The use of folates concomitantly with low-dose pulse methotrexate.

Toxicities related to low-dose weekly methotrexate are largely due to its antifolate properties. Preexisting folate deficiency is associated with methotrexate toxicity in some patients. At the onset of methotrexate therapy and throughout therapy, the physician should be vigilant regarding one or more nutrient deficiencies. A multivitamin and, where appropriate, specific daily folic acid supplements should be employed. The only regimen known presently (through controlled trials) to treat side effects is the low-dose folinic acid (leucovorin) protocol outlined herein. Folic acid may be helpful to treat mild gastrointestinal symptoms. Folinic acid supplementation should be considered prophylactically in those requiring methotrexate who are at increased risk of hepatic disease. Other possible factors besides methotrexate should always be considered with the onset of new patient complaints or laboratory abnormalities. Claims that folic acid therapy is safer and more convenient than folinic acid seem unwarranted when one reviews the literature carefully. Cost differences between folic acid supplementation and folinic acid supplementation have been exaggerated.

Rheumatic disease patients, prone to Sjögren's syndrome and/or lymphoma, mount an antibody response to BHRF1, the Epstein-Barr viral homologue of BCL-2.

The IgG response to Epstein-Barr virus (EBV) early antigens [BHRF1 (p 17.1), the viral homologue of bcl-2, and BMRF1 (p50.10), a DNA binding protein] was measured in patients with rheumatic disease to see whether there was any association with lymphoma. Patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Sjögren's syndrome (SS), rheumatic disease patients with lymphoma, patients with lymphoma who did not have a rheumatic disease and normal individuals were tested for the presence of anti-EA peptide antibodies by ELISA. Whereas antibodies to early EBV peptides were detected only in one normal individual, patients with rheumatic diseases, especially those with either SS and/or lymphoma, had a much higher frequency of antibody detection. Antibodies to BMRF1 p50.10 were found in 7-50% of patients, and to BHRF1 p17.1 in 4-27%, depending on the group studied. Patients with lymphoma lacking a rheumatic disease had a 2-fold lower frequency of anti-BHRF1 antibodies, compared to the lymphoma plus rheumatic disease group. The increased immune response to the EBV EA proteins in the rheumatic diseases probably reflects the presence of reactivated virus, and the BHRF1 protein (the viral homologue to bcl-2) could, via inhibiting apoptosis, contribute to the lymphoproliferative nature of these diseases.

Combination sulfasalazine and methotrexate in the management of rheumatoid arthritis.

I wished to review the pharmacology and current clinical experience with the combination of methotrexate and sulfasalazine as a management for rheumatoid arthritis. To date, no double blind randomized placebo controlled studies have been reported, though such studies are under way. Published experience is in excess of 100 patients and for as long as 8 years of followup. To date, the combination would appear to be well tolerated, with comparable toxicities to the individual agents taken as monotherapy. Withdrawal flare reports support a positive clinical effect of this combination. The results of ongoing controlled trials are awaited with interest.

Combination of sulphasalazine and methotrexate in the management of rheumatoid arthritis--view based on personal clinical experience.

Over the past fifteen years, there has been increasing interest in the use of combinations of medications to better suppress the inflammatory process that leads to progressive disability in most rheumatoid arthritis patients. We have been evaluating the combination of sulphasalazine and methotrexate for the last 8 years. Although these data are uncontrolled, our experience would suggest that this combination is well tolerated. Furthermore, flares of disease occurring with attempts to withdraw either of the two agents suggest that the combination may be effective when the use of these agents individually has not.

Detection of cytomegalovirus, Epstein-Barr virus and herpes virus-6 in patients with rheumatoid arthritis with or without Sjögren's syndrome.

