[Significance of clinically latent bacterial arthritis]. / Die Bedeutung der klinisch latenten bakteriellen Arthritis.

The classical septic bacterial arthritis is a rare event, but can be distinguished by unequivocal signs such as fibrin exudation and neutrophilic masses (pus). For a long time we have been observing an abortive form of bacterial arthritis in biopsies which subsides spontaneously without antibiotic intervention. Only very early during the course can Staphyolcoccus aureus or epidermidis be detected. Despite the brief presence of bacteria, enzymes from the neutrophils can destroy cartilage and bone. The fact that the attending physician had suspected a bacterial infection in only 7% of these patients highlights the diagnostic complexity. We have termed this form clinically latent bacterial arthritis (CLBA). Structural changes in the synovial membrane, e.g. in rheumatoid arthritis or osteoarthritis, predispose for a hematogenous seeding of endogenous staphylococci and trigger clinically unapparent, temporary infections. This clinically latent bacterial superinfection (CLSI) is also self-limiting, but the high degrading potential of the neutrophilic proteases makes CLSI a very probable contributing factor in joint destruction.

Recurring synovitis as a possible reason for aseptic loosening of knee endoprostheses in patients with rheumatoid arthritis.

We evaluated histologically samples of synovial tissue from the knees of 50 patients with rheumatoid arthritis (RA). The samples were taken during revision for aseptic loosening. The findings were compared with those in 64 knees with osteoarthritis (OA) and aseptic loosening and in 18 knees with RA without loosening. The last group had been revised because of failure of the inlay or the coupling system of a constrained prosthesis. All the patients had had a total ventral synovectomy before implantation of the primary prosthesis. In all three groups a foreign-body reaction and lymphocellular infiltration were seen in more than 80% of the tissue samples. Deposits of fibrin were observed in about one-third to one-half of the knees in all groups. Typical signs of the reactivation of RA such as rheumatoid necrosis and/or proliferation of synovial stromal cells were found in 26% of knees with RA and loosening, but not in those with OA and loosening and in those with RA without loosening. Our findings show that reactivation of rheumatoid synovitis occurs after total knee replacement and may be a cofactor in aseptic loosening in patients with RA.

Cell populations involved in pigmented villonodular synovitis of the knee.

OBJECTIVE: Pigmented villonodular synovitis (PVNS) of the knee is a tumor-like process of uncertain nature. We analyzed the involved cell populations, iron deposition, and cell proliferation in PVNS to propose a pathogenetic concept of this still elusive disease entity. METHODS: The study was performed on a series of 14 cases of localized PVNS of the knee. Histology and histochemistry were used to evaluate basic morphology and iron deposit distribution. Immunohistochemistry was performed to characterize the inflammatory cell infiltrate and to identify the proliferating cell compartments. In situ hybridization analysis using a cDNA probe against type I collagen was utilized to further characterize the mononuclear cell infiltrate. RESULTS: In addition to the classic features (mononuclear cell infiltrate, multinuclear giant cells, iron deposits, and stromal fibrosis) we observed a chronic inflammatory cell infiltrate in all PVNS samples, in which CD8 positive T cells were conspicuous. A high portion of non-phagocytotic cells resorbed iron and became CD68 positive. A proportion of mononuclear cells expressed type I collagen, thus resembling B synoviocytes. CONCLUSION: Our results suggest that preexisting chronic inflammation plays an important pathogenetic role in the PVNS disease process. Chronic inflammation increases the risk of articular bleeding and probably deranges the iron processing capacity of local synovial macrophages. The resulting iron overload could lead to a shift of iron storing cells from synovial macrophages to B synoviocytes and fibroblasts. A perpetuated proliferation and activation of these cells can explain why PVNS behaves like a neoplastic process.

Lack of evidence for an involvement of Epstein-Barr virus infection of synovial membranes in the pathogenesis of rheumatoid arthritis.

