Diseases 2.0: Rheumatoid Arthritis

September 18, 2009

raDiseases 2.0 – Bringing you the latest updates on disease pathophysiology and treatment

Rachana Jani MD

Faculty peer reviewed

Rheumatoid arthritis is a well-recognized but enigmatic disease afflicting the lives of thousands of individuals each year. The mysterious nature of RA has become increasingly uncovered as research has mapped various pathways of cytokine production and interleukin activation. However, in practice, we use clinical criteria to diagnose RA and evaluate the effectiveness of these new therapies.Though soon to be updated, the American College of Rheumatology (ACR) currently uses the following classification criteria to diagnose rheumatoid arthritis: morning stiffness greater than 1 hour, arthritis of three or more joints (PIP, MCP, wrist, elbow, knee, ankle, and MTP joints), involvement of wrist, MCP, or PIP joint, symmetric involvement, rheumatoid nodules, positive RF, radiographic changes of said joints. With the advent of multiple treatments for rheumatoid arthritis, ACR criteria have become the standard with which to compare trials and effectiveness of medications. ACR criteria measures improvement in at least three of the following five parameters: acute phase reactants, patient assessment, physician assessment, pain scale, disability/functional questionnaire. Often quoted are ACR 20,50 and 70 which indicates the percentage of patients who receive either 20, 50, or 70 percent improvement in tender and swollen joints as well as that percent improvement in three out of the above five criteria.

Early additions to the RA biologic arsenal include infliximab and etanercept – TNF antagonists, and anakinra – a recombinant IL-1 receptor antagonist. TNF-a is one of the cytokines that initiates and sustains the inflammatory pathway. IL-1 stimulates bone resorption and cartilage degradation. Though promising, these treatments are effective for only a subset of patients in this population. More recently in 2006, abatacept and rituximab were introduced. Abatacept interferes with signal transduction between the antigen presenting cell and the naïve T-cell via a fusion protein that competes with CD28 binding to CD80 and CD86. Without the binding of these co-stimulatory molecules, the pro-inflammatory T-cells cannot be fully activated. Largely used for people who have failed MTX and TNF inhibitors, abatacept has shown significant slowing of joint damage compared to placebo by ACR 20, 50 and 70 criteria at 1 year with sustained results into the second year [1]. Rituximab, known for its role in the treatment of B-cell lymphoma, is a CD20 antibody, expressed by both B-cell precursors and mature B-cells. B-cells, via CD40/CD40 ligand, are stimulated to induce the production of auto-antibodies to RF, citrullainated peptides, and rheumatoid arthritis antigen, which form immune complexes furthering joint damage [2]. Like abatacept, rituximab is indicated for patients who have failed prior biologic and/or MTX, or have a contraindication to other therapies. The DANCER and REFLEX trials , have shown significant ACR 20, 50 and 70 responses [3].

Tocilizimab, available since this September, targets the pro-inflammatory IL-6 that has been implicated in causing synovial fibroblast proliferation, and which functions as an agent for perpetuating joint damage by activating T- and B- cells in an autocrine fashion [4]. Activated synovial fibroblasts are implicated in joint damage. They produce matrix metalloproteinases, as well as inflammatory mediators including TNF-a, cytokines and prostaglandins,.. In this way, or by direct invasion, the synoviocytes destroy cartilage and bone. The CHARISMA trial showed a 61 and 63% ACR 20 response, compared to MTX with 41% response [5]. Most recently, the OPTION trial showed significant ACR 20, 50 and 70 responses versus placebo in addition to a 27% remission rate (8mg/kg) versus 0.8% with placebo at 24 weeks.

Anti-RANKL antibody, denosumab, more famous for treatment of osteoporosis, has also shown promising results to arrest bone erosion by osteoclast activation in a small study population with rheumatoid arthritis [6]. Osteoclasts, derived from monocytic cells, function via the RANKL-RANK-receptor system and are formed from the expression of MCSF and receptor activator of NF-kB ligand (RANKL). Both MCSF and RANKL are expressed by fibroblasts and activated T-cells, which bind to the surface of monocytes driving them to osteoclast formation and activation to resorb bone [7].

