Janus Kinase Inhibitors in Rheumatoid Arthritis Patients: Real-World Experience from a Regional Centre in Uk

Background/Aims Tofacitinib and baricitinib were the first orally available, targeted synthetic Janus kinase (JAK) inhibitors approved for the treatment of rheumatoid arthritis (RA) in the UK. Evidence suggests that JAK inhibitors are as efficacious as biological DMARDs in the treatment of RA. Their safety profile has been demonstrated in long term extension studies and RCTs. However, real-world, long-term data remains as important in bridging the gap between controlled studies and routine practice. We report our initial real-world experience of a cohort of RA patients commenced on JAKi before the SARS-CoV-2 pandemic within a regional centre in the UK. Methods All patients commenced on JAKi for the treatment of RA between February 2018 and March 2020 were identified from our in-house database. Data was retrospectively collected from clinical notes and electronic health records from February 2018 up until April 2022. This included patient demographics, disease duration, serological status, concurrent csDMARD usage, history of bDMARD exposure, duration of use and reason for discontinuation of the drug if appropriate. DAS- 28 scores were recorded at baseline and quarterly. SPSS (version 22.0) was used for data analysis. Results One hundred thirty patients were treated with JAK inhibitors (Tofacitinib 22%, Baricitinib 78%);80% female, mean (S.D.) age 61.5 (12.3) years. 92 (70.8%) patients were seropositive. 70 (53.8%) patients were on concurrent csDMARDs and 23 (17.7%) on concurrent steroids. The mean number of previous bDMARDs was 1.8 +/- 1.7;41 (31.5%) were bDMARD naive. The mean baseline DAS-28 ESR (S.D.) score was 5.96 (0.96). There were significant differences in mean DAS- 28 ESR scores (compared with baseline) of 1.54, 1.96, 2.41, 2.33 and 1.80 at 3, 6, 12, 18 and 24 months respectively (p<0.0001). Mean DAS-28 ESR scores were not statistically significant between bDMARD naive patients and those that had previously received bDMARDs. Overall JAKi retention rate was 66.9% with a mean follow up duration of 27.4+/-13.1 months. Persistence was 88.5%, 76.9%, 73.2% and 68.5% at 6, 12, 18, and 24 months, respectively. Of the 38 patients who stopped JAK inhibitors, 11 stopped due to inefficacy (6, primary inefficacy). 3 patients were lost to follow-up and 6 deceased. Cause of death was sepsis (2), venous thromboembolism (1) and unknown (3). 18 patients stopped because of adverse events (AEs). The most common AEs were recurrent infections (11), gastrointestinal side effects (9), lymphopenia (7), thromboembolic events (6) and herpes zoster (5). In total 6 (4.1%) patients had thromboembolic events which included pulmonary embolism (4) and deep vein thrombosis (1) and central retinal artery thrombosis (1). Conclusion JAK inhibitors in this real-world population of RA patients were effective in reducing disease activity and patients had high persistence rates. Recurrent infections, herpes zoster and thrombo-embolism remain adverse events of concern.

A Systematic Review of New Rheumatic Immune-Mediated Inflammatory Diseases (R-Imid) Following Sars-Cov-2 Vaccinations

