Autoimmunity Reviews 20 (2021) 102752

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Autoimmunity Reviews
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Tolerance and efficacy of anti-TNF currently used for severe non-infectious uveitis

A R T I C L E I N F O

Keywords
Uveitis
Anti-TNF
Adalimumab
Infliximab

Dear Editor, incidence rate of overall infections (0.45 versus 0.13, p = 0.01) and ENT
and dental infections (0.40 versus 0.08, p = 0.003). No permanent
Adalimumab obtained Marketing Authorization in Europe for severe
discontinuation of treatment due to any side effect was made. Anti-
non-infectious uveitis in 2018. However, experts in the uveitis field had
TNFαs are known to have potentially severe side effects, in particular by
been using anti-TNFs long before that date, convinced of their efficacy
facilitating infections. Nevertheless, our study shows a very reassuring
and safety [1,2]. In our expert uveitis center, we have been using anti-
incidence rate of adverse events (0.31 PPY). This incidence rate is lower
TNFs (adalimumab and/or infliximab) since 2005 for chronic severe
than those reported in prospective studies (4.2 and 10.5 PPY) [3–6]. No
non-infectious uveitis. We wanted to assess the safety conditions and
death or stay in intensive care was reported. The data are highly reas­
determine the predictive factors of efficacy in a retrospective study. All
suring even though the period since our study was made is insufficiently
the patients who received an anti-TNF (infliximab and/or adalimumab)
long to really assess the risk of cancer or demyelinating diseases [7,8].
for severe chronic non-infectious uveitis before 2018 were included. The
Our data suggests that infliximab causes more adverse side effects than
relapse and the state of ocular inflammation (quiescent or active) were
adalimumab with a significant difference in the incidence rate of in­
defined in accordance with the criteria of the Visual I and II studies
fections, including ENT and dental infections. This difference in toler­
[3,4]. 39 patients were included (74 eyes) and contributed to 90 ob­
ance was also found in other studies [2,9]. In our study population, no
servations. The baseline characteristics of patients were stratified ac­
patient had their treatment permanently discontinued due to intoler­
cording to quiescent (n = 13) or active (n = 26) uveitis at the initiation of
ance. Our observational study suggests that anti-TNF agents are effica­
anti-TNFα therapy (Table 1). 11 patients (22 eyes) were treated by
cious in preventing inflammatory relapse in patients treated for the
infliximab and 28 patients (52 eyes) were initially treated by adalimu­
acute phase of non-infectious uveitis. Our relapse rate was 11% at 1 year
mab. Among patients initially treated adalimumab, 6 patients (10 eyes)
and 19% at 2 years. In a more recent prospective study, the relapse rate
were secondarily treated by infliximab. Immunosuppressive load and
was estimated at 0.2 PPY, or 20% at 1 year [10]. Few studies have
corticosteroid sparing were analyzed separately using a linear regression
evaluated the benefit of anti-TNF therapy in patients with quiescent
model for continuous quantitative dependent variables. The median
uveitis. The goal of biotherapy is to keep the inflammation quiescent
daily corticosteroid dose decreased significantly in the two uveitis sub­
without corticosteroids or immunosuppressants. In VISUAL II, the 1-year
groups (p = 0.03 for quiescent, p < 0.001 for active). The median
relapse rate was approximately 45% [4]. In our series, the 1-year (4%)
immunosuppressive load had also decreased significantly 24 months
and 2-year (16%) relapse rates were lower. In the VISUAL III study, 74%
after initiation of biotherapy but only for the active subgroup: p = 0.25
patients remained quiescent at week-78 (compared to 85% at baseline),
for quiescent, p < 0.01 for active. Out of 90 observations, 14 relapses
with a higher relapse rate [5]. In a retrospective study with adalimumab,
were observed, with a median follow-up duration of 1.6 years. The
the relapse rate was 22% at 1 year [11]. Indeed, as for active uveitis,
probability of relapse was 0.04 (95% CI, 0.01 to 0.25) and 0.11 (95% CI,
efficacy and/or relapse rates vary among studies depending on the
0.05 to 0.23) at one year and 0.16 (95% CI, 0.05 to 0.42) and 0.19 (95%
populations included, and the precise outcomes considered. Our study
CI, 0.09 to 0.37) at two years, for quiescent uveitis and active uveitis,
confirms the corticosteroid-sparing effect of anti-TNFα, with a signifi­
respectively (Fig. 1). None of the factors studied was significantly
cant reduction in corticosteroid therapy from the first 6 months of
associated with relapse: age, sex, type of uveitis, etiologies, and previous
treatment onwards. This reduction is essential to reduce corticosteroid
treatments. No stay in intensive care or death was reported. 31 patients
side effects [12]. Between 61 and 93% reduction in corticosteroid intake
experienced an adverse reaction during treatment, with an incidence
was obtained depending on the study [2,13,14]. Complete discontinu­
rate of 0.31 adverse events per patient-year (PPY). Twenty patients
ation of steroids has been obtained in 39 to 93% of patients
presented with an infectious episode during follow-up, with an inci­
[10,11,14,15]. These rates are better than those obtained (20–40%)
dence rate of 0.20 PPY. Overall, infliximab treatment was less well
using conventional immunosuppressive treatments [16–19]. The
tolerated than adalimumab treatment with a significant difference in the

https://doi.org/10.1016/j.autrev.2021.102752
Received 26 October 2020; Accepted 1 November 2020
Available online 18 January 2021
1568-9972/© 2021 Elsevier B.V. All rights reserved.
N. Coste et al. Autoimmunity Reviews 20 (2021) 102752

