ADVANCES IN THE MANAGEMENT OF RHEUMATOID ARTHRITIS

Review Article ADVANCES IN THE MANAGEMENT OF RHEUMATOID ARTHRITIS M JOSHI* Our understanding of the pathology and management of rheumatoid arthritis (RA) has evolved significantly over last two decades. Since the 1990's it was known that irreversible joint damage occurred early in the disease and hence early use of DMARDs was recommended 1. Despite the available knowledge managing patients of rheumatoid arthritis was always a challenge. The textbook criteria for diagnosing the disease hardly seemed helpful in identifying early disease 2. The use of sequential monotherapy resulted in relatively poor remission rates 3. The evaluation of patients was mainly focussed on musculoskeletal manifestations and other systemic complications which were often missed 4. This was despite the fact that association of atherosclerosis and rheumatoid arthritis was well known 5. The last decade has seen radical change in every domain of management of RA. This article aims to provide an overview of key advances that have taken place over the last decade, focusing on: (1) improvements in laboratory tests and imaging methods for more specific and earlier diagnosis of RA; (2) therapeutic strategies and monitoring of disease control; and (3) development of newer treatments, which target specific molecules that play a key role in pathogenesis of RA. Advances in early diagnosis of RA Because of the need to make an early diagnosis of RA and lack of specific diagnostic *Assistant Professor, Department of Medicine, MGIMS. tests, it became necessary to identify better diagnostic methods. Diagnostic Tests 1. Anti CCP antibody (second generation):assays that detect anti-citrullinated peptide antibodies (ACPA) have become popular in recent years for diagnosing early rheumatoid arthritis because they are believed to be more specific than rheumatoid factor tests, with similar sensitivity 6. Though the few RA antibodies were identified in the early 1960s, but complex assay requirements and uncertainty about their in vivo antigenic target delayed their widespread diagnostic use 7. In the past decade, investigators have made advances in detecting and understanding these antibodies. Citrullination, a posttranslational modification catalyzed by calcium-regulated peptidylarginine deiminases, has been identified as the key process in the formation of proteins reactive against ACPA 8. A systematic review of the accuracy of anticitrullinated antibody in the diagnosis of RA concluded that the testing for second generation Anti CCP (Anti CCP2) should be part of work up of patients with early RA 9. However this relates more to the ability of Anti CCP to predict rapid radiologic disease progression rather than use in diagnosis of the disease. 2. Anti MCV antibody : Auto-antibodies against mutated and citrullinated vimentin (MCV) represent a novel diagnostic marker for rheumatoid arthritis (RA). Anti-MCV anti- 6

M Joshi bodies are associated with a more severe RA disease, as measured by DAS28 (Disease Activity Score), ESR (Erythrocyte Sedimentalcon Rate), and swollen joint count over time, compared with different generations of anti-ccp antibodies (anti-ccp2, CCP3, and CCP3.1 antibodies). Though radiological progression was predicted equally by all 4 autoantibodies 10. Recently, an increased sensitivity for anti-mcv compared to autoantibodies against cyclic citrullinated peptides (anti-ccp2) was shown in cohorts of patients with early RA and established disease. Based on this a lateral-flow immunoassay (rheumochec) has been developed for simultaneous detection of anti-mcv antibodies and rheumatoid factor (RF-IgG). This point of care test for detection of anti-mcv antibodies and RF-IgG provides high specificity for the diagnosis of RA and is likely to be useful in clinical practice due to its simplicity and its reliable performance 11. This test can greatly improve a timely management of RA and may help in screening patients with suspected RA in non-specialized settings prompting early referrals. 3. MRI : Plain radiographs had limitations for early diagnosis as they only revealed evidence of joint damage. The advent of magnetic resonance imaging (MRI) has, however, made it possible to study very early inflammatory changes of RA such as synovitis, joint effusion and bone marrow oedema. Erosions can be seen on MRI as early as 4 months from onset of symptoms. Bone marrow oedema, the precursor of erosions and joint damage, can be seen even earlier. There are, however, several drawbacks with routinely using MRI including limited availability, high expense and long examination times. 4. Ultrasound : Ultrasound seems more practical in use as it too can detect active inflammatory changes such as synovitis and increased synovial blood flow (the latter through Doppler ultrasound). It is more sensitive than clinical examination for detecting synovitis, 12 and better than plain radiographs for detecting erosive changes 13. It is cheap and non-invasive with no risk of ionising radiation. The use of diagnostic ultrasound for earlier diagnosis of RA has greatly increased in the last few years, and training courses are now regularly offered for rheumatologists. Clinical criteria With the availability of new diagnostic methods the need for a new clinical criterion was identified. American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) developed new classification criteria for RA in 2010 aimed at early diagnosis (Table 1) 14. These criteria are intended for patients with at least 1 joint with definite clinical synovitis (swelling, not just tenderness), and in whom the synovitis is not explained by another disease such as psoriasis, systemic lupus erythematosus, or gout. Patients are considered to have RA if they have a score of at least 6. These criteria are aimed at picking up early disease but do not intend to replace the clinical diagnoses which seem obvious in established disease. Table 1 : New classification criteria for rheumatoid arthritis* Symptom Score Joint involvement (0-5) 1 medium-large joint 0 2-10 medium-large joints 1 7

