Search

Objective: Women with psoriatic arthritis (PsA) may have reduced tumor necrosis factor inhibitor (TNFi) effectiveness compared to men. We examined sex differences in treatment response and retention rates during 24 months of follow‐up among patients with PsA initiating their first TNFi. Methods: Data from patients with PsA across 13 European Spondyloarthritis Research Collaboration Network registries starting their first TNFi were pooled. Logistic regression was used to analyze the association between sex and treatment response using low disease activity (LDA) according to the Disease Activity Score in 28 joints using the C‐reactive protein level (DAS28‐CRP) (<3.2) at six months as the primary outcome. Analyses were adjusted for age, country, conventional synthetic disease‐modifying antirheumatic drug treatment, and TNFi start year. Retention rates were explored using the Kaplan–Meier estimator. Results: We analyzed the treatment response of 7,679 patients with PsA (50% women) with available data on LDA at six months. At baseline, women and men had similar characteristics, including mean DAS28‐CRP (women vs men, 4.4 [SD 1.2] vs 4.2 [SD 1.2]), though patient‐reported outcome measures were worse in women. At six months, 64% of women and 78% of men had LDA (relative risk [RR] 0.82; 95% confidence interval [CI] 0.80–0.84). This difference was similar after adjustment (RR 0.83; 95% CI 0.81–0.85). TNFi retention rates were evaluated in 17,842 patients with PsA. Women had significantly lower retention rates than men at all time points (women 79%, 64%, and 50% vs men 88%, 77%, and 64% at 6, 12, and 24 months, respectively). Conclusion: Despite comparable disease characteristics at baseline, women with PsA have reduced treatment response and retention rates to their first TNFi, highlighting the need to consider sex differences in PsA research and management. [ABSTRACT FROM AUTHOR]

Objective: As first‐degree relatives (FDRs) of HLA–B27–positive patients with axial spondyloarthritis (SpA) have an increased risk of developing axial SpA, the objectives were 1) to evaluate the presence of highly specific imaging features as well as clinical signs of SpA at baseline and after 1 year of follow‐up, and 2) to describe the evolution toward clinical disease within 1 year of follow‐up in a cohort of seemingly healthy FDRs of HLA–B27–positive axial SpA patients. Methods: The Pre‐SpA cohort is a 5‐year prospective inception cohort of seemingly healthy FDRs of HLA–B27–positive axial SpA patients. Clinical and imaging features were collected and recorded. Results: At baseline, 19% of the FDRs reported inflammatory back pain, 32% current arthralgia, 3% arthritis (ever), 5% enthesitis (ever), and 1% dactylitis (ever), and 3% had an extraarticular manifestation. C‐reactive protein level was elevated in 16%, and erythrocyte sedimentation rate was elevated in 7%. On magnetic resonance imaging (MRI) views of sacroiliac joints, 10% had a Spondyloarthritis Research Consortium of Canada score of ≥2, 4% had a score of ≥5, and 4% had deep lesions. In total, 1% fulfilled the modified New York criteria for radiographic sacroiliitis. Clinical, MRI, and acute phase findings were equally distributed between HLA–B27–positive and –negative FDRs. After 1 year of follow‐up, clinical parameters did not change on the group level, but 6% of the FDRs were clinically diagnosed with axial SpA, of whom 86% were HLA–B27–positive. Conclusion: Features associated with SpA or imaging abnormalities were found in up to 32% of seemingly healthy FDRs, with an equal distribution between HLA–B27–positive and –negative FDRs. Progression to clinical axial SpA within 1 year of follow‐up was mainly observed in HLA–B27–positive FDRs. [ABSTRACT FROM AUTHOR]

