Risk of developing psoriatic arthritis in psoriasis cohorts with arthralgia: exploring the subclinical psoriatic arthritis stage.

OBJECTIVE: Subjects with subclinical psoriatic arthritis (PsA), defined as the presence of arthralgia in psoriasis (PsO), are at higher risk of PsA but scant real-world data exist. Our aims were to (1) estimate the probability of PsA development in subclinical PsA, (2) characterise subclinical PsA symptoms and (3) determine the clinical patterns at PsA diagnosis. METHODS: Patients with PsO, mainly subclinical PsA, were evaluated longitudinally in two European cohorts. The key outcome was new-onset PsA. Musculoskeletal symptoms including inflammatory and non-inflammatory symptoms before PsA diagnosis were collected. Occurrence of PsA was analysed with survival analysis and cumulative incidence functions (CIFs). RESULTS: 384 patients with PsO were included with a mean follow-up of 33.0 (±20.9) months. 311 of 384 (80.9%) had subclinical PsA with a PsA incidence rate of 7.7 per 100 patient-years. Subclinical PsA displayed a higher risk of PsA development compared with PsO (HR=11.7 (95% CI 1.57 to 86.7), p=0.016). The probability of new-onset PsA estimated by the CIF was 9.4% (95% CI 4.7% to 10.6%) at month 12 and 22.7% (95% CI 17.2% to 28.6%) at month 36. 58.9% of cases reported inflammatory symptoms in the months immediately prior to PsA diagnosis but prior non-inflammatory symptoms were evident in 83.9% prior to PsA diagnosis. Peripheral joint swelling was the predominant PsA presentation pattern (82.1%). CONCLUSIONS: The probability of PsA development among subclinical PsA was relatively high, emphasising the importance of emergent musculoskeletal symptoms when aiming for PsA prevention. Joint swelling was the dominant feature in new-onset PsA, likely reflecting clinical confidence in recognising joint swelling.

Exploring the Link Between Ankylosing Spondylitis and Inflammatory Bowel Disease: A Retrospective Cohort Study.

BACKGROUND: Ankylosing spondylitis (AS) and inflammatory bowel disease (IBD) are chronic conditions with overlapping pathogenic mechanisms. The genetic predisposition and inflammatory pathways common to both diseases suggest a syndemic relationship. While some evidence points to a connection between the two conditions, other reports do not support this link. OBJECTIVES: To investigate the association between AS and the subsequent incidence of IBD. To identify potential risk factors and effect modifiers that contribute to this relationship. METHODS: Utilizing the Chronic Disease Registry of Clalit Health Services, we conducted a retrospective cohort study of individuals diagnosed with AS between January 2002 and December 2018. We compared these patients with age- and sex-matched controls, excluding those with a prior diagnosis of IBD. Statistical analyses included chi-square and t-tests for demographic comparisons, and Cox proportional hazards models for evaluating the risk of IBD development, with adjustments for various co-morbidities and demographic factors. RESULTS: The study included 5825 AS patients and 28,356 controls. AS patients demonstrated a significantly higher incidence of IBD with hazard ratios of 6.09 for Crohn's disease and 2.31 for ulcerative colitis, after multivariate adjustment. The overall incidence of IBD in the AS cohort was significantly higher compared to controls. CONCLUSIONS: AS patients exhibit a markedly increased risk of developing IBD. These findings advocate for heightened clinical vigilance for IBD symptoms in AS patients and suggest the need for a multidisciplinary approach to patient care. Further research into the shared pathogenic pathways is needed to develop personalized treatment strategies and improve patient management.

Arthroplasty Rates and Risk in Familial Mediterranean Fever Patients: A large Population-Based Study.

