Validation of the Italian version of the ANCA-associated vasculitis patient-reported outcome (AAV-PRO) questionnaire.

Objectives: The primary objective of this study was the translation and validation of the ANCA-associated vasculitis patient-reported outcome (AAV-PRO) questionnaire into Italian, denoted as AAV-PRO_ita. The secondary objective was to evaluate the impact of ANCA-associated vasculitis (AAV) on quality of life (QoL) and work impairment in a large cohort of Italian patients. Methods: The study design took a prospective cohort study approach. First, the AAV-PRO was translated into Italian following the step guidelines for translations. The new AAV-PRO_ita questionnaire covered three disease domains: organ-specific and systemic symptoms and signs; physical function; and social and emotional impact. Second, Italian-speaking AAV patients were recruited from 17 Italian centres belonging to the Italian Vasculitis Study Group. Participants completed the AAV-PRO_ita questionnaire at three time points. Participants were also requested to complete the work productivity and activity impairment: general health questionnaire. Results: A total of 276 AAV patients (56.5% women) completed the questionnaires. The AAV-PRO_ita questionnaire demonstrated a good internal consistency and test-retest reliability. Female AAV patients scored higher (i.e. worse) in all thee domains, especially in the social and emotional impact domain (P < 0.001). Patients on glucocorticoid therapy (n = 199) had higher scores in all domains, especially in the physical function domain (P < 0.001), compared with patients not on glucocorticoid therapy (n = 77). Furthermore, patients who had at least one relapse of disease (n = 114) had higher scores compared with those who had never had one (n = 161) in any domain (P < 0.05). Finally, nearly 30% of the patients reported work impairment. Conclusion: The AAV-PRO_ita questionnaire is a new 29-item, disease-specific patient-reported outcome measuring tool that can be used in AAV research in the Italian language. Sex, glucocorticoids and relapsing disease showed the greatest impact on QoL.

The systemic score may identify life-threatening evolution in Still's disease: data from the GIRRCS AOSD-study group and the AIDA Network Still's Disease Registry.

OBJECTIVES: To evaluate the clinical usefulness of the systemic score in the prediction of life-threatening evolution in Still's disease. To assess the clinical relevance of each component of the systemic score in predicting life-threatening evolution and to derive patient subsets accordingly. METHODS: A multicenter, observational, prospective study was designed including patients included in the GIRRCS (Gruppo Italiano Di Ricerca in Reumatologia Clinica e Sperimentale) AOSD-study group and AIDA (AutoInflammatory Disease Alliance) Network Still's Disease Registry. Patients were assessed if variables to derive the systemic score were available. The life-threatening evolution was defined as mortality, whichever the clinical course, and/or macrophage activation syndrome (MAS), a secondary hemophagocytic lymphohistiocytosis associated with a poor prognosis. RESULTS: Totally 597 patients with Still's disease were assessed (age 36.6±17.3 years; male 44.4%). The systemic score, assessed as continuous variable, significantly predicted the life-threatening evolution (OR: 1.24, 95%CI:1.07-1.42; p=0.004). A systemic score ≥7 also significantly predicted the likelihood of a patient experiencing life-threatening evolution (OR: 3.36, 95%CI:1.81-6.25; p<0.001). Assessing the clinical relevance of each component of the systemic score, liver involvement (OR: 1.68, 95%CI:1.48-2.67; p=0.031) and lung disease (OR: 2.12, 95%CI:1.14-4.49; p=0.042) both significantly predicted life-threatening evolution. The clinical characteristics of patients with liver involvement and lung disease were derived, highlighting their relevance in multiorgan disease manifestations. CONCLUSION: The clinical utility of the systemic score was shown in identifying Still's disease at higher risk of life-threatening evolution in a large cohort. Furthermore, the clinical relevance of liver involvement and lung disease was highlighted.

A critical view on autoantibodies in lupus nephritis: Concrete knowledge based on evidence.

