Open Access

A follow-up to “Anti-cytokine therapy in chronic destructive arthritis” by Wim B van den Berg

Arthritis Research & Therapy20013:211

https://doi.org/10.1186/ar302

Received: 8 February 2001

Accepted: 3 April 2001

Published: 24 April 2001

Abstract

In recent years, the effectiveness of anti-TNF therapy in treating rheumatoid arthritis (RA) has become apparent. While trials of IL-1 receptor antagonist in RA have been encouraging, it clearly is more difficult to target two molecules (IL-1 α and β) than one (TNF-α). In his review article, Professor Wim van den Berg argues that both TNF-α and IL-1 must be blocked in RA and that although TNF is clearly a potent inflammatory molecule, the dominant cytokine in the subsequent degradation of the joint tissue is IL-1. This commentary discusses his hypothesis in light of animal studies and the limitations of the conclusions that can be drawn from them. More broadly, it discusses the biology of TNF-α and IL-1 and suggests explanations of why TNF-α is a pivotal cytokine in this disease.

Keywords

anti-TNF IL-1 IL-1ra rheumatoid arthritis TNF

In his review article [1], Professor van den Berg discusses anti-cytokine therapy of RA and hypothesises that, in order to prevent joint destruction, it is necessary to block IL-1 in addition to TNF. The rationale for this hypothesis stems largely from observations in experimental models of arthritis in rodents. However, as he points out in the abstract, the necessity arises "if elements of the models apply to the arthritic process in RA patients". This surely is the central point, and the critical question is whether animal models resemble the human disease process. This issue has been extensively debated and even in the best-defined models, such as collagen-induced arthritis in DBA/1 mice, the aggressive, acute nature of the disease makes it unlike human RA. The very lack of chronicity in experimental models is a major limitation. Although these models and cytokine transgenic mice, despite their drawbacks, have been an invaluable tool to test hypotheses in vivo and to further explore mechanisms in a real-life setting, they can never fully mimic human RA.

Perhaps one of the best-studied models illustrating the problem of extrapolation from animal models to human disease is one in the huTNF transgenic mouse developed by Kollias and colleagues a decade ago. Replacement with 3' UTR of β-globin of the normal regulatory untranslated region in the TNF gene resulted in chronic arthritis in the Tg 197 line; the development of this arthritis was specifically blocked by antihuman, but not antimouse, TNF-α antibodies [2]. However, what is clearly important (even central) to the development of arthritis in these mice is the fact that the trans gene is expressed as protein in the synovial fibroblasts [3]. Normal fibroblasts, while having the capability to make TNF mRNA, block the translation process [4,5]. This is expected as fibroblasts are found closely associated with extracellular matrix and the catabolic activity of this cytokine would be extremely detrimental in this environment. Thus, while the huTNF transgenic mouse has proved to be very useful in understanding TNF physiology and/or pathology, it is not a model for the human disease, not least because of the aberrant nature of cells expressing TNF protein. However, limitations apart, it is of interest that in these huTNF transgenic mice, a neutralizing monoclonal antibody to the murine type I IL-1 receptor completely prevented the development of arthritis, suggesting that IL-1 acts downstream of TNF in the pathogenesis of chronic arthritis [6]. The efficacy of this treatment may well be influenced by the lytic nature of this antibody, as it is also effective in collagen-induced arthritis [7].

The potent chondrogenic effects of IL-1 are well recognised, and it is clear that IL-1 activates chondrocytes and fibroblasts more potently than TNF does, a difference that may reflect the relative abundance of IL-1 receptors on these cells. In contrast, on monocytes and, indeed, more-differentiated macrophages, TNF is a much more potent activator than IL-1. Clearly, this difference reflects receptor distribution, as monocytes have very few IL-1 receptors [8] but relatively abundant p55 and p75 TNF receptors. The pathogenicity of a molecule is thus determined by its ability to activate a wide range of cells and to induce several other proinflammatory molecules, which together orchestrate the pathological process. This hypothesis in relation to TNF has been demonstrated both in animal models [9] and, more importantly, in human patients with RA after anti-TNF antibody therapy (reviewed [10]). Thus the cytokine/chemokine cascade is downregulated [11,12], endothelium is deactivated [13,14], matrix metalloproteinases are reduced [15], and formation of new blood vessels (angiogenesis) is also affected [16].

