Allen H. Mackenzie

Outcome of first-trimester exposure to low-dose methotrexate in eight patients with rheumatic disease

PURPOSE Methotrexate (MTX), when used to treat malignancy or psoriasis, has been implicated in anecdotal reports as a teratogen or abortifacient in the first trimester of pregnancy. We are unaware of any previous reports that describe the course of gestation and the effect on subsequent offspring in patients treated with low-dose oral MTX for rheumatoid arthritis, and therefore present our experience. PATIENTS AND METHODS We report on eight women experiencing 10 pregnancies. Mean number of weeks of gestation while taking MTX was 7.5 (range 2 to 20 weeks). Outcome of pregnancies included five full-term babies (FTB), three spontaneous abortions (SAB), and two elective abortions. RESULTS There were no significant differences in either the FTB or SAB group when considering risk factors including smoking, alcohol, concomitant medications, and age. One of three in the SAB group had recurrent abortions prior to MTX therapy. All five of the FTB group had uncomplicated pregnancies and deliveries. All offspring were of normal height and weight at birth with no physical abnormalities. All children reached growth, development, and intellectual stages normally, and their present mean age is 11.5 years. No observed learning disabilities or medical abnormalities have occurred in any of these children. CONCLUSION In this uncontrolled study we failed to demonstrate tertogenicity of MTX. However, the possibility of abortion due to MTX use remains.

Dose refinements in long-term therapy of rheumatoid arthritis with antimalarials

No eye disease was detected in over 900 rheumatoid arthritis patients treated with less than 4.0 mg/kg per day of chloroquine or less than 6.5 mg/kg per day of hydroxychloroquine for a mean of about seven years. I therefore consider these dosage rates safe, since they are below the threshold of retinal toxicity. This is based on more than 6,000 patient-years of drug exposure. That dosage threshold for retinopathy appears to be 5.1 mg/kg per day for chloroquine and 7.8 mg/kg per day for hydroxychloroquine according to my studies with these compounds. The daily dosage rate, rather than total drug accumulation, seems to determine the development of eye disease. To prevent overdosage, dosing should be calculated not on the actual weight of the patient but on ideal (lean) body weight. Furthermore, the patients renal and liver function should also be taken into account to avoid overdosage. Since exposure to light amplifies the risk of retinopathy in patients treated with antimalarials, dark sunglasses are recommended for patients spending much time in sunlight.

Ocular lesions in rheumatoid arthritis and related disorders with particular reference to retinopathy. A study of 741 patients treated with and without chloroquine drugs.

THE occurrence of ocular lesions of variable severity in patients with rheumatoid arthritis, discoid and systemic lupus erythematosus and other diseases who have received long-term chloroquine ther...

Folate supplementation in methotrexate-treated rheumatoid arthritis patients

Two hundred rheumatoid arthritis (RA) patients taking low dose methotrexate (MTX) were evaluated for adverse effects. During a mean follow up of 41.5 months, the mean cell volume (MCV) was elevated at some time during the course of treatment in 42 patients. The MCV was normal in the remaining 158 patients. One hundred ninety-eight patients were treated simultaneously with oral folic acid. With the exception of heartburn, which was seen more often in the high MCV group, there was no difference in the frequency of adverse effects attributable to MTX between groups. Severity of side effects and the frequency of MTX dose reduction and MTX discontinuation due to toxicity were also similar between groups. This analysis suggests that elevation of MCV in RA patients treated simultaneously with MTX and folate does not predict MTX toxicity. The authors also discuss the mechanism of action of MTX with regard to folate metabolism.

Differential diagnosis of rheumatoid arthritis

The differential diagnosis of subacute or chronic polyarthritic diseases, including rheumatoid arthritis, is based on recognizing a pattern of changes, with special emphasis placed on certain key features that possess higher specificity. The clinical history is by far the most important diagnostic tool and involves clear assessment of the distribution of joint involvement, whether pain is articular or extra-articular, whether a syndrome follows trauma or infection, and the duration of the process. The distribution of involved joints is a major contributor to differential diagnosis but can be misleading unless a skilled physical examination confirms objective synovitis. If present, nodules, which represent localization of the disease process, also offer a powerful tool in differential diagnosis. Rheumatoid nodules occur in about 20 percent of patients with well-developed rheumatoid arthritis. The effects of inflammation may be clinically detectable, but laboratory tests--e.g., the erythrocyte sedimentation rate and quantitative C-reactive protein--provide the most reliable evidence of inflammation. Synovial fluid analysis may reveal inflammatory changes and other abnormalities permitting diagnosis. Rheumatoid factor is present in about 80 percent of patients with rheumatoid arthritis but is not specific for this diagnosis.