Cardiovascular disease in spondyloarthritis: a narrative review of risk factors and the effect of treatments.

PURPOSE OF REVIEW: This review summarizes the recent evidence available regarding the epidemiology of cardiovascular disease in spondyloarthritis (SpA), including the effect of disease modifying drugs on cardiovascular risk. RECENT FINDINGS: People with SpA suffer from an increased risk of cardiovascular disease compared to the general population. This elevated risk is explained by the high prevalence of traditional cardiovascular risk factors and inflammation from disease activity leading to endothelial dysfunction and accelerated atherosclerosis. Consequently, the American College of Cardiology/American Heart Association and the European League Against Rheumatism recommend enhanced cardiovascular risk screening in SpA patients. There is evidence from observational studies that methotrexate and tumor necrosis factor inhibitors reduce the risk of cardiovascular events in SpA. Unlike what is observed in the general population, the use of nonsteroidal anti-inflammatory drugs does not appear to increase cardiovascular disease risk in SpA. SUMMARY: Cardiovascular diseases are increasingly recognized in patients suffering from SpA, especially axial SpA and psoriatic arthritis. Cardiovascular diseases can cause significant morbidity, mortality, and add to the overall disease burden. Disease modifying drugs may mitigate some of the cardiovascular risk; however, a multidisciplinary team is needed to monitor patients and improve cardiovascular health status.

Neutrophil-to-Lymphocyte Ratio and Platelet-to-Lymphocyte Ratio as Biomarkers in Axial Spondyloarthritis: Observational Studies From the Program to Understand the Longterm Outcomes in Spondyloarthritis Registry.

OBJECTIVES: This study was conducted to assess the utility of neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) in predicting radiographic sacroiliitis and active disease in axial spondyloarthritis (SpA) and to explore the association between use of a tumor necrosis factor inhibitor (TNFi) and these laboratory values compared with traditional inflammatory markers. METHODS: Observational data from the Program to Understand the Longterm Outcomes in Spondyloarthritis (PULSAR) registry were analyzed. We generated receiver operating characteristic curves to calculate laboratory cutoff values; we used these values in multivariable logistic regression models to identify associations with radiographically confirmed sacroiliitis and active disease. We also used logistic regression to determine the likelihood of elevated laboratory values after initiation of TNFi. RESULTS: Most study participants (n = 354) were White, male, and HLA-B27 positive. NLR (odds ratio [OR] 1.459, P = 0.034), PLR (OR 4.842, P < 0.001), erythrocyte sedimentation rate (OR 4.397, P < 0.001), and C-reactive protein (CRP) level (OR 2.911, P = 0.001) were independent predictors of radiographic sacroiliitis. Models that included PLR with traditional biomarkers performed better than those with traditional biomarkers alone. NLR (OR 6.931, P = 0.002) and CRP (OR 2.678, P = 0.004) were predictors of active disease, but the model that included both NLR and CRP performed better than CRP alone. TNFi use reduced the odds of elevated NLR (OR 0.172, P < 0.001), PLR (OR 0.073, P < 0.001), erythrocyte sedimentation rate (OR 0.319, P < 0.001), and CRP (OR 0.407, P < 0.001), but models that included NLR or PLR and traditional biomarkers performed best. CONCLUSIONS: These findings demonstrate an association between NLR and PLR and sacroiliitis and disease activity, with NLR and PLR showing response after TNFi treatment and adding useful clinical information to established biomarkers, thus perhaps assisting in management of axial SpA.

Current treatment and molecular targets for axial spondyloarthritis: Evidence from randomized controlled trials.

Axial spondyloarthritis (axSpA) is a chronic inflammatory disease that predominantly affects the axial skeleton and is characterized by inflammatory back pain. While much has been published regarding non-steroidal anti-inflammatory drugs and tumor necrosis factor inhibitors, other classes of medications which leverage alternate molecular mechanisms receive less attention. In this review, we summarize a few of the novel targets in axSpA, review the putative mechanism of action of therapies that focus on these targets, and reference the germane recently completed, ongoing, or proposed randomized controlled clinical trials. The agents addressed include inhibitors of interleukin-23, interleukin-17, janus kinases, granulocyte-macrophage colony-stimulating factor, macrophage migration inhibitory factor, antibodies recognizing T cell receptor beta variable 9 gene positive clones, as well as inhibitors of mitogen-activated protein kinase-activated protein kinase-2.

