Behcet’s disease (BD) is a multisystem, autoimmune inflammatory condition targeting multiple systems. The disease burden in terms of ocular complications is up to 70%, out of which uveitis is the commonest [1,2]. Behcet uveitis (BU) is dominant in Middle Eastern regions with uveitis presentation frequency of 14.6% in Saudi Arabia [3].

Ocular Behcet mostly being bilateral and non-granulomatous owes its pathology to vasculitis resulting in retinal vessel occlusion and ultimately the vasculopathy. Inadequate treatment and relapsing nature of disease are associated with marked visual threat in up to 35% of patients, so should be dealt with aggressively. Resilient ocular involvement usually fails to respond to conventional steroids and immunosuppressants [2,4,5,6]. Infliximab has a promising role in controlling grave ocular complications [7,8].

INX infusion, a chimeric monoclonal antibody, induces many autoantibodies (mainly ANA and dsDNA) which may be regarded as a cause of reduction in efficacy of this drug. The mechanism of autoantibodies production in patients on INX is still ambiguous, and various conjectures have been proposed. But the effect is achieved through Tumor Necrosis Factor alpha (TNF-α) blockade which suppresses the production of TNF-α through macrophages which in turn leads to unopposed production of autoantibodies [9,10].

INX has been utilized in autoimmune arthritis and Crohn’s disease with rewarding results [8,11]. We have been using this biological agent in our tertiary care hospital as a first line treatment because of its noteworthy role to preserve vision in refractory uveitis. Apart from its convincing out-turn, some studies highlight reduction of its efficacy owing to formation of autoantibodies. The markers which take part in minimization of therapeutic efficacy of INX need to be elucidated. To best of our knowledge there is only one study which addresses the relationship between ANA induction and INX efficacy in BU, while only few studies discussed other autoimmune conditions [12-16].

Behcet’s disease (BD) is a chronic, relapsing, multisystem inflammatory disorder of unknown etiology, characterized by a triad of recurrent oral ulcers, genital ulcers, and ocular inflammation. It is classified among variable vessel vasculitides, as it can involve arteries and veins of all sizes. The disease shows a distinct geographical distribution, being most prevalent along the ancient “Silk Road,” including regions of the Middle East, Mediterranean basin, and East Asia. Genetic predisposition, particularly association with HLA-B51, along with environmental and immunological factors, plays a crucial role in its pathogenesis [17].

Ocular involvement represents one of the most serious and vision-threatening manifestations of BD, occurring in up to 60–70% of patients during the disease course. Behcet uveitis (BU) is typically bilateral, recurrent, and non-granulomatous, often involving both anterior and posterior segments of the eye. The hallmark pathology is an occlusive retinal vasculitis, which can lead to retinal ischemia, macular edema, neovascularization, and optic nerve damage. Recurrent inflammatory episodes contribute cumulatively to irreversible structural damage, ultimately resulting in significant visual impairment or blindness if not managed appropriately. [18]

Despite advancements in therapeutic strategies, the management of BU remains challenging. Conventional treatment modalities, including systemic corticosteroids and immunosuppressive agents such as azathioprine, cyclosporine, and mycophenolate mofetil, are often associated with incomplete disease control, frequent relapses, and long-term adverse effects. A considerable proportion of patients exhibit refractory disease, necessitating the use of biologic agents targeting specific inflammatory pathways.

Tumor Necrosis Factor-alpha (TNF-α) is a key pro-inflammatory cytokine implicated in the pathogenesis of BD, particularly in mediating vascular inflammation and tissue damage. Infliximab (INX), a chimeric monoclonal antibody directed against TNF-α, has emerged as an effective therapeutic option for refractory BU. It has demonstrated rapid suppression of intraocular inflammation, reduction in relapse rates, and preservation of visual acuity in numerous clinical studies. Due to its potent anti-inflammatory effects, infliximab is increasingly being used as a first-line or early intervention therapy in severe ocular disease. [19, 20]

However, despite its clinical efficacy, infliximab therapy is not without limitations. One of the notable immunological consequences of anti-TNF therapy is the induction of autoantibodies, particularly antinuclear antibodies (ANA) and anti-double stranded DNA (anti-dsDNA) antibodies. The development of these autoantibodies is thought to result from immune dysregulation following TNF-α blockade, leading to altered apoptosis, impaired clearance of nuclear antigens, and a shift toward autoimmunity. Although these antibodies are often asymptomatic, their presence has been associated in some studies with reduced therapeutic efficacy, development of drug resistance, and, in rare cases, lupus-like syndromes

The clinical significance of ANA and anti-dsDNA induction in patients with Behcet uveitis receiving infliximab remains incompletely understood. While several studies in other autoimmune conditions, such as rheumatoid arthritis and inflammatory bowel disease, have suggested a correlation between autoantibody formation and diminished drug response, data specific to BU are scarce and limited. Furthermore, the prognostic implications of these autoantibodies in terms of treatment response, relapse rates, and long-term disease control have not been clearly established.

