Clinical characteristics, disease trajectories and management of vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome: a systematic review.

BACKGROUND: VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a newly discovered autoinflammatory condition characterised by somatic mutation of the UBA1 gene. The syndrome leads to multi-system inflammation affecting predominantly the skin, lungs and bone marrow. METHODS: We undertook a systematic review of the multisystem features and genotypes observed in VEXAS syndrome. Articles discussing VEXAS syndrome were included. Medline, Embase and Cochrane databases were searched. Information was extracted on: demographics, type and prevalence of clinical manifestations, genetic mutations and treatment. Meta-analysis using a random effects model was used to determine pooled estimates of serum markers. RESULTS: From 303 articles, 90 were included, comprising 394 patients with VEXAS. 99.2% were male, with a mean age of 67.1 years (SD 8.5) at disease onset. The most frequent diagnoses made prior to VEXAS were: relapsing polychondritis (n = 59); Sweet's syndrome (n = 24); polyarteritis nodosa (n = 11); and myelodysplastic syndrome (n = 10). Fever was reported in 270 cases (68.5%) and weight loss in 79 (20.1%). Most patients had haematological (n = 342; 86.8%), dermatological (n = 321; 81.5%), pulmonary (n = 297; 75.4%%) and musculoskeletal (n = 172; 43.7%) involvement, although other organ manifestations of varying prevalence were also recorded. The most commonly reported mutations were "c.122T > C pMET41Thr" (n = 124), "c.121A > G pMET41Val" (n = 62) and "c.121A > C pMet41Leu" (n = 52). Most patients received glucocorticoids (n = 240; 60.9%) followed by methotrexate (n = 82; 20.8%) and IL-6 inhibitors (n = 61, 15.4%). One patient underwent splenectomy; 24 received bone marrow transplants. CONCLUSION: VEXAS syndrome is a rare disorder affecting predominantly middle-aged men. This is the first systematic review to capture clinical manifestations, genetics and treatment of reported cases. Further studies are needed to optimise treatment and subsequently reduce morbidity and mortality.

Pulmonary manifestations, treatments and outcomes of IgG4-related disease-a systematic literature review.

Immunoglobulin G4-related disease (IgG4-RD) is a multisystem fibroinflammatory condition. A consistent feature of many cases is pulmonary infiltrates, or respiratory failure. This systematic literature review aims to summarise the pulmonary manifestations of IgG4-RD, including clinical outcomes and treatment. This review was registered on PROSPERO (CRD42023416410). Medline, Embase and Cochrane databases were searched for articles discussing IgG4-RD syndrome. Information was extracted on demographics, type and prevalence of pulmonary manifestations, treatment and clinical outcomes. Initially, after deduplication, 3123 articles were retrieved with 18 ultimately included. A pooled total of 724 patients with IgG4-RD were included, 68.6% male, mean age 59.4 years (SD 5.8) at disease onset. The most frequently described pulmonary manifestation was mediastinal lymphadenopathy (n = 186, 48.8%), followed by pulmonary nodules (n = 151, 39.6%) and broncho-vascular thickening (n = 85, 22.3%). Where treatment was reported, the majority of patients received glucocorticoids (n = 211, 93.4%). Other immunosuppressive therapy included cyclophosphamide (n = 31), azathioprine (n = 18), with mycophenolate mofetil (n = 6), rituximab (n = 6), methotrexate (n = 5) and other unspecified immunomodulators (50). Clinical outcomes were reported in 263 patients, where 196 patients had remission of their disease, 20 had relapse, 35 had stable disease, four had progression and eight patients died from complications of IgG4-RD. This systematic review summarises pulmonary manifestations, treatments and outcomes in patients with IgG4-RD. Pulmonary involvement in IgG4-RD is relatively common, leading to high levels of morbidity and mortality. Glucocorticoids remain the mainstay of treatment, but further work is required to explore the management of patients with pulmonary manifestations in association with IgG4-RD.

2022 EULAR recommendations for screening and prophylaxis of chronic and opportunistic infections in adults with autoimmune inflammatory rheumatic diseases.

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) antiviral treatment should be guided by HBV status defined prior to starting antirheumatic drugs. All patients positive for hepatitis-C-RNA should be referred for antiviral treatment. Also, patients who are non-immune to varicella zoster virus should be informed about the availability of postexposure prophylaxis should they have contact with this pathogen. Prophylaxis against Pneumocystis jirovecii seems to be beneficial in patients treated with daily doses >15-30 mg of prednisolone or equivalent for >2-4 weeks. CONCLUSIONS: These recommendations provide guidance on the screening and prevention of chronic and opportunistic infections. Their adoption in clinical practice is recommended to standardise and optimise care to reduce the burden of opportunistic infections in people living with AIIRD.