Deposition of autoantibodies in glomeruli is a key factor in the development of lupus nephritis (LN). For a long time, anti-dsDNA and anti-C1q antibodies were thought to be the main cause of the kidney damage. However, recent studies have shown that the list of autoantibidies that have renal tropism and deposit in the kidney in LN is increasing and the link between anti-dsDNA and renal pathology is weak due to potential confounders. Aspecific bindings of dsDNA with cationic antibodies and of anti-dsDNA with several renal antigens such as actinin, laminin, entactin, and annexinA2 raised doubts about the specific target of these antibodies in the kidney. Moreover, the isotype of anti-dsDNA in SLE and LN has never received adequate interest until the recent observation that IgG2 are preponderant over IgG1, IgG3 and IgG4. Based on the above background, recent studies investigated the involvement of anti-dsDNA IgG2 and of other antibodies in LN. It was concluded that circulating anti-dsDNA IgG2 levels do not distinguish between LN versus non-renal SLE, and, in patients with LN, their levels do not change over time. Circulating levels of other antibodies such as anti-ENO1 and anti-H2 IgG2 were, instead, higher in LN vs non-renal SLE at the time of diagnosis and decreased following therapies. Finally, new classes of renal antibodies that potentially modify the anti-inflammatory response in the kidney are emerging as new co-actors in the pathogenetic scenario. They have been defined as 'second wave antibodies' for the link with detoxifying mechanisms limiting the oxidative stress in glomeruli that are classically stimulated in a second phase of inflammation. These findings have important clinical implications that may modify the laboratory approach to LN. Serum levels of anti-ENO1 and anti-H2 IgG2 should be measured in the follow up of patients for designing the length of therapies and identify those patients who respond to treatments. Anti-SOD2 could help to monitor and potentiate the anti-inflammatory response in the kidney.

Agreement between local and central anti-synthetase antibodies detection: results from the Classification Criteria of Anti-Synthetase Syndrome project biobank.

OBJECTIVES: The CLASS (Classification Criteria of Anti-Synthetase Syndrome) project is a large international multicentre study that aims to create the first data-driven anti-synthetase syndrome (ASSD) classification criteria. Identifying anti-aminoacyl tRNA synthetase antibodies (anti-ARS) is crucial for diagnosis, and several commercial immunoassays are now available for this purpose. However, using these assays risks yielding false-positive or false-negative results, potentially leading to misdiagnosis. The established reference standard for detecting anti-ARS is immunoprecipitation (IP), typically employed in research rather than routine autoantibody testing. We gathered samples from participating centers and results from local anti-ARS testing. As an "ad-interim" study within the CLASS project, we aimed to assess how local immunoassays perform in real-world settings compared to our central definition of anti-ARS positivity. METHODS: We collected 787 serum samples from participating centres for the CLASS project and their local anti-ARS test results. These samples underwent initial central testing using RNA-IP. Following this, the specificity of ARS was reconfirmed centrally through ELISA, line-blot assay (LIA), and, in cases of conflicting results, protein-IP. The sensitivity, specificity, positive likelihood ratio and positive and negative predictive values were evaluated. We also calculated the inter-rater agreement between central and local results using a weighted κ co-efficient. RESULTS: Our analysis demonstrates that local, real-world detection of anti-Jo1 is reliable with high sensitivity and specificity with a very good level of agreement with our central definition of anti-Jo1 antibody positivity. However, the agreement between local immunoassay and central determination of anti-non-Jo1 antibodies varied, especially among results obtained using local LIA, ELISA and "other" methods. CONCLUSIONS: Our study evaluates the performance of real-world identification of anti-synthetase antibodies in a large cohort of multi-national patients with ASSD and controls. Our analysis reinforces the reliability of real-world anti-Jo1 detection methods. In contrast, challenges persist for anti-non-Jo1 identification, particularly anti-PL7 and rarer antibodies such as anti-OJ/KS. Clinicians should exercise caution when interpreting anti-synthetase antibodies, especially when commercial immunoassays test positive for non-anti-Jo1 antibodies.

What benefit-risk trade-offs are acceptable to rheumatoid arthritis patients during treatment selection? Evidence from a multicountry choice experiment.

