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 Table of Contents  
REVIEW ARTICLE
Year : 2015  |  Volume : 1  |  Issue : 1  |  Page : 12-15

Role of clofazimine in management of reactions in leprosy: A brief overview


Director, Bombay Leprosy Project, Mumbai, Maharashtra, India

Date of Web Publication1-Dec-2015

Correspondence Address:
V V Pai
Bombay Leprosy Project, Vidnyan Bhavan, 11, VN Purav Marg, Sion.-Chunabhatti, Mumbai - 400 022, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/WKMP-0110.170761

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  Abstract 


Clofazimine is a synthetic dye that has been used in the treatment of leprosy since many years. Its role in the treatment of lepra reactions was subsequently recognized. When the dose of 300 mg/day is used, it doubles the serum concentration of the drug and supposedly exerts potent anti-neutrophilic effect and inhibits of prostaglandins. Our personal experience with high dosages of clofazimine in type II lepra reactions and review of the literature suggests that clofazimine has been extremely useful in providing good and satisfactory results in leprosy patients suffering from these embarrassing conditions. The anti-inflammatory effect of clofazimine is greatly useful in managing recurrent and chronic type II reactions with its steroid-sparing effect and providing an alternate and in expensive option.

Keywords: Clofazimine, type II lepra reaction, treatment


How to cite this article:
Pai V V. Role of clofazimine in management of reactions in leprosy: A brief overview. Indian J Drugs Dermatol 2015;1:12-5

How to cite this URL:
Pai V V. Role of clofazimine in management of reactions in leprosy: A brief overview. Indian J Drugs Dermatol [serial online] 2015 [cited 2019 May 23];1:12-5. Available from: http://www.ijdd.in/text.asp?2015/1/1/12/170761




  Introduction Top


Clofazimine has been in use in the treatment of leprosy since 1962, although its role in the treatment of lepra reaction was first recognized in 1965. A clinical trial with clofazimine for the management of multibacillary leprosy patients was found to be effective as reported by Ganapati and Dongre [1] and the need for exploring the real indications was then stressed. Although its role in the management of type I reaction is not documented adequately, Pfaltzgraf (1989)[2] has referred to its role in controlling type I reaction too.


  About Clofazimine Top


This synthetic riminophenazine dye has been used in the treatment of leprosy for over five decades. Browne and Hogerzeil [3] showed the clinical and bacteriological improvement in lepromatous patients with its use. The drug has a mild bactericidal action against Mycobacterium leprae the effect being slightly less than dapsone. Though the exact mode of action is unknown, the drug possibly acts by blocking the template function of DNA.

The advantage with clofazimine is the anti-inflammatory action and its resultant efficacy in type II reactions. The possible mechanism of action being stimulation of prostaglandin E2 synthesis and inhibition of neutrophil motility together with selective suppression of Th 1 subtype of T-helper cells which may also add to its role in type II reactions. Its serum levels following 50 mg dose are around 0.5 µg while 300 mg dose results in only double the concentration. The drug passes into various organs and is stored as needle-like crystals preferentially in macrophages and cells of the reticuloendothelial system.

Its accumulation within the macrophages is advantageous and results in inhibition of the multiplication of intracellular M. leprae. A Large quantity of the drug accumulates in the skin, subcutaneous fat, liver, lungs, adrenals, kidneys, lymph nodes, and gastrointestinal tract. This accumulation in the tissues results in a discoloration of the organs and the skin.

The drug is slowly excreted from the body and usually takes 6–12 months on an average. Hence, it takes quite long for patients to regain their normal coloration. The accumulation of clofazimine in the macrophages possibly interferes with the capacity of macrophage to process and present antigens thereby preventing their mobilization and activation, interleukin 2 release.[4]

In view of its very long half-life of almost 2 months and marked tissue storage, it retains its activity even when given on daily or alternate basis. In fact, the basis of the monthly loading dose of clofazimine 300 mg given in adults along with the pulse dose of rifampicin in the World Health Organization (WHO) standard multidrug therapy in multibacillary leprosy is based on this principle.

