Importance of the second SARS-CoV-2 vaccination dose for achieving serological response in patients with rheumatoid arthritis and seronegative spondyloarthritis

ObjectivesTo assess the kinetics of humoral response after the first and second dose of messenger RNA (mRNA) vaccines in patients with inflammatory joint diseases compared with healthy controls (HC). To analyse factors influencing the quantity of the immune response.MethodsWe enrolled patients with rheumatoid arthritis (RA) and seronegative spondyloarthritis (SpA), excluding those receiving B-cell depleting therapies and assessed the humoral response to mRNA vaccines after the first and the second dose of the vaccine in terms of seroconversion rate and titre. We compared the results to a HC group and analysed the influence of therapies as well as other characteristics on the humoral response.ResultsSamples from 53 patients with RA, 46 patients with SpA and 169 healthy participants were analysed. Seroconversion rates after the first immunisation were only 54% in patients with inflammatory arthritis compared with 98% in the HC group. However, seroconversion rates were 100% in all groups after second immunisation. Patients developed reduced antibody titres after the first vaccination compared with HC, but there was no difference after the second dose. While disease modifying anti-rheumatic drug (DMARD) monotherapy did not affect antibody levels, seroconversion rates as well as titre levels were reduced in patients receiving a combination of DMARDs compared with HC.ConclusionsPatients with inflammatory joint diseases under DMARD therapy show impaired humoral responses to the first vaccine dose but excellent final responses to vaccination with mRNA vaccines. Therefore, the full course of two immunisations is necessary for efficient vaccination responses in patients with inflammatory arthritis under DMARD therapy.

POS0021 INTERMETATARSAL BURSITIS, A NOVEL FEATURE OF JUXTA-ARTICULAR INFLAMMATION IN EARLY RHEUMATOID ARTHRITIS: RESULTS FROM A LONGITUDINAL MRI-STUDY

Background:Rheumatoid arthritis (RA) is characterised by inflammation of the synovial lining. In addition to synovitis, the tendon sheaths of small hand and foot joints are also frequently inflamed. This results in tenosynovitis, which is often missed at clinical evaluation in early RA but visible on imaging, such as MRI. A third anatomical structure surrounded by a synovial lining is formed by the intermetatarsal bursae in the forefeet. Inflammation of these bursae (intermetatarsal bursitis; IMB) was recently identified at MRI-studies and shown to be specific for early RA.[1] This suggests that IMB is also a feature of early RA.Objectives:We hypothesised that if IMB is indeed an RA-feature, then (1) at diagnosis its presence associates with other measures of local inflammation (synovitis, tenosynovitis and osteitis) and (2) it responds to DMARD therapy similarly as these other local inflammatory measures. These hypotheses were tested in a comprehensive MRI-study.Methods:157 consecutive early RA patients underwent unilateral contrast-enhanced 1.5T MRI of the forefoot at diagnosis. MRIs were evaluated for presence of IMB and for synovitis, tenosynovitis and osteitis in line with the RA MRI scoring system (summed as RAMRIS-inflammation). MRIs at 4, 12 and 24 months were evaluated for presence and size of IMB-lesions in patients who had IMB at baseline and received early DMARD-therapy. Logistic regression was used for analyses at patient-level; generalised estimating equations were used for bursa-level analyses. Stratification for ACPA was performed.Results:69% of RA patients had ≥1 IMB. In multivariable analyses on bursa-level, presence of IMB was independently associated with local presence of synovitis and tenosynovitis (OR 1.69 (95%CI 1.12–2.57) and 2.83 (1.80–4.44), respectively), but not with osteitis. On patient-level, presence of IMB was most strongly associated with tenosynovitis (OR 2.92 (1.62–5.24)). During treatment with DMARDs, the average size of IMB-lesions decreased (Figure 1). This decrease was associated with decrease in RAMRIS-inflammation scores; most strongly with a decrease in synovitis but not in osteitis. Within ACPA-positive and ACPA-negative RA similar results were obtained.Conclusion:IMB particularly accompanies inflammation of the synovial lining of joints and tendon-sheaths, both regarding simultaneous occurrence at diagnosis and simultaneous treatment-response. These findings suggest that IMB represents juxta-articular synovial inflammation and indeed is a hallmark of early RA.References:[1]Dakkak YJ et al. Increased frequency of intermetatarsal and submetatarsal bursitis in early rheumatoid arthritis: a large case-controlled MRI study. Arthritis Res Ther 22, 277 (2020).Disclosure of Interests:None declared.

