Introduction on TNF/TNFRSFP
Tumor necrosis factor-α (TNF-α) belongs to the TNF/TNFR superfamily of proteins (TNFRSFP) which consists of structurally and functionally similar proteins. They are highly conserved and play important roles in innate immunity and host defenses, inflammation, apoptosis, lymphoid organ and tissue development, and homeostasis and organogenesis.
All of the TNF/TNFR proteins share the same basic homotrimer quaternary structure (Banner et al, 1993) with an elongated cystein-rich extracellular tail, transmembrane domain, and intracellular tail. While some members of the TNF receptor superfamily can signal for cell death, the majority do not have a death domain, and these receptors activate a wide variety of cellular functions such as lymphocyte costimulation, bone turnover, T-B cell interactions, and lymphocyte development and homeostasis.
The knowledge about the structure and function of TNF superfamily of cytokines, coupled with the invention of mAb technology, has revolutionized the treatment approach to many immune-mediated diseases in areas such as rheumatology, gastroenterology, and dermatology. Blocking TNF receptor-ligand interaction has proved very successful in treating diseases such as RA, juvenile idiopathic arthritis, cutaneous psoriasis, psoriatic arthritis, and Crohn’s disease. The list of indications for using this approach is rapidly expanding.
TNF-α is produced by stimulated myeloid cells. There are two TNF receptors, p55 (TNFR1) and p75 (TNFR2), that are widely expressed on most resting cells.
The role of TNF-α has been extensively studied in RA, which is a prototypic systemic deforming arthritis, affecting approximately 1% of the adult population. Studies on the pathogenic mechanisms of RA have revealed that TNF-α is a critical cytokine viewed as a ‘conductor’ in the inflammatory cascade (Choy and Panayi, 2001) that results in irreversible joint damage, bone and cartilage destruction (Bertolini et al, 1986; Saklatvala, 1986), significant morbidity and mortality (Pincus et al, 1984; Pincus and Callahan, 1986).
Following these discoveries, a series of pivotal trials in patients with RA showed the therapeutic benefit of TNF blockade (Elliott et al, 1993, 1994, 1995). Subsequently, three biologic agents, engineered to block TNF action, have been approved by the Food and Drug Administration (FDA) for clinical use in the United States (Table 1). They have been shown to be effective in a growing number of inflammatory conditions, including RA, psoriatic arthritis, ankylosing spondylitis, and Crohn’s disease.
Table 1. Biologic agents used in rheumatology
| ||Target molecule||Generic name||Brand name||Mode of action||US FDA-labeled indications||Administration|
|Cell-surface molecular target||TNF-α||Infliximab||Remicade™||Inhibits TNF binding to its receptor||RA, PsA, AS, Crohn’s disease, Plaque psoriasis||i.v.|
|TNF-α||Adalimumab||Humira™||Inhibits TNF binding to its receptor||RA, PsA, AS, Crohn’s disease||s.c.|
|IL-1R||Anakinra||Kineret™||Inhibits IL-1 binding to its receptor||RA||s.c.|
|IL-6R||Tocilizumab||MRA™, Actemra™||Inhibits IL-6 binding to its receptor||Under clinical investigation||i.v.|
|CD20||Rituximab, ocrelizumab||Rituxan™, MabThera™||Depletes B cell||RA, NHL||i.v.|
|CD22||Epratuzumab|| ||Non-depleting B cell immune modulation||Under clinical investigation||i.v.|
|CD25 (IL-2 receptor)||Daclizumab, basiliximab||Zenapax™, Simulect™||Inhibits IL-2 binding to its receptor||Renal transplant rejection||i.v.|
|CD80, CD86||Abatacept||Orencia™||Inhibits co-stimulation of B cells||RA||i.v.|
|Soluble target||TNF-α, TNF-β||Etanercept||Enbrel™||Inhibits TNF binding to its receptor||RA, PsA, AS, JIA||s.c.|
|TNF-α||Infliximab||Remicade™||Inhibits TNF binding to its receptor||RA, PsA, AS, Crohn’s disease, plaque psoriasis||i.v.|
|TNF-α||Adalimumab||Humira™||Inhibits TNF binding to its receptor||RA, PsA, AS, Crohn’s disease,||s.c.|
|BLyS||Belimumab||LymphoStat-B™||Inhibits B cell development||Under clinical investigation||i.v.|
Etanercept (Enbrel™, Immunex, Seattle, Washington, USA), a TNF receptor p75 Fc fusion protein (TNFR:Fc), is a soluble recombinant form of the extracellular domain of human TNFR2 receptor fused to the Fc fragment of human immunoglobulin G1 (IgG1). It binds to soluble TNF and LT-α, effectively neutralizing the biologic activity of TNF.
