Perceptions of Rheumatologists on Diagnosis of Psoriatic Arthritis in China.

Objective: High prevalence of undiagnosed psoriatic arthritis (PsA) and prolonged diagnostic delay are key troubles in the appropriate management of PsA. To analyze the possible causes for this phenomenon, a web-based nationwide survey was conducted to investigate rheumatologists' perceptions on PsA diagnosis in China. Methods: The electronic questionnaire consisting of 38 questions were designed by an expert panel and distributed with the online survey tool Sojump, which is a professional online survey platform. The completed questionnaires by real-name rheumatologists were collected. Results: A total of 1594 valid questionnaires were included. More than half of Chinese rheumatologists reported it was challenging to make a diagnosis of PsA. The four major challenges were "Difficulties in identification of atypical or hidden psoriasis", "Absence of diagnostic biomarkers", "No active self-report of history or family history of psoriasis" and "Various musculoskeletal manifestations". In diagnosing PsA, minor participants had incorrect knowledge of inflammatory arthropathy (13.7%), acute phase reactant (23.8%), and rheumatoid factor (28.7%). There were no significant differences in the knowledge of PsA and practice habits in diagnosing PsA between modern western medicine (WM)- and traditional Chinese medicine (TCM)-rheumatologists. The part-time rheumatologists were not as good as full-time rheumatologists in diagnosing PsA. Conclusions: About three quarters of Chinese rheumatologists are familiar with the elements in PsA diagnosis and have good practice habits in diagnosing PsA. Four main challenges in making PsA diagnosis are revealed. There was no significant difference in the knowledge of PsA between WM- and TCM-rheumatologists.

Therapeutic potential of russelioside B as anti-arthritic agent in Freund's adjuvant-induced arthritis in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Caralluma species are traditional edible herbs used in folkloric medicine as antidiabetic, antioxidant, antipyretic, antirheumatic, anti-inflammatory and anthelmintic agents. C. quadrangula was selected in this study to document the traditional use of the genus as anti-rheumatic treatment and the possible mechanisms of action. AIM OF THE STUDY: The higher mortality rates and shorter survival among the patients suffering from rheumatoid arthritis (RA) led to the increased interest on searching for new treatments for RA. Russelioside B (RB), a major pregnane glycoside found in C. quadrangula, was evaluated as a new anti-rheumatic agent. MATERIALS AND METHODS: The n-butanol fraction of C. quadrangula was chromatographed on a silica gel column to isolate RB. The adjuvant-induced arthritis (AIA) model was established in rats by intradermal injection of complete Freund's adjuvant (CFA) to evaluate its anti-arthritic effect. Ibuprofen was used as a reference drug. Forty rats were randomly divided into 5 groups (n = 8): normal (NOR); CFA model (CFA); ibuprofen, 5 mg/kg; RB, 25 mg/kg and RB, 50 mg/kg. The treatments were initiated from day 16 when AIA model was established and continued up to day 40. Serum diagnostic rheumatoid markers, inflammatory cytokines, oxidative stress biomarkers, cartilage and bone degeneration enzymes were assessed. RESULTS: RB at 50 mg/kg b. wt., showed significant decreases in the activities of hyaluronidase and ß-glucouronidase enzymes as well significant decreases in the levels of proinflammatory cytokines as nuclear factor-kappa-B (NF-κB), tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1ß (IL-1ß) compared to the CFA group; 11.04 ± 0.61 pg/mg protein, 4.35 ± 0.25 pg/mg protein, 3.32 ± 0.13 pg/mg protein & 2.75 ± 0.14 pg/mg protein for RB, 50 mg/kg b. wt. group vs. 25.33 ± 2.13 pg/mg protein, 25.65 ± 2.1 pg/mg protein, 22.20 ± 1.34 pg/mg protein & 13.27 ± 1.40 pg/mg protein for the arthritic group, respectively. The total antioxidant capacity (TAC) was significantly restored to normal values in RB, 50 mg/kg treated rats (4.01 ± 0.09 nmol/mL vs. 3.71 ± 0.27 nmol/mL) and the levels of myeloperoxidase (MPO) reduced by 10-folds of the CFA arthritic group. Bone histomorphometry revealed that RB treatment significantly attenuated the CFA-induced bone loss in a dose-dependent manner. CONCLUSIONS: These findings suggested that the anti-arthritic effect of RB was mediated through the reduction of the rheumatoid markers, anti-inflammatory and antioxidant action, inhibition of cartilage and bone degenerative enzymes as well as attenuation of bone loss and osteoclastogenesis.

