Chronic Proliferative Synovitis Research Articles

Unique Inflammatory Signature in Hemophilic Arthropathy: Epigenetic Changes Due to Interaction between Blood and Fibroblast-like Synoviocytes

Context: Hemophilic patients bleeding occur mainly into large joints such as knee, elbow or ankle. Severe recurrence of hemarthrosis leads to irreversible arthropathy called hemophilic arthropathy (HA) characterized by a progressive complete destruction of the joint with permanent pain, musculoskeletal disability and poor quality of life. Physiopathology of blood joint disease remains unclear. Some data suggest that HA and rheumatoid arthritis (RA) may share similar pathogenicity including elevation of inflammatory cytokines, chronic proliferative synovitis and cartilage destruction. However, in these two diseases the origin of inflammation differs and is linked to autoimmunity in RA and bleeding in HA. HA is the unique model of arthropathy in which resident cells like fibroblasts-like synoviocytes (FLS) are directly in contact with blood. Therefore, we hypothesized that FLS in HA could have a unique inflammatory signature as a consequence of contact with blood.Materials and methods: Human FLS were isolated from synovial tissues from five different HA patients and two non-HA patients at the time of knee or ankle joint arthroscopic synovectomy after informed consent were obtained from patients. Experiments with FLS cultures were performed between the third and the ninth passage. During that time, cultures were constituted of a homogeneous population of fibroblastic cells. THP-1 cells line has been used as a control.Results: FLS from hemophilic patients have a singular inflammatory cytokines profile- FLS (5x105 cells) were activated or not (medium) with LPS from Salmonella abortus equi (1 µg/ml) for 6 h and activated-cells supernatants were analyzed by ELISA. ELISPOT were performed with a panel of 105 different cytokines. After LPS stimulation, HA FLS expressed a unique profile of cytokines secretion, which differs from non-HA FLS and THP-1 cell line including IL-1α, IL-6 and IL-8 involved in innate immunity, IFN-γ, IL-5, IL-17A and IL-22 involved in adaptive immunity and MCP-1, M-CSF, MIF and MIP-3α involved in macrophages polarization.- Constitutive expression of IL-1 and IL-6 mRNA was detectable in all cells, but in contrast, as shown previously in normal FLS, no TNF-α mRNA was detectable. To investigate mechanisms responsible for the lack of IL-1 protein synthesis in LPS-activated HA FLS, cells were incubated with LPS for 3 h and then with 5 µg/ml actinomycin D. After 2h of actinomycin D treatment, IL-1 mRNA became lower in LPS-activated HA FLS versus LPS-activated non-HA FLS and THP-1 cells. These results indicate that de novo synthesized IL-1 mRNA has a short half-life in LPS-activated HA FLS.- Since cytokines mRNA seems to be unstable, we then investigated microRNA involvement in the regulation of cytokines. A miRNOME (Transcriptome Profiling miRNA, AFFYMETRIX) analysis showed that miRNAs expression was different between HA and nonHA FLS. Five have a very high difference in expression (hsa-miR664b-5p, hsa-miR4516, hsa-miR4289, hsa-miR6719-3p, hsa-miR675-5p), which potentially target mRNA involved in inflammatory pathways (NFKB, MAPK, Wnt/beta-catenin).In conclusion our study demonstrates for the first time that the presence of blood in contact with FLS may induce durable epigenetic changes that may participate to the pathophysiology of hemophilic arthropathy. DisclosuresMignot:Shire: Research Funding. Delarue:Roche: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Gilead: Consultancy, Honoraria. Frenzel:Shire: Research Funding.

