Guan et al. Journal of Neuroinflammation(2024) 21:133
https://doi.org/10.1186/s12974-024-03123-6

Journal of Neuroinflammation

Open Access

REVIEW

Decoding Behcet’s Uveitis: an In-depth review
of pathogenesis and therapeutic advances
Yuxuan Guan1,2, Fuzhen Li1, Na Li1 and Peizeng Yang1*
Abstract
Behcet’s disease (BD) is a rare but globally distributed vasculitis that primarily affects populations in the
Mediterranean and Asian regions. Behcet’s uveitis (BU) is a common manifestation of BD, occurring in over twothirds of the patients. BU is characterized by bilateral, chronic, recurrent, non-granulomatous uveitis in association
with complications such as retinal ischemia and atrophy, optic atrophy, macular ischemia, macular edema, andfurther neovascular complications (vitreous hemorrhage, neovascular glaucoma). Although the etiology andpathogenesis of BU remain unclear, numerous studies reveal that genetic factors (such as HLA-B51), dysregulated
immune responses of both the innate and adaptive immune systems, infections (such as streptococcus), andenvironmental factors (such as GDP) are all involved in its development. Innate immunity, including hyperactivityof neutrophils and γδT cells and elevated NK1/NK2 ratios, has been shown to play an essential role in this disease.
Adaptive immune system disturbance, including homeostatic perturbations, Th1, Th17 overaction, and Treg cell
dysfunction, is thought to be involved in BU pathogenesis. Treatment of BU requires a tailored approach based on
the location, severity of inflammation, and systemic manifestations. The therapy aims to achieve rapid inflammation
suppression, preservation of vision, and prevention of recurrence. Systemic corticosteroids combined with otherimmunosuppressive agents have been widely used to treat BU, and beneficial effects are observed in mostpatients. Recently, biologics have been shown to be effective in treating refractory BU cases. Novel therapeutictargets for treating BU include the LCK gene, Th17/Treg balance, JAK pathway inhibition, and cytokines such as
IL-17 and RORγt. This article summarizes the recent studies on BU, especially in terms of pathogenesis, diagnostic
criteria and classification, auxiliary examination, and treatment options. A better understanding of the significanceof microbiome composition, genetic basis, and persistent immune mechanisms, as well as advancements in
identifying new biomarkers and implementing objective quantitative detection of BU, may greatly contribute toimproving the adequate management of BU patients.
Keywords Behcet’s disease, Behcet’s uveitis, Adaptive immunity, Innate immunity, Biologics*Correspondence:
Peizeng Yang
peizengycmu@126.com
1
Department of Ophthalmology, Henan International Joint ResearchLaboratory for Ocular Immunology and Retinal Injury Repair, The First
Affiliated Hospital of Zhengzhou University, Henan Province Eye Hospital,
Zhengzhou 450052, People’s Republic of China
2
The Academy of Medical Sciences, Zhengzhou University,
Zhengzhou 450052, People’s Republic of China© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use,sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) andthe source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in thisarticle are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not includedin the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you willneed to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The
Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available
in this article, unless otherwise stated in a credit line to the data.

Guan et al. Journal of Neuroinflammation(2024) 21:133

Introduction
Behcet’s disease (BD), also known as Behcet’s syndrome[1], is a rare chronic recurrent vasculitis with unclear
etiology and pathogenesis. Up to date, BD is considereda heterogeneous disease with close association withgenetics (e.g., HLA-B51), immunity (innate and adaptive immunity), infections (e.g., streptococcus), and theenvironment (e.g., GDP) [2–6]. More than 60% of BD
patients have eye lesions, which can be the primary or
only manifestation of BD. The most common eye lesion
is uveitis, typically manifesting as recurrent bilateral
non-granulomatous uveitis. Behcet’s uveitis (BU) represents an immune-mediated intraocular inflammatory
disorder with potential risk of blinding [7, 8]. The uniquecomplications of BU are of high concerns, such as retinal
ischemia and atrophy, optic atrophy, macular ischemia,
macular edema, and further neovascular complications(vitreous hemorrhage, neovascular glaucoma). These arecommon complications that lead to permanent visualloss. It can develop alone or with systemic manifestations. Although modern immunosuppressive agents have
improved BU prognosis, approximately 20.4% of eyes
become blind due to recurrent episodes [8, 9].
In the therapeutic landscape of BU, the enduring pillars of glucocorticoids and immunosuppressants havebeen recently complemented by the emergence of biologics, providing new, promising management for thisdisease. The impetus for these advancements has beencatalyzed by fast-paced strides in the fields of genetics,
immunology, and technology, thus driving significant
breakthroughs in both experimental and clinical research
in BU.
Herein, this review article focuses on recent advancesin understanding the immunologic etiology and therapeutic advances that contribute to the pathogenesis of
BU. In addition to this, some insights are provided on
how to improve the diagnosis and management of BU in
practice.

Table 1 Nomenclature Variations of BD
Variation
Behcet’s Syndrome or
Behcet’s Disease
Silk Road Disease

Neuro-Behcet’s,
Ocular-Behcet’s
Adamantiades-Behcet’s
diseaseBehcet’s-associated Uveitis(BDU) or Behcet’s uveitis (BU)

Description
The most commonly used names worldwide, named after Hulusi Behçet who
first described the disease.
This older term, less commonly used
today, reflects the high prevalence ofthe disease along the historical Silk Road.
These terms refer to cases where the disease primarily affects a specific system.
This name is commonly used in Greece
and acknowledges the work of Benedictos Adamantiades.
This refers to uveitis in BD.

Page 2 of 28

History

BD has its earliest recorded description in the third bookof endemic diseases by Hippocrates. He indicated that
the Mediterranean region and Asian populations weremost affected by BD, which is how BD earned the nameold Silk Road disease [10]. The disease was first recognized by Hulusi Behçet in 1937, and it is characterized bya triad of recurrent clinical symptoms: oral ulcers, genital
ulcers, and ocular lesions [11, 12]. BD can be diagnosed
when oral ulcers are present and at least two of the following criteria are met: distinctive ocular lesions, typicalskin lesions, recurrent genital ulcers, or a positive skinpathology test [13, 14]. BD symptoms can be erratic, withsymptomatic or remission periods lasting months, years,
or decades. This condition has been given various names(Table 1).
Diagnostic and classification criteria

In clinical practice, there are no specific diagnostic tests
or histological features that can definitively identify BD.
Current diagnostic criteria rely on clinical symptoms andimaging findings.
The International Study Group for Behcet’s Disease(ISG), established in 1990, is widely used as the first truly
international standard with high specificity. Recurrent
oral ulcers plus 2 other criteria, including recurrent genital ulcers, eye lesions, skin lesions, and positive pathological tests, are sufficient for diagnosis [14]. Recurrent oral
ulcers are necessary for diagnosis, but the oral manifestations of patients in the early stages of the disease are
not completely consistent. Moreover, the differences in
the prevalence of diseases in different regions were notconsidered in the formulation of the criteria, so someregions with higher prevalence were ignored. In contrast,
the International Criteria for Behcet’s Disease (ICBD),
developed in 2014, incorporates neurological and vascular manifestations, improving diagnostic sensitivity but
reducing specificity [15]. Although useful for diagnostic
guidance, all criteria ignore the baseline probability of
disease in patients and may be more beneficial for differential diagnosis in non-endemic areas. The Standardization of Uveitis Nomenclature (SUN) working groupproposed in 2021 provides a unique framework for theidentification of BU and other non-infectious uveitis. In
particular, this classification standard includes focal retinal infiltration in the definition of ocular lesions, which
improves diagnostic accuracy and is suitable for clinical and translational studies [16]. It is limited by specificity and may inadvertently exclude cases with atypicalmanifestations or overlapping with other uveitis entities.
Therefore, clinicians should exercise caution when evaluating suspected BU patients and consider the broader
clinical context. In addition, Tugal-Tutkun et al. ‘s algorithm offers a promising way to diagnose adult BU based

Guan et al. Journal of Neuroinflammation(2024) 21:133

solely on ocular manifestations, providing a solution toclinicians’ bedside challenges [17].
The absence of universally acknowledged scoring criteria for BD poses a challenge. However, the Ocular Behcet
Disease Research Group of Japan introduced the Behcet’s
disease ocular attack score 24 (BOS24) scoring system
in 2014, which can evaluate the clinical inflammatory
activity.
BOS24 serves as a comprehensive measure for assessing ocular inflammation. This scoring system encompasses six distinct parameters, all of which are evaluatedon a per-ocular episode basis. The parameters encompass various aspects related to the eye, such as abnormalities in the vitreous, lesions located at the subfoveal
area, lesions found in the peripheral region of the fundus,
presence of cells in the anterior chamber, lesions affecting the posterior pole, and lesions affecting the optic disc.
This particular system of classification divides the retinal field into two main areas: the posterior pole and the
peripheral retina. The peripheral retina is then further
divided into quadrants for a more detailed analysis andunderstanding. This innovative system incorporates a setof specific parameters that are carefully chosen to ensure
consistency and accuracy in quantifying the severity ofocular inflammation. Through the implementation ofthese parameters, the BOS24 establishes a standardized
approach to assess the level of ocular inflammation in BD
patients [18].
Table 2 Differential diagnosis for BU
Major clinicalmanifestation
Anterior uveitis

Posterior uveitis

Panuveitis

Differential diagnoses
Ankylosing spondylitis
Inflammatory bowel disease
Reactive arthritis (Reiter’s syndrome)
HLA-B27-associated uveitis
Psoriatic arthritis
Herpetic anterior uveitis
Idiopathic anterior uveitis
Systemic lupus erythematosus-associatedretinal vasculitis
ANCA-associated vasculitis
Cytomegalovirus retinitis
Syphilitic retinitis
Frosted branch angiitis
Toxoplasmosis
Eales disease (retinal venous perivasculitis)
Acute retinal necrosis syndrome
Masquerade syndrome
Idiopathic retinal vasculitis
Idiopathic panuveitis with occlusive vasculitis
Sarcoidosis
Multiple sclerosis
Tubulointerstitial nephritis and uveitis syndrome
Masquerade syndrome
Tuberculous uveitis
Fungal endophthalmitis
Bacterial endophthalmitis

Page 3 of 28

Notably, BOS24 incorporates the grading scales developed by the SUN working group for scoring anteriorchamber cells, and follows the system proposed by Nussenblatt et al. for evaluating vitreous opacity [19, 20].
An important attribute of BOS24 is its reliance solely
on objective ocular findings per episode, explicitly
excluding patient-reported symptoms or subjective
examination outcomes such as visual acuity. Moreover,the scoring system focuses specifically on new inflammatory manifestations, excluding chronic inflammatory
signs. This clear-cut delineation ensures that BOS24
accurately captures the acute inflammatory burden ineach episode of BU.
In addition to diagnostic criteria, the differential diagnosis of BU is equally important (Table 2).
Epidemiology

