Cardiovascular Risk Assessment in Rheumatoid Arthritis: Accelerated Atherosclerosis, New Biomarkers, and the Effects of Biological Therapy.

Rheumatoid arthritis (RA), one of the most common of the chronic inflammatory autoimmune diseases (CIADs), is recognized as an independent cardiovascular risk factor. Traditional risk factors such as smoking, arterial hypertension, dyslipidemia, insulin resistance, and obesity are frequently found in RA. Given the increased risk of mortality and morbidity associated with cardiovascular disease (CVD) in RA patients, screening for risk factors is important. Moreover, there is a need to identify potential predictors of subclinical atherosclerosis. Recent studies have shown that markers such as serum homocysteine, asymmetric dimethylarginine, or carotid intima-media thickness (cIMT) are correlated with cardiovascular risk. Although RA presents a cardiovascular risk comparable to that of diabetes, it is not managed as well in terms of acute cardiovascular events. The introduction of biological therapy has opened new perspectives in the understanding of this pathology, confirming the involvement and importance of the inflammatory markers, cytokines, and the immune system. In addition to effects in inducing remission and slowing disease progression, most biologics have demonstrated efficacy in reducing the risk of major cardiovascular events. Some studies have also been conducted in patients without RA, with similar results. However, early detection of atherosclerosis and the use of targeted therapies are the cornerstone for reducing cardiovascular risk in RA patients.

Comprehensive Assessment of Multiple Sclerosis: From Immunotherapy and Immunopathogenesis to Predictive Biomarkers.

Background & Objective: Multiple sclerosis (MS) is an inflammatory neurological disorder that affects the central nervous system (CNS) and causes individuals to experience a variety of cognitive and physical problems. As proven by two decades of clinical experience with immunomodulatory therapies for MS, the disease progresses and relapses through several immunological pathways. New medicines aimed at remyelination and neurodegeneration are being developed; however, they need stronger evidence before being introduced into routine clinical care. The purpose of this study was a thorough assessment of MS immunopathology and predictive biomarkers. Methods: Immunotherapy, immunopathogenesis, and prognostic biomarkers were all parts of the search method. Only publications in English were considered for inclusion in the study. For that purpose, we went through the current state of knowledge around MS immunopathology and related biomarkers. Immunology, as well as the identification of increased inflammation as an important component of neurodegeneration, shaped our understanding of this disease aetiology. The relevant sources examined covered the years 2015-2021. Conclusion: We found biomarkers in the cerebrospinal fluid and blood that might be used for the prediction and diagnosis of MS, as well as for measuring treatment response and adverse effects. Many variables, including the role of some infectious organisms and the impact of environmental and social factors, might contribute to the immunological dysfunctions seen in MS. Patients with MS may benefit from better therapy options if a better understanding of MS biomarkers and immune response mechanisms would be obtained.

Immune-related conditions and cancer-specific mortality among older adults with cancer in the United States.

Immunity may play a role in preventing cancer progression. We studied associations of immune-related conditions with cancer-specific mortality among older adults in the United States. We evaluated 1 229 443 patients diagnosed with 20 common cancer types (age 67-99, years 1993-2013) using Surveillance Epidemiology and End Results-Medicare data. With Medicare claims, we ascertained immune-related medical conditions diagnosed before cancer diagnosis (4 immunosuppressive conditions [n = 3380 affected cases], 32 autoimmune conditions [n = 155 766], 3 allergic conditions [n = 101 366]). For each cancer site, we estimated adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for cancer-specific mortality associated with each condition, applying a Bonferroni cutoff for significance (P < 5.1 × 10-5 ). Bayesian metaanalysis methods were used to detect patterns across groups of conditions and cancers. We observed 21 associations with cancer-specific mortality at the Bonferroni threshold. Increased cancer-specific mortality was observed with rheumatoid arthritis for patients with melanoma (aHR 1.51, 95% CI 1.31-1.75) and breast cancer (1.24, 1.15-1.33)), and with hemolytic anemia for bladder cancer (2.54, 1.68-3.82). Significant inverse associations with cancer-specific mortality were observed for allergic rhinitis (range of aHRs: 0.84-0.94) and asthma (0.83-0.95) for cancers of the lung, breast, and prostate. Cancer-specific mortality was nominally elevated in patients with immunosuppressive conditions for eight cancer types (aHR range: 1.27-2.36; P-value range: 7.5 × 10-5 to 3.1 × 10-2 ) and was strongly associated with grouped immunosuppressive conditions using Bayesian metaanalyses methods. For older patients with several cancer types, certain immunosuppressive and autoimmune conditions were associated with increased cancer-specific mortality. In contrast, inverse associations with allergic conditions may reflect enhanced immune control of cancer.

