Molecular signatures and new candidates to target the pathogenesis of rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic, inflammatory joint disease of unknown etiology and pronounced interpatient heterogeneity. To characterize RA at the molecular level and to uncover pathomechanisms, we performed genome-wide gene expression analysis. We identified a set of 1,054 genes significantly deregulated in pair-wise comparisons between RA and osteoarthritis (OA) patients, RA and normal donors (ND), or OA and ND. Correlation analysis revealed gene sets regulated identically in all three groups. As a prominent example secreted phosphoprotein 1 (SPP1) was identified to be significantly upregulated in RA compared with both OA and ND. SPP1 expression was found to correlate with genes expressed during an inflammatory response, T-cell activation and apoptosis, suggesting common underlying regulatory networks. A subclassification of RA patients was achieved on the basis of proteoglycan 4 (PRG4) expression, distinguishing PRG4 high and low expressors and reflecting the heterogeneity of the disease. In addition, we found that low PRG4 expression was associated with a more aggressive disease stage, which is in accordance with PRG4 loss-of-function mutations causing camptodactyly-arthropathy-coxa vara-pericarditis syndrome. Altogether we provide evidence for molecular signatures of RA and RA subclasses, sets of new candidate genes as well as for candidate gene networks, which extend our understanding of disease mechanisms and may lead to an improved diagnosis.

[A rare coagulation disorder. Diagnostics and management in cases of hereditary dysfibrinogenemia]. / Seltene Ursache einer hämorrhagischen Diathese. Diagnostik und perioperatives Management bei hereditärer Dysfibrinogenämie.

Before elective surgery, it is mandatory that a precise history be taken to detect increased hemorrhagic diathesis and that thrombocytes, Quick/INR, and aPTT be determined. If pathological levels are found, further laboratory tests are necessary after frequent causes (e.g., liver cirrhosis) have been excluded. Single-factor analysis for the von Willebrand's factor antigen and if necessary further tests to check for von Willebrand's syndrome (multimeric analysis) as well as platelet function tests should be performed.Dysfibrinogenemia is a rare coagulation disorder, which causes elevated INR. It shows a wide spectrum of clinical manifestations including thrombophilia, excessive bleeding, and even asymptomatic cases. We present a 72-year-old patient with asymptomatic dysfibrinogenemia who needed hip replacement due to arthrosis. Lowered fibrinogen levels were substituted prior to operation and the clinical course afterwards was uneventful under additional prophylactic anticoagulation in order to prevent thrombosis. The case report illustrates the interdisciplinary teamwork which is very important in the management of patients with coagulation disorders.

Proposal for a histopathological consensus classification of the periprosthetic interface membrane.

AIMS: The introduction of clearly defined histopathological criteria for a standardised evaluation of the periprosthetic membrane, which can appear in cases of total joint arthroplasty revision surgery. METHODS: Based on histomorphological criteria, four types of periprosthetic membrane were defined: wear particle induced type (detection of foreign body particles; macrophages and multinucleated giant cells occupy at least 20% of the area; type I); infectious type (granulation tissue with neutrophilic granulocytes, plasma cells and few, if any, wear particles; type II); combined type (aspects of type I and type II occur simultaneously; type III); and indeterminate type (neither criteria for type I nor type II are fulfilled; type IV). The periprosthetic membranes of 370 patients (217 women, 153 men; mean age 67.6 years, mean period until revision surgery 7.4 years) were analysed according to the defined criteria. RESULTS: Frequency of histopathological membrane types was: type I 54.3%, type II 19.7%, type III 5.4%, type IV 15.4%, and not assessable 5.1%. The mean period between primary arthroplasty and revision surgery was 10.1 years for type I, 3.2 years for type II, 4.5 years for type III and 5.4 years for type IV. The correlation between histopathological and microbiological diagnosis was high (89.7%), and the inter-observer reproducibility sufficient (85%). CONCLUSION: The classification proposed enables standardised typing of periprosthetic membranes and may serve as a tool for further research on the pathogenesis of the loosening of total joint replacement. The study highlights the importance of non-infectious, non-particle induced loosening of prosthetic devices in orthopaedic surgery (membrane type IV), which was observed in 15.4% of patients.

