A randomized, multicentre, double-blind, parallel-group study to assess the adverse event-related discontinuation rate with celecoxib and diclofenac in elderly patients with osteoarthritis.

OBJECTIVE: To compare the adverse event (AE)-related discontinuation rate with celecoxib vs. diclofenac when given to reduce joint pain associated with knee or hip osteoarthritis (OA) in elderly patients. METHODS: This was a double-blind, randomized, multicentre, parallel-group, 1-year comparison of celecoxib 200 mg once daily and diclofenac 50 mg twice daily in 925 patients with OA aged > or = 60 years. Study visits were at baseline and at 4, 13, 26, 39, and 52 weeks. At each visit, the Patient's and Physician's Global Assessment of Arthritis (PaGAA, PhGAA), the Patient's Assessment of Arthritis Pain--Visual Analogue Scale (PAAP-VAS), and AEs were assessed. A concomitant health economic analysis was conducted throughout. RESULTS: The rate of study discontinuation due to AEs, laboratory abnormalities, and deaths was 27% for celecoxib and 31% for diclofenac (p = 0.22). The results of the arthritis/pain efficacy assessments were similar for celecoxib and diclofenac. Significantly fewer patients in the celecoxib group than the diclofenac group experienced cardiovascular/renal AEs (70/458 vs. 95/458, p = 0.039) or hepatic AEs (10/458 vs. 39/458, p<0.0001). Medication costs were higher for celecoxib than diclofenac but mean total treatment cost was slightly higher in the diclofenac group. CONCLUSION: Treatment with celecoxib 200 mg once daily and diclofenac 50 mg twice daily resulted in similar rates of AE-related study discontinuation in elderly patients with OA. Celecoxib and diclofenac demonstrated comparable efficacy in relieving the signs and symptoms of OA. However, the proportion of patients with cardiorenal and hepatic AEs was significantly lower in the celecoxib group than the diclofenac group.

A randomised placebo controlled 12 week trial of budesonide and prednisolone in rheumatoid arthritis.

OBJECTIVES: To compare budesonide, a locally acting glucocorticoid with minimal systemic exposure, with conventional glucocorticoid treatment and placebo in rheumatoid arthritis. METHODS: A double blind, randomised, controlled trial over 12 weeks in 143 patients with active rheumatoid arthritis, comparing budesonide 3 mg daily, budesonide 9 mg daily, prednisolone 7.5 mg daily, and placebo. Particular attention was paid to the pattern of clinical response and to changes in the four week period following discontinuation of treatment. RESULTS: There were improvements in tender joint count and swollen joint count on budesonide 9 mg compared with placebo (28% for tender and 34% for swollen joint counts, p<0.05). Prednisolone 7.5 mg gave similar results, while budesonide 3 mg was less effective. ACR20 response criteria were met by 25% of patients on placebo, 22% on budesonide 3 mg, 42% on budesonide 9 mg, and 56% on prednisolone 7.5 mg. A rapid and significant reduction in symptoms and signs in response to budesonide 9 mg and prednisolone 7.5 mg was evident by two weeks and maximal at eight weeks. There was no evidence that budesonide provided a different pattern of symptom control from prednisolone, or that symptoms became worse than placebo treatment levels after discontinuation of glucocorticoid treatment. Adverse effects attributable to glucocorticoids were equally common in all groups. CONCLUSIONS: The symptomatic benefits of budesonide 9 mg and prednisolone 7.5 mg are achieved within a short time of initiating treatment, are maintained for three months, and are not associated with any rebound in symptoms after stopping treatment.

A vegan diet free of gluten improves the signs and symptoms of rheumatoid arthritis: the effects on arthritis correlate with a reduction in antibodies to food antigens.

OBJECTIVE: Whether food intake can modify the course of rheumatoid arthritis (RA) is an issue of continued scientific and public interest. However, data from controlled clinical trials are sparse. We thus decided to study the clinical effects of a vegan diet free of gluten in RA and to quantify the levels of antibodies to key food antigens not present in the vegan diet. METHODS: Sixty-six patients with active RA were randomized to either a vegan diet free of gluten (38 patients) or a well-balanced non-vegan diet (28 patients) for 1 yr. All patients were instructed and followed-up in the same manner. They were analysed at baseline and after 3, 6 and 12 months, according to the response criteria of the American College of Rheumatology (ACR). Furthermore, levels of antibodies against gliadin and beta-lactoglobulin were assessed and radiographs of the hands and feet were performed. RESULTS: Twenty-two patients in the vegan group and 25 patients in the non-vegan diet group completed 9 months or more on the diet regimens. Of these diet completers, 40.5% (nine patients) in the vegan group fulfilled the ACR20 improvement criteria compared with 4% (one patient) in the non-vegan group. Corresponding figures for the intention to treat populations were 34.3 and 3.8%, respectively. The immunoglobulin G (IgG) antibody levels against gliadin and beta-lactoglobulin decreased in the responder subgroup in the vegan diet-treated patients, but not in the other analysed groups. No retardation of radiological destruction was apparent in any of the groups. CONCLUSION: The data provide evidence that dietary modification may be of clinical benefit for certain RA patients, and that this benefit may be related to a reduction in immunoreactivity to food antigens eliminated by the change in diet.

