Quality evaluation of the underlying evidence in the updated treatment recommendations for systemic lupus erythematosus.

OBJECTIVES: SLE is a multisystem autoimmune disorder known for its broad clinical spectrum. Recently, the European, British and Latin American rheumatology professional societies [EULAR, British Society for Rheumatology (BSR) and Pan-American League of Associations of Rheumatology (PANLAR)] published updated recommendations for SLE management. The objective of this study was to characterize the data supporting the updated recommendations, with the goal of highlighting areas that could benefit from additional high-quality research. METHODS: References were compiled from the recently published EULAR, BSR and PANLAR SLE treatment recommendations. Data collected from each study included publication year, treatment regimen, study design, sample size, inclusion and exclusion criteria and relevant SLE diagnostic criteria. Studies with less than 10 patients and those that did not specify the SLE diagnostic criteria used were excluded. RESULTS: Altogether, 250 studies were included in this study. The majority were prospective and retrospective cohorts (72%), with only a small percentage of randomized controlled trials (28%). The median (interquartile range) number of patients included was 37 (19-86). The revised ACR 1982 criteria were the most commonly used criteria for SLE diagnosis (52%), followed by the revised ACR criteria from 1997 (27%). Only a small proportion of studies included the use of disease activity scores when defining study population (15%). CONCLUSION: Our study has indicated a scarcity of sufficiently powered high-quality research referenced in the recently published SLE treatment guidelines. Well-designed large-scale studies utilizing the updated 2019 SLE diagnostic criteria are needed to better inform healthcare professionals caring for patients with SLE.

The impact of tocilizumab on anxiety and depression in patients with rheumatoid arthritis.

BACKGROUND: Mood disorders, such as anxiety and depression, are extremely prevalent among patients with rheumatoid arthritis (RA). In this study, we assessed the impact of treatment with tocilizumab (TCZ), an IL-6 antagonist, upon anxiety and depressive symptoms in a cohort of RA patients. MATERIALS AND METHODS: Study participants were adults diagnosed with RA who received a weekly subcutaneous injection of tocilizumab for 24 weeks. We used the Hamilton Depression (HDRS) and Anxiety (HAMA) scores in order to assess the severity of depression and anxiety, respectively. RA disease activity indices and depression and anxiety levels were assessed at baseline, 4 weeks and study completion. RESULTS: Ultimately, 91 patients were included in the study. The mean age was 54 years, and the majority were female (79%). The mean score in all disease activity indices as well as depression and anxiety levels decreased dramatically from baseline to study completion. Sixty patients (66%) demonstrated a significant decrease in anxiety and/or depression levels. When logistic regression was performed, an HDRS score indicative of depression at study baseline demonstrated an independent association with a significant psychiatric response whilst older age and increased baseline weight were negatively associated. HAMA and HDRA scores correlated with the following RA disease activity parameters, respectively; HAQ-DI (r = .4, .42), DAS28 (r = .29, .32) and CDAI (0.28 and 0.33), all of them were statistically significant (P < .01). CONCLUSIONS: This study has demonstrated a favourable impact of TCZ therapy on parameters reflecting depression and anxiety severity in patients with RA.

The long-term prognostic significance of sarcoidosis-associated pulmonary hypertension - A cohort study.

