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TNF-α Inhibition: The Need for a Tumor Necrosis Factor Thermostat

  • James R. O'Dell
    Correspondence
    Address reprint requests and correspondence to James R. O'Dell, MD, Department of Internal Medicine, University of Nebraska Medical Center, 983025 Nebraska Medical Center, Omaha, NE 68198–3025
    Affiliations
    University of Nebraska Medical Center, Omaha
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      With the approval of etanercept for the treatment of rheumatoid arthritis (RA) in 1998 and infliximab a year later, a new era in the treatment of RA began.
      • O'Dell JR
      Anticytokine therapy—a new era in the treatment of rheumatoid arthritis? [editorial].
      Clinicians now have the ability to inhibit the effects of tumor necrosis factor α (TNF-α) by 2 different approaches: the administration of either soluble TNF receptors (etanercept) or anti–TNF-α antibodies (infliximab). These biological agents allow us, for the first time, to target a specific cytokine, TNF-α. The clinical efficacy of these 2 new approaches has been impressive.
      • Elliott MJ
      • Maini RN
      • Feldmann M
      • et al.
      Randomised double-blind comparison of chimeric monoclonal antibody to tumour necrosis factor α (cA2) versus placebo in rheumatoid arthritis.
      • Maini RN
      • Breedveld FC
      • Kalden JR
      • et al.
      Therapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor α monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis.
      • Moreland LW
      • Baumgartner SW
      • Schiff MH
      • et al.
      Treatment of rheumatoid arthritis with a recombinant human tumor necrosis factor receptor (p75)-Fc fusion protein.
      • 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.
      • Kavanaugh AF
      Anti-tumor necrosis factor-α monoclonal antibody therapy for rheumatoid arthritis.
      • Bathon JM
      • Martin RW
      • Fleischmann RM
      • et al.
      A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis.
      • Lipsky PE
      • Van Der Heijde
      • St. Clair EW
      • et al.
      Infliximab and methotrexate in the treatment of rheumatoid arthritis.
      Not since glucocorticoids were first used to treat RA in 1949 have clinicians raved about such quick and dramatic responses. Unfortunately, just as the toxic effects of glucocorticoids appeared later, the sad case of fatal sepsis associated with etanercept, reported in this issue of the Proceedings,
      • Baghai M
      • Osmon DR
      • Wolk DM
      • Wold LE
      • Haidukewych GJ
      • Matteson EL
      Fatal sepsis in a patient with rheumatoid arthritis treated with etanercept.
      should remind us again that we need to proceed with some caution. Several crucial questions need to be addressed: Which patients should receive TNF inhibitors? What are the long-term toxic effects of these agents when used in clinical practice? How do we select the optimal amount of TNF inhibition for each patient?
      Tumor necrosis factor plays a central role in the immune system and appears to be particularly critical for innate immunity.
      Cytokines.
      It is an important mediator of local inflammation and appears to be vital in keeping infections localized. TNF-α results in local activation of vascular endothelium, release of nitric oxide with vasodilation, increased vascular permeability, increased expression of adhesion molecules on the endothelium of blood vessels, and increased expression of class II major histocompatibility molecules. The result is recruitment of inflammatory cells, immunoglobulins, and complement. Delivery of antigen to antigen-presenting cells in local lymph nodes increases, resulting in T-cell and B-cell activation. TNF-α also increases platelet activation and adhesion, which in turn result in local blood vessel occlusion and, thus, containment of infection. In the patient described in this issue of the Proceedings by Baghai et al,
      • Baghai M
      • Osmon DR
      • Wolk DM
      • Wold LE
      • Haidukewych GJ
      • Matteson EL