In addition to immunological factors, patient-related variables such as age, gender, body mass index (BMI), and the concomitant use of immunosuppressive agents may also influence treatment outcomes. However, existing literature provides inconsistent evidence regarding their role in modulating infliximab efficacy in BU.[21]

Given these gaps in knowledge, there is a need to further elucidate the relationship between infliximab-induced autoantibody formation and clinical outcomes in Behcet uveitis. A better understanding of these associations may help identify predictive markers of treatment response, optimize therapeutic strategies, and improve long-term visual prognosis in affected patients.

Therefore, the present study aims to evaluate the frequency of ANA and anti-dsDNA antibody induction following infliximab therapy and to analyze their association with the prognosis and response duration in patients with Behcet uveitis. Additionally, the study explores the influence of demographic factors and concomitant immunosuppressive therapy on treatment outcomes

Study setting

This retrospective study was carried out in King Abdul Aziz University Hospital, King Saud University, Riyadh, Saudi Arabia, after approval from institutional review board. The duration of study was from September 2019 to August 2020. Consent was not taken as this was a retrospective study which was fully anonymized in images and data set. Three predictors for INX efficacy were autoantibody induction i.e., ANA and dsDNA and concomitant use of immunosuppressants i.e. cyclosporine and mycophenolate mofetil in relation to demographic characteristics i.e. age, gender and BMI.

Inclusion criteria included all BU patients on INX infusion irrespective of duration of therapy. Patients on infliximab for diseases other than Behcet uveitis were excluded. To name some it includes cancers, chronic inflammatory conditions, systemic lupus erythematosus, spondyloarthropathies, ulcerative colitis and Crohn’s disease or rheumatoid arthritis

Laboratory tests and radiological exam

Medical fitness for receiving the drug was requested before each infusion with laboratory tests which included complete blood cell count, liver and kidney function tests, ANA, anti-DsDNA antibodies and chest x-ray. Protein Purified Derivative skin test (PPD) interpretation was also done.  ANA was considered significant above 1:80 and dsDNA was labeled positive at more than 10 IU/ml

Ophthalmic examination

Fundoscopy, Optical Coherence Tomography (OCT) and Fundus Fluorescein Angiography (FFA) were used as diagnostic tools of BD while fundus picture showed hypopyon, vitreous inflammation and opacity, retinal vasculitis, inflammatory vascular occlusion affecting arterial or venous retinal vessels or solitary/multifocal retinitis (Figure 1 a-c), the OCT showed macular edema or macular atrophy (Figure 2).

Improvement was observed on fundoscopy/fundus photo in the form of resolution of retinitis, hemorrhages and vitreitis (Figure 4 a,b). OCT showed the regression of disease in the subsidence of macular edema. FFA was not done for follow up of disease progression except if ischemia was suspected

Drug regimen

Infliximab was given in a dose of 5mg/kg I.V infusion over 2 hours at weeks 0, 2, 4 and then every 8 weeks. If inflammation was controlled, then the interval between the infusions was increased.

In case of any flare up the previous schedule of shorter interval was reinstated. If complete remission was achieved over a period of 18 month of treatment, the infliximab was discontinued

Early and delayed responders

Patients who stayed in remission for 18 months on OCT and fundoscopy after infliximab treatment regimen were labelled as early responders. Those who had relapse before 18 months were categorized as chronic or delayed responders

Efficacy assessment

The efficacy was observed by assessing remission versus relapse in the form of early and delayed response

Statistical analysis:

Statistical analysis was performed using SPSS version 21.0. Descriptive data were expressed as Mean ± SD. Chi-square test or Fisher's Exact Test (where cell counts were less than 5) was used to compare categorical variables, and independent samples Student's t-test was used for continuous variables. A p-value of <0.05 was considered statistically significant

Behcet’s disease (BD) is a chronic, relapsing, multisystem inflammatory disorder of unknown etiology, characterized by recurrent mucocutaneous, ocular, vascular, and neurological manifestations. It is classified as a variable vessel vasculitis, capable of affecting both arteries and veins of different calibers. The disease shows a distinct geographic clustering along the ancient Silk Road, particularly in the Middle East, Mediterranean region, and parts of Asia, suggesting a complex interplay of genetic susceptibility and environmental triggers in its pathogenesis.

