Fady Joseph

CSF oligoclonal band status informs prognosis in multiple sclerosis: a case control study of 100 patients

Objective: Oligoclonal band (OCB) negative multiple sclerosis (MS) is well recognised but uncommon, studied in only a few usually small case series. These reached differing conclusions on whether its clinical features or course differ from OCB positive disease. The study hypothesis was that a definitive study would not only be of clinical and prognostic value but also potentially offer information about the possible role of CSF oligoclonal immunoglobulins in MS disease processes. Methods: A collaborative cohort of well documented patients in southwest England and south Wales was used to identify and analyse a large group of patients with OCB negative MS and make comparisons with age and sex matched OCB positive controls. Results: An approximate minimum 3% of patients with MS were OCB negative. They were significantly more likely to exhibit neurological or systemic clinical features atypical of MS (headaches, neuropsychiatric features and skin changes). Non-specific MRI, blood and (other) CSF abnormalities were also more common, emphasising the need for continued diagnostic vigilance, although the incautious application of McDonald diagnostic criteria in OCB negative cases renders categorisation as “definite” MS more likely. Studying the uniformly assessed Cardiff group (69 patients), we found the prognosis for neurological disability was significantly better for OCB negative cases. The age adjusted hazard ratio for OCB negative and OCB positive subjects to reach Disability Scale Status (DSS) 4 and DSS 6 was, respectively, 0.60 (95% CI 0.39 to 0.93; p = 0.02) and 0.51 (95% CI 0.27 to 0.94; p = 0.03). Conclusion: There are clear clinical differences between OCB negative and OCB positive MS, in particular a better prognosis for disability. This is consistent with a secondary but nonetheless contributory role in disease process for intrathecally synthesised immunoglobulins.

Impact of the 2017 revisions to McDonald criteria on the diagnosis of Multiple Sclerosis

Revisions to diagnostic criteria for multiple sclerosis (MS) in 2017 allowed CSF-specific oligoclonal bands (OCBs) to confirm diagnosis in individuals with clinically isolated syndrome (CIS) and evidence of dissemination-in-space (DIS).1 We examined the impact that this change had on reaching a diagnosis of MS, when applied retrospectively to a population-based, real-life cohort of patients with CIS.

Multiple sclerosis: long‐term outcomes in ethnic minorities. Analysis of a UK population‐based registry

Multiple sclerosis (MS) is most frequent in Caucasian populations. However, studies of MS in other ethnic groups may offer unique insights into genetic and environmental influences on the disease, and data on long‐term outcomes in these patients is limited. In this work clinical features and time to disability milestones were investigated in ethnic minority (EM) patients with MS in a UK population and comparisons were made to a Caucasian cohort from the same region.

The antiphospholipid syndrome and its ‘non-criteria’ manifestations

The antiphospholipid syndrome is characterised by thrombotic and/or recurrent fetal loss/pregnancy morbidity associated with persistent antiphospholipid antibodies, namely lupus anticoagulant, anticardiolipin antibodies or anti-s2 glycoprotein-1 antibodies. It is defined as primary when occurring without any underlying autoimmune disorder or secondary when associated with chronic inflammatory conditions, such as systemic lupus erythematosus, Sjogren’s syndrome and rheumatoid arthritis. Although persistent antiphospholipid antibodies are associated with many other clinical manifestations, these are not considered diagnostic for the antiphospholipid syndrome. The most commonly associated neurological disorders are stroke, transient ischaemic attacks and migraine, but also sometimes epilepsy, transverse myelitis, multiple sclerosis-like presentations, ocular symptoms, Guillain-Barre syndrome, cognitive impairment, dementia and very rarely chorea. Neurologists frequently see patients who test positive for antiphospholipid antibody or lupus anticoagulant. These might be only mildly elevated, present transiently or have no discernible clinical relationship, and we therefore often appropriately dismiss them. Indeed, up to 5% of the normal population test positive for these antibodies. However, when significantly elevated and clinically relevant, they …

A contemporary study of mortality in the multiple sclerosis population of south east Wales

BACKGROUND Mortality studies in multiple sclerosis (MS) are valuable to identify changing disease patterns and inform clinical management. This study examines mortality in a British MS cohort. METHODS Patients were selected from the southeast Wales MS registry. Hazard of death was analysed using Cox proportional hazards regression, adjusted for onset age, annualised relapse rate, initial disease course, time to EDSS 4.0, sex, socioeconomic status, and onset year. Age- and sex-stratified standardised mortality ratios (SMRs) were calculated by EDSS scores. RESULTS Median time from MS diagnosis to death was 35.5 years and median age 73.9. Older onset age (hazard ratio [HR] 1.05, 95% confidence interval 1.03-1.06) was associated with increased hazard of death. Primary progressive course was associated with increased hazard of death in women (HR 2.04, 1.15-3.63) but not men (HR 1.23, 0.61-2.47). Slow time to EDSS 4.0 (HR 0.41, 0.28-0.60) and high socioeconomic status (HR 0.54, 0.37-0.79) were associated with reduced hazard of death. SMR increased from EDSS 6.0 (3.86, 2.63-5.47) but more substantially at EDSS 8.0 (22.17, 18.20-26.75). CONCLUSIONS Risk of death in MS varies substantially with degree of disability. This has important implications for clinical management and health economic modelling.

