Double-blind comparison of the antirheumatic activity and gastric side-effects of indomethacin used alone or in combination with a gastro-protective agent, proglumide.

A double-blind placebo controlled trial was carried out in 32 hospitalized patients with various rheumatic disorders to assess the therapeutic effectiveness and gastric tolerance of indomethacin (150 mg/day) used alone or in combination with proglumide (900 mg/day). Patients were treated for periods ranging from 20 to 28 days. The therapeutic response to both treatments, as assessed by objective criteria and final overall evaluation, was not significantly different. There was, however, a marked difference in gastric disturbance between the two groups. Uropepsinogen levels increased significantly during treatment in patients receiving indomethacin plus placebo but decreased significantly after Day 10 in those receiving proglumide. Although stomach X-ray or faecal occult blood investigations showed litle change from normal in either group, no gastric side-effects were reported in the proglumide patients whereas only 2 of the 16 patients receiving indomethacin plus placebo were entirely free of such side-effects throughout the trial, and most had developed gastric symptoms by the 9th day of treatment.

Flurbiprofen in rheumatoid arthritis therapy.

Preliminary findings are reported from an open study of 300 mg flurbiprofen daily in 24 patients and from 6 out of 30 patients treated so far in a double-blind crossover comparison of 300 mg flurbiprofen daily and 150 mg indomethacin daily in the treatment of rheumatoid arthritis. The results indicate that flurbiprofen is effective in relieving symptoms and is better tolerated than indomethacin. Using an experimental model in rats to assess the anti-inflammatory activity of flurbiprofen, data suggest that flurbiprofen is unable to prevent an immunological type of inflammation but is capable of modifying the type and extent of cellular infiltration.

Double-blind clinical evaluation of a new anti-inflammatory drug, protacine, versus indomethacin.

A double-blind clinical trial was carried out in 69 rheumatic in-patients to compare the efficacy and tolerance of a new, non-steroidal anti-inflammatory agent, protacine, with that of indomethacin. Patients received either 150 mg protacine or 50 mg indomethacin 3-times daily for 21 days. The time course of symptoms was recorded by semiquantitative scoring, as were side-effects. Uropepsinogen excretion, occult blood in faeces and standard physiological parameters were also monitored. Protacine globally decreased symptom scores by 58.5% and indomethacin by 24.3% (p less than 0.001). The computed time to reduce symptom scores by 50% was 17.2 days with protacine as compared to 39.2 days with indomethacin (p less than 0.001). Physiological parameters did not change, except white blood cells which decreased after protacine (each subject however, remaining well within the physiological range) and erythrocyte sedimentation rate, which decreased in both groups. Uropepsinogen excretion increased by 70% after protacine, and threefold after indomethacin (p less than 0.001). Occult blood search was positive in 1 patient receiving protacine, while 2 who were already positive before receiving protacine became negative during the treatment. Four patients taking indomethacin were found to be positive, 1 showing melaena. The one who was already positive before treatment showed increasing severity of occult bleeding during indomethacin administration. Frequency and severity of side-effects were significantly less with protacine (p = 0.004). In conclusion, protacine showed analgesic and anti-inflammatory actions significantly more potent and rapid than those of indomethacin, with significantly fewer and less severe side-effects.

Cogan's syndrome: unsuccessful outcome with early combination therapy.

Interstitial keratitis and vestibuloauditory symptoms (vertigo and hearing loss) are the typical signs of Cogan's syndrome, a rare inflammatory vascular disease. Signs of vasculitis in many organ systems may appear, among which neurologic problems are sometime predominant. The efficacy of glucocorticoids on the ocular and systemic symptoms is established, but their effect on hearing loss is unknown. We describe a case of Cogan's syndrome with neurological involvement in which early treatment with combination therapy (prednisolone and cyclosporin) failed to bring ear inflammation under control.

Interleukin-10 in rheumatoid arthritis.

We studied interleukin-10 (IL-10) levels in the blood and synovial fluid (SF) of 15 patients with RA and in the blood of 15 healthy donors (HD). RA IL-10 levels were significantly higher in SF than in blood (p = 0.001) and did not correlate with the disease activity nor with the therapy. RA patients showed significantly reduced blood IL-10 levels compared to the HD (p = 0.002), suggesting that IL-10 synthesis is depressed in RA. Since IL-10 has anti-inflammatory properties, reducing pro-inflammatory cytokine release by monocytes and down-modulating T cell function, its defect in RA may play a role in perpetuating RA synovitis.

Anti-enterobacteria antibodies in psoriatic arthritis.