BACKGROUND: Familial Mediterranean Fever (FMF) is a genetic disorder characterized by recurrent episodes of fever and inflammation in various organs, including the joints. Traditionally, the arthritis of FMF has been considered relatively harmless. However, anecdotal evidence has suggested that it may contribute to long-term joint damage, which may necessitate surgical joint replacement. This study aimed to investigate the rates of arthroplasty among FMF patients and compare it to the general population. METHODS: The study used the electronic database of the largest healthcare organization in Israel to identify 9,769 FMF patients diagnosed between 2000 and 2016. A similar number of age-, gender-, and residency-matched controls were also identified. The rates of arthroplasty were compared between the two groups. A logistic regression model predicting the need for arthroplasty within the FMF group was formed to identify potential risk factors. RESULTS: Of the 9,769 FMF patients, 114 (1.2%) underwent arthroplasty, compared with 64 (0.7%) of the control group [unadjusted odds ratio (OR)=1.79, 95% confidence interval (CI) 1.32-2.43; partially adjusted OR = 1.97, 95% CI 1.40-2.77; fully adjusted OR = 1.92, 95% CI 1.35-2.72]. Within the FMF cohort, those of North African origin had a significantly higher risk of arthroplasty (OR = 6.89, 95% CI 5.09-9.33; p< 0.001). CONCLUSION: FMF patients can experience long-term joint damage that may require arthroplasty. Although this complication is relatively uncommon in FMF patients, it occurs almost twice as frequently as compared with the general population. FMF patients of North African origin are at an even higher risk.

Unraveling the connection: Uveitis prevalence and risk factors in psoriasis patients - a population-based study.

The association between uveitis and spondyloarthropathy (SpA)-related conditions is well-established. However, evidence describing the link between uveitis and psoriasis, and psoriasis without concomitant SpA-related conditions is scarce and conflicting. This large-scale population-based study sought to describe the prevalence and features of uveitis among psoriasis patients in Israel as well as investigating the risk for uveitis in different subgroups of psoriasis patients compared to the general population. We conducted a retrospective study utilizing the electronic database of the Meuhedet Health Maintenance Organization. The study included all patients diagnosed with psoriasis between 2000 and 2020, each patient was matched with four controls based on age, sex, place of residence, and index date. Logistic regression models were employed to assess the association between psoriasis and uveitis while adjusting for the presence of SpA-related conditions. A total of 61 003 psoriasis patients and 244 012 matched controls were included. The prevalence of uveitis was 1.3% versus 1.1% respectively (OR 1.12; 95% CI 1.10-1.30; p < 0.001). When adjusting to psoriasis severity, concurrent SpA, and psoriasis treatment no significant association was found. The rates of uveitis among psoriasis patients with concurrent SpA-related conditions was 3.2% compared to 1.4% in controls without psoriasis or SpA (OR 2.38; 95% CI 2.00-2.83; p < 0.001), while in psoriasis patients without SpA, the rate of uveitis was 1.0% and was similar to controls. Although crude rates of uveitis were higher in patients with severe psoriasis compared to mild psoriasis (2.1% vs. 1.1%), after adjustment, no significant association compared to controls was found in either group. Our findings suggest that the positive association between psoriasis and uveitis is primarily mediated by the coexistence of other SpA-related conditions. These findings imply the presence of a shared pathogenetic mechanism and set the direction for a phenotypic-targeted screening strategy.

The association between psoriasis, psoriasis severity, and inflammatory bowel disease: a population-based analysis.

Background: The skin-gut axis, characterized by bidirectional communication between the skin and gut, plays a crucial role in the pathogenesis of psoriasis and inflammatory bowel diseases (IBD). Objectives: We aimed to explore the association between psoriasis and IBD and identify predictors associated with IBD development among patients with psoriasis. Design: Retrospective cohort study. Methods: A retrospective study which utilized an electronic database from the Meuhedet Health Maintenance Organization (MHMO) in Israel. Psoriasis was categorized as severe if any systemic agent or phototherapy was administered. Univariate and multivariate logistic regressions were used to identify specific predictors for IBD, with adjustments made for potential confounders. The study received approval from the Ethical Committee of the MHMO. Results: In total, 61,003 adult patients who were diagnosed with psoriasis between 2000 and 2022 were included. Among them, 1495/61,003 patients (2.4%) were diagnosed with IBD, as compared to 3834/244,012 patients (1.6%) in the non-psoriasis group [adjusted odds ratio (OR): 1.47; 95% confidence interval (CI): 1.37-1.56; p < 0.001]. Increased age (OR: 1.01; 95% CI: 1.01-1.02; p < 0.001), male gender (OR: 1.22; 95% CI: 1.03-1.45; p = 0.024), and Jewish ethnicity (OR: 2.5; 95% CI: 1.2-4.1; p < 0.001) were identified as significant risk factors for IBD. Spondyloarthropathies, including psoriatic arthritis (OR: 2.27; 95% CI: 1.86-2.77; p < 0.001) and ankylosing spondylitis (OR: 2.82; 95% CI: 1.5-5.32; p < 0.05), were associated with a higher prevalence of IBD. Furthermore, severe psoriasis was significantly associated with a higher likelihood of IBD, compared to mild psoriasis (OR: 16.03; 95% CI: 11.02-23.34; p < 0.001). Conclusion: A significant association between psoriasis and IBD was demonstrated, including its subtypes: Crohn's disease and ulcerative colitis. Moreover, such association may depend on psoriasis severity as determined by the treatment used. This association warrants further investigation and implies a potential need for closer monitoring of patients with severe psoriasis.

