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Tumor necrosis factor-alpha inhibitors: An overview of adverse effects

Tumor necrosis factor-alpha inhibitors: An overview of adverse effects
Author:
Bruce Kirkham, BA, MD, FRCP, FRACP
Section Editor:
Daniel E Furst, MD
Deputy Editor:
Philip Seo, MD, MHS
Literature review current through: Dec 2022. | This topic last updated: Sep 29, 2021.

INTRODUCTION — Inhibitors of tumor necrosis factor (TNF)-alpha are important treatments in a number of inflammatory conditions, including rheumatoid arthritis (RA), spondyloarthritis, psoriasis, and inflammatory bowel disease (IBD). TNF-alpha inhibitors offer a targeted strategy that contrasts with the nonspecific immunosuppressive agents traditionally used to treat most inflammatory diseases. However, multiple adverse effects of TNF-alpha inhibition have been identified through both clinical trials and post-marketing surveillance. These include:

Injection site reactions

Infusion reactions

Neutropenia

Infections

Demyelinating disease

Heart failure (HF)

Cutaneous reactions

Malignancy

Induction of autoimmunity

Problems associated with injection site reactions, infusion reactions, neutropenia, demyelinating disease, heart failure, and some less common adverse effects will be reviewed here. Other major complications of TNF-alpha therapy, such as tuberculosis, other infections, malignancy, and induction of autoimmunity, are discussed separately. (See "Tumor necrosis factor-alpha inhibitors: Bacterial, viral, and fungal infections" and "Tumor necrosis factor-alpha inhibitors and mycobacterial infections" and "Tumor necrosis factor-alpha inhibitors: Risk of malignancy" and "Tumor necrosis factor-alpha inhibitors: Induction of antibodies, autoantibodies, and autoimmune diseases".)

GENERAL ISSUES — The adverse effects associated with tumor necrosis factor (TNF)-alpha inhibitors are potentially serious. However, these risks must be interpreted in the context of the potential benefits and of the adverse effects associated with conventional therapies for the treatment of immune-mediated diseases (eg, glucocorticoids, methotrexate, cyclophosphamide, azathioprine), which are also significant and, in many cases, greater.

Thus, the decision to use an anti-TNF-alpha agent must be an individual one, based upon the specific clinical features and unique risk profile of a given patient.

As background to the overview of adverse events associated with TNF-alpha inhibition, we provide a brief review of TNF-alpha biology and the role of this cytokine in host defense.

An interesting perspective of the adverse effects of TNF inhibitor therapy, which suggests that the adverse event profile may differ between patients with different disorders, comes from a comparison of two prospective safety cohorts of patients with rheumatoid arthritis (RA) and psoriasis [1]. These cohorts (the Spanish Registry for Adverse Events of Biological Therapy in Rheumatic Diseases [BIOBADASER] and the Spanish Registry of Adverse Events Associated with Biologic Drugs in Dermatology [BIOBADADERM]) shared methods, including definitions for serious adverse events. There were many more patients with RA (16,230 person-years; follow-up of 3171 patients) than with psoriasis (2760 person-years; follow-up of 946 patients).

There was a much lower rate of serious adverse/mortal events in subjects with psoriasis (124) compared with RA (1248; multivariate incidence rate ratio, 0.6 [95% CI 0.5-0.7]). Patients with RA had higher rates of infections, cardiac/respiratory disorders, and infusion reactions (higher use of infliximab), while those with psoriasis had more skin/subcutaneous and hepatobiliary disorders. The differences persisted after correction for sex, age (the RA group was older), treatment, concomitant disease, hypertension, diabetes (more in psoriasis), hypercholesterolemia (more in psoriasis), and simultaneous therapy with methotrexate, and after excluding patients receiving glucocorticoids (RA 41.3 percent versus psoriasis 0.2 percent).

TNF-alpha biology — TNF-alpha is synthesized initially by activated macrophages and T cells as a transmembrane precursor protein. The cytoplasmic tail of this protein is then cleaved to release soluble TNF-alpha.

TNF-alpha, originally known as cachexin, was described in 1975 and recognized for its ability to lyse tumors in a variety of in vitro and mouse models (hence the name "tumor necrosis factor") [2]. The activity of TNF-alpha against tumors in laboratory models originally raised the possibility that inhibition of this cytokine might potentiate the clinical risk of malignancy. However, most subsequent longitudinal data suggest this is not the case. (See "Tumor necrosis factor-alpha inhibitors: Risk of malignancy".)

The biologic activity of TNF-alpha requires the aggregation of three TNF-alpha monomers to form trimeric TNF-alpha, which then acts by binding to one of two types of receptors: TNFR1 or TNFR2 [3,4]. TNFR1 and TNFR2 are also known as p55 and p75, respectively. The trimeric structure of the receptors mimics that of the active cytokine [5].

