Introduction: Uveitis is a well-known extra-rheumatological manifestation of juvenile idiopathic arthritis (JIA). Tumour necrosis factor(TNF) has been used to treat uveitis associated with inflammatory diseases. A new-onset uveitis under anti-TNF therapy is uncommon.
Case presentation: A 12-year-old male, affected since the age of 6 years, by a severe form of polyarticular JIA. When etanercept was started, hepresented panuveitis bilaterally, so we switched to infliximab with good response.
Conclusions: The TNF-soluble receptor could be considered as a possible promoter in inducing endogenous new-onset uveitis in JIA.
Anti-TNF therapy, etanercept, juvenile idiopathic arthritis, paradoxical effect, uveitis
Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in children. Uveitis is a well-known extra-rheumatologicalmanifestation of JIA which may lead to severe functional impairment. Tumour necrosis factor (TNF)-alpha blocking agents are increasingly used to treatchildren with JIA refractory to conventional therapy. Most reports have demonstrated resolution of refractory uveitis under anti-TNFα. However, casesof new-onset uveitis under anti-TNFα therapy are rarely reported.
We report herein a new case of paradoxical new onset of uveitis occurring under etanercept treatment in a patient with JIA.
A 6-year-old male child with no significant past medical or family history presented with progressive polyarthralgia and morningstiffness. Physical examination revealed bilateral arthritis of the wrists, proximal interphalangeal joint, knees and ankles. Laboratory findings showed anincrease in C-reactive protein (CRP) level and erythrocyte sedimentation rate (ESR). The rheumatoid factor and antinuclear antibodies (ANA) titres werenegative. Knee joint X-ray showed soft tissue swelling and wrist joint X-ray showed osteoporotic changes in the epiphysis of the lower end of radius andulna. Ophthalmological exam was normal. A diagnosis of seronegative polyarticular JIA was established. Methotrexate treatment (10 mg/m2 weekly) wasconducted, leading to complete resolution of articular manifestations. After 6 years of clinical remission under methotrexate, a severe arthritis flareoccurred. His joint disease was active as shown by DAS 28 at 5.1, while ophthalmologic examination with slit lamp did not show any signs of uveitis.Laboratory findings again showed increased ESR and CRP levels. Etanercept was administered subcutaneously at 0.4mg/kg twice weekly and methotrexate wascontinued. Two weeks after the first injection, and for the first time during his longstanding disease, he presented with painful red eyes and photophobia. Ophthalmologicexamination revealed anterior and posterior chamber inflammation of the two eyes. He was treated with oral steroids and beta-blocker ophthalmic drops.Etanercept was suspended and infliximab was started, with no side effects. There was a rapid decrease in his ocular inflammation and improvement in hiseye disease. After 20 months, arthritis was stable and complete remission of uveitis was obtained.
JIA is the most common cause of chronic anterior uveitis in childhood. Uveitis is strongly associated with the oligoarticularand seronegative polyarticular subgroups or the presence of ANA. Uveitis in JIA can worsen over time, with many sight-threatening complications, such ascataracts, keratopathies, synechiae and glaucoma. Posterior segment involvement in JIA is rare. This patient had no prior history of uveitis with regularophthalmological control.
Studies have shown that etanercept is associated with a risk of new-onset uveitis and uveitis flares in JIA patients. We are aware ofonly 13 cases of new-onset uveitis in JIA under TNF blockers, presented in Table 1.
