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To determine whether cigarette smoking increases the risk of rheumatoid arthritis among postmenopausal women.We followed a cohort of 31 336 women in Iowa who were aged 55 to 69 years in 1986 and who had no history of rheumatoid arthritis. Through 1997, 158 cases of rheumatoid arthritis were identified and validated based on review of medical records and supplementary information provided by physicians. Multivariable Cox proportional hazards regression was used to derive rate ratios (RRs) and 95% confidence intervals (CIs) for the association between cigarette smoking and rheumatoid arthritis.Compared with women who had never smoked, women who were current smokers (RR = 2.0; 95% CI: 1.3 to 2.9) or who had quit 10 years or less before study baseline (RR = 1.8; 95% CI: 1.1 to 3.1) were at increased risk of rheumatoid arthritis, but women who had quit more than 10 years before baseline were not at increased risk (RR = 0.9; 95% CI: 0.5 to 2.6). Both the duration and intensity of smoking were associated with rheumatoid arthritis. Multivariable adjustments for age, marital status, occupation, body mass index, age at menopause, oral contraceptive use, hormone replacement therapy, alcohol use, and coffee consumption did not alter these results.These results suggest that abstinence from smoking may reduce the risk of rheumatoid arthritis among postmenopausal women.

We examined the preliminary safety and efficacy of intravenous samarium-153-EDTMP (Sm-153) in the treatment of refractory rheumatoid arthritis (RA). In an open-label sequential group comparison of 0.5, 1.0, and 2.0 mCi/kg, Sm-153 was administered as a single intravenous infusion to 24 patients with refractory disease. Across treatment doses, the frequency of American College of Rheumatology (ACR) 20% responses was 25%, 29%, 25%, and 33% at 2, 4, 8, and 12 weeks, respectively. Expected significant declines in absolute neutrophil count, hemoglobin, and platelet counts were observed with nadirs seen between 2-4 weeks. Sm-153, at doses of 0.5 and 1.0 mCi/kg, is well tolerated but minimally effective in the treatment of refractory RA as measured using ACR response criteria.

To evaluate whether blood transfusion, alcohol use, or anthropometric characteristics are risk factors for rheumatoid arthritis (RA) in older women.These factors were evaluated in a prospective cohort study that was initiated in 1986, and included 31,336 women aged 55-69 years without a history of RA. Risk factor data were self-reported using a mailed questionnaire. Through 1997, 158 cases of RA meeting at least 4 of 7 American College of Rheumatology criteria were identified and validated by medical record review. The relative risk (RR) and 95% confidence interval (CI) were used as the measure of association, and were adjusted for the potential confounding effects of age, marital status, smoking history, age at menopause, and use of estrogen replacement therapy.History of blood transfusion was inversely associated with RA (multivariate RR = 0.72; 95% CI 0.48-1.08), and this association was stronger for rheumatoid factor (RF) positive disease (RR = 0.59; 95% CI 0.35-1.00). There were no associations for use of medications for hyper- or hypothyroidism or adult onset diabetes. Anthropometric factors (height, weight, body mass index, body fat distribution), leisure time physical activity, and alcohol use were not associated with risk of RA.A history of blood transfusion was inversely associated with RA, particularly RF positive RA. Anthropometric factors, physical activity, and alcohol use did not influence the risk of RA in this cohort of older women.

Objective The enzyme methylenetetrahydrofolate reductase (MTHFR) has been implicated in the metabolism of methotrexate (MTX) – the most common disease modifying antirheumatic drug used to treat rheumatoid arthritis (RA). MTHFR C677T and A1298C polymorphisms have been associated with increased cardiovascular (CV) events in non-RA populations. We explored the potential associations of MTHFR C677T, A1298C and MTX with decreased time-to-CV event in the prospective Veterans Affairs Rheumatoid Arthritis (VARA) registry. Methods VARA participants were genotyped for MTHFR polymorphisms. Demographic information, RA duration and auto-antibody status were collected upon enrolment into the registry. Disease activity was recorded at baseline and at follow-up visits. Patients9 baseline comorbidities and the outcome variable were defined using ICD-9 and CPT codes recorded in inpatient and outpatient patient treatment files. The combined CV event outcome included: myocardial infarction (MI), percutaneous transluminal coronary angioplasty, coronary artery bypass graft and stroke. Multivariable Cox proportional-hazards regression was used to model the time-to-CV event. Results Data were available for 1047 subjects. Post-enrolment CV events occurred in 406 patients. Prior MI was strongly associated with time-to-CV event (HR 6.65 (CI 5.31 to 8.33)), as was hyperlipidaemia (HR 1.64 (CI 1.32 to 2.05)). Methotrexate use was associated with a substantial decline in first CV events (HR 0.76 (CI 0.62 to 0.92)). MTHFR polymorphisms were not associated with decreased time-to-CV event. Conclusions Although MTHFR polymorphisms have previously been associated with increased CV events, we found no evidence that MTHFR status was associated with VARA patients9 time-to-CV event. Traditional CV risk factors conferred substantial CV risk, while methotrexate use was protective.

