Mild-to-Moderate Psoriasis - part 5 pot

Cyclosporin is effective in and approved for the treatment of matory dermatoses including psoriasis, but is limited by systemic side effectssuch as renal toxicity and hypertension, and t

9 Topical Calcineurin Inhibitors

Patricia Tinio and Mark G Lebwohl

Department of Dermatology, Mount Sinai School of Medicine, New York,

New York, U.S.A

The calcineurin inhibitors were developed as an alternative to topical andsystemic glucocorticoids for immunosuppressive therapy They were primar-ily used for the prevention of organ transplant rejection These drugs includecyclosporin and the macrolides tacrolimus (FK 506) and, most recently,pimecrolimus (SDZ ASM 981), which are known to modify immunefunction by inhibition of calcineurin-dependent reactions critical in theproduction of inflammatory cytokines (1)

Cyclosporin is effective in and approved for the treatment of matory dermatoses including psoriasis, but is limited by systemic side effectssuch as renal toxicity and hypertension, and topical cyclosporin has almostnegligible skin penetration (2,3)

inflam-Tacrolimus and pimecrolimus have smaller molecular weights givingthem the advantage of better skin penetration, which led to the development

of topical formulations Both topical tacrolimus and pimecrolimus do notcause skin atrophy mainly because calcineurin is not needed for collagensynthesis (1,4) This is in contrast to topical corticosteroids, which are asso-ciated with telangiectasia (Fig 1), atrophogenicity, striae (Fig 2), and otherlocal cutaneous adverse effects when used over a long period of time (5,6).Both tacrolimus and pimecrolimus belong to the group of macrolideimmunosuppressants, which are xenobiotics possessing a complex structure.They are derived from several strains of Streptomyces The first macrolide

to be developed was tacrolimus, which is produced by Streptomyces

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tsukubaensis (1) Several controlled trials have shown systemic tacrolimus to

be effective in the treatment of psoriasis (7,8) Pimecrolimus is an ascomycinderivative, which is produced by another strain of Streptomyces, Streptomyceshygropicus var ascomyceticus (1) One study has shown that systemic pimecro-limus is clinically highly effective in psoriasis and is well tolerated (9)

Figure 1 (See color insert) Telangectasia, ear

Figure 2 (See color insert) Striae distensae

to enter the nucleus and combine with its nuclear component NF-ATn.This crucial step then leads to the transcription of cytokines includinginterleukin (IL)-1, -2, -3, -4, transforming growth factor beta, and tumornecrosis factor alpha When tacrolimus and pimecrolimus combine withtheir intracellular receptors, they are able to bind calcineurin and preventthe dephosphorylation of NF-ATc, thus blocking the production ofproinflammatory cytokines (1–3,10).

One study found increased IL-8 and IL-8 receptor (IL-8R) levels

in psoriatic epidermis and tacrolimus in particular was shown totarget the keratinocyte IL-8R by inhibiting its function and expression invitro (11)

CLINICAL PROPERTIES

Accumulating evidence has revealed psoriasis to be a genetically directedimmunogenic inflammatory disease based on a self-reactive T-helper-1 (Th-1)response (12) Because of their chemical characteristics, tacrolimus andpimecrolimus can be effective for the topical treatment of inflammatoryskin disorders wherein T cells may play a crucial role in development (13).Mrowietz et al (13) demonstrated that pimecrolimus (1%) is similar inefficacy to clobetasol-17-propionate (0.05%) in plaque-type psoriasis whenapplied topically under occlusion for two weeks using the microplaqueassay, and no adverse drug effects were seen in any of the patients whoparticipated in the study (13)

Recently, a study that combined pimecrolimus ointment 0.1% in a mulation with 10% urea demonstrated that even without any occlusion, thepimecrolimus ointment 0.1%, in its experimental formulation, was effective

for-in treatfor-ing psoriasis plaques (14)

A pilot study by Zonneveld et al (15) in 1998 did not show similar cacy for 0.3% tacrolimus ointment in chronic plaque-type psoriasis Theirstudy compared calcipotriol ointment applied twice daily, and tacrolimusointment and placebo ointment applied once daily on psoriatic plaques

effi-Topical Calcineurin Inhibitors 107

An important and main difference from the earlier topical pimecrolimusstudy is that Zonneveld et al did not use occlusion.

