Arthritis-Symptom.com
 

About Us

Health News
64 condition specific health  news pages

Webmaster 

William P. Arend, MD
Division of Rheumatology
University of Colorado School of Medicine
Denver, CO

Summary Points

• Levels of IL-1 and TNF-a are increased in RA and allow migration of WBCs into inflammatory sites and the release of MMPs, which increase the inflammation and tissue damage.
• Etanercept and infliximab -- agents that block TNF-a -- result in clinical improvement in RA and limit bony damage.
• Anakinra, an IL-1 receptor antagonist, also results in clinical improvement of RA and limits bony damage.

 Introduction to Cytokines in Rheumatoid Arthritis

Cytokines are small molecular weight proteins that mediate communication between cells (1,2). The generic term “cytokines” includes colony-stimulating factors, growth factors, interleukins, and interferons.

Cytokines carry out their functions primarily in the immediate cell environment in tissues, although some cytokines may act at a distance by traveling through the bloodstream. Cytokines work by binding to specific receptors on target cell surfaces, stimulating responses in cells that result in the increased or decreased production of proteins.

Cytokines are involved as mediator molecules in normal biologic processes. These physiologic functions include growth and differentiation of hematopoietic, lymphoid, and mesenchymal cells, as well as orchestration of host defense mechanisms.

Cytokines act in a self-regulatory network that is intended to maintain homeostasis of the internal environment. However, the unregulated or inappropriate production of particular cytokines may lead to pathological consequences in autoimmune and inflammatory diseases (3,4).

The inhibition of production or effects of specific cytokines has reached the therapeutic marketplace. The objective of this brief review is to present the background on tumor necrosis factor alpha (TNF-a) and interleukin-1 (IL-1) in rheumatoid arthritis (RA) and to summarize the results of clinical trials on new therapeutic approaches to block these cytokines.

IL-1 and TNF-a

IL-1 and TNF-a have been implicated in pro-inflammatory mechanisms in many human diseases including inflammatory arthritis, inflammatory bowel disease, sepsis syndrome, and both acute and chronic inflammation of many organs (5,6). These cytokines are important in host defense against microorganisms that reside within cells, such as mycobacteria or listeria, as well as in other host defense responses and physiological processes.

IL-1 and TNF-a bind to different receptors but share many properties in mechanisms of disease. For purposes of this review, these cytokines will be considered together, but it should be noted that one cytokine or the other may predominate in a particular disease.

IL-1 and TNF-a are produced primarily by monocytes and tissue macrophages, and are major cytokines in the initial line of defense against pathogens as part of the innate immune system (7). The major effects of these cytokines in diseases include stimulation of adhesion molecule expression on endothelial cells and induction of the production and release of matrix metalloproteinases (MMPs) from fibroblasts, chondrocytes, osteoblasts, and other cells.

The end result of these unregulated effects of IL-1 and TNF-a include the migration of leukocytes and lymphocytes from the blood into inflammatory tissues and the degradation of connective tissues and cartilage. This produces inflammation and tissue destruction.

The reasons why IL-1 and TNF-a are produced in excess in RA and other diseases are not clear but may involve activation of macrophages by T lymphocytes and fibroblasts, as well as by soluble factors produced as part of the inflammatory response. Natural anti-inflammatory mechanisms exist to limit or dampen the effects of IL-1 and TNF-a. These mechanisms include the release of soluble cytokine receptors and the production of IL-1 receptor antagonist (IL-1Ra), a structural variant of IL-1 that binds to target cells but fails to stimulate intracellular responses (8).

Based on new knowledge on the importance of IL-1 and TNF-a in inflammation and tissue destruction in many human diseases, new therapeutic approaches have been developed to block the production or effects of these cytokines (9). Existing therapeutic agents such as corticosteroids, gold injections, and methotrexate may all work at least in part by blocking the production of IL-1 and TNF-a. However, the recent development of more potent anti-cytokine biologic agents has lead to dramatic clinical responses, particularly in RA.

