Synovial gene signatures associated with the development of rheumatoid arthritis in at risk individuals: A prospective study.

OBJECTIVE: To identify molecular changes in synovium before arthritis development in individuals at risk of developing rheumatoid arthritis (RA). MATERIALS AND METHODS: We included 67 IgM rheumatoid factor and/or anti-citrullinated protein antibody positive individuals with arthralgia but without arthritis. Synovial biopsies were collected after which individuals were prospectively followed for at least 2 years during which 17 developed arthritis. An exploratory genome-wide transcriptional profiling study was performed in 13 preselected individuals to identify transcripts associated with arthritis development (n = 6). Findings were validated using quantitative real-time PCR and immunohistochemistry in the total cohort. RESULTS: Microarray-based survival analyses identified 5588 transcripts whose expression levels in synovium were significantly associated with arthritis development. Pathway analysis revealed that synovial tissue of at risk individuals who later developed arthritis display higher expression of genes involved in adaptive immune response-related pathways compared to at risk individuals who did not develop arthritis. Lower expression was observed for genes involved in extracellular matrix receptor interaction, Wnt-mediated signal transduction and lipid metabolism. Two-way hierarchical clustering analyses of a 27-gene signature separated the total at risk cohort into two groups, where pre-RA individuals preferred to cluster together. Immunohistochemistry studies revealed more podoplanin positive cells and lower lipid droplet staining in synovial tissue from pre-RA individuals. CONCLUSION: Synovial alterations in adaptive immune response and lipid metabolism are associated with future development of arthritis. Since this data show synovial changes without overt cellular infiltration, these may be attributed to preclinical changes in resident synovial tissue cells such as fibroblasts, macrophages and tissue resident T cells.

Effect on efficacy and safety trial outcomes of also enrolling patients on ongoing glucocorticoid therapy in rheumatoid arthritis clinical trials of tocilizumab or adalimumab or methotrexate monotherapy.

BACKGROUND: In rheumatoid arthritis (RA) trials, inclusion of patients on background treatment with glucocorticoids (GCs) might impact efficacy and safety outcomes. OBJECTIVES: To determine if inclusion of patients on background GC use influenced efficacy and safety outcomes of RA randomised clinical trials on initiation of tocilizumab (TCZ) or adalimumab (ADA) or methotrexate (MTX) monotherapy. METHODS: Data of four double-blind RA randomised controlled trials (AMBITION, ACT-RAY, ADACTA and FUNCTION) with in total four TCZ, one ADA and two MTX monotherapy arms were analysed. Analyses of covariance of changes from baseline to week 24 in efficacy endpoints and radiographic progression up to week 104 were performed, correcting for relevant covariates. Incidence rates of serious adverse events (SAEs) were assessed. RESULTS: No statistically significant differences were found in efficacy parameters between background GC users and non-GC users, except for less radiographic progression associated with GC usage in one MTX arm. SAE rates were not statistically significantly different between GC users and non-GC users in the treatment arms. CONCLUSION: No effect of including patients on background GC treatment on efficacy and safety trial outcomes was found, with the exception of reduced radiological joint damage in one MTX arm.

Effects of B-cell directed therapy on the preclinical stage of rheumatoid arthritis: the PRAIRI study.

OBJECTIVES: We explored the effects of B-cell directed therapy in subjects at risk of developing autoantibodypositive rheumatoid arthritis (RA), who never experienced inflammatory arthritis before, and explored biomarkers predictive of arthritis development. METHODS: Individuals positive for both anti-citrullinated peptide antibodies and rheumatoid factor but without arthritis were included in a randomised, double-blind, placebo-controlled study to receive a single infusion of 1000 mg rituximab or placebo. RESULTS: Eighty-one individuals received treatment and were followed up for a mean of 29.0 (0-54) months, during which 30/81 (37%) individuals developed arthritis. The observed risk of developing arthritis in the placebo-treated group was 40%, which was decreased by 55% (HR 0.45, 95% CI 0.154 to 1.322) in the rituximab-treated group at 12 months. Rituximab treatment caused a delay in arthritis development of 12 months compared with placebo treatment at the point when 25% of the subjects had developed arthritis (p<0.0001). Erythrocyte sedimentation rate and the presence of anti-citrullinated α-enolase peptide 1 at baseline were significant predictors of arthritis development. CONCLUSIONS: A single infusion of 1000 mg rituximab significantly delays the development of arthritis in subjects at risk of developing RA, providing evidence for the pathogenetic role of B cells in the earliest, prearthritis stage of autoantibody positive RA.

