Peripheral Joint Inflammation Research Articles

AB0905 Late-onset spondyloarthropathy mimicking polymalgia rheumatica: Evidence from MRI

BackgroundPolymyalgia rheumatica (PMR) is a clinical syndrome, typically affecting older people, presenting with inflammatory musculoskeletal symptoms. Late onset rheumatoid arthritis is a well-known PMR mimic, but spondyloarthropathy (SpA) can also...

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

ObjectivesA pivotal MRI study of knee arthritis indicated that enthesitis was more frequently observed in established spondyloartritis (SpA) than rheumatoid arthritis (RA). Subsequent MRI and ultrasound studies, however, failed to...

Spondyloarthritiden - das neue Konzept

The characteristic features of spondyloarthritis are inflammation in the axial skeleton (sacroiliitis, spondylitis) and inflammation in peripheral joints (arthritis) and entheses (enthesitis). According to the leading clinical symptom SpA is today differentiated in the either predominant axial or the peripheral form. The axial SpA are further subdivided in ankylosing spondylitis and non-radiographic axial SpA. This subset is characterized by the absence of structural changes on conventional x-rays. In this review we describe the clinical symptoms, the diagnosis and therapy of patients with axial SpA.

Psoriatic arthritis: imaging techniques

Imaging techniques to assess psoriatic arthritis (PsA) include radiography, ultrasonography (US), magnetic resonance imaging (MRI), computed tomography (CT) and bone scintigraphy. The radiographic hallmark of PsA is the combination of destructive changes (joint erosions, tuft resorption, osteolysis) with bone proliferation (including periarticular and shaft periostitis, ankylosis, spur formation and non-marginal syndesmophytes). US has an increasing important role in the evaluation of PsA. In fact, power Doppler US is useful mainly for its ability to assess musculoskeletal (joints, tendons, entheses) and cutaneous (skin and nails) involvement, to monitor efficacy of therapy and to guide steroid injections at the level of inflamed joints, tendon sheaths and entheses. MRI allows direct visualization of inflammation in peripheral and axial joints, and peripheral and axial entheses, and has dramatically improved the possibilities for early diagnosis and objective monitoring of the disease process in PsA. MRI has allowed explaining the relationships among enthesitis, synovitis and osteitis in PsA, supporting a SpA pattern of inflammation where enthesitis is the primary target of inflammation. CT has little role in assessment of peripheral joints, but it may be useful in assessing elements of spine disease. CT accuracy is similar to MRI in assessment of erosions in sacroiliac joint involvement, but CT is not as effective in detecting synovial inflammation. Bone scintigraphy lacks specificity and is now supplanted with US and MRI techniques.

Interferon‐γ regulates discordant mechanisms of uveitis versus joint and axial disease in a murine model resembling spondylarthritis

The spondylarthritides (such as ankylosing spondylitis) are multisystem inflammatory diseases that frequently result in uveitis. Despite the common co-occurrence of uveitis with arthritis, there has been no explanation for the susceptibility of the eye to inflammation. Using an innovative intravital videomicroscopic approach, we discovered the coexistence of uveitis with axial and peripheral joint inflammation in mice immunized with cartilage proteoglycan (PG). The aim of this study was to elucidate the characteristics of uveitis and test the impact of interferon-γ (IFNγ) deficiency on the eye versus the joint and spine. Female T cell receptor (TCR)-transgenic mice or IFNγ-knockout mice crossed to TCR-transgenic mice were immunized with PG. Uveitis was assessed by intravital videomicroscopy and histology. The clinical and histopathologic severity of arthritis and spondylitis were evaluated. The bone remodeling process within the spine was assessed by whole-body near-infrared imaging. Immunoblotting and immunofluorescence staining were used to examine the expression of PG and ADAMTS-5 and to examine the cellular composition of eyes with uveitis. PG neoepitopes along with the aggrecanase ADAMTS-5 were present in the eye, as they were the joint. Anterior uveitis developed in response to PG immunization. The cellular infiltrate consisted mainly of neutrophils and eosinophils. Unexpectedly, IFNγ deficiency markedly exacerbated uveitis while ameliorating joint and spine disease, indicating divergent mechanisms that drive diseases in the eye versus the joints and spine. This study provides the first detailed description of a murine disease model in which uveitis coincides with arthritis and spondylitis. Our observations provide a great opportunity for understanding the pathogenesis of a relatively common but poorly understood disease.

