Serum alarmins and the risk of incident interstitial lung disease in rheumatoid arthritis.

OBJECTIVES: To quantify associations of serum alarmins with risk of rheumatoid arthritis-associated interstitial lung disease (RA-ILD). METHODS: Using serum collected at enrolment, three alarmins (interleukin [IL]-33, thymic stromal lymphopoietin [TSLP], and IL-25) were measured in a multicentre prospective RA cohort. ILD was classified using systematic medical record review. Cross-sectional associations of log-transformed (IL-33, TSLP) or quartile (IL-25) values with RA-ILD at enrolment (prevalent RA-ILD) were examined using logistic regression, while associations with incident RA-ILD developing after enrolment were examined using Cox proportional hazards. Covariates in multivariate models included age, sex, race, smoking status, RA disease activity score, and anti-cyclic citrullinated antibody positivity. RESULTS: Of 2,835 study participants, 115 participants (4.1%) had prevalent RA-ILD at baseline and an additional 146 (5.1%) developed incident ILD. There were no associations between serum alarmin concentrations and prevalent ILD in unadjusted or adjusted logistic regression models. In contrast, there was a significant inverse association between IL-33 concentration and the risk of developing incident RA-ILD in unadjusted (HR 0.73 per log-fold increase; 95% CI 0.57-0.95; p= 0.018) and adjusted (HR 0.77; 95% CI 0.59-1.00, p= 0.047) models. No significant associations of TSLP or IL-25 with incident ILD were observed. CONCLUSIONS: In this study, we observed a significant inverse association between serum IL-33 concentration and the risk of developing incident RA-ILD, but no associations with prevalent ILD. Additional investigation is required to better understand the mechanisms driving this relationship and how serum alarmin IL-33 assessment might contribute to clinical risk stratification in patients with RA.

SToRytelling to Improve Disease outcomes in Gout (STRIDE-GO): a multicenter, randomized controlled trial in African American veterans with gout.

BACKGROUND: Urate-lowering therapy (ULT) adherence is low in gout, and few, if any, effective, low-cost, interventions are available. Our objective was to assess if a culturally appropriate gout-storytelling intervention is superior to an attention control for improving gout outcomes in African-Americans (AAs). METHODS: In a 1-year, multicenter, randomized controlled trial, AA veterans with gout were randomized to gout-storytelling intervention vs. a stress reduction video (attention control group; 1:1 ratio). The primary outcome was ULT adherence measured with MEMSCap™, an electronic monitoring system that objectively measured ULT medication adherence. RESULTS: The 306 male AA veterans with gout who met the eligibility criteria were randomized to the gout-storytelling intervention (n = 152) or stress reduction video (n = 154); 261/306 (85%) completed the 1-year study. The mean age was 64 years, body mass index was 33 kg/m2, and gout disease duration was 3 years. ULT adherence was similar in the intervention vs. control groups: 3 months, 73% versus 70%; 6 months, 69% versus 69%; 9 months, 66% versus 67%; and 12 months, 61% versus 64% (p > 0.05 each). Secondary outcomes (gout flares, serum urate and gout-specific health-related quality of life [HRQOL]) in the intervention versus control groups were similar at all time points except intervention group outcomes were better for the following: (1) number of gout flares at 9 months were fewer, 0.7 versus 1.3 in the previous month (p = 0.03); (2) lower/better scores on two gout specific HRQOL subscales: gout medication side effects at 3 months, 32.8 vs. 39.6 (p = 0.02); and unmet gout treatment need at 3 months, 30.9 vs. 38.2 (p = 0.003), and 6 months, 29.5 vs. 34.5 (p = 0.03), respectively. CONCLUSIONS: A culturally appropriate gout-storytelling intervention was not superior to attention control for improving gout outcomes in AAs with gout. TRIAL REGISTRATION: Registered at ClinicalTrials.gov NCT02741700.

Associations between Adiponectin and the Development of Diabetes in Rheumatoid Arthritis.

