Search

Objectives To evaluate the safety of treatment strategies in patients with early RA. Methods Systematic searches of MEDLINE, EMBASE and PubMed were conducted up to September 2020. Double-blind randomized controlled trials (RCTs) of licensed treatments conducted on completely naïve or MTX-naïve RA patients were included. Long-term extension studies, post-hoc and pooled analyses and RCTs with no comparator arm were excluded. Serious adverse events, serious infections and non-serious adverse events were extracted from all RCTs, and event rates in intervention and comparator arms were compared using meta-analysis and network meta-analysis (NMA). Results From an initial search of 3423 studies, 20 were included, involving 9202 patients. From the meta-analysis, the pooled incidence rates per 1000 patient-years for serious adverse events were 69.8 (95% CI: 64.9, 74.8), serious infections 18.9 (95% CI: 16.2, 21.6) and non-serious adverse events 1048.2 (95% CI: 1027.5, 1068.9). NMA showed that serious adverse event rates were higher with biologic monotherapy than with MTX monotherapy, rate ratio 1.39 (95% CI: 1.12, 1.73). Biologic monotherapy rates were higher than those for MTX and steroid therapy, rate ratio 3.22 (95% CI: 1.47, 7.07). Biologic monotherapy had a higher adverse event rate than biologic combination therapy, rate ratio 1.26 (95% CI: 1.02, 1.54). NMA showed no significant difference between strategies with respect to serious infections and non-serious adverse events rates. Conclusion The study revealed the different risk profiles for various early RA treatment strategies. Observed differences were overall small, and in contrast to the findings of established RA studies, steroid-based regimens did not emerge as more harmful.

INTRODUCTION Janus Kinase inhibitors (JAKi) have shown to be highly effective in the treatment of immune-mediated inflammatory diseases, and several drugs in this class have been approved in recent years. As with all immunomodulatory therapies, careful assessment of any treatment-associated infection risk is essential to inform clinical decision-making. AREAS COVERED We summarise the current literature on infection rates among the licensed JAKi using published phase II/III trial results as well as post-licensing and registry data. EXPERT OPINION Data currently available for the licensed JAKi show an increased risk of infection across the class compared to placebo, most commonly affecting the respiratory and urinary tracts, nasopharynx and skin. This risk is dose-dependent, but similar at the licensed JAKi doses to that seen with biologic therapies. The risk is compounded by other risk factors for infection such as age and steroid co-prescription. Herpes zoster reactivation is more common with JAKi compared to other targeted immune modulation, making screening for varicella exposure and judicious vaccination in appropriate cohorts an advisable strategy. Crucially, these small risk increases must be balanced against the known harms (including infection) of uncontrolled autoimmune disease. JAKi are a safe and potentially transformative treatment when used for appropriately selected patients.

Background: COVID-19 vaccines have robust immunogenicity in the general population. However, data for individuals with immune-mediated inflammatory diseases who are taking immunosuppressants remains scarce. Our previously published cohort study showed that methotrexate, but not targeted biologics, impaired functional humoral immunity to a single dose of COVID-19 vaccine BNT162b2 (Pfizer-BioNTech), whereas cellular responses were similar. Here, we aimed to assess immune responses following the second dose.Methods: In this longitudinal cohort study, we recruited individuals with psoriasis who were receiving methotrexate or targeted biological monotherapy (ie, tumour necrosis factor [TNF] inhibitors, interleukin [IL]-17 inhibitors, or IL-23 inhibitors) from a specialist psoriasis centre serving London and South-East England. The healthy control cohort were volunteers without psoriasis, not receiving immunosuppression. Immunogenicity was evaluated immediately before, on day 28 after the first BNT162b2 vaccination and on day 14 after the second dose (administered according to an extended interval regimen). Here, we report immune responses following the second dose. The primary outcomes were humoral immunity to the SARS-CoV-2 spike glycoprotein, defined as titres of total spike-specific IgG and of neutralising antibody to wild-type, alpha (B.1.1.7), and delta (B.1.617.2) SARS-CoV-2 variants, and cellular immunity defined as spike-specific T-cell responses (including numbers of cells producing interferon-γ, IL-2, IL-21).Findings: Between Jan 14 and April 4, 2021, 121 individuals were recruited, and data were available for 82 participants after the second vaccination. The study population included patients with psoriasis receiving methotrexate (n=14), TNF inhibitors (n=19), IL-17 inhibitors (n=14), IL-23 inhibitors (n=20), and 15 healthy controls, who had received both vaccine doses. The median age of the study population was 44 years (IQR 33-52), with 43 (52%) males and 71 (87%) participants of White ethnicity. All participants had detectable spike-specific antibodies following the second dose, and all groups (methotrexate, targeted biologics, and healthy controls) demonstrated similar neutralising antibody titres against wild-type, alpha, and delta variants. By contrast, a lower proportion of participants on methotrexate (eight [62%] of 13, 95% CI 32-86) and targeted biologics (37 [74%] of 50, 60-85; p=0·38) had detectable T-cell responses following the second vaccine dose, compared with controls (14 [100%] of 14, 77-100; p=0·022). There was no difference in the magnitude of T-cell responses between patients receiving methotrexate (median cytokine-secreting cells per 106 cells 160 [IQR 10-625]), targeted biologics (169 [25-503], p=0·56), and controls (185 [133-328], p=0·41).Interpretation: Functional humoral immunity (ie, neutralising antibody responses) at 14 days following a second dose of BNT162b2 was not impaired by methotrexate or targeted biologics. A proportion of patients on immunosuppression did not have detectable T-cell responses following the second dose. The longevity of vaccine-elicited antibody responses is unknown in this population.Funding: NIHR Biomedical Research Centre at Guy's and St Thomas' NHS Foundation Trust and King's College London; The Psoriasis Association.

Objective: To describe the frequency and predictors of nonserious infections (NSI) and compare incidence across biologic agents within the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis (BSRBR-RA).Methods: The BSRBR-RA is a prospective observational cohort study. An NSI was defined as an infection that did not require hospitalization or intravenous therapy. Infections were captured from clinician questionnaires and patient diaries. Individuals were considered “at risk” from the date of initiation of biologic treatment for up to 3 years. Drug exposure was defined by agent: tumor necrosis factor inhibitor (TNFi), interleukin-6 (IL-6) inhibitor, B cell depletion (rituximab), or conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) alone. A multiple-failure Cox model was used with multivariable adjustment. Missing data were addressed using multiple imputation.Results: There were 17,304 NSI in 8,145 patients, with an event rate of 27.0 per person per year (95% confidence interval [95% CI] 26.6–27.4). Increasing age, female sex, comorbidity burden, glucocorticoid therapy, higher Disease Activity Score in 28 joints, and higher Health Assessment Questionnaire disability index were associated with an increased risk of NSI. There was a significant reduction in NSI risk with csDMARDs compared to biologic treatments. Compared to TNFi, IL-6 inhibition and rituximab were associated with a higher NSI risk (adjusted hazard ratio 1.45 [95% CI 1.29–1.63] and adjusted hazard ratio 1.28 [95% CI 1.14–1.45], respectively), while the csDMARD cohort had a lower risk (adjusted hazard ratio 0.64 [95% CI 0.59–0.70]). Within the TNFi class, adalimumab was associated with a higher NSI risk than etanercept (adjusted hazard ratio 1.11 [95% CI 1.05–1.17]).Conclusion: NSI occur frequently in RA, and predictors mirror those reported with serious infections. All biologics are associated with a greater risk of NSI, with differences observed between agents. While unmeasured confounding must be considered, the magnitude of effect is large, and a relationship between NSI and targeted immunomodulatory therapy likely exists.

