The possibilities of pharmacological treatment of cartilage damage in degenerative joint disease.

Osteoarthritis is the most common joint disease in the general population. In recent years there has been a significant expansion of knowledge pertaining to the complex parthogenesis of this degenerative disease and the roles played in its course by the inflammatory process, the various components of cartilage, and cytokines. Improved research methods and the introduction of new medications (including selective COX-2 inhibitors) for the treatment of osteoarthritis have made it possible to develop new treatment protocols. This article discusses contemporary views on the pharmacological treatment of osteoarthritis and the possibility of influencing the symptomatology of the disease and the structure of cartilage. Promising methods of treating osteoarthritis are presented.

Nabumetone induces less gastrointestinal mucosal changes than diclofenac retard.

The aim of the study was to compare the efficacy and the effects on the mucosa of the gastrointestinal tract (GIT) of nabumetone and diclofenac retard in patients with osteoarthritis (OA). An open, multicentre, randomised, comparative, endoscopy-blind parallel group study included 201 patients with nabumetone and 193 patients with diclofenac retard suffering from moderate to severe OA of the knee or hip joint. Twelve clinical efficacy variables were assessed and a portion of the population underwent gastroduodenoscopy. All patients exhibited significant improvement in pain severity and pain relief (p < 0.001 and p < 0.0001, respectively) but there were no differences between the groups for all the efficacy variables. Eleven per cent of patients on nabumetone and 19% on diclofenac experienced GIT side-effects. Sixty-nine patients with nabumetone and 61 with diclofenac underwent gastroduodenoscopy. The differences in the mucosal grade for the oesophagus, stomach and duodenum at baseline were not significant. In the oesophagus there were significantly less changes after treatment with nabumetone (p = 0.007) than with diclofenac; there were similar findings in the stomach (p < 0.001) but the difference in the duodenum was not significant. This study indicates that nabumetone and diclofenac retard have similar efficacy in the treatment of OA, but nabumetone has significantly fewer GIT side-effects.

Randomised controlled trial of Helicobacter pylori eradication in patients on non-steroidal anti-inflammatory drugs: HELP NSAIDs study. Helicobacter Eradication for Lesion Prevention.

BACKGROUND: The effect of Helicobacter pylori in patients receiving non-steroidal anti-inflammatory drugs (NSAIDs) is unclear. We investigated the effects of H. pylori eradication in patients with current or previous peptic ulceration, dyspepsia, or both who continued to use NSAIDs. METHODS: 285 patients were randomly assigned omeprazole 20 mg, amoxycillin 1000 mg, and clarithromycin 500 mg, twice daily (n=142, H. pylori eradication treatment), or omeprazole with placebo antibiotics (n=143, controls) for 1 week. All patients received omeprazole 20 mg once daily for 3 weeks until endoscopy, and, if the ulcer was not healed, 40 mg once daily until repeat endoscopy at 8 weeks. Ulcer-free patients with mild dyspepsia continued NSAIDs but not antiulcer treatment. We investigated ulcers with endoscopy at 1, 3, and 6 months and with carbon-13-labelled urea breath test at 3 months. FINDINGS: The estimated probability of being ulcer-free at 6 months was 0.56 (95% CI 0.47-0.65) on eradication treatment and 0.53 (0.44-0.62) on on control treatment (p=0.80). Time to treatment failure did not differ between groups for ulcers or dyspepsia alone, per-protocol analysis, or final H. pylori status. 66% (58-74) of the eradication group compared with 14% (8-20) of the control group had a final negative H. pylori result (p<0.001). Fewer baseline gastric ulcers healed among eradication-treatment patients than among controls (72 vs 100% at 8 weeks, p=0.006). INTERPRETATION: H. pylori eradication in long-term users of NSAIDs with past or current peptic ulcer or troublesome dyspepsia led to impaired healing of gastric ulcers and did not affect the rate of peptic ulcers or dyspepsia over 6 months.

Neutrophil gelatinase levels in plasma and synovial fluid of patients with rheumatic diseases.

