Collating the voice of people with autoimmune diseases: Methodology for the Third Phase of the COVAD Studies.

INTRODUCTION: The growing recognition of holistic patient care highlights the various factors shaping the quality of life of individuals with autoimmune and rheumatic diseases (AIRDs). Beyond the traditional disease measures, there is an emerging acknowledgment of the less-explored aspects, including subjective well-being, social determinants of health, comorbidities, mental health, and medication adherence. Moreover, digital health services have empowered patients to engage actively in decision-making alongside clinicians. To explore these domains within the context of AIRDs, the "Collating the Voice of People with Autoimmune Diseases" COVAD survey was conceived, a successor of the previous two COVAD surveys. In this document, we present the study protocol in comprehensive detail. METHODS: The COVAD-3 survey is a cross-sectional patient self-reported e-survey incorporating multiple widely accepted scales/scores to assess various aspects of patients' lifestyles objectively. To ensure the survey's accuracy and usability across diverse regions, it will be translated into multiple languages and subjected to rigorous vetting and pilot testing. It will be distributed by collaborators via online platforms and data will be collected from patients with AIRDs, and healthy individuals over eight months. Data analysis will focus on outcome measures related to various social, demographic, economic, and psychological factors. CONCLUSION: With the increasing awareness to adopt a holistic treatment approach encompassing all avenues of life, the COVAD-3 survey aims to gain valuable insights into the impact of social, demographic, economic, and psychological determinants of health on the subjective well-being in patients with AIRDs, which will contribute to a better understanding of their overall health and well-being.

Classical Examples of the Concept of the ASIA Syndrome.

Autoimmune/inflammatory syndrome induced by adjuvants (ASIA) was first introduced in 2011 by Shoenfeld et al. and encompasses a cluster of related immune mediated diseases, which develop among genetically prone individuals as a result of adjuvant agent exposure. Since the recognition of ASIA syndrome, more than 4400 documented cases have been reported so far, illustrated by heterogeneous clinical manifestations and severity. In this review, five enigmatic conditions, including sarcoidosis, Sjögren's syndrome, undifferentiated connective tissue disease, silicone implant incompatibility syndrome (SIIS), and immune-related adverse events (irAEs), are defined as classical examples of ASIA. Certainly, these disorders have been described after an adjuvant stimulus (silicone implantation, drugs, infections, metals, vaccines, etc.) among genetically predisposed individuals (mainly the HLA-DRB1 and PTPN22 gene), which induce an hyperstimulation of the immune system resulting in the production of autoantibodies, eventually leading to the development of autoimmune diseases. Circulating autonomic autoantibodies in the sera of patients with silicone breast implants, as well as anatomopathological aspects of small fiber neuropathy in their skin biopsies have been recently described. To our knowledge, these novel insights serve as a common explanation to the non-specific clinical manifestations reported in patients with ASIA, leading to the redefinition of the ASIA syndrome diagnostic criteria.

Pathophysiological Role and Therapeutic Implications of Vitamin D in Autoimmunity: Focus on Chronic Autoimmune Diseases.

Vitamin D is a pleiotropic secosteroid yielding multiple actions in human physiology. Besides the canonical regulatory activity on bone metabolism, several non-classical actions have been described and the ability of vitamin D to partake in the regulation of the immune system is particularly interesting, though far stronger and convincing evidence has been collected in in vitro as compared to in vivo studies. Whether vitamin D is able to regulate at physiological concentrations the human immune system remains unproven to date. Consequently, it is not established if vitamin D status is a factor involved in the pathogenesis of immune-mediated diseases and if cholecalciferol supplementation acts as an adjuvant for autoimmune diseases. The development of autoimmunity is a heterogeneous process, which may involve different organs and systems with a wide range of clinical implications. In the present paper, we reviewed the current evidences regarding vitamin D role in the pathogenesis and management of different autoimmune diseases.

Is cholecalciferol a potential disease-modifying anti-rheumatic drug for the management of rheumatoid arthritis?