[Leflunomide--the first specific disease-modifying drug against rheumatoid arthritis]. / Leflunomid--första riktade läkemedlet mot reumatoid artrit.

Rheumatoid arthritis (RA) is a disabling disorder with chronic inflammation leading to significant disability and pain if not treated early and effectively. Leflunomide is the first drug developed and registered specifically for modifying disease course in RA, and is a good complement to other forms of drug therapy currently in use. In clinical trials, leflunomide has been proven to exert an effect on clinical parameters of RA-inflammation superior to placebo and equal to methotrexate and sulphasalazine, while clinical response evidently begins somewhat earlier than on these other drugs. There appears to be a retarding effect on radiographic progression over 13 months comparable to that of methotrexate and sulphasalazine. The very long elimination half-life as well as side effects including nausea, diarrhea, and elevated liver enzymes (almost as frequent as with methotrexate) hamper its usefulness, and its definitive place in modern RA-therapy remains to be established.

Development of lupus-related side-effects in patients with early RA during sulphasalazine treatment-the role of IL-10 and HLA.

OBJECTIVE: The development of systemic lupus erythematosus (SLE)-related syndromes during treatment with sulphasalazine has been described and demonstrated to be influenced by genetic factors. The prevalence of this drug-induced condition and the immunological mechanisms involved are less known. The aim of this study was to determine the prevalence of sulphasalazine-induced lupus-like reactions in a well-defined early rheumatoid arthritis (RA) cohort and to analyse the roles of HLA haplotypes, autoantibodies and the B-cell stimulating cytokine interleukin-10 (IL-10) as possible underlying risk factors. Patients and methods. Forty-one consecutive patients with early RA, in whom sulphasalazine was used as the first disease-modifying anti-rheumatic drug in single therapy and was maintained for at least 6 months, were investigated for the occurrence of lupus-related events. Longitudinal analyses of rheumatoid factor (RF), antinuclear antibodies (ANA), anti-double-stranded DNA antibodies and serum IL-10 (ELISA) and the typing of HLA DR and DQ alleles were performed. RESULTS: Four of the 41 patients developed lupus-like disease. Three of four patients who had lupus-related events vs four of 37 patients without side-effects had an HLA DR 0301 haplotype. The patients developing lupus-related side-effects had increased levels of serum IL-10 and a high frequency of ANA in speckled patterns before the onset of therapy. CONCLUSION: The development of SLE-like symptoms and SLE-related autoantibody production was observed more commonly than expected, with an increased risk in patients with SLE-related HLA haplotypes, increased serum IL-10 levels and ANA in speckled patterns. The data suggest that immunomodulation associated with sulphasalazine treatment may contribute to the development of lupus-related reactions in genetically predisposed individuals.

Predisposing factors in sulphasalazine-induced systemic lupus erythematosus.

The aim of this study was to define predisposing factors in patients with sulphasalazine-induced systemic lupus erythematosus (SLE). Eleven patients with onset of SLE or SLE-like syndromes during sulphasalazine treatment are reported. Before the onset of SLE, five of the patients suffered from rheumatoid arthritis (RA), one from psoriatic arthropathy (PsoA), two from juvenile chronic arthritis (JCA) and three from ulcerative colitis (UC). At the time of diagnosis of drug-induced SLE, analysis of antinuclear antibodies (ANA), anti-double-stranded DNA antibodies (anti-dsDNA), anti-histone antibodies (anti-histones), acetylator status of the enzyme N-acetyltransferase 2 (NAT2) and HLA classification were performed. All patients were anti-DNA positive at disease onset and were determined to be slow acetylators. HLA A1 occurred in 4/10 patients, B8 in 5/10. HLA DR 3 was represented in one patient and DR 3(17) in five patients. The DQA1* 0501 allele was observed in 7/10 patients and DQB1 0201* in 6/10. Persistent SLE and development of nephritis were noted in patients with long duration of treatment and high cumulative dose of sulphasalazine (> 1000 g). In sulphasalazine-induced SLE, slow acetylator genotype and HLA haplotypes associated with idiopathic SLE seem to predict disease induction. Further, as the risk of developing persistent SLE and nephritis increases with long-standing sulphasalazine medication, it is of importance to monitor the patients with regard to signs of SLE during the entire treatment period.

Olsalazine-induced lupus syndrome.