Tattoo Granulomas With Uveitis.

Bilateral intraocular inflammation and simultaneous development of tattoo granulomas has been described in several case reports. The pathophysiology of this process is poorly understood, and it has been hypothesized that it could be a similar mechanism to systemic sarcoidosis versus a delayed hypersensitivity response. Granulomatous tattoo reaction with associated uveitis can manifest with or without evidence of systemic sarcoidosis, and it is usually responsive to immunosuppression and/or tattoo removal. We present a patient with no prior diagnosis of sarcoidosis who developed bilateral panuveitis and tattoo changes suggestive of tattoo granulomas with uveitis (TAGU). The patient was initially managed with intraocular steroids and systemic steroids with minimal improvement of symptoms. The patient later required steroid sparing therapy with a tumor factor inhibitor to achieve remission. There is a growing prevalence of tattooing among the general population and a low reported rate of tattooing complications. Granulomatous tattoo reaction with associated uveitis should be a consideration in patients with tattoos presenting with "idiopathic" uveitis.

2019 Update of the American College of Rheumatology/Spondylitis Association of America/Spondyloarthritis Research and Treatment Network Recommendations for the Treatment of Ankylosing Spondylitis and Nonradiographic Axial Spondyloarthritis.

OBJECTIVE: To update evidence-based recommendations for the treatment of patients with ankylosing spondylitis (AS) and nonradiographic axial spondyloarthritis (SpA). METHODS: We conducted updated systematic literature reviews for 20 clinical questions on pharmacologic treatment addressed in the 2015 guidelines, and for 26 new questions on pharmacologic treatment, treat-to-target strategy, and use of imaging. New questions addressed the use of secukinumab, ixekizumab, tofacitinib, tumor necrosis factor inhibitor (TNFi) biosimilars, and biologic tapering/discontinuation, among others. We used the Grading of Recommendations, Assessment, Development and Evaluation methodology to assess the quality of evidence and formulate recommendations and required at least 70% agreement among the voting panel. RESULTS: Recommendations for AS and nonradiographic axial SpA are similar. TNFi are recommended over secukinumab or ixekizumab as the first biologic to be used. Secukinumab or ixekizumab is recommended over the use of a second TNFi in patients with primary nonresponse to the first TNFi. TNFi, secukinumab, and ixekizumab are favored over tofacitinib. Co-administration of low-dose methotrexate with TNFi is not recommended, nor is a strict treat-to-target strategy or discontinuation or tapering of biologics in patients with stable disease. Sulfasalazine is recommended only for persistent peripheral arthritis when TNFi are contraindicated. For patients with unclear disease activity, spine or pelvis magnetic resonance imaging could aid assessment. Routine monitoring of radiographic changes with serial spine radiographs is not recommended. CONCLUSION: These recommendations provide updated guidance regarding use of new medications and imaging of the axial skeleton in the management of AS and nonradiographic axial SpA.

2019 Update of the American College of Rheumatology/Spondylitis Association of America/Spondyloarthritis Research and Treatment Network Recommendations for the Treatment of Ankylosing Spondylitis and Nonradiographic Axial Spondyloarthritis.

OBJECTIVE: To update evidence-based recommendations for the treatment of patients with ankylosing spondylitis (AS) and nonradiographic axial spondyloarthritis (SpA). METHODS: We conducted updated systematic literature reviews for 20 clinical questions on pharmacologic treatment addressed in the 2015 guidelines, and for 26 new questions on pharmacologic treatment, treat-to-target strategy, and use of imaging. New questions addressed the use of secukinumab, ixekizumab, tofacitinib, tumor necrosis factor inhibitor (TNFi) biosimilars, and biologic tapering/discontinuation, among others. We used the Grading of Recommendations, Assessment, Development and Evaluation methodology to assess the quality of evidence and formulate recommendations and required at least 70% agreement among the voting panel. RESULTS: Recommendations for AS and nonradiographic axial SpA are similar. TNFi are recommended over secukinumab or ixekizumab as the first biologic to be used. Secukinumab or ixekizumab is recommended over the use of a second TNFi in patients with primary nonresponse to the first TNFi. TNFi, secukinumab, and ixekizumab are favored over tofacitinib. Co-administration of low-dose methotrexate with TNFi is not recommended, nor is a strict treat-to-target strategy or discontinuation or tapering of biologics in patients with stable disease. Sulfasalazine is recommended only for persistent peripheral arthritis when TNFi are contraindicated. For patients with unclear disease activity, spine or pelvis magnetic resonance imaging could aid assessment. Routine monitoring of radiographic changes with serial spine radiographs is not recommended. CONCLUSION: These recommendations provide updated guidance regarding use of new medications and imaging of the axial skeleton in the management of AS and nonradiographic axial SpA.

