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Figure.
Drug-Induced Blue-Black and Gray Hyperpigmentation
Drug-Induced Blue-Black and Gray Hyperpigmentation

Hyperpigmentation predominant on the forehead and malar area of a patient with recurrent erythema nodosum leprosum.

Table.  
Clinicoepidemiologic Profile of Patients and Response to Treatment With Minocycline
Clinicoepidemiologic Profile of Patients and Response to Treatment With Minocycline
1.
Motta  AC, Pereira  KJ, Tarquínio  DC, Vieira  MB, Miyake  K, Foss  NT.  Leprosy reactions. Clinics (Sao Paulo). 2012;67(10):1145-1148.
PubMedArticle
2.
Pocaterra  L, Jain  S, Reddy  R,  et al.  Clinical course of erythema nodosum leprosum. Am J Trop Med Hyg. 2006;74(5):868-879.
PubMed
3.
Kumar  B, Dogra  S, Kaur  I.  Epidemiological characteristics of leprosy reactions. Int J Lepr Other Mycobact Dis. 2004;72(2):125-133.
PubMedArticle
4.
Garrido-Mesa  N, Zarzuelo  A, Gálvez  J.  Minocycline: far beyond an antibiotic. Br J Pharmacol. 2013;169(2):337-352.
PubMedArticle
5.
El-Khalawany  M, Shaaban  D, Sultan  M, Abd Alsalam  F.  Inhibition of angiogenesis as a new therapeutic target in the treatment of lepromatous leprosy. Clin Cosmet Investig Dermatol. 2012;5:1-6.
PubMed
6.
Maia  MV, Cunha Mda  G, Cunha  CS.  Adverse effects of alternative therapy (minocycline, ofloxacin, and clofazimine) in multibacillary leprosy patients in a recognized health care unit in Manaus, Amazonas, Brazil. An Bras Dermatol. 2013;88(2):205-210.
PubMedArticle
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Research Letter
September 2015

Minocycline for Recurrent and/or Chronic Erythema Nodosum Leprosum

Author Affiliations
  • 1Department of Dermatology, Venereology and Leprology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
JAMA Dermatol. 2015;151(9):1026-1028. doi:10.1001/jamadermatol.2015.0384

Erythema nodosum leprosum (ENL) is an immune-mediated complication of leprosy, with an overall prevalence of 24% to 50%.1,2 In this pilot study, we evaluate the role of minocycline in recurrent and/or chronic ENL.

Methods

This was a prospective pilot study to evaluate the efficacy and safety of minocycline in patients with recurrent and/or chronic ENL, undertaken after approval from the Institutes Ethics Committee of the Postgraduate Institute of Medical Education and Research. After screening, 10 patients with multibacillary leprosy and recurrent ENL (recurrence 6 weeks after stopping treatment for ENL)3 or chronic ENL (lasting >24 weeks)2 were recruited after providing written informed consent. Patients who were pregnant, had comorbid conditions, or were allergic to tetracyclines were excluded.

All patients were corticosteroid dependent and did not respond to corticosteroid-sparing agents for almost 18 months, when used alone or in combination (clofazimine, 100 mg, 3 times a day for 3 months; pentoxifylline, 800 mg, 3 times a day for 3 months; colchicine, 1.5 mg/d, for 3 months; azathioprine, 100-150 mg/d, for 3 months; and hydroxychloroquine, 400 mg/d, for 6 months). Episodes of ENL generally recurred when the prednisolone dose was tapered below 40 mg.

Minocycline, 100 mg/d, was initiated for up to 3 months along with gradual tapering of the prednisolone regimen to discontinuation. No other concomitant drug was administered. Baseline tests consisted of complete blood cell count, liver function, renal function, and antinuclear antibody, as well as chest radiography and ultrasonography of the abdomen. The complete blood cell count, liver function tests, and renal function tests were subsequently repeated at 3 and 6 months.

Results

The clinicoepidemiologic profile of the patients is in the Table. All patients had a bacterial index greater than 2 after successful completion of 1 year of World Health Organization–recommended multidrug therapy for multibacillary leprosy. Five patients had recurrent ENL, 4 had chronic corticosteroid-dependent ENL, and 1 had chronic corticosteroid- and thalidomide-dependent ENL. Four of the patients with chronic ENL had arthritis, 3 had acute neuritis, 2 had epididymo-orchitis, and 1 had lymphadenitis. The prednisolone regimen was able to be tapered, without relapse, in 3 patients after 4 weeks of minocycline treatment and in 5 patients after 8 weeks of minocycline treatment. Prednisolone treatment was stopped in these 8 patients after 16 to 18 weeks of tapering. During 1 year of follow-up, only 2 patients had recurrence of mild ENL, which responded to rest and paracetamol (acetaminophen). On average, there was a decrease in the bacterial index by at least 1 log during 1 year of follow-up. Except for hyperpigmentation (Figure), gastric pain (2 patients), vomiting (1 patient), and mild transaminitis (1 patient), no other adverse effects were observed.