| Author and references | Gender | Age (years) | JIA subgroup | Age at the onset of AJI | Type of TNF blockers | Interval between TNF-blocker initiation and the onset of uveitis (months) | type of uveitis | Treatment of uveitis | Modification of TNF blockers |
|---|---|---|---|---|---|---|---|---|---|
| V. Kakkassery et al (1) | F | 44 | NS | 14 | etanercept | 6 | Posterior uveitis | Oral corticosteroid | Switch to Infliximab |
| NS | 24 | NS | 15 | etanercept | 12 | Anterior uveitis | Topical corticostroid | Stop | |
| NS | 16 | NS | 9 | etanercept | 24 | Anterior uveitis | Topical corticostroid | Switch to Infliximab | |
| O. Kaipiainen-Seppänen et al (2) | F | 31 | Juvenile SA | 10 | etanercept | 8 | Anterior uveitis | Topical corticostroid | Switch to Infliximab |
| E. Martín-Mola et al (3) | NS | NS | Juvenile SA | NS | etanercept | NS | Anterior uveitis | NS | NS |
| NS | NS | Juvenile SA | NS | etanercept | NS | Anterior uveitis | NS | NS | |
| R.K. Saurenmann et al (4) | NS | NS | Psoriatic JIA | NS | etanercept | NS | NS | NS | NS |
| NS | NS | Extended oligoarticular JIA | NS | etanercept | NS | NS | NS | NS | |
| D. Wendling et al (5) | F | 6 | NS | 6 | etanercept | 14 | Anterior bilateral Chronic uveitis | Topical corticostroid | Switch to Infliximab |
| M | 5 | SA HLA-B27- | 3.5 | etanercept | 4 | Chronic anterior bilateral uveitis | Topical corticostroid | Switch to Infliximab | |
| H. Schmeling et al (6) | F | 17 | Polyarticular, seronegative | 6.5 | etanercept | 10 | NS | NS | NS |
| F | 10 | Exstended oligoarticular | 5 | etanercept | 12 | NS | NS | NS | |
| R.Scrivo et al (7) | F | 16 | NS | 8 | etanercept | 28 | Anterior uveitis | Topical corticostroid | Switch to Infliximab |
Table 1 - Cases of onset uveitis under TNF blockers
All these JIA cases were treated with etanercept.
The reason for the difference between the various TNF inhibitors and the risk of developing uveitis is unknown. In fact, the linkbetween etanercept and uveitis is quite complex and there are many controversies. Some observations suggest that etanercept is not involved ingenerating uveitis. Schmeling and Horneff[6] reported a cohort of 229 JIA patients treated with etanercept. Of this cohort, only two patients developednew-onset uveitis after initiation of etanercept, whereas several others experienced a flare of their previously diagnosed uveitis. Despite this, theauthors concluded that etanercept treatment did not influence the incidence and course of JIA-related uveitis.
Furthermore, some clinicians believe that etanercept may trigger uveitis in a susceptible patient, despite itsefficacy in treating joint diseases. Scrivo reported a cohort of 350 patients treated with etanercept, in whom new-onset anterior uveitis occurred in four,including one with JIA[7]. The authors suggested that monoclonal anti-TNF treatment, especially adalimumab[8], is preferable to the soluble TNF receptor agent inpatients experiencing recurrent uveitis flares. Uveitis onset may be considered as a paradoxical effect of anti-TNF therapy, so called because it appearedafter the initiation of the anti-TNF drugs that are normally used to treat it. In the majority of the cases in the literature, uveitis appeared at a timeduring which rheumatic disease manifestations were fully controlled, but in our patient the uveitis occurred during a JIA flare. The uveitis onset occurredafter an average duration of exposure to etanercept of 12.5 months (US registry)[9]. Our case is original since uveitis appears after the firstinjection and it was a panuveitis, suggesting that etanercept had a role in the onset of uveitis.
Treatment of new-onset uveitis under anti-TNF was local in most of the cases, with healing of the episode within 2 months.Discontinuation of anti-TNF could be necessary in some cases. In the US registry[9], four cases of uveitis under etanercept resolved after discontinuingthe medication, with a recurrence of uveitis on rechallenge in two of these patients. In our case, uveitis resolved under oral corticosteroids and whenetanercept was switched to infliximab. Adalimumab is considered the most effective anti-TNF in the treatment of uveitis associated with oligo- andpolyarticular JIAs, but could not be afforded in our case and infliximab proved to be successful.