Increased risk of osteoarthritis in patients with atopic disease.

OBJECTIVES: To determine the incidence of osteoarthrits (OA) in patients with atopic disease compared with matched non-exposed patients. METHODS: We conducted a retrospective cohort study with propensity score matching using claims data from Optum's de-identified Clinformatics Data Mart (CDM) (January 2003 to June 2019) and electronic health record data from the Stanford Research Repository (STARR) (January 2010 to December 2020). We included adult patients without pre-existing OA or inflammatory arthritis who were exposed to atopic disease or who were non-exposed. The primary outcome was the development of incident OA. RESULTS: In Optum CDM, we identified 117 346 exposed patients with asthma or atopic dermatitis (mean age 52 years; 60% female) and 1 247 196 non-exposed patients (mean age 50 years; 48% female). After propensity score matching (n=1 09 899 per group), OA incidence was higher in patients with asthma or atopic dermatitis (26.9 per 1000 person-years) compared with non-exposed patients (19.1 per 1000 person-years), with an adjusted odds ratio (aOR) of 1.58 (95% CI 1.55 to 1.62) for developing OA. This effect was even more pronounced in patients with both asthma and atopic dermatitis compared with non-exposed patients (aOR=2.15; 95% CI 1.93 to 2.39) and in patients with asthma compared with patients with chronic obstructive pulmonary disease (aOR=1.83; 95% CI 1.73 to 1.95). We replicated our results in an independent dataset (STARR), which provided the added richness of body mass index data. The aOR of developing OA in patients with asthma or atopic dermatitis versus non-exposed patients in STARR was 1.42 (95% CI 1.36 to 1.48). CONCLUSIONS: This study demonstrates an increased incidence of OA in patients with atopic disease. Future interventional studies may consider targeting allergic pathways for the prevention or treatment of OA.

Development of Osteoarthritis in Adults With Type 2 Diabetes Treated With Metformin vs a Sulfonylurea.

Importance: Metformin may have a protective association against developing osteoarthritis (OA), but robust epidemiological data are lacking. Objective: To determine the risk of OA and joint replacement in individuals with type 2 diabetes treated with metformin compared with a sulfonylurea. Design, Setting, and Participants: This retrospective cohort study used claims data from the Optum deidentified Clinformatics Data Mart Database between December 2003 and December 2019. Participants included individuals aged 40 years or older with at least 1 year of continuous enrollment and type 2 diabetes. Individuals with type 1 diabetes or a prior diagnosis of OA, inflammatory arthritis, or joint replacement were excluded. Time-conditional propensity score matching was conducted using age, sex, race, Charlson comorbidity score, and treatment duration to create a prevalent new-user cohort. Data were analyzed from April to December 2021. Exposures: Treatment with metformin or a sulfonylurea. Main Outcomes and Measures: The outcomes of interest were incident OA and joint replacement. Cox proportional hazard models were used to calculate adjusted hazard ratios (aHRs) of incident OA and joint replacement. In a sensitivity analysis, individuals only ever treated with metformin were compared with individuals only ever treated with a sulfonylurea, allowing for longer-term follow up of the outcome (even after stopping the medication of interest). Results: After time-conditional propensity score matching, the metformin and control groups each included 20 937 individuals (mean [SD] age 62.0 [11.5] years; 24 379 [58.2%] males). In the adjusted analysis, the risk of developing OA was reduced by 24% for individuals treated with metformin compared with a sulfonylurea (aHR, 0.76; 95% CI, 0.68-0.85; P < .001), but there was no significant difference for risk of joint replacement (aHR, 0.80; 95% CI, 0.50-1.27; P = .34). In the sensitivity analysis, the risk of developing OA remained lower in individuals treated with metformin compared with a sulfonylurea (aHR, 0.77; 95% CI, 0.65-0.90; P < .001) and the risk of joint replacement remained not statistically significant (aHR, 1.04; 95% CI, 0.60-1.82; P = .89). Conclusions and Relevance: In this cohort study of individuals with diabetes, metformin treatment was associated with a significant reduction in the risk of developing OA compared with sulfonylurea treatment. These results further support preclinical and observational data that suggest metformin may have a protective association against the development of OA; future interventional studies with metformin for the treatment or prevention of OA should be considered.

Cytotoxic CD8+ T cells target citrullinated antigens in rheumatoid arthritis.

