Abstract
Juvenile idiopathic arthritis (JIA), the most common chronic rheumatologic condition in childhood, remains a cause of significant morbidity, particularly in those with spondyloarthropathy, including psoriatic arthritis (PsA) and enthesitis-related arthritis (ERA). While secukinumab was recently approved for the treatment of children and adolescents with ERA and PsA, there is limited published data on its use in JIA, particularly in refractory cases, despite its efficacy in the treatment of adult arthritis. We aim to examine the use of this therapy in JIA in a single pediatric rheumatology center. A retrospective chart review was performed and 10 JIA patients who received treatment with secukinumab were identified. Data extracted included disease activity, patient demographics, comorbidities, medications, and laboratory data. Seven ERA, 2 PsA, and 1 poly JIA patient were treated with secukinumab at our center between April 2011 and July 2021. These patients had notably resistant disease, with a mean disease-modifying antirheumatic drug (DMARD) failure rate of 3.8. One hundred percent of patients who underwent magnetic resonance imaging (MRI) after being on at least 3 months of secukinumab therapy demonstrated improvement in their MRI findings. One patient developed a flare of uveitis while on secukinumab therapy, with no other adverse events recorded in our patients. Secukinumab therapy was recently approved for children and adolescents with ERA and PsA, and may offer an efficacious option given its demonstrated improvement in imaging and joint examination, as well as qualitative reports of pain, even in those who have failed other therapies. However, caution may be warranted in those with a history of uveitis and warrants further study.
Background
Despite advances in biologic therapies for the treatment of juvenile idiopathic arthritis (JIA), the most common chronic rheumatologic condition in childhood, remission rates are still only approximately 35% to 61%.1,2 Patients with uncontrolled disease face progressive joint destruction, gait dysfunction, and altered growth. 3 Furthermore, children with psoriatic arthritis (PsA) or enthesitis-related arthritis (ERA) have a relatively poor prognosis with significant disease-related morbidity.2,4-8 Studies have shown that secukinumab (Cosentyx), an interleukin (IL)-17 inhibitor, can improve enthesitis, dactylitis, and number of swollen and tender joints in the adult population with spondyloarthropathy (SpA).9,10 There is evidence that pediatric patients with inflammatory arthritis could benefit from treatments initially targeted toward adults with spondyloarthritis due to similarities in pathogenesis and clinical manifestations. 11 Furthermore, secukinumab recently received Food and Drug Administration (FDA) approval for children and adolescents with ERA and juvenile PsA, with a reported significantly longer time to flare and sustained improvement of signs and symptoms in treated patients. 12
Secukinumab is a recombinant fully humanized monoclonal antibody that inhibits interleukin-17, which is produced primarily by pro-inflammatory T helper 17 cells.13-15 It has been approved to treat adults with ankylosing spondylitis as well as PsA.13-15 Enthesitis-related arthritis is a subtype of JIA with features that overlap with adult SpA patients. 16 Enthesitis-related arthritis pathogenesis is believed to be secondary to dysfunction of HLA-B27, a risk allele for adult and pediatric SpA. HLA-B27 is associated with upregulation of the interleukin IL-23/IL-17 pathway and would therefore provide a therapeutic target in this patient population. 8 Of note, a population of CD4/CD8-negative T cells localized to the entheses has been shown to mediate IL-23-driven SpA in prior studies.4,17,18 In addition, further literature substantiates the overlap in genetic susceptibility to SpA and ERA due to endoplasmic reticulum aminopeptidase 1, which produce peptides presented on class I major histocompatibility complex molecules, and itself serves as a major risk gene for ankylosing spondylitis in adults and pediatrics.4,19 Psoriatic arthritis shares similarities with respect to both genetic and clinical features with other forms of SpA. Recent studies have also highlighted the importance of the IL-17, IL-23, and tumor necrosis factor (TNF)-alpha pathways in the development of psoriasis and PsA. 11 It has been shown that PsA patients are more likely to experience disease flares and have an overall lower health-related quality of life in comparison to other JIA subtypes, and therefore, this particularly vulnerable patient population would benefit from further investigation into therapeutic modalities to improve disease control. 12
To our knowledge, while phase 3 clinical trial data (Junipera) now supports the use of secukinumab in ERA in children and adolescents, there remain very few publications evaluating the use of secukinumab in the JIA patient population, and even fewer evaluating its utilization in refractory ERA and PsA pediatric cases upon literature review.8,9,14,15 We aim to examine the use of this therapy in JIA patients in our pediatric rheumatology clinic.
Methods
A retrospective chart review was performed to identify all JIA patients treated with secukinumab at our institute from April 2011 to July 2021. Patients were diagnosed with JIA and subtyped utilizing the current International League of Associations for Rheumatology (ILAR) classification criteria, which subdivides JIA into 7 categories defined by the number of joints involved, presence or absence of extra-articular manifestations, and presence or absence of additional markers including rheumatoid factor (RF) and HLA-B27. 16 Specifically, the ILAR criteria for ERA are arthritis plus enthesitis, or arthritis or enthesitis plus at least 2 of the following: sacroiliac tenderness or inflammatory back pain, HLA-B27 positivity, first-degree relative with HLA-B27-associated disease, acute anterior uveitis, and arthritis in a male individual older than 6 years. 8 Patients were not enrolled in experimental protocol for medication utilization given the nature of a retrospective clinical review. Data extracted included disease activity, patient demographics, comorbidities, medications utilized, and laboratory data. Refractory disease was defined as failure to respond to initial therapy. After consultation with the local institutional review board, no ethics board approval was required in accordance with the policy of our institution. Informed consent was obtained from all participants prior to the publication of any patient-related information.