BACKGROUND: Sarcoidosis is a multisystem, chronic, progressive, granulomatous disease. Sarcoidosis-associated pulmonary hypertension is a well described, but not common, complication of sarcoidosis. In small scale studies, it has been previously described as manifestation of advanced disease and was found to be associated increased morbidity and mortality. This study sought to assess the long-term prognostic significance of sarcoidosis-associated pulmonary hypertension (SAPH) by using data obtained from a large population-based registry which contains longitudinal follow-up data. METHODS: Utilizing the records of the largest healthcare provider in Israel, we extracted a cohort consisting of sarcoidosis patients and age-and-sex matched controls. Dates of sarcoidosis registration, pulmonary hypertension and death, as well as anthropometric information and medical comorbidities, were extracted from the database. A multivariate logistic regression model was used to find variables associated with pulmonary hypertension. Cox proportional hazards method and log-rank test were used for survival analysis. RESULTS: The cohort included 3993 sarcoidosis patients and 19,856 controls. Pulmonary hypertension was observed among 269 sarcoidosis patients (6.74%) vs. 400 controls (2.01%). Sarcoidosis was found as independently associated with pulmonary hypertension (OR 3.17). After a mean follow-up of 7.49 years (median 7.24, maximum 17.88 years), 710 (17.8%) of the sarcoidosis patients and 2121 (10.7%) of the controls had died. Both sarcoidosis and pulmonary hypertension were found to be significantly associated with an increased risk of all-cause mortality (HR 1.82 and HR 2.31, respectively). CONCLUSIONS: SAPH is associated with a poor prognosis. Proper screening methods may assess whether early identification and treatment improve life expectancy.

Patients With Vasculitides Admitted to the Intensive Care Unit: Implications From a Single-Center Retrospective Study.

BACKGROUND: Vasculitides are a group of disorders characterized by inflammation of vessels. Vasculitides may have life-threatening complications with significant morbidity and mortality; however, information regarding the outcome and prognosis of patients with vasculitides requiring intensive care unit (ICU) is scarce. METHODS: Data of patients with vasculitides admitted to the ICU of the Sheba Medical Center between the years 2000 and 2014 were retrieved retrospectively. Continuous variables were computed as mean (standard deviation), whereas categorical variables were recorded as percentages. In order to investigate the impact of clinical variables on mortality, Student t test and χ2 analyses were performed. RESULTS: Twenty-five patients with vasculitides were admitted to the ICU during the study period with mean age of 52 ± 14 years and sex ratio of male/female: 12/13. The mortality rate among these patients was 48%. Leading causes for ICU admission were infection (64%), disease exacerbation (34%), and hemorrhage (16%), while respiratory or cardiovascular involvement accounted for the majority of mortality during admission. An elevated Sequential Organ Failure Assessment (SOFA) score was significantly associated with mortality (P = .041). CONCLUSION: Our study confirms the high mortality rate among patients with vasculitides who require ICU care as well as the roles of infection and disease flare-up as causes for admission. An elevated SOFA score was found to be predictive of mortality.

The Powers of Flowers: Evaluating the Impact of Floral Therapy on Pain and Psychiatric Symptoms in Fibromyalgia.

BACKGROUND: Fibromyalgia is a syndrome of unknown etiology that is characterized by widespread pain, which severely impairs quality of life. Several forms of occupational and alternative therapy have demonstrated beneficial effects in fibromyalgia patients. OBJECTIVES: To assess the effects of participation in a floral design course on physical and psychiatric symptoms in a cohort of fibromyalgia patients. METHODS: This study was conducted as an observational study. Women diagnosed with fibromyalgia over the age of 18 were recruited to participate in one of two 12-week flower design (floristry) courses. Demographic details, disease activity indices, and anxiety and depression scores were calculated for all participants at baseline, week 12, and study completion. Physical and mental health of the two groups were compared throughout the study time-points. RESULTS: The study was completed by 61 female fibromyalgia patients who were included in the final analyses; 31 patients participated in the first floristry course and 30 in the second. Significant improvements in the 36-Item Short Form Survey physical and mental health components, visual analog scale, Fibromyalgia Impact Questionnaire, Hamilton Anxiety Rating Scale, and Hamilton Depression Rating Scale scores for the entire study population and for each group separately could be seen following participation in each floristry course. CONCLUSIONS: Participation in a floristry course may lead to a significant improvement in pain and psychiatric symptoms in fibromyalgia patients. These findings highlight the potential benefit of utilizing occupational therapy programs, such as a floristry course, for improving quality of life in fibromyalgia.

Borderline positive antineutrophil cytoplasmic antibodies (ANCA)-PR3/MPO detection in a large cohort tertiary center: lessons learnt from a real-life experience.

