574 J Neurol Neurosurg Psychiatry 2001;70:574–579 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.70.5.574 on 1 May 2001. Downloaded from Systematic review of immunomodulatory drugs for the treatment of people with multiple sclerosis: Is there good quality evidence on eVectiveness and cost? J Bryant, A Clegg, R Milne Abstract clinical and cost eVectiveness of health technolo- Objective—To review the clinical eVec- gies and provide guidance to the NHS. At the tiveness and costs of a range of disease time of writing, it is considering â-interferon and modifying drugs in multiple sclerosis. glatiramer in the treatment of multiple sclerosis. Drugs included are azathioprine, cladrib- Excluded from the NICE appraisal are several ine, cyclophosphamide, intravenous im- other disease modifying drugs that may be used munoglobulin, methotrexate, and in the treatment of this disease. A comprehen- mitoxantrone. sive appraisal of disease modifying drugs for the Methods—Electronic databases and bibli- treatment of multiple sclerosis should consider ographies of related papers were searched all competing alternatives. for randomised controlled trials (RCTs) This study is, to the best of our knowledge, the first systematic review of a range of disease and systematic reviews, and experts and modifying drugs for multiple sclerosis. We were pharmaceutical companies were con- commissioned by the NHS Research and tacted for further information. Inclusion Development Health Technology Assessment and quality criteria were assessed, data (HTA) programme to undertake a rapid system- extraction undertaken by one reviewer atic review to appraise the evidence on the eVec- and checked by a second reviewer, with tiveness and cost of azathioprine, cladribine, discrepancies being resolved through dis- cyclophosphamide, intravenous immunoglobu- cussion. Costs were obtained and cost- lin, methotrexate, and mitoxantrone in reducing eVectiveness papers sought. relapse rate and in limiting progression among Results—Seventeen studies met the inclu- people with multiple sclerosis. This paper sum- sion criteria for the review. Evidence for marises and takes forward analyses published in the clinical eVectiveness of the drugs full by the HTA programme.1 showed some reductions in relapse rates and/or progression to disability for people Methods with MS, although benefits may be less- Electronic databases (Medline, PubMed, Em- ened by wide ranging side eVects. Annual base, Cochrane Systematic Reviews Database, http://jnnp.bmj.com/ drug costs/patient are estimated to range Cochrane Controlled Trials Register, NHS from £60 to £10 200. No cost eVectiveness CRD DARE and NHS EED, and the National studies were found. Research Register) were searched for the Conclusion—Evidence for the eVective- period January 1980 to July 1999 (search ness of these drugs in multiple sclerosis is strategies available on request). Searches were problematic because there are few good restricted to English language studies. Addi- tional studies were identified through searching quality trials for each drug. Trials often on September 24, 2021 by guest. Protected copyright. have methodological limitations and use bibliographies of related publications and diVerent treatment regimes, patient through contact with experts. groups, and outcome measures. Well con- We included studies if they were systematic Wessex Institute for ducted trials using outcome measures reviews of randomised controlled trials (RCTs), Health Research and RCTs or cost utility studies that compared an Development, with clinical significance for groups of University of patients with diVerent types of multiple immunomodulatory drug (azathioprine, cladri- Southampton, sclerosis and long term follow up are bine, cyclophosphamide, intravenous immu- Biomedical Sciences needed if the evidence base of treatment noglobulin, methotrexate, and mitoxantrone) Building (Mailpoint with placebo or another immunomodulatory 728), Bassett Crescent for the disease is to be improved. (J Neurol Neurosurg Psychiatry 2001;70:574–579) drug; included people diagnosed with multiple East, Southampton sclerosis who met the criteria for treatment with SO16 7PX, UK J Bryant Keywords: multiple sclerosis; immunomodulatory immunomodulatory drugs; and used patient A Clegg drugs; eVectiveness based outcomes such as relapses, disease pro- R Milne gression, and side eVects. The list of drugs included in the review was derived from a provi- Correspondence to: Debate over the prescribing of â-interferons in sional list from the HTA programme modified MsJBryant [email protected] the treatment of multiple sclerosis continues, after consultation with clinical experts and despite good evidence showing some benefit but patient groups on the review advisory panel. Received 2 August 2000 and at high cost. In England and Wales, the National Cyclosporine, an immunosuppressant now in final form 21 December 2000 Institute for Clinical Excellence (NICE) has rarely used, was not included in the review Accepted 5 January 2001 been established to appraise the evidence on the because of its unacceptable