Vascular calcifications on hand radiographs in rheumatoid arthritis and associations with autoantibodies, cardiovascular risk factors and mortality.

OBJECTIVE: To examine whether vascular calcifications on hand films in RA might aid in determining mortality risk. METHODS: Hand radiographs from 906 RA patients were scored as positive or negative for vascular calcifications. Patient characteristics associated with vascular calcifications were assessed using multivariable logistic regression, and associations with mortality were examined using Cox proportional hazards regression. Cytokines and multiplex ACPA were measured in both groups. RESULTS: A total of 99 patients (11%) demonstrated radiographic vascular calcifications. Factors independently associated with vascular calcifications included diabetes [odds ratio (OR) 2.85; 95% CI 1.43, 5.66], cardiovascular disease at enrolment (OR 2.48; 95% CI 1.01, 6.09), prednisone use (OR 1.90; 95% CI 1.25, 2.91), current smoking (OR 0.06; 95% CI 0.01, 0.23) and former smoking (OR 0.36; 95% CI 0.27, 0.48) vs never smoking. In cytokine and ACPA subtype analysis, IL-4 and anti-citrullinated apolipoprotein E were significantly increased in patients with vascular calcifications in fully adjusted multivariable models. After multivariable adjustment, vascular calcifications were associated with an increase in all-cause mortality (hazard ratio 1.41; 95% CI 1.12, 1.78; P = 0.004). CONCLUSION: Vascular calcifications on hand radiographs were independently associated with increased all-cause mortality in RA. Mechanisms underpinning the associations of IL-4 and select ACPA with vascular calcifications and their utility as biomarkers predictive of cardiovascular disease risk in RA merit further study.

An Evaluation of Burnout Among US Rheumatology Fellows: A National Survey.

OBJECTIVE: To evaluate levels of burnout and correlates of burnout among US rheumatology fellows. METHODS: US rheumatology fellows were invited to complete an electronic survey in 2019. Burnout was assessed using the Maslach Burnout Inventory. Measures of depression, fatigue, quality of life, and training year were also collected. Open-ended questions about perceived factors to promote resiliency and factors leading to increased burnout were included. Bivariate and multivariate regression analyses were used to examine correlates of burnout. Open-ended responses were analyzed using thematic analysis. RESULTS: The response rate was 18% (105/582 pediatric and adult rheumatology fellows). Over one-third (38.5%) of postgraduate year (PGY) 4 and 16.7% of PGY5/6 fellows reported at least 1 symptom of burnout. Of PGY4 fellows, 12.8% met criteria for depression compared with 2.4% of PGY5/6 fellows. PGY4 fellows reported worse fatigue and poorer quality of life compared with PGY5/6. In multivariable models controlling for training year and gender, older age (> 31 years) was associated with lower odds of burnout. Thematic analysis of open-ended responses identified factors that help reduce burnout: exercise, family/friends, sleep, support at work, and hobbies. Factors contributing to burnout: pager, documentation, long hours, demands of patient care, and presentations and expectations. CONCLUSION: This national survey of US rheumatology fellows reveals that early trainee level and younger age are associated with worse levels of fatigue, quality of life, and burnout. Although awareness of and strategies to reduce burnout are needed for all fellows, targeted interventions for younger fellows and those in their first year of training may be of highest yield.

Exercise for bone health: rationale and prescription.

PURPOSE OF REVIEW: Patients frequently inquire about exercise as a means to improve bone strength and reduce osteoporotic fracture. Understanding the biologic mechanisms and the available clinical evidence supporting the role of exercise in bone health is the key to an educated discussion. RECENT FINDINGS: Exercise downregulates sclerostin expression by the osteocyte favoring osteoblastogenesis. These changes are enhanced by dynamic cyclical load with rest periods and may be promoted by low-amplitude high-frequency stimuli. In the prepubertal years, exercise results in periosteal gains, whereas exercise later in life maintains bone mass, reduces falls and probably associated fractures, and improves quality-of-life measures. SUMMARY: Future studies should examine the effect of exercise on bone strength and determine the minimum quantity and frequency and the exercise type most effective to reduce osteoporotic fractures.

Association of Agricultural, Occupational, and Military Inhalants With Autoantibodies and Disease Features in US Veterans With Rheumatoid Arthritis.

