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OBJECTIVES: The aim of this study was to investigate the effects of two nonsteroidal anti-inflammatory drugs (NSAIDs), nimesulide and sodium diclofenac, on the production of proteoglycans (PG), prostaglandin E2 (PGE2) and cytokines (IL-6 and IL-8) by human articular chondrocytes in vitro. METHODS: Enzymatically isolated chondrocytes were cultured under constant agitation in a well defined culture medium. Specific radioimmunoassays were used to quantify PG and PGE2 production. Cytokine production (IL-6 and IL-8) was assayed by enzyme amplified sensitivity immunoassays (EASIAs). RESULTS: At a concentration of 3 micrograms/ml, nimesulide did not affect the PG production by chondrocytes. This concentration was superior to the highest level of nimesulide found in the synovial fluid of patients with rheumatoid arthritis 3 hours after the last oral administration of nimesulide (100 mg twice daily for 7 days). At 6 micrograms/ml a significant reduction in the PG content was obtained in the cellular phase in 5 out of the 8 cultures investigated. No similar effect was observed in the culture supernatants. Above this concentration nimesulide inhibited PG production in a dose-dependent manner. At concentrations ranging from 0.005 to 1 microgram/ml diclofenac did not significantly alter PG production. At therapeutic concentrations PGE2 production was totally inhibited by nimesulide, thus suggesting that PG inhibition is not linked to PGE2 production. Nimesulide inhibited PGE2 production by unstimulated (IC50 = 6 ng/ml) and IL-1 beta-stimulated (IC50 = 6.9 ng/ml) chondrocytes. At these concentrations, PGE2 production was fully inhibited by diclofenac. Furthermore, both nimesulide and diclofenac at therapeutic concentrations significantly decreased spontaneous and IL-1 beta-stimulated IL-6 production by human chondrocytes, but did not modify IL-8 production. CONCLUSION: From the results of this study we conclude that nimesulide and diclofenac at therapeutic concentrations are potent inhibitors of PGE2 and IL-6 production while they do not modify proteoglycan or IL-8 production.

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Most available nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit both the constitutive cyclooxygenase-1 (COX-1) and the inducible cyclooxygenase-2 (COX-2), resulting in inhibition of prostaglandin (PG) and thromboxane (TX) biosynthesis. The inhibition of COX-2 might be the cause of the favourable anti-inflammatory, analgesic and antipyretic effects of NSAIDs, whereas that of COX-1 might result in unwanted gastrointestinal, renal and possibly other side-effects. Nimesulide is a sulfonanilide compound with anti-inflammatory properties. Its pharmacological profile (better inhibition of PG synthesis in inflammatory areas than in gastric mucosa), suggested that it might be a selective inhibitor of COX-2. In several in vitro assays using either purified COX-2 and COX-1 preparations or cell preparations (both from animal and human origins) expressing COX-1 or COX-2, ten out of eleven different groups have demonstrated that nimesulide selectively inhibits COX-2. The COX-2/ COX-1 inhibitory ratio varies, according to the assay preparation, from about 0.76 to 0.0004 i.e. a 1.3 to 2,512-fold higher selectivity for COX-2 than for COX-1. Moreover, an in vivo whole blood assay performed on healthy volunteers demonstrated a significant fall in COX-2 PGE2 production without any effect on COX-1 TXB2 production in subjects treated with nimesulide (100 mg b.i.d. for 2 weeks) versus no effect on COX-2 PGE2 and an almost total suppression of COX-1 TXB2 in subjects treated with aspirin (300 mg t.i.d. for 2 weeks). Nimesulide can thus be considered a relatively selective COX-2 inhibitor. At the recommended dosage of 100 mg b.i.d., it is as effective an analgesic and anti-inflammatory agent as classical NSAIDs, and a well-tolerated drug with few side-effects according to large-scale open studies and a global evaluation of a large number of controlled and non-controlled comparative trials.