The frequency of latent viral infection by cytomegalovirus (CMV), Epstein-Barr virus (EBV) and herpes virus-6 (HHV-6) was investigated in patients with RA with or without Sjögren's syndrome (SS) and in normal controls. Virus presence was determined by polymerase chain amplification of DNA isolated from peripheral blood mononuclear or polymorphonuclear cells and/or saliva-derived mononuclear/epithelial cells. Anti-viral antibodies and autoantibodies were also assayed. Patients with RA both with and without SS were found to have a significantly increased frequency of latent viral infection (two-fold higher, P = 0.035 for EBV and seven-fold higher, P = 0.018 for HHV-6) compared to normal controls but only in cells isolated from saliva. The increased frequency of virally infected cells from the saliva of patients with RA, regardless of the SS status, when compared to normal controls may reflect the ongoing inflammatory process, the impact of therapy and/or a less effective local immune responsiveness.

Chest radiographs as a screening test for diffuse idiopathic skeletal hyperostosis.

OBJECTIVE: To evaluate the sensitivity, specificity, predictive value, interrater reliability and intrarater reliability of using chest radiographs as a screening tool for the diagnosis of diffuse idiopathic skeletal hyperostosis (DISH). METHODS: After review of thoracic spine radiographs by 2 "gold standard" physicians, 45 patients with DISH meeting the criteria of Resnick and Niwayama were contrasted with 106 control patients consisting of 45 with thoracic spondylosis, 45 who lacked spondylosis and whose thoracic spine radiographs were otherwise normal for the age of the patient, and 16 with ankylosing spondylitis. The chest radiographs on the 151 subjects were placed in random order and read independently using an ordinal diagnostic certainty scale by 2 "test" radiologists, experienced in reading bone radiographs. Two months later the order of chest radiographs was rerandomized and the films reassessed by the same test radiologists. RESULTS: The averages for the diagnostic and population test characteristics were sensitivity = 77%; specificity = 97%; positive predictive value = 91%; and, negative predictive value = 91%. The area under the receiver operating characteristic curves was 0.975 and 0.976 for the radiologists, and kappa was 0.93, demonstrating that interrater reliability was high. On rereading the chest radiographs, intrarater reliability was exceptional (weighted kappa of 0.90 and 0.96 for the two test radiologists). DISH patients whose chest radiographs were read as not demonstrating DISH had significantly less extensive disease. CONCLUSIONS: We conclude that chest radiographs are a reliable and valid screening tool for the diagnosis of DISH.

Thyroid dysfunction in rheumatoid arthritis: a controlled prospective survey.

OBJECTIVES: To determine whether thyroid dysfunction is found with increased frequency in patients with rheumatoid arthritis (RA). METHODS: A controlled prospective survey was conducted on a cohort of patients with RA derived from a hospital clinic and a private surburban rheumatology practice. A control group with similar demographic features was generated from the same sources and included subjects with either osteoarthritis or fibromyalgia. Consecutive patients were evaluated over a six month period. The evaluation included a complete history and physical examination, and determination of serum thyroxine, free thyroxine, triiodothyronine, thyroid stimulating hormone (IRMA), antinuclear antibodies, and rheumatoid factor. RESULTS: Of the 91 women with RA evaluated, 29 (30%) had evidence of thyroid dysfunction compared with 10 (11%) of 93 controls. The excess thyroid dysfunction is due to either hypothyroidism or Hashimoto's thyroiditis and was independent of age, increasing duration of disease, rheumatoid factor, and antinuclear antibodies. CONCLUSIONS: Thyroid dysfunction is seen at least three times more often in women with RA than in women with similar demographic features with non-inflammatory rheumatic diseases such as osteoarthritis and fibromyalgia.

Low-dose methotrexate with leucovorin (folinic acid) in the management of rheumatoid arthritis. Results of a multicenter randomized, double-blind, placebo-controlled trial.

