Longitudinal Characterization of Autoantibodies to the Thyrotropin Receptor (TRAb) During Alemtuzumab Therapy: Evidence that TRAb May Precede Thyroid Dysfunction by Many Years.

BACKGROUND: Thyroid autoimmunity, especially Graves' disease or hypothyroidism with positive autoantibodies (TRAb) to the thyrotropin receptor (TSHR), occurs in 30-40% of patients with relapsing multiple sclerosis following treatment with alemtuzumab (ALTZ). ALTZ therapy therefore provides a unique opportunity to study the evolution of TRAb prior to clinical presentation. TRAb can stimulate (TSAb), block (TBAb), or not affect ("neutral") the TSHR function, causing hyperthyroidism, hypothyroidism, or euthyroidism, respectively. METHODS: A longitudinal retrospective analysis was conducted of TRAb bioactivity over a period of nine years in 45 multiple sclerosis patients receiving ALTZ using available stored serum. Of these 45 patients, 31 developed thyroid dysfunction (TD) and 14 remained euthyroid despite being followed for a minimum of five years (NO-TD). The presence of TRAb was evaluated at standardized time points: (i) before ALTZ, (ii) latest time available following ALTZ and before TD onset, and (iii) following ALTZ during/after TD onset. Serum TRAb were detected by published in-house assays (ihTRAb): flow cytometry detecting any TSHR-binding TRAb, and luciferase bioassays detecting TSAb/TBAb bioactivity. Purified immunoglobulin G was used to verify TSAb/TBAb in selected hypothyroid cases. Standard clinical automated measurements of TRAb, antithyroid peroxidase autoantibodies (TPOAb), thyrotropin, free thyroxine, and free triiodothyronine were also collected. RESULTS: Before ALTZ, combined ihTRAb (positive with flow cytometry and/or luciferase bioassay) but not automated TRAb were present in 5/16 (31.2%) TD versus 0/14 (0%) NO-TD (p = 0.017). Detectable ihTRAb preceded TD development in 9/28 (32.1%) and by a median of 1.2 years (range 28 days-7.3 years). Combination testing of ihTRAb and TPOAb at baseline predicted 20% of subsequent cases of hyperthyroidism and 83% of hypothyroidism. CONCLUSIONS: Evidence is presented that TRAb measured with custom-made assays can be detected prior to any change in thyroid function in up to a third of cases of ALTZ-related TD. Furthermore, the presence of ihTRAb prior to ALTZ treatment was strongly predictive of subsequent TD. The findings suggest that a period of affinity maturation of TRAb may precede clinical disease onset in some cases. Combined testing of TPOAb and ihTRAb may increase the ability to predict those who will develop TD following ALTZ.

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.

Annual rates of arterial thromboembolic events in medicare neovascular age-related macular degeneration patients.

PURPOSE: Smoking, age, and nutrition have been associated with the development of neovascular age-related macular degeneration (AMD) and can increase the risk of arterial thromboembolic events (ATEs). This study assesses annual rates of ATEs in new-onset neovascular AMD patients compared with matched controls. DESIGN: Retrospective study. PARTICIPANTS: New-onset neovascular AMD patients and age-, race-, gender-, and database length-matched controls from the 5% Medicare database. METHODS: We conducted a retrospective analysis of the 5% Medicare database from 2001 to 2003. New-onset neovascular AMD patients were included if they were > or =65 years old, had 2 diagnoses of neovascular AMD, and had at least 1 year of data before the first diagnosis of AMD within the dataset. A control group was constructed in a 3:1 ratio from those without a diagnosis of a major eye disorder and matched by age, race, gender, and length of data. Annual prevalence rates were determined for myocardial infarctions (MIs) and ischemic cerebral vascular accidents (CVAs). MAIN OUTCOME MEASURES: Rates of MIs and ischemic CVAs in new-onset neovascular AMD patients and matched controls from 2001 to 2003. RESULTS: There were 15771 new-onset neovascular AMD patients identified and matched with 46 408 controls. Average age was 80.5 years, with 64% > or =80; 65% were female; and 95.9% were white. Inpatient MI rates for neovascular AMD patients and controls were 2.2% and 2.2%, respectively (P = 0.74). Inpatient ischemic CVA rates for neovascular AMD patients and controls were 3.5% and 3.6%, respectively (P = 0.59). Myocardial infarction rates and ischemic CVA rates for both groups increased with age. Subgroups of patients with comorbidities known to be risk factors for ATEs (i.e., hypertension, hyperlipidemia, diabetes, and arrhythmias) had a higher rate of events. Patients with previous ATEs were also at a higher risk of subsequent events, at 7.4% for inpatient MI and 35.1% for inpatient ischemic stroke. CONCLUSION: Despite the shared risk factors associated with neovascular AMD and ATEs, Medicare beneficiaries with neovascular AMD had a rate of ATEs similar to that of matched controls. Rates of ATEs increased in patients with comorbidities and for patients with previous events.