Successful use of Tofacitinib in Reactive Arthritis Refractory to Conventional Therapies – A Case Series

Reactive arthritis is an immune mediated aseptic arthritis resulting from either genitourinary or gastrointestinal tract in a genetically susceptible host. It commonly presents as oligoarthritis of the lower limbs with or without extra articular features such as urethritis and non-purulent conjunctivitis. Therapies include NSAIDs, conventional DMARDs and rarely biologics in severe cases. We report successful use of tofacitinib in four cases of reactive arthritis who failed to respond to conventional therapies.

Biologic medicine inclusion in 138 national essential medicines lists

Background Essential medicines lists (EMLs) are intended to reflect the priority health care needs of populations. We hypothesized that biologic disease-modifying antirheumatic drugs (DMARDs) are underrepresented relative to conventional DMARDs in existing national EMLs. We aimed to survey the extent to which biologic DMARDs are included in EMLs, to determine country characteristics contributing to their inclusion or absence, and to contrast this with conventional DMARD therapies. Methods We searched 138 national EMLs for 10 conventional and 14 biologic DMARDs used in the treatment of childhood rheumatologic diseases. Via regression modelling, we determined country characteristics accounting for differences in medicine inclusion between national EMLs. Results Eleven countries (7.97%) included all 10 conventional DMARDs, 115 (83.33%) ≥5, and all countries listed at least one. Gross domestic product (GDP) per capita was associated with the total number of conventional DMARDs included (β11.02 [95% CI 0.39, 1.66]; P = 0.00279). Among biologic DMARDs, 3 countries (2.2%) listed ≥10, 15 (10.9%) listed ≥5, and 47 (34.1%) listed at least one. Ninety-one (65.9%) of countries listed no biologic DMARDs. European region (β1 1.30 [95% CI 0.08, 2.52]; P = 0.0367), life expectancy (β1–0.70 [95% CI -1.22, − 0.18]; P = 0.0085), health expenditure per capita (β1 1.83 [95% CI 1.24, 2.42]; P < 0.001), and conventional DMARDs listed (β1 0.70 [95% CI 0.33, 1.07]; P < 0.001) were associated with the total number of biologic DMARDs included. Conclusion Biologic DMARDs are excluded from most national EMLs. By comparison, conventional DMARDs are widely included. Countries with higher health spending and longer life expectancy are more likely to list biologics.

Immunoregulatory Effects of Adjuvant therapy with Statins in Rheumatoid Arthritis Population

Background: Rheumatoid arthritis (RA) is considered by symmetrical peripheral arthritis, synovitis & joint destruction. Statins, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme ductase, significantly reduce coronary artery disease by helping to lower plasma low-density lipoprotein cholesterol levels. Experimental studies, more recently, several clinical trials have convincingly shown that statins play a vital role in Rheumatoid arthritis, primarily due to their anti-inflammatory and immunomodulatory properties. Aim: To assess the effectiveness of statin adjunctive therapy versus standard treatment with disease-modifying antirheumatic drugs (DMARDs) in patients with RA. Methods: In this research, patients with a diagnosis of RA among the ages of 30 and 65 years were recruited according to the "Open Rheumatoid Pathologist" inclusion criteria. Among the selected patients, two distinct patient strata were identified. Strata 1 included 40 RA patients who are currently taking DMARDs with statins; Strata 2 included 40 patients with RA who are currently receiving DMARDs; observed for 6 months; To compare the outcomes of RA in both strata, standard parameters DAS28, ESR, and CRP were estimated. Results: There were eighty subjects included in the research; this study demonstrated a significant beneficial role of additional statin drugs when administered alongside conventional DMARDs in patients with active RA. The clinical significance index of disease activity in RA was significantly (P <0.05) lower in the statin adjuvant strata (strata 1) than in the conventional DMARD treatment strata (P <0.05). Strata 2) after 6 months of Continuous treatment. Two other important biochemical markers of RA disease activity, ESR and CRP, were also significantly lower in RA patients taking statins (strata 1) (P <0.05). Compared to strata 2, which includes only RA. the patient was treated with a conventional DMARD without statins. Conclusion: The results suggest a supportive and possibly beneficial role for statin therapy in cases of active RA, leading to clinically and biochemically significant improvements. Keywords: inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme is reductase, disease activity indicator 28,

