The 50 most-cited articles in Annals of the Rheumatic Diseases, 2022

OBJECTIVES: To quantify global, regional and country-specific estimates of epidemiology of systemic lupus erythematosus (SLE). METHODS: Four databases were systematically searched, and a Bayesian hierarchical linear mixed model was constructed to estimate the global, regional, and country-specific incidence and prevalence of SLE. RESULTS: 112 studies met the inclusion criteria. The global SLE incidence and newly diagnosed population were estimated to be 5.14 (1.4 to 15.13) per 100 000 person-years and 0.40 million people annually, respectively. In women, the values were 8.82 (2.4 to 25.99) per 100 000 person-years and 0.34 million people annually, while in men, the estimates were 1.53 (0.41 to 4.46) per 100 000 person-years and 0.06 million people annually, respectively. Poland, the USA and Barbados had the highest estimates of SLE incidence. Regarding prevalence, the global SLE prevalence and affected population were estimated to be 43.7 (15.87 to 108.92) per 100 000 persons and 3.41 million people, respectively. In women, the values were 78.73 (28.61 to 196.33) per 100 000 persons…

OBJECTIVE: Randomised trials of type I anti-CD20 antibodies rituximab and ocrelizumab failed to show benefit in proliferative lupus nephritis (LN). We compared obinutuzumab, a humanised type II anti-CD20 monoclonal antibody that induces potent B-cell depletion, with placebo for the treatment of LN in combination with standard therapies. METHODS: Patients with LN receiving mycophenolate and corticosteroids were randomised to obinutuzumab 1000 mg or placebo on day 1 and weeks 2, 24 and 26, and followed through week 104. The primary endpoint was complete renal response (CRR) at week 52. Exploratory analyses through week 104 were conducted. The prespecified alpha level was 0.2. RESULTS: A total of 125 patients were randomised and received blinded infusions. Achievement of CRR was greater with obinutuzumab at week 52 (primary endpoint, 22 (35%) vs 14 (23%) with placebo; percentage difference, 12% (95% CI -3.4% to 28%), p=0.115) and at week 104 (26 (41%) vs 14 (23%); percentage difference, 19% (95% CI 2.7% to 35%), p=0.026). Improvements in other renal response measures, serologies,…

OBJECTIVE: To develop and validate updated classification criteria for giant cell arteritis (GCA). METHODS: Patients with vasculitis or comparator diseases were recruited into an international cohort. The study proceeded in six phases: (1) identification of candidate items, (2) prospective collection of candidate items present at the time of diagnosis, (3) expert panel review of cases, (4) data-driven reduction of candidate items, (5) derivation of a points-based risk classification score in a development data set and (6) validation in an independent data set. RESULTS: The development data set consisted of 518 cases of GCA and 536 comparators. The validation data set consisted of 238 cases of GCA and 213 comparators. Age ≥50 years at diagnosis was an absolute requirement for classification. The final criteria items and weights were as follows: positive temporal artery biopsy or temporal artery halo sign on ultrasound (+5); erythrocyte sedimentation rate ≥50 mm/hour or C reactive protein ≥10 mg/L (+3); sudden visual loss (+3); morning stiffness in shoulders or neck, jaw or tongue…

Objectives To develop EULAR recommendations for screening and prophylaxis of chronic and opportunistic infections in patients with autoimmune inflammatory rheumatic diseases (AIIRD). Methods An international Task Force (TF) (22 members/15 countries) formulated recommendations, supported by systematic literature review findings. Level of evidence and grade of recommendation were assigned for each recommendation. Level of agreement was provided anonymously by each TF member. Results Four overarching principles (OAP) and eight recommendations were developed. The OAPs highlight the need for infections to be discussed with patients and with other medical specialties, in accordance with national regulations. In addition to biologic/targeted synthetic disease-modifying antirheumatic drugs (DMARDs) for which screening for latent tuberculosis (TB) should be performed, screening could be considered also before conventional synthetic DMARDs, glucocorticoids and immunosuppressants. Interferon gamma release assay should be preferred over tuberculin skin test, where available. Hepatitis B (HBV)…

