Tocilizumab in patients with juvenile idiopathic arthritis-associated uveitis
Authors: Pierre Quartier
Journal: The Lancet Rheumatology (2020)

Children with early-onset juvenile idiopathic arthritis can develop a chronic, anterior uveitis that is initially asymptomatic and affects both eyes; this also occurs in children with no arthritis but who typically have detectable antinuclear antibodies.1Ravelli A Martini A Juvenile idiopathic arthritis.Lancet. 2007; 369: 767-778Summary Full Text Full Text PDF PubMed Scopus (961) Google Scholar In the absence of early detection and effective treatment of anterior uveitis, severe complications often develop over time, leading to blindness in a substantial proportion of patients.2Kotaniemi K Arkela-Kautiainen M Haapasaari J Leirisalo-Repo M Uveitis in young adults with juvenile idiopathic arthritis: a clinical evaluation of 123 patients.Ann Rheum Dis. 2005; 64: 871-874Crossref PubMed Scopus (58) Google Scholar, 3Marvillet I Terrada C Quartier P et al.Ocular threat in juvenile idiopathic arthritis.Joint Bone Spine. 2009; 76: 383-388Crossref PubMed Scopus (28) Google Scholar Two recent placebo-controlled trials of patients with juvenile idiopathic arthritis-associated uveitis and an inadequate response to local steroid therapy and methotrexate showed that the anti-TNF antibody adalimumab was effective.4Ramanan AV Dick AD Jones AP et al.Adalimumab plus methotrexate for uveitis in juvenile idiopathic arthritis.N Engl J Med. 2017; 376: 1637-1646Crossref PubMed Scopus (167) Google Scholar, 5Quartier P Baptiste A Despert V et al.ADJUVITE: a double-blind, randomised, placebo-controlled trial of adalimumab in early onset, chronic, juvenile idiopathic arthritis-associated anterior uveitis.Ann Rheum Dis. 2018; 77: 1003-1011Crossref PubMed Scopus (62) Google Scholar However, some patients do not respond to adalimumab or have disease flares despite treatment. In patients with systemic-onset juvenile idiopathic arthritis or in those with juvenile idiopathic arthritis and a polyarticular disease course, blocking the interleukin-6 (IL-6) pathway with tocilizumab improves both systemic symptoms and arthritis.6De Benedetti F Brunner HI Ruperto N et al.Randomized trial of tocilizumab in systemic juvenile idiopathic arthritis.N Engl J Med. 2012; 367: 2385-2395Crossref PubMed Scopus (539) Google Scholar, 7Brunner HI Ruperto N Zuber Z et al.Efficacy and safety of tocilizumab in patients with polyarticular-course juvenile idiopathic arthritis: results from a phase 3, randomised, double-blind withdrawal trial.Ann Rheum Dis. 2015; 74: 1110-1117Crossref PubMed Scopus (180) Google Scholar Tocilizumab has also shown efficacy in patients with chronic non-infectious uveitis, particularly in resolving refractory uveitis-associated macular oedema.8Mesquida M Molins B Llorenç V et al.Twenty-four month follow-up of tocilizumab therapy for refractory uveitis-related macular edema.Retina. 2018; 38: 1361-1370Crossref PubMed Scopus (35) Google Scholar In The Lancet Rheumatology, Athimalaipet Ramanan and colleagues9Ramanan AV Dick AD Guly C et al.Tocilizumab in patients with anti-TNF refractory juvenile idiopathic arthritis-associated uveitis (APTITUDE): a multicentre, single-arm, phase 2 trial.Lancet Rheumatol. 2020; (published online Feb 7.)https://doi.org/10.1016/S2665-9913(20)30008-4Google Scholar report the results of the multicentre, single-arm, phase 2 APTITUDE trial, which assessed the safety and efficacy of tocilizumab in 21 children with juvenile idiopathic arthritis-associated uveitis refractory to both methotrexate and adalimumab. Tocilizumab was administered subcutaneously for 24 weeks at a fixed dose of 162 mg every 3 weeks in children weighing less than 30 kg, and every 2 weeks in those weighing 30 kg or more. The primary endpoint of the trial was treatment response, defined as a two-step decrease (or a decrease to zero) in the level of anterior chamber inflammation according to the standardisation of uveitis nomenclature (SUN) criteria10Jabs DA Nussenblatt RB Rosenbaum JT Standardization of uveitis nomenclature for reporting clinical data. Results of the first international workshop.Am J Ophthalmol. 