Richardus, Jan hendrik

Veen, Natasja

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EDITORIALEvidence based practice in leprosy: where do westand?NATASJA H.J. VAN VEEN &JAN HENDRIK RICHARDUSDepartment of Public Health, Erasmus MC, University MedicalCenter Rotterdam, PO Box 2040, 3000CA, The NetherlandsAccepted for publication 02 December 2008What is Evidence Based Medicine?Since the 1990s, the concept of ‘evidence based medicine’ (EBM) has received growinginterest. Its main rationale was the recognition that systematic synthesis of evidence fromhigh quality clinical research should be guiding clinical practice. Important developments inEBM included the introduction of structured abstracts and of systematic reviews.1 Nowadays,EBM can be described as ‘healthcare practice that is based on integrating knowledge gainedfrom the best available research evidence, clinical expertise, and patients’ values andcircumstances’.2 While results from randomised controlled trials (RCTs), and especially thesystematic review of several RCTs, are often considered as ‘best evidence’, RCTs are notsuitable for all types of clinical questions, such as assessing the accuracy of diagnostic tests orthe impact of prognostic factors. Evidence based medicine should therefore not be limited toRCTs and meta-analyses. Its main goal is to guide clinical decision making that is based onthe best available evidence.2,3Whether EBM has made a difference in the past decade was discussed in a special themeissue of the British Medical Journal (October 30, 2004). EBM has made a difference incontributing to the discussion and development of systematically collecting and summarisingevidence of clinical research. EBM has not only created enthusiasm, but has also receivedcriticism. For example, critics opposed the idea that EBM would restrict choices in terms ofpromoting a single ‘right’ way to practice, would declare RCTs as the only type of study to beuseful, or would be driven by costs and cost savings.2 One of the big challenges for EBM inthe coming years will be to implement clinical evidence into clinical practice. EBM shouldnot only produce best available evidence, but should also find effective ways forimplementation and to make this evidence accessible to clinicians, consumers, policy makers,and other stakeholders.2,4,5Correspondence to: Jan Hendrik Richardus (e-mail: j.richardus@erasmusmc.nl)Lepr Rev (2008) 79, 353–3570305-7518/08/064053+05 $1.00 q Lepra 353Evidence from Clinical and Epidemiological Studies in LeprosyPublication of clinical studies in leprosy dates back to the early 1950s when dapsone wasintroduced for the treatment of leprosy, and immune-suppressant drugs for the managementof leprosy reactions were examined. Over the years much research has been conducted in thefield of leprosy, gradually contributing to our knowledge base. Many clinical studieshowever, were small-scale and often did not fulfil the rigorous methodological criteria that wehave become accustomed to in clinical practice over the past two decades.Among the first larger multicentre randomised controlled trials (RCTs) were the THELEPtrials (1977–1983), which examined five multidrug regimens in 215 untreated multibacillaryleprosy (MB) patients. The results gave strong support to the intermittent, rifampicin-containing regimen (MDT) recommended by the WHO Study Group on Chemotherapy forLeprosy Control for the treatment MB leprosy.6 Clinical trials were also undertaken toestablish the value of a single-dose combination of rifampicin, ofloxacin and monocycline(ROM) to treat paucibacillary leprosy.7 The follow-up of these trials has unfortunately beenpoor. Recently, an international open trial was started of a uniform multi-drug therapyregimen for 6 months for all types of leprosy patients.8In the late 1980s and 1990s large prospective cohort studies were conducted, such asthe ALERT MDT Field Evaluation Study (AMFES),9 – 12 and the Bangladesh Acute NerveDamage Study (BANDS).13 – 15 These studies were instrumental in describing the incidenceof nerve function impairment (NFI) and in identifying risk factors and prognostic factors fornerve damage. An important off-shoot of BANDS was the development of a clinicalprediction rule for NFI in leprosy patients.16,17 The abundant data from these studies wereused to develop three multicentre RCTs in prevention of disability in leprosy (TRIPOD).18 – 20The trials, which started in 1998, examined the effects of prophylactic corticosteroids inpreventing NFI, and of corticosteroids for treating mild and long-standing NFI. In 1999 a newstudy was designed because of remaining questions regarding underlying mechanisms ofneuropathy, treatment of acute and recurrent nerve damage and reactions, and early diagnosisof nerve damage. This was the International Nerve Function Impairment and Reaction(INFIR) study, a prospective multicentre cohort study investigating prediction, detection andpathogenesis of peripheral neuropathy and reactions in leprosy.21 – 23After studies of chemoprophylaxis with dapsone in the 1970s in India,24 and in the 1990swith ROM in Micronesia,25 a large RCT on chemoprophylaxis (a single dose of rifampicin)for contacts of leprosy patients was initiated in 2002 in Bangladesh, the study on contacttransmission and chemoprophylaxis in leprosy (COLEP).26,27 The results of this study areexpected to be the basis for possible recommendations regarding the implementation ofchemoprophylactic strategies in leprosy control in future.Evidence from Systematic Reviews in LeprosyWe performed three Cochrane reviews to systematically evaluate the best availableinformation and evidence for interventions to treat nerve damage and reactions in leprosy.Two reviews assessed the effects of corticosteroids and decompressive surgery for treatingnerve damage in leprosy, respectively.28,29 In this issue of Leprosy Review a shortenedCochrane review on the role of corticosteroids in treating nerve damage is published. Thethird Cochrane review, which is in progress, examines the effects of interventions to treatH. J. van Veen and J. H. Richardus354ENL.30 Recently another Cochrane review has also been published on interventions for skinchanges caused by nerve damage in leprosy.31While Cochrane reviews focus on evidence from RCTs, we anticipated that only a fewRCTs had been conducted in the area of treating nerve damage and its consequences. Indeed,there were only three trials available involving 513 people on corticosteroids and two trialsinvolving 88 people on decompressive surgery. None of the trial results could be combined ina meta-analysis and we could not draw any robust conclusions about the effectiveness ofthese interventions for treating nerve damage in leprosy, especially on the longer-term. TheCochrane review on interventions for skin changes assessed the effects of self-care, dressingsand footwear in preventing and healing secondary damage to the skin in persons affected byleprosy. In this review eight trials with a total of 557 participants were included and it wasconcluded that there is a lack of high quality research in the field of ulcer prevention andtreatment in leprosy.31 In all Cochrane reviews the results of non-randomised studies werediscussed, since they may confirm evidence from RCTs or provide ‘second best’ availableevidence, especially if the studies were properly designed and conducted.Evidence Based Medicine in Leprosy PracticeEvidence from research has certainly led to better practice in leprosy control. Theintroduction of MDT has been a great step forward in reducing the number of people withleprosy, and identification of risk factors and prognostic factors of NFI has led to improveddiagnosis and monitoring of patients. But sometimes it is unclear whether practice has beenguided by best evidence or any evidence from research at all, as illustrated by therecommendations with respect to MDT treatment, especially for MB patients. In 1981, theWHO recommended a minimum of 2 years treatment for MB patients, which was shortenedto 24 months in 1994 and later further shortened to the currently recommended 12 months.32Relapse rates are