As the gene for TNF is transcribed and translated rapidly (faster than that for IL-1), it probably occupies a higher hierarchical position under conditions of cellular stress. The development of sepsis in baboons given a bolus of LPS is characterised by the sequential appearance of TNF, IL-1, and IL-6 in the blood [17,18]. Moreover the development of sepsis in these animals is blocked with anti-TNF antibody, which also abrogates the serum rise in IL-1 and IL-6. These findings are consistent with the pivotal role of TNF in RA that our group proposed in 1989 [19]. More recently, a paper published by Ulfgren and colleagues, using a modified immunohistochemical method, showed that, after TNF-blocking, synovial synthesis of both IL-1 and TNF was diminished [20]. Clearly, immunohistology is a limited technique, and in that study the number of patients was small and the cytokine profile heterogeneous, but the finding does further indicate the importance of TNF in the cytokine cascade in RA.

Are arguments about TNF versus IL-1 relevant? While IL-1 is a very potent proinflammatory cytokine, the real therapeutic problem rests with the requirement to neutralise both IL-1α and IL-1β in arthritic disease. In the setting of diseased tissue, the normally cell-bound form of IL-1 (IL-1α) is found in abundance as a soluble molecule [21]. Interleukin-1 receptor antagonist (IL-1ra) is a very efficient antagonist, but virtually all of the IL-1 receptors on a cell must be blocked to abrogate signalling [22]. Secondly, it is not clear why a substantial amount of IL-1ra remains intracellular. Thus, although the trials of recombinant IL-1ra in human RA look encouraging, the lack of a dose-response effect is of concern [23]. The efficacy of the anti-TNF modalities, particularly those with an IgG1 backbone, may contribute to the better pharmokinetics of these drugs than of IL-1ra. Alternatively, a different approach using IL-1ra, such as gene therapy, may prove to be more effective [24].

Does anti-TNF therapy prevent damage to cartilage and bone? In his article, van den Berg hinted that it does not. However, the publication of two full-length papers about two anti-TNF agents, infliximab and etanercept, has now made it very clear that anti-TNF treatment does indeed slow down or prevent joint damage in human RA [25,26]. What is particularly remarkable about the infliximab study was the observation that infliximab not only protected intact cartilage but also halted/reversed ongoing erosions. Furthermore, the group that did not respond clinically (as assessed by the criteria of the American College of Rheumatology) showed as much joint protection as the responders. In the case of infliximab trials, further investigation is needed to clarify how concomitant administration of weekly doses of methotrexate contributes to these clinical endpoints. However, these observations raise the real possibility that the proportion of RA patients that respond to anti-TNF therapy, at least as regards joint destruction, is actually much higher than expected from the observed reduction of symptoms and signs.

From the clinical trials described above, it is now clear that proinflammatory cytokines are good targets in RA disease. Furthermore, the mechanism of anti-TNF therapy has been extensively studied in the infliximab studies and it its effectiveness is clearly due to its ability to deactivate endothelium, reduce the cytokine cascade, reduce the production of matrix metalloproteinase, and prevent erosion. If blocking IL-1 results in a chondroprotective/ bone protective modality alone, this may not be enough. A good therapy in chronic inflammatory disease must achieve several objectives, including the amelioration of signs and symptoms of disease and the abrogation of joint destruction, and must also be safe. However, because RA is a chronic disease, a good therapy would also be one in which the cycle of chronicity was broken. It is unclear at present whether the anti-TNF or IL-1 antagonism therapies modulate the chronicity of the disease. Therefore, there is still ample room for modulation and improvement of these therapies, and in particular it is important to targeting the mechanism(s) leading to the disregulated production of these proinflammatory mediators in inflamed tissue.

Abbreviations

IL: 

interleukin

IL-1ra: 

interleukin-1 receptor antagonist

RA: 

rheumatoid arthritis

TNF: 

tumour necrosis factor.

Authors’ Affiliations

(1)
Kennedy Institute of Rheumatology Division, Imperial College School of Medicine