BackgroundIt is unclear if people with immune-mediated inflammatory diseases (IMIDs) (joint, bowel and skin) and on immune modifying therapy have increased risk of serious COVID-19 outcomes.MethodsWith the approval of NHS England we conducted a cohort study, using OpenSAFELY, analysingroutinely-collected primary care data linked to hospital admission, death and previously unavailable hospital prescription data. We used Cox regression (adjusting for confounders) to estimate hazard ratios (HR) comparing risk of COVID-19-death, death/critical care admission, and hospitalisation (March to September 2020) in: 1) people with IMIDs compared to the general population; and 2) people with IMIDs on targeted immune modifying drugs (e.g., biologics) compared to standard systemic treatment (e.g., methotrexate).FindingsWe identified 17,672,065 adults; of 1,163,438 (7%) with IMIDs, 19,119 people received targeted immune modifying drugs, and 200,813 received standard systemics. We saw evidence of increased COVID-19-death (HR 1.23, 95%CI 1.20, 1.27), and COVID-19 hospitalisation (HR 1.32, 95%CI 1.29, 1.35) in individuals with IMIDs overall compared to individuals without IMIDs of the same age, sex, deprivation and smoking status. We saw no evidence of increased COVID-19 deaths with targeted compared to standard systemic treatments (HR 1.03, 95%CI 0.80, 1.33). There was no evidence of increased COVID-19-related death in those prescribed TNF inhibitors, IL-12/23, IL7, IL-6 or JAK inhibitors compared to standard systemics. Rituximab was associated with increased COVID-19 death (HR 1.68, 95%CI 1.11, 2.56); however, this finding may relate to confounding.InterpretationCOVID-19 death and hospitalisation was higher in people with IMIDs. We saw no increased risk of adverse COVID-19 outcomes in those on most targeted immune modifying drugs for IMIDs compared to standard systemics.RESEARCH IN CONTEXTEvidence before this studyWe searched PubMed on May 19th, 2021, using the terms “COVID-19”, “SARS-CoV-2” and “rheumatoid arthritis”, “psoriatic arthritis” “ankylosing spondylitis”, “Crohn’s disease” “ulcerative colitis” “hidradenitis suppurativa” and “psoriasis”, to identify primary research articles examining severe COVID-19 outcome risk in individuals with immune-mediated inflammatory diseases (IMIDs) and those on immune modifying therapy. The studies identified (including matched cohort studies and studies in disease-specific registries) were limited by small sample sizes and number of outcomes. Most studies did not show a signal of increased adverse COVID-19 outcomes in those on targeted therapies, with the exception of rituximab. Additionally, disease-specific registries are subject to selection bias and lack denominator populations.Added value of the studyIn our large population-based study of 17 million individuals, including 1 million people with IMIDs and just under 200,000 receiving immune modifying medications, we saw evidence that people with IMIDs had an increased risk of COVID-19-related death compared to the general population after adjusting for potential confounders (age, sex, deprivation, smoking status) (HR 1.23, 95%CI 1.20, 1.27). We saw differences by IMID type, with COVID-19-related death being increased by the most in people with inflammatory joint disease (HR 1.47, 95%CI 1.40, 1.54). We also saw some evidence that those with IMIDs were more likely, compared to the general population, to have COVID-19-related critical care admission/death (HR 1.24, 95%CI 1.21, 1.28) and hospitalisation (HR 1.32, 95%CI 1.29, 1.35).Compared to people with IMIDs taking standard systemics, we saw no evidence of differences in severe COVID-19-related outcomes with TNF inhibitors, IL-17 inhibitors, IL-12/23 inhibitors, IL-6 inhibitors and JAK inhibitors. However, there was some evidence that rituximab was associated with an increased risk of COVID-19-related death (HR 1.68, 95%CI 1.11, 2.56) and death/critical care admission (HR 1.92, 95%CI 1.31, 2.81). We also saw evidence of an increase in COVID-19-related hospital admissions in people prescribed rituximab (HR 1.59, 95%CI 1.16, 2.18) or JAK inhibition (HR 1.81, 95%CI 1.09, 3.01) compared to those on standard systemics, although this could be related to worse underlying health rather than the drugs themselves, and numbers of events were small.This is the first study to our knowledge to use high-cost drug data on medicines supplied by hospitals at a national scale in England (to identify targeted therapies). The availability of these data fills an important gap in the medication record of those with more specialist conditions treated by hospitals creating an important opportunity to generate insights to these conditions and these medicationsImplications of all of the available evidenceOur study offers insights into future risk mitigation strategies and SARS-CoV-2 vaccination priorities for individuals with IMIDs, as it highlights that those with IMIDs and those taking rituximab may be at risk of severe COVID-19 outcomes. Critically, our study does not show a link between most targeted immune modifying medications compared to standard systemics and severe COVID-19 outcomes. However, the increased risk of adverse COVID-19 outcomes that we saw in people with IMIDs and those treated with rituximab merits further study.

Objective To evaluate drug survival with monotherapy compared with combination therapy with MTX in RA older adults. Methods Patients from the British Society for Rheumatology Biologics Register, a prospective observational cohort, who were biologic naïve and commencing their first TNF inhibitors (TNFi) were included. The cohort was stratified according to age: Results The analysis included 15 700 patients. Ninety-five percent were Conclusion TNFi monotherapy is associated with increased treatment failure. In older adults, the disadvantage of TNFi monotherapy on drug survival is no longer seen. Patients ≥75 have fewer discontinuations due to inefficacy than adverse events compared with younger patients. This likely reflects greater disposition to toxicity but perhaps also a decline in immunogenicity associated with immunosenescence.

Objectives To investigate the relationship between occurrence of serious infection (SI) and lymphocyte counts in patients with RA using data from a single centre. Methods We used routinely captured data from a single tertiary rheumatology centre to explore the relationship between lymphopenia and SI risk. Adult RA patients were included over a 5-year follow-up period. Admissions due to confirmed SI were considered. SI rate with 95% confidence intervals was calculated. The association between SI with baseline lymphocyte counts, time-averaged lymphocyte counts throughout all follow-up, and a nadir lymphocyte count was assessed using Cox proportional hazards regression. The relationship between lymphopenia over time and SI was analysed using a mixed-effect model of lymphocyte counts prior to SI. Results This analysis included 1095 patients with 205 SIs during 2016 person-years of follow-up. The SI rate was 4.61/100 patient-years (95% CI: 3.76, 5.65). Compared with patients with nadir lymphocyte counts >1.5 × 109 cells/l, nadir lymphopenia Conclusion Lymphocyte counts below

Objectives Observational cohort studies in early RA are a key source of evidence, despite inconsistencies in methodological approaches. This narrative review assesses the spectrum of methodologies used in addressing centre-level effect and case-mix adjustment in early RA observational cohort studies. Methods An electronic search was undertaken to identify observational prospective cohorts of >100 patients recruited from two or more centres, within 2 years of an RA or early inflammatory arthritis diagnosis. References and author publication lists of all studies from eligible cohorts were assessed for additional cohorts. Results Thirty-four unique cohorts were identified from 204 studies. Seven percent of studies considered centre in their analyses, most commonly as a fixed effect in regression modelling. Reporting of case-mix variables in analyses varied widely. The number of variables considered in case-mix adjustment was higher following publication of the STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) statement in 2007. Conclusion Centre effect is unreported or inadequately accounted for in the majority of RA observational cohorts, potentially leading to spurious inferences and obstructing comparisons between studies. Inadequate case-mix adjustment precludes meaningful comparisons between centres. Appropriate methodology to account for centre and case-mix adjustment should be considered at the outset of analyses.

Objective To evaluate whether polypharmacy is associated with treatment response and serious adverse events (SAEs) in patients with RA using data from the British Society for Rheumatology Biologics Register (BSRBR-RA). Methods The BSRBR-RA is a prospective observational cohort study of biologic therapy starters and a DMARD comparator arm. A logistic regression model was used to calculate the odds of a EULAR ‘good response’ after 12 months of biologic therapy by medication count. Cox proportional hazards models were used to identify risk of SAEs. The utility of the models were compared with the Rheumatic Disease Comorbidity Index using Receiver Operator Characteristic and Harrell’s C statistic. Results The analysis included 22 005 patients, of which 83% were initiated on biologics. Each additional medication reduced the odds of a EULAR good response by 8% [odds ratios 0.92 (95% CI 0.91, 0.93) P < 0.001] and 3% in the adjusted model [adjusted odds ratios 0.97 (95% CI 0.95, 0.98) P < 0.001]. The Receiver Operator Characteristic demonstrated significantly greater areas under the curve with the polypharmacy model than the Rheumatic Disease Comorbidity Index. There were 12 547 SAEs reported in 7286 patients. Each additional medication equated to a 13% increased risk of an SAE [hazard ratio 1.13 (95% CI 1.12, 1.13) P < 0.001] and 6% in the adjusted model [adjusted hazard ratio 1.06 (95% CI 1.05, 1.07) P < 0.001]. Predictive values for SAEs were comparable between the polypharmacy and Rheumatic Disease Comorbidity Index model. Conclusion Polypharmacy is a simple but valuable predictor of clinical outcomes in patients with RA. This study supports medication count as a valid measure for use in epidemiologic analyses.