To examine the clinical significance of neutrophil gelatinase in rheumatic diseases, plasma and synovial fluid (SF) gelatinase levels were determined in 62 patients with rheumatoid arthritis (RA), 12 patients with ankylosing spondylitis (AS), 18 patients with osteoarthritis (OA) and 17 healthy controls. The gelatinase level was measured by enzyme-linked immunoassay (ELISA). The assay had a sensitivity of 1 ng/ml and a working range of 5-25 ng/ml. Gelatinase levels were significantly higher in the plasma of patients with RA and of patients with RA complicated by amyloidosis or vasculitis as compared to those of healthy controls. Moreover, the mean value of gelatinase in the plasma of patients with RA complicated by vasculitis was found to be significantly higher than that of RA patients without vasculitis. A significant increase in gelatinase concentration was also observed in the plasma of AS patients but not in the plasma of patients with OA. The concentration of gelatinase in the RA SF samples was much higher (18-fold) than the level of the enzyme in the plasma of RA patients. There was also a higher concentration of gelatinase (four-fold) in OA SF compared with OA plasma. The results suggested that circulating gelatinase may reflect some degree of neutrophil activation in patients with inflammatory arthritis, especially in those with RA complicated by vasculitis. However, the results did not allow a differentiation between chronic and acute inflammation.

Modified expression of c-Fos and c-Jun proteins and production of interleukin-1 beta in patients with rheumatoid arthritis.

OBJECTIVE: To examine the relationship between the expression of c-Fos and c-Jun proteins and the METHODS: The expression of c-Fos and c-Jun proteins and the production of IL-1 beta in the PBMC of 11 patients with active RA was determine by Western blots and ELISA techniques, respectively. RESULTS: The spontaneous expression of c-Fos protein and the production of IL-1 beta was higher in RA patients. Under LPS treatment, the PBMC of both RA patients and healthy subjects produced similar high levels of IL-1 beta without any significant changes in the expression of c-Fos and c-Jun proteins. By contrast, PMA-induced production of IL-1 beta was impaired in RA patients and was preceded by the disregulated expression of c-Fos and c-Jun proteins when compared with healthy donors. CONCLUSION: It can be postulated that in some RA patients the spontaneously high production of IL-1 beta may be associated with the up-regulated expression of c-Fos protein in PBMC. On the other hand the impairment of IL-1 beta production in RA induced by the PKC-dependent pathway, may be related to disturbances in c-Fos and c-Jun protein expression. This dysfunction seems to be compensated by some unknown mechanisms implicated in LPS signalling, which is known to involve not only the PKC-mediated pathway.

Expression of muscarinic cholinergic receptors on lymphocytes in various subsets of rheumatoid arthritis and their variabilities connected with treatment.

OBJECTIVE: To investigate muscarinic cholinergic receptors on lymphocytes from various subsets of patients with rheumatoid arthritis (RA). METHODS: The level of muscarinic receptors on peripheral blood lymphocytes from 38 patients with various subsets of RA [5 with inactive, 13 with active RA, 13 with rheumatoid vasculitis and 5 with reactive secondary amyloidosis (RSA)] was determined by the binding studies of specific muscarinic ligand [3H] quinuclidinyl benzilate in comparison to healthy individuals. RESULTS: Expression of muscarinic cholinergic receptors on lymphocytes in patients with RA was significantly higher (mean 1022; SD +/- 567) compared to healthy individuals (mean 647; SD +/- 170) (p < 0.01). The phytohemagglutinin (PHA) stimulation index in acetylcholine treated lymphocytes in patients was statistically significantly lower than in healthy individuals (p < 0.05). The highest levels of muscarinic receptors on lymphocytes was observed in patients with RA with vasculitis and RSA and showed a significant correlation with disease activity. The number of muscarinic receptors on lymphocytes as well as PHA stimulation index in acetylcholine treated and untreated lymphocytes showed a tendency to decrease after the treatment. The number of muscarinic receptors on lymphocytes decreased significantly after the treatment only in the group of patients with clinical improvement (p < 0.05). CONCLUSION: Our results suggest that cholinergic stimulation may be connected with activity and/or heterogeneity of the disease in patients with RA.

Abnormalities in T cell interactions with the extracellular matrix proteins in a patient with Wegener's granulomatosis.