The clinical response with 50–100 mg daily dose of clofazimine is slow. Clofazimine is indicated in patients with type II reactions although its anti-inflammatory action is very slow. Clofazimine has a special role in the prevention and management of patients with chronic erythema nodosum leprosum (ENL) reactions.


  Review of Literature Top


In an earlier study by Ganapati and Dongre,[1] wherein they investigated the role of clofazimine in the treatment of 25 cases of reactive states of lepromatous and borderline leprosy and seven lepromatous patients not responding to dapsone, corticosteroids which had to be given for the control of reactions could be withdrawn and dapsone therapy reintroduced during the period of administration of clofazimine.

In this study, 20 patients who were subjects of repeated reactions mostly of the pustular type who could not be managed by the usual anti-reactive drugs and who invariably required corticosteroid therapy were selected. While the conventional therapy with salicylates, antimalarials, parenteral antimony compounds, etc., are adequate for controlling milder forms, the more severe and recurrent episodes invariably require powerful anti-inflammatory agents. At the time of inclusion in the trial, all the patients were in a state of moderate to severe reactions associated with fever, lymphadenitis, neuritis, proteinuria, etc. Most of them were already on maximum doses of 15–20 mg of prednisolone daily, posing as therapeutic problems, especially in view of the necessity to wean them from steroids.

While introducing clofazimine, the corticosteroids were continued, but it was possible to tail down their dose gradually over a period of 3–4 weeks. In all patients, clofazimine was started with a dose of 300 mg daily and continued for varying periods after the withdrawal of steroids, depending upon the control of severity of the reaction. In 15 out of the 20 patients, the drug was given for periods ranging from 6 weeks to 30 weeks. In 4 cases, however, this period was extended up to 42–83 weeks, since these were somewhat refractory and could not be controlled with the general prefixed schedule of therapy.

The results of clofazimine treatment were also equally impressive in the group of patients possibly harboring dapsone resistant bacilli (in view of their lack of improvement in spite of administration of dapsone under controlled conditions). Clinical regression was associated with a fall in the mean levels of the morphological index from 6.0 to 0.5. The need to realize the real indications of this highly useful drug in the treatment of leprosy was then stressed.

Role of clofazimine (B 663 or "Lamprene" Geigy) in the treatment of leprosy has been firmly established since Browne and Hogerzeil reported specific activity of the drug against M. leprae and its anti-inflammatory activity was subsequently brought out (Browne 1965), the indications for usage of clofazimine were clearly defined by Karat and Ramanujam.[5] However, it was and is unfortunate that this useful compound was not so widely employed, because of lack of availability and perhaps also the high cost. However, it is equally unfortunate that in situ ations where the drug is freely available and when patients can afford to pay for high cost of the drug, the indications of clofazimine has also not been properly understood by some physicians.

Therefore, this study summarizes the clinical experience with clofazimine in the treatment of patients predominantly in reactive states of leprosy as well as a few lepromatous patients who had persistent lesions in spite of regular treatment with maximum doses of dapsone.

In a double-blind controlled trial by Hastings et al.[6] in 24 lepromatous leprosy patients in reaction showed that clofazimine (Lamprene) controlled symptoms of ENL reaction in lepromatous leprosy better than prednisolone. Clofazimine also appeared to be significantly superior in preventing recurrence once the reaction had been controlled. There was a statistically significant rise in serum albumin among inpatients on clofazimine as compared with patients on prednisolone, but no difference in terms of neurological status, bacterial index, morphological index, and renal functions. Red/black hyperpigmentation was seen among practically all patients on clofazimine. No other side-effects or deleterious systemic effects were observed.

In a double-blind study by Katoch et al.[7] Three hundred PB patients (smear negative, indeterminate, tuberculoid, and borderline tuberculoid) were randomly allotted to two regimens, the control subjects (150 patients) receiving the standard WHO multidrug regimen of six doses of once a month rifampicin with daily dapsone therapy for 6 months, while the study group (150 patients) receiving 50 mg of clofazimine daily for 6 months in addition to the WHO regimen. After a stoppage of therapy, all the patients were followed up on placebo. The regimens were well tolerated.