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Oral indomethacin administration (2 mg/kg/d) was investigated in rats with adjuvant arthritis up to a period of 5 wk. Baseline low serum zinc levels in arthritic rats increased rapidly from the first week of indomethacin treatment (started 1 or 2 wk after disease induction), whereas baseline high serum copper decreased after 1-2 wk. After 3-4 wk of treatment, serum zinc levels returned to control values, but serum copper was somewhat higher in arthritic animals having received indomethacin 2 wk after disease induction than in controls. Clinical indices of inflammation simultaneously improved to reach control values at the end of the trial. Biological indicators of inflammation also improved, but did not reach control levels. Serum zinc correlated negatively with plasma fibrinogen (r = -0.69, p < 0.0005) and serum copper correlated positively with serum ceruloplasmin (r = 0.92, p < 0.0005) both in indomethacin-treated and untreated arthritic rats. Contrary to long-term glucocorticoid administration that was previously reported to maintain or aggravate hypozincemia, indomethacin treatment normalized perturbed zinc and copper status in arthritic animals.

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Lymphedema is a rare complication of rheumatoid arthritis (RA). Diagnosis is clinical: long-standing, painful swelling of a whole limb in association with RA. Cases described in the literature are predominantly of the upper limbs, sometimes bilateral. Diagnosis can be confirmed by biopsy of lymph nodes, lymphography, or preferably lymphoscintigraphy. The etiology of the edema is unknown. Mechanical obstruction and lymphangitis have been suggested. Pharmacological and surgical treatment of the edema have been disappointing, and treatment of the underlying RA does not improve the lymphedema. Physical treatment of the affected limb, such as massage, manual drainage techniques, light compression bandaging, and exercise, has been moderately effective.

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Theoretically, patients with chronic bronchitis are at risk for osteoporosis. Bone metabolism was assessed in 44 male chronic bronchitics treated with oral prednisolone (C+; n = 19) or with bronchodilatory drugs alone (C-; n = 25). In both groups, serum osteocalcin was lower (p less than 0.001) than in age- and sex-matched controls (mean (ng/ml) C+ 1.0, C- 1.9, controls 4.2), while testosterone was at the lower limit of the reference range. Low trabecular bone mineral density (BMD) was noted in the C- group (median Z score -1.0), but both cortical and trabecular BMD were depressed in the C+ group (-1.0 and -1.4, respectively). In conclusion, chronic bronchitics treated with corticosteroids, even at low doses, are at risk for osteoporosis. In both groups, additional factors such as hypogonadism might be responsible for low BMD and low osteocalcin levels. A decrease in bone formation is a possible mechanism of action.

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We describe a case of aggressive undifferentiated thyroid cancer associated with rapidly evolving hypertrophic osteoarthropathy (HOA) that developed at the time of pulmonary dissemination of the thyroid neoplasm. The syndrome appeared to be paraneoplastic, possibly due to a substance normally cleared by the lungs.

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Several studies in animals and humans have shown that copper metabolism could be affected by inflammation or by corticosteroids. The relative importance of these two factors, often imbedded in clinical practice, was assessed by investigating the effects of acute prednisolone administration (30 mg/kg, ip) on healthy and adjuvant arthritis rats. Plasma copper levels were significantly higher in arthritic rats compared to healthy animals, whereas there was a slight, but nonsignificant increase in liver copper. Acute prednisolone administration in healthy rats resulted in a significant increase in plasma copper (10-15%) as early as 4 h after corticosteroid administration, which was maintained for 12 h. In arthritic rats, the response was much higher (25-40%), but somewhat delayed and shorter. Liver copper was not clearly modified by prednisolone treatment in both groups. This time-controlled study showed that acute prednisolone administration increased plasma copper in both healthy and arthritic rats, but in different ways, indicating that inflammation and corticosteroids may act synergistically.