Summary Background Patients on therapeutic immunosuppressants for immune-mediated inflammatory diseases were excluded from COVID-19 vaccine trials. We therefore aimed to evaluate humoral and cellular immune responses to COVID-19 vaccine BNT162b2 (Pfizer-BioNTech) in patients taking methotrexate and commonly used targeted biological therapies, compared with healthy controls. Given the roll-out of extended interval vaccination programmes to maximise population coverage, we present findings after the first dose. Methods In this cohort study, we recruited consecutive patients with a dermatologist-confirmed diagnosis of psoriasis who were receiving methotrexate or targeted biological monotherapy (tumour necrosis factor [TNF] inhibitors, interleukin [IL]-17 inhibitors, or IL-23 inhibitors) from a specialist psoriasis centre serving London and South East England. Consecutive volunteers without psoriasis and not receiving systemic immunosuppression who presented for vaccination at Guy's and St Thomas' NHS Foundation Trust (London, UK) were included as the healthy control cohort. All participants had to be eligible to receive the BNT162b2 vaccine. Immunogenicity was evaluated immediately before and on day 28 (±2 days) after vaccination. The primary outcomes were humoral immunity to the SARS-CoV-2 spike glycoprotein, defined as neutralising antibody responses to wild-type SARS-CoV-2, and spike-specific T-cell responses (including interferon-γ, IL-2, and IL-21) 28 days after vaccination. Findings Between Jan 14 and April 4, 2021, 84 patients with psoriasis (17 on methotrexate, 27 on TNF inhibitors, 15 on IL-17 inhibitors, and 25 on IL-23 inhibitors) and 17 healthy controls were included. The study population had a median age of 43 years (IQR 31–52), with 56 (55%) males, 45 (45%) females, and 85 (84%) participants of White ethnicity. Seroconversion rates were lower in patients receiving immunosuppressants (60 [78%; 95% CI 67–87] of 77) than in controls (17 [100%; 80–100] of 17), with the lowest rate in those receiving methotrexate (seven [47%; 21–73] of 15). Neutralising activity against wild-type SARS-CoV-2 was significantly lower in patients receiving methotrexate (median 50% inhibitory dilution 129 [IQR 40–236]) than in controls (317 [213–487], p=0·0032), but was preserved in those receiving targeted biologics (269 [141–418]). Neutralising titres against the B.1.1.7 variant were similarly low in all participants. Cellular immune responses were induced in all groups, and were not attenuated in patients receiving methotrexate or targeted biologics compared with controls. Interpretation Functional humoral immunity to a single dose of BNT162b2 is impaired by methotrexate but not by targeted biologics, whereas cellular responses are preserved. Seroconversion alone might not adequately reflect vaccine immunogenicity in individuals with immune-mediated inflammatory diseases receiving therapeutic immunosuppression. Real-world pharmacovigilance studies will determine how these findings reflect clinical effectiveness. Funding UK National Institute for Health Research.

In January 2020, a new strain of coronavirus was described. Less than 3 months later, a pandemic was declared. Within 9 months, the first vaccine received emergency authorization.

Summary Objectives Multiple RCTs of interleukin-6 (IL-6) inhibitors in COVID-19 have been published, with conflicting conclusions. We performed a meta-analysis to assess the impact of IL-6 inhibition on mortality from COVID-19, utilising meta-regression to explore differences in study results. Methods Systematic database searches were performed to identify RCTs comparing IL-6 inhibitors (tocilizumab and sarilumab) to placebo or standard of care in adults with COVID-19. Meta-analysis was used to estimate the relative risk of mortality at 28 days between arms, expressed as a risk ratio. Within-study mortality rates were compared, and meta-regression was used to investigate treatment effect modification. Results Data from nine RCTs were included. The combined mortality rate across studies was 19% (95% CI: 18, 20%), ranging from 2% to 31%. The overall risk ratio for 28-day mortality was 0.90 (95% CI: 0.81, 0.99), in favour of benefit for IL-6 inhibition over placebo or standard of care, with low treatment effect heterogeneity: I2 0% (95% CI: 0, 53%). Meta-regression showed no evidence of treatment effect modification by patient characteristics. Trial-specific mortality rates were explained by known patient-level predictors of COVID-19 outcome (male sex, CRP, hypertension), and country-level COVID-19 incidence. Conclusions IL-6 inhibition is associated with clinically meaningful improvements in outcomes for patients admitted with COVID-19. Long-term benefits of IL-6 inhibition, its effectiveness across healthcare systems, and implications for differing standards of care are currently unknown.

Objectives Updated guidelines for patients with axial SpA (axSpA) have sought to reduce diagnostic delay by raising awareness among clinicians. We used the National Early Inflammatory Arthritis Audit (NEIAA) to describe baseline characteristics and time to diagnosis for newly referred patients with axSpA in England and Wales. Methods Analyses were performed on sociodemographic and clinical metrics, including time to referral and assessment, for axSpA patients (n = 784) recruited to the NEIAA between May 2018 and March 2020. Comparators were patients recruited to the NEIAA with RA (n = 9270) or mechanical back pain (MBP; n = 370) in the same period. Results Symptom duration prior to initial rheumatology assessment was longer in axSpA than RA patients (P 6 months, compared with 33.7% of RA patients and 76.0% of MBP patients. Following referral, the median time to initial rheumatology assessment was longer for axSpA than RA patients (36 vs 24 days; P Conclusion Diagnostic delay in axSpA remains a major challenge despite improved disease understanding and updated referral guidelines. Disease education is provided to fewer axSpA than RA patients, highlighting the need for specialist clinics and support programmes for axSpA patients.

Introduction: The Covid-19 pandemic in the United Kingdom has seen two waves; the first starting in March 2020 and the second in late October 2020. It is not known whether outcomes were different in the first and second waves. Methods: The study population comprised all patients admitted to a 1,500-bed London Hospital Trust between March 2020 and January 2021, who tested positive for Covid-19 by PCR within 3-days of admissions. Primary outcome was death within 28-days of admission. Socio-demographics (age, sex, ethnicity), hypertension, diabetes, obesity, baseline physiological observations, CRP, neutrophil, chest x-ray abnormality, remdesivir and dexamethasone were incorporated as co-variates. Proportional subhazards models compared mortality risk between wave 1 and wave 2. Cox-proportional hazard model with propensity score adjustment were used to compare mortality in patients prescribed remdesivir and dexamethasone. Findings: There were 3,457 COVID-19 admissions, 2,494 hospital discharges and 619 deaths. There were notable differences in age, ethnicity, comorbidities, and admission disease severity between wave 1 and wave 2. Twenty-eight-day mortality was higher during wave 1 (25.7% versus 13.2%). Mortality risk adjusted for co-variates was significantly lower in wave 2 compared to wave 1 [adjSHR 0.41(0.30, 0.56)p

Objective JAK inhibitor therapies are effective treatment options for immune-mediated inflammatory diseases (IMIDs), but their use has been limited by venous thromboembolism (VTE) risk warnings from licensing authorities. We undertook this study to evaluate the VTE risk of JAK inhibitors in patients with IMIDs. Methods Systematic searches of Medline and Embase databases from inception to September 30, 2020 were conducted. Phase II and phase III double-blind, randomized controlled trials (RCTs) of JAK inhibitors at licensed doses were included in our analyses. RCTs with no placebo arm, long-term extension studies, post hoc analyses, and pooled analyses were excluded. Three researchers independently extracted data on exposure to JAK inhibitors or placebo and VTE events (e.g., pulmonary embolism [PE] and deep vein thrombosis [DVT]) and assessed study quality. Results A total of 42 studies were included, from an initial search that yielded 619. There were 6,542 JAK inhibitor patient exposure years (PEYs) compared to 1,578 placebo PEYs. There were 15 VTE events in the JAK inhibitor group and 4 in the placebo group. The pooled incidence rate ratios (IRRs) of VTE, PE, and DVT in patients receiving JAK inhibitors were 0.68 (95% confidence interval [95% CI] 0.36-1.29), 0.44 (95% CI 0.28-0.70), and 0.59 (95% CI 0.31-1.15), respectively. Conclusion This meta-analysis of RCT data defines the VTE risk with JAK inhibitors as a class in IMID patients. The pooled IRRs do not provide evidence that support the current warnings of VTE risk for JAK inhibitors. These findings will aid continued development of clinical guidelines for the use of JAK inhibitors in IMIDs.

As efficacy and safety data emerge, differences between JAK inhibitor subclasses are appearing. JAK1 selective drugs, upadacitinib and filgotinib, have broadly come with the same overarching safety recommendations as other immunosuppressive drugs for RA: caution is needed regarding infection risk; monitoring for laboratory abnormalities, including lipids and muscle enzymes, is indicated. A distinguishing feature of JAK inhibitors is a risk for zoster reactivation. Numerically, overall rates of serious infection are similar among JAK inhibitor classes. There are currently no signals for diverticular perforation. VTE incidence rates were similar across comparator groups for the JAK1 selective agents. These observations are not yet conclusive evidence for different safety profiles between JAK1 selective agents and other JAK inhibitors. Differences in study population, design, and concomitant steroid use are examples of potential confounders. It is too early to draw conclusions on long-term outcomes such as malignancy and cardiovascular risk. Post-marketing pharmacovigilance studies will be essential.

