Peter Alping

Abstract

Multiple Sclerosis (MS) is a chronic autoimmune disorder of the central nervous system, characterized by the accumulation of demyelinating inflammatory lesions. Milder cases exist, but most patients eventually develop severe neurological symptoms and disability. However, this dire prognosis is likely to change with the increasing availability of modern, highly effective disease-modifying therapies (DMTs).

The rapid development of new therapies for MS has resulted in a quickly changing treatment landscape. Recently, the use of off-label rituximab has become the most used DMT for MS in Sweden. In addition to the purely pharmacological therapies, autologous haematopoietic stem cell transplantation (AHSCT) has emerged as an option for patients with severe disease.

The aim of this PhD project was to investigate risk-benefit aspects of DMTs for MS with a special focus on rituximab.

Study I was a cohort study comparing the effectiveness of rituximab and fingolimod in patients switching from natalizumab due to JC-virus positivity. In 256 patients, fewer relapses and contrast-enhancing lesions were observed in the rituximab group, within the first 1.5 years of the therapy switch. The rituximab group also reported fewer adverse events and better drug survival, compared with fingolimod. Rituximab appears to be the superior choice in this patient population and likely for highly active MS in general.

Study II was a validation of the Swedish MS Register, the main data source for MS research in Sweden. Among 3012 patients, data on treatment and Expanded Disability Status Scale (EDSS) was reasonably complete. Observations of Magnetic Resonance Imaging (MRI) were often missing or incomplete, but could partly be recovered from the medical records. Missingness varied by MS clinic and treatment. The proportion of missing was higher for the older injectable therapies, compared with newer DMTs, which has implications for comparative studies.

Study III was a cohort study assessing cancer risk in patients treated with rituximab, natalizumab, or fingolimod. Among 7477 therapy starts, we identified 78 cancers. After controlling for possible confounding, we found an increased risk of cancer for the fingolimod group, compared with both the rituximab group and the general population. It was not possible to assess if any specific type of cancer was driving this difference. No increased risk was found for rituximab or natalizumab, compared with the general population. These findings were in line with previous studies of rituximab in rheumatoid arthritis, but interestingly with a lower risk of breast cancer on rituximab than in the trial programme for ocrelizumab.

Study IV was a cohort study assessing safety outcomes for patients treated with the induction therapies AHSCT or alemtuzumab. Among 271 patients, one death occurred in the AHSCT group and four deaths occurred in the alemtuzumab group. The mortality rate for AHSCT was lower in our study than in most previous reports. AHSCT was associated with an increased risk of infection that diminished a few months after treatment. The incidence of thyroid disease with alemtuzumab was higher in our study than previously reported in clinical trials, but in line with other observational data. The rate of starting a new therapy was lower with both AHSCT and alemtuzumab, compared with conventional MS therapies.

Study V was a cohort study assessing cost-effectiveness for patients treated with rituximab, natalizumab, fingolimod, or dimethyl fumarate. Among 5924 therapy starts, rituximab was superior to the other therapies, resulting in both lower overall healthcare costs and fewer relapses. Mean cost savings per patient over five years were €34 000–€66 000 and mean number of prevented relapses 0.12–0.21, which translates to total cost savings of €307 000 000 and 1063 prevented relapses, over five years. The cost savings and lower number of relapses with rituximab were possible without any increase in other individual healthcare costs, such as prescription drugs, specialized outpatient visits, or inpatient care.

In summary, the data in the Swedish MS Register was of generally good quality, especially for data relating to therapy use, making the register a good resource for pharmacoepidemiologic studies. We found that AHSCT is an effective and safe inductiontype treatment for MS, with treatment-related mortality similar to other DMTs. However, there was an increased risk of infection around the time of treatment and a more longlasting risk of autoimmune thyroid disease. We found rituximab to be a cost-effective, safe, and well tolerated treatment for MS, resulting in fewer clinical relapses, fewer contrast-enhancing lesions on MRI, better drug survival, and no increased risk of cancer. Rituximab should be considered as an alternative first-line therapy for most MS patients with active, non-progressive disease. AHSCT should be considered for younger patients without severe disabilities, with clinical worsening and inflammatory signs not adequately controlled by regular therapies. Rituximab also appears to be the most attractive treatment option for MS patients in low-resource settings, where MS-approved alternatives are might be unavailable due to their high costs.