The disease modifying osteoarthritis drug diacerein is able to antagonize pro inflammatory state of chondrocytes under mild mechanical stimuli.

OBJECTIVE: To investigate the combination of mild mechanical stimuli and a disease modifying osteoarthritis drug (DMOAD) in inflammatory activated chondrocytes and to study the combination of drug and mechanical tension on the cellular level as a model for an integrated biophysical approach for osteoarthritis (OA) treatments. METHODS: Interleukin-1beta (IL-1ß) stimulated C28/I2 cells underwent mild mechanically treatment while cultured in the presence of the DMOAD diacerein. The pharmacological input of diacerein was evaluated by cell viability and cell proliferation measurements. Inflammation and treatment induced changes in key regulatory proteins and components of the extracellular matrix (ECM) were characterized by quantitative real-time PCR (qPCR). The effects on metalloproteinase-1 (MMP-1) activity and glycosaminoglycan (GAG) concentration in cell supernatants of treated cells were investigated. RESULTS: C28/I2 cells demonstrated significant changes in expression of inflammatory and cartilage destructive proteins in response to IL-1ß stimulation. The chondroprotective action of diacerein in mechanically stimulated cells was mediated by a decrease in interleukin-8 (IL-8), fibronectin-1 (FN-1), collagen type I (Col 1) and MMP-1 expression levels, respectively. Augmented expression of interleukin-6 receptor (IL-6R) and the fibroblast growth factor receptors (FGFRs) by diacerein was not abolished by mechanical treatment. The observed effects were accompanied by a reduced cell proliferation rate, attenuated cell viability and extenuated MMP-1 activity. CONCLUSION: Diacerein diversely regulates the expression of main regulatory proteins as well as components important to regenerate and set up ECM. Mechanical stimulation does not negatively influence the chondroprotective effect induced by diacerein treatment in immortalized human C28/I2 chondrocytes.

One-year-survey with multicenter data of more than 4,500 patients with degenerative rheumatic diseases treated with therapeutic nuclear magnetic resonance.

BACKGROUND AND OBJECTIVES: Nuclear magnetic resonance (NMR) has been shown to stimulate repair processes and cartilage and to influence pain signalling. It represents an alternative therapy for patients suffering from osteoarthritis (OA). To prove the clinical success of this new therapeutical method, validated measuring parameters are important that are convincing for pain and function in a one-year-follow-up. METHODS: During the course of its application over the last 10 years, over 4,500 protocols of a one-year-follow-up have been collected to record the outcome of NMR therapy. This report reflects the outcome of NMR therapy on patients with the following degenerative rheumatic diseases: OA of the knee (n = 2.770), OA of the hip (n = 673), OA of the ankle joint (n = 420) and chronic low back pain (n = 655). Data were collected at baseline, 6­8 weeks and 6 and 12 months following NMR treatment. RESULTS: Pain was reduced significantly 6 weeks after NMR treatment in the cases of all four examined indications and stayed measurably reduced up to 6 and 12 months. The improvements in all three forms of pain (pain on load, pain on motion, pain at rest) following NMR treatment were around 21­50% on average. CONCLUSIONS: Following therapy with NMR, patients with OA of all four types experienced a distinct improvement in their ability in functional parameters. Overall, the 10 years of a one-year-survey with multicenter data gathered on the effect of NMR therapy on patients verifiably proved its efficacy amongst patients with degenerative rheumatic diseases.

Effect of the NSAID nimesulide on the radical scavenger glutathione S-transferase in patients with osteoarthritis of the knee.

