[Insoles for the rheumatic foot. A clinical and pedobarographic analysis]. / Die Einlagenversorgung des rheumatischen Fusses. Eine klinische und pedobarographische Analyse.

BACKGROUND: Insoles are regarded as an appropriate tool for the management of rheumatic foot disorders. However, a quality control for this purpose has not been established. In our study, the clinical effectiveness of insoles used in patients with rheumatic foot disorders was addressed. In addition, we sought to establish pedobarography as a means of quality control for orthotic management of the rheumatic foot. MATERIAL AND METHODS: Our study included 20 rheumatoid arthritis patients with painful rheumatic foot deformities who were provided with insoles. Clinical data were obtained by physical examination and a 100-mm pain scale. Pedobarography was performed using the novel pedar cable system with new and individually designed insoles and after a 6-month follow-up. A shoe-only trial served as control. The parameters maximum force, peak pressure, force-time integral, and average pressure were analyzed in anatomical regions and an individually defined overloaded forefoot region. RESULTS: Clinical improvement was significant after a 6-month follow-up in spite of a heterogeneous group of patients. However, our results could not confirm consistent changes in plantar pressure distribution. CONCLUSION: As a conclusion, further efforts are necessary to establish a quality control for orthotic management of the rheumatic foot.

[Talonavicular arthrodesis for the rheumatoid foot]. / Die Arthrodese des Talonavikulargelenks beim rheumatischen Fuss.

BACKGROUND: Talonavicular joint fusion has been successfully applied for the surgical treatment of the rheumatoid foot. Several fixation techniques have been suggested for this purpose, however, with high rates of non-union. METHODS: Based on seven cases operated in our division, talonavicular joint fusion with two 3.5 mm compression screws and autologous bone grafting is discussed. Pain in the operated foot under weight-bearing conditions was assessed before surgery and after a mean follow-up of 35 months (range 3-58 months). RESULTS: Solid talonavicular fusion was achieved clinically and radiologically in all patients after 12 weeks. The surgery-related morbidity was low. At follow-up, weight-bearing pain was diminished compared to the preoperative status. CONCLUSIONS: Compression screw arthrodesis of the talonavicular joint in combination with autologous bone grafting is highly successful in rheumatoid arthritis patients.

[Bone scintigraphy and clinical outcome in rheumatoid gonarthritis].

AIM: For evaluation of the effect of radiosynoviorthesis (RSO) on the early and delayed uptake of (99m)Tc-biphosphonates and its relation to clinical outcome we studied these variables before and after radiosynoviorthesis performed on 41 knees affected by rheumatoid arthritis. METHOD: Thirty-seven patients with rheumatoid gonarthritis were treated by intraarticular injection with 185 MBq yttrium-90 citrate. In four of them both knees were treated so that 41 therapies were evaluated. On the average 35 days before and 120 days after radiosynoviorthesis, the early and delayed uptake of (99m)Tc-diphosphonate (DPD) was measured with a planar gamma camera. Early and late DPD uptake was quantified as a ratio between count values derived from rectangular ROIs placed on the knee treated and on the ipsilateral thigh. The severity of clinical symptoms was assessed on two 3-point rating scales averaged. RESULTS: 30 of the 41 cases favorably responded to radiosynoviorthesis. There was a significant correlation between clinical outcome and pretherapeutic early DPD uptake (EDU) (p<0.05), but not between outcome and pretherapeutic late DPD uptake (DDU). In the whole group, EDU decreased in approximately 76% of cases after therapy (p<0.05), DDU in 54% (p>0.05). In 25 of the 30 responders EDU decreased; EDU increased or remained constant in five of the eleven non-responders. The correlation between outcome and the difference in EDU was significant (r = 0.344; p<0.05). There was no such significant relationship between the difference between pre- and posttherapeutic DDU and clinical course. CONCLUSION: Three-phase bone scintigraphy may contribute to predict and assess the success of radiosynovior-thesis in rheumatoid arthritis of the knee joint.

Matrilin-3 in human articular cartilage: increased expression in osteoarthritis.