Background/Aims There are sporadic reports about the development of new rheumatic immune-mediated inflammatory diseases (R-IMIDs) in adults after receiving SARS-CoV-2 vaccines. This systematic review (SR) aimed to critically review and summarize the clinical profile, patient demographics, treatment, and prognosis of new-onset R-IMIDs following SARS-CoV-2 vaccination. Methods We retrieved English-language articles (Case reports and series and observational studies) on new-onset R-IMIDs following SARS-CoV-2 vaccination, published until June 2022, from standard databases (MEDLINE, Embase, Cochrane). The search strings used during the literature search incorporated 'SARS-CoV-2 vaccination' (along with related MeSH terms) and various key terms for R-IMIDs [which included (but was not limited to) inflammatory arthritis, connective tissue disease (CTD), vasculitis, systemic lupus erythematosus, Sjogren's syndrome, sarcoidosis, systemic sclerosis, idiopathic inflammatory myositis, anti-synthetase syndrome, Adult-onset Stills disease (AOSD), giant cell arteritis (GCA), and polymyalgia rheumatica (PMR)]. The protocol was registered in PROSPERO (CRD42022318561). Results Of the total 2179 articles retrieved, 1986 articles were excluded following the title- screening, and 107 articles that did not meet inclusion criteria. We included the remaining 86 articles (130 cases) upon full-text screening. Furthermore, we added four articles (six cases) based on a manual search, comprising 90 articles (136 cases) for final analysis. These 136 new R-IMID cases were reported from 27 different countries. Of these, more than one-third of the cases were reported from three countries (viz., Italy, Japan, and the USA). The patients had a mean age of 57 (range:17-90) years, and the majority were females (63.0%). Most patients developed R-IMIDs after receiving Pfizer-BioNTech vaccine (76;55%), followed by Oxford AstraZeneca vaccine (35;25%). The mean duration between SARSCoV- 2 vaccination and R-IMIDs development was 9.2 (range:1-90) days. The second dose of the vaccine resulted in more R-IMIDs (74;54%) than the first (53;39%). CTDs (34;25%) and small vessel vasculitis (33;24%) were the commonest R-IMID manifestations, followed by inflammatory arthritis and AOSD, each in 13 (9.5%) cases. Nearly half of the patients with CTDs had Idiopathic Inflammatory Myositis. PMR and GCA accounted for 16 (11.7%) and 5 (3.6%) cases, respectively. However, no cases of axial spondylarthritis were reported. Most (118;86%) R-IMID patients were treated with corticosteroids, with a small number receiving steroid-sparing drugs, such as methotrexate, rituximab and cyclophosphamide. Most (125;91%) went into either disease remission or improvement following the treatment. Only three patients were admitted to the intensive care unit (ICU) to manage their disease;One of them died due to fatal myositis and rhabdomyolysis;two surviving ICU patients had ANCA-associated vasculitis with lung involvement. Conclusion Although rare, this SR highlights the emergence of de novo R-IMIDs following SARS-CoV-2 vaccination. We cannot confirm the causality between the vaccination and the onset of R-IMID. However, further research is warranted in this area.

Patient perspectives and narratives

An understanding of telerheumatology is incomplete without considering the perspective of people who are living with rheumatic conditions and their experience using telehealth for the management of their disease. Notably, all but one of the authors of this chapter are patients themselves, individuals diagnosed in childhood or adulthood and living daily with inflammatory arthritis. This chapter first defines what is meant by the term "patient perspective" as it concerns access to, expectations of, and use of telerheumatology. The advantages and disadvantages of telerheumatology from patients' point of view are described, including previous research reporting collective patient satisfaction with telerheumatology. An overview of patient preparation needed for telerheumatology is also offered along with resources that rheumatologists may refer to when helping their patients plan for telemedicine visits. The chapter concludes with patient narratives of telerheumatology encounters during the COVID-19 pandemic. © The Author(s), under exclusive license to Springer Nature Switzerland AG 2022. All rights reserved.

CHANGES in PATIENT-REPORTED OUTCOME SCORES during COVID-19 PANDEMIC: DATA from the ARTHRITISPOWER REGISTRY

Background: The COVID-19 pandemic causes concern among patients with autoimmune and rheumatic disease (ARD) due to increased risk of infection and heightened isolation from social distancing.1 Objectives: Examine how mean patient-reported outcome (PRO) scores for mental, social and physical health fuctuated after COVID-19 vaccine availability was widespread in US. Methods: We conducted and reported on2 an initial analysis of January 2020-April 2021 where US participants (pts) of the ArthritisPower (AP) registry completed PROMIS measures of physical health (Physical Function, Pain Interference, Fatigue, Sleep Disturbance), mental health (Anger, Anxiety, Depression) and social health (Social Isolation, Emotional Support). Follow-up analysis was conducted May-December 2021. Only pts from initial analysis were included in follow-up. Null hypothesis was no change in monthly average scores across 23-month pandemic period. Analysis of means compared monthly assessment mean scores to overall mean score for each measure during study period. Pts with < 2 assessment time points and osteoarthritis with no ARD were excluded from analysis. Results: Total of 49,940 PRO scores were contributed by 2,266 pts during 23-month period, with 8,393 of the scores contributed from May-December 2021. Mean (standard deviation, SD) number of observations per pt was 5.6 (12.5). Pts were 87.6% female, 86.7% white, mean age of 52.1 (12.7) years. Rheumatoid arthritis (n=1,131, 49.9%) was the most common condition. Most commonly reported measures were Pain Interference, Fatigue, Sleep Disturbance and Physical Function, each with >11,000 total results (Table 1). Pts' mental and social health assessment scores improved then worsened during last 8 months of 2021 (Figure 1). Overall mean scores were: Anxiety 62.4 (12.5), Social Isolation 61.9 (10.5), and Anger 61.5 (12.8). From July-August, Social Isolation decreased by 1 SD. Compared to overall assessment mean, Anger declined by > / SD (53.3 [19.4]) in August and Anxiety declined by / SD (57.7 [11.3]) in September. By December, Anger rose by > / SD (68.6 [5.0]) of assessment mean. Pain Interference (mean: 63.3 [7.8]), Fatigue (62.6 [9.5]), and Sleep Disturbance (58.1 [9.0]) scores were signifcantly lower in May, June, July and August compared to the assessment mean, though none decreased by > / SD. Conclusion: ARD members of AP had mental, social and physical health scores improve during summer of 2021, corresponding with widespread availability of vaccines. However mental and social health scores worsened by December as US faced new variants of the virus.

