Search

Objectives: In radiographic axial spondyloarthritis (r-axSpA), spinal damage manifests as syndesmophytes and facet joint ankylosis (FJA). We evaluated whether the presence of one lesion increased the risk of the other lesion., Methods: Patients with r-axSpA underwent low-dose CT (ldCT) and MRI of the whole spine at baseline and 2 years. On ldCT, vertebrae were scored for presence and size of syndesmophytes; facet joints were assessed for ankylosis. MR images were assessed for inflammation. Two hypotheses were tested: (i) presence of FJA is associated with new syndesmophyte(s) on the same vertebral unit (VU) 2 years later, and (ii) presence of bridging syndesmophyte(s) is associated with new FJA on the same VU 2 years later. Two generalized estimating equations models were tested per hypothesis using increase of FJA/syndesmophytes (model A) or presence of FJA/syndesmophytes (model B) as outcome, adjusted for inflammation at baseline. Secondary analyses tested the hypotheses with outcomes on adjacent VUs and dose-response effects., Results: Fifty-one patients were included (mean age 49, 84% male, 82% HLA-B27+). Baseline bridging syndesmophytes occurred more often (range: 10-60% per VU) than FJA (range: 8-36%). Odds ratios (ORs) (95% CI) for presence of bridging syndesmophytes on development of FJA were 3.55 (2.03, 6.21) for model A and 3.30 (2.14, 5.09) for model B. ORs for presence of baseline FJA on new syndesmophytes were 1.87 (1.20, 2.92) for model A and 1.69 (0.88, 3.22) for model B. Secondary analyses yielded positive ORs for both hypotheses., Conclusions: Bone formation in vertebrae and in facet joints influence each other's occurrence, with the effect of syndesmophytes being larger than that of FJA., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Rheumatoid arthritis (RA) and spondyloarthritis (SpA) are associated with changes in body composition. Ectopic intramuscular fat (IMAT) may alter muscle function and contribute to cardiometabolic disorders. In a pilot study, we analyzed IMAT in the calf with peripheral quantitative computed tomography (pQCT) and examined correlations between IMAT quantity and body composition parameters. In 20 patients with active RA and 23 with active SpA, IMAT was correlated with visceral fat (VAT; r = 0.5143 and 0.6314, respectively; p < 0.05) and total lean mass (r = 0.5414 and 0.8132, respectively; p < 0.05), but not with whole body fat mass. Total lean mass mediated 16% and 33% of the effects of VAT on IMAT in RA and SpA, respectively. In both RA and SpA, calf muscle area was correlated with total lean mass (r = 0.5940 and r = 0.8597, respectively; p < 0.05) and fat area was correlated with total body fat (r = 0.6767 and 0.5089, respectively; p < 0.05) and subcutaneous fat (r = 0.6526 and 0.5524, respectively; p < 0.05). Fat area was inversely correlated with handgrip and walking tests, and it was associated with disease activity and disability. We showed that ectopic IMAT, measured with pQCT, was correlated with VAT, but not with total body fat, in RA and SpA. This result suggests that metabolically active fat was specifically associated with IMAT.

Objective: To compare immune cell phenotype and function in psoriatic arthritis (PsA) versus psoriasis in order to better understand the pathogenesis of PsA., Methods: In-depth immunophenotyping of different T cell and dendritic cell subsets was performed in patients with PsA, psoriasis, or axial spondyloarthritis and healthy controls. Subsequently, we analyzed cells from peripheral blood, synovial fluid (SF), and skin biopsy specimens using flow cytometry, along with high-throughput transcriptome analyses and functional assays on the specific cell populations that appeared to differentiate PsA from psoriasis., Results: Compared to healthy controls, the peripheral blood of patients with PsA was characterized by an increase in regulatory CD4+ T cells and interleukin-17A (IL-17A) and IL-22 coproducing CD8+ T cells. One population specifically differentiated PsA from psoriasis: i.e., CD8+CCR10+ T cells were enriched in PsA. CD8+CCR10+ T cells expressed high levels of DNAX accessory molecule 1 and were effector memory cells that coexpressed skin-homing receptors CCR4 and cutaneous lymphocyte antigen. CD8+CCR10+ T cells were detected under inflammatory and homeostatic conditions in skin, but were not enriched in SF. Gene profiling further revealed that CD8+CCR10+ T cells expressed GATA3, FOXP3, and core transcriptional signature of tissue-resident memory T cells, including CD103. Specific genes, including RORC, IFNAR1, and ERAP1, were up-regulated in PsA compared to psoriasis. CD8+CCR10+ T cells were endowed with a Tc2/22-like cytokine profile, lacked cytotoxic potential, and displayed overall regulatory function., Conclusion: Tissue-resident memory CD8+ T cells derived from the skin are enhanced in the circulation of patients with PsA compared to patients with psoriasis alone. This may indicate that aberrances in cutaneous tissue homeostasis contribute to arthritis development., (© 2021 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Objectives: The Assessment of SpondyloArthritis international Society health index (ASAS-HI) was designed to assess the global health of patients with spondyloarthritis, but its performance in psoriatic arthritis (PsA) is hardly known. We addressed the clinimetric properties of this instrument in patients with PsA., Methods: This was a cross-sectional observational study that included 90 consecutive patients with PsA. The measurement properties of ASAS-HI were analysed against the Disease Activity index for PSoriatic Arthritis (DAPSA) and the Psoriatic Arthritis Impact of Disease (PsAID) questionnaire. A multivariate analysis was performed to weigh the ASAS-HI items associated with DAPSA active disease and PsAID high impact., Results: Mean ASAS-HI was 5.8 (4.3). Convergent validity was high both against DAPSA (ρ 0.78, P < 0.0001) and PsAID (ρ 0.80, P < 0.0001). ASAS-HI showed a high discriminant capacity for both DAPSA remission [optimal criterion ≤ 2, area under the receiver operating characteristic curve (AUC) 0.92 (95% CI: 0.85, 0.97), P < 0.0001], and low activity [optimal criterion ≤6, AUC 0.87 (95% CI: 0.79, 0.94), P < 0.0001]. The ASAS-HI items significantly associated with DAPSA active disease were: 'I find it hard to stand for long' (β 4.48, P < 0.0001), 'I find it hard to concentrate' (β 2.94, P = 0.042) and 'I sleep badly at night' (β 1.86, P = 0.044). As for PsAID, the only item significantly associated with a high impact was 'I sleep badly at night' (β -3.29, P = 0.015)., Conclusion: We demonstrated construct validity of ASAS-HI, a spondyloarthritis instrument, for the assessment of global health in patients with PsA., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose: To confirm the interest of 3-dimensional ultrashort echo-time (3D-UTE) sequences to assess morphologic aspects in normal and pathological Achilles entheses in a rat model of spondyloarthropathy (SpA) with histological correlations, in comparison with conventional RARE T2 Fat-Sat sequences, and, furthermore, to evaluate the feasibility of a 3D multiecho UTE sequence performed before and after the intravenous injection of ultrasmall superparamagnetic iron oxide (USPIO) particles to assess macrophagic involvement in the Achilles enthesis in the same rat model of SpA., Materials and Methods: Fourteen rats underwent in vivo MRI of the ankle at 4.7 T, including a 3D RARE T2 Fat-Sat sequence and a 3D ultrashort echo-time (UTE) sequence for morphologic assessment at baseline and day 3 after induction of an SpA model, leading to Achilles enthesopathy in the left paw (right paw serving as a control). A 3D multiecho UTE sequence was also performed at day 3 before and then 24 (4 rats) and 48 (2 rats) hours after intravenous injection of USPIO. Visual analysis and signal intensity measurements of all images were performed at different locations of the Achilles enthesis and preinsertional area. Visual analysis and T2∗ measurements were performed before and after USPIO injection, on the 3D multiecho UTE sequence in the same locations. Normal and pathological values were compared by Wilcoxon signed-rank tests. MR findings were compared against histological data., Results: 3D-UTE sequences enabled morphologic identification of the anterior fibrocartilage and posterior collagenic areas of the Achilles enthesis. Visual analysis and signal intensity measurements distinguished SpA-affected entheses from healthy ones at day 3 ( P =0.02). After administration of USPIO, no differences in signals were detected. Similarly, both visual analysis and signal T2∗ measurements in the enthesis were unable to distinguish the SpA-affected tendons from healthy ones ( P =0.914). Neither the normal anatomy of the enthesis nor its pathological pattern could be distinguished using the standard RARE sequence. Histology confirmed the absence of USPIO in Achilles entheses, despite marked signs of inflammation., Conclusion: Unlike conventional RARE T2 Fat-Sat sequences, 3D-UTE sequences enable morphologic assessment of normal enthesis anatomy and early detection of abnormalities in pathological conditions. However, 3D multiecho UTE sequences combined with USPIO injections with T2∗ measurements were unable to detect macrophagic involvement in these pathological conditions.