TNFR1 and TNFR2 both exert multiple effects on the immune system, including the following [6]:

Stimulation of the release of the inflammatory cytokines interleukin (IL)-1beta, IL-6, IL-8, and granulocyte macrophage colony-stimulating factor (GM-CSF)

Upregulation of the expression of endothelial adhesion molecules (ICAM-1, VCAM-1, E-selectin) and chemokines (MCP-1, MIP-2, RANTES and MIP-1alpha)

Coordination of the migration of leukocytes to targeted organs

TNF-alpha and host defenses — TNF-alpha is important for macrophage activation, phagosome activation, differentiation of monocytes into macrophages, recruitment of neutrophils and macrophages, granuloma formation, and maintenance of granuloma integrity [7]. The effects of TNF-alpha on infection have been examined in animal experiments, including models that utilize neutralizing antibodies, disrupt transcription of the gene for TNF-alpha or one of its receptors, or lead to the overexpression of soluble TNF-alpha receptor [8-13].

Animal experiments have demonstrated the importance of TNF-alpha in protection against several pathogens including Mycobacterium tuberculosis, M. avium, M. bovis, Bacillus Calmette-Guérin (BCG), Aspergillus fumigatus, Histoplasma capsulatum, Toxoplasma gondii, Cryptococcus neoformans, and Candida albicans [9,11,14-16]. These organisms are not killed readily by host defense mechanisms but rather are sequestered within granulomas, which are comprised of a central core of macrophages, multinucleated giant cells, and necrotic debris surrounded by macrophages and lymphocytes [17]. TNF-alpha is required for the orderly recruitment of these cells and for continued maintenance of the granuloma structure [18].

TNF-alpha antagonists — Five inhibitors of TNF-alpha are approved for the treatment of a variety of inflammatory illnesses (eg, RA, Crohn disease) by the US Food and Drug Administration (FDA). These medications are:

Etanercept – A soluble p75 TNF-alpha receptor fusion protein

Infliximab – A chimeric (mouse/human) anti-TNF-alpha antibody

Adalimumab – A fully human monoclonal anti-TNF-alpha antibody

Certolizumab pegol – An antigen-binding fragment (Fab') of a humanized monoclonal antibody coupled to polyethylene glycol

Golimumab – A human anti-TNF-alpha monoclonal antibody

Infliximab, adalimumab, and golimumab are monoclonal antibodies. Etanercept is a soluble, bivalent TNF-alpha receptor. Certolizumab pegol is the antigen-binding fragment (Fab') of a humanized monoclonal antibody coupled to polyethylene glycol. Highly similar forms of some of these molecules, termed "biosimilars" are now being tested or have been licensed for use in some countries. A "biosimilar" is defined by the World Health Organization (WHO) as a "biotherapeutic product which is similar in terms of quality, safety and efficacy to an already licensed reference biotherapeutic product" [19]; "similarity" is defined as the "absence of a relevant difference in the parameter of interest." (See "Overview of biologic agents and kinase inhibitors in the rheumatic diseases", section on 'TNF inhibition'.)

Monoclonal antibodies — Infliximab and adalimumab both bind monomeric and trimeric TNF-alpha. Infliximab is a chimeric antibody with human constant region of immunoglobulin G (IgG)1 coupled to the variable regions of mouse anti-TNF-alpha. By contrast, adalimumab is a human monoclonal antibody comprised of the human constant region of IgG1 attached to human variable regions. Adalimumab is, therefore, a fully human monoclonal antibody. Golimumab is a human IgG1 kappa monoclonal antibody specific for human TNF-alpha that binds to both the soluble and transmembrane bioactive forms of human TNF-alpha.

Soluble fusion protein — Etanercept is a fusion protein consisting of two TNFR2 coupled to the constant region of human IgG1. In contrast to infliximab and adalimumab, etanercept binds not only to trimeric TNF-alpha but also to lymphotoxin, a cytokine once known as TNF-beta whose characteristics overlap those of TNF-alpha.

Pegylated Fab' fragment — Certolizumab pegol (formerly CDP870) is a covalently bonded construct consisting of an antigen-binding portion of a monoclonal antibody (Fab' fragment) covalently bonded to polyethylene glycol. The addition of polyethylene glycol may reduce the antigenicity and prolong the half-life of this anti-TNF-alpha agent. In contrast to infliximab and adalimumab, certolizumab does not contain an Fc portion and therefore does not induce complement activation, antibody-dependent cellular cytotoxicity, or apoptosis. The full impact of this structural change on the efficacy of the agent is not clear. Certolizumab is designed to be administered on an every-other-week basis by subcutaneous administration.

Therapeutic differences — Infliximab and adalimumab both have been approved for a broader clinical spectrum of activity than etanercept. For example, the former medications are effective in many cases of inflammatory bowel disease (IBD), uveitis, and sarcoidosis as well as RA, psoriatic arthritis, and the seronegative spondyloarthropathies [20]. In contrast, etanercept does not appear to be effective in IBD or in sarcoidosis [21,22]. Certolizumab pegol, which first received regulatory approval for use in Crohn disease, is now available for use in rheumatoid and psoriatic arthritis and ankylosing spondylitis/spondyloarthropathies in many countries.