Discussion

Minocycline is a second-line antileprosy drug. Besides having antimicrobial activity, it possesses anti-inflammatory and anti-apoptotic properties and causes inhibition of proteolysis, angiogenesis, and collagenase.4,5 Focal or systemic coinfections have been suggested as a possible risk factor for the development of leprosy reaction.1 It can be hypothesized that, apart from possessing a strong bactericidal effect against Mycobacterium leprae, minocycline may prevent ENL reactions by treating remote concomitant bacterial infections along with its other therapeutic properties.

Minocycline has been shown to have a neuroprotective effect in conditions such as Parkinson disease, Huntington disease, amyotrophic lateral sclerosis, Alzheimer disease, and spinal cord injury.4 By inhibiting microglial activation, minocycline exerts an antinociceptive effect in neuropathic pain, such as peripheral nerve injury, particularly when administered during the initial stages of injury.4 It could be speculated that the same mechanism of action would help in leprosy neuritis. However, this outcome could partially be credited to the use of prednisolone in our patients. Furthermore, the cost vs benefit analysis in our patients (12 weeks of therapy, Rs 1800 [US $30] per patient) was noteworthy, considering the improvement in general patient well-being and number of work hours saved.

Similar to other antileprosy drugs, minocycline is also known to precipitate ENL as a result of killing M leprae. In one study, 5 of 21 patients developed ENL after introducing alternative drug therapy, including minocycline.6 Hence, patients need careful supervision during the initial 6 to 8 weeks of treatment with minocycline.

To our knowledge, there are no reports on the use of minocycline in recurrent and/or chronic ENL. Eight (80%) of our patients responded to minocycline. Prolonged administration of prednisolone and other immunosuppressants has a risk of blunting the immune response, with concern of multiplication of persisting M leprae levels. Minocycline’s immunomodulatory, anti-inflammatory, neuroprotective, and anti-bacterial effects, as well as a relatively good safety profile, make it a suitable drug in the management of refractory recurrent and/or chronic ENL. Our observation, although from an uncontrolled study with a small number of patients, indicates that, with its unique mechanism of action, minocycline is a promising drug to control recurrent and/or chronic ENL.

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Article Information

Accepted for Publication: February 11, 2015.

Corresponding Author: Sunil Dogra, MD, FRCP, Department of Dermatology, Venereology and Leprology, Postgraduate Institute of Medical Education and Research, Sector 12, Chandigarh 160012, India (sundogra@hotmail.com).

Published Online: April 15, 2015. doi:10.1001/jamadermatol.2015.0384.

Author Contributions: Drs Narang and Dogra had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Narang, Dogra.

Acquisition, analysis, or interpretation of data: Narang, Sawatkar, Kumaran.

Drafting of the manuscript: Narang, Sawatkar, Kumaran.

Critical revision of the manuscript for important intellectual content: Dogra.

Statistical analysis: Sawatkar.

Administrative, technical, or material support: Dogra.

Study supervision: Narang, Kumaran, Dogra.

Conflict of Interest Disclosures: None reported.

References
1.
Motta  AC, Pereira  KJ, Tarquínio  DC, Vieira  MB, Miyake  K, Foss  NT.  Leprosy reactions. Clinics (Sao Paulo). 2012;67(10):1145-1148.
PubMedArticle
2.
Pocaterra  L, Jain  S, Reddy  R,  et al.  Clinical course of erythema nodosum leprosum. Am J Trop Med Hyg. 2006;74(5):868-879.
PubMed
3.
Kumar  B, Dogra  S, Kaur  I.  Epidemiological characteristics of leprosy reactions. Int J Lepr Other Mycobact Dis. 2004;72(2):125-133.
PubMedArticle
4.
Garrido-Mesa  N, Zarzuelo  A, Gálvez  J.  Minocycline: far beyond an antibiotic. Br J Pharmacol. 2013;169(2):337-352.
PubMedArticle
5.
El-Khalawany  M, Shaaban  D, Sultan  M, Abd Alsalam  F.  Inhibition of angiogenesis as a new therapeutic target in the treatment of lepromatous leprosy. Clin Cosmet Investig Dermatol. 2012;5:1-6.
PubMed
6.
Maia  MV, Cunha Mda  G, Cunha  CS.  Adverse effects of alternative therapy (minocycline, ofloxacin, and clofazimine) in multibacillary leprosy patients in a recognized health care unit in Manaus, Amazonas, Brazil. An Bras Dermatol. 2013;88(2):205-210.
PubMedArticle
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