The immune mechanisms that mediate synovitis and joint destruction in rheumatoid arthritis (RA) remain poorly defined. Although increased levels of CD8+ T cells have been described in RA, their function in pathogenesis remains unclear. Here we perform single cell transcriptome and T cell receptor (TCR) sequencing of CD8+ T cells derived from anti-citrullinated protein antibodies (ACPA)+ RA blood. We identify GZMB+CD8+ subpopulations containing large clonal lineage expansions that express cytotoxic and tissue homing transcriptional programs, while a GZMK+CD8+ memory subpopulation comprises smaller clonal expansions that express effector T cell transcriptional programs. We demonstrate RA citrullinated autoantigens presented by MHC class I activate RA blood-derived GZMB+CD8+ T cells to expand, express cytotoxic mediators, and mediate killing of target cells. We also demonstrate that these clonally expanded GZMB+CD8+ cells are present in RA synovium. These findings suggest that cytotoxic CD8+ T cells targeting citrullinated antigens contribute to synovitis and joint tissue destruction in ACPA+ RA.

Reduced chromatin accessibility to CD4 T cell super-enhancers encompassing susceptibility loci of rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is an inflammatory disease that manifests as a preclinical stage of systemic autoimmunity followed by chronic progressive synovitis. Disease-associated genetic SNP variants predominantly map to non-coding, regulatory regions of functional importance in CD4 T cells, implicating these cells as key regulators. A better understanding of the epigenome of CD4 T cells holds the promise of providing information on the interaction between genetic susceptibility and exogenous factors. METHODS: We mapped regions of chromatin accessibility using ATAC-seq in peripheral CD4 T cell subsets of patients with RA (n=18) and compared them to T cells from patients with psoriatic arthritis (n=11) and age-matched healthy controls (n=10). Transcripts of selected genes were quantified using qPCR. FINDINGS: RA-associated epigenetic signatures were identified that in part overlapped between central and effector memory CD4 T cells and that were to a lesser extent already present in naïve cells. Sites more accessible in RA were highly enriched for the motif of the transcription factor (TF) CTCF suggesting differences in the three-dimensional chromatin structure. Unexpectedly, sites with reduced chromatin accessibility were enriched for motifs of TFs pertinent for T cell function. Most strikingly, super-enhancers encompassing RA-associated SNPs were less accessible. Analysis of selected transcripts and published DNA methylation patterns were consistent with this finding. The preferential loss in accessibility at these super-enhancers was seen in patients with high and low disease activity and on a variety of immunosuppressive treatment modalities. INTERPRETATION: Disease-associated genes are epigenetically less poised to respond in CD4 T cells from patients with established RA. FUNDING: This work was supported by I01 BX001669 from the Veterans Administration.

Development and Evaluation of the Eight-Item Caregiver Self-Efficacy Scale (CSES-8).

BACKGROUND AND OBJECTIVES: This paper describes the development and evaluation of a short caregiving self-efficacy measure. The self-administered 8-item Caregiver Self-Efficacy Scale (CSES-8) was developed to reflect components of typical caregiver support interventions and to be practical for inclusion in future self-efficacy and caregiving research. RESEARCH DESIGN AND METHODS: We administered the CSES-8 in 2 samples: participants in an intervention for caregivers of persons with cognitive disabilities, and a voluntary online survey for caregivers of adults. We evaluated the completion rate, item-scale correlations, reliability, descriptive statistics, and preliminary construct validity of the CSES-8 in both samples, and sensitivity to change in the intervention sample. RESULTS: The intervention caregivers' sample (N = 158) was 85% female (mean age = 65 years). The online survey sample (N = 138) was 90% female (mean age = 78). In both samples, the CSES-8 had excellent internal consistency reliability (.89 and .88) and good distribution with sufficient variability to detect change. Test-retest reliability was good in the online sample (.73). As evidence of construct validity, most hypotheses were confirmed in both samples. The CSES-8 was sensitive to change at 6 months for caregivers in the intervention program (p < .001). DISCUSSION AND IMPLICATIONS: The CSES-8 is short, comprehensive with respect to common components of interventions to improve caregivers' quality of life, and sensitive to change. It can serve a useful role exploring mechanisms by which caregiver intervention studies work, and it can be helpful in examining whether self-efficacy mediates the effect of these interventions on various outcomes such as psychological well-being.

