Doi:10.1016/j.coph.2004.04.00

What next for rheumatoid arthritis therapy?Simon M Blakeà and Barbara A Swift Introduction of biological agents for the treatment of the chronic sis factor (TNF) and interleukin (IL)-1 in the pathogen- inflammatory joint disease rheumatoid arthritis has reinvigorated esis of the disease Despite these successes, these research into this debilitating disease. These agents have therapies do have their limitations: the potential (in the been shown to both act on the signs and symptoms of disease, case of anti-TNF therapy) to increase susceptibility to as well as retard the progression of joint destruction. However, infection, especially in those patients with latent tuber- these agents are not efficacious in all cases and their culosis ; a limited responder rate and a high cost.
expense and route of administration can severely limit their There is therefore not only a need to generate potentially use. Therefore the search continues not only for additional safer and more efficacious agents but also reduce the cost targets to help those individuals refractive to current therapy burden to the patient. This review focuses on the poten- but also for more affordable orally active small molecule tial for RA therapy beyond the current crop of TNF and IL-1 blockers. Particular attention will be paid to thecurrent biological approaches being pursued, as well as the targeting of signaling pathways that may be respons- Dept of Musculoskeletal Diseases, GlaxoSmithKline Pharmaceuticals, ible for their cellular release and/or activity.
1250 S Collegeville Road, Collegeville, PA 19426, USAÃe-mail: simon.m.blake@gsk.com Biological therapies beyond IL-1 and TNFblockade Current Opinion in Pharmacology 2004, 4:276–280 There is considerable evidence that cytokines other thanIL-1 and TNF play a pathogenic role in the onset and perpetuation of RA. For example, IL-6 levels are elevated Musculoskeletal pharmacologyEdited by Simon Blake and Michael Lark in RA joints and contribute to both local and systemicfeatures of RA. The reduction in susceptibility of IL-6 knockout mice to induction of arthritis also suggests a role for this cytokine in the development of joint inflamma- tion and extracellular matrix destruction Further-more, recent clinical data in a Phase II trial with ahumanized monoclonal antibody to the IL-6 receptor have demonstrated efficacy in RA patients . Despite these promising results, it should be noted that pre- clinical animal models and in vitro studies also indicate a potential anti-inflammatory and protective role for IL-6 The results of the ongoing Phase III trials investigat- peroxisome proliferation-activated receptor ing IL-6 blockade are therefore eagerly anticipated.
Other pro-inflammatory cytokines that have been impli-cated in the pathogenesis of RA are IL-15, IL-17 and IL-18. IL-18 is a member of the IL-1 protein family which has been shown to be present in rheumatoid synovitis, Rheumatoid arthritis (RA) is the most common chronic and is implicated in the Th1 response that is so predo- inflammatory disease affecting human joints. Its remitting minant in RA Antagonism of this cytokine with either time course and associated systemic pathologies do not antibodies or a recombinant binding protein has been only result in severe joint destruction and disability but shown to ameliorate established joint inflammation in a are also associated with mortality. The treatment options mouse model of RA Antagonism of the activity of the for this disease have in the past decade been revolution- potent T cell chemotactic cytokine IL-15 is also being ised by the introduction of biological agents that demon- studied for its therapeutic potential. Once again, pre- strate disease modifying anti-rheumatic drug activity. As clinical studies in a mouse model of RA using a soluble this name would suggest, such therapies have not only IL-15 receptor protein have demonstrated significant been shown to influence the signs and symptoms of the protective effects of this approach Early reports from disease (pain and inflammation) but have also demon- clinical studies with a fully human anti-IL-15 antibody strated a retardation of disease progression . The have provided encouraging data. However, these preli- success of these therapies has also served to confirm a minary data must be viewed with caution, as no placebo pivotal role for the inflammatory cytokines tumour necro- control was included . It is also clear that these results Current Opinion in Pharmacology 2004, 4:276–280 What next for rheumatoid arthritis therapy? Blake and Swift do not, at present, demonstrate a superior benefit when MAPKs respond to environmental stress, including UV, compared with comparable data from the currently mar- heat, osmotic shock and inflammatory cytokines. Given the stimulus response profile of p38 MAPK, it is notsurprising that this pathway has received the most atten- The most recent addition to the list of cytokines whose tion from researchers in the RA field . Over the past antagonism might provide therapeutic benefit in RA is decade, a large body of scientific and genetic evidence IL-17. Studies using mice deficient in this T cell-derived has amassed that indicates a critical role for the p38a cytokine demonstrated a reduced susceptibility to col- isoform of these enzymes in the production and subse- lagen-induced arthritis and, most recently, it was quent signaling of cytokines such as IL-1 and TNF, in demonstrated that an anti-IL-17 antibody reduced addition to other inflammatory mediators such as pro- inflammation and prevented joint destruction in an estab- staglandin E2 and nitric oxide. Several potent selective lished mouse model of RA However, it is unclear if inhibitors of p38a MAPK inhibitors have been shown to antagonism of this activity would supercede those of the be efficacious in a wide variety of pre-clinincal animal models of disease, including RA. Indeed, there are nowseveral reports of inhibitors being advanced into clinical Chronic destruction of bone is one of the hallmarks of RA.
