EULAR recommendations for the involvement of patient research partners in rheumatology research: 2023 update.

BACKGROUND: Since the publication of the 2011 European Alliance of Associations for Rheumatology (EULAR) recommendations for patient research partner (PRP) involvement in rheumatology research, the role of PRPs has evolved considerably. Therefore, an update of the 2011 recommendations was deemed necessary. METHODS: In accordance with the EULAR Standardised Operational Procedures, a task force comprising 13 researchers, 2 health professionals and 10 PRPs was convened. The process included an online task force meeting, a systematic literature review and an in-person second task force meeting to formulate overarching principles (OAPs) and recommendations. The level of agreement of task force members was assessed anonymously (0-10 scale). RESULTS: The task force developed five new OAPs, updated seven existing recommendations and formulated three new recommendations. The OAPs address the definition of a PRP, the contribution of PRPs, the role of informal caregivers, the added value of PRPs and the importance of trust and communication in collaborative research efforts. The recommendations address the research type and phases of PRP involvement, the recommended number of PRPs per project, the support necessary for PRPs, training of PRPs and acknowledgement of PRP contributions. New recommendations concern the benefits of support and guidance for researchers, the need for regular evaluation of the patient-researcher collaboration and the role of a designated coordinator to facilitate collaboration. Agreements within the task force were high and ranged between 9.16 and 9.96. CONCLUSION: The updated EULAR recommendations for PRP involvement are more substantially based on evidence. Together with added OAPs, they should serve as a guide for researchers and PRPs and will ultimately strengthen the involvement of PRPs in rheumatology research.

Patient research partner involvement in rheumatology research: a systematic literature review informing the 2023 updated EULAR recommendations for the involvement of patient research partners.

BACKGROUND: Patient research partners (PRPs) are people with a disease who collaborate in a research team as partners. The aim of this systematic literature review (SLR) was to assess barriers and facilitators to PRP involvement in rheumatology research. METHODS: The SLR was conducted in PubMed/Medline for articles on PRP involvement in rheumatology research, published between 2017 and 2023; websites were also searched in rheumatology and other specialties. Data were extracted regarding the definition of PRPs, their role and added value, as well as barriers and facilitators to PRP involvement. The quality of the articles was assessed. Quantitative data were analysed descriptively, and principles of thematic content analysis was applied to qualitative data. RESULTS: Of 1016 publications, 53 articles were included; the majority of these studies were qualitative studies (26%), opinion articles (21%), meeting reports (17%) and mixed-methods studies (11%). Roles of PRPs ranged from research partners to patient advocates, advisors and patient reviewers. PRPs were reported/advised to be involved early in the project (32% of articles) and in all research phases (30%), from the conception stage to the implementation of research findings. The main barriers were challenges in communication and support for both PRPs and researchers. Facilitators of PRP involvement included more than one PRP per project, training of PRPs and researchers, a supportive environment for PRPs (including adequate communication, acknowledgement and compensation of PRPs) and the presence of a PRP coordinator. CONCLUSION: This SLR identified barriers and facilitators to PRP involvement, and was key to updating the European Alliance of Associations for Rheumatology recommendations for PRP-researcher collaboration based on scientific evidence.

Arthritis in patients with very early systemic sclerosis: a comprehensive clinical and prognostic analysis.

