Treatment decisions in axial spondyloarthritis daily clinical practice are more than treat-to-target.

OBJECTIVE: 'Treat-to-target principles' are advised for axial spondyloarthritis (axSpA), although a clear target is not yet defined and targets do not always reflect inflammation. Treat-to-target use and motives for treatment choices in clinics are unknown. Therefore, we studied the presence of residual disease activity according physician's opinion, patient's opinion and composite indices and compared them to the subsequent treatment decisions. METHODS: This cross-sectional multicentre study included 249 patients with a clinical diagnosis of axSpA ≥6 months. Remission and low disease activity according to the BASDAI (<1.9 and <3.5, respectively) and physician's and patient's opinion were assessed. Questionnaires included patient-reported outcomes and patients and physicians completed questions regarding treatment decisions. RESULTS: A total of 115/249 (46%) patients were in remission according to the physician and 37% (n = 43) of these patients reached remission according to the BASDAI. In 51/83 (60%) of the patients with residual disease activity according to the physician and a BASDAI >3.5 the treatment was left unchanged, either because of low disease activity as rated by the physician [n = 15 (29%)] or because of a combination of low disease activity with non-inflammatory complaints or comorbidities [n = 11 (25%)]. Retrospective treat-to-target evaluations showed that treatments were most frequently intensified in patients with arthritis or inflammatory back pain and less often in patients with other (non-inflammatory) musculoskeletal comorbidities. CONCLUSION: This study shows that physicians do not always strictly apply treat-to-target in case of residual disease activity in axSpA. Usually, they accept low disease activity as satisfactory.

EULAR study group on 'MHC-I-opathy': identifying disease-overarching mechanisms across disciplines and borders.

The 'MHC-I (major histocompatibility complex class I)-opathy' concept describes a family of inflammatory conditions with overlapping clinical manifestations and a strong genetic link to the MHC-I antigen presentation pathway. Classical MHC-I-opathies such as spondyloarthritis, Behçet's disease, psoriasis and birdshot uveitis are widely recognised for their strong association with certain MHC-I alleles and gene variants of the antigen processing aminopeptidases ERAP1 and ERAP2 that implicates altered MHC-I peptide presentation to CD8+T cells in the pathogenesis. Progress in understanding the cause and treatment of these disorders is hampered by patient phenotypic heterogeneity and lack of systematic investigation of the MHC-I pathway.Here, we discuss new insights into the biology of MHC-I-opathies that strongly advocate for disease-overarching and integrated molecular and clinical investigation to decipher underlying disease mechanisms. Because this requires transformative multidisciplinary collaboration, we introduce the EULAR study group on MHC-I-opathies to unite clinical expertise in rheumatology, dermatology and ophthalmology, with fundamental and translational researchers from multiple disciplines such as immunology, genomics and proteomics, alongside patient partners. We prioritise standardisation of disease phenotypes and scientific nomenclature and propose interdisciplinary genetic and translational studies to exploit emerging therapeutic strategies to understand MHC-I-mediated disease mechanisms. These collaborative efforts are required to address outstanding questions in the etiopathogenesis of MHC-I-opathies towards improving patient treatment and prognostication.

18F-sodium fluoride PET-CT visualizes both axial and peripheral new bone formation in psoriatic arthritis patients.

PURPOSE: As bone formation is associated with psoriatic arthritis (PsA), positron emission tomography (PET) using a 18F-Fluoride tracer may enable sensitive detection of disease activity. Our primary aim was to determine the feasibility of whole-body 18F-sodium fluoride PET-CT in clinically active PsA patients to depict new bone formation (as a reflection of disease activity) at peripheral joints and entheses. Our secondary aim was to describe 18F-sodium fluoride findings in the axial skeleton. METHODS: Sixteen patients (female 10/16, age 50.6 ± 8.9 years) with PsA fulfilling CASPAR criteria or with a clinical diagnosis of PsA according to the treating rheumatologist and with ≥ 1 clinically active enthesitis site were included. Of each patient, a whole-body 18F-sodium fluoride PET-CT scan was performed. All scans were scored for PET-positive lesions at peripheral joints, enthesis sites and the spine. Clinical disease activity was assessed by swollen/tender joint count 44, enthesitis according to MASES and SPARCC scores. RESULTS: Out of 1088 evaluated joints, 109 joints showed PET enhancement, mainly in the interphalangeal and metatarsal joints of the feet (14/109, 12.9%) and the distal interphalangeal joints of the hands (14/109, 12.9%). PET positivity was found at 44/464 enthesis sites, mainly at the patella tendon insertion (11/44, 25%) and quadriceps tendon insertion (10/44, 22.7%). Of the PET-positive joints and enthesis sites, respectively 18.2% and 29.5% were clinically positive; 81.8% and 70.5% of the PET-positive joints and entheses respectively were clinically asymptomatic. In 11 patients, ≥ 1 axial PET-positive lesion was observed, mainly in the cervical spine. CONCLUSIONS: New molecular bone formation was observed on 18F-sodium fluoride PET-CT scans, in all domains in which PsA disease activity can be observed, with a substantial part showing no clinical symptoms. CLINICAL TRIAL REGISTRATION: EudraCT: 2017-004,850-40, registered on 13 December 2017.

