Serum protein profiling reveals distinct patient clusters in giant cell arteritis.

OBJECTIVES: We investigated the potential of serum proteins to distinguish clinical and molecular subtypes in patients with giant cell arteritis (GCA). METHODS: Proximity extension assays were used to analyse 1463 proteins in serum samples from patients with new-onset GCA (n = 16) and after achieving remission (n = 13). Unsupervised and supervised cluster analyses were performed. RESULTS: Unsupervised cluster analysis identified three distinct clusters based on the protein signature. Compared with cluster 2, patients of cluster 1 had less polymyalgia rheumatica symptoms, increased levels of macrophage migration inhibitory factor (MIF) and pronounced NF-kB, STAT5 and interleukin-1 signalling. The changes in serum proteins upon remission differed between cluster 1 and 2.Patients with cranial GCA were characterised by altered endothelial and Th17 signalling whereas patients not responding to treatment within the GUSTO-trial showed increased Th1 and diminished B cell signalling. Patients with anterior ischemic optic neuropathy displayed higher levels of CHI3L1 (YKL40), MMP12 and reduced levels of TIMP3. CONCLUSIONS: Protein profiling identifies patient clusters in GCA with distinct proteomic features and therefore likely different pathophysiology. These unique proteomic footprints might lead to more targeted treatments in future.

Skeletal Muscle Disorders: A Noncardiac Source of Cardiac Troponin T.

BACKGROUND: Cardiac troponin (cTn) T and cTnI are considered cardiac specific and equivalent in the diagnosis of acute myocardial infarction. Previous studies suggested rare skeletal myopathies as a noncardiac source of cTnT. We aimed to confirm the reliability/cardiac specificity of cTnT in patients with various skeletal muscle disorders (SMDs). METHODS: We prospectively enrolled patients presenting with muscular complaints (≥2 weeks) for elective evaluation in 4 hospitals in 2 countries. After a cardiac workup, patients were adjudicated into 3 predefined cardiac disease categories. Concentrations of cTnT/I and resulting cTnT/I mismatches were assessed with high-sensitivity (hs-) cTnT (hs-cTnT-Elecsys) and 3 hs-cTnI assays (hs-cTnI-Architect, hs-cTnI-Access, hs-cTnI-Vista) and compared with those of control subjects without SMD presenting with adjudicated noncardiac chest pain to the emergency department (n=3508; mean age, 55 years; 37% female). In patients with available skeletal muscle biopsies, TNNT/I1-3 mRNA differential gene expression was compared with biopsies obtained in control subjects without SMD. RESULTS: Among 211 patients (mean age, 57 years; 42% female), 108 (51%) were adjudicated to having no cardiac disease, 44 (21%) to having mild disease, and 59 (28%) to having severe cardiac disease. hs-cTnT/I concentrations significantly increased from patients with no to those with mild and severe cardiac disease for all assays (all P<0.001). hs-cTnT-Elecsys concentrations were significantly higher in patients with SMD versus control subjects (median, 16 ng/L [interquartile range (IQR), 7-32.5 ng/L] versus 5 ng/L [IQR, 3-9 ng/L]; P<0.001), whereas hs-cTnI concentrations were mostly similar (hs-cTnI-Architect, 2.5 ng/L [IQR, 1.2-6.2 ng/L] versus 2.9 ng/L [IQR, 1.8-5.0 ng/L]; hs-cTnI-Access, 3.3 ng/L [IQR, 2.4-6.1 ng/L] versus 2.7 ng/L [IQR, 1.6-5.0 ng/L]; and hs-cTnI-Vista, 7.4 ng/L [IQR, 5.2-13.4 ng/L] versus 7.5 ng/L [IQR, 6-10 ng/L]). hs-cTnT-Elecsys concentrations were above the upper limit of normal in 55% of patients with SMD versus 13% of control subjects (P<0.01). mRNA analyses in skeletal muscle biopsies (n=33), mostly (n=24) from individuals with noninflammatory myopathy and myositis, showed 8-fold upregulation of TNNT2, encoding cTnT (but none for TNNI3, encoding cTnI) versus control subjects (n=16, PWald<0.001); the expression correlated with pathological disease activity (R=0.59, Pt-statistic<0.001) and circulating hs-cTnT concentrations (R=0.26, Pt-statistic=0.031). CONCLUSIONS: In patients with active chronic SMD, elevations in cTnT concentrations are common and not attributable to cardiac disease in the majority. This was not observed for cTnI and may be explained in part by re-expression of cTnT in skeletal muscle. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03660969.