References

  1. van den Berg WB: Anti-cytokine therapy in chronic destructive arthritis. Arthritis Res. 2001, 3: 18-26. 10.1186/ar136.PubMedPubMed CentralView ArticleGoogle Scholar
  2. Keffer J, Probert L, Cazlaris H, Georgopoulos S, Kaslaris E, Kioussis D, Kollias G: Transgenic mice expressing human tumour necrosis factor: a predictive genetic model of arthritis. EMBO J. 1991, 10: 4025-4031.PubMedPubMed CentralGoogle Scholar
  3. Butler DM, Malfait AM, Mason LJ, Warden PJ, Kollias G, Maini RN, Feldmann M, Brennan FM: DBA/1 mice expressing the human TNF-alpha transgene develop a severe, erosive arthritis: characterization of the cytokine cascade and cellular composition. J Immunol. 1997, 159: 2867-2876.PubMedGoogle Scholar
  4. Kruys V, Marinx O, Shaw G, Deschamps J, Huez G: Translational blockade imposed by cytokine-derived UA-rich sequences. Science. 1989, 245: 852-855.PubMedView ArticleGoogle Scholar
  5. Kruys V, Kemmer K, Shakov A, Jongeneel V, Beutler B: Constitutive activity of the tumor necrosis factor promoter is canceled by the 3' untranslated region in nonmacrophage cell lines; a transdominant factor overcomes this suppressive effect. Proc Natl Acad Sci U S A. 1992, 89: 673-677.PubMedPubMed CentralView ArticleGoogle Scholar
  6. Probert L, Plows D, Kontogeorgos G, Kollias G: The type 1 interleukin-1 receptor acts in series with tumor necrosis factor (TNF) to induce arthritis in TNF-transgenic mice. Eur J Immunol. 1995, 25: 1794-1797.PubMedView ArticleGoogle Scholar
  7. Williams RO, Marinova-Mutafchieva L, Feldmann M, Maini RN: Evaluation of TNF-alpha and IL-1 blockade in collagen-induced arthritis and comparison with combined anti-TNF-alpha/anti-CD4 therapy. J Immunol. 2000, 165: 7240-7245.PubMedView ArticleGoogle Scholar
  8. Dinarello CA: The interleukin-1 family: 10 years of discovery. FASEB Journal. 1994, 8: 1314-1325.PubMedGoogle Scholar
  9. Marinova-Mutafchieva L, Williams RO, Mauri C, Mason LJ, Walmsley MJ, Taylor PC, Feldmann M: A comparative study into the mechanisms of action of anti-tumor necrosis factor alpha, anti CD4, and combined anti-tumor necrosis factor alpha/anti-CD4 treatment in early collagen-induced arthritis. Arthritis Rheum. 2000, 43: 638-644. 10.1002/1529-0131(200003)43:3<638::AID-ANR21>3.0.CO;2-R.PubMedView ArticleGoogle Scholar
  10. Feldmann M, Elliott MJ, Woody JN, Maini RN: Anti-tumor necrosis factor-alpha therapy of rheumatoid arthritis. Adv Immunol. 1997, 64: 283-350.PubMedView ArticleGoogle Scholar
  11. Charles P, Elliott MJ, Davis D, Potter A, Kalden JR, Antoni C, Breedveld FC, Smolen JS, Eberl G, de Woody K, Feldmann M, Maini RN: Regulation of cytokines, cytokine inhibitors, and acute-phase proteins following anti-TNF-alpha therapy in rheumatoid arthritis. J Immunol. 1999, 163: 1521-1528.PubMedGoogle Scholar
  12. Taylor PC, Peters AM, Paleolog E, Chapman PT, Elliott MJ, McCloskey R, Feldmann M, Maini RN: Reduction of chemokine levels and leukocyte traffic to joints by tumor necrosis factor α blockade in patients with rheumatoid arthritis. Arthritis Rheum. 2000, 43: 38-47. 10.1002/1529-0131(200001)43:1<38::AID-ANR6>3.0.CO;2-L.PubMedView ArticleGoogle Scholar
  13. Tak PP, Taylor PC, Breedveld FC, Smeets TJ, Daha MR, Kluin PM, Meinders AE, Maini RN: Decrease in cellularity and expression of adhesion molecules by anti-tumor necrosis factor alpha monoclonal antibody treatment in patients with rheumatoid arthritis. Arthritis Rheum. 1996, 39: 1077-1081.PubMedView ArticleGoogle Scholar
  14. Paleolog EM, Hunt M, Elliott MJ, Feldmann M, Maini RN, Woody JN: Deactivation of vascular endothelium by monoclonal anti-tumor necrosis factor α antibody in rheumatoid arthritis. Arthritis Rheum. 1996, 39: 1082-1091.PubMedView ArticleGoogle Scholar
