dear editor, Tuberculosis (TB) is one of the top 10 causes of death worldwide, with
approximately 10·0 million (range 9·0–11·1) active TB cases in 2017, occurring in
all countries and age groups, and estimates of 1·7 billion people having latent TB
infection (LTBI).1, 2 The lifetime risk for reactivation of LTBI is 5–10%,1 and some
immunosuppressant therapies increase this risk.3 Data on TB risk after anti‐interleukin
(IL)‐17A treatment in people are limited,4, 5, 6, 7 with no cases of LTBI reactivation
reported so far.3
We performed a post hoc analysis of the integrated safety data from 11 phase I–III
clinical trials of patients with moderate‐to‐severe plaque psoriasis treated with
any dose of the anti‐IL‐17A antibody ixekizumab.5 We report the baseline rates and
long‐term outcomes of 5730 patients, including patients with a history of treated
active TB or newly diagnosed LTBI. At screening, patients diagnosed with active TB
were excluded from participation, whereas patients with a documented history of successfully
treated TB without subsequent re‐exposure could enter the study. Presumed LTBI was
based on a positive tuberculin skin test (TST), defined as ≥ 5 mm induration 2–3 days
after intradermal injection, or interferon‐γ release assay [IGRA; QuantiFERON®‐TB
Gold or Gold‐In‐Tube (Cellestis, CA, U.S.A.), or T‐SPOT.TB® (Oxford Diagnostic Laboratories,
Memphis, TN, U.S.A.)]. Patients with LTBI were included after they underwent ≥ 4 weeks
of LTBI‐specific therapy (isoniazid and/or rifampicin) without hepatotoxicity and
completed an appropriate course of treatment during the trial. Patients were retested
annually. The integrated analysis included 5730 patients with a total of 13 479 patient‐years’
exposure to ixekizumab (median 1006 days, range 1–2236). The majority were white (n
= 5028; 87·8%) and male (n = 3874; 67·6%) with a mean ± SD age of 45·9 ± 13·1 years
and duration of psoriasis of 18·8 ± 12·2 years. Multiple data collection methods were
used to maximize the identification of historical TB cases and/or presumed LTBI at
baseline. We identified 188 patients (3·3%) meeting one or more of the following,
based on medical history data‐entry terms: (i) positive IGRA results (n = 111; 1·9%);
(ii) positive TST results (n = 31; 0·5%); (iii) documented history of TB in the medical
history data‐collection form [n = 104 (1·8%): one pulmonary TB; three TB (unspecified);
one erythema induration; 95 LTBI or positive TB test; four unspecified]; and (iv)
documented history of completing TB treatments in the previous or concomitant medication
data‐collection form [n = 123 (2·1%): one TB, 101 LTBI or positive TB test; 21 unspecified].
These 188 patients were enrolled in the studies: upon retesting, four had positive
IGRA/TST results after 286–819 days on ixekizumab treatment, with three discontinuing
and one continuing ixekizumab.
The risk of active TB in the general population varies significantly worldwide and
is associated with LTBI prevalence.1, 2 The majority of the study population (n =
4676; 81·6%) came from countries with a low incidence rate of active TB.1 Region‐specific
analysis of the presumed LTBI cases in ixekizumab‐treated populations confirmed a
smaller proportion of positive IGRA/TST results/LTBI cases at baseline in lower‐burden
regions than in regions with a higher burden of active TB (Table 1). During ixekizumab
treatment, 72 patients (1·3%) developed treatment‐emergent LTBI or positive IGRA/TST
results. Patients identified at < 52 weeks discontinued from the study owing to protocol
requirements; after protocol amendment, patients identified at ≥ 52 weeks with no
signs of active TB could remain in the study with concurrent LTBI therapy.7 During
the observation period (including a protocol‐specified minimum 12‐week follow‐up after
the last scheduled or early termination visit), no cases of active TB were reported
in the ixekizumab clinical development programme.
Table 1
Baseline latent tuberculosis cases by region ranked according to World Health Organization
(WHO) tuberculosis incidence rate
WHO region
TB incidencea
Safety population (n = 5730)b
LTBI baselinec
The Americas
28
3238 (56·5)
82 (2·5)
Europe
30
2114 (36·9)
83 (3·9)
Western Pacific
94
378 (6·6)
23 (6·1)
Eastern Mediterranean
113
0 (0)
0
South‐East Asia
226
0 (0)
0
Africa
237
0 (0)
0
All Regions
133
5730 (100)
188 (3·3)
Data cut‐off date was February 2017. TB, tuberculosis; LTBI, latent tuberculosis infection.
aActive TB infection cases/100,000 population (data from WHO).1
bPatients receiving ≥ 1 dose of ixekizumab in published studies (see Langley et al.).5
cIncludes cases positive for any of the following: tuberculin skin test, interferon‐γ
release assay, history of TB, completed TB treatments.
John Wiley & Sons, Ltd
Group size and study length are important factors when investigating infrequent safety
events, including LTBI reactivation or Mycobacterium tuberculosis infection. This
report includes one of the largest cohorts of patients treated with an IL‐17A inhibitor
and represents one of the longest exposures to ixekizumab reported to date. Nevertheless,
this study is limited by the lack of a suitable longer‐term control group.
Available data do not indicate that anti‐IL‐17A treatments increase the risk of active
TB in patients with a history of active TB or with LTBI.5, 6, 7, 8 The findings are
encouraging and of particular value to physicians who treat patients with an elevated
risk of TB. Nevertheless, ixekizumab should not be administered to patients with active
TB, and prophylactic treatment should be initiated in patients with LTBI before starting
ixekizumab treatment and completed in line with country‐specific guidelines. Regular
evaluation of patients for risk factors, and signs and symptoms of active TB is indicated
while on any immunomodulatory treatment.