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SUMMARY Certain drugs are a frequent source of antinuclear antibody (ANA) induction, and ANA is invariably present in the few patients who progress to the drug induced lupus syndrome. This report concerns the fine specificity of the ANA response to hydralazine, penicillamine, and sulphasalazine therapy. Using highly purified individual histones in fluorimetric assays, antihistone antibodies are always detectable, often in large amounts, but the pattern of response to individual histones is variable and not drug specific. In addition to the response to the three histones Hi, H2B, and H3 reminiscent of idiopathic systemic lupus erythematosus, antibody to histone H2A predominates in some drug induced cases. Contrary to previous thought, histones are not the sole target of the antinuclear response: we also demonstrate a significant correlation between ANA titre and antibody to poly(adenosine diphosphate-ribose). Like the histones, this is a macromolecule that can bind to deoxyribonucleic acid (DNA). It is proposed that drug induced damage to chromatin leads to ANA production, while drug induced impairment of complement activity may then enable these autoantibodies to mediate the lupus syndrome.

A new fluorimetric assay was used to measure the relative amounts of antibodies to individual nuclear histones in sera from 102 patients with systemic lupus erythematosus (SLE), mixed connective tissue disease, primary sicca syndrome, and rheumatoid arthritis with vasculitis. In SLE sera, the predominant responses were to histones H‐1, H‐2B, and H‐3, with marked elevations of binding to H‐1 and H‐2B in one‐third of the patients, and to H‐3 in one‐fourth; antibodies of both the IgG and IgM classes were also detected. In a few SLE sera, the pattern of histone response differed or was restricted to 1 immunoglobulin class. In mixed connective tissue disease, only 2 of 9 sera showed elevated histone binding activity, the response being predominantly to H‐3 in 1 patient and to H‐1 and H‐2B in the other. Binding to H‐2B was also prominent in 2 of 3 patients with primary sicca syndrome. The highest antihistone reactivity and the most heterogeneous response patterns were observed in patients who had rheumatoid arthritis with vasculitis; 6 of 8 of those sera had elevated histone reactivity. In SLE, the highest histone binding results were found among patients with a history of photosensitivity. Histones are closely associated with DNA in the nucleosome, and we speculate that antihistone antibodies could arise as a result of damage to DNA, induced by drugs or irradiation.

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