LONG-TERM AND BOOSTER VACCINATION RESPONSES IN PATIENTS WITH GIANT CELL ARTERITIS AND POLYMYALGIA RHEUMATICA

BackgroundVaccination remains essential in preventing morbidity of SARS-CoV-2 infections. We previously showed that >10mg/day prednisolone and methotrexate use were associated with reduced antibody concentrations four weeks after primary vaccination in patients with giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) [1].ObjectivesHere, we performed a follow-up study to measure the decay of antibody concentrations over time and the immunogenicity of SARS-CoV-2 booster vaccination.MethodsGCA/PMR patients included in the primary vaccination (BNT162b2 or ChAdOx1) study were asked again to donate blood samples six months after primary vaccination (n=24) and one month after booster vaccination (n=46, BNT162b2 or mRNA1273). Data were compared to that of age-, sex-, and vaccine-matched controls (n=58 and n=42, respectively).ResultsAntibody concentrations decreased faster over time in GCA/PMR patients than in controls, but this decrease was not associated with treatment during primary vaccination. Post-booster antibody concentrations were comparable between patients and controls. Antibody concentrations post booster vaccination associated strongly with antibody concentrations post primary vaccination, but not with treatment during booster vaccination. However, the fold-change of post-booster vaccination showed a slight negative correlation with the post-primary vaccine antibodies.ConclusionThese results indicate that patients with impaired vaccine responses after primary vaccination, have slightly stronger increases in humoral immunity after booster vaccination, but this is not enough to reach a similar protection. The decrease in humoral immunity, and subsequent increase after booster vaccination, is likely not impacted by prednisolone or methotrexate treatment. Rather, these treatments put the patients at an immunogenic disadvantage during primary SARS-CoV-2 vaccination, which is not fully repaired by a single booster vaccination. This longitudinal study in GCA/PMR patients stresses the importance of repeat booster vaccination for patients that used >10mg/day prednisolone or methotrexate during primary vaccination.Reference[1]van Sleen Y, van der Geest, Kornelis SM, Reitsema RD, Esen I, Terpstra JH, Raveling-Eelsing E, et al. Humoral and cellular SARS-CoV-2 vaccine responses in patients with giant cell arteritis and polymyalgia rheumatica. RMD open 2022;8(2):e002479.Figure 1.Acknowledgements:NIL.Disclosure of InterestsYannick van Sleen: None declared, Kornelis van der Geest Speakers bureau: Speaker fees from Roche, Grant/research support from: Grant support from Abbvie, Annemarie Buisman: None declared, Maria Sandovici: None declared, Debbie van Baarle: None declared, Elisabeth Brouwer: None declared.

INTAKE OF ACETAMINOPHEN SUPPRESSES ANTIVIRAL HUMORAL IMMUNE RESPONSES IN PATIENTS WITH RA FOLLOWING VACCINATION WITH ANTI SARS-CoV-2 mRNA BASED VACCINES

BackgroundAcetaminophen (APAP = paracetamol) may potentially impact vaccine-associated immune responses as the intake of APAP has been associated with a worse outcome in tumor patients receiving checkpoint inhibitors.[1]Different DMARD regimen have been shown to impair the humoral immune response to mRNA SARS-CoV-2 vaccines in patients with rheumatoid arthritis but the effect of paracetamol has not been explored thus far.ObjectivesTo analyse whether the intake of APAP may interfere with antiviral humoral immune responses following two doses of an anti-SARS-CoV-2 mRNA based vaccine in patients with rheumatoid arthritis (RA) on DMARD therapy.MethodsThe RECOVER trial (Rheumatoid Covid-19 Vaccine Immune Response) was a non-randomised, prospective observational control group trial and enrolled 77 RA patients on DMARD therapy and 21 healthy controls (HC). We performed a posthoc analysis of blood samples taken before the first vaccine dose (T0), two (T1) and three (T2) weeks after the first and second vaccine dose, and at 12 (T3) weeks. APAP intake was measured using ELISA. The antibody response (anti-S) to the receptor binding domain (RBD) within the SARS-CoV-2 S1 protein was measured with the Elecsys Anti-SARS-CoV-2-S (Roche Diagnostics GmbH) test. The neutralizing activity NT50 at week 12 was assessed using an HIV-based pseudovirus neutralization assay against Wuhan-Hu-1.ResultsBaseline characteristics of participants are detailed in Table 1. The immunogenicity analyses were based on 73 RA patients after exclusion of 4 patients with previously unnoticed SARS-CoV-2 infection (positive for anti-nucleoprotein at baseline). APAP was detected in serum samples from 34/73 (25%) RA patients and in 7/21 (33%) HC (least at one timepoint T0, T1 and/or T2). APAP intake in HC did not affect levels of anti-S at any timepoint and all HC developed potent neutralizing activity (NT50 ≥ 250) at week 12. RA patients, who tested positive for APAP at T1, showed comparable anti-S levels at T1, T2 and T3 compared to RA patients not exposed to APAP. The detection of APAP at T2 corresponded to lower anti-S levels at T2 (Figure 1 A, B). The detection of APAP at T2 was associated with a significantly lower SARS-CoV-2 neutralizing activity at week 12 compared to patients without perivaccination APAP exposure (p =0.04) (Figure 1 C).ConclusionA decrease of antiviral humoral immune responses was observed in RA patients (but not in HC) who were exposed to APAP at the time of the second mRNA vaccine dose compared to patients in whom APAP was not detected. Our data suggest that the use of paracetamol within the time period around vaccination may impair vaccine-induced immune responses in patients with an already higher risk for blunted immune responses.Reference[1]Bessede A et al. Ann Oncol 2022;33: 909-915Table 1.Baseline characteristics: RA patients and HC with/without APAP exposureRA APAP – n = 37RA APAP + n = 36p-valueHC APAP – n = 8HC APAP + n = 13p-valueAge (yrs), mean (± SD)62 (13)67 (10)0.07 (NS)45 (12)44 (14)0.90 (NS)Female sex, n (%)24 (65)19 (53)0.29 (NS)2 (25)5 (38)0.53 (NS)Vaccination type/schedulemRNA-1273, n (%)4 (11)8 (22.2)0.19 (NS)0 (0)0 (0)BNT162b2, n (%)33 (89)28 (77.8)0.19 (NS)8 (100)13 (100)RA disease characteristicsACPA ± RF, n (%)17/37 (46)19/36 (53)0.56 (NS)NANANARA disease duration (yrs ± SD)9.2 (9.8)10.2 (8.1)0.67 (NS)NANANADMARD therapycsDMARD-mono, n (%)13/37 (35)9/36 (25)0.35 (NS)NANANAbDMARD-mono/combo, n (%)16/37 (43)16/36 (44)0.92 (NS)NANANAtsDMARDs-mono/combo, n (%)8/37 (22)11/36 (31)0.38 (NS)NANANAPrednisone, n (%)15/37 (41)12/36 (33.3)0.52 (NS)NANANAMean daily dose prednisone (mg ± SD)4.6 ± 1.13.9 ± 2.30.39 (NS)NANANA* APAP = acetaminophenFigure 1.Acknowledgements:NIL.Disclosure of InterestsNone Declared.

