Letter to the Editor CHRONIC RECURRENT ENL, STEROID DEPENDENT: LONG-TERM TREATMENT WITH HIGH DOSE CLOFAZIMINE

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1 Lepr Rev 2003) 74, 386±389 Letter to the Editor CHRONIC RECURRENT ENL, STEROID DEPENDENT: LONG-TERM TREATMENT WITH HIGH DOSE CLOFAZIMINE Recent months have seen a surge of interest in the treatment of severe, chronic recurrent erythema nodosum leprosum ENL). 1±8 This is a serious problem, which for unknown reasons in the past few years has not received the attention it deserves. 9 It is certainly not uncommon when visiting leprosy clinics to nd such patients. They are often in dire need of effective and safe treatment, since there is a great danger that these patients with chronic recurrent ENL become steroid dependent, 2,8 due to the limitations and dangers of steroid treatment 8 and the limitations or non-availability of other effective drugs like thalidomide. 2,8 This may occur even when the underlying factors that have been recognized to contribute to the establishment of chronic ENL 2,5,8 have been adequately addressed e.g. chronic infections, anaemia, stress). It is not often realized that adjuvant drugs such as chlorpromazine 8,10 and a high dose of clofazimine may reduce the need for steroids. 2,4±10 The reasons for steroid dependency are not clear, but at least in some cases it can be prevented by some prudence when prescribing steroids: Reserve steroids only for severe ENL reaction 8,10 e.g. neuritis with increasing neuropathy, iridocyclitis, ulcerating skin lesions with fever or other organ involvement; arthritis, lymphadenitis, orchitis, hepatitis, not reacting to standard treatment). Start with high dose of steroids 1±2 mg/kg body weight). Reduce rapidly pulse therapy) 11±13 with intended maximum treatment duration of not more than 3±4 weeks the natural duration of an ENL attack 14 ). Try to prevent a maintenance dose. 13 If there is a recurrent attack during the tapering off period, the current dosage should be doubled. 13 When ef cacy is observed, the dosage should be tapered off again. The advice of WHO to continue steroids for at least 3 months e.g. PREDNIPAK), similarly to the treatment of reversal reactions, is asking for problems, since ENL is an episodic occurrence. 13,15 Moreover the advised initial dose is too low for most patients. 10 Based on experience from the past, 16±19 concurrent with steroids, a course of clofazimine should be prescribed. 2,4±8 In many countries e.g. Indonesia, Brazil), national guidelines advise the prescription of clofazimine particularly in cases of recurrent severe ENL. This is often not done. Prevent self-prescription of steroids by patients or inexperienced staff. Thalidomide has proven to be a very effective drug in cases of severe ENL; 1,2,7,10,13,20±29 however, it cannot completely replace steroids. 7,22,23 Signs and symptoms may resolve even more rapidly than with steroids, but in case of acute nerve damage and/or iridocyclitis, a high initial dose of steroids may be needed. 23 The problem with thalidomide is that it cannot be /03/ $1.00 q Lepra

2 Letter to the Editor 387 prescribed to women of child-bearing age who do not have 100% safe contraception. 20±29 Furthermore, in many countries thalidomide is not available. 2 Newer drugs such as cyclosporine are being put to clinical trials, but are expensive and probably not as effective 10,13,30 and not always available. Pentoxyfylline, advocated as an alternative to thalidomide, has showed some effect, 31±33 but some clinicians are not particularly impressed. 10,13,34 Clofazimine will not relieve acute symptoms. 16±19 It is not a very effective anti-enl drug and moreover is slow-acting. 16±19,35,36 In drug regimes, including WHO-MDT, fewer ENL reactions are recorded. 37±40 This suggests, therefore, that clofazimine could probably be used in the successful control of chronic recurrent ENL. In the Netherlands, among those who took dapsone monotherapy, 28% developed moderate to severe ENL. Over a period of 2 years from those on WHO-MDT, 14% developed ENL. After MDT, another 5% also developed ENL. 39 Clofazimine is widely available and only causes serious side effects abdominal problems, e.g. bowel obstruction, gastrointestinal bleeding, splenic infraction and hepatitis, dyspigmentation and dry ichthyotic skin 41±46 ) in a few patients. Patients who develop several bouts of ENL over a short period of time should be prescribed a high dose of clofazimine with a starting dose of 300 mg daily for at least 2 months, 4,18 together with drugs to relieve the acute symptoms e.g. steroids). When a patient continues having ENL reactions, 200±300 mg daily should be maintained for longer periods, and if the patient is on steroids, the steroids should be reduced slowly to zero) under the protective umbrella of clofazimine. When thalidomide is available and can be prescribed, it could be used or added to replace the steroids. 26 If no new ENL reactions appear and the patient is no longer on steroids, clofazimine can slowly be reduced to 200 mg daily for 2 months, to 100 mg daily for 2 months, etc. Clofazimine can be given in high doses over long periods to wean dependent patients from steroids. This is clearly not a magical solution, 35,36,48 and it can sometimes take a year or even more before the patient will be steroid free. However, this is far preferable to having steroiddependent patients to look after. It must be kept in mind that though most authors feel the improvement is a clofazimine effect, 16±19, 26 some authors are of the opinion that it may be just a time effect, the disease following its natural course. 3 It is our opinion that careful management of an ENL reaction may in many cases prevent steroid dependency, and that in the management there is a place for clofazimine. We would recommend its use and it should be made available also outside the blister packs. To nd a de nite answer to the question of the place of long-term, high-dose) clofazimine in the prevention and treatment of chronic recurrent, steroid-dependent ENL, a controlled clinical trial is warranted. Acknowledgement We thank Mrs Linda Lehman and Dr Hugh Cross for their advise on the use of the English language. Marechal Camara No. 350 sala 1002 PIETER A. M. SCHREUDER Fentro, Rio de Janeiro, RJ CEP: Brazil Pieter@hansen.org.br