Background The specific impact of disease measures and current treatments on the risk of serious infections for patients with Rheumatoid Arthritis (RA) are still unknown. In addition, few have examined these risks by type and site of infections. Objectives To assess the risk of serious infections by type and treatment in patients with RA compared to non-inflammatory rheumatic disease (NIRD) controls. Methods Patients enrolled in a longitudinal observational study, the National Data Bank for Rheumatic Diseases, were followed from 1998 to 2013. Infections requiring intravenous antibiotics or hospitalization were validated from hospitalization records, physician reports and death records. Infections were categorized as opportunist, by cause (bacterial, viral or fungal) and by syndrome (pneumonia, CNS, abdominal, bone, urinary, skin, and sepsis/blood). Survival analysis methods (Cox regression, time to first infection using time-varying covariates and Andersen-Gill multiple failures model) were applied to identify age- and sex-adjusted risk factors. These included demographics, clinical status, disease severity and medications (prednisone, and for RA: methotrexate (MTX), anti-TNF (TNF) and other biologics (nTNF)). Significant factors were then selected in the multivariate models. Results 20,941 RA and 6300 NIRD patients contributed 125,401 patient-years of exposure. Baseline characteristics by disease (RA:NIRD) were age (58:63 yrs), sex (78:80% female), HAQ (1.0: 0.9), comorbidities (1.7:1.8), and ever smoked (50:44%). The 2496 infections involved 1966 patients (1657:309). The Table shows the HRs for infections by type after adjusting for age, sex, smoking, education, comorbidity, pain, HAQ, and prednisone use. The impact of RA treatment group had similar adjustment. A significantly higher risk for all and bacterial infections were associated with RA. By site, only pneumonia, bone/joint, and sepsis seemed to differ in RA. None of the biologic classes appeared to be statistically associated with time to infection, both by type or site. Conclusions RA patients have an increased risk of serious infection of any type and bacterial cause when compared with NIRD patients. Additional exposure will be necessary to further delineate the risk for infection type in RA patients by individual drugs. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.3963

Background/Purpose: Rheumatoid arthritis (RA) is an inflammatory arthritis typically presenting in women in their fifth decade. Most individuals with RA have antibodies to citrullinated peptide antigens, such as anti-cyclic citrullinated peptide antibodies (CCP). In addition to genetic factors, cigarette smoking and periodontal disease (PD) secondary to Porphyromonas gingivalis are risk factors for RA. Some children with juvenile idiopathic arthritis (JIA) phenotypically resemble adults with seropositive RA, characterized by the presence of anti-CCP antibodies. Our objective was to investigate the association between anti-CCP antibodies and anti-P. gingivalis antibodies, as well as the association between anti-CCP antibodies and symptoms of PD, in children with CCP-positive (CCP+) JIA vs. children with CCP-negative (CCP−) JIA. Methods: Study participants included 77 children with CCP+JIA and 130 children with CCP-JIA. Antibodies to P. gingivalis, P. intermedia, and F. nucleatum outer membrane antigen were measured using ELISA in 71 children with CCP+JIA and 74 children with CCP-JIA. Oral health history and smoke exposure history were collected using a parent questionnaire from 37 children with CCP+JIA and 127 CCP-JIA. T-tests were used to compare means between the two groups; Chi-Square or Fisher's tests were used to compare categorical variables. Results: Children with CCP+JIA were more likely to be female (89% vs. 64%), older at the time of diagnosis (10.3 vs. 6 years), and either African American (29.9% vs. 11%) or Hispanic (17% vs. 9.2%) compared to children with CCP-JIA. Anti-P. gingivalis IgG antibody titers were significantly higher in the CCP+JIA cohort than in the CCP-JIA cohort (9.04 vs. 5.69; p < 0.003). Anti-P. intermedia IgG and anti-F. nucleatum IgG antibody titers were not different between the two groups. There was no association between CCP+JIA and smoke exposure in the prenatal period or in the 6 months prior to JIA symptom onset. Several symptoms of poor oral hygiene were higher among children with CCP+JIA: red/swollen gums (35% vs. 20%, p < 0.08), tender bleeding gums (41% vs. 24%, p < 0.06), pain on chewing (38% vs. 18%, p < 0.03), and never/rarely flossing (49% vs. 32%, p < 0.08). Of note, there was no significant difference in the frequency of cavities between children with CCP+JIA and children with CCP-JIA. When oral health comparisons were limited to Non-Hispanic white subjects, red/swollen gums (p < 0.003) and tender bleeding gums (p < 0.002) were even more prevalent in children with CCP+JIA compared to children with CCP-JIA. Conclusion: We have shown that children with CCP+JIA have higher titers of antibodies to P. gingivalis compared to children with CCP-JIA. Furthermore, children with CCP+JIA appear to have symptoms of poor oral health. There was no association between smoke exposure and CCP+JIA. To our knowledge, this is the first study to explore the relationship between these risk factors and the onset of CCP+JIA.