OBJECTIVES: Evaluate risk of major adverse cardiovascular events (MACE) with tofacitinib versus tumour necrosis factor inhibitors (TNFi) in patients with rheumatoid arthritis (RA) with or without a history of atherosclerotic cardiovascular disease (ASCVD) in ORAL Surveillance. METHODS: Patients with RA aged ≥50 years with ≥1 additional CV risk factor received tofacitinib 5 mg or 10 mg two times per day or TNFi. Hazard rations (HRs) were evaluated for the overall population and by history of ASCVD (exploratory analysis). RESULTS: Risk of MACE, myocardial infarction and sudden cardiac death were increased with tofacitinib versus TNFi in ORAL Surveillance. In patients with history of ASCVD (14.7%; 640/4362), MACE incidence was higher with tofacitinib 5 mg two times per day (8.3%; 17/204) and 10 mg two times per day (7.7%; 17/222) versus TNFi (4.2%; 9/214). HR (combined tofacitinib doses vs TNFi) was 1.98 (95% confidence interval (CI) 0.95 to 4.14; interaction p values: 0.196 (for HR)/0.059 (for incidence rate difference)). In patients without history of ASCVD, MACE HRs for tofacitinib…

OBJECTIVE: To evaluate the efficacy and safety of an oral selective tyrosine kinase 2 (TYK2) inhibitor, deucravacitinib, in patients with active psoriatic arthritis (PsA). METHODS: In this double-blind, phase II trial, 203 patients with PsA were randomised 1:1:1 to placebo, deucravacitinib 6 mg once a day or 12 mg once a day. The primary endpoint was American College of Rheumatology-20 (ACR-20) response at week 16. RESULTS: 0.0004) versus placebo (31.8%) at week 16. Both deucravacitinib doses resulted in significant improvements versus placebo (p≤0.05) in the multiplicity-controlled secondary endpoints of change from baseline in Health Assessment Questionnaire-Disability Index and Short Form-36 Physical Component Summary score and in Psoriasis Area and Severity Index-75 response. Improvements were also seen in multiple exploratory endpoints with deucravacitinib treatment. The most common adverse events (AEs) (≥5%) in deucravacitinib-treated patients were nasopharyngitis, upper respiratory tract infection, sinusitis, bronchitis, rash, headache and diarrhoea. There were no serious AEs…

OBJECTIVE: To assess the efficacy and safety of the type I interferon receptor antibody, anifrolumab, in patients with active, biopsy-proven, Class III/IV lupus nephritis. METHODS: This phase II double-blinded study randomised 147 patients (1:1:1) to receive monthly intravenous anifrolumab basic regimen (BR, 300 mg), intensified regimen (IR, 900 mg ×3, 300 mg thereafter) or placebo, alongside standard therapy (oral glucocorticoids, mycophenolate mofetil). The primary endpoint was change in baseline 24-hour urine protein-creatinine ratio (UPCR) at week (W) 52 for combined anifrolumab versus placebo groups. The secondary endpoint was complete renal response (CRR) at W52. Exploratory endpoints included more stringent CRR definitions and sustained glucocorticoid reductions (≤7.5 mg/day, W24-52). Safety was analysed descriptively. RESULTS: Patients received anifrolumab BR (n=45), IR (n=51), or placebo (n=49). At W52, 24-hour UPCR improved by 69% and 70% for combined anifrolumab and placebo groups, respectively (geometric mean ratio=1.03; 95% CI 0.62 to 1.71; p=0.905). Serum…

OBJECTIVES: To update the evidence on efficacy of DMARDs (disease-modifying antirheumatic drugs) and inform the taskforce of the 2022 update of the European Alliance of Associations for Rheumatology (EULAR) recommendations for management of rheumatoid arthritis (RA). METHODS: This systematic literature review (SLR) investigated the efficacy of conventional synthetic (cs), biological (b), biosimilar and targeted synthetic (ts)DMARDs in patients with RA. Medline, EMBASE, Cochrane CENTRAL and Web of Science were used to identify all relevant articles published since the previous update in 2019 to 14 January 2022. RESULTS: Of 8969 search results, 169 articles were selected for detailed review and 47 were finally included. Trials investigated the efficacy of csDMARDs, bDMARDs and tsDMARDs, DMARD switching, tapering and trials investigating different treatment strategies. The compounds investigated were csDMARDs (methotrexate (MTX), leflunomide, sulfasalazine, hydroxychloroquine), bDMARDs (abatacept, adalimumab, certolizumab-pegol, denosumab, etanercept, infliximab, levilimab, olokizumab,…