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.

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.

European bio-naïve spondyloarthritis patients initiating TNF inhibitor: time trends in baseline characteristics, treatment retention and response.

OBJECTIVES: To investigate time trends in baseline characteristics and retention, remission and response rates in bio-naïve axial spondyloarthritis (axSpA) and psoriatic arthritis (PsA) patients initiating TNF inhibitor (TNFi) treatment. METHODS: Prospectively collected data on bio-naïve axSpA and PsA patients from routine care in 15 European countries were pooled. Three cohorts were defined according to year of TNFi initiation: A (1999-2008), B (2009-2014) and C (2015-2018). Retention, remission and response rates were assessed at 6, 12 and 24 months. RESULTS: In total, 27 149 axSpA and 17 446 PsA patients were included. Cohort A patients had longer disease duration compared with B and C. In axSpA, cohort A had the largest proportion of male and HLA-B27 positive patients. In PsA, baseline disease activity was highest in cohort A. Retention rates in axSpA/PsA were highest in cohort A and differed only slightly between B and C. For all cohorts, disease activity decreased markedly from 0 to 6 months. In axSpA, disease activity at 24 months was highest in cohort A, where also remission and response rates were lowest. In PsA, remission rates at 6 and 12 months tended to be lowest in cohort A. Response rates were at all time points comparable across cohorts, and less between-cohort disease activity differences were seen at 24 months. CONCLUSION: Our findings indicate that over the past decades, clinicians have implemented more aggressive treatment strategies in spondyloarthritis. This was illustrated by shorter disease duration at treatment initiation, decreased retention rates and higher remission rates during recent years.

The Role of the Lymphatic System in the Pathogenesis and Treatment of Inflammatory Bowel Disease.

Although the number of therapeutic options for the treatment of inflammatory bowel disease (IBD) has increased in recent years, patients suffer from decreased quality of life due to non-response or loss of response to the currently available treatments. An increased understanding of the disease's etiology could provide novel insights for treatment strategies in IBD. Lymphatic system components are generally linked to immune responses and presumably related to inflammatory diseases pathophysiology. This review aims to summarize findings on immune-mediated mechanisms in lymphoid tissues linked with IBD pathogenesis and (potential) novel treatments. Enhanced innate and adaptive immune responses were observed in mesenteric lymph nodes (MLNs) and other lymphoid structures, such as Peyer's patches, in patients with IBD and in animal models. Furthermore, the phenomenon of lymphatic obstruction in the form of granulomas in MLNs and lymphatic vessels correlates with disease activity. There is also evidence that abnormalities in the lymphatic stromal components and lymph node microbiome are common in IBD and could be exploited therapeutically. Finally, novel agents targeting lymphocyte trafficking have been added to the treatment armamentarium in the field of IBD. Overall, gut-associated lymphoid tissue plays a key role in IBD immunopathogenesis, which could offer novel therapeutic targets.

Dual Blockade of TNF and IL-17A Inhibits Inflammation and Structural Damage in a Rat Model of Spondyloarthritis.

