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Journal of
Clinical Medicine
Review
Old and New Challenges in Uveitis Associated with
Behçet’s Disease
Julie Gueudry 1, * , Mathilde Leclercq 2, David Saadoun 3,4,5 and Bahram Bodaghi 6
Citation: Gueudry, J.; Leclercq, M.;
Saadoun, D.; Bodaghi, B. Old and
New Challenges in Uveitis
Associated with Behçet’s Disease. J.
Clin. Med. 2021,10, 2318. https://
doi.org/10.3390/jcm10112318
Academic Editor: Pascal Sève
Received: 13 April 2021
Accepted: 24 May 2021
Published: 26 May 2021
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1Department of Ophthalmology, Hôpital Charles Nicolle, F-76000 Rouen, France
2Department of Internal Medicine, Hôpital Charles Nicolle, F-76000 Rouen, France; mat3leclercq@gmail.com
3
Department of Internal Medicine and Clinical Immunology, AP-HP, Centre National de Références Maladies
Autoimmunes et Systémiques Rares et Maladies Autoinflammatoires Rares, Groupe Hospitalier
Pitié-Salpêtrière, F-75013 Paris, France; david.saadoun@aphp.fr
4Sorbonne Universités, UPMC Univ Paris 06, INSERM, UMR S 959,
Immunology-Immunopathology-Immunotherapy (I3), F-75005 Paris, France
5Biotherapy (CIC-BTi), Hôpital Pitié-Salpêtrière, AP-HP, F-75651 Paris, France
6Department of Ophthalmology, IHU FOReSIGHT, Sorbonne-AP-HP, Groupe Hospitalier Pitié-Salpêtrière,
F-75013 Paris, France; bahram.bodaghi@aphp.fr
*Correspondence: julie.gueudry@chu-rouen.fr; Tel.: +33-2-32-88-80-57
Abstract:
Behçet’s disease (BD) is a systemic vasculitis disease of unknown origin occurring in
young people, which can be venous, arterial or both, classically occlusive. Ocular involvement is
particularly frequent and severe; vascular occlusion secondary to retinal vasculitis may lead to rapid
and severe loss of vision. Biologics have transformed the management of intraocular inflammation.
However, the diagnosis of BD is still a major challenge. In the absence of a reliable biological marker,
diagnosis is based on clinical diagnostic criteria and may be delayed after the appearance of the
onset sign. However, therapeutic management of BD needs to be introduced early in order to control
inflammation, to preserve visual function and to limit irreversible structural damage. The aim of
this review is to provide current data on how innovations in clinical evaluation, investigations and
treatments were able to improve the prognosis of uveitis associated with BD.
Keywords: uveitis; retinal vasculitis; Behçet’s disease; anti-TNFαagent; tocilizumab; biologics
1. Introduction
Behçet’s disease (BD) is a systemic inflammatory disease of unknown origin, first
described by Hulusi Behçet, a Turkish dermatologist, in 1937. BD is a systemic form of
vasculitis of all calibers, involving both arteries and veins, affecting the entire body, at the
borderline between autoimmune diseases and auto-inflammatory
syndromes [1,2]
. BD
features include intraocular inflammation, arthritis, oral and genital ulcerations and skin le-
sions, but multiple visceral localizations (neurological, gastrointestinal and cardiovascular)
may also be involved. The evolution is unpredictable, due to more or less regressive flares.
Uveitis is one of the most severe complications of the disease [
3
]. Until the late 1990s, the
visual prognosis of patients with BD uveitis was unsatisfactory [
4
]. Since then, progress in
biologic therapy has transformed visual outcomes.
The aim of this review is to provide current data on how earlier diagnoses based on
clinical evaluation and investigations as well as therapeutic innovations and strategies
have greatly improved the prognosis of uveitis associated with BD.
2. Methodology and Literature Search
We conducted an unsystematic narrative review by selecting articles written in English
and French from PubMed/MEDLINE database published until March 2021. The keywords
used to screen the database were searched in Medical Subject Headings (MeSH) and
J. Clin. Med. 2021,10, 2318. https://doi.org/10.3390/jcm10112318 https://www.mdpi.com/journal/jcm
J. Clin. Med. 2021,10, 2318 2 of 21
were: (Behçet’s disease) AND (uveitis) AND (diagnosis) OR (prognosis) OR (therapy), and
(Behçet’s disease) AND (biologics) OR (biological agents).
3. Epidemiology of Uveitis Associated with Behçet’s Disease
BD has two main epidemiological characteristics that strongly guide the diagnosis.
Firstly, it is widespread throughout the world but is particularly present in the Mediter-
ranean basin, the Middle East and Asia, following the Silk Road. Average prevalence
rates are 20–420/100,000 inhabitants for Turkey, 2.1–19.5 for other Asian countries, 1.5–15.9
for southern Europe and 0.3–4.9 for northern Europe [
5
]. Interestingly, immigrants from
regions with a high prevalence of BD keep the same high risk close to that observed in their
countries of origin, highlighting the important role of genetics in BD [
5
], yet familial cases
are not frequent (less than 5%) [
6
]. However, a strong link with human leukocyte antigens
(HLA), specifically HLA-B51, was found, but the presence of HLA-B51 is insufficient to
confirm or invalidate BD diagnosis [7]. The second main epidemiological characteristic is
the occurrence of BD in young adults of both genders, most often between 15 and 45 years
old. Occasionally, BD can occur in young people below the age of 16 years in 4 to 26% of
cases and carries a strong genetic component. Boys have the worst outcomes with more
frequent neurological, ocular and vascular disease [8].
4. Prognosis of Behçet’s Disease Uveitis over Time
Ocular involvement is common in BD and is potentially severe, as it is sight-threatening.
BD uveitis may be responsible for a large number of cases of blindness or low vision in
countries where BD has a high prevalence. Several data have shown an improvement
in visual prognosis in treated patients. The oldest studies, before the 1980s, showed an
extremely poor visual prognosis. Mamo demonstrated in 1970 that in 39 BD patients,
the average length of time for blindness in the right or the left eye was approximately
3.6 years [
9
]. A lower rate of visual loss was described in patients managed after 1990,
interpreted as a reflection of the availability of cyclosporin A. The risk of vision impairment
at 5 and 10 years in male and female patients was 21% versus 10% and 30% versus 17%,
respectively [
10
]. The same team reviewed the records of patients managed in 1990–1994
and in 2000–2004. Visual acuity at three years was 20/200 or worse in 43/156 (27.6%) eyes
in the first group and 26/201 (12.9%) eyes in the second group (p< 0.001); this trend was
explained by an earlier aggressive therapy notably using conventional Disease-Modifying
Antirheumatic Drugs (cDMARDS) and biologics [
11
]. However, based on most recent
series, the blindness rate remained between 11 and 25% [12].