Comorbidities and extra-articular manifestations in difficult-to-treat rheumatoid arthritis: different sides of the same coin?

Despite the improvement in treatment for people with RA, ∼30% of patients remain symptomatic in the presence of optimized medical therapy, described as having 'difficult-to-treat' (D2T) RA. The average patient with RA has 1.6 other clinical conditions, which accumulate over time. Comorbidities are increasingly recognized as key contributors to D2T disease, and are themselves perpetuated by the D2T state. In this review, we discuss the commonest comorbidities in the context of D2T RA. We propose the need for a paradigm shift in the clinical and research agenda for comorbidities-including a need to consider and manage these prior to the development of D2T disease and not as an afterthought.

Multimorbidity in rheumatoid arthritis: common mechanistic links and impact and challenges in routine clinical practice.

Early identification and management of multimorbidity in patients with rheumatic and musculoskeletal diseases (RMDs), such as RA, is an integral, but often neglected, aspect of care. The prevalence and incidence of conditions such as osteoporosis, cardiovascular disease, pulmonary disease and malignancies, often co-existing with RA, continues to have significant implications for the management of this patient group. Multimorbidity in RMDs can be associated with inflammatory disease activity and target organ damage. Lifestyle factors, such as smoking and inactivity, further contribute to the burden of disease. Inflammation is the underlying factor, not just in RA but also many comorbidities. The current framework of a treat-to-target approach focuses on achieving early remission and inflammatory activity suppression. We describe how the comorbidity burden in people with RMDs impacts on disease outcome and treatment response. The importance of addressing comorbidity at an early stage and adopting a patient centred approach is critical in modern practice.

Assessment and diagnosis of the acute hot joint: a systematic review and meta-analysis.

OBJECTIVES: Prompt diagnosis of septic arthritis (SA) in acute native hot joints is essential for avoiding unnecessary antibiotics and hospital admissions. We evaluated the utility of synovial fluid (SF) and serum tests in differentiating causes of acute hot joints. METHODS: We performed a systematic literature review of diagnostic testing for acute hot joints. Articles were included if studying ≥1 serum or SF test(s) for an acute hot joint, compared with clinical assessment and SF microscopy and culture. English-language articles only were included, without date restriction. The following were recorded for each test, threshold and diagnosis: sensitivity, specificity, positive/negative predictive values and likelihood ratios. For directly comparable tests (i.e. identical fluid, test and threshold), bivariate random-effects meta-analysis was used to pool sensitivity, specificity, and areas under the curves. RESULTS: A total of 8443 articles were identified, and 49 were ultimately included. Information on 28 distinct markers in SF and serum, differentiating septic from non-septic joints, was extracted. Most had been tested at multiple diagnostic thresholds, yielding a total of 27 serum markers and 156 SF markers. Due to heterogeneity of study design, outcomes and thresholds, meta-analysis was possible for only eight SF tests, all differentiating septic from non-septic joints. Of these, leucocyte esterase had the highest pooled sensitivity [0.94 (0.70, 0.99)] with good pooled specificity [0.74 (0.67, 0.81)]. CONCLUSION: Our review demonstrates many single tests, individually with diagnostic utility but suboptimal accuracy for exclusion of native joint infection. A combination of several tests with or without a stratification score is required for optimizing rapid assessment of the hot joint.

Opportunistic optimization of inhaler technique in hospitalized adults with asthma: a two-phase educational study.

OBJECTIVE: To investigate effectiveness of two different educational methods to improve inhaler techniques in patients with prior diagnosis of asthma, hospitalized with a non-asthma-related diagnosis. METHODS: We undertook a real-world, opportunistic quality-improvement project. Inhaler technique in hospitalized patients with prior diagnosis of asthma was assessed in two cohorts over two 12-week cycles using a standardized device-specific proforma of seven-step inhaler technique, classed: "good" if 6/7 steps achieved; "fair" if 5/7 compliant; "poor" for others. Baseline data was collected in both cycles. Cycle one involved face-to-face education by a healthcare professional; cycle two involved additional use of an electronic device to show device-specific videos (asthma.org.uk). In both cycles, patients were reassessed within two days for improvements and the two methods compared for effectiveness. RESULTS: During cycle one 32/40 patients were reassessed within 48 h; eight lost to follow-up. During cycle two 38/40 patients were reassessed within 48 h; two lost to follow-up During cycle one, two and 12 had good/fair baseline technique respectively, and 26 poor. Most commonly missed steps were no expiry check/not rinsing mouth after steroid use. On reassessment 17% patients improved from poor to fair/good. During cycle two, initial technique assessment identified: 23 poor; 12 fair; five good. Post-videos, 35% of patients improved from poor to fair/good. Proportion of patients improving from poor to fair, or poor/fair to good increased in cycle two vs one (52.5% vs 33%). CONCLUSION: Visual instruction is associated with improved technique compared to verbal feedback. This is a user-friendly and cost-effective approach to patient education.

