Anti-TNF inhibitors in rheumatoid arthritis

Hanns-Martin Lorenz
MD
Assistant Professor of Medicine
Rheumatology/Clinical Immunology
Department of Medicine
University of Erlangen-Nürnberg
Germany
E:[email protected]

Rheumatoid arthritis (RA) is a chronic inflammatory disease leading to joint destruction, and is associated with increased mortality.(1,2) Since the pathogenesis of RA is unresolved, no causal therapy exists to date.

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With conventional therapy only 2% of patients experience a clinical remission for more than three years, and more than 50% of patients are disabled after five years. Hence the search for innovative therapeutic regimens in RA. In recent years intensive research into the pathogenesis of RA has yielded information that permits clearer insights into the mechanisms underlying the disease.

Among many cytokines expressed in the synovial tissue, tumour necrosis factor (TNF)-alpha deserves special attention because of its many proinflammatory properties on a variety of cells known to be involved in the process of tissue destruction in RA. These findings have led to the development of biological agents that neutralise TNF-alpha, such as infliximab, etanercept and adalimumab, which have been or will shortly be approved for the treatment of RA.

Immunobiological drugs in RA

Infliximab
The chimeric (human IgG1/mouse) neutralising TNF-alpha monoclonal antibody (mAb) infliximab (Remicade; Schering-Plough) has been tested in several double-blind, placebo-controlled clinical trials since 1992, either as monotherapy or in combination with low-dose methotrexate (MTX), the best established conventional disease-modifying antirheumatic drug (DMARD).(3–6)

When given intravenously over several hours at various dosages between 1 and 10mg/kg at weeks 0, 2, 6, and every eighth week thereafter, analysis of clinical parameters revealed a highly significant improvement over placebo in around 60–70% of patients, with a longer duration of improvement in the high-dose, 10mg/kg group. Most importantly, however, was that in all treatment groups average radiological progression was stopped over a two-year observation period (some patients with healing erosions, some with progression),(7,8) a result that had never been achieved before in any treatment regimen of RA. Infliximab is approved for the treatment of severe RA in combination with MTX.

Etanercept
Another TNF-alpha-blocking agent, a fusion protein of the Fc-part of the human IgG1 molecule and two TNF-alpha p75 receptors, etanercept (Enbrel; Wyeth), has been developed in parallel to infliximab for treatment of RA.

In several double-blind, placebo-controlled studies patients were treated with the fusion protein at concentrations of 0.25, 2.0 or 16mg/m(2) body surface area, and improvements were similar to those seen with infliximab. Finally, 25mg given twice weekly became the accepted dose.(9,10) After these monotherapeutic studies, a trial of combination therapy with etanercept and MTX confirmed the positive results of earlier studies.(11–13) Importantly, etanercept was effective in slowing the progression of joint erosion and was superior to MTX in this parameter as well.(13) Etanercept is approved for treatment of severe RA.

Adalimumab
The fully human anti-TNF mAb adalimumab (D2E7) has been administered both subcutaneously(14) and intravenously.(15) Both studies reported good tolerability and efficacy, with comparable results to etanercept and infliximab. In a follow-up, dose-finding phase II trial carried out over three months, 283 patients were randomised to one of four groups, receiving placebo or adalimumab at 20mg, 40mg or 80mg, given subcutaneously once weekly, with good results at all dosages.(16)

In parallel, radiographic analysis of these patients over one year revealed that adalimumab can stop development of erosions and slow disease progression, as determined by the Sharp JSN score.(17) However, this needs to be confirmed in a prospective trial. All of the available data have been communicated in abstract form only – no full paper has been published so far.

Side-effects
In general, these drugs are well tolerated. Injection site reactions to etanercept or adalimumab and allergic reactions, in part severe, to infliximab have been reported as the most frequent adverse events. A total of 10–15% of patients develop antinuclear antibodies, with 5–10% testing positive for IgG antibodies against double-stranded DNA,(12,18) with no differences between the three drugs. Extremely rare cases of clinically evident autoimmune reactions have been described (multiple sclerosis-like symptoms, aplastic anaemia and lupus-like syndromes), resolving after cessation of treatment.

No increased incidence of malignancies has been reported,(19–21) the long-term consequences of TNF-alpha blockade being unknown so far. Increased incidences of tuberculosis (infliximab and adalimumab) and rare cases of listeriosis as well as histoplasmosis and Pneumocystis carinii infections (infliximab) have been observed. Concomitant treatment with isoniazid is recommended for patients with a history of tuberculosis or positive skin test.

Costs
The yearly cost at standard dosage for infliximab is between e. 12,000 and e. 24,000 (depending on body weight and efficacy); etanercept costs up to e. 28,000.

Other indications
Etanercept is approved for juvenile RA, and infliximab for Crohn’s disease. Other indications are evolving: infliximab and etanercept are or will shortly be approved for the treatment of ankylosing spondylitis and psoriatic arthritis.

Positive observational results have been reported in the treatment of vasculitis, adult-onset Still’s disease, dermatomyositis, graft-versus-host disease, chronic reactive arthritis, sarcoidosis, chronic uveitis and autoimmune hepatitis.