OBJECTIVES: To evaluate malignancies and their associations with baseline risk factors and cardiovascular risk scores with tofacitinib versus tumour necrosis factor inhibitors (TNFi) in patients with rheumatoid arthritis (RA). METHODS: In an open-label, randomised controlled trial (ORAL Surveillance; NCT02092467), 4362 patients with RA aged ≥50 years with ≥1 additional cardiovascular risk factor received tofacitinib 5 (N=1455) or 10 mg two times per day (N=1456) or TNFi (N=1451). Incidence rates (IRs; patients with first events/100 patient-years) and HRs were calculated for adjudicated malignancies excluding non-melanoma skin cancer (NMSC), NMSC and subtypes. Post hoc analyses for malignancies excluding NMSC, lung cancer and NMSC included risk factors identified via simple/multivariable Cox models and IRs/HRs categorised by baseline risk factors, history of atherosclerotic cardiovascular disease (HxASCVD) and cardiovascular risk scores. RESULTS: IRs for malignancies excluding NMSC and NMSC were higher with tofacitinib (combined and individual doses) versus TNFi. Risk of lung cancer…

BACKGROUND: Low-dose glucocorticoid (GC) therapy is widely used in rheumatoid arthritis (RA) but the balance of benefit and harm is still unclear. METHODS: The GLORIA (Glucocorticoid LOw-dose in RheumatoId Arthritis) pragmatic double-blind randomised trial compared 2 years of prednisolone, 5 mg/day, to placebo in patients aged 65+ with active RA. We allowed all cotreatments except long-term open label GC and minimised exclusion criteria, tailored to seniors. Benefit outcomes included disease activity (disease activity score; DAS28, coprimary) and joint damage (Sharp/van der Heijde, secondary). The other coprimary outcome was harm, expressed as the proportion of patients with ≥1 adverse event (AE) of special interest. Such events comprised serious events, GC-specific events and those causing study discontinuation. Longitudinal models analysed the data, with one-sided testing and 95% confidence limits (95% CL). RESULTS: We randomised 451 patients with established RA and mean 2.1 comorbidities, age 72, disease duration 11 years and DAS28 4.5. 79% were on disease-modifying treatment,…

With the worldwide digitalisation of medical records, electronic health records (EHRs) have become an increasingly important source of real-world data (RWD). RWD can complement traditional study designs because it captures almost the complete variety of patients, leading to more generalisable results. For rheumatology, these data are particularly interesting as our diseases are uncommon and often take years to develop. In this review, we discuss the following concepts related to the use of EHR for research and considerations for translation into clinical care: EHR data contain a broad collection of healthcare data covering the multitude of real-life patients and the healthcare processes related to their care. Machine learning (ML) is a powerful method that allows us to leverage a large amount of heterogeneous clinical data for clinical algorithms, but requires extensive training, testing, and validation. Patterns discovered in EHR data using ML are applicable to real life settings, however, are also prone to capturing the local EHR structure and limiting generalisability outside the…

OBJECTIVES: To characterise the efficacy and safety of anifrolumab in patients with systemic lupus erythematosus (SLE) according to interferon gene signature (IFNGS), demographic and clinical subgroups. METHODS: We performed post hoc analyses of pooled data from the 52-week phase III TULIP-1/TULIP-2 placebo-controlled trials of intravenous anifrolumab in moderate-to-severe SLE. Outcomes were assessed in predefined subgroups: IFNGS (high/low), age, sex, body mass index, race, geographic region, age of onset, glucocorticoid use, disease activity and serological markers. RESULTS: In pooled data, patients received anifrolumab 300 mg (360/726) or placebo (366/726); 82.6% were IFNGS-high. IFNGS-high patients had greater baseline disease activity and were more likely to have abnormal serological markers versus IFNGS-low patients. In the total population, a greater proportion of patients treated with anifrolumab versus placebo achieved British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) response at week 52 (difference 16.6%; nominal p<0.001). BICLA response…