studies for RA, but none has so far advanced to the phase Emerging data in the past five years have highlighted the key role of the receptor activator of NFkB ligand(RANKL)/RANK receptor system in this pathogenic A second pathway, the involvement of which in the process . RANKL is expressed by T cells that have cytokine signaling cascade has generated much research been shown to induce and support the formation of bone interest, is that of the transcription factor nuclear factor- resorbing osteoclasts in vitro In two in vivo models of kB (NF-kB). In most unstimulated cells, NF-kB exists in RA in the rat and mouse, RANKL expression has been an inactive cytoplasmic form complexed to an inhibitor demonstrated at the sites of active bone resorption of kB (IkB) protein that masks its nuclear translocation . Furthermore, administration of the naturally sequence. Phosphorylation of IkB results in its proteo- occurring inhibitor of RANKL activity, osteoprotegrin, some driven degradation, releasing NF-kB and thus could prevent bone destruction in a model of chronic allowing its translocation to the nucleus and subsequent inflammatory joint disease in the rat (i.e. adjuvant gene transcription. Examples of these gene products induced arthritis) . In no study was there any include the inflammatory cytokines TNF, IL-1, IL-6, evidence of an anti-inflammatory effect of the antagonist.
the matrix-degrading matrix metalloprotease enzymes 1, Therefore, any therapeutic agent targeting this interac- 9 and 13, and other inflammatory mediators including tion should probably be used in combination with an anti- inducible nitric oxide synthase and cyclooxygenase-2 The enzyme responsible for phosphorylation ofIkB — IkB kinase (IKK) — consists of two subunits termed IKK-1 and IKK-2. Experimental data strongly It is clear from the data presented that a multitude of suggest that IKK-2 is the subunit required for NF-kB cytokines play a role in the initiation and perpetuation of activation by all known pro-inflammatory signals, includ- joint inflammation and destruction in RA. These data also ing cytokines . Therefore, identification of inhibitors underline the complexity of the cellular and molecular of the activity of this kinase subunit has become the pathways involved in this disease. It is therefore not focus of pharmaceutical based research . The fruits surprising that intense research is being focused upon of this research have recently begun to be revealed.
the identification of common signaling pathways for both Several companies have described inhibitors with an cytokine activity and release. Such research might identify IC50 for IKK-2 in the nanomolar range Several a target for orally active small molecular weight inhibitors.
of these inhibitors have now progressed into pre-clinicalin vivo models of inflammation. Data from these studies Cells are continuously being stimulated by signals ema- have demonstrated potent anti-inflammatory and joint nating from the environment. These signals are effi- protective effects when administered orally in models of ciently transmitted to the inside of the cell where RA in both mice and rats However, as with signaling complexes result in a response specific to the many orally active inhibitors, the safety and efficacy stimulus. A major component of these intracellular sig- profiles have yet to be fully determined. Such data will naling complexes are the mitogen-activated protein be key to their progression for the treatment of chronic kinases (MAPKs). To date, three distinct MAPK path- ways have been described in mammalian cells: extracel-lular signal regulated kinases, c-jun amino terminal kinase New targets coming under scrutiny in RA research are the and p38 MAPK. In general, the extracellular signal regu- peroxisome proliferation-activated receptors (PPARs).
