Abstract Anti-TNF-α therapies are the latest class of medications found to be associated with drug-induced lupus, a distinctive entity known as anti-TNF-α-induced lupus (ATIL) (Williams et al., Rheumatology (Oxford) 48:716-20,  2009; De Rycke et al., Lupus 14:931-7, 2005; De Bandt et al.,  Clin Rheumatol 22:56-61, 2003). With the widespread use of these agents, it is likely that the incidence of ATIL will increase. The onset of ATIL in patients with rheumatoid arthritis and Crohn&apos;s disease has been described, but the literature regarding the occurrence of this entity in patients with ankylosing spondylitis (AS) is scarce (De Bandt et al., Clin  Rheumatol 22:56-61, 2003; Ramos-Casals et al., Autoimmun  Rev 9:188-93, 2010; Perez-Garcia et al., Rheumatology  45:114-116, 2006). To our knowledge, few reports of switching anti-TNF-α therapy after ATIL in AS have been reported (Akgül et al., Rheumatol Int, 2012). Therefore, it is not clear whether the development of ATIL should prohibit switch to another therapy, since patients may respond to another anti-TNF-α agent (Akgül et a

Armando Malcata

Cátia Duarte

José António Pereira Da Silva

João Rovisco

Mariana Galante

Santiago

Tânia Santiago

CiteSeerX

CASE BASED REVIEW
A case of infliximab-induced lupus in a patient with ankylosing
spondylitis: is it safe switch to another anti-TNF-α agent?
Tânia Santiago & Mariana Galante Santiago &
João Rovisco & Cátia Duarte & Armando Malcata &
José António Pereira da Silva
Received: 1 June 2013 /Revised: 8 July 2013 /Accepted: 31 July 2013 /Published online: 17 August 2013
# Clinical Rheumatology 2013
Abstract Anti-TNF-α therapies are the latest class of medi-
cations found to be associated with drug-induced lupus, a
distinctive entity known as anti-TNF-α-induced lupus
(ATIL) (Williams et al., Rheumatology (Oxford) 48:716–20,
2009; De Rycke et al., Lupus 14:931–7, 2005; De Bandt et al.,
Clin Rheumatol 22:56–61, 2003). With the widespread use of
these agents, it is likely that the incidence of ATIL will
increase. The onset of ATIL in patients with rheumatoid
arthritis and Crohn's disease has been described, but the liter-
ature regarding the occurrence of this entity in patients with
ankylosing spondylitis (AS) is scarce (De Bandt et al., Clin
Rheumatol 22:56–61, 2003; Ramos-Casals et al., Autoimmun
Rev 9:188–93, 2010; Perez-Garcia et al., Rheumatology
45:114–116, 2006). To our knowledge, few reports of
switching anti-TNF-α therapy after ATIL in AS have been
reported (Akgül et al., Rheumatol Int, 2012). Therefore, it is
not clear whether the development of ATIL should prohibit
switch to another therapy, since patients may respond to
another anti-TNF-α agent (Akgül et al., Rheumatol Int,
2012; Bodur et al., Rheumatol Int 29:451–454, 2009;
Mounach et al., Clin Exp Rheumatol 26:1116–8, 2008;Williams
and Cohen, Int J Dermatol 50:619–625, 2011; Ye et al., J
Rheumatol 38:1216, 2011; Wetter and Davis, Mayo Clin Proc
84:979–984, 2009; Cush, Clin Exp Rheumatol 22:S141–147,
2004; Kocharla and Mongey, Lupus 18:169–7, 2009). A lack of
published experience of successful anti-TNF-α switching is a
cause of concern for rheumatologists faced with this challenging
clinical scenario. We report the case of a 69-year-old woman
with AS who developed infliximab-induced lupus, which did
not recur despite the subsequent institution of etanercept. The
authors review and discuss ATIL and the possible implications
for subsequent treatment with alternative anti-TNF-α agents.
Keywords Ankylosing spondylitis . Anti-TNF-α .
Anti-TNF-α-induced lupus . Drug-induced lupus . Infliximab
Case presentation
A 69-year-old female patient, with active ankylosing spondy-
litis (AS) (according to the modified New York criteria), was
referred to our department. The patient was initially treated
with sulfasalazine and nonsteroidal anti-inflammatory drugs
with an inadequate clinical response. Sulfasalazine was
discontinued, and she was started on infliximab 5mg/kg every
6 weeks with subsequent remission of the disease. Eight
months after the initiation of infliximab, she gradually devel-
oped general malaise, dyspnea, and acute thoracic pain.
On admission, she presented with dyspnea on exertion,
decreased breath sounds in the lung bases, and low arterial
oxygen saturation (94 %). The patient did not have fever or
skin lesions.
Laboratory investigations revealed positive titers of antinu-
clear antibody (ANA; 1:1,280), anti-double-stranded antibody
(anti-dsDNA, 23.8U/ml; normal, <4.2U/ml), and anti-histone
antibodies (45 U/ml; normal, <40 U/ml). Other anti-
extractable nuclear antigens as well as anti-cardiolipin anti-
bodies were negative. Additionally, C-reactive protein (CRP)
was 13.7 mg/dl (normal, <0.5 mg/dl), and erythrocyte sedi-
mentation rate (ESR) was 100 mm (normal, <20 mm/h). Full