It is increasingly clear that coexistent disease plays a pivotal role in RA outcome and that efforts aimed at specifically addressing these comorbidities need to be aggressively sought, investigated, and implemented once proven effective. RA-associated costs are currently increasing at twice the rate of the medical care index. Comorbidity in the setting of RA independently predicts disease-associated disability (a major cost component) and mortality, underscoring the need for a more comprehensive approach to RA, one that adequately addresses disease-specific comorbidities. At present, many primary and secondary preventative measures (Table 1) for RA-specific comorbidities remain largely unproved and require rigorous investigation in a randomized prospective fashion. Despite this ongoing need, advances are being made in our understanding of the underlying pathogenesis of these comorbid conditions and their relation with RA. This improved understanding should translate into further effective interventions. Bisphosphonates, for instance, have been shown to be effective in the prevention of GIOP and associated fractures. The past several years have seen other exciting therapeutic advances in RA. DMARD combinations have been shown to be more effective and no more toxic than MTX monotherapy. In addition to the recent release of COX-2 NSAIDs, three new disease-modifying agents (leflunomide, etanercept, and infliximab) have been added to the therapeutic armamentarium; these are options that have markedly changed the treatment landscape in RA. Although these important advances have generated much deserved optimism, the precise effect that these agents may have on RA-specific comorbidity remains to be seen. The next decade should prove to be an exciting time in RA management. Better identification, understanding, and management of RA comorbidities have great potential to improve quality of life and survival among our patients with RA.

Background Risks of hospitalized infections associated with newer biologic agents have not been well characterized in relation to risks with anti-TNF therapy, especially in rheumatoid arthritis (RA) patients with high comorbidity burdens. Objectives To compare the risk of hospitalized infections among RA patients switching from anti-TNF therapy to rituximab (RTX), abatacept (ABA) or another anti-TNF. Methods Using data from 2002-10 from the U.S. Veteran’s Health Administration, we identified a cohort of 38453 RA patients. Eligible patients started RTX, ABA, or anti-TNF therapy after prior exposure to another anti-TNF agent. To minimize confounding from channeling of cancer patients to certain biologics, patients with a history of cancer were excluded to form 2 cohorts: Exclusion for any type of prior cancer using all available data (3257 episodes, 2559 patients) or exclusion only for hematologic cancer in the prior 12 months (3848 episodes, 3018 patients). Baseline characteristics defined in 1 year prior to treatment initiation. Exposure was as-treated based upon days supply (injections) or usual dosing intervals (infusions), with 12 months assumed for RTX exposure. Current exposure was extended by 90 days for all biologics. The outcome was hospitalization with primary diagnosis code for bacterial infection. The hazard ratio (HR, 95% CI) for infection for RTX and ABA vs. anti-TNFs was calculated, adjusting for multiple potential confounders. Results 523 RTX, 366 ABA and 2959 anti-TNF switcher episodes were identified in RA patients without hematologic cancers; 15% of treatment episodes were further excluded with the more restrictive cancer exclusion to form a 2nd cohort. This cohort’s mean overall age was 60.8±10.7 years, 87% male, 25% diabetes, 15% COPD, 3% heart failure, and 66% used glucocorticoids. 2/3rd of the anti-TNF exposure was adalimumab. The most common types of hospitalized infections were pneumonia (36%), skin/soft tissue infections (26%), gastroenteritis (7%) and urinary tract infections (6%). In the less restrictive RA cohort, crude hospitalized infection rates/100person years were RTX: 15.9, ABA: 10.2 and anti-TNF: 12.7. In the less restrictive RA cohort, adjusted HRs for infection were comparable to or lower than for anti-TNF therapy: RTX: 0.85 (0.62-1.12) and ABA: 0.72 (0.50-1.10). In the more restrictive RA cohort, results were similar: adjusted HR for RTX: 0.76 (0.50-1.15) and ABA: 0.58 (0.36-0.93) compared to anti-TNF therapy. Multiple comorbidities and medications were associated with infections (diabetes HR=1.4, 95% CI 1.1-1.7; chronic lung disease HR=1.5, 1.1–1.9; prednisone >7.5mg/day HR=2.1, 1.6-2.7). Conclusions In older, predominantly male, US veterans with RA and high comorbidities, risks of hospitalized bacterial infections for patients treated with RTX or ABA were comparable to or lower than for patients switching to a different anti-TNF therapy (mostly ADA). Ongoing work is characterizing the comparative risks of opportunistic infections. Disclosure of Interest J. Curtis Consultant for: Roche/Genetech, UCB, Centocor CORRONA, Amgen, Pfizer, BMS, Crescendo, Abbott, S. Yang: None Declared, N. Patkar: None Declared, L. Chen: None Declared, J. Singh Grant/Research support from: Takeda, Savient, Consultant for: URL pharmaceuticals, Takeda, Ardea, Savient, Allergan, Novartis, G. Cannon: None Declared, T. Mikuls: None Declared, E. Delzell Grant/Research support from: Amgen, K. Saag Consultant for: Amgen; Lilly; Merck; Novartis; Savient; Ardea; Regeneron; URL, Abbott; DSMB – BioCryst; Roche; Lilly, M. Safford: None Declared, S. Duvall Grant/Research support from: Anolinx, LLC, Genentech, Roche, Amgen, Shire, K. Alexander Employee of: Genetech, P. Napalkov Employee of: Genetech, A. Kamauu Employee of: President- Anolinx LLC, J. Baddley Consultant for: Abbott, Merck