Association between seropositivity and discontinuation of tumor necrosis factor inhibitors due to ineffectiveness in rheumatoid arthritis.

INTRODUCTION/OBJECTIVES: Discontinuation of biologic therapy in rheumatoid arthritis is attributable to various reasons, with the most important cause being insufficient response. In this study, we investigated the association between rheumatoid factor (RF) and anti-citrullinated protein autoantibody (ACPA) status and the discontinuation of tumor necrosis factor inhibitors (TNFi) therapy due to insufficient response in bio-naïve rheumatoid arthritis (RA) patients. METHOD: This study included patients enrolled in the Tsurumai Biologic Communication Registry in Japan. The crude comparison of TNFi discontinuation due to ineffectiveness between seropositive and seronegative patients was analyzed using the cumulative incidence function of competing events and Gray test. We assessed the associations between baseline patient characteristics and discontinuation of TNFi therapy due to insufficient response using Fine-Gray proportional hazard regression. Fine-Gray proportional hazard analysis considered competing events of interest, including insufficient response, adverse event, palliation, and personal reasons. RESULTS: Of 1237 patients evaluated, 79.3% were positive for RF and 85.4% for ACPA; 72.6% were double positive and 11.1% were double negative. TNFi therapy had been discontinued because of insufficient response at 200 weeks in 19.8% RF-positive, 16.7% RF-negative, 23.0% ACPA-positive, and 13.8% ACPA-negative patients. There was a significantly higher discontinuation rate due to insufficient response in ACPA-positive patients than in ACPA-negative patients using Gray test, with a similar trend as that for RF status. RF positivity was significantly predictive of the discontinuation of TNFi therapy due to ineffectiveness using Fine-Gray proportional hazard regression analysis after adjusting for baseline characteristics, including age, sex, stage, class, disease activity at baseline, methotrexate use, and prednisolone use [hazard ratio 1.73 (95% confidence interval 1.07-2.80)]. CONCLUSIONS: Using Fine-Gray proportional hazard regression, we demonstrated that RF positivity was related to a higher discontinuation rate of TNFi therapy due to ineffectiveness in bio-naïve RA patients. Key Points • RF positivity is related to a higher discontinuation rate of TNFi therapy due to ineffectiveness. • ACPA is not predictive of a discontinuation of TNFi therapy due to ineffectiveness.

Human host defence peptide LL37 and anti-cyclic citrullinated peptide antibody in early inflammatory arthritis.

Objective: Antibodies to citrullinated peptides (anti-CCP) develop in individuals predisposed to rheumatoid arthritis (RA). Neutrophil extracellular traps are a major source of citrullinated antigens and the immunomodulatory host defence peptide LL-37. Vitamin D regulates LL-37 expression. This study assessed the associations of LL-37 and anti-CCP, vitamin D metabolites and vitamin D receptor (VDR) polymorphisms in early inflammatory arthritis (EIA). Methods: Serum LL-37, 25-hydroxy-vitamin D (25OHvitD) and anti-CCP were measured by ELISA in treatment naïve EIA (n = 181). VDR single nucleotide polymorphisms (Fok1, Bsm1, Apa1, Taq1, Cdx-2) and HLADRB1 shared epitope (SE) alleles were detected by DNA amplification. Associations were tested in multivariable models. Median (25%, 75%) or percentiles are reported. Results: Participants (70 % female, age 56 [45, 66] years, disease activity score [DAS28ESR3var] 3.7 [2.8, 4.8], 41 % anti-CCP positive, 68 % RA) had low serum 25OHvitD; 20.5 nmol/L (13.9, 29.0). In multivariable models, controlling for age, sex, SE, smoking and vitamin D deficiency, LL37 level (top quartile) associated with anti-CCP seropositivity (OR 22; 95% CI 4 to 104). Conclusions: Levels of circulating LL-37 are associated with anti-CCP seropositivity. LL37 activity may be one mechanism linking infection and toxin exposure to anti-CCP generation.

Economic Evaluation of Anticyclic Citrullinated Peptide Positivity in Rheumatoid Arthritis.