Body mass index and persistence of conventional DMARDs and TNF inhibitors in rheumatoid arthritis.

OBJECTIVES: Obese patients with rheumatoid arthritis (RA) may be more likely to discontinue therapy than non-obese patients, possibly signifying a more refractory phenotype. The purpose of this study was to examine the association between body mass index (BMI) and discontinuation rates for different RA treatments accounting for confounding factors. METHODS: Veterans Affairs administrative databases were used to define initial courses of methotrexate (MTX), hydroxychloroquine, sulfasalazine, prednisone, and self-injectable tumour necrosis factor inhibitors (TNFi). Discontinuation was defined as a lapse in drug refill >90 days. Using overweight BMI (25-30 kg/m2) as the referent group, multivariable Cox proportional hazards models were used to evaluate associations between BMI category and time to treatment discontinuation. RESULTS: There were 46,970 initial RA treatment courses identified from 2005-2014 among 23,669 Veterans with RA. In multivariable models, severe obesity (BMI >35 kg/m2), compared to overweight BMI, was not associated with treatment discontinuation with the exception of prednisone [HR 1.10 (1.04, 1.17) p<0.001]. Patients with low (<20 kg/m2) and normal BMI (20-25 kg/m2) were more likely to discontinue MTX, TNFi, and HCQ compared to overweight patients. Other factors associated with earlier MTX and/or TNFi discontinuation included female sex, black race, greater comorbidity, depression, malignancy, congestive heart failure, current smoking, and more recent calendar year. CONCLUSIONS: Obesity was not associated with therapy discontinuation among veterans with RA after accounting for confounding factors, suggesting that obesity is not a biological mediator of more refractory disease. Conversely, low BMI, comorbidity, and depression were identified as important predictors of drug discontinuation.

Chronic lung disease in U.S. Veterans with rheumatoid arthritis and the impact on survival.

Assess the impact of chronic lung diseases (CLD) on survival in rheumatoid arthritis (RA). Among participants in the Veterans Affairs Rheumatoid Arthritis (VARA) Registry, a prospective cohort of U.S. Veterans with RA, we identified CLD and cardiovascular disease (CVD) using administrative and registry data. Demographics, smoking status, RA characteristics including Disease Activity Score in 28 joints (DAS28), and disease-modifying anti-rheumatic drug (DMARD) use were obtained from registry data, which were linked to the National Death Index to obtain vital status. We evaluated associations of CLD with survival using the multivariable Cox regression models. Among a large (n = 2053), male-predominant (91%) RA cohort, 554 (27%) had CLD at enrollment. Mortality risk was increased 1.51-fold (95% CI 1.26-1.81) in RA patients with CLD after multivariable adjustment, a risk that was similar to that observed with CVD (HR CLD alone 1.46 [1.03-2.06]; CVD alone 1.62 [1.35-1.94]). Survival was significantly reduced in those with interstitial lung disease (ILD) as well as other forms of CLD. Mortality risk with methotrexate and biologic use was not different in those with CLD compared to those without (p interaction ≥ 0.15) using multiple exposure definitions and propensity score adjustment. Mortality risk is significantly increased in RA patients with CLD. This risk is attributable not only to ILD but also to other chronic lung conditions and does not appear to be substantially greater in those receiving methotrexate or biologic therapies. Comorbid lung disease should be targeted as a means of improving long-term outcomes in RA.

Functional intraepithelial lymphocyte changes in inflammatory bowel disease and spondyloarthritis have disease specific correlations with intestinal microbiota.