OBJECTIVE: Matrilin-3 is a member of the recently described matrilin family of extracellular matrix proteins containing von Willebrand factor A-like domains. The matrilin-3 subunit can form homo-tetramers as well as hetero-oligomers together with subunits of matrilin-1 (cartilage matrix protein). It has a restricted tissue distribution and is strongly expressed in growing skeletal tissues. Detailed information on expression and distribution of extracellular matrix proteins is important to understand cartilage function in health and in disease like osteoarthritis (OA). METHODS: Normal and osteoarthritic cartilage were systematically analysed for matrilin-3 expression, using immunohistochemistry, Western blot analysis, in situ hybridization, and quantitative PCR. RESULTS: Our results indicate that matrilin-3 is a mandatory component of mature articular cartilage with its expression being restricted to chondrocytes from the tangential zone and the upper middle cartilage zone. Osteoarthritic cartilage samples with only moderate morphological osteoarthritic degenerations have elevated levels of matrilin-3 mRNA. In parallel, we found an increased deposition of matrilin-3 protein in the cartilage matrix. Matrilin-3 staining was diffusely distributed in the cartilage matrix, with no cellular staining being detectable. In cartilage samples with minor osteoarthritic lesions, matrilin-3 deposition was restricted to the middle zone and to the upper deep zone. A strong correlation was found between enhanced matrilin-3 gene and protein expression and the extent of tissue damage. Sections with severe osteoarthritic degeneration showed the highest amount of matrilin-3 mRNA, strong signals in in situ hybridization, and prominent protein deposition in the middle and deep cartilage zone. CONCLUSION: We conclude that matrilin-3 is an integral component of human articular cartilage matrix and that the enhanced expression of matrilin-3 in OA may be a cellular response to the modified microenvironment in the disease.

[Cell proliferation in human arthrotic joint cartilage]. / Zellproliferation im humanen arthrotischen Gelenkknorpel.

OBJECTIVE: Osteoarthritic (OA) cartilage is histologically characterized by the appearance of cell clusters, which are probably generated by mitotic cell division. The aim of this study was to analyze the distribution and amount of proliferating chondrocytes in healthy and osteoarthritic cartilage systematically. MATERIALS AND METHODS: 6 normal and 43 osteoarthritic cartilage/bone samples were obtained during autopsies or total knee replacements. The cartilage specimens were stained with safranin-o and scored according to the Mankin-System. Proliferating chondrocytes were identified by immunohistochemical detection of the antigen PCNA. The number of proliferating chondrocytes was determined by counting 100 chondrocytes in each cartilage layer. RESULTS: In normal and osteoarthritic human cartilage, proliferating chondrocytes were detected. The amount of proliferating chondrocytes increased during the progression of OA cartilage changes. Expression of PCNA was determined in single chondrocytes and clustered chondrocytes. Chondrocyte cell division was activated specifically in cartilage with severe OA changes. CONCLUSIONS: Osteoarthritic chondrocytes, which are known to increase the synthesis of different matrix proteins, show the phenomenon of mitotic cells division. Whether the increased amount of proliferating chondrocytes fails to compensate the rate of apoptotic chondrocytes, or whether the generation of cell clusters represents only a fruitless repair effort is a subject of recent research. However, the induction of chondrocyte proliferation is a potential target in the treatment of OA.

Vascular endothelial growth factor in articular cartilage of healthy and osteoarthritic human knee joints.

OBJECTIVE: To determine the levels of vascular endothelial growth factor (VEGF) mRNA and protein expression in normal and osteoarthritic (OA) human articular cartilage, and whether VEGF expression alters during the progression of OA. METHODS: Sections from normal and OA human knee cartilage were immunotained with a polyclonal antibody recognising VEGF. In addition, total RNA was isolated from normal and osteoarthritic human knee cartilage and analysed by reverse transcriptase-polymerase chain reaction (RT-PCR) for VEGF mRNA expression. RESULTS: VEGF was found to be present in normal and OA human knee cartilage in all cartilage layers. A significant increase of VEGF immunopositive chondrocytes to up to approximately 82% was detected in severe OA cartilage compared with normal articular cartilage (approximately 56% of immunopositive chondrocytes). RT-PCR analysis showed the expression of VEGF also on the mRNA level. CONCLUSIONS: VEGF is expressed by articular chondrocytes in normal and OA human knee cartilage. The percentage of VEGF immunopositive chondrocytes significantly increases in late stages of the disease. The VEGF transcript levels encoding all four isoforms shows a big variability in samples from different donors, suggesting a distinct regulation of the expression of the four VEGF isoforms in normal and OA cartilage.