T cell interactions with the extracellular matrix proteins and cultured human endothelium were studied in a patient with Wegener's granulomatosis and other cases of vasculitis. Markedly enhanced costimulation of T-lymphoproliferative responses mediated by collagen and fibronectin were found in patients with severe forms of vasculitis, particularly with necrotizing changes. In addition, enhanced adhesion to collagen IV was found in the Wegener patient. T cell adhesion to resting and inflamed endothelium varied from normal to increased.

HLA typing and seropositivity in Finnish and in Polish patients with rheumatoid arthritis and amyloidosis.

We determined HLA-A, -B, -C and -DR antigens in 83 patients with rheumatoid arthritis (RA) and reactive secondary amyloidosis (RSA), 60 in Finland and 23 in Poland, and compared the results with control RA patients and blood donors. There were no significant differences in the frequencies of HLA between the RA patients with and those without RSA in either Finland or Poland, and no significant differences between the Finnish and Polish patients with RSA. All the RSA patients from Finland and 70% of the RSA patients from Poland were seropositive. In the development of RSA, the prolonged period of inflammatory stimuli may play a more important role than genetic factors.

[A comparative evaluation of combined immunocorrective therapy in rheumatoid arthritis with systemic manifestations (joint Soviet-Polish research)]. / Sravnitel'naia otsenka kompleksnoi immunokorrigiruiushchei terapii revmatoidnogo artrita s sistemnymi proiavleniiami (sovmestnoe sovetsko-pol'skoe issledovanie).

Thirty-two patients with rheumatoid arthritis were included in the trial. Each of them was assigned to one of the 4 groups comparable by the main features. Each group entered 8 patients. Group 1 patients underwent hemosorption weekly for 3 weeks. After the second procedure cyclophosphamide was added at a single IV dose 1000 mg. After the third procedure the treatment was continued with methotrexate (7.5 mg, weekly). Group 2 began the treatment with methotrexate (7.5 mg, weekly). Group 3 received cyclophosphamide 200 mg IV twice a week 6 times and then 200 mg weekly orally till a total dose of 2 g. Group 4 received azathioprine in a daily dose 100 mg. The treatment with nonsteroidal antirheumatic drugs and corticosteroids was continued unchanged. After 6 months we did not see significant differences between the 4 groups.

[Clinico-immunological characteristics of patients with rheumatoid arthritis and symptoms of cutaneous vasculitis (cooperative Soviet-Polish study)]. / Kliniko-immunologicheskaia kharakteristika bol'nykh revmatoidnym artritom s priznakami kozhnogo vaskulita (sovmestnoe Sovetsko- pol'skoe issledovanie).

The paper presents the results of a comparative study performed in the USSR and Poland of rheumatoid arthritis (RA) patients with extra-articular manifestations of the disease (with skin vasculitis and free of it). The comparison included clinical, biochemical and immunological parameters. The results confirm the role of immune complexes in the onset of vascular affections in RA. High incidence of sensitive polyneuropathy in patients with skin vasculitis allows one to define it as a sign of systemic vasculitis. Rheumatoid nodes occur with similar frequency in both groups. It is shown that the problem of vascular pathology in RA remains complex and that further studies are needed to specify mechanisms of vasculopathy development in RA.

Expression of muscarinic cholinergic receptors on lymphocytes during rheumatoid arthritis.

The level of muscarinic receptors on lymphocytes from rheumatoid arthritis (RA) patients in comparison with healthy individuals was determined by the binding studies of a specific muscarinic ligand [3H]-QNB in the presence of the competitive antagonist atropine. The response to phytohaemagglutinin and the influence of acetylcholine on this process in patients' lymphocytes was also studied. We have found direct correlation among PHA stimulation indices, the level of muscarinic receptors, and the influence of acetylcholine on PHA stimulation indices. Differences in these parameters occurring in systemic forms of RA as compared to other RA patients are also described and their possible mechanism discussed. The influence of cholinergic stimulation on the reactivity of lymphocytes after PHA in different forms of RA could depend on the number of muscarinic receptors present on the lymphocyte surface, as well as on the activity of soluble factors, which could modulate the functional state of the receptors.