POS1114 INFECTION RISK AMONG RHEUMATIC PATIENTS RECEIVING DENOSUMAB THERAPY: SINGLE CENTRE EXPERIENCE

Background:Osteoporosis (OS) is common in rheumatic diseasas (RMD). OS fracture leads to morbidity and premature mortality. The treatment for OS is well established with good long term safety profile. Oral bisphosphonate (BIS) is recommended as initial treatment option for both postmenopausal and glucocorticoid induced OS. Denosumab (DSB), is the noninferior alternative option. Despite its efficacy, DSB was linked with elevated infection risk in non RMD. Yet, data in RMD is lacking.Objectives:To determine the infection risk and associated factors in RMD patients receiving DSB.Methods:This is retrospective cohort study. Data was extracted from medical database (between Jan 2010 & Dec 2018) at Selayang Hospital, Malaysia. Descriptive statistical analysis, logistic regression (LR) and cox (proportional hazard) regression [CPHR] were the analysis methods.Results:50 cases were analysed. 96% were female. The median age was 72.5 ± 12.7 years. The primary rheumatological disorders were rheumatoid arthritis (48%), OS (24%) and systemic lupus erythematosus (10%). 92% had ≥ 1 comorbidity including metabolic/cardiovascular diseases (74%), chronic lung diseases (CLD) (40%) and diabetes mellitus (DM) (22%). 54% had disease modifying anti rheumatic drug (DMARD) therapy; majority (59.2%) received single conventional synthetic DMARD. Only 7.4% received combination biologic DMARD therapy. 28% had received prednisolone therapy, with dose < 7.5mg OD in 78.6%.The median age at DSB initiation was 71 ± 12.4 years. 38% had fracture history and 88% had received previous OS treatment.In total, 13 infection episodes were recorded. The infection risk was 26% & incidence rate was 134 cases per 1000 person-years. 84.6% required hospitalisation and 38.5% were severe cases. The mortality rate was 23.1%. The mean DSB treatment duration to first infection was 15.46 ± 11.9 months.Univariate LR showed infection risk and hospitalisation were higher with longer DSB treatment duration, OR 1.062 (95% CI: 1.010 - 1.117), p = 0.018) & OR 1.057 (95% CI: 1.003 - 1.114, p = 0.037), respectively. These risks were lower in absence of steroid use, OR 0.2 (95% CI: 0.051 - 0.784, p = 0.021) and OR 0.215 (95% CI: 0.052 - 0.889, p = 0.034), respectively. Additionally, infection risk was lower in absence of CLD, OR 0.188 (95% CI: 0.048 - 0.742, p = 0.017) and hospitalisation was lower without concomitant DM, OR 0.050 (95% CI: 0.050 — 0.950, p = 0.043). Yet, multivariate LR did not infer the above predictions, after adjustment made for age, gender, rheumatological diseases, comorbidity, DMARD therapy and steroid dosing. For severe infection and case fatality, no predictive factors were identified.CPHR showed patients without steroid use had lower fatality risk, HR 0.077 (95% CI: 0.007 - 0.864, p = 0.038). With confounding factors (age, gender, previous infection and comorbidity), the observed difference was insignificant.Conclusion:Risk of infection and hospitalisation could be higher in rheumatic patients receiving longer DSB treatment duration. Concomitant comorbidities (CLD and DM) might increase the risk of infection and/or hospitalisation.References:[1]Cummings SR, San Martin J, McClung MR, Siris ES, Eastell R, Reid IR, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med 2009;361:756–65.[2]Watts NB, Roux C, Modlin JF, Brown JP, Daniels A, Jackson S, Smith S, Zack DJ, Zhou L, Grauer A, Ferrari S. Infections in postmenopausal women with osteoporosis treated with denosumab or placebo: coincidence or causal association? Osteoporos Int. 2012;23(1):327–337.[3]Prabhakaran S, Pritchard C. Comparison of infection rates in patients receiving denosumab, denosumab and biologics and biologics alone in a suburban rheumatology clinic [abstract]. Arthritis Rheumatol 2014;66 Suppl 10:S409.[4]Bray V, Bagley A, West S, Etzel C, Kremer J, Kolfenbach J. Infection risk among patients receiving concurrent denosumab and biologic or non-biologic DMARD therapy: An analysis of the ConsortiumAcknowledgements:We would like to thank the Director General of Health Malaysia for his permission for this poster presentation.Disclosure of Interests:None declared.

