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 Table of Contents  
CASE REPORT
Year : 2019  |  Volume : 5  |  Issue : 1  |  Page : 38-41

Thalidomide-induced leukocytoclastic vasculitis in leprosy


Department of Dermatology, B.J. Government Medical College and Sassoon General Hospitals, Pune, Maharashtra, India

Date of Web Publication22-Jul-2019

Correspondence Address:
Dr. Pallavi Prataprao Patil
Department of Dermatology, B.J. Government Medical College and Sassoon General Hospitals, Pune, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijdd.ijdd_14_19

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  Abstract 


Thalidomide has become the gold standard for the treatment of erythema nodosum leprosum (ENL) within a few decades of its serendipitous discovery for this condition. It has also demonstrated efficacy in dermatoses such as recalcitrant oral aphthae, prurigo nodularis, and pyoderma gangrenosum. Despite a good safety profile, thalidomide is known to cause side effects such as sedation, constipation, peripheral neuropathy, and thromboembolism. Although rare and anecdotal, adverse cutaneous drug reactions (ACDRs) have been reported. Both thalidomide and its newer analogs have been implicated for maculopapular, urticaria-angioedema, Steven–Johnson-like, toxic epidermal necrolysis, and acneiform eruptions. Only a few cases of leukocytoclastic vasculitis (LCV) occurring in patients of multiple myeloma on this drug have been described till date. However, this unusual presentation of ACDR due to thalidomide in leprosy has not been hitherto documented. Herein, we describe a patient of lepromatous leprosy with ENL who developed thalidomide-induced LCV and discuss myriad aspects such as immunopathogenesis with emphasis on the possible role of various cytokines such as interleukin (IL)-2, IL-6, IL-12, and tumor necrosis factor-alpha.

Keywords: Leprosy, leukocytoclastic vasculitis, thalidomide


How to cite this article:
Belgaumkar VA, Patil PP, Chavan RB, Suryataley PR. Thalidomide-induced leukocytoclastic vasculitis in leprosy. Indian J Drugs Dermatol 2019;5:38-41

How to cite this URL:
Belgaumkar VA, Patil PP, Chavan RB, Suryataley PR. Thalidomide-induced leukocytoclastic vasculitis in leprosy. Indian J Drugs Dermatol [serial online] 2019 [cited 2019 Sep 18];5:38-41. Available from: http://www.ijdd.in/text.asp?2019/5/1/38/263088




  Introduction Top


Thalidomide is an immunomodulatory, antiangiogenic, and anti-inflammatory agent used in the treatment of multiple myeloma, myelodysplastic syndrome (MDS), systemic lupus erythematosus, Behcet's disease, rheumatoid arthritis, and graft versus host disease.

In 1965, Sheskin reported the effectiveness of thalidomide in the management of erythema nodosum leprosum (ENL).[1] It was approved by the USFDA in 1998 in the acute treatment of cutaneous manifestations of moderate-to-severe ENL and as maintenance therapy for the prevention and suppression of ENL recurrences.

The most common adverse effects of thalidomide are sedation, constipation, nausea, pruritus, neuropathy, tremor, rash, and edema.[2],[3] Among the adverse cutaneous drug reactions (ACDRs), maculopapular rash is most commonly reported with a frequency of 14%–16%.[3],[4] Leukocytoclastic vasculitis (LCV) due to thalidomide is an extremely rare presentation which led us to report this case.


  Case Report Top


A 30-year-old female presented with fever and multiple tender erythematous ulcerated nodules over the body for 3 weeks. A history of four previous episodes of painful nonulcerated nodules over the past year was elicited with each crop resolving spontaneously within a week. She denied arthralgia and ocular complaints. The patient was on multidrug therapy (dapsone 100 mg daily, rifampicin 600 mg monthly, and clofazimine 300 mg monthly and 50 mg daily) for leprosy for 2 months along with intermittent prednisolone. Attempts at tapering the steroid dose led to new crops of lesions, indicative of steroid dependency.

Except for tachycardia, her vital parameters were stable. Dermatological examination revealed multiple punched-out ulcers predominantly over the face and bilateral extremities and tender erythematous nodules over the trunk [Figure 1]. The ulnar and radial cutaneous nerves were symmetrically thickened and nontender with no motor deformities or trophic ulcers. Facial mooning and buffalo hump were notable steroid-induced side effects. Hematological investigations were normal except low hemoglobin (7 gm%). HIV serostatus was negative. Bacteriological index was 5+ (solid staining acid-fast bacilli). Histopathological examination confirmed the clinical diagnosis of lepromatous leprosy with ulcerated ENL.
Figure 1: Clinical image showing multiple punched-out ulcers over the face (ulcerated erythema nodosum leprosum)