Ossification of the ligamentum flavum of the spine (OLF) is rarely reported in individuals of European ancestry. It has, however, been observed in archaeological skeletons from Europe. The aim of this study was to revisit OLF rates, utilising a mid-nineteenth-century skeletal sample from Ireland. The hypothesis was that the OLF prevalence rate was similar to studies on non-Europeans. Spines from 345 individuals were analysed, and the extent of OLF recorded on the cranial and caudal attachment sites of each vertebra using the following classification system: Grade 0 (no change); Grade 1 (<2 mm); Grade 2 (2-4 mm); Grade 3 (≥4 mm). OLF was observed at prevalence rates of 83.6%. There was no disparity in prevalence based on sex, except for individuals aged 36-45 years at death in which the male rate was higher. Advancing age was a determining factor in the OLF occurrence with an onset in young adulthood (18-25 years), and most severe grades occurring over the age of 25 years. OLF coincides with spinal osteoarthritis, spondylosis deformans and Schmorl's nodes in both sexes, and with intervertebral osteochondrosis in females. The results of this study indicate that OLF is likely to be an understudied rather than rare condition in European populations.

Introduction: The prevalence of Sjögren's syndrome (SS) in patients with the diagnosis of SpA has been reported to be higher than normal population. Yet, the vice-versa is unclear. In this study, we aimed to investigate the prevalence of IBP, radiologic sacroiliitis and SpA in patients with primary SS., Methods: 85 patients followed at the rheumatology clinics of the Marmara and Kocaeli Universities with the diagnosis of primary SS between November 2011 and August 2012 were included in this study. The control group consisted of 100 age-and gender-matched patients. Inflammatory back pain and axial SpA were diagnosed according to the assessment of spondylo arthritis International Society (ASAS) criteria., Results: 83 patients were (97%) female and 2 (3%) were male. Mean age of the patients was 49.1 (±11) years. Mean disease duration was 7.3 (±4) years. The patient and control groups were comparable in terms of age and gender (p > 0.05). Inflammatory back pain was observed in 21 (24.7%) of 85 primary SS patients and in 4 (4%) of 100 control subjects (p < 0.001), radiographic sacroiliitis was demonstrated in 9 (10.5%) of primary SS patients and 2 (2%) of the control subjects (p = 0.025). Remaining SpA findings were not encountered in either group., Conclusion: inflammatory back pain and radiologic sacroiliitis is increased in patients with primary SS. Whether IBP, SI joint inflammation and radiologic sacroiliitis is due to the co-existence of SpA and primary SS or IBP is an underdiagnosed clinical feature of SS deserves further studies of large patient numbers.

Spondyloarthropathies, the second most frequently occurring form of chronic inflammatory arthritis, affects young adults in particular. However, a proper model with which to study the biology of this disease and to develop therapeutics is lacking. One of the most accepted animal models for this disease uses HLA-B27/Hu-β2m transgenic rats; however, only 30%-50% of male HLA-B27/Hu-β2m rats develop spontaneous, clinically apparent spondylitis and have a variable time until disease onset. Here, we report a high-incidence, low-variation spontaneous mouse model that delineates how the combination of inflammatory cytokine interleukin-27 (IL-27) signaling deficiency and mitogenic signaling (mutant p53R172H) in vivo, leads to bone loss in the vertebral bodies and ossification of the cartilage in the intervertebral discs. In this human disease-like mouse model, bone loss and pathogenic bone development are seen as early as 4 months of age in the absence of inflammatory aggregates in the enthesis or intervertebral disc.

Considerable progress has been made recently in understanding the complex pathogenesis and treatment of spondyloarthropathies (SpA). Currently, along with traditional disease modifying anti-rheumatic drugs (DMARDs), TNF-α, IL-12/23 and IL-17 are available for treatment of such diseases as ankylosing spondylitis (AS) and psoriatic arthritis (PsA). Although they adequately control inflammatory symptoms, they do not affect the abnormal bone formation processes associated with SpA. However, the traditional therapeutic approach does not cover the regenerative treatment of damaged tissues. In this regards, stem cells may offer a promising, safe and effective therapeutic option. The aim of this paper is to present the role of mesenchymal stromal cells (MSC) in pathogenesis of SpA and to highlight the opportunities for using stem cells in regenerative processes and in the treatment of inflammatory changes in articular structures., Competing Interests: The authors declare no conflict of interest.

Objective: The spondyloarthritides (SpA) are a group of rheumatic diseases characterized by ossification and inflammation of entheseal tissue, the region where tendon attaches to bone. Interleukin-23 (IL-23) is involved in the pathogenesis of SpA by acting on IL-23 receptor (IL-23R) expressed on enthesis-resident lymphocytes. Upon IL-23 binding, CD3+CD4-CD8- tissue-resident lymphocytes secrete IL-17A and IL-22, leading to inflammation, bone loss, and ossification. Knowledge about enthesis-resident lymphocytes remains fragmentary, and the contribution of entheseal γ/δ T cells in particular is not clear. This study was undertaken to investigate the presence of γ/δ T cells in the enthesis., Methods: We used 2-photon microscopy and flow cytometry to analyze entheseal lymphocytes from C57BL/6, Tcrd-H2BeGFP, Rorc-GFP, and IL-23R-eGFP mice. To analyze entheseal γ/δ T cells in IL-23-induced inflammation, Tcrd-H2BeGFP mice were crossed with mice of the susceptible B10.RIII background. Hydrodynamic injection of IL-23 minicircle DNA was performed for overexpression of IL-23 and induction of inflammation. Light-sheet fluorescence microscopy was used to visualize arthritic inflammation., Results: Activated Vγ6+CD27- γ/δ T cells were abundant in uninflamed entheseal tissue and constituted the large majority of retinoic acid receptor-related orphan nuclear receptor γt (RORγt)+IL-23R+ enthesis-resident lymphocytes. Fetal thymus-dependent γ/δ T cells were the main source of IL-17A at the enthesis. Under inflammatory conditions, γ/δ T cells increased in number at the Achilles tendon enthesis, aortic root, and adjacent to the ciliary body., Conclusion: Entheseal γ/δ T cells are derived from fetal thymus and are maintained as self-renewing tissue-resident cells. As main IL-17A producers within tissues exposed to mechanical stress including enthesis, γ/δ T cells are key players in the pathogenesis of IL-23-induced local inflammation., (© 2016, American College of Rheumatology.)