acceptably low with the 24-month treatment.33 There is no evidencehowever, to support the shortened duration of treatment to 12 months for MB patients. On thecontrary, published data show an increased risk of relapse in the long-term for patients withhigh bacterial loads.34 – 35 Changes in guidelines or recommendations should be based onevidence from well-conducted research to maintain effective leprosy control.36,37 Recently,the ILEP published a report with evidence-based graded recommendations on differentaspects of leprosy control, diagnosis and treatment.38ConclusionWhile the importance and value of evidence based medicine (EBM) and of well-designedRCTs have been acknowledged within the leprosy research and medical community, somemay still misunderstand the concept of EBM or worry about the ‘superiority’ of RCTs orsystematic reviews compared to non-randomised studies or clinical experience. But EBM isnot restricted to RCTs because many clinical questions cannot or need not be answered by aRCT (e.g. accuracy of diagnostic tests, the power of prognostic factors). And when evidenceof RCTs is lacking, one should identify and assess the next best available evidence. We canconclude that evidence based practice in leprosy has improved in recent years and that theconcept of EBM is becoming more accepted and established. On the other hand, there is stillEvidence based practice in leprosy 355much need for improvement in conducting clinical research in leprosy. Evidence from goodresearch is essential for good clinical practice, but it should guide, not dictate, clinicalpractice. Evidence based medicine must lead to practice where the best available researchevidence, clinical experience and patient’s values go hand in hand to achieve the best care andcure for individual patients.References1 Guyatt G, Cook D, Haynes B. Evidence based medicine has come a long way. BMJ, 2004; 329(7473): 990–991.2 Dickersin K, Straus SE, Bero LA. Evidence based medicine: increasing, not dictating, choice. BMJ, 2007;334(Suppl 1): s10.3 Sackett DL, Rosenberg WM, Gray JA et al. Evidence based medicine: what it is and what it isn’t. BMJ, 1996;312(7023): 71–72.4 Reilly BM. The essence of EBM. BMJ, 2004; 329(7473): 991–992.5 Straus SE, Jones G. What has evidence based medicine done for us? BMJ, 2004; 329(7473): 987–988.6 Levy L. The THELEP controlled clinical trials in lepromatous leprosy World Health Organization, Geneva, 1999.7 Gupte MD. Field trials of a single dose of the combination rifampicin-ofloxacin-minocycline (ROM) for thetreatment of paucibacillary leprosy. Lepr Rev, 2000; 71(Suppl): S77–S80.8 Kroger A, Pannikar V, Htoon MT et al. International open trial of uniform multi-drug therapy regimen for6 months for all types of leprosy patients: rationale, design and preliminary results. Trop Med Int Health, 2008;13: 594–602.9 Saunderson P, Gebre S, Desta K et al. The pattern of leprosy-related neuropathy in the AMFES patients inEthiopia: definitions, incidence, risk factors and outcome. Lepr Rev, 2000; 71: 285–308.10 Meima A, Saunderson PR, Gebre S et al. Factors associated with impairments in new leprosy patients: the AMFEScohort. Lepr Rev, 1999; 70: 189–203.11 Saunderson P, Gebre S, Byass P. ENL reactions in the multibacillary cases of the AMFES cohort in centralEthiopia: incidence and risk factors. Lepr Rev, 2000; 71: 318–324.12 Meima A, Saunderson PR, Gebre S et al. Dynamics of impairment during and after treatment: the AMFES cohort.Lepr Rev, 2001; 72: 158–170.13 Croft RP, Richardus JH, Nicholls PG, Smith WC. Nerve function impairment in leprosy: design, methodology,and intake status of a prospective cohort study of 2664 new leprosy cases in Bangladesh (The Bangladesh AcuteNerve Damage Study). Lepr Rev, 1999; 70: 140–159.14 Nicholls PG, Croft RP, Richardus JH et al. Delay in presentation, an indicator for nerve function status atregistration and for treatment outcome–the experience of the Bangladesh Acute Nerve Damage Study cohort.Lepr Rev, 2003; 74: 349–356.15 Richardus JH, Nicholls PG, Croft RP et al. Incidence of acute nerve