New And Emerging Therapies For Rheumatoid Arthritis

Review Article

NEW AND EMERGING THERAPIES FOR RHEUMATOID ARTHRITIS

Sundeep Kumar UpadhyayaSenior Consultant, Rheumatology Immunology,

Indraprastha Apollo Hospitals, Sarita Vihar, New Delhi 110 076, India.e-mail: sundeepupadhyaya@gmail.com, sundeepupadhyaya@hotmail.com

Rheumatoid Arthritis (RA) is a common rheumatological disorder. Many drugs including Anti TNF agentshave been used for the treatment of this condition. The result hitherto, have been excellent, but shortcomingsand the absence of complete remissions even in Anti TNF treated patients, makes the trial of newer agents,targeted to novel pathophysiologic molecules, all the more important and urgent. New insights in thepathogens of RA and three new biologics for RA have been discussed.

Key words: Abatacept, Emerging therapies, Rheumatoid arthritis, Rituximab, Tocilizumab.

INTRODUCTION

ANTI-TUMOR necrosis factor agents for the treatment ofrheumatoid arthritis (RA) have been in use both clinicallyand in trials for more than ten years. They are extremelyeffective and have hitherto been used in patients who havefailed multiple conventional DMARDs like Methotrexateand Leflunomide. They achieve ACR 50 and ACR 70clinical responses in a sizable number of patients and arewidely available in all developing countries includingIndia. Radiographic joint damage occurs in patients withrheumatoid arthritis (RA) in nearly 75% within the first 2years of disease [1]. Currently RA treatment approachesare focused on early intensive therapy with multipledisease modifying drugs (DMARDs). Methotrixate(MTX) is the first choice DMARD and often the anchordrug for combination regimens. An increasing proportionof patients are receiving newer DMARDs like leflunomideand biologics like anti TNF- products (etanercept andinfliximab) since the response rates with MTX alone arepoor. Indeed, combined use of MTX and an anti TNF-product is among the most potent treatments for RA. Yet,clinical trials of early RA treatment show that thiscombination generates ACR70 responses of only 35-45%[2,3]. The desired role of DMARD therapy is thus notrealized in most treatment regimens and theseshortcomings of currently approved therapies highlight theneed for investigating new strategic approaches and noveldrugs. This article reviews the new biologic therapeuticagents available for treatment in India.

New insights into RA pathogenesis

The failures and successes of new drugs evaluated forthe treatment of RA have provided new insights into themechanisms underlying the disease pathogenesis. Once a

persistent inflammatory reaction is established in thejoint, sustained remissions despite drug therapy are theexception rather than the rule. It is likely that currenttherapies are targeting common inflammatory pathwaysdownstream of the inciting events. These pathwaystherefore appear not to be unique to RA but are commonto several autoimmune inflammatory diseases. Many suchdiseases thus also respond to DMARDs and biologicsused for the treatment of RA (e.g. ulcerative colitis). That,anti TNF- products are extremely effective proves thefact that TNF- is an important pro-inflammatorycytokine driving the inflammatory response in RA [4]. Itis noteworthy that anti IL-1 products have yieldeddisappointing results. Therefore, not all cytokinesexpressed in the rheumatoid synovium are necessarilyviable therapeutic targets. However, the results fromclinical trials in the management of RA using anti IL-6and anti IL-15 are encouraging. Thus, targeting thesecytokines for the management of RA is logical. Although,anti-CD4, anti-CD5 and anti-CD52 products have failedto produce significant benefits in RA management(indicating that curbing T-cell activity alone is not thesolution), abatacept or CTLA4-Ig which blocks thestimulation of naïve T cells, has been found to beextremely effective in RA treatment. Activated T cellshave been seen in contact with macrophages; this cell-cellcontact has been shown in vitro to induce synovialfibroblast and macrophages to secrete damagingcytokines [5] (Fig.1). The B-cell is also a therapeutictarget largely based on the success of Rituximab therapyfor RA [6]. About 50% of patients who have RA, B-cells,T-cells and dendritic cells organize themselves intofollicular structures resembling germinal centres [7].When rheumatoid synovitis is reconstituted in specialmouse models of RA, B-cell depletion disrupts the

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tertiary lymphoid micro-structure and diminishes T-cellactivity/response [8]. Thus B-cell depletion may reduce T-cell activation and is a very important method forcontrolling inflammation in RA.