Objective: The Assessment of SpondyloArthritis international Society (ASAS) has previously published criteria for spondyloarthritis (SpA). In the Spines of Southern Denmark cohort, which included patients with persistent low back pain and an unknown proportion of patients with SpA, our objectives were 1) to estimate the prevalence of magnetic resonance imaging (MRI) findings and clinical features included in the ASAS criteria for SpA and 2) to explore the associations between MRI findings and clinical features., Methods: We included patients ages 18-40 years with persistent low back pain who had been referred to the Spine Centre of Southern Denmark. We collected information on clinical features (including HLA-B27 and high-sensitivity C-reactive protein) and MRI findings in the spine and sacroiliac (SI) joints., Results: Of 1,020 included patients, 537 (53%) had at least 1 of the clinical features included in the ASAS criteria for SpA. Three clinical features were common-inflammatory back pain according to the ASAS criteria, a good response to nonsteroidal antiinflammatory drugs (NSAIDs), and family history of SpA. The prevalence of these features ranged from 15% to 17%. Sacroiliitis on MRI according to the ASAS definition was present in 217 patients (21%). Of those 217 patients, 91 (42%) had the minimum amount of bone marrow edema required according to the ASAS definition (a low bone marrow edema score). The presence of HLA-B27, peripheral arthritis, a good response to NSAIDs, and preceding infection were independently positively associated with MRI findings in the SI joints (odds ratios [ORs] of 1.9-9.0). The remaining 8 clinical features were not positively associated with MRI findings. Importantly, only age was independently associated with low bone marrow edema score at the SI joints (OR of 1.1 per year)., Conclusion: In this population, 53% had at least 1 clinical feature included in the ASAS criteria for SpA, and 21% had sacroiliitis according to the ASAS definition; furthermore, the associations between the clinical and imaging domains were inconsistent. The results indicate a need for further investigation of the importance of these findings in SpA, including investigation of the minimum requirements for defining sacroiliitis on MRI., (© 2016, American College of Rheumatology.)

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., (© The Author 2015. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objective: Analysis of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) using pharmacokinetic modeling (PKM) provides quantitative measures that mirror microvessel integrity and can be used as an objective marker of the level of synovial inflammation. The aim of this study was to investigate the PKM parameters K(trans) , kep , and ve in a prospective cohort of disease-modifying antirheumatic drug (DMARD)-naive patients with early arthritis, and to validate the results by assessing their correlation with the number of synovial endothelial cells (ECs)., Methods: Forty-seven patients with early arthritis (arthritis duration <1 year, DMARD naive; comprising 14 patients with rheumatoid arthritis, 22 with unclassified arthritis, 6 with spondyloarthritis [SpA], and 5 with other arthritides) were included. At baseline, DCE-MRI was performed on an inflamed knee joint of each patient. These images were used to calculate the K(trans) (volume transfer constant between the plasma and extracellular extravascular space [EES]), the kep (transfer constant between the EES and plasma), and the ve (fractional volume of the EES). Second, markers of disease activity were collected. Finally, vascularity was evaluated by immunohistochemical analysis of synovial tissue samples obtained from the inflamed knee joints, using antibodies to detect von Willebrand factor (vWF), a marker of ECs., Results: The 3 PKM parameters differed significantly between diagnostic groups at baseline, with the highest K(trans) value being observed in patients with SpA (median 0.050/minute, interquartile range [IQR] 0.041- 0.069). Furthermore, the K(trans) , kep , and ve values correlated significantly with markers of disease activity. Finally, the PKM parameters K(trans) and kep , but not ve , correlated significantly with synovial expression of vWF (r = 0.647, P = 0.004 for K(trans) ; r = 0.614, P = 0.007 for kep ; r = 0.398, P = 0.102 for ve )., Conclusion: These results suggest that the K(trans) , kep , and ve can be used to detect synovial inflammation in patients with early arthritis, and these PKM parameters may be helpful in differential diagnosis. This approach may also be useful in translational research analyzing tissue microcirculation and angiogenesis., (© 2016, American College of Rheumatology.)

Objective: To investigate changes in magnetic resonance imaging (MRI)-assessed inflammation and structural lesions in the sacroiliac (SI) joints during treatment with adalimumab versus placebo., Methods: In a 48-week double-blind, placebo-controlled trial, 52 patients with spondyloarthritis were randomized to receive subcutaneous injections of either adalimumab 40 mg (n = 25) or placebo (n = 27) every other week for 12 weeks. Patients in the adalimumab group continued to receive and patients in the placebo group were switched to adalimumab 40 mg every other week for an additional 12 weeks. MRI of the SI joints was performed at weeks 0, 12, 24, and 48, and the images were assessed independently in a blinded manner using the modified Berlin and the Spondyloarthritis Research Consortium of Canada (SPARCC) MRI scores for inflammation and structural lesions of the SI joints., Results: At baseline, 56% of the adalimumab group and ∼72% of the placebo group had an MRI-assessed inflammation score of ≥1. Among the patients with inflammation at baseline, the mean percent reductions in MRI scores for inflammation from week 0 to 12 were greater in the adalimumab group compared with the placebo group (Berlin method, -62% versus -5%; SPARCC method, -58% versus -12% [both P < 0.04]). Furthermore, the mean SPARCC erosion score decreased (-0.6) and the SPARCC backfill score increased (+0.8) in the adalimumab group from week 0 to week 12. From week 12 to week 24, larger absolute reductions in the Berlin/SPARCC inflammation scores and the SPARCC erosion score and larger increases in the Berlin/SPARCC fatty lesion scores were seen in the placebo group compared with the adalimumab group. In univariate regression analyses (analysis of covariance) and multivariate stepwise regression analyses, treatment with adalimumab was independently associated with regression of the SPARCC erosion score from week 0 to 12 but not with changes in the other types of MRI lesions., Conclusion: Significant changes in the Berlin and SPARCC MRI-assessed inflammation scores and in the SPARCC MRI-assessed erosion scores occurred within 12 weeks after initiation of adalimumab. Tumor necrosis factor inhibitor treatment was associated with resolution of erosions and the development of backfill., (© 2016, American College of Rheumatology.)