Association between psoriatic disease severity and risk of inflammatory bowel diseases 1- Gut and skin barrier play an integral role in psoriasis and inflammatory bowel disease (IBD) development. 2- Shared genetic and environmental factors could explain the association between both diseases. 3- We report increased association between psoriasis and IBD, a relationship that is more pronounced in patients with severe psoriasis. 4- Patients with spondyloarthritis related diseases have a stronger association with IBD.

Biologic Treatment Modification Efficacy in Concurrent Inflammatory Bowel Disease and Ankylosing Spondylitis: A Retrospective Cohort Study at a Single Tertiary Center.

BACKGROUND: The link between ankylosing spondylitis (AS) and inflammatory bowel disease (IBD) is well-established, with concurrent prevalence estimates ranging from 5-10%. However, there are still significant gaps in our understanding, and a comprehensive treatment guideline for these co-diagnosed patients has yet to be established. Our objective was to explore patterns of treatment alterations following the diagnosis of AS in patients previously diagnosed with IBD, and vice versa. Additionally, we sought to determine how these modifications influence clinical outcomes in both conditions. METHODS: This retrospective data-based cohort study included patients with coexisting IBD and AS that were diagnosed between the years 2009-2022 and were followed by the gastroenterology and the rheumatology units of the Sheba Medical Center, Israel. The data were extracted from the electronic health record and included demographic information, medication history, treatment modification at the time of second diagnosis, and the characteristics and activity of both IBD and AS at the index time and at the 3-month mark. RESULTS: The study included a total of 68 patients, with a male predominance (40 patients, 59%). The median age was 43 years (IQR 31-55) and 78% had Crohn's disease (CD). The median duration between the diagnosis of the first disease to the second one was 4 years (IQR 1-9.5). A significant proportion of patients (85%) underwent treatment modification at their second diagnosis. Out of the total cohort, 28% initiated biological therapy, 17.6% switched their biologic regimen, and 16.2% discontinued NSAIDS. Patients who underwent biologic modifications at time of the second diagnosis (the initiation/switch/augmentation of a concurrent regimen) experienced significantly higher rates of clinical improvement in either IBD or AS at the 90-day follow-up compared to patients who did not (68% vs. 32%, p = 0.004), and biologic modification was found to be an independent predictor for clinical improvement (OR 3.69, CI 1.08-12.58, p = 0.037). CONCLUSIONS: Our findings suggest that biologic therapy modification at the time of the second diagnosis was associated with a higher rate of improvement in AS/IBD at the 90-day follow-up.

Big data- and machine learning-based analysis of a global pharmacovigilance database enables the discovery of sex-specific differences in the safety profile of dual IL4/IL13 blockade.

Background: Due to its apparent efficacy and safety, dupilumab, a monoclonal antibody that blocks Interleukin 4 (IL-4) and Interleukin 13 (IL-13), has been approved for treating T-helper 2 (Th2) disorders. However, adverse effects like local injection site reactions, conjunctivitis, headaches, and nasopharyngitis have been reported. Sex differences are known to influence both adaptive and innate immune responses and, thus, may have a bearing on the occurrence of these adverse effects. Nevertheless, the literature lacks a comprehensive exploration of this influence, a gap this study aims to bridge. Materials and Methods: A comprehensive data mining of VigiBase, the World Health Organization (WHO) global pharmacovigilance database which contains case safety reports of adverse drug reactions (ADRs) was performed to test for sex -specific safety response to dual IL4/IL13 blockade by dupilumab. The information component (IC), a measure of the disproportionality of ADR occurrence, was evaluated and compared between males and females to identify potential sexual dimorphism. Results: Of the 94,065 ADRs recorded in the WHO global pharmacovigilance database, 2,001 (57.4%) were reported among female dupilumab users, and 1,768 (50.7%) were among males. Immune/autoimmune T-helper 1 (Th1)-, innate- and T-helper 17 (Th17)-driven diseases and degenerative ones were consistently reported with a stronger association with Dupilumab in males than females. Some adverse events were more robustly associated with Dupilumab in females. Conclusion: Dupilumab has an excellent safety profile, even though some ADRs may occur. The risk is higher among male patients, further studies, including ad hoc studies, are needed to establish causality.

