The Initiation, but Not the Persistence, of Experimental Spondyloarthritis Is Dependent on Interleukin-23 Signaling

IL-17A is a central driver of spondyloarthritis (SpA), its production was originally proposed to be IL-23 dependent. Emerging preclinical and clinical evidence suggests, however, that IL-17A and IL-23 have a partially overlapping but distinct biology. We aimed to assess the extent to which IL-17A-driven pathology is IL-23 dependent in experimental SpA. Experimental SpA was induced in HLA-B27/Huβ2m transgenic rats, followed by prophylactic or therapeutic treatment with an anti-IL23R antibody or vehicle control. Spondylitis and arthritis were scored clinically and hind limb swelling was measured. Draining lymph node cytokine expression levels were analyzed directly ex vivo, and IL-17A protein was measured upon restimulation with PMA/ionomycin. Prophylactic treatment with anti-IL23R completely protected against the development of both spondylitis and arthritis, while vehicle-treated controls did develop spondylitis and arthritis. In a therapeutic study, anti-IL23R treatment failed to reduce the incidence or decrease the severity of experimental SpA. Mechanistically, expression of downstream effector cytokines, including IL-17A and IL-22, was significantly suppressed in anti-IL23R versus vehicle-treated rats in the prophylactic experiments. Accordingly, the production of IL-17A upon restimulation was reduced. In contrast, there was no difference in IL-17A and IL-22 expression after therapeutic anti-IL23R treatment. Targeting the IL-23 axis during the initiation phase of experimental SpA—but not in established disease—inhibits IL-17A expression and suppresses disease, suggesting the existence of IL-23-independent IL-17A production. Whether IL-17A can be produced independent of IL-23 in human SpA remains to be established

The Features of the Synovium in Early Rheumatoid Arthritis According to the 2010 ACR/EULAR Classification Criteria

OBJECTIVES: It has been shown in early arthritis cohorts that the 2010 ACR/EULAR criteria for rheumatoid arthritis (RA) enable an earlier diagnosis, perhaps at the cost of a somewhat more heterogeneous patient population. We describe the features of synovial inflammation in RA patients classified according to these new criteria. METHODS: At baseline, synovial tissue biopsy samples were obtained from disease-modifying antirheumatic drug (DMARD)-naïve early RA patients (clinical signs and symptoms <1 year). Synovial tissue was analyzed for cell infiltration, vascularity, and expression of adhesion molecules. Stained sections were evaluated by digital image analysis. Patients were classified according to the two different sets of classification criteria, autoantibody status, and outcome. FINDINGS: Synovial tissue of 69 RA patients according to 2010 ACR/EULAR criteria was analyzed: 56 patients who fulfilled the criteria for RA at baseline and 13 who were initially diagnosed as undifferentiated arthritis but fulfilled criteria for RA upon follow up. The synovium at baseline was infiltrated by plasma cells, macrophages, and T cells as well as other cells, and findings were comparable to those when patients were selected based on the 1987 ACR criteria for RA. There was no clear cut difference in the characteristics of the synovium between RA patients initially diagnosed as undifferentiated arthritis and those who already fulfilled classification criteria at baseline. CONCLUSION: The features of synovial inflammation are similar when the 2010 ACR/EULAR classification criteria are used compared to the 1987 ACR criteria

Hyaluronic Acid in Synovial Fluid Prevents Neutrophil Activation in Spondyloarthritis

Spondyloarthritis (SpA) patients suffer from joint inflammation resulting in tissue damage, characterized by the presence of numerous neutrophils in the synovium and synovial fluid (SF). As it is yet unclear to what extent neutrophils contribute to the pathogenesis of SpA, we set out to study SF neutrophils in more detail. We analyzed the functionality of SF neutrophils of 20 SpA patients and 7 disease controls, determining ROS production and degranulation in response to various stimuli. In addition, the effect of SF on neutrophil function was determined. Surprisingly, our data show that SF neutrophils in SpA patients have an inactive phenotype, despite the presence of many neutrophil-activating stimuli such as GM-CSF and TNF in SF. This was not due to exhaustion as SF neutrophils readily responded to stimulation. Therefore, this finding suggests that one or more inhibitors of neutrophil activation may be present in SF. Indeed, when blood neutrophils from healthy donors were activated in the presence of increasing concentrations of SF from SpA patients, degranulation and ROS production were dose-dependently inhibited. This effect was independent of diagnosis, gender, age, and medication in the patients from which the SF was isolated. Treatment of SF with the enzyme hyaluronidase strongly reduced the inhibitory effect of SF on neutrophil activation, indicating that hyaluronic acid that is present in SF may be an important factor in preventing SF neutrophil activation. This finding provides novel insights into the role of soluble factors in SF regulating neutrophil function and may lead to the development of novel therapeutics targeting neutrophil activation via hyaluronic acid or associated pathways