Topical tacrolimus 0.3% was also applied under occlusion on descaledpsoriatic skin in microplaques, and in this model topical tacrolimus showedefficacy (16) The psoriatic plaques were first descaled by overnight treat-ment with 2% salicylic acid in petrolatum before the medications wereapplied No adverse events at the site of application or systemic side effectswere observed

An eight-week, randomized, double-blind, vehicle-controlled, center trial demonstrated that 0.1% tacrolimus ointment was effective in thetreatment of facial and intertriginous psoriasis (Fig 3A and B) A significantdifference was observed between the 0.1% tacrolimus ointment group and thevehicle group, with 62.5% of the 0.1% tacrolimus ointment group showingclearing or almost total clearing compared to 31.5% in the vehicle group atthe end of eight weeks Itching, hyperesthesia, and burning were adverseevents reported for both treatment groups, but no systemic side effectswere noted (17)

multi-Pimecrolimus cream 1% was also shown to be safe and effective for thetreatment of inverse psoriasis in a multicenter, double-blind, randomizedstudy involving 57 patients At the conclusion of the study, 82% of thepatients in the pimecrolimus group considered their disease well or comple-tely controlled compared to 41% in the vehicle group Adverse events wereminimal and similar for both groups of patients (18)

Topical corticosteroids and calcipotriol are not ideally used in areas ofskin that are particularly thin and sensitive, such as the intertriginous areasand the face These areas are more prone to skin atrophy from corticoste-roid use, and calcipotriol causes significant local irritation It seems logical

to conclude that because topical tacrolimus is effective on descaled psoriaticskin, it would probably work well on the thinner areas such as the faceand flexural regions Several articles reported that 0.1% tacrolimus ointmentwas highly effective in the treatment of facial psoriasis and psoriasis of inter-triginous areas (Fig 4A and B) (5,19,20)

There has also been one case report of generalized pustular psoriasis,which cleared almost completely after seven days of applying topicaltacrolimus ointment (21) Approximately 10 g/day of tacrolimus was applied

on the entire body and the patient’s liver and renal functions were notaffected The authors attribute part of the efficacy of tacrolimus to thechange in barrier function and less hyperkeratotic skin seen in generalizedpustular psoriasis compared to chronic plaque-type psoriasis

It is evident that the type of formulation and method of application areimportant factors to consider in the use of topical tacrolimus andpimecrolimus in psoriasis (16) Also, because the skin of most patients withpsoriasis is hyperkeratotic, ways to improve drug penetration and the specificarea of the body affected with psoriasis should be taken into account

The most common reported adverse effects of topical tacrolimus apy include a sensation of skin burning, pruritus, and erythema (5,22).Recently, there was one report of deep dermatophytosis developing duringtopical tacrolimus therapy for facial psoriasis (23).

ther-Therapy of eyelid psoriasis can be problematic because topical costeroids are associated with the development of cataracts and glaucoma(24–27) Tacrolimus 0.1% ointment has been used safely to treat eyeliddermatitis twice daily for eight weeks without any effect on intraocularpressure (28) Irritation was noted to occur in 60% of patients

corti-Figure 3 (See color insert) Psoriasis plaques on face (A) before therapy; (B) aftertherapy Source: From Ref 5

Topical Calcineurin Inhibitors 109

Although they are relatively new, topical calcineurin inhibitors haveprovided clinicians with an effective and promising alternative to topicalcorticosteroids for the treatment of psoriasis, with the added benefit of anexcellent local and systemic side effect profile.

On March 10, 2005, the U.S Food and Drug Administration (FDA)decided to add a ‘‘black box’’ warning for the use of topical tacrolimus(Protopic) and topical pimecrolimus (Elidel1) This decision was based onthe finding of a theoretical risk of lymphoma or nonmelanoma skin cancerfrom these medications based on animal models The animal subjects were

Figure 4 (See color insert) Psoriasis plaques on intertriginous areas (A) beforetherapy; (B) after therapy Source: From Ref 5

given large doses of the drugs orally or the drugs were applied topically in avehicle that enhances penetration (29) Human studies have not substantiated

an association between topical tacrolimus or pimecrolimus and malignancies.Although definitive causation has not been established between topicaluse of tacrolimus and pimecrolimus and the development of cancer, severalcases of lymphoma and cutaneous tumors (sarcoma, squamous cell carci-noma, and malignant melanoma) were noted to occur after the use of thesedrugs (30) Of note, there have been several reports of cutaneous T-cell lym-phoma, a malignancy not associated with immunosuppressive therapy Thelatter lymphoma is often mistaken for eczema, and it is possible that patientstreated with tacrolimus or pimecrolimus had cutaneous T-cell lymphomarather than eczema at the time the topical medications were prescribed.The American Academy of Dermatology strongly believes that thesedrugs are safe with proper use, and acknowledges that it is the physician’sresponsibility to inform and educate patients regarding the benefits and risksinvolved, and to monitor the patients accordingly

