Contemporary study of multiple sclerosis disability in South East Wales.

BACKGROUND: A contemporary understanding of disability evolution in multiple sclerosis (MS) is an essential tool for individual disease management and planning of interventional studies. We have used prospectively collected longitudinal data to analyse disability progression and variation in a British MS cohort. METHODS: Cox proportional hazards regression was used to estimate hazard of Expanded Disability Status Scale (EDSS) 4.0 and 6.0. A continuous Markov model was used to estimate transitional probabilities for individual EDSS scores. Models were adjusted for age at MS onset, sex and disease-modifying treatments (DMTs) exposure. RESULTS: 2135 patients were included (1487 (70%) female, 1922 (89%) relapsing onset). 865 (41%) had used DMTs. Median time to EDSS 4.0 and 6.0 was 18.2 years (95% CI 16.3 to 20.2) and 22.1 years (95% CI 20.5 to 24.5). In the Markov model, the median time spent at EDSS scores of <6 (0.40-0.98 year) was shorter than the time spent at EDSS scores of ≥6 (0.87-4.11 year). Hazard of change in EDSS was greatest at EDSS scores <6 (HR for increasing EDSS: 1.02-1.33; decreasing EDSS: 0.34-1.27) compared with EDSS scores ≥6 (HR for increasing EDSS: 0.08-0.61; decreasing EDSS: 0.18-0.54). CONCLUSIONS: These data provide a detailed contemporary model of disability outcomes in a representative population-based MS cohort. They support a trend of increasing time to disability milestones compared with historical reference populations, and document disability variation with the use of transitional matrices. In addition, they provide essential information for patient counselling, clinical trial design, service planning and offer a comparative baseline for assessment of therapeutic interventions.

Sarcoidosis following alemtuzumab treatment for multiple sclerosis.

Despite proven efficacy of alemtuzumab in multiple sclerosis (MS), approximately 50% of individuals will develop a new autoimmune disease following treatment. To date, these have largely been antibody mediated and organ specific (primarily affecting the thyroid gland). In a retrospective case series of 187 patients from two UK specialist centres (Cardiff and Cambridge) followed up for a median of 10 years, we report three (1.6%) cases of sarcoidosis following alemtuzumab treatment of MS. This report increases the spectrum of auto-inflammatory disease following alemtuzumab and should be considered by clinicians when using this therapeutic agent for MS.

Alemtuzumab-induced remission of multiple sclerosis-associated uveitis.

PURPOSE: The purpose of the study was to report a case of multiple sclerosis (MS)-associated uveitis refractory to conventional immunosuppressants, with subsequent remission following treatment with alemtuzumab. METHODS: Case report Patient was treated with intravenous alemtuzumab, a lymphocyte depleting anti-CD52 monoclonal antibody that has recently been approved for use in relapsing MS. RESULTS: A 17-year-old female presented with bilateral optic neuritis and subsequently bilateral intermediate uveitis and secondary macular oedema. She was diagnosed with active relapsing MS for which she received treatment with alemtuzumab. The intraocular inflammation previously refractory to conventional immunosuppressants responded to alemtuzumab, inducing remission. CONCLUSIONS: To our knowledge, this is the first such report of alemtuzumab treatment in MS-associated ocular inflammatory disease and may demonstrate a potential utility for this drug in related conditions.

Targeted suppression of autoreactive CD8+ T-cell activation using blocking anti-CD8 antibodies.

CD8+ T-cells play a role in the pathogenesis of autoimmune diseases such as multiple sclerosis and type 1 diabetes. However, drugs that target the entire CD8+ T-cell population are not desirable because the associated lack of specificity can lead to unwanted consequences, most notably an enhanced susceptibility to infection. Here, we show that autoreactive CD8+ T-cells are highly dependent on CD8 for ligand-induced activation via the T-cell receptor (TCR). In contrast, pathogen-specific CD8+ T-cells are relatively CD8-independent. These generic differences relate to an intrinsic dichotomy that segregates self-derived and exogenous antigen-specific TCRs according to the monomeric interaction affinity with cognate peptide-major histocompatibility complex class I (pMHCI). As a consequence, "blocking" anti-CD8 antibodies can suppress autoreactive CD8+ T-cell activation in a relatively selective manner. These findings provide a rational basis for the development and in vivo assessment of novel therapeutic strategies that preferentially target disease-relevant autoimmune responses within the CD8+ T-cell compartment.

Alemtuzumab for Multiple Sclerosis.

Alemtuzumab is a humanised anti-CD52 monoclonal antibody approved for use in active, relapsing multiple sclerosis (MS). Administration results in a rapid depletion of circulating lymphocytes with a subsequent beneficial immune reconstitution. Early open-label experience and recent clinical trials have demonstrated a dramatic effect on relapse rates as well as a positive effect on radiological disease outcomes and disability measures. Despite a mechanism of action that results in profound lymphopaenia, opportunistic infections are rarely seen and no excess association with malignancy has been identified. However, acquired autoimmune disease (AID) is a common adverse event following treatment, necessitating rigorous monitoring in order to facilitate prompt detection and management. Despite this issue, a unique dosing schedule and durability of effect make alemtuzumab a welcome addition to currently available treatment options for MS.