The occurrence of certain antibacterial antibodies was studied in the sera of 22 healthy donors (HD) and 66 patients with different diseases. The cases investigated included 22 rheumatoid arthritis (RA), 22 non-arthritic-psoriasis (NAP), and 22 psoriatic arthritis (PA) patients. A complement fixation test was used with Yersinia enterocolitica 0:3 type (YEC), Yersinia pseudotuberculosis (YPT), Campylobacter jejuni (CJ), and Campylobacter fetus (CF) antigens; the detection of anti-Chlamydia trachomatis (CT) antibodies was carried out using an immunoperoxidase colorimetric slide test that allowed the detection of isotypes of specific antibodies. It was found that the synthesis of anti-CF, CJ, YEC, and YPT antibodies in NAP patients does not differ significantly from that of the HD group; on the contrary, the antibody levels were statistically higher in PA than in the other disease groups or in the healthy controls, although only anti-CF antibodies seemed to significantly differentiate (p = 0.000003) the PA group from the others. Anti-CT IgA antibody titers were found to be significantly higher in the PA as well as in the RA groups when compared with the controls, while the antibody levels in NAP patients showed no clear-cut difference with respect to those of either the arthritic patients or the healthy controls. By showing that anti-enterobacterial antibodies are increased in PA but not in NAP patients, our data furnish additional support to the thesis of a pathogenic role of bacterial infections in psoriatic arthritis.

Esophageal motility disorders in the rheumatic diseases: a review of 150 patients.

OBJECTIVE: Rheumatic diseases are a group of systemic disorders that may be concurrent with Raynaud's phenomenon and involvement of the internal organs, in particular the esophagus. Esophageal motor abnormalities have been widely described in systemic sclerosis, but have not frequently been reported in other diseases. In the present study we have examined the prevalence and pattern of esophageal motility disorders in different rheumatic diseases. METHODS: Esophageal manometry was performed on 150 patients, 21 males and 129 females, suffering from different rheumatic diseases (SSc, RA, SLE, MCTD, undifferentiated CTD, or DM/PM) and on 30 healthy controls. RESULTS: Functional involvement of the esophagus was demonstrated in all the rheumatic diseases considered, although at varying percentages. The frequencies of the functional abnormalities differed when each disease was considered separately. In SSc patients abnormalities were found more frequently in the lower esophageal sphincter (81.8%) and in the esophageal body (84.8%); data for the DM/PM and MCTD patients broadly overlapped. On the contrary, in SLE the lower sphincter appeared to be less (or even not at all) impaired, while the most specific disorder was an isolated abnormal peristalsis. RP did not always correlate with manometric changes in all of the groups studied. CONCLUSIONS: Three conclusions derive from our study: i) motor disorders affecting the esophagus were not only found in SSc, but also in all forms of non-lupus CTD; ii) the simultaneous involvement of the esophageal body and the lower esophageal sphincter is discriminant between non-lupus CTD and SLE; and iii) RP may be regarded as a condition pathogenetically unrelated to manometrically detected esophageal motor abnormalities.

Expression of membrane-bound peptidases (CD10 and CD26) on human articular chondrocytes. Possible role of neuropeptidases in the pathogenesis of osteoarthritis.

OBJECTIVE: To evaluate the cell surface expression of cell membrane-bound peptidases CD10 and CD26 on osteoarthritic (OA) chondrocytes, correlating it with the cell cycle phase and with the severity of OA lesions found in different load zones of the cartilage from human knees. METHODS: Chondrocytes freshly isolated from three different load zones of cartilage, obtained from 10 OA patients undergoing surgical knee replacement, were analyzed for the expression of CD10 and CD26 and for their cell cycle phase by flow cytometry. Statistical analysis was carried out using the multifactorial analysis of the variance with the LSD (least square difference) range test. The Chi square test was used to compare the cell cycle phases. RESULTS: Analysis of the chondrocyte cell cycle showed a significantly high proportion of cells in the S-phase in the maximum load zone in comparison with the minimum load zone (p < 0.001); the percentage of resting cells (G0/G1 phase) was significantly higher in the minimum load zone than in the maximum load zone (p < 0.001). The expression of CD10 and CD26 on chondrocytes was significantly reduced in the maximum load zone of the cartilage and was directly related to the progressive worsening of osteoarthritic lesions. CONCLUSIONS: These data demonstrate, for the first time, that articular chondrocytes express on their surface CD10 and CD26 peptidases. Neprilysin 3.4.24.11 (CD10) and dipeptidyl peptidase IV 3.4.14.15 (CD26) have been shown to play a specific role in the control of growth and differentiation of many cell types by cleaving growth factors able to promote cellular proliferation. Our results indicate that CD10 and CD26 are down-regulated in the maximum load zone of the knee OA cartilage: this condition may allow the increase of local levels of growth factors causing chondrocyte activation. Furthermore, as CD26 mediates cell binding to fibronectin and collagen, its reduction in osteoarthritic cartilage may reflect a perturbation of chondrocyte interactions with the extracellular matrix.