blood count, renal function, and serum C3 and C4 comple-
ment component levels were all within the normal range.
Chest radiography revealed cardiomegaly and diffuse bilateral
infiltrates. High-resolution computed tomography demon-
strated pericardial and small bilateral pleural effusions.
The corresponding author certifies that all authors approved the entirety
of the submitted material and contributed actively to the study.
T. Santiago (*) :M. G. Santiago : J. Rovisco :C. Duarte :
A. Malcata : J. A. P. da Silva
Clínica Universitária de Reumatologia (CURe), Hospitais da
Universidade de Coimbra, Praceta Mota Pinto,
3000-075 Coimbra, Portugal
e-mail: tlousasantiago@hotmail.com
Clin Rheumatol (2013) 32:1819–1822
DOI 10.1007/s10067-013-2361-9
Cultures of bronchoalveolar lavage were negative for bacteria
and fungi.
The diagnosis of infliximab-induced lupus-like syndrome
was established, and this medication was discontinued. Under
methylprednisolone (16 mg/day), diuretics, and oxygen ther-
apy, the pericardial and pleural effusion regressed dramatical-
ly. Her general health status improved, and on the 30th day of
treatment, CRP was 1.6 mg/dl, and ESR was 12 mm/h.
Twelve weeks later, she presented a severe flare of AS,
with widespread peripheral arthritis. Methotrexate was initiat-
ed at increasing doses up to 25 mg/week, associated with
methylprednisolone (6 mg/day). A repeat antibody profile
showed that anti-dsDNA antibody titers had decreased
(7.44 U/ml). At 6 months, her disease remained off control,
and the patient was started on etanercept (50 mg/week). Her
symptoms responded promptly to this medication. At the most
recent evaluation (8 months after starting etanercept), the
patient remained asymptomatic with no recurrence of lupus
symptoms, with anti-dsDNA being undetectable.
Discussion
Most of the previously reported cases of switch therapy after
anti-TNF-α-induced lupus (ATIL) occurred in patients with
rheumatoid arthritis (RA), psoriatic arthritis, and Crohn's dis-
ease [3]. Only a few cases were reported in AS [6]. Our patient
has tolerated the switch to etanercept without recurrence of
ATIL, suggesting that its occurrence should not prohibit
switching patients from one anti-TNF-α to another. The
presence of ATIL is less frequently observed in AS than in
RA. The latest update of the Spanish Study Group of Biolog-
ical Agents in Autoimmune Diseases (BIOGEAS) registry
reported only ten (7 %) patients with AS, compared to 101
patients (72 %) with RA, in a total of 140 patients who
developed ATIL [4]. Unfortunately, the total number of pa-
tients exposed to the risk per disease group is not provided in
the publication.
ANA positivity after anti-TNF-α therapy is well docu-
mented in AS (over 50 % of infliximab-treated patients and
10 % of etanercept-treated patients); however, this phenome-
non has not been associated with a greater risk of developing
ATIL [4].
Hereafter, the authors highlight relevant questions for rheu-
matologists faced with this challenging scenario in clinical
practice. To this purpose, wemade a careful search and review
of case series and single case reports published in the literature
on patients who have received an alternative anti-TNF-α after
ATIL (Table 1) [6–11]. A total of 15 cases were identified
(including our patient).
Are the diverse anti-TNF-α agents associated with different
risks of ATIL?
ATIL has been reported to occur with all anti-TNF-α agents,
thus seemingly representing a class effect [1, 2]. A retrospec-
tive French national study of patients with rheumatic diseases
on anti-TNF-α therapies estimated the incidence ATIL at
around 0.19 % for infliximab-treated patients, 0.18 % for
etanercept-treated patients, and 0.10 % for adalimumab-
Table 1 Summary of the reports describing patients treated with an alternative anti-TNF-α agent after ATIL
Article Patient
number
Diagnosis Anti-TNF-α-
inducing ATIL
Anti-TNF-α
after ATIL
Time between the two
therapies (months)
Follow-up
(months)
Lupus symptoms
recurrence
Cush [12] 1 RA IFX ADA Nr Nr No
2 RA ETA ETA Nr Nr No
3 Crohn's disease ETA ETA Nr Nr No
4 RA ETA ETA Nr Nr No
Wetter and Davis [11] 1 Crohn's disease IFX ADA 38 6 No
2 Crohn's disease IFX ADA 2 42 No
3 RA IFX ETA 19 41 No
4 RA IFX ADA 8 2.5 No
5 Crohn's disease IFX ETA, IFX, ADA 0 2 Yes (arthritis)
Kocharla and Mongey [13] 1 Crohn's disease IFX ADA 13 9 No
Ye et al. [10] 1 RA ADA ETA 1 48 No
2 RA IFX ETA 36 30 No
Williams and Cohen [9] 1 RA ADA, ETA Gol 0 6 No
Akgül et al. [6] 1 AS IFX ETA 1 3 No
This study 1 AS IFX ETA 6 6 No
IFX infliximab, ADA adalimumab, ETA etanercept, Gol golimumab, Nr not reported
1820 Clin Rheumatol (2013) 32:1819–1822
treated patients [5]. Only one patient was reported to have
developed ATIL while receiving certolizumab [2]. No cases
were reported with golimumab.