Remote Delivery of the Chronic Pain Self-management Program Using Self-directed Materials and Small-group Telephone Support: A Pilot Study.

A remote (telephone and tool kit) chronic pain program was studied using the RE-AIM (reach, effectiveness, adoption, implementation, and maintenance) framework. This 6-week pilot took place in underserved communities in Cleveland, Ohio. We determined reach by the diversity of the population, nearly 50% Black and mostly low income. Effectiveness over 7 weeks was shown with validated instruments (depression, pain, sleep, quality of life, self-rated health, and self-efficacy). Changes in pain, depression, and self-efficacy were significant. (p < .01). Remote implementation was accomplished by sending participants a box of materials (book, exercise and relaxation CDs, a self-test, and tip sheets). Participants also participated in peer-facilitated, weekly, scripted telephone calls. Maintenance was demonstrated as the study site has offered nine additional programs with more plan. In addition, 60 additional organizations are now offering the program. This proof-of-concept study offers an alternate to in-person chronic pain self-management program delivery.

Ultrasound evaluation of the hands and wrists in patients with systemic sclerosis: Osteophytosis is a major contributor to tender joints.

OBJECTIVE: To evaluate the prevalence and clinical associations of ultrasound (US) findings of inflammatory arthritis and joint and soft tissue pathology in patients with systemic sclerosis (SSc). METHODS: The hands and wrists of 43 SSc patients and 35 age-balanced controls were evaluated by clinical exam and musculoskeletal US. Synovial and tenosynovial pathology were assessed using semi-quantitative Gray Scale (GS) and Power Doppler (PD) scoring. US evaluation for osteophytes, erosions, ulnar artery occlusion, and median nerve cross-sectional areas was performed. Tender joints (TJ), swollen joints (SJ), modified Rodnan skin score (mRSS), digital ulcers, contractures, and calcinosis were evaluated. Concordance between US and physical exam findings at each joint region were assessed, and associations between their severity were analyzed. RESULTS: TJs and SJs were present in 44.2% and 62.8% of SSc patients, respectively. Inflammatory arthritis, defined as having both GS>0 and PD>0, was observed in 18.6% of SSc patients and no controls. There was a high concordance by joint region between GS synovial hypertrophy and osteophytes (κ=0.88) as well as TJs (κ=0.72). SSc patients had more osteophytes compared to controls (48.8% vs 22.9%, p = 0.018) as well as higher osteophyte severity (p = 0.033). CONCLUSIONS: Despite a high percentage of tender and swollen joints, less than 20% of SSc patients met criteria for inflammatory arthritis on US. The high concordance of osteophytes with GS synovial hypertrophy and tender joints suggest that osteophytosis may be a significant contributor to joint pain in SSc patients.

Arachidonic acid-regulated calcium signaling in T cells from patients with rheumatoid arthritis promotes synovial inflammation.

Rheumatoid arthritis (RA) and psoriatic arthritis (PsA) are two distinct autoimmune diseases that manifest with chronic synovial inflammation. Here, we show that CD4+ T cells from patients with RA and PsA have increased expression of the pore-forming calcium channel component ORAI3, thereby increasing the activity of the arachidonic acid-regulated calcium-selective (ARC) channel and making T cells sensitive to arachidonic acid. A similar increase does not occur in T cells from patients with systemic lupus erythematosus. Increased ORAI3 transcription in RA and PsA T cells is caused by reduced IKAROS expression, a transcriptional repressor of the ORAI3 promoter. Stimulation of the ARC channel with arachidonic acid induces not only a calcium influx, but also the phosphorylation of components of the T cell receptor signaling cascade. In a human synovium chimeric mouse model, silencing ORAI3 expression in adoptively transferred T cells from patients with RA attenuates tissue inflammation, while adoptive transfer of T cells from healthy individuals with reduced expression of IKAROS induces synovitis. We propose that increased ARC activity due to reduced IKAROS expression makes T cells more responsive and contributes to chronic inflammation in RA and PsA.

Effects of COVID-19 on Informal Caregivers and the Development and Validation of a Scale in English and Spanish to Measure the Impact of COVID-19 on Caregivers.

