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Background Biological disease-modifying antirheumatic drugs (bDMARDs) are effective in the treatment of rheumatoid arthritis. However, as bDMARDs may also lead to adverse events and are expensive, tapering them is of great clinical interest. Tapering according to disease activity-guided dose optimization (DGDO) does not seem to affect long term remission rates, but flares are frequent during this process. Our objective was to develop a model for the prediction of flares during bDMARD tapering using data from routine care and to evaluate its potential clinical impact. Methods We used a joint latent class model to repeatedly predict the probability of a flare occurring within the next 3 months. The model was developed using longitudinal data on disease activity (DAS28) and other routine care data from two clinics. Predictive accuracy was assessed in cross-validation and external validation was performed with data from the DRESS (Dose REduction Strategy of Subcutaneous tumor necrosis factor inhibitors) trial. Additionally, we simulated the reduction in number of flares and bDMARD dose when implementing the model as a decision aid during bDMARD tapering in the DRESS trial. Results Data from 279 bDMARD courses were used for model development. The final model included two latent DAS28-trajectories, bDMARD type and dose, disease duration, and seropositivity. The area under the curve of the final model was 0.76 (0.69–0.83) in cross-validation and 0.68 (0.62–0.73) in external validation. In simulation of prediction-aided decisions, the mean number of flares over 18 months decreased from 1.21 (0.99–1.43) to 0.75 (0.54–0.96). The reduction in he bDMARD dose was mostly maintained, increasing from 54 to 64% of full dose. Conclusions We developed a dynamic flare prediction model, exclusively based on data typically available in routine care. Our results show that using this model to aid decisions during bDMARD tapering may significantly reduce the number of flares while maintaining most of the bDMARD dose reduction. Trial registration The clinical impact of the prediction model is currently under investigation in the PATIO randomized controlled trial (Dutch Trial Register number NL9798).

Objective To establish the performance of (subsets of) the 2015 ACR/EULAR gout classification criteria in patients with unclassified arthritis, and to determine the value of dual-energy CT (DECT) herein. Reference was the MSU crystal detection result in SF at polarization microscopy. Methods We included subjects with acute, unclassified mono or oligoarthritis, who underwent SF analysis and DECT. Performance was assessed by calculating area under the receiver operating characteristic curve of (i) the clinical criteria subset, (ii) the clinical+serum urate subset and (iii) the full set (including DECT). Results Of the 89 subjects enrolled, 40 met the clinical+serum urate subset criteria, and 49 (55%) subjects did not. Of these 49, 30 had a negative microscopy result, of whom 15 had positive DECT; of these 15, 14 met the full set criteria only after adding the positive DECT result. For the clinical-only subset, the areas under the curves (AUCs) were 0.68 and 0.69 without and with DECT result, respectively, and for the clinical+serum urate subset without and with DECT, AUCs were 0.81 and 0.81, respectively (results not significant). Conclusion Adding the serum urate results to the clinical subset improves the performance, but adding the DECT result does not, neither does adding the DECT results to the clinical+serum urate subset. However, DECT seems to have an additive value in gout classification, especially when microscopy of SF is negative; 14/89 of patients (16%) only met the classification criteria with the use of DECT. Trial registration ClinicalTrials.gov, http://clinicaltrials.gov, NCT03038386.