Radiosynovectomy in pigmented villonodular synovitis.

BACKGROUND: Pigmented villonodular synovitis (PVS) is a very rare disorder characterized by a slowly progressive benign proliferation of synovial tissue. As yet, the mainstay of its treatment has been surgical or athroscopic synovectomy. However, the relapse rates reported are relatively high, ranging between 8% and 46%. The aim of this study was to evaluate the efficacy of a combined treatment with radiosynovectomy (RS) and surgical synovectomy. METHOD: We studied the effect of thirteen radiosynovectomies performed in eleven pigmented villonodular synovitis patients with Y-90 citrate or Re-186 sulfide. All patients had undergone intraarticular radiation therapy within 6 months after surgical synovectomy. Eight patients suffered from pigmented villonodular synovitis in the knee, the remaining three from pigmented villonodular synovitis in the hip. Two of eleven patients had to be treated twice, due to a relapse of symptoms occurring four months after the first treatment. Therapy responses were evaluated one year after the initial radiosynovectomy. Clinical response was assessed on three-point rating scales evaluating the degree of hydrops, rubor, and motility as well as the degree of pain, these four parameters were then averaged to an overall clinical score (CS). We also quantified the relative uptake of Tc-99m-diphosphonate in the joint involved on the blood pool (BUR) and delayed images (DUR). RESULTS: Clinical score decreased from 5.45 +/- 1.04 to 1.18 +/- 1.16 at one year after treatment (p < 0.005), and the blood pool from 0.51 +/- 0.36 to 0.08 +/- 0.44 (p < 0.005). Delayed images were not significantly changed: 0.66 +/- 0.71 versus 0.66 +/- 0.73 (p = 0.3). CONCLUSION: A combination of surgical synovectomy with radiosynovectomy is highly efficacious in treating clinical symptoms of pigmented villonodular synovitis. It also improves bone scintigraphic signs of inflammation, but has no influence on late diphosphonate uptake.

EULAR recommendations for the management of knee osteoarthritis: report of a task force of the Standing Committee for International Clinical Studies Including Therapeutic Trials (ESCISIT).

BACKGROUND: Osteoarthritis (OA) is the most common joint disease encountered throughout Europe. A task force for the EULAR Standing Committee for Clinical Trials met in 1998 to determine the methodological and logistical approach required for the development of evidence based guidelines for treatment of knee OA. The guidelines were restricted to cover all currently available treatments for knee OA diagnosed either clinically and/or radiographically affecting any compartment of the knee. METHODS: The first stage was the selection of treatment modalities to be considered. The second stage comprised a search of the electronic databases Medline and Embase using a combination of subject headings and keywords. All European language publications in the form of systematic reviews, meta-analyses, randomised controlled trials, controlled trials, and observational studies were included. During stage three all the relevant studies were quality scored. The summary statistics for validated outcome measures, when available, were recorded and, where practical, the numbers needed to treat and the effect size for each treatment were calculated. In the fourth stage key clinical propositions were determined by expert consensus employing a Delphi approach. The final stage ranked these propositions according to the available evidence. A second set of propositions relating to a future research agenda was determined by expert consensus using a Delphi approach. RESULTS: Over 2400 English language publications and 400 non-English language publications were identified. Seven hundred and forty four studies presented outcome data of the effects of specific treatments on knee OA. Quantitative analysis of treatment effect was possible in only 61 studies. Recommendations for the management of knee OA based on currently available data and expert opinion are presented. Proposals for a future research agenda are highlighted. CONCLUSIONS: These are the first clinical guidelines on knee OA to combine an evidence based approach and a consensus approach across a wide range of treatment modalities. It is apparent that certain clinical propositions are supported by substantial research based evidence, while others are not. There is thus an urgent need for future well designed trials to consider key clinical questions.