OBJECTIVE: Arthritis is associated with a worse prognosis in established systemic sclerosis (SSc). However, knowledge about its relevance in very early SSc (veSSc) is scarce. We aimed to assess the prevalence and phenotype of arthritis, as well as its prognostic impact, in patients with veSSc. METHODS: We analysed patients with veSSc, defined as presence of Raynaud's phenomenon and/or at least one of: puffy fingers, antinuclear antibodies (ANA), abnormal capillaroscopy, not fulfilling the ACR/EULAR classification criteria for SSc at baseline. We investigated associations between arthritis and clinical parameters, followed by a longitudinal analysis to investigate arthritis as a potential predictor of progression towards established SSc. RESULTS: We included 159 patients, of whom 108 had at least one follow-up visit. SSc-related arthritis occurred in 22/159 (13.8%) patients at baseline. Arthritis was mostly seronegative, symmetrical, oligo- or polyarticular, non-erosive, and rarely associated with elevation of inflammatory markers. More than half of the patients needed treatment with DMARDs. Anti-centromere antibodies were negatively associated with arthritis (OR: 0.707, 95% confidence interval 0.513-0.973, p = 0.033). Overall, 43/108 (39.8%) patients with follow-up progressed to established SSc during the observation time. Arthritis was not a significant predictor for progression to established SSc in a multivariable Cox regression. CONCLUSION: In this first comprehensive analysis, we found a similar prevalence of arthritis in veSSc as seen in established SSc. Moreover, the use of DMARDs indirectly suggests a relevant disease burden.

Therapeutic management of fibrosis in systemic sclerosis patients - an analysis from the Swiss EUSTAR cohort.

OBJECTIVES: Systemic sclerosis is a chronic autoimmune connective tissue disease leading to microvascular and fibrotic manifestations in multiple organs. Several treatment options and recommendations from different European countries are available. In this study, for which the ambit is Switzerland specifically, we aim to describe the treatment patterns of systemic sclerosis patients with fibrotic manifestations. METHODS: Systemic sclerosis patients were selected from six Swiss tertiary centres recorded in the multicentre, prospective European Scleroderma Trials and Research (EUSTAR) registry. Patients fulfilling the 2013 ACR/EULAR systemic sclerosis classification criteria at baseline were included. To determine the differences in treatment of varying degrees of fibrosis, four groups were identified: (1) patients with a modified Rodnan skin score (mRSS) >0; (2) those with mRSS ≥7; (3) those with interstitial lung disease (SSc-ILD), diagnosed by either chest X-Ray or high-resolution computed tomography; and (4) patients fulfilling one of the additional criteria for extensive interstitial lung disease, defined as interstitial lung disease involvement of >20% in high-resolution computed tomography, dyspnea NYHA-stage 3/4, or a predicted forced vital capacity (FVC) of <70%. RESULTS: A total of 590 patients with systemic sclerosis fulfilled the inclusion criteria. In this cohort, 421 (71.4%) had mRSS >0, of whom 195 (33.1%) had mRSS ≥7; interstitial lung disease was diagnosed in 198 of 456 (43.4%), of whom 106 (18.0 %) showed extensive interstitial lung disease. Regarding non-biologic disease-modifying medications (DMARDs), the most frequently prescribed was methotrexate, followed by hydroxychloroquine and mycophenolate mofetil. Rituximab and tocilizumab were most frequently used among the biologic DMARDs. Specifically, 148/372 (39.8%) of treated patients with skin fibrosis received methotrexate, mycophenolate mofetil or rituximab, and 80/177 (45.2%) with interstitial lung disease received cyclophosphamide, mycophenolate mofetil, tocilizumab or rituximab. Most patients received a proton-pump inhibitor, and few patients underwent hematopoietic stem cell transplantation. CONCLUSION: Overall, in Switzerland, a wide range of medications is prescribed for systemic sclerosis patients. This includes modern, targeted treatments for which randomised controlled clinical trial have been recently reported.

Histogram-Based Densitometry Index to Assess the Severity of Interstitial Lung Disease in Systemic Sclerosis in Standard and Low-Dose Computed Tomography.