Contains fulltext : 215793.pdf (Publisher’s version ) (Open Access) OBJECTIVES: This study was designed to propose a simple "Fast Track algorithm" for capillaroscopists of any level of experience to differentiate "scleroderma patterns" from "non-scleroderma patterns" on capillaroscopy and to assess its inter-rater reliability. METHODS: Based on existing definitions to categorise capillaroscopic images as "scleroderma patterns" and taking into account the real life variability of capillaroscopic images described standardly according to the European League Against Rheumatism (EULAR) Study Group on Microcirculation in Rheumatic Diseases, a fast track decision tree, the "Fast Track algorithm" was created by the principal expert (VS) to facilitate swift categorisation of an image as "non-scleroderma pattern (category 1)" or "scleroderma pattern (category 2)". Mean inter-rater reliability between all raters (experts/attendees) of the 8th EULAR course on capillaroscopy in Rheumatic Diseases (Genoa, 2018) and, as external validation, of the 8th European Scleroderma Trials and Research group (EUSTAR) course on systemic sclerosis (SSc) (Nijmegen, 2019) versus the principal expert, as well as reliability between the rater pairs themselves was assessed by mean Cohen's and Light's kappa coefficients. RESULTS: Mean Cohen's kappa was 1/0.96 (95% CI 0.95-0.98) for the 6 experts/135 attendees of the 8th EULAR capillaroscopy course and 1/0.94 (95% CI 0.92-0.96) for the 3 experts/85 attendees of the 8th EUSTAR SSc course. Light's kappa was 1/0.92 at the 8th EULAR capillaroscopy course, and 1/0.87 at the 8th EUSTAR SSc course. CONCLUSION: For the first time, a clinical expert based fast track decision algorithm has been developed to differentiate a "non-scleroderma" from a "scleroderma pattern" on capillaroscopic images, demonstrating excellent reliability when applied by capillaroscopists with varying levels of expertise versus the principal expert and corroborated with external validation.

INTRODUCTION: Systemic sclerosis (SSc) is a chronic autoimmune disease with multiorgan involvement. OBJECTIVE: Identify preferences and priorities among patients and health care professionals regarding care for SSc patients in The Netherlands. Develop ideas to improve quality of care. METHODS: A structured approach was followed to collect information from different perspectives to prepare a working conference. Qualitative and quantitative data from patients (n = 650), rheumatologists (n = 167), nurses (n = 51), and health professionals (n = 85) from regional centers and university hospitals were collected. In February 2018, a working conference was organized. Seventy-seven persons (including 10 SSc patients) from different backgrounds discussed the identified themes and survey results. Ideas to improve health care were formulated and prioritized using nominal group technique. RESULTS: Five key themes were identified: (1) shared care and multidisciplinary collaboration, (2) medical data exchange, (3) information for both patients and health care professionals, (4) patient empowerment, and (5) non-pharmacological care. Shared care was the preferred model of care in 49% of patients and 82% of physicians. However, current collaboration structures, especially between hospitals, should be improved. Suggestions for improvements were explicitly formulated agreements about referral, clear task division, treatment coordination, and exploration of novel ways to exchange medical records. The creation of a national web-based information hub was highly prioritized. CONCLUSION: In this mixed-method study, broad-based consensus was achieved and recommendations were developed to improve health care for SSc patients. The approach, recommendations, and challenges summarized in this paper can be of use for health care professionals and other actors involved in patients with rare, chronic, and multisystem conditions.

Objective This study aimed to assess the utility of dual energy CT (DECT) for diagnosing gout. Methods A systematic literature search was performed in PubMed, EMBASE and Cochrane Library. Studies evaluating the utility of DECT for diagnosing gout were included. Reference standards were detection of monosodium urate crystals at SF assessment or a validated set of criteria. The methodological quality of studies was evaluated according to the Quality Assessment of Diagnostic Accuracy Studies (QUADAS)-2 criteria. Data from person-based and joint-/localization-based evaluations were pooled separately, and subgroup analyses for disease stage/duration and reference standard were performed. Results Ten studies were included; in person-based evaluations, the pooled (95% CI) sensitivity and specificity were 0.81 (0.77, 0.86) and 0.91 (0.85, 0.95), respectively. In joint-based evaluations, they were 0.83 (0.79, 0.86) and 0.88 (0.83, 0.92), respectively. At short disease duration (⩽6 weeks), the pooled (95% CI) sensitivity and specificity at the joint level were 0.55 (0.46, 0.64) and 0.89 (0.84, 0.94), respectively. Conclusion DECT has a high diagnostic accuracy in established gout, but its diagnostic sensitivity is low in subjects with recent onset gout.