Postulation of Siddha tri-humoral vitiation in pathogenesis of novel Corona virus disease

Background: On March 12, 2020, WHO declared Novel Coronavirus disease as a pandemic outbreak all over the world. The outbreak had led the medical sector to a new platform, in the implementation of ancient knowledge of the Siddha medicine in treatment, management, and prevention of this prevailing pandemic. According to Siddha science, any vitiation in the life force is the main cause of diseases in human beings. pandemic diseases caused due to infectious microorganisms are called 'Kona' Noigal' in various Siddha literatures. Aim and objective: To classify the Novel Coronavirus disease based on the Siddha Humoural principles and to elicit the changes of Ninety-six Thatthuvam (Ninety - six basic principles), Uyir Thathukkal and Udal Thathukkal. Materials and methods: This study is accomplished mainly for literature research. Various Siddha texts such as Sattamuni gnanam, Agathiyar Gunavagadam, Agathiyar vallathi Naadi, Theraiyar Sekarappa, etc. were referred. Numerous research articles on COVID 19 were critically reviewed from Scopus, PubMed, Google Scholar, etc. Discussion: By critically reviewing the signs and symptoms of COVID-19 with Siddha science, the authors had thrown light especially on the involvement of all basic components of the Tri thodam particularly Mukkutram verupadu (Tri humoral vitiation) in eliciting the pathogenesis of the disease. Conclusion: In this scientific review, the authors have attempted to comprehend the pathogenesis of Novel coronavirus disease in the context of Siddha's basic principles.

A pragmatic proposal for triaging DXA testing during the COVID-19 global pandemic

The COVID-19 pandemic has resulted in huge disruption to healthcare provision, including to dual-energy X-ray absorptiometry (DXA) imaging. Increased waiting lists for DXA from the pandemic mean potential long and uncertain delays in treatment for osteoporosis. To address these increased waiting lists, we propose a rapid, simple, one-stop algorithm incorporating medication use (aromatase inhibitor, corticosteroid) and clinical risk stratification supplementing a standard FRAX assessment. Our pragmatic algorithm produces a recommendation to treat empirically, image with DXA, or observe. If applied, we model a significant reduction in DXA scan requirements with a corresponding reduction in treatment delays for those awaiting DXA. We estimate this will reduce DXA scan numbers by about 50%, whilst pragmatically ensuring those with the highest clinical need correctly receive treatment without delay. This algorithm will help many clinicians including general practitioners/family physicians prioritise DXA when they may not always have the expertise to make this judgement based on clinical information alone. Although we have used UK guidelines as an example, this approach is flexible enough for adaptation by other countries based on their local guidelines, licensing, prescribing requirements, and DXA waiting list times. There are some limitations to our proposal. However, it represents one way of managing the uncertainty of the current COVID-19 pandemic.