Vitamin D is a pleiotropic molecule with a well-characterised immunomodulatory activity in vitro; however, its potential clinical application in autoimmune conditions has yet to be clarified. Several authors have investigated the use of vitamin D as a disease-modifying anti-rheumatic drug (DMARD) in rheumatoid arthritis (RA), obtaining divergent conclusions. This systematic review summarises and critically analyses the findings of papers assessing the impact of vitamin D supplementation on pain relief, disease activity, functional status and flare rate. We conclude that the correction of hypovitaminosis D may have a beneficial effect on pain perception; moreover, the achievement of an adequate plasma vitamin D concentration obtained with high-dose regimens might evoke immunomodulatory activities of vitamin D and favourably impact on disease control. Nevertheless, the current evidence is still not strong enough to support the use of cholecalciferol as a DMARD in RA, and further studies are required to clarify this issue.

Rivaroxaban vs warfarin in high-risk patients with antiphospholipid syndrome.

Rivaroxaban is an effective and safe alternative to warfarin in patients with atrial fibrillation and venous thromboembolism. We tested the efficacy and safety of rivaroxaban compared with warfarin in high-risk patients with thrombotic antiphospholipid syndrome. This is a randomized open-label multicenter noninferiority study with blinded end point adjudication. Rivaroxaban, 20 mg once daily (15 mg once daily based on kidney function) was compared with warfarin (international normalized ratio target 2.5) for the prevention of thromboembolic events, major bleeding, and vascular death in patients with antiphospholipid syndrome. Only high-risk patients triple positive for lupus anticoagulant, anti-cardiolipin, and anti-ß2-glycoprotein I antibodies of the same isotype (triple positivity) were included in the study. The trial was terminated prematurely after the enrollment of 120 patients (59 randomized to rivaroxaban and 61 to warfarin) because of an excess of events among patients in the rivaroxaban arm. Mean follow-up was 569 days. There were 11 (19%) events in the rivaroxaban group, and 2 (3%) events in the warfarin group. Thromboembolic events occurred in 7 (12%) patients randomized to rivaroxaban (4 ischemic stroke and 3 myocardial infarction), whereas no event was recorded in those randomized to warfarin. Major bleeding occurred in 6 patients: 4 (7%) in the rivaroxaban group and 2 (3%) in the warfarin group. No death was reported. The use of rivaroxaban in high-risk patients with antiphospholipid syndrome was associated with an increased rate of events compared with warfarin, thus showing no benefit and excess risk. This trial was registered at www.clinicaltrials.gov as #NCT02157272.

Vitamin D and systemic lupus erythematous: a review of immunological and clinical aspects.

OBJECTIVES: To review the relationships between vitamin D status and systemic lupus erythematosus (SLE) concerning immunological, clinical aspects and possible effects of supplementation in disease modulation. METHODS: The literature was reviewed up to January 2017 for studies regarding the epidemiology, pathogenesis, immunological aspects, clinical implications and supplementation strategies. The focus was mainly on studies with implications on every day clinical practice. RESULTS: Vitamin D interacts with immune system mechanisms, therefore, it may be involved in the pathogenesis of autoimmune diseases. The literature is concordant on vitamin D insufficiency being endemic in SLE patients. Data on the correlation between SLE disease activity and circulating levels of vitamin D are controversial, as well as those related to the immunomodulatory effects of vitamin D supplementation. Novel areas of study are the relationship between constitutional symptoms and cognitive involvement of SLE and hypovitaminosis D, and the possible role of vitamin D in the formation of the atherosclerotic plaque, opening new avenues for the modulation of the cardiovascular risk. CONCLUSIONS: Future studies are needed to fully understand the relationship between hypovitaminosis D and different aspects of SLE. The most challenging topic will be to clarify supplementation strategies with vitamin D analogues that can be effective in modulating disease activity.

Undifferentiated connective tissue disease, fibromyalgia and the environmental factors.