To understand how the COVID-19 pandemic has affected caregivers, we assessed its perceived impact on caregiving through a new measure: the Caregiver COVID-19 Limitations Scale (CCLS-9), in Spanish and English. We also compared levels of caregiver self-efficacy and burden pre-COVID-19 and early in the pandemic. We administered surveys via internet to a convenience sample of caregivers in January 2020 (pre-pandemic, n = 221) and in April-June 2020 (English, n = 177 and Spanish samples, n = 144) to assess caregiver self-efficacy, depression, pain, and stress. We used the early pandemic surveys to explore the validity of the CCLS-9. The pre-COVID-19 survey and the April English surveys were compared to determine how the COVID-19 pandemic affected caregivers. The CCLS-9 had strong construct and divergent validity in both languages. Compared to pre-COVID-19, caregiver stress (p = .002) and pain (p = .009) were significantly greater early in COVID-19, providing evidence of its validity. COVID-19 added to caregiver stress and pain.

TNF-alpha inhibition for the treatment of cardiac sarcoidosis.

BACKGROUND: Tumor necrosis factor alpha (TNF-α) inhibitors are increasingly being used for treating refractory cardiac sarcoidosis. There is a theoretical risk, however, that these therapies can worsen heart failure, and reports on efficacy and safety are lacking. METHODS: We conducted a retrospective review of all cardiac sarcoidosis patients seen at Stanford University from 2009 to 2018. Data were collected on patient demographics, diagnostic testing, and treatment outcomes. RESULTS: We identified 77 cardiac sarcoidosis patients, of which 20 (26%) received TNF-α inhibitor treatment. The majority were treated for progressive heart failure or tachyarrhythmia, along with worsening imaging findings. All TNF-α inhibitor treated patients demonstrated meaningful benefit, as assessed by changes in advanced imaging, echocardiographic measures of cardiac function, and prednisone use. CONCLUSIONS: A large cohort (n = 77) of cardiac sarcoidosis patients has been treated at Stanford University. Roughly one-fourth of these patients (n = 20) received TNF-α inhibitors. Of these patients, none had worsening heart failure and all saw clinical benefit. These results help support the use of TNF-α inhibitors for the treatment of cardiac sarcoidosis based on real-world evidence and highlight the need for future prospective studies.

Development and validation of a rheumatologist satisfaction with practice scale: The rheumatologist satisfaction scale.

There is a paucity of succinct measures of physician satisfaction. As part of a Performance Improvement Project, we developed and piloted a simple questionnaire to determine rheumatologists satisfaction.Thirty 5 rheumatologists in the academic or private setting were sent opened-ended questions to determine the factors that made them satisfied or dissatisfied with respect to their rheumatology practice. From the responses we formed 14 questions 1 to 10 scale centering on satisfaction and dissatisfaction that was piloted in 30 rheumatologists and subsequently validated in 173 rheumatologists within the US and Latin America.Our combined sample included 173 rheumatologists (55 English and 118 Spanish-speaking respondents). The mean satisfaction for the combined sample was 6.92 (standard deviation=1.1, range 4.08-9.62). The strongest contributors to physician satisfaction were "Seeing interesting and challenging cases" (8.6 ±â€Š1.5) and "The ability to make a difference in patient's life" as well as "Establishing long term relationship with patients" (8.39 ±â€Š1.5). The strongest contributors to physician dissatisfaction were "Getting inappropriate referrals not in the scope of practice" (4.3 ±â€Š2.13) and "Time spent on documentation" (4.5 ±â€Š2.59). The scale had good reliability, relatively normal distribution, and little or no redundancy among items.A simple and practical questionnaire to measure physician satisfaction, in particular rheumatologists satisfaction, was developed, piloted and successfully validated on a predominately academic sample of rheumatologists within the US and Latin America. This scale will serve as a means to identifying potential barriers to the implementation of performance improvement projects in the practice of Rheumatology.

Recurrent carpal tunnel syndrome associated with extension of flexor digitorum muscle bellies into the carpal tunnel: A case series.

While the success or failure of carpal tunnel release ultimately depends on the interplay of a wide array of factors, a broad understanding of the normal anatomy of the carpal tunnel accompanied by awareness of the possible variations of the individual structures that make up its contents is crucial to optimizing surgical outcomes. While anatomic variants such as extension of the flexor digitorum muscle bellies have been described as a cause of primary carpal tunnel syndrome (CTS), there have been no reports depicting its association with recurrent CTS following initially successful carpal tunnel release, a finding with potentially significant prognostic implications that can aid in operative planning. In such cases where muscle extension is identified preoperatively, careful debulking of the muscle belly may be beneficial in improving long-term surgical outcomes.

