Twenty-three children with destructive polyarticular juvenile rheumatoid arthritis (JRA) were treated for 0 . 5 4 3 years (median 1.6 years) with weekly doses of methotrexate (MTX) (0.11-0.6 mg/kg/week). Serum levels of MTX at 1 hour and at 24 hours after drug administration were obtained at each dosage level and every 3 months after a stable dosage was achieved. No patient had serum levels of MTX that were in the toxic range nor evidence of hematologic, skin, mucous membrane, gastrointestinal, or pulmonary abnormalities. Ten patients had transiently elevated serum transaminase levels. Arthritis symptoms improved in 21 of these JRA patients, and the improvement was significantly associated with a mean 1-hour serum MTX level of 2 5 . 8 X lO-'M (P = 0.008) and a dosage of 2 0 . 3 mg/kg/week (P = 0.004). The 1-hour serum level of MTX was correlated with the MTX dosage (r = 0.28, P = 0.005).Our observations suggest that with close monitoring, MTX can be used safely at dosages as high as 0.6 mg/kg/ week, and improvement in the symptoms of JRA will become evident when the serum levels of MTX 1 hour after administration approach 6.0 x lO-'M.Methotrexate (MTX) is widely used for the treatment of inflammatory arthritis in adults, and it is

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In an attempt to map the gene (or genes) controlling the synthesis fo the fourth component of complement (C4), we performed linkage studies in a family with hereditary C4 deficiency. The proband, a seven-year-old boy with lupus erythematosus, consistently lacked deteftable serum C4 by both functional and protein measurements. The complement defect was transmitted as an autosomal recessive disorder. Eight of 15 family members were considered to be heterozygotes, seven because of low C4 levels and one because of genetic data (obligate heterozygote). The gene (or genes) coding for C4 deficiency appeared to be linked to the major histocompatibility complex (A2,B12,DW2 on the maternal side and A2,BW15,LD108 on the paternal side) and to other markers known to be in close proximity to the histocompatibility complex on chromosome 6 (phosphoglucomutase-3, glyoxalase-1 and properdin factor B).