ADVERSE EFFECTS

Injection site reactions — Skin reactions characterized by itching, pain, redness, irritation, bruising, or swelling at the site of medication injection are common but usually minor problems with subcutaneously administered agents (eg, etanercept, adalimumab, golimumab, and certolizumab pegol) [23]. Such injection site reactions (ISR) typically occur during the first month of treatment and last for three to five days. They can usually be managed, if needed, with measures including local cold packs, topical corticosteroids, and analgesia, and by varying the injection site; discontinuation of the medication is required in only a small number of patients. ISR generally do not prevent continued therapy. Estimated frequencies of ISR vary. As examples:

In one trial involving adalimumab with concomitant methotrexate, ISR were reported in 30 patients (9 percent) and were most often characterized by erythema, pain, pruritus, other nonspecified reactions, and hematomas (in 14, 8, 7, 4, and 3 patients, respectively) [24]. Reactions were mostly mild, but six were judged as moderate and one was severe, although injections were discontinued in only three patients.

Cumulative incidence of ISR in a six-month study of etanercept was 37 percent [25] but has been lower in some other trials. For example, in a trial comparing originator etanercept (Enbrel) with a biosimilar etanercept (SB4), ISR were more frequent in patients receiving the originator biologic (156 ISR in 51 patients [17 percent] versus 22 ISR in 11 patients [4 percent]) [26]. Most were mild and within two to eight weeks of commencing therapy.

Injection and infusion site reactions occurred in two trials involving certolizumab pegol in about 1 to 6 percent of patients [27,28].

In another trial, ISR were identified up to week 24 in 2 to 5 percent of patients receiving golimumab with methotrexate and 7.5 percent of those on golimumab alone [29].

Infusion reactions — Infusion reactions with infliximab are classified as one of two types:

Acute – Acute reactions are those that occur within 24 hours. Such reactions usually occur between 10 minutes and four hours after the start of the infusion.

Delayed – Delayed reactions develop between 1 and 14 days after the start of treatment but typically occur after five to seven days.

Both acute and delayed infusion reactions can be characterized further as mild, moderate, or severe, depending upon the accompanying signs and symptoms. Approximately 90 percent of infusion reactions that occur with infliximab are acute [30].

Acute infusion reactions — Acute infusion reactions sometimes represent true allergies, ie, immunoglobulin E (IgE)-mediated type I (anaphylactic) reactions that include hypotension, bronchospasm, wheezing, and/or urticaria [31,32]. (See "Anaphylaxis: Emergency treatment".)

True anaphylactic reactions occur in some patients treated with infliximab [33]. However, the great majority of acute infusion reactions that occur with infliximab treatment are characterized more by nonspecific symptoms and are classified more accurately as anaphylactoid (nonallergic) reactions [31]. These reactions are not mediated by IgE.

The frequency and severity of acute infusion reactions were evaluated in a study of 165 consecutive patients who received a total of 479 infliximab infusions [30]. The following observations were made:

Sixteen of the patients (10 percent) experienced at least one infusion reaction

The percentage of infusions that were complicated by a reaction was 6.1 percent

Mild, moderate, or severe reactions occurred in 3.1, 1.2, and 1.0 percent of infusions, respectively

The nature of infusion reactions that occur in the clinic often remains poorly defined. However, two findings in the previous study suggest that the acute infusion reactions did not represent IgE-mediated anaphylactic reactions [30]:

The reactions were generally managed successfully by reducing the rate of infusion. This approach to management would not have been effective for anaphylactic reactions.

In a substudy of 11 patients who suffered a total of 14 acute infusion reactions, both serum tryptase and serum IgE levels were normal in all six patients in whom they were measured [30].

Delayed infusion reactions — Delayed infusion reactions resemble serum sickness in the timing of their onset and their association with skin rash, diffuse joint pains, myalgias, and fatigue, sometimes accompanied by fever. Delayed reactions may represent mild type III (immune complex-mediated) reactions. (See "Serum sickness and serum sickness-like reactions".)

A large observational study using United States Medicare data evaluated the frequency of these hypersensitivity reactions (HSRs) among patients with rheumatoid arthritis (RA) receiving infliximab, abatacept, rituximab, tocilizumab, golimumab by infusion, and injected biologic agents [34]. From 725,591 biologic agent administrations, they identified 248 HSRs among 80,587 new users of biologic agents. Over six months, the cumulative incidence was low (<1 percent), with incidence ratios ranging from 2.4 (abatacept) to 239.5 (rituximab) per 106 person-days. After adjustment, using injectable anti-TNF inhibitor over 0 to 30 days as the referent, rituximab, infliximab, abatacept, and tocilizumab infusions were associated with a higher risk of HSR.

Prevention — A variety of strategies are helpful in preventing infliximab infusion reactions. Through the use of such strategies, infliximab can usually be readministered even to patients who have previously experienced severe (non-anaphylactic) reactions.