OBJECTIVE: Understanding preferences of patients with rheumatoid arthritis (RA) can facilitate tailored patient-centric care. This study elicited trade-offs that patients with RA were willing to make during treatment selection. METHODS: Patients with RA completed an online discrete choice experiment, consisting of a series of choices between hypothetical treatments. Treatment attributes were selected based on literature review and qualitative patient interviews. Eligible patients were ≥18 years old, diagnosed with RA, receiving systemic disease-modifying antirheumatic drug therapy, and residents of Europe or USA. Male patients were oversampled for subgroup analyses. Data were analysed using a correlated mixed logit model. RESULTS: Of 2090 participants, 42% were female; mean age was 45.2 years (range 18-83). Estimated effects were significant for all attributes (p<0.001) but varied between patients. Average relative attribute importance scores revealed different priorities (p<0.001) between males and females. While reducing pain and negative effect on semen parameters was most important to males, females were most concerned by risk of blood clots and serious infections. No single attribute explained treatment preferences by more than 30%. Preferences were also affected by patients' age: patients aged 18-44 years placed less importance on frequency and mode of treatment administration (p<0.05) than older age groups. Patients were willing to accept higher risk of serious infections and blood clots in exchange for improvements in pain, daily activities or administration convenience. However, acceptable trade-offs varied between patients (p<0.05). CONCLUSION: Treatment preferences of patients with RA were individual-specific, but driven by benefits and risks, with no single attribute dominating the decision-making.

Management of psoriatic arthritis: a consensus opinion by expert rheumatologists.

Background: Psoriatic arthritis (PsA) is a chronic inflammatory musculoskeletal disease involving several articular and extra-articular structures. Despite the important progresses recently made in all of the aspects of this disease, its management is still burdened by unresolved issues. The aim of this exercise was to provide a set of statements that may be helpful for the management of PsA. Methods: A group of 38 Italian rheumatologists with recognized expertise in PsA selected and addressed the following four topics: "early PsA," "axial-PsA," "extra-articular manifestations and comorbidities," "therapeutic goals." Relevant articles from the literature (2016-2022) were selected by the experts based on a PubMed search. A number of statements for each topic were elaborated. Results: Ninety-four articles were selected and evaluated, 68 out of the 1,114 yielded by the literature search and 26 added by the Authors. Each of the four topic was subdivided in themes as follows: transition from psoriasis to PsA, imaging vs. CASPAR criteria in early diagnosis, early treatment for "early PsA"; axial-PsA vs. axialspondyloarthritis, diagnosis, clinical evaluation, treatment, standard radiography vs. magnetic resonance imaging for "axial PsA"; influence of inflammatory bowel disease on the therapeutic choice, cardiovascular comorbidity, bone damage, risk of infection for "comorbidities and extra-articular manifestations"; target and tools, treat-to-target strategy, role of imaging for "therapeutic goals." The final document consisted of 49 statements. Discussion: The final product of this exercise is a set of statements concerning the main issues of PsA management offering an expert opinion for some unmet needs of this complex disease.

Derivation and validation of four patient clusters in Still's disease, results from GIRRCS AOSD-study group and AIDA Network Still Disease Registry.

BACKGROUND: Different patient clusters were preliminarily suggested to dissect the clinical heterogeneity in Still's disease. Thus, we aimed at deriving and validating disease clusters in a multicentre, observational, prospective study to stratify these patients. METHODS: Patients included in GIRRCS AOSD-study group and AIDA Network Still Disease Registry were assessed if variables for cluster analysis were available (age, systemic score, erythrocyte sedimentation rate (ESR), C reactive protein (CRP) and ferritin). K-means algorithm with Euclidean metric and Elbow plot were used to derive an adequate number of clusters. RESULTS: K-means clustering assessment provided four clusters based on means standardised according to z-scores on 349 patients. All clusters mainly presented fever, skin rash and joint involvement. Cluster 1 was composed by 115 patients distinguished by lower values of age and characterised by skin rash myalgia, sore throat and splenomegaly. Cluster 2 included 128 patients identified by lower levels of ESR, ferritin and systemic score; multiorgan manifestations were less frequently observed. Cluster 3 comprised 31 patients categorised by higher levels of CRP and ferritin, they were characterised by fever and joint involvement. Cluster 4 contained 75 patients derived by higher values of age and systemic score. Myalgia, sore throat, liver involvement and life-threatening complications, leading to a high mortality rate, were observed in these patients. CONCLUSIONS: Four patient clusters in Still's disease may be recognised by a multidimensional characterisation ('Juvenile/Transitional', 'Uncomplicated', 'Hyperferritinemic' and 'Catastrophic'). Of interest, cluster 4 was burdened by an increased rate of life-threatening complications and mortality, suggesting a more severe patient group.

Impact of csDMARDs adherence on clinical remission in patients with new-onset inflammatory arthritis: a prospective cohort study from the ELECTRA database.

