I report a case with ocular Behçet disease presenting as hypopyon-anterior uveitis refractory to conventional immunosuppressive drugs who was safely and effectively managed for 20 years by nonstop infusions of a modern anti-TNF agent, infliximab. A 14-year-old girl who had a history of recurrent oro-genital ulcers, arthralgia, and pathergy test positivity presented with the symptoms of bilateral blurred vision, ocular pain, photophobia, and lacrimation. Initial visual acuities were 20/25 bilaterally, and biomicroscopy revealed bilateral iridocyclitis with left shifting cold hypopyon formation in the anterior chamber of the eye. The diagnosis of ocular Behçet disease was made, and topical anti-inflammatory drops were initiated with a cycloplegic agent. In due course, the child complained of chronic floaters and decreased vision from 20/25 to 20/200 bilaterally. Vitreitis, retinitis, perivasculitis, and cystoid macular edema (CME) were encountered, and the combination of corticosteroid, azathioprine, and cyclosporine-A was immediately started. However, the child did not respond to this conventional management for 3 months. A prompt and dramatic response was obtained with repeated Remicade® (infliximab) infusions (weeks 0, 2, 6, and 10), which led to fast improvement in her systemic and ocular symptoms. Long-term remission of 20 years was obtained by regular infliximab infusions at each 6- to 9-week interval with stabilized vision (20/20) and resolution of CME. The present case shows the significant role of biologicals in pediatric severe panuveitis and that nonstop infliximab infusions initiated early led to rapid and long-term control of intraocular inflammation and recurrent sight-threatening uveitis attacks for protecting the vision in children with severe OBD.

© 2023 The Author(s). Published by S. Karger AG, Basel

Ocular Behçet disease (OBD), known as the “ancient Silk Road disease,” is a relapsing-remitting disorder with an overactive immune system that produces unpredictable outbreaks of exaggerated ocular inflammatory attacks, presenting as recurrent acute anterior uveitis (iridocyclitis) with or without hypopyon, vitreitis, occlusive vasculitis (periphlebitis), and retinitis [1]. Cold hypopyon is a pathognomonic sign of OBD that is characterized by an atypical “white eye,” which represents an intriguing inconsistency between the severity of intraocular anterior chamber inflammation (hypopyon) and the status of periglobal injection (uninjected eye in a “hot disease”). The prevalence of OBD is between 1/1,000 and 1/10,000 per year in Turkey and Japan and 1/300,000 per year in the USA [1].

OBD may first affect the anterior chamber of the eye in children and adults with potential sight-threatening complications that can result in permanent visual loss if appropriate and sufficient management is not initiated in time [2]. Therefore, a definitive suppression of ocular inflammatory attacks is mandatory on a long-term basis, and there is still no specific treatment for this blinding disorder [3]. The management strategy aims for fast control of anterior or panuveitis attacks, preventing irreversible ophthalmic damage, allowing immunosuppressant-sparing status and protecting visual acuity. For this reason, the detection of anterior and posterior segment involvement and the early recognition of insufficient efficacy of traditional immunosuppressants are vital to prevent severe ocular complications, especially in children.

The present case is the first report regarding the longest use of an anti-TNF agent for sight-threatening bilateral panuveitis in a child with OBD refractory to conventional immunosuppressants, presenting initially as hypopyon anterior uveitis. The case addresses the importance of timely initiation (preferentially as first-line usage) and nonstop continuation of the biological agent in selected cases. Informed written consent was obtained regarding the publication of the figures.

A 14-year-old girl was seen in our uveitis clinic with the main complaints of articular symptom exacerbations, genital ulcers, and recurrent and painful mouth macroulcers, which started months previously and erupted almost every 4–6 weeks, lasting about 10 days. The patient had papulopustular lesions on her extremities, and the pathergy test was found to be positive. A dermatologist had previously prescribed colchicine (0.5 mg b.i.d) for the girl’s skin lesions with topical corticosteroid applications and analgesics for her oral aphthous stomatitis and articular symptoms, respectively. In her initial admission, the chief ocular symptoms were blurred vision, global pain, photophobia, and lacrimation. The visual acuities were 20/25 in both eyes with intraocular pressures of 15-mm Hg bilaterally. Biomicroscopic evaluation revealed anterior uveitis bilaterally with left cold-macrohypopyon (Fig. 1a, b) that was shifting temporally with body posture within minutes (Fig. 1c). With these systemic findings and pathognomonic ocular signs, the diagnosis of OBD with anterior segment involvement was made according to the International Criteria for Behçet’s Disease [4]. No gastrointestinal or neurological involvement, erythema nodosum, or thrombophlebitis was present, and all other physical examinations were found to be normal. HLA-B51 analysis was not performed because we know it is negative in about 50% of Behçet’s cases. Increased white blood cell count and erythrocyte sedimentation rate were detected on laboratory evaluation. The remaining laboratory analysis such as biochemistry panel, urinalysis, ANA, anti-phospholipid antibody, CRP, HSV testing, syphilis antibody screen, and chest X-ray were negative or within normal limits. The CARE Checklist has been completed by the author for this case report and is attached as online supplementary material (for all online suppl. material, see www.karger.com/doi/10.1159/000528593).

