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provided by Elsevier - Publisher Connector Journal of the Saudi Society of Dermatology & Dermatologic Surgery (2011) 15,63–66
King Saud University Journal of the Saudi Society of Dermatology & Dermatologic Surgery www.ksu.edu.sa www.jssdds.org www.sciencedirect.com
CASE REPORT Erythema necroticans: A presenting manifestation of silent leprosy
Nazeeha Al Hayki *, Badria Al-Mahmoud Dermatology & Venereology Department, Hamad Medical Corporation, P.O. Box 3050, Doha, Qatar
Received 25 February 2011; accepted 30 March 2011 Available online 2 June 2011
KEYWORDS Abstract Leprosy reactions are rare expression of immunological perturbations that interrupt the Leprosy; usual chronic course and the clinical stability of patients with leprosy. Erythema nodosum leprosum Erythema nodosum (ENL) is an immune complex-mediated reaction that may complicate the course of multibacillary leprosum; leprosy. It generally occurs during antimycobacterial treatment and characterized by the appear- Erythema necroticans; ance of crops of brightly erythematous tender nodules or plaques. Severe ENL can become vesicular Multibacillary MDT or bollous and break-down and is termed erythema necroticans [Jobling, W.H., Mc Dougall, A.C., 1996. Leprosy reactions. In: Handbook of leprosy, 5th ed. CBS Publishers, New Delhi, pp. 82–91]. We present here a case of erythema necroticans, misdiagnosed as sweet’s syndrome, because he had never been presented with pre-existing evidence of leprosy nor had any antimycobacterial treat- ment. The clinical diagnosis is confirmed by microscopic pathology. The lesions resolved completely following multibacillary MDT, corticosteroids and Azathioprine. ª 2011 King Saud University. Production and hosting by Elsevier B.V. All rights reserved.
1. Introduction logical perturbations (Sehgal et al., 1988). Erythema nodosum leprosum (ENL) is an immune complex-mediated reaction that Leprosy is a disease of slow development that presents a wide may complicate the course of multibacillary leprosy. It generally spectrum of clinical, histopathological and immunological char- occurs during antimycobacterial treatment and characterized by acterization. Leprosy reactions are rare and not well-known the appearance of crops of brightly erythematous tender nod- states that interrupt the usual chronic course and the clinical sta- ules or plaques. Severe ENL can become vesicular or bollous bility of patients with leprosy. They are expression of immuno- and break-down and is termed erythema necroticans (Jobling and Mc Dougall, 1996). The extra Cutaneous manifestation * Corresponding author. Tel.: +974 4393331; fax: +974 4393058. include neuritis, iridocyclitis, orchitis and lymphadenopathy. E-mail address: [email protected] (N. Al Hayki). Fever and other constitutional symptoms are usually associated with it (JesU´s et al., 2007). We present here a case of necrotic ery- 2210-836X ª 2011 King Saud University. Production and hosting by thema nodosum leprosum, misdiagnosed as sweet’s syndrome, Elsevier B.V. All rights reserved. because he had never been presented with pre-existing evidence of leprosy nor had any antimycobacterial treatment. Peer review under responsibility of King Saud University. doi:10.1016/j.jssdds.2011.04.001 2. Case report
Production and hosting by Elsevier A 44 years old diabetic male from Indonesia, was referred from a private clinic for management of recurrent attacks of 64 N. Al Hayki, B. Al-Mahmoud severe and extensive painful skin lesions associated with fever tender. The ulner, lateral popliteal and great auricular nerves and deteriorating general condition. He has been diagnosed were thickened. Histopathologic analysis showed poorly de- clinically as Sweet’s syndrome and received monthly injections fined epithelioid granulomas with lepra cells and numerous of steroids during the past one year to control the attacks. On inflammatory cells including neutrophils, lymphocytes and examination, the