The tumor necrosis factor (TNF) and IL-23/IL-17 axes are the main therapeutic targets in spondyloarthritis. Despite the clinical efficacy of blocking either pathway, monotherapy does not induce remission in all patients and its effect on new bone formation remains unclear. We aimed to study the effect of TNF and IL-17A dual inhibition on clinical disease and structural damage using the HLA-B27/human ß2-microglobulin transgenic rat model of SpA. Immunized rats were randomized according to arthritis severity, 1 week after arthritis incidence reached 50%, to be treated twice weekly for a period of 5 weeks with either a dual blockade therapy of an anti-TNF antibody and an anti-IL-17A antibody, a single therapy of either antibody, or PBS as vehicle control. Treatment-blinded observers assessed inflammation and structural damage clinically, histologically and by micro-CT imaging. Both single therapies as well as TNF and IL-17A dual blockade therapy reduced clinical spondylitis and peripheral arthritis effectively and similarly. Clinical improvement was confirmed for all treatments by a reduction of histological inflammation and pannus formation (p < 0.05) at the caudal spine. All treatments showed an improvement of structural changes at the axial and peripheral joints on micro-CT imaging, with a significant decrease for roughness (p < 0.05), which reflects both erosion and new bone formation, at the level of the caudal spine. The effect of dual blockade therapy on new bone formation was more prominent at the axial than the peripheral level. Collectively, our study showed that dual blockade therapy significantly reduces inflammation and structural changes, including new bone formation. However, we could not confirm a more pronounced effect of dual inhibition compared to single inhibition.

Correction: HLA-C*07 in axial spondyloarthritis: data from the German Spondyloarthritis Inception Cohort and the Spondyloarthritis Caught Early cohort.

The original version of this Article contained an error in the spelling of the author Denis Poddubnyy, which was incorrectly given as Denis Podubbnyy. This has now been corrected in both the PDF and HTML versions of the Article.

HLA-C*07 in axial spondyloarthritis: data from the German Spondyloarthritis Inception Cohort and the Spondyloarthritis Caught Early cohort.

We aimed to assess the mRNA expression of MHC class 1-related molecules in ankylosing spondylitis (AS) patients vs healthy controls (HCs) and, subsequently, if the absence of HLA-C*07 is associated with genetic susceptibility to axial spondyloarthritis (axSpA). HLA-C*07 was assessed in (a) an exploratory cohort of 24 AS patients vs 40 HCs, (b) a confirmatory cohort of 113 AS patients and 83 non-radiographic axSpA patients from the GErman SPondyloarthritis Inception Cohort (GESPIC) vs 134,528 German potential stem cell donors, and (c) an early back pain cohort with 94 early axSpA patients vs 216 chronic back pain (CBP) patients from the SPondyloArthritis Caught Early (SPACE) cohort. In the exploratory cohort, 79% of the AS patients were HLA-C*07 negative compared to 35% of the HCs (p < 0.001). This difference was confirmed in GESPIC with 73% of AS patients being HLA-C*07 negative compared to 50% of the controls (p < 0.0001); 59% of the nr-axSpA patients were HLA-C*07 negative. In the SPACE cohort, 70% of the axSpA patients were HLA-C*07 negative compared to 44% of CBP patients (p < 0.0001); the association between HLA-C*07 negativity and a diagnosis of axSpA was independent from HLA-B*27. In conclusion, the absence of HLA-C*07 is associated with genetic susceptibility to axSpA.

Achieving remission in psoriatic arthritis by early initiation of TNF inhibition: a double-blind, randomised, placebo-controlled trial of golimumab plus methotrexate versus placebo plus methotrexate.

OBJECTIVES: Early initiation of effective treatment favours remission in rheumatoid arthritis, but it remains unknown if the same concept applies to psoriatic arthritis (PsA). Therefore, this study investigated whether the combination of golimumab plus methotrexate (MTX) as a first-line treatment is superior to MTX alone in inducing remission in PsA. METHODS: This investigator-initiated, multicentre, double-blind, randomised, placebo-controlled trial included 51 MTX and bDMARD-naive patients with PsA fulfilling the CASPAR criteria and with active disease at baseline (≥3 swollen joint count/tender joint count). Patients were randomised to golimumab (50 mg SC monthly)+MTX (n=26) (TNFi arm) or matched placebo+MTX (n=25) (MTX arm). MTX was started 15 mg/week and increased to 25 mg/week over 8 weeks. The primary endpoint was percentage of patients achieving Disease Activity Score (DAS) remission (<1.6) at week 22. Safety was assessed throughout the study. RESULTS: The primary efficacy endpoint was achieved by 81% in the TNFi arm versus 42 % in the MTX arm (p=0.004). This difference in DAS remission was already observed at week 8. A significant difference in favour of the golimumab+MTX arm at week 22 was also observed for other response criteria such as MDA, ACR20/50/70, disease measures and patient-reported outcomes. The occurrence rates of adverse event and treatment-emergent adverse event were similar in both arms. CONCLUSIONS: In patients with early PsA, DAS remission at week 22 was almost doubled with golimumab+MTX versus MTX alone. This double-blind, randomised, placebo-controlled study supports the concept that early initiation of TNFi in patients with PsA favours remission. TRIAL REGISTRATION NUMBER: NCT01871649.

