Clofazimine has been used in treatment of leprosy for over 50 years. It has mild bactericidal action against M. leprae as well as having suppressive effect on erythema nodosum leprosum (ENL).1–8 When the reduction in length of treatment with MDT from 24 months to 12 months for multibacillary cases, as advised by the World Health Organization (WHO), was implemented, it was noted that ENL appeared to be more of a problem.6,9 This was thought to be a result of patients receiving less clofazimine.

Clofazimine may indirectly interfere with the proliferation of T lymphocytes by promoting the release of E-series prostaglandins (PGs), especially PGE2 from neutrophils and monocytes which may have a significant role in controlling Type 2 reactions. However, its effect is only apparent when a certain critical level is reached. Sustained tissue levels of clofazimine may be more important than peak blood levels for its therapeutic effect.7,10,11

Many practising clinicians believe it is useful as an adjunct to steroids for managing ENL reactions, yet there is a dearth of published evidence from trials to show whether it is effective at high doses, either to prevent first episodes or to reduce recurrence of ENL, or for its steroid-sparing effect in chronic ENL, and very little evidence to determine the best regimen for ENL management. Different doses and durations may be found to be appropriate for each scenario.

In a double-blind controlled trial by Karat et al.12 There were 24 lepromatous leprosy patients in reaction who were randomly allocated to receive either clofazimine or prednisolone for 12 weeks and were followed-up for more than 4 months. It showed that clofazimine controlled symptoms of ENL reaction better than prednisolone. It also appeared to be significantly superior in preventing recurrence once the reaction had been controlled. There was no difference in terms of neurological status, bacterial index, morphological index, and renal function among inpatients on clofazimine, as compared with patients on prednisolone; the observed statistically significant rise in serum albumin may not be clinically important. Red/black hyperpigmentation was seen among practically all patients on clofazimine. No other side-effects or deleterious systemic effects were observed.

Recent studies with MDT-treated patients include a retrospective study done by Balagon et al.6 comparing two cohorts, involving 589 patients who were receiving either 12 or 24 months MBMDT and followed for at least 4 years. This study showed that ENL was not significantly more common, but it was longer-lasting and more severe in patients receiving only 12 months of MDT, as compared with those receiving 24 months treatment.

This was followed by a double-blind study, comparing 100 patients randomly allocated to either 100 mg daily clofazimine or placebo for 12 months after completion of 12 months MBMDT. The outcome measures used were a newly developed ENL severity scoring system, total steroid intake, incidence of new ENL episodes and duration of episodes. On some measures, including deaths likely to be related to steroid intake, the placebo group appeared to have more severe ENL, but none of the differences were statistically significant.13

The guidelines suggested by WHO for managing severe, chronic ENL with clofazimine (300 mg/day for 12 weeks, taper to 200 mg/day for 12 weeks then 100 mg/day for 12–24 weeks),6 are widely used and seem beneficial. A gradual improvement of ENL symptoms, steroid-sparing effect and preventing episodes of recurrence are observed among patients. However, none of the various guidelines or recommendations available (see Table  110,14–21) are based on results of good quality clinical trials supported by objective criteria and many clinicians use different regimens; consensus on best practice is still lacking. The precise indications for appropriate use of high dose clofazimine (both for ENL patients on MDT and for those who suffer ENL after release from treatment) need to be clarified.

Reversible dose-related skin discoloration, is the most common side effect of clofazimine. Whilst aesthetically undesirable it is not physically harmful and in many people with naturally darker skin tones this is tolerable. The associated xeroderma or ichthyosis, especially on exposed areas, is more problematic. Most studies of adverse effects of clofazimine in leprosy do not enumerate these “expected effects”.22–25 Dermatological effects rarely lead to discontinuation of the drug in TB cases.26. Used with other drugs for TB, clofazimine is associated with gastrointestinal side effects in 40–55% cases.27,28 At present, there is still no accurate assessment as to the frequency, nature and incidence of the gastro-intestinal side effects occurring with high dose clofazimine when used for leprosy. Nausea, and diarrhoea have been reported as commonly mild; weight loss has been observed occasionally, while severe abdominal pain is rare.29 However, a retrospective study of the use of clofazimine in TB showed a clear association between skin or gastrointestinal adverse effects and the combination of low body weight with higher drug dosage.30 Other serious adverse effects, such as pulmonary crystal deposition31,32 and cardiac dysrhythmias,33,34 are rare and mainly reported in patients receiving other drugs which interact, those with other medical conditions, and people who have received high dose clofazimine for excessively long periods. An early prospective study of people on high dose clofazimine for 2–8 years found no clinically significant effects on renal function, liver function or haematological parameters.35

Therefore, clofazimine is a relatively safe and a useful drug due to its anti-bacterial and anti-inflammatory effect. It is suitable for patients with steroid dependency, having recurrent ENL. As to its role in preventing the first occurrence of ENL, it has not yet been proven but this might be possible with high dose clofazimine. Future studies should be considered, preferably good quality randomised clinical trials supported by large sample size, with both specific eligibility criteria and objective criteria used for outcome measures. A study targeting patients who already had at least one episode of ENL, which has already obtained ethical approval and has funding approved by the Leprosy Research Initiative, will be conducted soon to validate the effect of high dose clofazimine in these patients. Whether or not extended coverage with clofazimine should also be given to those lepromatous and borderline lepromatous leprosy patients who are at high risk of developing ENL (but have not yet had a first episode), is still uncertain.