Etanercept

General adverse effects and adverse reactions

The therapeutic use and safety of etanercept have been reviewed [ ]. Mild-to-moderate injection site reactions were the most common adverse effects (42–49%), with a frequency 3.8–6 times greater than with placebo. Non-neutralizing antibodies to etanercept were rarely detected. Etanercept-treated patients more often developed new antinuclear antibodies or anti-double-stranded DNA antibodies, but no patient developed symptoms suggestive of an autoimmune disease during clinical trials.

Comparative studies

In a study of weekly oral methotrexate in two different doses (10 or 25 mg) or twice-weekly etanercept in 632 patients, etanercept produced fewer systemic adverse effects than methotrexate, but a higher incidence of injection site reactions [ ]. Despite theoretical concerns about the development of autoimmune reactions in patients taking etanercept, no evidence of clinical autoimmune disease emerged from this large trial.

In a double-blind study of 682 patients with rheumatoid arthritis randomized to etanercept alone, methotrexate alone, or a combination of the two, the rate of adverse events or study discontinuation related to an adverse event was similar in the three groups [ ]. In particular, there were no differences in the rates of infection and severe infections. There were no cases of tuberculosis, opportunistic infections, demyelinating diseases, or severe blood dyscrasias among the 454 patients who received etanercept, but only 363 completed the 1-year study. One etanercept-treated patient died from heart failure and suspected sepsis.

Placebo-controlled studies

In a double-blind study in 672 patients randomized to either placebo or etanercept subcutaneously at a low dose (25 mg once weekly), a medium dose (25 mg twice weekly), or a high dose (50 mg twice weekly) significantly more patients had improved psoriasis area-and-severity indices with etanercept compared with placebo at weeks 12 and 24 [ ]. Adverse events and infections occurred in similar proportions in each group. There were no cases of tuberculosis or opportunistic infections. Laboratory abnormalities were of mild to moderate intensity and did not necessitate withdrawal. Eight patients who received etanercept had serum samples positive for anti-etanercept antibodies. There were no differences in efficacy or adverse event profiles between these patients and those without antibodies.

In a double-blind, placebo-controlled study, 112 patients were randomized to placebo or etanercept 25 mg subcutaneously twice a week for 24 weeks [ ]. Etanercept resulted in significant improvements in psoriasis area-and-severity indices. Similar numbers of patients had adverse events in the two groups. Injection site reactions occurred more often with etanercept than placebo (9% versus 0% respectively). One patient who received etanercept developed guttate psoriasis, which was considered to be possibly related to the drug and another had worsening psoriasis after 4 days. Both withdrew from the study.

Favorable safety data have been observed in a phase III randomized controlled study (24-week studies) of etanercept in patients with chronic plaque psoriasis [ ].

Systematic reviews

In a systematic review of double-blind, randomized, controlled trials of alefacept (n = 3), efalizumab (n = 5), etanercept (n = 4), and infliximab (n = 4); in patients with psoriasis the relative risks of one or more adverse events in were significantly increased compared with placebo:

• alefacept: RR = 1.09; NNT _H = 15;

• efalizumab: RR = 1.15; NNT _H = 9;

• infliximab: RR = 1.18; NNT _H = 9.

Serious adverse events were increased in a sensitivity analysis of four efalizumab trials (n = 2443; RR = 1.92; NNT _H = 60) [ ].

Respiratory

The typical histological morphology of pulmonary rheumatoid nodules that developed during etanercept treatment has been reported [ , ]. Pulmonary granulomas during etanercept treatment can be coincidental and difficult to distinguish from other pulmonary complications, such as relapse of tuberculosis. In two patients with rheumatoid arthritis who underwent lung biopsy for etanercept-associated pulmonary granulomas, there were non-caseating granulomas containing birefringent particulate in one [ ] and caseating necrosis in the other [ ]. Infectious causes were ruled out. After etanercept withdrawal, the lesions resolved completely with steroid treatment in the first patient but persisted over 1 year despite antituberculosis treatment in the other.

Another case of pulmonary nodulosis in a patient taking etanercept has been reported [ ].

• A 50-year-old woman with rheumatoid arthritis was given etanercept 25 mg twice weekly and after 9 months developed pulmonary nodulosis. The etanercept was continued and there was no further progression of the nodulosis. Her symptoms resolved over time.

In three cases interstitial lung disease was exacerbated during standard dosage treatment regimens with etanercept [ , ].

Two patients receiving etanercept developed severe diffuse alveolar infiltrates culminating in ground-glass changes on high-resolution CT scans of the lung [ ].

• A 59-year-old woman with a 5-year history of seropositive erosive rheumatoid arthritis developed a demyelinating syndrome during etanercept therapy [ ].

