Systematic Review of Immunomodulatory Drugs for the Treatment of People with Multiple Sclerosis: Is There Good Quality Evidence on Evectiveness and Cost?

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. did not reach conventional significance. Odds of freedom from relapse at 3 years and Cost data were presented as annual drug relative risk of relapse were reported. The costs/patient, calculated using individual drug NNTs to prevent relapse at 1 year were calcu- costs (British National Formulary 1999 and lated as 10 and 7 (95%CI 3-infinity) respec- Southampton Drug Information Unit) and tively. The third study (score 2/5)6 did not dosages stated in trials, British National report on relapse rate. Formulary, or from expert opinion. Cladribine Results One study (score 3/5)16 considered patients QUANTITY AND QUALITY OF STUDIES with relapsing-remitting disease and reported Seventeen studies, either systematic reviews or the eVects of cladribine on relapse rate. RCTs, met the inclusion criteria. No studies of Comparison of the combined measure of

www.jnnp.com 576 Bryant, Clegg, Milne J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.70.5.574 on 1 May 2001. Downloaded from

frequency and severity of relapses using Methotrexate Mantel’s extension of the Mantel-Haenzel pro- One study of methotrexate (score 2/5)20 cedure showed a reduction in the cladribine reported the number of people experiencing group compared with placebo in patients with exacerbations, in a small subset of patients with relapsing-remitting disease, but there were no relapsing-remitting disease, and showed no significant diVerences between treatment overall diVerence in outcome between treat- groups in relapse rate. It was not possible to ment groups when considering all types of calculate NNTs from the data supplied. multiple sclerosis. The NNT was calculated as 23 (95%CI 4-infinity) at 18 months. Cyclophosphamide The one study of cyclophosphamide scoring Mitoxantrone Both trials of mitoxantrone reported significant 4/58 reported on the mean number of relapses reductions in relapses and exacerbations in patients with relapsing-remitting disease. among patients receiving mitoxantrone rather The cyclophosphamide group showed a de- than placebo or other treatment. In one study crease in the mean number of relapses (score 4/5)17 patients with relapsing-remitting compared with placebo but results did not disease receiving mitoxantrone had fewer achieve significance. The NNT was calculated relapses than patients on placebo during 2 from the data as 4 (95%CI 2-infinity). years of treatment. The other study (score 3/5)18 found significantly reduced mean annual Intravenous immunoglobulin relapse rates/patient for mitoxantrone and In the two studies of intravenous immu- methylprednisolone over 6 months of treat- noglobulin scoring 5/512 14 in patients with ment. The NNTs were calculated as 3 (95%CI relapsing-remitting multiple sclerosis, relapse 2–6) at 1 year and 3 (95%CI 2–37) at 6 months rate (reported as mean annual relapse rate and respectively. yearly exacerbation rate) was significantly reduced in the intravenous immunoglobulin EVIDENCE FOR DELAY IN DISEASE PROGRESSION group compared with placebo. The relative risk (TABLE 3) of relapse was estimated from these studies at Azathioprine 0.79 and 0.72, suggesting that there may be The systematic review4 and RCT (score 4/5)5 some benefit of treatment with intravenous examined azathioprine against placebo for immunoglobulin in relapsing-remitting multi- relapsing-remitting, relapsing-progressive and ple sclerosis. The NNTs were calculated as 3 progressive multiple sclerosis, and results sug- (95%CI 2–10) at 1 year and 6 (95%CI 4–61) at gested that there was slower progression in 2 years respectively. The third trial (score 3/5)13 disease severity among patients receiving aza- reported an increased number of patients with thioprine compared with controls. Although no relapses in the intravenous group, with not significant, these diVerences increased NNT calculated as 5 (95%CI 3-infinity). over time, up to 3 years. The NNT to prevent

Table 2 Summary of evidence of eVectiveness on relapse rate of disease modifying drugs in multiple sclerosis

NNT to prevent relapse http://jnnp.bmj.com/

At 1 year unless otherwise stated At longest follow up period Study EVectiveness on relapse rate (95% CI) (95% CI)

