Anti-nuclear antibodies, anti-DNA and C4 complement evolution in rheumatoid arthritis and ankylosing spondylitis treated with TNF-alpha blockers.

OBJECTIVE: To investigate autoantibody induction in rheumatoid arthritis (RA) and ankylosing spondylitis (AS) in a cohort of French patients treated with TNF-alpha blockers. METHODS: We tested the serum of patients for antinuclear antibodies (ANA), anti-DNA antibodies and C4 complement at baseline, and for each infusion for infliximab, and at month 3, 6 and 12 for etanercept. We looked for all signs suggesting a drug-induced lupus. We tried to correlate ANA and anti-DNA development with various clinical data, especially the response to treatment. RESULTS: 229 patients were included in the study. 159 were treated with infliximab (98 RA and 61 AS) and 125 with etanercept (116 RA and 9 AS). In the infliximab group, 43.6% of RA patients and 27.1% of AS had significant levels of ANA at baseline. This proportion increased during the follow up to 73% in RA patients and 52% in AS patients. The proportion of patients positive for anti-DNA antibodies increased from 0% to 9.5% in RA group, and from 0% to 2% in AS group. In the etanercept group, 58.5% of these patients had significant levels of ANA at baseline; this proportion raised to 63.3% in patients previously treated with infliximab, and fell to 20.6% in the patients who never received TNF-alpha blockers. No significant variation of ANA, anti-DNA and C4 levels was observed in the etanercept group. Only three patients developed clinical manifestations (chilblain lupus) possibly related to these auto-antibodies, two with infliximab and one with etanercept. CONCLUSION: The ANA induction was only observed under infliximab therapy. Thus, ANA induction seems not to be a therapeutic class effect. This difference between infliximab and etanercept treatment may be the consequence of differential capacity of a monoclonal antibody and a soluble receptor in inducing apoptotic cell death of the cells expressing TNF on their membrane.

Role of anti-tumour necrosis factor-alpha therapeutic agents in the emergence of infections.

There is increasing interest concerning the possible impact of anti-tumour necrosis factor (TNF)-alpha therapeutic agents on the emergence of infections. However, these agents do not seem to increase the incidence of adverse infectious events significantly. Published observations concern mostly infections of the urinary and upper respiratory tracts that develop in the setting of co-morbidities, such as anterior or concomitant immunosuppressive treatment. Infliximab appears to increase the risk of tuberculosis, but this effect has not been observed with other anti-TNF-alpha agents. To better characterise the adverse infectious effects associated with these agents, physicians should be encouraged to notify the microbiological data relating to all cases.

Effectiveness and safety profile of leflunomide in rheumatoid arthritis: actual practice compared with clinical trials.

OBJECTIVE: Leflunomide, an immunosuppressant agent for treating rheumatoid arthritis, was first marketed in France in 2000. Three years after its launch, we sought to assess its prescription patterns in the real world of prescription and use, and to see if its efficacy and safety profiles observed during clinical trials were confirmed. METHODS: All patients treated with leflunomide from May 2000 to April 2003 in the Department of Rheumatology of the Bordeaux University Hospital were identified, and their treatment patterns and outcome ascertained. This was compared to data from clinical trials. RESULTS: 116 were included (mean age = 55 years, 70% women). Almost 21.7% stopped treatment for lack of efficacy (after a mean delay of 3.6 months), 16% for secondary loss of efficacy (median = 7 months), and 32% for the occurrence of an adverse event (half within 4 months). Over a similar time frame in clinical trials, in patients of about the same age and sex but with less severe disease, the corresponding figures were 7-17% for lack or loss of efficacy, and 14-22% for adverse effects. At one year of follow-up, the discontinuation rate was 70% in the cohort compared to 28-47% in clinical trials. DISCUSSION: The differences between the two populations confirm the need to conduct post-marketing studies in order to obtain better knowledge on the effectiveness and safety of a new drug. In many cases, a simple drug utilization study can provide relevant information on the degree of shift between populations included in clinical trials and those treated in real life.