OBJECTIVE: To determine the association of inhalant exposures with rheumatoid arthritis (RA)-related autoantibodies and severity in US veterans. METHODS: Participants in the Veterans Affairs Rheumatoid Arthritis (VARA) registry were mailed surveys assessing occupational, agricultural, and military inhalant exposures. Demographic characteristics, disease activity, functional status, and extraarticular features were obtained from the VARA registry, while HLA-DRB1 shared epitope (SE) status, anti-cyclic citrullinated peptide (anti-CCP) antibodies, and rheumatoid factor (RF) were measured using banked DNA/serum from enrollment. Associations between inhalant exposures and RA-related factors (autoantibodies, severity, and extraarticular features) were assessed using multivariable linear and logistic regression models adjusted for age, sex, race, and tobacco use and stratified by SE status. Adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. RESULTS: Questionnaires were returned by 797 of 1,566 participants (50.9%). Survey respondents were older, more often White or male, and less frequently smokers, and had lower disease activity compared to nonrespondents. Anti-CCP positivity was more common among veterans exposed to burn pits (OR 1.66 [95% CI 1.02, 2.69]) and military waste disposal (OR 1.74 [95% CI 1.04, 2.93]) independent of other factors. Among participants who were positive for SE alleles, burn pit exposure (OR 5.69 [95% CI 2.73, 11.87]) and military waste disposal exposure (OR 5.05 [95% CI 2.42, 10.54]) were numerically more strongly associated with anti-CCP positivity. Several inhalant exposures were associated with the presence of chronic lung disease, but not with the presence of RF or the level of disease activity. CONCLUSION: Military burn pit exposure and military waste disposal exposure were independently associated with the presence of anti-CCP antibodies in RA patients. These findings are consistent with emerging evidence that various inhalant exposures influence autoantibody expression and RA risk.

2021 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis.

OBJECTIVE: To develop updated guidelines for the pharmacologic management of rheumatoid arthritis. METHODS: We developed clinically relevant population, intervention, comparator, and outcomes (PICO) questions. After conducting a systematic literature review, the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to rate the certainty of evidence. A voting panel comprising clinicians and patients achieved consensus on the direction (for or against) and strength (strong or conditional) of recommendations. RESULTS: The guideline addresses treatment with disease-modifying antirheumatic drugs (DMARDs), including conventional synthetic DMARDs, biologic DMARDs, and targeted synthetic DMARDs, use of glucocorticoids, and use of DMARDs in certain high-risk populations (i.e., those with liver disease, heart failure, lymphoproliferative disorders, previous serious infections, and nontuberculous mycobacterial lung disease). The guideline includes 44 recommendations (7 strong and 37 conditional). CONCLUSION: This clinical practice guideline is intended to serve as a tool to support clinician and patient decision-making. Recommendations are not prescriptive, and individual treatment decisions should be made through a shared decision-making process based on patients' values, goals, preferences, and comorbidities.

2021 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis.

OBJECTIVE: To develop updated guidelines for the pharmacologic management of rheumatoid arthritis. METHODS: We developed clinically relevant population, intervention, comparator, and outcomes (PICO) questions. After conducting a systematic literature review, the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to rate the certainty of evidence. A voting panel comprising clinicians and patients achieved consensus on the direction (for or against) and strength (strong or conditional) of recommendations. RESULTS: The guideline addresses treatment with disease-modifying antirheumatic drugs (DMARDs), including conventional synthetic DMARDs, biologic DMARDs, and targeted synthetic DMARDs, use of glucocorticoids, and use of DMARDs in certain high-risk populations (i.e., those with liver disease, heart failure, lymphoproliferative disorders, previous serious infections, and nontuberculous mycobacterial lung disease). The guideline includes 44 recommendations (7 strong and 37 conditional). CONCLUSION: This clinical practice guideline is intended to serve as a tool to support clinician and patient decision-making. Recommendations are not prescriptive, and individual treatment decisions should be made through a shared decision-making process based on patients' values, goals, preferences, and comorbidities.

Utilization of Care Outside the Veterans Affairs Health Care System by US Veterans With Rheumatoid Arthritis.