PURPOSE: We evaluated associations between adiponectin and the risk of diabetes among patients with rheumatoid arthritis (RA), a systemic inflammatory disease associated with metabolic disturbance. METHODS: This prospective cohort study included adults with RA from the Veteran's Affairs Rheumatoid Arthritis Registry. Adiponectin and inflammatory cytokines/chemokines were measured at enrollment on stored serum samples. Adiponectin levels were categorized and clinical variables were described across categories (<10 µg/mL; 10-40 µg/mL; > 40 µg/mL. Multivariable Cox proportional hazard models evaluated associations between adiponectin and incident diabetes adjusting for age, sex, race, smoking status, body mass index (BMI), disease-modifying therapy use, calendar year, and comorbidity. Testing for modification of effect in the context of elevated cytokines/chemokines was performed. RESULTS: Among 2595 patients included in the analysis, those with adiponectin levels >40 µg/mL (N = 379; 15%) were older and had lower BMI. There were 125 new cases of diabetes among 1,689 patients without prevalent disease at enrollment. There was an inverse association between adiponectin and incident diabetes, however, the association was positive among patients with adiponectin levels >40 µg/mL. Patients with levels >40 µg/mL were at higher risk compared to those with levels 10-40 µg/mL [HR: 1.70 (1.34,2.16) p < 0.001]. Those with adiponectin levels >40 µg/mL had significantly higher levels of inflammatory cytokines with evidence of a modified effect of adiponectin on diabetes risk in the setting of inflammation. CONCLUSIONS: The relationship between adiponectin and incident diabetes risk is U-shaped in RA. Patients with very high adiponectin levels have greater systemic inflammation and an altered relationship between adiponectin and diabetes risk.

Telemedicine Use During the COVID-19 Pandemic by Resilient Rheumatology Providers: A National Veterans Affairs Follow-up Survey.

OBJECTIVE: To assess rheumatology provider experience and practices at Veterans Affairs (VA) facilities during the coronavirus disease 2019 (COVID-19) pandemic. METHODS: We performed an anonymized follow-up national cross-sectional survey (November 5, 2020 to January 1, 2021) to assess provider resilience, experience, practices, views, and opinions about changes to medications and laboratory monitoring of veterans with rheumatic diseases. RESULTS: Of the 143 eligible VA rheumatology providers, 114 (80%) responded. Compared to the original survey, fewer providers reported using telephone visits (78% vs 91%, P = 0.009), and more used clinical video telehealth (CVT; 16% vs 7%, P = 0.04) or in-person visits (76% vs 59%, P = 0.007). Most providers were somewhat or very comfortable with the quality of clinical encounters for established but not new patients for telephone, video-based VA Video Connect (VVC), and CVT. The mean 2-item Connor-Davidson Resilience Scale score was 6.85 (SD 1.06, range 0-8), significantly higher than the original April-May 2020 survey score of 6.35 (SD 1.26; P = 0.004). When adjusted for age, sex, and ethnicity, high provider resilience was associated with significantly higher odds of comfort with technology and the quality of the VVC visit for the following: (1) established patients (odds ratio [OR] 1.72, 95% CI, 0.67-4.40 and OR 4.13, 95% CI 1.49-11.44, respectively) and (2) new patients (OR 2.79, 95% CI 1.11-7.05, and OR 2.69, 95% CI 1.06-6.82, respectively). CONCLUSION: Reassuringly, VA rheumatology providers became increasingly comfortable with video visits during the first 10 months of the COVID-19 pandemic. High provider resilience, and its association with better quality CVTs, raise the possibility that video visits might be an acceptable substitute for in-person visits under appropriate circumstances.

Immunologic rheumatic disorders.

We provide the basics for clinicians who might be called on to consider the diagnosis of diseases such as systemic lupus erythematosus (SLE) or rheumatoid arthritis (RA) in their practice. We will emphasize clinical recognition and first-line laboratory testing. Only characteristics of the classic rheumatic inflammatory diseases (ie, RA, seronegative spondyloarthropathy, SLE, antiphospholipid syndrome, Sjögren syndrome, scleroderma, and polymyositis/dermatomyositis) will be covered. In the past decade, treatment for RA and seronegative spondyloarthropathy has substantially improved. Their treatment has been revolutionized by the use of methotrexate and, more recently, TNF inhibitors, T-cell costimulation modulators, and B-cell depletion. The goal of RA treatment today is to induce a complete remission as early as possible in the disease process, with the mantra being "elimination of synovitis equals elimination of joint destruction." The hope is that if the major mediators of Sjögren syndrome, SLE, or scleroderma can be identified and then blocked, as in the example of TNF inhibitors in patients with RA, more specific treatments will become available. Thus RA has become an excellent model of this evolving paradigm. Through the identification of major mediators in its pathogenesis, novel and highly efficacious therapeutic agents have been developed.

Management of Rheumatic Diseases During the COVID-19 Pandemic: A National Veterans Affairs Survey of Rheumatologists.