A systematic review of the incidence, management and prognosis of new-onset autoimmune connective tissue diseases after COVID-19.

A literature review on new-onset autoimmune connective tissue diseases (ACTDs) following COVID-19 is lacking. We evaluated potential associations between COVID-19 and the development of new-onset ACTDs. The "population" was adults with disease terms for ACTDs, including systemic lupus erythematosus (SLE), Sjogren's syndrome, systemic sclerosis (SSc), idiopathic inflammatory myositis (IIM), anti-synthetase syndrome, mixed CTD and undifferentiated CTD, and "intervention" as COVID-19 and related terms. Databases were searched for English-language articles published until September 2022. We identified 2236 articles with 28 ultimately included. Of the 28 included patients, 64.3% were female, with a mean age was 51.1 years. The USA reported the most cases (9/28). ACTD diagnoses comprised: 11 (39.3%) IIM (including four dermatomyositis); 7 (25%) SLE; four (14.3%) anti-synthetase syndrome; four (14.3%) SSc; two (7.1%) other ACTD (one lupus/MCTD overlap). Of eight, four (14.3%) patients (including that with lupus/MCTD) had lupus nephritis. The average time from COVID-19 to ACTD diagnosis was 23.7 days. A third of patients were admitted to critical care, one for treatment of haemophagocytic lymphohistiocytosis in SLE (14 sessions of plasmapheresis, rituximab and intravenous corticosteroids) and nine due to COVID-19. 80% of patients went into remission of ACTD following treatment, while three (10%) patients died-one due to macrophage activation syndrome with anti-synthetase syndrome and two from unreported causes. Our results suggest a potential association between COVID-19 and new-onset ACTDs, notably in young females, reflecting more comprehensive CTD epidemiology. The most common diagnosis in our cohort was IIM. The aetiology and mechanisms by which ACTDs emerge following COVID-19 remain unknown and require further research.

Pulmonary manifestations in VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome: a systematic review.

BACKGROUND: VEXAS (vacuoles, E1 enzyme, X-linked, auto-inflammatory, somatic) syndrome is a newly described auto-inflammatory disease. Many cases feature pulmonary infiltrates or respiratory failure. This systematic review aimed to summarize respiratory manifestations in VEXAS syndrome described to date. METHODS: Databases were searched for articles discussing VEXAS syndrome until May 2022. The research question was: What are the pulmonary manifestations in patients with VEXAS syndrome? The search was restricted to English language and those discussing clinical presentation of disease. Information on basic demographics, type and prevalence of pulmonary manifestations, co-existing disease associations and author conclusions on pulmonary involvement were extracted. The protocol was registered on the PROSPERO register of systematic reviews. RESULTS: Initially, 219 articles were retrieved with 36 ultimately included (all case reports or series). A total of 269 patients with VEXAS were included, 98.6% male, mean age 66.8 years at disease onset. The most frequently described pulmonary manifestation was infiltrates (43.1%; n = 116), followed by pleural effusion (7.4%; n = 20) and idiopathic interstitial pneumonia (3.3%; n = 9). Other pulmonary manifestations were: nonspecific interstitial pneumonia (n = 1), bronchiolitis obliterans (n = 3), pulmonary vasculitis (n = 6), bronchiectasis (n = 1), alveolar haemorrhage (n = 1), pulmonary embolism (n = 4), bronchial stenosis (n = 1), and alveolitis (n = 1). Several patients had one or more co-existing autoimmune/inflammatory condition. It was not reported which patients had particular pulmonary manifestations. CONCLUSION: This is the first systematic review undertaken in VEXAS patients. Our results demonstrate that pulmonary involvement is common in this patient group. It is unclear if respiratory manifestations are part of the primary disease or a co-existing condition. Larger epidemiological analyses will aid further characterisation of pulmonary involvement and disease management.

The association between increased body mass index and response to conventional synthetic disease-modifying anti-rheumatic drug treatment in rheumatoid arthritis: results from the METEOR database.