Collagen antibody-induced arthritis (CAIA) leads to evoked and ongoing persistent pain-like behavior, but transient joint inflammation

Backgroundand objectivesJoint pain is one of the most common types of persistent pain, and it is frequently reported to be a bothersome symptom by rheumatoid arthritis (RA) patients. RA is...

Animal Models of Spondyloarthritis

The clinical spectrum of spondyloarthritis is included various diagnostic entities that share clinical, genetic and pathological characteristics. As human tissue specimens of the sacroiliac joints are very difficult to obtain, most of the new concepts have emerged from different animal models of disease. Animal models are available for the study of several different aspects of spondyloarthritis. The models include human leukocyte antigen (HLA) B-27 based on transgenic rat and mouse models, inflammationdriven models, and models of ankylosing enthesitis. Areas of investigation to which these models contribute include the role of HLA B-27, process of spinal and peripheral joint inflammation and calcification, immune responses to candidate antigens and the role of tumor necrosis factor.

Relapsing Polychondritis-associated Refractory Airway Stenosis

Relapsing polychondritis (RP) is a rare and debilitating rheumatic disease featuring recurrent and at times disseminated inflammation of cartilaginous structures, including auricles, eyes, peripheral joints, and airway1. Symptomatic airway compromise in RP is considered a common but severe cause of morbidity and mortality, which necessitates aggressive medical and bronchoscopic intervention2. We describe a refractory airway stenosis in a young patient with RP. A 24-year-old man attended our clinic because of progressive pain and swelling in his left ear that had progressed to the right side with tenderness in his right eye for 1 year. He had been diagnosed with auricle chondritis with scleritis …

Evidence for the prevention of enthesitis in HLA-B27/hβ2m transgenic rats treated with a monoclonal antibody against TNF-α

Transgenic rats with high expression of HLA-B27 and human β2-microglobulin (B27TR) develop a multisystem inflammatory disease resembling human inflammatory bowel disease (IBD) and spondyloarthropaties (SpA). Tumour necrosis factor α (TNF-α) has a crucial role in sustaining chronic inflammation in the gut and joints. The aim of this work was to evaluate whether TNF-α blockade could prevent or reduce the inflammation of peripheral joints in B27TR. A first group of 9-week-old B27TR received an anti-TNF-α monoclonal antibody (mAb) or an isotypic IgG2a,k up to the age of 18 weeks. An untreated group was monitored up to the age of 18 weeks and then randomly assigned to a 9-week treatment with anti-TNF-α mAb or IgG2a,k. Each rat was monitored for clinical IBD and peripheral joint manifestations. After sacrifice the colon and hind paws were examined for macroscopical and microscopical pathological changes. Early TNF-α blockade prevented, and late treatment improved IBD signs in B27TR. Erythema, oedema, inflammatory infiltrate close to the tendons and enthesis, proliferating chondrocyte-like cells, signs of new endochondral bone ossification and bone erosion were observed in peripheral joints of four out of six IgG2a,k-treated B27TR, both at 18 and 27 weeks. Immunopositivity for phosphorylated Smad1/5/8 indicated that the process of joint remodelling was activated in B27TR. Some entheses showed chondroid nodules. Anti-TNF-α treatment reduced inflammation and preserved the enthesis organization in most animals. Occasional and transient erythema and oedema were still present in three of six of the late anti-TNF-α-treated animals. Smad1/5/8 signalling was not inhibited by late anti-TNF-α treatment. In B27TR, articular involvement follows IBD onset and develops at entheses. Early TNF-α blockade prevents the onset of IBD and consequently the development of enthesitis in peripheral joints in the B27TR model of human SpA.

Magnetic resonance imaging in spondyloarthritis – how to quantify findings and measure response

Sensitive and reliable tools for monitoring disease activity and damage, and for prognostication, are essential in the management of patients with spondyloarthritis, including ankylosing spondylitis and psoriatic arthritis. Magnetic resonance imaging (MRI) allows direct visualisation of inflammation in peripheral and axial joints, and peripheral and axial entheses, and has dramatically improved the possibilities for early diagnosis and objective monitoring of the disease process in spondyloarthritis. Truthful, discriminative and feasible scoring systems are available for the assessment of inflammatory activity in the spine and sacroiliac joints in axial spondyloarthritis and in the hands of patients with peripheral psoriatic arthritis. Various systems for assessment of damage in axial and peripheral joints are available, but further studies are needed to document their value in clinical trials and clinical practice. The present article reviews key aspects of the status and recent important advances in MRI in spondyloarthritis, focussing on available MRI tools for assessing activity and damage in peripheral and, particularly, axial joints.