BACKGROUND: Anticyclic citrullinated peptide (anti-CCP) positivity may be a strong predictor of joint erosion and a potential biomarker for guiding treatment decisions for rheumatoid arthritis (RA). However, limited studies are currently available on the effect of anti-CCP positivity on health care utilization and/or medical costs of RA patients. OBJECTIVE: To investigate short-term and long-term direct health care expenditures associated with anti-CCP positivity in newly diagnosed RA patients. METHODS: A retrospective cohort study was conducted in adult RA patients within a U.S. integrated health care delivery system (January 1, 2007-June 30, 2015). Patients were required to have 2 RA diagnoses and treatment with a conventional or biologic disease-modifying antirheumatic drug (DMARD) within 12 months. The first RA diagnosis date was labeled as the index date, and patients were followed until they left the health plan, died, or reached the end of the study period. Patient demographics, anti-CCP results, comorbid conditions, and health care resource utilization during baseline (12 months before the index date) and follow-up periods were collected. Nationally recognized direct medical costs were assigned to health care utilization to calculate health care costs in 2015 U.S. dollars. The baseline differences between anti-CCP positivity and negativity and differences in censoring during follow-up were addressed using propensity scores. The mean differences in costs were estimated using recycled prediction methods. RESULTS: 2,448 newly diagnosed RA patients were identified and followed for a median of 3.7 years (range = 1-8 years). At baseline, 65.8% of patients were anti-CCP positive. Anti-CCP-positive patients had fewer comorbid conditions at baseline. During the first 12 months of follow-up, median (interquartile range) total health care expenditures for anti-CCP-positive and anti-CCP-negative patients were $6,200 ($3,563-$13,260) and $7,022 ($3,885-$12,995), respectively. After adjusting for baseline differences, total incremental mean cost associated with anti-CCP positivity during the first 12 months was estimated to be $2,163 per patient (P = 0.001). The annual incremental costs in anti-CCP-positive patients became progressively larger over time, from $2,163 during the first year to $5,062 during the fourth year. Anti-CCP positivity was associated with higher prescription, laboratory testing, and rheumatologist utilization. A higher percentage of anti-CCP-positive patients received 1 or more biologic DMARDs (11.6% for anti-CCP-positive vs. 5.7% for anti-CCP negative; P < 0.001) compared with anti-CCP-negative patients during the 12-month follow-up, which resulted in $2,499 in incremental prescription costs (P < 0.001). Total additional burden associated with anti-CCP positivity during the first 4 years was estimated to be $14,089 per patient. CONCLUSIONS: In newly diagnosed RA patients, higher economic burden associated with anti-CCP positivity was mainly driven by prescription costs. DISCLOSURES: This research and manuscript were funded by Bristol-Myers Squibb (BMS). Alemao and Connolly are employees and shareholders of BMS and participated in the design of the study, interpretation of the data, review/revision of the manuscript, and approval of the final version of the manuscript. An and Cheetham received a grant from BMS for this research. At the time of this study, An was employed by Western University of Health Sciences, and Cheetham was employed by Kaiser Permanente Southern California. Bider-Canfield, Kang, and Lin have nothing to disclose. Some study results were presented as a poster at the American College of Rheumatology Annual Meeting; November 5, 2017; San Diego, CA, and at the International Society for Pharmacoeconomics and Outcomes Research Meeting; May 19, 2018; Baltimore, MD.

Curcumin for the Management of Periodontitis and Early ACPA-Positive Rheumatoid Arthritis: Killing Two Birds with One Stone.

We propose curcumin as a preventive measure to avoid/manage periodontitis (PD), and as a natural immunosuppressant for rheumatoid arthritis (RA). PD, mainly caused by Porphyromonas gingivalis forming biofilm and leading to tooth decay, is a major public health issue and a risk factor for the development of RA in humans. P. gingivalis is able to trigger experimental autoimmune arthritis in animal models and in humans can induce citrullinated peptides, which not only are a source of anti-citrullinated antibodies (ACPAs), but also participate in autoreactive responses and disease development. Curcumin appears to have efficient anti-bacterial activity against P. gingivalis infection and biofilm formation. In addition to antibacterial, anti-oxidant, and anti-inflammatory action, curcumin exerts unique immunosuppressant properties via the inhibition of Th17 pro-inflammatory responses and promotion of regulatory T cells, thus suppressing autoimmunity. We introduce curcumin as a natural product for the management of both PD and RA-related autoreactivity, possibly also as a preventive measure in early RA or individuals at high risk to develop RA.