IMPACT OF THE COVID-19 PANDEMIC ON ADHERENCE TO DISEASE MODIFYING DRUGS AMONG PATIENTS WITH RHEUMATIC DISEASES: A POPULATION-BASED, INTERRUPTED TIME SERIES ANALYSIS

BackgroundAlthough studies have quantified adherence to medications among patients with rheumatic diseases (RD) during the COVID-19, lack of direct pre-pandemic comparison precludes understanding of impact of the pandemic.ObjectivesOur objective was to evaluate the effect of the COVID-19 pandemic on adherence to disease modifying drugs (DMARDs) including conventional synthetic (csDMARDs) and targeted synthetic (tsDMARDs).MethodsWe linked population-based health data on all physician visits, hospital admissions, and all dispensed medications, regardless of payer in British Columbia from 01/01/1996 to 3/31/2021. We identified prescriptions for csDMARDs (including methotrexate, hydroxychloroquine) and tsDMARDs, namely anti-TNFs (including infliximab, etanercept, adalimumab) and rituximab using drug identification numbers among indicated individuals with RD. We defined March 11, 2020, as the ‘index date' which corresponded to the date that mitigation measures for the COVID-19 pandemic were first introduced. We assessed adherence as proportion days covered (PDC), calculated monthly in the 12 months before and 12 months after the index date. We used interrupted time-series models, namely segmented regression to estimate changes and trends in adherence before and after the index date.ResultsOur analysis showed that the mean PDCs for all included DMARDs stayed relatively steady in the 12 months before and after mitigation measures were introduced (see Table 1). Adherence was highest among anti-TNFs, methotrexate, and azathioprine. Anti-TNFs were on a downward trajectory 12 months prior to the index date. Interrupted time-series modeling demonstrated statistically significant differences in the trends in PDCs post- vs. pre-mitigation measures for all anti-TNFS (slope [∂]: 1.38, standard error [SE]: 0.23), infliximab (∂: 1.35, SE: 0.23), adalimumab (∂: 0.82, SE: 0.25), and etanercept (∂: 1.07, SE: 0.25) (see Figure 1a). Conversely, the csDMARDs were on a flatter trajectory, and methotrexate (∂: -0.53, SE: 0.16), leflunomide (∂: 0.43, SE: 0.08), mycophenolate (∂: -1.26, SE: 0.48), cyclophosphamide (∂: 0.29, SE: 0.05), minocycline (∂: 0.04, SE: 0.02), chloroquine (∂: 0.02, SE: 0.00) showed statistically significant changes in estimated PDC trajectory after mitigation measures were introduced (see Figure 1b).ConclusionThis population-based study demonstrates that messaging and pandemic mitigation measures did not affect adherence to DMARDs.Table 1.Mean PDC 1 year before and after mitigation measures for the COVID-19 pandemic were introduced.MedicationMean PDC (%) 12 months before index dateMean PDC (%) 12 months after index datecsDMARDsmethotrexate28.926.8azathioprine21.819.5sulfasalazine16.214.9leflunomide14.313.0cyclosporine13.711.5hydroxychloroquine10.59.6mycophenolate4.52.9antimalarials4.43.9penicillamine3.53.4cyclophosphamide1.50.7chlorambucil1.20.4minocycline1.10.9gold0.50.2chloroquine0.10.0tsDMARDsanti-TNFs52.149.2infliximab41.838.3adalimumab40.336.8etanercept31.828.9rituximab3.42.9REFERENCES:NIL.Acknowledgements:NIL.Disclosure of InterestsNone Declared.