BACKGROUND: Enzyme-linked immunosorbent assay (ELISA) and indirect immunofluorescence (IIF) are the best strategies for antineutrophil cytoplasmic antibodies (ANCA) detection. In a minority of subjects, ELISA-based ANCA testing may result in a borderline positive titre. Therefore, we assessed the clinical significance of such a result. METHODS: This is a retrospective study, which included all subjects screened for ANCA subtypes (myeloperoxidase (MPO) or proteinase-3 (PR3)) with subsequent identification of borderline positive results, as determined by ELISA and retested using IIF. The demographic, clinical and laboratory data of subjects with borderline positive ANCA test results were extracted from their medical records. RESULTS: A total of 14,555 PR3/MPO-ANCA tests were performed with ELISA during the study period (2006-2016). Of the 14,555 PR3-ANCA antibody tests that were performed, 94 were borderline positive (titre 0.9-1.1), and of 14,555 MPO-ANCA antibody tests, 43 were borderline positive (titre 0.9-1.1). The male-to-female ratio was 1:1.08 and the mean age was 50.95±21.79 years. Four MPO-ANCA (9.30%) and 11 PR3-ANCA (11.70%) antibody borderline samples resulted positive on IIF testing. Subjects with borderline positive MPO-ANCA were found to have a poorer outcome in terms of renal failure and the requirement of dialysis. CONCLUSIONS: Subjects with borderline positive MPO-ANCA and positive p-ANCA (IIF) seem to have a less favorable outcome. Physicians should be aware of these findings and possibly perform a closer follow-up and routine screening for these subjects.

Plasmodium malariae in Israeli Travelers: A Nationwide Study.

BACKGROUND: Little is known about Plasmodium malariae, a relatively rare cause of malaria in returned travelers. Recently, polymerase chain reaction (PCR) use for malaria diagnosis has enhanced specificity of P. malariae detection. The study objective was to describe the unique aspects of P. malariae diagnosis and clinical course in travelers. METHODS: Malaria is a reportable disease in Israel. All PCR-proven P. malariae monoinfections in Israeli travelers between January 2008 and January 2017 were retrieved from the Ministry of Health Reference Parasitology Laboratory. Data regarding method and timing of diagnosis, clinical characteristics, and laboratory testing were collected from patient charts. RESULTS: Eighteen patients with P. malariae were included. All cases were acquired in Africa. During the study period, the relative proportion of P. malariae increased (2%-10% of all malaria cases). Malaria was identified by blood smear in 10 of 18 patients (56%) on admission, and by rapid antigen test in 5 of 18 (29%) patients only, while P. malariae speciation was correctly identified by smear in 2 of 18 (11%) patients. Though all patients reported fever, only 4 of 18 (22%) described a quartan fever course. In 7 of 18 (39%) patients, malaria was contracted despite prophylactic treatment. Five patients had prolonged prepatent periods (median, 55 days), all of whom received prior prophylaxis. CONCLUSIONS: The relative proportion of P. malariae is on the rise. Diagnosis in routine clinical settings is inadequate due to the low sensitivity and specificity of blood smears. PCR should be considered when clinical suspicion is high. Prophylaxis failure, which caused delayed clinical presentation, was documented.

Stroke among Rheumatoid Arthritis Patients: Does Age Matter? A Real-Life Study.

BACKGROUND/AIMS: Rheumatoid arthritis (RA) is a chronic, debilitating autoimmune disease that affects the joints and it is known to be associated with cardiovascular morbidity. However, the association between RA and stroke among different age groups has not been explored. The objective of our study was to evaluate the association between RA and stroke in different age strata. METHODS: Cross-sectional study, utilizing the database of Israel's largest healthcare provider. The proportion of stroke was compared between patients diagnosed with RA and age- and gender-matched controls. The study sample was divided into 2 age groups: young (≤65 years) and elderly (>65 years). Multivariable analysis was performed using logistic regression. RESULTS: The study included 11,782 RA patients and 57,973 age- and gender-matched controls. RA patients, primarily young, had more cardiovascular risk factors than controls. Stroke rates were significantly elevated among young RA patients in comparison with controls (3.74 vs. 2.20%, respectively, p < 0.001). In multivariate analysis, RA was found to be independently associated with stroke (OR 1.18, 95% CI 1.09-1.28). CONCLUSION: RA is independently associated with stroke, especially among RA patients under 65 years, for whom cardiovascular risk factors were more prominent. Physicians should advise RA patients to manage their risk factors strictly.