Predominant ligament-centric soft-tissue involvement differentiates axial psoriatic arthritis from ankylosing spondylitis.

Since the original description of spondyloarthritis 50 years ago, results have demonstrated similarities and differences between ankylosing spondylitis (AS) and axial psoriatic arthritis (PsA). HLA-B27 gene carriage in axial inflammation is linked to peri-fibrocartilaginous sacroiliac joint osteitis, as well as to spinal peri-entheseal osteitis, which is often extensive and which provides a crucial anatomical and immunological differentiation between the AS and PsA phenotypes. Specifically, HLA-B27-related diffuse bone marrow oedema (histologically an osteitis) and bone marrow fatty corners detected via magnetic resonance imaging, as well as radiographic changes such as sacroiliitis, vertebral squaring, corner erosions and Romanus lesions, all indicate initial bone phenotypes in HLA-B27+ axial disease. However, in much of PsA with axial involvement, enthesitis primarily manifests in ligamentous soft tissue as 'ligamentitis', with characteristic lesions that include para-syndesmophytes and sacroiliac joint bony sparing. Like axial PsA, diffuse idiopathic skeletal hyperostosis phenotypes, which can be indistinguishable from PsA, exhibit a thoracic and cervical spinal ligamentous soft-tissue tropism, clinically manifesting as syndesmophytosis that is soft-tissue-centric, including paravertebral soft-tissue ossification and sacroiliac soft-ligamentous ossification instead of joint-cavity fusion. The enthesis bone and soft tissues have radically different immune cell and stromal compositions, which probably underpins differential responses to immunomodulatory therapy, especially IL-23 inhibition.

Increased risk of osteoporosis and femoral neck fractures in patients with familial Mediterranean fever-a large retrospective cohort study.

OBJECTIVES: The direct impact of inflammatory conditions and their therapy with corticosteroids both contribute to an increased risk of osteoporosis with associated fractures. Familial-Mediterranean-Fever (FMF) is an autoinflammatory disorder not commonly treated with corticosteroids. Evidence regarding FMF association with osteoporosis and femur fractures is anecdotal. We aimed to evaluate the incidence and risk of osteoporosis and femoral neck fracture in FMF patients compared with the general population. METHODS: A retrospective cohort study using the electronic database of Clalit Health Services of all FMF patients first diagnosed between 2000-2016 and controls was evaluated including age and sex matched controls in 1:1 ratio. Follow-up continued until the first diagnosis of osteoporosis or fracture. Risk for these conditions was compared using univariate and multivariate cox-regression models. RESULTS: 9,769 FMF patients were followed for a median period of 12.5 years. 304 FMF patients were diagnosed with osteoporosis compared with 191 controls, resulting in an incidence rate (per 10 000 persons-years) of 28.8 and 17.8 respectively, and a crude HR of 1.62 (95%CI 1.35-1.93; p< 0.001). Patients were diagnosed with osteoporosis at a considerably younger age than controls (60.1 ± 12.4 vs 62.5 ± 11.0 years; p= 0.028). 56 FMF patients were diagnosed with femoral neck fracture compared with 35 controls, resulting in an incidence rate of 5.3 and 3.3 respectively, and a crude HR of 1.60 (95%CI 1.05-2.44; p< 0.05). CONCLUSION: FMF patients are at increased risk for osteoporosis and consequently femur fracture. Our findings emphasize the importance of considering bone health in the management of FMF patients.

The Risk and Predictors of Malignancies in Ankylosing Spondylitis Patients in Israel-A Retrospective Electronic Data-Based Study.