Integrin expression on chondrocytes: correlations with the degree of cartilage damage in human osteoarthritis.

OBJECTIVE: To verify the distribution of different types of beta 1 integrin on the plasma membrane of chondrocytes and to correlate the pattern of integrin expression to the severity of osteoarthritis (OA). METHODS: The articular cartilage of ten OA patients who had undergone surgical knee replacement for "genu varum" were studied. The cartilage was separated into three zones that macroscopically and microscopically showed a decreasing degree of anatomic lesions. After enzymatic digestion, the isolated chondrocytes were immediately challenged with monoclonal antibodies against the beta 1, alpha 1-6 and alpha v chains. The phenotypic study was paralleled by a cell cycle analysis performed by flow cytometry on chondrocytes stained with propidium iodide. RESULTS: Chondrocytes isolated from the articular cartilage of osteoarthritic patients expressed, in different percentages, all the alpha chains (alpha 1-6 and alpha v) of the beta 1 integrins. The alpha chain most frequently expressed was alpha 1, followed by alpha 3, alpha 5, alpha 2 and alpha v, with lesser amounts of alpha 4 and alpha 6. The beta 1 chain was expressed (on average) on the 40% of the chondrocytes regardless of the zone they were isolated from. Differential phenotypic analysis of the three zones showed that beta 1 integrins correlate inversely with the severity of the anatomic lesions and the cycle phase of the chondrocytes (the G0/G1 phase prevailed in the anatomically normal cartilage of the least damaged zone, and the S-phase in the most damaged zone). CONCLUSIONS: This study provides evidence of the existence of beta 1 integrins on the surface of chondrocytes from human OA cartilage, all of the alpha chains being represented, although in different percentages. Moreover, an inverse correlation was demonstrated between the severity of the anatomical changes found in the zones and the phenotypic/metabolic changes of the cells. These results, together with the well known inside-out signaling function of the adhesion molecules, highlight the key role of matrix interactions in the pathogenesis of the anatomic changes in OA.

Quality of life assessment during six months of NSAID treatment [Gonarthrosis and Quality of Life (GOAL) Study].

OBJECTIVE: To identify the time point of the greatest degree of improvement in daily living activities, pain and depression in patients with osteoarthritis (OA) of the knee during 6 months of treatment with NSAIDs, in order to define compliance and drop-out rate. METHODS: 107 patients were recruited into a multicentre, prospective, randomized, controlled trial comparing two treatments, piroxicam-beta-cyclodextrin (PBCD) and slow release diclofenac (DCL). RESULTS: The greatest improvement in quality of life occurred in both groups after 3 months, with a slight further gain observed by the end of treatment. The Stanford Health Assessment Questionnaire score improved (p < 0.05 vs baseline) at 3 and 6 months with PBCD and at 6 months with DCL. The Arthritis Impact Measurement Scale score improved (p < 0.05 vs baseline) after 6 months in both groups. Significant (p < 0.05 vs baseline) improvement in other psychological and pain scores were recorded in both groups after 3 and 6 months. Compliance with treatment at 3 months was 73% for PBCD and 72% for DCL, and was 60% in both groups at 6 months. CONCLUSIONS: The results of this study indicate that the optimal length of time for an NSAID trial in OA patients is 3 months, when assessment of daily living activities is considered as the main outcome criterion.

Markers of bone turnover: consideration on their clinical application in osteoporosis.

Osteoporosis is a condition in which an imbalance appears between bone resorption and formation, with bone resorption exceeding formation. However since the rate of bone loss varies significantly from one individual to another resulting in different degrees of osteoporosis, new biochemical techniques to measure products of bone resorption and bone formation have been used in the last years allowing us to evaluate the degree of bone turnover. Bone tissue is constituted of an inorganic component and an organic matrix of collagen and noncollagenous proteins. Suitable bone marker should report the formation and degradation of all these constituents. Today markers of bone formation and markers of bone resorption are available. According to recent literature and personal data assessment of bone metabolism by the specific biochemical markers is helpful to select osteoporotic patients with high or low bone turnover and these parameters should be used to evaluate whether bone remains sensitive to different therapies.

Isolated sternoclavicular joint arthritis in heroin addicts and/or HIV positive patients: three cases.

