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Design: The design of the study was to investigate the prevalence of the following: 1) premature ovarian failure (POF) in patients with autoimmune Addison's disease (AD); 2) steroid-producing cell antibodies (StCA) and steroidogenic enzymes (17α-hydroxylase autoantibodies and P450 side-chain cleavage enzyme autoantibodies) in patients with or without POF; and 3) the value of these autoantibodies to predict POF.Patients: The study included 258 women: 163 with autoimmune polyendocrine syndrome type 2 (APS-2), 49 with APS-1, 18 with APS-4, and 28 with isolated AD.Methods: StCA were measured by an immunofluorescence technique and 17α-hydroxylase autoantibodies and P450 side-chain cleavage enzyme autoantibodies by immunoprecipitation assays.Results: Fifty-two of 258 women with AD (20.2%) had POF. POF was diagnosed in 20 of 49 (40.8%) with APS-1, six of 18 (33.3%) with APS-4, 26 of 163 (16%) with APS-2, and none of 28 with isolated AD. In patients with APS-1 and APS-4, POF developed after AD, whereas it preceded AD in patients with APS-2. StCA were detected in 31 of 43 with POF (72%) and 51 of 198 without POF (25.7%). StCA were present in 22 of 38 with APS-1 (57.9%) (11 of 13 with POF); in five of 13 with APS-4 (38.5%) (three of four with POF); in 53 of 162 with APS-2 (32.7%) (17 of 26 with POF), and in one of 28 isolated AD patients (3.6%). Twelve of 13 patients with POF with a duration less than 5 yr (92.3%) and 18 of 25 with duration longer than 5 yr (72%) were StCA positive. Twenty-eight of 31 with POF (90.3%) were positive for at least one steroidogenic antibody. Forty-one women with AD less than 40 yr were followed up for a mean period of 9 yr. Eight of 21 women (38%) positive or seroconverted for steroidogenic autoantibodies developed POF at a mean age of 23 yr (six with APS-1, one with APS-2, and one with APS-4), and none of the 20 patients negative for steroidogenic autoantibodies developed POF.Conclusions: This study indicates that AD is frequently associated with POF and that steroidogenic antibodies are markers of patients with POF. Steroidogenic autoantibodies are predictive markers of POF in patients with AD. [ABSTRACT FROM AUTHOR]

Background: Fatigue is frequent in people with multiple sclerosis (pwMS) impacting physical and cognitive functions. Lower aerobic capacity and regional thalamic volume may be involved in the pathophysiology of fatigue in pwMS., Objectives: To identify associations between thalamic nuclei volumes, aerobic capacity and fatigue and to investigate whether the influence of aerobic capacity on fatigue in pwMS is mediated by thalamic integrity., Methods: Eighty-three pwMS underwent a clinical evaluation with assessment of fatigue (Modified Fatigue Impact Scale [MFIS]), including physical (pMFIS) and cognitive (cMFIS) components, and peak of oxygen uptake (VO2peak). PwMS and 63 sex- and age-matched healthy controls (HC) underwent a 3 T brain MRI to quantify volume of the whole thalamus and its nuclei., Results: Compared to HC, pwMS showed higher global MFIS, pMFIS and cMFIS scores, and lower VO2peak and thalamic volumes (p < 0.001). In pwMS, higher VO2peak was significantly associated with lower MFIS and pMFIS scores (r value = - 0.326 and - 0.356; pFDR ≤ 0.046) and higher laterodorsal thalamic nucleus (Dor) cluster volume (r value = 0.300; pFDR = 0.047). Moreover, lower Dor thalamic cluster volume was significantly associated with higher MFIS, pMFIS and cMFIS scores (r value range = - 0.305; - 0.293; pFDR ≤ 0.049). The volume of Dor thalamic cluster partially mediated the positive effects of VO2peak on both MFIS and cMFIS, with relative indirect effects of 21% and 32% respectively. No mediation was found for pMFIS., Conclusions: Higher VO2peak is associated with lower fatigue in pwMS, likely acting on Dor thalamic cluster volume integrity. Such an effect might be different according to the type of fatigue (cognitive or physical)., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Background: The hippocampus is a clinically relevant region where neurogenesis and neuroplasticity