BU exhibits a distinct geographical distribution, primarily observed along the ancient Silk Road, extending acrossthe vast expanse from East Asia to the Mediterranean
region [21]. Turkey records the highest incidence rate,with an estimated 420 cases per 100,000 individuals [22].
Noteworthy prevalence is also observed in Iran, Korea,
Japan, Greece, Israel, and Saudi Arabia [15]. Although theincidence in North America and Europe is lower, cases
have been identified on all continents [23]. This distribution pattern suggests a rational association with genetic
factors, potentially linked to the HLA-B51 gene [24].
BD was the leading cause of uveitis in a multicenter
registry in Turkey [25]. Subsequent studies carried out
by various international institutions have consistently
reaffirmed these findings and underscored the prevalentoccurrence of uveitis as a manifestation of BD [26–29].
This ocular complication not only damages the patient’s
overall well-being, but also poses a significant risk of permanent vision impairment.
Notably, there are complex connections that can beobserved between BU and other BD symptoms. We cansee a clear positive correlation between BU and botharthralgia and parenchymal neurological involvement.
On the other hand, there is an opposite association whenit comes to genital ulcers, gastrointestinal symptoms, andother systemic symptoms [30–33]. These complex interactions highlight the need for further investigation tobetter understand the multifaceted pathogenesis of BD.
Demographically, BU does not exhibit a specific age
limitation, but it most frequently emerges in individuals between 25 and 44 years [34]. Pediatric presentations
may deviate from the typical and display a more aggressive disease course [35]. The elderly may have milder
symptoms, but they are susceptible to complications
related to treatment due to existing comorbidities. Consequently, medications should be administered with caution in this population [36]. The interplay between BU

Guan et al. Journal of Neuroinflammation(2024) 21:133

and pregnancy remains enigmatic, necessitating cautious
therapeutic considerations to protect fetal health [37].
Clinically, BU typically exhibits as a chronic, recurrent,
bilateral non-granulomatous uveitis. The inflammation
primarily affects either the anterior (11.1%) or posterior(28.8%) segment of the eye, although panuveitis, which
involves inflammation in both segments concurrently,
occurs more frequently (60.2%) [11, 26, 38, 39].
BD exhibits a significant predominance in males, withnotable differences in prognosis based on gender. Specifically, male patients with BU experience a more rapid
decline in visual prognosis, as indicated by a substantially
5-year and 10-year risk of losing useful visual acuity [8,38]. These differences tied to gender may be attributed tothe influence of testosterone on the regulation of neutrophils and T helper 1 cells (Th1), potentially shedding lighton the increased morbidity observed in male BD patients[40].
Clinical features and complications

BU is recurrent and presents as anterior uveitis, posterior uveitis or panuveitis (Table 3). It usually involves
the whole eye, with bilateral involvement in 4 out of 5
patients. Men predominate and are at higher risk of losing useful vision than women. Although rare, isolatedcases of anterior uveitis are predominantly reported
among females [9, 38]. Smooth layered shifting hypopyon, diffuse vitritis, transient superficial retinal infiltrates, full-thickness retinal infiltrates, diffuse gliotic
sheathing of retinal veins, peripheral occlusive periphlebitis, retinal hemorrhages, and fluorescein angiography
revealing diffuse retinal capillary leakage, retinal capillary
Table 3 Common clinical manifestations of BU
Clinicalmanifestation
Anterior uveitis

Posterior uveitis

Panuveitis

Retinal vasculitis
Optic disc edema

Macular edema
Cystoid macularedema (CME)

Description
Inflammation of the anterior segment of theeye, characterized by redness, pain, photophobia, and sterile hypopyon.
Ocular inflammation, which encompasses
the posterior segment of the eye, specificallythe retina and choroid, can give rise to visual
impairments and the presence of floaters.
Ocular inflammation, which encompasses theposterior segment of the eye, specifically thesuperficial retinal infiltrates and precipitates
particularly seen in BU patients.
Inflammation of the retinal blood vessels, leading to vascular occlusion and hemorrhage.
Swelling of the optic disc due to increased
intracranial pressure or inflammation of the
optic nerve.
Accumulation of fluid in the macula, leading
to central vision loss and distortion.
A specific type of macular edema with cystlike spaces in the macula, affecting vision.

Page 4 of 28

nonperfusion, and optic disc hyperfluorescence/leakage, are suggestive of BU [17, 41]. One of the concerning
aspects of BU is its potential to cause irreversible vision
loss, as well as damage to other organs, and even death.
Younger males tend to have the poorest prognosis inthese cases.
Auxiliary examinations

The diagnostic and therapeutic options for BU areenhanced by a wide range of retina imaging techniquesthat effectively outline its pathophysiological changes.
Contemporary ophthalmological evaluations significantly
rely on imaging methods such as color photography,
B-scan ultrasonography, fundus fluorescein angiography,
laser flare-cell photometry, and optical coherence tomography (OCT). These technologies introduce fast andaccurate diagnostic possibilities, supported by the use ofmultiple imaging techniques [42, 43].
This suite of diagnostic tools ranges from classical color
photography, enabling vitreous opacity and retinal infiltration documentation, to the technologically advanced
OCT, illuminating macular afflictions and nuanced
retinal layer alterations [44]. Furthermore, projectionresolved optical coherence tomography angiography(PR-OCTA) has illuminated the existence of macular circulatory anomalies in both eyes, irrespective of the BU isunilateral or bilateral [45]. Despite its ability to provide a
detailed examination of retinal circulation, OCTA is limited in its ability to identify vascular leaks, which are typically detected through invasive methods that require theuse of dyes [46].
The major component of BU is retinal inflammation,rather than choroidal inflammation. Indocyanine green
angiography (ICGA) offers insights into choroidal inflammation and aids in distinguishing BU with predominant
retinal affliction from conditions primarily impacting thechoroid [47].
Fundus fluorescein angiography (FFA) provides valuable insights into both vascular and extravascular retinalthat may not be apparent through fundus microscopy.
These include vascular leakage, cystoid macular edema,
and retinal vascular occlusion, among others [8]. FFA candetect fundus changes caused by posterior uveitis andpanuveitis, determine the site and size of the lesion, anddynamically observe and evaluate the treatment effect.
FFA is an indispensable tool in diagnosing and monitoring BU. FFA is particularly useful in identifying diffuse
retinal capillary leakage, which presents as a fern-likepattern, indicating suboptimal response to therapy evenduring asymptomatic periods [42]. FFA is the gold standard for detecting and monitoring the leakage and occlusion of retinal vasculitis in BU patients [42, 48–50]. FFA
findings also have prognostic significance. In active BU
patients, disc neovascularization, macular window defectGuan et al. Journal of Neuroinflammation(2024) 21:133

and macular ischemia indicate poor visual prognosis [49].
It not only provides important information on the vascular and optic disc leaks, but also provides crucial clues forclinical judgment. For example, FFA can distinguish theunderlying cause (ischemia or pure inflammation) in thepresence of neovascularization of optic disc or whether
abnormal vessel clumps are shunt vessels or neovascularization in the scenario of retinal vascular occlusions.
Although FFA has limitations, such as its invasive nature,potential allergic reactions, and a lack of quantitative
measurements. It remains the golden standard among
multimodal imaging in BU.
Laser flare-cell photometry (LFCM) has emerged as aneffective and non-invasive tool for quantitatively evaluating intraocular inflammation in BU. It allows for precise detection and measurement of cells and proteins in
the front part of the eye. Compared to traditional slitlamp examinations, LFCM offers greater objectivity andaccuracy, especially in identifying moderate to severe
inflammation in the front part of the eye, which is a characteristic feature of BU [8]. Furthermore, the utilizationof LFCM proves to be advantageous when it comes tothe surveillance of continuous retinal vascular leakage inpatients who are experiencing clinical remission. The reason for this correlation lies in the fact that the degree offlare observed through LFCM analysis is directly linked
to the level of fluorescein angiographic leakage. Consequently, this connection reduces the necessity for frequent invasive procedures such as FFA [51].
Among them, fundus photography, FFA, and OCT continue to serve as the primary imaging modalities in BU.
Furthermore, thorough examination is being conducted
on potential biomarkers such as HLA-B51、tumor
necrosis factor-α (TNF-α), microRNAs, and specificsweat metabolites such as l-citrulline [52, 53]. In the caseof untreated active BD, an increased risk of uveitis has
been significantly associated with elevated serum IgAlevels and antibodies against cardiolipin, β2-glycoprotein
I, and prothrombin [54]. Although various autoantibodies and biomarkers associated with BU have been identified, their clinical significance remains to be further
validated.

Page 5 of 28

Etiology and pathogenesis
Genetic factors

The genetic composition of BD, situated within its epidemiological framework, deviates from the majority ofsystemic diseases. Interestingly, its worldwide presence
intersects with the historical Silk Road. Present discussions on genetics firmly establish the significance of
host genetic factors in determining susceptibility to BD(Table 4).
Although HLA-B51 is not currently used as a diagnostic marker, it plays a significant role as a genetic contributor in BU. HLA-B51 is positively correlated with ocularlesions but negatively correlated with gastrointestinal
lesions [4, 55]. The precise reasoning behind the association of HLA-B51 with BU is still a subject of scholarly discussion, particularly considering linkage disequilibrium.
However, it is important to acknowledge that HLA-B51
contributes to only a small portion (less than 20%) of thegenetic risk, suggesting that there may be other genetic
factors yet to be identified [56].
The endoplasmic reticulum aminopeptidase 1 (ERAP1)
is pivotal in modulating peptide configurations within
the endoplasmic reticulum (ER), thereby influencing the
peptides presented by human leukocyte antigen (HLA)
class I molecules. Certain ERAP1 variants have shown asignificant association with BD, especially in the context
of HLA class I. A noteworthy revelation was the linkageof the ERAP1 haplotype, Hap10, with BD. Remarkably,individuals carrying Hap10 and being homozygous for
HLA-B51 demonstrated an approximate elevenfold surge
in disease susceptibility. Though Hap10’s strong linkage
with BD is evident, its low prevalence ensures its limited
influence on global risk. However, the combined impactof HLA-B51 and Hap10 insinuates a profound genetic
mechanism underpinning BD susceptibility. Recent studies utilizing genome-wide association studies (GWAS)
and related functional annotations have brought attention to various susceptibility loci, such as HLA-B51,
HLA-A26, HLA-C0704 [5, 57], CCR1 [58], CCR1-CCR3,
ERAP1, KLRC4, STAT4 [59, 60], FUT2 [61], IL12A [62,63], IL10, IL23R-IL12RB2 [24, 64–66], TRAF5, TRAF3IP2[67], ADO-EGR2, CEBPB-PTPN1, IL1A-IL1B, IRF8,
LACC1, RIPK2 [68, 69], PTPN2 [70], STAT3 [71], IL23R

Table 4 Overview of genetic and environmental factors in BD
Factor
Genetic factors

HLA-B51
IL10, IL23R-IL12RB2 gene clusters
ERAP1
Other genetic loci
Environmental factors Infections
Oral and gut microbiome
Smoking
Geographic location

Description
Associated with BD and its uveitis manifestation
Genes involved in immune responses, linked to BD
Involved in antigen presentation, associated with BD in individuals with the HLA-B51 allele
Implicated through genome-wide association studies
Streptococci, Mycobacteria, Treponema pallidum, and others
Changes might play a role in disease onset and progression
May influence the onset and progression of the disease
More prevalent in countries along the Silk Road

Guan et al. Journal of Neuroinflammation(2024) 21:133[72, 73], miR-146a [74], and miR-182 [75] (Table 5).
However, the genetic aspects of BU are not yet fully
understood. Despite GWAS identifying HLA-B51 andother non-leukocyte antigen risk factors, a comprehensive genetic understanding of BU is still lacking, necessitating further investigation.
Innate immune system
Neutrophils hyperactivity