Advances in the management of rheumatoid arthritis Symptom 1-3 small joints (with or without involvement of large joints) 2 4-10 small joints (with or without involvement of large joints) 3 >10 joints (at least one small joint) 5 Serology (0-3) Negative rheumatoid factor and negative anti-citrullinated protein antibodies 0 Low positive rheumatoid factor or low positive anti-citrullinated protein antibodies 2 High positive rheumatoid factor or high positive anti-citrullinated protein antibodies 3 Acute phase reactants Normal C reactive protein and normal erythrocyte sedimentation rate 0 Abnormal C reactive protein or abnormal erythrocyte sedimentation rate 1 Duration of symptoms < 6 weeks 0 > 6 weeks 1 *patients need atleast 6 points or presence of joint erosions to be classifies as rheumatoid arthritis Evaluation of treatment response Early and aggressive therapy should be a part of management of all patients of rheumatoid arthritis as per recent guidelines. The concept of tight control has received much attention with the results of TICORA and CAMERA trials. In the Tight Control of Rheumatoid Arthritis (TICORA) 15 study, patients in the "tight control," or intensive, group had escalation of therapy if the specific cut off score was not achieved. In the routine therapy group clinical decisions were made based on clinician's judgement every 3 month on follow up and no specific targets were planned. The intensive group had lower disease activity scores and higher disease remission rates than the routine therapy group. In the Computer Assistant Management in Early Rheumatoid Arthritis (CAMERA) 16 trial, clinical decisions were made in accordance with computer decisions Score in the intensive group. On monthly follow up doses of methotrexate were adjusted to target a predefined quantitative response level. Both trials found reduced disease activity and radiographic progression and clinical remission in patients whose treatment was regularly adjusted than in those treated conventionally 15,16. These trials emphasized importance of using clinical assessment scores for appropriate results. Disease activity score 17 (DAS), Simplified Disease Activity Index (SDAI) and Clinical Disease Activity Index (CDAI) are the few commonly used scores to guide therapy (Table 2). The SDAI has the advantage over the DAS28 in that the calculations are not as cumbersome. CDAI on the other hand does not need ESR, CRP and so is relatively better for calculating final scores during consultation. Table 2 : Scoring Systems in RA S.No. Scoring System Joinsts Used Calculation Add. Considered Points 1. DAS 28 (0.56 X TJC) + (0.28 X SJC) + ESR, CRP (0.70 X Long ESR) + (0.014 X PGA) 2. SDAI 25 SJC + TJC Patient and Physician Global assessment, CRP * TJC = Total Joint Count SJC = Swollen Joint Count PGA = Patient Global assessment 8