Azathioprine Yudkin et al (1991)4 Odds of freedom from relapse at 3 years for 10* 14* at 3 years azathioprine patients 1.97 (95% CI 1.27-3.04) Milanese et al (1993)5 Relative risk of relapse over 3 years for control 7 (3 to inﬁnity) 3 (2 to 12) at 3 years patients 1.6 (95% CI 1.07-2.49) 6

Steck et al (1990) N/A N/A N/A on September 24, 2021 by guest. Protected copyright. Cladribine Beutler et al (1996)15 N/A N/A N/A Romine et al (1999)16 Non-significant eVects of cladribine on relapse No patient data N/A rate Cyclophosphamide (CYC) Hauser et al (1983)7 N/A N/A N/A Canadian Cooperative MS Study Group N/A N/A N/A (1991)9 Killian et al (1988)8 Non-significant eVect of CYC on relapse rate 4 (2 to infinity) N/A Likosky et al (1991)10 N/A N/A N/A Weiner at al (1993)11 N/A N/A N/A Intravenous immunoglobulin (IVIg) Achiron et al (1998)12 Yearly relapse rate: IVIg 0.59 v placebo 1.61 3(2to10) 3(2to7)at2years (p=0.006) Sorensen et al (1997)13 Patients with no relapses: IVIg 11 v placebo 6 5 (3 to infinity) at 6 months N/A (p=0.05) Fazekas et al (1997)14 Mean annual relapse rate: IVIg 0.52 v placebo N/A 6 (4 to 61) at 2 years 1.26 (p=0.0037) Methotrexate Currier et al (1993)20 Non-significant eVect on relapse rate N/A 23 (4 to infinity) at 18 months Goodkin et al (1995)19 N/A N/A N/A Mitoxantrone (MIT) Millefiorini et al (1997)17 DiVerence in mean: 1.73 fewer relapses with 3(2to6) 3(2to7)at2years MIT than placebo p=0.0002 over 2 years Edan et al (1997)18 Annual relapse rate: methylprednisolone 3 (2 to 37) at 6 months N/A +MIT 0.7 v methylprednisolone 3.0 (p<0.01)

*Calculated from data in systematic review, not from original trial data, using method described by Sackett.23

www.jnnp.com Systematic review of immunomodulatory drugs for the treatment of people with MS 577 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.70.5.574 on 1 May 2001. Downloaded from

Table 3 Summary of evidence of eVectiveness on disease progression of disease modifying drugs in MS

NNT to prevent worsening on EDSS

At 1 year unless otherwise stated At longest follow up period Study EVectiveness on disease progression (95% CI) (95% CI)

Azathioprine: Yudkin et al (1991)4 Non-significant delays in progression v placebo No patient data N/A Milanese et al (1993)5 Non-significant delays in progression v placebo −66 (−infinity to −3) 3 (2 to 6) at 3 years Steck et al (1990)6 Non-significant delays in progression No patient data N/A Cladribine: Beutler et al (1996)15 ANOVA based on 2 year crossover: EDSS 4(3to19) N/A F=10.19 (p=0.0026) and SRS F=23.46 (p<0.0001) Romine et al (1999)16 No significant diVerences between treatment No patient data N/A groups Cyclophosphamide: Hauser et al (1983)7 Change in EDSS at 1 year: CYC+ACTH −0.5 2(2to4) N/A v ACTH alone +0.7 (p<0.01) Canadian Cooperative MS Study No significant diVerences in EDSS between 11 (5 to infinity) −7 (minus infinity to −3) at 3 Group (1991)9 (+ prednisolone) treatment groups years Killian et al (1988)8 No significant diVerences in EDSS No patient data N/A Likosky et al (1991)10 No significant diVerences in EDSS −15 (minus infinity to −2) −10 (minus infinity to −2) at 2 years Weiner at al (1993)11 Results expressed as 38% stable/improved with 9 (5 to infinity) 21 (7 to infinity) at 3 years booster CYC vs 24% no boosters (p=0.04) Intravenous immunoglobulin: Achiron et al (1998)12 No significant diVerences between treatment No patient data N/A groups Sorensen et al (1997)13 No significant diVerences No patient data N/A Fazekas et al (1997)14 Mean change in EDSS at 2 years: IVIg −0.23 vs N/A 14 (5 to infinity) at 2 years placebo 0.12 (p=0.008) Methotrexate: Currier et al (1993)20 No significant diVerences N/A (4 to infinity) at 1.5 years results identical Goodkin et al (1995)19 Composite measure of treatment failure: MTX 3 (2 to 7) composite score 5, 3 (2 to 6) composite score, 7 (3 51.6% v placebo 82.8% (p=0.011) (3 to 44) EDSS to infinity) EDSS at 2 years Mitoxantrone: Millefiorini et al (1997)17 DiVerence in proportion of patients progressed 6 (3 to infinity) 4 (2 to 13) at 2 years 1 EDSS at 2 years: additional 18% on placebo (p=0.02) Edan et al (1997)18 Mean change in EDSS at 6 months: 5 (3 to 85) at 6 months N/A methylprednisolone+MIT −1.1 v methylprednisolone −0.1 (p<0.05)