Risk of hemorrhagic transformation after ischemic stroke in patients with antiphospholipid antibody syndrome.

BACKGROUND AND PURPOSE: Several rheumatologic conditions including systemic lupus erythematosus, antiphospholipid antibody (APS) syndrome, rheumatoid arthritis, and scleroderma are known risk factors for stroke. The risk of hemorrhagic transformation after an acute ischemic stroke (AIS) in these patients is not known. METHODS: We queried the Nationwide Inpatient Sample (NIS) data between 2010 and 2012 with ICD 9 diagnostic codes for AIS. The primary outcome was the development of hemorrhagic transformation. Multivariate predictors for hemorrhagic transformation were identified with a logistic regression model. Using SAS 9.2, Survey procedures were used to accommodate for hierarchical two stage cluster design of NIS. RESULTS: APS (OR 2.57, 95% CI 1.14-5.81, p = 0.0228) independently predicted risk of hemorrhagic transformation in multivariate regression analysis. Similarly, in multivariate regression models for the outcome variables of total charges of the hospitalization and length of stay (LOS), patients with APS had the highest charges ($56,286, p = 0.0228) and LOS (3.87 days, p = 0.0164) compared to other co-variates. Univariate analysis showed increased mortality in the APS compared to the non-APS group (11.68% vs. 7.16%, p = 0.0024). CONCLUSION: APS is an independent risk factor for hemorrhagic transformation in both thrombolytic and non-thrombolytic treated patients. APS is also associated with longer length and cost of hospital stay. Further research is warranted to identify the unique risk factors in these patients to identify strategies to reduce the risk of hemorrhagic transformation in this subgroup of the population.

Cutaneous Vasculitis in a Patient with Antiphospholipid Antibody Syndrome.

Antiphospholipid antibody syndrome (APS) is an acquired thrombophilia, caused by autoantibodies to anticardiolipin (aCL), or antibeta 2 glycoprotein I, or the presence of lupus anticoagulant (LA) in plasma. It is characterized by recurrent venous and/or arterial thrombi and/or pregnancy related morbidities. We present the case of a 52-year-old female with long-standing APS, who developed cutaneous vasculitis following a common cold. Most of the cutaneous manifestations of APS have been found to be thrombotic on histopathology without evidence of perivascular inflammation. Vasculitis is usually seen in APS patients with coexistent Systemic Lupus Erythematosus (SLE). However, our patient had evidence of vasculitis on skin biopsy and did not have SLE. Though rare, this is a disease process which must be considered in patients with primary APS which must be closely monitored for other vasculitic complications of APS, particularly diffuse alveolar hemorrhage.

Autosplenectomy Causing Catastrophic Pneumococcal Meningitis in a Patient with Lupus/Antiphospholipid Antibody Syndrome.

We present the case ofa26-year-old female who presented to the hospital with pneumococcal meningitis. A review of her records showed atrophic spleen, and a hypercoagulable workup was positive for Systemic Lupus Erythematous (SLE)/Antiphospholipid Antibody Syndrome (APS). An autosplenectomy from thrombotic occlusion of the splenic artery made her susceptible to pneumococcal meningitis. Autoimmune conditions, particularly SLE and APS, are important causes of hypercoagulable states in a young population, and earlier detection of these conditions and appropriate treatment helps to decrease morbidity and mortality among these patients.

Adult Onset Henoch-Schönlein Purpura: Case Report and Review of Literature.

Henoch-Schönlein purpura (HSP) is an IgA mediated small-vessel vasculitis, more common in children than adults. We present the case of a 37-year-old male who presented with complaints of nausea, vomiting, abdominal pain, purpuric rash over lower extremities, and migratory polyarthralgia five days after being treated with antibiotics for bronchitis. In addition to the abdominal pain, he developed diarrhea and colonic biopsy findings were suggestive of inflammatory bowel disease (IBD). Skin biopsy revealed leukocytoclastic vasculitis with direct immunofluorescence studies (DIF) staining of IgA deposition confirming the diagnosis of HSP. The clinical features of cutaneous eruption with abdominal complaints can be seen with either HSP or IBD; however the specific skin biopsy findings on DIF can distinguish between the two disease processes. Though HSP is primarily seen in the pediatric population, it is a disease process that must be considered in adults presenting with vasculitic skin rashes and abdominal complaints.