2614 Astrovirus Enteritis in an Immunocompetent Adult in the Setting of Chronic Proliferative Synovitis

INTRODUCTION: Astrovirus enteritis is a clinical entity seen mainly in children and immunocompromised adults resulting in severe diarrheal episodes. It is quite rarely implicated in acute gastroenteritis in immunocompetent adults with only few cases reporting its incidence. Here, we report a case of Astrovirus enteritis in an immunocompetent adult with chronic proliferative synovitis and positive ANA titers. CASE DESCRIPTION/METHODS: We present a 38-year-old woman with history of chronic proliferative synovitis who presented with acute nausea, crampy mid abdominal pain, and profuse non-bloody diarrhea after 12 hours of eating from a restaurant. The diarrheal episodes were associated with fevers up to 103oF with chills and rigors. The patient reported to have two recent sick contacts with similar diarrheal episodes and a course of amoxicillin 1 month ago for a dental indication. However, she denied any vomiting, recent meat, dairy or egg consumption or travel history. She had no past medical history of gastrointestinal complaints, immunosuppression or any new medications. Clinical examination only revealed mild abdominal diffuse tenderness. Initial clinical workup was remarkable for a mild leukocytosis, newly increasing AST and ALT, but normal total bilirubin, ALP and lipase levels. Microbiological investigation revealed positive Astrovirus in GI PCR, negative C. difficile assay and negative HIV status. An autoimmune workup revealed positive ANA titers of 1:80 in the setting chronic proliferative synovitis. The patient underwent supportive treatment for her diarrhea with Loperamide and IV fluids following which she improved clinically. DISCUSSION: Astrovirus is a positive single stranded RNA virus implicated in acute gastroenteritis in children and immunocompromised individuals. However, it has a low prevalence among healthy adults which is hypothesized to be due to acquired immunity gained from a prior childhood infection. In this patient, her chronic proliferative synovitis with raised ANA titers seems to have increased her predisposition to acquiring Astrovirus enteritis. Patients with chronic inflammatory conditions like SLE or synovitis seem to be more prone to viral infections due to their pro-inflammatory condition, making them more susceptible to infections that are otherwise cleared by the adult immune system. Hence, it is important to consider this clinical entity when assessing severe gastroenteritis in patients with pro-inflammatory status.

Agonistic anti‐human Fas monoclonal antibody induces fibroblast‐like synoviocyte apoptosis in haemophilic arthropathy: potential therapeutic implications

Haemophilic arthropathy (HA) is characterized by chronic proliferative synovitis leading to cartilage destruction and shares some pathological features with rheumatoid arthritis (RA). Apoptosis has been implicated in RA pathogenesis, and an agonistic anti-Fas monoclonal antibody (mAb) was found to induce RA fibroblast-like synoviocyte (FLS) apoptosis and suppress synovial hyperplasia in animal models of RA. The aim of this study was to evaluate the effect of anti-Fas mAb on HA-FLS. FLS were isolated from knee synovial biopsies from six HA patients, six RA patients and six healthy subjects. The expression of Fas in synovial biopsies was investigated by immunohistochemistry. FLS were stimulated with anti-Fas mAb at different concentrations, alone or in combination with tumour necrosis factor-α (TNF-α) and basic fibroblast growth factor (bFGF). Fas expression in FLS was assessed by Western blot. Cell viability was studied with the WST-1 assay. Active caspase-3 levels were measured using ELISA and Western blot. A strong Fas-immunoreactivity was observed in different cells of HA synovium, including FLS, inflammatory cells and endothelial cells. Fas antigen was constitutively overexpressed in cultured HA-FLS. Anti-Fas mAb had a significant cytotoxicity on HA-FLS in a dose-dependent manner, either alone or in combination with TNF-α and bFGF. These cytotoxic effects were due to the ability of anti-Fas to induce HA-FLS apoptosis, as shown by the increased active caspase-3 levels. Anti-Fas mAb exhibited a more pronounced pro-apoptotic effect on HA-FLS than RA-FLS. Fas antigen is highly expressed on HA-FLS and its stimulation by anti-Fas mAb may be an effective strategy to induce HA-FLS apoptosis.