      Fatal sepsis in a patient with rheumatoid arthritis treated with etanercept.
      these functions may have been critically inhibited.
      Although locally these effects of TNF-α are beneficial, systemically they may be disastrous, leading to clinical syndromes such as septic shock and disseminated intravascular coagulation. The critical part that TNF plays in malaria illustrates this paradox. Production of TNF is an important response to infection, but patients who make excessive amounts of TNF have higher mortality than others.
      • Kwiatkowski D
      • Bate CA
      • Scragg IG
      • Beattie P
      • Udalova I
      • Knight JC
      The malarial fever response—pathogenesis, polymorphism and prospects for intervention.
      Since TNF has been highly conserved during evolution, the good effects must outweigh the bad.
      Clearly, TNF has a central role in the pathological inflammatory response associated with RA.
      • Kavanaugh AF
      Anti-tumor necrosis factor-α monoclonal antibody therapy for rheumatoid arthritis.
      Evidence to support this statement includes excess TNF-α levels in the serum; the correlation between an abundance of macrophage products (TNF-α, interleukin 1, interleukin 6, and interleukin 8) in the synovial tissue and fluid, with the severity and activity of disease; and, most important, the consistent improvement in disease activity, both symptomatically and radiographically, when therapy is directed against TNF.
      • Elliott MJ
      • Maini RN
      • Feldmann M
      • et al.
      Randomised double-blind comparison of chimeric monoclonal antibody to tumour necrosis factor α (cA2) versus placebo in rheumatoid arthritis.
      • Maini RN
      • Breedveld FC
      • Kalden JR
      • et al.
      Therapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor α monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis.
      • Moreland LW
      • Baumgartner SW
      • Schiff MH
      • et al.
      Treatment of rheumatoid arthritis with a recombinant human tumor necrosis factor receptor (p75)-Fc fusion protein.
      • 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.
      • Kavanaugh AF
      Anti-tumor necrosis factor-α monoclonal antibody therapy for rheumatoid arthritis.
      • Bathon JM
      • Martin RW
      • Fleischmann RM
      • et al.
      A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis.
      • Lipsky PE
      • Van Der Heijde
      • St. Clair EW
      • et al.
      Infliximab and methotrexate in the treatment of rheumatoid arthritis.
      The safety profile of both etanercept and infliximab in controlled clinical trials has been impressive. The toxic effects have been similar to those of placebo except for injection site reactions. However, all but one of the published trials of etanercept and infliximab have compared these products with placebo and not with active drugs. Because of the short duration of these trials, the careful selection of patients, and the rigorous follow-up of study patients by physicians and other clinicians who have expertise with these agents, these results may not be directly applicable to the general population of patients with RA. Indeed, reports of cases of sepsis, pancytopenia, and demyelinating disease in patients receiving etanercept in the postmarket period have resulted in 2 warning letters to physicians and changes in the package insert. Further, in a recent Food and Drug Administration summary of post-licensure reports of infection during use of etanercept and infliximab,
      • Gershon S
      • Wise RP
      • Niu M
      • Siegel J
      Postlicensure reports of infection during use of etanercept and infliximab [abstract].
      infections were reported in 2444 patients prescribed etanercept and 928 patients who received infliximab. Further, infection was believed to be a contributing factor in the deaths of 93 etanercept patients and 27 infliximab patients. In the patients receiving infliximab, tuberculosis seemed to be particularly common. These numbers are difficult to interpret without comparable numbers for similar patients who were not taking these drugs.