3 388 Letter to the Editor Gracht KN Munnekeburen The Netherlands BEN NAAFS References 1 Bryceson A. Personal communication. On the treatment of chronic and recurrent. ENL Leprosy Mailing List, June 2 Krishnamoorthy. Personal communication. On the treatment of chronic and recurrent ENL. Leprosy Mailing List, 3 Opromolla DVA. Editorial. Hansenol Int, 2003; 28: in press. 4 Pai V. Personal communication. On the treatment of chronic and recurrent ENL. Leprosy Mailing List, 5 Revankar CR. Personal communication. On the treatment of chronic and recurrent ENL. Leprosy Mailing List, 6 Sala a A. Personal communication. On the treatment of chronic and recurrent ENL. Leprosy Mailing List, June 7 Van Brakel W. On the treatment of chronic and recurrent ENL. Personal communication. Leprosy Mailing List, 8 Warren G. On the treatment of chronic and recurrent ENL. Personal communication. Leprosy Mailing List, June 9 Rose P, Waters MF. Reversal reaction in leprosy and its management. Lepr Rev, 1991; 62: 113± Naafs B. Treatment of reactions and nerve damage. Int J Lepr, 1996; 64: S21± Pernambuco JC. Personal communication. ILSL Bauru, Mahajan VK, Sharma NL, Sharma RC, Sharma A. Pulse dexamethason, oral steroids and azathioprine in the management of erythema nodosum leprosum. Lepr Rev, 2003; 74: 171± Naafs B. Reactions: the body as battle eld III: Treatment. Memisa Medisch, 2003; 69: 343± De Souza Araujo HC. Febro leprotica. In: A lepraðestudos realisados em 40 paizes 1924±1927). Trab. do Inst. Oswaldo Cruz, Rio de Janeiro 1929, pp. 179± Naafs B. Reactions: new knowledge. TropGeogr Med, 1994; 46: 80± Helmy HS, Pearson JM, Waters MF. The treatment of moderately severe erythema nodosum leprosum with clofazimineða controlled study. Lepr Rev, 1971; 42: 167± Imkamp FM. A treatment of corticosteroid-dependent lepromatous patients in persistent erythema nodosum leprosum. A clinical evaluation of G30320 B663). Lepr Rev, 1968; 39: 119± Imkamp FM. The treatment of corticosteroid-dependent lepromatous patients in persistant Erythema nodosum leprosum with clofazimine. Lepr Rev, 1973; 44: 127± Plock H, Leiker DL. A long term trial with clofazimine in reactive lepromatous leprosy. Lepr Rev, 1976; 47: 25± Guerra JG, Penna GO, Castro LCM et al. Eritema Nodoso HanseÃnico: atualizacëaè o clõânica et terapeãutica. An Bras Dermatol Rio de Janeiro, 2002; 77: 389± Iyer CGS, Languillon J, Ramanujam K et al. WHO co-ordinated short-term double blind trial with thalidomide in the treatment of acute lepra reactions in male leprosy patients. Bull WHO, 1971; 45: 719± Lockwood D, Bryceson A. The return of thalidomideða reply. Lepr Rev, 2003; 74: 290± Naafs B. The return of thalidomideða reply. Lepr Rev, 2003; 74: 294± Parikh DA, Ganapati R, Revankar CR. Thalidomide in leprosy: study of 94 cases. Ind J Lepr, 1986; 58: 560± Pearson J., Vedagiri M. Treatment of moderately severe erythema nodosum leprosum with thaldomide- a double blind controlled trial. Lepr Rev, 1969; 40: 111± Ramu G, Girdhar A. Treatment of steroid dependent cases of recurrent lepra reaction with a combination of thalidomide and clofazimine. Lepr Ind, 1979; 51: 497± Sampaio SAP, ProencËa NG. Tratimento da reacëao leproâtica pela talidomide. Rev Paul Med, 1966; 68: Sheskin J, Convit J. Results of a double blind study of the in uence of thalidomide on the lepra reaction. Int J Lepr, 1969; 37: 135± Waters M. An internally-controlled double blind trial of thalidomide in severe erythema nodosum leprosum. Lepr Rev, 1971; 42: 26± Van Gompel A, Van den Enden E, Van den Ende J. Cyclosporin A is not very active in erythema nodosum leprosum. TropGeogr Med, 1994; 46: Sarno EN, Nery JA, Garcia CC, Sampaio EP. Is pentoxi lline a viable alternative in the treatment of ENL. Int J Lepr, 1995; 63: 570±571.