Nervous system

Postmarketing warnings about etanercept that have been issued by regulatory agencies and the manufacturers relate to a possible increased risk of demyelinating disorders, such as multiple sclerosis, myelitis, and optic neuritis, in patients with pre-existing or a recent history of demyelinating disorders [ ]. This was in keeping with the results obtained in a placebo-controlled trial of lenercept, another recombinant tumor necrosis factor alfa receptor immunoglobulin fusion protein, in 168 patients with multiple sclerosis; compared with placebo, significantly more patients randomized to lenercept had exacerbation of multiple sclerosis, and exacerbation also occurred earlier [ ].

Transverse myelitis of abrupt onset has also been reported [ ].

• A 45-year-old woman with resistant rheumatoid arthritis was given etanercept 25 mg twice weekly. Nine days later she developed total acute sensory loss, with flaccid paraplegia, fecal incontinence, and urinary retention. MRI imaging and cerebrospinal fluid analysis were consistent with a diagnosis of transverse myelitis. She also had positive antinuclear and anticardiolipin antibodies. After etanercept withdrawal and treatment with dexamethasone and cyclophosphamide, her motor function improved with no change in sensory function.

Neurological events suggestive of demyelinating disorders in patients treated with tumor necrosis factor alfa antagonists and reported to the FDA’s Adverse Events Reporting System have been reviewed [ ]. These included 17 cases temporarily associated with etanercept and two with infliximab, but complete information was lacking in a number of cases. One additional case with etanercept was more extensively detailed. The first symptoms occurred after a large range of delay after first drug administration (1 week to 15 months; mean 5 months) and mostly included paresthesia, optic neuritis, and confusion. MRI scans in 19 patients showed demyelination in various brain areas in 16. Although a causal relation was not proven, it is noteworthy that most patients improved after withdrawal and one patient had recurrent neurological symptoms after etanercept readministration. The various hypothetical mechanisms by which tumor necrosis factor alfa antagonists might produce demyelinating events have been discussed elsewhere [ ]. Briefly, they cause increased peripheral T cell autoreactivity, and their inability to cross the blood–brain barrier may account for exacerbation of central demyelinating disorders.

There have been further reports of demyelinating disorders in patients taking etanercept.

• A 37-year-old woman with rheumatoid arthritis was given subcutaneous etanercept 25 mg twice a week and developed demyelinating disease, which resolved after withdrawal of etanercept [ ].

• After 24 months of treatment with etanercept 50 mg a week for rheumatoid arthritis a 66-year-old woman developed demyelination in the spinal cord and cerebral cortex [ ].

• After 3 months treatment for rheumatoid arthritis with etanercept 25 mg twice weekly a 60-year-old patient developed reversible posterior leukoencephalopathy syndrome [ ].

• A 36-year-old woman received etanercept 25 mg twice weekly for psoriasis arthritis and developed multiple sclerosis after 4 months; even though the etanercept was withdrawn relapsing remitting multiple sclerosis persisted [ ].

• A 74-year-old woman developed progressive multifocal leukoencephalopathy after receiving a standard dosage of etanercept for rheumatoid arthritis for 7 months [ ].

• A 46-year-old woman with rheumatoid arthritis was given etanercept and after 22 months developed ophthalmic manifestations of demyelination of the central nervous system [ ]. Etanercept was withdrawn. Her symptoms abated but progressed about 2 months later. She was reported to have sequelae of the demyelination, despite some improvement 1 year after diagnosis.

Sensory systems

There have been two reports of anterior uveitis associated with etanercept in a 44-year-old woman with ankylosing spondylitis and a 31-year-old woman with juvenile rheumatic disease, both of whom had responded well to etanercept [ , ]. Both had a long-standing rheumatic disease with no previous episodes of uveitis before etanercept and one patient had severe relapse of uveitis on etanercept rechallenge. By contrast, two other patients who responded to etanercept, but also developed scleritis or uveitis, fully recovered with local and systemic treatment despite etanercept continuation [ ]. Although it was difficult to establish whether this condition was related to the underlying disease or to etanercept, these reports at least suggest that etanercept may fail to prevent ocular involvement in rheumatic disease.

• A 59-year-old woman developed symptomatic bilateral peripheral visual field loss shortly after starting to take etanercept [ ].

Four cases of optic neuritis associated with etanercept were revealed by a retrospective chart review between January 2003 and January 2005 in two Israeli medical centers (the Assaf Harofeh Medical Center and the Kaplan Medical Center) [ ].

Endocrine

• Transient hyperthyroidism occurred after 6 months of etanercept treatment in a 37-year-old woman with rheumatoid arthritis [ ].

However, a direct causal relation with etanercept was debatable, because there was complete resolution with propranolol and despite continuation of etanercept.