(Laurie Barclay, MD, July 2004)

Rheumatoid arthritis (RA) is typically a chronic disease characterized by inflammation of the synovial lining of multiple joints, with autoimmune manifestations involving other body systems and internal organs. Synovial inflammation causes acute joint pain, stiffness, warmth, redness and swelling. As leukocytes and inflammatory factors accumulate in the synovium, it thickens to form a pannus, which perpetuates inflammation and ultimately erodes the joint cartilage and bone, resulting in joint deformity and immobility.

RA affects 1%-2% of the general population, or 2.1 million Americans, with female to male ratio 3:1. Typical onset is in the fifth through seventh decades, but it can begin at any age, and there is a juvenile form of RA. Type 1 RA, which is the less common adult form, lasts only a few months and has no permanent sequelae, while type 2 is chronic and usually lifelong.

RA is an acquired autoimmune disease with a genetic predisposition, based on the presence of HLA-DR4 antibody in 70% of patients. Antibodies to IgG, known as rheumatoid factors (RF), are present in 60%-80% of adults with RA, and high titers are associated with increased severity of joint disease, systemic involvement, and poor prognosis for remission.

Although the exact cause is unknown, a combination of factors may be responsible, including an abnormal autoimmune response, genetic predisposition, and an environmental or biologic trigger, such as a viral infection or hormonal imbalance.

Helper T-cells in RA become overactive and attack collagen by stimulating production of B-cell-derived antibodies against IgG and cytokines including interleukins (ILs) and tumor necrosis factor (TNF). Some cytokines promote release of collagenase, cathepsin L, and other enzymes that destroy collagen. The T-cells also stimulate release of pro-inflammatory factors including leukotrienes and prostaglandins.

In addition to the HLA-DR4 antibody, other genetic factors predisposing to RA may include deficiency of corticotropin-releasing hormone and mutation of the P53 gene implicated in pannus development and progressive joint destruction.

Risk factors for RA include female sex, family history, heavy smoking, shorter reproductive life, blood transfusions, obesity, and treatment with interferon-alpha. Hay fever and other allergies appear to be protective.

Cardinal symptoms include morning stiffness, joint pain and swelling preferentially affecting the wrists, knuckles, knees and feet; subcutaneous nodules in about 20% of patients; ankle edema; and flu-like symptoms. Although RA is not fatal, complications may shorten lifespan by a few years. Type 2 RA is progressive, but it may become less aggressive over time.

Systemic complications may include peripheral neuropathy, anemia, scleritis, higher risk of infections related in part to treatment with immunosuppressive drugs, gastrointestinal problems, osteoporosis, lung disease, heart disease, lymphoma and other cancers, and periodontal disease.

Helpful diagnostic tests include RF, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and synovial fluid markers such as MMP-3 (matrix metalloproteinase 3). Although conventional X-rays are of limited diagnostic value, more helpful imaging techniques include dual energy x-ray absorptiometry, quantitative ultrasound, and magnetic resonance imaging.

In addition to pharmacotherapy, treatment of RA includes lifestyle changes involving diet, exercise and joint protection; joint surgery, low level laser therapy, and stem-cell transplantation. Nonsteroidal anti-inflammatory drugs (NSAIDs) relieve pain by reducing inflammation, but they do not modify the course of disease. These include COX-2 (cyclooxygenase-2) inhibitors such as celecoxib (Celebrex), rofecoxib (Vioxx), and valdecoxib (Bextra).

Although some existing drugs may modify disease activity (disease-modifying antirheumatic drugs or DMARDs), none are curative and all have significant adverse effects. Steroids may be used for different aspects of the disease than other DMARDs. Older DMARDS, including methotrexate, hydroxychloroquine, sulfasalazine, gold, D-penicillamine, cyclosporine, and leflunomide, all tend to lose effectiveness over time and may produce stomach and intestinal side effects.

