There are now five anti-tumour necrosis factor (TNF) drugs licenced for use in rheumatoid arthritis. This chapter examines the similarities and differences between the drugs and looks for clues with regard to their rational prescribing. The major difference is between the monoclonal antibody-based drugs and the soluble receptor etanercept. Etanercept exhibits the best drug survival and is also associated with a lower risk of opportunistic infections, particularly tuberculosis. Immunogenicity should explain some of the differences between the different drugs but the lack of standardised assays has hindered this area of research. The optimal approach to the patient who has failed their first anti-TNF remains unclear and awaits appropriate clinical trials. The safety profile of anti-TNFs has become clearer, largely through registry data. There is a small increase in serious and opportunistic infections but there does not appear to be a heightened cancer risk, and cardiovascular risk is probably reduced.
Tumour necrosis factor alpha (TNF) is a pleiotropic cytokine with an established place in the pathogenesis of rheumatoid arthritis (RA). It is known to play a role in host defence mechanisms and initiates the response to local injury but, in excess, TNF leads to inappropriate inflammation and consequent tissue damage . It is present in RA synovial fluid, and transgenic mice expressing high concentrations of TNF spontaneously develop an arthritis which is clinically and histopathologically similar to RA . Blockade of TNF ameliorates the murine disease, and these and additional observations led to clinical trials of the monoclonal anti-TNF antibody cA2, later known as infliximab, in patients with RA .
TNF exists in two forms: soluble TNF (sTNF) and membrane-associated TNF (mTNF) forms. sTNF is a homotrimer of 17 kDa monomers which is proteolytically cleaved from mTNF, itself a homotrimer of 26 kDa monomers. The major source of TNF in inflamed synovial tissue is the activated macrophage, but the pathological initiating stimulus for its production has not been identified. Both mTNF and sTNF are biologically active and bind to two TNF receptors: TNFR1 (p55, CD120a) and TNFR2 (p75, CD120b), which are expressed on a variety of cell types and signal through nuclear factor kappa B (NFκB) and MAP kinases to initiate pro-inflammatory gene transcription . Both receptors bind TNF and lymphotoxin (LTα3) but differ in their expression profiles. TNFR1 is constitutively expressed on the majority of cell types, with the exception of erythrocytes, whereas TNFR2 is inducible and preferentially expressed on endothelial and haematopoietic cells. mTNF itself can behave as both a ligand and receptor and, consequently, some anti-TNF agents exhibit agonistic properties and induce ‘reverse signalling’ into the cell .
Anti-TNF agents
There are now five TNF inhibitors available for the treatment of RA, three of which are full-length monoclonal antibodies: infliximab, adalimumab and golimumab ( Fig. 1 and Table 1 ). Infliximab is a chimeric protein composed of a murine variable region and human constant region. Golimumab and adalimumab are fully human antibodies, produced using recombinant DNA technology. The fourth agent, etanercept, is a fusion protein of two TNFR2 receptor extracellular domains and the Fc fragment (hinge, CH2 and CH3 domains) of human immunoglobulin 1 (IgG1). Certolizumab is a humanised Fab fragment conjugated to polyethylene glycol (PEG). The attachment of the 40-kDa PEG moiety increases the half-life of certolizumab to one comparable to an intact monoclonal antibody. The absence of an Fc prevents effector function such as complement-dependent lysis and antibody-dependent cell-mediated cytotoxicity (ADCC) .
| Infliximab | Adalimumab | Golimumab | Etanercept | Certolizumab | |
|---|---|---|---|---|---|
| Structure | Monoclonal antibody | Monoclonal antibody | Monoclonal antibody | P75TNFR/Fc fusion protein | PEGylated humanised Fab fragment |
| Fully human | No | Yes | Yes | Yes | No |
| Ligand | TNF | TNF | TNF | TNF & LTα3 | TNF |
| Molecular weight (kDa) | 150 | 150 | 150 | 150 | 95 |
| Half-life (days) | 8–10 | 10–14 | 12 ± 3 | 3 | 14 |
| Dosing route and frequency | Iv every 8 weeks following loading at weeks 0,2 and 6 | Sub-cut every 2 weeks | Sub-cut monthly | Sub-cut weekly | Sub-cut every 2 weeks |
Infliximab
Infliximab was the first anti-TNF to reach routine clinical use. In the phase III ATTRACT trial, patients with active RA and an inadequate response to methotrexate (MTX) continued MTX and were randomised to receive either placebo or one of four infliximab regimes: 3 mg kg −1 every 4 weeks or 8 weeks or 10 mg kg −1 every 4 weeks or 8 weeks. At 30 weeks, patients in the active treatment arms achieved an ACR 20 response rate of 50–58% versus 20% in the placebo group . Infliximab differs from the other available agents in its intravenous route of administration. This may be preferred by some patients (and ensures treatment compliance) but can be associated with infusion reactions. The licenced dose is 3 mg kg −1 at weeks 0, 2 and 6 followed by 3 mg kg −1 every 8 weeks. MTX co-therapy is mandatory and the dose of infliximab may be titrated up to 7.5 mg kg −1 in patients with an inadequate response or loss of response after 12 weeks .
