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Management of anti-TNF therapy-associated LLS involves withdrawal of anti-
TNF therapy with or without the addition of steroids or an immunosuppressive
agent. In the report by Ramos-Casals et al., 72/77 (94%) cases had withdrawal of
anti-TNF therapy, 31/77 (40%) of patients were treated with corticosteroids, and
7/77 (12%) received immunosuppressive agents (3 methotrexate, 1 cyclophospha-
mide, 1 leflunomide, 1 mycophenolate, and 1 azathioprine). All but one patient was
noted to have improvement [ 54 ]. It is important to keep in mind that despite
improvement in clinical symptoms after drug discontinuation, the elevated serologi-
cal markers may persist [ 53 ].
With resolution of symptoms after anti-TNF therapy is withdrawn, it is unclear
whether it would be safe to continue treatment with a different anti-TNF therapy
[ 60 ]. Our current knowledge on patient’s tolerance of alternative anti-TNF therapy
is limited to case reports [ 59 , 60 , 67 ]. Kocharla and Mongey reported a case where
a patient with CD developed infliximab-related LLS and was rechallenged with
adalimumab with no recurrence of LLS after 9 months of follow-up [ 67 ]. In a retro-
spective review by Wetter et al., 4 (80%) of 5 patients demonstrated no adverse
effects after treatment with a different anti-TNF therapy after developing LLS while
being treated with infliximab [ 59 ]. Three of these patients tolerated adalimumab as
an alternative treatment for 6 months, 8 months, and 42 months, respectively [ 59 ].
The other patient tolerated etanercept for 41 months [ 59 ]. The fifth patient in this
cohort tolerated etanercept for 2 months following discontinuation of infliximab.
However, the LLS reemerged 9 months after infliximab was reintroduced despite
the use of corticosteroid premedication before each infusion; there was also recur-
rence of LLS after switch from infliximab to adalimumab [ 59 ].
As the use of anti-TNF therapy becomes more common, it is essential for clini-
cians to promptly recognize symptoms and serological markers associated with
LLS. In most cases, withdrawal of drug results in resolution of LLS; however 40%
of patients will need a course of prednisone, and 12% will need an immune
suppressant to resolve the symptoms [ 54 ]. Given limited data on clinical outcomes
after patients with LLS are rechallenged with an alternative anti-TNF agent, clini-
cians should use caution with introduction of an alternative anti-TNF, especially as
more therapies become available for the treatment of IBD.
Hepatotoxicity
Clinical Presentation
Hepatotoxicity is a rare complication of anti-TNF therapy [ 68 – 71 ]. With lack of
population-based studies, the majority of our knowledge comes from case reports
and case series [ 68 – 71 ]. The true incidence of anti-TNF-related hepatotoxicity is
unknown but is estimated to be less than 1% [ 68 , 69 , 71 ]. Rodrigues et al. reviewed
medical records of over 600 patients undergoing anti-TNF therapy; they found only
seven patients who developed hepatitis with autoimmune features during anti-TNF
U. Wong and R.K. Cross