Biologic response modifiers, such as infliximab (Remicade) and etanercept (Enbrel), block the cytokine tumor necrosis factor (TNF) thought to be involved in the pathogenesis of RA. Because they are more specific, they tend to avoid generalized damage to the immune system. Disadvantages include lack of cure, effectiveness only during treatment, high cost (approximately $10,000 to $12,000 per year per patient) and potential long-term problems including infections and nerve injury.

CenterWatch has identified a pipeline of 28 drugs in various phases of development in RA. Most of these are specific immunomodulators blocking cytokines or other targets thought to be responsible for inflammation in RA, but some are improved NSAIDs.

Novartis has submitted a new drug application (NDA) for Prexige (lumiracoxib, COX 189), a COX-2 inhibitor with strong efficacy and gastrointestinal safety/tolerability superior to that of other NSAIDs. In phase II studies, efficacy was equal to that of diclofenac, the current European gold standard for treating patients with arthritis and pain.

Upper gastrointestinal safety and tolerability in 1,042 patients with osteoarthritis treated over 13 weeks was superior to that seen with ibuprofen. Gastroduodenal ulcers occurred in 15.7% of patients in the ibuprofen group, in 3.2% of the celecoxib group and in 4.3% and 4.0% in the Prexige groups treated with 200 mg daily and 400 mg daily, respectively.

Bristol-Myers Squibb is in phase III testing of BMS-188667 (CTLA4Ig), an immunosuppressant CD 152 antagonist which could be the first in a new class of agents called selective costimulation modulators. In a phase II dose-ranging study of 339 patients who also received methotrexate for six months, CTLA4Ig was superior to placebo at improving signs and symptoms of RA, as reflected in the American College of Rheumatology (ACR) score.

Of patients treated with 10 mg/kg by 30-minute intravenous infusion, 60% achieved ACR 20, or at least a 20% percent improvement, as did 35% of patients in the placebo group. ACR 50, or 50% improvement, occurred in 36.5% of the CTLA4Ig group and in 11.8% of the placebo group (P<.001). Patients receiving 10 mg/kg of CTLA4Ig also had clinically significant improvements in mental and physical health-related quality of life.

CTLA4Ig was generally well tolerated, with adverse events similar to those in the placebo group. The most common adverse events were headache, upper respiratory tract infection, musculoskeletal pain, and nausea and vomiting.

Genmab and Amgen have collaborated to complete phase II testing of HuMax-IL 15 (AMG-714), a fully humanized high-affinity neutralizing antibody against interleukin-15 (IL-15). In Genmab’s phase I/II trial, more than 60% of patients with RA achieved ACR 20, and 25% of patients achieved ACR 70. HuMax-IL15 was well tolerated in this study.

MedImmune has also completed phase II testing of Vitaxin, a monoclonal antibody reacting with alpha-V/beta-3, an integrin found on new blood vessels, activated macrophages, monocytes, and osteoclasts. It stimulates apoptosis, or programmed cell death, and blocks formation of new blood vessels and bone destruction mediated by osteoclasts.

Also in phase II testing by Elan Pharmaceutical Research is the humanized, monoclonal, alpha-4 integrin inhibitor Antegren (natalizumab). This selective adhesion molecule inhibitor, which is designed to selectively inhibit immune cells from leaving the bloodstream and migrating into chronically inflamed tissue, is also being evaluated in Crohn’s disease and multiple sclerosis.

Millennium Pharmaceuticals is pursuing a similar approach with MLN-1202, a humanized monoclonal antibody that blocks the chemokine receptor CCR2 found on the surface of monocytes and certain T cells. This receptor binds "hormone-like" chemokines, known as monocyte chemoattractant proteins, which attract monocytes and T cells to sites of injury and promote inflammation. Phase I clinical trials of MLN1202 in RA began in December 2002, and phase II trials are now underway.

A different type of immunomodulator in phase II testing is AT-001, developed by Androclus Therapeutics. This engineered oral peptide induces tolerance specifically in those T cells implicated in autoimmunity in RA, thereby blocking disease-related inflammation without affecting immunity to other antigens. In a phase I/IIa open label clinical trial, AT-001 had biological efficacy with no significant side effects. A multicenter phase II clinical trial is ongoing.