The treatment of severe hyponatremia.

Severe hyponatremia may be chronic (days) or acute (hours), symptomatic or asymptomatic. Severe chronic symptomatic hyponatremia (serum sodium concentration < 110 to 115 mM/liter) occurs most commonly in the syndrome of inappropriate antidiuretic hormone secretion (SIADH). The treatment of this hyponatremia is a challenge to practicing physicians, in part because an overly rapid correction of hyponatremia may cause brain damage. The latter sometimes takes the form of central pontine myelinolysis (CPM). On the basis of available clinical and experimental literature, the rate of correction of this symptomatic hyponatremia should be no more than 0.5 mM per liter per hour, and the initial treatment should be halted once a mildly hyponatremic range of the serum sodium concentration has been reached (approximately 125 to 130 mM/liter). In contrast, severe chronic asymptomatic hyponatremia may be treated sufficiently by a fluid restriction. On the other hand, severe symptomatic acute hyponatremia should be treated promptly and rapidly, using hypertonic saline, to initially reach a mildly hyponatremic level.

Changes in systemic levels of insulin-like growth factors and their binding proteins in patients with rheumatoid arthritis.

OBJECTIVE: To determine whether circulating levels of insulin-like growth factors and their binding proteins are altered in patients with adult onset rheumatoid arthritis. METHODS: Plasma-levels of insulin-like growth factor-I (IGF-I), IGF-II, IGF-binding-protein 2 (IGFBP-2), and IGFBP-3 were measured by radioimmunoassay in 53 patients with clinically active rheumatoid arthritis (RA) and in 51 control subjects. RESULTS: In RA patients plasma levels of IGF-II were lower (601 +/- 34 vs. 731 +/- 32 micrograms/L (mean +/- SEM); p = 0.005; Mann-Whitney rank sum test) than in age- and sex-matched controls (n = 30 per group). In contrast, plasma levels of IGFBP-2 (412 +/- 40 vs. 254 +/- 20 micrograms/L; p = 0.003) and IGFBP-3 were elevated in RA patients (3.34 +/- 0.19 vs. 2.87 +/- 0.21 mg/L; p = 0.019) as compared with the matched controls. The molar ratio of IGF-I to IGFBP-3 was significantly reduced in subjects with RA (0.18 +/- 0.01 vs. 0.24 +/- 0.02; p = 0.008). Furthermore, in RA patients plasma levels of IGFBP-2 were positively (r = 0.45), and levels of IGF-2 negatively (r = -0.45) correlated with circulating levels of C-reactive protein (p < 0.01 in both cases; Spearman rank correlation). CONCLUSION: Increased levels of IGFBPs in RA may result in the reduced availability of free IGFs that can bind to IGF receptors. The observed changes in the IGF system may thus participate in the catabolic processes in rheumatoid arthritis.

Grading of chronic synovitis--a histopathological grading system for molecular and diagnostic pathology.

The following is a proposition for a simple histopathological classification system to measure inflammation in synovial tissue. This synovitis-score is employed in conventionally stained routine sections, and is applicable to every kind of synovitis, irrespective of etiology and including the following relevant morphological alterations. First: hyperplasia/enlargement of synovial lining cell layer. Second: activation of resident cells/synovial stroma. Third: inflammatory infiltration. All defined histopathological qualities are graded from absent (0), slight (1) and moderate (2) to strong (3), with summaries ranging from 0 to 9. 0 to 1 corresponds to no synovitis (inflammatory grade = 0), 2 to 3 to a slight synovitis (inflammatory grade 1), 4 to 6 to a moderate synovitis (inflammatory grade 2), and 7 to 9 to a strong synovitis (inflammatory grade 3). Using this score, we analyzed 308 random specimens of synovial tissue from degenerative (osteoarthritis (OA)) and inflammatory joint diseases - reactive arthritis (ReA), psoriasis arthritis (PA) and rheumatoid arthritis (RA) - as well as synovial tissue from healthy individuals. The mean grade given to synovitis of RA turned out to be significantly higher than the mean grade of OA (p < 0.0005) and of healthy controls (p < 0.0005). On the contrary, no significant differences could be found between the mean grades of synovitis scores from patients with RA and those with PA and ReA. Another comparison between RA-synovitis types I and II according to the Stiehl classification resulted in type I (p < 0.0005), showing significantly higher values of inflammatory infiltration, and type II (p = 0.037), showing significantly higher values of stroma activation. Since in OA, synovitis is regarded as a result of degenerative cartilage destruction whereas in inflammatory joint diseases (RA, PA, ReA), synovitis is regarded to be the cause of cartilage destruction, it can be concluded that scores with considerable high values indicate the pathogenetic potential of synovitis and that the inflammatory score may be helpful in estimating the destructive potential of synovitis at the same time. Furthermore, the comparison of the score data with the Stiehl RA-synovitis types shows that the score enables us to discriminate the morphological peculiarities of the synovitis types. In experimental pathology, it could provide standardized information on molecular synovial tissue analyses where a correlation of molecular with morphological data is essential. In diagnostic pathology, this synovitis score (in combination with other typing systems) could provide basic and standardized information concerning the degree of inflammatory alterations in synovial tissue.