Adalimumab
The recombinant human monoclonal antibody adalimumab can be administered with or without MTX. Its effectiveness in combination with background MTX was established by Weinblatt et al., who randomised patients with an inadequate response to MTX to 20 mg, 40 mg or 80 mg of adalimumab subcutaneously every 2 weeks or placebo, whilst continuing MTX. ACR 20 responses at 24 weeks were 47.8%, 67.2% and 65.8% in the 20 mg, 40 mg and 80 mg groups, respectively, versus 14.5% for placebo . The PREMIER study confirmed that adalimumab was most effective when used in combination with MTX, providing a better clinical response and reduced radiographic progression . It is administered at a dose of 40 mg subcutaneously every 2 weeks, although this can be increased to weekly. The mean terminal half-life is 2 weeks .
Etanercept
Etanercept can also be prescribed with MTX or as monotherapy and is administered weekly by subcutaneous injection. Moreland et al. randomised patients with active RA and an inadequate response to MTX to etanercept 10 mg twice weekly, 25 mg twice weekly or placebo, whilst continuing MTX. At 24 weeks, the ACR 20 responses were 51%, 59% and 11%, respectively . Etanercept can be administered as 25 mg twice a week or 50 mg once a week. It has a mean elimination half-life of around 70 h. When anti-drug antibodies are provoked, these tend to be non-neutralising .
Golimumab
Golimumab is a human IgG1 monoclonal antibody also licenced for use with MTX. In the phase III GO-FORWARD trial, patients with an inadequate response to MTX were randomised to one of four groups: MTX with placebo injections, 100 mg golimumab with placebo capsules, 50 mg golimumab with MTX or 100 mg golimumab with MTX. All infusions were administered monthly. At week 14, the proportion of patients with an ACR 20 response was 33.1%, 44.4%, 55.1% and 56.2%, respectively . Golimumab did not demonstrate inhibition of radiographic damage at week 24 but none of the groups (including placebo) demonstrated significant progression over this time period: change in modified Sharp score was 0.6 ± 2.4, 0.3 ± 1.6, 0.6 ± 2.7 and 0.2 ± 1.3, respectively . Golimumab is administered at a dose of 50 mg monthly by subcutaneous injection. Its half-life is 12 ± 3 days .
Certolizumab
Certolizumab is a recombinant humanised antibody Fab fragment conjugated to PEG. It is the only anti-TNF produced in bacteria ( Escherichia coli ), which improves yields and could reduce production costs. PEGylation delays drug elimination by reducing renal clearance, decreasing proteolysis and potentially by decreasing immunogenicity. It may be administered with or without methotrexate . The effectiveness of certolizumab was demonstrated in the RAPID-1 trial in which patients with an inadequate response to MTX were randomised to receive 400 mg certolizumab at weeks 0, 2 and 4, followed by either 200 mg certolizumab every 2 weeks, 400 mg certolizumab every 2 weeks or placebo. All patients continued to take MTX. At week 24, the proportion of patients reaching an ACR 20 response was 58.8%, 60.8% and 13.6%, respectively . The RAPID-2 trial had a similar design and similar clinical outcomes and also demonstrated inhibition of radiographic progression . The efficacy of certolizumab monotherapy was demonstrated in the FAST4WARD trial . In this study, patients who had failed at least one DMARD were randomised to receive 400 mg certolizumab every 4 weeks or placebo. At 24 weeks, ACR 20 response rates were 45.5% and 9.3%, respectively. The licenced dose is 400 mg certolizumab at weeks 0, 2 and 4 followed by 200 mg fortnightly. It has a half-life of 14 days .
Biosimilars
The patent for etanercept is due to expire in 2012 and there is increasing interest in the development of anti-TNF biosimilars, the ‘follow-on’ versions of the original drug. Biological drugs such as the anti-TNFs are by definition manufactured from living cells. In this way, they differ from traditional, chemically synthesised, small molecule drugs. The latter can be readily copied by generic drug manufacturers with no concerns around chemical identity, which can be confirmed by techniques such as high-pressure liquid chromatography (HPLC). By contrast, the precise structure and characteristics of a biological drug are determined not only by its primary amino acid sequence but also by its glycosylation pattern and other subtle features, not all of which are immediately recognisable. In turn, these are influenced by the cell line and clone from which the biologic is produced, as well as by the precise culture conditions (pH, temperature, etc.) used to grow the cells . Biosimilar manufacturers generally will not have access to the precise manufacturing conditions used by the producers of the original biologic drug and so there is the potential for important differences to arise. These could affect the efficacy, immunogenicity or side-effect profile of the biosimilar. Even differences in the excipients used to stabilise a biologic drug, and the form of packaging, can have subtle influences. In the case of erythropoietin, a subtle change led to instances of pure red cell aplasia in recipients. This resulted from neutralising antibodies that cross-reacted on native, endogenous erythropoietin. The increase in immunogenicity arose from the replacement of human albumin as stabiliser with glycine and polysorbate 80 and highlights the potential consequences of subtle changes in production and manufacture .
Because of these potential pitfalls, the pre-licencing pathway for a biosimilar could remain relatively complex, with less cost savings than originally anticipated. With the first biosimilar RA drugs now entering clinical trials, the definitive answer should soon be known. It will also be important to have robust post-marketing surveillance in place for biosimilars, as well as registry data. The important message is that these should not be viewed as the generic equivalent of biologic drugs, and subtle but important distinctions may come to light once they are marketed.
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