Optimizing Anti-TNF-α Therapy: Serum Levels of Infliximab and Adalimumab Are Associated With Mucosal Healing in Patients With Inflammatory Bowel Diseases.

BACKGROUND & AIMS: It is not clear what serum levels of anti-tumor necrosis factor are associated with reduced intestinal inflammation in patients with inflammatory bowel disease (IBD). We aimed to identify serum levels of infliximab and adalimumab associated with mucosal healing in patients with IBD and to evaluate the putative gain in control of inflammation by incremental increases in drug levels. METHODS: We performed a retrospective cross-sectional study of 145 patients with IBD treated with infliximab (n = 78) or adalimumab (n = 67) at a medical center in Israel from 2009 through 2014. We collected data from colonoscopy examinations; mucosal healing was defined as simple endoscopic score of <3 or a Mayo score ≤1. These data were compared with serum levels of anti-tumor necrosis factor agents, clinical scores, and levels of C-reactive protein. RESULTS: Median serum levels of infliximab and adalimumab were significantly higher in patients with mucosal healing than patients with active disease (based on endoscopy) (for infliximab, 4.3 vs 1.7 µg/mL, P = .0002; for adalimumab, 6.2 vs 3.1 µg/mL, P = .01). Levels of infliximab above 5 µg/mL (area under the curve = 0.75; P < .0001) and levels of adalimumab above 7.1 µg/mL (area under the curve = 0.7; P = .004) identified patients with mucosal healing with 85% specificity. Increasing levels of infliximab beyond 8 µg/mL produced only minimal increases in the rate of mucosal healing, whereas the association between higher level of adalimumab and increased rate of mucosal healing reached a plateau at 12 µg/mL. In patients with measurable levels of infliximab >3 µg/mL, the presence of antibodies to infliximab was associated with a lower rate of mucosal healing compared with patients with similar drug level without antibodies (16% vs 50%, respectively; P = .003). CONCLUSIONS: In a retrospective study, we found significant association between serum levels of anti-tumor necrosis factor agents and level of mucosal healing. We propose that serum levels of 6-10 µg/mL for infliximab and 8-12 µg/mL for adalimumab are required to achieve mucosal healing in 80%-90% of patients with IBD, and that this could be considered as a "therapeutic window." Exceeding these levels produces only a negligible gain in proportion of patients with mucosal healing.

Evaluating the Impact of Black Box Warning Updates on the Reporting of Drug-Related Adverse Events: a Cross Sectional Study of the FAERS Database.

BACKGROUND: The Food and Drug Administration (FDA)'s Adverse Event Reporting System (FAERS) is a post-marketing surveillance system which relies on spontaneous reports of adverse drug reactions (ADRs). Our objective was to evaluate how black box warning (BBW) updates impact ADR reporting rates. RESEARCH DESIGN AND METHODS: We searched MEDWATCH for all BBW updates issued between January 2014 and December 2016 and categorized them as new, major, and minor. Rates of relevant ADR reports from the FAERS database in the 4 years preceding and following a BBW update were assessed among the different BBW categories. RESULTS: Forty BBW updates were included (16 major, 3 new, and 21 minor). A meaningful increase in the proportion of relevant ADRs of all ADRs reported following BBW updates was documented for 53% of new or major updates and 24% of minor updates (p = 0.06). The median percentage of reported relevant ADRs increased by 5% following new and major BBW updates and decreased by 30% following minor BBW updates (p = 0.3). CONCLUSIONS: Reporting of adverse events to the FAERS database is affected by the severity and timing of related BBW updates, highlighting the drawbacks of spontaneous reporting systems. Regulators should promote proactive pharmacovigilance strategies to cope with these limitations.