3 Nghiem P, Pearson G, Langley R Tacrolimus and pimecrolimus: from cleverprokaryotes to inhibiting calcineurin and treating atopic dermatitis J Am AcadDermatol 2002; 46(2):228–230

4 Nghiem P ‘‘Topical Immunomodulators?’’: introducing old friends and a newally, tacrolimus J Am Acad Dermatol 2001; 44(1):111–113

5 Freeman AK, Linowski GJ, Brady C, et al Tacrolimus ointment for the ment of psoriasis on the face and intertriginous areas J Am Acad Dermatol2003; 48(4):564–568

treat-6 Meingassner JG, Grassberger M, Fahrngruber H, Moore HD, Schuurman H,Stutz A A novel anti-inflammatory drug, SDZ ASM 981, for the topical andoral treatment of skin diseases: in vivo pharmacology Br J Dermatol 1997;137:568–576

7 The European FK 506 Multicentre Psoriasis Study Group Systemic tacrolimus(FK 506) is effective for the treatment of psoriasis in a double-blind, placebo-controlled study Arch Dermatol 1996; 132(4):419–423

8 Jegasothy BV, Ackerman CD, Todo S, Fung JJ, Abu-Elmagd K, Starzl TE.Tacrolimus (FK 506)—a new therapeutic agent for severe recalcitrant psoriasis.Arch Dermatol 1992; 128(6):781–785

9 Rapperberger K, Komar M, Ebelin ME, et al Pimecrolimus identifies a commongenomic anti-inflammatory profile, is clinically highly effective in psoriasis and iswell tolerated J Invest Dermatol 2002; 119(4):876–887

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10 Lemster B, Rilo HR, Carroll PB, Nalesnik MA, Thomson AW FK 506 inhibitscytokine gene and adhesion molecule expression in psoriatic skin lesions Ann N

Y Acad Sci 1993; 696:250–256

11 Schulz BS, Michel G, Wagner S, et al Increased expression of epidermal IL-8receptor in psoriasis Down-regulation by FK 506 in vitro J Immunol 1993;151(8):4399–4406

12 Ortiz-Urda S, Rappersberger K New immunosuppressive agents for treatingpsoriasis Hautarzt 2003; 54(3):230–236

13 Mrowietz U, Graeber M, Brautigam M, et al The novel ascomycin derivativeSDZ ASM 981 is effective for psoriasis when used topically under occlusion

Br J Dermatol 1998; 139(6):992–996

14 Mrowietz U, Wustlich S, Hoexter G, Graeber M, Brautigam M, Luger T Anexperimental ointment formulation of pimecrolimus is effective in psoriasis with-out occlusion Acta Derm Venereol 2003; 83:351–353

15 Zonneveld IM, Rubins A, Jablonska S, et al Topical tacrolimus is not effective

in chronic plaque psoriasis A pilot study Arch Dermatol 1998; 134(9):1101–1102

16 Remitz A, Reitamo S, Erkko P, Granlund H, Lauerma AI Tacrolimusointment improves psoriasis in a microplaque assay Br J Dermatol 1999; 141(1):103–107

17 Lehwohl M, Freeman AK, Chapman MS, Feldman Sr, Hartle JE, Henning A.Tacronimus Ointment Study Group Tacrolimus ointment is effective for facialand intertriginious psoriasis J Am Acad Dermatol 2004; 51:723–730

18 Gribetz C, Ling M, Lebwohl M, et al Pimecrolimus cream 1% in the treatment

of intertriginous psoriasis: a double-blind, randomized study J Am Acad matol 2004; 51(5):731–738

Der-19 Yamamoto T, Nishioka K Topical tacrolimus is effective for facial lesions ofpsoriasis Acta Derm Venereol 2000; 80(6):451

20 Clayton TH, Harrison PV, Nicholls R, Delap M Topical tacrolimus for facialpsoriasis Br J Dermatol 2003; 149(2):419–420

21 Ishiko A, Yokoyama T, Tanikawa A, Amagai M, Nagao K A case of ized pustular psoriasis treated with topical tacrolimus Arch Dermatol 2003;139(9):1219

general-22 Soter NA, Fleisher AB Jr, Webster GF, Monroe EM, Lawrence I The mus Ointment Study Group Tacrolimus ointment for the treatment of atopicdermatitis in adult patients: Part II, safety J Am Acad Dermatol 2001; 44:S39–S46