EDSS=Expanded disability status scale. worsening on EDSS could not be calculated Cyclophosphamide from the systematic review as data were not One study (score 1/5)7 in progressive multiple available. Therefore the NNT was calculated sclerosis suggested that cyclophosphamide from the one study that reported this outcome combined with adrenocorticotropic hormone − 5 may be of some benefit, with NNT to prevent as –66 (95%CI −infinity to 3) at 1 year. This http://jnnp.bmj.com/ represents a small and non-significant worsen- worsening on EDSS at 1 year calculated from ing in outcome on azathiprine: a result in the the data as 2 (95%CI 2–4). Another trial (score 11 opposite direction to the result in column 2 of 1/5) suggested that boosters of cyclophospha- table 3, which was based on a non-significant mide may slow progression, with NNT calcu- reduction in the mean changes in EDSS from lated as 9 (95%CI 5-infinity). The other studies (scores 4/5, 2/5, 2/5)8–10 did not confirm a baseline compared with placebo. Patients with delay in progression; this was to be expected in relapsing-progressive multiple sclerosis treated one trial8 which only included patients with on September 24, 2021 by guest. Protected copyright. with cyclosporine had a delay in progression relapsing-remitting multiple sclerosis. compared with azathioprine although results 6 were not significantly diVerent. No patient Intravenous immunoglobulin data were reported for calculation of NNT. One trial (score 5/5)14 in patients with relapsing-remitting disease, suggested that Cladribine there was some improvement in clinical One crossover study (score 3/5)15 reported disability in the intravenous immunoglobulin group compared with further deterioration in highly significant treatment eVects of cladrib- the placebo group after 2 years of treatment. ine on disease progression in chronic progres- The NNT was calculated as 14 (95%CI sive multiple sclerosis at both 1 year and 2 years 5-infinity) at 2 years. The other two studies compared with placebo. The NNT was calcu- (score 5/5, 3/5)12 13 did not produce significant lated from the data as 4 (95%CI 3–19). The 16 results, although this was not unexpected in other study (score 3/5), showed no delay in one study12 as only patients with relapsing- progression, but this can be expected as only remitting multiple sclerosis were included. patients with relapsing-remitting multiple scle- There were no patient data from which to cal- rosis were considered and disability accrues culate NNTs. more slowly in such patients and therefore progression may not be a good outcome measure Methotrexate for this group. No patient data were reported to Results from the study of methotrexate in allow calculation of NNT. chronic progressive multiple sclerosis (score

www.jnnp.com 578 Bryant, Clegg, Milne J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.70.5.574 on 1 May 2001. Downloaded from