patient had fair general condition, cushingoid rare eosinophils centered around blood vessels, nerves and ad- features. There are multiple geographic brownish macules all nexal structure occupying the superficial, mid and deep dermis over his trunk and extremities. The condition was diagnosed (Fig. 2A–C). Fite stain shows numerous acid fast organisms as postinflammatory hyperpigmentation and treated as such. (Fig. 3). Slit skin smear from the lesion showed BI of 3+, The patient has been advised to return to the clinic with any while IgM antiphenolic glycolipid I (anti-PGL-I) findings were new lesion. Within one month, the patient came to the clinic negative. All routine investigations were within normal limits by wheel chair. He presented with high grade, intermittent fe- except for raised ESR, C-reactive protein (CRP) and leukocy- ver, with other systemic symptoms such as, bone tenderness, tosis. Examination of other systems reveal high liver enzymes, myalgia, ankle and knee arthralgia, neuritis, edema and mal- otherwise it was unremarkable. Ocular examination and chest aise. He developed crops of painful skin lesions all over the X-ray did not reveal any abnormality. body including the face over a few days. He had similar recur- The diagnosis of borderline lepromatous leprosy presenta- rent episodes during the last 12 months. The patient had never tion with necrotic and bollous type eryhema nodosum lepro- presented with chronic skin lesions or neurologic deficit sug- sum was made. He started on (WHO) MB-MDT therapy gestive of leprosy. On admission, he was found having along with 40 mg daily prednisolone. After improvement of cushingoid features. There were multiple painful erythematous general condition, the ENL reaction was controlled and the tender nodules, erythema multiform-like lesions and skin patient became asymptomatic. He was discharged after two necrosis of various sizes present over the trunk and extremities, weeks on (WHO) MB-MDT therapy and with gradual taper- several of them with flaccid blister, sometime hemorrhagic or ing of the prednisolone over one month and stopped. One seropurulent (Fig. 1A–E). The joints were mildly swollen and month after stopping prednisolone, the patient developed a
Figure 1 (A–E) Multiple painful erythematous tender nodules. Erythema multiform like lesions and skin necrosis of varied sizes were present over the trunk and extremities, several of them with flaccid blister, sometime hemorrhagic or seropurulent.
Figure 2 (A–C) Histopathologic analysis showed poorly defines epithelioid granulomas with lepra cells and numerous inflammatory cells including neutrophils, lymphocytes and rare eosinophils centered around blood vessels, nerves and adnexal structure occupying the superficial, mid and deep dermis. Erythema necroticans: A presenting manifestationof silent leprosy 65
include surgical operations, pregnancy, parturition, lactation, menstruation, trauma, intercurrent illness, vaccination, physi- cal or mental stress and some time therapy (Verma and Pandhi, 1993; Zannatun et al., 2009). Tumor necrosis factor- a (TNF-a), a pro-inflammatory cytokine, plays an important role in the pathogenesis of ENL. There is activation of T-cell and macrophages, inducing production of large amounts of TNF-a (Kaushal et al., 2006). Additional source of TNF-a is the severe leukocytosis and the intense neutrophil infilterate in ENL lesions. Plasma levels of this cytokine have been found to be high during the episode of ENL (Sehgal et al., 1988). Figure 3 Fite stain shows numerous acid fast organisms. High CRP levels along with a positive correlation between ele- vated TNF-a and CRP levels in the serum of ENL patients has recurrent severe attack of ENL, with extensive skin lesions been reported (Foss et al., 1993). In the present case, the pa- associated with fever and joint pain. The dose of prednisolone tient presented with high serum level of CRP that regressed increased to 80 mg daily orally for 2 weeks. But, there