Preventive strategies include [30]:

Premedication with diphenhydramine (25 to 50 mg) and acetaminophen (650 mg) 90 minutes prior to infusion. Alternatively, patients can be given a second-generation, non-sedating antihistamine (eg, cetirizine 10 mg).

Use of a test dose of infliximab. The test dose begins at a rate of 10 mL/hour, followed by an increase of the infusion rate as tolerated every 15 minutes until the usual rate of 125 mL/hour is reached.

For patients with a history of anaphylaxis after infliximab, prednisone (50 mg every eight hours) should be given over the 24 hours prior to infliximab infusion, in addition to diphenhydramine and acetaminophen.

The use of methotrexate or azathioprine appears to reduce the risk of infusion reactions, probably through an effect on drug immunogenicity [33]. Strategies designed to combat the effects of antibodies that some patients develop to infliximab are presented elsewhere. (See "Tumor necrosis factor-alpha inhibitors: Induction of antibodies, autoantibodies, and autoimmune diseases".)

Treatment — As noted above, the vast majority of acute infusion reactions that occur with infliximab are not mediated by IgE and are not anaphylactic. The approach to treatment depends upon whether the reaction is graded as mild, moderate, or severe (table 1 and algorithm 1) [35]. Many reactions respond to stopping the infusion temporarily and providing hydration, diphenhydramine, and acetaminophen.

Delayed infusion reactions to infliximab can usually be treated with the combination of acetaminophen (650 mg four times daily) and an antihistamine, either diphenhydramine (50 mg daily or twice daily) or a second-generation antihistamine (eg, loratadine 10 mg daily).

Cytopenias — Neutropenia may occur in patients on tumor necrosis factor (TNF)-alpha inhibitors but is usually mild; other cytopenias are uncommon [36]. Pancytopenia and aplastic anemia are rare [37].

Neutropenia — A decrease in the number of peripheral blood neutrophils is common in patients who receive TNF-alpha inhibitors [36]. Neutropenia, defined as less than 2 X 109 cells/L, occurred during treatment with these medications in 19 percent of 367 patients with inflammatory arthritis [36]. Levels of less than 1.5 X 109/L were seen in 9 percent. The mechanism by which neutropenia occurs on these medications has not been defined.

The risk of neutropenia was significantly higher in patients with a past history of neutropenia while receiving other disease-modifying antirheumatic drugs (DMARDs; hazard ratio [HR] 3, 95% CI 1.7-5.3). Patients with neutropenia also had significantly lower baseline neutrophil counts compared with those who did not (4.2 X 109/L , 95% CI 3.8-4.6, versus 6.2 X 109/L, 95% CI 6.0-6.5). Similar findings were seen regardless of the clinical response to treatment and whether or not patients were also receiving methotrexate.

A decrease in neutrophils was seen in 74 percent of patients after two weeks of therapy (mean decrease in neutrophil counts of 1.1 X 109/L, 95% CI 0.9-1.3). Other white cell subsets, including lymphocytes, monocytes, and basophils, tended to increase (0.3, 0.6, and 0.1 X 109/L, respectively).

Most patients with neutropenia did not require discontinuation of therapy, but persistence or recurrence was often seen in those switched to another TNF-alpha inhibitor. Serious infections occurred in 6 percent (4 of 69) of the patients who experienced neutropenia (less than 2 X 109/L). Less than 1 percent (three) of all patients in the cohort developed a neutrophil count less than 0.5 X 109/L.

Because of the risk of neutropenia among patients treated with TNF-alpha inhibitors, it is appropriate to check a complete blood count within one month of starting one of these agents and then to repeat this test every three to six months, assuming that the patient’s white blood cell count is stable.

Infection — TNF-alpha is an important component of the immune system's response to a variety of infections, and use of TNF-alpha inhibitors has been associated with an increased risk of serious infections. These include bacterial infections (particularly pneumonia), zoster, tuberculosis, and opportunistic infections. (See "Tumor necrosis factor-alpha inhibitors: Bacterial, viral, and fungal infections" and "Tumor necrosis factor-alpha inhibitors and mycobacterial infections".)

Screening for latent tuberculosis infection should be performed before the initiation of TNF-alpha inhibitor therapy because of the increased risk of reactivation of latent tuberculosis. Patients with evidence of latent tuberculosis should initiate treatment for latent tuberculosis before starting a TNF-alpha inhibitor. The appropriate timing for starting a TNF-alpha inhibitor in such patients is discussed separately. (See "Tumor necrosis factor-alpha inhibitors and mycobacterial infections", section on 'Screening and prevention' and "Tumor necrosis factor-alpha inhibitors and mycobacterial infections", section on 'Latent tuberculosis infection'.)

Demyelinating disease — A potential link between TNF-alpha inhibitors and demyelinating disease has been suggested but not proven [38,39]. Concern regarding demyelination or the exacerbation of intercurrent demyelinating diseases in patients treated with TNF-alpha inhibitors stems from the use of a TNF-alpha inhibitor prototype, lenercept, in multiple sclerosis (MS). Lenercept, a recombinant TNF-alpha receptor p55-immunoglobulin fusion protein (sTNFR-IgG p55), was halted in clinical testing because of concerns related to adverse effects. In a clinical trial of 168 MS patients, those treated with lenercept had more frequent and severe exacerbations of MS than did the patients taking placebo [39].