      Which Patients Should Be Treated With TNF Inhibition?

      To date, only 1 trial has compared TNF inhibition with an active therapy: etanercept vs methotrexate in an early RA trial.
      • Bathon JM
      • Martin RW
      • Fleischmann RM
      • et al.
      A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis.
      All other trials compared either etanercept or infliximab with placebo
      • Elliott MJ
      • Maini RN
      • Feldmann M
      • et al.
      Randomised double-blind comparison of chimeric monoclonal antibody to tumour necrosis factor α (cA2) versus placebo in rheumatoid arthritis.
      • Moreland LW
      • Baumgartner SW
      • Schiff MH
      • et al.
      Treatment of rheumatoid arthritis with a recombinant human tumor necrosis factor receptor (p75)-Fc fusion protein.
      or looked at patients with sub-optimal responses to methotrexate and then added a TNF inhibitor or placebo.
      • Maini RN
      • Breedveld FC
      • Kalden JR
      • et al.
      Therapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor α monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis.
      • 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.
      • Lipsky PE
      • Van Der Heijde
      • St. Clair EW
      • et al.
      Infliximab and methotrexate in the treatment of rheumatoid arthritis.
      Therefore, little information is available to compare the efficacy of either etanercept or infliximab with conventional therapies. Most recent studies have focused on 2 distinct populations: patients with early disease or those who have had suboptimal responses to methotrexate therapy.
      In early disease, etanercept has been compared head to head with methotrexate.
      • Kavanaugh AF
      Anti-tumor necrosis factor-α monoclonal antibody therapy for rheumatoid arthritis.
      In this trial, patients receiving etanercept responded more quickly, but at 1 year, there was no difference in American College of Rheumatology 20, 50, and 70 response rates.
      • Felson DT
      • Anderson JJ
      • Boers M
      • American College of Rheumatology
      • et al.
      Preliminary definition of improvement in rheumatoid arthritis.
      Similarly, both agents appeared to dramatically reduce radiographic progression of RA; total Sharp scores (a primary outcome measure) were not different. Etanercept-treated patients did have fewer erosions during the first 4 months of the trial, supporting a quicker onset of disease control with etanercept. Although methotrexate is the most commonly used disease-modifying antirheumatic drug (DMARD) and, most believe, the most effective, recent trials have suggested that DMARD monotherapy, particularly if used without glucocorticoids, is not the most effective way to treat early RA.
      • O'Dell JR
      • Haire CE
      • Erikson N
      • et al.
      Treatment of rheumatoid arthritis with methotrexate alone, sulfasalazine and hydroxychloroquine, or a combination of all three medications.
      • Boers M
      • Verhoeven AC
      • Markusse HM
      • et al.
      Randomised comparison of combined step-down prednisolone, methotrexate and sulphasalazine with sulphasalazine alone in early rheumatoid arthritis [published correction appears in Lancet. 1998;351:220].
      • Mottonen R
      • Hannonen P
      • Leirisalo-Repo M
      • FIN-RACo Trial Group
      • et al.
      Comparison of combination therapy with single-drug therapy in early rheumatoid arthritis: a randomised trial.
      • Calguneri M
      • Pay S
      • Caliskaner Z
      • et al.
      Combination therapy versus monotherapy for the treatment of patients with rheumatoid arthritis.
      Trials comparing TNF inhibition with combination DMARD therapy in early RA would be of interest. Further, since it is increasingly believed that promptly controlling inflammation is critical and that TNF inhibition works very quickly, trials to investigate induction therapy with these products would seem attractive. One such simple design might place all patients on methotrexate and then compare 3 groups: (1) glucocorticoids in tapering doses (as done in the COBRA trial
      • Boers M
      • Verhoeven AC
      • Markusse HM
      • et al.
      Randomised comparison of combined step-down prednisolone, methotrexate and sulphasalazine with sulphasalazine alone in early rheumatoid arthritis [published correction appears in Lancet. 1998;351:220].
      ); (2) TNF inhibition for 3 months; and (3) TNF inhibition for the duration of the trial.
      Patients who have had suboptimal responses to methotrexate are perhaps the most well-studied group of patients. In this group, double-blind controlled trials have now shown 6 different approaches to be effective. Therapies that have been shown to produce additional benefit when added to methotrexate include cyclosporine,
      • Tugwell P
      • Pincus T
      • Yocum D
      • Methotrexate-Cyclosporine Combination Study Group
      • et al.
      Combination therapy with cyclosporine and methotrexate in severe rheumatoid arthritis.
      etanercept,
      • 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.
      infliximab,
      • Maini RN
      • Breedveld FC
      • Kalden JR
      • et al.
      Therapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor α monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis.
      • Lipsky PE
      • Van Der Heijde
      • St. Clair EW
      • et al.
      Infliximab and methotrexate in the treatment of rheumatoid arthritis.
      leflunomide,
      • Kremer JM
      • Caldwell JR
      • Cannon GW
      • et al.
      The combination of leflunomide and methotrexate in patients with active rheumatoid arthritis who are failing on methotrexate alone: a double-blind placebo controlled study [abstract].
      interleukin 1RA, and sulfasalazine and hydroxychloroquine.
      • O'Dell JR
      • Haire CE
      • Erikson N
      • et al.
      Treatment of rheumatoid arthritis with methotrexate alone, sulfasalazine and hydroxychloroquine, or a combination of all three medications.
      • O'Dell JR
      Triple therapy with methotrexate, sulfasalazine, and hydroxychloroquine in patients with rheumatoid arthritis.
      Unfortunately, most of these trials have compared active therapy with placebo, not very helpful information for a clinician trying to make an informed choice among these options. Moreover, since all these trials used different definitions of suboptimal methotrexate response, it is difficult or impossible to compare the results. Therefore, trials comparing active therapies head to head in this group of patients are critically needed.