was no by the end of the attacks. Taken together, leukocytosis, adequate control of ENL with this treatment, moreover, he TNF-a and CRP could be considered as laboratory parame- continued to develop new lesions with persistence of the fever ters to be used to follow up the acute inflammatory response and joint pain. Second-line drug such as Thalidomide has been in ENL (Foss et al., 1993). The management of ENL is a real suggested. Thalidomide was not available in our center. The challenge for clinicians; ENL has usually a relapsing and patient was treated with (WHO) MB-MDT, prednisolone re- remitting course that may last for several years, ENL produce duced to 40 mg daily. Azathioprine was added at a dose of greater disability than the underlying lepromatous leprosy and 100 mg daily (2 mg/kg /day). ENL lesions started healing with was the commonest reason for admission to the hospital (Levy complete relief within 4 weeks. Prednisolone was reduced by et al., 1973). Three types of ENL were identified: single acute 10 mg every week and then stopped after 4 weeks, while Aza- ENL, multiple acute ENL (repeated discrete episodes) and thioprine 50 mg daily was continued for 6 months then chronic ENL (continuous episodes). 92% of ENL reactions stopped. Complete blood count, liver and renal function tests are usually chronic and relapsing with unpredictable clinical were repeated every month during the azathioprine treatment course (Eonor et al., 2006). Our patient has almost nine recur- which remained unremarkable. The ENL never recurred. rent episodes of ENL during the last 12 months. Multiple drug therapy (MB-MDT) for borderline leproma- 3. Discussion tous leprosy should preferably be taken as per the recommen- dations of WHO (Eonor et al., 2006). In addition, treatment Erythema nodosum leprosum (ENL) is an immune complex- with prednisolone should be instituted for 12 weeks course. mediated reaction that may complicate the course of multibac- This overlooks the chronic, recurrent nature of ENL (WHO, illary leprosy and characterized by the appearance of crops of 1998). Although prednisolone is used as the first-line drug brightly erythematous tender nodules or plaques. Severe ENL for treating moderate and severe ENL, its effect in managing can become vesicular or bollous and break-down and is termed patients with ENL is less than adequate (Eonor et al., 2006). erythema necroticans (Jobling and Mc Dougall, 1996). The The WHO has recommended the antiinflammatory clofazi- small number of reported cases in the world literature suggests mine for chronic and severe ENL and as steroid-sparing agent that it is fairly uncommon (Verma and Pandhi, 1993; Davis (Pannikar, 2003). However, it takes 4–6 weeks for the effect of et al., 2002; Pandhi et al., 2005; Athanasia et al., 2008; clofazimine to be clinically detectable. Thus, it is not useful for Zannatun et al., 2009). Our patient shows polymorphic lesions the management of acute ENL (Eonor et al., 2006; WHO, clinically, less nodular than classical ENL, which is mainly 1998). Clofazimine 100 mg tablets are available only in MDT seen in the trunk, but has more erythematous, or violaceous blister packs for the patients in our center. macules and plaques distributed on the extremities. The Thalidomide is now considered the drug of choice for ENL. plaques have vesicles, bullae and necrotic skin. It was approved by the FDA in 1998 in the acute treatment of Although erythema nodosum leprosum occurs usually dur- moderate to severe ENL and preventing new episodes ing the treatment of lepromatous leprosy, there have been a (www.fda.gov). There are serious limitations to its use due to fair number of reports of untreated lepromatous leprosy with its teratogenic effects and potential neurotoxicity, causing it subtle initial changes, presenting de novo as ENL, or may to be banned in many countries (Pannikar, 2003). Our patient present with extraordinary manifestations, often with long de- may have benefited from this