Genome-wide association study of response to methotrexate in early rheumatoid arthritis patients.

Methotrexate (MTX) monotherapy is a common first treatment for rheumatoid arthritis (RA), but many patients do not respond adequately. In order to identify genetic predictors of response, we have combined data from two consortia to carry out a genome-wide study of response to MTX in 1424 early RA patients of European ancestry. Clinical endpoints were change from baseline to 6 months after starting treatment in swollen 28-joint count, tender 28-joint count, C-reactive protein and the overall 3-component disease activity score (DAS28). No single nucleotide polymorphism (SNP) reached genome-wide statistical significance for any outcome measure. The strongest evidence for association was with rs168201 in NRG3 (p = 10-7 for change in DAS28). Some support was also seen for association with ZMIZ1, previously highlighted in a study of response to MTX in juvenile idiopathic arthritis. Follow-up in two smaller cohorts of 429 and 177 RA patients did not support these findings, although these cohorts were more heterogeneous.

Characteristics of difficult-to-treat rheumatoid arthritis: results of an international survey.

OBJECTIVES: Patients with difficult-to-treat rheumatoid arthritis (RA) remain symptomatic despite treatment according to current European League Against Rheumatism (EULAR) management recommendations. These focus on early phases of the disease and pharmacological management. We aimed to identify characteristics of difficult-to-treat RA and issues to be addressed in its workup and management that are not covered by current management recommendations. METHODS: An international survey was conducted among rheumatologists with multiple-choice questions on disease characteristics of difficult-to-treat RA. Using open questions, additional items to be addressed and items missing in current management recommendations were identified. RESULTS: 410 respondents completed the survey: 50% selected disease activity score assessing 28 joints >3.2 OR presence of signs suggestive of active disease as characteristics of difficult-to-treat RA; 42% selected fatigue; 48% selected failure to ≥2 conventional synthetic disease-modifying antirheumatic drugs (DMARDs) AND ≥2 biological/targeted synthetic DMARDs; 89% selected inability to taper glucocorticoids below 5 mg or 10 mg prednisone equivalent daily. Interfering comorbidities, extra-articular manifestations and polypharmacy were identified as important issues missing in current management recommendations. CONCLUSIONS: There is wide variation in concepts of difficult-to-treat RA. Several important issues regarding these patients are not addressed by current EULAR recommendations.

Difficult-to-treat rheumatoid arthritis: an area of unmet clinical need.

Increased effectiveness of pharmacological treatments in early RA has led many to believe that difficult-to-treat, established RA is a condition of the past. However, there are still plenty of RA patients who continue to have signs and symptoms suggestive of inflammatory disease activity, despite consecutive treatment with multiple conventional synthetic and biological DMARDs. We argue that difficult-to-treat RA constitutes an area of unmet clinical need and propose a definition of this concept. An overview of what is known about the multiple contributory factors varying for each individual patient, and an approach towards improved patient-tailored management are presented. This management approach involves thorough assessment to determine whether persistence of signs and symptoms is based on inflammatory disease activity, and the role of comorbidities. Furthermore, it addresses medication-related issues, such as non-adherence, patient beliefs and expectations, and setting of realistic treatment goals.

Dominant B cell receptor clones in peripheral blood predict onset of arthritis in individuals at risk for rheumatoid arthritis.

