Objectives Patients with systemic sclerosis (SSc) are at increased risk for osteoporosis (OP) and associated fragility fractures. This study aimed to identify underlying risk factors for these conditions in patients with SSc.Methods This cross-sectional study was based on a large prospective cohort of patients with SSc using retrospectively collected bone health data. OP was defined as the presence of a T-score below -2.5 at the femoral neck or lumbar spine, a previous major osteoporotic fracture, or the prescription of anti-osteoporotic therapy.Results A total of 485 patients fulfilling the ACR/EULAR 2013 diagnostic criteria for SSc, followed in the Lille University Hospital, were included in the study. The prevalence of OP was 23%; fragility fractures occurred in 18% of patients. OP was associated with higher age, diffuse cutaneous subset, interstitial lung disease (ILD), anti-topoisomerase I positivity, treatment with glucocorticoids (GC) and DMARDs in univariable analysis. Multivariable analysis indicated that higher age (OR 1.06 [95%CI 1.04-1.08]), anti-topoisomerase I antibody positivity (OR 2.22 [1.18-4.16]) and treatment with GC (OR 4.48 [2.42-8.26]) were significantly and independently associated with OP.Conclusion Our study shows that OP risk in patients with SSc is determined by age, disease-related factors such as diffuse cutaneous subset, ILD and anti-topoisomerase I antibody positivity, but also treatment with GC independently of other factors.

The etiology of giant cell arteritis (GCA) and its predictors are incompletely understood. Previous studies have indicated reduced risk of future development of GCA in individuals with obesity and/or diabetes mellitus. There is limited information on blood lipids before the onset of GCA. The objective of the study was to investigate the relation between apolipoprotein levels and future diagnosis of GCA in a nested case–control analysis. Individuals who developed GCA after inclusion in a population-based health survey (the Malmö Diet Cancer Study; N = 30,447) were identified by linking the health survey database to the local patient administrative register and the national patient register. A structured review of medical records was performed. Four controls for every validated case, matched for sex, year of birth, and year of screening, were selected from the database. Anthropometric measures, self-reported physical activity, based on a comprehensive, validated questionnaire, and non-fasting blood samples had been obtained at health survey screening. Concentrations of apolipoprotein A-I (ApoA-I) and apolipoprotein B (ApoB) in stored serum were measured using an immunonephelometric assay. Potential predictors of GCA were examined in conditional logistic regression models. There were 100 cases with a confirmed clinical diagnosis of GCA (81

Background: Rheumatoid arthritis associated interstitial lung disease (RA-ILD), is an important extra-articular manifestation of rheumatoid arthritis (RA). The frequency, risk factors, and prognosis of RA-ILD are incompletely understood. Aims: To determine the prevalence and incidence, clinical characteristics and risk factors for development, and outcomes of persons with RA-ILD in the population of the Canterbury District Health Board (CDHB) catchment area. Methods: Individuals aged >= 18 years with RA, resident in the CDHB catchment area between 1 January 2006 and 31 December 2008 (Period One), and 1 January 2011 to 31 December 2013 (Period Two) were identified by medical record review and followed until 30 June 2019. Individuals with RA-ILD as defined by pre-specified criteria were identified. The association between demographic and clinical characteristics and RA-ILD development and mortality was examined using Cox-proportional hazards models. Results: The prevalence of RA-ILD per 100,000 was 10.97 (95 % CI 7.53,14.42) for Period One, and 14.74 (95 % CI 10.84,18.63) for Period Two. Among individuals evaluated for risk factors for RA-ILD development, the estimated cumulative incidence of ILD at 10 years was 4.47 % (95 % CI 3.14, 6.14). After adjusting for age, rheumatoid factor positivity (HR 3.73, 95 % CI, 1.32,10.56), extra-articular manifestations other than RA-ILD (HR 4.48, 95 % CI 2.36,8.48), and subcutaneous rheumatoid nodules (HR 4.66, 95 % CI 2.34, 9.26) were associated with increased risk of developing RA-ILD. The standardised mortality ratio for RA-ILD was 3.90 (95 % CI 2.55,5.72) compared to the general population. Extent of ILD on CT chest was associated with mortality (HR for >20% vs. < 20 % 4.47, 95 % CI 1.67,11.96). Conclusions: Clinically evident RA-ILD occurred in approximately 5 % of individuals with RA. Mortality was increased almost fourfold compared to the general population. Radiologic extent was the most important prognostic factor.