Background Comparison of adalimumab (ADA), etanercept (ETN), and infliximab (INF) use in clinical practice may provide important insight into the comparative effectiveness and cost of approved therapies. Objectives To examine persistence, dose escalation, clinical outcomes, and treatment costs with ADA, ETN, and INF for patients (pts) enrolled in the US Veterans Affairs RA (VARA) registry. Methods VARA links to VA pharmacy and administrative databases, and documents longitudinal assessments of disease activity and outcomes. VARA pts initiating ADA, ETN, or INF from 3/18/2003 to 9/30/2010 were identified with follow-up data collected for ≥12 months. This analysis was limited to first treatment course beginning ≥180 days after VARA enrollment. A treatment course was defined as continuous medication dispensing in the absence of ≥90-day gap. Dose escalation was ≥25% increase in weekly dose. Cost was determined by drug costs alone and including drug administration (dispensing/infusion costs). Results Data from 563 pts (204 ADA; 290 ETN; 69 INF) were analyzed (Table). No differences in persistence were seen (Fig A). Dose escalation was most common with INF followed by ADA (Fig B). Persistence post-escalation was similar for all agents. Mean DAS28 and change in DAS28 in 61 evaluable pts were similar for each drug. Average annual costs were highest for INF. Image/graph: Conclusions In VARA, persistence on ADA, ETN and INF was similar. Escalation was most common with INF and least frequent with ETN, and did not impact persistence. Drug costs were higher for INF than ADA and ETN. Persistence and DAS scores were similar regardless of dose escalation. Acknowledgements Research funded by VA Research Program and Immunex Corporation, a wholly owned subsidiary of Amgen Inc., and by Wyeth, which was acquired by Pfizer Inc. in October 2009. Disclosure of Interest G. Cannon Grant/research support from: Amgen Inc., S. DuVall Grant/research support from: Amgen Inc, Anolinx LLC, Genentech Inc, F. Hoffmann-La Roche Ltd, Merck & Co Inc, Mylan Specialty LP, and Shire PLC, C. Hayden: None Declared, L. Caplan: None Declared, J. Curtis Grant/research support from: Roche/Genentech, UCB, Centocor, CORRONA, Amgen, Pfizer BMS, Janssen, AbbVie, K. Michaud: None Declared, T. Mikuls Grant/research support from: Genentech/Roche, A. Reimold Grant/research support from: Lilly, Novartis, Janssen, Ardea, Consultant for: UCB, D. Collier Shareholder of: Amgen Inc., Employee of: Amgen Inc., D. Harrison Shareholder of: Amgen Inc., Employee of: Amgen Inc., G. Joseph Shareholder of: Amgen Inc., Pfizer Inc., Employee of: Amgen Inc., B. Sauer Grant/research support from: Amgen Inc.

Background Double-blind placebo controlled trials have demonstrated the efficacy of 16 different therapies in RA patients with active disease despite MTX. However, there have been no blinded trials comparing conventional combination therapy to biologicals in this population. This gap in knowledge is important since biologicals are substantially more expensive than conventional therapy and have different toxicities. We compared two treatment strategies, adding conventional oral DMARDs or adding a biological, etanercept, in patients with active disease despite MTX followed by switch to the other treatment when clinically indicated. Methods This investigator-initiated multinational double-blind non-inferiority trial randomized 353 patients with active RA despite MTX to treatment with triple DMARD therapy (MTX, sulfasalazine and hydroxychloroquine) or etanercept + MTX. Treatment continued for 48 wks, with blinded treatment switch at 24 wks for patients in either group if their disease activity had failed to improve by a clinically significant amount (ΔDAS28 of Results Study population baseline characteristics: mean age 57 yrs, 54% males, DAS28 = 5.8, disease duration 5.2 yrs and mean initial MTX dose 19.6 mg/wk. There were no significant differences between groups at baseline. Both groups improved significantly over 24 wks (p=0.001). The proportion of patients requiring a switch at 24 wks was nearly identical (27.0% for triple and 26.7% for etanercept). In patients who switched, both groups improved significantly (p Conclusions The strategy of continuing MTX with the addition of sulfasalazine and hydroxychloroquine is comparable to adding etanercept in RA patients with active disease despite MTX and results in similar benefits in disease measures, function and radiographic progression. At the health system level, the cost-saving potential and the cost-effectiveness of the strategy of starting with conventional DMARD combinations and then switching to biologicals in those who do not respond may be substantial. Acknowledgements Funding Sources: Cooperative Studies Program of the Department of Veterans Affairs Office of Research and Development, CIHR and NIAMS by interagency agreements. Placebo etanercept donated by Amgen Disclosure of Interest J. O’Dell: None Declared, T. Mikuls Grant/research support from: Genentech, T. Taylor: None Declared, V. Ahluwalia Grant/research support from: Abbott, Janssen, Roche, UCB, Consultant for: Abbott, Amgen/Wyeth, BMS, Janssen, Roche, Speakers bureau: Abbott, Janssen, Roche, M. Brophy: None Declared, S. Warren: None Declared, R. Lew: None Declared, C. Phibbs: None Declared, A. Anis: None Declared, A. Cannella: None Declared, G. Kunkel: None Declared, E. Keystone Grant/research support from: Abbott Laboratories; Amgen, Inc.; AstraZeneca Pharmaceuticals LP; Bristol-Myers Squibb; Centocor, Inc.; F. Hoffmann-LaRoche Inc.; Genzyme, Merck, Novartis Pharmaceuticals, Pfizer Pharmaceuticals, UCB, Consultant for: Abbott Laboratories; AstraZeneca Pharma, Biotest, Bristol-Myers Squibb Company; Centocor, Inc.; F. Hoffmann-LaRoche Inc.; Genentech Inc.; Merck, Nycomed, Pfizer Pharmaceuticals, UCB, Speakers bureau: Abbott Laboratories; Bristol-Myers Squibb Co.; F. Hoffmann-LaRoche Inc.; Merck; Pfizer Pharmaceuticals; UCB; Amgen; Abbott, Janssen Inc.