Effect of introducing biologics to patients with rheumatoid arthritis on the risk of venous thromboembolism: a nationwide cohort study

In the United States, 100,000–300,000 patients die from venous thromboembolism (VTE) each year, with more than 500,000 people related hospitalizations. While in Europe, 500,000 people die from VTE each year. Patients with rheumatoid arthritis are at increased risk of VTE. The use of biologics in patients with rheumatoid arthritis may be associated with an increased risk of VTE. We identified all patients who had been newly approved for Catastrophic Illness Card of rheumatoid arthritis extracted the claims data from the National Health Insurance research database and Registry for Catastrophic Illness Patient Database from 2003 to 2016. VTE was defined as the presence of inpatient VTE diagnostic codes (including DVT or PE) according to the discharge diagnosis protocol. An analysis of VTE variables indicated that the incidence of VTE in the biologic group (14.33/10,000 person-years) was higher than that in the conventional drug group (12.61/10,000 person-years). As assessed by the Cox proportional hazards model, the relative HR for VTE in the biologic group (HR: 1.11; 95% CI 0.79–1.55) versus that in the conventional drug group did not reach a significant difference. In conclusion, this study found no significant differences in risk were observed between the use of conventional DMARDs and biologics.

POS0465 DIFFERENT CLINICAL RELEVANCE OF ANTI-CITRULLINATED PROTEINS ANTIBODIES IN RA PATIENTS

Background:Anti-citrullinated proteins antibodies (ACPA) are a broad group of antibodies, including antibodies to citrullinated fibrinogen, antibodies to cyclic citrullinated peptide (anti-CCP), antibodies to modified citrullinated vimentin (anti-MCV), antibodies to citrullinated α-enolase.Objectives:To find a potential relationship between ACPA and disease activity, bone destruction, and ACPAs responses to various therapeutic regimens.Methods:The study included 232 patients (pts) with rheumatoid arthritis (RA); 90 pts (74 women, Me;IQR age 53.0 (38.0–58.5) years had early RA, with mean disease duration 5.0 (4.0–9.0) months, DAS 28 5.3 (4.4–6.1)); 142 pts had advanced stage of the disease (123 women, median age 51.0 (43.0–60.0) years, disease duration 56.0 (24.0–96.0) months, DAS 28 6.2 (5.5–6.8)). Pts with early RA received methotrexate (MTX) subcutaneously at average 17.5 mg dose once weekly. Pts with advanced RA received the following anti-B-cell therapy: 34 pts - rituximab (RTX); 20 pts - RTX biosimilar; 43 pts - tocilizumab (TCZ) in combination with conventional DMARDs. Serum anti-CCP and anti-MCV concentrations were measured using ELISA.Results:77 (85.6%) pts with early RA were high positive for anti-CCP, and 29 (70.7%) pts - high positive for anti-MCV. A positive correlation was found between anti-MCV and DAS 28 (r=0.4, p=0.04). As for advanced RA, 78 (80.4%) pts were high positive for anti-CCP, and 70 (79.5%) - for anti-MCV. There was a positive correlation between anti-MCV concentration and SDAI (r=0.4, p=0.02), as well as CDAI (r=0.4, p=0.02). No significant correlations were found between the anti-CCP levels and activity indices, anti-CCP and acute-phase parameters in both early and advanced RA groups. Higher total Sharp scores (96.5 (65.0-122.0)) were found in pts high positive for anti-MCV (n=79), compared to low-positive/negative (57.0 (31.0–88.0), respectively, (n=27, p<0.05). anti-MCV levels dropped significantly in pts on RTX and TCZ therapy at weeks 12 and 24 after initiation of treatment, while high anti-CCP concentration persisted throughout the treatment (Table 1)Conclusion:anti-MCV levels correlated with inflammatory activity and development of bone destruction, and were decreasing in pts on treatment. Anti-CCP was less responsive, showed minor changes during treatment, therefore its’ thorough monitoring was not feasible.Disclosure of Interests:None declared