Twenty Years of Targeted and Biologic Immunomodulatory Drugs: Postmarketing Modifications of Drug Labels Approved by the US Food and Drug Administration.

OBJECTIVE: To determine the extent and characteristics of postmarketing safety issues associated with targeted and biologic immunomodulatory drugs. METHODS: We searched Drugs@FDA to identify immunomodulatory drugs approved between January 1, 1998, and December 31, 2017. Supporting studies characteristics, regulatory pathways, and label modifications from approval to May 2020 were collected from drug labels. RESULTS: The study cohort included 31 drugs, mostly (n=23, 74%) monoclonal antibodies. The most common indications were rheumatologic disorders (n=10, 32%). A total of 372 postmarketing safety-related label modifications were identified, with a median duration of 5 years (interquartile range [IQR], 32 to 105 months) following initial approval. Most drugs were affected by modifications of warnings and precautions (n=25, 81%), 10 drugs (32%) were affected by black box warnings, and 3 drugs (10%) were withdrawn from the market. The most common safety issues were related to infections (n=109, 27%) followed by immunologic phenomena (n=99, 24%). The most common data source was postmarketing reports to pharmacovigilance programs (n=205, 55%). Drugs approved by the FDA through expedited regulatory pathways (n=12, 39%) had more postmarketing safety issues compared with those approved through regular approval (15.5 vs 9.8 per drug, respectively), with longer durations from approval to identification (6 years; IQR, 38 to 111 months, vs 4 years; IQR, 28 to 95 months). CONCLUSION: Safety issues associated with targeted and biologic immunomodulatory drugs are often identified postmarketing, with substantial time intervals following initial approval. Clinicians should follow updates of the safety profiles of immunomodulatory drugs closely and be vigilant for previously unidentified adverse events.

Suicidal Behavior in Fibromyalgia Patients: Rates and Determinants of Suicide Ideation, Risk, Suicide, and Suicidal Attempts-A Systematic Review of the Literature and Meta-Analysis of Over 390,000 Fibromyalgia Patients.

Background: Suicide is a leading cause of death worldwide, affecting ~800,000 people every year. Fibromyalgia is an extremely prevalent rheumatic disease with a predisposition for comorbid anxiety and depression, which are known risk factors for suicidal behavior. Suicidality and relevant risk factors for suicidal behavior have not been thoroughly studied in patients with fibromyalgia. Objectives: To investigate the risk of suicidal ideation and attempts in patients with fibromyalgia. Methods: A systematic review and meta-analysis was conducted and reported according to the "Preferred Reporting Items for Systematic reviews and Meta-analyses" (PRISMA) standards. Also, the gray literature was extensively searched. Results: Thirteen studies were included in the present systematic review and meta-analysis, including 394,087 fibromyalgia patients. Sample size ranged from 44 to 199,739 subjects, mean age ranged from 45.8 to 54.5 years while the female percentage with fibromyalgia ranged from 17.1 to 100.0%. The overall suicide ideation prevalence was 29.57% (95%CI 1.84-72.07), with an OR 9.12 of (95%CI 1.42-58.77), ranging from 2.34 (95%CI 1.49-3.66) to 26.89 (95%CI 5.72-126.42). Pooled suicide attempt prevalence was 5.69% [95%CI 1.26-31.34], with an OR of 3.12 [95%CI 1.37-7.12]. Suicide risk was higher with respect to the general population with an OR of 36.77 (95%CI 15.55-96.94), as well as suicide events with an HR of 1.38 (95%CI 1.17-1.71). Determinants of suicidality were found to be: employment status, disease severity, obesity and drug dependence, chronic pain and co-morbidities, in particular depression, anxiety, poor sleep, and global mental health. However, in some cases, after adjusting for psychiatric conditions, the threshold of statistical significance was not achieved. Conclusion: Fibromyalgia patients are particularly prone to suicide, in terms of ideation, attempt, risk and events, warranting a pre-emptive screening of their mental health status. Given the few studies available, the high amount of heterogeneity, the evidence of publications bias and the lack of statistical significance when adjusting for underlying psychiatric co-morbidities, further high-quality studies should be conducted. Clinical Trial Registration: ClinicalTrial.gov, identifier 10.17605/OSF.IO/Y4BUE.