Background Tumor necrosis factor (TNF)-blockers are effective in treating RA, but the benefit of switching between TNF-blockers is less clear. Objectives To examine switching, costs and factors associated with switching between adalimumab (ADA), etanercept (ETN), and infliximab (INF) in patients (pts) in the Veterans Affairs Rheumatoid Arthritis (VARA) registry following their first VA episode of TNF-blocker use. Methods VARA is a longitudinal, observational, cohort study of US veterans with RA. It links to VA pharmacy and administrative data and documents longitudinal assessments of RA disease activity and outcomes. VARA patients initiating ADA, ETN, or INF from March 2003 to Sept 2010 were identified and followed until Sept 2011. A treatment course was defined as continuous TNF-blocker use without ≥90-day gap. Cost of TNF-blockers with and without drug administration costs was determined for first and second courses. Results Data from 563 RA pts (204 ADA, 290 ETN, 69 INF) initiating therapy were analyzed. During observation (5.2±2.1 years), 47% had a single TNF-blocker course, 25% restarted the same TNF-blocker and 28% switched. Patients with a single course were older than pts with multiple courses. In the 61 pts with pre- and post-treatment DAS28, pts who switched had higher DAS28 on treatment than pts restarting the same TNF-blocker. DAS28 was similar before and after the second TNF-blocker course in both groups. Patients with ≥25% increase in dose or ETN as initial therapy were more likely to switch. In pts who switched, initial annualized costs were numerically higher in the first course and statistically significantly higher during the second course than for pts who restarted their TNF-blocker. Conclusions In VARA, approximately 50% of pts had at least 1 course of TNF-blocker treatment. Patients who switched had higher DAS28 scores during the initial course, a history of dose escalation with the initial agent and higher costs. Due to potential confounding factors inherent in observational studies, more research is needed to understand reasons for switching and the effects of switching TNF-blockers on overall outcomes in RA. Acknowledgements Research funded by VA Research Program and Immunex Corporation, a wholly owned subsidiary of Amgen Inc., and by Wyeth, which was acquired by Pfizer Inc. in October 2009. Disclosure of Interest G. Cannon Grant/research support from: Amgen, S. DuVall Grant/research support from: Amgen, Anolinx LLC, Genentech, F. Hoffman-LaRoche Ltd, Merck & Co, Mylan Specialty LP, Shire PLC, C. Hayden: None Declared, L. Caplan: None Declared, J. Curtis Grant/research support from: Roche/Genentech, UCB, Centocor, CORRONA, Amgen, Pfizer BMS, Janssen, AbbVie, K. Michaud Employee of: National Databank of Rheumatic Diseases, Wichita, KS, T. Mikuls Grant/research support from: Genentech/Roche, A. Reimold Grant/research support from: Lilly, Novartis, Janssen, Ardea, Consultant for: UCB, D. Collier Shareholder of: Amgen, Employee of: Amgen, G. Joseph Shareholder of: Amgen, Pfizer, Employee of: Amgen, D. Harrison Shareholder of: Amgen, Employee of: Amgen, B. Sauer Grant/research support from: Amgen