SAFETY ANALYSIS OF JAKINIBS IN REAL CLINICAL PRACTICE IN A COHORT OF 116 PATIENTS

BackgroundJanus kinase inhibitors (JAKinibs) have demonstrated efficacy in the treatment of rheumatoid arthritis (RA) and spondyloarthritis (SpA), although their safety profile continues to be analysed due to the possible increase in adverse events (AEs) in relation to anti-TNFs (mild and severe infections, haematological alterations, thromboembolism, increase in neoplasms).ObjectivesTo evaluate in real clinical practice the AEs of JAKinibs in a cohort of patients with RA and SpA. In addition, adherence and reasons for discontinuation (1st or 2nd failure, AE) are analysed.MethodsObservational study of 116 patients diagnosed with RA or SpA who received treatment with JAKinibis (tofacitinib, baricitinib, upadacitinib) after failure of treatment with different classical synthetic (FAMEsc) or biological (FAMEb) disease-modifying drugs. The following data were analysed: demographic characteristics of the patients, years of disease progression, 1st or 2nd failures and AE.ResultsMean age was 52 years, with Baricitinib being older (60 years -SD 13.6), higher prevalence of females in all groups, and a disease progression time of about 10 years. Mean number of FAMEsc was 1.6 and mean number of FAMEb was 2,3 to Tofacitinib(Tofa), 2,76 to Baricitinib(Bari) and 4,4 to Upadacitinib(Upa). 71 (63%) patients had active corticosteroid therapy. The median treatment time with Tofa was 8.8 months, Bari 9.5 and Upa 2.4 months.Most frequent AEs with Tofa were urinary tract infections(UTI) (11.9%, 7 cases) and headaches (8.47%, 5 cases). There were 3 cases of herpes zoster (5.1%), one of which was recurrent, and 2 cases respectively of tachycardia and gastrointestinal intolerance (3.4%). With Baricitnib, 2(5%) cases of UTI and 2(5%) of influenza A were reported. Most frequent AEs related to Upadacitinb are gastrointestinal intolerance, labialis and facial herpes, anterior uveitis and recurrent UTI, with 1 case for each adverse event. There were 4 success with Baricitinib treatment: 2 due to severe COVID, 1 influenza A and 1 due to stroke. 17 patients had 1st failure to Tofa(28.81%), 8 to Bari20.0%) and 3 to Upa(18.75%);7(11.86%) and 2(5%) patients had 2nd failure to Tofa and Bari respectively, no with Upa.Mean CRP to Tofa-SD 18.9-was 17.19, 20-SD 22.7- to Bari and 24.2-SD 27.40- to Upa. Mean ESR-SD 15.3- was 25.4, -SD 26.4 and 44.3 -SD 32-, respectively. At 6 months, 36(62%) were continuing on Tofa, 22(56%) on Bari and 4(27%) on Upa. At 12 months, 27(46.6%) were still on Tofa and 12 on Bari(30.8%) and no patients were on upa.Table 1.TofaBariUpaMean age496047Male19%18%20%Female81%82%80%Time course of disease(years)81111Permanence 6 months62%56%27%Permanence 12 months46,6%31%0%Patients with corticotherapy62%64%60%Previous biological drugs2,3 SD 22,8 SD 2,34,4 SD 2,9Patients who discontinued the drug62%59%33%Mean CRP at the end of treatment172024Mean end-of-treatment ESR252644Repeated AEsUTI(7) Headache(5) Shingles(3) Nephritic colic(2) Gastrointestinal intolerance(2) Tachycardia(2)UTI(4) Headache(2)Serious AEsShingles (3)Varicella encephalopathy(1) Stroke(1) Shingles (1)1st failure28,8%20%18,7%2nd failure11,9%5%0%SuccessSARS-Cov2(2) Influenza(1) Stroke(1)Figure 1. Months stay pharmacoConclusionMost frequent adverse events with JAKinibs are mild infections, except gastrointestinal complaints with upadacitinib. Serious adverse events, including 3 deaths from viral infections, were observed, mostly in patients over 65 years. Most frequent cause of discontinuation was treatment failure. We believe that further observational studies are needed to stratify and profile the risk of infection with JAKinibs.References[1]Atzeni F, Popa CD, et al. Safety of JAK inhibitors: focus on cardiovascular and thromboembolic events. Expert Rev Clin Immunol. 2022 Mar;18(3):233-244. Doi: 10.1080/1744666X.2022.2039630 Epub 2022 Feb 17.PMID: 35129033[2]Alves C, Penedones A,et al. The Risk of Infections Associated With JAK Inhibitors in Rheumatoid Arthritis: A Systematic Review and Network Meta-analysis. J Clin Rheumatol. 2022 Mar 1;28(2):e407-e414 PMID:33902098Ackn wledgements:NIL.Disclosure of InterestsNone Declared.

