Early effective suppression of inflammation in rheumatoid arthritis reduces radiographic progression.

OBJECTIVE: To evaluate the effect of early 'aggressive' drug treatment on radiographic progression in patients with recent-onset rheumatoid arthritis (RA), compared to conventional stepwise increasing intensity of treatment. DESIGN: Prospective follow-up study with an experimental group and a historical control group both divided into a high-risk subgroup and a low-risk subgroup, based on prognostic factors. The effect of the 'aggressive' and the conventional treatment strategy was compared between both high-risk groups; the low-risk groups, both treated according to the conventional treatment strategy, were used to ensure internal consistency between the experimental and the historical groups. PATIENTS: A total of 228 consecutive patients with recent-onset RA (complaints < 1 yr at study entry). METHODS: The 'aggressive' drug treatment consisted of institution of relatively fast-acting disease-modifying anti-rheumatic drugs (DMARDs) (sulphasalazine, methotrexate) immediately after diagnosis, and rapid adjustment of dosage and/or drug in the case of insufficient response as measured by a change in C-reactive protein (CRP) level. Radiographic damage was assessed according to a modified version of Sharp's method and cumulative disease activity expressed as CRP-area under the curve (CRP-AUC). The occurrence of side-effects was also evaluated. RESULTS: After 2 yr of follow-up, comparison of the two high-risk subgroups showed the radiographic progression in the 'aggressively' treated subgroup to be significantly lower than that in the control group [Sharp score: median (range) 26 (0-100) vs 35 (1-188); P = 0.03]. Cumulative CRP values were also significantly lower than in the control high-risk subgroup [CRP-AUC: median (range) 1963 (212-8515) vs 3025 (46-15 632) mg.week/1; P = 0.002). This was achieved without an increase in the occurrence of side-effects. There was no difference between the two low-risk subgroups with regard to entry characteristics, CRP-AUC values or radiological progression, indicating comparability between the two groups. CONCLUSION: Early 'aggressive' drug treatment, using sulphasalazine and/or methotrexate, aimed at reduction of the CRP level, significantly reduces the (rate of) radiographic progression in RA.

Remarkably similar response to gold therapy in HLA identical sibs with rheumatoid arthritis.

Two pairs of sibs with definite rheumatoid arthritis responded in a remarkably similar way to parenteral gold therapy, in terms of both toxicity and efficacy. Both pairs proved to be HLA identical. One of the pairs possessed the HLA antigens B8 and DR3, which have been associated with both drug toxicity and excellent clinical response. The other pair did not possess either of these antigens, suggesting that the reaction to gold therapy in patients with rheumatoid arthritis may be determined by other HLA or genetic factors coded for by chromosome 6, or both.

The influence of HLA phenotypes on the response to parenteral gold in rheumatoid arthritis.

One hundred and ten patients with rheumatoid arthritis (RA) were studied for a possible influence of HLA phenotypes on the reaction to parenteral gold in the first 6 months of treatment, in terms of both clinical response and toxicity. Frequencies of HLA-B8 and -DR3 were significantly increased in patients who responded excellently to gold treatment as compared with non-responders (p = 0.04 for both antigens). On the other hand, for HLA-DR7 there was a tendency for increased frequency in non-responders versus excellent and moderate responders (p less than 0.03; Pc = n.s.). Drug toxicity was higher in excellent than in non-responders (p less than 0.04), being exceptionally high in male excellent responders (85% versus 33% in females, p less than 0.01), probably due to the increased frequency in B8 and DR3 in the excellent responder group as a whole and in the excellent responder males in particular. We conclude that HLA antigens B8 and DR3 co-determine both toxicity and excellent clinical response to parenteral gold, whereas the presence of DR7 is possibly associated with non-response. In addition, we found sex differences in reaction to parenteral gold, which may be related to an increased frequency of HLA-B8 and -DR3 in male RA patients.