  15. Brennan FM, Browne KA, Green PA, Jaspar JM, Maini RN, Feldmann M: Reduction of serum matrix metalloproteinase 1 and matrix metalloproteinase 3 in rheumatoid arthritis patients following anti- tumour necrosis factor-alpha (cA2) therapy. Br J Rheumatol. 1997, 36: 643-650. 10.1093/rheumatology/36.6.643.PubMedView ArticleGoogle Scholar
  16. Paleolog EM, Young S, Stark AC, McCloskey RV, Feldmann M, Maini RN: Modulation of angiogenic vascular endothelial growth factor (VEGF) by TNFα and IL-1 in rheumatoid arthritis. Arthritis Rheum. 1998, 41: 1258-1265. 10.1002/1529-0131(199807)41:7<1258::AID-ART17>3.0.CO;2-1.PubMedView ArticleGoogle Scholar
  17. Hesse DG, Tracey KJ, Fong Y, Manogue KR, Palladino MA, Cerami A, Shires GT, Lowry SF: Cytokine appearance in human endotoxemia and primate bacteremia. Surg Gynecol Obstet. 1988, 166: 147-153.PubMedGoogle Scholar
  18. Fong Y, Tracey KJ, Moldawer LL, Hesse DG, Manogue KB, Kenney JS, Lee AT, Kuo GC, Allison AC, Lowry SF, Cerami A: Antibodies to cachectin/tumor necrosis factor reduce interleukin 1β and interleukin 6 appearance during lethal bacteremia. J Exp Med. 1989, 170: 1627-1633.PubMedView ArticleGoogle Scholar
  19. Brennan FM, Chantry D, Jackson A, Maini R, Feldmann M: Inhibitory effect of TNF alpha antibodies on synovial cell interleukin-1 production in rheumatoid arthritis. Lancet. 1989, ii: 244-247. 10.1016/S0140-6736(89)90430-3.View ArticleGoogle Scholar
  20. Ulfgren AK, Andersson U, Engstrom M, Klareskog L, Maini RN, Taylor PC: Systemic anti-tumor necrosis factor alpha therapy in rheumatoid arthritis down-regulates synovial tumor necrosis factor alpha synthesis. Arthritis Rheum. 2000, 43: 2391-2396. 10.1002/1529-0131(200011)43:11<2391::AID-ANR3>3.0.CO;2-F.PubMedView ArticleGoogle Scholar
  21. Butler DM, Maini RN, Feldmann M, Brennan FM: Modulation of proinflammatory cytokine release in rheumatoid synovial membrane cell cultures: comparison of monoclonal anti-TNFα antibody with the IL-1 receptor antagonist. Eur Cytokine Network. 1995, 6: 225-230.Google Scholar
  22. Arend WP, Malyak M, Guthridge CJ, Gabay C: Interleukin-1 receptor antagonist: role in biology. Annu Rev Immunol. 1998, 16: 27-55. 10.1146/annurev.immunol.16.1.27.PubMedView ArticleGoogle Scholar
  23. Bresnihan B, Alvaro-Gracia JM, Cobby M, Doherty M, Domljan Z, Emery P, Nuki G, Pavelka K, Rau R, Rozman B, Watt I, Willimas B, Aitchison R, McCabe D, Musikic P: Treatment of rheumatoid arthritis with recombinant human interleukin-1 receptor antagonist. Arthritis Rheum. 1998, 41: 2196-2204. 10.1002/1529-0131(199812)41:12<2196::AID-ART15>3.3.CO;2-U.PubMedView ArticleGoogle Scholar
  24. Kang R, Ghivizzani SC, Herndon JH, Robbins PD, Evans CH: Gene therapy for arthritis: principles and clinical practice. Biochem Soc Trans. 1997, 25: 533-537.PubMedView ArticleGoogle Scholar
  25. Lipsky PE, van der Heijde DM, St Clair EW, Furst DE, Breedveld FC, Kalden JR, Smolen JS, Weisman M, Emery P, Feldmann M, Harriman GR, Maini RN: Infliximab and methotrexate in the treatment of rheumatoid arthritis. N Engl J Med. 2000, 343: 1594-1602. 10.1056/NEJM200011303432202.PubMedView ArticleGoogle Scholar
  26. Bathon JM, Martin RW, Fleischmann RM, Tesser JR, Schiff MH, Keystone EC, Genovese MC, Wasko MC, Moreland LW, Weaver AL, Markenson J, Finck BK: A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis. N Engl J Med. 2000, 343: 1586-1593. 10.1056/NEJM200011303432201.PubMedView ArticleGoogle Scholar

Copyright

© BioMed Central Ltd 2001

Advertisement