lated kinases are activated by mitogenic and proliferative These constitute a three member family of ligand-acti- stimuli, whereas c-jun amino terminal kinases and p38 vated transcription factors (a, g and d) belonging to the Current Opinion in Pharmacology 2004, 4:276–280 nuclear hormone receptor family. Several synthesised strated that B cell depletion resulted in a significant ligands of these receptors are currently used clinically improvement in disease severity, as asessed using the as antihyperglycemic agents in the treatment of type 2 American College of Rheumatology criteria, in four out of diabetes mellitus The potential role of these recep- five RA patients. This study used a regimen of huma- tors in the inflammatory response was first shown when nized monoclonal antibody (rituximab) to the B cell PPARa-deficient mice demonstrated a prolonged inflam- antigen CD20 to target cells for depletion with intrave- matory response to the PPARa ligand leukotriene B4 nous cyclophosphamide and high-dose steroids. These These studies have now being expanded and it is clear initial studies have since been extended and the findings that the role of PPARs in the inflammatory process is not confirmed in a randomized placebo control study in 122 confined to PPARa, but might also include PPARg.
In in vitro studies, for example, PPARg and PPARa both The data presented above provide support for a role for physically interact with NFkB leading to the repression of both T and B cells in the perpetuation of chronic inflam- its activity which would be expected to result in a mation in RA. It also needs to be demonstrated that these reduced production of inflammatory mediators, as out- therapies are capable of halting radiological progression lined above. Further in vitro analysis has also demon- and therefore possessing true disease modifying activity.
strated that both PPARg and PPARa can inhibit the AP-1signaling pathway through its interaction with c-Jun Both PPARa and PPARg are expressed in cultured Over the past decade, the treatment of RA has advanced human chondrocytes and human articular cartilage significantly. Despite these advances, the need for thera- Additionally, studies in rat and human cartilage pies that have significant disease modifying anti-rheu- using a PPARg ligand have demonstrated an inhibitory matic drug activity remains an acute unmet medical need effect on IL-1-induced matrix metalloprotease-13 and in this disease. It is clear from those approaches outlined nitric oxide production These results suggest a above that the success of the anti-cytokine therapies has protective role for PPARg ligands in inflammatory joint driven major advances in cytokine biology. This in turn lesions. Possibly the most critical piece of evidence has highlighted possible novel approaches for the treat- demonstrating a primary role of these receptors in the ment of RA. Whether or not the next decade will be quite inflammatory cascade comes from recently reported in as revolutionary in terms of RA therapy remains to be vivo data. Oral administration of the small molecular seen. However, given the level of interest in RA research, weight PPARg ligand rosiglitazone in a rat model of the possibility of new therapies being added to the RA demonstrated significant reduction in inflammation rheumatoid clinicians’ armamentarium remains high.
and prevention of joint destruction . This wasaccompanied by a significant reduction in circulating levels of IL-1 and IL-6. These findings taken together The authors would like to thank Drs Scott Crowe and James Callahan support the use of PPARg ligands in the treatment of RA.
for providing constructive feedback on this manuscript.
Further research is needed to understand the potential anti-inflammatory effects of other PPAR family members.
Papers of particular interest, published within the annual period ofreview, have been highlighted as: Despite continuing debate over the relative role of the T cell in RA and the lack of success of several therapies Redlich K, Schett G, Steiner G, Hayer S, Wagner EF, Smolen JS: targeting these cells in this disease, data from recent Rheumatoid arthritis therapy after tumor necrosis factor and clinical observations still suggest a primary role for the interleukin-1 blockade. Arthritis Rheum 2003, 48:3308-3319.