Targeting the T-cell: Cytotoxic T-lymphocyteantigen 4-immunoglobulin (CTLA4-Ig):Abatacept

CTLA4-Ig represents a new class of molecules thatblocks the second stimulus for T-cell activation. Resting T-cells require two separate signals for full stimulation. Thefirst signal is the interaction of the processed peptide in themajor histo-compatibility (MHC) with the T cell receptor(TCR). The second signal is the engagement of the CD-28on T-cells with the CD80/86 (B7-1 or B7-2) on the surfaceof the antigen presenting cell (Fig.2). CTLA 4 is a second,high affinity receptor for both CD80 and CD86, bindingup-to a 1000 times as avidly to the B7 members as CD 28.The binding of CTLA 4-Ig to the B7 molecule thusprevents the interaction between CD80/86 and CD28,essentially blocking the second signal for T-cell activation(Fig. 2).

CTLA4-Ig or Abatacept is the fusion proteinconsisting of cytotoxic T-lymphocyte associated antigen 4(CTLA 4) covalently linked to the Fc region of a humanIgG1 molecule (Fig.3). Several large clinical trials haveproven the efficacy of CTLA4-Ig in the treatment of RA.In one early study, 339 patients who had active RA despitereceiving optimal doses of MTX, were randomly allocated

to receive either placebo (n=119) or abatacept, 2mg/kg(n=105) or 10mg/kg (n=115), intravenously, at days 1, 15and 30 and monthly thereafter for 12 months [9,10]. At sixmonths, the group receiving 10mg/kg of abatacept had abigger ACR 20 response rate than the placebo group (60%vs.35%). These responses were maintained at 12 months.However, the ACR 20 responses in the 2mg/kg group werenot different from the placebo, indicating that 10mg/kgper dose is the optimal dose for the treatment of RA.

In another recent trial, 393 patients who had aninadequate response to anti TNF- therapy plus MTX/other DMARD, were randomized in a ratio of 2:1 toreceive a fixed dose of abatacept (500mg, 750mg, or1000mg) at days 1, 15, 29, and then every 28 days throughday 141 [11]. At six months, the abatacept group wassuperior to the placebo group (ACR 20) was 50.4%vs.19.5%; P<0.001).

Abatacept may also be used in patients who have hadan inadequate response to MTX mono-therapy. In a studyinvolving 652 patients on stable MTX doses, patients wererandomly allocated in a 2:1 ratio to receive abatacept in afixed dose of 10mg/kg on days 1, 15, 29 and then every28 days through day 141 [12]. At 12 months, ACR 20, 50and 70 response rates were higher in the abatacept groupthan the placebo group (80% vs. 60%, 53.3% vs. 33.8%,and 26.7% vs. 12.7%, respectively; P<0.001 for allcomparisons between abatacept and placebo groups).There was also data generated to show a reducedradiographic progression in the abatacept group [13].

Fig.1. Role of T cells in rheumatoid arthritis pathogenesis.Antigen-presenting cells (ACPs) present processedpeptide to the TCR, which recognizes the peptidewithin the context of the MHC molecule. Otherreceptors must also be activated for full T-cellactivation to happen; these are represented by themolecules schematically depicted on the surface ofACPs, T cells synovicytes, and B cells. (Adapted fromJ.M. Kremer).

