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Present and Future of Combination Therapy of Autoimmune Diseases

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Present and Future of Combination Therapy of Autoimmune Diseases For reprint orders, please contact: EDITORIAL [email protected] Present and future of combination therapy of autoimmune diseases disease remission, enabling changes in dosing and ‘A dual therapeutic strategy targeting scheduling of those drugs with the least conven- the dominating proinflammatory ient safety profile, leading certainly to a more milieu as well as the more specific individualized approach to medicine and open- immune response is, in our view, ing the possibility of identifying a strategy leading especially promising.’ to long-lasting remission. Treatment regimens for rheumatological diseases Combination of nonbiologics have changed considerably over the past 20 years. It has become common practice, that patients are To date, treatment of rheumatoid arthritis (RA) started on disease-modifying antirheumatic mainly focused on the inflammatory pathogenic drugs (DMARDs) therapy early in the course of component of the disease. Significant progress in their disease. In order to achieve synergy without the induction of disease remission has been subsequent increase in toxicity, long-term remis- achieved by the use of powerful immunosuppres- sion and slowing of radiological damage, the sants and cytostatic drugs, such as corticosteroids, combination of several DMARDs with different methotrexate (MTX) and leflunomide, in the mechanisms of action was tested and found to be early stage of the disease [1,2]. Biologics have effective in some combinations [5,6]. For instance, recently been added for treatment-resistant dis- in two open-label randomized trials in patients ease, more specifically targeting components that with early RA, the combination of MTX, sulfa- play a role in the disease pathogenesis [3,4]. Unfor- salazine, hydroxychloroquine (HCQ) and pred- tunately, persistent disease remission can only be nisolone demonstrated greater clinical achieved as long as the drugs are administered, improvement and significantly less radiographic and only then can progression of joint damage be progression compared with a single DMARD prevented. In addition, since most of these agents with or without prednisone [2,7]. Many other induce a generalized and nonspecific inhibition of combinations are used in common practice, with immune response and inflammation, they can a general direct correlation between increased cause considerable immunodepression, leading to clinical efficacy and overlapping undesired complications that prompted US FDA to formu- effects, which limit the use of such combinations. late black-box warnings for some of these prod- The underlying reason for the synergistic effect ucts. A more specific modulation of the immune of these DMARDs is not fully known at present. Sarah TA Roord, response could theoretically overcome these pit- This effect may may be partly due to the influ- Berent J Prakken & falls. Some of these novel strategies are in the ence on each other’s pharmacokinetics; for exam- Salvatore Albani † clinical development stage. ple, HCQ leads to slower clearance and uptake †Author for correspondence University of California, The combination of treatment strategies with with a greater area under the curve for MTX in San Diego, Departments of different and complementary mechanisms of patients taking the combination of HCQ and Medicine & Pediatrics, action is likely to be more successful and is thus MTX [8]. The synergy may also be mechanistic 9500 Gilman Drive, being introduced into the standard of practice; by and affect both the adaptive and innate arms of La Jolla, CA 92093-0731, USA acting complementarily or synergistically, they can the immune response. For instance, MTX, as a Tel.: +1 858 534 0394; enhance efficacy. Cost and toxicity can be folate inhibitor, acts on rapidly proliferating cells, Fax: +1 858 822 5666; decreased, owing to the opportunity to administer which are purportedly composing the pool of [email protected] lower amounts of drugs than when they are given effector cells that may fuel autoimmune inflam- separately. Combination of nonbiologics, currently mation. Conversely, HCQ is an inhibitor of approved biologics and novel biologics will be dis- intracellular processes involved in antigen presen- cussed in this editorial. A dual therapeutic strategy tation, thus potentially affecting the repertoire of targeting the dominating proinflammatory milieu autoantigens available to effector cells [9]. as well as the more specific immune response is, in Unfortunately, a proportion of patients still our view, especially promising. Induction of spe- do not respond sufficiently to DMARD therapy, cific immune tolerance may provide a long-lasting and complementary approaches are needed. 