Update upon efficacy and safety of TNF-α inhibitors

Abstract

The ongoing progresses in the knowledge of the pathogenic mechanisms of various immune-mediated and inflammatory diseases as well as the availability of innovative biotechnological approaches have led to the development of new drugs that add to conventional treatments. Among these, tumor necrosis factor (TNF)-α inhibitors, that is, infliximab, adalimumab, etanercept, golimumab and certolizumab pegol, are now available for clinical use. This editorial discusses the recent indications of TNF-α inhibitors, the pretreatment considerations, the reported adverse events and, finally, the recommendations for its use in pregnancy.

Keywords:

• efficacy
• immune-mediated diseases
• safety
• TNF-α inhibitors

The ongoing progresses in the knowledge of the pathogenic mechanisms of various immune-mediated diseases such as rheumatoid arthritis (RA), ankylosing spondylitis (AS), psoriasis (Ps) and/or psoriatic arthritis (PsA) and the availability of innovative biotechnological approaches have led to the development of new drugs that add to conventional treatments. In particular, efforts have been made to design biologic drugs that are able to counteract the activity of different molecules (i.e., tumor necrosis factor-α (TNF-α), IL-1, CD20, CD22 and CD11a). TNF-α is a pro-inflammatory cytokine known to a have a central role in the initial host response to infection [1] and in the pathogenesis of the above-mentioned diseases. TNF-α blockers have demonstrated efficacy in large, randomized controlled clinical trials either as monotherapy or in combination with other anti-inflammatory or disease modifying anti-rheumatic drugs (DMARDs) [2,3]. Five TNF-α inhibitors are available for the clinical use: infliximab, adalimumab, etanercept, golimumab and certolizumab pegol. All these agents block the biologic effects of TNF-α although there are some differences in their structure, pharmacokinetics and mechanisms of action. The efficacy and safety profile of the TNF-α blockers can be considered, in general, as a class effect. Nevertheless, some differences may exist among the five agents.

Infliximab is a chimeric human/murine IgG1 monoclonal antibody (mAb) directed against TNF-α, which has been first approved in combination with methotrexate (MTX) for the treatment of RA. ATTRACT and ASPIRE studies confirmed that infliximab (3 mg/Kg intravenously at weeks 0-, 2- and 6- and 8-weekly thereafter) plus MTX provided greater clinical and functional benefits than treatment with MTX alone for the treatment of RA [4,5]. Infliximab alone (5 mg/Kg) has been also approved for the treatment of Ps, PsA, AS, Crohn's disease (CD) and ulcerative colitis refractory to conventional drugs [3,6,7]. Furthermore, infliximab is considered the treatment of choice for fistulizing CD [7]. Colombel et al. reported that infliximab plus azathioprine was the most effective treatment, for moderate-to-severe CD [8]. Episodic therapy with infliximab on relapse of CD is possible but is less efficacious and frequently is associated with problems resulting from the formation of antibodies to infliximab. If treatment is episodic, maintenance therapy with immunosuppression (azathioprine, MTX) is mandatory [9].

Adalimumab is a fully recombinant human IgG1 anti-TNF-α-specific mAb (3), which is approved for the treatment of Ps, PsA, RA, AS and CD [3,10]. The PREMIER study demonstrated that adalimumab (40 mg subcutaneously every other week) plus MTX was significantly superior to either MTX alone or adalimumab alone in improving signs and symptoms and inhibiting radiographic progression of early, aggressive RA [10,11]. Finally, Colombel et al. demonstrated that continuous treatment with adalimumab was more effective than a strategy of induction dosing followed by reinitiation of adalimumab with clinical deterioration for maintenance of clinical remission, improved quality of life outcomes, reduced flares and a decrease in the number of surgeries and risk of hospitalization in patients with active CD [12].

Golimumab is a human gamma-1 immunoglobulin-κ anti-TNF-α monoclonal antibody and is administered as a 50-mg subcutaneous injection once a month (6). Golimumab was approved for use with MTX in adults with moderate to severe RA, and with or without MTX or other DMARDs in adults with active PsA or active AS. Boyce et al. confirmed the efficacy of golimumab [13].