OBJECTIVE: To test the hypothesis that Epstein-Barr virus (EBV) infection of cells within the synovial membrane contributes to the pathogenesis of rheumatoid arthritis (RA). METHODS: Biopsy samples of synovial membrane from 37 patients with RA and from 51 patients with other joint diseases were studied for evidence of EBV infection using in situ hybridization specific for the EBV-encoded RNAs (EBERs). Latent membrane protein 1 (LMP1) and the lytic-cycle BZLF1 protein were detected by immunohistochemistry. RESULTS: Rare EBER-positive B lymphocytes were detected in 7 RA biopsy samples. EBV was not detectable in any other cells. Expression of the LMP1 and BZLF1 proteins of EBV was not observed in any of the samples. No EBV infection was detected in synovial membranes from patients with other joint diseases. CONCLUSION: Our data indicate that EBV infection is not directly involved in the pathogenesis of RA. Any contribution of EBV to the pathogenic process leading to RA is likely to be indirect.

Detection of sarcolectin-specific receptors like the cytokine macrophage migration inhibitory factor in rheumatoid nodules.

The objective of this study was the evaluation of the relation between the N-acetyl-neuraminic acid-binding endogenous lectin sarcolectin and the cytokine macrophage migration inhibitory factor (MIF) during development of rheumatoid nodules (RN) in seropositive rheumatoid arthritis (RA). Sarcolectin was purified and biotinylated. The binding patterns of this probe were analyzed in RN from patients with RA (n = 23) and compared with the distribution of antibodies with specificity for MIF, fibrin, fibronectin. In early RN, all areas of the inflammatory tissue displayed presence of receptors for sarcolectin. Macrophages were especially positive. In mature rheumatoid nodules binding of sarcolectin was restricted to the periphery of necrotic areas, to endothelial cells and perivascular connective tissue of marginal zones. Distribution patterns of MIF were similar but not identical. The histological staining characteristics demonstrate sarcolectin-binding receptors in RN that are altered upon disease progression. The finding suggests that specific interactions between this endogenous lectin and MIF may be involved in the course of RA.

Synovial lining, endothelial and inflammatory mononuclear cell proliferation in synovial membranes in psoriatic and reactive arthritis: a comparative quantitative morphometric study.

The extent of synovial cell proliferation in situ and its relationship to the destructive potential of rheumatoid arthritis (RA) is a matter of continuing debate. Notably, the situation has not been elucidated in other inflammatory arthritides [i.e. reactive (ReA) and psoriatic (PsA)], which, although they share some histopathological similarities with RA, develop different patterns of joint involvement. In order to estimate the proliferation of synovial cells in situ in PsA and ReA, and to compare this with RA and with 'non-inflammatory' joint lesions, we have utilized immunostaining of the Ki-67 antigen complemented with Ki-67/CD68 or Ki-67/leucocyte common antigen (LCA, clones 2B11 and PD7/26) double stainings to assess the extent of mononuclear inflammatory cell proliferation. Synovial samples analysed were from 33 patients: RA (n = 8), PsA (n = 13), ReA (n = 6) and six 'non-inflammatory controls' (degenerative or traumatic joint lesions). Thickening of the synovial lining (in particular in RA) and perivascular accumulations of mononuclear inflammatory cells, predominantly lymphocytes, were characteristic features in all synovitides. In contrast to the thickened avascular synovial lining in RA, in 5/13 cases with PsA, blood vessels were observed in the lining. The percentage of lining cells expressing Ki-67 antigen was higher in RA (median = 4.7, interquartile range [Q3-Q1] = 3.9, mean [95% CI] = 3.5 [1.7-5.2], P = 0.0063), PsA (median = 1.2, [Q3-Q1] = 1.9, mean [95% CI] = 1.6 [0.7-2.5], P = 0.007) and ReA (median = 1.4, [Q3-Q1] = 2.3, mean [95% CI] = 1.6 [0.1-3.1], P = 0.0235) than in controls (median = 0.1, [Q3-Q1] = 0.45, mean [95% CI] = 0.2 [0.07-0.5]). In this respect, the differences between different forms of the inflammatory arthritides were not statistically significant (P > 0.05). In RA, PsA and ReA, the percentage of labelled cells in the inflammatory mononuclear cell-rich areas was higher than in controls. The percentage of proliferating endothelial cells was also significantly higher in RA, PsA and ReA than in controls. However, in RA, endothelial expression of Ki-67 antigen was often seen in small blood vessels, whereas in PsA, Ki-67 antigen was preferably expressed in the medium to large blood vessels. Synovial lining cells of the monocyte/macrophage lineage (type A synoviocytes), but not stromal monocytes, demonstrated modest proliferation in situ. These results indicate that although proliferation of synovial lining fibroblasts is a prominent feature in RA, the extents to which this, or in situ proliferation of lymphocytes, contribute to the histopathology of PsA, ReA and RA are comparable. Vascular involvement is suggested by the proliferation of endothelial cells in RA, PsA and ReA in an overlapping manner, but, based on topological differences, such a response may represent diverse pathological features, such as angiogenesis, vascular enlargement and reparative responses to injury.