[Bone mineral density and bone metabolism in spondylarthropathies]. / Densité minérale et métabolisme osseux des spondylarthropathies.

AIMS: To study the prevalence of osteoporosis in a group of patients with spondyloarthropathy and to investigate bone turnover markers and correlation between bone mineral density and the age at the beginning of the disease. PATIENTS AND METHOD: Patients with spondyloarthropathy as defined by New York and ESSG criteria. Bone mineral density was measured at the lumbar spine and hip with Hologic QDR 1000. Serum levels of osteocalcin, deoxypyridinoline, 25 vitamin D, creatinine and parathyroid hormone were measured. RESULTS: 50 patients were included in the study: 37 men, mean age 40,2+/-13,8 years. Vertebral osteopenia was observed in 34% while femoral osteopenia occurred in 40% of patients. Serum vitamin D was low in 70% of patients without parathyroid hormone or kidney function modification. Markers of bone turn over were increased in 29% of patients. There was no correlation between these biological markers and the bone mineral density. We observed a significative correlation (P=0,02) between the age at the beginning of the disease and the bone mineral density. CONCLUSION: Osteopenia is present in patients with spondyloarthropathy without any correlation with the bone turnover biological markers. We observed a significative correlation between the age at the beginning of the disease and bone mineral density.

Clinical pharmacokinetics of low-dose pulse methotrexate in rheumatoid arthritis.

Low-dose pulse methotrexate has emerged as one of the most frequently used slow-acting, symptom-modifying antirheumatic drugs in patients with rheumatoid arthritis (RA) because of its favourable risk-benefit profile. Methotrexate is a weak bicarboxylic acid structurally related to folic acid. The most widely used methods for the analysis of methotrexate are immunoassays, particularly fluorescence polarisation immunoassay. After oral administration, the drug is rapidly but incompletely absorbed. Since food does not significantly affect the bioavailability of oral methotrexate in adult patients, the drug may be taken regardless of meals. There is a marked interindividual variability in the extent of absorption of oral methotrexate. Conversely, the intraindividual variability is moderate even over a long time period. Intramuscular and subcutaneous injections of methotrexate result in comparable pharmacokinetics, suggesting that these routes of administration are interchangeable. A mean protein binding to serum albumin of 42 to 57% is usually reported. Again, the unbound fraction exhibits a large interindividual variability. The steady-state volume of distribution is approximately 1 L/kg. Methotrexate distributes to extravascular compartments, including synovial fluid, and to different tissues, especially kidney, liver and joint tissues. Finally, the drug is transported into cells, mainly by a carrier-mediated active transport process. Methotrexate is partly oxidised by hepatic aldehyde oxidase to 7-hydroxymethotrexate. This main, circulating metabolite is over 90% bound to serum albumin. Both methotrexate and 7-hydroxy-methotrexate may be converted to polyglutamyl derivatives which are selectively retained in cells. Methotrexate is mainly excreted by the kidney as intact drug regardless of the route of administration. The drug is filtered by the glomeruli, and then undergoes both secretion and reabsorption processes within the tubule. These processes are differentially saturable, resulting in possible nonlinear elimination pharmacokinetics. The usually reported mean values for the elimination half-life and the total body clearance of methotrexate are 5 to 8 hours and 4.8 to 7.8 L/h, respectively. A positive correlation between methotrexate clearance and creatinine clearance has been found by some authors. Finally, the pharmacokinetics of low-dose methotrexate appears to be highly variable and largely unpredictable even in patients with normal renal and hepatic function. Furthermore, studies in patients with juvenile rheumatoid arthritis provide evidence of age-dependent pharmacokinetics of the drug. These features must be considered when judging the individual clinical response to methotrexate therapy. Various drugs currently used in RA may interact with methotrexate. Aspirin might affect methotrexate disposition to a greater extent than other nonsteroidal anti-inflammatory drugs without causing greater toxicity. Corticosteroids do not interfere with the pharmacokinetics of methotrexate, whereas chloroquine may reduce the gastrointestinal absorption of the drug. Folates, especially folic acid, have been shown to reduce the adverse effects of methotrexate without compromising its efficacy in RA. Finally, both trimethoprim-sulfamethoxazole (cotrimoxazole) and probenecid lead to increased toxicity of methotrexate, and hence should be avoided in patients receiving these drugs. A relationship between oral dosage and efficacy has been found in the range 5 to 20mg methotrexate weekly. The plateau of efficacy is attained at approximately 10 mg/m2/week in most patients. No clear relationship between pharmacokinetic parameters and clinical response has been demonstrated. Overall, the dosage must be individualised because of interindividual variability in the dose-response curve. This variability is probably related, at least in part, to the wide interindividual variability in the disposition of the drug.