OBJECTIVE: Mean lung attenuation, skewness, and kurtosis are histogram-based densitometry variables that quantify systemic sclerosis-associated interstitial lung disease (SSc-ILD) and were recently merged into a computerized integrated index (CII). Our work tested the CII in low-dose 9-slice (reduced) and standard high-resolution computed tomography (CT) scans to evaluate extensive SSc-ILD and predict mortality. METHODS: CT scans from patients with SSc-ILD were assessed using the software Horos to compute standard and reduced CIIs. Extensive ILD was determined following the Goh staging system. The association between CIIs and extensive ILD was analyzed with a generalized estimating equation regression model, the predictive ability of CIIs by the area under the receiver-operation characteristic curve (AUC), and the association between CIIs and death by Kaplan-Meier analysis. RESULTS: Among 243 patients with standard and reduced CT scans available, 157 CT scans from 119 patients with SSc-ILD constituted the derivation cohort. The validation cohort included 116 standard and 175 reduced CT scans. Both CIIs from standard (odds ratio [OR] 0.53, 95% CI 0.37-0.75; AUC 0.77, 95% CI 0.68-0.87) and reduced CT scans (OR 0.54, 95% CI 0.35-0.82; AUC 0.78, 95% CI 0.70-0.87) were significantly associated with extensive ILD. A threshold of CII ≤ -0.96 for standard CT scans and CII ≤ -1.85 for reduced CT scans detected extensive ILD with high sensitivity in both derivation and validation cohorts. Extensive ILD according to Goh staging (OR 2.94, 95% CI 1.10-7.82) and standard CII ≤ -0.96 (OR 1.78, 95% CI 1.24-2.56) significantly predicted mortality; a marginal P value was observed for reduced CII ≤ -1.85 (OR 1.27, 95% CI 0.93-1.75). CONCLUSION: Thresholds for both standard and reduced CII to identify extensive ILD were developed and validated, with an additional association with mortality. CIIs might help in clinical practice when radiology expertise is missing.

Characteristics and disease course of untreated patients with interstitial lung disease associated with systemic sclerosis in a real-life two-centre cohort.

BACKGROUND: Interstitial lung disease (ILD) is the leading cause of death in systemic sclerosis (SSc). According to expert statements, not all SSc-ILD patients require pharmacological therapy. OBJECTIVES: To describe disease characteristics and disease course in untreated SSc-ILD patients in two well characterised SSc-ILD cohorts. METHODS: Patients were classified as treated if they had received a potential ILD-modifying drug. ILD progression in untreated patients was defined as (1) decline in forced vital capacity (FVC) from baseline of ≥10% or (2) decline in FVC of 5%-9% associated with a decline in diffusing capacity for carbon monoxide (DLCO)≥15% over 12±3 months or (3) start of any ILD-modifying treatment or (4) increase in the ILD extent during follow-up. Multivariable logistic regression was performed to identify factors associated with non-prescription of ILD-modifying treatment at baseline. Prognostic factors for progression in untreated patients were tested by multivariate Cox regression. RESULTS: Of 386 SSc-ILD included patients, 287 (74%) were untreated at baseline. Anticentromere antibodies (OR: 6.75 (2.16-21.14), p=0.001), limited extent of ILD (OR: 2.39 (1.19-4.82), p=0.015), longer disease duration (OR: 1.04 (1.00-1.08), p=0.038) and a higher DLCO (OR: 1.02 (1.01-1.04), p=0.005) were independently associated with no ILD-modifying treatment at baseline. Among 234 untreated patients, the 3 year cumulative incidence of progression was 39.9% (32.9-46.2). Diffuse cutaneous SSc and extensive lung fibrosis independently predicted ILD progression in untreated patients. CONCLUSION: As about 40% of untreated patients show ILD progression after 3 years and effective and safe therapies for SSc-ILD are available, our results support a change in clinical practice in selecting patients for treatment.

The long non-coding RNA HOTAIR contributes to joint-specific gene expression in rheumatoid arthritis.