BACKGROUND: Dysbiosis occurs in spondyloarthritis (SpA) and inflammatory bowel disease (IBD), which is subdivided into Crohn's disease (CD) and ulcerative colitis (UC). The immunologic consequences of alterations in microbiota, however, have not been defined. Intraepithelial lymphocytes (IELs) are T cells within the intestinal epithelium that are in close contact with bacteria and are likely to be modulated by changes in microbiota. We examined differences in human gut-associated bacteria and tested correlation with functional changes in IELs in patients with axial SpA (axSpA), CD, or UC, and in controls. METHODS: We conducted a case-control study to evaluate IELs from pinch biopsies of grossly normal colonic tissue from subjects with biopsy-proven CD or UC, axSpA fulfilling Assessment of SpondyloArthritis International Society (ASAS) criteria and from controls during endoscopy. IELs were harvested and characterized by flow cytometry for cell surface markers. Secreted cytokines were measured by ELISA. Microbiome analysis was by 16S rRNA gene sequencing from rectal swabs. Statistical analyses were performed with the Kruskal-Wallis and Spearman's rank tests. RESULTS: The total number of IELs was significantly decreased in subjects with axSpA compared to those with IBD and controls, likely due to a decrease in TCRß+ IELs. We found strong, significant negative correlation between peripheral lymphocyte count and IEL number. IELs secreted significantly increased IL-1ß in patients with UC, significantly increased IL-17A and IFN-γ in patients with CD, and significantly increased TNF-α in patients with CD and axSpA as compared to other cohorts. For each disease subtype, IELs and IEL-produced cytokines were positively and negatively correlated with the relative abundance of multiple bacterial taxa. CONCLUSIONS: Our data indicate differences in IEL function among subjects with axSpA, CD, and UC compared to healthy controls. We propose that the observed correlation between altered microbiota and IEL function in these populations are relevant to the pathogenesis of axSpA and IBD, and discuss possible mechanisms. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02389075 . Registered on 17 March 2015.

Initiation of Disease-Modifying Therapies in Rheumatoid Arthritis Is Associated With Changes in Blood Pressure.

PURPOSE: This study reports the effect of disease-modifying therapies for rheumatoid arthritis (RA) on systolic and diastolic blood pressure (SBP, DBP) over 6 months and incident hypertension over 3 years in a large administrative database. METHODS: We used administrative Veterans Affairs databases to define unique dispensing episodes of methotrexate, leflunomide, sulfasalazine, hydroxychloroquine, tumor necrosis factor inhibitors, and prednisone among patients with RA. Changes in SBP and DBP in the 6 months before disease-modifying antirheumatic drug initiation were compared with changes observed in the 6 months after initiation. The risk of incident hypertension within 3 years (new diagnosis code for hypertension and prescription for antihypertensive) was also assessed. Multivariable models and propensity analyses assessed the impact of confounding by indication. RESULTS: A total of 37,900 treatment courses in 21,216 unique patients contributed data. Overall, there were no changes in SBP or DBP in 6 months prior to disease-modifying antirheumatic drug initiation (all P > 0.62). In contrast, there was a decline in SBP (ß = -1.08 [-1.32 to -0.85]; P < 0.0001) and DBP (ß = -0.48 [-0.62 to -0.33]; P < 0.0001) over the 6 months following initiation. The greatest decline was observed among methotrexate and hydroxychloroquine users. Methotrexate users were 9% more likely to have optimal blood pressure (BP) after 6 months of treatment. Patients treated with leflunomide had increases in BP and a greater risk of incident hypertension compared with patients treated with methotrexate (hazard ratio, 1.53 [1.21-1.91]; P < 0.001). CONCLUSIONS: Blood pressure may improve with treatment of RA, particularly with methotrexate or hydroxychloroquine. Leflunomide use, in contrast, is associated with increases in BP and a greater risk of incident hypertension.

Blood glucose changes surrounding initiation of tumor-necrosis factor inhibitors and conventional disease-modifying anti-rheumatic drugs in veterans with rheumatoid arthritis.

