HLA CLASS II POLYMORPHISM, RHEUMATOID ARTHRITIS OUTCOME AND INFLUENCE OF THE TREATMENT
L Lard1, K Vos1, H Visser1, M Hazes1, F Breedveld1, G Schreuder2, R de Vries2 and E Zanelli2 Depts of 1Rheumatology and 2Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.

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The need for early aggressive treatment in rheumatoid arthritis (RA) along with the heterogeneity of the disease implies the design of prognostic markers. The present study involved 145 newly diagnosed probable and definite RA patients enrolled in an early arthritis clinic (EAC). They were all typed for HLA-DQB1 and DRB1 and serum titers of rheumatoid factor (RF) and antibody against a citrulline-containing peptide (cfc1) were measured by ELISA (Arthritis Rheum 43:155). The output parameter was erosion of hands and feet at two-year follow-up as defined by a modified Sharp score. The influence of HLA on RA outcome was evaluated according to the Shared Epitope (SE) and RA protection (RAP) models (Human Immunol 60:152). SE-positive alleles were DRB1*0101, *0102, *0401, *0404, *0405, *0408 and *1001; predisposing DQ alleles according to RAP were DQB1*03/DQA1*03 (DQ3) and DQB1*0501/DQA1*01 (DQ5) while protective alleles were DRB1*0103, *0402, *1301 and *1302. Half of the patients were treated with conventional treatment, i.e. slow-acting disease-modifying anti-rheumatic drugs on average 4 months after entering the EAC, while half of them received the same drugs already at 2 weeks. In the conventional group, the median Sharp score at two years was 10 compared to only 4 in the early treatment group. However, the difference was significant only among cfc1+ patients (Sharp score 19 vs 8, p=0.025), SE+ patients (Sharp score 16 vs 6, p=0.022) and patients at risk according to RAP (RAP+)(Sharp score 17 vs 6.5, p=0.018). A series of stepwise logistic regression analyses showed that HLA was the best outcome predictor in the conventional group but that its effect was abolished by the early therapy. Combining RAP, RF and cfc1, we designed a prognosis marker. When only patients on conventional treatment with very mild disease at first diagnosis (Sharp score < 1) were included, we found using Receiver Operating Characteristic curves that the new prognosis marker had a sensitivity of 81% and a specificity of 94% for a Sharp score at two years of 4 or above. We conclude that HLA influences RA outcome early in the disease process and that HLA typing and autoantibody titers in newly diagnosed RA patients are valuable information for rheumatologists to design treatment.