Although patients with rheumatoid arthritis (RA) typically exhibit symmetrical joint involvement, some patients develop alternative disease patterns in response to treatment, suggesting that different molecular mechanism may underlie disease progression depending on joint location. Here, we identify joint-specific changes in RA synovium and synovial fibroblasts (SF) between knee and hand joints. We show that the long non-coding RNA HOTAIR, which is only expressed in knee SF, regulates more than 50% of this site-specific gene expression in SF. HOTAIR is downregulated after stimulation with pro-inflammatory cytokines and is expressed at lower levels in knee samples from patients with RA, compared with osteoarthritis. Knockdown of HOTAIR in knee SF increases PI-Akt signalling and IL-6 production, but reduces Wnt signalling. Silencing HOTAIR inhibits the migratory function of SF, decreases SF-mediated osteoclastogenesis, and increases the recruitment of B cells by SF. We propose that HOTAIR is an important epigenetic factor in joint-specific gene expression in RA.

Involving patients as research partners in research in rheumatology: a literature review in 2023.

OBJECTIVE: The inclusion of patient research partners (PRPs) in research projects is increasingly recognised and recommended in rheumatology. The level of involvement of PRPs in translational research in rheumatology remains unknown, while in randomised clinical trials (RCTs), it has been reported to be 2% in 2020. Therefore, we aimed to assess the involvement of PRPs in recent translational studies and RCTs in rheumatology. METHODS: We conducted a scoping literature review of the 80 most recent articles (40 translational studies and 40 RCTs) from four target diseases: rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus and lower extremity osteoarthritis. We selected 20 papers from each disease, published up until 1 March 2023, in rheumatology and general scientific journals. In each paper, the extent of PRP involvement was assessed. Analyses were descriptive. RESULTS: Of 40 translational studies, none reported PRP involvement. Of 40 RCTs, eight studies (20%) reported PRP involvement. These trials were mainly from Europe (75%) and North America (25%). Most of them (75%) were non-industry funded. The type of PRP involvement was reported in six of eight studies: six studies reported PRP participation in the study design or design of the intervention and two of them in the interpretation of the results. All the trials reporting the number of PRPs (75%), involved at least two PRPs. CONCLUSION: Despite a worldwide movement advocating for increased patient involvement in research, PRPs in translational research and RCTs in rheumatology are significantly under-represented. This limited involvement of PRPs in research highlights a persistent gap between the existing recommendations and actual practice.

Risk stratification using anti-citrullinated peptide antibodies (ACPA) in polyarticular subtypes of juvenile idiopathic arthritis in adulthood.

OBJECTIVES: Polyarticular juvenile idiopathic arthritis (pJIA) is a subset of juvenile idiopathic arthritis (JIA), divided into two subtypes according to the presence of rheumatoid factor: pJIA without rheumatoid factor (pJIA RF-) and pJIA with positive rheumatoid factor (pJIA RF+), this latter is characterised with more structural damage. Anti-citrullinated peptide antibodies (ACPA) are often associated with RF. The respective performance of ACPA versus RF in structural outcome in pJIA, and in particular in adulthood pJIA remains unknown. Therefore, the aim of this study was to determine whether ACPA could be of value to assess structural damage in pJIA persisting in adulthood. METHODS: Patients with pJIA and available data for ACPA, RF and X-ray were included retrospectively. Structural damage was assessed by two independent blinded investigators using Sharp Van Der Heijde scores. RESULTS: 56 pJIA adult patients were included: 62% (35/56) had pJIA RF+ and 38% (21/56) pJIA RF-. ACPA positivity in pJIA was significantly associated with presence of RF (96% vs 26%, P<0.001). RF positivity was significantly associated with higher Sharp van Der Heijde erosion and total scores (respectively P<0.01 and P<0.05). There were higher Sharp Van Der Heijde erosion, joint space narrowing and total scores in the pJIA ACPA+ subgroup than in the pJIA ACPA- subgroup, although there was no statistical significance. However, when adjusted on disease duration, pJIA ACPA+ patients had significantly higher erosion and total scores than pJIA ACPA- patients (P<0.05), and pJIA ACPA+ patients required more bDMARDs than pJIA ACPA- patients (P<0.05). Moreover, pJIA patients with high Sharp van Der Heijde joint space narrowing and total scores had significantly higher ACPA levels (P<0.01). A correlation was identified between ACPA levels and Sharp van Der Heijde total score (r=0.54, P<0.05). In the pJIA RF+ subgroup the presence of ACPA was associated with additional structural damage compared to no ACPA: sharp Van Der Heijde erosion, joint space narrowing and total scores were higher in the pJIA RF+ ACPA+ subgroup than in the pJIA RF+ ACPA- subgroup although these results did not reach significance. CONCLUSION: Our results suggest that pJIA RF+ ACPA+ adult patients may have a more severe articular phenotype than pJIA RF+ ACPA- patients. ACPA could bring an additional value to RF for pJIA patients regarding structural damage. Altogether our results show that RF and ACPA are associated with structural damage measured by Sharp Van Der Heijde score in pJIA persisting in adulthood.