Search of Official Nationwide Database in Japan for Adverse Events Associated with Disease-modifying Antirheumatic Drug Therapies: Focus on Therapies in Combination with Methotrexate Author

Disease-modifying antirheumatic drugs (DMARDs) are essential for rheumatoid arthritis (RA) therapy, and many synthetic and biologic drugs are available. DMARDs are frequently prescribed in combination with methotrexate (MTX), as it is the first-line drug. The adverse events (AEs) associated with DMARDs have sometimes unfavorable outcomes. Major AEs, particularly therapies in combination with methotrexate, were investigated in this study. A search of the website of the Japanese Pharmaceuticals and Medical Devices Agency for AEs associated with therapies with five DMARDs (MTX, tacrolimus, adalimumab, tocilizumab, and abatacept) reported from 2014 to 2016 was performed. The AEs searched included lymphoproliferative disease (LPD), cytopenia, interstitial pneumonia (IP), infectious pneumonia other than Pneumocystis jirovecii pneumonia (PCP) (i-Pn), and PCP. The number of cases of each AE and its ratio to the total number of cases of all AEs associated with each DMARD therapy were examined. Data were compared among AEs and DMARDs. MTX therapy in combination with other DMARDs was examined for rheumatoid arthritis (RA) cases. On the website, a total of 8874 cases were listed as having AEs associated with therapies with the five DMARDs. For MTX therapy, LPD was the most frequent (1438 cases, 36.4% of all AE cases), followed by cytopenia (10.9%), IP (6.2%), i-Pn (4.1%), and PCP (2.6%). Under therapy with any of the other four DMARDs, i-Pn showed the largest number of cases and the highest ratio (4.2–15.3%); other AEs varied in number and ratio. The proportion of use of MTX in combination with the four DMARDs was highest for PCP (67/71, 94.4%), followed by LPD (50/73, 68.5%), cytopenia (48/73, 65.8%), i-Pn (101/173, 58.4%,), and IP (36/80, 45.0%) (Table 1). In total, including cases reported for MTX therapy, 98.2% (1286/1309) of LPD cases, 88.5% (193/218) of cytopenia cases, 79.8% (174/218) of IP cases, 76.4% (233/305) of i-Pn cases, and 97.6% (165/169) of PCP cases had MTX. In conclusion, LPD was by far the most frequent AE associated with MTX therapy. PCP was strongly associated with the use of MTX in combination with another DMARD. For therapy with any of the other four DMARDs, i-Pn showed the highest ratio.

Biologic Drugs for Rheumatoid Arthritis in the Context of Biosimilars, Genetics, Epigenetics and COVID-19 Treatment

Rheumatoid arthritis (RA) affects around 1.2% of the adult population. RA is one of the main reasons for work disability and premature retirement, thus substantially increasing social and economic burden. Biological disease-modifying antirheumatic drugs (bDMARDs) were shown to be an effective therapy especially in those rheumatoid arthritis (RA) patients, who did not adequately respond to conventional synthetic DMARD therapy. However, despite the proven efficacy, the high cost of the therapy resulted in limitation of the widespread use and unequal access to the care. The introduction of biosimilars, which are much cheaper relative to original drugs, may facilitate the achievement of the therapy by a much broader spectrum of patients. In this review we present the properties of original biologic agents based on cytokine-targeted (blockers of TNF, IL-6, IL-1, GM-CSF) and cell-targeted therapies (aimed to inhibit T cells and B cells properties) as well as biosimilars used in rheumatology. We also analyze the latest update of bDMARDs’ possible influence on DNA methylation, miRNA expression and histone modification in RA patients, what might be the important factors toward precise and personalized RA treatment. In addition, during the COVID-19 outbreak, we discuss the usage of biologicals in context of effective and safe COVID-19 treatment. Therefore, early diagnosing along with therapeutic intervention based on personalized drugs targeting disease-specific genes is still needed to relieve symptoms and to improve the quality of life of RA patients.