a “Cold hypopyon” in the left eye (arrow) in a patient with OBD, which represents the “inconsistency” between the severity of intraocular inflammation (hypopyon in the anterior chamber) and the status of periglobal injection (“white” or “uninjected” eye in a “hot disease”). (Please compare the scleral whiteness of the left eye with hypopyon anterior uveitis with that of her right eye with mild iridocyclitis). b Close-up image of the same left eye with cold macro-hypopyon (arrow). c Pathognomonic sign of mobile hypopyon in OBD, which slowly shifts (within minutes) from its horizontal position into the lateral part of the eye upon permanent leaning to the left side (arrow).

For anterior uveitis, topical steroidal and nonsteroidal anti-inflammatory drops were prescribed frequently along with a cycloplegic agent. In the following days, however, the child complained of chronic floaters with progressively deteriorated visual acuities from 20/25 to 20/200 bilaterally, and posterior segment evaluation revealed vitreitis, retinitis, perivasculitis, and cystoid macular edema (CME). Upon obtaining these findings, a combination of systemic immunosuppressants including corticosteroids (1 mg/kg/d), azathioprine (Imuran®, 1–2.5 mg/kg/d), and cyclosporine-A (Sandimmune®; 5 mg/kg/d) were initiated, but she did not respond to this combined therapy after 3 months, and the visual acuities did not increase with refractory bilateral macular edema (Fig. 2a, 3a). Because of the severity of the disease, infliximab (Remicade®; a biologic agent targeting tumor necrosis factor-α [TNF-α]) was started (5 mg/kg) at weeks 0, 2, 6, and 10, then at each 6-week interval following latent tuberculosis being ruled out by purified protein derivate and chest radiography. The child demonstrated a dramatic and rapid response to repeated infliximab infusions, and both visual acuities increased to 20/20 within 10 days. All other immunosuppressants were gradually discontinued in due course. Anterior chamber evaluation revealed no active inflammation (no cells and no flare), and both retinal vasculitis and macular edema resolved (Fig. 2b, 3b). After 1 year, the first attempt at tapering was made. However, flares during infliximab tapering were encountered even when smaller interval changes, i.e., from 6 to 7 weeks, were attempted initially. Therefore, we had to continue this regimen for years (8 infusions per year) as we experienced uveitis recurrences when we targeted to increase the infusion intervals repeatedly from 6 to 9 weeks. Subsequent tapering attempts were made at every 6-month interval, though the result was the same. After 17 years, we were able to increase the interval finally to 9 weeks, and her ocular symptoms and signs were under control for the recent 3 more years. Further attempts at weaning have been made over the last 1 year, but today, the patient is still having 6 infusions per year. The patient was not co-treated with a DMARD. CBC, liver function tests, blood urea nitrogen, and serum creatinine levels were evaluated every 3 months, and the girl did not show any severe side effects during this period that required the discontinuation of the regimen. Colchicine was added to infliximab by a dermatologist for her recurrent genital ulcers during the last 12 months. Overall, 20 years have passed since the first initiation and nonstop use of infliximab, and the patient is now 34 years old with stabilized vision at 20/20 bilaterally. Due to such a successful clinical response, the patient continues the same regimen with intravenous infliximab infusions (5-mg/kg) that are repeated at each 9-week interval at present.

a Right refractory CME under the treatment with a combination of systemic conventional immunosuppressants (corticosteroids, azathioprine, cyclosporine-A). b Resolution of right CME following the initiation of infliximab treatment.

a Left macular edema without cystoid findings in the same patient that was unresponsive to abovementioned medications. b Resolution of macular thickening after the treatment.

In 2002 [5], we demonstrated that tumor necrosis factor-α (TNF-α), a pro-inflammatory cytokine, is increased in patients with OBD. Then, several articles reported successful responses to TNF-α inhibitors (biological response modifiers), such as infliximab and adalimumab, in sight-threatening uveitis including OBD with anterior and posterior segment involvement as they demonstrate corticosteroid-sparing effects [6, 7]. Indeed, we first used infliximab for the present child about 20 years ago, the time when the Turkish Health Ministry (like the FDA) approved its use for such cases. Given the aggressive course of the disease in the present case and her relatively younger age, infliximab infusion at doses of 5 mg/kg was immediately initiated without any delay since she did not respond to combination therapy of 3 traditional immunosuppressants. Of course, the infliximab regimen could be escalated to 7.5, 10 or 20 mg/kg [7]. However, the dose given for the present case was sufficient to completely control the intraocular inflammation and CME, though tapering or discontinuation of infliximab was not possible to date since recurrences of ocular and systemic symptoms were encountered with our every effort.