BACKGROUND: The onset of seropositive rheumatoid arthritis (RA) is preceded by the presence of specific autoantibodies in the absence of synovial inflammation. Only a subset of these at-risk individuals will develop clinical disease. This impedes efforts to implement early interventions that may prevent onset of clinically manifest disease. Here we analyse whether clonal changes in the B cell receptor (BCR) repertoire can reliably predict onset of signs and symptoms. METHODS: In a prospective cohort study in 21 individuals at risk for RA based on the presence of autoantibodies, the BCR repertoire of paired peripheral blood and synovial tissue samples was analysed using next-generation BCR sequencing. BCR clones that were expanded beyond 0.5% of the total repertoire were labelled dominant. The relative risk (RR) for onset of arthritis was assessed using the presence of ≥5 dominant BCR clones as cut-off. Findings in peripheral blood were validated in an independent prospective cohort of 50 at-risk individuals. Based on the test cohort, individuals in the validation cohort were considered positive if peripheral blood at study entry showed ≥5 dominant BCR clones. FINDINGS: Both in the test and validation cohort, the presence of ≥5 dominant BCR clones in peripheral blood was significantly associated with arthritis development after follow-up (validation cohort RR 6.3, 95% CI 2.7 to 15, p<1×10-4). Even when adjusted for a recently described clinical prediction rule the association remained intact (RR 5.0, 95% CI 1.2 to 20, p=0.024). When individuals developed arthritis, dominant BCR clones disappeared from peripheral blood and appeared in synovial tissue, suggesting a direct role of these clones in disease pathogenesis. INTERPRETATION: Dominant BCR clones in peripheral blood predict onset of clinical signs and symptoms of RA in at-risk individuals with high accuracy. Our data suggest that during onset of RA these clones shift from peripheral blood to the target tissue.

Reduced CLEC9A expression in synovial tissue of psoriatic arthritis patients after adalimumab therapy.

OBJECTIVES: We aimed to investigate the early changes in expression of C-type lectin domain family 9, member A (CLEC9A), a C-type lectin that is specifically expressed by the CD141(+) dendritic cell subset that is involved in cross-presentation to CD8(+) T cells, by evaluating gene and/or protein expression in three different compartments [skin, synovial tissue (ST) and serum] after short-term adalimumab treatment in PsA patients compared with placebo. METHODS: Patients with active PsA and psoriasis were randomized to receive adalimumab or placebo for 4 weeks. Synovial and skin biopsies were obtained before and after 4 weeks of treatment and serum samples 4 weeks, 12 weeks and 1 year after treatment. Skin and serum from healthy donors were used as control. CLEC9A expression was assessed by immunohistochemistry, double immunofluorescence using terminal deoxynucleotidyl transferase 2'-deoxyuridine 5'-triphosphate nick-end labelling (TUNEL), quantitative PCR and ELISA. RESULTS: CLEC9A expression was significantly higher in psoriatic skin compared with healthy donor. In psoriatic skin and PsA ST, CLEC9A(+) cells were in close proximity to TUNEL(+) cells. SF CLEC9A levels were significantly lower compared with paired PsA serum. Adalimumab treatment did not affect CLEC9A serum level and skin expression. However, ST CLEC9A protein expression was significantly decreased after adalimumab treatment compared with the placebo group while CLEC9A gene expression remained unchanged. There was a positive correlation between T cell numbers and ST CLEC9A protein expression. CD141(+) cell numbers and chemokine (C motif) receptor 1 expression were not affected with adalimumab treatment. CONCLUSION: Altogether, the present study suggests that the downregulation of synovial CLEC9A might be associated with a novel mechanism by which anti-TNF therapy might reduce CD8-mediated inflammation in PsA patients.

Automated joint space width quantification of hand and wrist joints: a proof of concept study.