Table 4 Annual drug costs/patient Discussion and conclusions Our rapid and systematic review summarises Drug Annual drug cost the quantity and quality of the evidence on six Azathioprine £300 (non-proprietary) immunomodulatory drugs for the treatment of Cladribine £6000 to £9000 people with multiple sclerosis. We found that Cyclophosphamide Up to about £60 Intravenous immunoglobulin £1600 to £10200 the 17 studies identified for inclusion in the Methotrexate £60 (non-proprietary) review were of variable quality. Although there Mitoxantrone £2000 were good quality studies, all too often these were of small size and/or short duration. As a 4/5)19 suggested a treatment eVect when using a consequence, it is not known how long any of composite outcome measure of treatment fail- the potential benefits of these drugs may last ure only. The NNT was calculated as 3 and whether if maintained they accumulate (95%CI 2–7) for the composite score and 5 over time. In those studies aVected by method- (95%CI 3–44) for EDSS alone. The other ological limitations, the most important were study (score 2/5)20 showed no overall diVerence inadequate blinding to treatment allocation, in outcome between the treatment groups poor description of withdrawals and drop outs, when considering all types of multiple sclerosis. and incomplete reporting of results and contextual information. Although some limita- Mitoxantrone tions are diYcult to avoid, they make interpret- Both trials of mitoxantrone reported significant ation of evidence diYcult and provide the delays in disability progression. The trial with opportunity for bias. In addition, comparisons patients with relapsing-remitting multiple scle- were restricted by the lack of consistency in rosis (score 4/5)17 showed that fewer patients treatment regimes, patient groups, and out- treated with mitoxantrone progressed one come measures used. Change in terminology point on the EDSS compared with patients on over time has also made interpretation diYcult, placebo. The NNT was calculated as 6 (95%CI with the term chronic progressive multiple 3-infinity). The other study (score 3/5)18 sclerosis now commonly divided into primary considered both patients with relapsing- and secondary progressive. Also, it should be remitting multiple sclerosis and those with sec- noted that the widely recognised quality ondary progressive disease treated with mitox- assessment method used here may reflect how antrone plus methylprednisolone, and showed well a study has been reported rather than the a greater improvement in mean EDSS com- actual methodological quality of the study.21 pared with patients receiving methylpred- Trials did not always report the most appro- nisolone alone. The NNT was calculated as 5 priate outcome measure for the patient group (95%CI 3–85) at 6 months. recruited to the study—for example, disability progression is reported for patients with SIDE EFFECTS relapsing-remitting multiple sclerosis although A range of adverse eVects was reported for disease progression may accrue more slowly in these six immunomodulatory drugs for multi- this group. However, severity of relapses may ple sclerosis, some of which were transient and be measured by change in disability. Some mild, others more severe. Azathioprine may studies recruited patients with relapsing and cause gastrointestinal side eVects, with up to progressive forms of disease but did not distin- http://jnnp.bmj.com/ 11% of patients reported in one study5 having guish patient groups in results. Side eVects are intolerable vomiting, which may aVect compli- not well measured or reported in the studies, ance. A wide range of side eVects was reported but need to be considered in terms of in all studies of cyclophosphamide, most com- individual patients and general compliance. monly alopecia, vomiting, nausea, amenor- Although these drugs have been shown to rhoea, and urticaria and this may not be well have some beneficial eVect on relapse rates or tolerated. For intravenous immunoglobulin, disease progression in diVerent groups of mild headache may occur transiently within the patients, these are limited and their benefit may on September 24, 2021 by guest. Protected copyright. first 24 hours of infusion. Mitoxantrone is gen- be lessened by the side eVects of treatment. erally well tolerated but may cause nausea, Azathioprine may reduce the relapse rate in amenorrhoea, and alopecia. Methotrexate is patients with relapsing-remitting, relapsing- reported as being tolerated reasonably well, but progressive, and progressive multiple sclerosis, side eVects include nausea and alopecia. but unpleasant side eVects are common and Cladribine is generally well tolerated. some patients are unable to tolerate them. Cladribine may be eVective in delaying disease COSTS OF MULTIPLE SCLEROSIS DRUGS progression in progressive multiple sclerosis, Annual drug costs (table 4) ranged widely from but seems to have little benefit in relapsing- £60/year for treatment with methotrexate to remitting multiple sclerosis. Cyclophospha- £10 200 for intravenous immunoglobulin. mide, when combined with adrenocortico- These costs do not include administration of tropic hormone or when used as a booster, may the drug, any other drugs prescribed with an slow progression but is associated with a wide immunomodulatory drug, or any costs associ- range of side eVects. Intravenous immu- ated with monitoring. It is not possible to noglobulin seems to reduce relapse rates quantify potential savings to the health care among patients with relapsing-remitting multi- and welfare sectors due to reduced admission ple sclerosis, but also has a wide range of side to hospital due to relapse, reduced disability, eVects. Methotrexate may have a beneficial and maintenance of employment by the patient eVect on patients with progressive disease, and carer. although this is only evident through a