Venous thromboembolism events among RA patients.

BACKGROUND: Rheumatoid arthritis (RA) is associated with an increased risk for venous thromboembolism. However, so far, relatively few and small size-based studies have been conducted. We aimed to investigate the link between RA and venous thromboembolism utilizing a large sample of subjects originating from a large data base. MATERIALS AND METHODS: The study was performed utilizing the medical database of Clalit Health Services, the largest healthcare provider in Israel. We enrolled all patients with RA and age- and gender-matched controls. Chi-square and t-tests were used for univariate analysis and a logistic regression model was used for a multivariate analysis. RA patients were compared to controls regarding the proportion of venous thromboembolic events (defined as deep vein thrombosis, pulmonary embolism or both). Multivariate logistic regression was employed to assess factors associated with thromboembolic events. RESULTS: The study included 11,782 patients with RA and 57,973 age- and gender-matched controls. RA patients had a higher rate of venous thromboembolism events compared with controls (6.92% vs. 3.18%, respectively, p<0.001). RA and mean C-reactive protein levels were found to be independently associated with the proportion of thromboembolic events (OR 2.27 for RA and 1.07 for each 1 mg/dL increment of mean C-reactive protein, respectively). CONCLUSION: RA and C-reactive protein levels are independently associated with venous thromboembolic events. Physicians should be aware of such findings and have a lower threshold for suspecting detecting such events in patients with RA, mainly those with mean high levels of C-reactive protein.

A systematic review of precipitating physical and psychological traumatic events in the development of fibromyalgia.

The role of physical and psychological trauma precipitating fibromyalgia is often encountered by physicians, yet a proper systematical review of this association is lacking. Literature searches identified 51 studies which examined the association of fibromyalgia with a preceding traumatic event of physical or emotional nature. The overall quality of evidence of studies included, as assessed by the GRADE criteria, was low, however the majority of studies described a significant association between prior physically traumatic events and the onset of chronic widespread pain or fibromyalgia. Elevated rates of psychological trauma in fibromyalgia patients were demonstrated across the literature and several studies indicate a mediating effect of post-traumatic stress disorder. Potential biological mechanisms for conversion of traumatic events into a chronic pain syndrome, such as fibromyalgia, are discussed.

Folate and B12 Levels Correlate with Histological Severity in NASH Patients.

BACKGROUND: The correlation between abnormal vitamin serum levels and chronic liver disease has been previously described in literature. However, the association between the severity of folate serum levels (B9), vitamin B12 and nonalcoholic steatohepatitis (NASH) has not been widely evaluated. Therefore, the aim of this study was to investigate the existence of such a correlation in a cohort of NASH patients. METHODS: All patients aged 18 years and older who were diagnosed with biopsy-proven NASH at the EMMS hospital in Nazareth during the years 2015-2017 were enrolled in this study. Data regarding demographic, clinical and laboratory parameters was collected. Patients with other liver diseases were excluded. RESULTS: Eighty-three NASH patients were enrolled during the study period. The mean age was 41 ± 11 years and the majority of patients were male. Mean values of folate and B12 were 9.85 ± 10.90 ng/mL and 387.53 ± 205.50 pg/mL, respectively. Half of the patients were presented with a grade 1 steatosis (43.4%), a grade 2 fibrosis (50.6%) and a grade 3 activity score (55.4%). The fibrosis grade was significantly correlated with low folate levels on multivariate analysis (p-value < 0.01). Similarly, low B12 levels were significantly associated with a higher fibrosis grade and NASH activity (p-value < 0.001 and p-value < 0.05 respectively). CONCLUSION: Our study demonstrated a statistically significant correlation between low levels of folate and vitamin B12 with the histological severity of NASH. These findings could have diagnostic and therapeutic implications for patient management and follow-up.

The link between COPD and ankylosing spondylitis: A population based study.