OBJECTIVES: To compare as proof of concept the sensitivity to change of automated quantification of radiographic wrist and hand joint space width (JSW) with scoring JSW according to the Sharp/van der Heijde scoring method (SHS) in two strategy groups of a treat-to-target and tight-control early rheumatoid arthritis (RA) study. METHODS: Digital radiographs were assessed for JSW changes of 134 patients of the 236 patients participating in the second Computer Assisted Management in Early Rheumatoid Arthritis trial, of whom both baseline and year 2 radiographs were available (year 1 radiographs n=125). Of those 134 patients, 70 started with methotrexate and prednisone (MTX+Pred) and 64 with MTX and placebo (MTX+Plac). JSW change over 1 and 2 years of the hands and wrists was assessed, applying both the joint space narrowing (JSN) subscore of the SHS by 2 readers and the automated assessment with the JSW quantification software 'JSQ'. For both methods, progression of JSW change of the hand and wrist was analysed using linear mixed modelling (dependent variable 'JSW', factor 'strategy group', covariate 'follow-up time in years', interaction term 'strategy group*follow-up time'; radiographs of baseline, year 1 and year 2 were used). For each method the standardised mean difference (SMD) for the change in JSW from baseline to year 2 between the treatment strategies was obtained using a non-parametric method. RESULTS: Patient characteristics of the current subpopulation were similar to those of the whole study population. JSN of the hand and wrist according to SHS at 2 years was present in 16 vs. 23% in the MTX+Pred group vs. the MTX+Plac group. The mean yearly progression rates of JSW change of the hands and wrists using JSQ were -0.00mm (95% confidence interval (CI) -0.01; 0.01) for MTX+Pred vs. -0.02mm (95%CI -0.03; -0.01) for MTX+Plac, p=0.045, and using SHS JSN they were 0.19 units (95%CI 0.09; 0.30) vs. 0.30 units (95%CI 0.14; 0.45) for MTX+Pred vs. MTX+Plac, p=0.271. The SMD for the change from baseline to year 2 between the treatment strategies was 0.37 for JSQ and 0.13 for SHS JSN. CONCLUSIONS: In this proof of concept study the yearly progression rate of JSW change of hand and wrist joints, according to the automated JSW quantification software package 'JSQ', was higher in the group initiating MTX+Plac than in the group initiating MTX+Pred. A similar trend was seen with the JSN assessment according to the SHS method of the hand and wrist. However, JSN of the hand and wrist according to SHS, the current gold standard to assess radiographic progression, was seen in only about 20%. Therefore, further studies are needed to conclude firmly that JSQ should be incorporated into quantitative scoring of radiographs in RA.

Peripheral joint inflammation in early onset spondyloarthritis is not specifically related to enthesitis.

OBJECTIVES: A pivotal MRI study of knee arthritis indicated that enthesitis was more frequently observed in established spondyloartritis (SpA) than rheumatoid arthritis (RA). Subsequent MRI and ultrasound studies, however, failed to consistently demonstrate primary synovitis in RA versus primary enthesitis in SpA. Therefore, the current study aimed to reassess enthesitis versus synovitis in peripheral arthritis by a combined imaging and histopathological study in early untreated disease. METHODS: MRI and mini-arthroscopic synovial biopsy sampling were performed in 41 patients with early untreated knee or ankle arthritis, who were diagnosed with SpA (n=13), RA (n=20) or crystal arthropathy (n=8) at follow-up. MRI evaluation of enthesitis and synovitis, and immunohistochemical characterisation of synovitis were performed by two observers blinded to diagnosis. RESULTS: MRI showed similar prevalence of perientheseal fluid/oedema (67% vs 75%), perientheseal bone marrow oedema (0% vs 10%) and entheseal enhancement (46% vs 47%) in SpA versus RA, respectively. The number and distribution of affected entheseal sites were not different between both diseases. The MRI synovitis score was significantly higher in SpA (median 1.4; IQR 1.1-1.5) compared with RA (median 0.5; IQR 0.0-1.3) (p=0.028). Synovial histopathology showed a numerical increase in infiltrating cells in SpA versus RA synovitis which reached significance for CD163 macrophages in the synovial sublining (p=0.030). There were no differences compared with the crystal arthropathy control group. CONCLUSIONS: Enthesitis on MRI is not a specific feature of peripheral arthritis in recent onset SpA versus RA. Synovitis is prominent in both diseases as evaluated by MRI and immunohistochemistry.

Local synovial engagement of angiogenic TIE-2 is associated with the development of persistent erosive rheumatoid arthritis in patients with early arthritis.