www.jnnp.com Systematic review of immunomodulatory drugs for the treatment of people with MS 579 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.70.5.574 on 1 May 2001. Downloaded from

composite measure of treatment failure. Mitox- measures for diVerent groups of people with antrone may benefit patients with relapsing- multiple sclerosis, alongside well conducted remitting multiple sclerosis through delayed comparative economic evaluations, are re- progression and reduce relapse rates, although quired. side eVects are reported. The main strength of this rapid systematic This review was funded by the NHS R and D Health Technol- ogy Assessment Programmes. The views and opinions expressed review is that it is comprehensive for a wide therein are those of the authors and do not necessarily reflect range of disease modifying drugs for multiple those of the NHS Executives. sclerosis, and methodologically sound, apply- ing consistent methods of critical appraisal and 1 Clegg A, Bryant J, Milne R. Disease modifying drugs for multiple sclerosis: a rapid and systematic review. Health presentation. The review was guided by the Technol Assess 2000;4. principles for undertaking a systematic review2 2 NHS Centre for Reviews and Dissemination. Undertaking systematic reviews of research on eVectiveness: CRD Guidelines and followed a research protocol which was for those carrying out or commissioning reviews. York: commented on by an advisory group. The NHSCRD, 1996. (CRD Report 4.) 3 Jadad AR, Moore A, Carroll D, et al. Assessing the quality of advisory group, comprising representation reports of randomised clinical trials: is blinding necessary? from a patient group, academic and clinical Control Clin Trials 1996;17:1–12. 4 Yudkin PL, Ellison GW, Ghezzi A, et al. Overview of neurology, and health authority advisors, azathioprine treatment in multiple sclerosis [comments]. informed the review from its initiation through Lancet 1991;338:1051–5. 5 Milanese C, La Mantia L, Salmaggi A, et al. A double blind to completion, oVering invaluable advice at all study on azathioprine eYcacy in multiple sclerosis: final stages. report. J Neurol 1993;240:295–8. 6 Steck AJ, Regli F, Ochsner F, et al. Cyclosporine versus aza- The systematic review focused on patient thioprine in the treatment of multiple sclerosis: 12 month clinical and immunological evaluation. Eur Neurol 1990;30: based outcome measures, such as disease pro- 224–8. gression, relapses, and side eVects. Studies 7 Hauser SL, Dawson DM, Lehrich JR, et al. Intensive immu- nosuppression in progressive multiple sclerosis. A rand- using non-patient outcomes only, specifically omized, three-arm study of high-dose intravenous cyclo- the use of MRI, were excluded from the review. phosphamide, plasma exchange, and ACTH. N Engl J Med The omission of MRI may be regarded as 1983;308:173–80. 8 Killian JM, Bressler RB, Armstrong RM, et al. Controlled weakening the strength of the review. However, pilot trial of monthly intravenous cyclophosphamide in multiple sclerosis. Arch Neurol 1988;45:27–30. uncertainty remains about the interpretation 9 The Canadian cooperative trial of cyclophosphamide and and clinical significance of MRI results in mul- plasma exchange in progressive multiple sclerosis. The tiple sclerosis.22 As such, it was decided to Canadian Cooperative Multiple Sclerosis Study Group [comments]. Lancet 1991;337:441–6. exclude results of MRI or other non-patient 10 Likosky WH, Fireman B, Elmore R, et al. Intense immuno- outcomes from the outset and this restriction is suppression in chronic progressive multiple sclerosis: the Kaiser study. J Neurol Neurosurg Psychiatry 1991;54:1055– unlikely to have introduced any bias into the 60. 