The Role of T Cells in Ovarian Physiology and Infertility.

Infertility affects one in six couples worldwide, with more than 48 million couples affected internationally. The prevalence of infertility is increasing which is thought to be attributed to delayed child-bearing due to socioeconomic factors. Since women are more prone to autoimmune diseases, we sought to describe the correlation between ovarian-mediated infertility and autoimmunity, and more specifically, the role of T cells in infertility. T cells prevent autoimmune diseases and allow maternal immune tolerance of the semi-allogeneic fetus during pregnancy. However, the role of T cells in ovarian physiology has yet to be fully understood.

Assessment of Cardiac Risk in Women with Autoimmune Disease.

PURPOSE OF REVIEW: The purpose of our review was to evaluate current standards in clinical practice in determining overall cardiac risk in female patients with chronic rheumatologic diseases. We hoped to not only summarize known cardiac manifestations of various chronic rheumatologic diseases but also determine the effectiveness of new risk scores in determining cardiac risk in this patient population. RECENT FINDINGS: Chronic rheumatologic diseases have been associated with various cardiac manifestations for some time, with initial studies involving risk of coronary artery disease (CAD) in rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). However, recent studies have shown numerous other cardiac manifestations associated with these and other chronic rheumatologic diseases. Risk scores have been used for several decades to help determine overall cardiac risk in the general population, but these risk scores have notoriously underestimated the risk of cardiac disease in woman and in patients with chronic rheumatologic diseases. These diseases, often with a female predominance, can impact long-term mortality and have devastating consequences if not monitored and treated appropriately. Thus, new risk scores have been developed over the last several years to help improve detection and awareness of cardiac disease in these patients. Novel modified risk scores have found some success at improving the detection of cardiac disease in patients with chronic rheumatologic diseases. Further studies looking at these risk scores need to determine the accuracy of these scores and where they fall short. With the advent of advanced imaging technologies, future risk scores may involve certain imaging-based markers to help guide accurate risk determination.

Treatment Equity in the Immunotherapy Era: Options for Patients with Both Autoimmune Disease and GU Cancers.

Numerous immunotherapeutic agents, such as immune checkpoint inhibitors (ICIs), have been approved for the treatment of genitourinary (GU) malignancies. While ICIs have improved treatment outcomes and expanded treatment options, they can cause immune-related adverse events (irAEs). The scope of irAEs is broad, and this paper aims to review the rheumatologic side effects associated with immunotherapy drugs approved for bladder cancer and renal cell carcinoma. IrAEs are graded by the common terminology criteria for adverse events (CTCAE), which ranges from 1 to 5. The management of irAEs includes corticosteroids or other immunosuppressive therapies, and it may require discontinuation of immunotherapy. Several real world experience studies suggest that most patients with pre-existing autoimmune diseases treated with ICI did not have to discontinue treatment due to immune-mediated side effects. While data suggest autoimmune side effects are manageable, patients with pre-existing autoimmune diseases are often excluded from immunotherapy clinical trials. Better understanding of these irAEs will improve its safety and expand its use in those with underlying autoimmune disease.

Polycystic ovary syndrome: epidemiologic assessment of prevalence of systemic rheumatic and autoimmune diseases.