The majority of leukocytes, known as neutrophils, serveas the foremost defense against infections. Although
they perform a vital function in innate immunity, there
is a potential for unintended harm to tissues, particularlyin the presence of inflammation. This damage primarily occurs through phagocytosis, degranulation, and therelease of neutrophil extracellular traps (NETs). Inflammation often leads to an increase in the number and lifespan of neutrophils [76, 77]. In the context of BD, there isa significant increase in neutrophil activity. This heightened activity may be associated with the HLA-B51 geneand elevated levels of interleukin-17 (IL-17). The activated neutrophils have a propensity to aggregate in close
proximity to blood vessels, whereby they release reactive oxygen species (ROS) and proteases. This process
eventually culminates in the impairment of the vascularendothelium [2, 11, 78, 79]. The neutrophil-lymphocyte
ratio (NLR) has been identified as a reliable biomarker toassess the extent of inflammation in BD and to evaluate
disease severity [80, 81]. Further studies on BD patients
have shown an enhancement in the oxidative burst andNADPH oxidase activities of neutrophils, resulting inincreased production of ROS [82, 83]. Neutrophils inthese patients also release various components such as
NETs, DNA, extracellular reticulated DNA structures,histones, and myeloperoxidase (MPO) [84]. Notably, thehistones from NETs play a dual role. They activate Th17
cells through intermediary cells like monocytes, and they
directly induce STAT3 phosphorylation in T cells. This
process results in the secretion of substances like IL-6,transforming growth factor-beta (TGF-β), and retinoid
acid-related orphan receptor gamma t (RORγt). These
substances further promote IL-17 production and thedifferentiation of Th17 cells, thereby amplifying NET formation (Fig. 1) [83, 85–87]. Additionally, elevated levelsof NETs have been linked to increased differentiation ofTh1 cells, specifically IFN-γ-producing CD4+ T cells. The
subsequent increase in histone H4 and oxidized DNA
within Th1 cells appears to trigger macrophage activation, resulting in enhanced production of IL-8 [88].
Hyperactivity of γδT cells

During the past 2 decades, there was a notable increase
observed in the number of γδT cells in peripheral bloodmononuclear cells (PBMCs) of BD patients. Normally,

Page 6 of 28

these γδT cells make up a small portion of the total
T cells, ranging from 0.5 to 5%. It is worth mentioning that γδT cells possess characteristics of both innate
and adaptive immunity, undergoing maturation throughinteractions with dendritic cells and pattern recognition
receptors. They express molecules such as the inducible co-stimulator (ICOS) and CD40, and secrete various cytokines including IL-2, IL-4, IL-10, IL-17, IFN-γ,
TNF-α, and granzyme (Fig. 1). These secreted molecules
play a role in Th1/Th2 responses, link innate and adaptive
immunity, and participate in autoimmune diseases.
Of particular interest, when it comes to oral pathogens,γδT cells may recognize these microbes through Heat
Shock Proteins (HSP) and their T cell receptors. Whenneutrophils engulf these pathogens, γδT cells detect
the resulting pathogenic compounds (such as (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate) and releasechemokines, notably CXCL8 (IL-8). The subsequent
recruitment of neutrophils and monocytes, along with
the induction of Th1 and Th17 responses, may contributeto the persistent inflammation observed in BD patients[89–92].
Elevated NK1/NK2 ratios

Natural killer (NK) cells, acting as cytotoxic lymphocytes
in the innate immune system, exhibit their functionality
independent of the constraints imposed by the major histocompatibility complex (MHC). Their primary function
revolves around immunosurveillance while also exhibiting the ability to produce a diverse range of cytokines,
including IFN-γ, IL-5, IL-13, GM-CSF, CCL3, and CCL4.
In BD patients, abnormalities in the functionality of NK
cells have been attributed to the presence of cytokines
such as IL-10 and IL-15 [93–95].
What is particularly intriguing is that NK cells can beclassified into two distinct types based on the cytokines
they produce: NK1 and NK2 (Fig. 1). NK1 cells are primarily responsible to produce IFN-γ, whereas NK2 cells
exhibit a broader role in immune modulation, producing
cytokines such as IL-5 and IL-13. In active cases of BD,
there is a prevalence of NK1 cells, whereas during periods of disease remission, NK2 cells dominate. This ratio
between NK1 and NK2 cells provides valuable insights
into the activity of the disease, as a higher NK1/NK2
ratio correlates with polarization towards a Th1 immune
response and an increase in BD activity [96–98].
Dendritic cells: gatekeepers of Immune Response

Dendritic cells (DCs) are important antigen-presenting
cells (APCs) that play a critical role in activating naïve
T lymphocytes and contributing to both cellular andhumoral immune responses. These cells play a crucialrole in maintaining the balance of the immune system
by connecting the innate and adaptive immunity. In

Locus
HLA-B51
HLA-A26
HLA-C0704
LACC1
CEBPBPTPN1RIPK2
ADOEGR2
ERAP1
IL10
IL10
IL10
IL23R-IL12RB2
IL23R-IL12RB2
IL23R-IL12RB2
IL23R
IL23R
IL23R
IL23R
STAT4
STAT4
TRAF5
TRAF5
TRAF5
TRAF5
TRAF5
TRAF5
IL1A-IL1B
IRF8
FUT2
KLRC4
CCR1
IL12A
IL12A
PTPN2
PTPN2
STAT3
miR-182

Variant
rs9316059
rs913678

rs10094579
rs224127

rs17482078
rs1518111
rs1800871
rs3024490
rs924080
rs12141431
rs1495965
rs17375018
rs17375018
rs11209032
rs11209032
rs7574070
rs897200
rs12569232
rs12569232
rs6540679
rs6540679
rs10863888
rs10863888
rs3783550
rs11117433
rs681343
rs2617170
rs7616215
rs17810546
rs1874886
rs7234029
rs7234029
rs2293152
rs76481776

Chr
6
6
6
13
20

8
10

5
1
1
1
1
1
1
1
1
1
1
2
2
1
1
1
1
1
1
2
16
19
12
3
3
3
18
18
17
7

TT
A
TT
TT
TT
CC
G
GG
G
A
AA
A
A
CG
GG
AG
GG
AG
GG
G
C
T
C
C
G
A
AG
GG
GG
C

A
A
4.56
1.45
1.47
1.34
1.50
1.53
1.56
1.86
1.57
1.48
1.69
1.27
1.45
0.617
1.583
1.750
0.536
1.343
0.769
1.33
0.63
1.36
0.78
0.65
2.06
1.61
1.549
0.466
1.712
0.60

1.302
1.274

Allele/genotype
OR
5.586
2.437
3.784
T
0.687
C
1.32

Table 5 HLA variants and susceptibility loci associated with BD

2.88–7.22
1.34–1.58
1.28–1.68
1.17–1.54
1.30–1.73
1.32–1.78
1.34–1.83
1.39–2.49
1.25–1.98
1.21–1.82
1.21–2.35
1.17–1.37
1.3–1.6
0.481–0.790
1.246–2.011
1.467–2.086
0.451–0.637
1.127–1.601
0.644–0.917
1.20–1.46
0.54–0.74
1.19–1.56
0.72–0.85
0.57–0.75
1.49–2.84
1.36–1.89
1.326–1.810
0.326–0.667
1.238–2.369
0.49–0.73

1.149–1.474
1.141–1.422

95%CI
5.151–6.657
1.976–3.005
2.709–5.286
0.607–0.777
1.22–1.42

TurkishDifferent geographic origins
Han Chinese
Han Chinese
Han Chinese
Han Chinese
Japanese
Han Chinese
Han Chinese
Han Chinese
Han Chinese
Turkish, Japanese
Han Chinese
Han Chinese
Han Chinese
Han Chinese
Han Chinese
Han Chinese
Han Chinese
TurkishTurkishIranian
Turkish, Japanese
IranianDifferent geographic origins
SpanishHan Chinese
Han Chinese
Han Chinese
Han Chinese

Han Chinese
Han Chinese

Ethnic group
Han Chinese
Han Chinese
Han Chinese
Han Chinese
Turkish, Iranian

2047
2430
1206
1206
1206
1206
612
338
338
338
338
2659
703
789
789
789
789
789
789
1990
1990
976
2659
973
336
408
906
906
503
820

1238
1238

Patients
1015
1015
1015
1238
2869

1908
2660
2475
2475
2475
2475
740
407
407
407
407
2648
2110
1601
1601
1601
1601
1601
1601
1779
1779
826
2648
828
5843
2122
2178
2178
615
1800

1458
1458

Controls
4502
4502
4502
1458
2605

4.73E − 11
3.54E − 18
5.88E − 08
2.80E-05
2.03E − 08
2.18E-08
1.2E − 08
3.47E − 04
8.88E − 04
1.26E − 03
0.024
1.29E − 09
6.20E − 09
1.08E − 03
1.40E − 03
3.60E − 09
1.22E − 11
0.009
0.027
2.12E − 08
2.73E − 08
7.27E-06
1.34E − 09
6.01E − 09
9.31E-06
1.62E − 08
1.43E-06
8.34E-04
0.021
1.81E-07

6.93E − 04
3.77E − 04

P value
3.75E-190
9.77E-18
6.07E-17
4.95E − 08
1.43E − 12

[59]
[64]
[66]
[66]
[66]
[66]
[24]
[73]
[73]
[73]
[73]
[59]
[60]
[67]
[67]
[67]
[67]
[67]
[67]
[68]
[68]
[61]
[59]
[58]
[62]
[63]
[70]
[70]
[71]
[75]

[69]
[69]

References
[5]
[5]
[5]
[69]
[68]

Guan et al. Journal of Neuroinflammation(2024) 21:133
Page 7 of 28

(2024) 21:133

Page 8 of 28

normal physiological conditions, DCs can be found invarious ocular tissues, including the central and limbal
epithelia, basal lamina, and sub-basal nerve plexus layer[99–101]. However, the precise mechanism behind theinhibition of DC maturation in these conditions requires
further investigation. DCs possess a distinctive capability in comparison to other APCs, as they can effectively
initiate the activation of naïve T cells and facilitate theirdifferentiation into Th1 and Th17 cells throughout the
progression of a disease (Fig. 1). When exposed to chemokines or cytokines, immature DCs undergo maturation and migrate to lymph nodes, leading to increased
expression of costimulatory molecules and MHC class
II molecules [101–105]. The immature state of DCs is
associated with the maintenance of immune tolerance.
BU patients showed elevated expression of MHC class
II and costimulatory molecules in the maturation profiles of peripheral blood DCs, even during periods of
non-inflammatory activity. This finding suggests thatthe transition from an immature to a mature DC state
may contribute to the chronic inflammation and relapse
observed in BU. Moreover, BD patients exhibited a lower
number of plasma cell-like DCs compared to healthy
individuals, indicating that these cells may contribute toinflammation by migrating to target organs [106, 107].
During inflammation, DCs secrete IL-6, which influences
the biological function of DCs and facilitates their activation [108]. The expression of programmed death ligand-1(PDL1) and its transcription factor interferon regulatory
factor I (IRF1) in DCs from active BU patients has beenfound to be decreased in recent studies. This decrease in
expression is observed to correlate with the level of disease activity [109]. Confocal imaging studies consistently
demonstrate an increased density of DCs in the corneas
of BU patients, regardless of disease severity [110].
Adaptive immune system
Role of T cells

OR, odds ratio; CI, confidence interval

Chr
7
5
5
20
20
3
3
3
1
6
4
4
4
13
13
13
Locus
miR-182
miR-146a
miR-146a
CD40
CD40
CCR1/CCR3
CCR1/CCR3
CCR1/CCR3TGFBR3
SUMO4
TLR2
TLR2
TLR2
UBAC2
UBAC2
UBAC2

Table 5 (continued)

