R eview Adverse events due to psoriasis treatment Adverse events due to psorins-is treatment F. Kokelj, C. Plozzer and G. Trevisan SUMM A RY Any treatment can cause some undesired reactions that may be local, systemic, predictable or unpredictable. In the present study we describe our experience concerning the incidence of drug reactions caused by the most common psoriatic treatments. Both topical, vitamin D derivatives and topical retinoids, or systemic, etretinate and cyclosporin A, can cause a large spectrum of adverse reactions that must be known and considered by both doctors and patients in order to obtain the best clinical results. In this paper we summarize our experience with the more common and recent treatments tor psoriasis. Introduction A good knowledge of all the side effects of different drugs is of great importance for the choice of treatment. Unfortunately, the side effects are often underevaluated for various reasons: both patients and doctors seem to be more interested in the efficacy and possibilities of new drugs than in their side effects, while drug com- panies play an increasing role in supporting clinical studies, research and symposia. As an example , we remind the number of studies on side effects presen teci at the last Eu ropean and International Symposia on Psoriasis (Table 1). It is clear that the increased number of presentations is not accompanied by an increase of reports on side effects. Drug reactions may be classified as predictable, dose-dependent and related to drug actions, and un- predictable, dose-independent and unrelated to drug actions. The predictable reactions are hyperdosage, side effects, seconda1y effects, and pharmacological inte- ractions , w hile intolerance, idiosyncrasy, allergy and pseudo-allergy belong to the unpredictable ones. The reactions to the treatment of p soriasis are usually predictable, while allergy, pseudo-allergy, intolerance and idiosyncrasy are extremely rare. In this paper we summarize our experience on adverse drug reactions caused by the most common and recent treatments fo r psoriasis. C alcipotriol Vitamin D derivatives represent one of the most important new topical treatments for psoriasis develo- ped in the last years. Calcipotriol is a structural analogue of the natura!, biologically active 1,25 (OH)2-D3. It is as active as calcitriol in inducing keratinocyte differen- acta dermatovenerologica A.P.A. Vol 8, 99, No 3 --- ---- - --------------- --------- 101 Adve,:,e events due to psoriasis treatment tiation and in inhibiting keratynocyte proliferation (1). Calcipotriol bas proven to be effective and well tolerated also in our experience. Side effects are relatively rare and consist of localized cutaneous reactions , observed in 4 % of our 192 patients (2). This incidence is lower than tbat described in literature - from 4 to 20 % - (3) and is probably due to the different criteria of enrolment. Allergic contact dermatitis to calcipotriol was described (4, 5) but we bave never observed any case. On tbe contraty, in 1995 we described three cases of persistent pigmentation on the site of application of ointment5 after repeated sunbatbing (6). Tbis observation is confirmed by other authors and for this reason we invite patients to apply tbe medication after the light treatment to avoid this undesirable effect. Tacalcitol Tacalcitol 1,24 (OH)2-D3, another side-chain deri- vative of calcitriol, bas demonstrated to be effective in treating moderate plaque psoriasis (7) . It is applied once daily (calcipotriol must be applied twice) and may be used also for psoriasis of the face its irritant power lower than tbat of calcipotriol. In tbe Italian multicenter study on tacalcitol (8), in whicb this cream was compared with betamethazone valerate ointment in 63 patients, we observed only two cases of itcbing on the site of application (3 %). In tbe last year we observed two cases, one of mile! and one of major skin irritation of the face in tbe area treated witb tacalcitol. In both cases tbere was no particular situation to justify this unexpected reaction. Tazarotene Tazarotene is the