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Meta-Analysis
. 2024 Dec 9;12(12):CD015005.
doi: 10.1002/14651858.CD015005.pub2.

Azathioprine for people with multiple sclerosis

Ben Ridley  1 , Francesco Nonino  1 , Elisa Baldin  1 , Ilaria Casetta  2 , Gerardo Iuliano  3 , Graziella Filippini  4
Affiliations
Meta-Analysis

Azathioprine for people with multiple sclerosis

Ben Ridley et al. Cochrane Database Syst Rev. .

Abstract

Background: Multiple sclerosis (MS) is an immune-mediated, chronic, inflammatory demyelinating disease of the central nervous system, impacting around 2.8 million people worldwide. Characterised by recurrent relapses or progression, or both, it represents a substantial global health burden, affecting people, predominantly women, at a young age (the mean age of diagnosis is 32 years). Azathioprine is used to treat chronic inflammatory and autoimmune diseases, and it is used in clinical practice as an off-label intervention for MS, especially where access to on-label disease-modifying treatments (DMTs) for MS is limited. Given this, a review of azathioprine's benefits and harms would be timely and valuable to inform shared healthcare decisions.

Objectives: To evaluate the benefits and harms of azathioprine (AZA) for relapsing and progressive multiple sclerosis (MS), compared to other disease-modifying treatments (DMTs), placebo or no treatment. Specifically, we will assess the following comparisons. AZA compared with other DMTs or placebo as first-choice treatment for relapsing forms of multiple sclerosis AZA compared with other DMTs or placebo for relapsing forms of MS when switching from another DMT AZA compared with other DMTs or placebo as first-choice treatment for progressive forms of MS AZA compared with other DMTs or placebo for progressive forms of MS when switching from another DMT SEARCH METHODS: We conducted an extensive search for relevant literature using standard Cochrane search methods. The most recent search date was 9 August 2023.

Selection criteria: We included randomised controlled trials (RCTs) lasting 12 months or more that compared azathioprine versus DMTs, placebo or no intervention in adults with MS. We considered evidence from non-randomised studies of interventions (NRSIs) as these studies may provide additional evidence not available from RCTS. We excluded cluster-randomised trials, cross-over trials, interrupted time series, case reports and studies of within-group design with no control group.

Data collection and analysis: We followed standard Cochrane methodology. There were three outcomes we considered to be critical: disability, relapse and serious adverse events (SAEs, as defined in the studies). We were also interested in other important outcomes: quality-of-life (QoL) impairment (mental score), short-term adverse events (gastrointestinal disorders), long-term adverse events (neoplasms) and mortality.

Main results: We included 14 studies: eight RCTs (1076 participants included in meta-analyses) and six NRSIs (1029 participants). These studies involved people with relapsing and progressive MS. Most studies included more women (57 to 83%) than men, with participants' average age at the onset of MS being between 29.4 and 33.4 years. Five RCTs and all six NRSIs were conducted in Europe (1793 participants); two RCTs were conducted in the USA (126 participants) and one in Iran (94 participants). The RCTs lasted two to three years, while NRSIs looked back up to 10 years. Four studies received some funding or support from commercial interests and five were funded by government or philanthropy; the other five provided no information about funding. There are three ongoing studies. Comparison groups included other DMTs (interferon beta and cyclosporine A), placebo or no treatment. Below, we report on azathioprine as a 'first choice' treatment compared to interferon beta for people with relapsing MS. None of the studies reported on any critical or important outcome for this comparison for progressive MS. No study was retrieved comparing azathioprine to placebo or other DMTs for either relapsing or progressive MS. Furthermore, the NRSIs did not provide information not already covered in the RCTs. Azathioprine as a first-choice treatment compared to other DMTs (specifically, interferon beta) for relapsing MS - The evidence is very uncertain about the effect of azathioprine on the number of people with disability progression over two years compared to interferon beta (risk ratio (RR) 0.19, 95% confidence interval (CI) 0.02 to 1.58; 1 RCT, 148 participants; very low certainty evidence). - Azathioprine may decrease the number of people with relapses over a one- to two-year follow-up compared to interferon beta (RR 0.61, 95% CI 0.43 to 0.86; 2 RCTs, 242 participants; low-certainty evidence). - Azathioprine may result in a possible increase in the number of people with SAEs over two years in comparison with interferon beta (RR 6.64, 95% CI 0.35 to 126.27; 1 RCT, 148 participants; low-certainty evidence). - The evidence is very uncertain about the effect of azathioprine on the number of people with the short-term adverse event of gastrointestinal disorders over two years compared to interferon beta (RR 5.30, 95% CI 0.15 to 185.57; 2 RCTs, 242 participants; very low certainty evidence). We found no evidence comparing azathioprine to other DMTs for QoL impairment (mental score), long-term adverse events (neoplasms) or mortality.