adverse eVects, www.jnnp.com Systematic review of immunomodulatory drugs for the treatment of people with MS 575 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.70.5.574 on 1 May 2001. Downloaded from Table 1 Details of studies of disease modifying drugs in multiple sclerosis Intervention Author and year of study Study design Type of MS Quality score Azathioprine Yudkin et al (1991)4 Systematic review (7 RCTs) n=793 RRMS, RPMS, NHS CRD 4/6 PMS Azathioprine Milanese et al (1993)5 RCT (placebo controlled, double blind) RRMS, RPMS, Jadad Score 4/5 n=40 PMS Azathioprine Steck et al (1990)6 RCT (open label) n=41 RPMS Jadad Score 2/5 Cladribine Beutler et al (1996)15 RCT (double blind, crossover) n=48 CPMS Jadad Score 3/5 Cladribine Romine et al (1999)16 RCT (placebo controlled, double blind) RRMS Jadad Score 3/5 n=52 Cyclophosphamide Hauser et al (1983)7 RCT (unblinded) n=18 MS Jadad Score 1/5 Cyclophosphamide+prednisolone Canadian Cooperative MS Study Group RCT n=168 RPMS, CPMS Jadad Score 2/5 (1991)9 Cyclophosphamide Killian et al (1988)8 RCT (double blind, crossover) n=14 RRMS Jadad Score 4/5 Cyclophosphamide Likosky et al (1991)10 RCT (single blind) n=41 CPMS Jadad Score 2/5 Cyclophosphamide Weiner at al (1993)11 RCT (single blind) n=256 PMS Jadad Score 1/5 Intravenous immunoglobulin Achiron et al (1998)12 RCT (placebo controlled, double blind) RRMS Jadad Score 5/5 n=40 Intravenous immunoglobulin Sorensen et al (1997)13 RCT (double blind, crossover) n=25 RRMS, RPMS Jadad Score 3/5 Intravenous immunoglobulin Fazekas et al (1997)14 RCT (placebo controlled, double blind) RRMS Jadad Score 5/5 n=148 Methotrexate Currier et al (1993)20 RCT (double blind) n=44 All MS Jadad Score 2/5 Methotrexate Goodkin et al (1995)19 RCT (double blind) n=60 CPMS Jadad Score 4/5 Mitoxantrone Millefiorini et al (1997)17 RCT (placebo controlled, double blind) RRMS Jadad Score 4/5 n=51 Mitoxantrone Edan et al (1997)18 RCT (double blind) n=42 RRMS, SPMS Jadad Score 3/5 RCT=Randomised controlled trial. CPMS=chronic progressive MS, RPMS=relapsing progressive MS, RRMS=relapsing-remitting MS, PMS=progressive MS, SPMS=secondary progressive MS. notably nephrotoxicity and hypertension, which cost utility were found. Table 1 presents study outweigh any modest clinical benefit and aVect details and quality scores for the diVerent compliance. Outcome measures, either relapses immunomodulatory drugs. The quantity and or disease progression, or both, are the primary quality of studies varied between the diVerent and secondary outcomes as reported in the immunomodulatory drugs. Evidence on the literature, regardless of whether strictly appro- eVectiveness of azathioprine came from a good priate for the type of multiple sclerosis under quality systematic review4 and two subsequent consideration. Side eVects are listed as reported RCTs: one good quality placebo controlled in the studies. double blind trial5 and one poor open label Included studies were assessed using standard RCT.6 Of the five RCTs assessing critical appraisal criteria, with the quality of sys- cyclophosphamide,7–11 only one was a good tematic reviews scored using criteria developed quality double blind crossover RCT.8 The by NHS CRD2 and RCTs using the scale devel- remaining four were of poor quality, either oped by Jadad et al.3 Decisions on inclusion cri- lacking descriptions of randomisation or details teria, quality criteria, and data extraction were of withdrawals, and none were double blinded. made by one reviewer. These decisions were Blinding is often diYcult due to the inevitable checked by a second reviewer, with any disagree- adverse eVects, such as alopecia. By contrast, ments resolved through discussion. the three RCTs12–14 examining intravenous http://jnnp.bmj.com/ Studies were combined through narrative immunoglobulin were of good or fairly good synthesis, as diVerences in the type and defini- quality. For both cladribine15 16 and mitox- tion of outcomes, patient characteristics (type antrone17 18 there were two fairly good RCTs, of disease pattern, duration of disease, and and for methotrexate there was one good qual- duration of follow up) and drug dose and ity19 and one poor quality RCT.20 administration prevented any meta-analysis. Numbers needed to treat (NNTs) with 95% EVIDENCE FOR THE EFFECTIVENESS ON RELAPSE on September 24, 2021 by guest. Protected copyright. confidence intervals (95% CIs) were calculated RATE (TABLE 2) where figures were presented in an appropriate Azathioprine form. For relapse outcomes, we calculated Two studies, the systematic review (score 4/6)4 NNTs to prevent relapse at 1 year and at the and the RCT (score 4/5),5 showed significantly longest follow up period; for disease progres- lower relapse rates among patients with sion, we calculated NNTs to prevent worsen- relapsing-remitting, primary progressive, or ing by one EDSS point at 1 year and at longest secondary relapsing progressive multiple scle- follow up period available. The NNTs were rosis receiving azathioprine than patients re- included even when the eVectiveness results ceiving placebo, after 3 years of treatment.