Effectiveness and safety of tocilizumab in patients with systemic sclerosis: a propensity score matched controlled observational study of the EUSTAR cohort.

OBJECTIVES: Tocilizumab showed trends for improving skin fibrosis and prevented progression of lung fibrosis in systemic sclerosis (SSc) in randomised controlled clinical trials. We aimed to assess safety and effectiveness of tocilizumab in a real-life setting using the European Scleroderma Trial and Research (EUSTAR) database. METHODS: Patients with SSc fulfilling the American College of Rheumatology (ACR)/EULAR 2013 classification criteria, with baseline and follow-up visits at 12±3 months, receiving tocilizumab or standard of care as the control group, were selected. Propensity score matching was applied. Primary endpoints were the modified Rodnan skin score (mRSS) and FVC at 12±3 months compared between the groups. Secondary endpoints were the percentage of progressive/regressive patients for skin and lung at 12±3 months. RESULTS: Ninety-three patients with SSc treated with tocilizumab and 3180 patients with SSc with standard of care fulfilled the inclusion criteria. Comparison between groups did not show significant differences, but favoured tocilizumab across all predefined primary and secondary endpoints: mRSS was lower in the tocilizumab group (difference -1.0, 95% CI -3.7 to 1.8, p=0.48). Similarly, FVC % predicted was higher in the tocilizumab group (difference 1.5 (-6.1 to 9.1), p=0.70). The percentage of progressive/regressive patients favoured tocilizumab over controls. These results were robust regarding the sensitivity analyses. Safety analysis confirmed previously reported adverse event profiles. CONCLUSION: Although this large, observational, controlled, real-life EUSTAR study did not show significant effectiveness of tocilizumab on skin and lung fibrosis, the consistency of direction of all predefined endpoints generates hypothesis for potential effectiveness in a broader SSc population.

An Optimized Tissue Dissociation Protocol for Single-Cell RNA Sequencing Analysis of Fresh and Cultured Human Skin Biopsies.

We present an optimized dissociation protocol for preparing high-quality skin cell suspensions for in-depth single-cell RNA-sequencing (scRNA-seq) analysis of fresh and cultured human skin. Our protocol enabled the isolation of a consistently high number of highly viable skin cells from small freshly dissociated punch skin biopsies, which we use for scRNA-seq studies. We recapitulated not only the main cell populations of existing single-cell skin atlases, but also identified rare cell populations, such as mast cells. Furthermore, we effectively isolated highly viable single cells from ex vivo cultured skin biopsy fragments and generated a global single-cell map of the explanted human skin. The quality metrics of the generated scRNA-seq datasets were comparable between freshly dissociated and cultured skin. Overall, by enabling efficient cell isolation and comprehensive cell mapping, our skin dissociation-scRNA-seq workflow can greatly facilitate scRNA-seq discoveries across diverse human skin pathologies and ex vivo skin explant experimentations.

Role of synovial fibroblast subsets across synovial pathotypes in rheumatoid arthritis: a deconvolution analysis.