OBJECTIVE: Many veterans enrolled in Veterans Affairs (VA) health care systems also receive care through other health care systems. Both VA and non-VA health care use must therefore be considered when conducting research in this population. This study characterized dual-care utilization in veterans with rheumatoid arthritis (RA) and explored associations with RA disease activity. METHODS: Through a questionnaire mailed to RA patients at 3 VA sites, veterans reported medical services by non-VA primary care and subspecialty providers, comorbidities, non-VA medications, and hospitalizations. Disease Activity Score in 28 joints (DAS28) and Multidimensional Health Assessment Questionnaire (MD-HAQ) scores were recorded during VA clinic visits, and respondent groups were compared. RESULTS: Of the 510 participants surveyed, 318 (62%) responded. Respondents were older (ages 69 versus 66 years; P = 0.006), more likely nonsmokers (80% versus 67%; P = 0.001), and had lower disease activity (DAS28 3.3 versus 3.8; P < 0.001, MD-HAQ 0.8 versus 0.9; P = 0.01) than nonrespondents (n = 192 [38%]). The respondents with a non-VA provider (n = 130 [41%]) were older (71 versus 68 years; P = 0.001) and had more education (14 versus 13 years; P = 0.021) than nondual-care users. Only 6% of respondents reported having a non-VA rheumatologist, with 2% receiving a non-VA prescribed biologic agent or disease-modifying antirheumatic drug. CONCLUSION: In this study, VA beneficiaries with RA had lower dual-care utilization than previously reported for the general VA population, with few patients receiving dual rheumatology care or non-VA RA medications. This survey suggests that most US veterans with RA who access VA care use the VA as their primary source of arthritis care.

Cause-Specific Mortality in Male US Veterans With Rheumatoid Arthritis.

OBJECTIVE: There has been limited investigation into cause-specific mortality and the associated risk factors in men with rheumatoid arthritis (RA). We investigated all-cause and cause-specific mortality in men with RA, examining determinants of survival. METHODS: Men from a longitudinal RA registry were followed from enrollment until death or through 2013. Vital status and cause of death were determined using the National Death Index. Crude mortality rates and standardized mortality ratios (SMRs) were calculated for all-cause, cardiovascular disease (CVD), cancer, and respiratory mortality. Associations with all-cause and cause-specific mortality were examined using multivariable Cox proportional hazards and competing-risks regression. RESULTS: There were 1,652 men with RA and 332 deaths. The leading causes of death were CVD (31.6%; SMR 1.77 [95% confidence interval (95% CI) 1.46-2.14]), cancer (22.9%; SMR 1.50 [95% CI 1.20-1.89]), and respiratory disease (15.1%; SMR 2.90 [95% CI 2.20-3.83]). Factors associated with all-cause mortality included older age, white race, smoking, low body weight, comorbidity, disease activity, and prednisone use. Rheumatoid factor concentration and nodules were associated with CVD mortality. There were no associations of methotrexate or biologic agent use with all-cause or cause-specific mortality. CONCLUSION: Men in this RA cohort experienced increased all-cause and cause-specific mortality, with a 3-fold risk of respiratory-related deaths compared to age-matched men in the general population. Further studies are needed in order to examine whether interventions targeting potentially modifiable correlates of mortality might lead to improved long-term survival in men with RA.

Associations of Circulating Cytokines and Chemokines With Cancer Mortality in Men With Rheumatoid Arthritis.

OBJECTIVE: To examine the potential of circulating cytokines and chemokines as biomarkers of cancer mortality risk in patients with rheumatoid arthritis (RA). METHODS: Male participants in the Veterans Affairs RA registry were followed up from the time of enrollment until death or December 2013. Cytokines and chemokines were measured in banked serum obtained at the time of enrollment, using a bead-based multiplex assay, and a previously developed cytokine score was calculated. Vital status and cause of death were determined through the National Death Index. Associations of cytokines with cancer mortality were examined using multivariable competing-risks regression. RESULTS: Among 1,190 men with RA, 60 cancer deaths (30 of which were attributable to lung cancer) occurred over 5,307 patient-years of follow-up. The patients had a mean age of 64.5 years, had established disease (median duration 8.7 years), were seropositive for rheumatoid factor (81%) or anti-cyclic citrullinated peptide antibody (77%), and frequently had a history of smoking (82% current or former). Seven of 17 analytes examined were individually associated with cancer mortality. The cytokine score was associated with overall cancer (subhazard ratio [SHR] 1.42, 95% confidence interval [95% CI] 1.08-1.85) and lung cancer (SHR 1.86, 95% CI 1.57-2.19) mortality in multivariable analyses. Those in the highest quartile of cytokine scores had a >2-fold increased risk of overall cancer mortality (P = 0.039) and a 6-fold increased risk of lung cancer mortality (P = 0.028) relative to the lowest quartile. A synergistic interaction between current smoking and high cytokine score was observed. CONCLUSION: Serum cytokines and chemokines are associated with cancer and lung cancer mortality in men with RA, independent of multiple factors including age, smoking status, and prevalent cancer.