With regard to TNF-alpha inhibitors approved by the US Food and Drug Administration (FDA), a 2001 review of cases of demyelinating disease in the FDA database revealed 19 associated with the use of these agents, 17 with etanercept and 2 with infliximab [40]. Adalimumab, golimumab, and certolizumab pegol had not been approved for clinical use at that time.

The following findings were reported [40]:

Symptoms of demyelination included confusion, ataxia, dysesthesia, and paresthesia.

Neurologic findings included facial nerve palsy, optic neuritis, hemiparesis, transverse myelitis, and ascending motor neuropathy consistent with the Guillain-Barré syndrome.

Magnetic resonance imaging findings suggestive of demyelination were present in the brain or spinal cord in most patients.

All neurologic events had a temporal relationship to anti-TNF-alpha therapy, and all improved partially or completely upon discontinuation of such therapy. One patient who had anti-TNF-alpha therapy reintroduced experienced a recurrence of symptoms.

During the time that the 17 cases of demyelinating disease associated with etanercept use were reported, 77,152 patients received etanercept therapy, representing a total of 55,313 patient-years [40]. The incidence of demyelinating disease in patients receiving etanercept was 31 per 100,000 patient-years of exposure, compared with 4 to 6 per 100,000 per year for the general population.

Similarly, optic neuritis has been reported in association with the use of etanercept, infliximab, and adalimumab [41]. Demyelinating peripheral nervous system disease has also been reported with these drugs [42,43]. In a cohort study using large United States healthcare databases, cases of optic neuritis were rare in patients on TNF inhibitors, with similar crude rates among anti-TNF and nonbiologic DMARD-treated groups (4.5 and 5.4 per 100,000 person-years, respectively) [44].

By contrast, linkage of the large DANBIO inflammatory arthritis cohort in Denmark with a national MS database reported eight incident MS cases that occurred during 113,527 person-years of therapy in the cohort receiving anti-TNF-alpha therapy [45]. When compared with inflammatory arthritis patients never receiving anti-TNF-alpha therapy (four cases), an increased risk of MS was observed in males, (standardized incidence ratio [SIR] 3.5; 95% CI 1.5–8.4) and in patients with ankylosing spondylitis (who were predominantly male; SIR 3.9; 95% CI 1.5–10.4), with an overall cohort SIR of 1.1 (95% CI 0.6–2.0). The number of cases is small and might under-report demyelination cases that do not enter the MS registry.

Although a causal relationship between TNF-alpha inhibitors and demyelinating disease remains uncertain, anti-TNF-alpha agents should generally be avoided in patients with established diseases that are associated with demyelination, such as MS; in addition, anti-TNF-alpha therapy should be discontinued immediately in any patient with suspected demyelination. Some RA experts are also cautious about using TNF-alpha inhibitors in patients with family histories of MS. (See "Evaluation and diagnosis of multiple sclerosis in adults" and "Initial disease-modifying therapy for relapsing-remitting multiple sclerosis in adults".)

Heart failure — Targeted TNF-alpha inhibitor use may be associated with heart failure (HF), although the data are mixed. Concern about this possible adverse effect stems from randomized trials of TNF-alpha inhibitors as a potential therapy for HF and from early postmarketing surveillance data gathered by the FDA [46].

Overview — Data regarding the risk of HF with the use of TNF-alpha inhibitors at the FDA-approved doses are inconclusive [47]. However, the labels of etanercept, infliximab, and adalimumab contain the following disease-related concern: "Use with caution in patients with HF or decreased left ventricular function; worsening and new-onset HF has been reported." In addition, infliximab is contraindicated at doses higher than 5 mg/kg in patients with moderate or severe HF (New York Heart Association [NYHA] class III/IV) (table 2). The golimumab and certolizumab pegol labels include similar wording.

Given the evidence to date, in patients with symptomatic HF, we suggest that treatment strategies other than TNF-alpha inhibitors should be employed. In a patient who develops HF while on a TNF-alpha inhibitor, a drug-induced cause should be suspected, and use of the medication should be suspended.

For patients with RA and mild (NYHA functional class I or II) (table 2) HF whose arthritis is refractory to other DMARDs or biologic agents, targeted TNF-alpha inhibition might be considered. If the use of anti-TNF-alpha treatment is entertained, we suggest the following:

Cardiology consultation

Baseline echocardiography with ejection fraction

Close follow-up

Avoidance of high TNF-alpha inhibitor doses (eg, more than infliximab 3 mg/kg, adalimumab 40 mg every two weeks, or etanercept 50 mg/week)

Prompt discontinuation of anti-TNF-alpha therapy if HF worsens

Despite concerns, the risk of HF remains uncertain, and reassuringly other studies have suggested that patients with RA receiving TNF inhibitors have an overall decrease in the incidence of cardiovascular events compared with those receiving nonbiologic DMARD therapies [48,49].