Objectives: Precursor Th17 lineage cells expressing CD161 are implicated in Rheumatoid Arthritis (RA) pathogenesis. CD4+CD161+ T-cells accumulate in RA joints and may acquire a non classical Th1 phenotype. The endogenous ligand for CD161 is lectin-like transcript 1 (LLT1). CD161/LLT1 ligation may co-stimulate T-cell IFN-γ production. We investigated the presence and identity of LLT1-expressing cells in RA synovial fluid (SF) and synovial tissue (ST). We also assessed levels of soluble LLT1 (sLLT1) in different phases of RA development., Methods: Paired samples of peripheral blood mononuclear cells (MC) and SFMC (n = 14), digested ST cells (n = 4) and ST paraffin sections (n = 6) from late-stage RA were analyzed for LLT1 expression by flow cytometry and immunohistochemistry. sLLT1 was measured using a sandwich ELISA. Sera and SF from late-stage RA (n = 26), recently diagnosed RA patients (n = 39), seropositive arthralgia patients (SAP, n = 31), spondyloarthropathy patients (SpA, n = 26) and healthy controls (HC, n = 31) were assayed., Results: In RA SF, LLT1 was expressed by a small proportion of monocytes. In RA ST, LLT1-expressing cells were detected in the lining, sublining layer and in areas with infiltrates. The LLT1 staining pattern overlapped with the CD68 staining pattern. FACS analysis of digested ST confirmed LLT1 expression by CD68+ cells. Elevated systemic sLLT1 was found in all patient groups., Conclusions: In RA joints, LLT1 is expressed by cells of the monocyte/macrophage lineage. Serum levels of sLLT1 were increased in all patient groups (patients with early- and late-stage RA, seropositive arthralgia and spondyloarthropathy) when compared to healthy subjects.

Human leucocyte antigen (HLA)-B27 expression is correlated with spondyloarthritis (SpA), but its role in disease pathogenesis remains unclear. The aim of the study was to determine whether HLA-B27 free heavy chain (FHC) contributes to SpA pathogenesis. Flow cytometry was used to analyse the FHC expression on CD3+ and CD14+ cells in the peripheral blood (PB) and synovial fluid (SF) from SpA patients, healthy controls, and rheumatoid arthritis (RA) patients. Human monocytic U937 cell lines stably expressing enhanced green fluorescence protein (EGFP)/HLA-B27, EGFP/HLA-A2 or EGFP alone were created to further investigate the relation between HLA-B27 and FHC expression. The relative FHC level on CD14+ PB cells was significantly higher in SpA patients than in controls, but lower than on the SF cells of SpA patients. No significant correlation was found for relative FHC expression with HLA-B27 or β2-microglobulin expression. HLA-B27-transfected U937 cells expressed higher FHC levels than either EGFP/HLA-A2- or EGFP-transfected cells. HLA class I FHC expression was significantly increased on monocytes of SpA patients and HLA-B27-transfected cells, implying that FHC, perhaps mostly derived from HLA-B27, plays an important role in SpA pathogenesis., (© 2014 John Wiley & Sons Ltd.)

Background: The objective of this study was to identify leukocyte cell types found within the synovia of patients with seronegative spondylarthropathies (SpA), such as ankylosing spondylitis (AS), using transcription based analyses., Methods: Leukocyte transcriptional profiles obtained from the NCBI's gene expression omnibus and prediction analysis of microarrays (PAM) was used to identify 25-gene leukocyte metagenes. Subsequently, transcriptional profiles from murine and clinical models of AS and SpA were interrogated to characterize the local infiltration of leukocytes in SpA synovia., Results: Analysis of a proteoglycan-induced murine model of AS reveals infiltration of dendritic cells, CD4+ T cells, monocytes, and natural killer cells to the spine. In human SpA and AS patients, transcriptional analysis of synovial biopsies revealed local infiltration of dendritic cells and CD4+ T cells., Conclusions: We identified leukocyte cell types that infiltrated the synovial of SpA patients. Our results imply a role for dendritic cells and CD4+ T cells in the local inflammation that underlies pathogenesis in patients with SpA.

Arthritic lesions have been frequently diagnosed in the fossil record, with spondyloarthropathy (a type of erosive and pan-mammalian arthritis) being one of the most common types described to date for mammals, though not restricted to this group. Here, we identify spondyloarthropathy in fossil bones from the late Pleistocene in Brazil assignable to a large glyptodont individual. Bone erosions in the peripheral joints (viz., the ulna, radius, left femur and tibiae-fibulae) associated with osteosclerosis allow the diagnosis of spondyloarthropathy. The presence of osteophytes in seven bones of the forelimbs (viz., the ulna and radius) and hind limbs (viz., the tibiae-fibulae, left femur and patellae) and a subchondral cyst in one element (viz., the left femur) indicate secondary osteoarthritis. A calcified deposition on the articular surface of the left patella indicates the presence of calcium pyrophosphate deposition disease, which, like the observed osteoarthritic alterations, likely represents a complication of spondyloarthropathy. This is the first report of spondyloarthropathy for xenarthrans.

Activation of caspase-1 by NALP3 inflammasomes has been shown to be important in initiating acute gouty arthritis. The objectives of this study were to measure the levels of caspase-1 in synovial fluid in gout and various arthritides, and to elucidate the clinical significance of caspase-1 levels in synovial fluid. Caspase-1, IL-1β, IL-18, and uric acid were measured in synovial fluid from 112 patients with gout and other arthritides, such as rheumatoid arthritis, osteoarthritis, and spondyloarthropathy. Caspase-1 in synovial fluid from patients with crystal-induced arthritis, inflammatory arthritis, osteoarthritis, and spondyloarthropathy was 35.9 ± 86.7, 49.7 ± 107.7, 2.1 ± 7.0, and 152.6 ± 155.7 pg/mL, respectively. The mean level and the frequency of high levels (≥125 pg/mL) of caspase-1 in spondyloarthropathy were significantly higher than those in the other arthritides including gout. Caspase-1 was detectible in the synovial fluid of patients with the various arthritides. Contrary to our hypothesis, the caspase-1 level in the synovial fluid of patients with gout was not higher than in that of other arthritides. High levels of caspase-1 may be helpful in differentiating spondyloarthropathy from other arthritides.

The presentation of short viral peptide antigens by human leukocyte antigen (HLA) class I molecules on cell surfaces is a key step in the activation of cytotoxic T lymphocytes, which mediate the killing of pathogen-infected cells or initiate autoimmune tissue damage. HLA-B27 is a well known class I molecule that is used to study both facets of the cellular immune response. Using mass spectrometry analysis of complex HLA-bound peptide pools isolated from large amounts of HLA-B*2705(+) cells, we identified 200 naturally processed HLA-B*2705 ligands. Our analyses revealed that a change in the position (P) 2 anchor motif was detected in the 3% of HLA-B*2705 ligands identified. B*2705 class I molecules were able to bind these six GlnP2 peptides, which showed significant homology to pathogenic bacterial sequences, with a broad range of affinities. One of these ligands was able to bind with distinct conformations to HLA-B27 subtypes differentially associated with ankylosing spondylitis. These conformational differences could be sufficient to initiate autoimmune damage in patients with ankylosing spondylitis-associated subtypes. Therefore, these kinds of peptides (short, with GlnP2, and similar low affinity to all HLA-B27 subtypes tested but with unlike conformations in differentially ankylosing spondylitis-associated subtypes) must not be excluded from future researches involving potential arthritogenic peptides.