BACKGROUND: Previous studies demonstrated unclear and vast variability in the association between Ankylosing Spondylitis (AS) and the risk of cancer. OBJECTIVES: To assess the risk of overall and site-specific malignancies for AS patients in Israel, while examining the role of comorbidities and immunomodulatory therapy. METHODS: We conducted a retrospective electronic data-based study including all AS patients diagnosed between 2002 and 2018, with no history of cancer prior to enrollment, with 5:1 ratio matched-control by age, gender, and place of residence. The odds Ratios (OR) for site-specific malignancies, comparing AS patients and controls, were calculated using logistic regression. Risk factors for malignancies within the AS cohort were evaluated in the same manner. RESULTS: This study comprised 5825 AS patients and 28,356 matched controls. There was a higher overall risk of cancer in AS patients compared to controls (OR = 1.4, 95% CI 1.24-1.6), specifically for solid malignancies (OR = 1.5, 95% CI 1.3-1.7), CNS (OR = 3.72, 95% CI 1.29-10.7), kidney (OR = 2.06, 95% CI 1.12-3.8), and malignancy of unknown primary (OR = 3.06, 95% CI 2.35-3.98). Regarding predictors for malignancy within AS patients, older age at diagnosis (OR = 1.31, 95%,CI 1.25-2.36), diabetes (OR = 1.52, 95% CI 1.18-1.97), IBD (OR = 2.61, 95% CI 1.75-3.89), and treatment with DMARDs (OR = 2.17, 95% CI 1.65-2.83) were associated with a higher risk of solid malignancies, while NSAIDs treatment alone had a protective effect for solid malignancies (OR = 0.78, 95% CI 0.61-0.99). No significant association was found between anti-TNF therapy and the risk of solid or hematologic malignancies within the AS group. CONCLUSION: AS is associated with an increased risk of overall and site-specific malignancies, with independently higher risk for older age, comorbidity of DM, IBD, and treatment with DMARDs.

The Prevalence of Dementia among Dermatomyositis and Polymyositis Patients: A Retrospective Cohort Study.

BACKGROUND: Polymyositis (PM) and dermatomyositis (DM) are inflammatory mediated myopathies characterized by progressive symmetric proximal muscle weakness and associated with extra-muscular involvement. Central nervous system complications are rarely reported with these diseases. OBJECTIVES: To investigate the association between dementia and PM/DM. METHODS: A retrospective cohort study was conducted using a database from Clalit Health Care, the largest health maintenance organization in Israel. Patients with a first recorded diagnosis of PM/DM were included and were compared with age- and sex-matched controls by a ratio of 1:5. The prevalence of dementia among PM/DM patients compared to controls was assessed using a univariate and a multivariable model. Binary logistic regression analysis was conducted to assess the association of different factors with dementia within the PM/DM cohort. RESULTS: The study included 2085 PM/DM cases (17.0%) and 10,193 age- and sex-matched controls (83.0%). During the follow-up time, 36 PM/DM patients were diagnosed with dementia compared to 160 controls, with a univariate hazard ratio (HR) of 1.10 (95% confidence interval [95%CI] 0.77-1.58). Within the PM/DM cohort, significant predictors for the development of dementia included increased age at diagnosis (5 years increment; OR 1.86, 95%CI 1.57-2.21, P < 0.001) and treatment with glucocorticoids (OR 5.40, 95%CI 1.67-17.67, P = 0.005). CONCLUSIONS: In our cohort, inflammatory myopathies were not associated with dementia. Age and treatment with glucocorticoids were associated with dementia. If dementia is diagnosed in patients with inflammatory myopathies, other systemic causes should be investigated.

EULAR points to consider for the definition of clinical and imaging features suspicious for progression from psoriasis to psoriatic arthritis.