Authors' conclusions: Azathioprine has been proposed as an alternative treatment for MS when access to approved, on-label DMTs is limited, especially in resource-limited settings. The limited evidence available suggests that azathioprine may result in a modest benefit in terms of relapse frequency, with a possible increase in SAEs, when compared to interferon beta-1b, for people with relapsing-remitting multiple sclerosis. The evidence for the effect on disability progression and short-term adverse events is very uncertain. Caution is required in interpreting the conclusions of this review since our certainty in the available evidence on the benefits and harms of azathioprine in multiple sclerosis is low to very low, implying that further evidence is likely to change our conclusions. An important limitation we noted in the available evidence is the lack of long-term comparison with other treatments and the failure of most studies to measure outcomes that are important to people with multiple sclerosis, such as quality of life and cognitive decline. This is especially the case in the evidence relevant to people with progressive forms of multiple sclerosis.

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Conflict of interest statement

FN is Joint Co‐ordinating Editor of the Cochrane Multiple Sclerosis and Rare Disease of the CNS review group. He was not involved in the editorial process of the review. FN works as an Epidemiologist and Neurologist within the Italian Public Health Service, at an outpatient clinic at the IRCCS Instituto delle Scienze Neurologiche di Bologna.

EB is a neurologist, working at an outpatient clinic at the IRCCS Instituto delle Scienze Neurologiche di Bologna. She is an author of a manuscript on ponesimod for the treatment of relapsing multiple sclerosis, and has received travel and meeting attendance support from Biogen, Roche, and Sanofi Genzyme; personal payments.

BR has worked as the Managing Editor of the Cochrane Multiple Sclerosis and Rare Disease of the CNS review group and is a Managing Editor with the Central Editorial Service. He was not involved in the editorial process of the review.

IC works at the IRCCS San Camillo Hospital, Venice, Italy.

GF is Joint Co‐ordinating Editor of the Cochrane Multiple Sclerosis and Rare Disease of the CNS review group; he was not involved in the editorial process of this review. GF was involved with MAIN trial 2014 (Massacesi 2014), funded by the AIFA (Italian Medicines Agency). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript, and GF declares that no competing interests exist. The MAIN trial was approved by ethics committees in the co‐ordinating centre (Careggi University Hospital, Ethic Committee, Florence) and in each of the participating centres (Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano; Clinica Neurologica, Novara; Università 'La Sapienza', Roma; Policlinico 'G Rodolico' Azienda Ospedaliero‐Universitaria, Catania; Clinica Neurologica 2, Genova; Azienda Ospedaliera Universitaria Integrata, Verona; Ospedale Clinicizzato 'Colle Dall’Ara', Chieti; Università di Sassari, Sassari; Università di Napoli, Napoli; Ospedale S Antonio, Padova; Ospedale Civile S Agostino‐Estense, Modena; Ospedale Santa Maria, Reggio Emilia; Policlinico Universitario Mater Domini, Catanzaro; Ospedale S Gerardo, Monza; Azienda Ospedaliero‐Universitaria S Anna, Ferrara; Ospedali Riuniti, Ancona; Istituto S Raffaele 'G. Giglio', Cefalu; Azienda Ospedaliero San Giovanni Battista, Università di Torino, Torino; Ospedale Sacro Cuore, Negrar; Ospedale Santa Chiara, Trento; Ospedale Regionale, Bolzano; Azienda Ospedaliero‐Universitaria Senese, Policlinico 'Le Scotte', Siena; Ospedale 'Misericordia e Dolce', Prato; Università degli Studi di Pisa, Pisa; Policlinico 'G Martino’ Messina; Università degli Studi di Palermo, Palermo; Università Cattolica, Policlinico Gemelli, Roma; Dipartimento Neuroriabilitativo ASL CN1, Cuneo; Luigi Gonzaga Hospital, Orbassano Ethics Committees). The MAIN trial adhered to Good Clinical Practice (GCP) guidelines and Declaration of Helsinki.