Sacroiliac Joint Involvement in A Patient With Hemophilia A: Case Report

Hemophilic arthropathy is characterized by chronic proliferative synovitis and cartilage destruction as a result of recurrent intra-articular bleeding . Hemophilic arthropathy can be seen in many joints such as knee , shoulder , hip and ankle . However, the information related to the sacroiliac joint involvement was not found in the accessible literature and electronic medium . In t his article, unilateral sacroiliac joint involvement is presented in a patient with hemophilia for 15 years who developed severe destruction in bilateral knees and admitted to our outpatient clinic because of pain over hip region. doi: http://dx.doi.org/10.4021/jh43e

Sinovite proliferativa crônica da articulação metacarpofalangiana em equinos: relato de caso

A Mangalarga foal was examined presenting both front limb lameness. The clinical examination revealed angular limb deformity and increased pain sensation, notably on the front left limb, which showed a reduced range of motion on the metacarpophalangeal joint. X-ray images indicated chronic proliferative synovitis in the above mentioned joint. Positive contrast arthrography confirmed a space occupying mass on the dorsoproximal surface of the joint. Due to the severity of the lesion, arthrostomy was performed followed by the removal of the proliferative tissue, to reduce the risk of pathological fracture on the distal end of the metacarpus III.

Physiopathology of haemophilic arthropathy

Haemophilic arthropathy, which shares some clinical and biological injury characteristics with rheumatoid arthritis, is characterized by two main features: chronic proliferative synovitis and cartilage destruction. It is the consequence of repeated extravasation of blood into joint cavities, but its exact pathogenesis, particularly with regard to early changes in the joint, is still incompletely understood. This review presents recent findings obtained in experiments performed in vitro and using animal models, which have improved our knowledge of the pathogenesis of haemophilic arthropathy. These experimental studies show that haemophilic arthropathy is a multifactorial event in which the deposit of iron in the joints appears to exert a central role. First, iron may promote the apoptosis of chondrocytes by catalysing the formation of oxygen metabolites; this may explain the fact that intra-articular blood exerts a directly harmful effect on cartilage before, and independent of synovial changes. Secondly, iron may also act on the synovial membrane by favouring its proliferation through the induction of proto-oncogenes involved in cellular proliferation and stimulation of inflammatory cytokines as well as abrogation of apoptosis. These two processes, one degenerative and cartilage-mediated, the other inflammatory and synovium-mediated could occur in parallel or sequentially. Overall, it may be expected that these experimental results will yield new therapeutic strategies capable of effectively preventing the occurrence of this still serious and common complication in patients with severe haemophilia.

Expression of vascular endothelial growth factor isoforms and their receptors Flt-1, KDR, and neuropilin-1 in synovial tissues of rheumatoid arthritis.

Angiogenesis is an indispensable process in the chronic proliferative synovitis and pannus formation of rheumatoid arthritis (RA). This study examined the expression of vascular endothelial growth factor (VEGF) isoforms and VEGF receptors, Flt-1, KDR and neuropilin-1, in RA and osteoarthritis (OA) synovia, and studied the relationship between their expression and the synovial angiogenesis. By RT-PCR analysis, the isoform VEGF(121) was constitutively expressed in all the RA (17/17 patients) and OA (8/8 patients) synovia. In contrast, the expression of the isoform VEGF(165) was observed in 41% of the RA synovia (7/17 patients), but was undetectable in the OA samples (0/8 patients). The receptor Flt-1 was almost constitutively expressed in RA (15/17 patients) and OA (8/8 patients) synovia, while the expression of KDR was detected in the synovia of six RA patients (6/17 patients; 35%) but none of the OA patients (0/8 patients). The expression of neuropilin-1, an isoform-specific receptor for VEGF(165) which enhances the binding of VEGF(165) to KDR, was also up-regulated in the same RA synovia that expressed KDR. Furthermore, there was a close correlation between the expression of isoform VEGF(165) and that of its receptors KDR and neuropilin-1. Morphometric analysis demonstrated that the vascular density is significantly higher in the RA synovial tissues with expression of VEGF(165), KDR, and neuropilin-1 than in those without their expression (p<0.01). In situ hybridization and immunohistochemical studies indicated that the cells expressing VEGF are macrophage-like synovial lining cells and spindle-shaped cells in the sublining cell layer. These results suggest that the selective up-regulation of the isoform VEGF(165) and its signalling via KDR and neuropilin-1 play an important role in the synovial angiogenesis which occurs in RA.

