Cytokines and Rheumatoid Arthritis

Cytokines, tiny proteins, are messengers of intercellular inflammation, immune response, and tissue repair or remodeling. Since the mid 1980s, researchers have identified dozens of cytokines and have studied their role in disease.¹ Improved understanding of the role of cytokines in the pathogenesis of rheumatoid arthritis (RA) has shifted treatment from the strictly empirical use of agents to the use of disease-modifying antirheumatic drugs (DMARDs) with proven clinical effectiveness.

RA affects ~2.5 million Americans. It typically begins between ages 25 and 50, with risk increasing with age. Women are 2.5 times more likely than men to develop the disorder. This chronic autoimmune disease can cause fatigue, occasional fever, morning stiffness, immobile joints, pain and inflammation in or around a joint, and a general sense of malaise. Approximately 25% of RA patients develop rheumatoid nodules. Anemia is a common problem. Neck pain, dry eyes and mouth, vasculitis, pericarditis, or pleuritis can occur.²

Researchers now believe that the cytokines tumor necrosis factor (TNF) and interleukin (IL)-1-beta contribute heavily to the characteristic inflammation and joint destruction of RA.^3,4 This insight has launched the development of biologic agents that target pivotal proinflammatory cytokines. Clinicians now prescribe DMARDs earlier in the course of RA, often combined with a TNF-blocking agent (etanercept, infliximab, or adalimumab) or the IL-1 receptor antagonist anakinra.^5-8

When considering new agents to treat RA, the FDA looks for 3 types of evidence: (1) improvement of signs and symptoms (eg, pain and morning stiffness); (2) prevention of structural damage (eg, joint destruction or joint space narrowing); and (3) prevention of disability. Well-structured clinical trials have demonstrated that TNF inhibitors, alone or with the traditional DMARD methotrexate (MTX), are superior to continued MTX monotherapy in all 3 areas. RA patients treated with combined TNF inhibitors and MTX have improved signs and symptoms of RA, less radiographic disease progression, good tolerance for these agents, and better medication adherence.^9-11

Using expanded understanding and the availability of new agents as a basis, clinicians are employing several new treatment strategies. Step-up therapy promotes the addition of a TNF antagonist to MTX. Parallel therapy involves the simultaneous use of MTX and a TNF antagonist. Step-down therapy involves the simultaneous use of MTX and a TNF antagonist, followed by MTX withdrawal. Four biologics are currently available, and selection will depend on clinician assessment of the side-effect profile and the patient's ability and preference.

Anakinra

Anakinra, an Escherichia coli?derived protein, is given subcutaneously daily at about the same time in doses of 100 mg. Injection site reactions are common, and serious infections have occurred in ~2% of patients. Its combination with TNF blocking agents has not been established as safe; small studies have shown an increased risk of infection.⁶

TNF-Alpha Inhibitors

The TNF-alpha agents are summarized in the Table.

Infliximab is currently approved to treat moderate-to-severe RA with MTX. Using data from a very recent trial, the manufacturer of infliximab (Centocor) has petitioned the FDA to include treatment of early RA in its labeling. This study randomized 1049 MTX-naive early RA patients to receive MTX and either placebo or 1 or 2 doses of infliximab at weeks 0, 2, and 6, and then every 8 weeks. At week 54, signs and symptoms had improved, progression of structural damage had slowed, and physical function was better in the infliximab-treated patients. The results of an additional small study suggested that infliximab reverses the destructive mechanisms of the disease in joints.¹²

Similarly, a very recent study of 619 patients with long-standing RA who responded poorly to MTX found that adalimumab combined with MTX offered significant sustained radiographic, clinical, and quality-of-life advantages over MTX alone.¹²

Hence, these agents may become useful interventions earlier in the course of RA. Agent selection will depend primarily on the patient's tolerance and the route that is most acceptable to the clinician and the patient.

Adverse Events

The role of TNF-alpha in the body should elucidate its serious adverse-reaction profile, but some findings defy expectation.

Cancer Risk

TNF provides tumor surveillance for some types of cancer, and its inhibition could theoretically increase the risk for malignancy. At this time, no clear increase in the risk of cancer has been identified. RA patients are already at increased risk for developing lymphoma, especially non-Hodgkin's lymphoma, with the odds increasing with increasing disease severity and activity. Researchers worry that chronic TNF depletion could magnify this risk.^13-15

Congestive Heart Failure and Multiple Sclerosis

Animal studies have suggested that TNF-alpha contributes to the pathologies of congestive heart failure (CHF) and multiple sclerosis (MS). In human CHF patients, TNF myocardium expression is up-regulated. TNF has been found at autopsy in active foci of MS, and MS patients have elevated TNF serum levels, correlating with disease progression.^16,17

These findings suggest that TNF suppression could improve CHF and MS.^18,19 This is not the case, however. Treatment with infliximab has been associated with higher all-cause mortality and hospital admission for worsening CHF. In RA clinical trials of TNF-alpha antagonists, new-onset and worsening CHF were not observed. However, postmarketing data with etanercept and infliximab identified 51 cases of CHF as of February 2002.^{20, 21} Hence, TNF antagonists should be avoided or used cautiously in RA patients with poorly controlled CHF.

Unfortunately, TNF antagonists lack efficacy in MS. A small number of cases of demyelinating disorders, including MS, have been reported to the FDA in patients treated with etanercept and infliximab.²⁰

Granulomas

TNF is critical for granuloma formation and maintenance. Granulomas are a host mechanism to contain mycobacteria proliferation. Animals infected with Mycobacterium tuberculosis cannot form adequate granulomas if TNF is depleted. Existing granulomas also dissolve.²² In humans, tuberculosis (TB) infections can occur rapidly after initiation of anti-TNF therapy, due to the reactivation of latent disease rather than to primary infection.²³

TB is largely preventable in human candidates for TNF antagonists. Susceptibility to TB increases in patients with diabetes mellitus or patients who are taking concurrent corticosteroids. Screening all candidates for TB before initiating treatment with TNF-blocking agents and initiating treatment with an antitubercular regimen almost eliminates the risk of TB.²⁴

Conclusion

According to the National Institutes of Health, the number of new cases of RA is dropping. Its incidence has fallen from ~62 cases per 100,000 in the decade 1955-1964 to 33 per 100,000 in the decade 1985-1996.²⁵ This finding suggests an environmental influence, but researchers are uncertain about specific influences. Regardless, with 1% of the population affected, agents that target inflammatory cytokines may provide relief to the millions of sufferers of RA.

Ms. Yeznach Wick is a senior clinical research pharmacist at the National Cancer Institute, National Institutes of Health. Dr. Zanni is a health systems consultant and a former mental health commissioner for Washington, DC. The views expressed are those of the authors and not those of any governmental agency.

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