Variant
rs76481776
rs2910164
rs2910164
rs4810485
rs1883832
rs13084057
rs13092160
rs13075270
rs1805110+ 438 C→T
rs2289318
rs2289318
rs3804099
rs3825427
rs9517668
rs9517701

Allele/genotype
OR
CC
0.58
CC
0.61
C
0.75
TT
1.98
TT
1.73
G
0.32
C
0.28
C
0.32
CC
0.617
C
1.7
CC
1.462
C
1.470
CT
0.626
T
1.5
T
1.4
G
1.4

95%CI
0.46–0.71
0.50–0.74
0.66–0.85
1.38–2.83
1.22–2.46
0.2–0.5
0.2–0.4
0.2–0.5
0.441–0.863
1.3–2.2
1.223–1.747
1.260–1.714
0.526–0.744
1.2–1.7
1.2–1.6
1.2–1.7

Ethnic group
Han Chinese
Han Chinese
Han Chinese
Han Chinese
Han Chinese
Han Chinese
Han Chinese
Han Chinese
Han Chinese
Han Chinese
Han Chinese
Han Chinese
Han Chinese
Han Chinese
Han Chinese
Han ChinesePatients
820
809
809
373
373
653
653
653
330
232
838
838
838
477
477
477

Controls
1800
1132
1132
402
402
1685
1685
1685
468
302
1600
1600
1600
1334
1334
1334

P value
3.25E-07
1.24E-05
1.33E-04
0.006
0.012
1.71E-07
6.50E-08
2.76E-07
0.03
0.002
0.001
6.89E-06
2.426E-06
6.9E-06
3.3E-04
2.9E-05

References
[75]
[74]
[74]
[269]
[269]
[270]
[270]
[270]
[271]
[272]
[273]
[273]
[273]
[274]
[274]
[274]

Guan et al. Journal of Neuroinflammation

T cells, central to adaptive immunity, have increasingly
been a focus in the study of BU pathogenesis (Fig. 1).
This increased interest can be traced back to the discovery in 2000 of clonally aggregated T cells in the anteriorchamber of BD patients [111, 112]. The importance of T
cell-mediated immune imbalances in BU has been underscored by recent transcriptome analyses conducted oniris samples. Specifically, the involvement of the T cell
receptor signaling pathway and the prominence of helper
T cell differentiation pathways highlight this connection.
The lymphocyte-specific protein tyrosine kinase (LCK),
which plays a critical role in T cell functions, has been
identified as a key player in BU. The activated LCK signaling pathway and elevated active LCK expressions
observed in BU indicate the potential of the LCK gene fortherapeutic developments in BU treatment [113].

Guan et al. Journal of Neuroinflammation(2024) 21:133

Page 9 of 28

Fig. 1 BU immunopathogenesis: Current understanding

The increased expression of Th1/Th17-associated cytokines has led to the activation of the JAK/STAT signaling pathway, which has been observed in monocytes
and CD4+ T cells [114–116]. The upregulation of gene

expression leads to the activation of CD4+ T cells, resulting in their transformation into Th17 cells. This process is
influenced by the release of inflammatory cytokines frommonocytes. Subsequently, Th17 cells attract neutrophils

Guan et al. Journal of Neuroinflammation(2024) 21:133

and intensify the inflammatory reaction. Within thescope of BD, the signaling of serum amyloid-A is recognized as a pivotal element in guiding the differentiationof Th17 cells [117, 118]. RNA-seq studies of CD8+ T cells
from BD patients have emphasized the importance of thecAMP-mediated signaling pathway in T cell activation.
Interestingly, sustained elevation in cAMP levels tends tohave an immunosuppressive effect [119, 120].
It has been shown that the affected regions are primarily infiltrated by CD8+ T cells. When comparing
BU patients to those with other uveitis subtypes such as
idiopathic recurrent acute anterior uveitis and Vogt-Koyanagi-Harada syndrome, it is observed that the aqueous
humor of BU patients contains a higher concentration of
CD8+ T cells, whereas CD4+ T cells dominate in the othersubtypes. Conversely, skin samples from BD patientstypically exhibit a higher presence of CD4+ T cells, alongwith fewer CD8+ T and CD56+ cells. This indicates a distinct intraocular immunomodulatory environment in BU
that is characterized by a more aggressive inflammatory
response. Furthermore, during active BU phases, CD8
bright CD56+ T cells secrete cytotoxic molecules such as
dissolved protein perforin and surface FasL. These cells
not only possess conventional CD8+ CTL cytolytic functions but also demonstrate NK-like cytotoxic activities.
Another notable feature of BU is the significant increasein NKT cells in both the aqueous humor and peripheral
blood. The primary subtype of NKT cells, CD8+ CD56+
cells, have the capability to exert strong cytotoxic effects,
which can lead to the lysis of vascular endothelial cells
through FasL- and perforin-dependent mechanisms, posing serious risks to vision. In contrast, patients with type1 diabetes, a standard immune-mediated inflammatory
disease, do not exhibit these characteristics. This emphasizes the uniqueness of CD8+ CD56+ cells as immune
effectors, which may play a crucial role in the visual
impairment observed in BU [121, 122]. The severe clinical manifestations of BU, in comparison to other types ofuveitis, may be attributed to this factor.
The Th1/Th2 balance responses holds significant
importance in the development of BU, with the Th1
response exerting a particularly strong influence. Th2
cells exhibit the capability to secrete cytokines with antiinflammatory properties, namely IL-4, IL-5, IL-10, andIL-13. On the other hand, Th1 cells are distinguished bytheir ability to generate pro-inflammatory agents suchas IL-2, IL-12, interferon, and tumor necrosis factor. It
is noteworthy that BD patients typically exhibit elevatedlevels of Th1-related cytokines in their bloodstream [123,124].
In the aqueous humor of BU patients, a notable
increase in the concentrations of multiple cytokines
is observed, which encompass IL-1ra, IL-2, IL-6, IL-8,
IP-10, IFN-γ, and TNF-α. Conversely, the levels ofPage 10 of 28

GM-CSF are diminished. These cytokine levels correspond to the presence of inflammatory cells, particularly
monocytes and neutrophils, emphasizing the potential
role of the innate immune system in the development of
BU. Interestingly, BU patients exhibit elevated concentrations of IL-15 in their aqueous humor, a characteristic
not observed in individuals with other uveitis types suchas human leukocyte antigen B27-associated uveitis, VogtKoyanagi-Harada syndrome, juvenile idiopathic arthritis,
and idiopathic uveitis. IL-15, which possesses immunomodulatory properties, enhances the proliferation andactivation of specific immune cells like NK cells, NKT
cells, and CD8+ T cells. The prominence of CD8+CD56+
NKT cells in BU suggests their potentially detrimentalrole in the progression of the disease. Furthermore, active
BU patients demonstrate a lack of the anti-inflammatory
cytokine, IL-10, highlighting the unique immune characteristics of BU. The distinct presence of pro-inflammatory cytokines like IFN-γ and TNF-α in BU, comparedto other forms of uveitis, suggests the potential for novel
therapeutic strategies. By identifying the specific immune
players and cytokines involved in the pathogenesis of BU,
scientific advancements may lead to tailored treatmentsthat alleviate symptoms and address the underlying causeof this immune disorder [125–128].
The significant presence of Th1 and Th17 cells in BD
patients highlights the critical involvement of the adaptive immune system in both the onset and advancementof the disease. Transcriptomic studies have revealed an
active NF-κB pathway in peripheral Th17 cells. Additionally, analysis techniques such as WGCNA and pathway
enrichment have highlighted the activation of APCs in
BD [11, 129]. The expression of IL-27, both at the mRNAand protein levels, is found to be reduced in the PBMCs
and serum of active BD patients. IL-27 is known for its
ability to suppress Th1 and Th17 cellular responses by
inhibiting the expression of certain pro-inflammatory
cytokines, including IL-1β, IL-6, and IL-23. Recent findings suggest that IL-27 can inhibit the differentiation of
Th17 cells through the IRF-8 pathway [104], indicatingthat increasing IL-27 levels may help alleviate the inflammatory responses observed in BD patients.
Another crucial pathway involved in the development of immune-mediated disorders, including BU, isthe IL-23/IL-17 axis [130, 131]. Increased levels of IL-23
prompt the transformation of naïve T cells into pathogenic Th17 cells. These cells then release pro-inflammatory cytokines like IL-17 A, IL-17 F, and IL-22, with thehelp of the intracellular JAK/STAT signaling cascade.
Additionally, IL-23 contributes to the ongoing inflammatory response by upregulating its receptor, IL-23R [96,132].
With regards to another cytokine, IL-33, a member of
the IL-1 family, interacts with the ST2 receptor, resulting

Guan et al. Journal of Neuroinflammation(2024) 21:133

in the activation of MAP kinase and NF-κB. This interaction induces the production of pro-inflammatory cytokines, facilitates the differentiation of Th1 and Th17 cells,
and is associated with the dysfunction of regulatory T
cells (Tregs) [133, 134]. BD patients in the active phasedisplay heightened levels of IL-33 and its soluble receptor
ST2 (sST2). An intriguing observation is the correlation
between ST2 levels and inflammatory markers such as
erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) in BD patients. A potential reduction in serum
ST2 levels has been observed following treatment withcolchicine [135]. Furthermore, the investigation of single
nucleotide polymorphisms within the IL-33 gene hasrevealed a correlation between the variants rs7044343
and rs2210463 and the occurrence of BU [136, 137].
Role of B cells

B cells are only a small part of the immune cells in BD,
but the function of regulatory B cells (Bregs) is increasingly recognized. The primary function of Bregs is to produce anti-inflammatory cytokines, which are crucial forthe proper functioning of regulatory T cells. By inhibiting T cell differentiation and suppressing autoimmune
reactions, Bregs play a vital role in maintaining immune
homeostasis. A noteworthy observation in BD patientsis the substantial decrease in IL-10 mRNA levels within
B cells. This finding opens up possibilities for developing
novel therapeutic approaches for uveitis [138].
A notable characteristic of BD is the pronounced
depletion of B cells, particularly Bregs. This depletion is
primarily associated with a decline in CD27+ memory
B cells expressing different immunoglobulin subsets,most notably IgM, IgG, and IgA, with a specific focus on
CD27+ IgA+ B cells. It is speculated that these cells may
migrate from the bloodstream to sites of inflammation.
Considering their correlation with disease activity, thesecells hold promise as potential biomarkers [139]. Furthermore, Breg counts have been found to be correlated withthe severity of BD and ESR values. Interestingly, there
appears to be a positive relationship between the numberof Bregs and the dosage of corticosteroids administeredto patients. However, recent studies suggest that theoverall count of B cells and the number of Bregs remain
consistent among BD patients, regardless of whether they
exhibit symptoms of BU [140]. This indicates that further
investigation is required to fully understand the preciserole and impact of B cells in the pathogenesis of BU.
Microbiological factors

Although there is no direct evidence linking BD to microbial infections such as viruses or bacteria, studies suggestthat infectious pathogens may play a role in triggering theimmune response associated with BD [2, 141]. Notably,
studies have found an increased presence of Th17 cells

