Biologics to the rescue: changing the treatment paradigm in juvenile idiopathic arthritis

Historically, the backbone of treatment for the chronic inflammatory disease juvenile idiopathic arthritis (JIA) was nonsteroidal anti-inflammatory drugs (NSAIDs), intra-articular corticosteroids, and/or non-biologic disease modifying anti-rheumatic drugs (DMARDs) such as methotrexate. Patients with severe disease, however, often had inadequate response to these traditional medications and could experience severe joint destruction and disability because of limited alternative therapies. Unlike the traditional medications, biologic DMARDs (Table) target specific cytokines and cellular communication steps involved in immune activation and regulation. Tumor necrosis factor alpha (TNF-α), interleukin-1 (IL-1), IL-6, IL-17A, IL-23, cytotoxic T lymphocyte associated protein 4 (CTLA-4), and cluster of differentiate 20 (CD20) all play a major role in the inflammatory process that result in the clinical manifestations of JIA. By targeting these steps, disease remission is now an attainable treatment goal for patients with JIA.^1-5

Biologic therapies for JIA | Credit: Pan A, Wu EY, Cannon L.

The anti–TNF-α agents are often the first-choice biologic agents prescribed for JIA when NSAIDs and nonbiologic DMARDs are not sufficient to control disease activity. These agents block the interaction of the pro-inflammatory cytokine TNF-α with its cell surface receptors, which reduces immune activation and the inflammatory response central to JIA.^1-5 Currently, etanercept, adalimumab, and golimumab are the anti–TNF-α biologics FDA approved for JIA. Etanercept was approved in 1999 and adalimumab in 2008 for moderate to severe active polyarticular JIA (pJIA) in patients at least aged 2 years.^6,7 Etanercept is a fully human, dimeric fusion protein that binds directly to circulating TNF-α. Adalimumab is a fully humanized monoclonal IgG1 antibody that binds soluble and membrane bound TNF-α. Both biologics are administered by subcutaneous injection; etanercept is given once weekly while adalimumab is given every other week. Approved in 2020, golimumab is the newest human monoclonal anti­–TNF-α antibody for pJIA. It is given intravenously with a loading dose at 0 and 4 weeks and then every 8 weeks thereafter.⁸ The subcutaneous formulation is not yet FDA approved for JIA. Although not FDA approved for JIA, infliximab is another intravenous anti–TNF-α agent that is sometimes used.^1-5

For many years the anti–TNF-α biologics were used for all types of JIA. The IL-1 and IL-6 cytokines, however, have been identified as better targets for auto-inflammatory diseases such as systemic JIA (sJIA). Anakinra, canakinumab, and rilonacept block cell signaling with IL-1. Anakinra is a human recombinant IL-1 receptor antagonist that is widely accepted by pediatric rheumatologists as a first-line option in the treatment of sJIA. Anakinra is given as a daily subcutaneous injection because of its short half-life. Canakinumab was approved in 2013 for sJIA.¹² It has the advantage of a longer half-life and is given subcutaneously every 4 weeks. Rilonacept has been shown to be an effective weekly option for sJIA based in some clinical studies. Tocilizumab is a humanized, monoclonal antibody that targets IL-6. It was approved in 2011 and 2013 for sJIA and pJIA, respectively, and is available as intravenous and subcutaneous injections.¹³

IL-17A and IL-23 have been more recently identified as targets for juvenile psoriatic arthritis (JPsA).^9-11 For treatment of JPsA, secukinumab is a human IgG1 monoclonal antibody that selectively binds to IL-17A, inhibits its interaction with the IL-17 receptor, and therefore decreases inflammation. It is also approved for use in patients with enthesitis-related arthritis. Ustekinumab is a human monoclonal antibody that binds to and interferes with the proinflammatory cytokines IL-12 and IL-23. It was recently approved by the FDA for treatment of psoriatic arthritis in pediatric patients as young as aged 6 years.^14,15

In addition to targeting cytokines, biologics can inhibit lymphocyte activation. These biologics are often considered for treatment when the patient has failed 1 or more of the other biologics in order to target a different mechanism. Abatacept is a CTLA-4-immunoglobulin fusion protein that binds CD80 and CD86, outcompeting CD28 and resulting in reduced T-cell activation.16 Additionally, rituximab is a chimeric monoclonal antibody that targets CD20 on B cells and is given intravenously. Although not indicated for JIA, it can be used for severe refractory cases.^2,4,5

Overall, the biologic agents are well tolerated; however, frequent monitoring for adverse effects is recommended. Injection site reactions are the most commonly reported minor adverse drug reaction with the subcutaneous formulations. Infusion reactions are also commonly encountered with the intravenous formulations. All the biologic agents have the potential to increase the risk of infection, notably tuberculosis. Therefore, all patients should be screened for tuberculosis and hepatitis B virus prior to initiation and throughout treatment. Additionally, patients should obtain routine toxicity labs to screen for potential increased liver enzymes or neutropenias.^16,17 Development of autoantibodies, especially with adalimumab, has been reported. Studies also show that there is an increased risk of malignancy with use of the anti–TNF-α agents, especially in combination with thiopurines such as azathioprine, which has been observed in patients with inflammatory bowel disease who were treated with both medications concurrently. Therefore, as more patients are started on biologics, it will be important to closely monitor them over time to determine long-term safety.^9,18,19

With a plethora of options, the choice of biologic agent depends on a variety of factors, including patient age, indication, clinical manifestations, disease severity, side effect profile, route of administration, and dosing frequency. Insurance coverage is also a major factor to consider. Depending on the insurance, some plans might have preferred biologic agents or might require the patient to have tried and failed certain agents such as traditional DMARDs prior to starting biologic agents. Often a prior authorization and sometimes an appeal letter are needed to obtain insurance approval. Without insurance coverage, biologic agents are extremely expensive.