GI declares that he has no conflicts of interest. GI is a neurologist. He previously worked in the public health system in Italy and is currently working as neurologist and psychiatrist in private practice.

Figures

1
1
PRISMA flow diagram for the study selection process
2
2
Risk of bias graph: judgements about each risk of bias item presented as a percentage across all included randomised controlled trials
3
3
Risk of bias summary: judgements about each risk of bias item for every included randomised controlled trial
4
4
Risk of bias (ROBINS‐I) assessments for non‐randomised studies of interventions Abbreviations
ROBINS‐I: Risk Of Bias In Non‐randomised Studies ‐ of Interventions
1.1
1.1. Analysis
Comparison 1: RRMS, treatment naive, azathioprine versus other DMT (interferon), Outcome 1: Disability: number of participants with disability progression (2‐year follow‐up)
1.2
1.2. Analysis
Comparison 1: RRMS, treatment naive, azathioprine versus other DMT (interferon), Outcome 2: Relapse: number of participants with clinical relapse (1‐ to 2‐year follow‐up)
1.3
1.3. Analysis
Comparison 1: RRMS, treatment naive, azathioprine versus other DMT (interferon), Outcome 3: Serious adverse events: number of participants with SAEs (2‐year follow‐up)
1.4
1.4. Analysis
Comparison 1: RRMS, treatment naive, azathioprine versus other DMT (interferon), Outcome 4: Short‐term adverse effects: numbers of participants with gastrointestinal disorders (1‐ to 2‐year follow‐up)
1.5
1.5. Analysis
Comparison 1: RRMS, treatment naive, azathioprine versus other DMT (interferon), Outcome 5: Other short‐term adverse effects: number of participants with hypersensitivity reactions (2‐year follow‐up)
1.6
1.6. Analysis
Comparison 1: RRMS, treatment naive, azathioprine versus other DMT (interferon), Outcome 6: Other long‐term adverse effects: number of participants with influenza‐like illness (2‐year follow‐up)
1.7
1.7. Analysis
Comparison 1: RRMS, treatment naive, azathioprine versus other DMT (interferon), Outcome 7: Other long‐term adverse effects: number of participants with leukopenia (2‐year follow‐up)
1.8
1.8. Analysis
Comparison 1: RRMS, treatment naive, azathioprine versus other DMT (interferon), Outcome 8: Other long‐term adverse effects: number of participants with hepatobiliary disorders (2‐year follow‐up)
1.9
1.9. Analysis
Comparison 1: RRMS, treatment naive, azathioprine versus other DMT (interferon), Outcome 9: Annualised relapse rate (2‐year follow‐up)
1.10
1.10. Analysis
Comparison 1: RRMS, treatment naive, azathioprine versus other DMT (interferon), Outcome 10: New or enlarging T2‐weighted MRI lesions: number of participants (2‐year follow‐up)
1.11
1.11. Analysis
Comparison 1: RRMS, treatment naive, azathioprine versus other DMT (interferon), Outcome 11: New gadolinium‐enhancing positive T1‐weighted MRI lesions: number of participants (2‐year follow‐up)
1.12
1.12. Analysis
Comparison 1: RRMS, treatment naive, azathioprine versus other DMT (interferon), Outcome 12: Treatment discontinuation due to adverse events: number of participants (1‐year follow‐up)
2.1
2.1. Analysis
Comparison 2: RRMS, treatment naive, azathioprine versus other DMT (cyclosporine A), Outcome 1: Disability: number of participants with disability progression (2‐year follow‐up)
2.2
2.2. Analysis
Comparison 2: RRMS, treatment naive, azathioprine versus other DMT (cyclosporine A), Outcome 2: Serious adverse events: number of participants with SAEs (2‐year follow‐up)
2.3
2.3. Analysis
Comparison 2: RRMS, treatment naive, azathioprine versus other DMT (cyclosporine A), Outcome 3: Short‐term adverse effects: number of participants with gastrointestinal disorders (2‐year follow‐up)
2.4