Human T lymphotropic virus type I in arthropathy and autoimmune disorders

The progressive nature of the disease and the persistent inflammation affecting various organs are common features of idiopathic autoimmune disorders of unknown etiology. Therefore, the HTLV-I-associated disorders described in the present review are outstandingly important models for our understanding of the pathologic mechanisms of organ-specific immune disorders. HTLV-I arthropathy is characterized by chronic inflammatory and proliferative synovitis with lymphoid follicles and pannus formation in the affected joints, indistinguishable from the findings in idiopathic RA. The presence of the tax gene in HTLV-I-negative SS patients suggests that it is responsible for the exocrine gland abnormality, characterized by extensive lymphoproliferative epithelial lesions. Furthermore, the pulmonary lesions of HTLV-I bronchopneumonopathy are similar to those of idiopathic interstitial pneumonitis. Based on these observations, the clinical findings associated with the immunologic abnormalities in HTLV-I-infected patients provide us with valuable information for understanding the pathogenetic mechanisms of chronic inflammatory conditions associated with immune regulatory disorders. Although the clinical and pathologic features of the 2 common HTLV-I-associated disorders, ATL and HAM/TSP, have been well characterized and are clearly distinguishable from those of the idiopathic forms of these disorders, other HTLV-I-related autoimmune diseases, e.g., arthropathy, SS, or bronchopneumonopathy, are clinically indistinguishable from the idiopathic forms of the diseases. Such similarity may serve as a clue to the pathogenetic mechanisms of idiopathic autoimmune disorders.

Arthroscopic Synovectomy of the Knee in Chronic Proliferative Synovitis

Arthroscopic Synovectomy of the Knee in Chronic Proliferative Synovitis

Chronic proliferative synovitis of the equine metacarpophalangeal joint.

Chronic proliferative synovitis of 27 metacarpophalangeal joints in 16 horses is described. The diagnosis was based on a history of lameness and, or, poor performance, pain on flexion of the metacarpophalangeal joint, the response to intra-articular anaesthesia, and plain and contrast radiography. Radiographic findings included concavity of the distal dorsal metacarpus proximal to the sagittal ridge, and an increase in size of the synovial tissue adjacent to the proximal, dorsal attachment of the joint capsule. Mineralisation of the synovial tissue was present in some joints, and chip fractures from the dorsal aspect of the proximal phalanx were also occasionally seen. Treatment by arthroscopic resection of the tissue gave excellent results.

THE SONOGRAPHIC DIAGNOSIS OF CHRONIC PROLIFERATIVE SYNOVITIS IN THE METACARPOPHALANGEAL JOINTS OF A HORSE

Chronic proliferative synovitis is an insidious condition affecting the metacarpophalangeal joints of horses. It results in proliferation of the synovium in the dorsal pouch of the joint in question. Treatment involves surgical excision, thus confirmation of the lesion is important. Classically this has been achieved by means of positive‐contrast arthrography, but this article addresses the attributes of ultrasonography, a less invasive imaging technique.

Inhibition by cyclosporin A of streptococcal cell wall‐induced arthritis and hepatic granulomas in rats

We investigated the effect of cyclosporin A, an inhibitor of T helper/inducer lymphocyte activation, on the development of streptococcal cell wall-induced arthritis and hepatic granulomas in female LEW/N rats. Continuous daily treatment with cyclosporin A, begun either 24 hours before or 7-12 days after streptococcal cell wall administration and continued for 6 weeks, resulted in significant inhibition of the chronic proliferative, erosive synovitis and total inhibition of hepatic granuloma formation. When cyclosporin A was stopped at 6 weeks, its effects continued for at least another 5 weeks, demonstrating long-term benefit without continued administration of the drug. In contrast, therapy given only during the acute phases of the experimental disease (days 1-12) did not inhibit the development of chronic disease. Cyclosporin A had no apparent effects on streptococcal cell wall antigen distribution or persistence in tissues. These data provide additional evidence of an important role for the T helper/inducer lymphocyte in the experimental model and suggest that cyclosporin A may be a useful probe in defining molecular and cellular processes involved in chronic proliferative and erosive synovitis.