The spondyloarthropathies are a group of rheumatic diseases that are associated with inflammation at anatomically distal sites, particularly the tendon-bone attachments (entheses) and the aortic root. Serum concentrations of interleukin-23 (IL-23) are elevated and polymorphisms in the IL-23 receptor are associated with ankyosing spondylitis, however, it remains unclear whether IL-23 acts locally at the enthesis or distally on circulating cell populations. We show here that IL-23 is essential in enthesitis and acts on previously unidentified IL-23 receptor (IL-23R)(+), RAR-related orphan receptor γt (ROR-γt)(+)CD3(+)CD4(-)CD8(-), stem cell antigen 1 (Sca1)(+) entheseal resident T cells. These cells allow entheses to respond to IL-23 in vitro-in the absence of further cellular recruitment--and to elaborate inflammatory mediators including IL-6, IL-17, IL-22 and chemokine (C-X-C motif) ligand 1 (CXCL1). Notably, the in vivo expression of IL-23 is sufficient to phenocopy the human disease, with the specific and characteristic development of enthesitis and entheseal new bone formation in the initial complete absence of synovitis. As in the human condition, inflammation also develops in vivo at the aortic root and valve, which are structurally similar to entheses. The presence of these entheseal resident cells and their production of IL-22, which activates signal transducer and activator of transcription 3 (STAT3)-dependent osteoblast-mediated bone remodeling, explains why dysregulation of IL-23 results in inflammation at this precise anatomical site.

Objectives: To establish how many children with HLA B27-positive juvenile undifferentiated spondyloarthritis (JuSpA) living in southern Italy develop axial disease after 5 years of disease., Methods: All children with B27-positive enthesitis-related arthritis (ERA) consecutively seen in a 7-year period were entered in a special register and were followed prospectively. Each patient was examined at 6-month intervals, even if asymptomatic. In patients with inflammatory spinal pain and/or buttock pain, MRI of the sacroiliac joints and spine was performed. Five years after inclusion, sacroiliac joint plain radiographs were obtained and read blindly after being mixed with those of control subjects., Results: Thirteen children, 9 boys and 4 girls, with B27-positive ERA and one girl with B27-positive isolated SpA dactylitis were seen in the study period. Their median age at disease onset and at our first examination were 10 (range 2-16) and 12 years (range 3-16), respectively. During follow-up, only one patient had axial symptoms, i.e. alternate buttock pain. MRI revealed moderate bone oedema at both sacroiliac joints. After five years of disease, no patient showed reduced spinal movement. No sign of sacroiliitis was seen in any patient and control on plain films. A new MRI of the sacroiliac joints of the patient who showed bone oedema in the first years of disease was normal., Conclusions: This study confirms that the onset of axial involvement in Italian Caucasian HLA-B27 positive children with ERA is rare in the first five years of disease.

Aim: To investigate the small bowel of seronegative spondyloarthropathy (SpA) patients in order to ascertain the presence of mucosal lesions., Methods: Between January 2008 and June 2010, 54 consecutive patients were enrolled and submitted to a video capsule endoscopy (VCE) examination. History and demographic data were taken, as well as the history of non-steroidal anti-inflammatory drug (NSAID) consumption. After reading each VCE recording, a capsule endoscopy scoring index for small bowel mucosal inflammatory change (Lewis score) was calculated. Statistical analysis of the data was performed., Results: The Lewis score for the whole cohort was 397.73. It was higher in the NSAID consumption subgroup (P = 0.036). The difference in Lewis score between NSAID users and non-users was reproduced for the first and second proximal tertiles of the small bowel, but not for its distal third (P values of 0.036, 0.001 and 0.18, respectively). There was no statistical significant difference between the groups with regard to age or sex of the patients., Conclusion: The intestinal inflammatory involvement of SpA patients is more prominent in NSAID users for the proximal/mid small bowel, but not for its distal part.

Spondyloarthropathies (SpA) are commonly observed extra-intestinal manifestations of both Crohn's disease (CD) and ulcerative colitis (UC), the two major forms of inflammatory bowel diseases (IBD). However, the immunological link between these two clinical entities is still poorly understood. Several lines of evidence indicate that SpA may originate from the relocation to the joints of the immune process primarily induced in the gut. The transfer of the intestinal inflammatory process into the joints implicates that immune cells activated in the gut-draining lymph nodes can localize, at a certain point of the intestinal disease, either into the gut or into the joints. This is indicated by the overlapping expression of adhesion molecules observed on the surface of intestinal and synovial endothelial cells during inflammation. Moreover bacterial antigens and HLA-B27 expression may be implicated in the reactivation of T cells at the articular level. Finally, accumulating evidence indicates that a T helper 17 cell-mediated immune response may contribute to IBD and IBD-related SpA with a crucial role played by tumor necrosis factor-alpha in CD and to a lesser extent in UC.

Subclinical gut inflammation has been described in up to two-thirds of patients with spondyloarthropathies (SpA). Arthritis represents an extra-intestinal manifestation of several gastrointestinal diseases, including inflammatory bowel disease (IBD), Whipple's disease, Behcet's disease, celiac disease, intestinal bypass surgery, parasitic infections of the gut and pseudomembranous colitis. Moreover about two-thirds of nonsteroidal anti-inflammatory drug users demonstrate intestinal inflammation. Arthritis may manifest as a peripheral or axial arthritis. The spondyloarthropathy family consists of the following entities: ankylosing spondylitis, undifferentiated spondyloarthritis, reactive arthritis, psoriatic arthritis, spondyloarthritis associated with IBD, juvenile onset spondyloarthritis. This topic reviews the major gastrointestinal manifestations that can occur in patients with SpA and in nonsteroidal anti-inflammatory drugs users.

Objective: To retrospectively evaluate the role of the various imaging techniques in the study of the sternocostoclavicular joint, in patients with spondyloarthropathies and other rheumatic conditions and to assess potential pitfalls in the radiological diagnosis., Subjects and Methods: Thirty patients, 11 male and 19 female, mean age 45 years, with involvement of the sternocostoclavicular joint as part of rheumatologic disorders (psoriatic arthritis, ankylosing spondylitis, Tietze syndrome, SAPHO syndrome, and condensing osteitis of the clavicle) were studied. Conventional radiography, CT, MRI and bone scintigraphy were performed. The following imaging findings were evaluated: soft tissue swelling, bone sclerosis, cortical bone erosions, joint space narrowing, subchondral sclerosis, periosteal new bone formation, synovial reaction and intrarticular effusion. All the images were independently reviewed by two musculoskeletal radiologists., Results: Conventional radiography demonstrated only sclerosis of the clavicula in 8 pts (26%) and the sternum in 3 pts (10%), cortical bone erosions in 7 pts (23%), joint space narrowing in 6 pts (23%) and periosteal bone formation in 2 pts (10%). At the CT examination sclerosis of the clavicula and the sternum was observed in 13 pts (44%), cortical bone erosions in 22 pts (76%), joint space narrowing in 10 pts (34%), ligament ossification in 12 pts (41%), subchondral sclerosis in 9 pts (34%) and periosteal bone formation in 10 pts (34%). The MRI was the most sensitive technique in the evaluation of the soft tissue swelling in 9 pts (56%), intrarticular effusion in 13 pts (81%) and synovial reaction in 13 pts (81%). Finally, bone scintigraphy showed an increased uptake at the sterno-costoclavicular joint in all patients who underwent the examination., Conclusion: The radiological evaluation of the anterior chest wall in patients with different rheumatic disorders represents a problem of difficult diagnostic evaluation both for the anatomic region complexity and for the variability of the radiographic findings. The integrated use of X-ray, CT, MRI and nuclear medicine is suggested to avoid misdiagnosis.