Objective: To report the primary (1‐year) results from PREVENT, the first phase III study evaluating secukinumab in patients with active nonradiographic axial spondyloarthritis (SpA). Methods: A total of 555 patients were randomized (1:1:1) to receive subcutaneous secukinumab 150 mg with a loading dose (loading dose [LD] group), secukinumab 150 mg without a loading dose (non–loading dose [NL] group), or placebo weekly and then every 4 weeks starting at week 4. The NL group received placebo at weeks 1, 2, and 3 to maintain blinding. Switch to open‐label secukinumab or standard of care was permitted after week 20. The study had 2 independent analysis plans, per European Union and non‐US (plan A; week 16) and US (plan B; week 52) regulatory requirements. The primary end point was 40% improvement in disease activity according to the Assessment of SpondyloArthritis international Society (ASAS40) criteria at week 16 (in the LD group) and at week 52 (in the NL group) in tumor necrosis factor inhibitor (TNFi)–naive patients. Safety analyses included all patients who received ≥1 dose of study treatment. Results: Overall, 481 patients completed 52 weeks of treatment, including 84.3% (156 of 185) in the LD group, 89.7% (165 of 184) in the NL group, and 86.0% (160 of 186) in the placebo group. The proportion of patients who switched to open‐label or standard of care between weeks 20 and 48 was 50.8% in the LD group, 47.3% in the NL group, and 64.0% in the placebo group. Both primary and all secondary end points were met at week 16. The proportion of TNFi‐naive patients who met ASAS40 was significantly higher for LD at week 16 (41.5%) and NL at week 52 (39.8%) versus placebo (29.2% at week 16 and 19.9% at week 52; both P < 0.05). No new safety findings were reported. Conclusion: Our findings indicate that secukinumab 150 mg provides significant and sustained improvement in signs and symptoms of nonradiographic axial SpA through 52 weeks. Safety was consistent with previous reports. [ABSTRACT FROM AUTHOR]

Objective: It remains unclear if and how inflammation and new bone formation in spondyloarthritis (SpA) are coupled. We undertook this study to assess the hypothesis that interleukin‐17A (IL‐17A) is a pivotal driver of both processes. Methods: The effect of tumor necrosis factor (TNF) and IL‐17A on osteogenesis was tested in an osteoblastic differentiation assay using SpA fibroblast‐like synoviocytes (FLS) differentiated with dexamethasone, β‐glycophosphatase, and ascorbic acid. IL‐17A blockade was performed in HLA–B27/human β2‐microglobulin (hβ2m)–transgenic rats, which served as a model for SpA in both prophylactic and therapeutic settings. Inflammation and new bone formation were evaluated by micro–computed tomography imaging, histologic analysis, and gene expression profiling. Results: TNF and IL‐17A significantly increased in vitro osteoblastic differentiation. In vivo, prophylactic blockade of IL‐17A significantly delayed spondylitis and arthritis development and decreased arthritis severity. Anti–IL‐17A treatment was also associated with prevention of bone loss and periosteal new bone formation. Therapeutic targeting of IL‐17A after the initial inflammatory insult also significantly reduced axial and peripheral joint inflammation. This treatment was again associated with a marked reduction in spinal and peripheral structural damage, including new bone formation. RNA sequencing of target tissue confirmed that IL‐17A is a key driver of the molecular signature of disease in this model and that therapeutic anti–IL‐17A treatment reversed the inflammatory signature and the selected gene expression related to bone damage. Conclusion: Both prophylactic and therapeutic inhibition of IL‐17A diminished inflammation and new bone formation in HLA‐B27/hβ2m–transgenic rats. Taken together with the ability of IL‐17A to promote osteoblastic differentiation of human SpA FLS, these data suggest a direct link between IL‐17A–driven inflammation and pathologic new bone formation in SpA. [ABSTRACT FROM AUTHOR]

Objective: Clinical trials of the anti–interleukin‐17A (anti–IL‐17A) antibody secukinumab have demonstrated a crucial role of the cytokine IL‐17A in the pathogenesis of spondyloarthritis (SpA); however, its cellular source in this condition remains a matter of controversy. Group 3 innate lymphoid cells (ILC3s) have been recently identified as potent producers of proinflammatory cytokines, including IL‐17A and IL‐22, in a number of different tissues. This study was undertaken to characterize the presence and composition of ILCs, and investigate whether these cells are an important source of IL‐17A, in the synovial tissue (ST) of patients with SpA. Methods: Matched ST, synovial fluid, and peripheral blood (PB) samples were obtained from SpA patients with actively inflamed knee joints. ILC subsets were characterized by flow cytometry. Gene expression analysis at the single‐cell level was performed directly ex vivo and after in vitro activation. An IL‐17A enzyme‐linked immunospot assay was used to detect IL‐17A–secreting cells. Results: ILCs, and particularly NKp44+ ILC3s, were expanded in inflamed arthritic joints. Single‐cell expression analysis demonstrated that ST ILCs were clearly distinguishable from ST T cells and from their PB counterparts. Expression of the Th17 signature transcripts RORC,AHR, and IL23R was detected in a large proportion of ST ILC3s. These cells were capable of inducing expression of IL22 and CSF2, but not IL17A, in response to in vitro restimulation. Conclusion: Our findings demonstrate that absolute and relative numbers of ILC3s are enriched in the synovial joints of patients with SpA. However, these cells are not a significant source of IL‐17A in this disease. [ABSTRACT FROM AUTHOR]