Page 11 of 28

in the peripheral blood of BD patients. It is hypothesizedthat alterations in bacterial composition and metabolism
contribute to immune system disruptions, particularly inthe balance between Th17 and Treg cells [142–145].
BD patients have shown a decrease in fecal concentrations of both Barnesiellaceae and Lachnospira, indicatinga shift in gut microbial composition that may be connected to immune irregularities [146]. In an interesting
study conducted by Shimizu et al. in 2018, fecal samples
from 13 BD patients and 27 healthy individuals wereanalyzed. The findings revealed a significant increase in
the relative abundance of Eggerthella lenta, along withsix other bacterial species, in BD patients. The authors
suggested that these gut microbes in BD patients could
potentially induce immune anomalies by influencing
nucleic acid and fatty acid synthesis, as indicated by the
results of PICRUSt functional annotation analysis [147].
Stool samples from active BD patients have shown adecreased presence of bacteria that produce butyrate[148]. In another intriguing study, gut microbes from BD
patients were transplanted into mice, resulting in weakened intestinal barrier strength and a reduction in three
short-chain fatty acids (SCFAs) - butyric acid, propionicacid, and valeric acid. These SCFAs are known to stimulate Treg cells in the intestines and feces. Single-cellsequencing performed on these mice revealed evidenceof activated neutrophils promoting the differentiation of
Th1 and Th17 cells in specific lymph nodes and spleencells [149, 150].
Other factors to consider in relation to BD include ahistory of tuberculosis (TB) infection and certain genetic
predispositions associated with susceptibility to TB,
which have been recognized as potential contributors
to the onset of BD [151]. Additionally, elevated levels ofantibodies against specific heat shock protein epitopes
from Mycobacteria and Streptococci have been observedin BD patients. It is interesting to note that human heatshock proteins exhibit similarities to these epitopes,
potentially leading to cross-reactive immune responses
and subsequent autoimmune reactions [152, 153]. In
another study, specific streptococcal strains were isolated
from BD patients with extraocular myopathy [154].
OthersA fascinating study conducted in mainland China investigated the relationship between air quality and the occurrence of uveitis. It was found that there was a strong
association between exposure to particulate matters lessthan 2.5 μm (PM2.5) and the development of non-infectious uveitis and uveitis associated with systemic diseases, particularly in males aged 20 to 50. Interestingly,
this association appeared to weaken over time, possibly
due to increased biological adaptation or the implementation of individual protective measures [155].

Guan et al. Journal of Neuroinflammation(2024) 21:133

Further investigation discovered that the positive association between increased PM2.5 levels and the occurrence of BU was exclusively observed in areas where
the Per capita gross domestic product (GDP) exceeded
the national average [156]. Japanese reports showing
decreased incidence and severity of BD over decades,
presumably associated with improved socioeconomic
conditions [157, 158]. Also, a recent report from Turkey
comparing BU patients with other noninfectious uveitis
showed that BU patients were from GDP regions and had
lower income [159]. Previous studies have emphasized
the connections between economic development and theprevalence of immune and inflammatory diseases [160,161]. Notably, economic growth itself showed an inverse
relationship with the incidence of uveitis, particularly inmale patients aged 20–50 years and markedly so in casesof BU [162]. The underlying reasons for this are not yet
fully understood but could be associated with enhancements in mental and overall health stemming from a risein GDP.
It raises contemplation that regions with a per capita
GDP surpassing the national average might indeed experience a spike in uveitis incidence. A prevailing hypothesis attributes this to the concurrent rise in exposure toPM2.5 [156]. The integration of these findings has significant ramifications, providing insights that could aid theformulation of preventive measures and treatment strategies for uveitis in nations undergoing swift economic
progression, especially those in the developing world.
Furthermore, the association between vitamin D and
BU is gradually recognized. In individuals of the Chinese
Han demographic, the DHCR7 gene, which is associatedwith the vitamin D pathway, has emerged as a potential
genetic predisposition for BD [163]. Recent research hasemphasized the protective role of 1,25-dihydroxy vitamin
D3 against BD. Interestingly, Vitamin D3 directly inhibits the differentiation of Th17 cells through the IRF-8
pathway [164]. A comprehensive study using Mendelianrandomization, which included Chinese and Turkish
samples with a total of 7,909 participants, demonstrated
a correlation between elevated levels of 25-hydroxyvitamin D and an increased risk for BD. This suggests thatcaution should be exercised by clinicians when considering prolonged or high-dose vitamin D supplementation[6].
To summarize this section, an important characteristic of BD pathogenesis is the dysregulation of immune
responses and the abnormal release of cytokines(Table 6). The available data provides substantial evidence
to suggest that bacterial factors might have a substantial
impact on the initiation of BD, thereby emphasizing thecomplex interaction between genetic predispositions
and environmental factors in the advancement of thedisease. These findings underscore the necessity forPage 12 of 28

comprehensive risk assessment strategies in clinical settings to identify individuals with an elevated risk for BD.
It is essential to further investigate this area to unravel
the complex biological processes underlying these associations. This knowledge could potentially lead to tailoredinterventions for susceptible populations.

Advances in therapies
Recent developments in therapeutic approaches for uveitis have highlighted the importance of a collaborative
effort among ophthalmologists, rheumatologists, andinternists, as emphasized by the 2018 European League
Against Rheumatism (EULAR) guidelines. The primary
goal is to effectively manage uveitis by reducing recurrent
episodes and controlling inflammation. Timely intervention is crucial in cases of BU, as complications suchas retinal ischemia and atrophy, optic atrophy, macularischemia, macular edema, and further neovascular complications (vitreous hemorrhage, neovascular glaucoma)
can lead to severe visual impairment or even blindness,and severely impacts the quality of life. Various factors,
including medication adjustments, disruptions in circadian rhythm, fluctuations in emotions, and excessive consumption of tobacco and alcohol, have been associatedwith the recurrence of BU [165–169].
To avoid unnecessary complications, it is essential toclosely monitor the outcomes of treatment and potential
side effects during the management of BU. The choiceof treatment strategies depends on the site of inflammation (e.g., anterior, posterior, or pan-uveitis), its severity,and underlying systemic conditions. The primary goalsof therapy involve promptly suppressing inflammation, minimizing leakage of FFA, preserving vision, andpreventing recurrence [170]. This section provides an
overview of the latest advancements in pharmacologicaloptions for the treatment of BU (Table 7).
Conventional therapies

Glucocorticoids (GCs) have a pivotal role in the management of BU. In milder cases of BU with isolated uveitis and no systemic manifestations, oral GCs are suitable.
For isolated anterior uveitis, topical GCs such as dexamethasone or betamethasone, along with ciliary musclerelaxing agents, are beneficial. In cases where immediate
inflammation reduction is needed at affected sites, pars
plana or retrobulbar GC injections can be used. However,
severe cases, particularly in younger males with earlyonset disease, may experience anterior uveitis progressing
to posterior forms, requiring systemic immunosuppression. These cases may need relatively high doses of systemic GCs to quickly control inflammation, followed bytapering to maintenance doses, ideally combined withimmunosuppressants like azathioprine for posterior uveitis management. However, we found that inflammation

Guan et al. Journal of Neuroinflammation(2024) 21:133

Page 13 of 28

Table 6 Cytokines in BD
Cytokine
IL-1raIL-1β
IL-2Species
Human
Human
Human

Group
BU vs. HC
BD vs. HC
BU vs. HC

IL-4
IL-6

Human
Human

BD vs. HC
BU vs. HC

IL-8

Human

BU/BD vs. HC

IL-10

Human

BU vs. HC

IL-12

Human

BU/BD vs. HC

IL-13

Human

BU/BD vs. HC

IL-15
IL-17 A

Human
Human

BU/BD vs. HC
BU/BD vs. HC

IL-17 F

Human

BU/BD vs. HC

IL-23

Human

BU/BD vs. HC

IL-27

Human

BU vs. HC

IL-33
IFN-γ

Human
Human

BD vs. HC
BU/BD vs. HC

IP-10
TNF-α

Human
Human

BU vs. HC
BU vs. HC

TGF-β
GM-CSF

Human
Human

BD vs. HC
BU vs. HC

Sample Type
AqueousSalivaAqueous
Serum
Serum
Aqueous
Serum
Aqueous
Serum
SalivaAqueous
Serum
Serum
Aqueous
Aqueous
NK cellsAqueousSerum
PBMC supernatants
Serum
PBMC supernatants
Serum
PBMC supernatants
PBMCs
PBMC supernatants
Serum
Serum
Serum
PBMC supernatantsAqueous
Aqueous
Serum
AqueousSalivaSerum
Aqueous

Regulation
Up
Up
Up

References
[128]
[275]
[124, 126, 128]

Up
Up

[92]
[124, 128]

Up

[124, 128, 275]

Down

[126]

Up

[124, 126]

Up

[98, 128]

Up
Up

[126]
[124, 276–278]Up[276–278]Up[276, 278]

Down

[104]

Up
Up

[135]
[92, 124, 126, 277, 278]

Up
Up

[128]
[124, 126–128, 275, 277]

Up
Down

[82, 86][128]

HC, healthy controls; Up, up-regulation of cytokine levels; Down, down-regulation of cytokine levels

was usually effectively controlled with relatively low dosesof GCs in Chinese patients [1, 8, 171]. Intravenous highdose methylprednisolone (IVPM) can improve visual clarity, reduce ocular inflammation, and prevent recurrences,often being more cost-effective than biologics [172]. In thesevere cases, drugs like cyclosporine A or TNF-α inhibitors may be necessary, with interferon-alpha as an alternative for those who cannot tolerate TNF-α treatments.
Topical steroid administration can be enhanced by theuse of an intravitreal dexamethasone implant (Ozurdex),either alone or in combination with other treatments[173]. Another promising option for uveitis treatment is
the intravitreal fludrocortisone implant (Iluvien, 0.19 mg).
However, caution should be exercised when using topicalsteroids in individuals with glaucoma [174]. Local depot
steroid injections should be avoided in patients with glau-coma or with a tendency to develop ocular hypertension
with any steroid treatment.
Careful monitoring is essential, especially for growtheffects in young patients, since long-term steroid use produces systemic side effects, including infections, hypertension, osteoporosis, and peptic ulcers. A collaborative
approach involving ophthalmologists, rheumatologists,
and internists is necessary for comprehensive patient
evaluations, weighing the pros and cons of different therapies, and ensuring patient compliance.
ImmunosuppressantsMedications have emerged as reliable and cost-effective
therapeutic options for the treatment of BU by suppressing the proliferation and function of immune cells.
However, their tolerability and effectiveness have limitations, despite often being co-administered with steroids.