Vaccine Efficacy after Rituximab Exposure: First Interim Analysis of Virtue Project on Behalf of West Midlands Research Consortium, UK

[Formula presented] Background: Anti-CD20 B cell depleting agents are amongst the most commonly used immunotherapeutics employed in the treatment of haematological malignancy and autoimmune diseases. By inducing peripheral B cell aplasia, anti-CD20 depleting agents are hypothesised to significantly impair serological responses to neoantigens, including the SARS-CoV-2 spike glycoprotein within SARS-CoV-2 vaccines. Seropositivity following SARS-CoV-2 is the strongest, measurable correlate of protection from severe COVID-19. Understanding the kinetics of B cell reconstitution and vaccine responsiveness following exposure to B cell depleting agents is essential to maximise vaccine efficacy in patients vulnerable to severe COVID-19. Methods: 80 patients with underlying haematological malignancy and 38 patients with underlying rheumatological disease previously treated with anti-CD20 B cell depleting agents were studied following their second dose of a SARS-CoV-2 vaccine (median time to sampling: 46.5d, IQR: 33.8-63.3). Lymphocyte subset (CD4, CD8, CD19, CD56/16) enumeration was performed using 6 colour flow cytometry (BD Trucount). Total anti-SARS-CoV-2 spike glycoprotein antibodies were measured by enzyme-linked immunosorbent assay (The Binding Site, Human Anti-IgG/A/M SARS-CoV-2-ELISA). The relationship between immune reconstitution following B cell depletion and vaccine responsiveness was explored. Results: In the haematology cohort (median age 70y, IQR 60.3-76.0, 62.5% male), overall seropositivity following vaccination was 60.0%. Individuals on active chemotherapy had significantly lower seroprevalence than those vaccinated following the completion of chemotherapy (22.7% vs 74.1%, p<0.0001). In the rheumatology cohort (median age 65y, IQR 58.3-70.8, 39.9% male), overall seropositivity was 69.4%. In both cohorts, vaccine non-responders had significantly smaller populations of peripheral CD19+ B cells (haematology: 0.20 vs 0.02 x10 9/L, p=0.004, rheumatology: 0.07 vs 0.01 x10 9/L, p=0.03). The magnitude of the antibody response following vaccination did not differ between recipients of Tozinameran and Vaxzeveria in either cohort. Vaccine responsiveness was lower in the first 6 months following B cell depletion therapy;42.9% in the haematology cohort and 33.3% in the rheumatology cohort, increasing to 100% and 75% respectively in individuals receiving their second dose 6-12 months following B cell depletion (Figure 1). B cell reconstitution in the 7-12 month window following B cell depletion was faster in haematology compared to rheumatology patients (77.8% v 22.2% achieving normal B cell count, p=0.005) and associated with improved vaccine responsiveness. However, persistent immunodeficiency occurred in some haematology patients following completion of treatment: 25% of patients who had completed therapy at least 36 months previously failed to respond to vaccination. In this cohort of vaccine non-responders, 83.3% of individuals had B cell numbers within the normal range. These patients had all previously been treated for follicular lymphoma suggesting a specific mechanism for long-range secondary immunodeficiency in these patients. Conclusions: Serological responsiveness to SARS-CoV-2 vaccines is poor during active chemotherapy for haematological malignancy and in the first 6 months following B cell depletion, regardless of underlying disease. Vaccine responsiveness significantly improves in the 7-12 month window following B cell depletion. Compared to haematology patients, B cell reconstitution is slower in rheumatology patients and associated with reduced vaccine responsiveness, possibly due to the use of additional concurrent disease-modifying anti-rheumatic therapies. Furthermore, long-term secondary immunodeficiency occurs in a minority of haematology patients. To maximise the efficacy from SARS-CoV-2 booster vaccination and optimal utilisation of available vaccine doses, immunisations should be delivered at least 6 months following the administration of anti-CD20 depleting drugs. Figure 1: Kinetics of return f vaccine responsiveness following B cell depletion in haematology and rheumatology patients. [Formula presented] Disclosures: Paneesha: Roche: Honoraria;Janssen: Honoraria;Gilead: Honoraria;Bristol Myers Squibb: Honoraria;AbbVie: Honoraria;Celgene: Honoraria. Drayson: Abingdon Health: Current holder of individual stocks in a privately-held company.