POS0642 THE IMPACT OF AGE ON DISCONTINUATION OF BIOLOGIC DMARDs IN PATIENTS WITH RHEUMATOID ARTHRITIS

Background:Rheumatoid arthritis (RA) is the most common autoimmune disease. Older patients treated with biologic DMARDs (bDMARDs) are at a significantly greater risk of adverse effects (AEs) [1]. However, the rate of drug discontinuation because of adverse effects caused by bDMARDs has not differed in elderly compared to younger patients in different registries.Objectives:Determine if drug discontinuation of bDMARDs differs by age in patients with rheumatoid arthritis in the Mexican Adverse Events Registry (BIOBADAMEX).Methods:BIOBADAMEX is a Mexican ongoing cohort of patients using bDMARDs since 2016. In this analysis we included all patients with diagnosis of RA with at least two assessments. Survival on bDMARDs was estimated using Kaplan-Meier analysis. Predictors of discontinuation, including age older than median age in the sample were investigated by Cox regression analyses.Results:Among 743 patients in the registry, 497 had RA diagnosis, from which, 214 had at least two assessments. At baseline, patients had a median (IQR) age of 53.4 (45-61) years old, median disease duration of 10.7 (6-17) months and median DAS28 of 4.7 (3-6). Conventional DMARDS were used by 185 (87%) patients and 94 (44%) patients used corticosteroids. Comorbidities were present in 194 (91%). The most common bDMARDs received at baseline were abatacept 59 (27%), tocilizumab 45(21%), adalimumab 31 (15%) and certolizumab 30 (14%). At the time of analysis, the median bDMARDs treatment duration was 21.0(13-34) months, 128 (59%) had discontinued treatment, 66 for inefficacy, 32 for adverse events and 30 for others. Fig 1 shows discontinuation rate curves in patients younger and older than median age. Cox proportional-hazards demonstrated no significant differences regarding age older than median age (HR 1.1, 95% CI 0.8-1.4, p=0.7), female sex (HR 1.2, 95% CI 0.7-1.9, p=0.44), use of corticosteroids (HR 1.2, 95% CI 0.9-1.6, p=0.20), comorbidities (HR 0.9, 95% 0.6-1.5, p=0.78), DAS28 (HR 0.9, 95% 0.9-1.1, p=0.93) or other factors.Figure 1.Discontinuation rate curves in patients younger and older than median age (< 53.4 and >=53.4 years old)Conclusion:This analysis did not show a role of age on discontinuation of bDMARDs in Mexican RA patients. Further longitudinal analyses will be performed including more patients to assess retention rate of bDMARDs and identify predictive variables of discontinuation in Mexican population.References:[1]Akter R, et al. Can Geriatr J. 2020 May 1;23(2):184-189.[2]Ikari Y, et al. Medicine (Baltimore). 2020 Dec 24;99(52):e23861.Disclosure of Interests:None declared

POS0460 ASSOCIATION OF ANTI-CITRULLINATED PROTEIN ANTIBODIES OF IgA SUBCLASSES WITH SUSTAINED REMISSION AND FLARE IN RHEUMATOID ARTHRITIS