OBJECTIVES: To integrate published single-cell RNA sequencing (scRNA-seq) data and assess the contribution of synovial fibroblast (SF) subsets to synovial pathotypes and respective clinical characteristics in treatment-naïve early arthritis. METHODS: In this in silico study, we integrated scRNA-seq data from published studies with additional unpublished in-house data. Standard Seurat, Harmony and Liger workflow was performed for integration and differential gene expression analysis. We estimated single cell type proportions in bulk RNA-seq data (deconvolution) from synovial tissue from 87 treatment-naïve early arthritis patients in the Pathobiology of Early Arthritis Cohort using MuSiC. SF proportions across synovial pathotypes (fibroid, lymphoid and myeloid) and relationship of disease activity measurements across different synovial pathotypes were assessed. RESULTS: We identified four SF clusters with respective marker genes: PRG4+ SF (CD55, MMP3, PRG4, THY1neg ); CXCL12+ SF (CXCL12, CCL2, ADAMTS1, THY1low ); POSTN+ SF (POSTN, collagen genes, THY1); CXCL14+ SF (CXCL14, C3, CD34, ASPN, THY1) that correspond to lining (PRG4+ SF) and sublining (CXCL12+ SF, POSTN+ + and CXCL14+ SF) SF subsets. CXCL12+ SF and POSTN+ + were most prominent in the fibroid while PRG4+ SF appeared highest in the myeloid pathotype. Corresponding, lining assessed by histology (assessed by Krenn-Score) was thicker in the myeloid, but also in the lymphoid pathotype + the fibroid pathotype. PRG4+ SF correlated positively with disease severity parameters in the fibroid, POSTN+ SF in the lymphoid pathotype whereas CXCL14+ SF showed negative association with disease severity in all pathotypes. CONCLUSION: This study shows a so far unexplored association between distinct synovial pathologies and SF subtypes defined by scRNA-seq. The knowledge of the diverse interplay of SF with immune cells will advance opportunities for tailored targeted treatments.

Stratification in systemic sclerosis according to autoantibody status versus skin involvement: a study of the prospective EUSTAR cohort.

BACKGROUND: The current subclassification of systemic sclerosis into cutaneous subtypes does not fully capture the heterogeneity of the disease. We aimed to compare the performances of stratification into LeRoy's cutaneous subtypes versus stratification by autoantibody status in systemic sclerosis. METHODS: For this cohort study, we assessed people with systemic sclerosis in the multicentre international European Scleroderma Trials and Research (EUSTAR) database. Individuals positive for systemic-sclerosis autoantibodies of two specificities were excluded, and remaining individuals were classified by cutaneous subtype, according to their systemic sclerosis-specific autoantibodies, or both. We assessed the performance of each model to predict overall survival, progression-free survival, disease progression, and different organ involvement. The three models were compared by use of the area under the curve (AUC) of the receiver operating characteristic and the net reclassification improvement (NRI). Missing data were imputed. FINDINGS: We assessed the database on July 26, 2019. Of 16 939 patients assessed for eligibility, 10 711 patients were included: 1647 (15·4%) of 10 709 were male, 9062 (84·6%) were female, mean age was 54·4 (SD 13·8) years, and mean disease duration was 7·9 (SD 8·2) years. Information regarding cutaneous subtype was available for 10 176 participants and antibody data were available for 9643 participants. In the prognostic analysis, there was no difference in AUC for overall survival (0·82, 95% CI 0·81-0·84 for cutaneous only vs 0·84, 0·82-0·85 for antibody only vs 0·84, 0·83-0·86 for combined) or for progression-free survival (0·70, 0·69-0·71 vs 0·71, 0·70-0·72 vs 0·71, 0·70-0·72). However, at 4 years the NRI showed substantial improvement for the antibody-only model compared with the cutaneous-only model in prediction of overall survival (0·57, 0·46-0·71 for antibody only vs 0·29, 0·19-0·39 for cutaneous only) and disease progression (0·36, 0·29-0·46 vs 0·21, 0·14-0·28). The antibody-only model did better than the cutaneous-only model in predicting renal crisis (AUC 0·72, 0·70-0·74 for antibody only vs 0·66, 0·64-0·69 for cutaneous only) and lung fibrosis leading to restrictive lung function (AUC 0·76, 0·75-0·77 vs 0·71, 0·70-0·72). The combined model improved the prediction of digital ulcers and elevated systolic pulmonary artery pressure, but did poorly for cardiac involvement. INTERPRETATION: The autoantibody-only model outperforms cutaneous-only subsetting for risk stratifying people with systemic sclerosis in the EUSTAR cohort. Physicians should be aware of these findings at the time of decision making for patient management. FUNDING: World Scleroderma Foundation.