BACKGROUND: JAK-inhibitors (JAKi), recently approved in rheumatoid arthritis (RA), have changed the landscape of treatment choices. We aimed to compare the effectiveness of four current second-line therapies of RA with different modes of action, since JAKi approval, in an international collaboration of 19 registers. METHODS: In this observational cohort study, patients initiating tumour necrosis factor inhibitors (TNFi), interleukin-6 inhibitors (IL-6i), abatacept (ABA) or JAKi were included. We compared the effectiveness of these treatments in terms of drug discontinuation and Clinical Disease Activity Index (CDAI) response rates at 1 year. Analyses were adjusted for patient, disease and treatment characteristics, including lines of therapy and accounted for competing risk. RESULTS: We included 31 846 treatment courses: 17 522 TNFi, 2775 ABA, 3863 IL-6i and 7686 JAKi. Adjusted analyses of overall discontinuation were similar across all treatments. The main single reason of stopping treatment was ineffectiveness. Compared with TNFi, JAKi were less often discontinued for…

OBJECTIVE: In 2011, the American College of Rheumatology (ACR) and EULAR endorsed provisional criteria for remission in rheumatoid arthritis (RA), both Boolean-based and index-based. Based on recent studies indicating that a higher threshold for the patient global assessment (PtGA) may improve agreement between the two sets of criteria, our goals were to externally validate a revision of the Boolean remission criteria using a higher PtGA threshold and to validate the provisionally endorsed index-based criteria. METHODS: We used data from four randomised trials comparing biological disease-modifying antirheumatic drugs to methotrexate or placebo. We tested the higher proposed PtGA threshold of 2 cm (Boolean2.0) (range 0-10 cm) compared with the original threshold of 1 cm (Boolean1.0). We analysed agreement between the Boolean-based and index-based criteria (Simplified Disease Activity Index (SDAI) and Clinical Disease Activity Index (CDAI)) for remission and examined how well each remission definition predicted later good physical function (Health Assessment Questionnaire (HAQ)…

OBJECTIVES: To evaluate the efficacy and safety of upadacitinib, a Janus kinase inhibitor, in patients with active ankylosing spondylitis (AS) with an inadequate response (IR) to biological disease-modifying antirheumatic drugs (bDMARDs). METHODS: Adults with active AS who met modified New York criteria and had an IR to one or two bDMARDs (tumour necrosis factor or interleukin-17 inhibitors) were randomised 1:1 to oral upadacitinib 15 mg once daily or placebo. The primary endpoint was Assessment of SpondyloArthritis international Society 40 (ASAS40) response at week 14. Sequentially tested secondary endpoints included Ankylosing Spondylitis Disease Activity score, Spondyloarthritis Research Consortium of Canada MRI spine inflammation score, total back pain, nocturnal back pain, Bath Ankylosing Spondylitis Functional Index, Bath Ankylosing Spondylitis Metrology Index and Maastricht Ankylosing Spondylitis Enthesitis Score. Results are reported from the 14-week double-blind treatment period. RESULTS: A total of 420 patients with active AS were randomised (upadacitinib 15 mg, n=211;…

OBJECTIVES: Granulocyte-macrophage colony-stimulating factor (GM-CSF) is implicated in pathogenesis of giant cell arteritis. We evaluated the efficacy of the GM-CSF receptor antagonist mavrilimumab in maintaining disease remission. METHODS: This phase 2, double-blind, placebo-controlled trial enrolled patients with biopsy-confirmed or imaging-confirmed giant cell arteritis in 50 centres (North America, Europe, Australia). Active disease within 6 weeks of baseline was required for inclusion. Patients in glucocorticoid-induced remission were randomly assigned (3:2 ratio) to mavrilimumab 150 mg or placebo injected subcutaneously every 2 weeks. Both groups received a 26-week prednisone taper. The primary outcome was time to adjudicated flare by week 26. A prespecified secondary efficacy outcome was sustained remission at week 26 by Kaplan-Meier estimation. Safety was also assessed. RESULTS: Of 42 mavrilimumab recipients, flare occurred in 19% (n=8). Of 28 placebo recipients, flare occurred in 46% (n=13). Median time to flare (primary outcome) was 25.1 weeks in the placebo group, but the…

Fibroblast-like synoviocytes or synovial fibroblasts (FLS) are important cellular components of the inner layer of the joint capsule, referred to as the synovial membrane. They can be found in both layers of this synovial membrane and contribute to normal joint function by producing extracellular matrix components and lubricants. However, under inflammatory conditions like in rheumatoid arthritis (RA), they may start to proliferate, undergo phenotypical changes and become central elements in the perpetuation of inflammation through their direct and indirect destructive functions. Their importance in autoimmune joint disorders makes them attractive cellular targets, and as mesenchymal-derived cells, their inhibition may be carried out without immunosuppressive consequences. Here, we aim to give an overview of our current understanding of the target potential of these cells in RA.