4 Letter to the Editor Moreira AC, Kaplan G, Villahermosa LG et al. Comparison of pentoxifylline, thalidomide and prednisolone in the treatment of ENL. Int J Lepr, 1998; 66: 61± Chatterjee M, Jaiswal AK. Does pentoxifylline nd a place in the armamentarium of leprologists in type II reaction. Ind J Lepr, 2002; 74: 329± Opromolla DVA. O tratemento das reacëoäes na hanseniase. Treatment of the reactions in leprosy. Hansenol Int, 2000; 25: 1±6. 35 Burte NP, Chandorkar AG, Muley MP et al. Clofazimine in lepra ENL) reaction, one year clinical trial. Lepr Ind, 1983; 55: 265± Mishra B, Girdhar BK. Limitations of clofazimine in the treatment of lepra reactions. Ind J Lepr, 1986; 58: 73± De Carsalade GY, Wallach D, Spindler E et al. Daily multi drug therapy for leprosy: results of a fourteen year experience. Int J Lepr, 1997; 65: 37± Li W, Ye G, Yang Z et al. Effect of three year multi-drug therapy in multi-bacillary leprosy patients. Proc Chin Acad Med Sci Peiking Union Med Coll, 1990; 5: 37± Post E, Chin-A-Lien RAM, Bouman C et al. Lepra in Nederland in de periode 1970±1991. Ned Tijdschr Geneesk, 1994; 138: 1960± Chattopadhyay SP, Gupta CM, Bhate RD et al. Evaluation of two multidrug regimes in hospitalized multibacillary leprosy cases. Ind J Lepr, 1989; 61: 196± Bhasin DK, Kumar B, Broor SL et al. Effect of clofazimine: detailed studies of small intestine functions. Ind J Lepr, 1985; 57: 364± Caver CV. Clofazimine induced ichthyosis and its treatment. CuÂtis, 1982; 29: 341± Goulart IM, Arbex GL, Carneiro MH et al. Efeitos adversos da poliquimioterapia em pacientes com hansenõâase: umlevantamento du cinco anos em um Centro de SauÂde da Universidade Federal de UberlaÃndia. Rev Soc BraÂs MeÂd Trop, 2002; 35: 453± Jopling WH. Complications of treatment with clofazimine Lamprene: B663). Lepr Rev, 1976; 47: 1±3. 45 Parizhskaya M, Youssouf NN, Di Lorenzo C, Goyal RK. Clofazimine enteropathy in a pediatric bone marrow transplant recipient. J Pediatr, 2001; 138: 574± Lal S, Garg BR, Hameedulla A. Gastro-intestinal side effects of clofazimine. Lepr Ind, 1981; 53: Sukpanichnant S, Hargrove NS, Kachintorn U et al. Clofazimine induced crystal storing histiocytosis producing chronic abdominal pain in a leprosy patient. Am J Surg Pathol, 2000; 24: 129± Groenen G, Janssens L, Kayembe T et al. Prospective study on the relationship between intensive bacterialcidal therapy and leprosy reactions. Int J Lepr, 1986; 54: 236±244.

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