Evolution of clinical trials for rheumatoid arthritis and spondyloarthritis

Purpose of review The present review presents an overview of the evolution in trial design from mainly randomized placebo-controlled efficacy trials to more strategic clinical trials in rheumatoid arthritis and spondyloarthritis. Additionally, it relates to how these differently designed trials have affected clinical practice. Recent findings Placebo-controlled clinical trials, comparing a new agent to placebo on a stable background, have resulted in the development of a wide array of therapeutic agents in rheumatoid arthritis and spondyloarthritis. However, these kind of trials do have some down sides as they do not provide evidence on the optimal strategy to use this multitude of treatments in daily clinical practice and the ethics concerning a placebo phase are often discussed. These and other concerns resulted in the emergence of various different types of trials in rheumatoid arthritis. A similar change of focus is now observed in spondyloarthritis clinical trials. We address literature on direct comparison ('head-to-head'), noninferiority trials, induction-maintenance, discontinuation, and treat-to-target/tight control clinical trials. Summary In recent years various clinical trials have been published with a design different from placebo-controlled clinical trials. These novel trial designs aimed to provide guidance on the optimal way to use the full range of targeted treatments available and to make it possible, in some design, to leave out the placebo. In rheumatoid arthritis, some of these more strategic type of trials have had a large impact on common practice. In spondyloarthritis, the first steps toward trials with a more strategic design have been taken, and it stands to reason that more will follow

The Role of the IL-23/IL-17 Axis in Disease Initiation in Spondyloarthritis: Lessons Learned From Animal Models

Spondyloarthritis (SpA) is a spectrum of chronic inflammatory joint diseases that frequently presents with inflammation of the axial skeleton, peripheral joints, entheses, skin, and gut. Understanding SpA pathogenesis has been proven challenging due to the limited availability of human target tissues. In recent years, the interleukin (IL)-23/IL-17 pathway has been implicated in the pathogenesis of SpA, in addition to the Tumor Necrosis Factor Alpha (TNF-α) cytokine. The underlying molecular mechanisms by which the IL-23/IL-17 pathway triggers disease initiation, both in the joints as well as at extra-musculoskeletal sites, are not precisely known. Animal models that resemble pathological features of human SpA have provided possibilities for in-depth molecular analyses of target tissues during various phases of the disease, including the pre-clinical initiation phase of the disease before arthritis and spondylitis are clinically present. Herein, we summarize recent insights gained in SpA animal models on the role of the IL-23/IL-17 pathway in immune activation across affected sites in SpA, which include the joint, entheses, gut and skin. We discuss how local activation of the IL-23/IL-17 axis may contribute to the development of tissue inflammation and the onset of clinically manifest SpA. The overall aim is to provide the reader with an overview of how the IL-23/IL-17 axis could contribute to the onset of SpA pathogenesis. We discuss how insights from animal studies into the initiation phase of disease could instruct validation studies in at-risk individuals and thereby provide a perspective for potential future preventive treatment

New treatment paradigms in spondyloarthritis

The review presents the recent rapid expansion of therapeutical options in spondyloarthritis. Additionally, it focuses on the importance of additional questions raised by the growing therapeutic possibilities related to the optimal use of these drugs. The emergence of new treatment options opens new avenues and opportunities for treating patients with nonresponse, contraindications, or intolerance for classic drugs. However, it becomes more relevant than ever to define not only drugs and treatment options but also treatment strategies. We address current literature and remaining questions on strategies such as early intervention, combination treatment, personalized medicine, and treat-to-target. Not only the treatment as such, but also the treatment strategy is crucial to reveal the full therapeutic potential and benefit for patients. Whereas cautious but crucial steps have been taken in the last years to explore these aspects, related to timing and sequence of treatment (including combination treatments), stratified medicine approaches, and treat-to-target strategies, it is now time for full-scale investment in prospective strategy trial

Rheumatoid synovial inflammation: pixel-by-pixel dynamic contrast-enhanced MR imaging time-intensity curve shape analysis--a feasibility study