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.

How common is truly benign MS in a UK population

Objectives The prevalence and definition of benign multiple sclerosis (BMS) remain controversial. Most definitions are based on the Expanded Disability Status Scale (EDSS), not encompassing the wider impact of disease. The explanation for favourable outcomes remains unclear. We aim to provide a detailed characterisation of patients with low EDSS scores at long disease durations. Methods We screened a population-based registry containing 3062 people with MS to identify individuals with unlimited walking ability at disease durations >15 years. A representative cohort underwent detailed clinical assessment and classified as having BMS according to EDSS score <3, no significant fatigue, mood disturbance, cognitive impairment or disrupted employment, and had not received a disease-modifying therapy. We determined patient-reported perceptions of MS status and made comparisons with EDSS-based definitions. Results Of 1049 patients with disease duration of >15 years, 200 (19.1%) had most recent EDSS score <4.0. Detailed contemporary clinical assessment of a representative sample of 60 of these patients revealed 48 (80%) had an EDSS score of <4.0, 35 (58%) <3.0 and 16 (27%) <2.0. Only nine (15%) fulfilled our criteria for BMS; impaired cognition (57%) and effects on employment (52%) the most common causes for exclusion. Meanwhile, 33/60 (69%) patients considered their disease benign. Population frequency for BMS was estimated at 2.9% (95% CI 2.0 to 4.1). Conclusions Comprehensive assessment reveals a small minority of people with MS who appear genuinely benign after 15 years. Study of such individuals may uncover insights about disease pathogenesis. However, discrepancy between patient perception and clinician perception of BMS undermines use of the term ‘benign’ in clinical settings.

PO158 Sarcoidosis following alemtuzumab treatment for multiple sclerosis

Alemtuzumab, a licensed treatment for relapsing multiple sclerosis (MS) has proven efficacy in reducing relapse rates and improving disability outcomes. However, despite these beneficial effects, approximately 50% of patients develop secondary autoimmune disease (AID). The constellation of AIDs reported thus far encompasses Th2, B cell/antibody-driven pathologies including thyroid autoimmunity, idiopathic thrombocytopenic purpura and Goodpasture’s syndrome. In contrast to this, we present two patients with MS treated with alemtuzumab whom subsequently developed systemic sarcoidosis, a Th1 mediated disease. The first case presented with chest pain and shortness of breath 8 years after the initial infusion of alemtuzumab with computed tomography (CT) of the thorax demonstrating widespread lymphadenopathy and peri-bronchovascular nodularity. Biopsy of a cervical lymph node demonstrated non-caseating granulomas with the changes considered consistent with sarcoidosis. Four years after initial infusion, the second case was found to have incidental right-sided hilar lymphadenopathy following routine Xray with CT demonstrating widespread lymphadenopathy. Subsequent sub-carinal lymph node core biopsy demonstrated granulomatous inflammation in association with a raised serum ACE and a diagnosis of sarcoidosis was made. To our knowledge, these are the first reported cases of Th1-cell mediated secondary autoimmunity following alemtuzumab for MS and we speculate on the possible immunological mechanisms to account for this.

0924 Tipping the balance

Alemtuzumab, a licensed treatment for relapsing multiple sclerosis (MS) has proven efficacy in reducing relapse rates and improving disability outcomes. However, despite these beneficial effects, approximately 50% of patients develop secondary autoimmune disease (AID). The constellation of AIDs reported thus far encompasses B cell/antibody-driven pathologies including thyroid autoimmunity, idiopathic thrombocytopenic purpura and Goodpasture’s syndrome. In contrast to this, we present two patients with MS treated with alemtuzumab whom subsequently developed systemic sarcoidosis, a T-cell mediated disease. The first case presented with chest pain and shortness of breath 8 years after the initial infusion of alemtuzumab with computed tomography (CT) of the thorax demonstrating widespread lymphadenopathy and peri-bronchovascular nodularity. Biopsy of a cervical lymph node demonstrated non-caseating granulomas with the changes considered consistent with sarcoidosis. Four years after initial infusion, the second case was found to have incidental right-sided hilar lymphadenopathy following routine Xray with CT demonstrating widespread lymphadenopathy. Subsequent sub-carinal lymph node core biopsy demonstrated granulomatous inflammation in association with a raised serum ACE and a diagnosis of sarcoidosis was made. To our knowledge, these are the first reported cases of T-cell mediated secondary autoimmunity following alemtuzumab for MS and we speculate on the possible immunological mechanisms to account for this.