COVID-19 SYMPTOMS AND DISEASE COURSE IN GERMAN PEDIATRIC RHEUMATOLOGY PATIENTS REPORTED TO BIKER

BackgroundCOVID-19 has shaped the world over the last 3 years. Although the risk for severe COVID-19 progression in children is low it might be aggravated by chronic rheumatic disease or treatment with immunosuppressive drugs.ObjectivesWe analyzed clinical data of COVID-19 cases among paediatric patients with rheumatic diseases reported to BIKER between March 2020 and December 2022.MethodsThe main task of the German BIKER (Biologics in Pediatric Rheumatology) registry is safety monitoring of biologic therapies in JIA. After the onset of the COVID-19 pandemic, the survey was expanded with a standardized form to proactively interview all participating centers about occurrence, presentation and outcome of SARS-CoV-2 infections in children with rheumatic diseases.ResultsA total of 68 centres participated in the survey. Clinical data from 928 COVID infections in 885 patients with rheumatic diseases could be analyzed. JIA was the most common diagnosis with (717 infections), followed by genetic autoinflammation (103 infections), systemic autoimmune diseases (78 infections), idiopathic uveitis (n=25), vasculitis (n=5).In 374 reported COVID infections (40%), patients were receiving conventional DMARDs, in 331 (36%) biologics, mainly TNF inhibitors (TNFi, n=241 (26%)). In 567 reports (61%) patients used either a biologic or a DMARD, in 339 reports patients (37%) did not use any antirheumatic medication including steroid.Over the last 3 years, COVID-19 occurred in Germany in 5 distinguishable waves, calendar weeks (CW) 10-30 in 2020, CW 21/2020 – 8/2021(both predominantly wild-type variant), CW 9-27 in 2021 (Alpha variant in the majority of infections), CW 28-51 in 2021 (Delta variant), since CW 52/2021 (several Omikron variants;Robert-Koch Institute: VOC_VOI_Tabelle.xlsx;live.com))In our cohort, patients with SARS-CoV-2 infection were slightly older during the 1st and 2nd wave (mean age 12.7+/-3.5 and 12.8+/-4.3 years) compared to the 4th and 5th wave with 11.4+/-3.9 and 11.4+/-4.2 years;p=0.01.160 asymptomatic SARS-CoV-2 infections were reported, frequencies of symptoms associated with COVID-19 are shown in table 1.Five patients were hospitalized for 4-7 days. A 3½-year-old female patient succumbed during the first wave with encephalopathy and respiratory failure. The patient had been treated with MTX and steroids for systemic JIA. Genetic testing revealed a congenital immunodeficiency. No other patient needed ventilation or intensive care. One case of uncomplicated PIMS in an MTX treated JIA patient was reported.The duration of SARS-CoV-2 infection-associated symptoms was markably shorter during the 5th wave with 6.7+/-5.1 days, compared with reports from the other 4 waves (Table1).The duration of symptoms was higher in MTX treated patients (10.2+/-8.4 days) compared to patients without treatment (7.7+/-10.8;p=0.004) or patients treated with TNFi (8.2+/-4.8, p=0.002). Although patients treated with steroids also had a longer duration of symptoms (9.7+/-7.0), this was not significant.ConclusionExcept for one patient with congenital immunodeficiency who died, no case of severe COVID-19 was reported in our cohort. At the time of infection, over 60% of patients had been treated with conventional DMARDs and/or biologics. Although MTX treated patients had a slightly longer duration of symptoms, antirheumatic treatment did not appear to have a negative impact on severity or outcome of SARS-CoV-2 infection.Table 1.Characteristics and frequency of symptoms in SARS-CoV-2 infectionsN or mean (SD)1st wave N=202nd wave N=843rd wave N=384th wave N=1245th wave N=662female14532775432age at COVID-19, years12.7 (3.5)12.8 (4.3)11.8 (3.5)11.4 (3.9)11.4 (4.2)asymptomatic126132694duration of symptoms;days,11.9 (14.7)9.2 (7.0)14.1 (11.6)10.3 (7.6)6.7 (5.1)fever1218541306cough1015652245rhinitis5261344289headache4161227171sore throat61139132musculosceletal pain2751348loss of smell/taste71162113fatigue4882680dizziness122116gastrointestinal symptoms151864dyspnea1117pneumonia11bronchitis1REFERENCES:NIL.Acknowledgements:NIL.Disclosure of Inter stsAriane Klein Speakers bureau: Novartis, Toni Hospach Speakers bureau: Speaking fee Novartis and SOBI., Frank Dressler Speakers bureau: Abbvie, Novartis, Pfizer, Advisory Boards Novartis and Mylan, Daniel Windschall Grant/research support from: research funds by Novartis, Roche, Pfizer, Abbvie, Markus Hufnagel: None declared, Wolfgang Emminger: None declared, Sonja Mrusek: None declared, Peggy Ruehmer: None declared, Alexander Kühn: None declared, Philipp Bismarck: None declared, Maria Haller: None declared, Gerd Horneff Speakers bureau: Pfizer, Roche, MSD, Sobi, GSK, Sanofi, AbbVie, Chugai, Bayer, Novartis, Grant/research support from: Pfizer, Roche, MSD, AbbVie, Chugai, Novartis.

SHOULD COMPLETE B-CELL DEPLETION BE SUSTAINED IN RITUXIMAB LONG-TERM TREATED PATIENTS FOR RHEUMATOID ARTHRITIS?

BackgroundComplete peripheral B cell depletion has been considered as a relevant indicator of short-term response to rituximab (RTX) in rheumatoid arthritis (RA) [1,2]. However, no information is available to validate this observation in RA patients long-term treated with RTX.ObjectivesTo determine whether sustained complete B cell (BC) depletion is associated with a better clinical response in RA patients long-term treated with RTX.MethodsRetrospective routine care study conducted in the Rheumatology department of Cochin hospital. We included consecutive patients fulfilling the ACR/EULAR 2010 classification criteria for RA hospitalized in 2021 for a new RTX infusion. All recruited patients had received at least 3 prior RTX infusions and had disease activity assessment (DAS28 and DAS28-CRP) and CD19 counts (Aquios, Beckman Coulter) available during each of the 4 last infusion visits. The primary endpoint was the course of DAS28 and DAS28-CRP, calculated the day of the last 4 infusion visits according to sustained complete (mean CD19 counts <18/µL) or incomplete (mean CD19 counts ≥18/µL) BC depletion. Secondary endpoints were the frequency of end-of-dose effect and patient self-reported RA flares at each infusion visit, as well as the course of pain/fatigue VAS, CRP and gammaglobulin levels according to complete or incomplete B cell depletion.ResultsWe included 126 patients (105 women, 83%) with a mean age of 64±12 years and a mean disease duration of 22± 5 years. Only 43 patients (34%) had maintained complete BC depletion during the last 4 infusions (mean CD19 counts 13±4/µL) (Figure 1A-B). Patients with incomplete BC depletion (n=83, mean CD19 counts: 77±73/µL, p<0.001) did not differ from those who maintained complete BC depletion in terms of age, gender, disease duration, structural damages and concomitant treatment.Patients with incomplete BC depletion had a higher frequency of rheumatoid factor (92% vs. 77%, p=0.018) and ACPA (84% vs. 72%, p=0.11);these patients had received RTX for a longer period (99±57 months vs. 69±47 months, p=0.003), with significantly higher number of infusions (14±7 vs. 12±6 infusions, p=0.037) and increased cumulative dose (10±6 g vs. 8±5 g, p=0.10) compared to patients with sustained complete BC depletion. On the other hand, their interval between 2 infusions was significantly longer (8±3 months vs. 6±1 months, p<0.001).The course of DAS28 and DAS28-CRP during the last 4 infusions was not different between the 2 groups (Figures 1C-D). The mean DAS28 and DAS28-CRP calculated at the time of last 4 infusion visits did not differ between patients with incomplete or sustained complete BC depletion (DAS28: 2.71±1.06 vs. 3.01±1.10, p=0.33 and DAS28-CRP: 2.53±0.88 vs. 2.88±0.84, p=0.095). The frequency of an end-of-dose effect and self-reported flares was similar between the 2 groups, as well as the evaluation of pain VAS, asthenia VAS, CRP and gammaglobulin levels (Figures 1E-H).ConclusionMaintaining complete BC depletion is not a therapeutic target to achieve in RA patients in long-term maintenance therapy with RTX. These results show that it is possible to space out RTX infusions to 8 months without loss of clinical benefit, which remains identical to that of patients treated every 6 months with sustained BC depletion. This result may have clinical implications during the COVID-19 pandemic since the antibody response to SARS-CoV-2 vaccination is preferentially obtained in patients with detectable B cells [3].References[1]Vital EM et al. Arthritis Rheum 2011;63:603–8.[2]Dass S et al. Arthritis Rheum 2008;58(10):2993–2999.[3]Avouac et al, Rheumatology 2022Figure 1.Course of mean (±SD) CD19, DAS28, DAS28-CRP, pain and fatigue VAS, CRP and gammaglobulins at the last 4 RTX infusion visits according to sustained complete or incomplete B cell depletion (CBCD and IBCD respectively).[Figure omitted. See PDF]Acknowledgements:NIL.Disclosure of InterestsNone Declared.