Background: Total shoulder arthroplasty is increasingly used in the treatment of arthritis. However, the effect of total shoulder arthroplasty on health-related quality of life has not been fully established. The goal of this systematic review and meta-analysis was to characterize the change in generic and shoulder-specific health-related quality-of-life measures resulting from total shoulder arthroplasty. Methods: We identified published studies reporting preoperative and postoperative health-related quality-of-life outcomes for patients receiving total shoulder arthroplasty. Health-related quality-of-life measures were identified, and meta-analysis was used to calculate standardized mean differences (SMDs, reflective of the effect size) and 95% confidence intervals for each scale. Results: Twenty studies (1576 total shoulder replacements) met the inclusion criteria. Outcome measures were analyzed after an average postoperative follow-up duration of 3.7 ± 2.2 years. The Short Form-36 demonstrated significant improvement in physical component summary scores (SMD = 0.7, p < 0.001) but not in mental component summary scores (SMD = 0.2, p = 0.37). Significant improvements were observed in the visual analog scale score for pain (SMD = −2.5, p < 0.001) and scores on three shoulder-specific measures: the Constant score (SMD = 2.7, p < 0.001), American Shoulder and Elbow Surgeons score (SMD = 2.9, p < 0.001), and Simple Shoulder Test (SMD = 2.3, p < 0.001). Conclusions: Total shoulder arthroplasty leads to significant improvements in scores for function and pain. Shoulder-specific measures of function consistently showed the greatest degree of improvement, with large effect sizes. Total shoulder arthroplasty also leads to significant improvements in overall physical well-being, with a moderate-to-large effect size. Level of Evidence: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Backgroundand objectives Porphyromonas gingivalis , a major periodontal pathogen, has been implicated in the pathogenesis of rheumatoid arthritis (RA). It is the only pathogenic prokaryote known to possess a bacterial peptidylarginine deiminase (PPAD), an enzyme that catalyses the post-translational modification of arginine to citrulline. The enzyme is surface expressed and citrullinates c-terminal arginines of human fibrinogen and enolase peptides. Here, the authors show that PPAD is capable of autocitrullination and able to raise an immune response in RA. Materials and methods PPAD was expressed as a GST/His-tagged fusion protein using a bacterial expression system. Site-directed mutagenesis using a PCR based method was used to create a PPAD mutant (mPPAD) with a single residue mutation (cysteine 351 to alanine) and with no enzymatic activity. Citrullination was determined by immunoblotting with an antimodified citrullinated antibody kit (AMC, New York, NY, USA). Mass spectrophotometry was carried out to verify PPAD-GST citrullination. ELISAs using recombinant PPAD and recombinant mPPAD were developed to test sera from patients with periodontitis (PD) (n=44), RA (n=82) and healthy controls (C) (n=80). Reactivity was expressed as arbitrary units per ml (AU/ml) using a standard curve. Results Sera from patients with RA, PD and healthy controls were tested for IgG antibodies to PPAD and showed that RA sera have a significantly elevated antiPPAD IgG response (mean 182.4 AU/ml) compared to PD (mean 96.4AU/ml; p Conclusions The authors present evidence that PPAD is capable of autocitrullination and its target site is not restricted to c-terminal peptide arginines. The antibody response to autocitrullinated PPAD was significantly elevated in RA patients compared to PD patients and controls. This indicates that PPAD is a potential novel antigen in RA and may form part of the anticitrullinated protein antigen response seen in this disease, thus substantiating a possible link between PD and RA.

Introduction Minocycline and doxycycline are safe and moderately effective disease-modifying anti-rheumatic drugs (DMARDs) in the treatment of early, DMARD-naïve rheumatoid arthritis (RA), although little is known about their use outside clinical trials. We characterize the use of minocycline and doxycycline in community-dwelling RA patients by examining associated prescribing patterns, patient-level determinants of use, and side-effect profiles. Methods We studied 15,716 patients with RA observed between 1998 and 2009 while participating in a long-term US observational study. Results Minocycline or doxycycline was prescribed by 18% of rheumatologists (interquartile range one to two patients per physician) to 9% of RA patients. Significant differences between minocycline-treated and doxycycline-treated patients and nontreated patients included age (58.4 years vs. 59.8 years), RA duration (14.8 years vs. 13.7 years), Caucasian race (93.7% vs. 89.7%), lifetime DMARDs and biologics (3.3 vs. 2.5), prednisone use (40.1% vs. 35.3%), and Medical Outcomes Study 36-Item Short Form Survey physical component summary score (35.0 vs. 36.4). In multivariable Cox regression, patients initiating minocycline or doxycycline had increased disease activity, more comorbidities, and a greater number of prior nonbiologic DMARDs. Side effects were reported by 17.8% of minocycline users and 11.8% of doxycycline users. Skin complaints accounted for 54% of minocycline patient-reported side effects. The most commonly effected organ systems for doxycycline were gastrointestinal (35.4%) and skin (33.7%). Approximately 75% of side effects were of mild or moderate severity. Conclusions Rheumatologists have not embraced minocycline or doxycycline as primary treatment options for RA and reserve their use primarily in patients with long-standing, refractory disease. These drugs are generally well tolerated, with skin complaints, nausea, and dizziness being the most common patient-reported side effects.

The online version of the original article can be found under doi:10.1007/s11999-009-0996-2.E. V. Fehringer, T. R. Mikuls, K. D. Michaud, J. R. O’DellNebraska Arthritis Outcome Research Center (NAORC),Omaha, NE, USAW. G. HendersonUniversity of Colorado Health Outcomes Program UCD, AMC,Denver, CO, USAW. G. HendersonDenver VA Medical Center, Denver, CO, USAE. V. Fehringer (&)Department of Orthopaedic Surgery and Rehabilitation,University of Nebraska Medical Center, 981080 NebraskaMedical Center, Omaha, NE 68198-1080, USAe-mail: evfehringer@unmc.edu