first receptor selective topical retinoid (9); it is a potent synthetic analogue of the acetylenic class of retinoids . In vivo it is rapiclly con- verted into its free acicl metabolite, tazarotenic acicl. Its most important sicle effect is the irritation on tbe site of application and around the treated plaque. The inci- dence of tbis side effect is variable (10) . In the first year of our experience witb tbis gel we observed numerous cases of burning irritation usually on tbe site of application C 45 % of the patients treated); in some cases it was sufficient to invite the patient to apply less gel on the plaque or to apply tazarotene eve1y second or third day in orcler to continue the treatment, while in 23 % of the cases the patients had to interrupt the application due to a severe reaction. We unclerline that a more cl e tailed explanation of tbe criteria of tazarotene application can decrease the incidence of tbis sicle effect. Retinoids ( etretinate) Retinoicls include a large number of syntbetic ancl natura! compounds derived from vitamin A and used for clifferent dermatological problems (11). Etretinate remains a first choice drug for clifferent forms of pso- riasis: it is effective ancl well tolerated when used in usually prescribecl doses (0,5-1 mg/ kg/clay), wbile its teratogenic effect remains its first ancl most important side effect. For tbis reason fertile women shoulcl not use it (12) . In table 2 we summarize our experience on a group of 109 patients affectecl with extensive vulgar psoriasis treatecl witb etretinate at a starting close of 0,6 - 1 mg/ kg/clay. Tbese dara are in agreement with those of otber authors (1 3, 14). We exp erienced a high percentage of side effects (92%). Nevertbeless only few patients bad to interrupt tbe treatment, 3 % of our pa- tients, and all of them for an important increase in tbe sernm lipid leve!; in all the other cases the reaction im- proved with the recluction of tbe dosage. CyclosporinA Cyclosporin A is the more recent systemic drug proposed for the treatment of severe forms of psoriasis. This immunosuppressive drug presents different side effects in relation to the closage used; consequently the spectrum of reactions observed during the treatment of Table 1. Number of reports presented at European Symposia on Psoriasis. Trieste 1978 Trieste 1983 Trieste 1988 Trieste 1993 Milan 1998 TOTAL REPORTS 33 49 68 92 184 REPORTS ON THERAPY o 20 30 39 71 REPORTS ON DRUG REACTIONS o o 1 (1,5 %) 2 (2 %) 1 (0,5 %) R e view 102 acta dermatovenerologica A.P.A. Vol 8, 99, No 3 R eview Table 2. lncidence of the different adverse reactions caused by etretinate in a group of 109 patients. Incidence of the d1fferent adverse reactions Labial xerosis 81 % Paronychia 33% Increased lipid serum level 26% Palmar and plantar thinning and scaling 24% Defluvium 11 % Visual disturbance 2% No side effects 13 % psoriasis is clifferent from those observed in transplanted patients, w hen the closage of cyclosporin is much higher. The most important problems (major adverse events) are the nephrotoxicity of cyclosporin , its immuno - suppressive action ancl the risk of cancer incluction (15, 16). We observed 2 cases of acute renal fa ilure ancl 1 case of hyp ertens ion in a group of 63 patients: a li these cases improved w ith the intenuption of the treatment and results of the tests returned to normal values . In table 3 we report our data on the inciclence of minor sicle effects in the same group of 63 p atients . The use of the new microemulsion formulation (Neoral) allowecl a recluction of the inciclence of sicle effects (15). These clata show the high frequency of sicle effects, present in more than 70 % of the cases. Usu ally the re duc tion of the dosage is sufficient to obtain the regression of this effect and only a few patients had to interrupt the treatment. (;ES Adverse events due tu psuriasis treatment Table 3. lncidence of minor side effects obser- ved in a group of 63 patients treated with cyclosporin A. Incidence qf' minor side ejf'ects Asthenia 58 % Cramps ancl muscle weakness 44% Heaclache 40% Hypertrichosis 