Phenotyping by persistent inflammation in systemic sclerosis associated interstitial lung disease: a EUSTAR database analysis.

BACKGROUND: Systemic sclerosis (SSc) is a heterogeneous disease with frequently associated interstitial lung disease (SSc-ILD). We aimed to determine the prognostic potential of phenotyping patients with SSc and SSc-ILD by inflammation and to describe disease trajectories stratified by inflammation and immunosuppressive treatment. METHODS: Patients from the European Scleroderma Trials and Research (EUSTAR) group cohort were allocated to persistent inflammatory, intermediate and non-inflammatory phenotypes if C-reactive protein (CRP) levels were ≥5 mg/L at ≥80%, at 20-80% and at <20% of visits, respectively. Cox regression models were used to analyse mortality risk and mixed effect models to describe trajectories of FVC and diffusing capacity for carbon monoxide (DLCO) %-predicted stratified by inflammation and immunosuppressive treatment. RESULTS: 2971 patients with SSc and 1171 patients with SSc-ILD had at least three CRP measurements available. Patients with SSc-ILD with a persistent inflammatory phenotype had a 6.7 times higher risk of mortality within 5 years compared with those with a persistent non-inflammatory phenotype (95% CI 3 to 15). In the inflammatory phenotype, FVC %-predicted was declining without (-1.11 (95% CI -2.14 to -0.08)/year), but stable with immunosuppressive treatment (-0.00 (95% CI -0.92 to 0.92)/year). In the non-inflammatory phenotype, patients with and without immunosuppressive treatment had a significant decline in FVC %-predicted, which was more pronounced in those with immunosuppressive treatment (-1.26 (95% CI -1.87 to -0.64) and -0.84 (95% CI -1.35 to -0.33)/year, respectively). CONCLUSIONS: Phenotyping by persistent inflammation provides valuable prognostic information, independent of demographics, disease duration, cutaneous subtype, treatment and SSc-ILD severity. The findings from this study support early immunosuppressive treatment in patients with SSc-ILD with persistent inflammation.

Diffusion-weighted magnetic resonance imaging for the diagnosis of giant cell arteritis - a comparison with T1-weighted black-blood imaging.

OBJECTIVES: To investigate the diagnostic performance of diffusion-weighted imaging (DWI) of the superficial cranial arteries in the diagnosis of giant cell arteritis (GCA). METHODS: Retrospectively, 156 patients with clinically suspected GCA were included. A new 4-point ordinal DWI rating scale was developed. A post-contrast, fat-suppressed, T1-weighted "black-blood" sequence (T1-BB) was rated for comparison. Ten arterial segments were assessed: common superficial temporal arteries, temporal and parietal branches, occipital and posterior auricular arteries bilaterally. The expert clinical diagnosis after ≥ 6 months of follow-up was the diagnostic reference standard. Diagnostic accuracy was evaluated for different rating methods. RESULTS: The study cohort consisted of 87 patients with and 69 without GCA. For DWI, the area under the curve was 0.90. For a cut-off of ≥ 2 consecutive pathological slices, DWI showed a sensitivity of 75.9%, a specificity of 94.2% and a positive likelihood ratio of 13.09. With a cut-off of ≥ 3 consecutive pathological slices, sensitivity was 70.1%, specificity was 98.6%, and the positive likelihood ratio was 48.38. For the T1-BB, values were 88.5%, 88.4% and 7.63, respectively. The inter-rater analysis for DWI with a cut-off of ≥ 2 pathological slices showed a kappa of 1.00 on the patient level and 0.85 on the arterial segment level. For the T1-BB the kappa was 0.78 and 0.79, respectively. CONCLUSION: DWI of the superficial cranial arteries demonstrates a good diagnostic accuracy and reliability for the diagnosis of GCA. DWI is widely available and can be used immediately in clinical practice for patients with suspected GCA.

Vision transformer assisting rheumatologists in screening for capillaroscopy changes in systemic sclerosis: an artificial intelligence model.