BACKGROUND: The transition from psoriasis (PsO) to psoriatic arthritis (PsA) and the early diagnosis of PsA is of considerable scientific and clinical interest for the prevention and interception of PsA. OBJECTIVE: To formulate EULAR points to consider (PtC) for the development of data-driven guidance and consensus for clinical trials and clinical practice in the field of prevention or interception of PsA and for clinical management of people with PsO at risk for PsA development. METHODS: A multidisciplinary EULAR task force of 30 members from 13 European countries was established, and the EULAR standardised operating procedures for development for PtC were followed. Two systematic literature reviews were conducted to support the task force in formulating the PtC. Furthermore, the task force proposed nomenclature for the stages before PsA, through a nominal group process to be used in clinical trials. RESULTS: Nomenclature for the stages preceding PsA onset, 5 overarching principles and 10 PtC were formulated. Nomenclature was proposed for three stages towards PsA development, namely people with PsO at higher risk of PsA, subclinical PsA and clinical PsA. The latter stage was defined as PsO and associated synovitis and it could be used as an outcome measure for clinical trials evaluating the transition from PsO to PsA. The overarching principles address the nature of PsA at its onset and underline the importance of collaboration of rheumatologists and dermatologists for strategies for prevention/interception of PsA. The 10 PtC highlight arthralgia and imaging abnormalities as key elements of subclinical PsA that can be used as potential short-term predictors of PsA development and useful items to design clinical trials for PsA interception. Traditional risk factors for PsA development (ie, PsO severity, obesity and nail involvement) may represent more long-term disease predictors and be less robust for short-term trials concerning the transition from PsO to PsA. CONCLUSION: These PtC are helpful to define the clinical and imaging features of people with PsO suspicious to progress to PsA. This information will be helpful for identification of those who could benefit from a therapeutic intervention to attenuate, delay or prevent PsA development.

Ankylosing spondylitis is associated with increased prevalence of valvular heart diseases: a cross-sectional population-based study.

BACKGROUND: Ankylosing spondylitis (AS) is a chronic inflammatory arthritis primarily affecting the sacroiliac joint and axial skeleton with associated extra-articular involvement including cardiovascular system disease including aortic valve disease with variable reported prevalence. The aim of this study is to determine the prevalence of heart valve disorders in AS patients. METHODS: This was a retrospective, population-based, cross-sectional study that retrieved data from the Clalit Health Services registry. Cases were defined as having AS, whereas controls were frequency matched by age and sex in a ratio of 5:1. The prevalence of valvular heart diseases was compared between the two groups; a multivariate logistic regression model was applied to estimate the association after controlling for potential confounders. RESULTS: We included 4082 AS patients and 20 397 controls frequency matched by age and sex. AS patients had a significantly higher prevalence of cardiovascular risk factors (P < .001) and a higher prevalence of valvular heart disease. In the multivariate logistic regression model, adjusting for multiple confounding factors, AS was independently associated with aortic stenosis [odds ratio (OR): 2.25, 95% confidence interval (CI): 1.57-3.23, P < 0.001], aortic insufficiency (OR: 2.44, 95% CI: 1.50-3.94, P < 0.001), and mitral insufficiency (OR: 1.75, 95% CI: 1.17-2.61, P < 0.001) but not mitral stenosis (OR: 1.31, 95% CI: 0.60-2.70, P = 0.47). CONCLUSIONS: Our study reports the increased risk of valvular heart diseases in patients with AS, possibly due to the inflammatory milieu associated with the disease process and the result of biomechanical stress affecting the enthesis-like valvular structures.

Functional IgG Autoantibodies against Autonomic Nervous System Receptors in Symptomatic Women with Silicone Breast Implants.

The association between the clinical picture of symptomatic women with silicone breast implants (SBI) and dysregulated immunity was in dispute for decades. In the current study, we describe for the first time the functional activity of purified IgG antibodies derived from symptomatic women with SBIs (suffering from subjective/autonomic-related symptoms), both in vitro and in vivo. We found that IgGs, derived from symptomatic women with SBIs, dysregulate inflammatory cytokines (TNFα, IL-6) in activated human peripheral blood mononuclear cells, compared to healthy-women-derived IgGs. Importantly, behavioral studies conducted following intracerebroventricular injection of IgGs derived from symptomatic women with SBIs (who have dysregulated circulating level of IgG autoantibodies directed against autonomic nervous system receptors) into mice brains demonstrated a specific and transient significant increment (about 60%) in the time spent at the center of the open field arena compared with mice injected with IgG from healthy women (without SBIs). This effect was accompanied with a strong trend of reduction of the locomotor activity of the SBI-IgG treated mice, indicating an overall apathic-like behavior. Our study is the first to show the potential pathogenic activity of IgG autoantibodies in symptomatic women with SBIs, emphasizing the importance of these antibodies in SBI-related illness.

Association of fibromyalgia with cancerous and non-cancerous gastrointestinal comorbidities: a cross-sectional study.