Background: Major improvements in the management of rheumatoid arthritis (RA) have made clinical remission an achievable and desirable goal but, despite the relevance gained by a profound disease suppression, many patients with RA still miss clinical remission due to several factors influencing disease activity, including treatment adherence. Objective: To evaluate the effect of adherence to conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) on the achievement of clinical remission in a cohort of patients with new-onset inflammatory arthritis. Study design: A prospective cohort study was conducted using the ELECTRA database, which consists of clinical data from patients followed at the IRCCS Policlinico San Matteo Foundation (Pavia, Italy), linked to regional administrative healthcare databases. Methods: We enrolled patients with new-onset active disease between January 2006 and December 2013 and followed them until their first clinical remission or end of follow-up (December 2015). To assess the association of csDMARD adherence with clinical remission, we estimated the csDMARD proportion of days covered (PDC) during follow-up. PDC was added to the main clinical adjustment covariates as a time-dependent variable in a proportional hazard Cox regression model. Results: The cohort included 324 patients with a mean (SD) age of 58 (13.9) and predominantly female (74.5%). A total of 219 patients (67.6%) achieved clinical remission during follow-up and 85 (26.2%) in the first 6 months (early clinical remission). Cox regression models showed that a 10% increment of PDC increased the probability of achieving clinical remission by 10% (p < 0.001) and the probability of early clinical remission by 21% (p = 0.03). Conclusion: Patients at disease onset with higher adherence to csDMARDs were more likely to achieve clinical remission and early clinical remission. Our study highlighted the importance of close monitoring of patients to increase their likelihood of following therapeutic indications and achieving favorable disease outcomes, such as lower disability.

Expert consensus on the treatment of patients with adult-onset still's disease with the goal of achieving an early and long-term remission.

We performed a comprehensive systematic targeted literature review and used the Delphi method to formulate expert consensus statements to guide the treatment of adult-onset Still's disease (AOSD) to achieve an early and long-term remission. Seven candidate statements were generated and reached consensus in the first round of voting by the panel of experts. We postulate: (i) In patients with AOSD with predominant arthritis at onset who achieved no disease control with glucocorticoids (GCs), the use of methotrexate can be considered, whereas the use of cyclosporin A and low-dose GCs should not (Statements 1-3); (ii) In patients with AOSD with poor prognostic factors at diagnosis, an IL-1 inhibitor (IL-1i) in addition to GCs should be taken into consideration as early as possible (Statement 4); (iii) A switch to an IL-6 inhibitor (IL-6i) may be considered in patients with AOSD with prevalent joint involvement, who are unresponsive or intolerant to IL-1i (Statement 5); (iv) Drug tapering or discontinuation may be considered in patients who achieved a sustained clinical and laboratory remission with IL-1i (Statement 6); (v) In patients with AOSD who failed to attain a good clinical response with an IL-1i, switching to an IL-6i may be considered in alternative to a different IL-1i. TNF-inhibitors may be considered as a further choice in patients with a prominent joint involvement (Statement 7). These statements will help clinicians in treatment decision making in patients with AOSD.

Janus kinase inhibitors effectively improve pain across different disease activity states in rheumatoid arthritis.

Pain remains one of the most difficult-to-treat domains in patients with rheumatoid arthritis (RA). In clinical trials, the Janus kinase inhibitors (JAKis) have demonstrated good efficacy in pain relief. Aim of our study was to evaluate the real-life effectiveness of JAKis in improving pain in patients with RA in different states of baseline disease activity. A monocentric prospective cohort of 181 RA patients starting treatment with JAKis was studied. Pain was evaluated on a 0-100 mm visual analogue scale (VAS). Clinically meaningful improvements over 24 weeks were defined as follows: proportion of patients achieving ≥ 30%, ≥ 50%, and ≥ 70% pain relief, and remaining pain ≤ 20 or ≤ 10 mm. Results were analysed after stratification for baseline inflammatory activity; patients with swollen joints and C-reactive protein ≤ 1 at treatment start were considered pauci-inflammatory. Proportion of patients who achieved ≥ 30%, ≥ 50% and ≥ 70% pain improvement at 24 weeks was 61.4%, 49.3% and 32.9%. Furthermore, 40.6% and 28.5% of the patients achieved thresholds of remaining pain equivalent to mild pain or no/limited pain. Pain improvements were more evident in patients naive to previous biologics, although nearly 30% of multiple failures achieved VAS ≤ 20 mm. No significant differences were observed in relation to monotherapy. Pauci-inflammatory patients at treatment start achieved good outcomes, with 40.4% experiencing ≥ 70% pain improvement, and 35.7% VAS ≤ 10 mm. JAKis show efficacy in pain relief in real life. The improvement of painful symptoms also in those patients with limited objective inflammation may open new perspectives on the management of difficult-to-treat RA.