Is current smoking status and its relationship to anti-cyclic citrullinated peptide antibodies a predictor of worse response to biological therapies in rheumatoid arthritis patients?

OBJECTIVE: To assess the association between smoking, anti-cyclic citrullinated peptide (anti-CCP) antibody status, and clinical efficacy of biological therapies in rheumatoid arthritis (RA) patients. METHOD: This retrospective clinical practice setting study included 1349 RA patients from the METEOR database (aged >18 years). We collected data on sociodemographics, smoking status (smoker, <10, 10-19, and >20 cigarettes/day; ex-smoker; non-smoker), baseline disease activity parameters and anti-CCP, previous disease-modifying anti-rheumatic drugs (DMARDs), biological therapy, combined therapy (steroids and DMARDs), and follow-up disease activity. Clinical efficacy was assessed by European League Against Rheumatism (EULAR) good/moderate response rates for all aggregated biological therapies, based on both smoking and anti-CCP status. RESULTS: The non-smoking RA patients were more often female at biological therapy initiation than the ex-smokers and smokers (91.1% vs 60.4% and 67.9%, respectively, p < 0.001), and ex-smokers were older than non-smokers and smokers (mean ± sd 56.5 ± 11.1, 53.5 ± 13.3 and 51.3 ± 11.0 years old, respectively; p < 0.001). In total, 845 (62.6%) were non-smokers, 214 (15.9%) ex-smokers, and 290 (21.5%) smokers [daily cigarettes smoked: 148 (11%) <11; 61 (4.5%) 11-20; and 81 (6%) >20]. Anti CCP-antibody status was similar in both groups. Non-smokers showed higher baseline DAS28 than ex-smokers and smokers (5.0 ± 1.5 vs 4.7 ± 1.4 and 4.7 ± 1.4, respectively; p < 0.001) and used more baseline steroids and DMARDs. A higher EULAR response rate was observed in non-smokers than in ex-smokers and smokers (73% vs 65% and 64.1%, respectively; p = 0.004). Drug survival was higher in non-smokers compared to ex-smokers and smokers [57.7 months (46.4-53.8), 38.6 (30.3-46.8), and 50.1 (41.8-58.4); p < 0.001, respectively]. CONCLUSION: In daily clinical practice, non-smokers respond better than smokers to biological therapy, but this does not result in better drug survival.

The association between omega-3 fatty acid biomarkers and inflammatory arthritis in an anti-citrullinated protein antibody positive population.

Objectives: Higher circulating omega-3 fatty acids (n-3 FAs) are associated with a lower prevalence of anti-CCP antibodies and RF in subjects without RA. We examined whether, in anti-CCP+ subjects, n-3 FAs also play a role in development of inflammatory arthritis (IA). Methods: At Colorado-based health fairs from 2008 to 2014, participants without a previous diagnosis of RA who were anti-CCP3+ (n = 47) were recruited into a follow-up study; symptom assessments and joint examinations were conducted every 6 months for the determination of IA. We measured n-3 FAs as a percentage of total lipids in red blood cell membranes (n-3 FA%) at each visit. Results: We detected IA in 10 anti-CCP3+ subjects (21%) at the baseline visit. Increased total n-3 FA% in red blood cell membranes [odds ratio (OR) = 0.09, 95% CI: 0.01, 0.76], specifically docosapentaenoic acid (OR = 0.16, 95% CI: 0.03, 0.83) and docosahexaenoic acid (OR = 0.23, 95% CI: 0.06, 0.86), was associated with a lower odds of IA at the baseline visit, adjusting for n-3 FA supplement use, current smoking, RF+, elevated CRP+ and shared epitope. We followed 35 of the anti-CCP3+ subjects who were IA negative at baseline and detected 14 incident IA cases over an average of 2.56 years of follow-up. In a time-varying survival analysis, increasing docosapentaenoic acid significantly decreased risk of incident IA (hazard ratio = 0.52, 95% CI: 0.27, 0.98), adjusting for age at baseline, n-3 FA supplement use, RF+, CRP+ and shared epitope. Conclusion: n-3 FAs may potentially lower the risk of transition from anti-CCP positivity to IA, an observation that warrants further investigation.