The era of biologic therapies has revolutionized treatment and outcomes for patients with JIA. These agents significantly increase the diversity of treatment options available for JIA and are heavily incorporated into the ACR guidelines for treatment of JIA.²⁰ Further research will help analyze long-term safety and efficacy of current biologics as well as discover new biologics to continue to advance the treatment of JIA.

To read more from the April, 2023, issue of Contemporary Pediatrics®, click here.

References

1. Cakan M, Ayaz NA, Karadag SG, Tanatar A. The necessity, efficacy and safety of biologics in juvenile idiopathic arthritis. North Clin Istanb. 2019;7(2):118-123. doi:10.14744/nci.2019.57873
2. Vanoni F, Minoia F, Malattia C. Biologics in juvenile idiopathic arthritis: a narrative review. Eur J Pediatr. 2017;176(9):1147-1153. doi:10.1007/s00431-017-2960-6
3. Zaripova LN, Midgley A, Christmas SE, Beresford MW, Baildam EM, Oldershaw RA. Juvenile idiopathic arthritis: from aetiopathogenesis to therapeutic approaches. Pediatr Rheumatol Online J. 2021;19(1):135. doi:10.1186/s12969-021-00629-8
4. Onel K, Rumsey DG, Shenoi S. Juvenile idiopathic arthritis treatment updates. Rheum Dis Clin North Am. 2021;47(4):545-563. doi:10.1016/j.rdc.2021.07.009
5. McCurdy D, Parsa MF. Updates in juvenile idiopathic arthritis. Adv Pediatr. 2021;68:143-170. doi:10.1016/j.yapd.2021.05.014
6. Adalimumab. Prescribing information. Abbvie; 2021. Accessed July 24, 2022. https://www.rxabbvie.com/pdf/humira.pdf
7. Etanercept. Prescribing information. Amgen; 2022. Accessed July 24, 2022. https://www.pi.amgen.com/-/media/Project/Amgen/Repository/pi-amgen-com/Enbrel/enbrel_pi.pdf
8. Golimumab. Prescribing information. Janssen; 2021. Accessed July 24, 2022 https://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/SIMPONI+ARIA-pi.pdf
9. Zaripova LN, Midgley A, Christmas SE, Beresford MW, Baildam EM, Oldershaw RA. Juvenile idiopathic arthritis: from aetiopathogenesis to therapeutic approaches. Pediatr Rheumatol Online J. 2021;19(1):135. doi:10.1186/s12969-021-00629-8
10. Dewitt EM, Kimura Y, Beukelman T, et al. Consensus treatment plans for new-onset systemic juvenile idiopathic arthritis. Arthritis Care Res (Hoboken). 2012; 64(7):1001–1010. doi:10.1002/acr.21625
11. Cabrera N, Avila-Pedretti G, Belot A, et al. The benefit-risk balance for biological agents in juvenile idiopathic arthritis: a meta-analysis of randomized clinical trials. Rheumatology (Oxford). 2020;59(9):2226-2236. doi:10.1093/rheumatology/keaa170
12. Canakinumab. Prescribing information. Novartis; 2020. Accessed July 24, 2022. https://www.novartis.com/us-en/sites/novartis_us/files/ilaris.pdf
13. Tocilizumab. Prescribing information. Genentech; 2021. Accessed July 24, 2022. https://www.gene.com/download/pdf/actemra_prescribing.pdf
14. Secukinumab. Prescribing information. Novartis; 2021. Accessed Aug 2, 2022. https://www.novartis.com/us-en/sites/novartis_us/files/cosentyx.pdf
15. Ustekinumab. Prescribing information. Janssen; 2022. Accessed Aug 10, 2022. https://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/STELARA-pi.pdf
16. Abatacept. Prescribing information. Bistol Myers Squibb; 2021. Accessed July 24, 2022. https://packageinserts.bms.com/pi/pi_orencia.pdf
17. Klein A, Klotsche J, Hügle B, et al. Long-term surveillance of biologic therapies in systemic-onset juvenile idiopathic arthritis: data from the German BIKER registry. Rheumatology. 2020;59(9):2287-2298. doi:10.1093/rheumatology/kez577
18. Shiff NJ, Beukelman T. Pharmacosurveillance in juvenile idiopathic arthritis. Rheum Dis Clin North Am. 2021;47(4):643-653. doi:10.1016/j.rdc.2021.07.012
19. Lemaitre M, Kirchgesner J, Rudnichi A, et al. Association between use of thiopurines or tumor necrosis factor antagonists alone or in combination and risk of lymphoma in patients with inflammatory bowel disease. JAMA. 2017;318(17):1679-1686. doi:10.1001/jama.2017.16071
20. Ringold S, Angeles-Han ST, Beukelman T, et al. 2019 American College of Rheumatology/Arthritis Foundation guideline for the treatment of juvenile idiopathic arthritis: therapeutic approaches for non-systemic polyarthritis, dacroiliitis, and rnthesitis. Arthritis Care Res (Hoboken). 2019;71(6):717-734. doi:10.1002/acr.23870