A comprehensive overview of juvenile idiopathic arthritis: From pathophysiology to management.

Rheumatoid Arthritis (RA) is a progressive autoimmune disease. It is among the most widespread chronic illnesses in children, with an annual incidence of 1.6 to 23 new instances per 100,000 adolescents. About 1 child in every 1000 develops Juvenile Idiopathic Arthritis (JIA) type of chronic arthritis. The cause of JIA is not well known but what known is that it involves inflammation of the synovium and destruction of tissues in joints which can cause early-onset of oligo articular JIA. It is challenging to diagnose the condition in some children who initially complain of pain and joint swelling as there is no blood test discovered that can confirm the diagnoses of JIA. As JIA patients are immunosuppressed due to the use of drugs, making them vulnerable to catch infections like COVID-19 which can lead to cardiovascular diseases having high rate of morbidity and mortality. The comorbidity like Diabetes has higher incidence in these patients resulting in synergistic effect on inflammation. Currently, the connection of genetics in JIA provides evidence that HLA Class I and II alleles have a role in the pathophysiology of various subtypes of JIA which includes inflammation in the axial skeletal. The primary objective of therapy in juvenile idiopathic arthritis is the suppression of clinical symptoms. The pharmacological approach includes use of medications like DMARDs, NSAIDs etc. and non-pharmacological approach includes physiotherapy, which helps in restoring normal joint function and herbs as adjuvants which has the benefit of no side effects.

Immunopharmacology/Musculoskeletal System Pharmacology: Overview

The rapid technological advancement over the past few decades has profoundly influenced the scientific approaches that shape the therapeutic landscape. Undoubtedly, immunopharmacology is an important player in the modern era of transition toward precision medicine that is largely defined by the identification of patient-specific therapies. According to the Immunopharmacology Section - ImmuPhar of the International Union of Basic and Clinical Pharmacology (IUPHAR), immunopharmacology is considered to be the youngest area of pharmacology dealing with the selective modulation, mostly up- or down-regulation, of specific immune responses that are often accomplished by immune cell subsets with specialized functions. Although the recent biotechnological progress has made available new classes of drugs with improved selectivity and/or specificity, agents possessing immunomodulating activities have been used in clinical practice for more than 70years. A pertinent example from the late 1940s is the counteraction of the inflammatory response upon administration of cortisone in patients with rheumatoid arthritis. © 2022 Elsevier Inc. All rights reserved

Guselkumab-Associated Pulmonary Disease and Diffuse Alveolar Hemorrhage with Drug Rash with Eosinophilia and Systemic Symptoms.

Psoriasis is a common skin condition worldwide. Moderate-to-severe disease is treated with biologic or non-biologic disease-modifying anti-rheumatic drugs. These include tumor necrosis factor (TNF)-a inhibitors, interleukin (IL)-17 inhibitors, and IL-23 inhibitors. Case reports of inhibitors of TNF-a and IL-12p40 subunits causing interstitial pneumonia (IP) have been published in the literature, but no case of anti-IL-23p19 subunit biologics causing IP and acute respiratory distress syndrome (ARDS) has been reported before. We report a case of a patient with restrictive lung disease secondary to a body mass index of 36.54 kg/m2, obstructive sleep apnea, and psoriasis, who developed IP and ARDS presumed to be secondary to guselkumab, an anti-IL-23p19 subunit monoclonal antibody. He was on ustekinumab, an anti-IL-12/23p40 for the treatment of psoriasis, but was switched to guselkumab eight months before the presentation, and since then he had been complaining of progressive shortness of breath. He initially presented to the hospital after having drug reaction with eosinophilia and systemic symptoms (DRESS) after being started on amoxicillin for a tooth infection. He was treated with high-dose intravenous steroids but developed progressive shortness of breath. Broad-spectrum antibiotics were added. An extensive infectious, autoimmune, and hypersensitivity work-up was undertaken, which returned negative. A bronchoscopy with bronchoalveolar lavage was performed, which revealed diffuse alveolar hemorrhage (DAH). His lung imaging and oxygenation progressively got worse; hence, no lung biopsy was taken. He was intubated and required inhaled nitric oxide, but due to the lack of improvement, the family elected for comfort measures, and the patient was extubated and passed away. To our knowledge, this is the first case of an association between guselkumab, IP, ARDS, and DAH. Rare instances of DAH with DRESS have been reported before. Whether it was DRESS or guselkumab that caused DAH was uncertain in our patient. Clinicians should monitor for DAH and shortness of breath in patients on guselkumab so that more data can be obtained and studied in the future.