[Importance of newly defined epiphyseal version in diagnosis and therapy of epiphysiolysis capitis femoris (additional data to epiphyseal dislocation and epiphyseal torsion)]. / Bedeutung einer neu definierten Epiphysenversion für die Diagnostik und Therapie der Epiphyseolysis capitis femoris (Ergänzung zur Epiphysendislokation und Epiphysentorsion).

The displacement of the femoral epiphysis in epiphyseolysis capitis femoris is usually determined by measuring both the epiphysis-diaphysis angle (ED angle) in the plane of the dislocation and the epiphysis-torsion angle (ET angle) in the torsional plane. In this paper we define an epiphyseal version angle (EV angle) in the sagittal plane of the femur, calculate it trigonometrically and show it in diagrams and tables. The clinical application of the EV angle indicates that in cases of displacement with an ED angle of less than 135 degrees, absolute displacement is better shown than with the ET angle. Additionally, the EV angle improves our comprehension of the 3-D displacement due to the fact that, in the "Lauenstein" x-ray, the femur is increasingly projected more in a sagittal plane with increasing abduction. The essential correction using the Imhäuser-osteotomy is also done in the sagittal plane. The ability of the orthopaedic surgeon to visualize the situation in three dimensions is also improved by this additional standard plane.

Incidence of early postoperative cognitive dysfunction and other adverse events in elderly patients undergoing elective total hip replacement (THR).

In elderly patients cognitive dysfunction and other adverse events (AEs) can impair the outcome of surgical procedures. As THR is performed with increasing frequency in aging populations, it is important to know the impact of these problems on the postoperative result. In this prospective cohort study 60 patients older than 65 years (66.7% female, 33.3% male) who received THR were included. The cognitive function was measured preoperatively, one week and six months postoperatively by the mini-mental state test (MMSE). Shortly after surgery 4 patients (6.7%) developed postoperative cognitive dysfunction, which has recovered at six-months-follow-up. In 41 patients (68.3%) AEs were recorded. Postoperative anemia occurred as the most common AE (n=32; 53.3%). During hospital stay older patients are at an increased risk for AEs. The incidence of postoperative cognitive dysfunction was observed less often than expected. Further research is necessary to assess the effect of early interventions in case of cognitive dysfunction. With use of a simple and quickly performed test like the MMSE patients can be effectively screened for impaired cognitive function. Secure identification of those patients is mandatory to avoid complications with harmful long-term effects.

[Intra-articular steroid therapy for inflammatory rheumatic diseases in children and adolescents]. / Die intraartikuläre Steroidtherapie bei entzündlichrheumatischen Krankheiten des Kindes- und Jugendalters.