Patients with common variable immunodeficiency (CVID) can develop immune dysregulation complications such as autoimmunity, lymphoproliferation, enteritis, and malignancy, which cause significant morbidity and mortality. We aimed to (i) assess the potential of serum proteomics in stratifying patients with immune dysregulation using two independent cohorts and (ii) identify cytokine and chemokine signaling pathways that underlie immune dysregulation in CVID. A panel of 180 markers was measured in two multicenter CVID cohorts using Olink Protein Extension Assay technology. A classification algorithm was trained to distinguish CVID with immune dysregulation (CVIDid, n = 14) from CVID with infections only (CVIDio, n = 16) in the training cohort, and validated on a second testing cohort (CVIDid n = 23, CVIDio n = 24). Differential expression in both cohorts was used to determine relevant signaling pathways. An elastic net classifier using MILR1, LILRB4, IL10, IL12RB1, and CD83 could discriminate between CVIDid and CVIDio patients with a sensitivity of 0.83, specificity of 0.75, and area under the curve of 0.73 in an independent testing cohort. Activated pathways (fold change > 1.5, FDR-adjusted p

Objective In end-stage knee osteoarthritis, total knee arthroplasty (TKA) may finally become inevitable. At a relatively young age, this comes with the risk of future revision surgery. Therefore, in these cases, joint preserving surgery such as knee joint distraction (KJD) is preferred. Here we present 5-year follow-up data of KJD. Design Patients ( n = 20; age Results Five-years posttreatment, patients still reported clinical improvement from baseline: ΔWOMAC (Western Ontario and McMaster Universities Arthritis Index) +21.1 points (95% CI +8.9 to +33.3; P = 0.002), ΔVAS (visual analogue scale score) pain −27.6 mm (95%CI −13.3 to −42.0; P < 0.001), and minimum radiographic joint space width (JSW) of the most affected compartment (MAC) remained increased as well: Δ +0.43 mm (95% CI +0.02 to +0.84; P = 0.040). Improvement of mean JSW (x-ray) and mean cartilage thickness (MRI) of the MAC, were not statistically different from baseline anymore (Δ +0.26 mm; P = 0.370, and Δ +0.23 mm; P = 0.177). Multivariable linear regression analysis indicated that KJD treatment was associated with significantly less progression in mean and min JSW (x-ray) and mean cartilage thickness (MRI) compared with natural progression (all Ps Conclusions KJD treatment results in prolonged clinical benefit, potentially explained by an initial boost of cartilaginous tissue repair that provides a long-term tissue structure benefit as compared to natural progression. Level of evidence, II.

TCR repertoire studies in RA have yielded conflicting data. These studies were initiated on the premise that clonal expression of T cells at the site of inflammation could serve as a target for immune therapies designed on the basis of the option to inactivate or eliminate the presumed pathogenic T cells. These analyses have demonstrated the existence of a highly diverse overall TCR repertoire on the basis of extensive usage of TCR V genes both in synovial fluid and tissue. However, clusters of RA patients can be recognized who share increased usage frequencies of defined TCR V genes among synovial fluid or synovial tissue lymphocytes. Subsequent analysis of the CDR3 regions among diverse overall TCR repertoires have revealed the presence of conserved amino acid sequences in the CDR3 regions of the variable portions of TCRs in T lymphocytes derived from the site of inflammation. These findings suggest that a selective, antigen-driven expansion of T lymphocytes is occurring in the inflamed joints. Parallel to the TCR-repertoire studies, we investigated whether vaccines prepared from synovial T cells could modulate T-cell reactivity. The studies were based on previous work on TCV in animals, revealing that attenuated non-specific T-cell lines could serve as a vaccine. The results obtained in 13 RA patients showed no clear indication for a cellular or humoral immune response. Our experience with TCV in RA patients showed that this technique is feasible and safe. We found some evidence for a modulated T-cell reactivity both in vivo and in vitro. These results show at least some immunomodulatory effect af T-cell vaccination, although the antigen specificity of the effect of this intervention remains to be shown. Because of the convincing studies in animals and MS patients, further studies in RA should focus on the effect of vaccination using vaccines prepared from disease-inducing cells. In this respect, determination of the CDR3 regions of synovial T cells could lead to the identification of those T cells that are relevant for the disease.