Among the various systemic manifestations, ocular involvement remains one of the most severe and vision-threatening complications of Behcet’s disease. Uveitis associated with BD is typically bilateral, recurrent, and non-granulomatous in nature, often involving both anterior and posterior segments of the eye. The underlying pathology is primarily an occlusive retinal vasculitis, which can lead to irreversible structural damage including macular edema, retinal ischemia, and optic atrophy. If inadequately treated, repeated inflammatory episodes significantly increase the risk of permanent visual impairment and blindness

The management of Behcet uveitis (BU) poses a considerable therapeutic challenge due to its aggressive course and high relapse rate. Conventional treatment strategies, including systemic corticosteroids and immunosuppressive agents, have shown variable efficacy and are frequently associated with adverse effects and incomplete disease control. A subset of patients develops refractory disease, necessitating the use of targeted biological therapies aimed at specific inflammatory mediators.

Tumor Necrosis Factor-alpha (TNF-α) has been identified as a key cytokine in the inflammatory cascade of BD, leading to the development of anti-TNF therapies such as infliximab. Infliximab has demonstrated significant efficacy in controlling ocular inflammation and preserving visual function in patients with refractory BU. However, its use has also been associated with immunological alterations, particularly the induction of autoantibodies such as antinuclear antibodies (ANA) and anti-double stranded DNA (anti-dsDNA), the clinical implications of which remain an area of ongoing investigation.

Total 30 patients (male=27, female=3) were enrolled in our study. Data demographics is shown in table 1

Table 1: Patients (n=30) demographic characteristics in study

      Data are presented as mean ± SD

SBP: systolic blood pressure; DBP: diastolic blood pressure; MAP: mean arterial pressure

Prior to treatment, all 30 participants tested negative for autoantibodies (ANA and dsDNA). Following infliximab therapy, 26 patients (86.6%) developed autoantibodies: 19 (73.1%) were ANA-positive and 7 (26.9%) were dsDNA-positive.

Of the 26 autoantibody-positive patients, 23 (88.5%) were delayed responders and only 3 (11.5%) were early responders. Among ANA-positive patients, 16/19 (84.2%) showed delayed response, while 3/19 (15.8%) achieved early response; however, this difference was not statistically significant (p=0.200). All 7 dsDNA-positive patients (100%) demonstrated delayed response with no early responders in this group, though this also did not reach statistical significance (p=0.120), likely due to the small sample size No statistically significant association was found between age or BMI and treatment response (p>0.05 for all comparisons), as shown in Table 2.

Figure 5: Frequency distribution of autoantibodies (ANA, dsDNA) induction in patients (n=30)

during first three cycles of INX treatment

Table 2: Relationship between demographics (age, BMI) of autoantibody induced patient

and response to infliximab treatment

Chi-square analysis revealed no statistically significant relationship between age or BMI and treatment response (all p-values > 0.05)

Only few (n=3) patients showed no recurrence of ocular inflammatory signs, while majority (n=23) presented with relapsing episodes of eye inflammation during 18 months follow up period. 10 patients showed up in ophthalmology clinic multiple times and 13 patients experienced only one episode of uveitis. In all early responders INX was discontinued due to attainment of good visual acuity and quiescent ocular examination signs in them.

Regarding positivity of ANA and dsDNA versus infliximab response, most (16 out of 19 [84.2%]) of the ANA induced patients were delayed responders, while 15.8 % showed early response (p=0.200). Similarly, all 7 (100%) dsDNA induced group of patients showed relapse of ocular attacks, with no dsDNA positive patient achieving an early response (p=0.120).  In dsDNA induced group of patients, all seven (100%) showed relapse of ocular attacks. Complete representation of autoantibodies relationship is presented in a flow chat (figure 6

Figure 6: Flow chart representation of relationship between response of BU patients to INX therapy versus autoantibodies (ANA and dsDNA) positivity and negativity. Pts:patients, + : positive, - : negative.

Simultaneous administration of cellcept and cyclosporine was applied to 12 and 16 patients, respectively. Only two patients were solely on infliximab due to observation of mild fundoscopic ocular signs of BU in them. Despite their synergistic use we found early response in only 6 (21.4%) patients (figure 7)

Figure 7: Flow chart representation of relationship between response of BU patients to INX therapy versus patients on concomitant immune suppressants therapy. Res.= response

Autoantibody induction post INX can lead to frequent recurrence of uveitis in BD as compared to patients with non-induction of autoimmunity.