T cell in RA. Interaction of the costimulatory molecules Feldmann M, Brennan FM, Foxwell BM, Maini RN: The role of TNF CD80 and CD86 with the CD28 receptor on the T cell is alpha and IL-1 in rheumatoid arthritis. Curr Dir Autoimmun 2001,3:188-199.
one of two interactions required for effective T cell Keane J, Gershon S, Wise RP, Mirabile-Levens E, Kasznica J, activation, the other being an interaction between T cell Schwieterman WD, Siegel JN, Braun MM: Tuberculosis receptor/antigen and major histocompatibility complex. A associated with infliximab, a tumor necrosis factor alpha-neutralizing agent. N Engl J Med 2001, 345:1098-1104.
fusion protein therapeutic, CTLA-4Ig, which targets theinteraction of the CD28 receptor on the T cell with CD80 Wong PK, Campbell IK, Egan PJ, Ernst M, Wicks IP: The role of theinterleukin-6 family of cytokines in inflammatory arthritis and and CD86, appears to be effective in RA, as demonstrated bone turnover. Arthritis Rheum 2003, 48:1177-1189.
Boe A, Baiocchi M, Carbonatto M, Papoian R, Serlupi-Crescenzi O:Interleukin 6 knock-out mice are resistant to antigen-induced In terms of a therapeutic approach, the B cell has prob- experimental arthritis. Cytokine 1999, 11:1057-1064.
ably been the most overlooked cell present in the RA Choy EH, Isenberg DA, Garrood T, Farrow S, Ioannou Y, Bird H, synovium. That was until the publication in 2001 of a Cheung N, Williams B, Hazleman B, Price R et al.: Therapeuticbenefit of blocking interleukin-6 activity with an anti- study by Edwards and Cambridge which demon- interleukin-6 receptor monoclonal antibody in rheumatoid Current Opinion in Pharmacology 2004, 4:276–280 What next for rheumatoid arthritis therapy? Blake and Swift arthritis: a randomized, double-blind, placebo-controlled, 23. Karin M, Yamamoto Y, Wang QM: The IKK NF-kappa B system: dose-escalation trial. Arthritis Rheum 2002, 46:3143-3150.
a treasure trove for drug development. Nat Rev Drug Discov Details the phase II clinical trial results with the anti-IL-6 receptor anti- body. This study was conducted in 45 patients and was the first demon- A very thorough review of the biological rationale for inhibition of the stration of a significant effect of inhibiting IL-6 in a randomized controlled NF-kB pathway for the treatment of chronic diseases. This review also includes a summary of the current status for many of the newly describedsmall molecule inhibitors of this pathway.
Liew FY, Wei XQ, McInnes IB: Role of interleukin 18 inrheumatoid arthritis. Ann Rheum Dis 2003, 62(Suppl 2):ii48-ii50.
24. Burke JR, Pattoli MA, Gregor KR, Brassil PJ, MacMaster JF, McIntyre KW, Yang X, Iotzova VS, Clarke W, Strnad J et al.: Plater-Zyberk C, Joosten LA, Helsen MM, Sattonnet-Roche P, BMS-345541 is a highly selective inhibitor of I kappa B kinase Siegfried C, Alouani S, van De Loo FA, Graber P, Aloni S, Cirillo R that binds at an allosteric site of the enzyme and blocks et al.: Therapeutic effect of neutralizing endogenous IL-18 NF-kappa B-dependent transcription in mice. J Biol Chem 2003, activity in the collagen-induced model of arthritis. J Clin Invest 25. Castro AC, Dang LC, Soucy F, Grenier L, Mazdiyasni H, Ruchatz H, Leung BP, Wei XQ, McInnes IB, Liew FY: Soluble Hottelet M, Parent L, Pien C, Palombella V, Adams J: Novel IKK IL-15 receptor alpha-chain administration prevents murine inhibitors: beta-carbolines. Bioorg Med Chem Lett 2003, collagen-induced arthritis: a role for IL-15 in development of antigen-induced immunopathology. J Immunol 1998,160:5654-5660.
26. Murata T, Shimada M, Sakakibara S, Yoshino T, Kadono H, Masuda T, Shimazaki M, Shintani T, Fuchikami K, Sakai K et al.: 10. McInnes IB, Gracie JA, Harnett M, Harnett W, Liew FY: New Discovery of novel and selective IKK-beta serine-threonine strategies to control inflammatory synovitis: interleukin 15 and protein kinase inhibitors. Part 1. Bioorg Med Chem Lett 2003, beyond. Ann Rheum Dis 2003, 62(Suppl 2):ii51-ii54.