Tacroli-23 Yamamoto T, Nishioka K Deep dermatophytosis during topical tacrolimustherapy for psoriasis Acta Derm Venereol 2003; 83(4):291–320

24 Tan MH, Lebwohl M, Esser AC, Wei H The penetration of 0.005% fluticasonepropionate ointment in eyelid skin J Am Acad Dermatol 2001; 45(3):392–396

25 Renfro L, Snow JS Ocular effects of topical and systemic steroids DermatolClin 1992; 10(3):505–512

26 Eisenlohr J Glaucoma following the prolonged use of topical steroid medication

to the eyelids J Am Acad Dermatol 1983; 8(6):878–881

27 Costagliola C, Cati-Giovannelli B, Piccirillo A, Delfino M Cataracts associatedwith long-term topical steroids Br J Dermatol 1989; 120(3):472–473

28 Freeman AK, Serle J, VanVeldhuisen P, et al Tacrolimus ointment in the ment of eyelid dermatitis Cutis 2004; 73(4):267–271.

treat-29 Niwa Y, Terashima T, Sumi H Topical application of the immunosuppressanttacrolimus accelerates carcinogenesis in mouse skin Br J Dermatol 2003; 149:960–967

30 Wooltorton E Eczema drugs tacrolimus (Protopic) and pimecrolimus (Elidel):cancer concerns CMAJ 2005; 172(9):1179–1180

Topical Calcineurin Inhibitors 113

Department of Dermatology, University of California San Francisco,

San Francisco, California, U.S.A

John Y M Koo

Department of Dermatology, Psoriasis and Skin Treatment Center,University of California San Francisco Medical Center,

San Francisco, California, U.S.A

Topical agents for the treatment of psoriasis are indicated for patients with anyamount of affected body surface area, but are the mainstay of therapy forpatients whose affected area is less than 10% of their body surface area.Among the traditional options of topical therapies for mild to moderate psori-asis are coal tar, anthralin, salicylic acid, and lactic acid All four topicaltherapies have been used for many years and are proven safe and effective.However, recently newer topical agents such as calcipotriol and tazoratenehave reduced the use of these older agents This chapter will give an overview

of the use of these four agents in the treatment of mild to moderate psoriasis.COAL TAR

There are several types of tar including wood tar, shale tar, and coal tar used

in the treatment of skin conditions Coal tar is the liquid byproduct of thedistillation of bituminous coal and has a pungent smell (1) Use of coal

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tar for skin conditions has been ongoing for over millenniums Present daypreparations closely resemble the coal tar that Dioscorides described andcalled ‘‘asphalt’’ almost 2000 years ago (2) Mechanism of action is stillunknown in part due to the over 10,000 ingredients contained in coal tar.However, its antipruritic, anti-inflammatory, and antipsoriatic effects havebeen clinically evidenced since ancient times (3) Coal tar’s low cost, efficacy,and safety profile have made it one of the mainstays of mild to moderatepsoriasis therapy during the decades preceding and following WorldWar II Coal tar is available in several preparations including ointment,cream, lotion, shampoo, gel, solutions, and soaps These products areavailable in multiple concentrations Crude coal tar is often available in threeconcentrations, 2%, 5%, and 10%, and is mainly used in Goeckermantherapy Goeckerman therapy is named after the man who first used thistreatment regimen for psoriasis in 1925 (4) Goeckerman therapy involvesthe application of crude coal tar to the entire body including unaffected areasfor several hours a day along with ultraviolet B (UVB) phototherapy.Because Goeckerman therapy involves the use of ‘‘black’’ tar as opposed tothe more elegant but less effective ‘‘brown’’ tar such as liquor carbonisdetergens (LCD), this previously was an inpatient treatment, but the modernmodified version involves a more convenient Monday through Friday outpa-tient regimen conducted in psoriasis ‘‘day treatment centers.’’ LCD, an alcoholextract of crude coal tar, is one of the most widely used refined preparations ofcoal tar, which is more cosmetically acceptable and available in a solutionform The solution vehicle makes it ideal for its primary use for scalp psoriasis,but is not as effective as ‘‘black’’ coal tar LCD can also be compounded byspecialty pharmacies in an aquaphor base that is suitable for use on bodylesions Most preparations of topical tar are designed for once daily application

at night, but may be used more often if the patient is willing

Coal tar efficacy has been investigated in several trials Goeckermantherapy efficacy was investigated in an open-label study by Lee and Koo.This study examined 25 consecutive Goeckerman patients admitted toUniversity of California, San Francisco (UCSF) Psoriasis TreatmentCenter and showed that 100% reached psoriasis area severity index (PASI)