5. Diagnosis of Uveitis Associated with Behçet’s Disease
The diagnosis of BD remains a clinical diagnosis of exclusion in the absence of specific
biological or histological markers. In incomplete forms, particularly in the absence of
cutaneous and mucosal lesions or in patients with inaugural uveitis, the diagnosis is
difficult, whereas the visual prognosis depends on the rapid initiation of appropriate
treatment. In low-prevalence areas, the diagnosis may not be established, especially since
uveitis with hypopyon is frequent in uveitis associated with HLA-B27 and other multiple
etiologies may cause retinal vasculitis. It is therefore essential to be able to diagnose BD
as early as possible by recognizing the associated ophthalmologic features and applying
specific and relevant diagnostic criteria both for ocular involvement and systemic disease.
5.1. Diagnosis of Systemic Behçet’s Disease
BD diagnosis is based on clinical classification criteria. The key mucosal features
in BD are oral and genital ulcers, recurrent and disabling [
7
,
13
]. Other skin lesions in-
clude pseudofolliculitis or erythema nodosum. Joint involvement is mostly non-erosive
monoarthritis. However, BD is often not diagnosed until several years after the appearance
of the onset sign [
14
]. Several classification criteria for BD diagnosis exist. The International
Study Group (ISG) criteria, established in 1990, required the presence of oral ulcers and at
J. Clin. Med. 2021,10, 2318 3 of 21
least two other items, including genital ulcer, dermatological lesion, i.e., pseudofolliculitis
and/or erythema nodosum, ocular involvement and/or pathergy phenomenon [
15
]. Its
sensitivity has been estimated at 85%, linked to the fact that criteria could fail to recognize
atypical and/or early BD clinical presentation, especially since the criterion of oral ulcers
is mandatory [
16
]. To improve its sensitivity, these criteria were revised in 2013, in the
International Criteria for the Classification of Behçet’s Disease (ICBD), which assigns a
score of 2 points each for ocular lesions, oral ulcers and genital ulcers, and 1 point each
for skin lesions, central nervous system involvement and vascular manifestations. The
pathergy test, when used, was assigned 1 point. A patient scoring
≥
4 points is classified
as having BD with an estimated sensitivity of 94.8% [
17
]; the aim is to obtain a definite
and earlier diagnosis in order to avoid severe complications by referring patients to expert
centers to begin appropriate treatment. In countries where BD is rare, like France, diagnosis
seems more probable in patients from geographical areas where BD is highly prevalent;
likewise, BD family history increases the likelihood of diagnosis [7].
5.2. Diagnosis of Uveitis Associated with Behçet’s Disease
5.2.1. Clinical Characteristics and Investigations
Uveitis is the most frequent form of ocular involvement and is described in 28 to 70%
of patients according to the literature [
1
,
18
]. Both the anterior and posterior segments of the
eye may be affected. Nonetheless, other uncommon presentations of ocular involvement
are described, such as conjunctival ulcers, episcleritis, scleritis, keratitis, isolated optic
neuritis, papilledema, orbital inflammation and extraocular muscle palsies. The age at
onset is between 20 and 30 years, rarely at 50 years or older. Panuveitis is the most frequent
presentation and is more commonly found in men. Ocular involvement is mostly bilateral,
i.e., around 80%, and can be the initial presentation. Bilateralization can occur and may
be rapid, on average 2 years. A large retrospective Turkish study of 880 patients with
BD uveitis has shown that male patients have a younger age at onset and more severe
disease [10].
BD uveitis has several distinctive clinical features that distinguish it from other uveitic
entities and from other systemic autoimmune diseases. Ocular uveitis is characterized by
recurrent flares of intraocular inflammation. Isolated anterior uveitis is rare and affects
less than 15% of patients. It is clinically manifested by sudden acute onset, visual acuity
decrease, ocular redness, periorbital pain, photophobia and tearing. BD uveitis is always
non-granulomatous, associated with anterior chamber flare and cells. It may be compli-
cated by posterior synechiae. Hypopyon reflects the severity of uveitis. The incidence of
hypopyon in other large series of BD uveitis ranges from 5.4 to 32.4% [
19
]. Recurrence
of anterior uveitis may be complicated by glaucoma. Ocular hypertonia is the result of
angle closure by anterior synechiae or pupillary closure, inflammation or local or systemic
corticosteroid administration [12].
Posterior ocular involvement is the most frequent and the most severe form of uveitis,
as it affects the visual prognosis. It manifests itself by an isolated decrease in visual acuity
or may be asymptomatic. It can present white-yellowish, hemorrhagic retinitis areas of
variable number and distribution. Their presence may be associated with a severe loss of
vision when the macular area is involved (Figure 1).
Vitreous haze and cells may limit access to the fundus. Vasculitis in BD is frequent
and most of the time venous but can be arterial or both. BD vasculitis is classically
occlusive in nature [
19
]. These peripheral ischemic areas may be complicated by preretinal
or papillary neovascularization, which may cause retinal hemorrhage, vitreous hemorrhage
or neovascular glaucoma. Macular edema may occur and affect the visual prognosis. In
the case of significant bilateral papilledema, cerebral imaging should be performed to
detect cerebral thrombophlebitis or inflammatory neuropathy. Capillaropathies are seen
on fluorescein retinal angiography [
12
]. Complications caused by recurrent posterior
inflammatory flares include retinal atrophy, vascular sclerosis, optic atrophy, neovascular
glaucoma and retinal detachment [3].
J. Clin. Med. 2021,10, 2318 4 of 21
J. Clin. Med. 2021, 10, x FOR PEER REVIEW 4 of 22
(a) (b)
(c) (d)
Figure 1. (a) Retinal photography of the right eye of a patient with Behçet’s disease showing a
white infiltrate in the inter-papillomacular area associated with retinal edema and hemorrhage. (b)
Fluorescein angiography showing vascular staining in the involved area. (c) Two months later,
retinal photography showing retinal and optic atrophy with resolution of the infiltrate. (d) Two
months later, spectral domain OCT scan showing atrophy of the inner retinal layers.
Vitreous haze and cells may limit access to the fundus. Vasculitis in BD is frequent
and most of the time venous but can be arterial or both. BD vasculitis is classically occlu-
sive in nature [19]. These peripheral ischemic areas may be complicated by preretinal or
papillary neovascularization, which may cause retinal hemorrhage, vitreous hemorrhage
or neovascular glaucoma. Macular edema may occur and affect the visual prognosis. In
the case of significant bilateral papilledema, cerebral imaging should be performed to de-
tect cerebral thrombophlebitis or inflammatory neuropathy. Capillaropathies are seen on
fluorescein retinal angiography [12]. Complications caused by recurrent posterior inflam-
matory flares include retinal atrophy, vascular sclerosis, optic atrophy, neovascular glau-
coma and retinal detachment [3].
Identification of ocular posterior segment involvement is essential for the diagnosis,
to define severity and prognosis and to monitor response to treatment. Sequential retino-
graphy of transient retinal lesions such as vasculitis or retinal necrosis areas can guide the
diagnosis. Moreover, localized retinal nerve fiber layer defects not associated with a reti-
nochoroidal scar, in the absence of glaucoma, could guide diagnosis of BD uveitis. They
are linked to past foci of retinitis, which are transient and resolve without scar formation,
and so could be missed [20].