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She was asked to continue multidrug therapy (excluding dapsone on account of anemia), and thalidomide was added in a dose of 100 mg twice daily. Worsening and appearance of new ulcerated ENL continued until the 4th day. Two days later, she developed multiple tender palpable purpura with central vesiculation over the bilateral shins and back [Figure 2]. Considering this to be a variant of ENL, the dose of thalidomide was increased to 100 mg thrice daily with subsequent appearance of new crops of palpable purpura. Other differentials such as erythema multiforme were ruled out due to the absence of mucosal and palmoplantar involvements. All other potential triggers (infective foci) were precluded on clinical examination and investigations. Platelet count, bleeding time, clotting time, and prothrombin time were within the normal limits.
Figure 2: Clinical image showing multiple palpable purpura with central vesiculation over the bilateral shins

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Histopathological examination revealed endothelial proliferation with surrounding minimal dermal infiltrate of neutrophils, without panniculitis, confirming LCV [Figure 3]. To elucidate the putative role of rifampicin and thalidomide, both the drugs were withheld, and Naranjo's causality assessment scale was calculated after sequential rechallenge.[5] This was 0 (doubtful) for rifampicin and 8 (possible) for thalidomide. Lesions completely resolved within 2 days of thalidomide withdrawal with no recurrence during 4-week follow-up [Figure 4].
Figure 3: Skin biopsy from purpuric lesion (H and E, × 40) showing endothelial proliferation with surrounding neutrophilic infiltrate

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Figure 4: Clinical image showing resolution of leukocytoclastic vasculitis lesions within 2 days of thalidomide withdrawal

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  Discussion Top


LCV is a neutrophil and FcR-dependent vasculitis of the postcapillary venules initiated by immune complex deposition and subsequent leukocyte recruitment resulting in a characteristic histologic finding of neutrophil nuclear debris and fibrinoid necrosis. This clinically presents as palpable purpura predominantly on the lower extremities with or without vesiculation. Drug-induced vasculitis involves multifactorial mechanisms and generally occurs within 7–21 days of the first exposure. Most drugs (penicillin, non-steroidal anti-inflammatory drugs, sulfonamides, and cephalosporins) are low-molecular-weight haptens requiring formation of a complex to stimulate antibody formation and drive an immune response. Thalidomide has several pharmacologic and immunomodulatory effects with proven efficacy in various autoimmune conditions including LCV.[6] Thalidomide as the cause for LCV has been reported in three cases[2],[7],[8] treated for multiple myeloma, a phenomenon aptly referred to as “therapeutic paradox.”[9] This is only the fourth reported case of thalidomide-induced vasculitis overall and probably the first in a patient of leprosy with ENL. Another interesting feature in our case is the onset of lesions within just 2–3 days of drug initiation which is much shorter than the previously reported cases (3–6 months).[2] Furthermore, the other accompaniments of LCV (abdominal pain, arthralgia, and renal involvement) were absent in our case. Sudden onset of palpable purpura in a patient with leprosy may be an unusual manifestation of Type 2 reaction or induced by other factors such as concomitant infections and drugs. Rare variants of ENL such as erythema multiforme-like or purpuric/hemorrhagic and bullous have been reported[10] but were ruled out on histopathology in the present case. Rifampicin usually causes idiopathic thrombocytopenic purpura-like nonpalpable purpura. The small number of rifampicin-induced vasculitis cases reported so far have occurred in patients on daily rifampicin (antituberculosis regimen).[11] Although ACDRs (maculopapular, urticaria-angioedema, Steven–Johnson-like, toxic epidermal necrolysis, acneiform, and undefined) are more frequent with lenalidomide,[12],[13] their prevalence is variable (3%–46%) with thalidomide.[5]

There is no unique clinical, pathological, or laboratory marker to differentiate between drug-induced vasculitis and other vasculitides. A thorough history and clinical examination with Naranjo's algorithm helped us clinch the diagnosis of thalidomide-induced vasculitis. It has been suggested that thalidomide might induce an immune-stimulatory effect that leads to autoimmune disease such as LCV in the context of malignant diseases such as multiple myeloma and MDSs; however, the exact pathophysiology of similar phenomena in nonmalignant diseases such as leprosy remains unclear. A possible hypothesis can be postulated based on the circulating cytokine milieu in leprosy. Haslett et al.[14] have demonstrated that administration of thalidomide in ENL was associated with a marked but transient increase in ex vivo mitogen-induced expression of interleukin-2 (IL-2) and interferon-γ by CD4+ and CD8+ T-cells that was noted on treatment day 7, but these returned to pretreatment levels by day 21. They also observed that while plasma tumor necrosis factor-alpha levels were not high at baseline and increased only modestly, plasma levels of IL-12 increased steadily during thalidomide treatment. The above-mentioned finding and high levels of Th2 cytokines (IL6) already circulating in lepromatous leprosy patients with Type 2 reaction[15] may enhance Bcell responses and potentiate immune complex formation, thereby facilitating LCV.