Clinical trials in heart failure — Clinical trials of both etanercept and infliximab were performed with the hypothesis that TNF-alpha inhibition would improve cardiac function in patients with HF [50-52]. Two major randomized, placebo-controlled trials evaluated etanercept as a possible therapy HF: the RENAISSANCE trial (925 pts) and the RECOVER trial (1123 pts) [50,51].

In the combined analysis of these two trials (ie, RENEWAL), etanercept was found to have no effect on the death or chronic HF hospitalization end point. The relative risk for etanercept-treated patients was 1.1 (95% CI 0.9-1.3). On the basis of prespecified stopping rules, both trials were terminated prematurely because of futility. In addition to excluding any clinically relevant benefit of etanercept on the rate of death or hospitalization due to chronic HF, RENEWAL also raised concerns about the possible exacerbation of HF in some patients treated with TNF-alpha inhibitors.

These concerns were confirmed in a trial involving infliximab as a therapy for HF, known as the ATTACH trial [52]. In this trial, the major inclusion criteria were NYHA class III or IV HF (table 2) and a left ventricular ejection fraction less than 35 percent. One hundred and fifty patients were divided into three treatment groups: placebo, infliximab 5 mg/kg, and infliximab 10 mg/kg. After induction therapy, no further infliximab was given; patients were followed for one year. An analysis of all-cause mortality at one year showed eight deaths (16 percent) in the infliximab 10 mg/kg group, compared with four (8 percent) in both the infliximab 5 mg/kg and placebo groups.

FDA reports of heart failure — The FDA published a summary of 47 cases of HF associated with etanercept or infliximab reported to the Adverse Events Response System (AERS) through February, 2002 [46]. Thirty-eight of these patients developed new-onset HF, and nine experienced an HF exacerbation.

Among the 38 patients with new-onset HF, 19 had no identifiable risk factors such as coronary artery disease, hypertension, history of myocardial infarction, or diabetes, and 10 were under the age of 50 years. After TNF-alpha inhibition was discontinued and therapy for HF began, 3 of these 10 patients had complete resolution of HF, six improved, and one died.

Adalimumab and heart failure — Because of the adverse experiences reported with etanercept and infliximab with regard to HF, no treatment trials of adalimumab in HF have ever been attempted but a review of the safety of adalimumab in global clinical trials was released by the manufacturer [53]. Among 10,050 patients with RA of at least three years' duration who had a total of 12,066 patient-years of exposure to adalimumab, the event rate of HF was 0.26 per 100 patient-years. The HF event rate in 542 patients with less than three years of RA and 917 patient-years of exposure was 0.11 per 100 patient-years. A lower HF event rate (0.05 per 100 patient-years) was noted in an analysis of United States postmarketing safety of adalimumab with 55,384 patient-years of exposure from 2002 to 2004 [54].

Registry data and cohort studies — Data from a registry of patients with rheumatic disease suggested that RA is associated with an increased risk of HF, but that this risk might be attenuated by TNF inhibition [55]. A two-year study of nearly 16,000 patients with either RA or osteoarthritis reported that HF was more common among patients with RA than those with osteoarthritis (3.9 versus 2.3 percent), even after adjustment for differences in baseline demographic characteristics. However, HF was less common among RA patients treated with TNF inhibitors (3.1 versus 3.8 percent), even after adjustments for baseline HF risk factors.

A subsequent study of 20,243 patients from four different healthcare benefit cohorts in the United States, which compared HF risk in new users of TNF inhibitors with new users of nonbiologic (synthetic) DMARDs (with similar baseline covariates), found no significant increase in the risk of either new or recurrent HF in the patients begun on a TNF inhibitor [56]. Oral glucocorticoid use was associated with a dose-dependent increase in the risk of HF, which was seen in patients receiving at least 5 mg daily of prednisone (HR 1.54, 95% CI 1.09-2.19), but glucocorticoid use did not modify the risk with TNF inhibitors. Subgroup analysis found elevated risk in patients who initiated TNF inhibitor therapy before 2002 (HR 2.17, 95% CI 0.45-10.50, test for interaction p = 0.036). The reasons for the increased risk prior to 2002 are uncertain, but in October 2001 a warning was issued regarding HF and TNF inhibitors, and it is possible that patients thought by their treating clinicians to be at increased risk of heart failure were then disproportionately not treated with a TNF inhibitor, resulting subsequently in a lower rate of adverse events.

Additionally, in a cross-sectional study of patients with RA compared with age- and gender-matched controls, the prevalence of HF was not significantly different between patients treated with nonbiologic DMARDs and TNF inhibitors, or other biologic DMARDs (25, 22, and 27 percent, respectively) [57]. Likewise, a cohort of Veterans Administration patients with RA and without RA compared with a similar group who had received anti-TNF therapy showed no difference among the groups in either HF exacerbation or mortality [58].