The present unique case with OBD in a young girl who initially presented with hypopyon anterior uveitis addresses the importance of timely initiation of the biologic anti-TNF agent and highlights the role of long-lasting therapy. Continuous infusion of infliximab for many years may be the only treatment option for sight-threatening pediatric posterior or panuveitis refractory to traditional immunosuppressive drugs, notably when both eyes are involved. Recent reports have supported the present case and recommended anti-TNF-α agents as first-line therapy to manage naive or recurrent episodes of acute sight-threatening uveitis in OBD patients [8]. Opportunistic infections, reactivation of tuberculosis, and injection-related hypersensitivity may be anticipated after long-term use, though we did not encounter these with the present patient. We do not know yet when we should withdraw the agent. Increasing the interval of infliximab or its complete withdrawal should be considered carefully with close monitoring for ocular recurrences. Given that OBD mainly afflicts children and adults in their most productive years, dermatologists, rheumatologists, and ophthalmologists supervising such patients should be careful with the early recognition of posterior segment involvement as uveitis management in OBD differs from extraocular diseases with high ocular morbidity from sight-threatening relapsing inflammatory attacks.

It is of course difficult to say that “it is safe to use biologics for life,” especially for such a young girl. However, as stated above, the young girl did not respond to systemic corticosteroid, azathioprine, and cyclosporine-A for months, and her vision rapidly decreased from 20/25 to 20/200 bilaterally. So, it seems that the biologic’s ocular “benefits outweigh risks,” and we could not find another strategic plan. However, we followed the patient closely for possible adverse effects of the biologic. Indeed, we tried to discontinue the drug after 1 year, but flares during infliximab tapering were encountered at every attempt as stated. Uveitis was under control with this biological during the long follow-up period, and systemic recurrence was taken under control by colchicine for the last year. To protect her vision, we had to continue this drug and hopefully did not encounter any systemic adverse drug reaction up until now. In the literature, serious biological drug-associated adverse events have been reported to be 10% in patients treated with infliximab [9].

Repeated long-term infliximab infusions lasting 20 years were therefore found to be safe and effective in reducing the number of relapses in refractory panuveitis with a fast regression and complete quiescence of CME, indicating that biological response modifiers offer tremendous potential in the treatment of pediatric OBD. It should be kept in mind that OBD may present as cold hypopyon (white eye in a hot disease) formation, and such a finding may hide the severe inflammation in the posterior segment of the eye. The discovery of biologicals has opened a new era for the management of sight-threatening OBD, and many patients can be weaned off of treatment after appropriate length of control without recurring. However, in some cases, it is difficult to taper or discontinue the biologicals completely. But still, 10 questions should be clarified for pediatric cases: (1) what is the optimal initial dosage, frequency, and duration of therapy?; (2) how much longer to treat the present patient with infliximab after 20 years have passed?; (3) how and when to taper or discontinue the anti-TNF-α agent?; (4) what is the exact role of infliximab alone or in combination with immunosuppressants in OBD?; (5) is adalimumab superior to infliximab in pediatric OBD, or which biological is the best?; (6) should the anti-TNF-α agent be given for a scheduled time or upon each recurrence?; (7) what biologicals should be used in case of infliximab failure?; (8) should this be the first-line therapy for every pediatric OBD before conventional immunosuppressive drugs?; (9) what is the best policy to prevent frequent relapses; and finally, (10) can intravitreal infliximab injections be effective in pediatric OBD? Unless all these questions are answered, children with OBD have the possibility of losing their vision permanently at their younger ages. But still, we now have enough current therapeutic options for preventing children from going blind as a result of severe OBD.

Ethical approval is not required for this study in accordance with local or national guidelines. All procedures followed were in accordance with ethical standards and the Helsinki Declaration. Written informed consent was obtained from the patient for publication of the details and any accompanying images. Although the first treatment was given to the child when she was 14 years old, written informed consent was obtained from the patient herself for publication of the details and any accompanying images since the patient is not a child anymore after 20 years of follow up.

The author has no conflicts of interest to declare.

No funding was received by the author.

Conceptualization, writing, validation, review, and editing: Cem Evereklioglu.

All data generated or analyzed are included in this article. Further inquiries can be directed to the corresponding author.

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