The access route through the anatomical snuffbox in ultrasound-guided synovial biopsy of the wrist allows for a safe and effective collection of tissue samples in inflammatory arthritis.

BACKGROUND: A proof-of-concept study to evaluate the feasibility and safety of minimally invasive ultrasound (US)-guided synovial biopsy of the radiocarpal (RC) joint using the anatomical snuffbox as an access route. METHODS: Twenty consecutive patients with active chronic arthritis of the wrist underwent minimally invasive US-guided synovial biopsy of the RC joint using the anatomical snuffbox as the access route. Samples were retrieved from 3 predetermined biopsy target sites of the RC synovia (proximal, vault, and distal site), aiming for a minimum of 12 samples. The procedure's feasibility was evaluated based on the number and histological quality of retrieved tissue fragments tested on pre-defined histometric parameters. The safety and tolerability of the procedure were assessed through 1-week and 1-month follow-up clinical evaluations. RESULTS: A median number of 17 fragments (≥ 1 mm diameter size at macroscopic evaluation) per procedure was processed for histopathology (range 9-24) and dedicated to the study. At the histopathologic evaluation, a gradable tissue (visible lining layer and ≥ 4 fragments with IST) was recognized in 19/20 biopsies (95%), and all pre-defined histometric parameters were judged applicable and successfully measured in 19/19 gradable biopsies. All three biopsy target sites showed sampling accessibility. The entire procedure was generally well tolerated. At the 1-month follow-up, no patients showed infectious complications. CONCLUSIONS: The access route through the anatomical snuff box in US-guided synovial biopsies of the RC joint allows for a safe and targeted collection of adequate tissue samples. This modification of the traditional access route may allow easier, repeatable, and safer sampling of anatomically distinct areas of the wrist in the course of arthritis.

Cytomegalovirus colitis unmasking human immunodeficiency virus infection as a cause of IgA vasculitis.

BACKGROUND: Human immunodeficiency virus (HIV) has a protean clinical picture, in rare instances manifesting as systemic autoimmune disorders such as vasculitides. HIV-induced autoimmune diseases often do not respond well to systemic immunosuppressive therapy. Opportunistic infections may occur in patients with either acquired immunodeficiency syndrome (AIDS) or heavy immunosuppressive treatment, and can further complicate the clinical presentation. CASE PRESENTATION: A patient presenting with immunoglobulin A (IgA) vasculitis (IgAV) with treatment-refractory purpuric skin rash and suspect intestinal vasculitis was discovered to have AIDS. HIV was the trigger of IgAV, and cytomegalovirus (CMV) colitis mimicked intestinal vasculitis. Antiretroviral treatment improved both CMV colitis and the control of the autoimmune disease. CONCLUSIONS: An autoimmune disease relapsing despite adequate immunosuppressive treatment and/or the presence of recurrent severe opportunistic infections may be clues to an underlying HIV infection.

Synovial and serum B-cell signature of autoantibody-negative rheumatoid arthritis versus autoantibody-positive rheumatoid arthritis and psoriatic arthritis.

OBJECTIVES: Autoantibody-negative rheumatoid arthritis (RA) differs from autoantibody-positive RA in several clinical aspects, possibly underpinned by pathogenetic differences. At present, the role of adaptive immune responses in autoantibody-negative RA remains unclear. Here, we investigated the synovial and serum immunophenotype indicative of B-lymphocyte involvement across the spectrum of autoantibody-positive and -negative chronic arthritides. METHODS: Ultrasound-guided synovial biopsies were retrieved from 131 patients: 43 autoantibody-positive RA, 35 autoantibody-negative RA, 25 polyarticular psoriatic arthritis (PsA), 28 oligoarticular PsA. Samples were analysed for the degree of histological inflammation, B-lymphocyte infiltration and the distribution of different pathotypes (lympho-myeloid, myeloid, pauci-immune). Serum levels of the B-cell chemoattractant CXCL13 were compared among groups. RESULTS: Synovitis scores and CD68+ sublining macrophage infiltration were comparable irrespective of clinical diagnosis and disease subtype. In contrast, the degree of B-lymphocyte infiltration and the frequency of lympho-myeloid synovitis in autoantibody-negative RA were lower than those of autoantibody-positive RA (mean [SD] 1.8 [1] vs 2.4 [0.6], p = 0.03 and 38.2% vs 62.9%, p = 0.07, respectively), and similar to polyarticular PsA. Oligoarticular PsA had the lowest B-cell scores. Serum CXCL13 was associated with lympho-myeloid synovitis and followed a similar gradient, with the highest levels in autoantibody-positive RA, intermediate and comparable levels in autoantibody-negative RA and polyarticular PsA, and low levels in oligoarticular PsA. CONCLUSIONS: The synovial and serum immunophenotype indicative of B-lymphocyte involvement in autoantibody-negative RA differs from autoantibody-positive RA and more closely resembles that observed in polyarticular PsA. The pathobiological stratification of chronic inflammatory arthritides beyond clinical diagnosis may fuel personalised treatment strategies.