4 páginas, 2 figuras, 2 tablas.-- Spanish Scleroderma Group., Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of the skin and internal organs that leads to profound disability and premature death. To identify new SSc susceptibility loci, we conducted the first genome-wide association study in a population of European ancestry including a total of 2,296 individuals with SSc and 5,171 controls. Analysis of 279,621 autosomal SNPs followed by replication testing in an independent case-control set of European ancestry (2,753 individuals with SSc (cases) and 4,569 controls) identified a new susceptibility locus for systemic sclerosis at CD247 (1q22–23, rs2056626, P = 2.09 × 10−7 in the discovery samples, P = 3.39 × 10−9 in the combined analysis). Additionally, we confirm and firmly establish the role of the MHC (P = 2.31 × 10−18), IRF5 (P = 1.86 × 10−13) and STAT4 (P = 3.37 × 10−9) gene regions as SSc genetic risk factors., This work was supported by the following grants: T.R.D.J.R. was funded by the VIDI laureate from the Dutch Association of Research (NWO) and Dutch Arthritis Foundation (National Reumafonds). J.M. was funded by GEN-FER from the Spanish Society of Rheumatology, SAF2009-11110 from the Spanish Ministry of Science, CTS-4977 from Junta de Andalucía, Spain and in part by Redes Temáticas de Investigación Cooperativa Sanitaria Program, RD08/0075 (RIER) from Instituto de Salud Carlos III (ISCIII), Spain (J.M.). R.B. is supported by the I3P Consejo Superior de Investigaciones Científicas program funded by the 'Fondo Social Europeo'. B.Z.A. is supported by the Netherlands Organization for Health Research and Development (ZonMW grant 016.096.121). B.K. is supported by the Dutch Diabetes Research Foundation (grant 2008.40.001) and the Dutch Arthritis Foundation (Reumafonds, grant NR 09-1-408). Genotyping of the Dutch control samples was sponsored by US National Insitutes of Mental Health funding, R01 MH078075 (R.O.A.). The German controls were from the PopGen biobank (to B.K.).

Background. The clinical utility of performing repeat biopsies during lupus nephritis flares is questionable and data pointing towards frequent class switches are based on the old WHO classification. This retrospective study investigates the hypothesis that clinically relevant switches from proliferative to non-proliferative lesions and vice versa as determined by the new ISN/RPS classification are a rare event and that repeat biopsies are unnecessary in many cases. Methods. Thirty-five patients with lupus nephritis and one or more repeat renal biopsies were included. Eighty-four biopsies were blindly reassessed according to the ISN/RPS classification. Results. Twenty-five patients had one repeat biopsy, 6 patients had two and 4 patients had three repeat biopsies. Forty-nine comparisons between reference and repeat biopsies could be made. In 25 cases (54.3%), there was no shift in ISN/RPS class on repeat biopsies. In 41 instances, paired biopsies showed proliferative lesions both on reference and repeat biopsies, whereas five of six cases with non-proliferative lesions on a reference biopsy switched to proliferative lesions on a repeat biopsy. Clinically significant class switches during lupus nephritis flares were more frequent in patients with non-proliferative lesions in their reference biopsy (P < 0.001). Conclusion. The results show that patients with proliferative lesions in the original biopsy rarely switch to a pure non-proliferative nephritis during a flare. Therefore, a repeat biopsy during a lupus nephritis flare is frequently not necessary if proliferative lesions were found in the reference biopsy. However, in the case of a non-proliferative lesion in the reference biopsy, class switches are frequently found and repeat biopsies are advisable.

Nat. Genet. 42, 426–429 (2010); published online 11 April 2010; corrected after print 23 March 2011 In the version of this article initially published, incorrect affiliations were published for Lorenzo Beretta and Rafaella Scorza. The correct affiliation for Lorenzo Beretta and Rafaella Scorza is “Referral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico and University of Milan”.

In this study we analyzed the usage frequencies of the TCR V-gene segments by alpha beta+ T cells present in synovial fluid of 17 patients with chronic arthritis, including rheumatoid arthritis. The results of this study, obtained from semiquantitative PCR analyses, showed that in all patients most of the TCR V alpha- and V beta-gene segments could be detected both in fresh PBMCs and in fresh SFMCs. The relative frequencies of use of these V-region genes were variable between the different patients. Although there was some skewing of increased usage frequencies of particular TCR V alpha and V beta genes among SFMC-derived TCRs when compared with PBMCs, we could not correlate such increased TCR V-gene usage with the inflammation in the joints as a disease-specific marker.