Fluorescein angiography (FA) is the gold standard imaging modality for retinal vas-
culature. FA is a mandatory tool for the assessment of inflammatory fundus conditions
due to posterior uveitis; the leakage on FA identifies retinal vasculitis and is a crucial
Figure 1.
(
a
) Retinal photography of the right eye of a patient with Behçet’s disease showing a white
infiltrate in the inter-papillomacular area associated with retinal edema and hemorrhage. (
b
) Fluo-
rescein angiography showing vascular staining in the involved area. (
c
) Two months later, retinal
photography showing retinal and optic atrophy with resolution of the infiltrate. (
d
) Two months
later, spectral domain OCT scan showing atrophy of the inner retinal layers.
Identification of ocular posterior segment involvement is essential for the diagno-
sis, to define severity and prognosis and to monitor response to treatment. Sequential
retinography of transient retinal lesions such as vasculitis or retinal necrosis areas can guide
the diagnosis. Moreover, localized retinal nerve fiber layer defects not associated with a
retinochoroidal scar, in the absence of glaucoma, could guide diagnosis of BD uveitis. They
are linked to past foci of retinitis, which are transient and resolve without scar formation,
and so could be missed [20].
Fluorescein angiography (FA) is the gold standard imaging modality for retinal vascu-
lature. FA is a mandatory tool for the assessment of inflammatory fundus conditions due
to posterior uveitis; the leakage on FA identifies retinal vasculitis and is a crucial marker
for BD uveitis activity [
21
]. Specific signs of inflammatory activity include increased retinal
vein tortuosity, vessel wall staining and leakage from retinal vessels and from the optic
disc (Figures 2and 3). Fern-like capillary leakage is the most characteristic FA finding of
BD uveitis and may be present even when uveitis seems inactive.
J. Clin. Med. 2021,10, 2318 5 of 21
J. Clin. Med. 2021, 10, x FOR PEER REVIEW 5 of 22
marker for BD uveitis activity [21]. Specific signs of inflammatory activity include in-
creased retinal vein tortuosity, vessel wall staining and leakage from retinal vessels and
from the optic disc (Figures 2 and 3). Fern-like capillary leakage is the most characteristic
FA finding of BD uveitis and may be present even when uveitis seems inactive.
Figure 2. Late phase of ultra-wide field fluorescein angiography showing papillary hyperfluorescence, extensive retinal
capillaropathy and peripheral occlusive vasculitis in Behçet’s disease uveitis.
Figure 3. Late phase of ultra-wide field fluorescein angiography showing peripheral capillaropathy and vasculitis in the
macular area responsible for visual acuity loss during Behçet’s disease uveitis.
Optical Coherence Tomography (OCT) is based on an optical phenomenon, combin-
ing the analysis of wavelengths of reference light and light reflected by the structures of
the eye. OCT produces axial section images of the fundus. OCT is complementary to FA,
in particular to diagnose and to monitor macular complications such as macular edema,
retinal cysts, retinal serous detachment, epiretinal membranes, vitreomacular traction, fo-
veal atrophy and macular holes [22].
Figure 2.
Late phase of ultra-wide field fluorescein angiography showing papillary hyperfluorescence, extensive retinal
capillaropathy and peripheral occlusive vasculitis in Behçet’s disease uveitis.
J. Clin. Med. 2021, 10, x FOR PEER REVIEW 5 of 22
marker for BD uveitis activity [21]. Specific signs of inflammatory activity include in-
creased retinal vein tortuosity, vessel wall staining and leakage from retinal vessels and
from the optic disc (Figures 2 and 3). Fern-like capillary leakage is the most characteristic
FA finding of BD uveitis and may be present even when uveitis seems inactive.
Figure 2. Late phase of ultra-wide field fluorescein angiography showing papillary hyperfluorescence, extensive retinal
capillaropathy and peripheral occlusive vasculitis in Behçet’s disease uveitis.
Figure 3. Late phase of ultra-wide field fluorescein angiography showing peripheral capillaropathy and vasculitis in the
macular area responsible for visual acuity loss during Behçet’s disease uveitis.
Optical Coherence Tomography (OCT) is based on an optical phenomenon, combin-
ing the analysis of wavelengths of reference light and light reflected by the structures of
the eye. OCT produces axial section images of the fundus. OCT is complementary to FA,
in particular to diagnose and to monitor macular complications such as macular edema,
retinal cysts, retinal serous detachment, epiretinal membranes, vitreomacular traction, fo-
veal atrophy and macular holes [22].
Figure 3.
Late phase of ultra-wide field fluorescein angiography showing peripheral capillaropathy and vasculitis in the
macular area responsible for visual acuity loss during Behçet’s disease uveitis.
Optical Coherence Tomography (OCT) is based on an optical phenomenon, combining
the analysis of wavelengths of reference light and light reflected by the structures of the
eye. OCT produces axial section images of the fundus. OCT is complementary to FA,
in particular to diagnose and to monitor macular complications such as macular edema,
retinal cysts, retinal serous detachment, epiretinal membranes, vitreomacular traction,
foveal atrophy and macular holes [22].
5.2.2. Strategy for Definite and Earlier Diagnosis of Behçet’s Disease Uveitis
As described above, BD uveitis diagnosis is usually established in the presence of
a coherent ocular clinical presentation and extraocular manifestations according to clas-
sification criteria. The different symptoms of BD can develop over several years [
23
].
J. Clin. Med. 2021,10, 2318 6 of 21
Furthermore, uveitis could be the first manifestation of the disease, reported in 6–20%
of patients [
10
,
24
,
25
], when extraocular manifestations of the disease may not yet have
appeared. Recently, Tugal-Tutkun et al. proposed an algorithm to allow BD uveitis to be
diagnosed solely on ophthalmological criteria. In this study, the most relevant signs for the
BD uveitis diagnosis in patients with vitritis were: presence of foci of retinitis, occlusive
retinal vasculitis, diffuse retinal capillary leakage on FA and absence of granulomatous
anterior uveitis or choroiditis. However, these findings need to be confirmed in larger
patient cohorts. Even though relapsing-remitting course showed a high clinical value, this
criterion was not relevant in this retrospective evaluation because patients were treated
before spontaneous resolution [26].
FA remains the gold standard to diagnose and monitor BD uveitis. However, it is
a time-consuming procedure that requires the injection of a fluorescent dye, which may
be associated with severe allergic reaction. As a result, FA in clinical practice cannot be
performed as often as necessary to best monitor the activity of patients with BD uveitis
and therapeutic adaptation. In contrast, OCT is a non-invasive tool used to visualize the
fundus. Furthermore, OCT can provide useful markers of previous posterior ocular flares
such as outer plexiform layer elevations associated with focal inner nuclear layer collapse
(Figure 4) [27]; this could help with retrospective diagnosis in case of clinical suspicion.