The authors describe three patients in whom septic arthritis of the sternoclavicular joint (SCJ) occurred, drug addiction and human immunodeficiency virus (HIV) infection representing the predisposing conditions. Infectious arthritis is well known in intravenous drug users, but it is rare in HIV positive patients, who are prone to bacterial infections from usual or unusual microorganisms. In one case, staphylococcus aureus methicillin sensitive was responsible for septic arthritis. In another case, SCJ infection was associated with pneumonitis.

Mononuclear cells are not involved in BGP synthesis and secretion.

Osteocalcin or bone GLA protein (BGP) is found at high levels in only two tissues, the extracellular matrix of bone and dentine. Tissue culture experiments have demonstrated that BGP is synthesized by two osteoblastic osteosarcoma cell lines (ROS 2/3 and 17/2) and by normal osteoblastic cells in primary culture. BGP was not found in rat cartilage nor in liver, kidney, lung, spleen, brain, heart, thymus, skeletal muscle. In this study secretion of BGP was assayed by RIA in the supernatants of 48-hour cultures of peripheral blood lymphocytes or monocytes. Lymphocyte cultures were carried out using RPMI-1640 supplemented with L-glutamine and antibiotics at the concentration of 1 x 10(6) cells/ml and activated by PHA (10 ng/ml). Peripheral blood monocytes were purified by adherence to plastic Petri dishes and treated with cold PBS supplemented with EDTA. Monocytes were cultured as previously described and stimulated with LPS (50 micrograms/ml). Cell-free supernatants were obtained by centrifugation and stored at -20 degrees C, until the BGP assay was performed. The authors did not observe secretion of detectable amounts of BGP in the supernatants of short-term lymphocyte or monocyte cultures. These data indicate that circulating mononuclear cells are not involved in BGP synthesis and secretion.

Systemic sclerosis stimulates angiogenesis in the chick embryo chorioallantoic membrane.

Skin biopsies from patients with systemic sclerosis (SSc) were investigated for their angiogenic activity by using the chick embryo chorioallantoic membrane (CAM) assay. Ten samples of SSc and 10 of normal skin from age- and sex-matched subjects were grafted onto the CAM, and the angiogenic response in pathological and control implants was assessed on histological sections by a planimetric point-count method 4 days after grafting. The vascular counts in the area underlying the SSc were significantly higher than those of normal skin and a dense mononuclear cell infiltrate was detectable around the blood vessels in pathological specimens. These results suggest that SSc may promote angiogenesis, perhaps leading to the release of several angiogenic factors. Moreover, the role played in the angiogenic response by the inflammatory cells forming the cellular infiltrate is suggested by this study.

25-Hydroxycholecalciferol in experimental osteoporosis.

UNLABELLED: The authors, using the experimental pattern of bone rarefaction induced by a low calcium diet, tried to determine if 25-hydroxycholecalciferol, administered at doses and according to procedures similar to those used in osteoporosis, might interfere in such a process of rarefaction. The statistical evaluation of the results concerning the size of the amount of spongy bone presented evidence for the sharp decrease in the specific bone volume in rats placed on a low calcium diet as compared to control rats. Such a difference is found even between rats treated with 25-OH-D3. Nonetheless, the authors reported a difference--although not statistically significant--that indicated an increase in the amount of bone in rats on a normal diet but treated with vitamin D as compared to control rats. IN CONCLUSION: 25-OH-D3 by itself, the diet being the same, was not able to ameliorate the amount of bone.

Evaluation of mineral metabolism and bone turnover in osteoporotic females treated with phosphorus and salmon calcitonin.

Twenty-five patients with radiological and clinical evidence of osteoporosis were studied. Nineteen patients received oral phosphorus at a dose of 1,000 mg/die for 10 days followed by salmon calcitonin (100 U MRC/die) for 20 days. Six patients received only oral calcium at a dose of 1,000 mg/die). In the first group, a significant increase in serum osteocalcin and parathyroid hormone, after administration of phosphorus and persisting after treatment with salmon calcitonin, was found. No variation in the controls was observed. In a later study, a significant increase in serum 1,25 dihydroxyvitamin D (1,25(OH)2D3), after receiving phosphorus and persisting after salmon calcitonin, was demonstrated. In accordance with the authors' results, phosphorus could be considered a useful activator of bone formation and this stimulus by parathyroid hormone was mediated. Finally, the positive effects of phosphorus on circulating 1,25(OH)2D3 must be considered for a good treatment protocol of osteoporosis.

Early alteration of synovial membrane in osteoarthrosis.