OBJECTIVES: The first objective of this study was to implement and assess the performance and reliability of a vision transformer (ViT)-based deep-learning model, an 'off-the-shelf' artificial intelligence solution, for identifying distinct signs of microangiopathy in nailfold capilloroscopy (NFC) images of patients with SSc. The second objective was to compare the ViT's analysis performance with that of practising rheumatologists. METHODS: NFC images of patients prospectively enrolled in our European Scleroderma Trials and Research group (EUSTAR) and Very Early Diagnosis of Systemic Sclerosis (VEDOSS) local registries were used. The primary outcome investigated was the ViT's classification performance for identifying disease-associated changes (enlarged capillaries, giant capillaries, capillary loss, microhaemorrhages) and the presence of the scleroderma pattern in these images using a cross-fold validation setting. The secondary outcome involved a comparison of the ViT's performance vs that of rheumatologists on a reliability set, consisting of a subset of 464 NFC images with majority vote-derived ground-truth labels. RESULTS: We analysed 17 126 NFC images derived from 234 EUSTAR and 55 VEDOSS patients. The ViT had good performance in identifying the various microangiopathic changes in capillaries by NFC [area under the curve (AUC) from 81.8% to 84.5%]. In the reliability set, the rheumatologists reached a higher average accuracy, as well as a better trade-off between sensitivity and specificity compared with the ViT. However, the annotators' performance was variable, and one out of four rheumatologists showed equal or lower classification measures compared with the ViT. CONCLUSIONS: The ViT is a modern, well-performing and readily available tool for assessing patterns of microangiopathy on NFC images, and it may assist rheumatologists in generating consistent and high-quality NFC reports; however, the final diagnosis of a scleroderma pattern in any individual case needs the judgement of an experienced observer.

Comparison of clinical features between patients with anti-synthetase syndrome and dermatomyositis: Results from the MYONET registry.

OBJECTIVES: To compare clinical characteristics, including the frequency of cutaneous, extramuscular manifestations, and malignancy, between adults with anti-synthetase syndrome (ASyS) and dermatomyositis (DM). METHODS: Using data regarding adults from the MYONET registry, a cohort of DM patients with anti-Mi2/-TIF1É£/-NXP2/-SAE/-MDA5 autoantibodies, and a cohort of ASyS patients with anti-tRNA synthetase autoantibodies (anti-Jo1/-PL7/-PL12/-OJ/-EJ/-Zo/-KS) were identified. Patients with DM sine dermatitis or with discordant dual autoantibody specificities were excluded. Sub-cohorts of patients with ASyS with or without skin involvement were defined based on presence of DM-type rashes (heliotrope rash, Gottron's papules/sign, violaceous rash, shawl sign, V sign, erythroderma, and/or periorbital rash). RESULTS: In total 1,054 patients were included (DM, n = 405; ASyS, n = 649). In ASyS cohort, 31% (n = 203) had DM-type skin involvement (ASyS-DMskin). A higher frequency of extramuscular manifestations, including Mechanic's hands, Raynaud's phenomenon, arthritis, interstitial lung disease, and cardiac involvement differentiated ASyS-DMskin from DM (all p< 0.001), whereas higher frequency of any of four DM-type rashes: heliotrope rash (n = 248, 61% vs n = 90, 44%), violaceous rash (n = 166, 41% vs n = 57, 9%), V sign (n = 124, 31% vs n = 28, 4%), and shawl sign (n = 133, 33% vs n = 18, 3%) differentiated DM from ASyS-DMskin (all p< 0.005). Cancer-associated myositis (CAM) was more frequent in DM (n = 67, 17%) compared with ASyS (n = 21, 3%) and ASyS-DMskin (n = 7, 3%) cohorts (both p< 0.001). CONCLUSION: DM-type rashes are frequent in patients with ASyS; however, distinct clinical manifestations differentiate these patients from classical DM. Skin involvement in ASyS does not necessitate increased malignancy surveillance. These findings will inform future ASyS classification criteria and patient management.

[Dermatomyositis and juvenile dermatomyositis]. / Dermatomyositis und juvenile Dermatomyositis.

Dermatomyositis (DM) is an inflammatory multisystem disease of unknown etiology, which can already occur in children but first onset can also be in older adulthood. Myalgia and muscle weakness can occur later in the course of the disease or even be completely absent in some forms. Classical signs on the skin include heliotrope rash, facial erythema, Gottron's papules and nailfold capillary abnormalities. For the diagnosis, screening for the presence of myositis-specific autoantibodies has become increasingly more relevant. Muscle enzymes may be elevated but not in approximately one third of patients. In the absence of typical clinical or serologic findings, additional examination methods such as nailfold capillaroscopy, magnetic resonance imaging, electromyography, skin or muscle biopsies may help to establish the diagnosis. Depending on the clinical and serological subtype, additional screening for gastrointestinal or cardiopulmonary involvement should be considered. In adults, an age-appropriate tumor screening should also be performed. Apart from corticosteroids as induction therapy, biologics and small molecule inhibitors are gaining in importance in addition to conventional disease-modifying anti-rheumatic drugs and intravenous immunoglobulins. The prognosis for DM and juvenile DM (JDM) has improved. Most patients recover at least to some extent; however, a few patients die and a minority develop persisting muscle atrophy or severe calcinosis.