In addition to systemic medication,physiotherapy, and operative measures, intraarticular therapy with corticosteroids (iaST) is a well established treatment for juvenile idiopathic arthritis (JIA). IaST is indicated in children whose inflamed joints do not respond sufficiently to systemic antiarthritic drugs and is normally carried out under in-patient conditions. Triamcinolone hexacetonide (TH) is the drug of choice for iaST because of its well documented, long-lasting effects. In younger children or those who require simultaneous injections into multiple joints, a short general anesthesia is useful, while single injections in older children can be administered after topical application of a local anesthetic. Intensive physiotherapy after iaST is important for regaining mobility lost due to the arthritis, and 2 or 3 days of post-injection rest should be adhered to after iaST of joints of the lower extremities. Several studies demonstrate long-lasting remission in the majority of the injected joints in JIA patients, with good pain-relief, improved mobility, and a significant delay in further joint destruction in comparison with joints in which the synovitis could not be adequately controlled. Various sub-types of JIA have been shown to respond differently to iaST. Intraarticular steroids can also be used to treat coxitis, since recent data failed to show a subsequent increase in the rate of femoral head necrosis. Septic arthritis, the most feared complication after iaTH, seems to be extremely rare in children. Other complications, like periarticular calcifications or subcutaneous atrophy, also occur only rarely, provided the steroid is injected correctly. The present data indicate that iaST is an effective and safe treatment for JIA. The therapeutic approach to children with JIA is multidisciplinary, and these young patients should be treated in specialised centres.

[Interposition-arthroplasty of the elbow in a child as delayed treatment of an unreduced multifragmentary fracture of the distal humerus: result after 77 years--case report and review of the literature]. / Interpositionsarthroplastik des Ellenbogens bei einem Kind wegen veralteter distaler Humerusmehrfragmentfraktur: Ergebnis nach 77 Jahren - Fallbericht und Literaturübersicht.

Post-traumatic stiffness of the elbow joint in children after unreduced multifragmentary fractures of the distal humerus can be successfully treated by interposition arthroplasty. A case with long-term follow up is described, and the literature discussed.

[No improvement of joint cartilage healing after trauma by the administration of insulin-like growth factor I, epidermal growth factor and fibroblast growth factor in rabbits]. / Keine Verbesserung der Gelenkknorpelheilung nach Trauma durch intraarticuläre Gabe von insulinartigem Wachstumsfaktor I, epidermalem Wachstumsfaktor und Fibroblasten-Wachstumsfaktor beim Kaninchen.

Insulin-like growth factor I (Somatomedin C), epidermal growth factor, and fibroblast growth factor exert a stimulatory effect on articular chondrocyte metabolism in vitro. We studied the effect of these peptides on the repair of standardized full-thickness articular cartilage defects in the knee-joints of 32 young adult rabbits. In our in vivo study, the growth factors failed to stimulate cartilage cell replication, chondrocyte proteoglycan synthesis or defect filling. The trauma, however, had a significant stimulatory effect on the mitotic activity of the chondrocytes near the defect, but not on the synthesis of sulfated proteoglycans.

[Value of synovial analysis for prognosis of matrix synthesis of transplanted chondrocytes]. / Stellenwert der Synoviaanalyse für die Prognose der Matrixsynthese transplantierter Chondrozyten.

Successful transplantation of autologous chondrocytes for repair of articular cartilage defects requires an undisturbed matrix-synthesis of the transplanted cells. This, in turn, is dependent on the composition of the synovial fluid (SF) of the respective joint. We addressed the question whether analysis of a patient's SF can predict the rate of matrix-synthesis of articular cartilage exposed to this SF in vitro. SF was obtained from 115 patients with disorders of the knee, including gonarthrosis (n = 44), meniscal tears (n = 10), rheumatoid arthritis (n = 53), and reactive arthritides (n = 8). In the SF, the following parameters were determined: Interleukin-1 beta, IL-6, IL-8, IL-1-RA, TNF alpha, Insulin-like growth-factor I (IGF-I), IGF-II, IGF-binding protein-2 (IGFBP-2), IGFBP-3 as well as total proteinase activity and total collagenase activity. To assess the effect of SF on the matrix synthesis of articular chondrocytes, bovine cartilage was incubated in the presence of SF, and the rate of proteoglycan synthesis subsequently determined. In some cases, a monoclonal antibody directed against IGF-I was added. SF from patients with OA or trauma, respectively, stimulated PG-synthesis of bovine cartilage more markedly than did SF from patients with rheumatic arthritides. On the average, 60 percent of the SF-induced increase of cartilage matrix synthesis could be titrated out by an anti-IGF-I-AB. The best predictor for the SF-effects on PG-synthesis of exposed cartilage was the proportion of free IGF-I (r = 0.573, p < 0.001, Spearman rank correlation) followed by the SF-concentrations of IGF-I (with a positive sign), IGFBP-3, IL-1 beta, and TNF alpha (all with a negative sign). According to our data, IGF-I is the most important anabolic factor in human SF with respect to cartilage PG-synthesis. The proportion of free IGF-I seems to be of special importance in this regard. Low SF-levels of free IGF-I could be identified as a possible risk-factor for a sub-optimal protoeglycan synthesis of chondrocytes exposed to this synovial milieu.