Low molecular weight, orally available, ‘small molecules’ which target and inhibit components of the Janus family tyrosine kinase (JAK) enzyme inflammatory signalling cascade have been lately considered as an important alternative to biologic therapies for rheumatoid arthritis (RA). JAK signalling is used by a number of pro-inflammatory cytokines known to be involved in RA pathogenesis, notably IL-6. Therefore, several JAK inhibitors with variable degrees of selectivity and specificity for the JAK enzymes have been investigated in treatment of RA. To date, two JAK inhibitors, tofacitinib and baricitinib, have been approved for treatment of RA in certain regions. This chapter discusses the safety, efficacy, trials, and future directions of these two JAK inhibitors.

Background Missing clinical outcome data are a common occurrence in longitudinal studies. Data quality in clinical audit is a particular cause for concern. The relationship between departmental levels of missing clinical outcome data and care quality is not known. We hypothesise that completeness of key outcome data in a national audit predicts departmental performance. Methods The National Clinical Audit for Rheumatoid and Early Inflammatory Arthritis (NCAREIA) collected data on care of patients with suspected rheumatoid arthritis (RA) from early 2014 to late 2015. This observational cohort study collected data on patient demographics, departmental variables, service quality measures including time to treatment, and the key RA clinical outcome measure, disease activity at baseline, and 3 months follow-up. A mixed effects model was conducted to identify departments with high/low proportions of missing baseline disease activity data with the results plotted on a caterpillar graph. A mixed effects model was conducted to assess if missing baseline disease activity predicted prompt treatment. Results Six thousand two hundred five patients with complete treatment time data and a diagnosis of RA were recruited from 136 departments. 34.3% had missing disease activity at baseline. Mixed effects modelling identified 13 departments with high levels of missing disease activity, with a cluster observed in the Northwest of England. Missing baseline disease activity was associated with not commencing treatment promptly in an adjusted mix effects model, odds ratio 0.50 (95% CI 0.41 to 0.61, p Conclusions We have shown that poor engagement in a national audit program correlates with the quality of care provided. Our findings support the use of data completeness as an additional service quality indicator.

Background Patients with rheumatoid arthritis (RA) are at an increased risk of infection. Most attention has been given to serious infections, but these are the tip of the iceberg. Non-serious infections (NSI) are far more frequent, and although not life-threatening, have potential to impact treatment outcomes (drug survival) and quality of life. Our objective was to describe frequency of NSI and compare incidence of NSI by biologic drug within the British Society for Rheumatology Biologics Register (BSRBR-RA). Methods The BSRBR-RA is a prospective observational cohort study. NSI was identified as not requiring hospitalisation, intravenous therapy or leading to disability or death. Infections were captured from clinician questionnaires and patient diaries. Individuals were considered ‘at risk’ from the date of commencing biologic treatment for 3 years. Drug exposure was defined by agent; TNF inhibitor, IL-6 inhibitor, anti-CD20 or csDMARD only. To account for a high frequency of events, a multiple-failure Cox model was used. Multivariable adjustment included age, gender, DAS28-ESR, HAQ-DI, disease duration, smoking, steroid usage, year recruited to BSRBR-RA, line of biologic therapy and cumulative infection number. Results There were 17,304 NSI in 10,099 patients, with an event rate of 27.0 per year (95% CI 26.6 to 27.4). Increasing age, female gender, comorbidity burden, corticosteroid therapy, DAS28 and HAQ-DI were associated with an increased risk of NSI. The rate of NSI was numerically lowest with csDMARDs. Compared to TNFi, IL-6 inhibitor had a higher risk of NSI, whilst the csDMARD cohort had a lower risk. Between the TNFi agents, adalimumab had a higher risk than etanercept (Table 1). Conclusion These results confirm that NSI is a frequent occurrence for patients, which historically has received little attention in research literature. The data suggest biologics increase the risk of NSI, especially IL-6 inhibition. Whilst unmeasured confounding must be considered, the magnitude of effects are large and it seems likely that a causal link between targeted immunosuppression and NSI risk exists. Further research is needed to understand the impact of NSI on clinical outcomes including drug survival and quality of life. Disclosures K. Bechman: None. K. Halai: None. S. Norton: None. A.P. Cope: None. K.L. Hyrich: Honoraria; AbbVie paid to the institution and grant income from Pfizer and Bristol-Myers Squibb for activities outside of this work. J.B. Galloway: Honoraria; for speaking or attending conferences from AbbVie, Bristol-Myers Squibb, Celgene, Janssen, Pfizer and Union Chimique Belge.

Background There is an established increase risk of infection in rheumatoid arthritis (RA). Most published data examine serious events, which affect 3-5% of patients annually. Approximately half of the patients experience non-serious infection, which does not require parental antibiotics or hospitalisation. Sinusitis events affecting patients on biologics (particularly TNF inhibition) have been observed but not well described, with a prevalence of 2-17%. Sinusitis is associated with treatment discontinuation and surgical interventions. We aim to describe the rates of sinusitis with different RA treatment strategies and provide estimates of risk difference. Methods The population was adults with RA, enrolled in the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis registry (BSRBR-RA) during the first 3 years of study on biologic treatment. The predictor was treatment strategy at the time of event (csDMARD only, TNF inhibitors, IL-6 inhibitors and anti-CD20). The primary outcome was sinusitis according to MeddraPT codes reported by patients (via patient diary) or clinician (on an adverse event form). A multi-failure Cox survival model was used to compare risk across treatment groups. A multivariate model adjusted for confounders (age, gender, entry year in BSRBR-RA, disease duration, baseline disease activity by DAS-28, HAQ, comorbidities, smoking status and steroid use. Results 23,584 patients were included, contributing to a total of 64,035 patient-years of follow up. There were 797 infective events in 580 patients. This corresponded to a rate of 0.95 per year (95% CI 0.87 to 0.1.02). The sinusitis rate was numerically highest with anti-CD20 (Rituximab) and lowest with csDMARDs (Table 1). In the adjusted Cox proportional hazard model, all 3 biologics strategies had a significantly higher rate of sinusitis compared to csDMARD cohort; (TNFi 2.76 (95%CI 1.85 to 4.12); IL-6R 2.51 (1.00 to 6.29); anti-CD20 3.14 (1.46 to 6.72). Conclusion Sinusitis is more common in patients prescribed biologics compared to the csDMARD. The highest rate was seen with rituximab. This would fit biologically, as the primary immunodeficiency phenotype of recurrent sinusitis aligns with antibody defects e.g. common variable immunodeficiency. However, it is interesting to observe that sinusitis is more common across the treatment classes. Disclosures K. Halai None. K. Bechman None. S. Norton None. A.P. Cope None. K.L. Hyrich Honoraria; AbbVie paid to the institution and grant income from Pfizer and Bristol-Myers Squibb for activities outside of this work. J.B. Galloway Honoraria; or speaking or attending conferences from AbbVie, Bristol-Myers Squibb, Celgene, Janssen, Pfizer and Union Chimique Belge.

Background Trial data indicate an increased risk of VTE with JAK inhibition. The EMA and FDA have given regulatory advice for their use as a result. To understand the context of any association, we need to understand VTE risk in the background population. Our objective was to describe the changing epidemiology of VTE risk including a breakdown of DVT and PE in the general population in England, over a 20-year period. Methods We utilised hospital episodes statistics data to study all patients presenting for hospital care in England between 1 January 1998 and 31 December 2017. We identified VTE events using ICD10 codes I26.0, I26.9, I80.1, I80.2 and I80.3. To estimate annualised event rates, we used the number of finished consultant episodes for admitted care where the primary diagnosis was VTE for the numerator; the denominator was the whole population estimate, from the office for National Statistics, for the relevant year for England. Rates were calculated per 100,000 population, and the Cochrane Armitage test was used to evaluate statistical significance of trends over time. Linear regression allowed modelling of estimates over time, with model assumptions tested using residual versus fitted plots. To explore non-linearity, we used a cubic spline model. Results The average VTE rate across the 20 years was 127/100,000. VTE rates have increased over time, climbing from 108/100,000 in 1998, to 151/100,000 in 2017. The relative frequency of DVTs and PEs has changed over this time: in 1998 DVT was more frequent than PE (rates 68/100,000 and 40/100,000 respectively). By 2018 this ratio had reversed (DVT 52/100,000: PE 98/100,000). This change was statistically significant (p < 0.0001). DVT rates declined in a linear manner over time. PE rates increased with a non-linear pattern, with a sharp rise apparent between 2008 and 2010. Conclusion The inversion in the frequency of DVTs and PEs is consistent with previous findings using European data. One possible explanation is changing diagnostics (CTPA replacing V/Q), capturing previously subclinical PE events. Limitations include our ecologic design as well as lack of linkage to mortality records. The presumed VTE risk associated with JAK inhibition is small. It is plausible that future shifts in population wide patterns of VTE could obscure or amplify any effect attributable to JAK inhibitors. As longer-term observational data become available, it is crucial they are interpreted in the context of background population trends. Disclosures S. Baroncini: None. M. Yates: None. K. Bechman: None. S. Patel: None. A. Rutherford: None. A. Kleymann: None. J. Galloway: None.