ANA and dsDNA incitation after INX treatment have been studied in BD and other autoimmune diseases as well. It is documented to be positive in majority of the patients along with observation of rising titers over a period of therapy. In data of different autoimmune diseases, 65% showed ANA induction and statistically significant increase in number of patients with anti-dsDNA [17]. INX treatment-induced autoantibodies are common in BD and in one study, ANA was developed in 65% and dsDNA in 35% of subjects. Our findings were consistent with the previous literature and showed ANA (>1:80) and anti-dsDNA (>10 IU/ml) positivity in 73.1% and 26.9% patients respectively. The highest ANA titer observed was 1:320 while dsDNA was 509 IU/ml. None of these patients experienced lupus-like clinical manifestations which is consistent with the study of Elezoglou et al [18].

The non-significant p-values observed may reflect Type II error due to the small sample size (n=30) rather than a true absence of association. Larger multicenter studies are warranted to confirm these findings. Our institute has been using primary infliximab infusion with concomitant immunosuppressants according to the patient’s clinical profile. Despite various untoward side effects of anti-TNF α and other immunosuppressants, they have been infused in 90% of BD patients and commonest utilization is to reduce BD visual morbidity [7,19]. Considering heterogeneous prognostic efficacy of this drug around 35% of BU patients may end up in blindness even being treated with belligerent immunosuppressant regimen [17, 20].

Response to anti-TNF α agents by patients suffering from autoimmune diseases can be dissimilar and delayed efficacy of these agents has been noticed in the recent decade and being increasingly reported with time, though the mechanism is still ambiguous [21,22]. Approximately one third of the initial visual loss is reversible with infliximab treatment and has tendency to reduce the risk of severe visual dissipation from 24% to 13% after 10 years. Apart from its worthwhile contribution to reduce morbidity in multiple autoimmune conditions, there is also evidence of 30% non- responders and 50% patients with disease relapse [23-25].

Studies conducted on rheumatoid arthritis and psoriasis patients showed poor efficacy of infliximab in association with ANA and anti-dsDNA antibodies, but only few studies on this subject are reported so far [13-16,22,26]. We could retrieve only one study conducted on 17 patients in Japan by Iwata et al. addressing the relationship between antibody induction and efficacy of infliximab in refractory BU. This study suggested recurrence of visual inflammatory symptoms during 6 months after INX administration in 60% ANA positive and 33.3% ANA negative subjects compared to our results of 69.6% and 30.4% respectively. Majority (76.4%) of the participants became ANA positive during the course of infliximab treatment similar to our study (73.1%) [12]. Supporting the above-mentioned literature, our study depicted similar results of poor outcome in 88.5% of ANA and dsDNA positive patients who were undergoing infliximab therapy [21,27]. We therefore can propose that these autoantibodies are one of the indicators of hindrance to the INX effectual response, but reliability needs to be further explored.

Though the data on concomitant use of immunosuppressants with infliximab is available, but to the best of our knowledge the effectiveness on outcome of infliximab was not addressed in these researches [2]. Since infliximab is used as primary treatment for the patients of BU in our setting, our data represented that addition of other immunosuppressants in patients on infliximab infusion did not cast any beneficial or adverse effect on efficacy of infliximab. Despite these results giving an impression of their inutile outcome, there is still needed to see usefulness of their concomitant use over large number of patients and a comparison with a control group to draw more representable results.

A study on certain groups of autoimmune patients showed the need for discontinuation of infliximab in patients above the age of 65 years due to potential morbid side effects [27]. However, no data is available so far to evaluate the age criteria for favorable effect of infliximab. Our study indicates that age may not be marked as a predictor of infliximab efficacy.  The study conducted on BMI predictability of infliximab response supported our observation that BMI has no impact on infliximab response [28].

The limitation of our study is limited sample size and uneven distribution of patinets between early and delayed response groups can be the cause of statistically insignificance, which limits the power to detect meaningful differences between groups. Retrospective design and lack of control group to see the prognostic effect of autoimmune antibodies are also limiting factors. Although most of autoantibody positive patients were delayed responders, but p value was insignificant. Further long-term prospective studies with larger sample size are warranted to determine the factors which are directly associated with the efficacy of infliximab in the treatment Behcet’s intraocular inflammation

Infliximab induces autoantibody (ANA and dsDNA) in majority of the subjects with ANA induction in most compared to dsDNA. Majority of patients with these specific autoantibodies induction showed delayed response which may be a predictor of reduced effectiveness of drug in BU patients, but its reliability needs to be further analyzed. Concomitant use of immunosuppressants appears to have no beneficial role in INX response.

Acknowledgment: Special thanks to Miss Melinda Guibaobon and Reena Sarath Babu for helping us in data collection

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