TNF-a Blockade in the Treatment of RA

The two available TNF-a blockers are etanercept, a form of soluble TNF receptors, and infliximab, a monoclonal antibody to TNF. Etanercept is delivered by subcutaneous (SC) injections of 25 mg twice weekly each whereas infliximab is given by intravenous infusion at 0, 2, and 6 weeks and every 8 weeks thereafter. The indications for use of these biologic agents in the treatment of RA are unresponsiveness to the usual disease-modifying drugs, including methotrexate in high dose and in combination with other drugs, or intolerable side effects to these agents. Etanercept is approved for use with or without methotrexate whereas infliximab is approved for use only with methotrexate.

A series of publications over the past five years have described the results of clinical trials with etanercept in RA. The initial clinical trials are summarized in Table 1 (10-12). Either used alone or in combination with methotrexate, etanercept led to significant clinical improvement as measured by the ACR 20, 50, and 70. It was observed that stopping etanercept after 3 months led to a return of active synovitis. The major side effects to etanercept were injection site reactions and mild upper respiratory tract symptoms. In addition, 5% of treated patients developed anti-double-stranded DNA antibodies at 6 months.

In the most recent trial in RA, 632 patients with early RA (< 3 years) were treated either with etanercept at 10 or 25 mg SC twice weekly or with methotrexate (mean dose 19 mg/week) (13). Although the percentages of patients achieving ACR 20, 50, and 70 levels of improvement were no different at 12 months, the patients treated with 25 mg injections of etanercept exhibited slightly more rapid responses over the first 4 months. In addition, 72% of the patients who received the higher dose of etanercept exhibited no increase in radiographic erosions at 1 year in comparison to 60% of the patients who received methotrexate. Etanercept also has been shown to be effective in the treatment of polyarticular juvenile rheumatoid arthritis (14).

A monoclonal antibody to TNF-a, infliximab, also has been shown to be effective in the treatment of RA (15). In the original controlled trial, patients receiving a single or multiple infusions of infliximab demonstrated early efficacy (16,17). However, human antibodies to the murine IgG developed in over half of these patients and possibly were associated with reduced clinical responses.

Infliximab was next evaluated in combination therapy with methotrexate (18). A trial carried out over 4 months described a Paulus 20 or 50 response in 50% to 60% of patients treated with 5 infusions of infliximab at 1, 3, or 10 mg/kg combined with methotrexate, compared to up to 10% of patients treated with methotrexate alone. Patients receiving infliximab alone at the higher 2 doses exhibited lower percentages of Paulus 50 responses. However, the development of human antibodies to murine IgG was greatly reduced by the concomitant treatment with methotrexate.

The results of more recent clinical trials of infliximab given in combination with methotrexate are summarized in Table 2 (19,20). In studies carried out over 7 to 12 months, significantly higher ACR 20, 50, and 70 responses were observed in patients receiving infliximab 3 or 10 mg/kg every 4 to 8 weeks, along with methotrexate at a median dose of 15 mg/wk, in comparison to methotrexate alone. In addition, patients treated with the combination of infliximab and methotrexate over 12 months demonstrated an absence of radiographic evidence of progressive joint damage whether or not they exhibited a clinical response.

Side effects to treatment with infliximab included the development of antinuclear antibodies in up to 68% of patients and of anti-DNA antibodies in 10% (21). A few patients treated with infliximab developed clinical symptoms of systemic lupus erthematosus (SLE), with these manifestations responding to discontinuation of the agent. Other adverse events observed in patients treated with the combination of infliximab and methotrexate, compared with methotrexate alone, included upper respiratory infections, sinusitis, pharyngitis, and headache. Infusion reactions have also occurred with infliximab.

Recent publications have described the appearance of additional serious side effects to treatment with TNF-blocking agents.   Whether these therapeutic agents predispose to the development of malignancy will require longer-term follow-up studies.

Voluntary reporting to the FDA described the reactivation of latent tuberculosis in 70 patents treated with infliximab (22). Tuberculosis also has developed after treatment with etanercept, but whether this complication occurs equally with both forms of anti-TNF therapy is not known. Both anti-TNF agents may predispose to other infectious complications, primarily with intracellular pathogens such as listeria and fungi.