OBJECTIVE: To examine the role of vascular endothelial growth factor (VEGF) and angiopoietin signaling in the diagnosis and disease outcome of patients with early arthritis. METHODS: Fifty patients with early arthritis (disease duration <1 year) who had not been treated with disease-modifying antirheumatic drugs (DMARDs) were monitored prospectively and were classified at baseline and after 2 years as having undifferentiated arthritis (UA), rheumatoid arthritis (RA), or spondyloarthritis (SpA). All patients underwent arthroscopic synovial biopsy at baseline. Synovial expression of VEGF, VEGF receptor, angiopoietin 1 (Ang-1), Ang-2, TIE-2, and activated p-TIE-2 was evaluated by immunohistochemistry. Serum levels of VEGF, Ang-1, and Ang-2 were measured by enzyme-linked immunosorbent assay. Secreted products of macrophages stimulated with Ang-1 and Ang-2 were measured using a multiplex system. RESULTS: Expression of Ang-1 was comparable between the patients with RA at baseline and patients with UA who fulfilled the criteria for RA over time (UA/RA), and it was significantly higher in patients with RA (P < 0.05) or UA/RA (P < 0.005) than in patients with SpA. TIE-2 and p-TIE-2 were more highly expressed in patients with RA (P < 0.005) or UA/RA (P < 0.05) than in patients with SpA. Ang-1 significantly enhanced the tumor necrosis factor-dependent macrophage production of cytokines and chemokines that are known to be elevated in the synovial fluid of patients with early RA. In RA, relative TIE-2 activation predicted the development of erosive disease (R(2) = 0.35, P < 0.05). CONCLUSION: Local engagement of synovial TIE-2 is observed during the earliest phases of RA, suggesting that TIE-2 signaling may contribute to disease development and progression or may indicate an attempt to protect against these processes. Early therapeutic targeting of TIE-2 signaling may be useful in improving outcome in arthritis.

Smoking and overweight determine the likelihood of developing rheumatoid arthritis.

OBJECTIVES: Rheumatoid arthritis (RA) is a prototypic chronic inflammatory disease with a debilitating course if untreated. A genetic predisposition for RA is known, and its occurrence is associated with the presence of autoantibodies in the serum and with environmental factors. It is unknown if smoking and overweight are contributory factors for developing RA in individuals with RA-specific autoantibodies in the serum. METHODS: Fifty-five individuals at risk for developing RA, based on the presence of RA-specific autoantibodies in the serum, who never had any evidence of arthritis upon physical examination, were followed over time. Smoking was assessed as being never or ever smoker and body mass index as <25 (normal) or ≥25 kg/m² (overweight). Clinical endpoint was the occurrence of arthritis. Proportional hazard regression analysis was performed to investigate the potential of (combinations of) variables in predicting the onset of arthritis over time. RESULTS: After a median follow up time of 13 (IQR 6-27) months, 15 individuals (27%) developed arthritis. Smoking was associated with the development of arthritis (HR (95% CI): 9.6 (1.3 to 73.0); p=0.029). Overweight was, independently of smoking, associated with arthritis (HR (95% CI): 5.6 (1.3 to 25.0); p=0.023). The overall arthritis risk of 28% after a median of 27 months follow up increased to 60% in individuals with a smoking history combined with overweight. CONCLUSIONS: This is the first prospective study showing that smoking and overweight increase the risk of development of arthritis in a cohort of autoantibody-positive individuals at risk for developing RA. These results show the importance of life style factors in development of RA and should be critically evaluated in future clinical research aimed at disease prevention.

Selective involvement of ERK and JNK mitogen-activated protein kinases in early rheumatoid arthritis (1987 ACR criteria compared to 2010 ACR/EULAR criteria): a prospective study aimed at identification of diagnostic and prognostic biomarkers as well as therapeutic targets.

OBJECTIVES: To investigate the expression and activation of mitogen-activated protein kinases in patients with early arthritis who are disease-modifying antirheumatic drug (DMARD) naïve. METHODS: A total of 50 patients with early arthritis who were DMARD naïve (disease duration <1 year) were prospectively followed and diagnosed at baseline and after 2 years for undifferentiated arthritis (UA), rheumatoid arthritis (RA) (1987 American College of Rheumatology (ACR) and 2010 ACR/European League Against Rheumatism (EULAR) criteria), or spondyloarthritis (SpA). Synovial biopsies obtained at baseline were examined for expression and phosphorylation of p38, extracellular signal regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) by immunohistochemistry and digital analysis. Synovial tissue mRNA expression was measured by quantitative PCR (qPCR). RESULTS: ERK and JNK activation was enhanced at inclusion in patients meeting RA criteria compared to other diagnoses. JNK activation was enhanced in patients diagnosed as having UA at baseline who eventually fulfilled 1987 ACR RA criteria compared to those who remained UA, and in patients with RA fulfilling 2010 ACR/EULAR criteria at baseline. ERK and JNK activation was enhanced in patients with RA developing progressive joint destruction. JNK activation in UA predicted 1987 ACR RA classification criteria fulfilment (R(2)=0.59, p=0.02) after follow-up, and disease progression in early arthritis (R(2)=0.16, p<0.05). Enhanced JNK activation in patients with persistent disease was associated with altered synovial expression of extracellular matrix components and CD44. CONCLUSIONS: JNK activation is elevated in RA before 1987 ACR RA classification criteria are met and predicts development of erosive disease in early arthritis, suggesting JNK may represent an attractive target in treating RA early in the disease process.