Background:Understanding key mechanisms of flare development and sustained remission is one of the acute goals in modern rheumatology. Anti-citrullinated protein antibodies (ACPA) are the most abundant and specific autoantibodies in rheumatoid arthritis (RA) patients. However, the impact of ACPA of IgA isotype is poorly defined. IgA ACPA were previously shown to have a higher percentage of IgA2 in comparison to total IgA; and a correlation between IgA2% ACPA with the DAS28 score was observed in a previous study [1]. Of note, IgA1 and IgA2 were shown to exhibit different effector functions, with IgA2 being pro-inflammatory, which might be the background for its role in RA [1].Objectives:We aimed to investigate, whether IgA ACPA could be used as a predictive factor for flare development in RA; and to look further into the changes in IgA ACPA levels in patients remaining in stable remission versus patients developing flare.Methods:We analysed serum of 111 patients from a multicentre randomized controlled trial ‘RETRO’. The study observational period was 12 months. Patients in the trial had to be in stable remission (DAS28-ESR<2.6) for a minimum of 6 months and were randomized into 3 different treatment arms: continuation of treatment, tapering by 50% or a gradual tapering until discontinuation [2]. IgA ACPA concentrations were measured with an enzyme-linked immunosorbent assay on CCP2-pre-coated plates.Results:60% of patients had IgG-ACPA. IgA ACPA levels were higher among the IgG-ACPA-positive patients (median 4.7 versus 2.24 µg/ml, p<0.0001). Baseline IgA1 and 2 ACPA levels were not different between patients who had a flare later on in the study period and those remaining in remission, showing no predictive value for flare development. However, the percentage of IgA2 in ACPA was correlating with the first registered DAS28 after flare (r=0.36, p=0.046). After the 12 months study period, IgA2 ACPA as well as IgA2% ACPA decreased significantly in patients who remained in stable remission by 17.5% (median, p<0.0001) and 13.6% (p=0.0006), respectively. By contrast, there was no significant change in IgA2 ACPA levels over time in patients who developed a flare. IgA1 ACPA levels remained stable over time. Disease management strategies did not seem to influence IgA ACPA levels in a specific way, as baseline levels were similar between patients on biological and conventional DMARDs and changes in levels after 12 months did not depend on the assignment to either of the study arms.Conclusion:Neither IgA1 nor IgA2 ACPA levels were predictive of flare development or associated with treatment strategies (though rituximab, JAK-inhibitors and abatacept were not amongst treatment options). However, in patients remaining in sustained remission after 1 year a decrease in IgA2 and IgA2% ACPA was observed and IgA2% ACPA was associated with DAS28 score registered after flare. This could be an indication towards ACPA of IgA2 isotype contributing to the severity of flare, alongside other factors, and its reduction being associated with a prolonged state of remission.References:[1]Steffen U, Koeleman CA, Sokolova MV, et al. IgA subclasses have different effector functions associated with distinct glycosylation profiles. Nat Commun 11, 120 (2020).[2]Haschka J, Englbrecht M, Hueber AJ, et al. Relapse rates in patients with rheumatoid arthritis in stable remission tapering or stopping antirheumatic therapy: interim results from the prospective randomised controlled RETRO study. Ann Rheum Dis. 75:45-51 (2016).Disclosure of Interests:None declared

POS1467-HPR SEVERE RESPIRATORY INFECTIONS IN RHEUMATOID ARTHRITIS PATIENTS WITH BIOLOGIC THERAPY. COMPARATIVE STUDY BETWEEN VACCINATED AND NON VACCINATED PATIENTS