11 Weiner HL, Mackin GA, Orav EJ, et al. Intermittent cyclo- review. phosphamide pulse therapy in progressive multiple Another potential opportunity for bias was sclerosis: final report of the Northeast Cooperative the lack of unpublished studies and the restric- Multiple Sclerosis Treatment Group [comments]. Neurol- ogy 1993;43:910–8. tion of the research to English language studies 12 Achiron A, Gabbay U, Gilad R, et al. Intravenous only. Although companies manufacturing the immunoglobulin treatment in multiple sclerosis. EVect on relapses. Neurology 1998;50:398–402. drugs and experts in the topic area were 13 Sorensen PS, Wanscher B, Jensen CV, et al. Intravenous contacted, no additional unpublished studies immunoglobulin G reduces MRI activity in relapsing multiple sclerosis. Neurology 1998;50:1273–81. were obtained. 14 Fazekas F, Deisenhammer F, Strasser Fuchs S, et al. Randomised placebo-controlled trial of monthly intra- http://jnnp.bmj.com/ Some of the drugs considered in this review venous immunoglobulin therapy in relapsing-remitting are expensive. That of course does not mean multiple sclerosis. Austrian Immunoglobulin in Multiple Sclerosis Study Group [comments]. Lancet 1997;349:589– they should not be prescribed: what will matter 93. to those who formulate clinical policy, whether 15 Beutler E, Sipe JC, Romine JS, et al. The treatment of at the hospital or national level, is the balance chronic progressive multiple sclerosis with cladribine. Proc Natl Acad Sci USA 1996;93:1716–20. of benefits, harms, acceptability to patients, 16 Romine JS, Sipe JC, Koziol JA, et al. A double-blind, and costs. This will require a full economic placebo-controlled, randomized trial of cladribine in relapsing-remitting multiple sclerosis. Proc Assoc Am Physi- evaluation, probably in the form of a cost- cians 1999;111:35–44. 17 Millefiorini E, Gasperini C, Pozzilli C, et al. Randomized on September 24, 2021 by guest. Protected copyright. eVectiveness or cost-utility study. A recent sys- placebo-controlled trial of mitoxantrone in relapsing- tematic review of the cost-utility of â-interferon remitting multiple sclerosis: 24 month clinical and MRI in multiple sclerosis found four studies but outcome. J Neurol 1997;244:153–9. 18 Edan G, Miller D, Clanet M, et al. Therapeutic eVect of concluded that none of them provided a full mitoxantrone combined with methylprednisolone in multi- comparison of relevant healthcare strategies.24 ple sclerosis: a randomised multicentre study of active disease using MRI and clinical criteria [comments]. J Neurol Further economic evaluations of a wider range Neurosurg Psychiatry 1997;62:112–8. 19 Goodkin DE, Rudick RA, VanderBrug Medendorp S, et al. of possible interventions, such as improved Low-dose (7.5 mg) oral methotrexate reduces the rate of supportive care, were needed so that scarce progression in chronic progressive multiple sclerosis [comments]. Ann Neurol 1995;37:30–40. resources could be used eVectively. 20 Currier RD, Haerer AF, Meydrech EF. Low dose oral meth- Access to good quality evidence on the clini- otrexate treatment of multiple sclerosis: a pilot study [pub- cal and cost eVectiveness of disease modifying lished erratum appears in J Neurol Neurosurg Psychiatry 1994;57:528]. J Neurol Neurosurg Psychiatry 1993;56: drugs for multiple sclerosis is restricted by 1217–8. concerns over the methodological rigour of 21 Juni P, Witschi A, Bloch R, et al. The hazards of scoring the quality of clinical trials for meta-analysis. JAMA 1999;282: studies and the variations between treatment 1054–60. 22 Kappos L, Moeri D, Raude EW. Predictive value of regimes, patients groups, and outcome meas- gadolinium-enhanced magnetic resonance imaging for ures. Current evidence suggests that disease relapse rate and changes in disability or impairment in multiple sclerosis; a meta-analysis. Lancet 1999;353:964–9. modifying drugs provide some limited benefit 23 Sackett DL, Deeks JJ, Altman DG. Down with odds ratios! to people with multiple sclerosis, but with a Evidence Based Medicine 1996;1:164–6. 24 Bryant J, Clegg A, Milne R. Cost utility of drugs for multi- wide range of side eVects. Further long term ple sclerosis: systematic review places study in context. RCTs using clinically significant outcome BMJ 2000;320:1474.