J. Clin. Med. 2021, 10, x FOR PEER REVIEW 6 of 22
5.2.2. Strategy for Definite and Earlier Diagnosis of Behçet’s Disease Uveitis
As described above, BD uveitis diagnosis is usually established in the presence of a
coherent ocular clinical presentation and extraocular manifestations according to classifi-
cation criteria. The different symptoms of BD can develop over several years [23]. Further-
more, uveitis could be the first manifestation of the disease, reported in 6–20% of patients
[10,24,25], when extraocular manifestations of the disease may not yet have appeared. Re-
cently, Tugal-Tutkun et al. proposed an algorithm to allow BD uveitis to be diagnosed
solely on ophthalmological criteria. In this study, the most relevant signs for the BD uve-
itis diagnosis in patients with vitritis were: presence of foci of retinitis, occlusive retinal
vasculitis, diffuse retinal capillary leakage on FA and absence of granulomatous anterior
uveitis or choroiditis. However, these findings need to be confirmed in larger patient co-
horts. Even though relapsing-remitting course showed a high clinical value, this criterion
was not relevant in this retrospective evaluation because patients were treated before
spontaneous resolution [26].
FA remains the gold standard to diagnose and monitor BD uveitis. However, it is a
time-consuming procedure that requires the injection of a fluorescent dye, which may be
associated with severe allergic reaction. As a result, FA in clinical practice cannot be per-
formed as often as necessary to best monitor the activity of patients with BD uveitis and
therapeutic adaptation. In contrast, OCT is a non-invasive tool used to visualize the fun-
dus. Furthermore, OCT can provide useful markers of previous posterior ocular flares
such as outer plexiform layer elevations associated with focal inner nuclear layer collapse
(Figure 4) [27]; this could help with retrospective diagnosis in case of clinical suspicion.
(a) (b)
(c) (d)
Figure 4.
(
a
) Retinal photography of the right eye showing area of whitish retinal necrosis related
to Behçet’s disease and (
b
) its appearance on OCT as focal inner nuclear layer thickening; (
c
) its
resolution 2 months later and (d) its appearance on OCT as focal inner nuclear layer collapse.
J. Clin. Med. 2021,10, 2318 7 of 21
A more recent technology, Enhanced Depth Imaging OCT (EDI-OCT) provides de-
tailed and measurable images from the choroid. A recent study demonstrated that sub-
foveal choroidal thickness might reflect macular vasculitis or inflammation; its measure-
ment could be a noninvasive tool to investigate macular inflammation activity in BD
uveitis [
28
]. However, it should be noted that a study with contradictory results, showing
no increase in thickening of choroid during active BD uveitis, was also published [29].
A major limitation of FA is its inability to image the entire retinal capillary system. Op-
tical Coherence Tomography Angiography (OCTA) is an innovative and recent technique
in ophthalmology. OCTA is a fast, noninvasive diagnostic imaging technique, detecting
movement in blood vessels, without dye injection and allows depth-resolved visualization
of the retinal and choroidal vasculature. Several studies have recently investigated its role
in describing microvascular changes in BD uveitis. OCTA has been found to allow better
visualization of microvascular macular area changes such as capillary dropout, increased
foveal avascular zone, telangiectasias, shunts and areas of neovascularization in compari-
son with FA in eyes with active BD uveitis. The deep capillary plexus seems to be more
affected than the superficial capillary plexus [
30
–
32
]. However, FA remains essential to
detect retinal vascular and capillary leakage at the macular area and at the peripheral retina
and to affirm uveitis activity [
33
]; although OCTA can detect areas of retinal ischemia, it is
not able to identify retinal vasculitis.
Furthermore, several recent publications analyzed with interest changes in retinal
microvascularization in BD patients without uveitis, before the emergence of evident
clinical findings. Parafoveal microvasculature seems to be involved in BD patients with
uveitis and in BD patients without uveitis [
34
–
37
]; likewise, peripapillary microvascular
changes could be detected by OCTA in BD patients without clinical ocular involvement [
38
].
FA was performed to ensure absence of any vascular leakage or subclinical vasculitis [
34
].
In one study published in 2019, no difference was observed in any measurement between
BD patients without uveitis and healthy controls (51 eyes from BD patients without uveitis
vs. 53 eyes from healthy individuals) [
39
]. Large-scale studies are needed to clarify the role
of OCTA. However, this non-invasive and rapid technique seems to provide a benefit for
BD patients in diagnosis, follow-up and prognosis of associated uveitis and could even
provide an additional argument for patients with suspected BD. It can also improve the
assessment of a known disease without ocular damage and can consequently modify the
treatment decision.
Conventional color retinography and FA are limited in their field of view. Most fundus
cameras can capture a maximum of 60
◦
of the entire fundus at a time. While a mosaic can
be performed to enlarge field of view, the entire fundus cannot be imaged simultaneously.
Ultra-wide-field imaging, providing a 200
◦
angle of photographic, autofluorographic and
angiographic ocular fundus views, has recently been introduced in ophthalmology. In
a prospective observational study of 23 patients with non-infectious retinal vasculitis,
the authors showed that disease activity and uveitis management were changed when
ultra-wide-field angiography was added to standard imaging (60
◦
) [
40
]. In the future, it
is likely to become an essential tool for the diagnosis, treatment and follow-up of retinal
vasculitis, in particular when associated with BD. However, additional studies are needed
to clarify how this improved identification of otherwise unrecognized peripheral retinal
changes will impact treatment decisions, patient prognosis and outcomes [41,42].
The laser flare meter can be used to monitor the degree of inflammation, as its values
would correlate with the amount of vascular leakage visible on FA [43].
6. Treatment Modalities and Perspectives
6.1. Treatment Aims
BD prognosis is dominated by ocular, neurological and vascular damage, with a poor
functional and/or vital prognosis. Ocular involvement is severe and frequent, rapidly in-
volving the visual prognosis. The incidence of ophthalmological impairment in BD patients
is close to 70% [
3
]. It is characterized by acute flare-ups that may regress spontaneously.
J. Clin. Med. 2021,10, 2318 8 of 21
During periods of remission, the eyes are calm or mildly inflammatory. The objectives of
therapeutic management of BD uveitis are to rapidly and effectively control inflammation
in order to preserve visual function and limit irreversible structural damage, but also to
treat the chronic subclinical inflammation, to prevent relapses and ocular complications,
to limit ophthalmological and general side effects of iatrogenic causes and to control the
associated systemic manifestations [
44
,
45
]. A multidisciplinary team and approach are
essential. Furthermore, care and follow-up of ocular involvement should be handled by an
ophthalmologist familiar with chronic ocular inflammatory diseases.
6.2. Conventional Immunosuppressants
Azathioprine and cyclosporin A are the only two immunosuppressants evaluated in
randomized controlled trials (RCT). Azathioprine (2.5 mg/kg/day), in a large placebo-
controlled trial, led to significantly reduced hypopion uveitis relapses and new eye disease
after 24 months. In the azathioprine group, no serious adverse events were reported,
whereas in the placebo group, one patient died of pulmonary artery aneurysm [
46
]. Cy-
closporin A was evaluated in three RCT [
47
–
49
]. The response rates reported were between
80 and 91%, but side effects were frequent [
47
–
51
]. Cyclosporin A was more effective than
cyclophosphamide [
49
]. However, its side effects, in particular nephrotoxicity, may cur-
rently limit its use in an uveitis context [
52
]. A 15-year longitudinal study using methotrex-
ate (7.5–15 mg/week) showed visual acuity improvement and decrease in 46.5% and 37.2%
of patients with BD uveitis, respectively [
53
]. However, methotrexate, mycophenolate
mofetil and tacrolimus are not usually used in BD uveitis management. Alkylating agents
are not recommended anymore due to their safety profile, in particular, malignancies and
infertility. Biologics appear to be more effective and safer [54].