Computed tomography-based radiomics decodes prognostic and molecular differences in interstitial lung disease related to systemic sclerosis.

BACKGROUND: Radiomic features calculated from routine medical images show great potential for personalised medicine in cancer. Patients with systemic sclerosis (SSc), a rare, multiorgan autoimmune disorder, have a similarly poor prognosis due to interstitial lung disease (ILD). Here, our objectives were to explore computed tomography (CT)-based high-dimensional image analysis ("radiomics") for disease characterisation, risk stratification and relaying information on lung pathophysiology in SSc-ILD. METHODS: We investigated two independent, prospectively followed SSc-ILD cohorts (Zurich, derivation cohort, n=90; Oslo, validation cohort, n=66). For every subject, we defined 1355 robust radiomic features from standard-of-care CT images. We performed unsupervised clustering to identify and characterise imaging-based patient clusters. A clinically applicable prognostic quantitative radiomic risk score (qRISSc) for progression-free survival (PFS) was derived from radiomic profiles using supervised analysis. The biological basis of qRISSc was assessed in a cross-species approach by correlation with lung proteomic, histological and gene expression data derived from mice with bleomycin-induced lung fibrosis. RESULTS: Radiomic profiling identified two clinically and prognostically distinct SSc-ILD patient clusters. To evaluate the clinical applicability, we derived and externally validated a binary, quantitative radiomic risk score (qRISSc) composed of 26 features that accurately predicted PFS and significantly improved upon clinical risk stratification parameters in multivariable Cox regression analyses in the pooled cohorts. A high qRISSc score, which identifies patients at risk for progression, was reverse translatable from human to experimental ILD and correlated with fibrotic pathway activation. CONCLUSIONS: Radiomics-based risk stratification using routine CT images provides complementary phenotypic, clinical and prognostic information significantly impacting clinical decision making in SSc-ILD.

Staphylococcus aureus impairs dermal fibroblast functions with deleterious effects on wound healing.

Chronic wounds are a major disease burden worldwide. The breach of the epithelial barrier facilitates transition of skin commensals to invasive facultative pathogens. Therefore, we investigated the potential effects of Staphylococcus aureus (SA) on dermal fibroblasts as key cells for tissue repair. In co-culture systems combining live or heat-killed SA with dermal fibroblasts derived from the BJ-5ta cell line, healthy individuals, and patients with systemic sclerosis, we assessed tissue repair including pro-inflammatory cytokines, matrix metalloproteases (MMPs), myofibroblast functions, and host defense responses. Only live SA induced the upregulation of IL-1ß/-6/-8 and MMP1/3 as co-factors of tissue degradation. Additionally, the increased cell death reduced collagen production, proliferation, migration, and contractility, prerequisite mechanisms for wound closure. Intracellular SA triggered inflammatory and type I IFN responses via intracellular dsDNA sensor molecules and MyD88 and STING signaling pathways. In conclusion, live SA affected various key tissue repair functions of dermal fibroblasts from different sources to a similar extent. Thus, SA infection of dermal fibroblasts should be taken into account for future wound management strategies.

[Secondary Immunodeficiency in Rheumatology]. / Sekundäre Immundefekte in der Rheumatologie.

Secondary Immunodeficiency in Rheumatology Abstract. For the treatment of autoimmune and autoinflammatory diseases an immunosuppressive therapy with conventional, small molecule or biological disease modifying anti-rheumatic drugs (DMARDS) plays a key role. This may lead to secondary immunodeficiency with an increased risk for infections, which we discuss in the present article. The risk for reactivation of chronic hepatitis B increases particularly with glucocorticoid dosages of ≥ 20mg/d for longer than four weeks, with B-cell-depleting therapies, followed by anti-TNF-α-inhibitors. The latter also represent a risk for the reactivation of latent tuberculosis. High doses of glucocorticosteroids for prolonged periods increase the risk for pneumonia with Pneumocystis jirovecii, especially if combined with other DMARDs. An elevated risk for Herpes zoster exists for B-cell depletion, TNF-α-inhibition and for JAK blockade. Severe immunosuppression (B-cell depletion, cyclophosphamide, mycophenolate mofetil, JAK inhibitors, prednisone ≥ 20mg/d or combination therapy) increase the risk for severe COVID-19 infections.