11. Nakae S, Nambu A, Sudo K, Iwakura Y: Suppression of immune 27. Roshak A, Marshall L, Carlson K, Podolin P, Bolognese B, induction of collagen-induced arthritis in IL-17-deficient mice.
Hoffman S, Imburgia C, Li YH, Lang X et al.: A small molecule inhibitor of IjB kinase blocks inflammation and protects jointintegrity in in vivo models of arthritis. Inflamm Res 2002, 12. Nakae S, Saijo S, Horai R, Sudo K, Mori S, Iwakura Y: IL-17 production from activated T cells is required for thespontaneous development of destructive arthritis in mice 28. McIntyre KW, Shuster DJ, Gillooly KM, Dambach DM, deficient in IL-1 receptor antagonist. Proc Natl Acad Pattoli MA, Lu P, Zhou XD, Qiu Y, Zusi FC, Burke JR: A highly selective inhibitor of I kappa B kinase, BMS-345541,blocks both joint inflammation and destruction in 13. Lubberts E, Koenders MI, Oppers-Walgreen B, collagen-induced arthritis in mice. Arthritis Rheum 2003, van den Bersselaar L, Coenen-de Roo CJ, Joosten LA, van den Berg WB: Treatment with a neutralizing anti-murine Describes the in vitro and in vivo biology for a small molecule inhibitor of interleukin-17 antibody after the onset of collagen-induced IKK-2. The paper demonstrates the potent anti-inflammatory and joint arthritis reduces joint inflammation, cartilage destruction, and protective activity of this molecule in a mouse model of RA.
bone erosion. Arthritis Rheum 2004, 50:650-659.
Study demonstrating that the therapeutic blockade of IL-17 resulted in a 29. Meriden T: Progress with thiazolidinediones in the significant anti-inflammatory and joint protective effect in a pre-clinical management of type 2 diabetes mellitus. Clin Ther 2004, 14. Blake SM, James IE: Receptor Activator of NF-kB Ligand 30. Devchand PR, Keller H, Peters JM, Vazquez M, Gonzalez FJ, (RANKL). In The Cytokine Handbook. Edited by Thomson AW, Wahli W: The PPARalpha-leukotriene B4 pathway to Lotze MT. London: Harcourt Press; 2003.
inflammation control. Nature 1996, 384:39-43.
15. Kotake S, Udagawa N, Hakoda M, Mogi M, Yano K, Tsuda E, 31. Delerive P, De Bosscher K, Besnard S, Vanden Berghe W, Takahashi K, Furuya T, Ishiyama S, Kim KJ et al.: Activated human Peters JM, Gonzalez FJ, Fruchart JC, Tedgui A, Haegeman G, T cells directly induce osteoclastogenesis from human Staels B: Peroxisome proliferator-activated receptor alpha monocytes: possible role of T cells in bone destruction in negatively regulates the vascular inflammatory gene response rheumatoid arthritis patients. Arthritis Rheum 2001, by negative cross-talk with transcription factors NF-kappaB and AP-1. J Biol Chem 1999, 274:32048-32054.
16. Kong YY, Feige U, Sarosi I, Bolon B, Tafuri A, Morony S, 32. Chung SW, Kang BY, Kim SH, Pak YK, Cho D, Trinchieri G, Kim TS: Capparelli C, Li J, Elliott R, McCabe S et al.: Activated T cells Oxidized low density lipoprotein inhibits interleukin-12 regulate bone loss and joint destruction in adjuvant arthritis production in lipopolysaccharide-activated mouse through osteoprotegerin ligand. Nature 1999, 402:304-309.
macrophages via direct interactions between peroxisome 17. Romas E, Sims NA, Hards DK, Lindsay M, Quinn JW, Ryan PF, proliferator-activated receptor-gamma and nuclear factor- Dunstan CR, Martin TJ, Gillespie MT: Osteoprotegerin reduces kappa B. J Biol Chem 2000, 275:32681-32687.
osteoclast numbers and prevents bone erosion in collagen- 33. Sabatini M, Bardiot A, Lesur C, Moulharat N, Thomas M, Richard I, induced arthritis. Am J Pathol 2002, 161:1419-1427.