In addition, demyelination has been described in 19 patients after TNF blockade, 17 following etanercept and 2 after infliximab (23). Thus, anti-TNF therapy should not be used in patients with known infections, or should be stopped should infections develop, and these therapies should be avoided in patients with SLE, multiple sclerosis, or poorly defined neurological syndromes.

IL-1 Inhibition in the Treatment of RA

An inhibitor of IL-1, anakinra, has recently been approved by the FDA for the treatment of RA. This therapeutic agent is the interleukin-1 receptor antagonist (IL-1Ra) molecule (8). As opposed to the anti-TNF therapies that bind TNF around cells, preventing their interaction with cell surface receptors, anakinra competitively inhibits IL-1 binding to cells at the receptor level.

An initial clinical trial in 175 patients with active RA examined the use of daily SC injections of 3 doses of anakinra or placebo over 2 months (24). This therapeutic agent was shown to be safe with injection site reactions the major side effect, although the trial was too small to establish efficacy.

A subsequent clinical trial examined treatment of 472 patients with active RA with daily SC injections of anakinra or placebo over 6 months (25). An ACR 20 response was observed in 39%, 34%, and 43%, respectively, of patients treated with 30, 75, or 150 mg of anakinra in comparison to 27% who received placebo. An injection site reaction again was the main adverse reaction, leading to a 5% withdrawal rate in the highest dose group. The radiological progression of disease was significantly reduced in all 3 treatment groups in comparison to the control patients (26).

The results of a recently reported trial of anakinra used in combination with methotrexate are summarized in Table 3 (27). At the most optimal dose examined, 1.0 mg/kg/day SC injection, 42%, 24%, and 10%, respectively, of patients treated with anakinra demonstrated ACR 20, 50, and 70 responses at 6 months, compared to 23%, 4%, and 0% in the placebo group.

Injection site reactions led to withdrawal of 7% of the patients in this group, and 1.2% of patients developed leukopenia (WBC < 3,000) that reversed after discontinuation of treatment. No increased incidence of significant infections was observed. However, longer-term follow-up studies are necessary to assess the possible risk of developing infections or malignancies with anakinra treatment.

Treatments Under Development

In addition to the 3 therapeutic agents discussed above, other anti-cytokine agents are under development. Several alternative approaches to blocking TNF are already undergoing clinical study.

Additional approaches to inhibition of IL-1 include the use of soluble type II IL-1 receptors or an agent called the “IL-1 Trap,” consisting of the extracellular regions of the IL-1 receptor and IL-1 receptor accessory protein molecules. Initial reports of studies looking at IL-15 and IL-17 blockade in RA also are potentially promising.

Conclusions

Numerous cytokines are involved in pathophysiologic mechanisms in RA. Both TNF-a and IL-1 mediate events of inflammation and tissue destruction in this disease. Biologic agents that specifically inhibit the effects of TNF-a or IL-1 are effective in the treatment of RA patients who respond poorly to methotrexate.

However, the use of these agents needs to be monitored carefully for possible side effects, including the development of infections. Additional anti-cytokine agents for the treatment of rheumatoid arthritis are under further development.

1. Arend WP. Mediators of inflammation, tissue destruction, and repair. B. Growth factors and cytokines. In Primer on the Rheumatic Diseases, 12th ed. Atlanta: Arthritis Foundation, 2001. pp 58-66.

2. Lotz MH. Cytokines and their receptors. In Arthritis and Allied Conditions, 14th ed. Lippincott, Williams, & Wilkins, Philadelphia: 2001. pp 436-77.

3. Feldmann M, Brenan FM, Maini RN. Role of cytokines in rheumatoid arthritis. Annu Rev Immunol 1996;14:397-440.

4. Choy EHS, Panayi GS. Cytokine pathways and joint inflammation in rheumatoid arthritis.  N Engl J Med 2001;344:907-16.

5. Vassali P. The pathophysiology of tumor necrosis factors. Annu Rev Immunol 1992;10:411-52.

6. Dinarello CA. Biologic basis for interleukin-1 in disease. Blood 1996;87:2095-147.

7. Arend WP. The innate immune system in rheumatoid arthritis. Arthritis Rheum 2001:44:2224-34.

8. Arend WP, Malyak M, Guthridge CJ, et al. Interleukin-1 receptor antagonist: role in biology. Annu Rev Immunol 1998;16:27-55.