Fig.2 Mechanism of action of the CTLA4-Ig molecule.Because CTLA4 binds to CD80/CD86 with muchgreater avidity than CD28 (and CD28 binds to bothCTLA4 and CD80/CD86), the presence of the artificialconstruct molecule will also selectively bind CD28,thus preventing full T-cell activation as well assubsequent B cell activation. (Adapted from J.M.Kremer)

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IL-6 inhibition is clinically achieved by blocking theIL-6 receptor (IL-6R). In a placebo controlled trial using arecombinant, humanized, monoclonal antibody againstthe IL-6R receptor (tocilizumab). In patients withrefractory RA, ACR20 and ACR50 responses wereachieved in 78 and 40% respectively [17]. Mild elevationsof cholesterol and moderate elevations of liver enzymeswere observed in the tocilizumab group. In another studypatients with disease duration of less than 5 years wererandomly allocated to receive either tocilizumab, 8mg/kg,intravenously every 4 weeks or another conventionalDMARD (MTX but not leflunomide/biologics) [18]. At52 weeks the tocilizumab group showed less radiographicprogression than the conventional DMARD group. TheACR20, ACR50 and ACR70 responses were 89%, 70%and 47% vs. 35%, 14% and 6% in the tocilizumab andDMARD groups, respectively.

SUMMARY

The new anti rheumatic/biologic drugs will bring newtherapeutic possibilities and challenges for the treatmentof RA. These new agents will allow the clinician to usenovel induction regimens, combination therapies, andtailor-made therapies for the individual RA patient. Newpotent induction regimens may allow drug free holidays tobecome a realistic goal, thus mitigating the possible sideeffects of long term immuno suppressive drugs. For e.g. inthe BeST study 56% of 120 patients who started thetreatment of early RA with infliximab in combination withMTX were able to maintain a low disease activity evenafter stopping infliximab [19]. These and otherencouraging results will provide motivation for similarinduction regimens in early RA.

MTX monotherapy may not survive as the acceptablestandard of care for the treatment of RA since most recentstudies feature combination regimens. Pioneering

The toxicity profile of abatacept has been very favorable[14].

Targeting the B-cell: Rituximab (anti CD20monoclonal antibody)

CD20 is expressed on the B-cells from the pre-B cellthrough the mature stage, but is absent on stem cells andplasma cells. Rituximab eleminates B-cells by binding toCD20, and causes an antibody-dependent cellular cyto-toxicity, which finally leads to a transient depletion ofCD20 positive B-cells. Several large clinical trials haveproven the efficacy and safety of Rituximab for RA. In oneearly clinical trial (randomized, double blind, controlledstudy) involving rituximab alone, MTX alone, rituximab +cyclophospha-mide, and rituximab + MTX, most of theACR20 and ACR 50 responses were significantly lesser inthe MTX only group vs. all the other rituximab groups [6].Adverse events in the form of hypotension, hypertension,cough, pruritis and rash were related to the firstinflammations in the rituximab groups.

Rituximab has also been investigated as an option forRA patients who have failed anti TNF- therapy. In oneclinical trial patients who had failed concomitant MTX(10-25mg/wk) and anti TNF- therapy, subjects wererandomized to receive rituximab or placebo [15]. ACR20and ACR 50 responses were significantly better in therituximab group.

Targeting a specific cytokine: Anti IL-6,tocilizumab

IL-6 is another cytokine which plays an important rolein the pathogenesis of RA (Fig.4). IL-6 is abundantlyexpressed on T-cell, macrophages and fibroblasts in therheumatoid synovium. More importantly, serum IL-6concentrations have been shown to correlate with diseaseactivity and radiological joint damage [16].

Fig. 4. Articular effects of IL-6.

Fig 3. Schematic representation of the structure of theCTLA4 molecule. A human CTLA4(CD152) trans-membrane protein is fused with an IgGI Fc moleculeto make the CTLA4-Ig, which is given intravenously.

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treatments for early and moderate RA are no just emergingtherapies for this condition, they qualify as currenttherapies.

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