Objective.To investigate predictors of flare in rheumatoid arthritis (RA) patients with low disease activity (LDA) and to evaluate the effect of flare on 12-month clinical outcomes.Methods.Patients with RA who were taking disease-modifying antirheumatic drugs and had a stable 28-joint count Disease Activity Score (DAS28) < 3.2 were eligible for inclusion. At baseline and every 3 months, clinical (DAS28), functional [Health Assessment Questionnaire–Disability Index (HAQ-DI), EQ-5D, Functional Assessment of Chronic Illness Therapy Fatigue scale (FACIT-F), Medical Outcomes Study Short Form-36 (SF-36)], serum biomarkers [multibiomarker disease activity (MBDA) score, calprotectin, CXCL10], and imaging data were collected. Flare was defined as an increase in DAS28 compared with baseline of > 1.2, or > 0.6 if concurrent DAS28 ≥ 3.2. Cox regression analyses were used to identify baseline predictors of flare. Biomarkers were cross-sectionally correlated at time of flare. Linear regressions were performed to compare clinical outcomes after 1 year.Results.Of 152 patients, 46 (30%) experienced a flare. Functional disability at baseline was associated with flare: HAQ-DI had an unadjusted HR 1.82 (95% CI 1.20–2.72) and EQ-5D had HR 0.20 (95% CI 0.07–0.57). In multivariate analyses, only HAQ-DI remained a significant independent predictor of flare (HR 1.76, 95% CI 1.05–2.93). At time of flare, DAS28 and its components significantly correlated with MBDA and calprotectin, but correlation coefficients were low at 0.52 and 0.49, respectively. Two-thirds of flares were not associated with a rise in biomarkers. Patients who flared had significantly worse outcomes at 12 months (HAQ-DI, EQ-5D, FACIT-F, SF-36, and radiographic progression).Conclusion.Flares occur frequently in RA patients with LDA and are associated with worse disease activity, quality of life, and radiographic progression. Higher baseline HAQ-DI was modestly predictive of flare, while biomarker correlation at the time of flare suggests a noninflammatory component in a majority of events.

Objective.Vaccination is a key strategy to reduce infection risk in patients with rheumatoid arthritis (RA) and is advocated in internationally recognized rheumatology society guidelines. The aim was to evaluate to the effect of antirheumatic drugs on influenza and pneumococcal vaccine immunogenicity.Methods.We conducted a systematic literature review and metaanalysis comparing the humoral response to influenza (pandemic and seasonal trivalent subunit vaccines) and pneumococcal (23-valent pneumococcal polysaccharide vaccine, 7- and 13-valent pneumococcal conjugated vaccines) vaccination in adult patients with RA treated with antirheumatic drugs. Vaccine immunogenicity was assessed by seroprotection rates measured 3 to 6 weeks postimmunization. Risk ratios (RR) and 95% CI were pooled.Results.Nine studies were included in the metaanalysis (7 studies investigating antirheumatic drug exposures and influenza humoral response, 2 studies investigating pneumococcal vaccine response). Influenza vaccine responses to all subunit strains (H1N1, H3N2, B strain) were preserved with methotrexate (MTX) and tumor necrosis factor inhibitor (TNFi) drug exposure. MTX but not TNFi drug exposure was associated with reduced 6B and 23F serotype pneumococcal vaccine response (RR 0.42, 95% CI 0.28–0.63 vs RR 0.98, 95% CI 0.58–1.67); however, limited data were available to draw any firm conclusions. Combination of MTX with tocilizumab or tofacitinib was associated with reduced pneumococcal and influenza vaccine responses.Conclusion.Antirheumatic drugs may limit humoral responses to vaccination as evidenced by pneumococcal responses with MTX exposure; however, they are safe and should not preclude immunization against vaccine-preventable disease. Vaccination should be considered in all patients with RA and encouraged as part of routine care. (Systematic review registration number: PROSPERO 2016: CRD42016048093.)

Background We report the first adult case of Neisseria meningitidis W-135 presenting with meningococcal arthritis and myopericarditis concomitantly, without other classical features of meningococcal disease. Case presentation A 67-year-old Caucasian man presented with acute-onset polyarthralgia, myalgia, and fever. On examination he had polyarticular synovitis. An electrocardiogram (ECG) demonstrated ST-elevation in leads I, II, III, aVF, and V2-V6 without reciprocal depression, and a high-sensitivity troponin level was significantly elevated. Cardiac magnetic resonance (CMR) imaging on day five of admission demonstrated patchy pericardial enhancement. Neisseria meningitidis W-135 was isolated from both synovial fluid and blood cultures. The clinical outcome was favourable with intravenous ceftriaxone and myopericarditis treatment (colchicine and ibuprofen). Conclusions We conclude that this is a rare case of disseminated Neisseria meningitidis W-135 presenting with acute polyarticular septic arthritis and myopericarditis, without other classical features of systemic meningococcal disease. The earlier described entity of primary meningococcal arthritis (PMA) can present in patients with meningococcal bacteraemia, and may not be distinct from disseminated meningococcal disease, but rather an atypical presentation of this. Electronic supplementary material The online version of this article (10.1186/s12879-017-2845-3) contains supplementary material, which is available to authorized users.

The travel-related infection risks in the significantly immunocompromised traveler are complex and comprise vaccine preventable, vector-borne, and other nonvaccine preventable infections. A thorough risk assessment should be performed before travel and advice sought from relevant specialists. Immunosuppression used to treat autoimmune diseases and their mechanisms of action need particular consideration.This risk assessment needs to take the patient's beliefs and preferences into account. It is also important not to neglect noninfectious travel considerations.

Background The B cell chemoattractant CXCL13 is a promising biomarker in rheumatoid arthritis (RA), with a plausible role in supporting diagnosis, monitoring disease activity and as a prognostic value. It is a key chemokine driving the formation of lymphoid follicles within the inflamed synovium. The objective of this systematic review was to evaluate the role of CXCL13 as a viable biomarker in RA. Methods We conducted a systematic literature review of all published cohort and randomised controlled trials evaluating the role of CXCL13 in RA. The primary outcomes were; i) CXCL13 levels in RA patients compared to healthy controls, ii) the correlation between CXCL13 and markers of disease activity, and iii) the association between CXCL13 and treatment response. Results The search produced 278 articles, of which 31 met the inclusion criteria. Of the 12 studies evaluating CXCL13 expression in early or established RA, all reported higher levels than that seen in healthy controls. Twelve of sixteen studies reported a weakly positive correlation between CXCL13 and markers of disease activity including DAS28 and swollen joint count, with rho values between 0.20–0.67. In 2 studies, CXCL13 levels correlated with ultrasonographic evidence of synovitis. Eighteen studies assessed CXCL13 in response to therapeutic intervention. The majority signified a fall in levels in response to treatment including biologics and Janus kinase (JAK) inhibition. In some, this reduction was only seen in treatment responders. High CXCL13 levels predicted failure to achieve disease remission with csDMARDs. The evidence for treatment prediction with biologics was conflicting. Conclusion Despite evidence to suggest a role in diagnosing RA and in detecting synovitis, the heterogeneity of studies included in this review limit our ability to draw robust conclusions. At present there are inadequate results to justify the routine use of CXCL13 as a biomarker in RA routine clinical practice.