Mycoplasma fermentans, but not M penetrans, detected by PCR assays in synovium from patients with rheumatoid arthritis and other rheumatic disorders.

AIM/BACKGROUND: Mycoplasmas, especially Mycoplasma fermentans, were suggested more than 20 years ago as a possible cause of rheumatoid arthritis but this hypothesis was never substantiated. In view of the superior sensitivity of the polymerase chain reaction (PCR) assay over culture, the aim was to use this method to seek M fermentans and M penetrans in synovial samples from patients with various arthritides. METHODS: Synovial fluid samples (n = 154) and synovial biopsy specimens (n = 20) from 133 patients with various rheumatic disorders were stored at -80 degrees C for between one and 40 months. Aliquots (500 microliters) of the synovial fluid samples were centrifuged and the deposit, and also the synovial biopsy specimens (approximately 1 g) were placed in lysis buffer with proteinase K for DNA extraction. The DNA was tested by using a semi-nested PCR assay for M fermentans and a single-round PCR for M penetrans. RESULTS: M fermentans was detected in the joints of eight (21%) of 38 patients with rheumatoid arthritis, two (20%) of 10 patients with spondyloarthropathy with peripheral arthritis, one (20%) of five patients with psoriatic arthritis, and four (13%) of 31 patients with unclassified arthritis. M fermentans was not found in the joints of the seven patients with reactive arthritis, the 29 with osteoarthritis or post-traumatic hydrarthrosis, the nine with gouty arthritis, nor the four with chronic juvenile arthritis. M penetrans was not detected in any sample. CONCLUSIONS: These findings show that the presence of M fermentans in the joint is associated with inflammatory rheumatic disorders of unknown cause, including rheumatoid arthritis. However, whether this organism triggers or perpetuates disease of behaves as a passenger remains conjectural.

Periganglionic foraminal steroid injections performed under CT control.

PURPOSE: The purpose of our study was to evaluate the efficacy of direct intraforaminal steroid injections into the periganglionic space in the treatment of radicular pain. METHODS: Periganglionic infiltrations were performed in 41 patients with acute or chronic radicular pain. Neuroradiologic imaging in all patients showed foraminal stenosis due to degenerative disorders or herniated disk. All injections were performed under CT control. RESULTS: Seventy percent of patients had significant pain reduction, with the greatest success (90% of patients) in those whose foraminal stenosis was due to degenerative disorders; 45% of patients with foraminal herniated disks had pain relief. CONCLUSION: Intraforaminal steroid injection is useful in the treatment of radicular pain, particularly in cases of foraminal degenerative stenosis.

Central analgesic effects of aspirin-like drugs.

Aspirin-like drugs mainly include paracetamol, salicylates and other non-steroidal anti-inflammatory drugs, and metamizole. Their analgesic effect is classically ascribed to a peripheral site of action, within the pain-processing site. There is, however, convincing evidence that a central component contributes to the overall analgesia provided by these agents. Experimental and clinical studies referring to this challenging proposal are reviewed here. The exact site and mode of action of aspirin-like drugs within the central nervous system remains controversial. It is likely that supraspinal mechanisms play an important role. Some experiments lend support to the involvement of monoaminergic control systems. Other data indicate that these drugs act centrally through the inhibition of cyclo-oxygenase activity. The interactions between prostaglandins and various neurotransmitters suggest that both mechanisms may be linked.

Piroxicam concentrations in plasma and synovial fluid after a single dose of piroxicam-beta-cyclodextrin.