BACKGROUND: Polycystic ovary syndrome (PCOS) causes anovulation and hyperandrogenism. Hormonal imbalance is known to contribute to systemic autoimmune diseases. OBJECTIVE: To examine the frequency of certain rheumatic diseases in PCOS. METHODS: This retrospective study utilized and analyzed electronic medical records from January 2004 through February 2020. A diagnosis of PCOS and specified rheumatic diseases was searched using ICD-9 and ICD-10 codes. A total of 754 adult patients with PCOS and 1,508 age- and body mass index-matched patients without PCOS were included. Frequencies of the rheumatic diseases were compared between PCOS and non-PCOS subjects or literature data. RESULTS: The prevalence of rheumatoid arthritis (RA) was found to be 2.25% (17/737) in the PCOS patients, numerically higher than 1.26% (19/1489) in the non-PCOS subjects. The difference was significant with a confidence level of 90% (1.04-3.15) but not at 95% with an odds ratio of 1.808 (95% CI = 0.934-3.4, p = 0.0747). When compared with the literature data from the US female population, the prevalence of RA in PCOS patients was significantly higher (2.25% vs. 1.40%, p < 0.0001). Among the autoimmune diseases examined, both systemic sclerosis (0.40% vs. 0.0%, p = 0.0369) and undifferentiated connective tissue disease (0.53% vs. 0.0%, p = 0.0123) were significantly more frequent in the PCOS patients than the non-PCOS. Additionally, PCOS patients had a significantly higher frequency of osteoarthritis than non-PCOS patients (5.44% vs. 2.92%, p = 0.0030) with an odds ratio of 1.913 (95% CI = 1.239-2.955). CONCLUSION: We have shown unprecedentedly that certain rheumatic diseases are more prevalent in PCOS. This study provides important insight into autoimmunity in association with PCOS. Key Points • Polycystic ovary syndrome is postulated to cause systemic autoimmune disease due to its hormonal imbalance. • We conducted the first epidemiologic assessment of the prevalence of systemic autoimmune diseases. • Certain autoimmune and rheumatic diseases are more prevalent in polycystic ovary syndrome.

Comparison of frailty associated factors between older adult patients with rheumatoid arthritis and community dwellers.

PURPOSE: To determine whether frailty associated factors differ between community dwellers and older adult patients with rheumatoid arthritis (RA). METHODS: We used the cross-sectional data for patients with RA from the RA epidemiological quality-of-life study (n = 210, mean age 71.8 ± 3.7 years) and community dwellers from the Japan Gerontological Evaluation Study (n = 53,255, mean age 71.7 ± 4.0 years). Frailty status was assessed using the Kihon Checklist (KCL), and the primary outcome was frailty (KCL score ≥8 points). Information on predictor variables, including age, sex, marital status, educational level, body mass index (BMI), drinking and smoking status and social participation were obtained from a standardized questionnaire. We employed Poisson regression to calculate the prevalence ratio (PR) of frailty according to its predictors. RESULTS: We found frailty in 37.6% of the patients with RA and 15.7% of the community dwellers. In the multivariate models, BMI and social participation were independently associated with frailty in patients with RA (BMI <18.5: PR, 1.62; 95% confidence interval [CI] 1.09-2.41. BMI ≥25.0: PR, 1.81; 95% CI 1.20-2.71. Active social participation: PR, 0.61; 95% CI 0.42-0.87) and community dwellers (BMI <18.5: PR, 1.77; 95% CI 1.67-1.88. BMI ≥25.0: PR, 1.27; 95% CI 1.22-1.33. Active social participation: PR, 0.46; 95% CI 0.44-0.48). All other predictors were significantly associated with frailty in the community dwellers. CONCLUSION: Maintaining appropriate body weight and participating in social activities are important for preventing frailty in patients with RA as well as community dwellers.

Burden and cost of comorbidities in patients with neuromyelitis optica spectrum disorder.