Pulmonary disease — TNF inhibitors have been used for the treatment of various lung diseases and for systemic inflammatory rheumatic disorders with or without pulmonary manifestations. Adverse effects on the lung have included [59]:

Granulomatous disease – There are a number of case reports of sarcoid-like disease; discontinuation of the TNF inhibitor with or without a course of glucocorticoids generally led to resolution of symptoms.

Pulmonary fibrosis/interstitial lung disease – Most of these patients had RA, many had a background of pulmonary disease (especially interstitial lung disease [ILD]), and methotrexate use was common in this group (and can also be associated with hypersensitivity pneumonitis). ILD appears to have a poorer prognosis than granulomatous disease; some patients die of pulmonary fibrosis. In one study, patients with RA and pre-existing ILD who were receiving TNF inhibitor therapy had similar mortality rates to RA patients with ILD receiving nonbiologic DMARDs [60]. However, more patients receiving TNF inhibitor therapy had the cause of death attributed to ILD, although reporting bias could not be excluded.

Treatment of several pulmonary diseases, including asthma, sarcoidosis, and pulmonary fibrosis, has resulted in inconsistent benefit, usually described in case reports or small studies, but not replicated in larger trials [59]. Benefit has not been observed in chronic obstructive pulmonary disease.

Hepatotoxicity — The risk of hepatotoxicity associated with TNF-alpha inhibitors appears to be small. In January 2004, at least 35 postmarketing reports of severe hepatic reactions had been received by the FDA, leading to a warning to health care professionals [61]. Various types of hepatic involvement have been noted, including acute liver failure, hepatitis, and cholestasis. Fatal liver disease and cases requiring liver transplantation have been reported. The mechanisms involve drug-induced liver injury (DILI), cholestatic liver injury, and autoimmune liver disease.

Most reports of serious liver outcomes pertain to infliximab, often when used at higher doses for Crohn disease. The drug label for all TNF-alpha inhibitor medications carries a warning about the possibility of severe hepatic reactions, with jaundice or marked increase in serum alanine or aminotransferases. Subsequent reviews have further indicated that this rare adverse event may vary according to the disease being treated as well as the type of TNF-alpha inhibitor [62].

The largest study, involving 6861 patients with RA treated with TNF-alpha inhibitors, noted alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) levels >1 times upper limit of normal (ULN) in 17.6 percent of patients, and >2 times ULN in 2.1 percent, most of which were not persistent and did not result in change of therapy [63]. Higher levels, >3 or 5 times ULN, were found in 0.57 and 0.13 percent of cases, respectively (ie, 48 patients, of whom only 5 had pre-existing liver disease). Abnormal liver function tests (LFTs) were increased in those taking concomitant methotrexate and leflunomide. Infliximab was more likely than adalimumab to be related, and etanercept showed no increase compared with patients receiving conventional DMARD therapy.

Compared with RA, other types of arthritis such as psoriatic arthritis are associated with higher rates of concomitant liver disease and may also have higher rates of TNF-alpha inhibitor-induced autoimmune liver disease. A report from Korea found that 23.7 percent of patients (86 out of 363) receiving TNF-alpha inhibitors for ankylosing spondylitis followed for a mean of 3.7 years showed abnormal LFT on two consecutive tests, most one to two times ULN, with 15 percent >3 times ULN [64]. Patients with higher ALT levels were found to have liver disease such as nonalcoholic fatty liver disease. Most patients continued TNF-alpha inhibitors, with LFT changes reverting to normal, followed by subsequent elevation, even in 9 of 13 who changed TNF-alpha inhibitors.

The use and risks of TNF inhibitors in patients with viral hepatitis, including hepatitis B and C, are described separately. (See "Tumor necrosis factor-alpha inhibitors: Bacterial, viral, and fungal infections", section on 'Viral infections' and "Hepatitis B virus reactivation associated with immunosuppressive therapy".)

Cutaneous reactions — A variety of dermatologic conditions have been reported in association with TNF-alpha inhibitors. These include:

Injection site and infusion reactions (see 'Injection site reactions' above and 'Infusion reactions' above)

Cutaneous viral (eg, herpes zoster and varicella), bacterial, and fungal infections (see 'Infection' above)

Psoriasis and psoriatic-like skin changes (see 'Psoriatic skin lesions' below)

Eczematous dermatitis [65]

Cutaneous manifestations of systemic lupus erythematosus (see "Tumor necrosis factor-alpha inhibitors: Induction of antibodies, autoantibodies, and autoimmune diseases", section on 'Systemic lupus erythematosus')

Leukocytoclastic vasculitis (see "Tumor necrosis factor-alpha inhibitors: Induction of antibodies, autoantibodies, and autoimmune diseases", section on 'Vasculitis')

Lichen planus and lichen planus-like eruptions [66]

Rare possible alopecia [67]

The frequency of cutaneous adverse events (CAE) was evaluated in a study involving 5437 patients with chronic rheumatologic diseases who had 17,330 patient-years of exposure to TNF inhibitors (infliximab, etanercept, and adalimumab in 46, 30, and 23 percent, respectively) [68]. A total of 920 CAE were identified (incidence rate [IR] per 1000 patient-years of 53). The most common CAE were infection, infusion reactions, autoimmune skin diseases, and skin malignancy (IR 28, 15, 5, and 3 per 1000 patient-years, respectively). A total of 89 serious CAE occurred (IR 5.1 per 1000 patient-years); drug discontinuation was common (32 percent of all patients and 53 percent of patients with any CAE).