Current Smoking Negatively Affects the Response to Methotrexate in Rheumatoid Arthritis in a Dose-responsive Way, Independently of Concomitant Prednisone Use.

OBJECTIVE: Current smoking reduces clinical response to several disease-modifying antirheumatic drugs. It is unknown if this is also the case for prednisone. We aimed to determine whether current smoking affects the clinical response to concomitant prednisone in a methotrexate (MTX)-based treatment strategy. METHODS: In the CAMERA-II trial (isrctn.com identifier: 70365169), patients with early rheumatoid arthritis (RA) initiated an MTX-based strategy and were randomized to concomitant prednisone (MTX + pred) or placebo (MTX + PBO) for 24 months. Linear mixed modeling was performed with Disease Activity Score assessing 28 joints (DAS28) as the dependent variable, and strategy group and current smoking status as independent variables, correcting for relevant covariates. The interaction between current smoking and strategy was tested to find out whether the effect of current smoking on clinical response was different between the strategy groups with prednisone or PBO. RESULTS: Current smoking was significantly associated with higher DAS28 over time (mean difference with nonsmokers 0.57 [95% CI 0.22-0.92, P < 0.01]). This association was not different between the strategy groups with prednisone or PBO (P = 0.73). The negative effect of current smoking on DAS28 was dose dependent. CONCLUSION: Current smoking in patients with early RA significantly reduces the clinical effect of an MTX-based strategy, independent of whether concomitant prednisone is used. This effect is dose dependent.

Effectiveness of TOcilizumab in comparison to Prednisone In Rheumatoid Arthritis patients with insufficient response to disease-modifying antirheumatic drugs (TOPIRA): study protocol for a pragmatic trial.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease, predominantly affecting joints, which is initially treated with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs). In RA patients with insufficient response to csDMARDs, the addition of prednisone or tocilizumab, a biological DMARD (bDMARD), to the medication has been shown to be effective in reducing RA symptoms. However, which of these two treatment strategies has superior effectiveness and safety is unknown. METHODS: In this multicenter, investigator-initiated, open-label, randomized, pragmatic trial, we aim to recruit 120 RA patients meeting the 2010 ACR/EULAR classification criteria for RA, with active disease defined as a Clinical Disease Activity Index (CDAI) > 10 and at least one swollen joint of the 28 assessed. Patients must be on stable treatment with csDMARDs for ≥ 8 weeks prior to screening and must have been treated with ≥ 2 DMARDs, of which a maximum of one tumor necrosis factor inhibitor (a class of bDMARDs) is allowed. Previous use of other bDMARDs or targeted synthetic DMARDs is not allowed. Patients will be randomized in a 1:1 ratio to receive either tocilizumab (subcutaneously at 162 mg/week) or prednisone (orally at 10 mg/day) as an addition to their current csDMARD therapy. Study visits will be performed at screening; baseline; and months 1, 2, 3, 6, 9, and 12. Study medication will be tapered in case of clinical remission (CDAI ≤ 2.8 and ≤ 1 swollen joint at two consecutive 3-monthly visits) with careful monitoring of disease activity. In case of persistent high disease activity at or after month 3 (CDAI > 22 at any visit or > 10 at two consecutive visits), patients will switch to the other strategy arm. Primary outcome is a change in CDAI from baseline to 12 months. Secondary outcomes are additional clinical response and quality of life measures, drug retention rate, radiographically detectable progression of joint damage, functional ability, and cost utility. Safety outcomes include tocilizumab-associated adverse events (AEs), glucocorticoid-associated AEs, and serious AEs. DISCUSSION: This will be the first randomized clinical trial comparing addition of oral prednisone or of tocilizumab head to head in RA patients with insufficient response to csDMARD therapy. It will yield important information for clinical rheumatology practice. TRIAL REGISTRATION: This trial was prospectively registered in the Netherlands Trial Register on October 7, 2019 (NL8070). The Netherlands Trial Register contains all items from the World Health Organization Trial Registration Data Set.