AIM: To determine the scope of acute hypoglycemic effects for certain anti-rheumatic medications in a large retrospective observational study. METHODS: Patients enrolled in the Veterans Affairs Rheumatoid Arthritis (VARA) registry were selected who, during follow-up, initiated treatment with tumor necrosis factor inhibitors (TNFi's, including etanercept, adalimumab, infliximab, golimumab, or certolizumab), prednisone, or conventional disease-modifying anti-rheumatic drugs (DMARDs), and for whom proximate random blood glucose (RBG) measurements were available within a window 2-wk prior to, and 6 mo following, medication initiation. Similar data were obtained for patients with proximate values available for glycosylated hemoglobin A1C values within a window 2 mo preceding, and 12 mo following, medication initiation. RBG and A1C measurements were compared before and after initiation events using paired t-tests, and multivariate regression analysis was performed including established comorbidities and demographics. RESULTS: Two thousands one hundred and eleven patients contributed at least one proximate measurement surrounding the initiation of any examined medication. A significant decrease in RBG was noted surrounding 653 individual hydroxychloroquine-initiation events (-3.68 mg/dL, P = 0.04), while an increase was noted for RBG surrounding 665 prednisone-initiation events (+5.85 mg/dL, P < 0.01). A statistically significant decrease in A1C was noted for sulfasalazine initiation, as measured by 49 individual initiation events (-0.70%, P < 0.01). Multivariate regression analyses, using methotrexate as the referent, suggest sulfasalazine (ß = -0.58, P = 0.01) and hydroxychloroquine (ß = -5.78, P = 0.01) use as predictors of lower post-medication-initiation RBG and A1C values, respectively. Analysis by drug class suggested prednisone (or glucocorticoids) as predictive of higher medication-initiation event RBG among all start events as compared to DMARDs, while this analysis did not show any drug class-level effect for TNFi. A diagnosis of congestive heart failure (ß = 4.69, P = 0.03) was predictive for higher post-initiation RBG values among all medication-initiation events. CONCLUSION: No statistically significant hypoglycemic effects surrounding TNFi initiation were observed in this large cohort. Sulfasalazine and hydroxychloroquine may have epidemiologically significant acute hypoglycemic effects.

Body Mass Index, Weight Loss, and Cause-Specific Mortality in Rheumatoid Arthritis.

OBJECTIVE: To examine associations of body mass index (BMI) and weight loss with cause-specific mortality in rheumatoid arthritis (RA). METHODS: A cohort of US veterans with RA was followed until death or through 2013. BMI was categorized as underweight, normal, overweight, and obese. Weight loss was calculated as the 1) annualized rate of change over the preceding 13 months, and 2) cumulative percent. Vital status and cause of death were obtained from the National Death Index. Multivariable competing-risks regression models were utilized to assess the time-varying associations of BMI and weight loss with cause-specific mortality. RESULTS: Among 1,600 participants and 5,789 patient-years of followup, 303 deaths occurred (95 cardiovascular, 74 cancer, and 46 respiratory). The highest weight-loss rate and weight-loss percent were associated with a higher risk of cardiovascular mortality (rate: subdistribution hazard ratio [sHR] 2.27 [95% confidence interval (95% CI) 1.61-3.19]; percent: sHR 2.31 [95% CI 1.06-5.01]) and cancer mortality (rate: sHR 2.36 [95% CI 1.11-5.01]; percent: sHR 1.90 [95% CI 1.00-3.62]). Overweight BMI was protective of cardiovascular mortality (sHR 0.59 [95% CI 0.38-0.91]), while underweight BMI was associated with a near 3-fold increased risk of respiratory mortality (sHR 2.93 [95% CI 1.28-6.67]). Incorporation of time-varying BMI and weight loss in the same models did not substantially alter individual associations for cardiovascular and cancer mortality, but an association between weight-loss percentage and respiratory mortality was attenuated after BMI adjustment. CONCLUSION: Both BMI and weight loss are predictors of cause-specific mortality in RA. Weight loss is a strong predictor of cardiovascular and cancer mortality, while underweight BMI is a stronger predictor of respiratory mortality.

Gastrointestinal and Hepatic Disease in Vasculitis.

Vasculitis is an inflammatory condition that targets the blood vessels, which may occur in isolation or as a component of a systemic inflammatory condition. Although many of the vasculitides can directly affect the organs of the gastrointestinal system, some types exhibit a proclivity for certain gastrointestinal and hepatic organs. Often a patient presents with nonspecific symptoms, delaying the diagnosis and treatment of the underlying vasculitis. Vasculitis can also present with severe manifestations, such as upper gastrointestinal bleeds and bowel perforation. It is important to identify the signs and symptoms of vasculitis in gastrointestinal system and institute appropriate treatment.

Clinical Outcomes and Biologic Costs of Switching Between Tumor Necrosis Factor Inhibitors in US Veterans with Rheumatoid Arthritis.