2005; 140: 509-516Summary Full Text Full Text PDF PubMed Scopus (2436) Google Scholar at week 12. The authors prespecified that a response in more than seven patients was required to justify a larger phase 3 trial. The primary outcome was not met, because only seven of 21 patients achieved a significant improvement in anterior chamber inflammation after 12 weeks. Additionally, only six (30%) of 20 patients using topical corticosteroid eye drops at baseline were able to reduce the number of eyedrops to less than two per eye per day. Macular oedema was resolved in three (75%) of four patients with macular oedema at baseline. Despite the negative primary outcome, the authors concluded that tocilizumab was beneficial in a subset of patients, in particular those with baseline macular oedema. Some limitations of this study were correctly described by the authors, including the small sample size, the absence of a control group, and the severity of disease. Indeed, only difficult-to-treat patients were included in this trial, because their uveitis was refractory to both methotrexate and anti-TNF therapy. Additionally, most patients had developed marked, chronic inflammation, as assessed by the presence of high numbers of cells in the anterior chamber on slit lamp examination. One key issue that the authors did not fully address is the following: the better care physicians are able to provide these patients—because of an increased awareness of uveitis, better interactions between ophthalmologists and paediatric rheumatologists, and the availability of more effective treatments—the smaller the proportion of patients who will have marked inflammation on slit lamp examination. Many patients were not eligible for inclusion in the APTITUDE trial because of the requirement for a cellular SUN score greater than 1+ (scale comprises 0, 0·5+, 1+, 2+, 3+, and 4+) on two readings in the preceding weeks, which was the minimal level of inflammation required at baseline to assess subsequent improvement using the SUN criteria.10Jabs DA Nussenblatt RB Rosenbaum JT Standardization of uveitis nomenclature for reporting clinical data. Results of the first international workshop.Am J Ophthalmol. 2005; 140: 509-516Summary Full Text Full Text PDF PubMed Scopus (2436) Google Scholar However, even in the absence of detectable cells on slit lamp examination, uveitis might be active and require more effective therapy, as shown in the ADJUVITE trial,5Quartier P Baptiste A Despert V et al.ADJUVITE: a double-blind, randomised, placebo-controlled trial of adalimumab in early onset, chronic, juvenile idiopathic arthritis-associated anterior uveitis.Ann Rheum Dis. 2018; 77: 1003-1011Crossref PubMed Scopus (62) Google Scholar in which uveitis activity was assessed by the more sensitive laser flare photometry method. Because of the availability of adalimumab in many countries and its recent approval for use in juvenile idiopathic arthritis-associated uveitis, there are likely to be more patients who have inadequate responses to both methotrexate and adalimumab, but less severe chronic inflammation, and possibly a higher probability to respond to a third-line treatment. Another limitation of the APTITUDE trial was the use of tocilizumab at the same dose as used in children with polyarticular-course juvenile idiopathic arthritis, with no dose increases permitted. In such difficult-to-treat patients as those included in the APTITUDE trial, use of more frequent injections (as is recommended in patients with systemic-onset disease), or increased dosing in patients with no response or partial response to the initial dose of tocilizumab would have been worth considering. Furthermore, in addition to adalimumab and tocilizumab, other treatments have been or are being tested in patients with juvenile idiopathic arthritis-associated chronic anterior uveitis, including in an ongoing international trial of the JAK inhibitor baricitinib (NCT04088409). Such efforts together with earlier recognition of ocular inflammation will help to further lower the burden of ocular complications in these young patients. I have received consultancy or speaking fees from AbbVie, Bristol-Myers Squibb, Chugai-Roche, Lilly, Novartis, Novimmune, and Swedish Orphan Biovitrum; and I have participated in a data safety monitoring board for Sanofi. Tocilizumab in patients with anti-TNF refractory juvenile idiopathic arthritis-associated uveitis (APTITUDE): a multicentre, single-arm, phase 2 trialThe primary endpoint was not met, and thus the results do not support a phase 3 trial of tocilizumab in patients with juvenile idiopathic arthritis-associated uveitis. Importantly, data on the use of tocilizumab in clinical practice is now captured in national registries. Despite this trial not meeting the threshold required to justify a larger phase 3 trial, several patients responded to treatment; as such, tocilzumab might still be a therapeutic option in some children with uveitis refractory to anti-TNF drugs, given the absence of other treatment options. Full-Text PDF Open Access