Bologna C

Oral contraception, parity, breast feeding, and severity of rheumatoid arthritis.

OBJECTIVE: To investigate the influence of breast feeding, use of the oral contraceptive pill (OCP), and parity on rheumatoid arthritis (RA). METHODS: One hundred and seventy six women with RA were compared with 145 control subjects; all had at least one child. RA patients were classified as having severe (n = 82) or mild disease (n = 89) according to clinical joint evaluation, radiological score, biological inflammation, and the presence of HLA-DR1 or -DR4 alleles. RESULTS: The mean age of RA patients was 58 years, and the mean age at the time of diagnosis of RA was 46 years. The mean time between onset of RA and the first birth was 23.6 (SD 3.8) years. The OCP user rates were 33% in the RA group and 47.6% in the control group (p < 0.02). OCP use was related to the mothers year of birth. The relative risk for developing RA was 0.598 (95% confidence interval (CI) 0.33 to 1.1) in women who had used OCP for more than five years compared with those who had never used OCPs. In contrast, the age at which the first pregnancy occurred, the number of children breast fed, and the duration of breast feeding were comparable in RA patients and healthy subjects. Among the RA patients, parity, duration of breast feeding, and the number of breast fed children were significantly increased in those with severe disease. Having more than three children increased the risk of developing severe disease 4.8-fold when adjusted for age and OCP use. Forty six percent of women with severe RA had a history of breast feeding duration greater than six months before disease onset, compared with 26% of patients with mild disease (p < 0.008). Having more than three breast fed children increased the risk of poor disease prognosis 3.7-fold. In contrast, OCP use had a protective role in the course of RA (44% of RA patients with mild disease were OCP users, compared with 21.7% of those with severe RA; p < 0.001). Among those using OCP for more than five years, the relative risk of developing severe disease was 0.1 (95% CI 0.01 to 0.6), after adjustment for age, parity, and breast feeding. CONCLUSION: Our results suggest that parity, and to a lesser extent breast feeding, before RA onset worsened RA prognosis, whereas OCP use had a protective role. Prolactin and oestrogen may have a role in these effects.

Effects of moderate renal insufficiency on pharmacokinetics of methotrexate in rheumatoid arthritis patients

OBJECTIVES To determine the effects of impaired renal function on the pharmacokinetics of methotrexate (MTX) in rheumatoid arthritis (RA) patients. METHODS 77 RA patients were included in this study. MTX was administered intramuscularly (7.5 to 15 mg). Subjects were divided into four groups, according to their creatinine clearance (CLCR); group 1: CLCR lower than 45 ml/min; group 2: CLCR between 45 and 60 ml/min, group 3: CLCR between 61 and 80 ml/min and group 4: CLCRhigher than 80 ml/min. Blood samples were collected from each subject before drug administration and at two and eight hours after administration. Individual pharmacokinetic parameters were estimated using a Bayesian approach. RESULTS MTX concentrations (total and free) were 1.3 to 1.6-times higher in group 1 than in groups 2, 3, and 4. For total and free MTX, t1/2 eliminations were 22.7 hours in group 1, 13.5 hours in group 2, 12 hours in group 3, and 11 hours in group 4. Clearance of total MTX was 64, 92, 96, 115 ml/min in groups 1 to 4, respectively, it was 118, 163, 171, 206 ml/min in groups 1 to 4 for the free MTX, respectively. Volume of distribution averaged 2.16 l/kg in group 1, 1.92 l/kg in group 2, 1.61 l/kg in group 3, and 1.56 l/kg in group 4. Elimination half life was significantly increased and total clearance was significantly reduced with the degree of renal impairment. Linear regression revealed good correlations between clearance values of MTX and creatinine clearance. CONCLUSION Individual testing is required rather than a general decrease of the MTX dose based only on CLCR.

Study of eight cases of cancer in 426 rheumatoid arthritis patients treated with methotrexate

OBJECTIVE To report cancer cases in 426 rheumatoid arthritis patients treated with methotrexate, and determine whether there was an increased incidence of cancer compared with patients never treated with methotrexate (rheumatoid controls) and to the whole regional population. METHODS The duration of methotrexate treatment was 37.4 (SD 27.9) months. This population was compared with 420 rheumatoid arthritis controls and with a regional population of 812 344 people. Life table analysis was performed to compare the cancer incidence in the two rheumatoid populations. Adjustment for potentially confounding factors was done. The indirect standardisation method was used to compare each rheumatoid population with the regional population. RESULTS Eight cases of cancer (1.88%; 4.04 cases/1000 person years) were diagnosed in the methotrexate population v six (1.43%; 58.8 cases/1000 person years) in the rheumatoid controls. The life table method showed a higher incidence of cancer in the rheumatoid controls (P = 0.0001). In a multivariate analysis (Cox model), the only significant factor explaining this difference in the cancer incidence was age (P = 0.02). In the regional population there were 6418 new cases of cancer (0.79%; 2.85 cases/1000 person years). By the indirect standardisation method, the ratio of observed cases to expected cases of cancer in each of the rheumatoid populations was not significantly different from 1. CONCLUSIONS In these eight cases, methotrexate was not found to be responsible for generating cancers. However, because of data regarding lymphomas and methotrexate, and because of the short follow up, especially in the control group, longer prospective studies are warranted.

Radiolabelled lymphocyte migration in rheumatoid synovitis.

OBJECTIVES--To study the ability of technetium-99m hexamethyl propylene amineoxime (HMPAO) labelled lymphocyte scintigraphy to quantify synovial inflammation, and to analyse the kinetics of lymphocyte retention in the joints of patients with rheumatoid arthritis (RA). METHODS--After isolation of the lymphocytes, the cells were radiolabelled in vitro with 250 MBq 99mTc-HMPAO. The scans were performed 30 minutes, three hours and 20 hours after injection. RESULTS--An increase of the scintigram signal obtained at 20 hours was associated with a high joint swelling and joint pain score (F test = 3.07, p < 0.002), but not with the radiological score. A positive joint scintigram was predictive of active synovitis. Although the scintigram variation over time did not reach statistical significance, the kinetics of the scintigram signal tended to differ according to the disease duration: in early RA, active arthritis could be clearly imaged as early as 30 minutes, increased at three hours and the signal intensity persisted at 20 hours. In contrast, in long standing disease, the affected joints were imaged at 30 minutes, persisted unchanged at three hours, and the scintigram score decreased significantly at 20 hours. CONCLUSIONS--The study shows that 99mTc-HMPAO joint scintigraphy may be used to detect and to localise active rheumatoid arthritis.

Variation in the serum IgA concentration and the production of IgA in vitro in rheumatoid arthritis treated by sulfasalazine

Sulfasalazine is an efficient treatment for rheumatoid arthritis (RA), but its mode of action is not known. In RA, a correlation has been demonstrated between disease activity and the secretion of immunoglobulin A (IgA) by peripheral blood lymphocytes (PBL) in culture. Furthermore, the IgA-producing cells of the peripheral blood have been shown to originate from the mucous-associate lymphoid tissue (MALT). We studied the variations in the total IgA concentration in the serum of RA patients, and the secretion of IgA by PBL after 7 days culture in vitro, before and after treatment with sulfasalazine. A significant decrease in the serum IgA concentraton was obtained, but there was no modification of the spontaneous increase in the in vitro IgA synthesis by circulating monoclear cells. Our results suggested that the decrease in serum IgA concentration after treatment with sulfasalazine was not linked to a decrease in the IgA secretion by PBL. This does not favour a direct effect of sulfasalazine on the mucous-associated lymphoid tissue.