Unmet Needs in Systemic Sclerosis Understanding and Treatment: the Knowledge Gaps from a Scientist's, Clinician's, and Patient's Perspective.

Systemic sclerosis (SSc) is a highly heterogeneous disease caused by a complex molecular circuitry. For decades, clinical and molecular research focused on understanding the primary process of fibrosis. More recently, the inflammatory, immunological and vascular components that precede the actual onset of fibrosis, have become a matter of increasing scientific scrutiny. As a consequence, the field has started to realize that the early identification of this syndrome is crucial for optimal clinical care as well as for understanding its pathology. The cause of SSc cannot be appointed to a single molecular pathway but to a multitude of molecular aberrances in a spatial and temporal matter and on the backbone of the patient's genetic predisposition. These alterations underlie the plethora of signs and symptoms which patients experience and clinicians look for, ultimately culminating in fibrotic features. To solve this complexity, a close interaction among the patient throughout its "journey," the clinician through its clinical assessments and the researcher with its experimental design, seems to be required. In this review, we aimed to highlight the features of SSc through the eyes of these three professionals, all with their own expertise and opinions. With this unique setup, we underscore the importance of investigating the role of environmental factors in the onset and perpetuation of SSc, of focusing on the earliest signs and symptoms preceding fibrosis and on the application of holistic research approaches that include a multitude of potential molecular alterations in time in an unbiased fashion, in the search for a patient-tailored cure.

The multi-biomarker disease activity score tracks response to rituximab treatment in rheumatoid arthritis patients: a post hoc analysis of three cohort studies.

BACKGROUND: A multi-biomarker disease activity (MBDA) score has been validated as an objective measure of disease activity in rheumatoid arthritis (RA) and shown to track response to treatment with several disease-modifying anti-rheumatic drugs (DMARDs). The objective of this study was to evaluate the ability of the MBDA score to track response to treatment with rituximab. METHODS: Data were used from 57 RA patients from three cohorts treated with rituximab 1000 mg and methylprednisolone 100 mg at days 1 and 15. The MBDA score was assessed in serum samples obtained at baseline and 6 months. Spearman's rank correlation coefficients were calculated for baseline values, 6-month values, and change from baseline to 6 months (∆), between MBDA score and the following measures: disease activity score assessing 28 joints (DAS28) using erythrocyte sedimentation rate (ESR) or high-sensitivity C-reactive protein (hsCRP), ESR, (hs)CRP, swollen and tender joint counts assessing 28 joints (SJC28, TJC28), patient visual analogue scale for general health (VAS-GH), health assessment questionnaire (HAQ), and radiographic progression over 12 months using Sharp/van der Heijde score (SHS), as well as six bone turnover markers. Additionally, multivariable linear regression analyses were performed using these measures as dependent variable and the MBDA score as independent variable, with adjustment for relevant confounders. The association between ∆MBDA score and European League Against Rheumatism (EULAR) response at 6 months was assessed with adjustment for relevant confounders. RESULTS: At baseline, the median MBDA score and DAS28-ESR were 54.0 (IQR 44.3-70.0) and 6.3 (IQR 5.4-7.1), respectively. MBDA scores correlated significantly with DAS28-ESR, DAS28-hsCRP, ESR and (hs)CRP at baseline and 6 months. ∆MBDA score correlated significantly with changes in these measures. ∆MBDA score was associated with EULAR good or moderate response (adjusted OR = 0.89, 95% CI = 0.81-0.98, p = 0.02). Neither baseline MBDA score nor ΔMBDA score correlated statistically significantly with ∆SHS (n = 11) or change in bone turnover markers (n = 23), although ∆SHS ≥ 5 was observed in 5 (56%) of nine patients with high MBDA scores. CONCLUSIONS: We have shown, for the first time, that the MBDA score tracked disease activity in RA patients treated with rituximab and that change in MBDA score reflected the degree of treatment response.