AIMS: The efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs) in rheumatic diseases depends on their concentrations within the joint. We determined piroxicam concentrations in plasma and synovial fluid (SF) after a single oral dose of 20 mg in the form of one tablet of piroxicam-beta-cyclodextrin. METHODS: 45 patients, aged 21 to 84 years, presenting with an effusion of the knee, related to degenerative or inflammatory joint disease, were included in this study after having given their written consent. One blood and one SF sample were drawn concomitantly in each patient from 0.5 to 48 h after NSAID administration. Piroxicam assays were performed by high performance liquid chromatography. Pharmacokinetic parameters were obtained from the mean plasma and synovial concentrations measured at various sampling times. RESULTS: The peak concentration was higher in plasma (2.51+/-0.25 microg/ml) than in SF (1.31+/-0.76 microg/ml), but the elimination half-life was much longer in SF (90.7 h) than in plasma (32.5 h). The SF/plasma area under the concentration-time curve ratio (evaluating the quantity of NSAID transferred from the blood to the joint) was equal to 0.39. CONCLUSIONS: Piroxicam contained in piroxicam-beta-cyclodextrin diffused well into the SF where its pharmacokinetic profile corresponded to that of a long half-life NSAID.

Epicondylitis after treatment with fluoroquinolone antibiotics.

We report two cases of epicondylitis of the elbow occurring after treatment with fluoroquinolone antibiotics. Both patients had intense pain which appeared very shortly after the first dose of the drug and was not relieved by conservative treatment. Ultrasonography revealed extensive inflammatory lesions with pseudonecrotic areas. MRI confirmed the lesions and also showed a subclinical abnormality of the adjoining tendons. The persistent nature of the pain was the indication for surgical release of the extensor mechanism. After operation pain disappeared completely and the patients were able to return to their normal activities. Lesions of the tendo Achillis are a well-known side-effect of treatment with fluoroquinolone. Our two cases show that such lesions may occur elsewhere. They also indicate the need for caution when prescribing these antibiotics to patients at risk of tendon lesions, such as top-level sportsmen or patients on dialysis or steroid treatment.

Arthropathy associated with anti-Jo-1 antibody.

Anti-Jo-1 antibody is associated with an overlap syndrome usually described as the association of idiopathic inflammatory myopathy, pulmonary fibrosis and polyarthritis. We report three observations illustrating different aspects of arthropathy associated with anti-Jo-1 antibody. Two patients presented with a deforming and erosive arthritis affecting the hands, periarticular calcifications and dislocation of the interphalangeal (IP) joint of the thumb. The third patient, who had a short disease course, presented only with a mild non-erosive polyarthritis of both hands, metacarpophalangeal joint narrowing and periarticular calcifications. All the patients had interstitial pulmonary syndrome. Only two of them had myositis. An arthropathy characterized by erosive arthritis of the fingers, with dislocation of the IP joint of the thumb and periarticular calcifications, seems to be specifically associated with anti-Jo-1 antibody.

Cholesterol crystal embolization simulating focal myositis.

Cholesterol crystal embolization usually produces characteristic skin lesions. We report a case responsible for myositis of the calf without suggestive skin lesions. The outcome in this 58-year-old patient was spontaneously favorable. Cholesterol crystal embolization can produce a range of clinical symptoms, with the skin, kidneys, and eyes being the most common targets. Generalized forms can result in systemic disease. The diagnosis rests on histological findings, and the treatment is symptomatic. Anticoagulants have been shown to worsen the manifestations, whereas antiplatelet therapy may be useful.

[Methotrexate and non-steroidal anti-inflammatory agent combination in rheumatoid arthritis]. / Association méthotrexate et anti-inflammatoire non stéroïdien au cours de la polyarthrite rhumatoïde.

