Tocilizumab for Severe Chronic Anterior Uveitis Associated with Juvenile Idiopathic Arthritis in a Pediatric Patient

Vision-threatening JIA (juvenile idiopathic arthritis)-associated uveitis unresponsive to corticosteroids, immunosuppressive drugs, and anti-TNF agents is likely to require further biologic response modifier therapy to target alternate cytokines involved in the inflammatory pathways.1 We present one case of anterior nongranulomatous uveitis in a pediatric patient refractory to anti-TNF therapy who responded favorably to tocilizumab (TCZ), a monoclonal antibody against the interleukin-6 receptor (IL-6).

A 12-year-old Caucasian boy with a history of undifferentiated JIA according to ILAR classification was referred in 2010 for progression of anterior nongranulomatous uveitis of the left eye, which was diagnosed in 2001 when he was 3 years old (3–4+ cells, no flare).2 The patient was both HLA-B27 and ANA positive, and had a family history that was significant for psoriasis (first-degree relative), diabetes, and Crohn disease. Manifestations of his JIA, which began in 2000, included difficulty ambulating as a result of right calf atrophy, hind foot valgus, and significant ankylosing arthritis of the right tibiotalar, subtalar, talonavicular, navicular cuneiform, and calcaneal cuboid joints assessed by MRI. He was treated with indomethacin, methotrexate (MTX), and intraarticular triamcinolone hexacetonide injections until he was treated surgically via fusion of tarsal bones in 2012.

The course of uveitis prior to referral was known to be chronic (anterior chamber cells grade 1+ for greater than 3 months), and at presentation he had active anterior uveitis of the left eye (OS) per SUN criteria with 1+ cells and 1+ flare, while the anterior chamber (AC) of the right eye (OD) had no cells and no flare.3 Corrected visual acuity (VA) with pinhole was 20/50 OD and 20/40 OS. Complications of uveitis at the time of presentation included peripheral band keratopathy OD, epiretinal membrane (in both eyes, OU), foveal atrophy secondary to a history of macular edema OS and posterior subcapsular cataract OD with prior cataract extraction, posterior chamber intraocular lens implant (2004), and steroid-induced glaucoma OD treated with trabeculectomy (2008). Prior to referral, topical, oral, and intravitreal corticosteroids for uveitis, as well as etanercept, followed by cyclosporine A, infliximab, then adalimumab had limited effectiveness in controlling his uveitis and arthritis.

With uveitis flare-ups continuing despite twice the normal dose of adalimumab (40 mg/week), the maximum dose of MTX, and inability to taper prednisone below 20 mg, the decision was made to start abatacept (April 2011; 500 mg at 0, 2, 4 weeks loading, then 500 mg/month). One month following abatacept treatment, there were 0.5+ cells AC OS and prednisone was tapered to 10 mg. Following the fourth abatacept infusion (late June 2011) the patient developed an anaphylactic reaction, which required the cessation of abatacept. Prednisone was increased to 50 mg followed by a rapid taper to 25 mg within 7 days. Following these events he developed active bilateral uveitis (3–4+ cells and 3+ flare OD and 2+ cells, 2+ flare OS).

In August 2011,the patient was started on rituximab given as two infusions at a dose of 500 mg/m² 2 weeks apart. Following the rituximab infusions, the patient had severe chronic uveitis (4+ cells, trace flare) in the right eye (pseudophakic) despite ongoing therapy with prednisone (20 mg daily), and thus was treated with periocular triamcinolone injections on three separate occasions. He received the first injection in August 2011 (2+ cells, 2+ flare OD) followed by a second 2 weeks later at the end of August (1+ cells, no flare OD) and a third 6 weeks later in October (trace cells, 2+ flare OD). During this time, the visual acuity decreased from 20/40 to 20/100 OD with posterior capsular opacification of the intraocular lens implant, which was treated with a YAG laser capsulotomy. A 12-week period of uveitis inactivity followed the series of periocular injections while the patient was managed with topical corticosteroid (<3 drops per day), the maximum dose of MTX, and prednisone tapered from 20 to 5 mg po daily. In January 2012, 20 weeks after the final rituximab infusion, a severe episode of uveitis occurred in the left eye (2+ cells, 1+ flare) with elevated intraocular pressure (35 mmHg OD; 14 mmHg OS), suspected bleb failure, and failure of treatment with frequent topical steroid (prednisolone every 2 h; dexamethasone daily at bedtime). Immune phenotyping at this point showed the recurrence of a B-cell population (after initial complete depletion), with 4% CD19-, CD20-positive cells. The recurrence of inflammation responded slowly to topical corticosteroid treatment with prednisolone every 2 h and dexamethasone daily at bedtime (2+ cells, 1+ flare OS at 1, 2, and 3 weeks; 1+ cells OS at 4 weeks; trace cells OS at 6 weeks); however, remission of his uveitis was achieved in 8 weeks and remained stable at the start of TCZ therapy (no cells, no flare OS).