PURPOSE OF REVIEW: The aim of this study was to discuss the role of environmental factors in the induction and perpetuation of autoimmunity, with particular focus on undifferentiated connective tissue disease (UCTD) and fibromyalgia. These two entities may share undefined clinical and laboratory features and recognize environmental exposures as triggering factors. From this particular point of view, both UCTD and fibromyalgia may resemble the picture of the 'Autoimmune/Inflammatory Syndrome Induced by Adjuvants' (ASIA). RECENT FINDINGS: A case-control study on environmental exposures showed that patients with UCTD were significantly more exposed to several adjuvants (vaccines, metal implants, proximity to metal factories and foundries) than age and sex-matched healthy controls. UCTD exposed to major ASIA triggers (vaccines, silicone) displayed typical features of ASIA (general weakness, chronic fatigue, irritable bowel syndrome) in the context of a predisposing genetic background (familiarity for autoimmunity). SUMMARY: The induction and perpetuation of autoimmunity is a complex process that requires the interaction between the individual genetic background and the environment. Environmental factors are gaining increasing attention since the description of ASIA, a syndrome that includes symptoms typically seen in patients with fibromyalgia and UCTD. A recent case-control study focusing on environmental exposures suggested that nearly half of patients with UCTD may fall within the ASIA spectrum.

Winter lupus flares are associated with low vitamin D levels in a retrospective longitudinal study of Italian adult patients.

OBJECTIVES: Patients with systemic lupus erythematosus (SLE) are prone to hypo-vitaminosis D because of their photosensitivity. Vitamin D (vit.D) has beneficial effects not only on bone metabolism but also on the function of the immune system. The relationship between SLE disease activity and vit.D status is controversial and little is known on the effects of current supplementation strategies given for osteoporosis in raising vit.D levels. METHODS: Vit.D levels were measured longitudinally in 50 SLE patients from Northern Italy at two time-points (winter and summer) during disease remission. Thirty patients were also evaluated during a flare. As controls, 170 healthy donors were enrolled. All the samples were analysed for 25-OH vit.D levels by a chemiluminescence assay (DiaSorin SpA, Italy). RESULTS: SLE patients had lower vit.D levels than controls in the summer (median 29.4 vs. 39.2 ng/ml, p=0.005) but not in the winter (26.4 vs. 21.6 ng/ml). During wintertime, 36 SLE patients were supplemented with vit.D drops (n=24; 48%), vit.D+calcium tablets (n=12; 24%), while 14 (28%) received no supplementation. Patients on oral drops had significantly higher vit.D levels than patients on tablets. The median weekly dosage was higher for oral drops than for tablets (6250 vs. 4560 UI, p=0.009). Winter flares were associated with lower vit.D levels in comparison with remission during the same season for each patient (21.1 vs. 30 ng/ml). CONCLUSIONS: Current strategies of vit.D supplementation seem to be not sufficient for reaching an optimal vit.D status in Italian SLE patients. Vit.D and calcium tablets were less effective, probably because of lower vit.D content and poorer compliance. Vit.D insufficiency detected in the wintertime can be either a predisposing factor for flare or the consequence of the flare itself in SLE patients.

Novel aspects of Sjögren's syndrome in 2012.

Sjögren's syndrome (SS) is a systemic progressive autoimmune disease characterized by a complex pathogenesis requiring a predisposing genetic background and involving immune cell activation and autoantibody production. The immune response is directed to the exocrine glands, causing the typical 'sicca syndrome', but major organ involvement is also often seen. The etiology of the disease is unknown. Infections could play a pivotal role: compared to normal subjects, patients with SS displayed higher titers of anti-Epstein-Barr virus (EBV) early antigens, but lower titers of other infectious agent antibodies such as rubella and cytomegalovirus (CMV) suggest that some infections may have a protective role against the development of autoimmune disease. Recent findings seem to show that low vitamin D levels in patients with SS could be associated with severe complications such as lymphoma and peripheral neuropathy. This could open new insights into the disease etiology. The current treatments for SS range from symptomatic therapies to systemic immunosuppressive drugs, especially B cell-targeted drugs in cases of organ involvement. Vitamin D supplementation may be an additional tool for optimization of SS treatment.