Etanercept, alone or in combination with methotrexate, has been shown to be effective in patients with early and long-standing RA in randomized, double-blind, placebo-controlled clinical trials (Moreland et al, 1997; Weinblatt et al, 1999; Bathon et al, 2000) with sustained response over 2 years (Genovese et al, 2002). It is also approved for treatment of polyarticular juvenile RA (Lovell et al, 2000), plaque psoriasis, active psoriatic arthritis in adults, and for treatment of adult patients with chronic moderate to severe plaque psoriasis (Mease et al, 2000) as well as active ankylosing spondylitis (Gorman et al, 2002). The usual dose of etanercept is 25 mg for adults and 0.4 mg kg−1 for children twice a week subcutaneous injections for treatment of RA, psoriatic arthritis, and ankylosing spondylitis. Comparable clinical benefit in adults with RA has been demonstrated with a once-weekly injection of 50 mg (Keystone et al, 2004a,b).
Infliximab (Remicade™, Centocor, Inc., Malvern, Pennsylvania, USA), is a chimeric mAb composed of the antigen-binding region of a mouse anti-TNF monoclonal antibody and the constant region of human IgG1 (Winterfield and Menter, 2004). It binds to both soluble and transmembrane TNF-α with high affinity (Targan et al, 1997). Infliximab is approved for use in patients with RA who have had an inadequate response to methotrexate alone (Lipsky et al, 2000). The combination of infliximab and methotrexate was superior in reducing signs and symptoms and slowing the progression of joint damage in patients with active (Lipsky et al, 2000) and early (St Clair et al, 2004) RA compared with methotrexate alone, with efficacy sustained for up to 2 years (Maini et al, 2004).
Another monoclonal antibody against TNF-α is adalimumab (Humira™, Abbott Laboratories, North Chicago, Illinois, USA). It is a recombinant, fully humanized IgG1 anti-TNF-α monoclonal antibody with low immunogenicity. It has been FDA approved for moderate-to-severe RA (Furst et al, 2003; Weinblatt et al, 2003; Weisman et al, 2003; Keystone et al, 2004a,b), psoriatic arthritis, moderate-to-severe Crohn’s disease, and ankylosing spondilitis. The recommended dose is 40 mg subcutaneously every 2 weeks alone or concomitantly with methotrexate.
The safety profile of anti-TNF biologics has become an area of active post-marketing evaluation because of concerns of potential adverse events some of which were not documented during the clinical trials phase, such as infections, malignancies and lymphoma, demyelinating disorders, aplastic anemia, congestive heart failure, and vasculitis (Mohan et al, 2004; Richette et al, 2004). These concerns were addressed by the FDA Arthritis Advisory Committee http://www.fda.gov/ohrms/dockets/ac/03/transcripts/3930T1.htm. Injection site reaction has been the most commonly reported adverse reaction with the subcutaneously administered drugs (20–40%) (Moreland et al, 1999). Hypersensitivity reaction associated with infliximab is more rare, although more serious (Maini et al, 1999).
Patients treated with anti-TNF medications are at increased risk of conventional bacterial and opportunistic infections (Warris et al, 2001; Helbling et al, 2002; Kamath et al, 2002; Lee et al, 2002; Nakelchik and Mangino, 2002). Oral and esophageal candidiasis in patients treated with anti-TNF agents can be rarely seen in dental practice (Ricart et al, 2001). The risk of serious and life-threatening infections is also increased (Bongartz et al, 2006). Reactivation of latent tuberculosis is a particular complication that usually develops within the first few months of therapy, presenting as atypical extrapulmonary and miliary disease. For that reason screening for latent tuberculous infection is strongly recommended prior to initiation of any TNF-blocking agents.
Immunogenicity has been observed during anti-TNF therapy with the development of ANA and anti-double-stranded DNA (anti-dsDNA) antibodies of IgM isotype, but their clinical significance is still a matter of debate. Adding methotrexate to the regimen reduces the incidence of these and other antibodies.
Additional areas of concern are potentially demyelinating syndromes (Mohan et al, 2001) and increased morbidity and mortality in patients with congestive heart failure while on anti-TNF medications.
Malignancy and lymphoma have been documented in RA patients treated with TNF blockers in clinical trials (Bongartz et al, 2006). However, patients with RA have an increased risk of lymphoproliferative diseases and non-Hodgkin’s lymphoma in particular (standardized incidence ratio: 2.4–8.9) (Isomaki et al, 1978; Matteson et al, 1991; Gridley et al, 1993; Baecklund et al, 1998), based on epidemiological studies from pre-biologics era. All these facts complicate the interpretation of the post-marketing data trying to link the use of anti-TNF agents and lymphoma, and the debate is still open.