CYCLOSPORIN A (SANDIMMUN NEORAL) IN THERAPY FOR PSORIASIS AND PSORIATIC ARTHRITIS

The involvement of immune mechanisms in the pathogenesis of psoriatic arthritis (PA) is noted to give grounds to use immunoactive compounds (disease- modifying agents - basic anti-inflammatory drugs -BAIDs), such as cyclosporin A (CsA), in this disease. The data available in the literature permit a high assessment of CsA as one of the BAIDs in the treatment of PA and psoriasis. CsA is stated to monitor the course of this disease, acts on inflamed peripheral joints, decreases the clinical and laboratory activity of PA, positively affects the PA-afflicted skin, and can induce remission of psoriasis.

Dendritic cells from spondylarthritis‐prone HLA–B27–transgenic rats display altered cytoskeletal dynamics, class II major histocompatibility complex expression, and viability

Spondylarthritis (SpA) is characterized by spinal and peripheral joint inflammation, frequently combined with extraarticular manifestations. Despite the well-established association of SpA with the class I major histocompatibility complex (MHC) allele HLA-B27, there are still different, parallel hypotheses on the relationship between HLA-B27 and disease mechanisms. The present study was undertaken to investigate several characteristics of mature dendritic cells (DCs), which are believed to be essential for triggering disease in a model of SpA in HLA-B27-transgenic rats. We combined different whole-proteome approaches (2-dimensional polyacrylamide gel electrophoresis and iTRAQ) to define the most aberrant molecular processes occurring in spleen DCs. Videomicroscopy and flow cytometry were used to confirm both cytoskeletal and class II MHC expression deficiencies. Our proteome studies provided evidence of up-regulation of proteins involved in class I MHC loading, and unfolded protein response, along with a striking down-regulation of several cytoskeleton-reorganizing proteins. The latter result was corroborated by findings of deficient motility, altered morphology, and decreased immunologic synapse formation. Furthermore, class II MHC surface expression was reduced in DCs from B27-transgenic rats, and this could be linked to differences in class II MHC-induced apoptotic sensitivity. Finally, we found reduced viability of the CD103+CD4- DC subpopulation, which likely exerts tolerogenic function. Taken together, our findings have different important implications regarding the physiology of B27-transgenic rat DCs, which have a putative role in spontaneous disease in these rats. In particular, the reduced motility and viability of putatively tolerogenic CD4+ DCs could play an important role in initiating the inflammatory process, resulting in SpA.

Other Future Targeting Therapy Beyond TNF-α Inhibitor in Patients with Spondyloarthropathy

Spondyloarthropathy defines a group of diseases characterized by chronic inflammation of axial or peripheral joints with a variety of mucocutaneous, ophthalmic lesions. Evidence showed that these disorders are autoimmune in origin with T cells, B cells and monocytes/macrophages playing major roles. In addition, cytokines secreted by these immune cells also were considered indispensible to the triggering of these diseases. Before the era of biological agents, non-steroidal anti-inflammatory drugs (NSAIDS) were only drugs proved to be useful in treating patients with spondyloarthropathy. None of disease-modifying anti-rheumatic drugs (DMARDS) were considered effective in modification of disease course, especially in axial symptom. Thanks to the invention of biological agents, both clinical and radiological parameters were found to improve after targeting therapy. The efficacy of tumor necrosis factor blockage in patients with spondyloarthropathy is almost as effective as in patients with rheumatoid arthritis. New insight of pathogenesis uncovered novel molecules involved, which were potential targets in the future.

Absence of a classically activated macrophage cytokine signature in peripheral spondylarthritis, including psoriatic arthritis

Peripheral spondylarthritis (SpA) is characterized by macrophages that express CD163, a marker of alternative activation (M2). The purpose of this study was to assess whether this differential infiltration with macrophage subsets was associated with a different local inflammatory milieu in SpA as compared with rheumatoid arthritis (RA). The effect of SpA and RA synovial fluid (SF) on macrophage polarization was tested in vitro on normal peripheral blood monocytes. SF levels of classically activated macrophage (M1)-derived and alternatively activated macrophage (M2)-derived mediators were analyzed by enzyme-linked immunosorbent assay and multiparameter Luminex bead assay in 47 patients with non-psoriatic SpA, 55 with RA, and 15 with psoriatic arthritis (PsA). Paired synovial biopsy samples were analyzed histologically. SF from SpA patients promoted preferential expression of the M2 markers CD163 and CD200R in vitro, even if SF levels of the prototypical M2-polarizing factors (interleukin-4 [IL-4], IL-13, and IL-10) were not increased as compared with those in RA SF. Despite a similar degree of overall joint inflammation in SpA and RA, SpA synovitis displayed strongly reduced SF levels of M1-derived, but not M2-derived, mediators, such as tumor necrosis factor alpha (TNFalpha), IL-1beta, IL-12p70, and interferon-gamma-inducible protein 10. SF levels of M1-derived mediators correlated well with peripheral joint inflammation in RA, but neither these mediators nor IL-1alpha and IL-17 did so in SpA. Of interest, the SF cytokine profile in PsA, a more destructive subtype of SpA, was similar to that in non-psoriatic SpA. The local inflammatory milieu is clearly different in SpA as compared with RA peripheral arthritis. Synovitis in SpA, including that in PsA, is characterized by a selective decrease in M1-derived proinflammatory mediators, such as TNFalpha and IL-1beta.