COVID-19-associated ulcerative colitis flare: A bad breakout

Introduction: COVID-19 can trigger autoimmune responses via molecular mimicry. Retrospective studies of COVID-19 patients have showed up to 50% prevalence of autoimmune disease related autoantibodies. We report a patient with a history of ulcerative colitis (UC) who presented with a UC flare and COVID-19 infection was later found during evaluation as a possible trigger. Case description/methods: A 31-year-old Black female presented to the hospital with abdominal pain and bloody diarrhea for 10 days. Patient also endorsed a cough productive of thick yellow sputum. Past history-ulcerative colitis on mesalamine. Physical exam-temperature-98.7F, blood pressure-138/92 mmHg, pulse-120/min, respiratory rate-18/min, O2 saturation-100%/room air, wheezing present in b/l lung fields, abdomen-nondistended, hypoactive bowel sounds, soft, tender to palpation in the left lower quadrant, no guarding/rebound or masses. Laboratory-hemoglobin 12.8 g/ dL, C-reactive protein-77.8 mg/L (Ref: <10), positive stool guaiac, SARS-CoV-2-positive, fecal calprotectin >3000 ug/g (Ref: <549). CT of the abdomen/pelvis showed inflammatory/infectious thickening of the transverse colon likely reflecting a nonspecific colitis and a patchy area of pneumonic infiltrate in the posterior medial lung base. Intravenous fluids, Metronidazole 500 mg IV TID, Ciprofloxacin 400 mg IV Q12H and Solumedrol 60 mg IV Daily were started. Sigmoidoscopy with biopsy-moderate to severe colitis extending from the descending colon to the rectum without any dysplasia or granulomas. With IV steroids the patient reported improvement in her diarrhea and was able to tolerate her meals. Solumedrol was changed to prednisone 40 mg daily for 2 weeks and the patient was discharged with outpatient close gastroenterology follow up. Discussion: Viral infections including COVID-19 are known to trigger autoimmunity through molecular mimicry, activating immune responses to antigenic epitopes distinct from the disease causing epitopes (epitope spreading), activating T cells in an antigen independent manner (bystander activation) or exposing cryptic epitope's (epitope which is otherwise hidden). In turn, immunosuppressive therapies used to treat autoimmune disorders may increase the risk of COVID-19. Though it is now known that COVID-19 can trigger autoimmunity further studies are required to understand the exact immunopathogenesis. Such studies may provide more insights to prevent and treat diseases of the immune system. (Figure Presented).

Successful patient education on COVID-19 vaccine safety in a large rheumatology cohort using interactive mobile-phone video technology: context, results, and next steps

Background: There are reported concerns of patient misunderstanding of the COVID-19 pandemic and vaccination safety. It is particularly important that these are understood in patients taking complex immunusuppressive therapies. Rapid delivery of targeted and up-to-date video messages from clinicians sent directly to patients could address patient uncertainty, and improve COVID-19 vaccination uptake. Innovative SMS (short message service) based video message has already shown promise in delivering COVID-19 information to patients [1]. We present our experience in creating a tailored vaccine information video sent directly to our large cohort of patients in the UK with a range of rheumatic diseases and report on the learning points going forward. Objectives: Our three objectives were: (1) educate our patients using an interactive mobile video information resource outlining the safety of the COVID vaccination in these patient groups;(2) better understand our patients' views of the COVID-19 vaccine;(3) evaluate the patient experience of this approach. Methods: We designed and recorded an 8-minute interactive web-based video delivered education resource designed for mobile phones. This included: aims of the video;details of licenced vaccines;UK vaccination schedule;frequently asked questions;links to national charity resources;our clinician recommendations;a rheumatologist being vaccinated;case studies;and summary data. We produced a simple mobile phone web-based evaluation of the resource, including anonymised patient demographics, their understanding of the safety of the vaccine pre/ post video, and their user experience. Resource and evaluation were piloted by local healthcare professionals, our Patient Participation Group, a national charity, and approved by senior management. We distributed this to our follow-up patient cohort via our hospital SMS provider on 21.12.20, at the start of roll-out of UK vaccines, containing a link to the resource and evaluation. Results: Of a cohort of 10,981 patients, we had 8886 mobile phone numbers. At Day 14, we recorded 2358 video views (26.3%) and 664/2358 completed evaluations (28.1%). Only one person reported being unable to watch the video. Before watching the video, 348/664 patients (52.4%) were unsure if the vaccine was safe and/or recommended for them, rising to 626/664 (94.3%) post-video. Reasons for uncertainty after the video (38/664) included drug allergy and fertility concerns. Following the video, 509/664 patients (76.6%) reported that they were more likely to have the vaccination. The majority of the patients (614/660, 93.0%) agreed that the method was a helpful method to share such information.Age distribution of our whole cohort, patients with mobile phones, and responders were similar: Age >50 was 80.4%,76.3%,and 88.6% respectively. A large proportion was treated with immunosuppressive medication (61.3% conventional DMARD, 39.4% biological DMARD and 17.6% corticosteroids). Gender and case mix for responders were similar to published data from our cohort: female 74.0%;rheumatoid arthritis commonest disease (389/664, 58.5%). Conclusion: To our knowledge, this is the first study to show the potential for SMS linked interactive multimedia message for patient education. The multimedia component allows users to easily navigate to relevant sections, and access a choice of linked resources. We demonstrate this low-cost technology is simple, effective and well placed to assist physicians in educating patients during a time when face-to-face contact is proving to be difficult. We have shown high levels of patient satisfaction, reassurance, and self-reported behaviour change. Such technology has potential utility for national bodies, primary and secondary care groups, and merits further research.