2.4. Analysis
Comparison 2: RRMS, treatment naive, azathioprine versus other DMT (cyclosporine A), Outcome 4: Other short‐term adverse effects: number of participants with hypersensitivity reactions (2‐year follow‐up)
2.5
2.5. Analysis
Comparison 2: RRMS, treatment naive, azathioprine versus other DMT (cyclosporine A), Outcome 5: Other long‐term adverse effects: number of participants with long‐term AEs: leukopenia (2‐year follow‐up)
2.6
2.6. Analysis
Comparison 2: RRMS, treatment naive, azathioprine versus other DMT (cyclosporine A), Outcome 6: Other long‐term adverse effects: number of participants with hepatobiliary disorders (2‐year follow‐up)
2.7
2.7. Analysis
Comparison 2: RRMS, treatment naive, azathioprine versus other DMT (cyclosporine A), Outcome 7: Other long‐term adverse effects: number of participants with infections (2‐year follow‐up)
2.8
2.8. Analysis
Comparison 2: RRMS, treatment naive, azathioprine versus other DMT (cyclosporine A), Outcome 8: Other long‐term adverse effects: number of participants with CNS disorders (paresthesia) (2‐year follow‐up)
2.9
2.9. Analysis
Comparison 2: RRMS, treatment naive, azathioprine versus other DMT (cyclosporine A), Outcome 9: Other long‐term adverse effects: number of participants with skin and subcutaneous tissue disorders (hypertrichosis) (2‐year follow‐up)
2.10
2.10. Analysis
Comparison 2: RRMS, treatment naive, azathioprine versus other DMT (cyclosporine A), Outcome 10: Annualised relapse rate (2‐year follow‐up)
2.11
2.11. Analysis
Comparison 2: RRMS, treatment naive, azathioprine versus other DMT (cyclosporine A), Outcome 11: Treatment discontinuation due to adverse events: number of participants (2‐year follow‐up)
3.1
3.1. Analysis
Comparison 3: RRMS, treatment naive, azathioprine versus placebo, Outcome 1: Disability: number of participants with disability progression (2‐ to 3‐year follow‐up)
3.2
3.2. Analysis
Comparison 3: RRMS, treatment naive, azathioprine versus placebo, Outcome 2: Relapse: number of participants with clinical relapse (2‐ to 3‐year follow‐up)
3.3
3.3. Analysis
Comparison 3: RRMS, treatment naive, azathioprine versus placebo, Outcome 3: Serious adverse events: number of participants with SAEs (2‐year follow‐up)
3.4
3.4. Analysis
Comparison 3: RRMS, treatment naive, azathioprine versus placebo, Outcome 4: Short‐term adverse effects: number of participants with gastrointestinal disorders (3‐year follow‐up)
3.5
3.5. Analysis
Comparison 3: RRMS, treatment naive, azathioprine versus placebo, Outcome 5: Long‐term adverse effects: number of participants with neoplasms (15‐year follow‐up)
3.6
3.6. Analysis
Comparison 3: RRMS, treatment naive, azathioprine versus placebo, Outcome 6: Mortality: overall number of deaths (3‐year follow‐up)
3.7
3.7. Analysis
Comparison 3: RRMS, treatment naive, azathioprine versus placebo, Outcome 7: Mortality: overall number of deaths (14‐year follow‐up)
3.8
3.8. Analysis
Comparison 3: RRMS, treatment naive, azathioprine versus placebo, Outcome 8: Other short‐term adverse events: number of participants with hypersensitivity reactions (2‐ to 3‐year follow‐up)
3.9
3.9. Analysis
Comparison 3: RRMS, treatment naive, azathioprine versus placebo, Outcome 9: Other long‐term adverse events: number of participants with leukopenia (3‐year follow‐up)
3.10
3.10. Analysis
Comparison 3: RRMS, treatment naive, azathioprine versus placebo, Outcome 10: Other long‐term adverse events: number of participants with hepatobiliary disorders (2‐ to 3‐year follow‐up)
3.11
3.11. Analysis
Comparison 3: RRMS, treatment naive, azathioprine versus placebo, Outcome 11: Other long‐term adverse events: number of participants with infections (2‐year follow‐up)
3.12
3.12. Analysis