The differential expressions of 78-kDa glucose-regulated protein of infiltrating plasma cells in peripheral joints with the histopathological variants of rheumatoid synovitis

IntroductionThe local production of pathogenic autoantibodies by plasma cells in synovium is one of the hallmarks of rheumatoid arthritis (RA). There may be a potential link between ectopic lymphoid neogenesis and the local autoimmunity in rheumatoid synovium. The unfolded protein response (UPR) has key roles in the development and maintenance of plasma cells secreting immunoglobulin. This study was designed to explore the potential links between the activation of the UPR of infiltrating plasma cells in inflamed peripheral joints and the histopathological variants of rheumatoid synovitis as well as the local production of pathogenic autoantibodies.MethodsThe variants of rheumatoid synovium were histopathologically classified into follicular and diffuse synovitis. Immunohistochemical and double-immunofluorescent stainings were performed to detect the expression of 78-kDa glucose-regulated protein (GRP78), a marker of activation of the UPR, in infiltrating plasma cells of synovium, and flow cytometry and immunoblotting analyses were performed to quantify GRP78 in plasma cells of synovial fluid in inflamed peripheral joints of RA. The detections were also taken in osteoarthritis (OA) as controls. The synovial fluid levels of anti-cyclic citrullinated peptide antibodies (anti-CCP) (IgG) were quantified with the enzyme-linked immunosorbent assay and corrected to those of total IgG in RA.ResultsExpressions of GRP78 were more intensive in infiltrating plasma cells in RA synovium relative to those in OA synovium (P < 0.001) and in synovium with follicular synovitis relative to that with diffuse synovitis (P < 0.001). Analyses by flow cytometry and immunoblotting showed that there was a significant upregulation of GRP78 of plasma cells from synovial fluid of RA compared with that of OA (P < 0.05) and from synovial fluid of follicular synovitis relative to that of diffuse synovitis (P < 0.05). Moreover, a positive relationship between the expression of GRP78 of plasma cells from synovial fluid and the corrected synovial levels of anti-CCP (IgG) was seen in RA (P < 0.001).ConclusionsThere may be a link between enhanced activation of the UPR of plasma cells and ectopic lymphoid neogenesis as well as the local production of anti-CCP (IgG) in inflamed peripheral joints of RA.

Clinical features and epidemiology of spondyloarthritides associated with inflammatory bowel disease

Inflammation of axial and/or peripheral joints is one of the most frequent extra-intestinal manifestations complicating the clinical course and therapeutic approach in inflammatory bowel diseases (IBD). The frequency of these complications seems to be similar for both diseases, Crohn's disease and ulcerative colitis. Arthritis associated with IBD belongs to the category of spondyloarthropathies. Axial involvement ranges from isolated inflammatory back pain to ankylosing spondylitis, whereas peripheral arthritis is noted in pauciarticular and in polyarticular disease. Asymptomatic radiological involvement of the sacroiliac joints is reported to occur in up to 50% of patients. Other musculoskeletal manifestations such as buttock pain, dactylitis, calcaneal enthesitis, and thoracic pain are frequently underdiagnosed and, consequently, are not treated appropriately. Several diagnostic approaches and criteria have been proposed over the past 40 years in an attempt to correctly classify and diagnose such manifestations. The correct recognition of spondylarthropathies needs an integrated multidisciplinary approach in order to identify common therapeutic strategies, especially in the era of the new biologic therapies.