6.3. Interferons
Interferons are cytokines that can be synthesized by most cells and have antiviral,
antiproliferative and immunomodulatory properties. Their efficacy and tolerance were
analyzed in BD patients [
55
–
57
]. Several studies emphasized the efficacy and tolerance of
interferon
α
2a (IFN-
α
2a) in adults and in children with BD uveitis [
58
–
64
]. First treatment
modalities, i.e., doses ranging from 3 to 9 million UI daily versus thrice a week regimen,
duration administration and corticosteroid tapering vary widely among studies. Subcuta-
neous IFN-
α
2a (3 million UI thrice a week) is effective and safe for the long-term manage-
ment of refractory BD uveitis. It has a potent corticosteroid-sparing effect [
65
]. A partial or
complete response is estimated in around 90% of treated BD uveitis patients [
54
]. Moreover,
it would also allow in some cases long-term remission even after discontinuation [
66
–
68
].
However, IFN-
α
2a production was recently stopped and it is no longer commercially avail-
able. Pegylated interferon-alpha-2a (PEG-IFN-
α
2a), administered once a week, remains
available. In an RCT, adding PEG-IFN-
α
2a to the drug regimen of BD patients with or
without ocular involvement did not significantly reduce the cortico-dependence threshold
at 1 year. However, in patients on corticosteroids at baseline, post hoc analysis demon-
strated that adding PEG-IFN-
α
2a reduced the corticosteroid dose required for significant
improvement in quality of life [
69
]. Small case series reported IFN-
α
2b or IFN-
α
2a efficacy
in BD uveitis [
70
,
71
], even though IFN-
α
2a was described to be more effective than IFN-
α
2b [
72
]. Further studies are needed on the pegylated form efficacy on active disease and
maintenance therapy of BD uveitis. The main limitation of interferon treatment is tolerance,
with the occurrence of a frequent flu-like syndrome and severe psychological disorders
that can lead to suicide attempts [
66
]. However, compared with anti-TNF
α
agents, it does
not promote severe infection, especially tuberculosis.
6.4. Anti-TNFαAgents
Biologics have dramatically changed BD uveitis management, although their use is
based on uncontrolled studies with few randomized controlled trials [
73
]. In a recent
retrospective study, ocular inflammation was controlled earlier with anti-TNF
α
agents
J. Clin. Med. 2021,10, 2318 9 of 21
compared to cDMARD in non-anterior non-infectious uveitis, and better corticosteroid
sparing was achieved [
74
]. Currently, five anti-TNF
α
agents are available; infliximab and
adalimumab are the two mainly used in BD uveitis.
Infliximab is a murine–human chimeric monoclonal antibody (mAb) against soluble
and transmembrane forms of TNF
α
. In BD, the usual dose is 5 mg/kg, intravenously,
which may be increased to 10 mg/kg. Infusions are repeated after 2 and 6 weeks and then
every 4 to 6 weeks. Infliximab was first reported for ocular inflammation in BD in 2001 [
75
].
Then, the published evidence consisted mainly in reports of the open use of infliximab. A
retrospective comparison of infliximab vs. cyclosporin A during the first 6-month treatment
period in BD showed infliximab to be more effective in reducing acute episodes of BD
uveitis, although no significant improvement was observed in visual acuity [
76
]. After
infliximab, a rapid improvement of visual acuity and decrease of ocular inflammation
starting at 24 h was almost always reported among 158 patients [
77
]. In 89% of these
patients, significant reduction of uveitis relapses was observed. Despite the lack of RCTs,
infliximab was approved in Japan for the treatment of “Behçet’s disease complicated with
refractory uveoretinitis, which does not respond to conventional therapies” (Osaka, Japan,
26 January 2007, JCN Newswire). Moreover, a prospective comparative study comparing
acute panuveitis relapses in BD management showed that infliximab (5 mg/kg), at the
onset of uveitis, is significantly faster in controlling ocular inflammation than intravitreal
triamcinolone (4 mg) or high-dose methylprednisolone (3 day, 1 g/d) [
78
]. Control of acute
ocular inflammation in BD is mandatory to avoid permanent loss of vision; therefore, an
intravenous infliximab infusion should always be considered for BD panuveitis relapses.
No studies comparing infliximab and IFN-
α
2a have been published; however, a recent
meta-analysis showed similar remission rates, with a sustained remission rate higher in
the IFN-
α
2a group (71%) compared to infliximab (43%). Infliximab has a more rapid
onset of action; rates for improving visual acuity were 46% for IFN-
α
2a and 76% for
infliximab. Withdrawal rates due to side effects were similar, i.e., 5.5% (INF-
α
2a group) vs.
5% (infliximab group) [79].
Adalimumab is a fully human mAb binding TNF
α
. The benefit of adalimumab is
subcutaneous administration at a dose of 40 mg every 2 weeks in adults after a loading
dose of 80 mg in uveitis. Adalimumab was approved in 2016 for use in the management of
non-infectious intermediate, posterior and panuveitis. Adalimumab efficacy and safety
in BD uveitis have been progressively reported. Adalimumab was first successfully used
in case series [
80
–
82
], and then in several retrospective studies [
83
–
85
]. The two RCTs vs.
placebo VISUAL I and VISUAL II evaluated efficacy and safety of adalimumab in active
and inactive non-infectious uveitis of any etiology, respectively [
86
,
87
]; there were too few
BD uveitis patients to be analyzed specifically.
A recent meta-analysis was conducted to assess the effectiveness and safety of anti-
TNF
α
agents in the management of BD uveitis among 18 clinical trials, i.e., 3 prospective
and 15 retrospective studies, from January 2010 to December 2019, with a minimum follow-
up of 6 months and at least 10 patients with BD uveitis. The overall uveitis remission rate
was 68% (95% CI 0.59 to 0.79), visual acuity improvement rate was 60% (95% CI 0.47 to
0.77) and central macular thickness decrease was 112.70
µ
m (95% CI 72.8 to 153.0) with
a significant corticosteroid-sparing effect. In this review, 2.62% of patients had serious
side effects [
88
]. Furthermore, Vallet et al. retrospectively evaluated the adalimumab
and infliximab efficacy in 160 refractory uveitis, including 36% of BD uveitis. These two
anti-TNF
α
agents appeared to be similar in terms of efficacy and BD uveitis was linked to
a 3-fold increase in the complete response rate [89].
In case of failure of a first anti-TNF
α
agent, a switch to another can be useful. In
124 BD patients described by Vallet et al., 31 patients received a second line of anti-TNF
α
agent due to lack of efficacy, side effects or patients’ decision. Concerning ocular manifes-
tations, complete and partial responses were reported in 12 (67%) and 5 (28%) patients,
respectively [
90
]. An observational multicenter study was recently conducted, comparing
the efficacy of infliximab and adalimumab as a first-line treatment in refractory BD uveitis.