Introduction A deletion polymorphism in glutathione S-transferase Mu-1 (GSTM1-null) has previously been implicated to play a role in rheumatoid arthritis (RA) risk and progression, although no prior investigations have examined its associations with anticitrullinated protein antibody (ACPA) positivity. The purpose of this study was to examine the associations of GSTM1-null with ACPA positivity in RA and to assess for evidence of interaction between GSTM1 and HLA-DRB1 shared epitope (SE). Methods Associations of GSTM1-null with ACPA positivity were examined separately in two RA cohorts, the Veterans Affairs Rheumatoid Arthritis (VARA) registry (n = 703) and the Study of New-Onset RA (SONORA; n = 610). Interactions were examined by calculating an attributable proportion (AP) due to interaction. Results A majority of patients in the VARA registry (76%) and SONORA (69%) were positive for ACPA with a similar frequency of GSTM1-null (53% and 52%, respectively) and HLA-DRB1 SE positivity (76% and 71%, respectively). The parameter of patients who had ever smoked was more common in the VARA registry (80%) than in SONORA (65%). GSTM1-null was significantly associated with ACPA positivity in the VARA registry (odds ratio (OR), 1.45; 95% confidence interval (CI), 1.02 to 2.05), but not in SONORA (OR, 1.00; 95% CI, 0.71 to 1.42). There were significant additive interactions between GSTM1 and HLA-DRB1 SE in the VARA registry (AP, 0.49; 95% CI, 0.21 to 0.77; P < 0.001) in ACPA positivity, an interaction replicated in SONORA (AP, 0.38; 95% CI, 0.00 to 0.76; P = 0.050). Conclusions This study is the first to show that the GSTM1-null genotype, a common genetic variant, exerts significant additive interaction with HLA-DRB1 SE on the risk of ACPA positivity in RA. Since GSTM1 has known antioxidant functions, these data suggest that oxidative stress may be important in the development of RA-specific autoimmunity in genetically susceptible individuals.

Introduction The purpose of the present manuscript is to test the hypothesis that arthrotropic localization and synovial cell internalization account for the unique capacity of N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-dexamethasone conjugate (P-Dex, a macromolecular prodrug of dexamethasone) to induce sustained amelioration of joint inflammation and inhibition of tissue damage in an animal model of inflammatory arthritis. Methods Rats with adjuvant-induced arthritis (AA) were treated with P-Dex, free dexamethasone, saline or HPMA homopolymer. To define the biodistribution of P-Dex, conjugates with different imaging labels were given to AA rats and analyzed. Isolated joint tissues were evaluated by fluorescence-activated cell sorting (FACS) and immunohistochemical staining. Cellular uptake of P-Dex and its effects on apoptosis and production of proinflammatory cytokines were examined using human monocyte-macrophages and fibroblasts. Results A single systemic administration of P-Dex completely suppressed AA for >20 days. Magnetic resonance imaging demonstrated higher HPMA copolymer influx into the inflamed joints than the normal joints. Immunohistochemistry and FACS analyses of arthritic joints revealed extensive uptake of the polymer conjugate by synovial fibroblasts and myeloid lineage cells. The capacity of P-Dex to suppress inflammation was confirmed in monocyte-macrophage cultures in which P-Dex treatment resulted in suppression of lipopolysaccharide-induced IL-6 and TNFα release. Similarly, TNFα-induced expression of matrix metalloproteinases (MMP1 and MMP3) in synovial fibroblasts from a rheumatoid arthritis patient was suppressed by P-Dex. P-Dex showed no detectable effect on monocyte apoptosis. Conclusions P-Dex provides superior and sustained amelioration of AA compared with an equivalent dose of free dexamethasone. The arthrotropism and local retention of P-Dex is attributed to the enhanced vascular permeability in arthritic joints and the internalization of P-Dex by synovial cells. The uptake and processing of P-Dex by macrophages and fibroblasts, and downregulation of proinflammatory mediators, provides an explanation for the sustained anti-inflammatory efficacy of P-Dex in this model of inflammatory arthritis.

Hydroxychloroquine (HCQ) is an antimalarial agent that is commonly used to treat rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). The present report documents a case of hypoglycaemia due to HCQ in a patient with SLE and diabetes mellitus type 2, in which the HCQ completely replaced the need for daily subcutaneous insulin.

In this review, we critically evaluate the case-control studies examining the relationship between rheumatoid arthritis (RA) and periodontitis, two common chronic inflammatory diseases with a similar host-mediated pathogenesis. We review the "two-hit" periodontitis model that our group previously proposed, in which we elucidate how a systemic disease such as RA can potentially exacerbate or initiate periodontitis. Furthermore, we discuss adjunctive host modulation therapy, originally developed for periodontitis (i.e., subantimicrobial-dose doxycycline alone or in combination with an anti-inflammatory agent), to simultaneously mitigate RA and periodontitis. Finally, we review studies describing periodontal treatment effects on both RA disease activity measures and systemic inflammation. Current evidence suggests that an association exists between periodontitis and RA. Well-designed multicenter longitudinal clinical trials and studies with sufficient sample sizes are needed to ascertain the temporal relationship between these two diseases and whether periodontal treatment can reduce the severity of RA or prevent its onset.

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 (β = -0.58, P = 0.01) and hydroxychloroquine (β = -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 (β = 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.

Background Evidence suggests that the presence of peptidyl arginine deiminase type 4 (PAD4) antibodies is associated with radiographic-severity rheumatoid arthritis (RA) among Caucasian patients. The presence of anti-PAD4 antibodies that were cross-reactivity against PAD3 was associated with more aggressive erosive disease (compared with the presence of anti-PAD4 antibodies without anti-PAD3 crossreactivity) in Caucasian RA patients. The objectives of this study were to determine the prevalence of serum anti-PAD4 and anti-PAD4/PAD3 cross-reactive autoantibodies in African Americans with RA and whether these antibodies associate with radiographic severity and radiographic progression. Methods Serum anti-PAD4 and anti-PAD4/PAD3 antibodies were measured by immunoprecipitation, and the temporal trends in titers were analyzed. We compared total radiographic scores among anti-PAD4-positive, anti-PAD4/PAD3-positive, and anti-PAD4-negative patients and used a zero-inflated negative binomial model to determine associations between radiographic severity and antibody status. Logistic regression was used to analyze radiographic progression. Results Of 192 African-American patients with RA, 73 % were anti-citrullinated peptide/protein antibody (ACPA)-positive, 46 out of 192 (24 %) of whom had serum anti-PAD4 antibodies. Median (interquartile range) total Sharp van der Heijde radiographic scores were 2 (1–97.5) in ACPA-positive patients and 0 (0–3) in ACPA-negative patients (P