OBJECTIVE: Osteoarthritis (OA) of the knee is a secondary inflammatory, painful disease of the knee joint with increasing destruction of the articular cartilage. In the inflammatory process the formation of free radicals (reactive oxygen species, ROS) plays a major role in progression of disease and in the subsequent destruction of joint cartilage. The aim of this pilot study was to examine the antioxidative potency of the non-steroidal anti-inflammatory drug (NSAID) nimesulide on glutathione S-transferase (GST), an enzymatic free radical scavenger. In addition, the effects on matrix metalloproteinase MMP-3 and its antagonist tissue inhibitor of matrix-metalloproteinase 3 (TIMP-1) were determined. RESEARCH DESIGN AND METHODS: This was an open-pilot study on 20 patients (aged 41-71 years old) suffering from painful OA of the knee, treated for 3 weeks with nimesulide 100 mg b.i.d. Twenty-three healthy subjects (aged 23-57 years), not age matched, served as a comparison group. GST, MMP-3 and TIMP-1 were measured by enzyme-immunoassays. Clinical symptoms and joint function were measured using the WOMAC Index. RESULTS: During the 3-week treatment period with nimesulide 100 mg b.i.d., both scavenger GST and the TIMP-1/MMP-3 ratio significantly increased. This change was accompanied by significant clinical improvement in terms of pain reduction, stiffness and joint function. Two adverse events occurred possibly related to nimesulide treatment: one case of moderate eyelid swelling, and one case of moderate diarrhea with no abnormality in the endoscopic examination. CONCLUSIONS: These results confirm the antioxidative properties of the study drug, indicating that nimesulide, beside its known anti-inflammatory properties, also shows an evident antioxidative activity that adds further supportive evidence to its key role in the treatment of OA patients (thanks to the absence of degenerative effects on cartilage).

Inhibitory effects of leflunomide therapy on the activity of matrixmetalloproteinase-9 and the release of cartilage oligomeric matrix protein in patients with rheumatoid arthritis.

OBJECTIVE: To determine the effects of the disease modifying antirheumatic drug (DMARD) leflunomide on the expression of the matrix metalloproteinase MMP-1 (collagenase) and the activity of MMP-9 that are believed to play a major role in cartilage destruction associated with inflammation in patients with rheumatoid arthritis (RA). Serum concentrations of cartilage oligomeric matrix protein (COMP) should offer promise for monitoring tissue degradation in the RA joints during a 6-month therapy with leflunomide. METHODS: Thirty-six patients with RA meeting the ACR-criteria were recruited for the study in a multicentre trial. A dose of 20 mg leflunomide/day (after a 3-day 100 mg/day loading dose), an isoxazole derivate and inhibitor of the "de novo" pyrimidine synthesis, was administered for a study period of 6 months. MMP-1, the activity of MMP-9 and COMP values were measured in serum by enzyme immuno assay. The very sensitive acute phase protein serum amyloid A (SAA) was also determined by EIA. The measurements were performed before and after 3 and 6 months of leflunomide therapy. RESULTS: High levels of active MMP-9, COMP and SAA were detected in the sera of the patients with RA prior to the start of the leflunomide therapy compared to normal control sera. A significant reduction of the MMP-9 activity levels was seen after 3 months immunomodulation with leflunomide and was maintained after 6 months (p < 0.01). The degradation marker COMP and the inflammation marker SAA decreased significantly after 6 months (p < 0.04, respectively p < 0.01). There was also an insignificant tendency of MMP-1 reduction in serum after 6 months. CONCLUSION: This study demonstrated that a DMARD therapy with leflunomide can cause positive effects on cartilage degradation and inflammation achieving reductions in the acute phase protein SAA, the enzymatic attack of MMPs and the loss of the cartilage matrix component COMP.

Efficacy and tolerance of an oral enzyme combination in painful osteoarthritis of the hip. A double-blind, randomised study comparing oral enzymes with non-steroidal anti-inflammatory drugs.