OBJECTIVE: To assess the experience, views, and opinions of rheumatology providers at Veterans Affairs (VA) facilities about rheumatic disease health care issues during the COVID-19 pandemic. METHODS: We performed an anonymized cross-sectional survey, conducted from April 16 to May 18, 2020, of VA rheumatology providers. We assessed provider perspectives on COVID-19 issues and resilience. RESULTS: Of the 153 eligible VA rheumatologists, 103 (67%) completed the survey. A significant proportion of providers reported a ≥50% increase related to COVID-19 in visits by telephone (53%), video-based VA video connect (VVC; 44%), and clinical video telehealth with a facilitator (29%). A majority of the responders were somewhat or very comfortable with technology for providing health care to established patients during the COVID-19 pandemic using telephone (87%), VVC (64%), and in-person visits (54%). A smaller proportion were comfortable with technology providing health care to new patients. At least 65% of rheumatologists considered telephone visits appropriate for established patients with gout, osteoporosis, polymyalgia rheumatica, stable rheumatoid arthritis, stable spondyloarthritis, or osteoarthritis; 32% reported a rheumatology medication shortage. Adjusted for age, sex, and ethnicity, high provider resilience was associated with significantly higher odds ratios (ORs) of comfort with technology for telephone (OR 3.1 [95% confidence interval (95% CI) 1.1-9.7]) and VVC visits for new patients (OR 4.7 [95% CI 1.4-15.7]). CONCLUSION: A better understanding of COVID-19 rheumatic disease health care issues using a health-system approach can better inform providers, improve provider satisfaction, and have positive effects on the care of veterans with rheumatic disease.

Coronary Artery Disease Phenotype Detection in an Academic Hospital System Setting.

BACKGROUND: The United States, and especially West Virginia, have a tremendous burden of coronary artery disease (CAD). Undiagnosed familial hypercholesterolemia (FH) is an important factor for CAD in the U.S. Identification of a CAD phenotype is an initial step to find families with FH. OBJECTIVE: We hypothesized that a CAD phenotype detection algorithm that uses discrete data elements from electronic health records (EHRs) can be validated from EHR information housed in a data repository. METHODS: We developed an algorithm to detect a CAD phenotype which searched through discrete data elements, such as diagnosis, problem lists, medical history, billing, and procedure (International Classification of Diseases [ICD]-9/10 and Current Procedural Terminology [CPT]) codes. The algorithm was applied to two cohorts of 500 patients, each with varying characteristics. The second (younger) cohort consisted of parents from a school child screening program. We then determined which patients had CAD by systematic, blinded review of EHRs. Following this, we revised the algorithm by refining the acceptable diagnoses and procedures. We ran the second algorithm on the same cohorts and determined the accuracy of the modification. RESULTS: CAD phenotype Algorithm I was 89.6% accurate, 94.6% sensitive, and 85.6% specific for group 1. After revising the algorithm (denoted CAD Algorithm II) and applying it to the same groups 1 and 2, sensitivity 98.2%, specificity 87.8%, and accuracy 92.4; accuracy 93% for group 2. Group 1 F1 score was 92.4%. Specific ICD-10 and CPT codes such as "coronary angiography through a vein graft" were more useful than generic terms. CONCLUSION: We have created an algorithm, CAD Algorithm II, that detects CAD on a large scale with high accuracy and sensitivity (recall). It has proven useful among varied patient populations. Use of this algorithm can extend to monitor a registry of patients in an EHR and/or to identify a group such as those with likely FH.

Cardiometabolic risk factors in siblings from a statewide screening program.

BACKGROUND: The Coronary Artery Risk Detection in Appalachian Communities (CARDIAC) Project is a state-wide risk factor screening program that operated in West Virginia for 19 years and screened more than 100,000 5th graders for obesity, hypertension, and dyslipidemia. OBJECTIVES: We investigated siblings in the CARDIAC Project to assess whether cardiometabolic risk factors (CMRFs) correlate in siblings. METHODS: We identified 12,053 children from 5752 families with lipid panel, blood pressure, and anthropometric data. A linkage application (LinkPlus from the U.S. Centers for Disease Control and Prevention) matched siblings based on parent names, addresses, telephone numbers, and school to generate a linkage probability curve. Graphical and statistical analyses demonstrate the relationships between CMRFs in siblings. RESULTS: Siblings showed moderate intraclass correlation coefficient of 0.375 for low-density lipoprotein cholesterol (LDL-C), 0.34 for high-density lipoprotein cholesterol (HDL-C), and 0.22 for triglyceride levels. The body mass index (BMI) intraclass correlation coefficient (0.383) is slightly better (2%) than LDL-C or HDL-C, but the standardized beta values from linear regression suggest a 3-fold impact of sibling LDL-C over the child's own BMI. The odds ratio of a second sibling having LDL-C < 110 mg/dL with a first sibling at that level is 3.444:1 (Confidence Limit 3.031-3.915, P < .05). The odds ratio of a sibling showing an LDL-C ≥ 160 mg/dL, given a first sibling with that degree of elevated LDL-C is 29.6:1 (95% Confidence Limit: 15.54-56.36). The individual LDL-C level correlated more strongly with sibling LDL-C than with the individual's own BMI. Seventy-eight children with LDL-C > 160 mg/dL and negative family history would have been missed, which represents more than half of those with LDL-C > 160 mg/dL (78 vs 67 or 54%). CONCLUSIONS: Sibling HDL-C levels, LDL-C levels, and BMIs correlate within a family. Triglyceride and blood pressure levels are less well correlated. The identified CMRF relationships strengthen the main findings of the overall CARDIAC Project: an elevated BMI is not predictive of elevated LDL-C and family history of coronary artery disease poorly predicts cholesterol abnormality at screening. Family history does not adequately identify children who should be screened for cholesterol abnormality. Elevated LDL-C (>160 mg/dL) in a child strongly suggests that additional siblings and parents be screened if universal screening is not practiced.