Background The association between rheumatoid arthritis (RA) and periodontitis is well established. Some children with juvenile idiopathic arthritis (JIA) phenotypically resemble adults with RA, characterized by the presence of anti-cyclic citrullinated peptide (CCP) antibodies. We sought to investigate an association between CCP-positive JIA and symptoms of periodontitis and antibodies to oral microbiota. Methods Antibodies to oral pathogens Porphyromonas gingivalis, Prevotella intermedia, and Fusobacterium nucleatum were measured using ELISA in 71 children with CCP-positive JIA and 74 children with CCP-negative JIA. Oral health history was collected from 37 children with CCP-positive JIA and 121 children with CCP-negative JIA. T-tests, Chi-square tests, Mann–Whitney U tests, and multivariable regression were used to compare the groups. Results Compared to those with CCP-negative JIA, children with CCP-positive JIA were more likely to be female, older and non-Caucasian. Anti-P. gingivalis (p

Introduction We evaluated the safety of current treatment regimens for patients with RA and HBV in a large US cohort. Methods We identified biologic and nonbiologic treatment episodes of RA patients using 1997 to 2011 national data from the US Veterans Health Administration. Eligible episodes had evidence of HBV infection (HBV surface antigen, HBV core antibody, HBV e-antibody and/or HBV DNA) and had a baseline alanine aminotransferase (ALT) 100 IU/mL. Results were reported as the cumulative incidence of treatment episodes achieving hepatotoxicity at 3, 6 and 12 months post biologic exposure. Results Five hundred sixty-six unique RA patients with HBV contributed 959 treatment episodes. Mean age was 62.1 ± 10.3 years; 91.8% were male. Hepatotoxicity was uncommon, with 26 events identified among 959 episodes (2.7%) within 12 months. Hepatotoxicity was comparable between biologic and nonbiologic DMARDs (2.6% vs. 2.8%, P = 0.87). The median time between HBV screening and starting a new RA drug was 504 days (IQR 144, 1,163). Follow-up HBV testing occurred among 14 hepatotoxicity episodes (53.8%) at a median of 202 days (IQR 82, 716) from the date of ALT elevation. A total of 146 (15.2%) treatment episodes received at least one test for HBV DNA at any point in the observation period. Conclusions Among US veterans with RA and HBV the risk of hepatotoxicity is low (2.7%), and comparable between biologic and nonbiologic DMARDS (2.8% vs. 2.6%, P = 0.87). HBV testing associated with DMARD initiation or hepatotoxicity was infrequent. Electronic supplementary material The online version of this article (doi:10.1186/s13075-015-0628-z) contains supplementary material, which is available to authorized users.

Introduction Administrative claims data have not commonly been used to study the clinical effectiveness of medications for rheumatoid arthritis (RA) because of the lack of a validated algorithm for this outcome. We created and tested a claims-based algorithm to serve as a proxy for the clinical effectiveness of RA medications. Methods We linked Veterans Health Administration (VHA) medical and pharmacy claims for RA patients participating in the longitudinal Department of Veterans Affairs (VA) RA registry (VARA). Among individuals for whom treatment with a new biologic agent or nonbiologic disease-modifying agent in rheumatic disease (DMARD) was being initiated and with registry follow-up at 1 year, VARA and administrative data were used to create a gold standard for the claims-based effectiveness algorithm. The gold standard outcome was low disease activity (LDA) (Disease Activity Score using 28 joint counts (DAS28) ≤ 3.2) or improvement in DAS28 by > 1.2 units at 12 ± 2 months, with high adherence to therapy. The claims-based effectiveness algorithm incorporated biologic dose escalation or switching, addition of new disease-modifying agents, increase in oral glucocorticoid use and dose as well as parenteral glucocorticoid injections. Results Among 1,397 patients, we identified 305 eligible biologic or DMARD treatment episodes in 269 unique individuals. The patients were primarily men (94%) with a mean (± SD) age of 62 ± 10 years. At 1 year, 27% of treatment episodes achieved the effectiveness gold standard. The performance characteristics of the effectiveness algorithm were as follows: positive predictive value, 76% (95% confidence interval (95% CI) = 71% to 81%); negative predictive value, 90% (95% CI = 88% to 92%); sensitivity, 72% (95% CI = 67% to 77%); and specificity, 91% (95% CI = 89% to 93%). Conclusions Administrative claims data may be useful in evaluating the effectiveness of medications for RA. Further validation of this effectiveness algorithm will be useful in assessing its generalizability and performance in other populations.

Meeting abstracts High-fat diets and chronic alcohol consumption (CAC) can both induce a low-grade inflammation. We report that when CAC (16.6% of total calories) is administered in combination with the Lieber-DeCarli high-fat diet an additive myeloid response is induced. This increase in