Certolizumab pegol differs from the other anti-TNF-α by its structure, composed of the Fab antigen-binding domain of a humanized monoclonal anti-TNF-α antibody combined with polyethylene glycol to increase its half-life in the body [14]. Certolizumab pegol (400 mg subcutaneously at weeks 0, 2 and 4 followed by 200 mg every 2 weeks) in combination with MTX is indicated for the treatment of moderate to severe, active RA [11,12]. Schreiber et al. suggested that certolizumab (400 mg subcutaneously four times weekly) was effective in patients with moderate to severe CD [15]. Vavricka et al. confirmed the efficacy of certolizumab pegol for the treatment of CD: of note, response and remission rates were 70 and 40% (week 6) and 67 and 36%, (week 26), respectively [16]. However, Sandborn et al. reported that certolizumab favored clinical remission in patients with increased concentrations of C-reactive protein [17].

Etanercept is not a monoclonal antibody, but a fusion protein that acts as a ‘decoy receptor’ for TNF-α and acts competitively to inhibit the binding of TNF-α to its cell surface receptor [3]. Etanercept (25 mg/two times per week subcutaneously or 50 mg once a week) has been approved for the treatment of chronic plaque Ps, PsA, other than RA, AS and juvenile RA [3]. Although TNF-α inhibitors were first developed for patients with RA, they were subsequently also approved for the use in patients with AS. The increased expression of TNF-α in serum and at the sacroiliac joints in patients with AS and the close immunological relationship between spondyloarthropathies and CD were the main reason to consider TNF-α inhibitors as a new therapeutic option for these patients [18,19]. Two agents are currently utilized in the treatment of AS, infliximab and etanercept, and open-label trials have demonstrated the efficacy and safety of both these drugs [19,20]. Patients treated with etanercept showed an improvement in the Bath Ankylosing Spondylitis Disease Activity Index ≥ 50% [18]. Furthermore, other open-label trials have demonstrated the efficacy and safety of TNF-α inhibitors for the treatment of Ps and PsA [21-23]. Furthermore, the differences in the mechanism of action of the TNF-α inhibitors are also reflected by the variable response rate observed in patients with CD who respond well to infliximab and adalimumab but not to etanercept. Of note, infliximab binds specifically to TNF-α, whereas etanercept binds and neutralizes both TNF-α as well as lymphotoxin-α, which might yield differential immunomodulatory effects and contribute to the varying efficacy between the two agents in the treatment of CD [24].

Patients who fail to tolerate one TNF-α inhibitor can be switched to another TNF-α inhibitor if allowed by the nature of the adverse event.

Although TNF-α inhibitors are generally well tolerated, physicians should be aware of the potential adverse events of these drugs. Reactivation of latent tuberculosis (LTB) infection [25], and the overall risk of opportunistic infections, should be considered before the beginning of therapy [3]. A patient eligible for anti-TNF-α therapy should undergo a careful medical history that includes tuberculosis risk factors, such as birth or residence in a region of high tuberculosis prevalence, previous tuberculosis or other risk factors that may facilitate tuberculosis acquisition (i.e., corticosteroid treatment). Appropriate screening with Mantoux test and chest X-ray should be performed before starting treatment [3]. However, negative Mantoux test should be interpreted with caution in any patient treated with immunosuppressive drugs as they are more likely to have false-negative Mantoux test results. Accordingly, a number of tuberculosis cases have occurred in subjects who had negative Mantoux test before starting TNF-α inhibitor therapy [26]. By contrast, previous BCG vaccination may cause false-positive Mantoux test results. Of note, new tests for the diagnosis of LTB, including interferon-γ-release assays, have recently been developed and have been proven to be more specific for LTB than the Mantoux test in immunocompetent subjects [26]. Recommendations for screening, diagnosis and treatment of LTB infection are reported in Table 1.

Table 1. Recommendations for screening, diagnosis and treatment of latent tuberculosis infection in patients receiving or scheduled to receive TNF-α inhibitors.