PURPOSE: To analyze the distribution of different shapes of time-intensity curves (TICs) in synovial tissue of patients with rheumatoid arthritis (RA) and to compare relative numbers of TIC shapes between patients with RA and healthy control subjects. MATERIALS AND METHODS: This prospective study was approved by the institutional review board; patients and control subjects gave written informed consent. Dynamic contrast material-enhanced magnetic resonance (MR) imaging of the knee joint in five patients with early RA and in five control subjects was performed. Parametric maps showing seven TIC shape types were created. Spatial information of the synovial TIC shape distribution pattern and relative number of TIC shapes were calculated on a three-dimensional region of interest. Relative TIC shape numbers were compared by using a nonparametric Mann-Whitney U test. RESULTS: Synovial enhancement in patients with RA consisted of type 2 TIC shapes (slow enhancement) with heterogeneous zones of types 3 (fast enhancement followed by plateau phase), 4 (fast enhancement followed by early washout phase), and 5 (fast enhancement followed by slow enhancement increase) TIC shapes, compared with almost only type 2 TIC shapes in control subjects. The heterogeneous zones were seen in the lateral and medial knee compartments and around the cruciate ligaments. A significantly higher relative number of type 4 TIC shapes was observed in the patient group compared with the control group (16.5% vs 6.9%, P = .008). CONCLUSION: The pixel-by-pixel dynamic contrast-enhanced MR imaging TIC shape analysis may help distinguish patients with RA from control subjects on the basis of the relative number of type 4 TIC shapes. This study provides the rationale for future research to evaluate the utility of this approach in clinical practic

Ideal target for psoriatic arthritis? Comparison of remission and low disease activity states in a real-life cohort

Background Psoriatic arthritis (PsA) recommendations state that the target of treatment should be remission or low disease activity (LDA). We used a real-life dataset to compare different potential targets. Methods 250 patients with PsA considered in an acceptable disease state according to their rheumatologist were included. Targets for remission were the Disease Activity Index for Psoriatic Arthritis (DAPSA) and clinical DAPSA (cDAPSA) remission (4), very low disease activity (VLDA) and Psoriatic Arthritis Disease Activity Score 1.9. LDA targets analysed were the DAPSA 14, cDAPSA 13, minimal disease activity (MDA) and adjusted MDA targets: MDAjoints with both tender joint count (TJC) and swollen joint count (SJC) mandated, MDAskin (psoriasis area and severity index (PASI) mandated) and MDAjoints&skin with TJC, SJC and PASI mandated. Results Comparison of the several candidate targets demonstrates that VLDA is achieved by the lowest proportion of patients and includes patients with the lowest residual disease activity compared with the other remission targets. The modified MDA measures are the most stringent targets for LDA in terms of residual disease on joints, psoriasis and enthesitis within patients achieving the target. In both remission and LDA, the inclusion of C reactive protein did not show an added value. The exclusion of a skin domain, as in the DAPSA measures, resulted in negligence of skin disease and a negative impact on the quality of life in some patients. Conclusions The different remission and LDA targets show us significant overlap between measures, but these measures targeting the same definition do differ in terms of allowance of residual disease. Inclusion of laboratory markers seems unnecessary, although exclusion of a skin domain may result in psoriasis not being assessed resulting in residual impactful skin diseas

Pixel-by-pixel analysis of DCE MRI curve patterns and an illustration of its application to the imaging of the musculoskeletal system

Dynamic contrast enhanced (DCE) MRI is a widespread method that has found broad application in the imaging of the musculoskeletal (MSK) system. A common way of analyzing DCE MRI images is to look at the shape of the time-intensity curve (TIC) in pixels selected after drawing an ROI in a highly enhanced area. Although often applied to a number of MSK affections, shape analysis has so far not led to a unanimous correlation between these TIC patterns and pathology. We hypothesize that this might be a result of the subjective ROI approach. To overcome the shortcomings of the ROI approach (sampling error and interuser variability, among others), we created a method for a fast and simple classification of DCE MRI where time-curve enhancement shapes are classified pixel by pixel according to their shape. The result of the analysis is rendered in multislice, 2D color-coded images. With this approach, we show not only that differences on a short distance range of the TIC patterns are significant and cannot be appreciated with a conventional ROI analysis but also that the information that shape maps and conventional standard DCE MRI parameter maps convey are substantially differen

Smoking and overweight determine the likelihood of developing rheumatoid arthritis

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. 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. 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. 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 preventio