Comparison 3: RRMS, treatment naive, azathioprine versus placebo, Outcome 12: Other long‐term adverse events: number of participants with skin and subcutaneous tissue disorders (2‐year follow‐up)
3.13
3.13. Analysis
Comparison 3: RRMS, treatment naive, azathioprine versus placebo, Outcome 13: Treatment discontinuation due to adverse events: number of participants (2‐ to 3‐year follow‐up)
4.1
4.1. Analysis
Comparison 4: PMS, treatment naive, azathioprine versus placebo, Outcome 1: Disability: number of participants with disability progression (2‐ to 3‐year follow‐up)
4.2
4.2. Analysis
Comparison 4: PMS, treatment naive, azathioprine versus placebo, Outcome 2: Relapse: number of participants with clinical relapse (2‐ to 3‐year follow‐up)
4.3
4.3. Analysis
Comparison 4: PMS, treatment naive, azathioprine versus placebo, Outcome 3: Long‐term adverse effects: number of participants with neoplasms (3‐year follow‐up)
4.4
4.4. Analysis
Comparison 4: PMS, treatment naive, azathioprine versus placebo, Outcome 4: Mortality: overall number of deaths (3‐year follow‐up)
4.5
4.5. Analysis
Comparison 4: PMS, treatment naive, azathioprine versus placebo, Outcome 5: Other short‐term adverse effects: number of participants with hypersensitivity reactions (2‐ to 3‐year follow‐up)
4.6
4.6. Analysis
Comparison 4: PMS, treatment naive, azathioprine versus placebo, Outcome 6: Other long‐term adverse effects: number of participants with leukopenia (3‐year follow‐up)
4.7
4.7. Analysis
Comparison 4: PMS, treatment naive, azathioprine versus placebo, Outcome 7: Other long‐term adverse effects: number of participants with infections (1‐ to 3‐year follow‐up)
4.8
4.8. Analysis
Comparison 4: PMS, treatment naive, azathioprine versus placebo, Outcome 8: Treatment discontinuation due to adverse events: number of participants (3‐year follow‐up)
5.1
5.1. Analysis
Comparison 5: Non‐randomised studies of interventions, Outcome 1: Disability: number of participants with disability progression (1‐year follow‐up)
5.2
5.2. Analysis
Comparison 5: Non‐randomised studies of interventions, Outcome 2: Relapse: number of participants with clinical relapse (1‐year follow‐up)
5.3
5.3. Analysis
Comparison 5: Non‐randomised studies of interventions, Outcome 3: Quality‐of‐life impairment (mental score): mean change in MSQOL‐54 mental composite score (1‐year follow‐up)
5.4
5.4. Analysis
Comparison 5: Non‐randomised studies of interventions, Outcome 4: Other short‐term adverse effects: number of people with influenza‐like symptoms (1‐year follow‐up)
5.5
5.5. Analysis
Comparison 5: Non‐randomised studies of interventions, Outcome 5: Quality‐of‐life impairment (physical score): mean change in MSQOL‐54 physical composite score (1‐year follow‐up)
5.6
5.6. Analysis
Comparison 5: Non‐randomised studies of interventions, Outcome 6: Disability: number of participants with disability progression (1‐year follow‐up)
5.7
5.7. Analysis
Comparison 5: Non‐randomised studies of interventions, Outcome 7: Relapse: number of participants with clinical relapse (1‐year follow‐up)
5.8
5.8. Analysis
Comparison 5: Non‐randomised studies of interventions, Outcome 8: Quality‐of‐life impairment (mental score): mean change in MSQOL‐54 mental composite score (1‐year follow‐up)
5.9
5.9. Analysis
Comparison 5: Non‐randomised studies of interventions, Outcome 9: Long‐term adverse effects: number of participants with neoplasms (10‐year range of follow‐up)
5.10
5.10. Analysis
Comparison 5: Non‐randomised studies of interventions, Outcome 10: Quality‐of‐life impairment (physical score): mean change in MSQOL‐54 physical composite score (1‐year follow‐up)
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References