Late quadriceps tendon rupture at the donor site following cruciate ligament reconstruction using central quadriceps tendon graft.

Central quadriceps tendon (CQT) graft has been successfully used as a viable autograft option in cruciate ligament reconstruction of the knee. The prime emphasis in the majority of the literature is given to surgical details of quadriceps graft harvesting and outcome of cruciate ligament reconstruction. There is less discussion about donor site morbidity in CQT graft, and it is less frequent as compared to that in bone patellar tendon bone graft. We report an extremely unusual case of late quadriceps tendon rupture at the donor site following anterior cruciate ligament reconstruction using CQT graft.

A Potential Role for PGE and IL-14 (HMW-BCGF) in B-Cell Hyperactivity of Patients with Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is a disease characterized by the prolonged production of high-affinity autoantibodies resulting in direct and immune complex-mediated tissue damage. Because autoantibody responses occur over several years, memory B cells are likely to be involved. Interleukin-14 (IL-14) is a cytokine implicated in the generation and maintenance of normal memory B cells. Many of the actions of IL-14, including inhibition of antibody synthesis and upregulation of IL-14 receptors (IL-14R), are dependent on the formation of prostaglandin E (PGE) and subsequently cAMP. We observed that IL-14 induces phospholipase A(2) (PLA(2))-dependent release of arachidonic acid from phosphatidylcholine and phosphatidylinositol. Production of PGE is blocked by the PLA(2) inhibitor bromophenacyl bromide. Exogenous PGE (misoprostol) induces similar inhibition of antibody synthesis and increases in IL-14R as IL-14. Lymphocytes from patients with inactive SLE were noted to spontaneously produce PGE. Lymphocytes from normal donors produced PGE only after Sac-activation and IL-14 stimulation. Peripheral B and T lymphocytes from SLE patients, but not normal donors, spontaneously produced IL-14. Increased numbers of peripheral B lymphocytes from patients with inactive SLE expressed IL-14R, when compared to normal donors. Thus, increased production of IL-14 and PGE in SLE may result in expansion of a memory B-cell population capable of long-term autoantibody production. Further study will be necessary to confirm these preliminary findings and to examine in greater depth the regulation of PGE and IL-14 in SLE patients and normal donors.

A report on four new cases of nephrogenic fibrosing dermopathy in chronic hemodialysis patients.

Nephrogenic fibrosing dermopathy (NFD) is a rare clinical entity affecting patients with renal failure, often on chronic dialysis or after transplantation. The patient profile at risk for this debilitating condition is undefined. Lack of awareness of the condition has hampered epidemiologic work in identifying the etiology. We present four chronic hemodialysis (HD) patients who developed this disease. The patients' ages ranged from 26 to 75 years, and they had received HD from between 20 months and 10 years before the diagnosis of NFD. Two patients had a history of renal transplantation. All patients had progressive thickening and woody induration of the skin associated with contractures, leading to difficult ambulation, and permanent disability within weeks of the diagnosis. In one case, the diaphragm, psoas muscle, and pericardium were involved. The latter is likely the first report of pericardial involvement of NFD. In all four patients, the skin findings were restricted to the extremities, sparing the trunk and face. Skin biopsy findings included thickened dermis with particularly thickened collagen bundles, fibroblast proliferation, minimal mucin deposition, and nearly absent inflammation. The pathologic findings were distinct from scleromyxedema and scleroderma. We found no laboratory evidence of autoimmune disease or thyroid dysfunction to account for alternate etiologies. CD34-positive cells were documented in the skin biopsies as well as in the diaphragm, psoas muscle, and pericardial tissue of the concerned case. NFD is a novel fibrosing disorder of progressively debilitating nature which needs further clinical characterization and recognition to guide investigation of its pathogenesis.