What destroys the joint in rheumatoid arthritis?

The immunological disturbance in rheumatoid arthritis (RA) gives rise to a nonspecific inflammatory reaction mediated by cells and cytokines. This immunological nonbacterial synovitis, however, does not destroy the articular cartilage. The destruction of joint structures is the effect of tumor-like aggressive synoviogenic cell elements (TLP). These TLP formations are not observed in any other type of arthritis. TLP formations are strictly avascular and short-lived. After they have decayed, a collagenous pannus remains. Invasion and destruction of joint structures are brought about by several types of proteases, synthesized and secreted by highly active TLP cells. The TLP formations possess more than twice the affinity for adjacent bone than for the articular cartilage. In these formations, four oncogenes could be identified. In the course of RA disease, TLP formations can recur. Thus, the joint damage can summate with time. The oncological character of the aggressive process in RA demands new therapeutical considerations to protect RA patients from destruction of their joints.

[Results of new research in the area of osteoarthritis]. / Neue Forschungsergebnisse auf dem Gebiet der Osteoarthrose.

In the course of time, general components of the hyaline cartilage, chondrocytes and cartilage matrix, can lose its quality due to nutritive, toxic and enzymatic influences but also due to excessive mechanical usage so that the hyaline articular cartilage fulfils no longer its function as a hydroelastic bumper. This results in progressive mechanical cartilage destruction and sklerosing reconstruction of the subchondral bone. The parts of the matrix that are freed by the mechanical abrasion can function as inflammatory mediators and set an accompanying synovitis going. It is this secondary synovitis that then leads to a painful manifestation of osteoarthrosis. In this case, an antiphlogistic therapy is necessary, because during a secondary synovitis cytokines are set free that endanger the yet intact articular cartilage.

[Osteoarthritis in light of the results of new research]. / Osteoartroza u svjetlu rezultata novih istrazivanja.

Chondrocyte and cartilage matrix can in the course of time lose in quality due to nutritive, toxic and enzymatic influences, but also due to excessive mechanical usage so that the hyaline articular cartilage can no longer fulfill its function as a hydroelastic bumper. The results are progressive mechanical cartilage destruction and sklerosing reconstruction of the subchondral bone. The parts of the matrix that are freed by the mechanical abrasion can function as inflammatory mediators and set an accompanying synovitis going. It is this secondary synovitis that then leads to a painful manifestation of osteoarthritis. In this case, an antiphlogistic therapy is necessary, because during a secondary synovitis cytokines are set free that endanger the yet intact articular cartilage.

[Critical considerations of the pathogenesis of "soft tissue rheumatism" (fibromyalgia) and its therapeutic consequences]. / Kritische Uberlegungen zur Pathogenese des "Weichteilrheumatismus" (Fibromyalgie) und ihre therapeutischen Konsequenzen.