Fradin A: Effects of agonists of peroxisome proliferator- 18. Bolon B, Campagnuolo G, Feige U: Duration of bone protection activated receptor gamma on proteoglycan degradation and by a single osteoprotegerin injection in rats with adjuvant- matrix metalloproteinase production in rat cartilage in vitro.
induced arthritis. Cell Mol Life Sci 2002, 59:1569-1576.
Osteoarthritis Cartilage 2002, 10:673-679.
19. Campagnuolo G, Bolon B, Feige U: Kinetics of bone protection by 34. Bordji K, Grillasca JP, Gouze JN, Magdalou J, Schohn H, Keller JM, recombinant osteoprotegerin therapy in Lewis rats with Bianchi A, Dauca M, Netter P, Terlain B: Evidence for the adjuvant arthritis. Arthritis Rheum 2002, 46:1926-1936.
presence of peroxisome proliferator-activated receptor (PPAR)alpha and gamma and retinoid Z receptor in cartilage.
20. Kumar S, Boehm J, Lee JC: p38 MAP kinases: key signalling PPARgamma activation modulates the effects of molecules as therapeutic targets for inflammatory diseases.
interleukin-1beta on rat chondrocytes. J Biol Chem 2000, Nat Rev Drug Discov 2003, 2:717-726.
All encompassing review of the discovery and development of smallmolecule inhibitors of p38 MAPK.
35. Fahmi H, Di Battista JA, Pelletier JP, Mineau F, Ranger P, Martel-Pelletier J: Peroxisome proliferator–activated receptor 21. Roshak AK, Callahan JF, Blake SM: Small-molecule inhibitors of gamma activators inhibit interleukin-1beta-induced nitric NF-kappaB for the treatment of inflammatory joint disease.
oxide and matrix metalloproteinase 13 production in human Curr Opin Pharmacol 2002, 2:316-321.
chondrocytes. Arthritis Rheum 2001, 44:595-607.
22. Ghosh S, Karin M: Missing pieces in the NF-kappaB puzzle.
36. Cheng S, Afif H, Martel-Pelletier J, Pelletier JP, Li X, Farrajota K, Lavigne M, and Fahmi H: Activation of peroxisome proliferator- Current Opinion in Pharmacology 2004, 4:276–280 activated receptor gamma inhibits interleukin-1beta.
trial evaluating CTLA-4Ig and LEA29Y eighty-five days after the first infusion. Arthritis Rheum 2002, 46:1470-1479.
37. Cuzzocrea S, Mazzon E, Dugo L, Patel NS, Serraino I, Di Paola R, 39. Edwards JC, Cambridge G: Sustained improvement in Genovese T, Britti D, De Maio M, Caputi AP et al.: Reduction in the rheumatoid arthritis following a protocol designed to deplete B evolution of murine type II collagen-induced arthritis by lymphocytes. Rheumatology (Oxford) 2001, 40:205-211.
treatment with rosiglitazone, a ligand of the peroxisomeproliferator-activated receptor gamma. Arthritis Rheum 2003, 40. Szechinski J, Filipowicz-Sosnowska A, Close D, Stevens RM, Felicia-Szczepanski L, Shaw TM: Efficacy and safety of The first description of the anti-inflammatory properties of a PPARg rituximab, a B-cell targeted chimeric monoclonal antibody: a agonist in a pre-clinical in vivo model of RA.
randomised, placebo controlled trial in patients withrheumatoid arthritis [abstract]. Arth Rheum 2002, 38. Moreland LW, Alten R, Van den Bosch F, Appelboom T, Leon M, Emery P, Cohen S, Luggen M, Shergy W, Nuamah I et al.: The first report on the use of rituximab in RA patients. Four out of five Costimulatory blockade in patients with rheumatoid arthritis: a patients demonstrated a response to this therapy as assessed using pilot, dose-finding, double-blind, placebo-controlled clinical American College of Rheumatology criteria.
Current Opinion in Pharmacology 2004, 4:276–280

Source: http://www.biol.uni.wroc.pl/biol2003/RANKL/Blake,2004,WhatNextForRhArthTherapy.pdf