75 by 12 weeks of treatment and 95% reached it by eight weeks (Figs 1and 2) (5) This is a remarkable efficacy considering the fact that, in theyears 2003–2004 when this study was conducted, only the most recalcitrantpsoriasis patients, most of whom have failed many other, more convenienttreatment options such as entanercept, alefacept, efaluzimab, methotrexate,actretin, outpatient phototherapy, and of course topicals, were usually theones referred to Goeckerman therapy

Another study by Menter and Cram evaluated the efficacy andremission time following Goeckerman treatment In this study, 300 patientstreated with the Goeckerman regimen were followed for one or more years.Average time to reach 90% clearing of the skin was 18 treatment days

Ninety percent of the patients remained clear for a minimum of eightmonths and 73% were clear for one year or longer (6) It should be notedthat this two-center (Dallas, Texas and San Francisco, California) studywas carried out in the early 1980s before the advent of Health MaintenanceOrganizations (HMOs) and managed care when patients with generalized

Figure 1 (See color insert) Psoriasis area severity index (PASI) scores of 25 cutive Goeckerman patients treated at the University of California, San Francisco(UCSF) Psoriasis Treatment Center Source: From Ref 5

Weeks After Starting Goeckerman Therapy

Figure 2 Percent of patients achieving psoriasis area severity index (PASI) 75 with

4, 8, and 12 weeks Goeckerman therapy Source: From Ref 5

Treatment of Mild-to-Moderate Psoriasis 117

psoriasis had ready access to Goeckerman therapy In today’s practicealmost two decades later, Goeckerman therapy is primarily being utilized

by psoriasis patients who have failed multiple other treatment methods thatrequire less commitment in time and energy The remission time seen todaycan be as good as was documented by Menter and Cram, but primarily inthose with na€

ve generalized psoriasis who have good insurance and gainaccess to Goeckerman therapy The remission time of the more typical recal-citrant psoriasis patients referred for Goeckerman therapy today are generallyshorter but still observed by the authors to be better than outpatient photo-therapy and most biologics Efficacy of coal tar lotion has also been studied

A study by Goodfield et al compares efficacy of a new 1% coal tar lotionpreparation (Exorex) to conventional 5% coal tar lotion (Alphosyl) in mild

to moderate psoriasis One hundred and fifty-eight patients received 1% prietary coal tar lotion and 166 patients received conventional 5% coal tarlotion applied to skin three times a day for 12 weeks The mean PASIdecreased by 2.4 with 1% proprietary coal tar lotion and 1.5 with 5%conventional coal tar lotion (7)

pro-Interestingly, there was some controversy about the effectiveness ofcoal tar in the mid-1980s A study by Stern et al in 1986 concluded that coaltar did not provide any added benefit to outpatient UVB phototherapy Thisstudy compared 22 outpatients who treated one side of their body with taroil and the other side of their body with oil vehicle twice daily and alsoreceived outpatient suberythemogenic doses of UVB phototherapy threetimes per week This study evidenced no significant difference between thetar oil half and the oil vehicle half of the body, with only a 9% reduction

in the average UVB dose required for clearing on the tar oil half (8) ever, it should be noted that both the tar oil and oil vehicle were applied justprior to phototherapy Tar has been shown to block UVB and this mostlikely was the reason for lack of benefit of tar with suberythemogenic doses

How-of UVB witnessed in this study A study by Lebwohl et al (9) confirms tar’sability to block UVB light For this very reason, in Goeckerman therapy,especially with ‘‘black’’ tar (as opposed to brown tar or LCD), UVB photo-therapy is always given prior to the application of ‘‘black’’ tar Since thiscontroversial publication, there have been studies to validate the usefulness

of coal tar with UVB A study by Lowe et al indicates that tar is a beneficialaddition to suberythemogenic doses of UVB In this study, tar was notapplied prior to phototherapy More rapid improvement was evidenced inthe group treated with topical tar and suberythemogenic UVB than in thegroup with oil base and suberythemogenic UVB—effectively reducingthe exposure to UVB in the patients treated with topical tar This same arti-cle also examined the combination of tar extract in oil and erythemogenicdoses of UVB in hairless mice Erythemogenic dosages of UVB producedalmost maximal inhibition of DNA synthesis with or without coal tar(10) In general, for the ordinary psoriasis patient erythemogenic UVB is