occur throughout the whole lifespan. Neuroinflammation and cardiorespiratory fitness (CRF) may influence hippocampal integrity by modulating the processes promoting neurogenesis and neuroprotection that contribute to the preservation of functions. This study aimed to investigate the effects of neuroinflammation and CRF on hippocampal volume in multiple sclerosis (MS) patients with relapsing-remitting (RR) and progressive (P) clinical phenotypes. The influence of neuroinflammation and CRF on brain, grey matter (GM) and thalamic volumes was also assessed to determine whether the effects were specific for the hippocampus., Method: Brain 3T structural MRI scans and maximum oxygen consumption (VO 2 max), a proxy of CRF, were acquired from 81 MS patients (27 RR and 54 P) and 45 age-matched and sex-matched healthy controls. T2-hyperintense white matter lesion volume (T2-LV) and choroid plexuses volume (CPV) were quantified as neuroinflammatory measures. Associations of demographic, clinical, neuroinflammatory and CRF measures with normalised brain, GM, hippocampal and thalamic volumes in relapsing-remitting MS (RRMS) and progressive MS patients were assessed using Shapley and best subset selection regression., Results: For most volumetric measures, the largest portions of variance were explained by T2-LV (variable importance (VI)=9.4-39.4) and CPV (VI=4.5-26.2). VO 2 max explained the largest portion of variance of normalised hippocampal volume only in RRMS patients (VI=16.9) and was retained as relevant predictor (standardised β=0.374, p=0.023) with T2-LV (standardised β=-0.330, p=0.016)., Conclusions: A higher CRF may play a specific neuroprotective role on MS patients' hippocampal integrity, but only in the RR phase of the disease., Competing Interests: Competing interests: PP received speaker honoraria from Roche, Biogen, Novartis, Merck Serono, Bristol Myers Squibb and Genzyme. He has received research support from Italian Ministry of Health and Fondazione Italiana Sclerosi Multipla. MM reports grants and personal fees from Almiral. She was awarded a MAGNIMS-ECTRIMS fellowship in 2020. MF is Editor-in-Chief of the Journal of Neurology, Associate Editor of Human Brain Mapping, Neurological Sciences and Radiology; received compensation for consulting services from Alexion, Almirall, Biogen, Merck, Novartis, Roche, Sanofi; speaking activities from Bayer, Biogen, Celgene, Chiesi Italia SpA, Eli Lilly, Genzyme, Janssen, Merck-Serono, Neopharmed Gentili, Novartis, Novo Nordisk, Roche, Sanofi, Takeda and TEVA; participation in Advisory Boards for Alexion, Biogen, Bristol-Myers Squibb, Merck, Novartis, Roche, Sanofi, Sanofi-Aventis, Sanofi-Genzyme, Takeda; scientific direction of educational events for Biogen, Merck, Roche, Celgene, Bristol-Myers Squibb, Lilly, Novartis, Sanofi-Genzyme; he receives research support from Biogen Idec, Merck-Serono, Novartis, Roche, Italian Ministry of Health, and Fondazione Italiana Sclerosi Multipla. MAR received consulting fees from Biogen, Bristol Myers Squibb, Eli Lilly, Janssen, Roche; and speaker honoraria from AstraZeneca, Biogen, Bristol Myers Squibb, Bromatech, Celgene, Genzyme, Horizon Therapeutics Italy, Merck Serono SpA, Novartis, Roche, Sanofi and Teva. She receives research support from the MS Society of Canada, the Italian Ministry of Health and Fondazione Italiana Sclerosi Multipla. She is Associate Editor for Multiple Sclerosis and Related Disorders., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Impairment of cardiovascular control is common in multiple sclerosis (MS), possibly due to damage of strategic brain regions such as the insula. Aerobic training (AT) targets cardiopulmonary system and may represent a neuroprotective strategy., Purpose: To investigate whether insular damage (T2-hyperintense lesions and volume) is associated with cardiovascular fitness (CF) and influences AT effects in MS., Methods: Sixty-one MS patients were randomized to an AT intervention group (MS-AT) and a motor training control group (MS-C). At baseline and after training (24 sessions over 2-3 months), peak of oxygen consumption (VO2max), heart rate reserve (HRR), 6-min walk test (6MWT) and whole brain and insula MRI data were collected. Two healthy control (HC) groups were enrolled for CF and MRI data analysis., Results: At baseline, MS patients vs HC showed impaired VO2max, HRR and 6MWT (p < 0.001) and widespread gray matter atrophy, including bilateral insula. In MS patients, left insula T2-lesion volume correlated with HRR (r = 0.27, p = 0.042). After training, MS-AT, especially those without insular T2-hyperintense lesions, showed 6MWT improvement (p < 0.05) and a stable insular volume, whereas MS-C showed left insular volume loss (p < 0.001)., Conclusions: By increasing 6MWT performance, our results suggest that AT may improve walking capacity and submaximal measure of CF in MS patients. Such beneficial effect may be modulated by insula integrity., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

A 61-year-old man was observed to develop type 1 diabetes mellitus following a 3-month treatment with recombinant alpha-2b peginterferon combined with ribavirin for chronic hepatitis C. Serum samples, collected before the start of therapy and 2 months after the diagnosis of diabetes mellitus, revealed islet-cell antibodies at a titer of 20 and 40 JDF-U, respectively, and glutamic acid decarboxylase autoantibodies at a value of 76.5 and 196 IU/ml, respectively. Antibodies to second islet autoantigen were persistently negative. HLA class II typing revealed the presence of DRB1*04/DRB1*14, DQA1*0303-0104 and DQB1*04-0503 alleles. Eight months after the onset of type 1 diabetes mellitus, the patient is still receiving 30 IU insulin daily; the liver function tests are normal and serum hepatitis C virus RNA is negative. These data confirm that, in patients with potential diabetes mellitus, the disease may become manifest as a side-effect during therapy with peginterferon-alpha plus ribavirin. The patient as a candidate for interferon treatment should therefore be investigated, in addition to thyroid autoimmunity, also for pancreatic autoantibodies before starting therapy.

Objective: Patients with autoimmune Addison's disease (AAD) are prone to develop other autoimmune manifestations. An increased prevalence of celiac disease (CD) has recently been demonstrated in Northern European patients with AAD. IgA deficiency is the most frequent type of immunodeficiency among humans and is present in about one in every 600 individuals in the population. IgA deficiency is frequent in patients with other autoimmune diseases, but data concerning AAD are still unavailable., Design: The aim was to define the prevalence of CD and of IgA deficiency in a group of Italian patients with AAD., Methods: One hundred and nine patients with AAD were enrolled and examined for tissue transglutaminase autoantibodies of the IgA class, circulating levels of IgA and adrenal cortex antibodies., Results: Two (1.8%) of the patients were affected by already diagnosed CD and were already on a gluten-free diet. Out of the remaining 107 patients, four (3.7%) were found to be positive for IgA antibodies to human tissue transglutaminase. Three of the four patients who were positive for tissue transglutaminase autoantibodies agreed to undergo endoscopy and duodenal biopsies and, in one, a latent form of CD was identified. The clinical, silent or latent form of CD was present in six out of 109 (5.4%). This prevalence was significantly higher (P = 0.0001) than that reported for the Northern Italian population which was equal to 0.063%. Specifically, CD was present in 12.5% of the autoimmune polyglandular syndrome (APS) type 1 cases, in four out of 60 (6.7%) of the APS type 2 cases and in one out of 40 (2.5%) of the isolated AAD cases. IgA deficiency was present in two out of 109 patients (1.8%), all of whom had normal IgG anti-gliadin. Autoantibodies to the adrenal cortex were detected in 81 out of 109 patients (74.3%)., Conclusions: In patients with AAD there is a high prevalence of both CD and IgA deficiency. Consequently, it is important to screen for CD with tissue transglutaminase autoantibodies of the IgA class and for IgA levels.