Background Adverse drug reactions (ADR) associated with sulphasalazine (SS) use and leading to its withdrawal occur in 20-30% of rheumatoid arthritis (RA) patients treated with SS and include dose-dependent (gastrointestinal and central nervous system abnormalities) and immunomediated (vasculitis, pneumonitis, hepatitis, leucopenia, agranulocytosis, haemolytic and aplastic anemia) events [1,2].

Objectives To reveal genetic markers associated with SS adverse reactions in RA patients and to estimate their prognostic value.

Methods In the observational trial of RA patients (n=500: 405 women, 95 men) treated with disease modifying antirheumatic drug SS was used in 11.6% (58/500) of patients. SS withdrawal due to the adverse reactions was registered in 43.1% (25/58; CI₉₅ 31.2-55.9%) of them. This level of ADR frequency associated with SS use was considered as SS adverse reactions pretest probability (P_pre). Association between SS ADR and a number of genetic markers (erythrocytic antigens of AB0 and Rh₀ blood groups and leucocyte antigens of A, B, C, DR, DQ locuses of major histocompatibility complex) was investigated. All markers were dichotomic (marker⁺, marker^–). Statistical significance of the revealed association was estimated by Fisher exact test. Likelihood ratio of positive (LR⁺) and negative (LR^–) tests and prognostic odds ratio (pOR) as well as post-test probability (P_post) of SS adverse reactions were calculated.

Results Gastrointestinal ADR were registered in 20.7% (12/58) of patients, mucocutaneous ADR in 8.6%, urine analysis abnormalities in 8.6%, and haematological abnormalities in 5.2% of patients. The rates of SS adverse events were significantly higher in the case of following phenotypes:

• – HLA-A1⁺ vs HLA-A1^–: 80.0% (8/10) and 35.5% (11/31), p_2-t=0.0265;

• – HLA-A2^– vs HLA-A2⁺: 64.0% (16/25) and 18.8% (3/16), p_2-t=0.0092;

• – HLA-B8⁺ vs HLA-B8^–: 87.5% (7/8) and 36.4% (13/33), p_2-t=0.0157;

• – HLA-B15^– vs HLA-15⁺: 54.5% (18/33) and 12.5% (1/8), p_2-t=0.0268.

On the basis of these findings operational parameters of the revealed markers were determined as predictors of A₁ outcome (SS ADR⁺) and A₂ outcome (SS ADR^-):

• – HLA-A1: pOR=7.3; A1⁺: LR⁺=4.6, P_post=77.7%; A1^–: LR^–=0.64, P_post= 32.6%;

• – HLA-A2: pOR=7.7; A2^–: LR⁺=2.1, P_post=61.4%; A2⁺: LR^–=0.27, P_post= 17.0%;

• – HLA-B8: pOR=12.3; B8⁺: LR⁺=8.1, P_post=86.0%; B8^–: LR^–=0.66, P_post= 33.3%;

• – HLA-B15: pOR=8.4; B15^–: LR⁺=1.4, P_post=51.5%; B15⁺: LR^–=0.17, P_post= 11.4%.

Conclusions Revealed phenotypes are useful as supplementary predictors of SS adverse reactions in RA patients in the case of uncertain prognosis (outcome A₃, P_post≥95% for the approval of the hypothesis (A₁ outcome) or P_post≤5% for the acceptance of the alternative hypothesis (A₂ outcome).

1. Box SA and Pullar T. Sulphasalazine in the treatment of rheumatoid arthritis. Br J Rheumatol 1997;36:382-386.

2. Van Riel PLCM, Van Gestel AM, Van De Putte LBA. Long-term usage and side effect profile of sulphasalazine in rheumatoid arthritis. Br J Rheumatol. 1995;34:40-42.

Disclosure of Interest None Declared