BACKGROUND: Few data exist on the association between increased BMI and response to conventional synthetic DMARDs (csDMARDs) in RA. We aimed to explore the association between increased (overweight or obese) BMI on csDMARD prescribing, MTX dose and disease activity over 12 months. METHODS: Participants in an international RA database were stratified into early (<1 year post-diagnosis) and established RA. EULAR response, 28-joint DAS (DAS28) remission and treatments were recorded at baseline, 6 months and 12 months. Increased BMI was explored in early and established RA as predictors of good EULAR response, DAS28 remission, number of csDMARDs and MTX dose, using logistic and linear regression. RESULTS: Data from 1313 patients, 44.3% with early RA, were examined. In early RA, increased BMI was not significantly associated with remission. In established RA, obese patients on monotherapy were significantly less likely to achieve good EULAR response or DAS28 remission at 6 months and more likely to be treated with combination csDMARDs compared with normal BMI. In patients taking MTX, overweight and obese patients with early and established RA were exposed to higher MTX doses (mono- and combination therapy), with a mean dose of 20 mg/week, compared with 15 mg/week in those of normal BMI. CONCLUSION: We observed that compared with patients with normal BMI, overweight and obese individuals experienced more intensive csDMARD exposures. Similar response rates were observed in early RA but increased BMI was associated with reduced response in established RA. Optimization of targeted RA treatment remains important, particularly in those with increased BMI where response in established disease may be attenuated.

The use and context of the term 'multimorbidity' in rheumatoid arthritis: a systematic literature review.

This systematic literature review aimed to analyse terms describing coexisting conditions in the RA literature, informing the need for an operationalized definition of multimorbidity. Articles discussing RA with multimorbidity, published 1946 until August 2020, were identified. The primary outcome was the use and/or definition of 'multimorbidity' in RA. Information extracted included terms defining coexisting conditions, the use of a comorbidity/multimorbidity score and the use of 'index disease' to describe RA (more applicable to comorbidity than multimorbidity). Thirty-nine articles were included. Eight articles used the term 'multimorbidity', 18 used 'comorbidity' and 12 used both terms, 7 synonymously. One used no term. Fourteen articles fully defined the term. The number of co-existing conditions described in included studies was one-121. Twelve articles used a comorbidity/multimorbidity score. Four articles described RA as the 'index disease'. Our results demonstrate inconsistent use of the term multimorbidity. Improved assessment of multimorbidity is indicated in RA patients, including an operationalized use and definition.

Google search data as a novel adjunct to patient and public involvement in rheumatology research.

Patient and public involvement is essential in the design and implementation of research studies to ensure research remains relevant and in line with public priorities. Public views on a given area of research may be sought via platforms such as focus groups or surveys. Here, we present the use of an openly available Google search data query tool, which may be used alongside traditional forms of patient and public involvement in research to highlight public perceptions and priorities. We used an online search query tool ("AnswerThePublic.com") to explore public Google searches relating to "arthritis," and an exemplar rheumatic disease, "rheumatoid arthritis." The most common searches relating to these diseases included quality of life, treatment, prognosis, as well as impacts on life, including work. However, they also reveal concerns that may be more difficult to elicit in face-to-face focus groups, such as questions on alcohol consumption in arthritis, and impacts on mental health. Using public search engine data in research, alongside the important traditional methods of patient and public involvement, is a cost-effective and time-efficient method of gauging public views and concerns on a given topic. It may facilitate broad scoping searches of public priorities and help to guide future research questions.

Oral antipsychotic prescribing and association with neighbourhood-level socioeconomic status: analysis of time trend of routine primary care data in England, 2011-2016.

BACKGROUND: Increasing rates of antipsychotic prescribing have been reported previously, particularly for second-generation antipsychotics (SGAs), which are generally better tolerated than the older first-generation antipsychotics (FGAs). Prescribers, however, may exert bias, favouring prescriptions of novel drugs for patients of higher socioeconomic status (SES). We aimed to examine time trends in: (1) prescriptions of oral FGAs vs. SGAs and (2) associations between antipsychotic prescriptions and neighbourhood-level SES in England between 2011 and 2016. METHODS: We used publicly available data for prescriptions made in primary care and linked general practices' postcodes with the Index of Multiple Deprivation (IMD) as a measure for neighbourhood-level SES. Absolute numbers of antipsychotic prescriptions were calculated. Linear regression analysis was used to examine the association of SGA vs. FGA prescription pattern with time and with SES. RESULTS: A total of 27,486,000 oral antipsychotics were prescribed during the study period, mostly SGAs (n = 21,700,000; 78.9%). There was a significant increase in the ratio of SGA/FGA prescriptions over time (ß = 0.376, 95% CI 0.277-0.464, P < 0.001). Individual FGAs were increasingly prescribed in areas of lower SES and the converse for SGAs except amisulpride. During the study period, a significantly larger proportion of total SGA prescriptions relative to total FGAs were made in areas of higher SES (ß = 0.182, 95% CI 0.117-0.249, P < 0.001). CONCLUSION: Prescriptions of antipsychotics continue to rise overall, with SGAs taking preference especially in areas of higher SES. The pattern of antipsychotic prescription favouring people in areas of lower social deprivation carries implications on inequalities even among sub-groups of people with mental disorders.