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) is associated with various comorbidities, including non-autoimmune and autoimmune conditions. The burden and cost of illness for NMOSD are unclear, particularly in the context of comorbidities. METHODS: Claims data from IBM MarketScan Commercial and Medicare Supplemental Databases between 2014 and 2018 were analyzed. Patients with NMOSD were specified as having inpatient or outpatient claims for NMOSD diagnosis or specific NMOSD symptoms claims and no subsequent claims for multiple sclerosis (MS) or use of MS disease-modifying therapy (DMT). Continuous enrollment ≥ 6 months before and ≥ 1 year after the first claim (index date) was required for study inclusion. Total costs stratified by comorbidities within 12 months post-index date were calculated per patient and compared 1:5 with matched non-NMOSD controls. RESULTS: A total of 162 patients with NMOSD and 810 non-NMOSD controls were evaluated. A significantly higher proportion of NMOSD patients had comorbidities than non-NMOSD controls (66.7% vs 41.5%; P < 0.001). Concomitant autoimmune disease occurred in 19.1% vs 4.9% (P < 0.001) of patients with NMOSD vs non-NMOSD controls. NMOSD patients incurred significantly higher total median (interquartile range) healthcare costs per patient ($68,386.48 [$23,373.54-$160,862.70]) than matched non-NMOSD controls with autoimmune disease ($17,215.13 [$6715.48-$31,441.93]; P < 0.001) or patients with NMOSD without autoimmune comorbidity ($23,905.42 [$8632.82-$67,251.54]; P = 0.022). Similarly, patients with NMOSD and non-autoimmune comorbidities incurred higher median healthcare costs than matched controls. CONCLUSIONS: Patients with NMOSD experience significant disease burden and cost that are amplified by comorbidities. Effective therapies are needed, particularly for patients with concomitant autoimmune disease.

Applications of Protein Microarrays in Biomarker Discovery for Autoimmune Diseases.

Dysregulated autoantibodies and cytokines were deemed to provide important cues for potential illnesses, such as various carcinomas and autoimmune diseases. Increasing biotechnological approaches have been applied to screen and identify the specific alterations of these biomolecules as distinctive biomarkers in diseases, especially autoimmune diseases. As a versatile and robust platform, protein microarray technology allows researchers to easily profile dysregulated autoantibodies and cytokines associated with autoimmune diseases using various biological specimens, mainly serum samples. Here, we summarize the applications of protein microarrays in biomarker discovery for autoimmune diseases. In addition, the key issues in the process of using this approach are presented for improving future studies.

Burden of illness among subgroups of patients with primary Sjögren's syndrome and systemic involvement.

OBJECTIVES: To describe how patients with primary SS (pSS) and systemic organ involvement are classified and clustered in routine practice. METHODS: This multinational, cross-sectional survey of real-world quantitative data was conducted across Europe and the US. Rheumatologists who treated seven or more adult patients per month with pSS and current/past systemic manifestations undertook a survey before completing a patient record form capturing demographic, clinical and treatment information for their next six eligible patients. Patients with a completed patient record form were invited to complete a patient self-completion questionnaire capturing insights into their disease and treatment. Subgroups were defined by physicians' assessment of disease severity; clusters were derived based on key clinical characteristics using latent class analysis. RESULTS: Rheumatologists completed 316 physician surveys and 1879 patient record forms; 888 patients completed the patient self-completion questionnaire. pSS severity reflected organ involvement and symptomatology. Latent class analysis produced five clusters distinguished by the organ systems involved and the presence of pain and fatigue symptoms at the time of the survey. A minority of patients [n = 67 (4%)] were categorized with multiple organ involvement and the highest frequency of pain and fatigue. A total of 324 patients (17%) were categorized as 'low burden'. The remaining three clusters exhibited high frequencies of articular involvement but were distinguished by the extent of other organ system involvement. CONCLUSION: Cluster analysis using a real-world cohort of patients with pSS and systemic organ involvement highlights the heterogeneous presentation of patients with pSS and confirms the importance of pain and fatigue as well as organ involvement when determining disease burden.

A Bayesian approach to restricted latent class models for scientifically structured clustering of multivariate binary outcomes.

This paper presents a model-based method for clustering multivariate binary observations that incorporates constraints consistent with the scientific context. The approach is motivated by the precision medicine problem of identifying autoimmune disease patient subsets or classes who may require different treatments. We start with a family of restricted latent class models or RLCMs. However, in the motivating example and many others like it, the unknown number of classes and the definition of classes using binary states are among the targets of inference. We use a Bayesian approach to RLCMs in order to use informative prior assumptions on the number and definitions of latent classes to be consistent with scientific knowledge so that the posterior distribution tends to concentrate on smaller numbers of clusters and sparser binary patterns. The paper derives a posterior sampling algorithm based on Markov chain Monte Carlo with split-merge updates to efficiently explore the space of clustering allocations. Through simulations under the assumed model and realistic deviations from it, we demonstrate greater interpretability of results and superior finite-sample clustering performance for our method compared to common alternatives. The methods are illustrated with an analysis of protein data to detect clusters representing autoantibody classes among scleroderma patients.