[Percentile graphs in the documentation of acetabular angle in children with hip dysplasia. A tool in the diagnosis and quality control of its treatment]. / Perzentil-Graphiken für die Dokumentation des Pfannendachwinkels bei Kindern mit Hüftdysplasie. Ein Hilfsmittel für die Diagnostik und die Qualitätskontrolle der Behandlung.

The acetabular index (AI; Hilgenreiner 1925) has proven to be a reliable parameter for the radiological diagnosis of developmental hip dysplasia (DDH). Age-dependent normal values and ranges of the AI are well documented. These data, however, have so far not been presented graphically in a way which would have made them suitable for patient data documentation on a routine basis (calculation of percentiles, time-axis with log scale, smoothing). We have therefore created graphs meeting these requirements, based on a previous examination of the AI of 719 girls and 428 boys (Tönnis and Brunken 1968). These graphs have meanwhile proven to be a useful and time-saving tool for the diagnosis as well as quality control of the treatment in children with DDH.

Independent effects of interleukin 1 on proteoglycan synthesis and proteoglycan breakdown of bovine articular cartilage in vitro.

We studied the effects of human recombinant interleukin-1 beta on proteoglycan metabolism of bovine articular cartilage in organ culture. IL-1 was more potent in inhibiting synthesis (IC50 4 ng/mL) than in stimulating breakdown of proteoglycans (EC50 200 ng/mL). Inhibition of proteoglycan synthesis began to plateau earlier (2 days) than stimulation of proteoglycan release (4 days). Both effects could be neutralized with a polyclonal anti-IL-1 beta antibody; however, higher antibody titers were required to block IL-1 effects on proteoglycan synthesis than to neutralize those on proteoglycan release. Chloroquine, but not hydrocortisone, blocked IL-1-mediated proteoglycan breakdown. Both drugs, however, augmented IL-1-induced inhibition of proteoglycan synthesis. Our data suggest that the effects of IL-1 on articular cartilage proteoglycan synthesis and proteoglycan breakdown can be regulated independently.

Association between degree of bone-erosion and synovial fluid-levels of tumor necrosis factor alpha in the knee-joints of patients with rheumatoid arthritis.

OBJECTIVE: To determine whether concentrations of cytokines and matrix-degrading enzymes in synovial fluid of patients with rheumatoid arthritis or osteoarthritis are associated with the degree of bone-destruction in the same joint. METHODS: Determination of Interleukin-1 alpha, IL-1 beta, IL-1-receptor-antagonist, IL-6, IL-8, tumor necrosis factor alpha (by ELISA), collagenase-activity and caseinase-activity (by substrate-assays) in the SF (knee) of patients with RA (n42) or OA (n35). The degree of bone-destruction was assessed radiographically. RESULTS: SF cytokine- and enzyme-levels were higher in patients with RA than in those with OA. In the RA group, SF-levels of TNF alpha were positively correlated with the degree of bone destruction of the respective joint. No correlation was found between radiographically assessed joint changes and SF-concentrations of other cytokines, enzyme activities, serum CRP, or duration of disease. In the OA-group, none of the examined parameters was associated with the degree of joint destruction. CONCLUSIONS: Our data may support the assumption of TNF alpha playing an important role in joint destruction in RA. Possible alternative conclusions are discussed.

