Elevated liver enzyme tests among patients with rheumatoid arthritis or psoriatic arthritis treated with methotrexate and/or leflunomide.

INTRODUCTION: Potential hepatotoxicity associated with disease-modifying antirheumatic drugs (DMARDs) requires laboratory monitoring. In patients with rheumatoid arthritis (RA) or psoriatic arthritis (PsA), the incidence of elevated alanine aminotransferase/aspartate aminotransferase (ALT/AST) enzymes associated with methotrexate (MTX), leflunomide (LEF) and MTX+LEF versus other DMARDs was examined. METHODS: Patients with RA and PsA enrolled in the Consortium of Rheumatology Researchers of North America (CORRONA) initiating DMARDs were identified. Abnormalities were identified when either was 1- or 2-fold times above the upper limits of normal (ULN). Odds ratios (OR) between MTX/LEF dose and elevated ALT/AST enzymes were estimated using generalised estimating equations. Interaction terms for use of MTX+LEF quantified the incremental risk of the combination compared with each individually. RESULTS: Elevated ALT/AST levels (>1x ULN) occurred in 22%, 17%, 31% and 14% of patients with RA receiving MTX, LEF, MTX+LEF or neither, respectively; elevations were 2.76-fold (95% CI 1.84 to 4.15) more likely in patients with PsA. Elevations >2x ULN occurred in 1-2% of patients on MTX or LEF monotherapy compared with 5% with the combination. After multivariable adjustment and compared with either monotherapy, the combination of MTX and LEF was associated with a greater risk according to MTX dose used as part of the combination: MTX 10-17.5 mg/week, OR 2.91 (95% CI 1.23 to 6.90); MTX > or =20 mg/week, OR 3.98 (95% CI 1.72 to 9.24). CONCLUSIONS: Abnormal ALT/AST levels developed in 14-35% of patients with RA or PsA initiating DMARD therapy. The risks were incrementally greater in those with PsA and in those receiving MTX (> or =10 mg/day) + LEF. These findings should help inform monitoring for potential hepatotoxicity in these patient populations.

The assessment of disease activity and outcomes in psoriatic arthritis.

Psoriatic Arthritis (PsA) is a common condition that significantly impacts affected patients. The introduction of novel therapeutic agents for PsA has generated considerable interest in both clinical trials and in clinical care. Thus, there is a great need for standardized outcome measures to assess the activity of disease and the response to therapy. Because psoriasis is a heterogeneous and multi-faceted condition, defining outcome measures has been a challenge. To date, such measures have largely been adapted from related diseases, as described in this essay. Further research is needed to further develop outcome measures for PsA to facilitate optimal treatment of patients with PsA.

Cytoreduction of ovarian cancer with the Cavitron ultrasonic surgical aspirator.

The Cavitron ultrasonic surgical aspirator was used for cytoreduction in ten patients with intra-abdominal malignancy (nine ovarian and one fallopian tube). The mean age was 65 years, and eight patients had stage IIIC disease. Standard surgical techniques were used to resect the adnexa, uterus, and omentum. The Cavitron was used to remove disease from the diaphragm, spleen, stomach, and small bowel without resection or injury. These nongenital viscera would have required resection using surgical techniques for cytoreduction. The mean Cavitron surgical time was 49 minutes. Cytoreduction by the Cavitron facilitates tumor removal and reduces the requirement for nongenital visceral resection.

Serum concentrations of salicylate and naproxen during concurrent therapy in patients with rheumatoid arthritis.

The kinetic interaction between salicylate and naproxen was investigated in 25 rheumatoid arthritis patients. Kinetic interactions were tested in serum after patients had been on each drug regimen for 1 month. Salicylate decreased serum naproxen concentration from 89.5 mg/liter to 65.9 mg/liter (P less than 0.001) and increased serum naproxen clearance by 56%. Naproxen had minimal effect on serum salicylate concentrations.

A strategy for reaching therapeutic salicylate levels in patients with rheumatoid arthritis using standardized dosing regimens.

After one to 2 weeks of 45 mg/kg/day choline magnesium trisalicylate (CMT) in 2 divided doses, 51 of 71 patients with rheumatoid arthritis (72%) had observed steady state serum salicylate concentrations between 150 and 300 mg/l (mean salicylate: 213 +/- 10 mg/l), although 17 later required dose adjustment. CMT dosing was changed in 37 cases by using the formula: dosing rate = total clearance X concentration. The expected and observed concentrations were not different (p = 0.31); thus, this formula can help calculate salicylate dosing changes to bring the serum salicylate level to within the therapeutic range.

A controlled study of concurrent therapy with a nonacetylated salicylate and naproxen in rheumatoid arthritis.