Chondrocyte differentiation in human osteoarthritis: expression of osteocalcin in normal and osteoarthritic cartilage and bone.

Osteocalcin (OC), which is a marker of the mature osteoblasts, can also be found in posthypertrophic chondrocytes of the epiphyseal growth plate, but not in chondrocytes of the resting zone or in adult cartilage. In human osteoarthritis (OA), chondrocytes can differentiate to a hypertrophic phenotype characterized by type X collagen. The protein- and mRNA-expression pattern of OC was systematically analyzed in decalcified cartilage and bone sections and nondecalcified cartilage sections of human osteoarthritic knee joints with different stages of OA to investigate the differentiation of chondrocytes in OA. In severe OA, we found an enhanced expression of the OC mRNA in the subchondral bone plate, demonstrating an increased osteoblast activity. Interestingly, the OC protein and OC mRNA were also detected in osteoarthritic chondrocytes, whereas in chondrocytes of normal adult cartilage, both the protein staining and the specific mRNA signal were negative. The OC mRNA signal increased with the severity of OA and chondrocytes from the deep cartilage layer, and proliferating chondrocytes from clusters showed the strongest signal for OC mRNA. In this late stage of OA, chondrocytes also stained for alkaline phosphatase and type X collagen. Our results clearly show that the expression of OC in chondrocytes correlates with chondrocyte hypertrophy in OA. Although the factors including this phenotypic shift in OA are still unknown, it can be assumed that the altered microenvironment around osteoarthritic chondrocytes and systemic mediators could be potential inducers of this differentiation.

Osteopontin is expressed by adult human osteoarthritic chondrocytes: protein and mRNA analysis of normal and osteoarthritic cartilage.

Osteopontin, a sulfated phosphoprotein with cell binding and matrix binding properties, is expressed in a variety of tissues. In the embryonic growth plate, osteopontin expression was found in bone-forming cells and in hypertrophic chondrocytes. In this study, the expression of osteopontin was analyzed in normal and osteoarthritic human knee cartilage. Immunohistochemistry, using a monoclonal anti-osteopontin antibody was negative on normal cartilage. These results were confirmed in Western blot experiments, using partially purified extracts of normal knee cartilage. No osteopontin gene expression was observed in chondrocytes of adult healthy cartilage, however, in the subchondral bone plate, expression of osteopontin mRNA was detected in the osteoblasts. In cartilage from patients with osteoarthritis, osteopontin could be detected by immunohistochemistry, Western blot analysis, in situ hybridization, and Northern blot analysis. A qualitative analysis indicated that osteopontin protein deposition and mRNA expression increase with the severity of the osteoarthritic lesions and the disintegration of the cartilaginous matrix. Osteopontin expression in the cartilage was limited to the chondrocytes of the upper deep zone, showing cellular and territorial deposition. The strongest osteopontin detection was found in deep zone chondrocytes and in clusters of proliferating chondrocytes from samples with severe osteoarthritic lesions. These data show the expression of osteopontin in adult human osteoarthritic chondrocytes, suggesting that chondrocyte differentiation and the expression of differentiation markers in osteoarthritic cartilage resembles that of epiphyseal growth plate chondrocytes.

Expression of thrombospondin-1 and its receptor CD36 in human osteoarthritic cartilage.