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In order to test the sensitivity of leucocyte zinc determination in the assessment of zinc status, an isolation procedure of mononuclear (MNC) and polymorphonuclear (PMNC) cell fractions was developed. Zinc concentrations in cells from healthy subjects were (mean +/- SD, in mumol/10(10) cells): 0.81 +/- 0.24 in MNC and 0.55 +/- 0.06 in PMNC. In patients suffering from several diseases known to be associated with a marginal impairment in zinc status (cirrhosis, cancer, obesity, endocrine and rheumatic diseases), these concentrations did not differ from those in controls except in rheumatic patients in whom MNC zinc was increased (1.05 +/- 0.42 mumol/10(10) cells) and correlated with erythrocyte sedimentation rate (r = 0.41, P less than 0.01). This relation was also significant in the whole study population (r = 0.39, P less than 0.01). Leucocyte zinc therefore appears to have a limited value in the assessment of marginally impaired zinc status, except in inflammatory states.

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Rheumatoid arthritis (RA) is an inflammatory disease affecting mainly the joints. In addition, signs of systemic disease are likely to be present although they are not always clinically evident. Oesophageal motility dysfunction, present in 75% of progressive systemic sclerosis patients, was also reported in various other connective tissue diseases. The present study involved 32 rheumatic patients devoid of any gastrointestinal complaints or diseases: 16 RA, nine Raynaud's syndrome and seven mild osteoarthritis as controls. Oesophageal transit was assessed by using 81Krm radionuclide scan, a sensitive and non-invasive technique. Diffusing lung capacity for carbon monoxide (DLCO) was performed as evidence of subclinical systemic involvement. Abnormal oesophageal transit was observed in 5/16 RA (31%). Two of them were subsequently discarded due to the presence of asymptomatic goiter and asymptomatic gastrointestinal reflux leaving 3/14 RA for analysis. They all had extra-articular features (EAF) (pericarditis, nodules) and two of them had diminished DLCO. Two with Raynaud's syndrome had abnormal oesophageal transit but none of the controls had abnormal oesophageal transit. Upper gastrointestinal dysfunction after exclusion of symptomatic patients appears thus to be not very frequent in RA, even when a sensitive technique is used. Radionuclide transit scanning of the oesophagus is not a more useful method than others in detecting early EAF in RA.

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Starting from the experimental design of the established 'Zinc Tolerance Tests', the absorption and distribution of the essential trace element zinc in humans was investigated in 10 subjects by performing a pharmacokinetic study of the serum zinc profile after oral administration of a pharmacological dose of the metal, i.e. 0.69 mmol (45 mg) zinc as ZnSO4.7 H2O. The adopted experimental conditions include frequent measurements of serum concentrations, a total investigation time of 8 h after ingestion, and a correction of basal zinc levels taking into account the circadian variation. Rebound effects were evidenced in the time versus concentration curves showing a regular recycling of the element in the digestive tract. Estimation of the parameters by an original method allowed us to calculate the characteristics of the cycles. The first one occurred after 1.4 h, before the time needed for appearance of the maximum concentration which was around 2.3 h, and exhibited mean reabsorption of 70% of administered dose. The subsequent ones, maximum 5 during the investigation period, appeared at regular intervals of approximately 1.2 h, with a decrease in the quantity reabsorbed. These observations are consistent with the previously reported endogenous secretion of zinc, a physiological mechanism contributing to zinc homeostasis.

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Several studies in animals and humans have independently demonstrated that zinc metabolism is significantly affected either by inflammation or by glucocorticoid administration. The relative importance of these two factors was assessed in this study by the investigation of the effects on serum zinc concentrations of acute and chronic prednisolone treatments in adjuvant arthritis rats and in healthy controls animals. Acute steroid administration (3 mg/kg, i.p.) caused a rapid drop in serum zinc followed by a quick recovery, regardless to the fact that these concentrations were normal (healthy animals) or already reduced by the inflammatory process. However, the modification occurred faster in inflamed animals. Chronic steroid administration (0.58 to 0.78 mg/kg/day during 1 to 4 weeks) had a more complex effect. A previous experiment in healthy rats demonstrated that such a treatment only induced a slight decrease in serum zinc. In adjuvant arthritis animals, the early steroid treatment of the induced process promoted a further decrease in serum zinc level while a delayed treatment did not result in additional changes.

