253eases [ 82 ]. The majority of reported cases have complete or near-complete resolution
of neurological symptoms after discontinuation of anti-TNF therapy and the addi-
tion of glucocorticoid [ 81 , 82 , 84 , 86 ]. In the case series by Andreadou et al., all four
patients were asymptomatic at 3-month follow-up after discontinuation of the
offending drug, treatment with intravenous corticosteroid, and a prednisone taper
[ 86 ]. Mohan et al. noted that one patient had a positive rechallenge with etanercept
[ 82 ]. Patients who develop demyelinating diseases while on anti-TNF therapy are
not recommended to be rechallenged with the same or a different anti-TNF agent
[ 82 , 84 ].
Heart Failure
Clinical Presentation
Anti-TNF therapy, previously thought to be a potential treatment option for heart
failure, has been shown to be associated with new onset or progression of heart
failure [ 92 ]. More than two decades ago, Levine et al. demonstrated that patients
with advanced heart failure, on average, had a higher serum level of TNF-α when
compared with age-matched healthy controls [ 93 ]. Despite initial data demonstrat-
ing short-term safety and clinical improvement in patients with New York Heart
Association (NYHA) Class III or greater heart failure [ 94 , 95 ], large randomized
placebo-controlled trials with etanercept were terminated early due to poor clinical
outcome and a trend toward increased mortality [ 96 , 97 ]. Another prospective ran-
domized placebo-controlled trial demonstrated that high-dose infliximab (10 mg/kg)
was associated with increased hospitalization and increased risk of death (hazard
ratio 2.84, 95% CI 1.01–7.97, p = 0.04) [ 98 ].
The true incidence of anti-TNF therapy-related heart failure is unknown. The
majority of knowledge is based on information obtained from drug monitoring data-
bases and adverse event reporting systems where overreporting, underreporting, or
misclassification of diagnosis may occur. Furthermore, the lack of denominators
makes it impossible to calculate event rates. In safety analyses of 10,050 RA patients
treated with adalimumab, new-onset heart failure was reported in 0.3% and progres-
sion of heart failure was reported in 7% of patients [ 99 ]. The overall rate of heart
failure associated with adalimumab based on these analyses was 0.06 events per 100
patient-years in the post-marketing surveillance [ 99 ]. Similarly, in a nationwide
comprehensive monitoring system for RA patients treated with etanercept in Sweden,
there was a reported heart failure rate of 0.04 events per 100 patient-years [ 100 ].
In 2003, Kwon et al. published a case series describing reports of heart failure
after anti-TNF therapy, using the FDA’s MedWatch program [ 92 ]. A total of 38
patients had new onset and nine patients had worsening heart failure after receiving
either etanercept or infliximab [ 92 ]. The median age among the 38 patients with
new-onset heart failure was 62 years (range 17–87 years) and the median age among
the nine patients with heart failure exacerbation was 70 years (range 57–74 years)
14 Noninfectious and Nonmalignant Complications of Anti-TNF Therapy