INTRODUCTION

Uveitis refers to inflammation of the uvea. However, the term has also been used to refer more broadly to inflammation within the eye and, therefore, to adjacent structures such as the retina.

Regarding its etiology, uveitis can be categorized as infectious or non-infectious. Amongst the known causes of non-infectious uveitis are systemic immune mediated diseases like Behçet’s syndrome (BS) that when difficult to treat require the administration of immunosupressive drugs, like anti-TNFα inhibitors.

CASE DESCRIPTION

A 37-year-old woman presented with recurrent oral and genital ulceration, inflammatory polyarthritis, and a previous episode of anterior uveitis requiring a cycle of systemic corticosteroids over several years before being referred to the Autoimmune Diseases Outpatient Unit, where she was diagnosed with BS and treated with colchicine and prednisolone.

The patient maintained low disease activity for a period of 10 years, after which, she developed a new episode of anterior uveitis. A cycle of high dose systemic corticosteroids was again required but this time the patient presented with a new flare during dose tapering. A decision to initiate a corticosteroid-sparing agent was then made, with azathioprine being the chosen agent. However, an early switch to methotrexate was needed due to intolerance of azathioprine. The clinical response was initially satisfactory, but 3 months later the ocular symptoms recurred, and a new bout of oral ulceration appeared concurrently (Behçet’s Disease Activity Index 3). Adalimumab (ADA) 40 mg every 2 weeks was then started, with a good initial clinical response. However, 4 months later, the patient presented with a sudden and severe decrease of visual acuity in her right eye (2/10), without ocular pain, photophobia, eye floaters or dysphotopsias. No other systemic symptoms were noted. On examination, neither eye redness, synechiae or changes in ocular motility and or in the fundus were apparent. A graphic representation of this case timeline can be found in Figure 1.

The initial bloodwork showed no elevated inflammatory markers; therefore, a flare of BS was unlikely. A lumbar puncture was then performed, showing a normal cerebrospinal fluid (CSF) composition: 4 cells/µl, proteins 0.33 g/l and glucose 57 mg/dl (serum level of 100 mg/dl). Although this finding rendered both infectious and autoimmune causes less probable, extensive testing for both was the next step.

Concerning the former, no bacterial or fungal growth was detected on cultural exams and India ink preparation for Cryptococcus, VDRL and TTPA for syphilis, acid-fast stain, culture, and polymerase chain reaction of CSF for Mycobacterium tuberculosis and viral serologies for cytomegalovirus, Epstein-Barr virus, herpes simplex and zoster were all negative. Serologies for human immunodeficiency virus, hepatitis B and C and a blood panel for the detection of zoonotic diseases (included Anaplasma, Ehrlichia, Borrelia, Coxiella, Babesia and Rickettsia) on blood were all negative. Concerning the latter, both the IgG index and angiotensin-converting enzyme level were lower than their respective cut-off values and no oligoclonal bands were detected in CSF. Anti-neuronal, NMDAR, VGKC, MOG and aquaporin-4 antibodies were also negative.

The last step consisted of several imaging tests, which included an orbit and brain computerized tomography scan, intracranial vessel wall and spinal magnetic resonance imaging, a transthoracic echocardiogram and a carotid doppler, which showed no alterations. However, a sensory evoked potentials test revealed a functional compromise at the pre-chiasmatic level.

Considering the aforementioned investigation, iatrogenic optic neuropathy induced by ADA seemed the most probable cause and, a decision to suspend the treatment was made. A new cycle of high dose systemic corticosteroids consisting of three pulses of methylprednisolone 750 mg followed by prednisolone 1 mg/kg/day with a quick tapering over 4 weeks was also started, with gradual improvement on visual acuity (6/10 at the time of writing).

DISCUSSION

The wide variety of ocular manifestations associated with autoimmune diseases range from minor disturbances to sight-threatening conditions that require immediate medical intervention. In some cases, anti-TNF inhibitors will be needed to stop further progression. However, anti-TNFα inhibitors have been associated with paradoxical reactions including ocular adverse effects, mainly anterior uveitis^[1]. Optic neuritis has also been reported as a potential manifestation, albeit much rarer. The SABER study, the first large cohort study examining optic neuritis incidence in patients treated with these agents, estimated an incidence of 5-10 cases per 100.000 patient-years, a rate similar to that in patients who started non-biologic immunosuppressive therapies^[2]. Moreover, it seemed that its development was highly dependent on a previous history of neuritis or demyelinating diseases. In all the cases collected patients had rheumatoid arthritis, psoriatic arthritis, axial spondyloarthritis or inflammatory bowel disease. Since then, other case reports and retrospective studies identified new optic neuritis cases related to anti-TNFα agents, but always in patients with autoimmune diseases more associated with musculoskeletal manifestations, inflammatory bowel disease or uveitis^[3-5].

In our case, a Naranjo score of 6 suggested a probable adverse drug reaction and made this diagnosis more robust. To our knowledge, this is the first case of optic neuritis in a patient with BS, and it not only strengthens the evidence regarding a relationship between optic neuritis and anti-TNFα therapy, but also suggests that this association is independent from the type of rheumatic disease for which the patient received treatment, whether it was vasculitis or an autoimmune disease with preferential gastrointestinal or musculoskeletal manifestations.