Influence of inflammatory and non-inflammatory rheumatic disorders on the clinical and biological profile of type-2 diabetes.

OBJECTIVE: To study the profile of type-2 diabetes (T2D) in patients with RA or OA. METHODS: This observational, multicentre, cross-sectional study included, over a 24-month period, consecutive patients with adult-onset diabetes and RA or OA. We collected demographics, disease activity and severity indices, current treatments for RA and diabetes, history and complications of diabetes. A systematic blood test was performed, assessing inflammatory, immunological and metabolic parameters. The homoeostasis model assessment (HOMA)2-S was used to assess insulin resistance. RESULTS: We included 167 patients with T2D, 118 with RA and 49 with OA. RA and OA patients had severe T2D with suboptimal metabolic control and a biological profile of insulin resistance. Insulin resistance was significantly higher in RA than in OA patients after stratification on age, BMI and CS use [HOMA2-S: 63.5 (35.6) vs 98.4 (69.2), P < 0.001]. HOMA2-S was independently associated with DAS28 [odds ratio (OR): 4.46, 95% CI: 1.17, 17.08]. T2D metabolic control was not related to disease activity and functional impairment, but HbA1c levels were independently associated with bone erosions (OR: 4.43, 95% CI: 1.18, 16.61). Treatment with low-dose CSs was not associated with decreased insulin sensitivity or increased HbA1c levels. Treatment with TNF-α inhibitors was associated with increased insulin sensitivity compared with patients not receiving biologics [101.3 (58.71) vs 60.0 (32.5), P = 0.001]. CONCLUSION: RA patients display severe T2D with inflammation-associated insulin resistance. These findings may have therapeutic implications, with the potential targeting of insulin resistance through the treatment of joint and systemic inflammation.

Improving risk-stratification of rheumatoid arthritis patients for interstitial lung disease.

OBJECTIVE: To determine the performance of 3 circulating markers for the diagnosis and the progression of interstitial lung disease (ILD) associated with rheumatoid arthritis (RA). METHODS: Serum concentrations of 3 circulating markers, lung epithelial-derived surfactant protein D (SPD), chemokine CCL-18 and Krebs von den Lungen-6 glycoprotein (KL-6), were measured by ELISA in consecutive patients with established RA. These patients were recruited from 3 tertiary centers and they all had been investigated by chest high-resolution computed tomography (HRCT). For a subset of French patients, a follow-up HRCT was available (mean interval between HRCT: 3±1.5 years). RESULTS: Among the 147 included patients (age: 66 ± 12 years, 69% women, disease duration 11 ± 10 years), 40 (27%) had RA-ILD on chest HRCT. SPD, CCL18 and KL-6 concentrations were significantly higher in patients with RA-ILD. ROC curve analysis to assess the diagnostic abilities of the three markers for the diagnosis of RA-ILD showed a superiority of KL-6 (Area under the curve, AUC: 0.79 95% CI 0.72-0.86) compared to SPD (AUC: 0.66 95% CI 0.58-0.74) and CCL18 (AUC: 0.62, 95% CI 0.53-0.70). The sensitivity of KL-6 for the diagnosis of RA-ILD was 68% with a specificity of 83%. The combination of KL-6 with SPD and CCL18 improved its diagnostic ability, with increased sensitivity from 68% to 77%, specificity from 83% to 97%. Increased KL-6 levels were independently associated with the presence of RA-ILD after the adjustment on other RA-ILD risk factors. In the French subset with longitudinal data, baseline KL-6 serum levels were predictive of ILD progression and the degree of ILD progression on HRCT was proportional to baseline KL-6 concentrations. CONCLUSION: These results show that KL-6 is a relevant circulating marker for the diagnosis and might be an interesting marker for the progression of RA-ILD.

