title: Biological agents in rheumatoid arthritis: which ones could be used in combination?
abstract: Rheumatoid arthritis is a chronic inflammatory disease. Established treatment is limited because of the clinical response or the induction of adverse effects. New biological agents evaluated for treatment of rheumatoid arthritis have shown varied clinical success. These agents target cytokines such as tumour necrosis factor-alpha (TNFalpha), interleukin (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 have shown clinical effectiveness in double-blind placebo-controlled trials. These include the primatised nondepleting anti-CD4 monoclonal antibody (mAb) CE9.1 (keliximab), the TNFalpha-blocking mAbs cA2 (infliximab) and CDP-571, the human recombinant soluble TNFalpha receptors p55 (lenercept) and p80, as well as the human recombinant IL-1 receptor antagonist protein, anakinra. Thus, only these agents qualify for evaluation of combination treatment in rheumatoid arthritis. Rationales for combination therapy include: combining drugs with different sites of action to increase efficacy or with different toxicities to minimise risk; combining drugs with different kinetics, thus improving clinical activity; using a combination of drugs for the prevention of tachyphylaxis; or using a second drug which helps to prevent or delay the development of resistance to the first one. In addition, combination therapy could help to prevent or minimise adverse effects caused by treatment with biological agents. Based on knowledge from trials with biological agents, and on the different properties attributed to the established disease-modifying antirheumatic drugs (DMARDs) in ex vivo and in vitro studies, we propose evaluation of the following combination regimens involving biological agents. First, biological agents targeting TNFalpha (such as the mAbs cA2 or CDP-571, or the TNFalpha receptor p55-IgG1 fusion protein) given as a single infusion for rapid clinical response could be followed by continuation treatment with methotrexate, possibly combined with chloroquine, azathioprine or cyclosporin. Combination of specific anti-TNFalpha strategies with sulfasalazine should be avoided because of the induction of double-stranded DNA antibodies seen after TNFalpha blockade in vivo and reports on a systemic lupus erythematosus-like syndrome as an adverse effect during treatment with biological agents directed against TNFalpha or with sulfasalazine. Alternatively, continuous inhibition of TNFalpha or IL-1 with TNFalpha receptor p80-IgG1 fusion protein or IL-1 receptor antagonist, respectively, could be combined with methotrexate, with the disadvantage of a slower initial improvement of clinical symptoms. Combination regimens with the primatised CD4 mAb could include methotrexate as concomitant medication, with chloroquine or sulfasalazine as additional medication. Importantly, combination of different biological agents might induce more severe adverse effects than seen with monotherapy. Thus, protocols involving combinations of biological agents with established DMARDs promise better acceptance than combinations of 2 new and as yet unestablished drugs with possibly synergistic adverse effects because of their antigenic properties.
authors.affiliation: Department of Medicine III, Institute for Clinical Immunology and Rheumatology, University of Erlangen-Nuremberg, Erlangen, Germany. Hannes.Lorenz@med3.med.uni-erlangen.de
authors.forename: M
authors.initials: M
authors.lastname: Lorenz
authors.forename: J R
authors.initials: JR
authors.lastname: Kalden