Adalimumab: viable treatment option for pediatric refractory uveitis?

Abstract

Non-infectious childhood uveitis, with its chronic nature, has the potential for long-term complications and possible blindness. Although strongly associated with an underlying autoimmune systemic disease like juvenile idiopathic arthritis, a significant number of cases are idiopathic. Treatment protocols for pediatric uveitis start with steroids as their safety profile is well known, but their associated systemic and ocular complications, especially in children, rule out their long -term use. Immunosuppressives have been used as second step for control and maintenance, but they have significant side effects and limited efficacy in recalcitrant cases. Therefore, treatment options have been extended to TNF-α inhibitors such as infliximab and adalimumab which have shown good success in patients not responding to immunosuppressives. Significantly, a waning off of clinical efficacy has been observed in patients with chimeric biologics like infliximab. Adalimumab, a fully humanized antibody, has shown promise in treating refractory cases of systemic, as well as intraocular, inflammation. In recent years, its use has been extended to childhood refractory uveitis. It offers several advantages over infliximab including easier administration, cost-effectiveness, better patient compliance and a lower rate of adverse events. This review analyzes the clinical and pharmacological features of adalimumab and its role in refractory pediatric uveitis.

Keywords::

• adalimumab
• pediatric uveitis
• refractory uveitis
• TNF-α inhibitors

Financial & competing interests disclosure

The research was supported by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Chronic noninfectious pediatric uveitis refractory to immunosuppressive has potential for significant long-term complications and possible blindness. Treatment warrants early intervention with biologics.

• Absence of randomized controlled clinical trials regarding uveitis in children leaves treatment with immunosuppressive drugs and biologics supported only at evidence level III (expert opinion, clinical experience or descriptive studies). In this scenario, a step-by-step therapeutic approach is currently considered the standard care for childhood chronic uveitis.

• According to the stepladder approach of treatment extended to childhood uveitis, the first step in treating noninfectious uveitis in children is use of corticosteroids drops and/or tablets. In case of failure to achieve remission, or need for long-term suppression, immunomodulation is usually required.

• The use of immunosuppressive is considered as the second step in therapy. Methotrexate is the preferred first-line steroid-sparing immunosuppressive, especially in patients with juvenile idiopathic arthritis.

• In case of subsequent failure of immunosuppressive therapy, a biological modifier drug, in addition to topical/systemic corticosteroids, is shown to be of benefit.

• Among the biological modifiers, adalimumab has shown considerable benefit in treating children. It has been suggested to use adalimumab as the first biologic for better primary control and extended benefit.

• TNF inhibitors will not show a clinical response even on switching between various TNF inhibitors if the autoimmune disease is not mediated by the TNF pathway. Therefore, in case of nonresponse to TNF-α inhibitors, it may be of benefit to change the biologic group.

• The cost of using adalimumab is high, especially in pediatric patients with more number of years of disease. Immunosuppressive drugs like methotrexate are known to increase efficacy of adalimumab by synergistic effect and reducing antidrug antibody. That helps in reducing the overall dose of adalimumab needed to control inflammation, thus reducing overall cost of treatment.

• Development of antidrug antibodies affects the long-term response of the drug. It has been noted that patients of rheumatoid arthritis with antidrug antibodies have a higher disease activity, rarely come into remission and discontinue treatment more often and earlier than patients without antidrug antibodies.

• Timing of starting adalimumab is of importance in pediatric uveitis as struggle to control inflammation leads to devastating ocular complications. Early adalimumab therapy for faster and better control of refractory uveitis is being recommended.

• Safety profile of the drug has been studied over a maximum period of 4 years so far. Long-term effects are as of now unknown. It becomes more relevant in children because of developmental issues as well as more life-years of treatment involved.