Leprosy Mailing List – December 31st, 2012
Ref.: Clofazimine in leprosy
From: G Warren, Sydney, Australia
Dear Dr Schreuder,
I refer to Mrs Nthabiseng Ntlama's message dated Dec. 28th, 2012. I notice the cry of distress. I will address here her request of information about the use of clofazimine in the treatment of erythema nodosum leprosum (ENL) or type 2 reaction and, I will also add something about the use of clofazimine as part of the standard anti-leprosy regimens. Yes, I realise that there is not much written about the detailed use of clofazimine for type 2 leprosy reaction.
History and some references
I was one of those involved in the initial drug trials in the 1960s for the use of clofazimine or B663 as it was known as then. As a direct result I published "A preliminary report of the use of B663" in Leprosy Review Vol 39 in 1968; this was a direct result of the paper I presented on the subject at the International Leprosy Conference in London in 1968. I followed that up with a further paper in 1970 also in Leprosy Review Vol 41, "The use of B663 in the treatment of Chinese leprosy Patients with Chronic reaction."
Management of leprosy
Whenever we diagnosed a new leprosy patient we checked for anaemia, parasites, malnutrition, diabetes and other medical problems that could of themselves decrease the ability of the patient to improve on treatment. They need to be adequately treated to ensure the body can turn its full resources against the leprosy bacilli and, we gave any relevant therapy e.g. iron and vitamins and dewormed &/or gave antimalarials. The bodies ability to deal with the leprosy infection is directly related to the whole state of health of the patient.
Treatment of multibacillary leprosy
Standard recommendation for treating multibacillary [slit-skin smear positive] leprosy disease is the use of a triple therapy [multi-drug therapy or MDT] with rifampicin, dapsone and clofazimine. To many people this regimen sounds silly but, remember the leprosy bacillus [Mycobacterium leprae] multiplies only once in about 14 days so, the monthly dose of rifampicin is actually given after every second multiplication of the bacilli and it kills up to 99% of all the bacteria it can reach within its half-life which is only one day. To strengthen the regimen we added more clofazimine which is a mild bactericidal drug and also an anti-inflammatory and a bacteriostatic and dapsone which is more bactericidal then clofazimine.
ENL reaction developing before anti-leprosy treatment
Many patients affected by the borderline lepromatous (BL) and lepromatous (LL) forms of leprosy only report to clinics to commence anti-leprosy treatment because they are coming into ENL reaction and the erythematous lesions/nodules are attracting attention. If this is occurring one realises that the body is already attempting to fight the bacilli and those bacilli that are being destroyed produce antigens that require to be neutralised. It is the body's inflammatory reaction, antibody to fight antigen, that produces the erythema and in severe cases the fever and malaise. So the patient requires anti-inflammatory drugs.
We would start treatment of these patients on a relatively high dose of clofazimine as monotherapy to make the most of its anti-inflammatory effect while it does exert some antibacterial effect as well; 100mgms of clofazimine daily seems adequate for most, but if ENL is already severe it may be better to give 200mgms or even 300mgms daily (for those with heavy body mass) for the first month or two, to rapidly build up the anti-inflammatory effect. Some workers suggest clofazimine and dapsone be given initially, because of the fear of developing resistance on monotherapy. I do not think that is needful as we have never seen B663 resistance develop in a patient on clofazimine alone and, dapsone resistance is common in many areas, so may not really help control the infection and may produce other undesirable side effects. This monotherapy regimen would only continue for 6-8 weeks after which time it is usually safe to add more anti-leprosy drugs; preferably add dapsone daily initially and then, if other medical problems are under control, after another month add rifampicin, once monthly. The addition of the rifampicin will increase the rate of killing of the leprosy bacilli and this will liberate more antigen but hopefully the clofazimine ought to be able to deal with this problem, as it is slowly secreted and has a long half life..
ENL reaction developing after anti-leprosy treatment
The monthly dose of rifampicin rapidly kills many bacilli and this may result in a rapid rise in antigen levels, which in BL and LL cases may then encourage the development of ENL. In some countries, it became very common for patients to get ENL within a few weeks of commencing MDT. This would sometimes have the result that the patient would refuse to come for further treatment saying the triple therapy had made them worse. So, we needed to win the patient's confidence, not lose it. A dose of 200-300mgms daily is often recommended for no more than 3 months, to be used instead of steroids and, it is effective and can often eliminate the need for giving steroids at all.
Clofazimine as steroid-sparing drug in the treatment of ENL
I have often used clofazimine to get the patient off steroids when these have already been given for reaction. In the 1960s we found that using 200-300mgms daily of clofazimine as monotherapy, enabled us to wean patients off steroids even when they had had steroids for many months. Clofazimine is an excellent anti-inflammatory, and its adequate use often eliminates the use of steroids and in many countries the use of steroids is fraught with danger because of problems with follow up and withdrawal. For patients already on MDT when they first show ENL it may be possible to increase the clofazimine (as the only anti-leprosy drug) to 200 or 300mgms daily and treat any other medical problems and then once the ENL has decreased the steroids can be reduced and then the dose of clofazimine slowly reduced till the patient is on the standard dose of 50-100mgms (depending on weight etc.) daily. In relatively recent years, say the last 20, I have rarely ever used steroids for ENL. Patients can be managed by good medical therapy and clofazimine will provide the extra assistance needed; though it may be wisest to stop the rifampicin for a few months till the body comes into equilibrium.
Side effects
Even used in high dosage in many dozens of patients, we did not really see any toxic effects though one or two patients did develop some gastric symptoms which on thorough investigation including biopsy were said to be due to deposition of the clofazimine in the gut, and did regress after the clofazimine was reduced to the 50mgms level. The clofazimine does result in pigmentation of the skin and the intensity of the discolouration depends on the severity of the inflammation. Hence in mild pure LL patients the whole face may appear a uniform "sunburnt" colour but when there are definite areas of nodulation those areas will be very dark. In mid-borderline (BB) patients the circular rings of their lesions become very obvious. Unfortunately in patients with light coloured skins this discolouration may discourage their co-operation, until they realise that those on clofazimine are really much better off. The patient can be assured that the colour will slowly fade once the clofazimine ceases and it will not leave any permanent discolouration. There is no contra-indication to giving clofazimine during pregnancy* and the baby will not be discoloured [* see ME Duncan, ENL reaction in pregnancy, LML Nov. 17th, 2012]
Conclusions
I am very keen on more use of clofazimine. To summarise the situation now, over 50 years later, I still believe that clofazimine is an excellent answer to managing reaction prone leprosy patients. Yes, I like clofazimine and if I had to choose only one drug to treat leprosy I would choose clofazimine.
I am quite happy to answer queries if Mrs Ntlama wishes to write me.
Yours sincerely,
Grace Warren
In Hong Kong (1959-1975) now in Sydney, Australia.
Previously Advisor in Leprosy and Reconstructive Surgery for The Leprosy Mission in Asia (1975-1995)
LML - S Deepak, B Naafs, S Noto and P Schreuder
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Contact: Dr Pieter Schreuder << editorlml@gmail.com >>.
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