function impairment and reactions in leprosy:a prospective cohort analysis after 5 years of follow-up. Int J Epidemiol, 2004; 33: 337–343.16 Croft RP, Nicholls PG, Steyerberg EW et al. A clinical prediction rule for nerve-function impairment in leprosypatients. Lancet, 2000; 355(9215): 1603–1606.17 Schuring RP, Richardus JH, Steyerberg EW et al. Preventing nerve function impairment in leprosy: validation andupdating of a prediction rule. PLoS Negl Trop Dis, 2008; 2: e283.18 Smith WC, Anderson AM, Withington SG et al. Steroid prophylaxis for prevention of nerve function impairmentin leprosy: randomised placebo controlled trial (TRIPOD 1). BMJ, 2004; 328(7454): 1459.19 Van Brakel WH, Anderson AM, Withington SG et al. The prognostic importance of detecting mild sensoryimpairment in leprosy: a randomized controlled trial (TRIPOD 2). Lepr Rev, 2003; 74: 300–310.20 Richardus JH, Withington SG, Anderson AM et al. Treatment with corticosteroids of long-standing nerve functionimpairment in leprosy: a randomized controlled trial (TRIPOD 3). Lepr Rev, 2003; 74: 311–318.21 van Brakel WH, Nicholls PG, Das L et al. The INFIR Cohort Study: investigating prediction, detection andpathogenesis of neuropathy and reactions in leprosy. Methods and baseline results of a cohort of multibacillaryleprosy patients in north India. Lepr Rev, 2005; 76: 14–34.22 van Brakel WH, Nicholls PG, Wilder-Smith EP et al. Early diagnosis of neuropathy in leprosy-comparingdiagnostic tests in a large prospective study (the INFIR Cohort Study). PLoS Negl Trop Dis, 2008; 2: e212.23 Marlowe SN, Hawksworth RA, Butlin CR et al. Clinical outcomes in a randomized controlled study comparingazathioprine and prednisolone versus prednisolone alone in the treatment of severe leprosy type 1 reactions inNepal. Trans R Soc Trop Med Hyg, 2004; 98: 602–609.24 Noordeen SK. Prophylaxis–scope and limitations. Lepr Rev, 2000; 71(Suppl): S16–S19; Discussion S9–20.25 Diletto C, Blanc L, Levy L. Leprosy chemoprophylaxis in Micronesia. Lepr Rev, 2000; 71(Suppl): S21–S23;Discussion S4–5.H. J. van Veen and J. H. Richardus35626 Moet FJ, Oskam L, Faber R et al. A study on transmission and a trial of chemoprophylaxis in contacts of leprosypatients: design, methodology and recruitment findings of COLEP. Lepr Rev, 2004; 75: 376–388.27 Moet FJ, Pahan D, Oskam L et al. Effectiveness of single dose rifampicin in preventing leprosy in close contactsof patients with newly diagnosed leprosy: cluster randomised controlled trial. BMJ, 2008; 336(7647): 761–764.28 Van Veen NH, Nicholls PG, Smith WC, Richardus JH. Corticosteroids for treating nerve damage in leprosy.Cochrane Database Syst Rev, 2007; : CD005491.29 van Veen NHJ, Schreuders TAR, Theuvenet WJ, et al. Decompressive surgery for treating nerve damage inleprosy. Cochrane Database Syst Rev (accepted).30 van Veen NHJ, Lockwood DNJ, van Brakel WH et al. Interventions for erythema nodosum leprosum. (Protocol)Cochrane Database Syst Rev, 2008; : CD006949.31 Reinar LM, Forsetlund L, Bjorndal A, Lockwood D. Interventions for skin changes caused by nerve damage inleprosy. Cochrane Database Syst Rev, 2008; : CD004833.32 World Health Organization. WHO Expert Committee on Leprosy. World Health Organ Tech Rep Ser, 1998; 874:1–43.33 Lockwood D. Leprosy. Clin Evid, 2002; 8: 709–720.34 Girdhar BK, Girdhar A, Kumar A. Relapses in multibacillary leprosy patients: effect of length of therapy. LeprRev, 2000; 71: 144–153.35 Baohong J. Does there exist a subgroup of MB patients at greater risk of relapse after MDT? Lepr Rev, 2001;72: 3–7.36 Lockwood DN, Kumar B. Treatment of leprosy. BMJ, 2004; 328(7454): 1447–1448.37 Lockwood DN. Leprosy elimination-a virtual phenomenon or a reality? BMJ, 2002; 324(7352): 1516–1518.38 ILEP. Report of the International Leprosy Association Technical Forum 2002. London; 2002.Evidence based practice in leprosy 357

Evidence based practice in leprosy: where do we stand?

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Evidence based practice in leprosy: where do we stand?

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