A role for lipid rafts in C1q-triggered O2- generation by human neutrophils.

Calreticulin, a candidate C1q receptor, was shown recently to be present on the surface of human neutrophils in association with glycosylphosphatidylinositol (GPI) anchored proteins, particularly CD59. In this study, we show that antibodies to CD59, as well as to every other GPI-anchored protein tested, inhibited the C1q-triggered release of O(2)(-) from PMN. Methyl beta cyclodextrin (M beta CD) treatment of the cells to disrupt lipid rafts also prevented C1q-triggered O(2)(-) production. beta(2) integrin-dependent co-stimulation is required for O(2)(-) production from PMN, however M beta CD had no effect on LFA-1 or Mac-1-mediated adhesion, soluble iC3b binding to PMN, or spreading and migration, all of which suggested that PMN integrin function remained intact. Flow cytometric analysis of PMN treated with M beta CD showed upregulation of PMN granule-associated integrins and a corresponding increase in integrin activation-reporter epitopes, in contrast to the decreased expression of GPI-anchored antigens. These data support a model where lipid rafts and their associated GPI-anchored proteins are critical for C1q-triggered O(2)(-) production, consistent with a model where calreticulin serves as the C1q receptor for O(2)(-) production from PMN.

Adherence with bisphosphonate therapy in US veterans with rheumatoid arthritis.

OBJECTIVE: Pharmacy Benefits Management program data for patients enrolled in the Veterans Affairs Rheumatoid Arthritis (VARA) registry were linked with clinical data to determine bisphosphonate adherence and persistence among US veterans with rheumatoid arthritis (RA) and to determine factors associated with adherence. METHODS: The primary outcome measures were the duration of bisphosphonate therapy and the medication possession ratio (MPR). Patients with an MPR <0.80 were classified as nonadherent. Potential covariates considered in the analysis included patient demographics, RA disease activity and severity parameters, and factors associated with osteoporosis risk. Associations of patient factors with duration of therapy and adherence were examined using multivariable regression modeling. RESULTS: Bisphosphonates were prescribed to 573 (41.5%) of 1,382 VARA subjects. The mean ± SD duration of therapy for bisphosphonates was 39.2 ± 31.4 months. A longer duration of therapy correlated with older age, more years of education, and dual x-ray absorptiometry testing. The mean ± SD MPR of VARA subjects for bisphosphonate therapy was 0.69 ± 0.28; 302 (52.7%) were nonadherent. In multivariate analyses, nonadherence with bisphosphonate therapy was associated with a longer duration of RA disease (odds ratio [OR] 1.02, 95% confidence interval [95% CI] 1.00-1.04) and duration of bisphosphonate therapy >32 months (OR 1.63, 95% CI 1.04-2.57). Whites were less likely to have a low MPR compared with nonwhites (OR 0.52, 95% CI 0.30-0.88). CONCLUSION: Nonadherence with bisphosphonates was common in this cohort of RA patients and was associated with nonwhite ethnicity, a longer duration of RA disease, and a greater duration of bisphosphonate therapy.

Neoplasm mimics of rheumatologic presentations: sialadenitis, ocular masquerade syndromes, retroperitoneal fibrosis, and regional pain syndromes.