Objective: Secukinumab (anti–interleukin‐17A [anti–IL‐17A]) is an effective therapy for ankylosing spondylitis and psoriatic arthritis, the prototypical forms of spondyloarthritis (SpA). We undertook this study to determine whether secukinumab modulates the immunopathology of target lesions without blunting systemic immune responses, using peripheral SpA as a model. Methods: Twenty patients with active peripheral SpA were included in a 12‐week open‐label trial with secukinumab (300 mg once weekly from baseline to week 4 and then every 4 weeks thereafter). Outcomes included clinical response, cytokine production by peripheral blood cells using TruCulture technology, and histologic and real‐time quantitative polymerase chain reaction analysis of synovial biopsy samples before and after treatment. Results: All patients completed the 12‐week study without severe adverse events (AEs) or severe treatment‐related AEs. The efficacy end point, the number of patients meeting the American College of Rheumatology 20% improvement criteria (achieving an ACR20 response) at 12 weeks, was achieved by 13 of the 20 patients, of whom 8 achieved an ACR50 response and 5 achieved an ACR70 response, with rapid and significant improvements in all clinical disease activity measures. Clinical improvement in joint counts was associated with a histologic decrease in synovial sublining macrophages (P = 0.028) and neutrophils (P = 0.004), both of which are sensitive synovial biomarkers of inflammatory response in peripheral SpA, as well as with decreased synovial expression of IL‐17A messenger RNA (mRNA) (P = 0.010) but not of tumor necrosis factor mRNA. Systemically, secukinumab treatment decreased the C‐reactive protein level and the erythrocyte sedimentation rate (both P < 0.01), and also decreased matrix metalloproteinase 3 production in the TruCulture system (P < 0.05). However, with the exception of IL‐17A itself, the capacity of peripheral blood cells to produce a broad panel of cytokines and chemokines upon stimulation with microbial antigens was not affected. Conclusion: This mechanism‐of‐action study in peripheral SpA indicates that clinical improvement with secukinumab treatment is paralleled by immunomodulation of inflamed target tissues without compromising systemic immune responses. [ABSTRACT FROM AUTHOR]

Objective: To compare magnetic resonance images (MRIs) of the sacroiliac (SI) joints of healthy subjects and individuals with known mechanical strain acting upon the SI joints to those of patients with axial spondyloarthritis (SpA) and patients with chronic back pain. Methods: Three readers who had received standardized training and were blinded with regard to study group randomly scored MRIs of the SI joints of 172 subjects, including 47 healthy individuals without current or past back pain, 47 axial SpA patients from the Spondyloarthritis Caught Early (SPACE) cohort (with a previous MRI confirmed positive for sacroiliitis), 47 controls with chronic back pain (irrespective of MRI results) from the SPACE cohort, 7 women with postpartum back pain, and 24 frequent runners. MRIs were scored according to the Assessment of SpondyloArthritis international Society (ASAS) definition and Spondyloarthritis Research Consortium of Canada (SPARCC) index. Results: Of the 47 healthy volunteers, 11 (23.4%) had an MRI positive for sacroiliitis, compared to 43 (91.5%) of 47 axial SpA patients and 3 (6.4%) of 47 patients with chronic back pain. Three (12.5%) of the 24 runners and 4 (57.1%) of the 7 women with postpartum back pain had a positive MRI. Using a SPARCC cutoff of ≥2 for positivity, 12 (25.5%) of 47 healthy volunteers, 46 (97.9%) of 47 positive axial SpA patients, 5 (10.6%) of 47 controls with chronic back pain, 4 (16.7%) of 24 runners, and 4 (57.1%) of 7 women with postpartum back pain had positive MRIs. Deep bone marrow edema (BME) lesions were not found in healthy volunteers, patients with chronic back pain, or runners, but were found in 42 (89.4%) of 47 positive axial SpA patients and in 1 (14.3%) of 7 women with postpartum back pain. Conclusion: A substantial proportion of healthy individuals without current or past back pain has an MRI positive for sacroiliitis according to the ASAS definition. Deep (extensive) BME lesions are almost exclusively found in axial SpA patients. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 (R2 = 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. [ABSTRACT FROM AUTHOR]

