The Cochrane Multiple Sclerosis and Rare Diseases of the CNS Group, in collaboration with the Multiple Sclerosis International Federation (MSIF), has contributed to the development of newly published evidence-based recommendations on the use of rituximab for multiple sclerosis (MS). These recommendations draw heavily on the Cochrane systematic review of rituximab for MS (Rituximab for people with multiple sclerosis) and were developed using the GRADE Evidence-to-Decision (EtD) Framework.

Access the full recommendations here: Recommendations for the use of off-label rituximab for the treatment of multiple sclerosis in low-resource settings 

Around the world, access to licensed MS DMTs remains uneven. Many health systems face challenges related to affordability, availability, and restrictive reimbursement policies, with the result that a substantial number of people with MS are unable to receive MS licensed therapies. Off-label treatments therefore play a prominent role in clinical practice in many countries, particularly those with limited health resources. Rituximab is one such therapy: although not licensed for MS, it has been widely used for more than two decades for autoimmune and malignant conditions and is the most commonly used off-label DMT for MS globally.

The need to provide transparent, evidence-informed guidance for settings where treatment choices are limited was the primary motivation for MSIF’s guideline initiative.

The Cochrane MS and Rare Diseases of teh CNS review identified low-certainty evidence for the benefits and harms of rituximab in MS, largely because few randomized controlled trials are available, sample sizes are small, and much of the evidence originates from observational comparative studies. Despite these limitations, the accumulated data consistently suggest that rituximab reduces relapse rates, improves MRI outcomes, and may slow disability progression, with effects broadly similar to those of licensed therapies.

The MSIF panel issued seven research questions and recommendations, each framed as conditional because of the very low certainty of the underlying evidence. 

For people with relapsing forms of MS, rituximab was suggested over no treatment both for those who were treatment naive and for those switching from another DMT. Rituximab was also considered an appropriate alternative to several licensed DMTs when access to those therapies is limited or absent. The panel judged that rituximab appears to offer larger benefits relative to interferon and glatiramer acetate, and moderate benefits compared with natalizumab and dimethyl fumarate, drawing on indirect comparisons.

For people with active forms of progressive MS, rituximab was suggested over no treatment for both treatment-naive patients and those switching from another DMT. However, the panel did not issue a recommendation comparing rituximab with other DMTs in treatment-naive progressive MS, due to a lack of sufficient evidence. Throughout, the panel emphasised that clinical decision-making must consider disease activity, treatment goals, individual risk factors, and the availability of alternatives.

Rituximab has the potential to help reduce inequities in access to MS treatment. Rituximab is off-patent, and multiple biosimilars are available at comparatively low cost. Because it is used for several other conditions, many healthcare systems already possess the necessary supply chains, clinical expertise, and infrastructure to administer the drug safely. Its episodic dosing every six to twelve months may also present logistical advantages in settings with limited infusion capacity or where frequent monitoring is challenging. The guideline therefore suggests that rituximab could represent a feasible and cost-effective option for many low-resource healthcare systems, particularly where no licensed monoclonal antibody therapies for MS are reimbursed or available.

Significant knowledge gaps remain, particularly regarding long-term disability outcomes, cognitive effects, optimal dosing strategies, and treatment in people with advanced disability. Many ongoing trials are expected to provide more definitive evidence in the coming years. High-quality randomized studies conducted in diverse global settings will be essential for strengthening future recommendations.

With thanks to all the members of the MS International Federation (MSIF) Off-Label Taskforce Nick Rijke, Bassem Yamout, Deanna Saylor, Francesco Nonino, Graziella Filippini, Thomas Piggott, Joanna Laurson-Doube, Laura Amato, Tapas Kumar Banerjee, Kathy Costello, Cinzia Del Giovane, Nicola De Stefano, Najoua ABKARI, Gavin Giovannoni, Hans-Peter Prof. Hartung, Aukje Mantel-Teeuwisse, Andrea Prato, Mohammad Ali Aahraian, Fatima Suleman, Simona Vecchi, Maya Zeineddine, Shanthi Viswanathan, Holger Schünemann.