MANAGEMENT OF A PATIENT WITH ANKYLOSING SPONDYLITIS TYPE SPONDYLOARTHRITIS AND LATENT TUBERCULOSIS INFECTION

Ankylosing spondylitis (AS) is one of the most common types of spondylarthritis (SpA) and Disease-Modifying Antirheumatic Drug (DMARD) is one of the modalities for treating the disease. An increased risk of latent tuberculosis infection (LTBI) reactivation in rheumatic patients receiving DMARD has been reported. Management of patients with rheumatic diseases who are also infected with LTBI needs to be understood in order not tobecome active TB. We reported a case of a 57-year-old man with AS. Patient was planned to be treated with DMARD so that hepatitis and TB screening performed. It was discovered that this patient had LTBI. The prophylactic therapy for TB was given. DMARD therapy started 1 month after TB prophylactic therapy was given. For monitoring the disease progression,anamnesis, physical, laboratory, and radiology examination performed regularly.

A study of high sensitive C-reactive protein in rheumatoid arthritis patients

Background: Rheumatoid arthritis (RA) is not only merely limited to joints but has many extraarticular features. The major cause of mortality in RA is cardiovascular disease (CVD). Inflammation in RA predispose them to succumb to CVD. The aim of this study to observe whether therapy with disease-modifying anti-rheumatic drugs (DMARD) decreases inflammation and if it does so than it can be said that decrease the risk to develop CVD. Aim and objectives were to assess hs-CRP level in early and established RA both at diagnosis and again at 3 months of DMARD therapy and compare between them.Methods: Total 58 early RA (group A) and 58 established (group B) DMARD naïve RA patients were included in the study. Age, BMI, haemoglobin, random blood sugar, lipid profile, ESR, hs-CRP, RA factor and anti-CCP were measured. All of them were treated with DMARD and hs-CRP was again assessed after 3 months.Results: The mean hs-CRP level at diagnosis was 6.14±1.90 mg/l in group A while it was 10.39±3.13 mg/l in group B. The mean hs-CRP level after 3 months of DMARD was 2.56±1.35mg/l in group A while it was 7.91±3.13 mg/l in group B. The mean reduction in hs-CRP level in early RA (3.58±0.99 mg/l) was statistically significantly (p<0.001) higher than that in established RA (2.48±0.09 mg/l). Conclusions: DMARD decreases level of inflammation in RA more efficiently if initiated early in the course of the disease.

Subclinical synovitis in arthralgia: how often does it result in clinical arthritis? Reflecting on starting points for disease-modifying anti-rheumatic drug treatment

Objectives According to guidelines, clinical arthritis is mandatory for diagnosing RA. However, in the absence of clinical synovitis, imaging-detected subclinical synovitis is increasingly used instead and is considered as a starting point for DMARD therapy. To search for evidence we studied the natural course of arthralgia patients with subclinical synovitis from three longitudinal cohorts and determined the frequencies of non-progression to clinically apparent inflammatory arthritis (IA) (i.e. ‘false positives’). Methods Subclinical synovitis in the hands or feet of arthralgia patients was visualized with US (two cohorts; definition: greyscale ≥2 and/or power Doppler ≥1) or MRI (one cohort; definition: synovitis score ≥1 by two readers). Patients were followed for 1 year on for IA development; two cohorts also had 3 year data. Analyses were stratified for ACPA. Results Subclinical synovitis at presentation was present in 36%, 41% and 31% in the three cohorts. Of the ACPA-positive arthralgia patients with subclinical synovitis, 54%, 44% and 68%, respectively, did not develop IA. These percentages were even higher in the ACPA-negative arthralgia patients: 66%, 85% and 89%, respectively. Similar results were seen after 3 years of follow-up. Conclusion Replacing clinical arthritis with subclinical synovitis to identify RA introduces a high false-positive rate (44–89%). These data suggest an overestimation regarding the value of ACPA positivity in combination with the presence of subclinical synovitis in patients with arthralgia, which harbours the risk of overtreatment if DMARDs are initiated in the absence of clinical arthritis.