M Joshi For radiologic assessment of progression of disease multiple clinical trials have validated modified Sharps18 method. In the assessment of 44 joint scores of MCP, PIP, MTP, first Interphalageal joint of toe, first carpo-metacarpal joint, carpal joints an increase in the score of over 5 in a year indicates poor prognosis. Newer molecules for treatment of RA It is now well validated that biologic therapies have changed the way rheumatoid arthritis is managed. The target specific therapies either act on the cytokines or its receptors; thus modify immune mediated damage during the "window of opportunity". Examples of potential targets in RA include cytokines such as TNFa, IL1 and IL6, B cells, molecules that cause interaction between antigen presenting cells and T cells, RANK ligand (receptor activator of nuclear factor kb ligand), and small molecules that mediate intracellular signalling. Currently, FDA has nine biologics approved for the treatment of RA, including TNF inhibitors (infliximab, etanercept, adalimumab, certolizumab pegol, and golimumab), anakinra (IL-1 receptor antagonist), abatacept (CTLA4-Ig fusion protein), rituximab (anticd20 antibody), and tocilizumab (anti-il-6 receptor antibody). Rituximab and tocilizumab are currently approved for RA patients who have failed treatment with at least 1 TNF inhibitor. TNF ALPHA BLOCKERS : The tumor necrosis factor or TNF alpha blockers/inhibitors were the first of the biologic drugs approved for treatment. Maini et al 19 were instrumental in bringing to lime light the role of tumour necrosis factor alpha (TNFa) blockers in the treatment of inflammatory arthritis. Infliximab and etanercept, followed by adalimumab, were the first TNF alpha blockers. As per the FDA approval, infliximab should be used in combination with methotrexate. Multiple clinical trials have demonstrated that TNF inhibitors are more effective when combined with methotrexate. 20 Multiple studies have demonstrated a significant benefit of early treatment with TNF inhibitors and methotrexate, suggesting that there may be a window of opportunity for early intervention that has lasting benefits to patients with regards to disease progression. Of particular importance is the "Anti-TNF Trial in Rheumatoid Arthritis with Concomitant Therapy" (ATTRACT) 19 study and the treatment of early-ra patients in the " Active controlled Study of Patients Receiving Infliximab for Treatment of Rheumatoid Arthritis of Early Onset" (ASPIRE) 20 study. The ATTRACT study was a large randomized trial of anti-tnf-a treatment in patients with RA in about 428 patients. All patients received methotrexate and then were randomised to treatment groups receiving a placebo or infliximab 3 mg/ kg or 10 mg/kg, every 4 weeks or 8 weeks. The patients in the intervention arm receiving infliximab with MTX had significant improvement of symptoms (50 % vs 17%) and better radiologic outcome which was maintained over 102 weeks on follow up. The ASPIRE study was the largest infliximab trial conducted in over 1049 patients. The patients presenting with early RA of less than 3 years received either MTX therapy alone or infliximab (3 or 6 mg/ kg). Patients were evaluated on the basis of percentage of ACR improvement from the baseline to week 54. Again infliximab therapy resulted in better radiologic results, functional improvement, though with higher rate of serious infections, particularly pneumonia. 9

Advances in the management of rheumatoid arthritis ANAKINRA : The other approved biologic response modifier is Anakinra, an IL-1 receptor antagonist. It is administered as a daily subcutaneous injection and has efficacy in treating RA when used alone or in combination with MTX. It is not commonly used since the TNF-inhibitors show much greater efficacy in comparison and have a more convenient dosing regimen. RITUXIMAB : B cell depletion is beneficial for RA because B cells play an important role in pathogenesis by serving as antigen presenting cells, activating T cells, and producing RF. Based on the results of DANCER 21 study and REFLEX 22 study, the drug is approved in patients failing TNF alpha blockers. It is now approved by NICE for use in combination with methotrexate in RA patients who fail treatment with at least one anti-tnf drug. It is given by intravenous infusion on two separate occasions 14 days apart. Unlike anti-tnf, rituximab is not associated with risk of reactivation of tuberculosis, and previous history of cancer is not a contraindication. ABATACEPT : Abatacept is a biologic agent that blocks T-cell activation through inhibition of CD28-B7 mediated costimulation of the T-cell. Structurally, abatacept is a recombinant, fully human fusion protein of human CTLA-4 and the Fc domain of human IgG1. Abatacept has been shown to be effective in treating clinical symptoms in RA patients who have previously had an inadequate response to TNF inhibitors. Abatacept is approved by the FDA for treatment of patients with moderate to severe RA that have had an inadequate response to methotrexate or TNF inhibitors. More recently, a subcutaneous form of abatacept has been shown to have comparable efficacy and safety with the intravenous formulation in a non-inferiority trial and has been approved by the FDA. TOCLIZIMAB : Tocilizumab is a humanized antibody directed against the IL-6 receptor, which acts to overcome effect of IL6 cytokine produced by a large number of cells involved in the pathogenesis of RA. The OPTION trial demonstrated the efficacy of tocilizumab in treating RA patients who were poor responders to methotrexate, and the RADIATE trial demonstrated the efficacy in poor responders to TNF blockers 23,24. Accordingly, the FDA has approved tocilizumab for the treatment of patients with moderate to severe RA that have had an inadequate response to TNF inhibitors. UNDER DEVELOPMENT : Several other drugs are currently in development. Denosumab is a monoclonal antibody against RANKL. RANKL plays a key role in the differentiation of macrophages to osteoclasts as well as activation of osteoclasts to cause rheumatoid bone erosions. Blocking the action of RANKL with denosumab is therefore likely to be useful in preventing erosions. Apart from TNFa, IL1 and IL6, several other cytokines such as IL15, IL17, IL32, lymphotoxins and B lymphocyte stimulator (BlyS) play an important role in perpetuating the inflammatory reaction in RA. Each of these is a potential target. Apart from drugs that target cytokines and receptors, small molecules known as kinase inhibitors, which target intracellular molecules that are involved in signal transduction, are also currently in development. Protein kinase inhibitors have received most attention recently for the treatment of rheumatoid arthritis, in particular janus kinases or JAKs, spleen tyrosine kinase or SyK, and p38 mitogen-activated protein kinases or MAPK. Initial trial results with new JAK and SyK inhibitors look very promising. Other new targets in early stage of development are regulatory 10

