease co rse.
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`n s mmary, since its advent in 1972, cyclosporine as played a very val able role, not only in t e treatment of many
dermatoses b t also in t e expansion of o r knowledge of t e imm nopat op ysiology of many dermatologic conditions. `ts
serendipito s discovery in 1979 for psoriasis c anged t e entire field of psoriasis researc from t at of a yperproliferative,
keratinocyte-driven disorder to t at of an ³imm ne-driven´ disease, paving t e way for t e s bseq ent biologic revol tion in
psoriasis. Beca se of its rapid onset of action and marked efficacy, cyclosporine is partic larly sef l in t e
treatment ofsignificant flares of c taneo s disease²especially psoriasis and atopic dermatitis²t at are nresponsive to
ot er t erapies, and also as a bridging agent d ring t e ind ction of ot er maintenance agents. Wit a growing
armamentari m oft erape tic alternatives, intermittent t erapy s o ld no longer be necessary and long-term treatment
wit cyclosporine is only advocated in exceptional cases. `n t ese patients, combination or rotational t erapy can be sed to
minimize c m lative dosage and long-term side effects. `n general, owever, treatment for more t an 1 year s o ld be
avoided w ere possible. Side effects are dose dependent, related to t e d ration of t erapy, and reversible on discontin ation
once treatment g idelines are followed and caref l monitoring is practiced. ×yclosporine is a dr g in common se in o r
clinical practice and one we are very comfortable wit , provided t at t e aforementioned g idelines are closely followed. `t is
a dr g t at s o ld be an integral part of o r t erape tic armamentari m and be considered for broader se by t e
dermatologic comm nity.

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We t ank Drs Stacy Hinson and Nesrin A. On r for t eir istopat ologic image of c ronic cyclosporine-ind ced nep ropat y,
and ×ristina Martinez for er tec nical s pport.