Treatment of rheumatoid arthritis in patients with concomitant chronic hepatitis C infection.

Hepatitis C virus (HCV) infection is present in 1.8% of the general US population and its prevalence worldwide is estimated at 2-3%. HCV infected patients with concomitant rheumatoid arthritis (RA) pose a particular challenge to the rheumatologist because of the risks of treatment with disease-modifying medications in patients with chronic liver infection. In this paper the difficulties of diagnosing RA in HCV patients and the safety of RA treatment in patients with both conditions are discussed.

Spinal gout mimicking paraspinal abscess: A case report.

Gout is usually thought of as a peripheral joint disease. However, case reports are available describing gouty lesions in the spine. We report a case of a 51 year old African American woman with no previous history of gout who presented with lower back pain and fever and was found to have multiple small fluid collections in the paraspinal muscles at the L3 to L5 levels on the MRI. She was empirically treated with antibiotics, since the fluid was not accessible for drainage initially. Unsuccessful antibiotic therapy and an episode of peripheral gout during this hospitalization prompted the diagnosis of axial gout as the cause for the paraspinal lesions in this patient. CT guided aspiration of the paraspinal lesions confirmed monosodium urate (gout) crystals under polarized microscopy.

A truncated T antigen expressed from an alternatively spliced BK virus early mRNA.

The early region of BK virus (BKV) is known to encode two well-characterized tumour (T) antigens, large T antigen (TAg) and small T antigen (tAg). In this study, we provide evidence of a third early BKV mRNA that codes for an additional early region product with an apparent molecular mass of 17-20 kDa. This truncated form of TAg (truncTAg) is expressed from an alternatively spliced mRNA that is derived from the excision of a second intron from the mRNA encoding TAg. The first 133 aa of truncTAg are identical to those of TAg but the additional splice results in translation from a different reading frame, adding three new amino acids before reaching a stop codon. TruncTAg is expressed in both BKV-transformed and lytically infected cells and it is found to be primarily localized to the nucleus. The function of BKV truncTAg is likely to be relevant to transformation, similar to the additional T antigens of simian virus 40, JC virus and mouse polyomavirus.

Methotrexate (MTX) pathway gene polymorphisms and their effects on MTX toxicity in Caucasian and African American patients with rheumatoid arthritis.

OBJECTIVE: Research has examined the association of folate-dependent gene polymorphisms with methotrexate (MTX) toxicity in racially homogenous patients with rheumatoid arthritis (RA). We examined the influence of MTX transporter gene polymorphisms on MTX toxicity in 2 racial groups of patients with RA. METHODS: Using a retrospective cross-validation approach, the association of polymorphisms in 6 genes in the MTX cellular pathway with MTX toxicity was examined in training and validation cohorts. The genes analyzed were ATP-binding cassette transporter B1 (ABCB1), C1 (ABCC1), C2 (ABCC2), folylpolyglutamyl synthase (FPGS), methylenetetrahydrofolate reductase (MTHFR), and thymidylate synthase (TYMS). Both cohorts included Caucasian Americans and African Americans. Statistical analyses consisted of Fisher exact tests, multivariable logistic regression models, and survival analyses. RESULTS: Four of 25 variants displayed significant associations with MTX toxicity in the training cohort. The intronic single-nucleotide polymorphism (SNP) ABCC2 IVS 23+56 T --> C was associated with alopecia in Caucasians (p = 0.035). ABCB1 1236 C --> T was associated with overall toxicity (p = 0.013); ABCC2 1249 G --> A with gastrointestinal toxicity (p = 0.009); and ABCC2 1058 G --> A with hepatotoxicity (p = 0.04) in African Americans. These 4 SNP and the MTHFR 677 C --> T variant were assessed in the validation cohort. Of these, only the MTHFR 677 C --> T SNP was associated with alopecia, and only in African Americans (p = 0.032). The ABCC2 IVS 23+56 T --> C genotype influenced toxicity-related time to discontinuation or dose decrease in the Caucasian validation cohort (p < 0.0001). CONCLUSION: In addition to SNP in folate-dependent genes, MTX transporter gene SNP may be important markers of MTX toxicity in RA. Such pharmacogenetic associations are race-specific.