Other treatments on the forefront include targets for B-cells, more recently elucidated cytokines, and newer TNF antagonists. New B-cell inhibitors are belimumab and atacicept. These two therapies target B-cell activation factor (BAFF) also recognized as B-lymphocyte stimulator (BlyS), a key component in the production of auto-antibodies and perpetuation of aberrant B-cell hyperactivity [14]. Cytokines such as IL-15 and IL-17 are also under investigation. IL-15 inhibitors slowed the progression of active disease and resulted in reduced cartilage and bone destruction, with ACR 20, 50, and 70 responses showing 63%, 38%, and 25%. IL-17 is induced by many factors that result in synovial inflammation and cartilage and bone destruction. Animal models have shown a reduction in clinical disease severity with the inhibition of IL-17. Multiple other cytokines are under investigation as therapeutic targets such as IL-23, in addition to an inhibitor of Jak3, which has been implicated in signal transduction of IL-2, 4,7, 9, 15, and 21 [8,9].

The list of investigational therapeutics does not end there – in addition to newer pegylated and human anti-TNF agents, certolizumab and golimumab, other mediators such as leukotrienes (a,B) and chemokines (CXCL13 and CCL21) have also been evaluated as targets for therapy [10].

It may seem overwhelming to explore several targets for one disease. However, it is the redundancy in the immune system and the multiple inflammatory pathways that are triggered that do not allow for one effective therapy. Moreover, the precarious nature of immunomodulatory agents makes the therapeutic treatment range quite narrow, where clinical remission is limited by infection and toxicity, thus further demanding an aggressive search for the rheumatoid panacea.

Dr. Jani is a 3rd year internal medicine resident at NYU Medical Center

Peer reviewed and commentary by Pamela Rosenthal MD, Assistant Professor, NYU Division of Rheumatology

Per the above thoughtful review, patients who suffer from Rheumatoid Arthritis are benefitting from an explosion of targeted therapies. For our patients, our goal is to prevent joint damage and control the inflammation that is the hallmark of the disease. The new therapies have given patients and physicians alike a whole new and fascinating toolbox. However, it is important to keep in mind that Methotrexate, remains the mainstay of Rheumatoid Arthritis therapy. Methotrexate is both the first line drug of choice, and is often adjunctive therapy in the background of biologic therapy.

Nonetheless the explosion of targeted biologic therapies has taught us some very interesting lessons about the immune system. Somehow we can interfere with the functioning of apparently key immune regulatory players, yet continue to enjoy the protection of a broadly still functional immune response. However we have also learned that judicious and selective use of targeted biologic therapy is prudent. Poly-biologic therapy greatly increases the risk of infection. Equally the inhibition of different targets leaves us vulnerable to selective spectrum of pathogens and side effects, TNF inhibition and reactivation TB being the most well known example.

As we enter the second phase of the biologic pharmacology era we look forward to improved patient outcomes as well as the learning how to best use these and other therapies. Equally we look forward to the day when we better understand the etiology of Rheumatoid Arthritis and hence might even develop a chance for cure.

1. Kremer JM et al. Effects of abatacept in patients with methotrexate-resistent active rheumatoid arthritis. Ann Intern Med 2006: 144: 865-76.
2. Emery JC et al. The efficacy and safety of rituximab in patients with active rheumatoid arthritis despite methotrexate treatment: results of a phase IIb randomized, double-blind, placebo-controlled, dose-ranging trial. Arthritis Rheum 2006:54:1390-400.
3. Van Snick J. Interleukin-6: an overview. Annual Rev of Immun 1990: 8:253-278.
4. Maini RN et al. Double-blind randomized controlled clinical trial of the interleukin-6 receptor antagonist, tocilizumab, in European patients with rheumatoid arthritis who had an incomplete response to methotrexate. Arthritis Rheum 2006: 54:2817-29.
5. Cohen SB et al. RANKL inhibition with denosumab reduces progression of bone erosions in patients with rheumatoid arthritis: month 6 MRI results. Arthritis Rheum 2006: 54: S831
6. Schett G. Cells of the synovium in rheumatoid arthritis. Osteoclasts. Arth Res and Ther. 2007: 9: 203.
7. Seyler TM et al. BlyS and APRIL in rheumatoid arthritis. J Clin Invest 2005: 115: 3083-92.
8. Kim HR et al. Up-regulation of IL-23p19 expression in rheumatoid arthritis synovial fibroblasts by IL-17 through PI3-kinase, NF-kB and p38 MAPK-dependent signaling pathways. Rheum 2007: 46:57-64.
9. Comparison of six CP-690,550 doses versus placeboe each combined with methotrexate, for the treatment of rheumatoid arthritis. www.clinicaltrials.gov/ct/show/NCT00413660?order=2. 2007.
10. Gerlag DM et al. Novel approaches for the treatment of rheumatoid arthritis: lessons from the evaluation of synovial biomarkers in clinical trials. Best Prac and Res Clin Rheum 2008: 22: 311-23.

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