Understanding the Disproportionate Burden of Rheumatic Diseases in Indigenous North American Populations.

Studies have described a high incidence and prevalence of several rheumatic diseases in indigenous North American populations. Conditions studied most frequently with consistently high burden of disease include rheumatoid arthritis, spondyloarthritis, and systemic lupus erythematosus. Crystal-induced arthritis has been reported to have a lower prevalence than expected. Information about genetic and environmental risk factors is available for some of these conditions. An awareness of the epidemiology of rheumatic diseases in indigenous North American populations is important for clinicians involved in caring for patients in these populations as well as for planning health service delivery in these communities.

The economic burden of systemic lupus erythematosus in commercially- and medicaid-insured populations in the United States.

OBJECTIVE: To estimate the economic burden of systematic lupus erythematous (SLE), stratified by disease severity, in commercially- and Medicaid-insured US populations. METHODS: Adults (≥18 years) with SLE treated with antimalarials, selected biologics, immunosuppressants, and systemic glucocorticoids (2010-2014) were identified within the commercial and Medicaid insurance IBM MarketScan® databases (index date = first SLE medication claim). Both cohorts were stratified into mild (receiving antimalarial or glucocorticoid monotherapy ≤5 mg/day) versus moderate/severe SLE (receiving glucocorticoids >5 mg/day, biologic, immunosuppressant, or combination therapy) during a 6-month exposure period. All-cause healthcare utilization and costs were evaluated during the 12 months following the exposure period. RESULTS: Among 8231 commercially-insured patients, 32.6% had mild and 67.4% had moderate/severe SLE by our definition. Among 802 Medicaid-insured patients, 25.2% had mild and 74.8% had moderate/severe SLE. Adjusted mean total healthcare costs, excluding pharmacy, for moderate/severe SLE patients were higher than for mild SLE patients in the commercially-insured ($39,021 versus $23,519; p < 0.0001) and Medicaid-insured populations ($56,050 versus $44,932; p = 0.06). In both SLE severity populations total unadjusted costs were significantly higher among Medicaid-insured than commercially-insured patients. CONCLUSION: Commercially-insured patients with treatment suggesting moderate/severe SLE incurred significantly higher adjusted mean healthcare costs, excluding pharmacy, compared with mild SLE patients. While not reaching statistical significance, moderate/severe Medicaid-insured patients had higher costs then mild SLE patients. Total unadjusted healthcare costs were significantly higher among Medicaid-insured than commercially-insured patients. These differential costs are important to consider and monitor when implementing interventions to improve health and reduce healthcare spending for SLE.

Treatment patterns and medical cost of systemic lupus erythematosus patients in Japan: a retrospective claims database study.

Aim: To describe the characteristics and medication treatment patterns, healthcare resource utilization (HRU), and associated costs in Japanese patients with systemic lupus erythematosus (SLE).Methods: Claims data from the Japan Medical Data Center (JMDC) database were used to identify patients with SLE-related claims from 2010 to 2017. Algorithms were developed to retrospectively categorize patients by disease severity, treatment experience, and SLE-related manifestations such as lupus nephritis and central nervous system lupus. Descriptive and multivariate analyses were used to describe treatment pattern and estimate HRU and associated costs for the SLE cohort overall and by disease severity and complications.Results: Among 4,733 eligible patients, 2,072 (43.8%) were treatment naïve, 2,214 (46.8%) were previously treated for SLE, and 447 (9.4%) did not receive any treatment. Mean (SD) age of the total SLE cohort was 45.2 (13.1) years and mean (SD) follow-up duration was 1,137.3 (758.0) d. Based on disease severity, 1,383 (29.2%) patients had mild, 2,619 (55.3%) patients had moderate, and 731 (15.4%) patients had severe SLE. Patients on glucocorticoids (both oral and parenteral) received add-on medications the most (35.5%, p < .001). Mean annual cost per SLE patient in the post-index period, inclusive of hospitalizations, outpatient visits, and pharmacy was ¥436,836; ¥1,010,772; and ¥2,136,780 for patients with mild, moderate, and severe SLE, respectively.Limitations: The database only captured information on patients up to 75 years of age. Due to the nature of the database, biases regarding conditions that attribute to the spectrum of SLE severity, flare incidences, or individual physical status cannot be ruled out.Conclusions: This study describes the treatment patterns and economic burden experienced by Japanese patients with SLE. The results highlight an unmet need to derive better treatment strategies for patients with SLE to effectively address the disease burden in Japan.