OBJECTIVE: Thrombospondin-1 (TSP-1), a trimeric glycoprotein, is involved in cell-matrix interactions of various tissues, particularly in cartilage. Biochemical analyses show expression of TSP-1 in human cartilage, but its cellular source as well as the presence of its main surface receptors CD36 and CD51 in normal and osteoarthritic cartilage remain unknown. Therefore, to localise TSP-1 and its receptors immunohistochemistry and in situ hybridisation were used. METHODS: Radioactive in situ hybridisations with an RNA probe that encodes TSP-1 combined with immunostaining were carried out to investigate the expression patterns of TSP-1, CD36, and CD51 in seven normal and 23 osteoarthritic human cartilage samples. RESULTS: In normal cartilage TSP-1 was present mainly in the middle and upper deep zone. RNA expression was predominantly seen over chondrocytes of the middle zone. CD36 was found in chondrocytes of the superficial and upper middle zone. In mild and moderate osteoarthritic cartilage an increased number of TSP-1 expressing chondrocytes were seen and an increased pericellular staining close to the surface. In severe osteoarthritic cartilage a decrease in the number of TSP-1 synthesising chondrocytes and a strong reduction in matrix staining were observed. Most of these severe osteoarthritic samples showed a strongly enhanced number of CD36 positive chondrocytes. CONCLUSION: The cellular source of TSP-1 in normal cartilage is mainly mid-zone chondrocytes, which also express CD36. In early osteoarthritic cartilage lesions an increase of TSP-1 was seen, whereas reduced TSP-1 synthesis is paralleled by a strong decrease in TSP-1 protein staining in severe osteoarthritis. Furthermore, in severe osteoarthritic cartilage the number of CD36 immunostained chondrocytes is significantly increased.

Arthroscopic synovectomy of the knee joint in early cases of rheumatoid arthritis: follow-up results of a multicenter study.

A retrospective multicenter study on a total of 93 knee joints in 81 patients with early forms of rheumatoid arthritis treated by arthroscopic synovectomy was carried out. During the average follow-up period of 33 months, the patients' clinical state showed appreciable improvement. The Lysholm score modified by Klein and Jensen increased from 43.2 points preoperatively to 78.1 points at follow-up. Also, the Insall score (knee score and functional score) showed a highly significant increase of 25.7 and 25.2 points to 71.2 and 80.2 points, respectively. Patients receiving additional radiation synovectomy showed a highly significantly better result than those receiving synovectomy alone. Among the individual variables investigated, pain, swelling, and walking distance in particular were improved. Only radiologically was a mild worsening observed (from Larsen stage 1.57 preoperatively to 1.95 at follow-up). The follow-up examination revealed no synovitis in 80.6% of the patients. Subjectively, 76.4% of the patients assessed the results to be good or very good, with only 7.5% remaining unsatisfied. 90.3% of the patients declared themselves in retrospect willing to undergo the operation again.

Hepatocyte growth factor in human osteoarthritic cartilage.

OBJECTIVE: Hepatocyte growth factor/scatter factor is a potent mitogen, morphogen and motogen for a variety of mainly epithelial cells. Hepatocyte growth factor is synthesized by mesenchymal cells and can be found in various tissues. The objective of this study was to investigate the expression and distribution patterns of this pleiotropic growth factor and its receptor, the product of the proto-oncogene c-met in normal and osteoarthritic human knee cartilage. METHODS: Five normal and 14 osteoarthritic human cartilage samples graded histomorphologically by Mankin Score, were studied by radioactive in-situ hybridization and immunohistochemistry for the expression of Hepatocyte growth factor and the c-met receptor. RESULTS: Hepatocyte growth factor could be found by immunohistochemistry in the territorial matrix surrounding the chondrocytes of calcified cartilage and within the deep zone of normal cartilage. Chondrocytes of these cartilage zones showed also positive c-met receptor-staining. Moreover, a small number of chondrocytes in the superficial and intermediate zone showed c-met staining. In accordance with the increased hepatocyte growth factor staining of osteoarthritic cartilage, an enhanced expression of hepatocyte growth factor-RNA by chondrocytes of the deep zone as well as the deeper mid zone was observed. Contrary to normal cartilage, c-met was identified immunohistochemically in osteoarthritic chondrocytes of all cartilage zones. CONCLUSION: These results indicate that hepatocyte growth factor seems to be acting in an autocrine/paracrine manner in normal and osteoarthritic cartilage. The ubiquitous presence of the HGF/HGF-receptor complex in osteoarthritic chondrocytes suggests that hepatocyte growth factor may contribute to the altered metabolism in osteoarthritic cartilage.

Expression of type VI collagen in normal and osteoarthritic human cartilage.