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    1. Cavazzuti M, Merelli E, Tassone G, Mavilla L. Lesion load quantification in serial MR of early relapsing multiple sclerosis patients in azathioprine treatment. A retrospective study. European Neurology 1997;38(4):284-90. [DOI: 10.1159/000113395] - DOI - PubMed
Cendrowski 1971 {published data only}
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Ellison 1984 {published data only}
    1. Ellison GW, Myers LW, Mickey MR, Frane MV, Tourtellotte WW, Spina CA, et al. Therapeutic trials in multiple sclerosis: azathioprine. Annals of the New York Academy of Sciences 1984;436:361-5. [DOI: 10.1111/j.1749-6632.1984.tb14806.x] - DOI - PubMed
Lhermitte 1984 {published data only}
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Markovic‐Plese 2003 {published data only}
    1. Markovic-Plese S, Bielekova B, Kadom N, Leist TP, Martin R, Frank JA, et al. Longitudinal MRI study: the effects of azathioprine in MS patients refractory to interferon beta-1b. Neurology 2003;60(11):1849-51. [DOI: 10.1212/01.wnl.0000071218.34009.af] [PMID: ] - DOI - PubMed
Mertin 1982 {published data only}
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Patzold 1978 {published data only}
    1. Patzold U, Haller P, Haas J, Pocklington P, Deicher H. Treatment of multiple sclerosis with levamisole and azathioprine. Comparison of the effectiveness, of an 'immunostimulative' and 'immunosuppressive' treatment (author's translation) [Therapie der Multiplen Sklerose mit Levamisol und Azathioprin. Vergleich der Wirksamkeit einer "immunstimulierenden" und "immunsuppressiven" Behandlung]. Nervenarzt 1978;49(5):285-94. [PMID: ] - PubMed
Patzold 1982 {published data only}
    1. Patzold U, Hecker H, Pocklington P. Azathioprine in treatment of multiple sclerosis: final results of a controlled study of its effectiveness covering 115 patients. Journal of the Neurological Sciences 1982;54:377-94. [DOI: 10.1016/0022-510x(82)90201-5] - DOI - PubMed
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Ravnborg 2009 {published data only}
    1. Ravnborg M, Bendtzen K, Christensen O, Jensen PE, Hesse D, Tovey MG, et al. Treatment with azathioprine and cyclic methylprednisolone has little or no effect on bioactivity in anti-interferon beta antibody-positive patients with multiple sclerosis. Multiple Sclerosis 2009;15(3):323-8. [DOI: 10.1177/1352458508099476] - DOI - PubMed
Ring 1974 {published data only}
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Rosen 1979 {published data only}
    1. Rosen JA. Prolonged azathioprine treatment of non-remitting multiple sclerosis. Journal of Neurology, Neurosurgery and Psychiatry 1979;42:338-44. [DOI: 10.1136/jnnp.42.4.338] - DOI - PMC - PubMed
Steck 1990 {published data only}
    1. Steck AJ, Regli F, Ochsner F, Gauthier G. Cyclosporine versus azathioprine in the treatment of multiple sclerosis: 12-month clinical and immunological evaluation. European Neurology 1990;30:224-8. [DOI: 10.1159/000117351] - DOI - PubMed
Zeeberg 1985 {published data only}
    1. Zeeberg IE, Heltberg A, Fog T. Follow-up evaluation after at least two years' treatment with azathioprine in a double-blind trial. European Neurology 1985;24:435-6. [DOI: 10.1159/000115838] - DOI
Zeeberg 1986 {published data only}
    1. Zeeberg IE. Azathioprine assessment in progressive multiple sclerosis. Clinical aspects. In: Hommes OR, editors(s). Multiple Sclerosis Research in Europe. Lancaster, England: MTP Press, 1986:62-70. [DOI: 10.1007/978-94-009-4143-4_9] - DOI