Objective The molecular processes driving the distinct patterns of synovial inflammation and tissue remodeling in spondylarthritis (SpA) as compared to rheumatoid arthritis (RA) remain largely unknown. Therefore, we aimed to identify novel and unsuspected disease-specific pathways in SpA by a systematic and unbiased synovial gene expression analysis. Methods Differentially expressed genes were identified by pan-genomic microarray and confirmed by quantitative polymerase chain reaction and immunohistochemical analyses of synovial tissue biopsy samples from patients with SpA (n = 63), RA (n = 28), and gout (n = 9). The effect of inflammation on gene expression was assessed by stimulating fibroblast-like synoviocytes (FLS) with synovial fluid and by analysis of synovial tissue samples at weeks 0 and 12 of etanercept treatment. Results Using very stringent statistical thresholds, microarray analysis identified 64 up-regulated transcripts in patients with SpA synovitis as compared to those with RA synovitis. Pathway analysis revealed a robust myogene signature in this gene set. The myogene signature was technically and biologically reproducible, was specific for SpA, and was independent of disease duration, treatment, and SpA subtype (nonpsoriatic versus psoriatic). Synovial tissue staining identified the myogene expressing cells as vimentin-positive, prolyl 4-hydroxylase β-positive, CD90+, and CD146+ mesenchymal cells that were significantly overrepresented in the intimal lining layer and synovial sublining of inflamed SpA synovium. Neither in vitro exposure to synovial fluid from inflamed SpA joints nor in vivo blockade of tumor necrosis factor modulated the SpA-specific myogene signature. Conclusion These data identify a novel and disease-specific myogene signature in SpA synovitis. The fact that this stromal alteration appeared not to be downstream of local inflammation warrants further analysis of its functional role in the pathogenesis of the disease. [ABSTRACT FROM AUTHOR]

Objective Studies comparing spondylarthritis (SpA) to rheumatoid arthritis (RA) synovitis suggest that innate immune cells may play a predominant role in the pathogenesis of SpA. Recent observations have indicated a marked synovial mast cell infiltration in psoriatic SpA. We therefore undertook the present study to investigate the potential contribution of mast cells to synovial inflammation in SpA. Methods Synovial tissue and fluid were obtained from patients with either nonpsoriatic or psoriatic SpA (n = 82) and patients with RA (n = 50). Synovial biopsy tissue was analyzed by immunostaining and used in ex vivo cultures. Synovial fluid was analyzed by enzyme-linked immunosorbent assay. Results We observed a strong and specific increase of c-Kit-positive mast cells in the synovium from patients with SpA compared to the synovium from patients with RA synovitis, which was independent of disease subtype (nonpsoriatic versus psoriatic), disease duration, and treatment. Staining of mast cell granules, analysis of synovial fluid, and results in ex vivo tissue culture did not indicate increased degranulation in SpA synovitis. However, mast cells expressed significantly more interleukin-17 (IL-17) in SpA than in RA synovitis, and mast cells constituted the major IL-17-expressing cell population in the SpA synovium. Ex vivo targeting of synovial mast cells with the c-Kit inhibitor imatinib mesylate significantly decreased the production of IL-17 as well as other proinflammatory cytokines in synovial tissue cultures. Analysis of paired pre- and posttreatment synovial tissue samples indicated that the mast cell/IL-17 axis in SpA was not modulated by effective tumor necrosis factor (TNF) blockade. Conclusion The specific and TNF-independent increase in IL-17-expressing mast cells may contribute to the progression of synovial inflammation in peripheral SpA. [ABSTRACT FROM AUTHOR]

The article discusses the study conducted on various patients showing positive result for the blood test Human Leukocyte Antigen B27 (HLA-B27) in order to understand the presence of spondyloarthropathy (SpA). It examines the tests in patients with the use of magnetic resonance imaging (MRI). It states the reason the inflammation of the sacroiliac join (SI joints)

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., (Copyright © 2013 by the American College of Rheumatology.)