OBJECTIVE: To determine whether the side effects of methotrexate can be decreased by the concurrent use of leucovorin, without affecting the efficacy of the methotrexate. METHODS: We conducted a multicenter randomized, double-blind, placebo-controlled trial of leucovorin administration, 2.5-5.0 mg orally, to be given 24 hours after the single, weekly, oral dose of methotrexate. Every 3 weeks for 52 weeks, patients were evaluated for rheumatic disease activity and side effects. Dosage adjustments for both methotrexate and leucovorin were made as needed, according to a defined protocol. The primary outcome evaluated was the frequency of study withdrawals because of side effects and/or inefficacy. Secondary outcomes evaluated included the frequency of side effects and the relative efficacy of methotrexate in the leucovorin and placebo treatment groups. RESULTS: Ninety-two evaluable patients were analyzed (44 took leucovorin and 48 placebo). Twenty-two patients withdrew early because of side effects unresponsive to our protocol, and 1 because of inefficacy; 17 had been taking placebo and 6 had been taking leucovorin (35% versus 14%, P < 0.02). The number of visits during which side effects were reported was reduced by almost 50% in the leucovorin treatment group (P < 0.001). There were significant reductions in the frequencies of all common side effects. At 52 weeks, disease activity was similar in both patient groups. CONCLUSION: The methotrexate-leucovorin protocol used significantly reduces common side effects of methotrexate therapy without significantly altering efficacy.

High dose intravenous methotrexate for refractory rheumatoid arthritis.

Eight patients with active rheumatoid arthritis were given high dose intravenous methotrexate (MTX) (500 mg/m2) followed by oral leucovorin every 2 weeks for up to 6 months. All patients enrolled had previously failed conventional MTX therapy. Five patients completed 6 months of therapy. Three withdrew early, one due to inefficacy, one due to gastrointestinal intolerance and one due to sciatica requiring hospital admission. Fifty percent or greater improvements were seen in 5 of 8 clinical variables in those patients who completed 6 months of therapy. Six of 8 improvements achieved statistical significance at 24 weeks. Upon discontinuing therapy, patients flared within 8 to 12 weeks. Those who were maintained by low dose MTX after the high dose protocol were able to sustain their improvement throughout the subsequent 6 months of followup.

Complications of immunosuppression associated with weekly low dose methotrexate.

Complications of immunosuppression are thought to be rare with the use of low dose pulse methotrexate (MTX) for nonneoplastic conditions. We describe 4 complications of immunosuppression observed in a group of 41 patients who had received MTX for at least 6 months, during a 2-year period. We report the first case of a reversible lymphoproliferative disorder similar to that reported with immunosuppressive therapy associated with organ transplantation. Two cases of disseminated herpes zoster and 1 case with Pneumocystis carinii pneumonia are described. As the indications for the use of low dose MTX broaden and older patients with other comorbid diseases are included, our experience suggests that complications of immunosuppression with prolonged use of MTX may be seen more commonly.

Combination methotrexate and sulfasalazine in the management of rheumatoid arthritis: case observations.

Four patients with rheumatoid arthritis received a combination of methotrexate and sulfasalazine for a mean of 24 months (range 20-28 months). All 4 patients experienced clinical improvement, with a reduction in the number of involved joints and in morning stiffness. In all 3 patients who had previously taken methotrexate, we were able to reduce the dosage, and the prednisone dosage was reduced in 2 of 3 patients who had previously taken that drug. No serious toxicity was observed in any patient.

Effects of furosemide on the oral cavity.

Furosemide, a potent loop diuretic, has been reported to cause xerostomia, a sensation of oral dryness. We obtained urine and salivary secretions from five normal males after oral intake of either 0.5 mg/kg body weight of furosemide or placebo. The experimental treatment resulted in a five-fold increase in urinary output. In contrast, analysis of salivary secretions indicated there were no significant differences in flow rates, total output, total protein, or Na+, K+, or Cl- concentrations following drug or placebo. Subjectively, xerostomia was experienced 10 times more frequently after ingestion of furosemide. These data suggest that, in vivo, furosemide had a greater effect on the kidney than on the salivary gland and that the sensation of oral dryness is not solely a function of the quantitative salivary output.