Interstitial lung disease (ILD) is a frequent manifestation of rheumatoid arthritis (RA) that is associated with high mortality. RA-ILD may initially be asymptomatic, and lung function may be markedly impaired by the time it is diagnosed. The course of RA-ILD is highly variable, with some patients experiencing no discernable progression or a slow decline, whereas others experience more rapid deterioration. Some patients develop progressive pulmonary fibrosis, which is associated with high mortality. Although risk factors for the progression of RA-ILD have been identified, including older age, worse lung function, and a usual interstitial pneumonia pattern on high-resolution computed tomography, it is not possible to predict the course of RA-ILD in an individual patient. The association between RA disease activity and progression of RA-ILD remains unclear. Regular monitoring is important to enable the prompt identification of progression and early intervention to preserve lung function. The management of RA-ILD requires a multidisciplinary and individualized approach, taking account of the severity and progression of articular and lung disease, risk factors for the progression of RA-ILD, and the patient's preferences, and may include immunosuppression, antifibrotic therapy, and supportive care.

In 2006, we published an eponyms article in The Lancet on what was hitherto referred to as "Wegener's granulomatosis" 1 describing research we had begun in the early 2000s 2 into aspects of Wegener's biography that had not been reported previously (Table 1).As a result, several professional bodies recommended "granulomatosis with polyangiitis" as the new name for the disease in 2011 3 .Here, we reflect on the journey twenty years after we first embarked on it.We also discuss whether it is legitimate and appropriate for physicians to carry out such work, acknowledge a diversity of opinion and share advice for others in medicine who would like to ask questions about the eponyms in their respective fields.

Objective: The aim of this study was to investigate the relationship between biomarkers associated with metabolism and subsequent development of GCA. Method Participants in the population-based Malmo Diet Cancer Study (MDCS; N = 30 447) who were subsequently diagnosed with GCA were identified in a structured process. Matched: GCA-free controls were selected from the study cohort. Baseline plasma samples were analysed using the antibody-based OLINK proteomics metabolism panel (92 metabolic proteins). Analyses were pre-designated as hypothesis-driven or hypothesis-generating. In the latter, principal component analysis was used to identify groups of proteins that explained the variance in the proteome. Results: There were 95 cases with a confirmed incident diagnosis of GCA (median 12.0 years after inclusion). Among biomarkers with a priori hypotheses, adhesion G protein-coupled receptor E2 (ADGRE2) was positively associated [odds ratio (OR) per S.D. 1.67; 95% CI 1.08-2.57], and fructose-1,6-bisphosphatase 1 (FBP1) was negatively associated (OR per S.D. 0.59; 95% CI 0.35-0.99) with GCA. In particular, ADGRE2 levels were associated with subsequent GCA in the subset sampled <8.5 years before diagnosis. For meteorin-like protein (Metrnl), the highest impact on the risk of GCA was observed in those patients sampled closest to diagnosis, with a decreasing trend with longer time to GCA (P = 0.03). In the hypothesis-generating analyses, elevated levels of receptor tyrosine-like orphan receptor 1 (ROR1) were associated with subsequent GCA. Conclusion: Biomarkers identified years before clinical diagnosis indicated a protective role of gluconeogenesis (FBP1) and an association with macrophage activation (ADGRE2 and Metrnl) and proinflammatory signals (ROR1) for development of GCA.

Polymyalgia rheumatica is an inflammatory disease producing pain and stiffness, mainly in the shoulders and pelvic girdle, in people older than 50 years. Elevation of acute phase reactants is common due to the inflammatory nature of the disease. Since there are no specific diagnostic tests, diagnosis requires the exclusion of other diseases with similar presentations. Imaging has helped to identify the pathological substrate of polymyalgia rheumatica and it is increasingly used to support clinical diagnosis or to detect coexistent giant cell arteritis. Although polymyalgia rheumatica does not clearly impair survival or organ function, it can have a detrimental effect on quality of life. Glucocorticoids at 12.5-25.0 mg prednisone per day are effective in inducing remission in most individuals but, when tapered, relapses occur in 40-60% of those affected and side-effects are common. Assessment of disease activity can be difficult because pain related to common comorbidities such as osteoarthritis and tendinopathies, can return when glucocorticoids are reduced, and acute phase reactants are increased less during flares in individuals undergoing treatment or might increase for other reasons. The role of imaging in assessing disease activity is not yet completely defined. In the search for more efficient and safer therapies, tocilizumab and sarilumab have shown efficacy in randomised controlled trials and additional targeted therapies are emerging. However, judicious risk-benefit balance is essential in applying therapeutic innovations to people with polymyalgia rheumatica.