In 7.5% of patients on clofazimine-containing regimen, lesions showed persisting activity at the time of stoppage of therapy, compared with 16% on the control regimen. This activity subsided spontaneously, more rapidly, in the study group (80% compared with 30% in the control group) in 6 months. Two patients in the control group and one patient in the study group developed a late reaction. There were no relapses in the study group, whereas, two patients relapsed in the control group during a follow-up of 2.5–3.5 years.

In a study by Pai et al.,[8] wherein the investigation was to assess its specific role in both reactional states with special emphasis on type I reaction in 82 patients, who had recurrent and chronic reactions (no response to prednisolone) and then treated with clofazimine (300 mg daily) for minimum 6 months [Graph 1] were studied with reference to clinical and neurological status, it was observed that in 67 (81.7%) out of 82 patients, the severity and frequency of such episodes of reactions was well controlled.

Clinical improvement was also observed in 82% of patients with type I reaction and 81% of 51 patients with type II reaction responded well [Figure 1]. This alternate interventional drug or a secondary line of drug like clofazimine not only helps in the management of recurrent type II reactions, but also helps to wean off patients dependent on steroids and also preempts them from steroid adverse effects while acting as a steroid sparing agent.
Figure 1: Management of necrotic ENL with prednisolone and clofazimine (a) Pretreatment (b) Post-treatment (after 3 months of therapy).

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  Adverse Effects Top


The brownish red discolouration secondary to deposition of clofazimine in the skin is fairly common. It is more marked on sun-exposed areas including face and results in low acceptability amongst the fairer individuals. Besides brownish pigmentation, xerosis, and icthyosis of the skin with brownish color on the extensors is seen which is markedly localized to the lesions.



In an investigation by Job et al.,[9] wherein skin biopsy specimens from two lepromatous leprosy patients with dark brown pigmentation who were receiving long-term clofazimine therapy were studied. Ceroid-lipofuscin pigment was demonstrated inside macrophages that contained numerous phagolysosomes. These contained lipids and clofazimine that appeared as electron-lucent vacuoles and a lipofuscin pigment that was electron dense, granular and lamellated. Although the presence of the drug in tissues contributed to the skin pigmentation, the main cause was drug-induced, reversible ceroid lipofuscinosis.

In patients with reactions receiving a higher dose of 200–300 mg for long periods of time the effects are due to clofazimine deposition in RE cells of various organs. In women, this may result rarely in abdominal problems like pain and/or diarrhea which in turn may lead to malabsorption.

In another study by applied behavior analysis Karat et al.,[10] 51 leprosy patients receiving long-term clofazimine have undergone systematic clinical laboratory testing in the search for any toxicity secondary to the drug. In approximately, 220 patient-years of observation and in analyzing approximately 40,000 test results, no statistically significant changes in the direction of abnormality was observed in serum glutamic oxalacetic transaminase, thymol turbidity, serum globulins, uric acid, alkaline phosphatase, white blood cell count or differential, hematocrit, hemoglobin, blood urea nitrogen, serum creatinine, serum cholesterol, serum albumin, serum potassium, serum calcium, stool for occult blood, routine urinalysis, or reticulocyte count.

Statistically significant changes toward abnormality were found in fasting blood sugar and total serum bilirubin. These statistically significant changes in the direction of abnormality were of a small magnitude and were not associated with related clinical signs or symptoms, and do not seem to be of major clinical significance. Despite the accumulation of relatively massive amounts of the drug in various tissues, clofazimine appears remarkably free of serious or life-threatening toxicity clinically. Although the skin and gastrointestinal side-effects of clofazimine limit its usefulness, on the evidence to date, its advantages outweigh its disadvantages in those leprosy patients for whom it is indicated.

In our experience, even in patients with lesions on face with persisting erythema or lesions of recurrent nature with erythema and or edema too respond very well to anti-inflammatory doses of clofazimine given in higher doses of 300 mg/day in divided doses administered and tapered over a period of 6 months [Table 1].{Table 1}

This observation was evident in a study by Pai et al.,[11] wherein patients with recurrent type I reaction on face or those with persistent erythematous and edematous plaques or patches not responsive to conventional course of steroids were administered with anti-inflammatory schedule of prednisolone and clofazimine who responded satisfactorily with no further recurrence or persistence of lesions on face [Figure 2]. The anti-inflammatory effect of clofazimine appears to be also useful in managing persisting or recurrent type I reaction with a steroid sparing effect.
Figure 2: Management of face lesions (a) Persistent Type I reaction over the face (Pretreatment) (b) Post-treatment (Prednisolone + Clofazimine after 27 months of therapy.