References to studies awaiting assessment

Aimard 1978 {published data only}
    1. Aimard G, Confavreaux C, Trouillas P, Devic M. Treatment of multiple sclerosis by azathioprine. About 77 cases studied during 10 years (author's translation)] [L'azathioprine dans le traitement de la sclérose en plaques. Une expérience de 10 ans à propos de 77 malades]. Revue Neurologique 1978;134(3):215‐22. [PMID: ] - PubMed
Ciesielski 1974 {published data only}
    1. Ciesielski T, Burczyk-Popko I, Goralski H, Sypniewski J, Cendrowski W. Treatment of multiple sclerosis with azathioprine (Imuran) [Wyniki leczenie azatiopryna (imuranem) chorych na stwardnienie rozsiane]. Polski Tygodnik Lekarski 1974;29(3):101‐2. [PMID: ] - PubMed
Confavreux 1980 {published data only}
    1. Confavreux C, Aimard G, Devic M. Computerized analysis of 349 multiple sclerosis cases. Natural history of the disease. Evaluation of a continuous immunosuppressive therapeutic trial with azathioprine. Lyon Medical 1980;243(10):595-602. [EMBASE: L10061229]
Danielczyk 1973 {published data only}
    1. Danielczyk W. D penicillamine in the treatment of multiple sclerosis. Therapiewoche 1973;23(48):4704-10. [EMBASE: L4120570]
Ellison 1981 {published data only}
    1. Ellison GW, Myers LW, Shih WH. Immunologic aspects of azathioprine and steroid treatment of multiple sclerosis. Neurology 1981;31(4):147. [EMBASE: L11065456]
Frick 1971 {published data only}
    1. Frick E, Angstwurm H, Späth G. [Immunosuppressive therapy of multiple sclerosis. 1. Preliminary communication on the results of treatment with azathioprine and anti-lymphocytic globulin]. Munchener Medizinische Wochenschrift 1971;113(7):221-31. [PMID: ] - PubMed
Frick 1974a {published data only}
    1. Frick E, Angstwurm H, Strauss G. Immunsuppressive treatment of multiple sclerosis. 2. Critical review of general results (author's translation) [Immunsuppressive therapie der multiplen sklerose. 2. Kritischer bericht über allgemeine erfahrungen]. Munchener Medizinische Wochenschrift 1974;116(45):1987. [PMID: ] - PubMed
Frick 1974b {published data only}
    1. Frick E, Angstwurm H, Strauss G. Immunosuppressive treatment of multiple sclerosis. 3. Results of treatment with azathioprine and antilymphocytic globulin (author's translation) [Immunosuppressive therapie der multiplen sklerose. 3. Eigene behandlungsergebnisse mit azathioprin und antilymphozytenglobulin]. Munchener Medizinische Wochenschrift 1974;116(48):2105-12. [PMID: ] - PubMed
Frick 1977 {published data only}
    1. Frick E, Angstwurm H, Blomer R, Strauss G. Immunosuppressive treatment of multiple sclerosis. 4. Results of treatment with azathioprine and antilymphocyte globulin (author's translation) [Immunsuppressive therapie der multiplen sklerose. 4. Mitteilung: behandlungsergebnisse mit azathioprin und antilymphozytgenglobulin]. Munchener Medizinische Wochenschrift 1977;119(35):1111-4. [PMID: ] - PubMed
Gentile 1972 {published data only}
    1. Gentile A, Stella L. Preliminary clinical experiences obtained with immunological therapy of multiple sclerosis [Esperienze cliniche preliminari ottenute con una terapia "immunologica" nella sclerosi multipla]. Annali Sclavo 1972;14(6):726-32. [PMID: ] - PubMed
Ghezzi 1989 {published data only}