Background:Rheumatoid arthritis (RA) patients are at increased risk of severe infections due to the disease itself, and the immunosuppressive treatment. Vaccination programs are designed to decrease the risk of infections.Objectives:In patients with RA treated with biologic therapy (BT) our aim was to assess a) the incidence of severe respiratory infections and b) to compare the risk between vaccinated and non vaccinated patients.Methods:Observational study of 431 patients diagnosed with RA that iniciated BT. One group of patients participated in a vaccination program from October 2011 to October 2016 (Group 1). The other group was not included in the vaccination program (Group 2). The follow-up was made until June 2017 with a minimum follow-up period of 8 months and a maximum of 5.5 years.Information on severe respiratory infections, defined as those that required hospitalization or at least one dose of intravenous antibiotic treatment at the emergency room, was retrieved from the hospital medical records.Results:We studied 431 patients (335 women/96 men); mean age 63.4±13.7 years. In the vaccination program (group 1) were included 299 (69.37%) patients and in the group 2 132 patients (30.63%). The main features of both groups are summarized in Table 1.During the follow-up, we registered 299 hospital admissions due to severe respiratory infections in both groups (incidence density 9.9 (95% CI: 6.9-13.6).In group 1, vaccinated patients, this incidence density was reduced to 7.1 (95% CI: 4.1-11.6). Figure 1.The vaccination program reduced the general incidence of severe respiratory infection in 44%.Conclusion:RA patients with BT included in the vaccination program present a lower incidence of severe respiratory infections compared with non vaccinated patients.Table 1.Main general features at BT onsetGroup 1Vaccination programN=299Group 2Non vaccination programN=132pAge (years) mean±SD61.32±13.0467.97±14.170.32Women, n (%)231 (77.3%)105 (79.5%)0.59Duration of RA (months) mean±SD73.24±10.4112.62±60.2Positive RF/ Positive ACPA, n (%)177(59.2)/172 (57.52%)93(70.5%)98 (74.24%)0.02/0,01Erosive disease, n (%)116 (38.8%)70 (53%)0.06Vasculitis, n (%)15 (5%)2 (1.5%)0.08Interstitial lung disease n (%)12 (4%)7 (5.3%)0.54Subcutaneous nodules n (%)16 (5.4%)6 (4.5%)0.72Corticosteroids299 (100%)132 (100%)1Number of conventional DMARDs, mean±SD1.66±0.892.03±1.050.3Figure 1.Disclosure of Interests:None declared

POS0632 THE LONGITUDINAL ASSOCIATIONS OF METHOTREXATE AND BIOLOGIC USE ON HOSPITAL ADMISSION FOR RHEUMATOID ARTHRITIS PATIENTS IN WESTERN AUSTRALIA POPULATION (1995- 2014)

Background:Rheumatoid arthritis (RA) carries a substantial burden for patients and society in terms of morbidity, enduring disability, and costs [1]. The Australian Pharmaceutical Benefits Scheme (PBS) has subsidised biological disease-modifying anti-rheumatic drugs (B-DMARDs) since 2003 [2].Objectives:We examined the impact of B-DMARDs availability on RA hospitalisation rate in the Western Australia (WA) population pre- and post- B-DMARDs introduction to the PBS (1995-2002 and 2003-2014).Methods:Population PBS dispensing data for WA of DMARD were obtained and converted to defined daily doses (DDD)/1000 population/day using the WA population census. RA inpatient records were extracted from the WA Hospital Morbidity Data Collection using ICD-9 codes 714 and ICD-10 codes M05.00–M06.99). Principal component analysis (PCA) was applied to determine the relationship between DMARDs use and RA hospital admission rates.Results:There was a total of 17,125 patients who had 50,353 admissions with a diagnostic code for RA during the study period. DMARD use for RA rose from 1.45 to 3.19 DDD/1000 population/day over 1995-2014 (Figure 1). In 1995-2002, the number of RA admissions fell from 7.9 to 2.6 per 1000 hospital separations, then dropped further from 2.9 to 1.9 per 1000 hospital separations in 2003-2014. Based on PCA analysis, conventional DMARDs (methotrexate) and B-DMARDs dispensing had an inverse association with hospital admissions for RA.Conclusion:The increased availability of conventional and biological DMARDs for RA was associated with a significant decline in hospital admissions for RA patients in WA.References:[1]Boonen A, Severens JL (2011) The burden of illness of rheumatoid arthritis. Clin Rheumatol 30:3-8.[2]Medicare Australia (2020) Pharmaceutical Benefits Schedule statistics. http://medicarestatistics.humanservices.gov.au/statistics/pbs_item.jsp.Figure 1.The hospital separations and total drugs use patterns of RA in 1995-2014 in Western Australia.Acknowledgements:Supported by an Australian Government Research Training Program PhD Scholarship at the University of Western Australia.Disclosure of Interests:Khalid Almutairi: None declared, Johannes Nossent Speakers bureau: Janssen, David Preen: None declared, Helen Keen Speakers bureau: Pfizer Australia, Abbvie Australia, Charles Inderjeeth Speakers bureau: bureau: Eli Lilly