OBJECTIVES: Several studies have shown a higher prevalence of irritable bowel syndrome (IBS) among patients with fibromyalgia yet, data regarding association between fibromyalgia and other gastrointestinal disorders have been relatively overlooked. Our aim was to investigate the association between fibromyalgia and gastrointestinal disorders including both benign and malignant conditions. METHODS: We conducted a retrospective cross-sectional study based on the comprehensive electronic database of the largest health maintenance organisation in Israel. All subjects with a diagnosis of fibromyalgia in their medical records and age- and sex-matched controls were included in the study. We investigated the association of fibromyalgia with benign gastrointestinal disorders including IBS, gastroesophageal reflux disease (GERD), peptic ulcer disease (PUD), celiac disease, Crohn's disease, ulcerative colitis, and with gastrointestinal malignancies including colorectal, pancreatic, stomach, liver, and bile duct cancers. RESULTS: The study enrolled 18,598 patients with fibromyalgia and 36,985 controls. The mean age was 56.5 years (standard deviation=14) with a female predominance (91%). Fibromyalgia was significantly associated with IBS (OR 4.61, 95% CI 4.09-5.2, p<0.001), GERD (OR 2.62, 95% CI 2.5-2.75, p<0.001), PUD (OR 2.13, 95% CI 1.98-2.3, p<0.001), celiac disease (OR 2.08, 95% CI 1.63-2.65, p<0.001), Crohn's disease (OR 1.85, 95% CI 1.408-2.32, p<0.001) and ulcerative colitis (OR 1.81, 95%CI 1.4-2.33, p<0.001). Nonetheless, no significant differences were found regarding the prevalence of gastrointestinal malignancies between the fibromyalgia patients and controls. CONCLUSIONS: Our findings suggest that FM is positively associated with various benign but not malignant GI disorders.

Increased risk for stroke in patients with familial Mediterranean fever: results from a large population-based study.

OBJECTIVE: The association between chronic inflammatory conditions and cardiovascular disease is well established. Considering FMF, few studies exist investigating the risk of ischaemic heart disease, and none address the risk of stroke. We aimed to evaluate the incidence and risk for stroke in FMF patients compared with the general population. METHODS: A retrospective cohort study using the electronic database of Clalit Health Services (CHS), the largest health organization in Israel. All FMF patients diagnosed between 2000 and 2016 were included and matched with control according to age, gender and place of residence. Follow-up continued until the first diagnosis of stroke or death. The incidence of stroke was compared between the groups using univariate and multivariate models adjusting for cardiovascular risk-factors. RESULTS: A total of 9769 FMF patients and a similar number of controls were followed up for a median period of 12.5 years. The mean age at the beginning of the follow-up was 25.7 years. In total, 208 FMF patients were diagnosed with stroke compared with 148 controls, resulting in an incidence rate (per 10 000 persons-years) of 19.8 (95% CI 17.2, 22.7) and 13.9 (95% CI 11.8, 16.4), respectively, and a crude HR of 1.42 (95% CI 1.15-1.76; P < 0.001). In a multivariate analysis, FMF patients who developed amyloidosis with related or non-related renal failure demonstrated significant stroke risk (HR = 2.16; 95% CI 1.38, 3.38; P < 0.001), as well as for those who did not develop these complications (HR = 1.32; 95% CI 1.04, 1.67; P < 0.05). CONCLUSION: FMF patients are at increased risk for stroke regardless of known complications.

Vitamin D Insufficiency is Associated with Higher Incidence of Dementia, a Large Community-Based Retrospective Cohort Study.