The impact of COVID-19 on rheumatology patients in a large UK centre using an innovative data collection technique: prevalence and effect of social shielding.

OBJECTIVES: We sought to gain insight into the prevalence of COVID-19 and the impact stringent social distancing (shielding) has had on a large cohort of rheumatology (RD) follow-up patients from a single large UK centre. METHODS: We linked COVID-19-related deaths, screening and infection rates to our RD population (1.2.20-1.5.20) and audited active rheumatology follow-up patients through survey data communicated via a linked mobile phone SMS message. We assessed epidemiology, effect of stringent social distancing (shielding) and quality of life (HRQoL) by Short Form 12 (SF12). RESULTS: There were 10,387 active follow-up patients, 7911 had linked mobile numbers. 12/10,387 RD patients died from COVID-19 (0.12%); local population 4131/7,415,149 (0.12%). For patients with mobile phones, 1693/7911 (21%) responded and of these, 1605 completed the SF12. Inflammatory arthritis predominated 1174/1693 (69%); 792/1693 (47%) were shielding. Advice on shielding/distancing was followed by 1372/1693(81%). 61/1693 (4%) reported COVID-19 (24/61 shielding); medication distribution was similar in COVID and non-COVID patients. Mental SF12 (MCS) but not physical (PCS) component scores were lower in COVID (60) vs. non-COVID (1545), mean differences: MCS, - 3.3; 95% CI - 5.2 to - 1.4, P < 0.001; PCS, - 0.4; 95% CI, - 2.1 to 1.3). In 1545 COVID-negative patients, those shielding had lower MCS (- 2.1; 95% CI - 2.8 to - 1.4) and PCS (- 3.1, 95% CI - 3.7 to - 2.5), both P < 0.001. CONCLUSIONS: Our full RD cohort had no excess of COVID deaths compared to the general local population. Our survey data suggest that shielding adversely affects both mental and physical health in RD. These data broaden our understanding of shielding, indicating need for further study.

A pragmatic proposal for triaging DXA testing during the COVID-19 global pandemic.

The COVID-19 pandemic has resulted in huge disruption to healthcare provision, including to dual-energy X-ray absorptiometry (DXA) imaging. Increased waiting lists for DXA from the pandemic mean potential long and uncertain delays in treatment for osteoporosis. To address these increased waiting lists, we propose a rapid, simple, one-stop algorithm incorporating medication use (aromatase inhibitor, corticosteroid) and clinical risk stratification supplementing a standard FRAX assessment. Our pragmatic algorithm produces a recommendation to treat empirically, image with DXA, or observe. If applied, we model a significant reduction in DXA scan requirements with a corresponding reduction in treatment delays for those awaiting DXA. We estimate this will reduce DXA scan numbers by about 50%, whilst pragmatically ensuring those with the highest clinical need correctly receive treatment without delay. This algorithm will help many clinicians including general practitioners/family physicians prioritise DXA when they may not always have the expertise to make this judgement based on clinical information alone. Although we have used UK guidelines as an example, this approach is flexible enough for adaptation by other countries based on their local guidelines, licensing, prescribing requirements, and DXA waiting list times. There are some limitations to our proposal. However, it represents one way of managing the uncertainty of the current COVID-19 pandemic.