As these biologic agents have similar mechanisms of ac-
tion, it is difficult to understand the differences in the devel-
opment of ATIL, but one of the hypothesis is that it may be
due to differences in bioavailability, the stability of the drug/
TNF complex, and possibly, the development of autoanti-
bodies and antidrug antibodies [5].
Should the occurrence of ATIL impose the withdrawal
of the causative anti-TNF-α agent?
BIOGEAS recently issued guidelines for the management of
autoimmune diseases associated with anti-TNF-α [4, 5]. They
recommend that the treatment should be tailored to the sever-
ity of individual clinical and immunological presentation. For
mild involvement (general features, articular, or cutaneous),
the group recommends withdrawal of anti-TNF-α therapy but
allows the option of continuing therapy under close supervi-
sion if the physician feels this to be indicated. For severe
involvement (pulmonary, renal, or neurological), the cessation
of anti-TNF-α therapy together with the initiation of cortico-
steroids and other immunosuppressive agents is required.
Our patient developed severe pulmonary involvement with
pericardial and pleural effusion, and we decided to stop the
anti-TNF-α agent and to start oral glucocorticoids.
In general, ATIL presents with mild findings that improve
within several months (mean, 2.9 months; range, 1–6 months)
after stopping the anti-TNF-α therapy [5]. In our case, the
ATIL developed 8 months after therapy, and its manifestations
ceased within 3 months after discontinuation of infliximab,
which is consistent with previous reports.
Can patients with ATIL be safely switched to an alternative
anti-TNF-α agent?
There is limited evidence to support or refute the safety of
switching to another anti-TNF-α agent (Table 1). However, 14
of the 15 patients who were switched to another anti-TNF-α
after ATIL tolerated the new treatment without recurrence of
lupus symptoms [6–13].
One report describes four patients who successfully re-
ceived an alternative anti-TNF-α agent after ATIL, without
recurrence of symptoms; three patients continued treatment
with the causative anti-TNF-α agent (etanercept); and the
fourth patient received adalimumab [12]. Wetter and Davis'
describe 14 patients with ATIL, of which five were
rechallenged with alternative anti-TNF agents. In four cases
initially treated with infliximab, the switch was successful to
adalimumab (three patients) and etanercept (one patient) [11].
The fifth of these patients, who represents the only published
case of recurrence of ATIL after anti-TNF switch, was initially
treated with etanercept and failed the switch to both
adalimumab and infliximab in separate attempts. Williams
and Cohen reported recently a successful case of initiation of
golimumab for 6 months after etanercept-induced lupus in a
patient with RA [9].
Recently, another investigator reported a patient with AS
who developed infliximab-induced lupus but did not recur
after switching to etanercept [6].
Based in our review, the mean follow-up after the switch
was 17.7 months (range, 2–48 months), with four (36 %)
patients having at least 24 months of follow-up (Table 1)
[6–13].
Are all anti-TNF-α agents equally safe as alternative agents?
Adalimumab (six patients) and etanercept (nine patients) were
the two alternative agents chosen for the 14 patients who
attempted to continue anti-TNF-α therapy. Successful switch
to infliximab or rituximab has not been documented. On the
basis of this scarce evidence available, etanercept and
adalimumab would seem to be the agents of choice as alter-
natives to infliximab and, to each other, in the case of ATIL.
However, these findings have to be interpreted cautiously.
Based on our review of the literature and experience, many
patients with ATIL will tolerate another anti-TNF-α agent
without recurrence. Thus, the condition seems to be drug
specific rather than class related. Hence, this condition should
not be taken as an absolute contraindication to an alternative
anti-TNF-α agent, even if these patients should be carefully
monitored for signs and symptoms of relapse.
Disclosures None.
References
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Anti-TNF alpha-induced systemic lupus erythematosus. Clin
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Clin Rheumatol (2013) 32:1819–1822 1821
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to another? Lupus 18:169–7
1822 Clin Rheumatol (2013) 32:1819–1822


A case of infliximab-induced lupus in a patient with ankylosing spondylitis: is it safe switch to another anti-TNF-α agent?

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A case of infliximab-induced lupus in a patient with ankylosing spondylitis: is it safe switch to another anti-TNF-α agent?

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