Objective: To investigate the relation between biomarkers of inflammation and subsequent development of GCA. Method: Participants in the population-based Malmo Diet Cancer Study (MDCS; N=30 447), established 1991-96, who were subsequently diagnosed with GCA, were identified in a structured process. GCA-free controls, matched for sex, year of birth and year of screening were selected from the study cohort. Baseline plasma samples were analysed using the antibody-based OLINK proteomics inflammation panel (92 inflammatory proteins). Analyses were pre-designated as hypothesis-driven or hypothesis-generating. In the latter, principal component analysis was used to identify groups of proteins that explain the variance in the proteome. Within components selected based on eigenvalues, proteins with a factor loading of >0.50 were investigated. Results: Ninety-four cases with a confirmed incident diagnosis of GCA (median 11.9 years after inclusion) were identified. Among biomarkers with a priori hypotheses, IFN-gamma was positively associated with GCA [odds ratio (OR) per S.D. 1.52; 95% CI 1.00, 2.30]. Eight biomarkers in the hypothesis-generating analyses were significantly associated with development of GCA. Among these, higher levels of IFN-gamma (OR 2.37; 95% CI 1.14, 4.92) and monocyte chemotactic protein 3 (MCP3) (OR 4.27; 95% CI 1.26, 14.53) were particularly associated with increased risk of GCA in the subset sampled <8.5 years before diagnosis. Several other proteins known to be important for T cell function were also associated with GCA in these analyses, e.g. CXCL9, IL-2, CD40 and CCL25. Conclusion: Elevated IFN-gamma levels were found years prior to diagnosis of GCA. T cell activation may precede the clinical onset of GCA.

ObjectivesTo develop treat-to-target (T2T) recommendations in giant cell arteritis (GCA) and polymyalgia rheumatica (PMR). MethodsA systematic literature review was conducted to retrieve data on treatment targets and outcomes in GCA/PMR as well as to identify the evidence for the effectiveness of a T2T-based management approach in these diseases. Based on evidence and expert opinion, the task force (29 participants from 10 countries consisting of physicians, a healthcare professional and a patient) developed recommendations, with consensus obtained through voting. The final level of agreement was provided anonymously. ResultsFive overarching principles and six-specific recommendations were formulated. Management of GCA and PMR should be based on shared decisions between patient and physician recognising the need for urgent treatment of GCA to avoid ischaemic complications, and it should aim at maximising health-related quality of life in both diseases. The treatment targets are achievement and maintenance of remission, as well as prevention of tissue ischaemia and vascular damage. Comorbidities need to be considered when assessing disease activity and selecting treatment. ConclusionThese are the first T2T recommendations for GCA and PMR. Treatment targets, as well as strategies to assess, achieve and maintain these targets have been defined. The research agenda highlights the gaps in evidence and the need for future research.

Giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) are closely related conditions characterized by systemic inflammation, a predominant IL-6 signature, an excellent response to glucocorticoids, a tendency to a chronic and relapsing course, and older age of the affected population. This Review highlights the emerging view that these diseases should be approached as linked conditions, unified under the term GCA-PMR spectrum disease (GPSD). In addition, GCA and PMR should be seen as non-monolithic conditions, with different risks of developing acute ischaemic complications and chronic vascular and tissue damage, different responses to available therapies and disparate relapse rates. A comprehensive stratification strategy for GPSD, guided by clinical findings, imaging and laboratory data, facilitates appropriate therapy and cost-effective use of health-economic resources. Patients presenting with predominant cranial symptoms and vascular involvement, who usually have a borderline elevation of inflammatory markers, are at an increased risk of sight loss in early disease but have fewer relapses in the long term, whereas the opposite is observed in patients with predominant large-vessel vasculitis. How the involvement of peripheral joint structures affects disease outcomes remains uncertain and understudied. In the future, all cases of new-onset GPSD should undergo early disease stratification, with their management adapted accordingly.