drug, but it is not available in our lay before the diagnosis of leprosy is considered (Zannatun center, and the cost is out of reach of the patient. The search et al., 2009; Mc Dogall and Archibald, 1977). Here, we de- for an effective alternatives, led to experiencing second-line scribe a case present with necrotic ENL as presenting manifes- drugs such as pentoxifyline (Sales et al., 2007), mycophenolate tation of subtle borderline lepromatous leprosy; he had no mofetil (Kalian and Raghubir, 2008), Azathioprine (Kaushal previous evidence of neurologic deficit or chronic skin lesions et al., 2006) and infliximab (Williame et al., 2006) with incon- suggestive of this chronic infection. The condition was difficult sistent results. We have chosen Azathioprine for our patient to diagnose clinically; numerous tender nodules and plaques because it has strong antiinflammatory effect and has also been and necrotic lesions with seropurulent blisters led to the initial shown to inhibit TNF-a. The drug has been effectively used on misdiagnosis of Sweet’s Syndrome. But, what provokes the long-term basis as a steroid-sparing agent. Its long-term safety, subtle leprosy from its dormant to express ENL reaction? adverse effects and monitoring have been well studied The probable trigger factors associated with ENL reaction (Kaushal et al., 2006). 66 N. Al Hayki, B. Al-Mahmoud
4. Conclusion Kalian, B., Raghubir, B., 2008. Management of erythema nodosum leprosum by mycophenolate mofetil. Indian J. Dermatol. 53 (3), 142–143. We report this case because experience shows that in non- Kaushal, K.V., Srivastava, P., Anil, M., 2006. Kamna Verma. Role of endemic areas such as State of Qatar and with the growing azathioprine in preventing recurrences in a patient of recurrent number of immigrants arriving for work, diagnostic dilemma erythema nodosum leprosum. Lepr. Rev. 77, 225–229. posed in correctly identifying patients with chronic infectious Levy, L., Fasal, P., Levan, N.E., Freedman, R.I., 1973. Treatment of diseases such as leprosy, lead to long delay before the correct erythema nodosum leprosum with thalidomide. Lancet 2, 324–325. diagnosis was considered, and subsequently the use of inappro- Mc Dogall, A.C., Archibald, G.C., 1977. Lepromatous leprosy priate therapies such as corticosteroids, which can potentially presenting with swelling of the legs. Br. Med. J., 23–24. worsen the disease. Practicing physicians need to have a high Pandhi, D., Mehta, S., Agrawal, S., Singal, A., 2005. Erythema nodosum leprosum necroticans in a child-an unusual manifesta- clinical index of suspicion and to be aware of the extraordinary tion. Int. J. Lepr. Mycobact. Dis. 73 (2), 122–126. presentation of the different chronic infectious diseases that Pannikar, V., 2003. The return of thalidomide: new uses and renewed make them hard to diagnose. concerns. Lepr. Rev. 74, 286–288. Sales, A.M., de Matos, H.J., Nery, J.A.C., Duppre, N.C., Sampaio, References E.P., Sarno, E.N., 2007. Double-blind trial of the efficacy of pentoxifyline vs thalidomide for the treatment of type II reaction in Athanasia, T., Angelo, V.M., Raffaele, G., Paolo, F., Enrico, N., leprosy. Brazilian J. Med. Biol. Res. 40, 243–248. Elvio, A., 2008. Necrotic erythema nodosum leprosum as the first Sehgal, V.N., Srivastava, G., Sundharam, J.A., 1988. Immunology of manifestation of borderline lepromatous leprosy. Arch. Dermatol. reactions in leprosy. Current status. Int. J. Dermatol. 27, 157–162. J. 144 (6), 818–820. Verma, K.K., Pandhi, R.K., 1993. Necrotic erythema nodosum Davis, S.V., Shenoi, S.D., Balachandran, C., Pai, S.B., 2002. A fatal leprosum; presenting manifestation of lepromatous leprosy. Int. case of erythema necroticans. Indian J. Lepr. 74 (2), 145–149. J. Lepr. Other Mycobact. Dis. 61 (2), 293–294. Eonor, P., Sumanjain, R.R., Syed, M., Obdulita, T., Sujai, S., Diana, Expert WHO, 1998. Committee on Leprosy. World Health Organ. N.J.L., 2006. Am. J. Trop. Med. Hyg. 74 (5), 868–879. Tech. Rep. Ser., pp. 1–43