Azathioprine vs methotrexate in eosinophilic granulomatosis with polyangiitis: a monocentric retrospective study.

OBJECTIVES: To analyse effectiveness, safety, and steroid-sparing effect of AZA and MTX as induction of remission and maintenance treatment in eosinophilic granulomatosis with polyangiitis. METHODS: We retrospectively collected data from 57 patients divided in 4 groups according to treatment: MTX/AZA as first-line agents (MTX1/AZA1) in non-severe disease, or as second-line maintenance therapy (MTX2/AZA2) in severe disease previously treated with CYC/rituximab. During the first five years of treatment with AZA/MTX we compared the groups according to: remission rate (defined as R1: BVAS = 0, R2: BVAS = 0 with prednisone ≤5mg/day, R3-MIRRA definition: BVAS = 0 with prednisone ≤ 3.75 mg/day), persistence on therapy, cumulative glucocorticoid (GC) dose, relapse, and adverse events (AE). RESULTS: There were no significant differences in remission rates (R1) in each group (63% in MTX1 vs 75% in AZA1, p= 0.53; 91% in MTX2 vs 71% in AZA2, p= 0.23). MTX1 allowed R2 more frequently in the first 6 months compared with AZA1 (54% vs 12%, p= 0.04); no patients receiving AZA1 achieved R3 up to the first 18 months (vs 35% in MTX1, p= 0.07). Cumulative GC dose was lower for MTX2 vs AZA2 (6 g vs 10.7 g at 5 years, p= 0.03). MTX caused more AE compared with AZA (66% vs 30%, p= 0.004), without affecting the suspension rate. No differences emerged in time-to-first relapse, although fewer patients treated with AZA2 had asthma/ENT relapses (23% vs 64%, p= 0.04). CONCLUSION: A significant proportion of patients achieved remission with both MTX and AZA. MTX1 had an earlier remission on lower GC dose, MTX2 had better steroid-sparing effect.

Age at diagnosis influences the clinical phenotype, treatment strategies and outcomes in patients with giant cell arteritis: results from the observational GCAGE study on a large cohort of 1004 patients.

BACKGROUND: Immune and vascular ageing are proposed risk factors for giant cell arteritis (GCA). Data on the impact of age at diagnosis of GCA on the clinical presentation and course of the disease are scarce. METHODS: Patients with GCA followed at referral centres within the Italian Society of Rheumatology Vasculitis Study Group were enrolled up to November 2021. Patients were grouped according to age at diagnosis: ≤64, 65-79 and ≥80 years old. RESULTS: The study included 1004 patients, mean age 72.1±8.4, female 70.82%. Median follow-up duration was 49 (IQR 23-91) months. Patients in the oldest group (≥80 years) had significantly more cranial symptoms, ischaemic complications and risk for blindness compared with the groups 65-79 and ≤64 years (blindness: 36.98% vs 18.21% vs 6.19%; p<0.0001). Large-vessel-GCA was more frequent in the youngest group (65% of patients). Relapses occurred in 47% of patients. Age did not influence the time to first relapse, nor the number of relapses. Older age was negatively associated with the number of adjunctive immunosuppressants. Patients >65 years old had 2-3 fold increased risk for aortic aneurysm/dissection up to 60 months follow-up. Serious infections, but not other treatment-related complications (hypertension, diabetes, osteoporotic fractures), were significantly associated with older age. Mortality occurred in 5.8% of the population with age >65, cranial and systemic symptoms as independent risk factors. CONCLUSIONS: The highest risk of ischaemic complications, aneurysm development, serious infections and the possible undertreatment make of GCA a very challenging disease in the oldest patients.