Infiltrations of plasma cells in synovium are highly associated with synovial fluid levels of APRIL in inflamed peripheral joints of rheumatoid arthritis

Infiltration of plasma cells can be a histopathological hallmark of articular synovium with rheumatoid arthritis (RA). A proliferation-inducing ligand (APRIL) may have key roles in homeostasis and development of B cells, and the differentiation of B cells into plasma cells. This study was designed to explore the relationships between the infiltrations of plasma cells in synovium and the synovial fluid levels of APRIL in inflamed peripheral joints of RA. Synovium and synovial fluid were sampled from 21 RA patients underwent arthroscopic synovectomy for inflamed peripheral joints. The variants of rheumatoid synovium were classified into the follicular and diffuse synovitis by hematoxylin and eosin staining, and the infiltrations of plasma cells in rheumatoid synovium were quantified under the light microscope. The synovial fluid levels of APRIL were measured with the enzyme-linked immunosorbent assay. The mean number of infiltrating plasma cells in synovium and the mean synovial fluid level of APRIL were significantly increased in follicular synovitis compared with those in diffuse synovitis (P = 0.009, and P = 0.018, respectively), and there was a highly positive association between the infiltrations of plasma cells and the synovial fluid levels of APRIL among all of the RA patients (Rs = 0.776, P < 0.001). These findings suggest that the local production of APRIL may be associated with the ectopic lymphoid neogenesis in rheumatoid synovium and may have a role in contributing to the infiltration of plasma cells in synovium within inflamed peripheral joints of RA.

Psoriatic arthritis: therapeutic principles

From the dermatologic point of view, psoriatic arthritis (PsA) was seen for a long time as a rare complication of psoriasis. Recent studies, however, reveal a high prevalence of PsA among patients with psoriasis, and the impact of PsA due to chronic inflammation of peripheral joints, axial joints, and periarticular structures leading to radiologic progression, functional impairment, and reduction in quality of life is well recognized. Substantial improvement in understanding immunopathology of PsA has led to a variety of new therapeutic options. This article reviews the current therapeutic principles for PsA.

The abundant synovial expression of the RANK/RANKL/Osteoprotegerin system in peripheral spondylarthritis is partially disconnected from inflammation

Spondylarthritis (SpA) and rheumatoid arthritis (RA) have different patterns of bone damage, with more pronounced bone erosions in RA. The RANK/RANKL/osteoprotegerin (OPG) system plays a central role in bone resorption by promoting the maturation and activation of osteoclasts. To assess the potential role of this system in the distinct bone phenotype, we studied the synovial expression of these mediators in SpA and RA peripheral synovitis. Synovial biopsy specimens were obtained from the actively inflamed peripheral joints of 35 patients with SpA and 19 patients with RA. Paired synovial biopsy samples were obtained from 24 patients with SpA after tumor necrosis factor alpha (TNFalpha) blockade. Synovial tissue sections were immunostained for RANKL, OPG, RANK, and TRAP and assessed by semiquantitative scoring and digital image analysis. After extensive validation of the reactivity and specificity of the antibodies, we demonstrated the abundant expression of RANKL and OPG in SpA synovitis. RANKL was expressed by both fibroblast-like synoviocytes and sublining T lymphocytes. RANK-positive osteoclast precursors but no mature TRAP-positive osteoclasts were present in the inflamed tissue. The expression of these mediators was not different between patients with nonpsoriatic SpA, patients with psoriatic SpA, and patients with RA, was not related to the degree of systemic or local inflammation, and was not significantly modulated by highly effective treatment with TNFalpha blockers. Only the subset of patients with the best systemic response to TNFalpha blockade had decreased RANKL expression in the intimal lining layer. The relative protection against bone erosions in SpA cannot be explained by qualitative or quantitative differences in the synovial expression of RANKL, OPG, and RANK. The abundant expression of these factors in SpA peripheral synovitis is largely disconnected from systemic and local inflammation.

Other seronegative spondyloarthropathies

Seronegative spondyloarthropathies are a group of overlapping forms of inflammatory joint disease, the most common conditions being ankylosing spondylitis and psoriatic arthritis. Other less common conditions include reactive arthritis, enteropathic arthritis and SAPHO (synovitis, acne, pustolosis, hyperostosis, osteitis). Shared features include a propensity to affect the spine, an association with anterior uveitis and HLA-B27, involvement of the enthesis, and the absence of rheumatoid factor. Psoriatic arthritis has several distinctive characteristics that may vary from patient to patient and include frequent involvement of distal interphalangeal joints, dactylitis, new bone formation within the enthesis, osteolysis and ankylosis. Genetic factors are important with HLA-CW6 containing haplotypes associated with psoriasis and peripheral joint inflammation and HLA-B27 associated with axial involvement especially sacroiliitis. The advent of anti-TNF antagonists provides an important new dimension to treatment options for those with progressive disease.