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Onset of LLS has been reported to range from 10 days to 54 months after initia-
tion of anti-TNF [ 60 ]. In a case series of 92 patients who developed SLE or LLS
after anti-TNF therapy (infliximab = 40, etanercept = 37, and adalimumab = 15), the
mean latency of onset was 41 weeks after anti-TNF therapy [ 54 ]. Clinical and
immunologic data were available in 72 of these patients: 68 (94%) had positive
autoantibodies, 57 (79%) with positive ANA, 52 (72%) with dsDNA antibodies, 8
(11%) with antiphospholipid antibodies, and 7 (10%) with anti-Smith antibodies
[ 54 ]. Sixty-four (89%) patients had cutaneous features, 28 (39%) had musculoskel-
etal manifestations, and 21 (29%) had systemic symptoms including fever, malaise,
and asthenia [ 54 ]. SLE cutaneous features including malar rash, photosensitivity,
and/or discoid lupus were seen in 48 (67%), arthritis in 22 (31%), cytopenia in 16
(22%), serositis in 9 (12%), and nephropathy in 5 (7%).
Risk Factors
Patients who develop autoantibodies and LLS tend to be older and of female gender
[ 53 – 55 , 61 , 62 ]. When Beigel et al. examined factors associated with the develop-
ment of LLS in IBD patients treated with an anti-TNF therapy, they found that
increased age is a risk factor for developing ANA titers ≥ 1:240 (odds ratio 1.06,
95% CI 1.03–1.09, P < 0.001) and for developing LLS (odds ratio 1.08, 95% CI
1.03–1.13, P = 0.002) [ 52 ]. Moulis et al. analyzed 39 LLS cases associated with
anti-TNF therapy, the majority of patients who were affected were females with a
female to male ratio 10:1 [ 62 ]. Similarly, in the case series by Ramos-Casals et al.
where epidemiologic data was available for 62 patients who developed LLS after
anti-TNF therapy, there was a female to male ratio of 5:1 [ 54 ]. These findings are
similar to the female to male ratio in patients with SLE. A meta-analysis consisting
of 16 studies with a total of 11,934 SLE patients demonstrated an average female to
male ratio of 9:1 [ 63 ]. SLE is more prevalent in women because of differences in the
metabolism of sex hormones [ 64 ].
The two antibodies ANA and dsDNA, part of the immunologic criteria for SLE,
have been examined as potential predisposing factors for the development of LLS
[ 52 , 54 ]. In the case series by Ramos-Casals et al., 72 patients with anti-TNF
therapy- related lupus met SLE criteria; 57 (79%) and 52 (72%) of these patients
were found to have positive ANA and dsDNA, respectively [ 54 ]. However, the
threshold titers used for positivity of these two antibodies were not reported [ 54 ]. In
another case series published by Biegel et al. consisting of 180 IBD patients treated
with an anti-TNF therapy, dsDNA antibody values ≥9 U/mL were shown to be
associated with the development of LLS (P = 0.02) [ 52 ]. In this cohort, no associa-
tion was found between ANA titer ≥ 1:240 and development of LLS [ 52 ].
Given the low incidence of LLS and limited data, it remains unclear whether
concomitant immunomodulator is protective against autoantibody formation and
development of LLS. In the case series published by Biegel et al. described previ-
ously, concomitant immunomodulator was shown to be protective against ANA
U. Wong and R.K. Cross