Evaluation of intra-articular thio-tepa in rheumatoid arthritis.

The potential action of cytotoxic agents such as alkylating drugs and antimetabolites on the immune response and inflammatory process has suggested their trial in the treatment of rheumatic diseases. Nitrogen mustard was tried initially both by intravenous and intra-articular injection in the therapy of rheumatoid arthritis and gave variable responses (Jimenez Diaz, 1951; Jimenez Diaz, Lopez Garcia, Merchante, and Perianes, 1951; Shutkin, 1951; Phillips, Phillips, and Caraway, 1952; Cohen, Rose, and Cooper, 1953; Scherbel, 1957; Scherbel, Schuchter, and Weyman, 1957; Scherbel, Mackenzie, and Atdjian, 1963). Scherbel and others (1957) noted a rapid and prolonged decrease in joint swelling after the intra-articular injection of nitrogen mustard in patients with rheumatoid arthritis, but not a corresponding satisfactory relief of pain. He, therefore, combined steroids with nitrogen mustard for intra-articular injection and obtained more beneficial results. When a purine antagonist, 6-mercaptopurine, was administered to patients with systemic lupus erythematosus the responses were equivocal (Lee, Meiselas, Zingale, and Richman (1961). The development of adjuvant-induced arthritis in rats has been successfully inhibited by 6-mercaptopurine (Kalliomaki, Saarimaa, and Toivanen, 1964). Methotrexate has been used experimentally in psoriatic arthritis (O'Brien, Van Scott, Black, Eisen, and Bunim, 1962; Black, O'Brien, Van Scott, Auerbach, Eisen, and Bunim, 1964). Recently, thio-tepa (N, N', N2 triethylenethiophosphoramide) has been reported to give satisfactory improvement after intra-articular administration to patients with rheumatoid arthritis (Flatt, 1962; Gross, 1963; Pace, Kantor, and McEwen, 1964). Some of the latter results are difficult to interpret because thio-tepa was, in many instances, combined with steroids or local anaesthetics for intra-articular injection. Rheumatoid arthritis is a disease in which rheumatoid factor(s), an abnormal antibody(s) or antibody-like substance(s), is frequently present. Alkylating agents interfere with antibody production and, therefore, could inhibit the possible immune reaction and inflammatory changes characteristic of rheumatoid arthritis. It seemed appropriate to study this possibility in more detail. Thio-tepa, an alkylating agent, was selected for study because it can be placed in solution at a pH which is not irritating to the tissues and, consequently, can be given by all parenteral routes. The present investigation describes our results after intra-articular injection of thio-tepa into the knee joint of nineteen patients with rheumatoid arthritis.