INTRODUCTION: Active metabolite of vitamin D has neuro-immunomodulatory and neuroprotective properties. However, there is still a debate about the potential association between low serum levels of hydroxy-vitamin D and increased risk for dementia. OBJECTIVES: To determine an association between hypovitaminosis D and dementia for different 25-hydroxyvitamin-D (25(OH)D) serum level cutoffs. METHODS: Patients were identified utilizing the database of Clalit Health Services (CHS), the largest healthcare provider in Israel. For each subject, all available values of 25(OH)D during the study period, which lasted from 2002 to 2019, were obtained. Rates of dementia were compared across different cutoffs of 25(OH)D levels. RESULTS: Cohort included 4278 patients, of whom 2454 (57%) were women. The mean age at the beginning of follow-up was 53 (±17). During the 17-year study period, a total of 133 patients (3%) were diagnosed with dementia. In a fully adjusted multivariate analysis, the risk for dementia was almost 2-fold higher in patients with an average of vitamin D insufficiency (<75 nmol/l) measurements (OR = 1.8, 95% C.I. = 1.0-3.2) compared to reference values (≥75 nmol/l). Patients with vitamin D deficiency (<50 nmol/l) demonstrated higher rates of dementia (OR = 2.6, 95% C.I. = 1.4-4.8). In our cohort, patients were diagnosed with dementia at a younger age in the deficiency (77 vs. 81 P-value = 0.05) and the insufficiency groups (77 vs. 81 P-value = 0.05) compared to the reference values (≥75 nmol/l). CONCLUSION: Insufficient levels of vitamin D are associated with dementia. Dementia is diagnosed at a younger age in patients with insufficient and deficient vitamin D levels.

Autoimmune/inflammatory syndrome induced by adjuvants (ASIA) in 2023.

In 2011, a syndrome entitled ASIA (Autoimmune/inflammatory Syndrome Induced by Adjuvants; Shoenfeld's syndrome) was first described. ASIA aimed to organize under a single umbrella, the existing evidence regarding certain environmental factors which possess immune stimulatory properties, in order to shed light on a common pathway of autoimmune pathogenesis. Such environmental immune stimulators, or adjuvants, include among others: aluminum salts as in vaccines, various medical implants, as well as various infectious agents. After the launch of the ASIA syndrome, the expansion and recognition of this syndrome by different researchers from different countries began. During the past decades, evidence had been accumulating that (auto)immune symptoms can be triggered by exposure to environmental immune stimulatory factors that act as an adjuvant in genetically susceptible individuals. A panoply of unexplained subjective and autonomic-related symptoms has been reported in patients with ASIA syndrome. The current review summarizes and updates accumulated knowledge from the past decades, describing new adjuvants- (e.g. polypropylene meshes) and vaccine- (e.g. HPV and COVID vaccines) induced ASIA. Furthermore, a direct association between inflammatory/autoimmune diseases with ASIA syndrome, will be discussed. Recent cases will strengthen some of the criteria depicted in ASIA syndrome such as clear improvement of symptoms by the removal of adjuvants (e.g. silicone breast implants) from the body of patients. Finally, we will introduce additional factors to be included in the criteria for ASIA syndrome such as: (1) dysregulated non-classical autoantibodies directed against G-protein coupled receptors (GPCRs) of the autonomic nervous system and (2)) small fiber neuropathy (SFN), both of which might explain, at least in part, the development of 'dysautonomia' reported in many ASIA patients.

The risk of osteoporosis in patients with ankylosing spondylitis-A large retrospective matched cohort study.

BACKGROUND: Ankylosing spondylitis (AS) is associated with increased bone turnover and systemic inflammation. Osteoporosis is common but frequently underappreciated in AS, studies regarding the incidence of osteoporosis in AS are limited and based on small cohorts. The aim of this study is to assess the risk of osteoporosis in patients with AS compared to matched controls. METHODS: A population based retrospective cohort study using data retrieved from a large electronic medical record in Israel, the Clalit health services. Included patients that were diagnosed with AS from January 2002 to December 2018 were followed for development of osteoporosis. The incidence of osteoporosis was compared between AS and controls and a logistic regression model was used to assess the interaction between AS and osteoporosis. RESULTS: The study included 5476 AS patients, and 27,657 age- and sex-frequency matched controls. The incidence of osteoporosis in AS patients was significantly higher than controls (4.7% vs 2.8%, p<0.001) in the whole cohort as well as when stratified by sex. Osteoporosis developed earlier in patients with AS versus controls (4.1 vs 5.2 years, p<0.001). In multivariate analysis and after adjustment to several potential confounders, AS was found to independently associated with osteoporosis (HR 1.83, 95%CI 1.58-2.11, p<0.0001). CONCLUSIONS: Our study confirms the higher incidence and earlier development of osteoporosis in patients with AS. Such finding highlights the increased need of awareness and earlier detection of such comorbidity allowing prompt treatment to prevent undesired sequalae including increased risk of fractures.