J. Clin. Med. 2021,10, 2318 10 of 21
In both groups (103 infliximab patients and 74 adalimumab patients), after 1 year, all ocular
parameters improved, with a significant difference in best-corrected visual acuity, anterior
chamber inflammation and vitritis in the adalimumab group, compared to the infliximab
group. However, a faster improvement of anterior chamber inflammation and vitritis was
described with infliximab, even though the adalimumab group did not receive a loading
dose. A higher retention rate was observed in the adalimumab group (95.24% vs. 84.95%;
p= 0.042)
; infliximab and adalimumab were stopped due to lack of efficacy in 17.5% and
in 14.9%, respectively. Interestingly, no significant difference was reported between the
two treatments for improvement of vasculitis and macular edema [91].
The cumulative retention rate of adalimumab in 54 BD uveitis patients was evaluated
at 76.9% at 12 months and at 63.5% at 48 months of follow-up. It was not modified
by the use of concurrent DMARDs or by different lines of biologic agents. Moreover,
retention rates were not lower in cases of known negative prognostic factors for BD ocular
involvement, such as male gender, early age at disease onset and the duration of uveitis [
92
].
Similarly, the cumulative retention rates of infliximab in 40 BD uveitis patients at 12-, 24-,
60- and 120-month follow-up were 89.03%, 86.16%, 75.66% and 47.11%, respectively, not
modified by the use of concomitant DMARDs or by negative known prognostic factors.
A significantly lower retention rate was observed when infliximab was administered
following other biologics. At 10-year follow-up, discontinuation was due to: secondary
failure (six patients), primary failure (two patients), side effects (four patients), prolonged
disease remission (two patients) and switch to subcutaneous treatment (one patient) [
93
].
Recently, Horiguchi et al. showed that infliximab monotherapy was effective and not
inferior to combination therapies, i.e, colchicine or corticosteroids for refractory BD uveitis
over a 10-year follow-up [94].
In case of inefficacy of infliximab, an increased dose or an increased frequency of
administration was described in BD uveitis management [
91
]. Similarly, for adalimumab,
an increased frequency of administration, i.e., weekly, was recently described in uveitis,
with encouraging results but not specifically in this indication [95,96].
Etanercept is a fusion protein, which is a soluble receptor binding soluble TNFαand
preventing it from binding to target cells. Etanercept has lower efficacy for uveitis treatment
than anti-TNFαantibodies [97].
Golimumab is a fully human anti-TNF
α
mAb. Several case reports and series re-
ported successful control of severe uveitis, especially in juvenile idiopathic arthritis and
BD [98–102].
Certolizumab pegol is a pegylated recombinant humanized mAb against TNF
α
. Pegy-
lation leads to its delayed elimination. Data on use of certolizumab-pegol for BD uveitis
are currently limited.
Anti-TNFαagents are associated with an increased risk of tuberculosis [103]. Screen-
ing for latent tuberculosis is recommended for all patients before starting therapy. Severe
opportunistic infections, in particular those with intracellular microorganisms, may oc-
cur. Demyelinating events, including exacerbations of preexisting multiple sclerosis, were
reported [
104
–
108
]. There is no evidence for an increased risk of solid tumor or lymphopro-
liferative disease with anti-TNF
α
agents [
109
,
110
], except non-melanoma skin cancer [
111
].
All anti-TNF
α
agents can induce antinuclear antibodies; however, the development of
anti-TNF
α
-induced lupus is more rarely reported. Local complications at the drug admin-
istration site have been frequently observed. Anti-TNF
α
agents may induce neutralizing
antibodies, resulting in loss of efficacy and the appearance of infusion reactions [
112
]. New
onset and worsening of congestive heart failure have been described [
109
]. Sarcoidosis is
a rare and paradoxical side effect during anti-TNF
α
treatment, as well as occurrence of
psoriasis [97].
6.5. Peri or Intraocular Treatment
Intravitreous or periocular injections of corticosteroids as adjuvant treatment in addi-
tion to systemic treatment could be proposed in the event of unilateral flare. Intra-ocular
J. Clin. Med. 2021,10, 2318 11 of 21
pressure elevation and cataract development are the main side effects in addition to the
absence of systemic disease control. This option can be used as a bridging therapy await-
ing escalation in therapy or in rare cases of absolute contraindication to some systemic
therapies [113].
A first study of 15 patients with BD uveitis treated with intravitreal infliximab injec-
tions (1.5 mg intravitreal infliximab) showed a significant improvement in visual acuity,
with a significant decrease in retinal vasculitis, retinitis and macular thickness [
114
]. Simi-
larly, a second study showed that intravitreal infliximab appeared to be safe and effective
in treating uveitis in 20 BD patients [
115
]. However, contradictory results regarding its
safety and efficacy have also been reported in a more recent study in 16 patients. Four eyes
developed severe immunological reaction and failure to control inflammation was de-
scribed in the majority of eyes [
116
]. Intravitreal adalimumab was not successful in chronic
refractory cystoid macular edema, i.e., reduction of central retinal thickness and improve-
ment of visual acuity [
117
]; no ocular or systemic adverse events were observed. Then,
intravitreal adalimumab was shown in a very small patient population to be effective in
improving the best-corrected visual acuity, controlling inflammation, limiting uveitis flare
and decreasing macular edema in non-infectious uveitis, including BD uveitis [
118
,
119
].
Otherwise, contradictory results concerning the safety of intravitreal adalimumab have
been reported [
117
,
120
–
122
]. Further studies regarding the concentration and toxic effects
of intravitreal anti-TNFαagents are required, although their efficacy is uncertain.
Intravitreal bevacizumab was shown to be well tolerated and an effective supplemen-
tary therapy for chronic uveitis cystoid macular edema, particularly in BD; however, the
median period of efficacy was short [123].
6.6. Retinal Laser Photocoagulation
Development of optic disc neovascularization is a severe complication of BD uveitis.
Although scatter laser photocoagulation may be necessary in eyes with extensive retinal
ischemia, inflammatory mechanisms seem to be essential in its pathogenesis. Therefore, in
these cases, treatment intensification is appropriate and laser photocoagulation should be
avoided [44].
6.7. BD Uveitis Management Recommendations
Due to its severity, BD uveitis was the first uveitis for which anti-TNF
α
agents were rec-
ommended [
124
]. EULAR recommendations on BD treatment were recently updated [
79
];
likewise, French recommendations were recently proposed [
7
,
125
]. In case of posterior seg-
ment ocular involvement, glucocorticoids should never be used alone. Systemic immuno-
suppressive agents such as azathioprine, cyclosporin A, IFN-
α
, infliximab or adalimumab
should be proposed, depending on the risk of infection such as tuberculosis with anti-
TNF
α
agents, tolerability of IFN-
α
2a, physicians’ experience and reimbursement policies.
Patients presenting with an initial or recurrent episode of acute sight-threatening uveitis
should be treated with high-dose glucocorticoids and infliximab or interferon-alpha [
79
].