Clinical characteristics of obese patients with adult-onset Still's disease. Data from a large multicentre cohort.

OBJECTIVES: To evaluate the impact of obesity in patients with adult-onset Still's disease (AOSD) and to assess their clinical characteristics and disease outcomes. METHODS: The clinical features of AOSD patients with a body mass index (BMI)≥30 were assessed among those included in the multicentre Gruppo Italiano di Ricerca in Reumatologia Clinica e Sperimentale (GIRRCS) cohort. RESULTS: Out of 139 AOSD patients, who had BMI registered in our database, 26 (18.7%) had a BMI≥30. A lower rate of sore throat (P<0.05), pericarditis (P<0.05), and pleuritis (P<0.05) was shown in obese patients. Additionally, obese patients showed higher values of C-reactive protein (CRP) (P<0.05) and ferritin (P<0.05) than others. Furthermore, obese patients were characterised by biologic disease-modifying antirheumatic drug (bDMARD) failure in subsequent follow-up (P<0.05). They also presented higher rate of comorbidity than non-obese patients (P<0.05). Finally, obesity predicted the presence of a chronic disease course in both univariate (HR: 1.72, 95%CI: 1.03-2.51, P<0.05) and multivariate analyses (HR: 1.85, 95%CI: 1.45-2.89, P<0.05). Obesity was also a significant predictor of bDMARD failure in AOSD patients in both univariate (HR: 3.03, 95%CI: 1.42-6.45, P<0.01) and multivariate analyses (HR: 3.59, 95%CI: 1.55-8.27, P<0.01). CONCLUSION: Obese patients at the time of diagnosis of the disease were characterised by a lower prevalence of sore throat, serositis, as well as by higher values of CRP and ferritin. Obesity was also a predictive factor for a chronic disease course and bDMARD failure, thus highlighting a subset of patients with AOSD to be carefully managed.

Tumor necrosis factor-α inhibitor-related autoimmune disorders.

Biotechnological monoclonal antibodies and receptor antagonists capable of targeting specific inflammatory actors, such as cytokines, cytokines receptors, co-stimulatory molecules or leukocyte populations, have emerged as an alternative to conventional therapies for treating systemic inflammatory diseases with immune pathogenesis. However, there is no doubt that, with a frequency that is not exceptionally high but also not negligible, immunotherapies can favour the development of systemic and organ-specific immune-mediated disorders. It has become increasingly evident that interference with a specific immune pathway may favour the activation of opposing compensatory signalling, which may exacerbate underlying subclinical disorders or cause immune-mediated diseases completely different from the underlying disease. The 'compensatory immunological switch' has emerged primarily in patients treated with tumor necrosis factor (TNF) -α inhibitors, the first biological drugs approved for treating systemic inflammatory diseases with immune pathogenesis. In this Review, we describe the clinical features and predisposing factors of the main TNF-α inhibitor-related autoimmune disorders, organising them into subclinical serological autoimmunity, autoimmune disorders other than those for which TNF-α inhibitors are indicated, and paradoxical reactions. We also discuss the underlying pathogenetic mechanisms and precautions for use in the therapeutic management of these patients. Better understanding of the complex phenomenon of the 'compensatory immunological switch', which TNF-α inhibitors and other biological drugs might trigger, can help not only appropriately managing immune-mediated disorders, but also better interpreting the heterogeneity of the pathogenetic mechanisms underlying certain chronic inflammatory conditions that, although different from each other, are arbitrarily placed in the context of overly generic nosological entities.

Updates on the diagnosis and monitoring of giant cell arteritis.

This mini-review offers a critical appraisal of the currently employed imaging or histopathological tools to diagnose and monitor giant cell arteritis (GCA). An overview of the most updated evidence and current application of color duplex ultrasonography (US), temporal artery biopsy (TAB), 18-fluorodeoxyglucose [18F] FDG-PET/CT, magnetic resonance imaging, and computed tomography angiography is provided. The main limitations of each tool, and the most relevant research developments are discussed. The review highlights the complementary value of the available modalities to ensure a correct diagnosis of GCA, and to provide valuable prognostic information. Novel evidence is accumulating to support the role of imaging, and particularly US, as a monitoring tool for the disease, opening new perspectives for the future management of large vessel vasculitis.