10.2217/17460816.1.6.649 © 2006 Future Medicine Ltd ISSN 1746-0816 Future Rheumatol. (2006) 1(6), 649–655 649 EDITORIAL – Roord, Prakken & Albani Major disadvantages of the use of DMARDs are significantly, compared with MTX or that they are not specific (and therefore lead to anti-TNFα treatment alone [12–20]. The combi- side effects) and that they must be administered nation treatments led to a decrease in disease continuously to retain efficacy. activity, reduction of disability, an increase in remission rates and even a decrease in progres- Combination of currently sion of joint damage. Unfortunately, the exact approved biologics mechanism underlying this synergistic effect is Greater success with fewer side effects can be not currently known, but may be explained in expected by more specifically targeting pro- part by a decreased amount of neutralizing anti- inflammatory cytokines that are known to play a bodies against TNF antagonists [21]. Further- role in the autoimmune process, such as tumor more, knowledge on the influence of MTX on necoris factor (TNF)α, interleukin (IL)-1 or -6. T cells and the inflammatory process has been Several biological agents have been identified expanding in recent years, and may also provide that can block these cytokines: some explanation for the combinatory effect of • Enbrel (Etanercept®), a soluble TNF receptor MTX with anticytokine treatment. MTX pro- fusion protein, targets TNFα; motes the release of the endogenous anti- • Remicade (Infliximab®), a chimeric anti- inflammatory mediator adenosine, presumably TNFα antibody, targets TNFα; through its capacity to increase intracellular 5-aminoimidazole-4-carboxamide ribonucle- •Humira (Adalimumab®), a recombinant otide (AICAR) concentrations [22]. Adenosine human anti-TNFα antibody, targets TNFα; has a central role in regulation of inflammatory ® • Kineret (Anakinra ), an IL-1 receptor responses, one of which is the contribution to antagonist (IL1-RA), neutralizes IL-1; the resolution of inflammation, both by down- •MRA® (a humanized IL-6 receptor antibody) regulating macrophage activation and by targets IL-6. advancing T-helper (Th)2 versus Th1 cell The use of these agents has shown clinical effi- development [23]. Direct evidence for the pro- cacy in several clinical trials, but the fact that the motion of a more anti-inflammatory environ- effects are only temporary, their cost is high and ment by MTX was gained in early RA patients, severe side effects may occur, such as an increase where a decrease in T-cell-derived TNFα was in serious infections and possibly lymphomas observed, together with an increase in IL-10- due to anti-TNFα treatment, is hampering their producing T cells [24]. In in vitro experiments, success [3,10]. MTX was demonstrated to increase IL-10 and The potential for additive or synergistic effects -4 gene transcription as well as decrease IFNγ of two biologics has been tested in the treatment gene transcription [25]. Therefore the combina- of RA by adding kineret to treatment with tion of blocking proinflammatory cytokines by enbrel. However, no additional clinical effect was anticytokine biologics with the promotion of a demonstrated, whereas an increased safety risk more anti-inflammatory environment by MTX did become apparent, due to higher incidence of may work synergistically. serious infections, injection site reactions and Hence, an important step towards obtaining neutropenia [11]. Therefore, the combination of disease remission and slowing of radiological two anticytokine biologics is not recommended. damage has been obtained by combining several Conversely, a field with great potential is the DMARDs or combining MTX and anticytokine combination of biologics that target different biologics. However, the effects only last while the immunopathogenic pathways; therefore exploit- drugs are administered. ing a potential complementarity in mechanism of action. However, these approaches are at the Combination of currently approved initial stage of clinical testing to ascertain both biologics with novel biologics efficacy and tolerability. The induction of specific immune tolerance would ideally spare the patient generalized Combination of nonbiologics with immune suppression and could be expected to currently approved biologics provide a long-lasting effect (and maybe even a Promising results were obtained when combining cure) that is devoid of side effects. The induction MTX with a biological agent. The combination of immune tolerance requires the identification of MTX with anti-TNFα or IL-1RA treatment is of the appropriate target. Efforts at inducing tol- found to improve the clinical outcome erance independent of a specific antigenic target 650 Future Rheumatol. (2006) 1(6) Combination therapy of autoimmune diseases – EDITORIAL are mainly based on molecules interfering with physiological
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