OBJECTIVE: The objective of this study was to establish the non-inferiority of an oral enzyme therapy (Phlogenzym-(PE)) as compared to the non-steroidal anti-inflammatory drug (NSAID) diclofenac (DC) in patients with osteoarthritis (OA) of the hip. METHODS: Ninety patients presenting with painful episodes of OA of the hip were treated for 6 weeks in one study centre in a phase III, randomised, double blind, parallel group trial. Altogether, 45 patients were treated in the PE group and 45 patients were treated in the DC group. Primary efficacy criteria were: WOMAC dimensions pain, joint stiffness and function, and Lequesne index as multiple endpoint according to O'Brien. The efficacy criteria were analysed applying the test of non-inferiority with regard to mean changes and frequencies, t-test, U test, ANCOVA and descriptive methods. RESULTS: Within the 6 weeks observation period, the adjusted changes from baseline to endpoint of the target parameters worked out as follows (adjusted differences, mean +/- SEM): WOMAC subscale pain (PE -10.3 +/- 1.2, DC -9.5 +/- 1.2), WOMAC subscale joint stiffness (PE -3.9 +/- 0.5, DC -3.6 +/- 0.5), WOMAC subscale physical function (PE -31.7 +/- 3.5, DC -29.7 +/- 3.5), Lequesne's index (PE -2.89 +/- 0.47, DC -2.27 +/- 0.47). Non-inferiority of PE as compared to DC with regard to the O'Brien's global sum of the standardised adjusted changes from baseline to endpoint in pain, stiffness, physical function, and Lequesne's index was established with p = 0.0025. PE was simultaneously non-inferior as compared to DC with regard to the 4 single endpoints: WOMAC subscale pain (p = 0.0033), WOMAC subscale joint stiffness (p = 0.0061), WOMAC subscale physical function (p = 0.0039), Lequesne's index (p = 0.0008) (closed test procedure). The equivalence tests remained insignificant due to comparatively lower effects of DC. For 71.1% of the PE patients and for 61.4% of the DC patients rates of good or very good global investigator assessments of efficacy were calculated (test of non-inferiority: p = 0.0011). In the majority of patients, tolerability was judged in both drug groups as very good or good. CONCLUSION: This trial showed significant non-inferiority from 6 weeks treatment with PE in patients with OA of the hip with regard to the WOMAC dimensions pain, stiffness and physical function, to Lequesne's index, to the investigator and patients assessments of efficacy, and to the responder rates based on pain, physical function, and patient assessment of efficacy. With regard to drug tolerability some tendencies in favour of PE were detected. However, in this study there was no real difference between PE and DC 100 mg/day, implying an equal benefit-risk relation between the substances. PE may well be recommended for the treatment of patients with osteoarthritis of the hip with signs of inflammation as indicated by a high pain level.

Preferential type 1 chemokine receptors and cytokine production of CD28- T cells in ankylosing spondylitis.

OBJECTIVE: To examine serum levels of type 1 and type 2 chemokines and lymphocytic expression of chemokine receptors, and to compare the results with lymphocytic cytokine production in patients with ankylosing spondylitis (AS). METHODS: Twelve patients with AS (mean (SD) age 44.9 (14.7) years) and 27 healthy controls (46.4 (12.8) years) were enrolled into the study. The expression of chemokine receptors (CCR-5, CXCR-3, CCR-4) and cytokines (interferon gamma (IFNgamma), interleukin (IL)2, IL4, IL10, tumour necrosis factor alpha (TNFalpha)) on CD28(+) and CD28(-) T cell subtypes was analysed by a three colour FACS technique of peripheral blood samples. Serum ELISAs were performed to detect the CCR-5 ligands CCL-5, CCL-3; the CXCR-3 ligands CXCL-10, CXCL-9; and the CCR-4 ligand, CCL-17 before and after administration of the TNFalpha blocking agent infliximab. RESULTS: CD4(+)CD28(-) T cells had higher ratios of CXCR-3 to CCR-4 than CD4(+)CD28(+) T cells. Both, CD4(+) and CD8(+)CD28(-) T cells of patients with AS produced more IFNgamma, TNFalpha, and IL10 than their CD28(+) counterparts (p<0.05), and lacked the production of IL2 and IL4. Serum levels of CXCL-9 were increased in patients with AS to 59.2 pg/ml (34.1-730.5) compared with 32.5 pg/ml (20.0-79.5) in healthy controls (p = 0.016). The levels of both type 1 (CCL-5, CXCL-9) and type 2 chemokines (CCL-17) decreased under blockade of TNFalpha (p<0.05). CONCLUSIONS: The profile of chemokine receptor expression and cytokine production by CD28(-) T cells suggests a type 1 immune reaction in AS, although IL10 is frequently produced by CD28(-) T cells. Treatment with TNFalpha blocking antibodies decreased both types of chemokines in patients' sera.

Effect of nimesulide on metalloproteinases and matrix degradation in osteoarthritis: a pilot clinical study.