Cutaneous lesions associated with TNF inhibitor therapy have been described in several studies of patients with inflammatory bowel disease (IBD) [69-72]. The largest of these involved a cohort of 917 consecutive patients with IBD on such therapy for a median of 3.5 years, in whom 264 (29 percent) developed skin lesions (12.4 per 100 patient-years) [69]. Specific cutaneous lesions included (from most to least common) psoriasiform eczema, eczema, xerosis cutis, palmoplantar pustulosis, and psoriasis (in 31, 24, 11, 5, and 4 percent, respectively); other abnormalities were present in an additional 26 percent of patients, including bacterial folliculitis, acne vulgaris, alopecia areata, and various other mostly infectious and inflammatory skin lesions. The majority were managed effectively by a dermatologist experienced in seeing such patients and without discontinuation of TNF inhibitor therapy. Limitations of the analysis and its generalizability included the lack of a control group and the early referral within one academic center for evaluation and treatment by a single dermatologist. Generally similar findings are seen in the different studies, although frequencies of specific types of skin lesions do vary between the reports.

Psoriatic skin lesions — Psoriatic skin lesions can be induced by anti-TNF-alpha therapy. The pathogenesis may involve unopposed production of interferon-alpha by skin plasmacytoid dendritic cells as a result of changes in cytokine balance [73-76]:

A 2010 review identified 207 cases in which psoriatic skin lesions developed in patients treated with a variety of anti-TNF-alpha agents for one of several indications, including RA, spondyloarthritis, IBD, and psoriatic arthritis. Pustular psoriasis was common, although all forms were reported [73]. Partial or complete resolution occurred often with psoriasis treatment in most patients, with 66 percent of cases continuing treatment with an anti-TNF-alpha agent. One report of a higher incidence with adalimumab [74] is not supported by the other reports [75].

The FDA reported data from the Food and Drug Administration Adverse Event Reporting System (2004 to 2011) in patients using TNF inhibitors for licensed and approved indications. As this project focused on drugs used in Crohn disease, etanercept was excluded [76,77].

Malignancy — The risk of malignancy associated with the use of TNF-alpha inhibitors is presented separately. (See "Tumor necrosis factor-alpha inhibitors: Risk of malignancy".)

Autoimmunity and autoantibodies — The risk of autoimmunity associated with the use of TNF-alpha inhibitors is presented separately. (See "Tumor necrosis factor-alpha inhibitors: Induction of antibodies, autoantibodies, and autoimmune diseases".)

Pregnancy and breastfeeding — The risks and use of the TNF inhibitors during pregnancy and breastfeeding are described in detail separately. (See "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Tumor necrosis factor inhibitors'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Side effects of anti-inflammatory and anti-rheumatic drugs".)

SUMMARY

The tumor necrosis factor (TNF)-alpha inhibitors have multiple potential adverse events, which include:

Injection site reactions

Infusion reactions

Neutropenia

Infections

Demyelinating disease

Heart failure (HF)

Pulmonary disease

Hepatotoxicity

Cutaneous reactions, including psoriasis

Malignancy

Induction of autoimmunity

Infusion reactions with infliximab are classified as one of two types:

Acute – Acute reactions are those that occur within 24 hours. Such reactions usually occur between 10 minutes and four hours after the start of the infusion. Management of acute infusion reactions depends upon the severity. (See 'Acute infusion reactions' above.)

Delayed – Delayed reactions develop between 1 and 14 days after the start of treatment, but typically occur after five to seven days. (See 'Delayed infusion reactions' above.)

TNF-alpha inhibitors have been associated with the development or exacerbation of neurologic disorders associated with demyelination, such as multiple sclerosis (MS). However, the true nature of this association (real or spurious) has not been established. (See 'Demyelinating disease' above.)

Anti-TNF-alpha therapy should be discontinued immediately in any patient with suspected demyelination. Reported neurologic findings include confusion, ataxia, dysesthesia, paresthesia, facial nerve palsy, optic neuritis, hemiparesis, transverse myelitis, and ascending motor neuropathy.

Targeted TNF-alpha inhibitor use may be associated with the development or exacerbation of HF. Concern about this possible adverse effect stems from randomized clinical trials of TNF-alpha inhibitors as a potential therapy for HF and from postmarketing surveillance data gathered by the US Food and Drug Administration (FDA). (See 'Heart failure' above.)

Patients with symptomatic HF should be treated with strategies other than TNF-alpha inhibitors. In a patient who develops HF while on a TNF-alpha inhibitor, a drug-induced cause should be suspected, and use of the medication should be suspended.

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges John Stone, MD, who contributed to an earlier version of this topic review.

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