The lack of clinical response to rituximab, even when the CD19- and CD20-positive cells were depleted, led to the decision to start TCZ at a dose of 8 mg/kg every 4 weeks in April 2012. The visual acuity improved to his baseline of 20/40 OD and 20/20 OS. However, the intraocular pressure became elevated OS and could not be controlled with maximum topical and oral medical therapy for glaucoma. Quiescence of uveitis was initially achieved for 20 weeks on TCZ therapy with oral prednisone 2 mg per day and MTX (25 mg injection), and in August 2012, he underwent surgical implant of a Baerveldt tube shunt OS. Postoperative inflammation (1+ cells. 1+ flare OS) resolved in 3 weeks with a short course of topical corticosteroid (prednisolone every 2 h; dexamethasone daily at bedtime). Eight weeks later, a recurrence of uveitis occurred in October following orthopedic surgery to fuse tarsal bones in his right foot. The dosage of TCZ was escalated to 8 mg/kg every 2 weeks and quiescence was achieved 1 week after the first infusion under the new dosing schedule. After 7 infusions (14 weeks) of TCZ 8 mg/kg at the 2-week interval his uveitis has remained quiescent with no cells OU while on topical corticosteroid twice daily and methotrexate (25 mg injection), but without relying on any oral corticosteroid. The TCZ infusion intervals had to be increased subsequently to every 3 weeks because of the occurrence of neutropenia, a known side effect of TCZ. His arthritis, which failed to remain in remission on any of the previous medications, improved significantly with TCZ infusions, as demonstrated by MRI imaging. The chronic destructive changes in his midfoot region nevertheless required surgical fusion of tarsal bones for pain relief.

Interleukin-6 is a pleiotropic cytokine produced by synovial fibroblasts, macrophages, and monocytes, which is important for the differentiation of Th-17 cells and the terminal differentiation of B cells.3 The IL-6 signaling pathway is known to cause ocular inflammation through the stimulation of Th-17 while inhibiting regulatory T-cell generation.4 Th-17 stimulation releases IL-17, inducing the secretion of IL-6, IL-8, PGE2, MCP-1, and G-CSF, causing chronic inflammation. TCZ is a humanized monoclonal antibody against the specific IL-6 receptor.4 TCZ has been successfully used to treat children with systemic-onset JIA because of the direct implication of IL-6 in the pathogenesis of disease.5 The clinical use of TCZ in the treatment of JIA-associated uveitis in published case series in adults showed some success in the treatment of anterior uveitis, even in patients with severe disease that was refractory to high doses of topical and systemic corticosteroid treatment and DMARDs, including at least one TNF-inhibitor.6 To our knowledge, there is only one other reported case in which TCZ was used to treat JIA-associated uveitis in a pediatric patient.7 TCZ was successful in controlling this patient's uveitis, which had been refractory to corticosteroids, MTX, adalimumab, and infliximab.7

In our patient, TCZ therapy achieved remission of uveitis that was refractory to systemic corticosteroids, the maximum dose of MTX, and multiple biologics, including infliximab, adalimumab, abatacept, and rituximab. Abatacept, which induced an infusion reaction, is a CTLA-4-Ig that attenuates T-cell activation via the inhibition of the CD80/86;CD28 co-stimulatory pathway.8 While abatacept is known to have low immunogenicity, 3% of abatacept-treated patients develop antibodies that neutralize the drug and are directed to the CTLA-4 portion of the compound, which can illicit an adverse immune response.8

Our patient showed little response to rituximab after a 16-week period and immune phenotyping showed an early repopulation in CD19-, CD20-positive cells, leading us to consider TCZ. The onset of action of rituximab is variable and a delay of up to 4 months has been described in various autoimmune diseases.9 Our patient's initial improvement following the rituximab infusions was likely due to serial periocular steroid injections that were necessary to control a significant uveitis flare-up.

Our patient's uveitis was in remission for 20 weeks with an 8-mg/kg dose of TCZ every 4 weeks. One recurrence of uveitis during TCZ therapy was attributed to surgery to implant the Baerveldt tube shunt and was controlled with a short course of topical steroid therapy. The other recurrence of uveitis during TCZ therapy was associated with the orthopedic surgery to fuse the tarsal bones in his right foot. This episode resolved after three and a half weeks with topical steroid (prednisolone hourly).

There are no current guidelines for treatment of uveitis with TCZ. TCZ 8 mg/kg every 2 weeks is the approved dose for systemic JIA patients in the most parts of the world.10 At the maximum dose of TCZ, adverse events such as infection, neutropenia, and increased aminotransferase levels are common.10 During treatment, our patient developed neutropenia that subsequently resolved when we increased the infusion interval from 2 to 3 weeks. Lastly, it is important to note that with TCZ infusions, our patient was able to discontinue oral prednisone, which was unsuccessfully tapered over the course of his previous treatments. TCZ is a promising treatment option for JIA-associated uveitis in pediatric patients that has been refractory to other biologics and MTX therapy. Further studies are needed to develop practice guidelines and evaluate the optimal dosages and efficacy of TCZ in patients with JIA-associated uveitis.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.