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  Conclusion Top


Therefore, considering the versatile nature of the drug, clofazimine seems to be a useful drug not only as an anti-bacterial drug but also as an alternate intervention for management of type II ENL reaction in leprosy. In fact, its role in the management of type I reaction or persistent lesions or lesions on the face has also been underestimated and perhaps has not been properly understood. In such patients, clofazimine has been extremely useful in providing good and satisfactory results in leprosy patients suffering from these embarrassing conditions. The anti-inflammatory effect of clofazimine is greatly useful in managing recurrent and chronic type II reactions with steroid-sparing effect and providing an alternate and cheaper drug of intervention.

Declaration of patient consent

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

Acknowledgments

I am thankful to the patients at Bombay Leprosy Project (BLP) for their support and cooperation provided in understanding the role of the drug and the donors for their encouragement and support and secretarial assistance provided by Mr. Sanjay Kulkarni, Computer Assistant, BLP, in preparing the manuscript. We are thankful to all the Donors for their kind support in carrying out leprosy relief work and research activities.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Ganapati R, Dongre VV. Clinical trial with clofazimine in leprosy. Bombay Hosp J 1976;18:23-6.  Back to cited text no. 1
    
2.
Pfaltzgraf RE. The management of reaction in leprosy. Int J Lepr 1989;57:103-9.  Back to cited text no. 2
    
3.
Browne SG, Hogerzeil LM. "B 663" in the treatment of leprosy. Preliminary report of a pilot trial. Lepr Rev 1962;33:6-10.  Back to cited text no. 3
[PUBMED]    
4.
Girdhar BK. Chemotherapy: Drugs used in leprosy including newer drugs. In: Kar HK, Kumar B, editors. IAL Textbook of Leprosy. 1st ed. Delhi: Jaypee Brothers Medical Publishers (P) Ltd.; 2010. p. 335-52.  Back to cited text no. 4
    
5.
Karat AB, Ramanujam K. A century of progress in the therapy of leprosy. Int J Lepr 1973;41:382-91.  Back to cited text no. 5
    
6.
Hastings RC, Jacobson RR, Trautman JR. Long-term clinical toxicity studies with clofazimine (B663) in leprosy. Int J Lepr Other Mycobact Dis 1976;44:287-93.  Back to cited text no. 6
[PUBMED]    
7.
Katoch K, Natarajan M, Katoch VM, Singh HB, Bhatia AS. Chemotherapy trial in paucibacillary leprosy using clofazimine. Indian J Lepr 1999;71:311-24.  Back to cited text no. 7
    
8.
Pai VV, Bhosale HB, Pai RR, Ganapati R. Role of clofazimine in the management of reactions in leprosy. Powai, Mumbai; 32nd National Conference of Indian Association of Dermatologists, Venerologists and Leprologists: 22nd-25th January, 2004. p. 102.  Back to cited text no. 8
    
9.
Job CK, Yoder L, Jacobson RR, Hastings RC. Skin pigmentation from clofazimine therapy in leprosy patients: A reappraisal. J Am Acad Dermatol 1990;23 (2 Pt 1):236-41.  Back to cited text no. 9
    
10.
Karat AB, Jeevaratnam A, Karat S, Rao PS. Double-blind controlled clinical trial of clofazimine in reactive phases of lepromatous leprosy. Br Med J 1970;1:198-200.  Back to cited text no. 10
[PUBMED]    
11.
Pai VV, Gaikwad V, Ganapati R. Facial lesions in leprosy – An analysis. Int J Lepr 2002;70:120A.  Back to cited text no. 11
    


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  In this article
Abstract
Introduction
About Clofazimine
Review of Literature
Adverse Effects
Conclusion
References
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