Safety and effectiveness of abatacept in systemic sclerosis: The EUSTAR experience.

OBJECTIVE: To analyze the safety and effectiveness of abatacept (ABA) given in routine care to patients with systemic sclerosis (SSc). METHODS: Retrospective multicenter observational study that enrolled patients with SSc treated with ABA. We collected epidemiological data and clinical outcomes. First, we analyzed the frequency of adverse effects. Secondly, we compared the evolution of different organ manifestations during ABA treatment. We collected data from 6 months before start of therapy to the last follow-up the following parameters: modified Rodnan Skin Score (mRSS), joints, lung and gastrointestinal involvement, concomitant medications, and laboratory tests. RESULTS: Data on twenty-seven patients with SSc were collected (93% females; 67% limited SSc). Rheumatoid arthritis was the most frequent concomitant autoimmune disease. ILD was present in 15 patients. Anti-Scl 70 antibodies were present in 13 patients and rheumatoid factor and ACPA antibodies were present in eight and seven patients respectively. The main indication to use abatacept was joint involvement (59%) followed by myositis (26%). A total of 16 adverse effects were reported in 28 months of abatacept treatment including five that required hospitalization. Most of them occurred in the first 3 months after starting abatacept. After 12 months, the number of tender and swollen joints decreased compared to baseline (p<0.03 and p<0.02 respectively). Moreover, a beneficial effect of abatacept on HAQ-DI at 3 and 6 months (p<0.05) and on morning stiffness at 6 and 12 months (p<0.03) was observed. We also observed a decrease in the modified Rodnan skin score (p<0.05). No changes in lung or gastrointestinal involvement were found. CONCLUSIONS: ABA demonstrated a good safety profile and seems to have some effectiveness on joint involvement and related disability in SSc patients treated in routine care.

Circulating lung biomarkers in idiopathic lung fibrosis and interstitial lung diseases associated with connective tissue diseases: Where do we stand?

Interstitial lung diseases (ILDs) are complex diseases with various courses where personalized medicine is highly expected. Biomarkers are indicators of physiological, pathological processes or of pharmacological response to therapeutic interventions. They can be used for diagnosis, risk-stratification, prediction and monitoring of treatment response. To better delineate the input and pitfalls of biomarkers in ILDs, we performed a systematic review and meta-analysis of literature in MEDLINE and Embase databases from January 1960 to February 2019. We focused on circulating biomarkers as having the highest generalizability. Overall, 70 studies were included in the review and 20 studies could be included in the meta-analysis. This review highlights that ILD associated with connective tissue diseases (CTD-ILD) and idiopathic pulmonary fibrosis (IPF) share common biomarkers, suggesting common pathophysiological pathways. KL-6 and SP-D, could diagnose lung fibrosis in both IPF and CTD-ILD, with KL-6 having the strongest value (OR: 520.95[110.07-2465.58], p<0.001 in IPF and OR:26.43[7.15-97.68], p<0.001 in CTD-ILD), followed by SPD (OR: 33.81[3.20-357.52], p = 0.003 in IPF and 13.24 [3.84-45.71] in SSc-ILD), MMP7 appeared as interesting for IPF diagnosis (p<0.001), whereas in SSc, CCL18 was associated with ILD diagnosis. Both CCL18 and KL-6 were predictive for the outcomes of ILDs, with higher predictive values for CCL18 in both IPF (OR:10.22[4.72-22.16], p<0.001 and in SSc [2.62[1.71-4.03], p<0.001). However, disease specific biomarkers are lacking and large longitudinal studies are needed before the translational use of the potential biomarkers in clinical practice. With the recent availability of new effective therapies in ILDs, further studies should assess response to treatment.