    1. Ghezzi A, Di Falco M, Locatelli C, Zaffaroni M, Caputo D, Marforio S, et al. Clinical controlled randomized trial of azathioprine in multiple sclerosis. In: Gonsette RE, Delmotte P, editors(s). Recent Advances in Multiple Sclerosis Therapy. Amsterdam: Elsevier, 1989:345–6. [CENTRAL: CN-00716237]
Göpel 1972 {published data only}
    1. Göpel W, Benkenstein H, Banzhaf M. [Immunosuppressive therapy of multiple sclerosis using cyclophosphamide and imuran. Report on 57 cases]. Das Deutsche Gesundheitswesen 1972;27(41):1955-61. [PMID: ] - PubMed
Handouk 2009 {published data only}
    1. Handouk Y, De Riso S, Perticaroli E, Danni M, Angeleri V, Provinciali L. Cancer risk in a MS population treated with immunosuppressants. Multiple Sclerosis 2009;15(9):S250. [EMBASE: L70100979]
Hervet 1974 {published data only}
    1. Hervet E, Barrat J, Darbois Y, Faguer C. Letter: Teratogenic effects of medications [Lettre: Effets tératogènes des médicaments]. Nouvelle Presse Medicale 1974;3(37):2419. [PMID: ] - PubMed
Hitzchke 1979 {published data only}
    1. Hitzchke B, Schumm N, Meyer-Rienecker H, Schroeter P. Efficacy and adverse effects of immunosuppressive therapy in diseases of the encephalomyelitis disseminata type (multiple sclerosis). Zentralblatt fur Allgemeine Pathologie und Pathologische Anatomie 1979;123(1):148-9. [EMBASE: L9213845]
Lhermitte 1984 {published data only}
    1. Lhermitte F, Marteau R, Roullet E, Saxcé H, Loridan M. [Prolonged treatment of multiple sclerosis with average doses of azathioprine. An evaluation of 15 years' experience]. Revue Neurologique 1984;140(10):553-8. [PMID: ] - PubMed
Schluep 1991 {published data only}
    1. Schluep M, Steck AJ, Despland PA, Regli F, Ochsner F, Berrut E, et al. Efficacy and tolerance of cyclosporin A in the treatment of multiple sclerosis [Efficacité et tolérance de la cyclosporine A dans le traitement de la sclérose en plaques]. Schweizerische Rundschau fur Medizin Praxis. 1991;80(24):670‐2. [PMID: ] - PubMed
Wilkerson 1975 {published data only}
    1. Wilkerson LD, Lisak RP, Zweiman B. Azathioprine therapy effects on antimyelin and other antibodies in multiple sclerosis. Federation Proceedings 1975;34(3):no. 4245. [EMBASE: L6027434]
Yankov 1980 {published data only}
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References to ongoing studies

EUDRACT 2006‐004937‐13 {published data only}
    1. EUDRACT 2006-004937-13. M.A.I.N. trial [Multicentee [sic] randomized controlled study of azathioprine versus iterferon beta in relapsing remitting multiple sclerosis]. www.clinicaltrialsregister.eu/ctr-search/trial/2006-004937-13/IT (first received 4 July 2007).
NCT03653273 {published data only}
    1. NCT03653273. Disease modifying therapies withdrawal in inactive secondary progressive multiple sclerosis patients older than 50 years (STOP-I-SEP). clinicaltrials.gov/ct2/show/NCT03653273 (first received 31 August 2018).
NCT04106830 {published data only}
    1. NCT04106830. Clinical and imaging patterns of neuroinflammation diseases in China (CLUE) [Prospective cohort study of clinical and imaging patterns of neuroinflammation diseases (CLUE)]. clinicaltrials.gov/ct2/show/NCT04106830 (first received 27 September 2019).

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