In osteoarthritis (OA) the balance between cartilage degeneration and repair is disturbed. The aim of this pilot clinical study was to examine the effects of a nonsteroidal anti-inflammatory drug, nimesulide, on the synthesis of matrix metalloproteinases (MMPs) which are important enzymes in cartilage proteolysis. Cartilage oligomeric matrix protein (COMP), a component of the extracellular matrix, was used as an indicator of accelerated joint erosion. Radiologically proven painful OA of the knee or hip was treated with 100 mg nimesulide twice daily for 3 weeks. MMP-1, -3 and -8 and COMP were measured by immunoassays, and clinical investigations were made on pain, and on disease intensity using the WOMAC scale. During treatment with nimesulide, in addition to clinical improvement and less pain, serum levels of MMP-3, MMP-8 and COMP fell indicating a beneficial effect on cartilage catabolism.

[Cardiovascular manifestations in inflammatory rheumatic diseases]. / Kardiovaskuläre Manifestationen bei entzündlich rheumatischen Erkrankungen.

Inflammatory rheumatic diseases show an increased cardiovascular mortality. The reasons for this are unclear. Possible associations between atherosclerosis and autoimmune diseases like rheumatoid arthritis and systemic lupus erythematosus can be illustrated.

Association between serum pepsinogen A and C levels, serum gastrin concentrations and Helicobacter pylori antibodies.

Pepsinogen A and C as well as gastrin were measured in the serum of 117 patients with rheumatic diseases. Moreover, the patients were divided up in groups by aids of a semiquantitative, rapid enzyme immunoassay for detection of Helicobacter pylori: 20 patients without H. pylori antibodies (AB) negative, 18 positive + (= weak AB-titre), 21 positive +2 (medium AB-titre), and 58 positive +3 (high AB-titre). The semiquantitative determinations of H. pylori-AB correlated with pepsinogen A, C and gastrin. Patients with H. pylori-AB positive +3 showed significantly higher values of pepsinogen C (p < or = 0.01) as well as pepsinogen A and gastrin (p < or = 0.05) than H. pylori-AB negative patients. Significantly increased levels of pepsinogen A (> 150 ng/ml) and C (> 25 ng/ml) were found to occur in 39% and 100% of patients with high H. pylori-AB titres. The measurement of serum pepsinogen C concentrations may provide additional diagnostic information of the extent of mucosal lesions in patients with positive H. pylori-AB titres treated with antirheumatic drugs. Our findings suggest that the semi-quantitative classification of positive AB-results can be useful in cases determining H. pylori infection and mucosal irritation if other investigations are not available.

[Adhesion molecule ICAM-1 in patients with chronic polyarthritis--effects of inpatient rehabilitation]. / Das Adhäsionsmolekül ICAM-1 bei Patienten mit chronischer Polyarthritis--Einflüsse einer stationären Rehabilitation.

In rheumatoid arthritis (RA) the adhesion molecule ICAM-1 mediates the adhesion of leucocytes following subsequent transendothelial migration including interactions and adhesion of several cell types such as fibroblasts, T-lymphocytes and synoviocytes. Significantly increased ICAM-1 levels were measured in the acute phase of RA. The correlation of ICAM-1 levels with the pteridine neopterin (p < or = 0.01) may reflect the role of this adhesion molecule in modulation of immune responses. Despite the significantly higher levels of acute phase reactions parallel to the elevated ICAM-1 levels, no correlations were found between ICAM-1 and erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and serum-Amyloid A (SAA). During an in-patient multidisciplinary rehabilitation programme the levels of ICAM-1 in serum and the majority of all investigated laboratory and clinical parameters such as ESR, CRP, SAA, fibrinogen, pain, swollen and painful joint count, morning stiffness and health assessment questionnaire improved.

[Results of a multidisciplinary rehabilitation concept in patients with chronic lumbar syndromes]. / Ergebnisse eines multidisziplinären Rehabilitationskonzepts bei Patienten mit chronischen Lumbalsyndromen.