The term "fibrositis" for generalized tendomyopathia that can still be found in Anglo-American literature is obsolete. The term implies that the disease has inflammatory qualities and can be treated by antiphlogistic means. Using light or electron microscopy we could find no evidence for an inflammatory process in the either tendon or muscle tissues. The term fibromyalgia makes clear that two totally different tissues are affected: 1. the bradytrophic collagenous connective tissue that requires little oxygen 2. the highly active skeletal muscles, made up of muscle cells that require a high amount of oxygen. The way these two tissues react to disorders therefore is also totally different: The collagenous tendon and capsular tissue react to lack of oxygen and overstrain by excessive formation of fibroblasts and dissolution of collagen fibres. Muscle tissue reacts to nerval irritations by pathological muscle tone in extensive areas of human body. This indurative myoitis does not lead to muscle damage, because the increased demand for oxygen is compensated by an increased supply. In the case of excessive focal contracture in myogelosis the tissue-pO2 sinks below the level vital to the muscle cells. By means of electron microscopy we could detect severe damage to, even dissolution of, myofilaments. Therapy for "muscular rheumatism" thus requires normalisation of the pathological tone with the help of antitonic substances or physiotherapy.

Spontaneous expression of immediately-early response genes c-fos and egr-1 in collagenase-producing rheumatoid synovial fibroblasts.

In view of the important role of interstitial collagenase in the pathogenesis of rheumatoid arthritis (RA), we studied the expression of fibroblast-type collagenase in rheumatoid synovium and searched for its potential transcription factors, namely the oncoprotein c-fos and the early-growth-response gene-1 (egr-1), an inducible zinc-finger encoding gene. Elevated levels of RNA sequences complimentary to c-fos and egr-1 cDNA probes could be detected in cytoplasmic extracts of collagenase-expressing synovial fibroblast-like cells when compared to equivalent RNA amounts isolated from control fibroblasts. Utilizing immunocytochemistry, immunoreactivity for c-fos oncoprotein was found in 13 of 19 joint specimens obtained from patients with active RA. These oncoprotein data were positively correlated to the collagenase expression in the same specimens. Moreover, immunohistochemical analysis confirmed the localization of both oncoprotein c-fos and fibroblast-type collagenase within synovial fibroblast-like cells attached to bone erosions.

Pathways of destruction in metacarpal and metatarsal joints of patients with rheumatoid arthritis.

219 metatarsal (MTP) and 69 metacarpal (MCP) capitulae obtained during surgery from patients with definite rheumatoid arthritis (RA) were histologically evaluated. This evaluation, focussing on primary pathways of joint destruction by tumor-like proliferated synovial cell masses revealed 3 pathways of aggression: Pathway A: In 15% aggression onto the articular cartilage only. Pathway B: In 49% direct invasion exclusively into the cortical bone. Pathway C: In 36% a "forceps-like" aggression, a combination of A and B in which the joint is attacked from both sides. In contrast to the hitherto conventional concepts, the findings of this study reveal a clear preference of the synovial aggression for the cortical bone rather than for the articular cartilage. The different concepts of joint destruction in RA are being discussed in the light of our findings. Thus, future pathogenetic considerations with regard to joint destruction in RA should take this fact into consideration.

Cathepsin B in synovial cells at the site of joint destruction in rheumatoid arthritis.

Based on the concept that proteolytic enzymes, like cathepsins, are associated with tissue destruction, we investigated the expression of the matrix-degrading cysteine proteinase cathepsin B in synovial tissues from the joints of patients with rheumatoid arthritis. The data indicate an enhanced transcription of cathepsin B in synovial cells when compared with normal fibroblasts, cathepsin B-producing epithelial tumor cells (SW1116), or fibroblasts derived from inflamed tonsils. Immunolocalization of cathepsin B appeared to be restricted mainly to the synovial cells attached to cartilage and bone at sites of rheumatoid joint erosion.

[Osteoarthritis in the light of current research findings]. / Die Osteoarthrose im Licht neuer Forschungsergebnisse.

Chondrocyte and cartilage matrix can in the course of time lose in quality due to nutritive, toxic and enzymatic influences but also due to excessive mechanical usage so that the hyaline articular cartilage can no longer fulfill its function as a hydro-elastic bumper. This results in progressive mechanical cartilage destruction and sclerosing reconstruction of the subchondral bone. The parts of the matrix that are freed by the mechanical abrasion can function as inflammatory mediators and set an accompanying synovitis going. It is this secondary synovitis that then leads to a painful manifestation of osteoarthritis. In this case, an antiphlogistic therapy is necessary, because during a secondary synovitis cytokines are set free that endanger the yet intact articular cartilage.