9. Arend WP, Dayer JM. Inhibition of the production and effects of interleukin-1 and tumor necrosis factor a in rheumatoid arthritis. Arthritis Rheum 1995;38:151-60.

10. Moreland LW, Baumgartner SW, Schiff MH, et al. Treatment of rheumatoid arthritis with a recombinant human tumor necrosis factor receptor (p75)-Fc fusion protein. New Engl J Med 1997;337:141-7.

11. Moreland LW, Schiff MH, Baumgartner SW, et al. Etanercept therapy in rheumatoid arthritis. A randomized, controlled trial. Ann Intern Med 1999;130:478-86.

12. Weinblatt ME, Kremer JM, Bankhurst AD, et al. A trial of etanercept, a recombinant tumor necrosis factor receptor:Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. New Engl J Med 1999;340:253-9.

13. Bathon JM, Martin RW, Fleischmann RM. A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis. N Engl J Med 2000;343:1586-93.

14. Lovell DJ, Giannini EH, Reiff A. Etanercept in children with polyarticular juvenile rheumatoid arthritis. N Engl J Med 2000;342:763-9.

15. Feldmann M, Elliott MJ, Woody JN, et al. Anti-tumor necrosis factor-a therapy of rheumatoid arthritis. Adv Immunol 1997;64:283-350.

16. Elliott MJ, Maini RN, Feldmann M, et al. Randomised double-blind comparison of chimeric monoclonal antibody to tumour necrosis factor a (cA2) versus placebo in rheumatoid arthritis. Lancet 1994;344:1105-10.

17. Elliott MJ, Maini RN, Feldmann M, et al. Repeated therapy with monoclonal antibody to tumour necrosis factor a (cA2) in patients with rheumatoid arthritis. Lancet 1994;344:1125-7.

18. Maini RN, Breedveld FC, Kalden JR, et al. Therapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor a monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis. Arthritis Rheum 1998;41:1552-63.

19. Maini R, St. Clair EW, Breedveld F, et al. Infliximab (chimeric anti-tumour necrosis factor a monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomized phase III trial. Lancet 1999;354:1932-9.

20. Lipsky PE, van der Heijde D, St. Clair EW, et al. Infliximab and methotrexate in the treatment of rheumatoid arthritis. New Engl J Med 2000;343:1594-602.

21. Charles PJ, Smeenk RJT, De Jong J, et al. Assessment of antibodies to double-stranded DNA induced in rheumatoid arthritis patients following treatment with infliximab, a monoclonal antibody to tumor necrosis factor a. Findings in open-label and randomized placebo-controlled trials. Arthritis Rheum 2000;43:2383-90.

22. Keane J, Gershon S, Wise RP, et al. Tuberculosis associated with infliximab, a tumor necrosis factor a-neutralizing agent. New Engl J Med 2001;345:1098-104.

23. Mohan N, Edwards ET, Cupps TR, et al. Demyelination occurring during anti-tumor necrosis factor a therapy for inflammatory arthritides. Arthritis Rheum 2001;44:2862-9.

24. Campion GV, Lebsack ME, Lookabaugh J, et al. Dose-range and dose-frequency study of recombinant human interleukin-1 receptor antagonist in patients with rheumatoid arthritis. Arthritis Rheum 1996;39:1092-101.

25. Bresnihan B, Alvaro-Gracia JM, Cobby M, et al. Treatment of rheumatoid arthritis with recombinant human interleukin-1 receptor antagonist. Arthritis Rheum 1998;41:2196-204.

26. Jiang Y, Genant HK, Watt I, et al. A multicenter, double-blind, dose-ranging, randomized placebo-controlled study of recombinant human interleukin-1 receptor antagonist in patients with rheumatoid arthritis. Radiologic progression and correlation of Genant and Larsen scores. Arthritis Rheum 2000;43:1001-9.

27. Cohen S, Hurd E, Cush J, et al. Treatment of rheumatoid arthritis with anakinra, a recombinant human interleukin-1 receptor antagonist, in combination with methotrexate. Results of a twenty-four-week, multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2002;46:614-24.