Biopsy specimens of the synovial membrane were obtained during arthroscopy and surgical meniscectomy from the knees of 20 patients with meniscus lesions. The aim of this study was to identify the morphological and immunological changes which appear in the synovium during the earliest phase of osteoarthrosis. Interstitial deposits of IgG and, in some cases, C3 were found not only in patients with evident arthrotic degeneration (cartilaginous lesions and synovitis), but also in patients who showed no overt arthrotic changes. Furthermore, light and electron microscopy showed an increased number of mast-cells with peculiar semilunar or piecemeal aspects of their secretory granules. These ultrastructural modifications are characteristic of slow, chronic release of mediators in response to a constant, moderate degranulatory stimulus. Our findings suggest that synovial changes may occur before the advent of cartilage degeneration and that the latter may be directly influenced by early pathological changes in the synovial membrane.

Chondrocyte phenotyping in human osteoarthritis.

Cell-ECM (extracellular matrix) interactions are believed to play a key role in maintaining the normal structure of tissues such as cartilage. Cell surface adhesion molecules have been reported to mediate chondrocyte binding to ECM proteins in human normal cartilage but the behaviour of these molecules in human osteoarthritic cartilage is unknown. We studied receptor matrix proteins on freshly isolated chondrocytes obtained from 10 patients with osteoarthritis (OA). Chondrocytes were isolated by enzymatic digestion from three zones of the articular cartilage with a different degree of macroscopic and microscopic damage and chondrocyte phenotype was defined by flow cytometry. Chondrocytes strongly expressed beta1, integrin but not beta3 integrin. LFA-1 (CD18/CD11a) and ICAM-1 (CD54) antigens were almost undetectable. Interestingly, beta1 expression was significantly higher in the minimally damaged zone than in the zones with medium and maximum damage. These data show that beta1-integrin-mediated chondrocyte-ECM interactions decrease in osteoarthritic cartilage suggesting that perturbations of chondrocyte-matrix signalling occurs during OA.

Chondroprotection with chondroitin sulfate.

The remarkable insights into the pathogenesis of osteo-arthrosis (OA) have also affected the therapeutic field. Efforts have been made to find drugs which would somehow block or slow down the evolution of this disease. In this connection, a major contribution has been made by the investigations on glycosaminoglycans (GAGs), which play a crucial role in the physiology of joint cartilage. It was thus suggested that proper supplementation with GAGs might enable chondrocytes to replace the proteoglycans (PG). Galactosaminoglucuronoglycan sulfate (GAGGS) has been used for this purpose. In preliminary clinical trials, GAGGS exhibited a remarkable tolerability and good therapeutic efficacy. GAGs are generally able to inhibit certain enzymes present in the synovial fluid which may damage joint cartilage (elastase, hyaluronidase). Moreover, GAGGS has also been shown to act as an anti-inflammatory drug since it has an inhibitory effect over the complement. All these data supply evidence that, in theory, GAGGS may have a chondroprotective effect in patients with OA. In addition to the positive results of preliminary clinical trials, the use of GAGGS in OA therapy is based on the fact that this drug is absorbed by the body, is concentrated in the cartilages and produces no toxic or teratogenic effects. In the clinical studies performed so far, although of the open type, GAGGS has always yielded clinical improvement both of painful symptoms and of limited function thanks to its proven anti-inflammatory activity. Thus once the results from other ongoing trials (double blind) are available, hopefully GAGGS will in fact become a basic drug for OA therapy.

Indoprofen in rheumatic patients with acute episodes: a multicentre trial.

The results are reported of an open multicentre trial in 228 rheumatic patients with flare-ups. Fourteen centres adopting the same investigational protocol collaborated in the study. Indoprofen was administered for 1 week at a daily dosage of 1000 mg according to a treatment schedule used with success in acute gouty arthritis: a 400 mg i.v. bolus was followed by 200 mg (1 tablet) t.i.d. Subjective (pain) and objective variables were used for reliable assessment of activity. Marked reduction of pain intensity was already noticeable on day 1 of treatment and was followed by progressive improvement in subjective and objective variables for all the diagnoses considered. According to the patients' own overall assessments, results were good or very good in more than 50% of cases. The best outcomes were obtained in low back pain, acute gout and psoriatic arthritis. At the end of treatment only 7.4% of patients experienced no change or deterioration of symptoms. Adverse reactions, consisting mostly of mild and reversible gastrointestinal disturbances, were reported by 9.2% of patients, but only in 1.8% was treatment discontinued. Indoprofen administered according to the above schedule is an appropriate treatment for acute episodes of rheumatic diseases.