Arthroscopic synovectomy in the treatment of hemophilic synovitis.

Chronic proliferative synovitis is a frequent complication of hemophilia for which effective treatments are lacking. Over a three year period we employed arthroscopic surgery on 7 knees in 6 patients with hemophilic synovitis refractory to standard treatment including anti‐inflammatory drugs, prophylactic factor infusion and physical therapy. Operative findings included diffuse villous synovial proliferation covering most cartilagenous surfaces of joint spaces in all six cases, varying degrees of articular erosion, osteochondral defects, and various forms of meniscal tear. One patient with an advanced degree of arthropathy had an extensive scar and interarticular fibrous band adhesions. Peri‐operatively morbidity was minimal, permitting early institution of physical therapy. Joint effusion resolved within one month of surgery. During the 6 month to 3 year post‐operative follow‐up, bleeding frequency was markedly reduced in all cases. In contradistinction to open surgical synovectomy, which encountered an unacceptably high incidence of post‐operative reduction in joint mobility, the range of knee joint motion after arthroscopic synovectomy was well preserved or improved in 4 of 6 patients. Two patients have lost the range of knee joint motion in post‐arthroscopic follow‐up; one patient sustained a tibial fracture requiring a long leg cast on the same knee, and the other had severe arthropathy with a reduced range of motion prior to arthroscopy. All patients have experienced pain relief and improved knee function. We conclude that arthroscopic synovectomy is a promising treatment of chronic hemophilic synovitis of the knee with low surgical morbidity and with long‐term benefit comparable to or better than that reported with open synovectomy.

Caprine arthritis-encephalitis syndrome (CAE): a review.

Caprine arthritis-encephalitis syndrome (CAE) is a viral disease of domestic goats characterized by chronic proliferative synovitis and periarthritis of adult goats while acute afebrile leukoencephalomyelitis is characteristic in goat kids. The causative agent, a Lentivirus, is transmitted from adult goats to kids via the colostrum or lateral transmission also occurs. The CAE virus is worldwide in distribution. All breeds and ages of goats are susceptible to infection, and once established it persists throughout the animal's life. A diagnosis can be based on the clinical signs, pathological changes, and demonstration of serum antibody levels. A vaccine is not available. Control or eradication of the disease is based on periodic serological testing, culling of all CAE antibody-positive animals, and separation of kids from adults following birth.

Experiences in diagnostic and surgical arthroscopy in the horse.

This paper reviews the current status of diagnostic and surgical arthroscopy in the horse. Arthroscopy has been used as a diagnostic aid since 1974 and is useful for evaluation of abnormalities in synovial membrane and articular cartilage. Surgical arthroscopy is a more recent advance that has replaced conventional arthrotomy in 90 per cent of the author's cases. Clinical conditions currently being treated using arthroscopic techniques rather than arthrotomy include all chip fractures in the carpus, chip fractures of the first phalanx, chronic proliferative synovitis in the fetlock and osteochondritis dissecans of the femoropatellar and tibiotarsal joints. The equipment requirements and basic techniques are reviewed. Convalescent time following surgery is decreased and the cosmetic appearance improved compared to arthrotomy. Considerable experience is required for competent surgery which, in turn, is necessary for this method to have advantage over previous conventional techniques.

Connective tissue activation. XV. Stimulation of glycosaminoglycan and DNA synthesis by a polymorphonuclear leukocyte factor.