French recommendations stated that in case of sight-threatening involvement, patients
must be treated with high doses of corticosteroids associated with anti-TNF
α
or IFN-
α
;
intravenous infliximab (5 mg/kg at weeks 0, 2, 6 and then every 4 to 6 weeks) or subcuta-
neous adalimumab (80 mg dose initially, then 40 mg/15 days) can be used [
7
]. Intravitreal
corticosteroid injection is a therapeutic option in patients with unilateral flare as an adjunct
to systemic treatment [7,79].
In isolated anterior uveitis, treatment is based on topical corticosteroids. However,
systemic immunosuppressants could be considered, such as azathioprine, if there are
factors of higher risk of more severe disease, such as young age, early onset of the disease
and male gender [7,79].
During BD uveitis management, decrease or withdrawal of immunosuppressive or
immunomodulating treatment should be considered only after a 2-year remission, and an
expert examination is advised [
7
]. How to stop immunosuppressive drug in BD uveitis
J. Clin. Med. 2021,10, 2318 12 of 21
has not yet been defined. Martín-Varillas et al. proposed a strategy to progressively taper
adalimumab in BD, by increasing the delay between each injection by one week, which
allowed the control of ocular inflammation and resulted in fewer side effects [
126
].
Figure 5
summarizes the management of severe BD.
J. Clin. Med. 2021, 10, x FOR PEER REVIEW 12 of 22
IFN-α; intravenous infliximab (5 mg/kg at weeks 0, 2, 6 and then every 4 to 6 weeks) or
subcutaneous adalimumab (80 mg dose initially, then 40 mg/15 days) can be used [7]. In-
travitreal corticosteroid injection is a therapeutic option in patients with unilateral flare as
an adjunct to systemic treatment [7,79].
In isolated anterior uveitis, treatment is based on topical corticosteroids. However,
systemic immunosuppressants could be considered, such as azathioprine, if there are fac-
tors of higher risk of more severe disease, such as young age, early onset of the disease
and male gender [7,79].
During BD uveitis management, decrease or withdrawal of immunosuppressive or
immunomodulating treatment should be considered only after a 2-year remission, and an
expert examination is advised [7]. How to stop immunosuppressive drug in BD uveitis
has not yet been defined. Martín-Varillas et al. proposed a strategy to progressively taper
adalimumab in BD, by increasing the delay between each injection by one week, which
allowed the control of ocular inflammation and resulted in fewer side effects [126]. Figure
5 summarizes the management of severe BD.
Figure 5. Proposed algorithm for management of severe Behçet’s disease (BD) uveitis.
6.8. Biologics beyond Anti-TNFα Agents
6.8.1. Anti-Interleukin-6 Agents
Tocilizumab (TCZ) is a humanized anti-interleukin-6 (IL-6) receptor mAb, inhibiting
IL-6 pathway to prevent IL-6 from binding to its receptor. TCZ is authorized worldwide
for various inflammatory diseases, such as rheumatoid arthritis, giant cell arteritis and
Still’s disease. It is available intravenously monthly or subcutaneously weekly. IL-6 inhib-
itors may be effective in the management of posterior uveitis and macular edema in BD
uveitis. In the prospective STOP-Uveitis study, intravenous TCZ was found to be safe and
equally effective in both naïve and previously treated patients with non-anterior non-in-
fectious uveitis, mostly idiopathic, i.e., one BD uveitis among 37 [127]. TCZ has also
Figure 5. Proposed algorithm for management of severe Behçet’s disease (BD) uveitis.
6.8. Biologics beyond Anti-TNFαAgents
6.8.1. Anti-Interleukin-6 Agents
Tocilizumab (TCZ) is a humanized anti-interleukin-6 (IL-6) receptor mAb, inhibiting
IL-6 pathway to prevent IL-6 from binding to its receptor. TCZ is authorized worldwide for
various inflammatory diseases, such as rheumatoid arthritis, giant cell arteritis and Still’s
disease. It is available intravenously monthly or subcutaneously weekly. IL-6 inhibitors
may be effective in the management of posterior uveitis and macular edema in BD uveitis.
In the prospective STOP-Uveitis study, intravenous TCZ was found to be safe and equally
effective in both naïve and previously treated patients with non-anterior non-infectious
uveitis, mostly idiopathic, i.e., one BD uveitis among 37 [
127
]. TCZ has also shown, in
a retrospective study, its efficacy in 5 cases of BD uveitis refractory to IFN-
α
and anti-
TNF
α
agents, when administered intravenously, i.e., 8 mg/kg [
128
], and in 11 cases of BD
uveitis refractory to anti-TNF
α
agents [
129
]. In this last study, TCZ was only effective in
extraocular manifestations among three patients. Furthermore, a recent review concluded
that TCZ represented a promising therapy for refractory ocular-, neuro- and vasculo-BD,
but was not recommended for mucocutaneous and articular involvement [
130
]. TCZ
seems to be useful in refractory macular edema treatment associated with non-infectious
uveitis. Vegas-Revenga et al. showed, in a multicenter retrospective study, significant
macular edema reduction and visual acuity improvement in 25 patients, including 7 with
BD uveitis [131].
J. Clin. Med. 2021,10, 2318 13 of 21
An increased risk of infection is the most frequent serious side effect reported, es-
pecially gastrointestinal events. Anti-IL-6 agents have been associated with elevations
in serum concentrations of transaminases, pancreatitis, gastrointestinal perforations in
patients with preexisting risk factors and increased serum lipid concentration [
132
]. Inter-
estingly, a study in rheumatoid arthritis patients showed a low immunogenicity of TCZ,
whether or not there was an association with conventional immunosuppressants [133].
6.8.2. Anti-Interleukin-1 Agents
Three anti-interleukin-1 (IL-1) agents have been studied in BD treatment: anakinra,
an IL-1 receptor antagonist protein; canakinumab, a human anti-IL-1
β
mAb; and gevok-
izumab, a humanized anti-IL-1
β
mAb. Their place in the management of BD uveitis
remains unclear, based on contradictory findings in the literature. In a recent randomized,
double-masked, placebo-controlled trial in patients having recently experienced a BD
uveitis exacerbation (40 subcutaneous gevokizumab vs. 43 placebo), gevokizumab did not
significantly reduce the median time to relapse [
134
]. However, in a previous open-label
study, a single gevokizumab infusion resulted in a rapid and sustained reduction in ocular
inflammation in seven patients with refractory BD uveitis [
135
]. These encouraging results
were then confirmed in a prospective, open-label, randomized phase 2 trial in 21 BD uveitis
patients treated with gevokizumab every 4 weeks intravenously or subcutaneously [136].
Furthermore, anakinra showed control of ocular inflammation in three out of four BD
uveitis refractory to anti-TNF
α
agents. However, patients experienced relapse over
time [
137
]. In a retrospective multicenter study, anakinra and canakinumab were shown to
be efficacious and safe in 73% out of 30 patients, including 16 with BD uveitis, even though
patients could benefit from therapeutic adaptation or switch to the other anti-IL-1. Side
effects were, in all cases, represented by local cutaneous reactions [
138
]. In an observa-
tional study, anakinra or canakinumab were studied in 19 BD uveitis and improved retinal
vasculitis and decreased the rate of uveitis relapses, i.e., from 200/100 patients per year
to 48.87/100 patients per year during 12 months; no significant effect was measured in
macular thickness and visual acuity [139].