  Conclusion Top


The discovery of the efficacy of thalidomide has revolutionized ENL management. LCV is an extremely rare and notable complication of thalidomide therapy, and its occurrence in leprosy may pose a diagnostic dilemma and therapeutic challenge.

Acknowledgment

Dr. Vasudha Belgaumkar is supported by the BJGMC-JHU HIV-TB Training Program funded by Fogarty International Center of the US National Institutes of Health (grant #D43TW00957). The content of this publication is solely the responsibility of the authors and does not represent the official views of the National Institutes of Health.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understands that name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Sheskin J. Thalidomide in the treatment of lepra reactions. Clin Pharmacol Ther 1965;6:303-6.  Back to cited text no. 1
    
2.
Yildirim ND, Ayer M, Küçükkaya RD, Alpay N, Mete O, Yenerel MN, et al. Leukocytoclastic vasculitis due to thalidomide in multiple myeloma. Jpn J Clin Oncol 2007;37:704-7.  Back to cited text no. 2
    
3.
Neben K, Moehler T, Benner A, Kraemer A, Egerer G, Ho AD, et al. Dose-dependent effect of thalidomide on overall survival in relapsed multiple myeloma. Clin Cancer Res 2002;8:3377-82.  Back to cited text no. 3
    
4.
Han SH, Park SH, Kim JH, Lee JJ, Kwon SY, Kwon OS, et al. Thalidomide for treating metastatic hepatocellular carcinoma: A pilot study. Korean J Intern Med 2006;21:225-9.  Back to cited text no. 4
    
5.
Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30:239-45.  Back to cited text no. 5
    
6.
Cem Ar M, Soysal T, Hatemi G, Salihoglu A, Yazici H, Ulku B. Successful management of cryoglobulinemia-induced leukocytoclastic vasculitis with thalidomide in a patient with multiple myeloma. Ann Hematol 2005;84:609-13.  Back to cited text no. 6
    
7.
Witzens M, Moehler T, Neben K, Fruehauf S, Hartschuh W, Ho AD, et al. Development of leukocytoclastic vasculitis in a patient with multiple myeloma during treatment with thalidomide. Ann Hematol 2004;83:467-70.  Back to cited text no. 7
    
8.
Kara A, Belli AA, Atalas E, Karakus V, Dere Y. Leukocytoclastic vasculitis due to thalidomide. Dermatologica Sinica 2017;35:50-1.  Back to cited text no. 8
    
9.
Adya KA, Inamadar AC, Palit A. Paradoxes in dermatology. Indian Dermatol Online J 2013; 4:133-42.  Back to cited text no. 9
[PUBMED]  [Full text]  
10.
Gunawan H, Yogya Y, Hafinah R, Marsella R, Ermawaty D, Suwarsa O. Reactive perforating leprosy, erythema multiforme-like reactions, sweet's syndrome-like reactions as atypical clinical manifestations of type 2 leprosy reaction. Int J Mycobacteriol 2018;7:97-100.  Back to cited text no. 10
[PUBMED]  [Full text]  
11.
Blajchman MA, Lowry RC, Pettit JE, Stradling P. Rifampicin-induced immune thrombocytopenia. Br Med J 1970;3:24-6.  Back to cited text no. 11
    
12.
Sviggum HP, Davis MD, Rajkumar SV, Dispenzieri A. Dermatologic adverse effects of lenalidomide therapy for amyloidosis and multiple myeloma. Arch Dermatol 2006;142:1298-302.  Back to cited text no. 12
    
13.
Loree JM, Cai E, Sheffield BS, Dutz JP, Villa D, Shepherd LE, et al. Leukocytoclastic vasculitis following lenalidomide during the treatment of follicular lymphoma. Leuk Lymphoma 2017;58:711-4.  Back to cited text no. 13
    
14.
Haslett PA, Roche P, Butlin CR, Macdonald M, Shrestha N, Manandhar R, et al. Effective treatment of erythema nodosum leprosum with thalidomide is associated with immune stimulation. J Infect Dis 2005;192:2045-53.  Back to cited text no. 14
    
15.
Belgaumkar VA, Gokhale NR, Mahajan PM, Bharadwaj R, Pandit DP, Deshpande S. Circulating cytokine profiles in leprosy patients. Lepr Rev 2007;78:223-30.  Back to cited text no. 15
    


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  [Figure 1], [Figure 2], [Figure 3], [Figure 4]



 

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