Objective.To describe trends in acute hospital admissions due to gout in England, with rheumatoid arthritis (RA) as a comparator, alongside prescribing trends for common gout medications.Methods.An ecological study was performed using UK National Health Service (NHS) Digital Hospital Episode Statistics data to calculate the incidence of unplanned admissions with primary diagnoses of gout or RA in adults in England between April 2006 and March 2017. NHS Digital Community Prescription data for allopurinol, febuxostat, and colchicine were considered over a similar period.Results.The incidence of unplanned gout admissions increased by 58.4% over the study period, from 7.9 admissions per 100,000 population in 2006/07 to 12.5 admissions per 100,000 population in 2016/17 (p < 0.0001). Gout admissions increased as a proportion of all hospital admissions, and accounted for 349,768 bed-days cumulatively. Unplanned RA admissions halved over the study period, from 8.6 admissions per 100,000 population in 2006/07 to 4.3 admissions per 100,000 population in 2016/17 (p < 0.0001). Community prescriptions dispensed for allopurinol and colchicine have increased by 71.4% and 165.6%, respectively, since 2006 (p < 0.0001). Febuxostat prescriptions have increased 20-fold since 2010 (p < 0.0001), when prescription data became available.Conclusion.Acute gout admissions in England increased between 2006 and 2017, accompanied by increasing prescription of gout therapies. Acute admissions due to RA halved over the same time period. These data call for aggressive target-driven therapy for this highly treatable disease.

Background: Despite advances in the treatment of rheumatoid arthritis (RA), pain and psychological symptoms remain a burden for many patients. The precise relationship between inflammation and patient reported symptoms, such as pain, fatigue and mental health in the disease is unclear. However, evidence suggests that over time there may be discordance between inflammation and patient reported outcomes, such that some patients with low inflammation will experience persistent symptoms. It is hypothesised that three distinct patient sub-groups exist; low inflammation/low symptoms, low inflammation/high symptoms, and high inflammation/high symptoms. Objectives: To identify sub-groups of patients with respect to inflammatory markers and levels of P&PS over time. Methods: Demographic, clinical and laboratory data were recorded at baseline (pre-treatment), 6, 12, and 18-months from 239 early RA patients recruited to the Towards A Cure for Early Rheumatoid Arthritis (TACERA) cohort. Individual components of the DAS28 (tender joints, swollen joints, ESR, CRP and patient global) at post-treatment assessments, along with patient reported visual analogue scales for pain, fatigue and the SF-36 Mental Component Score (MCS) were used to identify sub-groups using longitudinal latent class analysis (LCA). Logistic regression models identified variables associated with class membership at 6, 12 and 18-months follow-up. Results: LCA indicated two rather than the hypothesised three sub-groups; low inflammation/low symptoms and low inflammation/high symptoms. This was likely because ESR and CRP were well controlled by 6-months and maintained by 18-months for the majority of individuals. There were 86 (36%) 59 (35%) and 41 (39%) classified as having high symptoms at 6, 12 and 18-months. 78% of patients initially in the low symptom group remained in the low symptom group between 6 and 18-months. Rheumatoid Factor (RF) positivity and higher baseline fatigue were associated with high symptoms at 6months; decreasing ESR from 6 to 12-months was associated high symptoms at 12months, and having high symptoms at 12-months, along with reduced Swollen Joint Count (SJC), CRP and MCS from month 12 to 18 was associated with high symptoms at 18-months. Conclusion: Tight treatment control resulted in controlled Inflammation by 6-months, resulting in just two main patient sub-groups; those with low and high P&PS. Over one-third of patients experienced high pain and psychological symptoms. Membership of the high symptom group was associated with RF positivity but was mainly driven by prior symptom experience. Whilst inflammatory control remains a primary target, other treatments targeting pain, fatigue and mental health must be considered to reduce the burden of disease. Disclosure of Interests: Lewis Carpenter: None declared, Katie Bechman: None declared, Andrew Cope: None declared, Elena Nikiphorou: None declared, James Galloway Consultant for: Pfizer Inc, Sam Norton: None declared

Objective.Understanding the placebo response is critical to interpreting treatment efficacy, particularly for agents with a ceiling to their therapeutic effect, where an increasing placebo response makes it harder to detect potential benefit. The objective of this study is to assess the change in placebo responses over time in rheumatoid arthritis (RA) randomized placebo-controlled trials (RCT) for drug licensing authorization.Methods.The Cochrane Controlled Trials Register database was searched to identify RCT of biological or targeted synthetic disease-modifying antirheumatic drugs (DMARD) in RA. Studies were excluded if patients were conventional synthetic DMARD (csDMARD)–naive, not receiving background csDMARD therapy, or were biologic experienced. Metaregression model was used to evaluate changes in American College of Rheumatology (ACR) 20, ACR50, and ACR70 treatment response over time.Results.There were 32 trials in total: anti–tumor necrosis factor therapy (n = 15), tocilizumab (n = 4), abatacept (n = 2), rituximab (n = 2), and Janus kinase inhibitors (n = 9). From 1999 to 2018, there was no significant trend in the age or sex of patients in the placebo arm. Disease duration, swollen joint count, and 28-joint count Disease Activity Score using erythrocyte sedimentation rate at baseline all significantly declined over time. There was a statistically significant increase in placebo ACR50 and ACR70 responses (ACR50 β = 0.41, 95% CI 0.09–0.74, p = 0.01; ACR70 β = 0.18, 95% CI 0.04–0.31, p = 0.01) that remained significant after controlling for potential confounders.Conclusion.There has been a rise in the placebo response in RA clinical trials over the last 2 decades. Shifting RA phenotype, changes in trial design, and expectation bias are possible explanations for this phenomenon. This observation has important implications when evaluating newer novel agents against established therapies.

Background:Diagnostic delay is a significant problem in axial spondyloarthritis (axSpA), and there is a growing body of evidence showing that delayed axSpA diagnosis is associated with worse clinical, humanistic and economic outcomes.1 International guidelines have been published to inform referral pathways and improve standards of care for patients with axSpA.2,3Objectives:To describe the sociodemographic and clinical characteristics of newly-referred patients with axSpA in England and Wales in the National Early Inflammatory Arthritis Audit (NEIAA), with rheumatoid arthritis (RA) and mechanical back pain (MBP) as comparators.Methods:The NEIAA captures data on all new patients over the age of 16 referred with suspected inflammatory arthritis to rheumatology departments in England and Wales.4 We describe baseline sociodemographic and clinical characteristics of axSpA patients (n=784) recruited to the NEIAA between May 2018 and March 2020, compared with RA (n=9,270) and MBP (n=370) during the same period.Results:Symptom duration prior to initial rheumatology assessment was significantly longer in axSpA than RA patients (p6 months, compared to 33.7% of RA patients and 76.0% of MBP patients; 32.6% of axSpA patients had symptom durations of >5 years, compared to 3.5% of RA patients and 24.6% of MBP patients (Figure 1A). Following referral, median time to initial rheumatology assessment was longer for axSpA than RA patients (36 vs. 24 days; pOf the subset of patients with peripheral arthritis requiring EIA pathway follow-up, fewer axSpA than RA patients had disease education provided (77.5% vs. 97.8%; pConclusion:We have shown that diagnostic delay remains a major challenge in axSpA, despite improved disease understanding and updated referral guidelines. Patient education is an unmet need in axSpA, highlighting the need for specialist clinics. MSK-HQ scores demonstrated that the functional impact of axSpA is no less than for RA, whereas HAQ-DI may underrepresent disability in axSpA.References:[1]Yi E, Ahuja A, Rajput T, George AT, Park Y. Clinical, economic, and humanistic burden associated with delayed diagnosis of axial spondyloarthritis: a systematic review. Rheumatol Ther. 2020;7:65-87.[2]NICE. Spondyloarthritis in over 16s: diagnosis and management. 2017.[3]van der Heijde D, Ramiro S, Landewe R, et al. 2016 update of the ASAS-EULAR management recommendations for axial spondyloarthritis. Ann Rheum Dis. 2017;76(6):978-91.[4]British Society for Rheumatology. National Early Inflammatory Arthritis Audit (NEIAA) Second Annual Report. 2021.Acknowledgements:The National Early Inflammatory Arthritis Audit is commissioned by the Healthcare Quality Improvement Partnership, funded by NHS England and Improvement, and the Welsh Government, and carried out by the British Society for Rheumatology, King’s College London and Net Solving.Disclosure of Interests:Mark Russell Grant/research support from: UCB, Pfizer, Fiona Coath: None declared, Mark Yates Grant/research support from: UCB, Abbvie, Katie Bechman: None declared, Sam Norton: None declared, James Galloway Grant/research support from: Abbvie, Celgene, Chugai, Gilead, Janssen, Lilly, Pfizer, Roche, UCB, Jo Ledingham: None declared, Raj Sengupta Grant/research support from: AbbVie, Biogen, Celgene, Lilly, MSD, Novartis, Pfizer, Roche, UCB, Karl Gaffney Grant/research support from: AbbVie, Biogen, Cellgene, Celltrion, Janssen, Lilly, Novartis, Pfizer, Roche, UCB.