Future perspectives
The efficacy of anti-TNF inhibitors in therapy of RA is best evidenced by the findings that average radiological progression was halted over two years during infliximab/MTX treatment. However, one needs to continue to register and carefully analyse all side-effects occurring after repeated and long-lasting blockade of TNF-alpha, as the long-term consequences of TNF-alpha blockade are still unknown. Moreover, prospective selection criteria of RA patients qualifying for early anti-TNF therapy are not available so far.

Given the high costs of immunobiologicals, consensus reports recommend that only after the failure of at least two DMARDs should RA patients be treated with anti-TNF drugs. For the same reasons, nonbiological inhibitors of TNF signalling, translation and activation are under development.

Not all patients respond to TNF-blockade. These patients might better profit from new immunobiologicals like CTLA4-Ig, anti-IL-15 or IL-18 antibodies, which are in early clinical studies.

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References

1. Harris ED. Rheumatoid arthritis: pathophysiology and implications for therapy. N Engl J Med 1990; 322:1277-83.
2. Pincus T, Callaghan LF. Taking mortality in rheumatoid arthritis seriously – predictive markers, socio-economic status and comorbidity. J Rheumatol 1986;13:841-5.
3. Elliott MJ, Maini RN, Feldmann M, et al. Treatment of rheumatoid arthritis with chimeric monoclonal antibodies to TNF-a. Arthritis Rheum 1993; 36:1681-90.
4. Elliott MJ, Maini RN, Feldmann M, et al. Randomised double-blind comparison of chimeric monoclonal antibody to tumor necrosis factor alpha (cA2) versus placebo in rheumatoid arthritis. Lancet 1994;344:1105-10.
5. Maini RV, 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.
6. Maini R, St Clair EW, Breedveld F, et al. Infliximab (chimeric anti-tumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. ATTRACT Study Group. Lancet 1999;354:1932-9.
7. Lipsky PE, van der Heijde DM, St Clair EW, et al. Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-tumor necrosis factor trial in rheumatoid arthritis with concomitant therapy study group. N Engl J Med 2000;343:1594-602.
8. Lipsky PE, van der Heijde DM, St Clair EW, et al. 102 week clinical and radiological results from the ATTRACT trial: a 2 year, randomized controlled phase 3 trial of infliximab in patients with active RA despite MTX. Arthritis Rheum 2000;43:S269.
9. Moreland LW, Baumgartner SW, Schiff MH, et al. Treatment of rheumatoid arthritis with a recombinant human tumor necrosis factor (p75)-Fc fusion protein. N Engl J Med 1997;337:141-7.
10. Moreland LW, Schiff MH, Baumgartner SW, et al. Etanercept therapy in rheumatoid arthritis. A randomized, controlled trial. Ann Intern Med 1999;130:478-86.
11. 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. N Engl J Med 1999;340:253-9.
12. Weinblatt ME, Kremer JM, Lange M, Burge DJ. Long-term safety and efficacy of combination therapy with methotrexate and etanercept. Arthritis Rheum 1999;42:S401.
13. Finck B, Martin R, Fleischmann R, et al. A phase III trial of etanercept vs. methotrexate (MTX) in early rheumatoid arthritis (Enbrel ERA trial). Arthritis Rheum 1999;42:S117.
14. Schattenkirchner M, Krüger K, Sander O, et al. Efficacy and tolerability of weekly subcutaneous injections of the fully human anti-TNF-antibody D2E7 in patients with rheumatoid arthritis – results of a phase I study. Arthritis Rheum 1998;41:S57.
15. van de Putte LBA, van Riel PLCM, den Broeder A, et al. A single dose placebo controlled phase I study of the fully human anti-TNF-antibody D2E7 in patients with rheumatoid arthritis. Arthritis Rheum 1998;41:S57.
16. van de Putte BA, Rau R, Breedveld FC, et al. One year efficacy results of the fully human anti-TNF antibody D2E7 in rheumatoid arthritis. Arthritis Rheum 2000;43:S269.
17. Rau R, Herborn G, Sander O, et al. Long-term treatment with the fully human anti-TNF antibody D2E7 slows radiographic disease progression in rheumatoid arthritis. Arthritis Rheum 1999;42:S400.
18. Charles PJ, Elliott MJ, Feldmann M, Maini RN. Development of anti dsDNA antibodies in patients with rheumatoid arthritis treated with a chimeric monoclonal antibody to TNF alpha. EULAR J 1995;24:B114.
19. Kavanaugh A, Schaible T, DeWoody K, et al. Long-term follow-up of patients treated with infliximab in clinical trials. Arthritis Rheum 1999;42:S401.
20. Moreland LM, Cohen SB, Baumgartner S, et al. Long-term use of etanercept in patients with DMARD-refractory rheumatoid arthritis. Arthritis Rheum 1999;42:S401.
21. Landewe RBM, van den Borne BEEM, Moens H, et al. The distribution of malignant neoplasms in rheumatoid arthritis is skewed compared to the general population. Arthritis Rheum 1999;42:S279.

Resources
European League Against Rheumatism (EULAR)
Witikonerstrasse 15
8032 Zürich Switzerland
T:+41 13839690
W:www.EULAR.org
EULAR Congress
18–21 June 2003
Lisbon
American College of Rheumatology (ACR)
1800 Century Place
Suite 250
Atlanta, GA 30345
USA
W:www.rheumatology.org
T:+1 404 633 3777
ACR Congress
24–28 October 2003
Orlando, Florida