      How Do We Suppress TNF Just Enough?

      The pivotal role that TNF plays in the immune system should make us concerned about degrees of inhibition. All patients with RA are different; logically, the degree of TNF inhibition that will be optimal to control disease may vary from patient to patient. This may depend on simple things, such as the patient's weight or drug clearance/metabolism, but also on much more complicated things like each patient's innate TNF production and balance of TH1 and TH2 functions, the relative TNF role in each patient's RA, and many other factors. Ideally, we would learn to titrate our therapy to produce the amount of TNF inhibition that controls the disease without crippling important immune functions. In other words, a TNF thermostat is needed that would allow the clinician to dial the level of TNF inhibition desired to maximize the benefit and minimize the toxic effects. With the central role that TNF plays in our immune system, it is naive to believe that complete blocking of TNF for long periods of time will be without toxic effects. I believe that if we block TNF well enough for long enough considerable problems will occur.
      Until we have a better understanding of how to obtain the optimal degree of TNF inhibition for each individual patient that will provide control of RA without impairing vital immune functions, and until the studies are done to compare TNF inhibition to conventional DMARDs, as discussed above, some guidelines would seem prudent.

      Guidelines

      • 1.
        Patients with new-onset RA should initially be treated with conventional DMARDs.
      • 2.
        Physicians, especially primary care physicians, need to be aware of the possibility of severe infections in patients on these agents and the need to stop TNF inhibition at the first sign of infection of any kind. With the role that TNF plays in keeping infections localized, time is critical. These agents should be restarted only when the infection has completely resolved.
      • 3.
        Patients should be aware of these risks, should stop their medications promptly if any infection (including skin infection) or fever occurs, and contact their physician for further guidance.

      Conclusions

      TNF inhibition is a welcome addition to the armamentarium of the clinician striving to control RA. It is critical that we pursue an aggressive agenda of clinical trials to define which patients benefit most from TNF inhibition. Further, studies to elucidate the optimal degree of TNF inhibition that is safe and effective in each patient are crucial. Armed with a better understanding of how to optimize TNF inhibition in individual patients, it is anticipated that these agents will become increasingly important treatments for appropriately selected patients with RA.