Angiotech Pharmaceuticals is in phase II development of Paxceed (micella paclitaxel), an intravenous chemotherapy agent with anti-inflammatory and immunomodulatory properties. The Cremophor® EL-free systemic paclitaxel formulation, designed for patients with active, widespread disease, allows lower dosing and reduces the incidence of hypersensitivity reactions.

Because Paxceed is a metalloprotenaise inhibitor, it can theoretically protect the cartilage in addition to stopping inflammation. Another advantage is synergism rather than competition with recently developed anti-TNF therapies.

In preclinical studies, Paxceed was more effective than methotrexate in preventing joint damage and in blocking several processes involved in RA progression. In a phase I study of 15 patients with advanced RA previously failing treatment with at least one DMARD, Paxceed was safe and well-tolerated at three different doses. With doses of 75 mg/m2, 75% of the patients met ACR 20 improvement criteria.

In September of 2002, Angiotech began enrollment in an open-label, multicenter phase 2 study to determine efficacy as reflected in RA signs, symptoms, and radiographic progression.

AtheroGenics is in phase II testing of AGIX-4207, a selective, orally administered v-protectant modulator of TNF-alpha induced redox-sensitive inflammatory genes (VCAM-1 and MCP-1). By targeting a specific subset of TNF-alpha activity, AGIX-4207 may specifically reduce chronic inflammation in RA without broad-based immunosuppression. It may therefore be synergistic with the COX-2 inhibitors, DMARDs and TNF-a modulators.

In a single and multiple dose phase I trial, AGIX-4207 was well tolerated, with adverse events generally mild and clinically insignificant. Subjects in this study reached and maintained blood levels in the target range based on an animal model.

A recently completed phase II safety and biomarker study tested safety and tolerability of AGIX-4207 in patients currently being treated with infliximab infusions. In this randomized, double-blind trial, there were 8 to 10 patients in each of three treatment arms. Three weeks before their next scheduled infliximab infusions, patients received either placebo or one of two, two-week dosing regimens of AGIX-4207 150 mg once daily. AGIX-4207 was safe and well tolerated without serious adverse events, discontinuations from therapy, new laboratory abnormalities, or changes in QTc interval.

In this study, AGIX-4207 also had an anti-inflammatory effect on ESR (92% inhibition compared with placebo) and other inflammatory markers over a three-week period. OSCAR (Oral Suppression of Cellular Inflammation Attenuates Rheumatoid Arthritis) is a phase II multicenter, randomized, double-blind, placebo-controlled trial of AGIX-4207 in which approximately 220 patients will be enrolled.

AtheroGenics has also completed a Phase I clinical trial to assess the safety and tolerability of AGIX-4207 given intravenously to healthy volunteers, because the intravenous formulation may be useful in RA when rapid attainment of therapeutic drug levels is needed. Specific indications could include patients with flares, patients who are intolerant of protein-based parenteral TNF inhibitors, hospitalized patients undergoing surgery, and patients unable to take oral medication.

Neurogen is in phase II testing of NGD 2000-1, a small molecule C5a antagonist blocking the activity of the pro-inflammatory C5a protein at its receptor.

Interleukin-1 (IL-1) trap (RGN-303) is a cytokine antagonist developed by Regeneron Pharmaceuticals. In a Phase II clinical trial of approximately 200 patients with RA, RGN-303 demonstrated evidence of clinical activity with favorable safety and tolerability.

Can-Fite BioPharma is in phase I/II testing of CF-101, a metabolically stable, specific agonist of the A3 adenosine receptor. In Phase I trials, therapeutic doses were safe with no adverse events, and preclinical studies showed very high efficacy in disease modification of RA. A randomized, double blind, dose-ranging phase II trial will also evaluate disease modifying properties in RA.

More precisely targeted immunomodulators in RA have at least the theoretical advantage of enhanced disease-modifying efficacy while avoiding the complications of widespread immunosuppression. Time will tell whether these specific therapies in fact fulfill this potential.