OBJECTIVE: To develop a composite responder index in primary Sjögren's syndrome (pSS): the Sjögren's Tool for Assessing Response (STAR). METHODS: To develop STAR, the NECESSITY (New clinical endpoints in primary Sjögren's syndrome: an interventional trial based on stratifying patients) consortium used data-driven methods based on nine randomised controlled trials (RCTs) and consensus techniques involving 78 experts and 20 patients. Based on reanalysis of rituximab trials and the literature, the Delphi panel identified a core set of domains with their respective outcome measures. STAR options combining these domains were proposed to the panel for selection and improvement. For each STAR option, sensitivity to change was estimated by the C-index in nine RCTs. Delphi rounds were run for selecting STAR. For the options remaining before the final vote, a meta-analysis of the RCTs was performed. RESULTS: The Delphi panel identified five core domains (systemic activity, patient symptoms, lachrymal gland function, salivary gland function and biological parameters), and 227 STAR options…

OBJECTIVE: To assess and compare the incidence of venous thromboembolism (VTE) in patients with rheumatoid arthritis (RA) treated with Janus kinase inhibitors (JAKi), tumour necrosis factor inhibitors (TNFi) or other biological disease modifying antirheumatic drugs (bDMARDs). For contextualisation, to assess VTE incidences in the Swedish general population and in the RA source population. METHODS: We performed a nationwide register-based, active comparator, new user design cohort study in Sweden from 2010 to 2021. The Swedish Rheumatology Quality Register was linked to national health registers to identify treatment cohorts (exposure) of initiators of a JAKi, a TNFi, or a non-TNFi bDMARD (n=32 737 treatment initiations). We also identified a general population cohort (matched 1:5, n=92 108), and an 'overall RA' comparator cohort (n=85 722). Outcome was time to first VTE during the follow-up, overall and by deep vein thrombosis (DVT) and pulmonary embolism (PE). We calculated incidence rates (IR) and multivariable-adjusted HRs using Cox regression. RESULTS: Based on 559 incident VTE…

Objectives To find causal genes for rheumatoid arthritis (RA) and its seropositive (RF and/or ACPA positive) and seronegative subsets. Methods We performed a genome-wide association study (GWAS) of 31 313 RA cases (68% seropositive) and ~1 million controls from Northwestern Europe. We searched for causal genes outside the HLA-locus through effect on coding, mRNA expression in several tissues and/or levels of plasma proteins (SomaScan) and did network analysis (Qiagen). Results We found 25 sequence variants for RA overall, 33 for seropositive and 2 for seronegative RA, altogether 37 sequence variants at 34 non-HLA loci, of which 15 are novel. Genomic, transcriptomic and proteomic analysis of these yielded 25 causal genes in seropositive RA and additional two overall. Most encode proteins in the network of interferon-alpha/beta and IL-12/23 that signal through the JAK/STAT-pathway. Highlighting those with largest effect on seropositive RA, a rare missense variant in STAT4 (rs140675301-A) that is independent of reported non-coding STAT4-variants, increases the risk of seropositive RA…

Objective Rheumatoid arthritis (RA) is a progressive disease including four stages, where gut microbiome is associated with pathogenesis. We aimed to investigate stage-specific roles of microbial dysbiosis and metabolic disorders in RA. Methods We investigated stage-based profiles of faecal metagenome and plasma metabolome of 76 individuals with RA grouped into four stages (stages I–IV) according to 2010 RA classification criteria, 19 individuals with osteroarthritis and 27 healthy individuals. To verify bacterial invasion of joint synovial fluid, 16S rRNA gene sequencing, bacterial isolation and scanning electron microscopy were conducted on another validation cohort of 271 patients from four RA stages. Results First, depletion of Bacteroides uniformis and Bacteroides plebeius weakened glycosaminoglycan metabolism (p<0.001), continuously hurting articular cartilage across four stages. Second, elevation of Escherichia coli enhanced arginine succinyltransferase pathway in the stage II and stage III (p<0.001), which was correlated with the increase of the rheumatoid factor…