Insulin-like growth factor I accelerates recovery of articular cartilage proteoglycan synthesis in culture after inhibition by interleukin 1.

Interleukin 1 (IL-1) is a cytokine which induces cartilage proteoglycan (PG) depletion by inhibiting PG synthesis and increasing PG breakdown. Insulin-like growth factor I (IGF-I), in contrast, is known to promote matrix formation. We examined the effects of both mediators in a bovine tissue culture model. IL-1 dose-dependently inhibited PG formation of articular cartilage [half-maximal effect (EC50) at 4 ng/ml], while PG synthesis was increased by IGF-I (EC50 = 15 ng/ml). After inhibition of PG formation with IL-1 for 2 days and subsequent removal of free IL-1, addition of IGF-I dose-dependently accelerated restoration of the original rate of synthesis with a half-maximal effect at 20 ng/ml and a maximal effect at 50 ng/ml. The IGF-I concentration required to elicit a half-maximal effect on cartilage PG synthesis remained constant in the absence or presence of IL-1. We therefore conclude that inhibition of cartilage PG synthesis by IL-1 is not effected by damage to the IGF receptor. Synovial fluid (SF) of 40 patients with rheumatoid arthritis (RA) was found to contain 64 +/- 6 ng IGF-I/ml (mean +/- SEM). The reported effects of IGF-I in vitro therefore occurred at concentrations comparable to those present in joints in vivo. IL-1 beta was detectable (> 0.5 pg/ml) in 38 of 40 RA-SF samples (mean 28 +/- 6 pg/ml).(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of high-dose methotrexate on the development of cartilage lesions in a lapine model of osteoarthrosis.

To determine whether systemic administration of methotrexate (MTX) can prevent joint destruction in experimental osteoarthrosis (OA) in rabbits, the disorder was induced unilaterally in the knee joints of 40 rabbits by partial medial meniscectomy and sectioning of the medial collateral and both cruciate ligaments. A sham operation (arthrotomy only) was performed in another four animals. Effects on the cartilage of the femoral condyles were studied after 6 and 12 weeks. Twelve weeks after induction, femoral and tibial osteophyte formation was demonstrated on radiographs in all cases. Marked cartilage damage was found histologically (median Mankin score 10 vs 1 for non-operated controls; P < 0.05, Wilcoxon test). Cartilage proteoglycan (GAG) content (dye binding assay) was reduced in operated joints [63 +/- 8 (mean +/- SEM) vs 75 +/- 6 micrograms chondroitin sulfate/mg cartilage wet weight], and the leukocyte count in the joints was elevated (226 +/- 14 vs 7 +/- 3 leukocytes per microliter joint aspirate after injection of 0.5 ml saline solution; both P < 0.05, Wilcoxon test). The rate of GAG synthesis was unchanged (ex vivo labelling with 35S-sulfate). Treatment with MTX (30 mg x kg body weight-1 x week-1 i.m., starting 12 h postoperatively) reduced cartilage damage (median Mankin score 8 vs 10 for placebo, P < 0.05, Mann-Whitney U-test), but had no significant effect on the other parameters tested. No significant MTX effects were observed on cartilage from nonoperated joints. Our data indicate that MTX may have a limited therapeutic effect in experimental OA in the rabbit.

Low plasma levels of insulin-like growth factor I in Perthes' disease. A controlled study of 59 consecutive children.

We studied Insulin-like Growth Factor I (IGF I) plasma levels, standing height, and weight in 59 consecutive children with Perthes' disease and 59 matched controls. The plasma-IGF I levels, measured by radioimmunoassay after acid ethanol extraction, were reduced in affected children during the first 2 years after the diagnosis of Perthes' disease. Partially paralleling the alterations in IGF I plasma levels, there was a tendency towards growth arrest and impaired weight-gain during early-stage disease, followed by catch-up growth and increased weight-gain. No relation was found between degree of femoral head involvement, according to Catterall (1971), and IGF I plasma-levels or body mass. Our data may reflect an impaired synthesis or release of IGF I relative to age in Perthes' disease, or changes in the affinity or metabolism of IGF binding proteins. The observed changes seem to be of a temporary nature.