A 73 year-old woman with ulcerative colitis developed skin rashes after long-standing sulphasalazine treatment. After a switch to olsalazine, she developed a severe SLE with multiorgan involvement. When the treatment was terminated, the disease manifestations and serological findings resolved.

Mechanisms for lipoxin A4-induced neutrophil-dependent cytotoxicity for human endothelial cells.

In a model of vasculitis we have evaluated mechanisms for how neutrophil polymorphonuclear granulocytes (PMNs) kill cultured human umbilical vein endothelial cells (HUVECs) in vitro (as release of chromium 51) in response to the double dioxygenation product of arachidonic acid, lipoxin A4 (LXA4) and to formyl-methionyl-leucyl-phenylalanine (fMLP). The cytolysis induced by LXA4 and fMLP was dose dependent, with maximum values at 100 nmol/L (which caused a 2.7-fold and 2.3-fold increases of 51Cr release, respectively, relative to buffer-treated controls). LXA4 also conferred a peak of cytotoxicity at 0.1 nmol/L (which caused a 2.2-fold increase in 51Cr release). Leukotriene B4, platelet activating factor (PAF), and zymosan-activated serum were inefficient. Phorbol myristate acetate caused the most prominent cytotoxicity, which was first evident at 1 mumol/L. The LXA4 effect was abrogated by superoxide dismutase, catalase, alpha 2-macroglobulin, and alpha 1-antitrypsin but not by mannitol. Addition of a monoclonal antibody (mAb) to CD18 also inhibited neutrophil-dependent cytotoxicity to LXA4 and fMLP. MAbs to intercellular adhesion molecule-1 or P-selectin blocked 100% and 52%, respectively, of the LXA4-induced cytotoxicity. Neutrophils from a patient with chronic granulomatous disease were incapable of mediating any cytotoxicity. The LXA4 effect was inhibited by the PAF receptor antagonist WEB-2086 and by treating neutrophils with pertussis toxin. Thus this novel effect of LXA4, as a potent promoter of neutrophil-mediated cytotoxicity for HUVECs, is a process dependent on PMN adhesion proteins, oxygen radicals, and proteases, and it is apparently associated with endogenous PAF expression and requires pertussis-sensitive G proteins.

Neutrophil membrane potential changes and homotypic aggregation kinetics are pH-dependent: studies of chronic granulomatous disease.

Activated polymorphonuclear neutrophil granulocytes (PMN) from patients with chronic granulomatous disease (CGD) show reduced electron-proton shifts and an inability to acidify the cell. We studied whether this impaired pH-regulating capacity affected PMN membrane potential changes and the kinetics of homotypic aggregation by changing the extracellular pH over a wide range. At pH 7.4 normal PMN showed a rapid, transient membrane depolarization to leukotriene B4 (LTB4) and a slower response to N-formyl-methionyl-leucyl-phenylalanine. In contrast, PMN from 13 patients with CGD exhibited no or minute depolarization to these stimuli and 77% of tested patients with CGD displayed absence or marked reductions of the disaggregation to LTB4. On acidification of pH 5.0 to 6.4, PMN membrane depolarization appeared in six of nine tested patients. Likewise, disaggregation became evident in all of three patients. On alkalinization of normal PMN to pH 8.0 to 9.0, membrane depolarization and disaggregation to LTB4 disappeared, and cells reacted as CGD PMN. This change was not due to inefficient signal transduction, because normal PMN enhanced the superoxide ion production to N-formyl-methionyl-leucyl-phenylalanine on this alkalinization. Cytosolic pH changes in resting and LTB4-activated CGD cells at pH 6.0, 7.4, and 8.5 were similar those in control cells but for absence of an initial acidification. Thus neutrophil membrane potential changes and aggregation kinetics to LTB4 are abnormal in patients with CGD and return toward normal on extracellular acidification.

Lipoxin A4 induces neutrophil-dependent cytotoxicity for human endothelial cells.

The authors have assessed the capacity of neutrophil granulocytes (PMN) to kill cultured human umbilical-vein endothelial cells (HUVEC) in vitro (as release of 51Cr) in response to the recently described double dioxygenation product of arachidonic acid, lipoxin A4 (LXA4). LXA4 conferred a marked cytotoxicity, whereas formyl-methionyl-leucyl-phenylalanine (fMLP) was less potent. The LXA4 and fMLP effects were dose dependent, with a maximum at 100 nM (which caused 2.7- and 2.3-fold increases of 51Cr release, respectively, relative to buffer-treated controls). The LXA4 and fMLP responses increased with the PMN concentration, depended on the fetal calf serum concentration, incubation temperature and duration and the presence of calcium and magnesium ions.

Pubertal development in elite juvenile gymnasts. Effects of physical training.