OBJECTIVE: This study was undertaken in order to study the expression of type VI collagen in normal and osteoarthritic human knee cartilage. METHODS: Seventy-two osteoarthritic cartilage/bone samples were obtained form 29 patients with primary OA undergoing surgery for a total knee replacement. Normal cartilage was collected from five human knees at the time of autopsy. Type VI collagen protein was localized using a polyclonal anti human type VI collagen antibody, the corresponding mRNA was detected with an 310 base antisense probe, specific for the alpha2(VI) collagen chain. RESULTS: In normal cartilage, type VI collagen protein is concentrated pericellularly around the chondrocytes of all cartilage zones. In the middle and deep zones, type VI collagen was also found in the interterritorial matrix. Type VI collagen mRNA expression was detected in chondrocytes of all cartilage zones. In moderately affected osteoarthritic cartilage, type VI collagen expression was increased. An intensive immunohistological interterritorial staining for type VI collagen was observed in the middle and deep cartilage zones. Specific mRNA signals were also increased especially in the middle and deep cartilage zone. In the superficial zone and calcified cartilage of these samples, type VI collagen mRNA expression was restricted to focal areas. In severe osteoarthritic cartilage, an intensive staining for type VI collagen mRNA was found in clusters of proliferating chondrocytes and in the deep cartilage zone. Type VI collagen was localized pericellularly and in the matrix of chondrocyte clusters. Furthermore, chondrocytes from the deep zone showed a territorial distribution of type VI collagen. CONCLUSIONS: These results demonstrate that in normal and osteoarthritic cartilage, type VI collagen is expressed in a zone specific pattern. The observed increase of type VI collagen expression in osteoarthritis suggests a potential role in the disease process.

[Metabolic activation of chondrocytes in human osteoarthritis. Expression of type II collagen]. / Metabolische Aktivierung der Chondrozyten bei der humanen Arthrose. Expression von Kollagen Typ II.

OBJECTIVE/METHODS: Type II collagen is the dominating collagen in articular cartilage. It is essential for the structural integrity and the biomechanical properties of cartilage. Using immunohistology and in situ hybridization we systematically analyzed the protein and mRNA-expression of type II collagen in cartilage/bone sections without any signs of osteoarthritis and osteoarthritic samples with various degrees of osteoarthritis. RESULTS: In normal articular cartilage without any histologic signs of osteoarthritis type II collagen was distributed homogeneously. An expression of the type II collagen-mRNA was not detectable in any of these samples. In cartilage sections with a roughening of the cartilage surface and a superficial loss of the safranin O staining as early histologic signs of osteoarthritis the immunohistologic staining for type II collagen was reduced in the deep cartilage zone. An expression of the type II collagen-mRNA was found in 19 of 35 preparations. This expression, however, was restricted to the middle and deep zone of cartilage. A good and reproducible correlation of the specific gene and protein expression was found in samples with more severe osteoarthritic lesions. CONCLUSIONS: Detailed information on metabolic changes and the activation of chondrocytes in osteoarthritic cartilage are important to characterize certain stages of osteoarthritis and thus identify new prognostic factors. Increasing knowledge of the factors regulating the matrix synthesis and degradation in cartilage will provide the basis for new disease modifying therapies in osteoarthritis.

Measurement of cartilage thickness in the human knee-joint by magnetic resonance imaging using a three-dimensional gradient-echo sequence.

We studied human specimens and compared data on cartilage thickness measurements with magnetic resonance imaging by using an image analysing system with corresponding histological sections in the middle of each sector. The findings are based on 768 measurements in 26 knee joints. Overall, there was very good magnetic resonance/anatomic correlation (r=0.88). The poorest correlation was in the sectors of the femur (r=0.69). The correlation seemed not to be dependent on the grade of osteoarthritic cartilage lesions. Despite good correlation rates, the mean magnetic resonance/anatomic difference (absolute values) was 0.41 mm (standard deviation (SD) 0.34 mm) or 18.08% (SD 18.9%). Imaging techniques need to be improved if the assessment of cartilage thickness by this means is to be of clinical relevance.