Safety of the COVID-19 vaccination in children with juvenile idiopathic arthritis-A observational study from two pediatric rheumatology centres in Poland.

Introduction: The safety of COVID-19 vaccines in children with juvenile idiopathic arthritis (JIA) is the concern of patients and their parents and doctors in the current pandemic reality. The main objective of the study was to evaluate the safety of COVID-19 vaccine in patients with JIA. Method: A cohort study based on short clinical follow-up of 43 children with JIA was conducted in the years 2021-2022 in two centres of paediatric rheumatology in Poland. All patients received mRNA COVID-19 vaccine. The patients' data were collected using appropriate validated questionnaire. Disease activity was evaluated using Juvenile Arthritis Disease Activity Score 27-joint count (JADAS-27). Results: Ten (22.7%) children had COVID-19 infection before getting COVID-19 vaccine. After first dose of COVID-19 vaccine 25/43 (58.1%) patients presented typical adverse events: arm pain or oedema at the application side or weakness. Also, twenty five (58.1%) children had side effects after second dose of this vaccine, however the spectrum of the symptoms was wider (additionally: headache, fever, lymphadenopathy, arrhythmia). Thirteen out of 43 (30.2%) patients had active disease before and 8/43 (18.6%) after COVID-19 vaccination, while the degree of JADAS-27 activity was higher in the study group before COVID-19 vaccination (p = 0.047). Conclusions: Our study found out that children and adolescents with JIA with remission without treatment or on the long-term treatment-cDMARDs or even bDMARDs, can be safely vaccinated for COVID-19. Moreover, the study found that COVID-19 vaccination does not interfere with the JIA treatment and does not exacerbate symptoms of the disease and that vaccination protected against developing COVID-19 in children with JIA even on treatment.

COVID-19 in Patients with Rheumatic Disease Using Immunomodulatory Drugs: Imaging Findings and Predictors of Hospitalization.

INTRODUCTION: SARS-CoV-2 causes more severe symptoms in most chronic diseases, and rheumatic disease is no exception. This study aims to investigate whether there is an association between the use of immunomodulatory medications, including conventional disease-modifying agents (csDMARDs), glucocorticoids, and biologic DMARDs, and outcomes such as hospitalization and lung involvement in patients with rheumatic disease with COVID-19. METHODS: We performed a cross-sectional study on 177 COVID-19 cases with rheumatologic diseases using immunomodulatory drugs as their regular treatment. All patients were evaluated regarding their initial chest computed tomography (CT) scan, COVID-19 symptoms, and comorbidities. We ran predictive models to find variables associated with chest CT-scan involvement and hospitalization status. RESULTS: CT findings showed lung involvement in 87 patients with chest CT-scan severity score (C-ss) of less than 8 in 59 (33%) and more than 8 in 28 (16%) of our patients. Of all patients, 76 (43%) were hospitalized. Hospitalized patients were significantly older and had more comorbidities (P = 0.02). On multivariate analysis, older age [odds ratio (OR) 1.90, 95% confidence interval (CI) 1.31-3.08] and comorbidity (OR 2.75, 95% CI 1.06-3.66) were significantly associated with higher odds of hospitalization (P = 0.03). On multivariate analysis, older age (OR 1.15, 95% CI 0.94-2.01), pulmonary diseases (OR 2.05, 95% CI 1.18-3.32), and treatment with csDMARDs (OR 1.88, 95% CI 0.37-1.93) were associated with higher C-ss (P = 0.039). CONCLUSIONS: This study found that advanced age and comorbidities, similar to the general population, are risk factors for hospitalization in patients with COVID-19 with rheumatic disorders. Administration of csDMARDs, older age, and pulmonary disorders were linked to increased risk of COVID-19 pneumonia in these individuals.

Risk of exacerbation of rheumatic disease after COVID-19 vaccination

Objectives: To investigate the risk of flare-ups after COVID-19 vaccination in patients with rheumatic disease. Method(s): A total of 1617 patients with rheumatic diseases were identified from three rheumatology clinics. Patients were interviewed for demographic data, disease activity, and vaccination status. Clinical disease flare up was determined independently by expert opinion by managing rheumatologists. Change of serum markers and medications were retrieved from medical records. The risk of exacerbation of rheumatic disease, change in serum markers, and escalation of rheumatic medications between vaccinated and non-vaccinated patients were determined using cox, linear and logistic regression models respectively. Possible confounding factors were also taken into consideration. Result(s): There were 562 (34.76%) patients received COVID-19 vaccine. After vaccination, rheumatic disease (HR = 2.10, P < 0.001), inflammatory arthritis (HR = 2.71, P < 0.001), rheumatoid arthritis (RA) (HR = 2.03, P = 0.002), spondyloarthritis (SpA) (HR = 4.78, P < 0.001), autoimmune disease (HR = 1.77, P = 0.01), and systemic lupus erythematosus (SLE) (HR = 1.99, P = 0.02) were associated with clinical flare up. Adult still's disease (B = 12.76, P = 0.03) was associated with an increase in CRP level. Escalation of rheumatic medications were not associated with COVID-19 vaccination in all diseases. Subgroup analyses showed only mRNA vaccine was associated with disease flare ups. Conclusion(s): COVID-19 vaccine was associated with minor disease flare up but not escalation of rheumatic medications. In the absence of absolute contraindications, full COVID-19 vaccination in patients with rheumatic disease should be encouraged by managing rheumatologists.