      REFERENCES

        • O'Dell JR
        Anticytokine therapy—a new era in the treatment of rheumatoid arthritis? [editorial].
        N Engl J Med. 1999; 340: 310312
        • Elliott MJ
        • Maini RN
        • Feldmann M
        • et al.
        Randomised double-blind comparison of chimeric monoclonal antibody to tumour necrosis factor α (cA2) versus placebo in rheumatoid arthritis.
        Lancet. 1994; 344: 1105-1110
        • Maini RN
        • Breedveld FC
        • Kalden JR
        • et al.
        Therapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor α monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis.
        Arthritis Rheum. 1998; 41: 1552-1563
        • Moreland LW
        • Baumgartner SW
        • Schiff MH
        • et al.
        Treatment of rheumatoid arthritis with a recombinant human tumor necrosis factor receptor (p75)-Fc fusion protein.
        N Engl J Med. 1997; 337: 141-147
        • 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: 253-259
        • Kavanaugh AF
        Anti-tumor necrosis factor-α monoclonal antibody therapy for rheumatoid arthritis.
        Rheum Dis Clin North Am. 1998; 24: 593-614
        • Bathon JM
        • Martin RW
        • Fleischmann RM
        • et al.
        A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis.
        N Engl J Med. 2000; 343: 1586-1593
        • Lipsky PE
        • Van Der Heijde
        • St. Clair EW
        • et al.
        Infliximab and methotrexate in the treatment of rheumatoid arthritis.
        N Engl J Med. 2000; 343: 1594-1602
        • Baghai M
        • Osmon DR
        • Wolk DM
        • Wold LE
        • Haidukewych GJ
        • Matteson EL
        Fatal sepsis in a patient with rheumatoid arthritis treated with etanercept.
        Mayo Clin Proc. 2001; 76: 653-656
      1. Cytokines.
        in: Abbas AK Lichtman AH Pober JS Cellular and Molecular Immunology. 3rd ed. WB Saunders Co, Philadelphia, Pa1997: 250-277
        • Kwiatkowski D
        • Bate CA
        • Scragg IG
        • Beattie P
        • Udalova I
        • Knight JC
        The malarial fever response—pathogenesis, polymorphism and prospects for intervention.
        Ann Trop Med Parasitol. 1997; 91: 533-542
        • Gershon S
        • Wise RP
        • Niu M
        • Siegel J
        Postlicensure reports of infection during use of etanercept and infliximab [abstract].
        Arthritis Rheum. 2000; 43: 2857
        • Felson DT
        • Anderson JJ
        • Boers M
        • American College of Rheumatology
        • et al.
        Preliminary definition of improvement in rheumatoid arthritis.
        Arthritis Rheum. 1995; 38: 727-735
        • O'Dell JR
        • Haire CE
        • Erikson N
        • et al.
        Treatment of rheumatoid arthritis with methotrexate alone, sulfasalazine and hydroxychloroquine, or a combination of all three medications.
        N Engl J Med. 1996; 334: 1287-1291
        • Boers M
        • Verhoeven AC
        • Markusse HM
        • et al.
        Randomised comparison of combined step-down prednisolone, methotrexate and sulphasalazine with sulphasalazine alone in early rheumatoid arthritis [published correction appears in Lancet. 1998;351:220].
        Lancet. 1997; 350: 309-318
        • Mottonen R
        • Hannonen P
        • Leirisalo-Repo M
        • FIN-RACo Trial Group
        • et al.
        Comparison of combination therapy with single-drug therapy in early rheumatoid arthritis: a randomised trial.
        Lancet. 1999; 353: 1568-1573
        • Calguneri M
        • Pay S
        • Caliskaner Z
        • et al.
        Combination therapy versus monotherapy for the treatment of patients with rheumatoid arthritis.
        Clin Exp Rheumatol. 1999; 17: 699-704
        • Tugwell P
        • Pincus T
        • Yocum D
        • Methotrexate-Cyclosporine Combination Study Group
        • et al.
        Combination therapy with cyclosporine and methotrexate in severe rheumatoid arthritis.
        N Engl J Med. 1995; 333: 137-141
        • Kremer JM
        • Caldwell JR
        • Cannon GW
        • et al.
        The combination of leflunomide and methotrexate in patients with active rheumatoid arthritis who are failing on methotrexate alone: a double-blind placebo controlled study [abstract].
        Arthritis Rheum. 2000; 43: S224
        • O'Dell JR
        Triple therapy with methotrexate, sulfasalazine, and hydroxychloroquine in patients with rheumatoid arthritis.
        Rheum Dis Clin North Am. 1998; 24: 465-477

      Linked Article

      • Fatal Sepsis in a Patient With Rheumatoid Arthritis Treated With Etanercept
        Mayo Clinic ProceedingsVol. 76Issue 6
        • Preview
          Patients with long-standing, severe, erosive rheumatoid arthritis who have extra-articular manifestations and have undergone joint replacement surgery are at increased risk for serious infection and premature mortality. New therapies, including cytokine antagonists, hold great promise for improving the course of rheumatoid arthritis. However, they have powerful anti-inflammatory effects that may mask symptoms of serious infection. We report a case of fatal pneumococcal sepsis occurring in a 37-year-old woman with rheumatoid arthritis treated with the tumor necrosis factor antagonist etanercept and suggest management strategies for early detection and management of this complication.
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