The aim of our pilot study was to evaluate the influence of a multidisciplinary rehabilitation programme on various parameters of pain and function in 88 patients suffering from chronic low back pain caused by disc herniation (46 patients) or after lumbar discectomy (42 patients). We used an exercise-based multidisciplinary programme during a four-week in-patient treatment: active physiotherapy, exercise training and back school, organized in group therapies combined with passive techniques of physiotherapy (heat, massage, electrotherapy, medicated bath) with a daily duration of treatment exceeding three hours. Symptoms and functions improved simultaneously with the reduction of pain. The results of the visual analogue scale improved significantly in both groups (conservatively treated group p < 0.0001, after lumbar discectomy p < 0.005). As for the McGill pain questionnaire, however, only the group with conservatively treated disc herniations changed significantly for the better. We found an improvement in Roland-Morris' disability questionnaire in both groups, which reached statistical significance only in the group after lumbar discectomy. Forward-backward bending (kyphometer measurement as described by Debrunner), ameliorated significantly in both groups. Our results indicate that an exercise based multidisciplinary rehabilitation programme can improve pain and function even in patients suffering from definitely chronic low back pain caused by disc herniation or after lumbar discectomy.

[Reducing pain by oral enzyme therapy in rheumatic diseases]. / Schmerzreduktion durch eine orale Enzymtherapie bei rheumatischen Erkrankungen.

Proteolytic enzymes have analgesic, effects, besides the wellknown antiinflammatory and edema-reducing properties. These analgesic effects are based on the inhibition of inflammation and in addition to that on direct influences on the nociceptors. All that explains the therapeutical effects of such enzymes in degenerative-rheumatic and soft tissue rheumatic diseases in which inflammatory or immunologic processes are not in the forefront. In recent years a significant reduction of pain in various rheumatic diseases, concerning these aspects, was shown in several clinical studies. The clinical trial in patients with periarthritis of shoulder showed statistical equivalence of pain reduction, whether they were treated with phlogenzym or diclofenac. Likewise in the trial of patients suffering from painful osteoarthritis of the knee, there was a statistical equivalence of the pain-scores, comparing diclofenac and enzymes. The study of painful vertebral syndromes again resulted in equivalence of the treatment with NSAIDs compared to therapy with enzymes.

[Results of inpatient postoperative rehabilitation after hip replacement]. / Ergebnisse der stationären postoperativen Rehabilitation nach Hüftgelenkersatz.

The study was performed as a pilot study evaluating the benefit of a 4-week inpatient postoperative rehabilitation programme. We examined 177 patients admitted after total hip replacement. We found statistically significant improvements of joint mobility, muscle power, gait, walking distance and a significant reduction of various pain parameters. The decline in usage of crutches, improvements in the activities of daily living and the positive patients' assessments were of striking evidence. A short time inpatient postoperative rehabilitation programme achieved significant success through an acceptable expenditure of treatment and resulted in substantially increased mobility and autonomy of the patients.

High levels of macrophage inflammatory protein-1alpha correlate with prolactin in female patients with active rheumatoid arthritis.

The relationship between the endocrine immune modulator prolactin and the macrophage activation parameter MIP-1alpha (macrophage inflammatory protein-1alpha) was investigated in 61 females with rheumatoid arthritis (RA). The chemokine MIP-1alpha was found to be twice as high in active than in inactive RA. Parallel to the inflammatory activity (acute phase response and joint count) and high levels of MIP-1alpha there were markable changes of serum prolactin. MIP-1alpha seems to have an influence on the pituitary hormone secretion. A significant correlation between prolactin and MIP-1alpha (r = 0.67; p < or = 0.00001) point out the bidirectional influence of the immune and endocrine system in RA.

S(+)-ibuprofen (dexibuprofen)--Excellent tolerance has not to be combined with poor clinical efficacy.

S(+)-ibuprofen (dexibuprofen) is an NSAID offering a lot of advantages in the treatment of rheumatism and pain. A randomized double-blind, parallel group study in 110 patients showed equivalence in efficacy of 900 mg dexibuprofen (Seractil 300 mg, Gebro Fieberbrunn, Austria) vs. 150 mg diclofenac sodium. Regarding tolerance there was a trend to superiority of dexibuprofen. Therefore dexibuprofen can be characterized as an effective and very tolerable drug against inflammation and pain.