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The relationships between some parameters of the immune response and selenium were investigated in five patients receiving home parenteral nutrition for short-bowel syndrome. They were first submitted to a relative depletion by providing 20 micrograms selenium/day as L-selenomethionine for 1 mo. Then, daily selenium intake was raised to 200 micrograms for 2-4 mo. On entering the study, the patients presented a relatively good health status, and immunological parameters were at the lowest limit of the normal range. Four patients rapidly responded to the 200-micrograms supplementation by a continuous increase in their plasma selenium levels, whereas the fifth patient showed a moderate and late increase. At the end of the trial, there was an improvement in the lymphocyte response to pokeweed and phytohemagglutinin mitogens in four patients and to CD3 in three patients. The response to two of three antigens (Candidin, Varidase) tested was also enhanced in the same patients, but the response to the third antigen (tetanus toxoid) was uniformly low in all patients. The only patient showing essentially no immune improvement after selenium supplementation was the one with a low and delayed increase in plasma selenium. This study supports a role for selenium in the maintenance of an optimal immune response in humans.

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The effect of selenium supplementation on plasma selenium concentrations and lymphocyte-proliferation responses to mitogens was investigated in 22 elderly institutionalized subjects. Subjects were assigned to a 6-mo trial with either 100 micrograms Se/d (as selenium-enriched yeast) or a placebo. Plasma selenium concentrations of the selenium-supplemented group increased from 0.84 +/- 0.26 to 1.55 +/- 0.33 mumol/L (mean +/- SD) after 2 mo and the values plateaued thereafter. The mean response of lymphocytes to mitogens in elderly subjects tended to be lower than responses in healthy adults, although responses remained within the 5-95% confidence-interval limit for healthy adults. During selenium supplementation the proliferative response to pokeweed mitogen increased significantly (+79% of baseline concentrations after 4 mo, P less than 0.01) and reached the upper limit of the usual range for adults after 6 mo (+138%, P less than 0.001). In accordance with previous studies in animals and in vitro, this investigation demonstrates for the first time immunostimulatory properties of selenium-enriched yeast in elderly humans.

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Selenium is involved in several important biochemical pathways relevant to rheumatic diseases. Experimental and clinical studies suggest that selenium modulates the inflammatory and immune responses. Patients suffering from inflammatory rheumatic diseases often have low selenium levels, but this finding does not correlate with disease severity. Selenium supplementation needs stricter selection criteria and better ascertainment of dose to obtain a stimulatory or inhibitory effect relevant to the disease state. Prevention of marginal selenium deficiency by moderate supplementation might enhance host defense mechanisms.

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Percutaneous efficacy and tolerability of a new topical indomethacin spray compared with a corresponding placebo product were evaluated in a double-blind, randomized crossover study in 30 patients with tendinitis, i.e. 28 patients with peri-arthritis of the shoulder and two with epicondylitis. Each patient was treated with 4% indomethacin spray or the corresponding placebo product three to five times daily for a period of 14 days and then received the other treatment for the same period of time. The indomethacin spray demonstrated a clear efficacy compared with the placebo based on both objective criteria (elevation, abduction and internal rotation) and subjective criteria (spontaneous pain, pain on movement, pressure-induced pain, functional disturbances and sleep disturbances). Tolerability was excellent: only two patients had minor local cutaneous irritation with the indomethacin spray, which did not require interruption of treatment. Treatment with indomethacin spray appeared to be effective in 80% and well-tolerated in 93% of the patients studied.

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