It is well known that methotrexate (MTX), used at high dosage in cancer patients, must not be combined with a non-steroidal anti-inflammatory drug (NSAID) because of high risk of side effects; prescribed at low dosage (< or = 15 mg per week) in rheumatoid arthritis patients, MTX is often combined with an NSAID. Some cases reported in the literature underline the potential toxicity of the association of low dose MTX with an NSAID, but most of the pharmacological studies do not confirm this hypothesis. Except for salicylates, NSAIDs do not affect the absorption, distribution, protein binding, area under the curve, half-life, or the elimination of MTX. Therefore, if necessary, MTX (< or = 15 mg per week) can be combined with an NSAID during the treatment of rheumatoid arthritis.

[Environmental factors and iatrogenic elements in systemic scleroderma and related syndromes. Review of the literature]. / Les facteurs d'environnement et les éléments iatrogènes dans la sclérodermie systémique et les syndromes apparentés. Revue de la littérature.

The etiology of scleroderma remains unknown. Although a genetic susceptibility seems to play a role, some environmental and iatrogenic factors have been suggested to trigger the disease. Contact for many months or years with natural or synthetic "toxic" products (by inhalation, cutaneous contact, injection, swallowing or surgical implant) could be implicated in the development of typical scleroderma or pseudo-scleroderma. These products are either occupational or non occupational like those used at home in daily life. We will sum up the knowledges about this subject.

[Osteomalacia. Histologic definition and significance of the histodynamic analysis on undecalcified bone]. / L'ostéomalacie. Définition histologique et intérêts de l'étude histodynamique sur os non décalcifié.

Bone histomorphometry has a major significance in metabolic bone diseases, and especially in osteomalacia. This technique needs a strict methodology with quantitative analysis on undecalcified bone and measure of calcification rate. Histologic definition of osteomalacia includes hyperosteoidosis, characterized by thickened osteoid edges, and decrease of calcification rate. Histodynamic analysis on undecalcified bone provides interest in diagnosis, prognosis and supervision of this affection.

[Acute chondrolysis on primary protrusio acetabuli in children]. / Chondrolyse aiguë sur coxopathie protrusive primitive de l'enfant.

Two cases of acute chondrolysis of the upper femoral epiphysis associated with protrusio acetabuli are reported in two girls respectively 13 and 12 Y.O. The disease was unilateral in one patient and bilateral in other. Acute chondrolysis is characterized by onset of pain, restricted movements of the hip and evolution to an hip ankylosis within a few months. As usual no evidence of inflammatory disease could be shown at biology or at pathology of synovial membrane or of femoral head. CT and MR studies proved to be contributive in the first case. It's the author's opinion that in these 2 cases, chondrolysis appears as a complication of preexistent Protrusio Acetabuli.

[Deforming arthropathy associated with the presence of anti Jo-1 antibody in polymyositis. A new case]. / Arthropathie déformante associée à la présence de l'anticorps anti Jo-1 au cours de la polymyosite. Une nouvelle observation.

A deforming arthropathy confined to the hands developed in a woman with polymyositis of three year's duration. Roentgenograms showed distal subluxations of several fingers, especially the thumb, asymmetrical marginal erosions of the phalanges and periarticular calcifications. These roentgenographic findings are considered to be specific of polymyositis associated with anti-Jo-1 antibody.

[Side-effects during treatment of rheumatoid arthritis with methotrexate]. / Effets indésirables observés au cours du traitement de la polyarthrite rhumatoïde par le méthotrexate.

Methotrexate is the drug with the highest long-term continuation rate in rheumatoid arthritis patients. However, toxicity is the main reason for methotrexate withdrawal. Most adverse effects are mild abnormalities, such as digestive symptoms, stomatitis, elevations in transaminase levels, and moderate decreases in peripheral blood cell counts. Potentially life-threatening effects include hypersensitivity pneumonitis and pancytopenia. Cirrhosis is less common than in patients with psoriasis. Opportunistic infections and Epstein-Barr virus-related lymphomas have been reported. Neurological disorders, cutaneous reactions and renal lesions have been ascribed to low-dose methotrexate. Prior renal dysfunction and concomitant administration of a number of drugs, including cotrimoxazole, have been shown to increase methotrexate toxicity. However, susceptibility to the toxic effects of methotrexate varies widely across individuals. The effectiveness of folate supplementation in preventing methotrexate toxicity remains controversial.