Background:The number of immune-modulatory drugs used to treat immune-mediated inflammatory diseases (IMIDs) has exponentially increased in recent decades. While effective in controlling disease, serious infection remains a concern.Accurate information on immune-modulatory drugs, including infections, is required to guide prescribing decisions. The “summary of product characteristics” (SmPC) by the European Medicines Agency (EMA) provides a useful repository of information on adverse events e.g. infections, from clinical trials and post-marketing pharmacovigilance (1).To date, no comparison has been undertaken on reported infection frequencies across SmPCs for immune-modulators.Objectives:To compare infection frequency, site and type across the most commonly-prescribed immune-modulatory drugs used to treat IMIDs, using information provided by SmPCs.Methods:A drug was included if licensed in Europe for treatment of one of the following: rheumatoid arthritis, axial spondyloarthritis, connective tissue disease, autoimmune vasculitis, autoinflammatory syndromes, inflammatory bowel disease (Crohn’s and ulcerative colitis), psoriasis, multiple sclerosis and other rarer conditions.The Electronic Medicines Compendium (EMC) was searched for commonly prescribed immune-modulatory drugs used for the above indications. SmPC documents were manually searched for information on infection frequency, extracted from sections 4.4 and 4.8. Infection frequency was recorded as per convention in the SmPC: very common (≥1/10); common (≥1/100 to 25% of included SmPCs were screened and extracted by a second reviewer. Disagreements were resolved with input from a third reviewer.Results:In total, 39 drugs were included, used across 20 indications: nine conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs), six targeted synthetic DMARDs (tsDMARDs; four Janus kinase [JAK] inhibitors, two sphingosine 1-phosphate receptor modulators) and 24 biologic DMARDs (17 cytokine-targeted; seven cell-targeted).Twelve sites of infection were recorded. Minimal or no site information was available for most csDMARDs and siponimod, certolizumab pegol and rituximab. The most common sites of infection are listed by drug group in Figure 1. Upper respiratory tract was the most common site, especially with bDMARDs. Lower respiratory, ear/nose/throat (including sinusitis) and urinary tract infections were moderately common, with clustering within drug groups. No drugs reported risk of cardiac infections; the eye, musculoskeletal, neurological, oral and reproductive sites were the least commonly-reported sites of infection.Infection data for 27 distinct pathogens were recorded, the majority viruses, especially with bDMARD use. Herpes simplex and zoster were the most frequently listed (mainly with bDMARDs and tsDMARDs), followed by influenza. Common non-viral causes of infection were candida and tinea species.Variable or absent reporting was noted for opportunistic infections (e.g. tuberculosis and fungi) and certain high-prevalence viruses e.g. Epstein-Barr.Conclusion:The SmPC literature reports differences in infection risk, by site and pathogen, between immune-modulatory drugs. The findings can be used to visualise differences and aid treatment decisions. However, some of the patterns we have shown lack face-validity to clinicians familiar with real-world safety data. The data fail to capture risk of rare infections, are likely skewed by trial selection criteria, varying number of trials per drug and quirks of individual study-reporting methodologies.The findings highlight the need for robust post-marketing pharmacovigilance studies.References:[1]A Guideline on Summary of Product Characteristics Module 1.3. 2008.Disclosure of Interests:None declared.

The past decade has witnessed an explosion in trial data on JAK inhibitors (JAKi). These small molecules target the Janus kinase - signal transducer and activator of transcription (JAK-STAT) pathway, blocking crucial cytokines across a septum of rheumatic diseases. As a class, JAKi are beginning to demonstrate efficacy on par, if not superior to biologics. Two first generation JAKi are licensed for use in inflammatory arthritis; tofacitinib and baricitinib. Next-generation JAKi have been designed with selective affinity for one JAK enzymes, the aim to reduce unwanted adverse effects without declining clinical efficacy. Emerging data with selective JAK1 inhibitors upadacitinib and filgotinib looks very promising. Despite differences in selectivity between JAKi, an overlap exists in their safety profiles. Across the class, a characteristic safety signal is emerging with viral opportunistic infections, particularly herpes zoster. Post marketing drug surveillance will be essential in evaluating the long-term risk with these agents.

Pharmacovigilance registries of biologics were established to evaluate the risk of adverse events that may be missed in trials due to shorter durations and homogeneous samples. This review will present the strengths and weaknesses of registry data in addressing patient safety issues. Since their inception, scope has broadened because registries represent a relatively inexpensive approach to answering many clinical questions, both research and non-research focused. They achieve high statistical power, allow direct comparability, and offer a level of detail about adverse events not possible with trial data. Registries have been central in clarifying the risk of infection and malignancy with anti-TNF therapy, despite the limitations of selection and channelling bias, incomplete case capture, unmeasured confounding, and the inability to infer causality. Routinely collected data from electronic health records and national audits offer alternative real-world resources, further assisting patients and clinicians in understanding the risks of biologic therapy choices.

Objectives To evaluate the risk of serious infection (SI) and herpes zoster (HZ) in rheumatoid arthritis patients receiving JAK inhibitors. Methods We conducted a systematic literature review and meta-analysis of phase II and III randomized controlled trials of tofacitinib (5 mg bid), baricitinib (4 mg od) and upadacitinib (15 mg od). Patient-exposure years were calculated. A per-protocol analysis was applied, incorporating follow-up time from patients randomized to placebo who cross into the treatment arm. Pooled incidence rates per 100 person-years of SI and HZ were calculated. Incidence rate ratios (IRRs) of drug vs placebo were compared using a meta-synthesis approach. Results Twenty-one studies were included in the meta-analysis; 11 tofacitinib (5888 patients), six baricitinib (3520 patients) and four upadacitinib studies (1736 patients). For SI, the incidence rates were 1.97 (95% CI: 1.41, 2.68), 3.16 (95% CI: 2.07, 4.63) and 3.02 (95% CI: 0.98, 7.04), respectively. The IRRs comparing treatment arm to placebo were statistically non-significant: 1.22 (95% CI: 0.60, 2.45), 0.80 (95% CI: 0.46, 1.38) and 1.14 (95% CI: 0.24, 5.43), respectively. For HZ, the incidence rates were 2.51 (95% CI: 1.87, 3.30), 3.16 (95% CI: 2.07, 4.63) and 2.41 (95% CI: 0.66, 6.18), respectively. The IRR of HZ comparing baricitinib with placebo was 2.86 (95% CI: 1.26, 6.50). Non-significant IRRs were seen with tofacitinib and upadacitinib: 1.38 (95% CI: 0.66, 2.88) and 0.78 (95% CI: 0.19, 3.22), respectively. Indicator opportunistic infections excluding HZ were too rare to provide meaningful incidence rates. Conclusion The absolute SI rates were low. However across the JAK inhibitors, the incidence of HZ is higher than expected for the population (3.23 per 100 patient-years). While the risk was numerically greatest with baricitinib, indirect comparisons between the drugs did not demonstrate any significant difference in risk. Systematic review registration number Prospero 2017 CRD4201707879.

Background Tapering or discontinuation of anti-TNF therapy appears to be feasible, safe and effective in a selected proportion of Rheumatoid Arthritis (RA) patients. Depression is highly prevalent in RA and may impact on flare incidence through a number of mechanisms. It is an independent predictor for flare in patients with active disease and is negatively associated with remission.1 To date, there are no studies directly addressing the role of depression, anxiety or low mood in predicting flares in patients tapering their biological therapy. Objectives To investigate if psychological and functional states predict flare in RA patients with low disease activity (LDA) or in remission who undergo treatment tapering of their anti-TNF agents. Methods This study is a post-hoc analysis of the OPTTIRA trial,2 a multi-centre, prospective, randomised, open label study investigating anti-TNF tapering in established RA patients in sustained LDA. Baseline patient-reported outcomes including HAQ-DI, EQ-5D, FACIT-F, and SF-36 including the Mental Health Index (MHI) component were collected. The MHI has been validated as a screening tool for depression in RA patients.3 The primary outcome was flare, defined as an increase in DAS28 ≥0.6, and at least one additional swollen joint. Logistic regression was used to identify patient-reported outcomes that predict flare, adjusting for baseline covariates (age, gender, treatment arm, DAS28 and BMI). Results 97 were randomised into a tapering arm, either by 33% or 66% of their anti-TNF dose. The majority of patients were on methotrexate in combination with their anti-TNF therapy (n=67, 69%) and the median disease duration was 11 years [IQR: 7–17]. Seventy three (75%) fulfilled DAS28 remission criteria (DAS28 Conclusions Baseline DAS28 and mental health predict flare events in patients in LDA who taper their anti-TNF agents. Other psychological and functional states, measured by patient-reported outcome do predict flare events although the effect size is small and does not persist when adjusting for known predictors. Based on these findings, an assessment of functional and mental health states should be considered prior to biologic tapering. References [1] Michelsen B, et al. Ann Rheum Dis2017;76(11):1906–1910. [2] Ibrahim F, et al. Rheumatology2017;56(11):2004–2014. Acknowledgements Funding: The trial was funded by Arthritis Research UK (grant reference number 18813) Disclosure of Interest None declared