INTRODUCTION: The purpose of this study was to evaluate clinical outcomes and drug/administration costs of treatment with tumor necrosis factor inhibitor (TNFi) agents in US veterans with rheumatoid arthritis (RA) initiating TNFi therapy. The analysis compared patients initiating and continuing a single TNFi with patients who subsequently switched to a different TNFi. METHODS: Data from patients enrolled in the Veterans Affairs Rheumatoid Arthritis (VARA) registry who initiated treatment with adalimumab, etanercept, or infliximab from 2003 to 2010 were analyzed. Outcomes included duration of therapy, Disease Activity Score based on 28 joints (DAS28), and direct drug and drug administration costs. RESULTS: Of 563 eligible patients, 262 initiated a single TNFi therapy, 142 restarted their initial TNFi after a ≥90-day gap in treatment (interrupted therapy), and 159 switched to a different TNFi. Patients who switched had higher mean DAS28 before starting TNFi therapy than patients with single or interrupted therapy: 5.3 vs 4.5 or 4.6, respectively. Mean duration of the first course was 34.3 months for single therapy, 18.3 months for interrupted therapy, and 17.7 months for switched therapy. Mean post-treatment DAS28 was highest for patients who switched TNFi. Mean annualized costs for first course were $13,800 for single therapy, $13,200 for interrupted therapy, and $14,200 for switched therapy; mean annualized costs for second course were $12,800 for interrupted therapy and $15,100 for switched therapy. CONCLUSION: Patients who switched TNFi had higher pre-treatment DAS28 and higher overall costs than patients who received the same TNFi as either single or interrupted therapy. FUNDING: This research was funded by Immunex Corp., a fully owned subsidiary of Amgen Inc., and by VA HSR&D Grant SHP 08-172.

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.

Changes in Body Mass Related to the Initiation of Disease-Modifying Therapies in Rheumatoid Arthritis.

OBJECTIVE: Unintentional weight loss is important and can be predictive of long-term outcomes in patients with rheumatoid arthritis (RA). This study was undertaken to assess how primary therapies for RA may influence changes in body mass index (BMI) in RA patients from a large administrative database. METHODS: Unique dispensing episodes of methotrexate, prednisone, leflunomide, and tumor necrosis factor inhibitors (TNFi) administered to RA patients were identified from the US Department of Veterans Affairs pharmacy databases. Values for C-reactive protein (CRP) level and BMI closest to the time point within 30 days of the treatment course start date and at follow-up time points were linked. Missing laboratory values were imputed. Weight loss was defined as a decrease in BMI of >1 kg/m(2) . Regression models were used to evaluate changes in BMI during each drug treatment as compared to treatment with methotrexate. To assess the impact of confounding by indication, propensity scores for use of each drug were incorporated in analyses using matched-weighting techniques. RESULTS: In total, 52,662 treatment courses in 32,859 RA patients were identified. At 6 months from the date of prescription fill, weight gain was seen among patients taking methotrexate, those taking prednisone, and those taking TNFi. On average, compared to methotrexate-treated patients, prednisone-treated patients had significantly more weight gain, while leflunomide-treated patients demonstrated weight loss. In multivariable models, more weight loss (ß = -0.41 kg/m(2) , 95% confidence interval [95% CI] -0.46, -0.36; P < 0.001) and a greater risk of weight loss (odds ratio 1.73, 95% CI 1.55, 1.79; P < 0.001) were evident among those receiving leflunomide compared to those receiving methotrexate. Treatment with prednisone was associated with greater weight gain (ß = 0.072 kg/m(2) , 95% CI 0.042, 0.10; P < 0.001). These associations persisted in analyses adjusted for propensity scores and in sensitivity analyses. CONCLUSION: Leflunomide is associated with significantly more, but modest, weight loss, while prednisone is associated with greater weight gain compared to other therapies for RA.

American College of Rheumatology/Spondylitis Association of America/Spondyloarthritis Research and Treatment Network 2015 Recommendations for the Treatment of Ankylosing Spondylitis and Nonradiographic Axial Spondyloarthritis.

