Leprosy Mailing List – January 29, 2020
Ref.: (LML) Leprosy Diagnosis and Treatment - Continued Dialogue
From: Robert Gelber, San Francisco, USA
Dear Pieter,
In LML (Diagnosis and Treatment, September 4, 2019-Attachment 1), I invited the WHO and Novartis, on behalf of the unanimous voice of LML contributors, to reinstate and encourage skin smears worldwide, which had previously informed the basis of classification for treatment purposes in the monotherapy era and more than a decade of MDT (1982-1995) and to omit the addition of clofazimine to the treatment of PB leprosy.
In LML (Diagnosis and Treatment September 6, 2019 – Attachment 2), Dr. Saunderson took up that challenge in part but only confined to "diagnosis," without addressing the need of clofazimine for PB leprosy. Dr. Saunderson stated that he generally agreed with me and championed the utility of ultrasound to determine nerve enlargement, over a positive skin smear, both recently added by the WHO for a leprosy diagnosis. As with all infectious diseases, definitive diagnosis best requires actual identification of the causative organism. Skin smears provide this for leprosy. Anesthetic skin patches and nerve enlargement are but clinical manifestations of leprosy, finding the organism provides an unequivocal diagnosis. In TT/BT (PB) leprosy, skin lesions may appear atypical and not be anesthetic, while nerve enlargement may not be present or noticeable. In MB (LL, BL) leprosy, skin smears are invariably strongly positive and at multiple sites. What was missing from Saunderson's presentation was what he actually agreed with and what he did not and measures of what he or others are taking to address the two stated serious concerns of the leprosy community.
Skin smears are safe, minimally invasive, easy to perform and process and were regularly utilized successfully worldwide until 1995 when they were no longer provided the basis to determine a treatment regimen and soon thereafter abandoned. Skin smears provide clinicians, not only with a solid basis for a leprosy diagnosis but, also, a criteria to determine treatment regimen and duration, the likelihood of type1 and type 2 reactions during the leprosy course, and an objective measure of improvement or treatment failure. Most importantly, we1 found in the most thorough evaluation of MB relapse following two-year MDT, that an initial high BI and a skin biopsy of BL/LL to be an excellent criteria to earmark those patients at risk for relapse and, also, those not at risk, thereby providing a subset of MB patients who would benefit from continued antimicrobial therapy after the completion of MDT and those where it is not necessary. While Saunderson is right that immunologic and molecular tests are being pursued for several infectious diseases, including tuberculosis and malaria, currently microscopy remains the hallmark and "gold standard" for those diagnoses, as it is, also, for a leprosy diagnosis. It is one thing to include a positive smear as a criteria for a leprosy diagnosis, but without a mandate and strong encouragement to programs that have long lost their ability to be performed, it is entirely likely that will not occur.
The difficulty with the clinical diagnosis of nerve enlargement is not just that as Dr. Saunderson claimed that the clinical skills have been lost but that for even the most seasoned leprologists on clinical grounds alone nerve enlargement is often uncertain and in the general health services even more so. In support of the ultrasound utility in confirming nerve enlargement Saunderson2 provided only a single publication 20 years ago and admits ultrasonography is not generally available and has no proved specificity. I am well aware that a few reference centers have had experience with ultrasound to assess nerve enlargement when clinical findings are ambiguous, but these remain largely unpublished. Furthermore, the costly equipment, training and experience required for the successful application of ultrasound is rarely available where leprosy is endemic. In January 2019, Kumaran3 presented findings of ultrasound evaluation in 30 newly diagnosed leprosy patients (16 MB and 14 PB of four nerves, ulnar, median, lateral popliteal, and posterior tibial) and compared those findings with clinical assessment of nerve enlargement by very experienced leprologists, concluding that "ultrasonography is still at a preliminary stage" and at most "could complement other diagnostic investigations." In this study, the mean nerve cross-sectional diameter of all four nerves was statistically significantly greater in MB patients than in PB patients. The authors lamented ultrasound's lack of defined normal range of the cross-sectional diameter of individual nerves by age, sex, and occupation, dependence on fully trained and experienced technologists, and limited reliability for finding mild nerve enlargement when these were found clinically. Though Dr. Saunderson projected that ultrasound will be available in five or ten years in district hospitals, that future utility remains as yet uncertain.