The purpose of this study was to analyze the expression of the two proinflammatory cytokines IL-20 and IL-24 and their shared receptors in rheumatoid arthritis and spondyloarthropathy. IL-20 was increased in plasma of rheumatoid arthritis patients compared with osteoarthritis patients and IL-24 was increased in synovial fluid and plasma of rheumatoid arthritis and spondyloarthropathy patients compared with osteoarthritis patients. IL-20 and IL-24 mRNA was only present at low levels in the synovium. In the synovial membrane, IL-20 protein was present in mononuclear cells and neutrophil granulocytes whereas IL-24 protein was observed in endothelial cells and mononuclear cells. IL-20 receptor type 1 and IL-22 receptor were expressed by granulocytes in the synovial fluid. In synovial fluid mononuclear cell cultures, stimulation with recombinant human IL-20 or recombinant human IL-24 induced monocyte chemoattractant protein 1 (CCL2/MCP-1) secretion, but not tumour necrosis factor alpha mRNA synthesis or IL-6 secretion. Both IL-20 and IL-24 showed correlations to CCL2/MCP-1 in plasma from rheumatoid arthritis and spondyloarthropathy patients. This study associates IL-20 and IL-24 to the synovium of rheumatoid arthritis and spondyloarthropathy and results indicate that the two cytokines contribute to disease pathogenesis through recruitment of neutrophil granulocytes and induction of CCL2/MCP-1.

Objective: To investigate the molecular mechanism responsible for the reduced capacity of dendritic cells (DCs) from HLA-B27-transgenic rats to form conjugates with naive T cells., Methods: We monitored interactions between DCs derived from HLA-B27-transgenic, HLA-B7-transgenic control, and nontransgenic rats and naive CD4+ T cells. Chemoattraction was studied in Transwell assays, and the formation of an immunologic synapse was examined by videomicroscopy and electron microscopy. Involvement of specific molecules in the defective interaction was examined in antibody-blocking assays., Results: T cells migrated normally toward B27 DCs, but upon contact, the frequency of T cells undergoing a Ca2+ response was decreased, indicating impaired immunologic synapse formation. The immunologic synapse formed between B27 DCs and T cells appeared to be normal, as assessed by electron microscopy and by the Ca2+ response. Blocking lymphocyte function-associated antigen 1 on T cells or blocking activated leukocyte cell adhesion molecules on DCs inhibited an equivalent proportion of conjugates from forming between B27 or control DCs and T cells, whereas blocking CD86 on DCs and blocking CD28, CD2, or CD4 on T cells inhibited a greater number of conjugates from forming with control DCs, indicating specific involvement of costimulatory molecules in the reduced formation of conjugates with B27 DCs. Mature B27 molecules on the DC surface were responsible for this decreased formation of conjugates., Conclusion: In the HLA-B27-transgenic rat model of spondylarthropathy, mature B27 molecules expressed by DCs impair the formation of an antigen-independent immunologic synapse with naive CD4+ T cells by interfering with the engagement of costimulatory molecules. This phenomenon could potentially affect the production and/or maintenance of regulatory T cells and contribute to the expansion of pathogenic CD4+ T cells.

Objective: Because different tumor necrosis factor alpha (TNFalpha) blockers may have distinct immunomodulatory effects on specific disease manifestations, the present study was carried out to investigate the immunomodulating effects of etanercept on peripheral synovitis in the spondylarthropathies (SpA)., Methods: Peripheral joint disease was assessed clinically, histologically, and radiologically in a prospective 2-year study of 20 patients with SpA treated with etanercept. Synovial tissue biopsy samples obtained at weeks 0, 12, and 52 were analyzed by histology and immunohistochemistry for the extent of inflammation, changes to tissue architecture, and matrix degradation. Serum levels of myeloid-related protein 8 (MRP-8)/MRP-14, matrix metalloproteinase 3 (MMP-3), and cartilage oligomeric matrix protein (COMP) were determined by enzyme-linked immunosorbent assay., Results: Etanercept induced a rapid and sustained clinical improvement of peripheral joint disease. Histologic synovitis was down-regulated, with a profound reduction in global cellular infiltration and T lymphocytes, but not B lymphocytes. The most prominent change in markers of inflammation was a reduction in the different macrophage subsets (CD68, CD163, MRP-8, and MRP-14), but this was not paralleled by a decrease in serum MRP-8/MRP-14. Structural changes included normalization of lining layer hyperplasia and a moderate reduction in vascularity. However, no effect on the microarchitecture of lymphoid aggregates was observed. In terms of an effect on matrix degradation, the synovial expression of MMP-3 and MMP-9 was down-modulated in correlation with a rapid and profound decrease in serum MMP-3. At week 52, serum COMP levels were also reduced. No significant radiologic disease progression was observed in these patients over a 2-year period., Conclusion: Use of etanercept effectively down-modulated the immunopathologic processes of SpA synovitis, both in the short term and in the long term.

Objective: To characterize experimentally induced spondylarthropathy (SpA) in arthritis-susceptible inbred mice and in their F(1) and F(2) hybrid generations of susceptible and resistant mouse strains., Methods: SpA was induced in susceptible BALB/c and C3H/HeJCr (C3H) strains of mice, and in their F(1) and F(2) generations derived from intercrosses with arthritis- and/or spondylitis-resistant DBA/2 and DBA/1 parent strains, by systemic immunization with cartilage proteoglycan (PG) aggrecan. The incidence and severity of PG-induced spondylitis (PGIS) were scored histologically, and these scores for spine involvement were correlated with serum antibody and cytokine levels and with in vitro T cell responses to cartilage PG., Results: PGIS was induced by systemic immunization with cartilage PG in adjuvant, and approximately 60-70% of susceptible mouse strains and their F(2) hybrids developed spondylitis either with or without arthritis. Adjuvants, particularly those activating the innate immune system and enforcing the Th1 dominance, had significant effects on the outcome and progression of SpA. The DBA/1 strain appeared to carry genes protecting this strain and its F(1) and F(2) hybrids from spondylitis, whereas the DBA/2 strain, although resistant to PGIS, harbored genes permitting PGIS in its hybrid generations. Arthritis- and/or spondylitis-susceptible BALB/c and C3H parent strains and their F(2) hybrids exhibited the highest incidence and severity of spondylitis., Conclusion: PGIS, a murine model of autoimmune spondylitis, shows similarities to ankylosing spondylitis. Segregation of susceptibility to PG-induced arthritis (PGIA) from that to PGIS in different genetic crosses suggests that PGIA and PGIS are separate diseases. Therefore, this model allows for the elucidation of genetic components involved in the etiology of SpA, independent of those controlling the susceptibility to PGIA.

