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 (Ppre). 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 (Ppost) 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), p2-t=0.0265;
– HLA-A2– vs HLA-A2+: 64.0% (16/25) and 18.8% (3/16), p2-t=0.0092;
– HLA-B8+ vs HLA-B8–: 87.5% (7/8) and 36.4% (13/33), p2-t=0.0157;
– HLA-B15– vs HLA-15+: 54.5% (18/33) and 12.5% (1/8), p2-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, Ppost=77.7%; A1–: LR–=0.64, Ppost= 32.6%;
– HLA-A2: pOR=7.7; A2–: LR+=2.1, Ppost=61.4%; A2+: LR–=0.27, Ppost= 17.0%;
– HLA-B8: pOR=12.3; B8+: LR+=8.1, Ppost=86.0%; B8–: LR–=0.66, Ppost= 33.3%;
– HLA-B15: pOR=8.4; B15–: LR+=1.4, Ppost=51.5%; B15+: LR–=0.17, Ppost= 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, Ppost≥95% for the approval of the hypothesis (A1 outcome) or Ppost≤5% for the acceptance of the alternative hypothesis (A2 outcome).
Box SA and Pullar T. Sulphasalazine in the treatment of rheumatoid arthritis. Br J Rheumatol 1997;36:382-386.
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