6.8.3. Anti-Interleukin-17 Agents
In active BD uveitis, anti-interleukin-17A (IL-17A) has been found to be significantly
upregulated in human peripheral blood mononuclear cells. Secukinumab, the only anti-IL-
17 agent studied in uveitis management to date, is a fully human mAb [
140
]. It was studied
subcutaneously against placebo in three RCTs. The SHIELD study analyzed 118 non-
anterior BD uveitis, while the INSURE study analyzed 31 non-anterior non-BD uveitis and
the ENDURE study analyzed 125 quiescent non-anterior non-BD uveitis. In the SHIELD
study, the primary endpoint, i.e., the reduction in rate of uveitis recurrence did not meet
statistical significance, as in the other two studies. However, the secondary efficacy data
from SHIELD and INSURE could suggest a potential benefit of secukinumab in reducing
the use of concurrent immunosuppressants [141].
Nevertheless, a prospective study suggested the efficacy of intravenous secukinumab
in active chronic non-infectious uveitis which required systemic immunosuppression in
16 patients, including one BD uveitis [
142
]; similarly, in a subsequent prospective study,
intravenous secukinumab was observed to be more effective and tolerated in patients with
non-infectious uveitis who required corticosteroid-sparing immunosuppressive therapy,
compared with subcutaneous secukinumab in 37 patients without BD uveitis [143].
In a retrospective multicenter study evaluating 15 BD patients, refractory to treatment
with colchicine, DMARDs and at least one anti-TNF
α
agent, the efficacy and safety of
secukinumab have been reported in the treatment of mucosal and articular manifestations.
At the time of secukinumab introduction, one patient with active anterior uveitis did not
experience ocular relapse throughout follow-up [144].
J. Clin. Med. 2021,10, 2318 14 of 21
These conflicting results may indicate that the strategy of blocking Il-17 may still
be useful in the management of uveitis, probably by adjusting the dose received and
controlling plasma therapeutic levels according to the route of administration.
6.8.4. Anti-Interleukin-12/23 Agents
Ustekinumab is a fully humanized mAb with high affinity for IL-12 and IL-23, which
seems to play a crucial role in non-infectious uveitis [
145
]. Promising results for uveitis
associated with inflammatory bowel disease and psoriatic arthritis were reported [
146
–
148
].
Efficacy data on BD uveitis is not yet known. STELABEC-2, a phase 2 open-label study
evaluating active posterior and pan-uveitis in BD uveitis, has finished recruiting patients,
but results are not yet published (clinicaltrials.gov). Moreover, ustekinumab seems to be
effective in controlling colchicine-resistant oral ulcers associated with BD [149,150].
6.8.5. Other Biologics
Rituximab, B cell targeted therapy, is a chimeric mAb against CD20. Davatchi et al.,
in 2010, successfully tested, in a single blind randomized control study, the efficacy of
rituximab associated with methotrexate vs. a combination of pulse cyclophosphamide and
azathioprine in improving BD ocular involvement; no significant difference was observed
between groups [151].
Alemtuzumab is a humanized mAb anti-CD52, able to induce a rapid and long-
term B and T cell depletion. In a first study, 18 patients received a single infusion of
alemtuzumab, including five BD patients with ocular involvement; complete or partial
remission was described for all these patients at 6 months of follow-up. All patients
received an antifungal and antiviral prophylactic treatment [
152
]. In another retrospective
long-term study, 32 patients with BD received 60 courses of alemtuzumab between 1994
and 2013. Twenty-one patients presented ocular involvement and all of them achieved
remission. Thyroid dysfunction was a frequent side effect, i.e., seen in 25% of patients.
Antiviral and antifungal prophylaxis was also systematically administered [153].
Abatacept, T cell targeted therapy, is a recombinant fusion protein which can block
CD-80 and CD-86 on antigen-presenting cells, necessary for its activation. Short-term
efficacy was described in a case report of refractory BD-associated scleritis [154].
Daclizumab is a humanized mAb binding the CD25 unit of IL-2 receptor, which was
studied during a randomized, placebo-controlled trial in 17 BD patients. Daclizumab was
not superior in preventing relapse and tapering immunosuppressive drugs compared with
placebo [
155
]. In 2018, it was withdrawn from the market after reports of autoimmune
encephalitis [156].
6.8.6. Targeted Synthetic Disease-Modifying Antirheumatic Drugs
Targeted synthetic Disease-Modifying Antirheumatic Drugs (tsDMARDs) comprise
several types of agents such as phosphodiesterase inhibitors and kinase inhibitors. Their
small size gives them a high level of bioavailability and moreover tsDMARDs have a low
rate of immunogenicity [157].
Anti-Janus Kinase
Tofacitinib is an anti-Janus Kinase (JAK) 1/3 inhibitor, approved for autoinflamma-
tory diseases such as rheumatoid arthritis, ulcerative colitis and psoriatic arthritis. A
first study of 13 patients with refractory BD suggested its safety and possible efficacy in
vascular and articular involvement. No ocular involvement was described and patients
with gastrointestinal-BD responded poorly [
158
]. In a case series including two patients,
tofacitinib appeared to be a potential new treatment option for refractory, non-infectious
idiopathic uveitis or scleritis [
159
]. Encouraging preliminary results have recently been
reported in uveitis associated with juvenile idiopathic arthritis [160,161].
J. Clin. Med. 2021,10, 2318 15 of 21
Apremilast
Apremilast is a phosphodiesterase 4 inhibitor modulating cytokines that are up-
regulated in BD. Its efficacy has been demonstrated in BD oral ulcers in phase 2 and
3 randomized
placebo-controlled trials and it is now approved in this indication. Neverthe-
less, its possible role in the management of BD uveitis has not been studied yet [162–164].
7. Conclusions
Despite diagnostic and therapeutic innovations, BD uveitis remains a severe condi-
tion. Biologics have transformed the management of intraocular inflammation, but in
the absence of a reliable biological marker and possible subclinical ophthalmological in-
volvement, the early diagnosis of BD remains a major challenge. Improvements in ocular
multimodal imaging will probably allow a better evaluation of patients. However, there
are still cases of BD uveitis that are refractory to the recommended treatment and studies
comparing the different existing biologics will help to improve management. The thera-
peutic armamentarium is expanding, with probably useful alternatives to anti-TNF
α
or
interferons. However, some questions remain unanswered, such as treatment duration and
long-term strategies.
Author Contributions:
Conceptualization, J.G. and B.B.; methodology, J.G.; validation, M.L., D.S.
and B.B.; investigation, J.G.; resources, J.G.; data curation, J.G.; writing—original draft preparation,
J.G.; writing—review and editing, M.L., D.S. and B.B.; visualization, M.L., D.S. and B.B.; supervision,
B.B. All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Acknowledgments:
The authors are grateful to Nikki Sabourin-Gibbs (Rouen University Hospital)
for her help in editing the manuscript.
Conflicts of Interest: The authors declare no conflict of interest.
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