M Joshi T cell activation agonist, granulocyte colonystimulating factor (GCSF) and granulocytemacrophage colony-stimulating factor (GMCSF) antagonists. Thus, there is scope for significant expansion of the therapeutic armamentarium of RA in the next few years. CONCLUSION : The recent developments in the management strategies for rheumatoid arthritis have made significant contribution to reducing the disease progression and improving outcomes of the patients. Identifying the candidates early in 'window of opportunity" and aggressive target oriented approach can prove to be a boon to the patients in long run. The addition of biologic agents to the armamentarium of available disease modifying agents early in course of the disease can result in satisfying functional recovery and even remission in patients of RA. With judicious use of medications and careful monitoring quality of life of patients with RA can be surely improved. References 1. Weinblatt ME. Rheumatoid arthritis: treat now, not later! Ann Intern Med 1996;124:773e4 2. Suresh E. Diagnosis of early rheumatoid arthritis: what the non-specialist needs to know. J R Soc Med 2004;97:421e4 3. Wolfe F, Hawley DJ, Cathey MA. Termination of slow acting antirheumatic therapy in rheumatoid arthritis: a 14-year prospective evaluation of 1017 consecutive starts. J Rheumatol 1990;17:994e1002. 4. Anon. Guidelines for the management of rheumatoid arthritis. American College of Rheumatology Ad Hoc Committee on Clinical Guidelines. Arthritis Rheum 1996;39:713e22. 5. del Rincon ID, Williams K, Stern MP, et al. High incidence of cardiovascular events in rheumatoid arthritis cohort not explained by traditional cardiac risk factors. Arthritis Rheum 2001;44:2737e45. 6. Levesque MC, Zhou Z, Moreland LW. Anti-cyclic citrullinated peptide testing for the diagnosis of rheumatoid arthritis and the quest for improved sensitivity and predictive value [Editorial]. Arthritis Rheum. 2009;60:2211-5. 7. Bizzaro N, Mazzanti G, Tonutti E, Villalta D, Tozzoli R. Diagnostic accuracy of the anticitrulline antibody assay for rheumatoid arthritis. Clin Chem. 2001;47:1089-93. 8. Gyo rgy B, To th E, Tarcsa E, Falus A, Buza s EI. Citrullination: a posttranslational modification in health and disease. Int J Biochem Cell Biol. 2006; 38:1662-77. 9. Whiting et al. Systematic Review: Accuracy of Anti-Citrullinated Peptide Antibodies for Diagnosing Rheumatoid Arthritis. Ann Intern Med. 2010;152:456-464. 10. Innala L, Kokkonen H, Eriksson C, Jidell E, Berglin E, Rantapaa-Dahlqvist S. Antibodies against mutated citrullinated vimentin are a better predictor of disease activity at 24 months in early rheumatoid arthritis than antibodies against cyclic citrullinated peptides. J Rheumatol 2008;35:1002_8. 11. Renger F, Bang H, Fredenhagen G, Natusch A, Backhaus M, Feist E, Egerer K, Burmester GR. "Anti-MCV Antibody Test for the Diagnosis of Rheumatoid Arthritis Using a POCT-Immunoassay". American College of Rheumatology, 2008 Annual Scientific Meeting, poster presentation. http:// acr.confex.com/acr/2008/webprogram/ Paper2009.html. 12. Szkudlarek M, Narvestad E, Klarlund M, et al. Ultrasonography of the metatarsophalangeal joints in rheumatoid arthritis: comparison with magnetic resonance imaging, conventional radiography, and clinical examination. Arthritis Rheum 2004;50: 2103e12. 13. Magnani M, Salizzoni E, Mule R, et al. Ultrasonography detection of early bone erosions in the metacarpophalangeal joints of patients with 11

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