Guan et al. Journal of Neuroinflammation(2024) 21:133

Page 14 of 28

Table 7 Current and emerging therapies for BU: therapeutic actions and side effects
Therapy
category
Supportive
treatment

Treatment

Mechanism of action

To prevent infection, it is advised to abstain
from consuming
stimulating foods,
tobacco, and alcohol.
Additionally, it isrecommended to
avoid any form of
trauma, such as tooth
extraction.
Corticosteroids
Topical and Systemic Anti-inflammatory and immunosuppresCorticosteroids
sive via cytokine suppression and immune
cell activity inhibition
Immunosuppres- Azathioprine
Inhibits purine synthesis, reducing T-cellsive agentsproliferation and cytokine production
Cyclosporine A
Inhibition of T-cell function by calcineurin
Methotrexate

Adalimumab

Inhibits dihydrofolate reductase, decreasing DNA synthesis and immune cellproliferation
Alkylating agent that interferes with DNA
replication
Monoclonal antibody targeting TNF-α, apro-inflammatory cytokine
Monoclonal antibody against TNF-α

Golimumab

Monoclonal antibody against TNF-α

Certolizumab pegol

Monoclonal antibody against TNF-α

Anakinra

IL-1 receptor antagonist reducing IL1-mediated inflammation
Monoclonal antibody against IL-1β

Chlorambucil
Biologics
TNF-alphaantagonists

IL-1 antagonists

Infliximab

Canakinumab
Janus Kinase(JAK) inhibitors

Tofacitinib
Upadacitinib

Emerging
therapies

Secukinumab
Ustekinumab

Common side effects

Serious side effects--

Increased intraocular pressure, osteoporosis

Immunosuppression, delayed
wound healing

Bone marrow suppression,
gastrointestinal disturbances
Increased uric acid, lipids,
and blood pressure
Hepatotoxicity, gastrointestinal upset

Hepatotoxicity, increased
infection risk
Hepatotoxicity and parenchymal nerve involvement
Bone marrow suppression,
pneumonitis

Nausea, vomiting, hair loss,
bone marrow suppression
Infusion reactions

Risk of infection, increased riskof secondary malignancies
Increased infection risk, development of antibodies
Increased infection risk, development of antibodies
Risk of serious infections, liver
toxicity,

Injection site reactions
Injection site reactions,
upper respiratory tract
infections
Injection site reactions,
upper respiratory tract
infections
Injection site reactions

Risk of serious infections, liver
toxicity,
Increased infection risk

Increased infection risk, development of antibodies
Inhibits JAKs involved in cytokine signaling Headache, diarrhea
Blood disorders, increased
infection risk
JAK inhibitor
Upper respiratory tract infec- Risk of serious infections,tions, headache, nausea
thrombosis, liver enzyme
elevation
Monoclonal antibody targeting IL-17 A
Injection site reactions
Upper respiratory tract
infections
Monoclonal antibody against IL-12 andInjection site reactions
Upper respiratory tractIL-23
infections

Among these medications, antimetabolites such as azathioprine and methotrexate, as well as T-cell inhibitors
like cyclosporine A, are currently used in BU for systemic
immunosuppression with the goals of preserving visionand preventing recurrence [175, 176].
Azathioprine (AZA) has been found to be effective inslowing down the progression of BU and reducing complications related to oral and genital ulcers and arthritis at

Injection site reactions

a dose of 2.5 mg/kg/day [175]. A study involving 157 BU
patients suffering from active posterior uveitis or panuveitis showed that a combination of corticosteroids (0.5
to 1 mg/kg/day) and AZA (2.5 mg/kg/day) led to total orpartial remission in 93% of the patients, while also improving visual acuity. This allowed for a lower average dose oforal prednisone, which can lessen the risk of steroid side
effects. In general, AZA has less severe side effects and iswell tolerated in most patients, making it a reliable andGuan et al. Journal of Neuroinflammation(2024) 21:133

efficient BU treatment. Its efficacy correlates with theseverity of retinal vasculitis or vision loss and is enhancedwith early administration [177]. It is also considered compatible for use in adolescent BU populations, often in
combination with long-term steroid therapy [174].
Cyclosporine A (CsA) is one of the most effective immunosuppressants for treating refractory BU and oral ulcers,skin lesions, and genital ulcers with long-term stable efficacy [171, 178, 179]. The daily dose is usually 3 to 5 mg/kg.
Administration of 5 mg/kg/day CsA to active BU patients
may significantly improve their vision within six months[8, 176, 180]. However, the application of CsA is restrictedby its side effects, which include nephrotoxicity, elevatedblood pressure, increased levels of liver enzymes, andgastrointestinal issues. Also, treatment of CsA increases
the probability of parenchymal nerve involvement andelevates ALT/AST in BU patients, and the risk is greater
when used alone than in combination with other drugs[181]. Other side effects of CsA are elevated uric acid,
hyperlipidemia, and hypertension [179]. Therefore, careful dose adjustments tailored to individual patients arenecessary.
Methotrexate (MTX) is recognized as the least toxic
immunosuppressive agent utilized in the managementof posterior uveitis. A research study was conducted toassess the effects of a treatment regimen comprising prednisolone (0.5 mg/kg/day) and MTX (7.5 to 15 mg/week)
on BU patients. Notable improvements were observed
across posterior uveitis (PU), visual acuity (VA), andretinal vasculitis (RV), with PU displaying the most significant effectiveness. The total adjusted disease activity
index (TADAI) diminished in 80% of the subjects [182].
Chlorambucil , administered at a daily dose of 2 to 6 mg,
has demonstrated potential in reducing BU relapses, controlling ocular inflammation, and improving systemic
symptoms. Its benefits can persist even after discontinuation of the drug, and some patients may be able to reduceor stop steroid therapy. A retrospective study found thatmost BU patients responded to chlorambucil, and its use
early in the disease resulted in better visual preservation.
However, its dose-related side effects, like malignancy andmyelosuppression, severely limit its application. Otherside effects include nephrotoxicity, gastrointestinal reactions, leukopenia, infections, and temporary amenorrhea
in women [183, 184]. One study reported that a shortterm high-dose (mean duration: 23 weeks; mean total
dose: 2.2 g) chlorambucil treatment was safer than a longterm application, with guaranteed efficacy. During thefollow-up period, no malignancies were discovered [185].
In conclusion, while immunosuppressive agents offer a
promising way to the management of BU, a cautious andPage 15 of 28

individualized approach that balances efficacy and potential side effects is crucial. Collaboration among specialists
is essential to tailor treatment plans to the specific needsof each patient.
Biologics

Medications are monoclonal antibodies produced
through genetic engineering that can rapidly improvedisease and should be administered on the clinical characteristics of the patients [186].
TNF-alpha antagonists

The introduction of TNF-alpha (TNF-α) antagonists hasbrought about a significant change in the treatment of
BU, leading to new therapeutic possibilities and a deeper
understanding of the disease’s pathogenesis. Over thelast two decades, these inhibitors have become the primary approach in managing severe uveitis manifestations
in BD. Interestingly, BU patients tend to respond betterto anti-TNF-α agents compared to those with idiopathic
uveitis [187, 188].
In a groundbreaking development in 2017, adalimumab received approvals from both the US Food andDrug Administration (FDA) and the European Medicines
Evaluation Agency (EMEA) for treating non-infectious
uveitis. This approval was supported by numerous clinical studies consistently demonstrating the safety andeffectiveness of TNF-α monoclonal antibodies in thelong-term treatment of BU [189–192]. Furthermore,
adalimumab and infliximab have comparable efficacy
in the treatment of refractory BU. This remains true
whether they are used as standalone treatments or in
combination with other therapeutic agents like azathioprine (AZA) and methotrexate (MTX). These findings
highlight the exceptional potential of anti-TNF-α agentsin the treatment of BU [192, 193].
Adalimumab (ADA) , is a recombinant IgG1 monoclonal antibody that is specially designed to target TNF-α. It
is a completely humanized antibody that exhibits a strong
binding affinity for p55 and p75 TNF receptors. Throughits binding to these receptors, ADA effectively suppresses
the activity of both the membrane-bound and soluble
forms of TNF-α [194]. This inhibitory action is crucial in
the treatment of non-infectious intermediate, posterior,or panuveitis, especially in cases where conventional therapeutic strategies have proven to be ineffective.
To initiate treatment, a subcutaneous dose of 80 mg isusually administered, followed by a maintenance dose of
40 mg every other week. Clinical outcomes have shown
positive results with ADA therapy. Notable improvements include a significant reduction in intraocularinflammation, an enhancement in best-corrected visualacuity (BCVA), and a decrease in macular thickness asGuan et al. Journal of Neuroinflammation(2024) 21:133

measured by OCT. Additionally, recurrence rates havebeen observed to decrease, indicating the safety andefficacy of ADA in the management of BU. The efficacy
of ADA is not limited to patients who are newly introduced to the drug. Even patients who have failed primaryanti-TNF-α treatments have experienced benefits whenswitched to ADA or other alternative anti-TNF-α agents[193, 195]. It is important to note that both ADA and infliximab can be used for the long-term treatment of BU,
as their efficacy does not change even when used concurrently with DMARDs (Disease-Modifying Antirheumatic
Drugs). ADA has also demonstrated efficacy in severe
refractory BU patients, even in the presence of adverse
prognostic indicators [196, 197]. While ADA is generally
well-tolerated, some patients may experience localized
reactions at the injection site [198]. Recent research highlights the potential of combining ADA with conventional
therapies, particularly in the treatment of refractory
BU-induced retinal vasculitis (RV). These combination
treatments have shown superior outcomes compared to
traditional therapies alone. Although patients on ADA
often achieve stable long-term results, there may be aslightly increased risk of adverse events. Therefore, anindividualized and flexible approach is recommended
when administering ADA to ensure optimal outcomes[199, 200].
Infliximab (IFX) is a chimeric monoclonal antibody
made up of both human and mouse components. It isengineered to have a high binding affinity for both soluble
and membrane-bound forms of TNF-α. In 2001, Sfikakis
et al. pioneered the use of a single infusion of IFX (5 mg/kg) to treat five patients with recurrent BU, all experiencing rapid and sustained remission with no notable side
effects during the observation period [201]. Subsequentclinical trials have consistently emphasized the potential
effectiveness of IFX in the management of patients withrefractory BU. It has been identified as a primary treatment for refractory retinitis caused by BD. The administration of IFX requires careful optimization, especiallyfor patients who have achieved remission. For those who
experience a relapse, the recommended treatment regimen involves the continuation of intravenous IFX at adose of 5 mg/kg every eight weeks [202]. Infusion intervals are shortened in patients who experience relapse
during IFX treatment and higher doses (more than 5 mg/kg) can be administered as well. A notable feature of IFX
is its rapid therapeutic effect. Just a single infusion at adose of 5 mg/kg has been observed to almost resolve all
ocular manifestations of BU entirely within 28 days. This
encompasses the resolution of retinal vasculitis, the disappearance of persistent symptoms such as macular cystoid edema, and significant improvements in visual acuity.
The overall recurrence rate also drops substantially. While

Page 16 of 28

some patients do experience relapses, administering IFX
again post-relapse has shown to be effective [203, 204].
The efficacy of IFX as a monotherapy might be slightly
inferior compared to when it’s combined with CsA. Interestingly, after discontinuation of IFX, approximately 40%
of patients maintained remission of their ocular inflammation for up to three years. This suggests that IFX offers
a prolonged therapeutic effect, and discontinuation might
be feasible for patients who demonstrate stable inflammatory control over an extended period [205]. A long-term(decade-long) clinical study further attested to the efficacy of IFX in managing BU. Patients showed significant
visual function improvements and had a reduced incidence of ocular complications, such as glaucoma, during
their follow-up. IFX also exhibited potential in managing
overall BD symptoms, beyond just the ocular manifestations [206]. For patients where Interferon-alpha (IFN-α)therapy proves ineffective, IFX emerges as a viable alternative [207]. An important observation was that patientswith uveitis symptoms for less than 18 months derived
more benefits from IFX treatment. This underscores thepotential advantages of initiating IFX therapy early in the
disease course [208, 209]. However, caution is warranted
when considering discontinuation of IFX. Even in patients
who achieved long-term remission, extraocular manifestations, such as recurrent oral ulcers, were prevalent a
year post-IFX discontinuation [210]. While IFX is generally well-tolerated, mild infusion reactions are common
adverse events. However, clinicians should be wary of thepotential for more serious complications, including severe
infections (like reactivation of latent TB) and malignancies [198, 202].
A comparative analysis between IFX and ADA in thetreatment of refractory BU has demonstrated the effectiveness of both drugs. Both IFX and ADA have shown
positive therapeutic effects, but a multicenter study with
one-year follow-up showed that ADA had better resultsin terms of improvement in anterior chamber inflammation, improvement in vitritis, and BCVA [198].
Golimumab (GOL), a recent addition to the anti-TNF
armamentarium, stands out due to its lower likelihoodof inducing neutralizing antibodies compared to IFX andADA [211]. Five refractory BU cases (8 eyes) treated withstandard doses of GOL (50 mg every four weeks) were
followed up for 12 months, and 7/8 (87.5%) eyes were
found to have complete control of intraocular inflammation, demonstrating that GOL treatment significantly
reduces the number of BU recurrences and rapidly
regresses active retinal vasculitis (RV) [212]. GOL also
demonstrated significant reductions in macular center
thickness, vitreous opacity grading, and anterior chamber cell grading. The results of these studies suggest that
GOL has the potential to become a mainstay for thetreatment of refractory BU, especially in patients whoGuan et al. Journal of Neuroinflammation(2024) 21:133

