BIOLOGICAL AGENTS IN RHEUMATOID-ARTHRITIS - WHICH ONES COULD BE USED IN COMBINATION

Rheumatoid arthritis is a chronic inflammatory disease. Established tr eatment is limited because of the clinical response or the induction o f adverse effects. New biological agents evaluated for treatment of rh eumatoid arthritis have shown varied clinical success, These agents ta rget cytokines such as tumour necrosis factor-alpha (TNF alpha), inter leukin (IL)-1 or IL-6, or cell surface molecules such as CD4, CD5, CD7 , IL-2 receptor, CDw52 or CD54, Amongst these new drugs, only a few ha ve shown clinical effectiveness in double-blind placebo-controlled tri als, These include the primatised nondepleting anti-CD4 monoclonal ant ibody (mAb) CE9.1 (keliximab), the TNF alpha-blocking mAbs cA2 (inflix imab) and CDP-571,the human recombinant soluble TNF alpha receptors p5 5 (lenercept) and p80, as well as the human recombinant 1L-1 receptor antagonist protein. anakinra. Thus, only these agents qualify for eval uation of combination treatment in rheumatoid arthritis. Rationales fo r combination therapy include: (i) combining drugs with different site s of action to increase efficacy or with different toxicities to minim ise risk; (ii) combining drugs with different kinetics, thus improving clinical activity; (iii) using a combination of drugs for the prevent ion of tachyphylaxis; or (iv) using a second drug which helps to preve nt or delay the development of resistance to the first one. In additio n, combination therapy could help to prevent or minimise adverse effec ts caused by treatment with biological agents. Based on knowledge from trials with biological agents, and on the different properties attrib uted to the established disease-modifying antirheumatic drugs (DMARDs) in ex vivo and in vitro studies, we propose evaluation of the followi ng combination regimens involving biological agents. First, biological agents targeting TNF alpha (such as the mAbs cA2 or CDP-571, or the T NF alpha receptor p55-IgG1 fusion protein) given as a single infusion for rapid clinical response could be followed by continuation treatmen t with methotrexate, possibly combined with chloroquine, azathioprine or cyclosporin. Combination of specific anti-TNF alpha strategies with sulfasalazine should be avoided because of the induction of double-st randed DNA antibodies seen after TNF alpha blockade in vivo and report s on a systemic lupus erythematosus-like syndrome as an adverse effect during treatment with biological agents directed against TNF alpha or with sulfasalazine. Alternatively, continuous inhibition of TNF alpha or IL-1 with TNF alpha receptor p80-IgG1 fusion protein or IL-1 recep tor antagonist, respectively, could be combined with methotrexate. wit h the disadvantage of a slower initial improvement of clinical symptom s. Combination regimens with the primatised CD4 mAb could include meth otrexate as concomitant medication, with chloroquine or sulfasalazine as additional medication. Importantly, combination of different biolog ical agents might induce more severe adverse effects than seen with mo notherapy. Thus, protocols involving combinations of biological agents with established DMARDs promise better acceptance than combinations o f 2 new and as yet unestablished drugs with possibly synergistic adver se effects because of their antigenic properties.