[Pathogenetic aspects of arthrosis and its therapeutic aspects]. / Pathogenetische Aspekte der Arthrose und ihre therapeutischen Aspekte.

The hitherto accepted idea that articular cartilage is merely bradythrophic tissue which, like a shoe sole, is subjected to continuous wear and tear, as a whole must be revised by considering the growing biochemical, biophysical, and ultrastructural research of the matrix components. The chondrocyte is the single living element of the cartilage: Type-II collagenous fibres and the proteoglycans are its products. To what extent the regulation of collagen production and above all the steady-state regulation is controlled by a superordinating regulation is still not known. However, we must absolutely postulate such. In the mechanics of the joint there are two antagonists which confront each other: 1. the (to a large degree) intellectually regulatable physical strain; and 2. the quality of the cartilage matrix. This represents a refined hydroelastic system. Research into the biochemistry and biophysics continuously provides an increasing abundance of new data on the molecular biological mechanisms, which 1. induce the degradation of proteoglycans and collagens; 2. increase the synthesis of the matrix components; 3. antagonize the degradation, and 4. inhibit the synthesis. In addition, an interaction of these factors can also be expected. Moreover, new information on the components and structures of the matrix is continuously gathered. Up to now, we know of 14 different types of collagen, which on the other hand are accessible to various degradative enzymes. The most important, and--from the standpoint of the biomechanics--the most interesting element/building block is, however, the proteoglycan molecule, whose excessive water-binding capacity enables the hydroelasticity of the hyaline cartilage.(ABSTRACT TRUNCATED AT 250 WORDS)

Expression of the collagenolytic and Ras-induced cysteine proteinase cathepsin L and proliferation-associated oncogenes in synovial cells of MRL/I mice and patients with rheumatoid arthritis.

Based on the observation that rheumatoid joint destruction is related to the presence of transformed-appearing proliferating synovial lining cells attached to cartilage and bone at the site of early destruction, we searched for the expression of proliferation- and transformation-associated oncoproteins in synovial tissues from patients with early destructive rheumatoid arthritis (RA). Immunolocalization of Ras and Myc proteins was found in about 70% of the RA cases and was restricted to the proliferating synovial lining cells. The cysteine proteinase, cathepsin L, which has been shown to be the major ras-induced protein in ras-transformed murine NIH 3T3 cells, was detected in 50% of the RA cases, predominantly in synovial cells attached to cartilage and bone at the site of joint destruction. Moreover, utilizing cytoplastic dot hybridization analysis, we demonstrated the presence of RNA sequences complementary to human cathepsin L in primary cultures of human synovial cells from RA joints and complementary to murine cathepsin L in synovial lining cells derived from MRL/l mice developing spontaneously a RA-like disease. Significant levels of ras oncogene transcripts and products in human RA synovial cells associated with an increased expression of the cathepsin L gene indicate that this collagen-degrading enzyme may contribute to the destruction of cartilage and bone in RA.

Immunohistochemical localization of HTLV-I p19- and p24-related antigens in synovial joints of patients with rheumatoid arthritis.

In formalin-fixed, paraffin-embedded synovial tissues from patients with early proliferative rheumatoid arthritis (RA), immunoreactivity could be demonstrated utilizing monoclonal IgG antibodies reactive with the p19 and p24 protein of human T cell leukemia virus (HTLV-I). Additionally, surgical specimens of fresh unfixed synovial tissues from patients with RA also demonstrated immunoreactivity. At the light microscopic level, both HTLV-I antigens were detected in approximately 45% of the rheumatoid synovial tissues by the immunocolloidal gold method with silver enhancement (IGSS) and the avidin-biotin-complex technique (ABC), whereas six of eight of the frozen RA specimens stained positive by immunofluorescence. Patients whose synovial tissues were immunoreactive by immunofluorescence were seronegative to HTLV-I antigens as determined by ELISA and immunoblotting. Conversely, cases with osteoarthritis, juvenile rheumatoid arthritis, psoriatic arthritis, Dupuytren's contracture, and gangrene were shown to be nonreactive by immunohistochemistry. The results indicate that expression of antigens is related to or crossreactive with HTLV-I in synovial tissues from patients with rheumatoid arthritis.