22% Gastro-intestinal clisturbance 13% Gingival hyperplasia 11 % No side effects 28% Conclusions Any treatrnent, both topical or systemic, presents the possibility of som e adverse reactions; in p articular, systemic drugs cause m o re important preclictable ancl unpredic table reactions in comparison w ith topical treatment ancl our data confirm the high inciclence: on/y 13 % of the p atients treated with etretinate and 28 % of those treated with cyclosporin do not really present any side e.ffect, tha t sometimes are mild but sometimes influence the ir life quality. On the contrary, topical treatment is b etter tolerated even if minor side effects are possible . Ali th ese problem s may influen ce the compliance an d for this reason it is important that both doctors and patients consider ancl know the diffe rent aclverse reactions as well as the risk/ benefit ratio of the different treatments in o rder to obtain the expected results . l. Binderup L, Bramm E. Effects of a novel vitamin D analogue MC 903 on cell proliferation and differentiation in vitro and on calcium metabolism in vivo. Biochem Pharmacol 1988; 37: 889-95 2. Lavaroni G, Plozzer C, Torsello P, Kokelj E Effetti collaterali del trattamento con calcipotriolo !opico (MC 903): nostra esperienza di tre anni. Chronica Dermatologica, 1986, VI, 37-41 3. BarthJonesJ, Comparison ofCalcipotriol ointmentwith betamethasonevalerate ointment and dithrenol and lnvestigation of the long term safety and efficacy of Calcipotriol. Acta Derm Vener 1994, Suppl. 186: 46 4. Yip J, Goodfield M. Contact dermatitis from MC903, a topical vitamin D3 analogue. Contact Dermatitis 1991; 25 : 139-40 5. Bruynzeel DP, Ho! CW, Nieboer C. Allergic contact dermatitis to calcipotriol. Br J Dermatol, 1992; 126: 66 6. Kokelj F, Lavaroni G, Perkan V, Plozzer C. Hyperpigmentation due to Calcipotriol (MC 903) plus Heliotherapy in Psoriatic Patients. Tiuee Case Repo11s. Acta Der Venereol (Stockh), 1995; 75: 307-9 7. Matsunaga T, Yamamoto M, Mimura H. 1,24 (R)-dihydroxivitamin D3, a novel active form ofvitamin D3 \vith high activity for inducing epidermal differentiation but decreased hypercalcemic activity. J Dermatol 1990; 17: 135-42 8. Gruppo Italiano di studio sul Tacalcitolo. Tacalcitolo ointment is an efficacious and well tolerated treatment for psoriasis. J Europ Ac Vener, 1996; 6: 142-6 acta dermatovenerologica A.P.A. Vol 8, 99, No 3 -------------------- - - ----- - ---- 103 Adverse events due to psoriasis treatment Review AUTHORS' ADDRESSES 104 9. Chandraratna R.A.S. Tazarotene: the first receptor-selective topical retinoid for the treatment of psoriasis. J AmAcadDermatol, 1997; 37(2) Suppl. 12-17 10. Marks R. Clinical safety of tazarotene in the treatment of plaque psoriasis. J AmAcad Dermatol, 1997; 37 (2): Suppl. 25-33 11. Bollag W. The development of retinoids in experimental and clinical oncology and dermatology. J Am Acad Dermatol 1983; 9: 797-805 12. Geiger JM, Baudin M and Saurat JK. Teratogenic risk with Etretinate and Acitretin treatment. Dermatology, 1994; 139: 109-16 13. Michaelsson G, Berquist A, Vahlquist A et al. The influence of "Tigason" (Ro 10-9359) on the serum lipoproteins in man. Br J Dermatol 1981; 105: 201-5 14. Windhorst DB, Nigra T. General clinical toxicology of oral retinoids. J Am Acad Dermatol 1982; 6: 675-82 15. von Graffenried B, Friend D, Shand N et al„ Cyclosporin A (Sandimmun) in autoimmune disorders. In: Thompson AN ed. Cyclosporin: mode of action and clinical applications. Kluver Academic Pub. 1989; 213-5 16. Mason J. Rena! side-effects of Cyclosporin A. Br J Dermatol 1990; 122 (36): 71-77 17. Kokelj F, Plozzer C, Trevisan G. Conversione dalla Ciclosporina in formulazione tradizionale a quella in microemulsione (Neoral); valutazione dell'efficacia e tollerabilita clinica in 63 pazienti psoriasici. G Ital Dermatol Venereol 1999; 134: 147-51 Franco J{okelj, MD, Institute oj Dermatology, University of Trieste, Os pedale di Cattinara, 34149 Trieste, Italy Carmela Plozzer, MD, same address Giusto Trevisan, MD, professor and chairman, same address acta dermatovenerologica A.P.A. Vol 8, 99, No 3