To its credit, the WHO added to the diagnosis of leprosy itself a positive skin smear and nerve enlargement. Unfortunately to add the two new criteria to the diagnosis of leprosy without the resources to reliably observe them in the vast majority of clinical settings now faced by our patients is surely a meaningless gesture, leaving once again anesthetic patches as the only criteria for a leprosy diagnosis.
Professor Lockwood admirably (LML November 20, 2019) in a fine and well documented paper4 took issue with the inclusion of clofazimine in the regimen for PB leprosy. That case she considered was solely based on two studies with few patients and with serious design limitations that claimed the addition of clofazimine to the PB regimen resulted in a speedier resolution of skin lesions.
Furthermore, in the era proceeding MDT I participated as a member of the W H O Scientific Working Group of the Therapy of Leprosy (THELEP) that found that, unlike MB leprosy which permits an objective measure of antimicrobial efficacy, namely loss of viable M leprae, PB leprosy has no such valid criteria to permit a measure of improvement. In fact, skin lesions of PB leprosy on effective treatment may improve in a major way, only somewhat or not at all, while the rate of improvement when it occurs is so variable it is not amenable to interpretation. Also, PB leprosy responds without relapse to both dapsone monotherapy and PB MDT without the addition of clofazimine. Finally, adding clofazimine to the PB regimen would be associated with its serious toxicity, skin discoloration. In an earlier era when only dapsone and clofazimine were available to treat leprosy several patients spontaneously requested that I not use that medicine that "made them black". All the preceding make a significant case as to why clofazimine should not be part of the PB regimen.
I believe there must be other reasons for the addition of clofazimine to the PB regimen. Perhaps it is cost effective to have only one regimen to treat all forms of leprosy or that Novartis has a proprietary interest in the inclusion of clofazimine as important to the treatment for all forms of leprosy. However, it is critical that new treatment recommendations are made, as for all therapy, only in the best interest of patients and with proven efficacy and the avoidance of toxicity. The addition of clofazimine to the PB regimen does not add efficacy and adds toxicity.
While at the Manila Congress both the WHO and Novartis presented in plenary sessions, neither dealt with our two issues, nor was time available to raise questions and dialogue. I first attended the 10th International Congress, in Bergin, Norway in 1973 and now the Manila one, number 20. At Congresses until the 17th, all had in plenary session a lengthy address on leprosy chemotherapy. At the 17th Congress in Hyderabad, India, the late and distinguished Dr Ji Baohong presented the findings from several leprosy centers that MB relapse after completing MDT was at an unacceptably high double-digit frequency. After that valid presentation, no longer was a lecturer invited to present on the current status and recent developments in the antimicrobial therapy of leprosy, the most important intervention available to prevent disability, deformity and disease transmission.
At the Manila conference, I presented the findings that all finite therapy of MB leprosy, including MDT, results in a high frequency of relapse. While MDT has been falsely proclaimed by the WHO to result in a reliable cure of all forms of leprosy and even its elimination and both successes became official doctrine, forging the ground that led to a deterioration of leprosy detection and treatment, loss of active case detection programs and the cessation of antimicrobial research. Surely, when the disease has been found reliably curable and eliminated, all studies on further antimicrobials and regimen ceased. All mouse footpad laboratories experienced to monitor newer drugs and regimens in clinical trials were closed and with them, the remaining and demanding technical skills lost. Several contributors, including myself, have proposed that an improved MDT may provide more regular cure. The one most regularly discussed for that purpose includes rifampin, minocycline and moxifloxacin, all three previously found bactericidal in both mice and MB clinical trials, rather than the current MDT composed of only one bactericidal agent, rifampin.
Robert Gelber
San Francisco, USA
References
1 Robert H. Gelber, The relapse rate in MB leprosy patients treated with 2-years of WHO-MDT is not low. Intl. J. Leprosy, 2004, pages 493-500.
2 P. Saunderson, et al., A proposal based on experience in the AMFES project, ALERT, Ethiopia, Lepr Rev, 2000, pages 34-42.
3 M. S. Kumaran, et al., Ultrasonography versus clinical examination in detecting leprosy neuropathy. Lepr Rev, 2019, pages 364–370.
4 Diana N. J. Lockwood, et al., Three drugs are unnecessary for treating paucibacillary leprosy—A critique of the WHO guidelines, PLOS, 2019.
LML - S Deepak, B Naafs, S Noto and P Schreuder
LML blog link: http://leprosymailinglist.blogspot.it/
Contact: Dr Pieter Schreuder << editorlml@gmail.com
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