Background Observational cohort studies have been utilised extensively in early Rheumatoid Arthritis (RA), regularly conducted across multiple centres spanning regional and national boundaries. Case-mix and centre effect are considerations essential for determining comparability of results, and likely prevalence of bias. There is currently no standardised approach for case-mix and centre effect adjustment in early RA observational cohorts. Objectives Describe the spectrum of methodologies used to address case-mix and centre level effects on outcomes in multi-centre early RA observational cohort studies. Methods Inclusion criteria were cohorts recruiting from 2 or more centres with 100 or more subjects, with a Rheumatologist diagnosis of RA or EIA within the last 24 months. A systematic electronic search of publications was undertaken. Papers were reviewed by two researchers independently. Reference lists of included papers were reviewed for further relevant publications. A search of all included papers’ authors was also conducted. Detail on cohort characteristics, case-mix data collection and adjustment, and consideration of centre-level effect in analyses were collected. Results 1047 papers were identified from the initial search. A total of 20 unique cohorts were identified. Reference review and author search produced 14 more, to make a total of 34 unique observational cohorts drawn from 205 papers. The cohorts were mainly conducted in Europe (24/34, 71%), With 2 (6%) from less economically developed regions. The period of data collection was between 1955 and 2017. Case-mix: All cohorts considered case-mix in some form (e.g. age and gender), but with heterogenous approaches. The figure displays the relative frequencies of sociodemographic variable consideration across all included papers. Centre effect: 18/205 (9%) of the included papers accounted for centre in their results, utilising a range methodologies. Where reported, centre had a significant impact. Conclusions The degree of case-mix reporting varied widely, and few studies addressed centre effect. Where analysed, a centre level impact was clearly apparent. A failure to incorporate centre into analyses can lead to unrecognised bias as a result of confounding by centre. It must be acknowledged that including case-mix variables and adjusting for centre substantially reduces power, and it is likely that many of the reported observations may have lost statistical significance had case-mix and centre effect been addressed more completely. This is the first systematic review of centre effect and case-mix in early RA, and highlights a challenging field deserving further research. Disclosure of Interest None declared

Background Gender has been reported to play a role in attainment of RA remission (1), but the data are inconsistent. The impact of gender in early RA therefore warrants further investigation. Objectives To assess the impact of gender on early RA outcomes. Methods An audit, designed as a national prospective longitudinal observational study, was conducted to assess early RA care. All NHS providers in England and Wales were required to participate. Follow up data were captured over 3 months for subjects with a diagnosis of RA. Logistic regression was used to estimate associations between gender and DAS-28 response. Smoking status, baseline disease activity, age, antibody status, symptom duration, referral times, and treatment were considered in multivariate models. Results 136 of 146 eligible trusts submitted data. 11,752 subjects consented, 5,622 were diagnosed with RA. DAS-28 response was available for 2234/5622 (39.7%). Male patients had a similar 3 month improvement in their DAS-28 to females, despite having a lower mean baseline score. Male gender associated with a higher rate of good EULAR response (DAS improvement >1.2, follow up DAS The male excess in good EULAR response was more pronounced in seronegative compared with seropositive RA (1.98 (CI 1.4–2.8) compared to 1.21 (0.96–1.53)). Conclusions The association of male gender with improved outcomes in early RA has not been shown before in a national cohort of this scope. Previous work suggests seronegative individuals achieve greater clinical response (2), here we present this effect amplified in men. To the authors9 knowledge this is a new finding. This is likely multifactorial, with biological effect of gender, greater diagnostic uncertainty and higher reporting of global scores in women all potentially playing a role. References Svensson B, Andersson M, Forslind K, Ajeganova S, Hafstrom I. Persistently active disease is common in patients with rheumatoid arthritis, particularly in women: a long-term inception cohort study. Scan rheum. 2016;45(6):448–55. Barra L, Pope JE, Orav JE, et al. Prognosis of seronegative patients in a large prospective cohort of patients with early inflammatory arthritis. Rheum. 2014;41(12):2361–9. Disclosure of Interest None declared

The past decade has witnessed an explosion in trial data on JAK inhibitors (JAKi). These small molecules target the Janus kinase - signal transducer and activator of transcription (JAK-STAT) pathway, blocking crucial cytokines across a septum of rheumatic diseases. As a class, JAKi are beginning to demonstrate efficacy on par, if not superior to biologics. Two first generation JAKi are licensed for use in inflammatory arthritis; tofacitinib and baricitinib. Next-generation JAKi have been designed with selective affinity for one JAK enzymes, the aim to reduce unwanted adverse effects without declining clinical efficacy. Emerging data with selective JAK1 inhibitors upadacitinib and filgotinib looks very promising. Despite differences in selectivity between JAKi, an overlap exists in their safety profiles. Across the class, a characteristic safety signal is emerging with viral opportunistic infections, particularly herpes zoster. Post marketing drug surveillance will be essential in evaluating the long-term risk with these agents.

Background The predominant forms of adult large vessel vasculitis (LVV) are giant cell arteritis (GCA) and Takayasu arteritis (TA). Cardiac involvement in LVV is a cause of morbidity and mortality, particularly in TA. Cardiac failure is most commonly secondary to uncontrolled arterial hypertension or myocardial ischaemia. Pulmonary hypertension and aortic valve incompetence following ascending aortic dilatation represent other serious cardiovascular complications. However, cardiac failure as a consequence of myocarditis is rarely reported, principally in single case reports or in autopsy studies. Methods The Imperial College LVV database was, retrospectively, reviewed to identify patients with cardiac involvement at presentation. Patients with evidence for myocarditis were identified. The cardiac presentation, imaging studies and subsequent medical and surgical management were reviewed in detail. Results The cohort included 139 patients with TA and 24 with GCA. Sixteen presented with cardiac failure without a history of ischaemic coronary heart disease, 14 (10%) with TA and 2 (8.3%) with GCA. Cardiovascular disease identified at presentation included aortic regurgitation (n = 11), myocarditis (n = 4) and hypertensive cardiomyopathy secondary to renal artery stenosis (n = 1). Those patients with evidence of myocarditis at presentation (2.8%) underwent transthoracic echocardiography and cardiac magnetic resonance imaging (CMR). These non-invasive techniques were sufficient for diagnosis of clinically significant myocarditis. Furthermore, they were subsequently used to monitor response to treatment, with serial improvement in left ventricular ejection fraction (LVEF) observed in all 4 patients (p < 0.05). Prednisolone plus cyclophosphamide (CyC) therapy was associated with significant improvement in heart failure symptoms and LVEF in 3 cases. In one case where CyC was contraindicated, tocilizumab treatment led to marked improvement in cardiac symptoms. Conclusion Clinically significant myocarditis in LVV remains a rare but serious presentation. Non-invasive imaging techniques offer an alternative to the gold-standard myocardial biopsy. Initial aggressive immunosuppressive therapy is recommended and led to significant improvements in LVEF and cardiac status.

Sarcoidosis is a systemic disease of unknown aetiology that is characterized by granulomatous inflammation that can develop in almost any organ system. Musculoskeletal manifestations are seen in up to one-third of patients, ranging from arthralgia through to widespread destructive bone lesions. Inflammatory tendon lesions and periarticular swelling are more common than true joint synovitis. Despite advances in our understanding of the pathophysiology of the disease, diagnosis remains challenging. Definitive diagnosis, irrespective of organ site involvement, hinges on histological confirmation of non-caseating granuloma combined with an appropriate clinical syndrome. Musculoskeletal involvement usually develops early in the disease course. Imaging modalities, particularly fluorodeoxyglucose PET, are helpful in delineating the extent of involvement and measuring disease activity. Bone involvement may only become apparent following isotope imaging. Corticosteroids remain the cornerstone of treatment. MTX is the steroid-sparing agent of choice unless there is renal involvement. Biologic therapies are sometimes used in severe disease, although the evidence base for efficacy is inconsistent.