have not received prior TNF therapy. Mild adverse effects
included elevated liver enzymes, fatigue, and a rash [213].
Certolizumab pegol (CZP) has a therapeutic effect on
refractory BU that is outside the drug indications. There
was a significant reduction in relapses after initiating GOL
or CZP, with no discernible difference in the two drugs’
efficacy or survival. When other anti-TNF-α drug treatments are ineffective, GOL and CZP are alternative treatment options that can significantly reduce the frequencyof relapses and preserve visual function [214]. CZP distinguishes itself from other anti-TNF-α drugs by lacking
an Fc region, which interacts with the neonatal Fc receptor (FnRn). This structural difference results in a lower
rate of placental transfer, making CZP a safer therapeutic
option during pregnancy [215]. Studies have shown thatCZP effectively reduces intraocular inflammation andpreserves vision during gestation without causing harmto the newborn [216].
There is growing interest in the localized management of uveitis through intravitreal injections of antiTNF agents. Early investigations suggest that this modeof administration allows for the rapid attainment oftherapeutic drug levels in the eye. Furthermore, intravitreal injections of both IFX and ADA have demonstrated a favorable safety profile, exhibiting neither
toxicity nor immunogenicity. Despite these advantages,
the short duration of action of intravitreal IFX necessitates repeated injections. As BD is a systemic condition,
a comprehensive assessment of the efficacy and safety
of intraocular versus systemic medications is needed. It
is possible that future treatments may incorporate both
local and systemic anti-TNF medications [194].
BU patients who have achieved remission with repeatedanti-TNF therapy may have their dose gradually reducedor their injection interval extended. TNF-α inhibitors can
reduce the oral dose of GC, a phenomenon known as thesteroid-sparing effect [193]. The steroid-sparing effect isan additional benefit of anti-TNF therapy. Patients whoachieve remission with repeated anti-TNF doses may beable to reduce the dosage or extend the dosing interval.
By effectively reducing inflammation, TNF-α inhibitors
can decrease or eliminate the need for corticosteroids,
thereby reducing the risk of steroid-related side effects.
This potential to decrease BU recurrence compared to
traditional treatments offers hope for preventing irreversible vision loss [217]. However, anti-TNF therapy
is not without its risks. Systemic inhibition of TNF canlead to severe infections, including the activation of TB
or reactivation of hepatitis B virus [218]. There are otherpotential side effects associated with the use of TNF-α,
including exacerbation of heart failure, neuro-demyelinating lesions and dyslipidemia [219, 220]. Therefore,
it is crucial for clinicians to use TNF drugs judiciously

Page 17 of 28

and regularly monitor their patients. The mechanism bywhich TNF-α functions likely involves the activation ofmacrophages, interactions with T cells, and T-cell-driven
B cell responses.
Interferon-alphaInterferon serves as a powerful immunomodulatory
agent that has significantly changed the therapeutic
landscape for BU [221, 222]. Its efficacy may be related
to the decrease in dysfunctional Treg cells, Th17 cells,
CD4+ T lymphocytes, and increase in IL-10 [223–225].
In recent guidelines, the EULAR advocates using highdose corticosteroids, infliximab, or IFN-α for BU patients
presenting with severe ocular manifestations. Based ontreatment response following conventional therapy, EserOzturk et al. split 25 BU patients receiving IFN-α into
three groups: non-responsive group, complete remission
group, and partial remission group. IFN-α was deliveredat a dose of 6 million units (MU) daily over one week,then 3 MU per day. After clinical remission, IFN-α 3 MU
was administered as a maintenance dose every other day.
Assessing BCVA, central macular thickness (CMT), andFFA, 21 patients in total, accounting for 84% of the study
population, exhibited enhancements after IFN-α therapy administration. Satisfactory results were obtained
within a month, with rapid resolution of active inflammation and improvement of mean BCVA and CMT in
all patients. Inflammatory episodes were never observedin the group with full remission, whereas increasing the
IFN-α dose was effective in the partial remission group[226]. Besides being effective in treating ocular manifestations, IFN-α has proven to be particularly effective
for BU patients with concomitant macular edema [227].
One of the noteworthy attributes of IFN-α therapy is thepotential to achieve long-term remission post-drug withdrawal, indicating its potential for sustained therapeutic
effects. Initiating IFN-α therapy early in the disease trajectory appears to yield better outcomes [226].
A recent study has shown that the co-inhibitory molecule PDL1 is upregulated by IFNα-2a in dendritic cells of
BU patients in an IRF1-dependent manner and that PDL1mRNA expression levels are linked to the treatment efficacy. Treatment with IFNα-2a led to CD4+ T cell apoptosis, without any significant changes in Treg frequency,
and resulted in decreased Th1 and Th17 frequency andreduced levels of IFN-γ and IL-17. Suppression of theTh1/Th17 immune response corresponded to uveitis
remission. Moreover, IFNα stimulated IL-10 secretion by
CD4+ T cells in BU patients, which then hindered IL-17
secretion by PBMCs. In conclusion, the therapeutic benefits of IFNα-2a in BU are mediated by dendritic cells andCD4+ T cells [109].
In a monocentric retrospective investigation, Shi etal. incorporated 30 patients afflicted by refractory BU,

Guan et al. Journal of Neuroinflammation(2024) 21:133

who underwent IFN-α2a therapy at Peking Union Medical College Hospital between February 2015 and June
2018. Utilized as an adjuvant to traditional treatment
in patients with poor prognosis led to treatment success in 26 individuals, representing 86.7% of the cohort.
Throughout the follow-up period, most patients could
achieve a reduction in steroid hormone and immunosuppressant dosage, or even complete discontinuation of
immunosuppressant use, with a significant decrease inocular inflammatory recurrence. No unresolved adverse
drug reactions were observed [228].
Another study involving 36 patients with severe BU
manifestations showed the efficacy of IFN-α in alleviating vasculitis, papillitis, and macular edema. There wasalso a notable decline in the mean annual recurrence
rate per patient, even post-discontinuation of the interferon therapy [229, 230]. Pegylated interferon is a derivative of IFN-α that improves the solubility of IFN protein
and prolongs its half-life. Therefore, in cases where IFN-α
needs to be used three times a week, peg-IFN-α only
needs to be used once a week at a frequency sufficient toensure the therapeutic effect. A small case series involving four patients with severe refractory BU found that
peg-IFN-α has a potential long-term effect for the treatment of severe uveitis, reducing the number of injections,improving the quality of life of patients, and improving
treatment adherence [231]. There were notable variationsin the management of ocular inflammation and goodpatient tolerability comparing the average number of episodes, visual acuity, ocular inflammation, FA score, disease activity, and side effects between IFX and IFN-α fortreating refractory BU. When comparing IFX and IFN-α
for the treatment of refractory BU, it was observed that
IFN-α is a favorable therapeutic choice for BU patients
who do not respond to conventional therapies, even considering its elevated risk of side effects [207, 227].
A direct comparison between IFNα-2a and corticosteroids versus CsA and corticosteroids over a 12-month
period showed superior outcomes with IFN-α treatment,with significantly lower BOS24 scores, greater rates of
BCVA, full remission, and more stable remission of intraocular inflammation. The advantages of IFN-α surpass
those of CsA, which had a short-lived effect, a greater
incidence of side effects, and a notable absence of significant steroid-sparing effect [179].
While IFN-α is typically well-tolerated, certain patients
may encounter side effects like fever, fatigue, muscle pain,
headache, and other flu-like symptoms. Other rare side
effects include mild bone marrow suppression and elevated liver enzymes. However, with a multidisciplinary
approach, most side effects are reversible [226].
Collectively, IFN-α has emerged as a reliable andeffective treatment option for refractory BU. Itsability to reduce the need for steroids and other

Page 18 of 28

immunosuppressants, combined with its superior outcomes when used in the initial stages of the disease,solidifies its position in the therapeutic arsenal against
BU.
CD20 antagonists

Rituximab has been explored as a therapeutic option
for B cell-mediated diseases by targeting the CD20 antigen found on B cell surfaces. In the case of refractory BU,
rituximab has shown promising treatment outcomes.
Specifically, two doses of 1000 mg each of rituximab,
administered 15 days apart, have significantly reduced
uveitis activity and associated symptoms in patients withretinal vasculitis and edema [232]. However, the current
data on the utility of rituximab for BU is still insufficient
to definitively address the side effects associated with uveitis treatment [233].
CD52 antagonists

Alemtuzumab has also been investigated for its potential in BU treatment. Alemtuzumab is directed against
CD52, a protein found on the surface of lymphocytes
and macrophages. This targeting results in the depletionof T cells and, ultimately, the reconstitution of immune
function within the CD4+ cell subset [234]. Studies haveshown that alemtuzumab can induce remission, reducesteroid dependency, and generally be well-tolerated in
BU patients. However, careful assessment is required
before its administration due to potential side effects like
lymphopenia and thyroid function abnormalities [235].
Additionally, alemtuzumab has demonstrated efficacy intreating non-infectious uveitis associated with other conditions like multiple sclerosis [236].
IL-1 antagonists

Anakinra (ANA) and Canakinumab (CAN) , as IL-1
antagonists, may serve as a treatment option for BU
patients exhibiting resistance to traditional therapy and/or presenting contraindications for TNF-α inhibitors,
such as latent TB or chronic/active infectious disease. A
retrospective examination of 36 BD patients treated with
ANA or CAN, conducted by Fabiani et al., revealed that
IL-1 blockade demonstrated favorable therapeutic efficacy
in BU and BD patients with extended disease duration.
The therapeutic impact of ANA (100 mg/day) or CAN(150 mg/8 weeks) proved to be both rapid and enduring[237]. The results of observational studies have shown that
IL-1 inhibitors can treat refractory BU and have excellent
safety [238]. ANA is an interleukin-1 receptor antagonist,
whereas CAN operates as an anti-interleukin-1 beta antibody. Fabiani et al. explored the roles of ANA and CAN
in 19 patients with refractory BU (involving 31 affectedeyes). They found that IL-1 inhibition therapy contributed to a considerable reduction in recurrence rates 12