Previous studies of combinations of nonsteroidal drugs used in the treatment of rheumatoid arthritis (RA) have yielded conflicting results. We used standard methods to measure disease activity and high pressure liquid chromatography to measure plasma drug concentrations. We used doses of choline magnesium trisalicylate, adjusted to achieve therapeutic serum salicylate concentrations, and naproxen in a randomized, double-blind, placebo-controlled cross-over study of full dose trisalicylate (CMT), full dose naproxen (N), full dose of both (CMT-N), and half dose of both (cmt-n) to examine their relative efficacy and toxicity in treating RA. CMT-N was statistically superior to all other treatments in only 1 of 12 efficacy variables, but was equal to N and better than CMT or cmt-n for 7 variables. There were minimal differences among treatments for the other 4 efficacy variables. The mean percentage difference for the efficacy variables between CMT-N and N was 3%, between CMT-N and CMT was 10.6%, and between CMT-N and cmt-n was 10.5%. Thirteen percent of patients manifested toxic reactions during the initial open dose-adjustment salicylate run-in phase. During the double-blind phases of the study, CMT-N was more toxic than N, CMT, or cmt-n (7.5% versus 3.4%, 1.8%, and 3.7%, respectively). Tinnitus was more common when full-dose CMT was used; N (N or CMT-N) was associated with increased skin toxicity. Gastrointestinal complaints were equally common with all regimens. CMT-N, although sometimes statistically superior to CMT, N, or cmt-n, showed no clinically important additive or synergistic effect versus N or CMT alone.

Effects of lysosomotropic weak bases on infection of BHK-21 cells by Sindbis virus.

The effects of the lysosomotropic weak bases chloroquine, ammonium chloride, and amantadine as well as dansylcadaverine (an inhibitor of receptor mediated endocytosis) on the replication of Sindbis virus in tissue-cultured cells was examined. Chloroquine had no effect on the expression of virus-induced homologous interference. None of these drugs significantly affected the ability of a complex of a cell and single virion to form an infectious center. Chloroquine and ammonium chloride were found to inhibit the synthesis of virus RNA in established infections when added early in infection. These drugs also inhibited the production of progeny virions when added any time after infection. These results suggest that the antiviral activity of these agents may not be due to an ability to prevent transport of the virus genome into the cell cytoplasm.

Availability of salicylate from salsalate and aspirin.

Salicylate availability from salsalate (SSA) and aspirin (ASA) was examined in six rheumatoid arthritis patients in a multiple-dose double-blind crossover study. Doses contained equimolar amounts of salicylic acid. After initial ASA treatment to achieve therapeutic salicylate levels (150 to 300 micrograms/ml) the patients received equimolar doses of SSA or ASA. When steady state was achieved patients were hospitalized, and blood and urine specimens were obtained during three dosing intervals and during the washout period that followed. Thereafter, patients were placed on the alternate medication for at least a week and the in-hospital pattern was repeated. Despite insignificant differences in absorption of the formulations, as measured by urinary salicylate recovery, the plasma salicylic acid AUC was lower after SSA. Evidence indicates that this apparent lower availability of salicylate from SSA is due to incomplete hydrolysis to salicylic acid, the unhydrolyzed SSA being excreted mainly as glucuronide conjugates.

Hypertrophic osteoarthropathy and pseudomembranous enterocolitis.

We describe a 25-year-old male with juvenile onset diabetes mellitus who developed severe pseudomembranous enterocolitis with intractable diarrhea for which he was maintained on total parenteral nutrition. Subsequently, he developed clinical signs and typical radiological manifestations of hypertrophic osteoarthropathy (HOA) associated with hemolytic anemia, proteinuria and immunoglobulin deficiency. Immune complexes were not detected in either sera and synovial fluid.

Steady-state serum salicylate levels in hospitalized patients with rheumatoid arthritis. Comparison of two dosage schedules of choline magnesium trisalicylate.

When the total daily drug dose was individualized to produce a steady-state serum salicylate concentration between 20 and 35 mg/dl, clinically acceptable fluctuations of serum concentrations occurred during both twice daily and three times daily administration. In 6 rheumatoid arthritis patients receiving choline magnesium trisalicylate, mean steady-state serum levels were the same, and the ranges of hourly mean concentrations during 8 and 12 hour dosage intervals were 19 to 27 mg/dl and 17 to 30 mg/dl, respectively. Changing the dosing interval from 8 to 12 hours required a 50% increase in the fractional doses, but resulted in an increase of only 3 mg/dl in mean peak concentration and a ddecrease of 1 mg/dl in mean minimum concentration.