OBJECTIVE: To provide evidence-based recommendations for the treatment of patients with ankylosing spondylitis (AS) and nonradiographic axial spondyloarthritis (SpA). METHODS: A core group led the development of the recommendations, starting with the treatment questions. A literature review group conducted systematic literature reviews of studies that addressed 57 specific treatment questions, based on searches conducted in OVID Medline (1946-2014), PubMed (1966-2014), and the Cochrane Library. We assessed the quality of evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) method. A separate voting group reviewed the evidence and voted on recommendations for each question using the GRADE framework. RESULTS: In patients with active AS, the strong recommendations included use of nonsteroidal antiinflammatory drugs (NSAIDs), use of tumor necrosis factor inhibitors (TNFi) when activity persists despite NSAID treatment, not to use systemic glucocorticoids, use of physical therapy, and use of hip arthroplasty for patients with advanced hip arthritis. Among the conditional recommendations was that no particular TNFi was preferred except in patients with concomitant inflammatory bowel disease or recurrent iritis, in whom TNFi monoclonal antibodies should be used. In patients with active nonradiographic axial SpA despite treatment with NSAIDs, we conditionally recommend treatment with TNFi. Other recommendations for patients with nonradiographic axial SpA were based on indirect evidence and were the same as for patients with AS. CONCLUSION: These recommendations provide guidance for the management of common clinical questions in AS and nonradiographic axial SpA. Additional research on optimal medication management over time, disease monitoring, and preventive care is needed to help establish best practices in these areas.

American College of Rheumatology/Spondylitis Association of America/Spondyloarthritis Research and Treatment Network 2015 Recommendations for the Treatment of Ankylosing Spondylitis and Nonradiographic Axial Spondyloarthritis.

OBJECTIVE: To provide evidence-based recommendations for the treatment of patients with ankylosing spondylitis (AS) and nonradiographic axial spondyloarthritis (SpA). METHODS: A core group led the development of the recommendations, starting with the treatment questions. A literature review group conducted systematic literature reviews of studies that addressed 57 specific treatment questions, based on searches conducted in OVID Medline (1946-2014), PubMed (1966-2014), and the Cochrane Library. We assessed the quality of evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) method. A separate voting group reviewed the evidence and voted on recommendations for each question using the GRADE framework. RESULTS: In patients with active AS, the strong recommendations included use of nonsteroidal antiinflammatory drugs (NSAIDs), use of tumor necrosis factor inhibitors (TNFi) when activity persists despite NSAID treatment, not to use systemic glucocorticoids, use of physical therapy, and use of hip arthroplasty for patients with advanced hip arthritis. Among the conditional recommendations was that no particular TNFi was preferred except in patients with concomitant inflammatory bowel disease or recurrent iritis, in whom TNFi monoclonal antibodies should be used. In patients with active nonradiographic axial SpA despite treatment with NSAIDs, we conditionally recommend treatment with TNFi. Other recommendations for patients with nonradiographic axial SpA were based on indirect evidence and were the same as for patients with AS. CONCLUSION: These recommendations provide guidance for the management of common clinical questions in AS and nonradiographic axial SpA. Additional research on optimal medication management over time, disease monitoring, and preventive care is needed to help establish best practices in these areas.

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.

Weight Loss, the Obesity Paradox, and the Risk of Death in Rheumatoid Arthritis.

OBJECTIVE: In contrast to what is observed in the general population, a low body mass index (BMI) has been associated with accelerated mortality in patients with rheumatoid arthritis (RA). The aim of this study was to assess whether weight loss might explain these seemingly paradoxical observations. METHODS: Our study included patients identified from the Veterans Affairs (VA) RA Registry. Dates of death were abstracted from VA electronic medical records. The BMI at each study visit and the change from the previous visit were determined. The maximum BMI of each patient was also obtained from medical records. The annualized rate of BMI loss was determined from the slope of change (per year) in BMI over visits within the preceding 13 months. Cox multivariable proportional hazards models were used to assess associations between BMI measures and mortality. RESULTS: In a sample of 1,674 patients, 312 deaths occurred over 9,183 person-years. A loss in BMI of ≥1 kg/m(2) was associated with a greater risk of death, after adjustment for demographics, comorbidities, BMI, smoking, and RA therapies (hazard ratio [HR] 1.99, 95% confidence interval [95% CI] 1.53-2.59, P < 0.001). This association remained significant in a subsample analysis adjusting for C-reactive protein and physical function (HR 1.81, 95% CI 1.36-2.41, P < 0.001). Weight loss at an annualized rate of ≥3 kg/m(2) was associated with the greatest risk of death (HR 2.49, 95% CI 1.73-3.57, P < 0.001). Low BMI (<20 kg/m(2) ) in patients with a history of obesity (>30 kg/m(2) ) was associated with the greatest risk (HR 8.52, 95% CI 4.10-17.71, P < 0.001). CONCLUSION: Weight loss is a strong predictor of death in patients with RA. These observations may explain the observed obesity paradox and do not support a biologically protective role of obesity.