Human synovial fibroblasts in culture have been stimulated to augment hyaluronate synthesis and glucose utilization by connective tissue activating peptides (CTAP) extracted from human spleen, lymphocytes, platelets, granulocytes, and tumour cells. The platelet-derived mediator CTAP-III also stimulated DNA synthesis in synovial fibroblasts, but CTAP-I from lymphocytes and spleen did not. The present study demonstrates the mitogenic potential of a granulocyte mediator (CTAP-PMN). Normal granulocytes were prepared with Ficoll-diatrizoate gradients, platelet contamination being estimated by phase microscopy and by radioimmunoassay for the platelet-specific protein, beta-thromboglobulin. CTAP-PMN preparations derived from 4 x 10(7) cells/ml stimulated culture 3H-thymidine incorporation to 3.56 +/- 1.32 (SD) times control levels. Although exposure of preparations to thiols reduced their mitogenicity, CTAP-PMN was relatively heat-stable. SDS gel electrophoresis of active fractions suggested a molecular weight between 12,700 and 15,700 daltons. In double immunodiffusion, antisera to CTAP-III showed no reactivity with CTAP-PMN. CTAP-PMN or other granulocyte factors capable of stimulating fibroblast DNA synthesis may play a role in chronic proliferative synovitis or in other settings where exudative inflammation is accompanied by connective tissue growth.

Autoimmunity to type II collagen an experimental model of arthritis.

We have found that intradermal injection of native type II collagen extracted from human, chick or rat cartilage induces an inflammatory arthritis in approximately 40% of rats of several strains whether complete Freund's adjuvant or incomplete Freund's adjuvant is used. Type I or III collagen extracted from skin, cartilage proteoglycans and alpha1(II) chains were incapable of eliciting arthritis, as was type II collagen injected without adjuvant. The disease is a chronic proliferative synovitis, resembling adjuvant arthritis in rats and rheumatoid arthritis in humans. Native type II co-lagen modified by limited pepsin digestion still produces arthritis, suggesting that type-specific determinants residing in the helical region of the molecule are responsible for the induction of disease. Since homologous type II collagen emulsified in oil without bacterial preparations regularly causes the disease, this new animal model of arthritis represents a unique example of experimentally-inducible autoimmunity to a tissue component.

Lymphopenia produced by polyethylene- 32P strips applied to the rabbit appendix

Local, continuous irradiation of the rabbit appendix was produced by attaching to the outer surface of the organ polyethylene strips impregnated with the β-emitting isotope 32P. This procedure reduced the level of small lymphocytes in the blood to 20–25% of the preoperative level after 1 week. The labeling index of small lymphocytes after a single injection of 3H-thymidine showed that there was little or no reduction in the rate of lymphocyte production after attachment of 32P strips. It is argued that the most likely mechanism of the lymphopenia is destruction of a major population of blood lymphocytes which recirculate continuously between the blood and the lymphoid tissue of the appendix. The existence of lymphocyte recirculation within the appendix is regarded as additional evidence that this organ serves a peripheral lymphoid function. Although marked lymphopenia was maintained for 8 weeks or longer, no defect in antibody formation or skin graft rejection was detected. Candida albicans infection of joints progressed and then regressed in similar manner in both groups, leaving a chronic proliferative synovitis lasting for at least 2–3 months.

Synovitis induced by intra-articular inoculation of inactivated Mycoplasma mycoides in calves

The intra-articular inoculation of heat-inactivated M. mycoides in young calves induced an acute fibrino-purulent synovitis, which progressed to a chronic proliferative synovitis. Intra-articular inoculation of heat-inactivated M. laidlawii also induced an acute fibrinous synovitis in young calves. It is postulated that factors which induce increased vascular permeability and fibrinous exudation are released from concentrated suspensions of dead mycoplasmas. Focal connective tissue necrosis was seen in synovia of joints inoculated with inactivated M. mycoides. The formation of fibrin deposits was the primary pathogenic factor in the acute synovitis, and the progression to a chronic proliferative synovitis is attributed to persistence of these deposits and a concomitant disturbance of physiological mechanisms associated with the synovial membrane. Intra-articular inoculation of fluid used to wash harvested M. mycoides induced chronic synovitis. Extensive washing of the organisms did not reduce the pathogenicity of the inactivated preparation. The possibility that M. mycoides released endotoxin-like factors after death of the cell is discussed.