Guan et al. Journal of Neuroinflammation(2024) 21:133

months post-treatment initiation compared to the same
duration before treatment initiation. Additionally, it significantly ameliorated retinal vasculitis in both short andlong-term contexts, as well as reduced the average steroid
dosage. However, the combination of IL-1 inhibitors andimmunosuppressants did not enhance efficacy. Patients
receiving concomitant DMARDs exhibited a higher rateof BU relapse relative to those undergoing monotherapy.
In conclusion, ANA and CAN are effective and safe treatment options for BU, significantly reducing ocular inflammatory response activity, alleviating retinal vasculitis,
preventing visual impairment, and significantly reducing
steroid dose [239].
Gevokizumab , a recombinant humanized variant
monoclonal antibody, impedes IL-1 receptor activation
by binding to human interleukin (IL)-1β. A phase II investigation involving the administration of 30 or 60 mg ofgevokizumab intravenously or subcutaneously every fourweeks to BU patients experiencing recent acute oculardeterioration or at risk thereof, yielded rapid control of
intraocular inflammation within one week, accompanied
by favorable steroid-sparing effects [240]. Despite demonstrating a good safety profile in the expanded study,
gevokizumab failed to substantially reduce the risk ofvisual deterioration, leading to the study’s primary endpoint not being met. Consequently, it is not advised as a
BU treatment based on the current, somewhat promising
results [241, 242]. As such, further exploration of IL-1β
pathway regulation in BU patients is warranted.
Furthermore, the administration of IL-1 inhibitors has
the advantage of reducing the dosage of GC, leading tosteroid-sparing effect. This reduction is beneficial as it
minimizes the systemic and ocular-related side effects
associated with prolonged GC use.
IL-6 antagonists

Tocilizumab (TCZ) , a fully-humanized monoclonal
antibody, acts on both membrane-bound and soluble
IL-6 receptors, presenting a promising approach fortreating BU, especially in instances where the condition
is refractory. Inhibiting IL-6 can suppress the productionof autoantibodies and rectify imbalances between autoantigen-specific Th17 and/or Th1-Treg [243]. TCZ has
produced rapid and long-term improvements in ocular
manifestations of BU, including anterior chamber cells,
vitreous inflammation, chorioretinitis, and retinitis, but
has limited efficacy in treating extraocular manifestations. Tocilizumab application may reduce the dose of
GC and produce a steroid-sparing effect [244]. Macular
cystoid edema, the most common complication of BU,
can resolve rapidly after the first TCZ infusion, indicatingthat TCZ has great therapeutic potential for patients withrefractory uveitis macular edema. Mild and rare treat-

Page 19 of 28

ment-related side effects include fatigue, chest tightness,transient elevation of serum LDL cholesterol (low-density
lipoprotein) levels, and leukopenia [245]. In a recent multicenter retrospective observational research, tocilizumab
showed higher efficacy against BU than IFX and ADA at
six months of treatment and induced complete remissionof macular edema in uveitis patients [246]. It demonstrates that TCZ is a secure and successful therapy for BU.
TCZ also has a therapeutic effect on arthritis and phlebitisin BD but is ineffective in treating oral/genital ulcers andskin mucosal manifestations [247].
IL-17 a antagonists

Secukinumab , a human monoclonal antibody with ahigh affinity for interleukin-17 A, has been determined
to be ineffective in the treatment of BU. In a phase III
randomized controlled trial involving 118 BU patients,
administering subcutaneous injections of secukinumab–
initiated with 300 mg dose every two weeks, followed
by a maintenance dose of 300 mg every four weeks—did
not succeed in reducing the recurrence rate of uveitis or
improving BCVA. The primary treatment endpoint was
not fulfilled, and it was also shown that the treatmentgroup experienced more non-ocular adverse events thanthe control group did [248]. A proof-of-concept study
found that compared with 300 mg subcutaneous injection 4 times every two weeks, secukinumab 30 mg/kg
twice intravenously every four weeks may be necessary todeliver secukinumab in therapeutic concentrations. Highdose intravenous secukinumab has shown positive efficacy in patients with active chronic noninfectious uveitis
who required corticosteroid-sparing immunosuppressive
therapy [249]. However, there are also cases of new-onset
BD reported in ankylosing spondylitis patients treatedwith secukinumab [250]. Secukinumab is currently not
used to treat uveitis in BD.
IL-23 antagonists

Ustekinumab is a fully-humanized monoclonal antibody
designed to target the shared p40 subunit of IL-23 andIL-12. It has been observed that patients with active BU
present higher serum levels of IL-23 compared to thosewith the inactive form of the disease [132]. Although there
are limited studies and reports available on the efficacy
of ustekinumab for treating BU, there exists a case reportthat details a successful instance of treating a BU patient.
In this case, the patient received subcutaneous injections of ustekinumab, administered at 45 mg at weeks 0
and 4, and subsequently every 12 weeks, demonstrating
effectiveness over a 3-month duration [251]. Typical side
effects encompass nasopharyngitis, headache, abdominal
pain, and joint pain [252].

Guan et al. Journal of Neuroinflammation(2024) 21:133

Janus kinase inhibitors (JAKi)

Tofacitinib functions as a JAK1/3 inhibitor, influencing both innate and adaptive components of the immune
system. This mechanism is achieved by blocking the signaling pathways of multiple cytokines and interferons,
such as IL-2, IL-4, IL-6, IL-23, IFN-γ, and IFN-α, leading
to the regulation of immune responses. As a small molecule, tofacitinib possesses the potential to traverse theblood-retinal barrier with greater efficacy compared toconventional drugs. Tofacitinib 5 mg given twice daily
significantly improves BCVA by reducing retinal leakage
and decreasing recurrence, is well tolerated, and is therefore expected to be the first choice for treating BU in the
future [253].
Upadacitinib , a selective inhibitor targeting JAK-1, hasgarnered attention for its therapeutic potential in BU. In a
recent study, the efficacy of upadacitinib was investigatedin BU patients who exhibited inadequate responses toconventional therapies and anti-TNF-α treatments. Following the administration of upadacitinib to one adultand one pediatric patient, notable improvements wereobserved. Both patients experienced enhancements invisual acuity, effective control of intraocular inflammation, and resolution of macular edema. Importantly, no
severe adverse events were reported during the follow-up
period, underscoring the promising safety profile of upadacitinib in the management of BU [254].
JAKi offers a new option for BU patients, particularly
those whose uveitis has not responded well to conventional and biological DMARDs [255].
Chinese medicines

BD belongs to the “fox confusion disease” category in
Chinese medicine. According to Chinese medicine, theformation of BD is internally related to the deficiency of
spleen qi caused by factors such as physical constitution,
diet, and emotion. Externally, the disease develops due tothe invasion of the body by the evil of dampness and heat.
Longdan Xiegan Decoction (Lobelia, Gardenia, Scutellaria, Mouton, Zedoary, Plantago, Bupleurum, Glycyrrhiza, Angelica, Radix et Rhizoma) can regulate CD4/
CD8 and Th17/Treg balance, thus effectively alleviating
inflammation in experimental autoimmune uveitis (EAU)
eyes and regulating systemic immune status [256].
Berberine, an isoquinoline alkaloid with a unique tetracyclic structure isolated from Chinese herbal medicine, has been found to have immunomodulatory effects
in several inflammatory models [257, 258]. In uveitis, it
has been confirmed that it can significantly ameliorate
the BU and EAU, and there are two possible pathways.
One is to affect genes belonging to chromatin remodelingand immune-related pathways, directly acting on T cells
or indirectly through DC to regulate Treg/Th17 balance.

Page 20 of 28

The second is to increase the number of immunomodulatory bacteria in the gut microbiome [259–261].
These studies open new avenues of thought. Chinese
medicine or natural products possess unique inherent
principles for treating the disease and other T cell-related
conditions. It is anticipated that a unified standard for
Chinese medicine treatment of BU will emerge, potentially offering unforeseen therapeutic benefits in managing BU.
OthersProgranulin (PGRN), an immunomodulatory molecule,has been observed to be downregulated during active
disease phases in BD patients. Preliminary studies in animal models suggest that PGRN has the potential to alleviate EAU by reducing Th1 and Th17 cell populations,while simultaneously promoting the polarization of Treg
cells. These findings suggest that PGRN may become apotential therapeutic target for BU in future investigations [262].
In addition to pharmaceutical treatments, dietarymodifications are emerging as potential therapeuticstrategies for BD. More specifically, diets rich in butyrate
have shown promising effects by reducing the production of ROS in lymphocytes, monocytes, and neutrophilsamong BD patients. Furthermore, these dietary adjustments have been associated with decreased levels of CRP
and increased overall plasma antioxidant capacity. These
modifications contribute to a balanced inflammatory
response, decreased disease activity, and reduced relianceon steroids [263]. The “hygiene hypothesis” holds that BD
patients are more likely to live in poor sanitary conditions, characterized by lower monthly income, a historyof parasites, use of dried cow dung as fuel, less bathingor brushing, and close contact with pigs and pork [264,265]. The oral health status of BD patients is often worrisome, such as oral infection, need for tooth extraction,
caries, loss of teeth, and an elevated plaque index score,
which may be potential mediators of disease severity[266–268]. Hence, improving oral and personal hygiene
may be beneficial.
These findings emphasize the importance of a comprehensive approach to managing BD, which should integrate dietary, lifestyle, and pharmacological interventions
to optimize patient outcomes.

Conclusions and future work
Taken together, uveitis is one of the primary clinical signsof BD. This manifestation is attributed to a combinationof immune dysregulation, genetic predispositions, andthe involvement of microbial elements. These elements
have the potential to trigger aberrant immune responses
that ultimately lead to the onset of the disease.

Guan et al. Journal of Neuroinflammation(2024) 21:133

The treatment of BU extends beyond conventional
pharmacological interventions. Lifestyle choices, environmental factors, and dietary habits have been acknowledged for their ability to influence disease activity,
presenting a multi-faceted approach to managing thecondition. Various molecular and cellular targets, such as
the LCK gene, ERAP1, the balance of Th17 and Treg cells,
the JAK signaling pathway, PGRN, and key cytokines like
IL-17 and RORγt, have been identified as potential avenues for innovative therapeutic interventions.
Biologics have revolutionized the management ofrefractory BU due to their targeted mechanisms ofaction. However, there is still ongoing work to optimize
BU treatment. Some current medications, while effective, have limitations, ranging from incomplete disease
control to the occurrence of unwanted side effects. Thisemphasizes the urgent need for therapeutic options that
not only offer improved efficacy but also greater tolerability for patients.
The future of BU treatment looks promising. With
continued research and a deeper understanding of thedisease’s pathophysiology, the medical community is
well-positioned to develop novel therapeutic strategies.
These advancements, combined with a comprehensive
approach to patient care, aim to not only regulate diseaseactivity but also enhance the overall quality of life for BU
patients. As we move forward, the integration of stateof-the-art research, traditional wisdom, and patient-centered care will pave the way for a brighter future for thosebattling BU.
Author contributions
YG conceived the idea, analyzed the data, and drafted the manuscript. FL, NL,
and PY completed the final editing and revision of the manuscript. All authors
read and approved the final manuscript.
Funding
The work was supported by Major Program of Medical Scienceand Technology Project of Health Commission of Henan Province(SBGJ202101011), Medical Science and Technology Project of HealthCommission of Henan Province (SBGJ2020003031), National Natural Science
Foundation Key Program (82230032 and 81930023), and National Natural
Science Foundation Project (81970792 and 82101108).
Data availability
No datasets were generated or analysed during the current study.

Declarations
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.

Page 21 of 28

Take-home messages

Much progress has been made in the study of BU, butthere are still gaps in the understanding of its pathogenesis and the optimization of treatment options.Recent
studies have identified the interaction of genetic,
immune, and environmental factors, emphasizing theimportant influence of microbial elements. In addition,
the therapeutic potential of biologics and natural products has provided a new dimension to the treatment
paradigm of BU.These advances not only fill the gaps inexisting research, but also herald the future of subtle andeffective BU treatments, emphasizing the value of integrative therapeutic strategies.
Received: 5 January 2024 / Accepted: 4 May 2024

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