Diagnostic measures for patients with systemic sclerosis-associated myopathy.

OBJECTIVES: To evaluate the clinico-serological profile and to assess diagnostic parameters of myopathy in patients with systemic sclerosis (SSc)-associated myopathy. METHODS: We explored the profiles of SSc-myopathy patients and matched non-myopathy SSc patients as well as different diagnostic measures for muscle affection. Additionally, the muscle performance of SSc-myopathy patients, assessed by the Manual Muscle Test for 8 muscle groups (MMT-8) and the Functional Index-2 (FI-2), was compared with that of patients with primary myositis. RESULTS: In SSc-myopathy patients, the following features occurred significantly more often even after Bonferroni correction for multiple comparisons: immunosuppressive treatment (56.0% vs. 24.1%; p=0.0003), elevated levels of creatine kinase (CK) (48.3% vs. 5.3%, p<0.0001), anti-PM-Scl antibodies (30.4% vs. 4%, p=0.00048), and absence of RNA Polymerase III antibodies (7.3% vs. 28.3%, p<0.0001). The MMT-8 showed a mild muscle weakness in SSc-myopathy as well as in primary myositis patients with similar age and sex. Muscle endurance tested by the FI-2 was generally compromised in both cohorts, yet the distribution pattern of affected muscle groups differed between the two cohorts. CONCLUSIONS: We confirmed previously described clinic-serological characteristics of SSc-myopathy patients. Our study suggests that autoantibody profile and CK levels may be helpful in establishing the diagnosis of SSc-myopathy. Whole-body MRI might be more accurate to capture the disease extent than MRI of selected muscle groups. Functional muscle tests validated for primary myositis did not perform well for the assessment of muscle function in patients with SSc-myopathy. Both, potential confounders such as skin, joint, and cardiovascular involvement as well as lack of sensitivity might have negatively affected the test performance in this population.

The Hospital Anxiety and Depression Scale in patients with systemic sclerosis: a psychometric and factor analysis in a monocentric cohort.

OBJECTIVES: To evaluate the feasibility, validity, reliability, and responsiveness of the Hospital Anxiety and Depression Scale (HADS) and to analyse its model structure in patients with systemic sclerosis (SSc). METHODS: In this study, 316 SSc patients were included; of these, 159 participated in the responsiveness analysis. Psychometric properties were tested in analogy to the Outcome Measures in Rheumatology (OMERACT) filter and an exploratory and confirmatory factor analysis was performed to examine the structure of HADS. RESULTS: The HADS showed adequate feasibility, validity, reliability, and responsiveness to clinically relevant worsening of the disease. For our population of SSc patients, the HADS model with two sub-scales, HADS-A and HADS-D, and a general scale HADS-S, measuring anxiety, depression, and distress, respectively, was most appropriate. The rates of anxiety, depression, mixed anxiety-depressive disorder (MADD) and distress identified by HADS were 32.2%, 25.9%, 18.5%, and 49.5%, respectively, in our cohort. CONCLUSIONS: The psychometric properties of the HADS make it useful for screening in SSc, where anxiety, depression, MADD, and distress represent a significant burden to patients.

Evaluation of botulinum toxin A injections for the treatment of refractory chronic digital ulcers in patients with systemic sclerosis.

OBJECTIVES: To evaluate the therapeutic benefit of botulinum toxin A (BTX-A) injections for digital ulcers (DU) in patients with systemic sclerosis (SSc). METHODS: A systematic literature review was performed and the identified articles were selected by two reviewers and analysed with respect to date of publication, inclusion and exclusion criteria, number and age of participants, volume of BTX-A, injection sites, outcomes, and adverse events. In addition, in the Zurich cohort, 7 SSc patients were eligible for the study and were assessed for the duration of DU to heal, duration of DU-free periods, changes in frequency and numbers of prescribed vasodilators, pain and blood flow. RESULTS: In five articles from the systematic review, at least 48% of DU had healed and up to 100% reduction in VAS for pain was reported. Our 7 patients (median age of 53 (47-82) years) had in median 2.5 (2-4) DU and were injected with a median BTX-A volume of 90 (50-100) units per hand. Of the 31 DU in all patients, 77% (n=24) healed. Time to wound closure was in median 8 (4-12) weeks and the DU-free duration was in median 8 (3-10) months. In 80% of the cases, at least one vasodilator was stopped or could be administered less frequently. An improvement of blood flow and pain was reported in 60% of the cases. CONCLUSIONS: BTX-A injections might be of benefit for the treatment of chronic, refractory DU in selected SSc patients, yet a sufficiently powered prospective study will be needed as ultimate proof.

