245formation (p = 0.05) and LLS development (p = 0.04) [ 52 ]. Others have found that
ANA and dsDNA can be detected in CD patients despite being on concurrent immu-
nomodulator while receiving infliximab, but how this rate compares to those who
are not on concurrent immunomodulator is unclear [ 12 , 58 ].
Pathophysiology
The pathophysiology of anti-TNF therapy-induced LLS is not clearly defined, but
several hypotheses have been proposed on the development of autoantibodies. Anti-
TNF therapy induces apoptosis in inflammatory cells; the release of antigenic par-
ticles during this process may stimulate autoantibody formation in susceptible
individuals and may lead to the development of LLS [ 60 , 65 ]. This hypothesis is
supported by the finding of increased plasma nucleosome levels after infliximab
treatment [ 66 ]. Another hypothesis is that patients on anti-TNF therapy are prone to
infection which would activate polyclonal B lymphocytes to stimulate autoantibody
production [ 60 ]. A third potential mechanism by which TNF antagonists could
induce autoantibody formation is by humoral autoimmunity activation via inhibi-
tion of cytotoxic T-lymphocyte response [ 60 ].
Diagnosis and Management
Diagnosis of LLS requires early recognition of a constellation of symptoms including
arthralgia, joint swelling, myalgia, rash, erythema, fever, and/or serositis in patients
treated with anti-TNF therapy [ 52 , 55 ]. In patients with only joint manifestations, the
differential diagnosis includes delayed hypersensitivity reaction to infliximab, type 1
or 2 arthritis related to underlying IBD, and other causes. Oral ulcers and classic
malar rash associated with SLE are less common in LLS, but patients with LLS can
present with an erythematous purpuric rash and photosensitivity [ 54 , 56 ]. LLS rarely
involves the central nervous or the renal systems [ 55 , 56 ]. Although there are no diag-
nostic criteria for LLS, the diagnosis of LLS is generally made based on clinical
features as described previously, the presence of ANA and anti-dsDNA autoantibod-
ies, and notable improvement of symptoms within days or weeks after the offending
drug is discontinued. The ANA and anti-dsDNA titers used in the report by Biegel
et al. for the diagnosis of LLS were ≥1:240 and ≥9 U/mL though different thresholds
for autoantibody positivity have been used in other studies [ 52 , 58 ].
Autoantibody formation is common after treatment with anti-TNF therapy. As
such, there is a subgroup of patients who develop drug-induced autoimmunity in the
form of elevated autoantibody titers without clinical symptoms [ 53 ]. It is not recom-
mended for these patients to have their anti-TNF withdrawn, because few actually
progress to develop LLS [ 53 ]. As such, we do not recommend that providers serially
monitor ANA and dsDNA levels in patients being treated with anti-TNF agents.
14 Noninfectious and Nonmalignant Complications of Anti-TNF Therapy