Twenty-two female teenagers engaged in elite gymnast training were prospectively studied during a five-year period and their pubertal development was recorded. Height and weight, as well as stage of development according to Tanner, were registered every six months. FSH, LH, TSH and prolactin were measured in girls who had not yet had their first menstrual period. Twenty-two healthy school girls in the same age group who were not actively engaged in physical exercise served as a control group. Pubertal development was completed during the observation period in all the gymnasts but one, who had primary amenorrhea at the age of eighteen. As a group, the gymnasts had a significantly delayed age of menarche compared to the control group and to normal Swedish girls. They also had significantly less body fat and were shorter and lighter than the control group. They grew much more slowly and did not have the distinct growth spurt seen in the controls. The final height of six of the gymnasts was less than the expected height. The frequency of injuries was high in the gymnasts, which might be a result of hard training combined with late menarche and low body fat.

[Rheumatologists' current tasks]. / Reumatologins nya arbetsuppgifter.

The main tasks for contemporary rheumatology include finding methods for the early identification of patients with inflammatory arthropathy, the use and development of prognostic indicators of the degree of aggressiveness required in treatment, and well structured and comprehensive follow-up treatment modalities administered in new ways and of the many new modalities that are under development. Success in these respects will entail close liaison with primary care and with other related disciplines. Dynamic developments are to be expected concerning the introduction of new generations of immunoregulatory agents.

The effect of endothelin, neuropeptide Y, calcitonin gene-related peptide and substance P on neutrophil functions.

Neuropeptides are putative mediators of inflammation. At physiological concentrations substance P has been shown to prime polymorphonuclear neutrophil granulocyte (PMN) chemiluminescence (CL). In the present study we show also that both endothelin and neuropeptide Y (NPY), but not calcitonin gene-related peptide (CGRP) are able to prime PMN oxidative metabolism. At similar nanomolar concentrations SP and endothelin (but not NPY) also primed formyl-methionyl-leucyl-phenylalanine (fMLP)-induced rises of cytosolic calcium. On the other hand, NPY caused a direct and dose-related increase of cytosolic calcium concentrations. None of the mentioned neuropeptides primed PMN aggregation or directly induced CL, aggregation or chemotaxis over a wide range of concentrations (1 fM-1 microM).

Effects of an essential fatty acid-supplemented diet on leukotriene B4-induced rat neutrophil functions.

This study evaluated the effect of dietary supplementation with the essential fatty acid linoleic acid to 10% of the energy content of a diet on the stimulus-response coupling of rat peritoneal neutrophils. When stimulated with leukotriene B4 neutrophils from essential fatty acid supplemented rats responded with a significantly more pronounced oxidative metabolism (assessed as luminol augmented chemiluminescence) relative to control cells from rats on a normal 3% of total energy essential fatty acid diet. Chemiluminescence response to the formylpeptide N-formyl-norleucyl-leucyl-phenylalanine-norleucyl-thyrosyl-leucine was similarly enhanced. In contrast, responses elicited by the lectin concanavalin A did not differ between the two dietary groups. In response to leukotriene B4 a dose-related inhibition of neutrophil aggregation was observed, whereas chemotaxis did not differ between the two groups. Thus, linoleate supplementation is associated with a stimulus-specific modulation of neutrophil oxidative and aggregatory responses suggesting an effect on early, conceivably receptor-linked, steps of the stimulus-response coupling.

Antirheumatic effects of fasting.

Total fasting induces within a few days a substantial reduction of joint pain, swelling, morning stiffness, and other arthritic symptoms in patients with rheumatoid arthritis. This remission subsides slowly after discontinuation of fasting. Its mechanisms are complex and involves diminished activation of neutrophils and lymphocytes and decreased generation of leukotrienes and of concentrations of serum complement factors, as well as of other proinflammatory systems. Moreover, ketosis and other metabolic and endocrine changes may be of significance for symptom expression and recognition.

The effect of 20-trifluoromethyl leukotriene B4 on neutrophil functional responses.

20-trifluoromethyl-leukotriene B4 (20CF3-LTB4) is a stable derivative of leukotriene B4 (LTB4) that is not subjected to omega-oxidation to less active metabolites. 20CF3-LTB4 was as potent as LTB4 as a chemotactic, adhesion-promoting and aggregatory agent for human neutrophils, but had only 11 +/- 3% of the ability to induce an oxidative response. Nonetheless, both compounds were equally efficient in order to confer a rapid and monophasic increment of the concentration of cytosolic calcium. The kinetics of the calcium, aggregatory and chemiluminescent responses to 20CF3-LTB4 were similar to that of LTB4. These findings suggest that the insertion of the trifluoromethyl group into the LTB4 molecule causes a shift of the biological activity profile, suggesting that 20CF3-LTB4 binds mainly to high affinity LTB4 receptors. Moreover, the similarity of the response kinetics of LTB4 and 20CF3-LTB4 suggests that the mechanism for the rapid and transient responses of LTB4 is not due to its omega-oxidation.