Objectives To explore current management practices for PMR by general practitioners (GPs) and rheumatologists including implications for clinical trial recruitment. Methods An English language questionnaire was constructed by a working group of rheumatologists and GPs from six countries. The questionnaire focused on: 1: Respondent characteristics; 2: Referral practices; 3: Treatment with glucocorticoids; 4: Diagnostics; 5: Comorbidities; and 6: Barriers to research. The questionnaire was distributed to rheumatologists and GPs worldwide via members of the International PMR/Giant Cell Arteritis Study Group. Results In total, 394 GPs and 937 rheumatologists responded to the survey. GPs referred a median of 25% of their suspected PMR patients for diagnosis and 50% of these were returned to their GP for management. In general, 39% of rheumatologists evaluated patients with suspected PMR >2 weeks after referral, and a median of 50% of patients had started prednisolone before rheumatologist evaluation. Direct comparison of initial treatment showed that the percentage prescribing >25 mg prednisolone daily for patients was 30% for GPs and 12% for rheumatologists. Diagnostic imaging was rarely used. More than half (56%) of rheumatologists experienced difficulties recruiting people with PMR to clinical trials. Conclusion This large international survey indicates that a large proportion of people with PMR are not referred for diagnosis, and that the proportion of treatment-naive patients declined with increasing time from referral to assessment. Strategies are needed to change referral and management of people with PMR, to improve clinical practice and facilitate recruitment to clinical trials.

OBJECTIVES:To establish a framework by which experts define disease subsets in systemic sclerosis associated interstitial lung disease (SSc-ILD). METHODS:A conceptual framework for subclinical, clinical and progressive ILD was provided to 83 experts, asking them to use the framework and classify actual SSc-ILD patients. Each patient profile was designed to be classified by at least four experts in terms of severity and risk of progression at baseline; progression was based on 1-year follow-up data. A consensus was reached if ≥75% of experts agreed. Experts provided information on which items were important in determining classification. RESULTS:Forty-four experts (53%) completed the survey. Consensus was achieved on the dimensions of severity (75%, 60 of 80 profiles), risk of progression (71%, 57 of 80 profiles) and progressive ILD (60%, 24 of 40 profiles). For profiles achieving consensus, most were classified as clinical ILD (92%), low risk (54%) and stable (71%). Severity and disease progression overlapped in terms of framework items that were most influential in classifying patients (forced vital capacity, extent of lung involvement on high resolution chest CT [HRCT]); risk of progression was influenced primarily by disease duration. CONCLUSIONS:Using our proposed conceptual framework, international experts were able to achieve a consensus on classifying SSc-ILD patients along the dimensions of disease severity, risk of progression and progression over time. Experts rely on similar items when classifying disease severity and progression: a combination of spirometry and gas exchange and quantitative HRCT.

Some patients with rheumatoid arthritis develop interstitial lung disease (RA-ILD) that develops into progressive pulmonary fibrosis. We assessed the efficacy and safety of nintedanib versus placebo in patients with progressive RA-ILD in the INBUILD trial. The INBUILD trial enrolled patients with fibrosing ILD (reticular abnormality with traction bronchiectasis, with or without honeycombing) on high-resolution computed tomography of >10 https://www.globalmedcomms.com/respiratory/INBUILD_RA-ILD .

Polymyalgia rheumatica is an inflammatory disease producing pain and stiffness, mainly in the shoulders and pelvic girdle, in people older than 50 years. Elevation of acute phase reactants is common due to the inflammatory nature of the disease. Since there are no specific diagnostic tests, diagnosis requires the exclusion of other diseases with similar presentations. Imaging has helped to identify the pathological substrate of polymyalgia rheumatica and it is increasingly used to support clinical diagnosis or to detect coexistent giant cell arteritis. Although polymyalgia rheumatica does not clearly impair survival or organ function, it can have a detrimental effect on quality of life. Glucocorticoids at 12·5-25·0 mg prednisone per day are effective in inducing remission in most individuals but, when tapered, relapses occur in 40-60% of those affected and side-effects are common. Assessment of disease activity can be difficult because pain related to common comorbidities such as osteoarthritis and tendinopathies, can return when glucocorticoids are reduced, and acute phase reactants are increased less during flares in individuals undergoing treatment or might increase for other reasons. The role of imaging in assessing disease activity is not yet completely defined. In the search for more efficient and safer therapies, tocilizumab and sarilumab have shown efficacy in randomised controlled trials and additional targeted therapies are emerging. However, judicious risk-benefit balance is essential in applying therapeutic innovations to people with polymyalgia rheumatica.