HLA associations in aurothioglucose- and D-penicillamine-induced haematotoxic reactions in rheumatoid arthritis.

HLA phenotype frequencies were studied in 21 rheumatoid arthritis (RA) patients with haematotoxic reactions to aurothioglucose (AuTG) or D-penicillamine (DP), 65 matched RA controls and 277 healthy controls. Antigens B8 and DR3 were significantly increased in the toxic RA patient group as compared to both RA controls and healthy controls. These contrasts were strongest in the patients with AuTG-induced thrombocytopenia or leucopenia: all patients developing either reaction to this drug were B8- and/or DR3-positive (p less than 0.001), 7 (78%) being positive for both antigens. In the patient group with DP-induced reactions these antigens were also increased but these differences were not significant. In the latter group the prevalence of antigen DR4 was high, especially in the patient group with DP-induced thrombocytopenia, all 12 patients with this type of reaction being DR4 positive. Our data suggest that haematotoxic reactions to AuTG and DP develop primarily (or even exclusively) in genetically predisposed RA patients. Furthermore, the HLA phenotype contributing to an increased risk seems not to be the same for the two anti-rheumatic drugs studied.

The relationship between aurothioglucose- and D-penicillamine-induced proteinuria.

We studied patients with rheumatoid arthritis who have been treated with aurothioglucose (Au) and subsequently with D-penicillamine (DP), and who developed drug-induced proteinuria, over a 10-year period. Twelve patients developed Au-induced and 19 DP-induced proteinuria. Of the 12 patients with Au-induced proteinuria, only 2 (17%) developed DP-induced proteinuria, indicating a slightly increased risk as compared with the overall incidence (9.3%) of this reaction in 168 DP-treated patients. In addition, only a minority (2 out of 19, 10.6%) of patients with DP-induced proteinuria had previous Au-induced proteinuria. These data may indicate that different mechanisms are operative in Au and DP-induced proteinuria, as is also suggested by the finding that HLA-DR3 was present more frequently in the latter (50%) than in the former (21%). A history of previous Au-induced proteinuria is insufficient reason to deny these patients the benefits of subsequent treatment with DP.

HLA-DR antigens and proteinuria induced by aurothioglucose and D-penicillamine in patients with rheumatoid arthritis.

By means of a case-control study we investigated the association between HLA phenotypes and the development of proteinuria after aurothioglucose or D-penicillamine treatment in patients with rheumatoid arthritis (RA). HLA-DR3 was markedly increased in 44 treatment cases compared with 66 RA controls (46 versus 18%, p = 0.002). HLA-DR3 positive patients were at greater risk during treatment with D-penicillamine (RR 10.1, p = 0.001) than gold treated cases (RR 1.7, p = 0.365). The associations between HLA-DR3 and nephrotic syndrome (RR = 6.3, p = 0.004) and early onset proteinuria (RR = 5.4, p less than 0.001) were stronger compared with uncomplicated proteinuria (RR = 3.1, p = 0.017) and late-onset proteinuria (RR = 1.6, p = 0.459), respectively. It appears that genetic factors in RA influence the development, the degree and the time of onset of drug induced proteinuria.

Side-effects of azathioprine treatment in rheumatoid arthritis: analysis of 10 years of experience.

Our experience with azathioprine in the treatment of rheumatoid arthritis covers ten years, during which 91 rheumatoid patients (66 female and 25 male) received this drug, with a median treatment period of 36 months. Total follow-up experience, during and after treatment, was 399 person years. Twelve patients died. The principal causes of death were malignant neoplasm (six patients) and cardiovascular diseases (three patients). The mortality in our patients was compared to that of the general Dutch population by the Standardised Mortality Ratio (SMR). In the male patient group a significant excess of both total mortality and mortality from malignancy was observed. The female patients showed no differences from the general population. In this follow-up study, no lymphoreticular tumours occurred during or after azathioprine therapy.