Impaired micronutrients and prealbumin in patients with established and very early systemic sclerosis.

OBJECTIVES: Gastrointestinal involvement and impaired nutritional status are frequent in patients with systemic sclerosis (SSc). Hereby, we hypothesised that micronutrients and/or prealbumin could be deficitary in SSc. METHODS: Patients with SSc and very early SSc (veSSc) were prospectively included. Clinical assessment, data recording and quality controls followed EUSTAR standards. The UCLA SCTCGIT 2.0 questionnaire was applied and the serum levels of zinc, selenium, prealbumin, holotranscobalamin, folic acid were measured. RESULTS: Half (52.4%) of the 176 patients with established SSc showed a deficiency in at least one of the measured nutrients. The most frequent deficit was seen in folic acid (17.9%), followed closely by selenium, prealbumin and zinc (around 15% each). Nearly a fifth (19%) of these patients had multiple deficiencies. Patients with more severe disease, including advanced skin fibrosis, positive ACR 1980 classification criteria, anemia and elevated serum inflammation markers were more likely to be nutrient deficient. Lower BMI<20kg/m2 was associated with several nutrient deficiencies. Prealbumin deficiency was associated with more frequent stomach symptoms and methotrexate therapy. A third of veSSc patients (27%, 44/74) presented a nutrient deficiency, mostly of zinc (10%). Surprisingly, micronutrient deficiencies were not associated with usual parameters of gastrointestinal involvement. CONCLUSIONS: These novel data reveal deficiencies in micronutrients and/or prealbumin are a frequent burden in patients with SSc. Moreover, these correlate with clinical aspects of the disease. Especially patients with advanced disease appear at high risk for an impaired nutrient status, suggesting that screening of micronutrients status should be performed in these patients.

Visualisation of interstitial lung disease by molecular imaging of integrin αvß3 and somatostatin receptor 2.

OBJECTIVE: To evaluate integrin αvß3 (alpha-v-beta-3)-targeted and somatostatin receptor 2 (SSTR2)-targeted nuclear imaging for the visualisation of interstitial lung disease (ILD). METHODS: The pulmonary expression of integrin αvß3 and SSTR2 was analysed in patients with different forms of ILD as well as in bleomycin (BLM)-treated mice and respective controls using immunohistochemistry. Single photon emission CT/CT (SPECT/CT) was performed on days 3, 7 and 14 after BLM instillation using the integrin αvß3-targeting 177Lu-DOTA-RGD and the SSTR2-targeting 177Lu-DOTA-NOC radiotracer. The specific pulmonary accumulation of the radiotracers over time was assessed by in vivo and ex vivo SPECT/CT scans and by biodistribution studies. RESULTS: Expression of integrin αvß3 and SSTR2 was substantially increased in human ILD regardless of the subtype. Similarly, in lungs of BLM-challenged mice, but not of controls, both imaging targets were stage-specifically overexpressed. While integrin αvß3 was most abundantly upregulated on day 7, the inflammatory stage of BLM-induced lung fibrosis, SSTR2 expression peaked on day 14, the established fibrotic stage. In agreement with the findings on tissue level, targeted nuclear imaging using SPECT/CT specifically detected both imaging targets ex vivo and in vivo, and thus visualised different stages of experimental ILD. CONCLUSION: Our preclinical proof-of-concept study suggests that specific visualisation of molecular processes in ILD by targeted nuclear imaging is feasible. If transferred into clinics, where imaging is considered an integral part of patients' management, the additional information derived from specific imaging tools could represent a first step towards precision medicine in ILD.

Revised European Scleroderma Trials and Research Group Activity Index is the best predictor of short-term severity accrual.