Objective: To examine whether spondylarthropathy (SpA) disease manifestations would combine in any ordered pattern among patients from SpA multiplex families., Methods: SpA patients (n = 540) belonging to 190 multiplex families were thoroughly investigated. Clinical data was collected, systematic pelvic radiographs were taken, and HLA-B27 status was determined. The patterns of SpA manifestations were examined by several methods, including multiple correspondence analysis, nonhierarchical and hierarchical clustering, and discriminant analysis., Results: The nonhierarchical cluster analysis allowed us to classify patients, independent of disease duration, into 2 major groups of comparable size. Group A contained a majority of the women, whereas group B predominantly consisted of men. The 2 groups were very similar regarding axial symptoms, radiographic sacroiliitis, and uveitis. Group B was characterized by a younger age at onset and a higher frequency of clinical enthesitis, peripheral arthritis, dactylitis, psoriasis, and inflammatory bowel disease than group A. Patients belonging to those groups exhibited some degree of familial aggregation, thereby supporting their intrinsic validity., Conclusion: Pattern analysis of SpA manifestations among familial SpA allowed us to recognize 2 main clusters independent of disease duration. Furthermore, there was a trend toward aggregation by cluster among families, suggesting that they are determined by specific genetic factors. These clusters may indeed correspond to different severity patterns.

Considering the relation between synovial inflammation and global disease activity in rheumatoid arthritis (RA) and the distinct but heterogeneous histology of spondyloarthropathy (SpA) synovitis, the present study analyzed whether histopathological features of synovium reflect specific phenotypes and/or global disease activity in SpA. Synovial biopsies obtained from 99 SpA and 86 RA patients with active knee synovitis were analyzed for 15 histological and immunohistochemical markers. Correlations with swollen joint count, serum C-reactive protein concentrations, and erythrocyte sedimentation rate were analyzed using classical and multiparameter statistics. SpA synovitis was characterized by higher vascularity and infiltration with CD163+ macrophages and polymorphonuclear leukocytes (PMNs) and by lower values for lining-layer hyperplasia, lymphoid aggregates, CD1a+ cells, intracellular citrullinated proteins, and MHC-HC gp39 complexes than RA synovitis. Unsupervised clustering of the SpA samples based on synovial features identified two separate clusters that both contained different SpA subtypes but were significantly differentiated by concentration of C-reactive protein and erythrocyte sedimentation rate. Global disease activity in SpA correlated significantly with lining-layer hyperplasia as well as with inflammatory infiltration with macrophages, especially the CD163+ subset, and with PMNs. Accordingly, supervised clustering using these synovial parameters identified a cluster of 20 SpA patients with significantly higher disease activity, and this finding was confirmed in an independent SpA cohort. However, multiparameter models based on synovial histopathology were relatively poor predictors of disease activity in individual patients. In conclusion, these data indicate that inflammatory infiltration of the synovium with CD163+ macrophages and PMNs as well as lining-layer hyperplasia reflect global disease activity in SpA, independently of the SpA subtype. These data support a prominent role for innate immune cells in SpA synovitis and warrant further evaluation of synovial histopathology as a surrogate marker in early-phase therapeutic trials in SpA.

At present only few biological data are available to indicate whether psoriatic arthritis (PsA) is part of the spondyloarthropathy (SpA) concept, whether it is a separate disease entity or a heterogeneous disease group with oligoarticular/axial forms belonging to SpA and polyarticular forms resembling rheumatoid arthritis (RA). To address this issue with regard to peripheral synovitis, we compared the synovial characteristics of PsA with those of ankylosing spondylitis (AS)/undifferentiated SpA (USpA) and RA, and compared the synovium of oligoarticular versus polyarticular PsA. Synovial biopsies were obtained from patients with RA, nonpsoriatic SpA (AS + USpA), and oligoarticular and polyarticular PsA. The histological analysis included examination(s) of the lining layer thickness, vascularity, cellular infiltration, lymphoid aggregates, plasma cells and neutrophils. Also, we performed immunohistochemical assessments of CD3, CD4, CD8, CD20, CD38, CD138, CD68, CD163, CD83, CD1a, CD146, alphaVbeta3, E-selectin, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, S100A12, intracellular citrullinated proteins and major histocompatibility complex (MHC)-human cartilage (HC) gp39 peptide complexes. Comparing SpA (PsA + AS + USpA) with RA, vascularity, and neutrophil and CD163+ macrophage counts were greater in SpA (P < 0.05), whereas lining layer thickness and the number of CD83+ dendritic cells were greater in RA (P < 0.05). In RA, 44% of samples exhibited positive staining for intracellular citrullinated proteins and 46% for MHC-HC gp39 peptide complexes, whereas no staining for these markers was observed in SpA samples. We excluded influences of disease-modifying antirheumatic drug and/or corticosteroid treatment by conducting systematic analyses of treated and untreated subgroups. Focusing on PsA, no significant differences were observed between PsA and nonpsoriatic SpA. In contrast, vascularity (P < 0.001) and neutrophils were increased in PsA as compared with RA (P = 0.010), whereas staining for intracellular citrullinated proteins and MHC-HC gp39 peptide complexes was exclusively observed in RA (both P = 0.001), indicating that the same discriminating features are found in PsA and other SpA subtypes compared with RA. Exploring synovial histopathology between oligoarticular and polyarticular PsA, no significant differences were noted. Moreover, intracellular citrullinated proteins and MHC-HC gp39 peptide complexes, which are specific markers for RA, were observed in neither oligoarticular nor polyarticular PsA. Taken together, these data indicate that the synovial histopathology of PsA, either oligoarticular or polyarticular, resembles that of other SpA subtypes, whereas both groups can be differentiated from RA on the basis of these same synovial features, suggesting that peripheral synovitis in PsA belongs to the SpA concept.

Objective: The Achilles tendon insertion is associated with a complex of adjacent fibrocartilages, a bursa, and a fat-pad, and is functionally much more than a focal insertion. This has important implications for a better understanding of the spondylarthropathies (SpA). However, the degree to which other insertions form comparable "enthesis organs" has not been established. The aim of this study was to demonstrate the applicability of the enthesis organ concept to other insertion sites., Methods: Both joint-related (articular) and extraarticular entheses were removed from 28 sites in the limbs of formalin-fixed cadavers (age at death 70-101 years) that had been donated for anatomic study. The samples were prepared for paraffin histologic analysis and sectioned longitudinally. The presence and extent of enthesis organs was evaluated at each site in serial sections stained with Masson's trichrome and toluidine blue., Results: Articular enthesis organs were found at 14 entheses, including the attachments of the digital extensor tendons and collateral ligaments, the cruciate ligaments, tibialis anterior, the lateral collateral ligament of the knee, and the popliteal tendon. Extraarticular enthesis organs were seen at 2 sites, the biceps brachii and patellar tendon insertions. In all enthesis organs, sesamoid and/or periosteal fibrocartilage was present in close association with synovium., Conclusion: The concept of an enthesis organ is of general significance in understanding attachment sites and may explain the diverse pathologic changes, including synovitis, bursitis, and extracapsular changes, seen adjacent to tendon/ligament entheses in SpA. These findings may provide insight into the reason the target tissues in SpA are apparently so diverse., (Copyright 2004 American College of Rheumatology)