Tests to exclude TB infections in immunocompromised patients	TST < 5 mm as a negative result TST > 5 mm as a positive result Use with caution IFN-γ-release assays for the risk of false positive Chest X-ray performed in case of positive TST
Risk factors for TB infections	Birth/extended residence in country where TB is prevalent Residence in congregate setting (e.g., prison) Substance abuse (injection or noninjection) Health-care employment in centers that treat TB Chest X-ray findings consistent with previous TB
Treatment for TB infections	9 months of daily isoniazid or 4 months of rifampicin either alone or in combination with isoniazid if epidemiologic and clinical circumstances suggest a probability of LTBI Consider starting treatment with TNF-α inhibitor after 3 weeks of anti-LTBI therapy

TST: Tuberculosis skin test; LTBI: latent tuberculosis (TB) infection.

A small number of Histoplasma capsulatum, Coccidioides immitis, Listeria monocytogenes, invasive fungal (candidiasis and aspergillosis) infections, retropharyngeal abscesses and palmoplantar pustulosis have been reported [27]. Some cases of Pneumocystis jiroveci (carinii) pneumonia and a case of visceral leishmaniasis have been reported [27]. The most frequent potential adverse events of TNF-α inhibitor drugs are: i) infusion reactions with infliximab and ii) injection-site reactions to subcutaneously administered drugs. Mild infusion reactions (i.e., headache, itch, urticaria, nausea) and cutaneous injection-site reactions (i.e., local erythema and swelling), which usually subside within 24 h, can be treated with premedication with anti-histaminic drugs and, when needed, with glucocorticoids [3]. Severe infusion reactions (i.e., angioedema and shock) have been reported in patients under infliximab therapy. As infliximab is a chimeric human/mouse anti-TNF-α antibody, it may induce the synthesis of neutralizing antibodies, which could reduce the efficacy of the drug. MTX is usually coadministered to control both the rheumatic disease and the development of neutralizing antibodies [3]. In spite of its fully human sequence, the production of antibodies to adalimumab has been also reported, which may reduce the efficacy of the drug and induce the development of adverse drug reactions and exanthema [7,27]. Malignancies (i.e., lymphomas), autoimmune diseases and demyelinating diseases have been reported. Nevertheless, there is evidence that in RA patients the risk for lymphoma is irrespective of treatment [27] and there were no reported cases of hepatosplenic T-cell lymphoma in patients with inflammatory bowel disease who receive only TNF-α inhibitors [28].

The risk for development of systemic autoimmune diseases is low, and at present there is no recommendation for the monitoring of autoantibody titers during anti-TNF-α therapy [27]. TNF-α inhibitor therapy should be avoided in patients with preexisting multiple sclerosis and discontinued immediately when new neurologic signs and symptoms occur [27]. Few cases of neutropenia not complicated by serious infections and rare cases of severe fibrosing alveolitis have been described [27]. The overall incidence of adverse events and the percentage of each group of side effects are reported in Table 2.

Table 2. Overall incidence of adverse events and percentage of each group of side effects.

	Percentage
Overall incidence of adverse events	53
TB	3
Other infections	2
Skin site reactions	10
Infusion reactions	2
Alveolitis	1
Lymphoma	< 1
Demyelinating disease	< 1
Neutropenia	< 1
Systemic autoimmune disease	< 1

Finally, caution should be taken when TNF-α inhibitors are used during pregnancy, as human experience is still extremely limited. Indeed, US Food and Drugs Administration classifies all of these agents as category B and they are generally regarded as being safe to continue until the time of conception, at which point therapy should be stopped.

Expert opinion

TNF-α inhibitors represent a new class of drugs that have revolutionized our clinical management of chronic inflammatory diseases. Physicians need to be aware of the potential efficacy and risks of treatment with these agents. Due to the need for continued therapy with these drugs to maintain disease remission, long-term observations for efficacy and toxicity are required and information should be appropriately provided to patients regarding their potential benefits and risk. However, patients receiving TNF-α inhibitors may be more likely to be admitted to the hospital if they have an infection. Treatment with TNF-α inhibitors has been recognized as risk factor for active TB and most cases of TB develop after treatment initiation corresponding to reactivation of LTB infection. Finally, the role of TNF-α inhibitors in carcinogenesis is yet in dispute. Although observational studies have not indicated any increased overall risk of short- and long-term cancer in patients treated with TNF-α inhibitors, the possible association with cancer raises concern.

Declaration of interest

The authors state no conflict of interest and have received no payment in preparation of this manuscript.