Does prednisolone reduce the rate of killing of the bacilli?

Leprosy Mailing List, November 7th, 2008

Ref.: Does prednisolone reduce the rate of killing of the bacilli?
From: Warren G., Sydney, Australia


Dear Dr Salvatore,

Fascinating story, I refer to Dr Ranawaka’s LML message about histoid leprosy dated October 31st, 2008. I would be interested to know the ethnicity of the patient. In my international travels I have seen quite a number of patients with similar problems, but most of them are Chinese or East Asian.

I am glad that Dr Ranawaka does skin smears and the M.I and I assume B.I. The fact that she was still MI 5% after 13 months of blister packs certainly accents teaching I am always giving. In the LL (and many BL) patients the 12 months of blister packs is Not adequate to “kill” all the bacilli. The fact that she has had 3 months of prednisolone in the middle is relevant as the nodules appeared in the month after the prednisolone ceased. My teaching for many years is that Prednisolone while saving nerve function by reducing inflammation and the resultant fibrosis also reduces the Rate of killing of the bacilli. When counting up the months on MDT, I DO NOT count the months in which the patient had prednisolone. Your case accents this. Even after another 3-4 months on MDT her MI was still 5%. I wonder what the BI at the time she started prednisolone was and wonder what the initial BI and MI were, and if any other records were kept of levels during those first 12 months. I would be fascinated to know them.

In Hong Hong (1959-74) we had excellent lab technicians who did B.I. and M.I. on every patient every 3 months. Initial High BI and MI were always carefully recorded. If a patient had a BI of 5-6 and MI of 5-10% we knew it would probably be 5-6 years before they were BI=0. If they were on Prednisolone we observe that the BI did not actually fall during the months on Prednisolone. Dr Ranawaka’s patient I think shows the effect on the prednisolone. I hope he would have other BI and MI readings. I suspect that the BI and MI fell initially, as the Rifampycin killed the bacilli, but while on Prednisolone the bacilli were multiplying again. I would love some figures to show that. MDT did not come in till after that hospital with its excellent facilities had closed and most other places these days do not do BI and MI!

You had the patient on MDT, I suspect that there was no real need to add the ofloxacin. The MI had fallen before the nodules ulcerated. Nodules, described as Histoid are recognised as being due to resistance to the drug being given or to discontinuation of the drugs. This fits in perfectly with the steroids reducing the efficiency of the MDT as stated above. I suspect there is no real indication of resistance especially if the patient was taking the medication correctly; was she?

Of course we must realise she could have caught drug resistance leprosy. Is it common in her home area? In Ethiopia at one time it was found that 50% of all new leprosy patients had DDS resistant bacilli! But that is part of the reason for MDT= 3 drugs. As far as I know No patient has developed Clofazimine resistant leprosy, under treatment even as monotherapy; yes, resistance to dapsone and rifampycin do occur but there is little real evidence of resistance developing under treatment when all three drugs are correctly taken. The fact that the nodules ulcerated does not really signify resistance. Ulceration of nodules is not uncommon and you state the nodules are reducing in number. Good, I would not give more prednisolone it slows healing of the ulcers and encourages secondary infection and is not really going to do much to save nerves which I gather have not yet shown many problems. Those problems will appear in 5-10 years time as the fibrosis that is already in the nerves, due to the severity of the initial infection, squeezes the life out of the nerves causing paraesethesia and slowly increasing muscle weakness. The damage to nerves due to the true LL infection and “normal mild ENL” is not reduced by prednisolone which may delay its clinic symptoms but does not reverse the nerve damage already caused.

Other means of reducing or controlling reaction may in fact reduce other long term problems. No one can prove or disprove that! I find “tranquilisers very good in reaction. Initially it was phenobarb! Later Clofazamine. Now-days Amytriptaline (NOT DIAZAPAM) stops the patient worrying and helps them sleep and some cases of reaction I tracked as being due to “worry etc”.