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.

New treatment paradigms in spondyloarthritis.

PURPOSE OF REVIEW: 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. RECENT FINDINGS: 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. SUMMARY: 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 trials.

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 disease.

Residual disease activity in psoriatic arthritis: discordance between the rheumatologist's opinion and minimal disease activity measurement.

Objective: To assess how many PsA patients with an acceptable disease state according to the treating rheumatologist have quiescent disease defined as minimal disease activity (MDA). Methods: This cross-sectional study included 250 PsA patients. To assess current clinical practice as closely as possible, acceptable disease state was not determined by predefined activity measures, but instead was defined by asking rheumatologists to refer those patients whom they considered sufficiently treated. Patients were evaluated for current disease activity including clinical assessments and patient reported outcomes (PROs). Results: One-third (88/250) of the patients with acceptable disease state according to the rheumatologist did not fulfil MDA (MDA-). The presence of tender joints and patient pain and global disease activity scores most frequently contributed to not fulfilling MDA (not achieved in 83, 82 and 80%, respectively). However, also objective signs of disease activity were higher in the MDA- than MDA+ patient group: a swollen joint count >1 occurred in 35% vs 7% (P < 0.001), enthesitis >1 in 14% vs 3% (P = 0.002) and Psoriasis Area and Severity Index >1 in 43% vs 26% (P = 0.002). Residual disease was more frequent in females, elder patients and those with a raised BMI, independent of the treatment schedule, and negatively influenced PROs of function and quality of life. Conclusion: One-third of the PsA patients with acceptable disease state according to the treating rheumatologist did not fulfil the MDA criteria and had residual disease activity on both subjective and objective disease activity measurements. As residual disease activity was associated with worse PROs, future strategy trials should evaluate if treatment adjustments are beneficial for this patient group.

Immunopathology of synovitis: from histology to molecular pathways.

Increased knowledge about pathological processes active in inflammatory joint diseases is needed to initiate personalized medicine based on targeted treatments in the future. The molecular and cellular pathways that are active during joint inflammation may differ between the various inflammatory joint diseases, between different patient subgroups within one disease, or even between different stages of the disease in a single patient. In this review, we evaluate synovial inflammation in terms of descriptive histopathology through to more functional studies on human synovial tissue inflammation in RA and SpA, in phenotypic subgroups of RA and SpA patients, and during the disease course of both diseases.

Reproducibility of DCE-MRI time-intensity curve-shape analysis in patients with knee arthritis: A comparison with qualitative and pharmacokinetic analyses.

PURPOSE: To compare the between-session reproducibility of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) combined with time-intensity curve (TIC)-shape analysis in arthritis patients, within one scanner and between two different scanners, and to compare this method with qualitative analysis and pharmacokinetic modeling (PKM). MATERIALS AND METHODS: Fifteen knee joint arthritis patients were included and scanned twice on a closed-bore 1.5T scanner (n = 9, group 1), or on a closed-bore 1.5T and on an open-bore 1.0T scanner (n = 6, group 2). DCE-MRI data were postprocessed using in-house developed software ("Dynamo"). Disease activity was assessed. RESULTS: Disease activity was comparable between the two visits. In group 1 qualitative analysis showed the highest reproducibility with intraclass correlation coefficients (ICCs) between 0.78 and 0.98 and root mean square-coefficients of variation (RMS-CoV) of 8.0%-14.9%. TIC-shape analysis showed a slightly lower reproducibility with similar ICCs (0.78-0.97) but higher RMS-CoV (18.3%-42.9%). The PKM analysis showed the lowest reproducibility with ICCs between 0.39 and 0.64 (RMS-CoV 21.5%-51.9%). In group 2 TIC-shape analysis of the two most important TIC-shape types showed the highest reproducibility with ICCs of 0.78 and 0.71 (RMS-CoV 29.8% and 59.4%) and outperformed the reproducibility of the most important qualitative parameter (ICC 0.31, RMS-CoV 45.1%) and the within-scanner reproducibility of PKM analysis. CONCLUSION: TIC-shape analysis is a robust postprocessing method within one scanner, almost as reproducible as the qualitative analysis. Between scanners, the reproducibility of the most important TIC-shapes outperform that of the most important qualitative parameter and the within-scanner reproducibility of PKM analysis.