Mitigation of Rheumatic Arthritis in a Rat Model via Transdermal Delivery of Dapoxetine HCl Amalgamated as a Nanoplatform: In vitro and in vivo Assessment.

PURPOSE: Dapoxetine HCl (DH), a selective serotonin reuptake inhibitor, may be useful for the treatment of rheumatic arthritis (RA). The purpose of this study was to investigate the therapeutic efficacy of transdermal delivery of DH in transethosome nanovesicles (TENVs). This novel delivery of DH may overcome the drawbacks associated with orally administered DH and improve patient compliance. METHODS: DH-TENV formulations were prepared using an injection- sonication method and optimized using a 33 Box-Behnken-design with Design Expert® software. The TENV formulations were assessed for entrapment efficiency (EE-%), vesicle size, zeta potential, in vitro DH release, and skin permeation. The tolerability of the optimized DH-TENV gel was investigated using a rat skin irritation test. A pharmacokinetic analysis of the optimized DH-TENV gel was also conducted in rats. Moreover, the anti-RA activity of the optimized DH-TENV gel was assessed based on the RA-specific marker anti-cyclic cirtullinated peptide antibody (anti-CCP), the cartilage destruction marker cartilage oligomeric matrix protein (COMP) and the inflammatory marker interleukin-6 (IL-6). Level of tissue receptor activator of nuclear factor kappa-Β ligand (RANKL) were also assessed. RESULTS: The optimized DH-TENV formulation involved spherical nanovesicles that had an appropriate EE- % and skin permeation characteristic. The DH-TENV gel was well tolerated by rats. The pharmacokinetics analysis showed that the optimized DH-TENV gel boosted the bioavailability of the DH by 2.42- and 4.16-fold compared to the oral DH solution and the control DH gel, respectively. Moreover, it significantly reduced the serum anti-CCP, COMP and IL-6 levels and decreased the RANKL levels. Furthermore, the DH-TENV gel attenuated histopathological changes by almost normalizing the articular surface and synovial fluid. CONCLUSION: The results indicate that DH-TENVs can improve transdermal delivery of DH and thereby alleviate RA.

Economic Analysis of the Use of Anti-DFS70 Antibody Test in Patients with Undifferentiated Systemic Autoimmune Disease Symptoms.

OBJECTIVE: In patients with antinuclear antibodies (ANA) and undifferentiated features of systemic autoimmune disease, the coexistence of monospecific anti-dense fine speckled 70 (anti-DFS70) antibodies is associated with a lower risk of progression to overt disease. Therefore, they might help in correctly classifying ANA- positive patients and avoiding unnecessary followup diagnostic procedures. The aim of this study was to analyze the economic effect of the introduction of the anti-DFS70 antibody test in a hospital setting. METHODS: A case-control study was performed to detect monospecific anti-DFS70 antibodies in ANA-positive subjects with undifferentiated features (cases, n = 124) and with a defined systemic autoimmune disease (controls, n = 290). Based on current clinical practice, a decision tree was developed to represent the disease course of patients with undifferentiated features in the subsequent 3 years. A budget impact analysis (BIA) was performed to estimate the effect of implementing the screening for anti-DFS70 antibodies in the case group on the total costs. A sensitivity analysis was conducted to calculate the effect of the uncertainty of the input variables on the results. RESULTS: Among the 124 patients in the case group, 5 (4.0%) tested positive for anti-DFS70 antibodies versus 4/290 (1.4%) in the control group (p = not significant). The mean cost per patient under the current clinical practice decreased from €3274 to €3192 in our scenario. The BIA reports cost savings of €10,128. CONCLUSION: The introduction of anti-DFS70 antibody test would avoid unnecessary followup diagnostic procedures and minimize the use of health resources generated by suspicion of a potential systemic autoimmune disease.