BACKGROUND: The European Scleroderma Trials and Research Group (EUSTAR) recently developed a preliminarily revised activity index (AI) that performed better than the European Scleroderma Study Group Activity Index (EScSG-AI) in systemic sclerosis (SSc). OBJECTIVE: To assess the predictive value for short-term disease severity accrual of the EUSTAR-AI, as compared with those of the EScSG-AI and of known adverse prognostic factors. METHODS: Patients with SSc from the EUSTAR database with a disease duration from the onset of the first non-Raynaud sign/symptom ≤5 years and a baseline visit between 2003 and 2014 were first extracted. To capture the disease activity variations over time, EUSTAR-AI and EScSG-AI adjusted means were calculated. The primary outcome was disease progression defined as a Δ≥1 in the Medsger's severity score and in distinct items at the 2-year follow-up visit. Logistic regression analysis was carried out to identify predictive factors. RESULTS: 549 patients were enrolled. At multivariate analysis, the EUSTAR-AI adjusted mean was the only predictor of any severity accrual and of that of lung and heart, skin and peripheral vascular disease over 2 years. CONCLUSION: The adjusted mean EUSTAR-AI has the best predictive value for disease progression and development of severe organ involvement over time in SSc.

Vasodilators and low-dose acetylsalicylic acid are associated with a lower incidence of distinct primary myocardial disease manifestations in systemic sclerosis: results of the DeSScipher inception cohort study.

OBJECTIVES: To investigate the influence of vasodilator drugs on the occurrence of features depending on myocardial ischaemia/fibrosis (ventricular arrhythmias, Q waves, cardiac blocks, pacemaker implantation, left ventricular ejection fraction (LVEF) <55%, and/or congestive heart failure and sudden cardiac death) in systemic sclerosis (SSc). METHODS: 601 patients with SSc were enrolled from 1 December 2012 to 30 November 2015 and had a second visit 0.5-4 years apart. 153 received no vasodilators; 448 received vasodilator therapy (ie, calcium channel blockers and/or ACE inhibitors or angiotensin II receptor blockers or combinations of them), 89 of them being also treated with either endothelin receptor antagonists or PDE5 inhibitors or prostanoids. Associations between the occurrence of myocardial disease manifestations and any demographic, disease and therapeutic aspect were investigated by Cox regression analysis. A Cox frailty survival model with centre of enrolment as random effect was performed. RESULTS: During 914 follow-up patient-years, 12 ventricular arrhythmias, 5 Q waves, 40 cardiac blocks, 6 pacemaker implantations and 19 reduced LVEF and/or congestive heart failure (CHF) occurred. In multivariate Cox regression analysis, vasodilator therapy was associated with a lower incidence of ventricular arrhythmias (p=0.03); low-dose acetylsalicylic acid (ASA) with a lower incidence of cardiac blocks and/or Q waves and/or pacemaker implantation (p=0.02); active disease with a higher incidence of LVEF <55% and/or CHF and cardiac blocks and/or Q waves and/or pacemaker implantation (p=0.05). CONCLUSIONS: The present study might suggest a preventative effect on the occurrence of distinct myocardial manifestations by vasodilator therapy and low-dose ASA.

Prediction of progression of interstitial lung disease in patients with systemic sclerosis: the SPAR model.

OBJECTIVES: To identify the predictive clinical characteristics and establish a prediction model for the progression of mild interstitial lung disease (ILD) in patients with systemic sclerosis (SSc). METHODS: Patients with SSc from two independent prospective cohorts were included in this observational study. All patients fulfilled the 2013 American College of Rheumatology/European League Against Rheumatism criteria, had mild ILD at baseline diagnosed by High-Resolution Computed Tomography (HRCT), available baseline and ≥1 annual follow-up pulmonary function tests and no concomitant pulmonary hypertension or airflow obstruction. ILD progression was defined as a relative decrease in forced vital capacity (FVC)%≥15%, or FVC%≥10% combined with diffusing capacity for carbon monoxide %≥15% at 1-year follow-up. Candidate predictors for multivariate logistic regression were selected by expert opinion based on clinical significance. A prediction model for ILD progression was established in the derivation cohort and validated in the multinational validation cohort. RESULTS: A total of 25/98 and 25/117 patients with SSc showed ILD progression in the derivation cohort and the validation cohort, respectively. Lower SpO2 after 6 min walk test (6MWT) and arthritis ever were identified as independent predictors for ILD progression in both cohorts. The optimal cut-off value of SpO2 after 6MWT for predicting ILD progression was determined as 94% by receiver operating characteristic curve analysis. The derived SPAR model combining both predictors (SPO2 and ARthritis) increased the prediction rate from 25.5% to 91.7% with an area under the curve (95% CI) of 0.83 (0.73 to 0.93). CONCLUSIONS: The evidence-based SPAR prediction model developed in our study might be helpful for the risk stratification of patients with mild SSc-ILD in clinical practice and cohort enrichment for future clinical trial design.