Humoral and cellular immune responses in persons with rheumatoid arthritis after a third dose of mRNA COVID-19 vaccine.

OBJECTIVE: Disease-modifying anti-rheumatic drugs (DMARDs) that treat rheumatoid arthritis (RA) may reduce immune responses to COVID-19 vaccination. We compared humoral and cell-mediated immunity before and after a 3rd dose of mRNA COVID vaccine in RA subjects. METHODS: RA patients that received 2 doses of mRNA vaccine enrolled in an observational study in 2021 before receiving a 3rd dose. Subjects self-reported holding or continuing DMARDs. Blood samples were collected pre- and 4 weeks after the 3rd dose. 50 healthy controls provided blood samples. Humoral response was measured with in-house ELISA assays for anti-Spike IgG (anti-S) and anti-receptor binding domain IgG (anti-RBD). T cell activation was measured after stimulation with SARS-CoV-2 peptide. Spearman's correlations assessed the relationship between anti-S, anti-RBD, and frequencies of activated T cells. RESULTS: Among 60 subjects, mean age was 63 years and 88% were female. 57% of subjects held at least 1 DMARD around the 3rd dose. 43% (anti-S) and 62% (anti-RBD) had a normal humoral response at week 4, defined as ELISA within 1 standard deviation of the healthy control mean. No differences in antibody levels were observed based on holding DMARDs. Median frequency of activated CD4 T cells was significantly greater post- vs. pre-3rd dose. Changes in antibody levels did not correlate with change in frequency of activated CD4 T cells. CONCLUSION: Virus-specific IgG levels significantly increased in RA subjects using DMARDs after completing the primary vaccine series, though fewer than two-thirds achieved a humoral response like healthy controls. Humoral and cellular changes were not correlated.

Vaccination for SARS-CoV-2 in Patients With Psoriatic Arthritis: Can Therapy Affect the Immunological Response?

Background: A few studies on vaccination in patients with rheumatic diseases, including arthritis, connective tissue diseases, vasculitis, and psoriatic arthropathy (PsA), demonstrated reduced production of neutralizing antibodies to SARS-CoV-2 Spike RBD (receptor-binding domain contained in the N-terminal of the S1 globular head region) when compared to the general population. Objective: The aim of our study was to observe whether different therapies for PsA [methotrexate, anti-TNF antibodies, soluble TNF receptor (etanercept) or IL-17 inhibitors] have a different impact on SARS-CoV-2 vaccination in a homogeneous population of patients. Methods: We enrolled 110 PsA patients in remission, assessed with Disease Activity in PSoriatic Arthritis (DAPSA). Of these: 63 were in treatment with anti-TNF-α therapy (26 etanercept, 15 certolizumab, 5 golimumab, 17 adalimumab); 37 with anti-IL17 secukinumab; 10 with methotrexate. All patients underwent vaccination for SARS-CoV-2 with mRNA BNT162b2 vaccine. Assessment of absolute and percentage lymphocyte subsets and anti-SARS-CoV-2 Spike RBD IgG antibody value 3 weeks after the second vaccine dose were performed. In addition, the serum antibody levels of 96 healthy healthcare workers (HCW) were analyzed. Results: The mean disease activity assessed with DAPSA score was 2.96 (SD = 0.60) with no significant differences between patients under different medications (p = 0.779). Median levels of neutralizing antibodies to SARS-CoV-2 Spike RBD were 928.00 binding antibody unit (BAU)/mL [IQR 329.25, 1632.0]; 1068.00 BAU/ml [IQR 475.00, 1632.00] in patients taking MTX, 846.00 BAU/ml [IQR 125.00, 1632.00] in patients taking etanercept, 908.00 BAU/mL [IQR 396.00, 1632.00] in patients taking anti-IL17 and 1148.00 BAU/ml [IQR 327.00, 1632.00] in patients taking TNF-α inhibitors, without statistically significant differences between these groups. Mean serum antibody level of HCW group was 1562.00 BAU/ml [IQR 975.00, 1632.00], being significantly higher than in the patient group (p = 0.000816). Absolute and percentage count of lymphocyte subsets were not statistically different between the subgroups under different treatments and when compared with HCW. Conclusions: As for other rheumatic diseases on immunomodulatory treatment, our data showed a reduced humoral response in PsA patients compared to the control group. However, antibody response did not significantly differ between groups treated with different medications.

Examining the safety of relaxed drug monitoring for methotrexate in response to the COVID-19 pandemic.

Objectives: This is a retrospective study that set out to assess the safety, feasibility and cost savings of temporary relaxed blood test monitoring for patients on MTX under the rheumatology service that was rolled out during the coronavirus pandemic. Methods: This is a single-centre study that reviewed the blood tests of all patients who received an MTX prescription from the trust between December 2019 and November 2020. After the application of inclusion and exclusion criteria, the blood testing intervals and findings were analysed and collated. The cost of the blood tests was obtained from the laboratory. Results: A total of 1194 patients were identified as having received an MTX prescription. After applying inclusion and exclusion criteria, 462 patients were included. Of these, 395 (85%) patients had a blood test within the standard 3-month schedule and 67 had blood tests within the relaxed blood monitoring schedule. Six patients had an abnormality identified on their blood tests, but no harm was caused by any of these abnormalities. The intervention resulted in a cost savings of at least £1187 from the blood test costs alone. Conclusion: MTX is a widely used steroid-sparing agent that requires regular blood test monitoring to reduce adverse outcomes for patients. During extraordinary circumstances such as a pandemic, relaxing the interval between monitoring blood tests in stable patients is a feasible intervention. A relaxed monitoring blood test interval for a set period is safe, achievable and cost effective.