In your patient, you state she did have Type 1 Reaction, hence your giving Prednisolone was fair enough to reduce the acute effect on the nerves. But I feel that the dangers of long term prednisolone are enough to recommend the benefits of changing onto High dose Clofazimine, especially in the LL/BL patients. In Chinese LL/BL patients admitted in my hospital in severe type 1 reaction I would start therapy with High Clofazimine (200-300mgms daily) and steroids and add the First Rifamycin after 3-4 weeks when the Reaction was more controlled and the clofazimine level was reaching its anti-reaction blood levels. In the 1980s we found that when starting LL/BL patients on MDT, if there was any suggestion of reaction we would start them on high Clofazamine and then a month later add the Rifampycin and dapsone. Rationale= the effective killing of bacilli by RFD leads to a sudden increase in antigen and this may cause signs of reaction. Many patients stated that they got reaction (ENL) days 3-6 after the Rifampycin. But if the patient has the initial month of high Clofazimine its levels in the body help to reduce the antigen-antibody reactions that cause ENL.

For patients developing reaction when already on MDT I would add the high Clofazimine and other anti=reaction drugs and just give 6-12 weeks steroids (if reaction severe enough) and add the extra 3 months onto total duration of MDT. Once the reaction is controlled and after the steroids are stopped the Clofazimine can be slowly reduced say by 1-200mgms per week yes, I said per week, once each month, carefully watching for any signs of reaction. And probably continue the clofazimine for many months after the MDT stopped.

In your patient I would suggest continue normal MDT (Ofloxacin if you wish) for at least 24 months counting without the months on Prednisolone. But I would prefer to keep checking her BI from 6 sites widely spread. The buttock is one of the last areas to become negative in these cases. I would keep her on MDT till smear negative all areas! But as I know many would not agree, so after 24 months MDT, I often continue with Clofazimine alone, 50-100mgms daily.

As I stated, when I was involved in the drug (clofazimine) trial in the 1960/70s we found that monotherapy with Clofazimine was enough to control ENL and prevent bacilli multiplying and eventually “cure the patient”. So I still tend to use it as Mono after an initial blast with MDT so that the Rifampycin can help get rid of the multiplying bugs, but even Rifamypycin does not get all of all the bacilli that hide in the basement membranes.

My Contacts in late 1960s gave me some fascinating information. Patients were given Rifampycin orally under supervision daily, for 5 years, by that time the skin smears were negative. But biopsies of nerves still showed normal bacilli! Once the therapy was stopped these organisms come out and start multiplying again. Yes we are seeing lots of “Relapse” or at least I certainly have seen them in the last 10 years but with the new methods of diagnosis and registration they do not all get listed as relapse, they may be listed as new patients.

I appreciate that many third world countries depend on WHO supplies of MDT so much follow their guide lines which I am sorry to say I cannot really support for patients who have complications.

I am afraid I am unlikely to be convinced that the new shortened MDT is enough treatment for the severe LL patients with high BI and MI initially, especially if they get reaction. Clofazimine is an effective anti-reaction drug. When I got it in the late 1960s I had number of long term LL patients with chronic ENL when were virtually hooked on prednisolone. By careful therapy we were able to get them onto high Clofazimine and then off all steroids. Then their BI started to fall and eventually got them off all anti-reaction medication! If I could use only one drug for leprosy it would be Clofazimine.

Sudden thought: your patient is female, is she menopausal? We found, also in Hong Kong that severity of reaction could be reduced by given pre=menopausal women hormone therapy to prevent ovulation? We thought it helped, why? I do not know.

Well what a mixed medley! The treatment of leprosy is far from straightforward.

All the best.

Grace Warren.
Previously Medical Superintendent Hong Kong leprosy Hospital 1960-1974,
Adviser in leprosy and reconstructive surgery in Asia for the Leprosy Mission 1975-2000.