BACKGROUND: Ankylosing spondylitis (AS) is one of the most common and severe subtypes of the spondyloarthropathies. Extra-articular involvement among AS patients, including lung disease, has been described widely. Chronic obstructive pulmonary disease (COPD) has been linked to several autoimmune diseases, however, very few studies have investigated the association between AS and COPD. OBJECTIVE: To assess whether an association exists between AS and COPD. MATERIAL AND METHODS: A population-based cross-sectional study was conducted using data retrieved from the largest electronic medical records database in Israel, the Clalit Health Services (CHS). Patients were defined as having AS or COPD when there was at least one such documented diagnosis in their medical records. The proportion of COPD was compared between AS patients and controls. A logistic regression model was used to estimate the association between AS and COPD in a multivariate analysis adjusted for age, gender and smoking status. RESULTS: The study included 4076 patients with AS and 20,290 age- and sex-frequency matched controls. The proportion of COPD in AS patients was higher than in controls (46% vs. 18%, respectively, p < .001). Multivariate logistic regression demonstrated a robust independent association between AS and COPD (OR 1.225, p = .031). CONCLUSION: Our study supports an association between AS and COPD, further extending the link between COPD and autoimmune diseases. This finding highlights the importance of smoking cessation in AS patients and raises the question of whether COPD screening may be warranted.

Alzheimer's Disease in Systemic Sclerosis Patients: A Nationwide Population-Based Cohort Study.

BACKGROUND: Neurological features are often overlooked in systemic sclerosis (SSc) patients and little is known about the link between dementia and SSc. OBJECTIVES: We sought to investigate whether an association exists between Alzheimer's disease (AD) and SSc, as well as assess the impact of a dual diagnosis on mortality rates, by performing an extensive data analysis on a large subject sample. METHODS: We utilized the medical database of the Clalit-Health-Services in a case-control study. Patients with SSc were compared with age- and sex-matched controls with regard to the prevalence of AD and its impact on their mortality. RESULTS: Our study included 2,431 SSc patients and 12,377 age- and sex-matched controls. The mean age of the study population was 63.32±18.06 years and the female to male ratio was 4.5:1. 134 (5.5%) cases had AD as a co-morbidity in comparison with 749 (5.9%) of the controls. The mortality rate was 12.5% among controls and 26.2% among SSc cases. On the Cox multivariate survival analysis, diagnosis of SSc and AD demonstrated significant HRs (2.35 (95% CI 2.05-2.69, p < 0.0001) and 2.19 (95% CI 1.94-2.48, p < 0.0001), respectively). SSc patients with AD had a relative risk of death of 2.35 (95% CI: 1.44-3.83) in comparison with SSc patients without AD. CONCLUSION: AD is a predictor of death in SSc and therefore preemptive screening may be warranted. Further studies are needed to evaluate whether improvements in the medical regimen for SSc may lead to a reduction in AD development and possibly to increased survival as well.

Vitamin D, autoimmunity and recurrent pregnancy loss: More than an association.

Recurrent pregnancy loss (RPL) affects close to 1% of couples; however, the etiology is known in only about 50% of the cases. Recent studies show that autoimmune dysregulation is a probable cause of RPL, which in some cases may be overlooked. In order for a pregnancy to proceed to term, early modulation of immunologic response is required to induce tolerance to the semi-allogenic fetus. Certain subsets of both the innate and adaptive immune responses play a role in the induction of fetomaternal tolerance. A relatively predominant T-cell helper (Th) 2 and T regulatory (Treg) cell population seem to favor a better pregnancy outcome, whereas Th1 and Th17 cell populations appear to have an opposite effect. Lately, the role of vitamin D in the modulation of immune response was established. Vitamin D has been shown to promote a more favorable environment for pregnancy through various mechanisms, such as enhancement of the shift toward Th2 cells and regulation of immune cell differentiation and cytokine secretion. Therefore, it seems that vitamin D deficiency sways the balance toward a worse outcome and may play a part in recurrent pregnancy loss. This review sheds light on the immunologic changes, which occur in early pregnancy and the regulatory role vitamin D has in the maintenance of this delicate balance.