Can hydroxychloroquine be used for COVID-19-induced arthritis? A debatable hypothesis.

Hydroxychloroquine (HCQ) is a known disease-modifying antirheumatic drug for rheumatoid arthritis. It is also being used in viral arthritis on many occasions. HCQ is also being used to treat coronavirus disease 2019, but the results are not satisfactory. HCQ has been shown to have antiviral effects. In this context, we have a hypothesis that HCQ may be used as a treatment option in post-coronavirus disease 2019 arthritis.

Effects of Biologic Therapies on the Chance of COVID-19 Infection Among Rheumatoid Arthritis and Lupus Patients During the First Wave of the Pandemic.

Background: Patients with rheumatic diseases taking immunosuppressive medications might be at an increased risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Despite the effectiveness of using combined conventional and biological disease-modifying anti-rheumatic drugs(bDMARDs) in managing rheumatic diseases, there have been concerns that taking biological agents may have an additive effect on getting infected with COVID-19. This study evaluates the impact of taking biological agents on altering the chance of getting infected with SARS-CoV-2 in rheumatoid and lupus patients compared to traditional DMARDs. Methods: We carried out a cross-sectional survey study from February 2020 to January 2021 on patients diagnosed with lupus and rheumatoid arthritis disease. COVID-19 infection was confirmed by the presence of symptoms and signs of the disease and para-clinical findings such as lymphopenia and elevated C-reactive protein (CRP) and positive chest CT scan or polymerase chain reaction (PCR) of COVID-19. Results: Out of 591 patients included in this study, 422 (71.4%) had rheumatoid arthritis (RA), and 169 (28.6%) had systemic lupus erythematosus (SLE). Among them, 56 (9.5%) cases were diagnosed with COVID-19 infection. No association was found between age, gender, or type of rheumatological diseases and SARS-CoV-2. There was a significant association between COVID-19 infection and treatment with biological drugs (P-value<0.05) regardless of the type of rheumatologic disease. Interestingly, the analysis revealed that the type of biologic drug also altered the chance of COVID-19 infection; In fact, patients who took TNF inhibitors were significantly at a higher risk of disease than those taking Rituximab (P-value=0.000). Identical results were observed among RA patients (P-value<0.001), however, all 5 (3%) lupus cases treated with Rituximab infected with covid 19. Conclusion: This study develops a better understanding of the risk of immunosuppressive medications for SARS-CoV-2 infection. Patients treated with conventional and biological medicine had a higher disease risk than those taking exclusively conventional drugs. However, more studies are required to deliberate the relation of the reviewed factors with the severity of COVID-19.

Comparison of Respiratory Complications of COVID-19 among Patients with Rheumatological Conditions Taking Biological Disease-Modifying Anti-Rheumatic Drugs and Conventional Synthetic Disease-Modifying Antirheumatic Drugs

Objective: To compare the respiratory complications of COVID-19 among patients with rheumatological conditions taking bDMARDs and csDMARDs at Pak Emirates Military Hospital Rawalpindi. Study Design: Comparative prospective study. Place and Duration of Study: Pak Emirates Military Hospital, Rawalpindi Pakistan from Mar to May 2020. Methodology: Patients diagnosed with COVID-19 on polymerase chain reaction having previously rheumatological conditions managed either with bDMARD or cs DMARD were included in the study. They were followed up for three weeks after the positive polymerase chain reaction. Complications leading to the use of oxygen or ICU support or death were compared in both groups of patients. Results: A total of 82 patients with any rheumatological condition managed either with bDMARD or csDMARD tested positive for covid-19 on polymerase chain reaction and were included in the final analysis. 30 (36.6%) patients were taking bDMARDs while 52 (63.4%) were taking csDMARD. In addition, 4 (4.8%) low dose oxygen therapy, 5 (6.1%) required moderate dose oxygen therapy, while 5 (6.1%) required severe dose oxygen therapy or intensive care unit support. 2 (2.4%) patients died within the three weeks. The requirement of moderate or severe dose oxygen and intensive care unit support was found statistically significantly more in the group taking csDMARDS. Conclusion: The presence of complications of COVID-19 and the requirement of oxygen and intensive care unit support were present in some of the patients taking DMARDs. Among the DMARDs, bDMARDs were less linked with complications, but large studies with better design required better results. © 2022, Army Medical College. All rights reserved.

Experiences during the COVID-19 Pandemic among People with Inflammatory Arthritis: "Reopening of Society Is Harder than Lock-Down"-A Qualitative Interview Study.

People with inflammatory arthritis (IA) treated with immunosuppressive disease-modifying anti-rheumatic drugs (DMARDs) were initially considered to have an increased risk of severe illness from the SARS-CoV-2 virus compared to the general population. The aim of this study was to explore how people with IA experienced restrictions during the pandemic and the possible impact of vaccination on their protection against COVID-19 and their everyday lives. Nineteen people with IA were interviewed in May-August 2021; shortly thereafter they were enrolled in the Danish national COVID-19 vaccination programme. Concurrently, society gradually reopened after a national complete lockdown. The analysis was inspired by inductive qualitative content analysis. Participants expressed a lack of targeted information on the specific risk associated with IA if they contracted COVID-19. They had to define their own level of daily-life restrictions to protect themselves and their families. They were impacted by inconsistent announcements by the authorities, and some expressed concerns regarding the potential influence of DMARDs on vaccine effectiveness. A societal spirit of being "in this together" emerged through the lockdown, and some were concerned that the reduced level of restrictions in the reopened society would put them at higher risk of a COVID-19 infection and force them to continue self-isolating.