Objective Interstitial lung disease (ILD) is an important cause of mortality in some patients with rheumatoid arthritis (RA). Patient-level factors may predict which patients with RA are at the highest risk of developing ILD and are therefore candidates for screening for this complication of the underlying disease.Methods A systematic literature review was performed using PubMed, Embase and Scopus over a 10-year period up to July 2021. Publications reporting patient-level factors in patients with RA with and without ILD that were assessed before development of ILD (or were unchanged over time and therefore could be extrapolated to before development of ILD) were retrieved for assessment of evidence. Genetic variation in MUC5B and treatment with methotrexate were not included in the assessment of evidence because these factors have already been widely investigated for association with ILD.Results We found consistent associations of age, sex, smoking status and autoantibodies with development of ILD. For biomarkers such as Krebs von den Lungen 6, which have been shown to be diagnostic for ILD, there were no publications meeting criteria for this study.Conclusions This analysis provides an initial step in the identification of patient-level factors for potential development of a risk algorithm to identify patients with RA who may be candidates for screening for ILD. The findings represent a useful basis for future research leading to an improved understanding of the disease course and improved care for patients with RA at risk of development and progression of ILD.

Background The most common extraarticular manifestation of rheumatoid arthritis (RA) is the rheumatoid nodule, which is reported to affect about 30% of patients with RA.[1] The development of rheumatoid nodules has been associated most strongly with high disease activity, seropositive status, and more rapid progression of joint destruction. Despite significant changes in RA treatment and decreasing incidence of seropositive RA, no recent population-based studies have assessed the epidemiology of rheumatoid nodules. Objectives We aim to investigate changes in rheumatoid nodule incidence over time. Methods This study evaluated rheumatoid nodule incidence trends using an inception cohort that included all adult patients from a geographically well-defined area who met the 1987 American College of Rheumatology criteria for RA between 1/1/1985 and 12/31/2014. Patients were followed until the earlier of death, migration from the region, or 12/31/2000 (for patients with incident RA in 1985-1994) or 12/31/2008 (for 1995-2007 patients) or 10/15/2022 (for 2008-2014 patients). Patients were divided into two cohorts based on the incidence date of RA, an early cohort from 1985-1999 and a later cohort from 2000-2014. Medical records were reviewed manually, and the incidence date of rheumatoid nodules was recorded if determined to be present either by clinical judgment and/or histopathology. The 10-year cumulative incidence of rheumatoid nodules was estimated in each cohort. Cox proportional hazard models adjusted for age, sex and calendar year were used to determine associations between specific demographic and RA disease data with rheumatoid nodules. Results 907 patients were included in this study, 296 (67% female) in the 1985-1999 cohort and 611 (70% female) in the 2000-2014 cohort. The mean follow-up period between these cohorts, respectively, was 9.1 and 7.4 years. Baseline characteristics (earlier cohort, latter cohort) included rheumatoid factor (RF) positive (70%, 59%), joint erosions in the first year of RA (24%, 29%), and ever smoker (57%, 47%). The 10-year cumulative incidence of rheumatoid nodules was 31% in the 1985-1999 cohort and 16% in the 2000-2014 cohort (hazard ratio [HR] 0.52, 95% confidence interval [CI] 0.39-0.70). Identified risk factors for the development of rheumatoid nodules included RF positivity (HR 4.38, 95%CI 2.37-8.09), erosions (HR 2.53, 95%CI 1.64-3.91), current smoker (HR 2.09, 95%CI 1.30-3.37), male sex (HR 1.77, 95%CI 1.14-2.73), methotrexate use (HR 1.77, 95%CI 1.09-2.86) and other DMARDs (HR 2.07, 95%CI 1.14-3.74) (Table 1). Conclusion The incidence of rheumatoid nodules has decreased substantially over time. More research is needed to understand the drivers of this improvement and implications on RA disease outcomes. Reference [1] Myasoedova E, Crowson CS, Turesson C, Gabriel SE, Matteson EL. Incidence of extraarticular rheumatoid arthritis in Olmsted County, Minnesota, in 1995-2007 versus 1985-1994: a population-based study. J Rheumatol. 2011;38(6):983-989. Acknowledgements: NIL. Disclosure of Interests None Declared.