Table 1
Baseline patient characteristics (n = 39).
Characteristics Quiescent (n = 13) Active (n = 26) P

Age, y, median 52 (43–60) 44 (24–58) 0.10

Male gender, n (%) 7 (54) 16 (62) 0.65
Etiologies, n (%) 0.006
None 0 (…) 12 (46)
Birdshot chorioretinopathy 4 (31) 6 (23)
Serpiginous choroidopathy 2 (15) 0 (…)
Vogt-Koyanagi-Harada disease 2 (15) 1 (3.9)
Sarcoidosis 0 (…) 1 (3.9)
Behçet disease 2 (15) 3 (11)
Spondylarthropathy 2 (15) 1 (3.9)
Relapsing polychondritis 1 (7.7) 0 (…)
Rheumatoid/ Juvenile arthritis 0 (…) 2 (7.8)
Bilateral uveitis, n (%) 13 (100) 24 (92) 0.54
Indication for biotherapy, n (%) 0.60
Corticosteroid dependence 3 (23) 4 (15)
Corticosteroid resistance 0 (…) 1 (3.9)
Anterior treatment failure 6 (46) 14 (54)
Anterior treatment side effects 4 (31) 4 (15)
Uveitis severity 0 (…) 3 (11)
Time from diagnosis to treatment, month median 10 (6–14) 4 (1–7) 0.004
History of immune suppressive therapy, n (%) 12 (92) 18 (69) 0.22
Methotrexate 3 (23) 7 (27) 0.79
Mycophenolate mofetil 4 (31) 5 (19) 0.45
Azathioprine 7 (54) 10 (38) 0.36
Ciclosporine 6 (46) 4 (15) 0.04
Interferon 1 (7.7) 1 (3.8) 0.99
Intravenous immunoglobulines 1 (7.7) 3 (11) 0.99
Therapy with oral corticosteroids, n (%) 10 (77) 21 (81) 0.78
Prednisone dosage, mg/jour, median 10 (6–20) 20 (9–35) 0.25
Baseline immune suppressive burden, median 2 (1–3) 2 (1–5) 0.41

In univariate analysis, the characteristics of the patients at inclusion were compared using the Chi-square test or Fisher’s exact
probability; and the Student test or Wilcoxon’s non-parametric test in case of skewed distribution, for quantitative variables.

present study also shows that anti-TNFα treatment allows an overall
reduction in the use of all types of immunosuppressant, with a signifi­
cant decrease in the immunosuppressant load from the first 6 months of
treatment, but in the active uveitis subgroup only. In Behçet’s disease
with ocular involvement, infliximab reduced the need for immunosup­
pressive therapy in 68% of cases, and allowed a complete stop of
immunosuppressive therapy in 10–33% of cases [20,21]. Our study has
several limitations: retrospective data collection and the relatively small
number of patients included may explain why seemingly relevant clin­
ical differences could not be validated due to a lack of statistical power.
We evaluated adalimumab and infliximab indifferently and the study
design did not allow a direct comparison of the two treatments, although
they appear to be comparable according to several studies, nor the effect
of the frequency and/or dose of the treatments [2,22,23]. In conclusion,
this observational study suggests that the use of anti-TNFs for uveitis is
safe and effective. No predictor of good clinical response could be
identified. Adalimumab and infliximab appear to be equivalent in terms
of efficacy, but it should be noted that tolerance seems less good for
infliximab.

Fig. 1. Kaplan-Meier estimates of relapse for uveitis

treated with biotherapy (n = 90).
The time to relapse since the initiation of biotherapy
was analyzed as survival data, and right censored.
The proportion of relapse-free patients was estimated
at various time-points (6 months, 1 year, and 2 years)
using the Kaplan Meier method. The statistical unit of
analysis was the treatment regimen with one of the
two anti-TNFαs, for each eye. Thus, a patient’s eye
could be included twice in the analysis if the patient
had successively received one and then the other of
the two anti-TNFαs, regardless of the order of these
treatments. The relapse hazard ratios associated with
the characteristics at inclusion were estimated using a
“frailty” model to take into account the non-
independence of variables from the same patient.

2
N. Coste et al.
Acknowledgement
We thank Alison Foote (Grenoble Alpes University Hospital, France)
for translating the manuscript.
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Nicolas Costea,b,*, Alexis Bocquetc,*, José Labarered,
Rachel Semecasa,b,e, Florent Aptela,b,e, Alban Derouxc,
Laurence Bouilletc,*, Christophe Chiqueta,b,e
a
Grenoble Alpes University, Grenoble, France
b
Department of Ophthalmology, Grenoble Alpes University Hospital,
Grenoble, France
c
Department of Internal Medicine, Grenoble Alpes University Hospital,
Grenoble, France
d
Quality of Care Unit, INSERM CIC1406, Grenoble Alpes University
Hospital, Univ. Grenoble Alpes, Grenoble F-38043, France
e
Hypoxia and Physiopathology Laboratory HP2, INSERM U1042,
University Grenoble Alpes, Grenoble, France
*
Corresponding author at: Grenoble Alpes University, Grenoble,
France.
E-mail address: LBouillet@chu-grenoble.fr (L. Bouillet).