Objective: To explore prospectively the value of synovial histopathology in comparison with the value of classic parameters for diagnostic classification of spondylarthropathy (SpA) and rheumatoid arthritis (RA) in patients with an atypical disease presentation., Methods: Synovial biopsy samples were obtained from 154 consecutive patients presenting for diagnostic evaluation; 67 patients fulfilled the classification criteria for RA, SpA, or other well-defined disease at the time of arthroscopy (cohort 1), and an additional 53 patients were classified after a full diagnostic reevaluation at 6 months (cohort 2). Synovial parameters with diagnostic value were identified in cohort 1 and were compared prospectively with classic diagnostic parameters in cohort 2., Results: Staining with anticitrulline, staining with monoclonal antibody 12A (recognizing HLA-DR shared epitope-human cartilage glycoprotein 39(263-275) complexes), and crystal deposition had positive predictive values (PPVs) for diagnosis of >90% in patients with an atypical disease presentation (cohort 2). Using these 3 parameters, a diagnosis was predicted by synovial histopathology in 39.6% of cohort 2 patients and turned out to be correct in 90.5% of these patients at 6 months of followup. Using a multiparameter model rather than single histopathologic parameters, even better results were obtained, with a diagnostic prediction in 79.2% of samples and a PPV of 81.0%. In comparison, a similar multiparameter model using classic diagnostic criteria rather than synovial histopathology performed poorly in cohort 2; the sensitivity was 56.6% and the PPV was 73.3%, with an inferior capacity to predict SpA. Especially for the presence of crystals and anticitrulline staining, the analysis of synovial tissue had a clear added value to the analysis of synovial fluid or serum in patients with an atypical presentation., Conclusion: This proof-of-concept study indicates that synovial histopathology can contribute to the multiparametric diagnostic classification of inflammatory arthritis in patients with an atypical presentation.

CD25+CD4+ regulatory T cells participate in the regulation of immune responses. We recently demonstrated the presence of CD25brightCD4+ regulatory T cells with a capacity to control T cell proliferation in the joints of patients with rheumatoid arthritis. Here, we investigate a possible accumulation of these regulatory T cells in the inflamed joint of different rheumatic diseases including rheumatoid arthritis. The studies are also extended to analyze whether cytokine production can be suppressed by the regulatory T cells. Synovial fluid and peripheral blood samples were obtained during relapse from 36 patients with spondyloarthropathies, 21 adults with juvenile idiopathic arthritis and 135 patients with rheumatoid arthritis, and the frequency of CD25brightCD4+ T cells was determined. Of 192 patients, 182 demonstrated a higher frequency of CD25brightCD4+ T cells in synovial fluid than in peripheral blood. In comparison with healthy subjects, the patients had significantly fewer CD25brightCD4+ T cells in peripheral blood. For functional studies, synovial fluid cells from eight patients were sorted by flow cytometry, and the suppressive capacity of the CD25brightCD4+ T cells was determined in in vitro cocultures. The CD25brightCD4+ T cells suppressed the production of both type 1 and 2 cytokines including interleukin-17, as well as proliferation, independently of diagnosis. Thus, irrespective of the inflammatory joint disease investigated, CD25brightCD4+ T cells were reduced in peripheral blood and enriched in the joint, suggesting an active recruitment of regulatory T cells to the affected joint. Their capacity to suppress both proliferation and cytokine secretion might contribute to a dampening of local inflammatory processes.

Objective: To investigate expression of the endogenous antagonist of interleukin 18 (IL-18) bioactivity, IL-18 binding protein isoform a (IL-18BPa), in fibroblast-like synoviocytes (FLS)., Methods: Long-term cultured FLS from rheumatoid arthritis (RA), osteoarthritis (OA) and spondylarthropathy patients were analysed for spontaneous and cytokine-induced IL-18BPa expression. Messenger RNA and release of IL-18BPa were assessed by semi-quantitative and quantitative real-time reverse transcriptase-polymerase chain reaction (RT-PCR) as well as immunoblot analysis, respectively., Results: All investigated FLS cultures expressed low amounts of IL-18BPa transcripts. However, there was no detectable release of IL-18BPa from unstimulated synoviocytes. Of the investigated cytokines, only interferon (IFN)-gamma markedly up-regulated IL-18BPa mRNA levels. Induction was accompanied by release of IL-18BPa immunoreactivity from FLS. Conditioned media from IFN-gamma-stimulated FLS cultures reduced IL-12/IL-18-dependent IFN- production by peripheral blood mononuclear cells., Conclusion: The present data imply that IFN--activated synoviocytes mediate a negative feedback loop via IL-18BPa, which may limit IL-18 biological activity in arthritis.

Objective: Stylohyoid apparatus might be an anatomic region in the cervical spine involved by enthesopathy. The aim of this study was to assess the elongation and/or ossification at the stylohyoid apparatus in the degenerative or inflammatory diseases such as ankylosing spondylitis (AS), psoriatic arthropathy (PsA) and cervical spondyloarthrosis (CS) in which cervical spine involvement can be seen., Methods: Twenty-eight patients with AS, 25 patients with PsA, 31 patients with CS and 50 controls who did not have any complaints or symptoms related with elongated styloid process (SP) were included in the study. On the lateral cervical radiographs, the anterior and posterior aspects of each vertebral body and intervertebral disk were carefully evaluated for the presence and severity of syndesmophytes, osteophytes or ossification of the adjacent longitudinal ligaments in the patient group. The entire osseous length of the SP was measured on the lateral and lateral oblique mandibular or cervical views or the anteroposterior views radiographs in the patients and controls., Results: There were statistically significant differences between the patients with AS and control group and between the patients with PsA and control group with respect to the length of SP. The dimension of syndesmophytes or ligamentous ossification of the cervical spine involving C5-6 intervertebral disk level were significantly correlated with length of SP in the patients with AS., Conclusion: Elongated SP might be another manifestation of enthesopaty in cervical spine of the spondyloarthropathies.

Objective: To study the role of biomechanical factors and HLA-B27 in plantar fasciitis., Methods: T1-weighted and T2 spectral presaturation with inversion recovery (fat suppressed) magnetic resonance imaging (MRI) sequences of the plantar fascia insertion and adjacent bone were performed on 28 patients with plantar fasciitis; 17 had spondylarthropathy (SpA)-associated disease, and 11 had mechanically induced disease. The relationship between the degree of bone edema, scored on a semiquantitative scale (from absent to severe), and the patient's HLA-B27 status was determined., Results: On MRI, edema within the soft tissue at the enthesis was evident in both groups. Bone edema in the adjacent calcaneum was evident in 64.7% (11 of 17) of patients with SpA and in 45% (5 of 11) of those with mechanically induced disease (P = 0.441). HLA-B27 was identified in 9 (53%) of the patients with SpA but in none (0%) of those with mechanically induced disease. All 6 of the SpA patients with extensive bone edema but none of the 5 SpA patients with mild bone edema were HLA-B27 positive (P = 0.002)., Conclusion: The association of HLA-B27 with bone pathology in early enthesitis may have implications for a better understanding of the pathogenesis of SpA.