The EuroMyositis registry: an international collaborative tool to facilitate myositis research.

AIMS: The EuroMyositis Registry facilitates collaboration across the idiopathic inflammatory myopathy (IIM) research community. This inaugural report examines pooled Registry data. METHODS: Cross-sectional analysis of IIM cases from 11 countries was performed. Associations between clinical subtypes, extramuscular involvement, environmental exposures and medications were investigated. RESULTS: Of 3067 IIM cases, 69% were female. The most common IIM subtype was dermatomyositis (DM) (31%). Smoking was more frequent in connective tissue disease overlap cases (45%, OR 1.44, 95% CI 1.09 to 1.90, p=0.012). Smoking was associated with interstitial lung disease (ILD) (OR 1.32, 95% CI 1.06 to 1.65, p=0.013), dysphagia (OR 1.43, 95% CI 1.16 to 1.77, p=0.001), malignancy ever (OR 1.78, 95% CI 1.36 to 2.33, p<0.001) and cardiac involvement (OR 2.40, 95% CI 1.60 to 3.60, p<0.001).Dysphagia occurred in 39% and cardiac involvement in 9%; either occurrence was associated with higher Health Assessment Questionnaire (HAQ) scores (adjusted OR 1.79, 95% CI 1.43 to 2.23, p<0.001). HAQ scores were also higher in inclusion body myositis cases (adjusted OR 3.85, 95% CI 2.52 to 5.90, p<0.001). Malignancy (ever) occurred in 13%, most commonly in DM (20%, OR 2.06, 95% CI 1.65 to 2.57, p<0.001).ILD occurred in 30%, most frequently in antisynthetase syndrome (71%, OR 10.7, 95% CI 8.6 to 13.4, p<0.001). Rash characteristics differed between adult-onset and juvenile-onset DM cases ('V' sign: 56% DM vs 16% juvenile-DM, OR 0.16, 95% CI 0.07 to 0.36, p<0.001). Glucocorticoids were used in 98% of cases, methotrexate in 71% and azathioprine in 51%. CONCLUSION: This large multicentre cohort demonstrates the importance of extramuscular involvement in patients with IIM, its association with smoking and its influence on disease severity. Our findings emphasise that IIM is a multisystem inflammatory disease and will help inform prognosis and clinical management of patients.

Functional disability and its predictors in systemic sclerosis: a study from the DeSScipher project within the EUSTAR group.

Objectives: The multisystem manifestations of SSc can greatly impact patients' quality of life. The aim of this study was to identify factors associated with disability in SSc. Methods: SSc patients from the prospective DeSScipher cohort who had completed the scleroderma health assessment questionnaire (SHAQ), a disability score that combines the health assessment questionnaire and five visual analogue scales, were included in this analysis. The effect of factors possibly associated with disability was analysed with multiple linear regressions. Results: The mean SHAQ and HAQ scores of the 944 patients included were 0.87 (s.d. = 0.66) and 0.92 (s.d. = 0.78); 59% of the patients were in the mild to moderate difficulty SHAQ category (0 ⩽ SHAQ < 1), 34% in the moderate to severe disability category (1 ⩽ SHAQ < 2) and 7% in the severe to very severe disability category (2 ⩽ SHAQ ⩽ 3). The means of the visual analogue scales scores were in order of magnitude: overall disease severity (37 mm), RP (31 mm), pulmonary symptoms (24 mm), gastrointestinal symptoms (20 mm) and digital ulcers (19 mm). In multiple regression, the main factors associated with high SHAQ scores were the presence of dyspnoea [modified New York Heart Association (NYHA) class IV (regression coefficient B = 0.62), modified NYHA class III (B = 0.53) and modified NYHA class II (B = 0.21; all vs modified NYHA class I)], FM (B = 0.37), muscle weakness (B = 0.27), digital ulcers (B = 0.20) and gastrointestinal symptoms (oesophageal symptoms, B = 0.16; stomach symptoms, B = 0.15; intestinal symptoms, B = 0.15). Conclusion: SSc patients perceive dyspnoea, pain, digital ulcers, muscle weakness and gastrointestinal symptoms as the main factors driving their level of disability, unlike physicians who emphasize objective measures of disability.