IgG4-RSD should be suspected in any patient presenting with lacrimal or salivary gland enlargement, particularly if male and manifesting mild glandular dysfunction. A serum IgG4 level, if increased, may be helpful, although a gland biopsy staining for IgG4-positive plasma cells is the definitive test. Primary low-grade B cell lymphomas of the glandular tissue, specifically MALT lymphoma and other glandular malignancy, should be considered, particularly in patients with asymmetric glandular enlargement. Patients with idiopathic uveitis should have a thorough evaluation to exclude malignancy, in particular PIOL and melanoma in adults, and diffuse retinoblastoma and ALL in children. RF remains a diagnostic challenge and atypical features such as outward displacement of the retroperitoneal structures should raise the suspicion for a malignant infiltrative process. CRPS rarely may be the first presentation of an occult malignancy and requires a thorough review of age-appropriate cancer screening. Carpal tunnel syndrome, if bilateral or associated with other systemic features, should prompt a search for amyloidosis.

Rheumatologic sequelae and challenges in organ transplantation.

Despite the increasing success of transplantation, graft recipients experience a high burden of musculoskeletal symptoms that may hinder quality of life. Post-transplant musculoskeletal problems may result from sequelae of the organ dysfunction that indicated the transplant or from the subsequent anti-rejection therapy. Rheumatology consultants need to be familiar with the spectrum of musculoskeletal syndromes presenting in these unique patients and their appropriate treatment in the context of complex drug regimens and immunosuppression.

Nonpharmacological approaches to improve bone health and reduce osteoporosis.

PURPOSE OF REVIEW: With an aging population, osteoporosis has become a public health concern and an area of increased awareness among both patients and medical practitioners. Timely screening and pharmacologic treatment of low bone mass effectively reduces fracture risk. Nonpharmacologic interventions, however, deserve equal emphasis both in the prevention and treatment of osteoporosis. RECENT FINDINGS: Recent advances in bone biology have established that exercise in the form of short, repetitive mechanical loading leads to the greatest gains in bone strength. As demonstrated by both observational and randomized exercise intervention trials, these gains are best achieved in childhood but can be maintained in adulthood with continued regular weight-bearing exercise. In the later years, evidence supports the implementation of balance training to decrease fall risk, especially in elderly patients with low bone mass. Following an osteoporotic fracture, a multidisciplinary rehabilitation program with an emphasis on early mobilization, fall prevention, use of orthoses, and noninvasive surgical procedures is emerging as a promising approach. SUMMARY: Clinically, these findings should imply greater emphasis on high impact exercise during skeletal growth and on maintenance of weight bearing and balance training in the later years. Future research should examine the effect of these interventions on fracture prevention.

RhoH is required to maintain the integrin LFA-1 in a nonadhesive state on lymphocytes.

Lymphocyte function-associated antigen 1 (LFA-1) is relatively nonadhesive on resting lymphocytes; however, the mechanisms underlying changes in its adhesiveness are poorly understood. In this study, we generated a Jurkat T cell clone, J+hi1.14, that contained low amounts of mRNA for RhoH, a leukocyte-specific inhibitory Rho family member. J+hi1.14 cells expressed constitutively adhesive LFA-1 and the cells bound spontaneously to intracellular adhesion molecules 1, 2 and 3. Reconstitution of RhoH mRNA expression in J+hi1.14 cells reverted the adhesion phenotype to that of wild-type. We obtained similar results using RNA interference in peripheral blood lymphocytes. These data demonstrate that RhoH is required for maintenance of lymphocyte LFA-1 in a nonadhesive state.

The integrin alpha-subunit leg extends at a Ca2+-dependent epitope in the thigh/genu interface upon activation.

Two activation-dependent Abs to the integrin alphaL-subunit were used to study conformational rearrangement of alphaLbeta2 on the cell surface. Activation lowered the concentration of Ca2+ required for maximal expression of each epitope. Each Ab requires the Ca2+-binding loop in the integrin genu and nearby species-specific residues in the thigh domain. Key thigh residues are shielded from Ab in the bent integrin conformation by the alpha-subunit calf-1 domain and the nearby bent beta leg, suggesting that extension at the genu is required for epitope exposure. Activating stimuli and alpha/beta I-like small molecule antagonists demonstrate that exposure of epitopes in the integrin alpha- and beta-subunit legs is coordinate during integrin activation. A coordinating residue donated by the calf-1 domain is as important as Ca2+ for mAb binding. Together with inspection of the alphaV structure, this result suggests that the genu/calf-1 interface is maintained in integrin activation, and that extension occurs by a rearrangement at the thigh/genu interface.