Azathioprine versus Beta Interferons for Relapsing-Remitting Multiple Sclerosis: A Multicentre Randomized Non-Inferiority Trial

Abstract

For almost three decades in many countries azathioprine has been used to treat relapsing-remitting multiple sclerosis. However its efficacy was usually considered marginal and following approval of β interferons for this indication it was no longer recommended as first line treatment, even if presently no conclusive direct β interferon-azathioprine comparison exists. To compare azathioprine efficacy versus the currently available β interferons in relapsing-remitting multiple sclerosis, a multicenter, randomized, controlled, single-blinded, non-inferiority trial was conducted in 30 Italian multiple sclerosis centers. Eligible patients (relapsing-remitting course; ≥2 relapses in the last 2 years) were randomly assigned to azathioprine or β interferons. The primary outcome was annualized relapse rate ratio (RR) over 2 years. Key secondary outcome was number of new brain MRI lesions. Patients (n = 150) were randomized in 2 groups (77 azathioprine, 73 β interferons). At 2 years, clinical evaluation was completed in 127 patients (62 azathioprine, 65 β interferons). Annualized relapse rate was 0.26 (95% Confidence Interval, CI, 0.19–0.37) in the azathioprine and 0.39 (95% CI 0.30–0.51) in the interferon group. Non-inferiority analysis showed that azathioprine was at least as effective as β interferons (relapse RRAZA/IFN 0.67, one-sided 95% CI 0.96; p<0.01). MRI outcomes were analyzed in 97 patients (50 azathioprine and 47 β interferons). Annualized new T2 lesion rate was 0.76 (95% CI 0.61–0.95) in the azathioprine and 0.69 (95% CI 0.54–0.88) in the interferon group. Treatment discontinuations due to adverse events were higher (20.3% vs. 7.8%, p = 0.03) in the azathioprine than in the interferon group, and concentrated within the first months of treatment, whereas in the interferon group discontinuations occurred mainly during the second year.The results of this study indicate that efficacy of azathioprine is not inferior to that of β interferons for patients with relapsing-remitting multiple sclerosis. Considering also the convenience of the oral administration, and the low cost for health service providers, azathioprine may represent an alternative to interferon treatment, while the different side effect profiles of both medications have to be taken into account.Trial RegistrationEudraCT 2006-004937-13

Long‐term evolution of multiple sclerosis disability in the treatment era

“…[22][23][24] A noninferiority clinical trial showed that azathioprine had comparable efficacy to IFN therapy. 22 There are fewer available efficacy data for mycophenolate mofetil; however, we estimated the impact of this antimetabolite based on open-label observations 23 as well as that of teriflunomide, which has a related mechanism of action, and is an FDA-approved MS therapy with efficacy similar to that of IFN beta-1a. 25 The second tier was referred to as high-potency therapy and included natalizumab, rituximab, mitoxantrone, and cyclophosphamide.…”

Oral drugs in multiple sclerosis therapy: an overview and a critical appraisal

“…Annualized new T2 lesion rate was 0.76 (95% CI: 0.61-0.95) in the azathioprine and 0.69 (95% CI: 0.54-0.88) in the IFN-b group. Treatment discontinuations due to AEs were higher (20.3 vs 7.8%, p = 0.03) in the azathioprine than in the interferon group, and concentrated within the first months of treatment [166]. These data shed new lights on an old oral drug as azathioprine that requires closer clinical monitoring during the first year to titrate the dose to the lymphocyte count, and to manage the early gastrointestinal issues, monitoring for the small percentage of patients who cannot tolerate the drug due to genetic variations.…”

“…However, recently, new findings showed the possibility to consider azathioprine as an inexpensive treatment option for RRMS. A randomized single-blinded multicenter CT suggested that azathioprine is at least as effective in reducing both relapses (the primary end point) and new brain lesions (the main secondary outcome measure) as IFN-b1a (Avonex, Biogen Idec; Rebif, Merck Serono) or IFN-b1b (Betaferon, Bayer) [166]. One hundred and fifty RRMS patients were randomized in two groups (77 azathioprine, 73 IFN-b).…”

Current immunotherapies for multiple sclerosis and neuromyelitis optica spectrum disorders: the similarities and differences

“…Anti-CD20, attacks B-cells and plasmoblasts NMOSD [159] , RRMS [160,161] , PPMS [162] Azathioprine 2-3 mg/(kg•day) , po Inhibits purine nucleotide synthesis; activates mitochondrial apoptotic pathway; activated T-cell apoptosis [163,164] NMOSD [159,165,166] , RRMS [167] Mycophenolate mofetil CellCept 1000-3000 mg/day, po Blocks guanine nucleotide production; inhibits lymphocyte proliferation [168,169] NMOSD [170][171][172] DMD: disease-modifying drug; IFN: interferon; sc: subcutaneous; iv: intravenous; im: intramuscular; po: per os; RRMS: relapsingremitting multiple sclerosis; SPMS: secondary progressive multiple sclerosis; PPMS: primary progressive multiple sclerosis; MHC: major histocompatibility complex; NMOSD: neuromyelitis optica spectrum disorders 14 mg, 20.2% DMF [135] Placebo, GA and mycophenolate mofetil, and is probably the best choice at present [184][185][186][187] . Rituximab is a human-mouse chimeric monoclonal antibody against CD20, which is a regulatory factor for the early activation and differentiation of B-cells.…”