Results
We identified 10 JIA patients treated with secukinumab at our center: 7 with ERA, 2 with PsA, and 1 with polyarticular JIA (poly JIA). The ERA, PsA, and poly JIA patients fulfilled the ILAR criteria for their respective diagnosis. 10 Patient disease characteristics and epidemiologic data are summarized in Table 1. Seventy percent of patients were female. Three patients were HLA-B27 positive. We have outlined the prior therapies, joint examination, and imaging findings before and after treatment with secukinumab (Table 1). These patients demonstrated resistant disease, with a mean disease-modifying antirheumatic drug (DMARD) failure rate of 3.8. One hundred percent of patients who underwent magnetic resonance imaging (MRI) after being on at least 3 months of secukinumab therapy had noted objective improvement on their MRI findings, even after failing prior therapies (including patients 1, 3, 4, 6, 7, and 8 with noted improved or resolved arthritis per Table 1). The single polyarticular JIA patient (patient 8) experienced some improvement in arthritis but did not achieve good disease control. The remaining patient with poor response to secukinumab was only on therapy for approximately 2 months before discontinuation (patient 9). The 2 PsA patients experienced improvement in their skin disease. Of note, one JIA patient developed a flare of her uveitis after transitioning to secukinumab therapy despite improvement in joint disease. Her uveitis improved with addition of subcutaneous methotrexate and did not require discontinuation of secukinumab. There was a single patient with access bias, although he was able to obtain insurance approval after several months (patient 5).
Clinical, Imaging, and Demographic Characteristics of Patients treated with Secukinumab at our Center.
Abbreviations: JIA, juvenile idiopathic arthritis; RF, rheumatoid factor; HLA, human leukocyte antigen; CCP, cylic citrullinated peptide; N/A, not applicable.
Patient 1
A 16-year-old girl presented at 11 years of age with symptoms of limited range of motion of the bilateral hips, knees, and ankles, as well as pain at several entheses. She was diagnosed with psoriatic JIA and started on and subsequently failed leflunomide (2016), methotrexate (1/2017), and adalimumab (10/2017) due to ongoing arthritis and enthesitis. Due to development of headaches and rash, she was switched from adalimumab to etanercept (12/2019) and methotrexate was restarted in 2/2020 due to persistent enthesitis. As a result of persistent active disease, she was switched to secukinumab in 2020 with resultant improvement in symptoms and normalization of imaging. Of note, she was transitioned from methotrexate to sulfasalazine 12/2020 due to nausea with methotrexate. Outline of patients prior therapies are listed in Supplemental Table 1.
Patient 2
A 20-year-old woman presented at 10 years of age with symptoms of limited range of motion, swelling, and pain in the small joints of her hands. She was diagnosed with polyarticular JIA and started on methotrexate (oral in 2014, then subcutaneous in 2015). Due to worsening of her asthma, she was switched to leflunomide (2015) with good tolerance but limited efficacy in arthritis control. She was subsequently started on etanercept (2017) which failed to control her symptoms, and then transitioned to adalimumab (every 2 weeks in January 2019, then weekly in March 2019 due to ongoing disease activity). Of note, it was later found that she had history of skin lesions as a young child prior to arthritis treatment that were suspected to be psoriasis. Due to continued active arthritis, oral methotrexate was added to her regimen in 7/2020, but then discontinued due to diarrhea. In 2021, due to her persistent joint symptoms as well as development of significant psoriatic lesions, she was re-classified as PsA and started on secukinumab with noted improvement in her joint symptoms and physical examination on follow-up, though with continued active psoriasis. Secukinumab dose was increased from 150 to 300 mg with improvement in skin disease.
Patient 3
A 16-year-old boy presented at 11 years of age with left hip pain and stiffness, as well as MRI findings consistent with aggressive inflammatory arthritis. He was started on etanercept at diagnosis, but due to persistent hip arthritis, transitioned to adalimumab (2017). Repeat MRI after 5 months on adalimumab showed no improvement in effusions or synovitis and noted worsening in bone erosions and edema, and he therefore was changed to secukinumab in addition to receiving an intra-articular steroid injection (2018). Repeat MRI in 2018 showed improvement in inflammation, and MRI in 2019 showed resolution of synovitis. Patient has remained in remission on secukinumab.
Patient 4
A 16-year-old girl presented at 5 years of age with pain, swelling, and limited range of motion in her left knee, ultimately diagnosed with spondyloarthritis with sacroiliitis and uveitis. She was started on naproxen and her arthritis went into remission approximately 1 year later (2008) allowing for discontinuation of naproxen. In 2009, she developed bilateral uveitis, prompting treatment with topical prednisone drops and later initiation of methotrexate (oral in 2011 which was subsequently tapered resulting in disease flare and therefore transitioned to subcutaneous in 2013). She was noted to have persistent effusions of the bilateral knees despite dose increase in methotrexate (2016) and underwent bilateral knee injections. In 2017, MRI revealed bilateral sacroiliitis and she was started on adalimumab after failing scheduled naproxen with increased dose of subcutaneous methotrexate. She continued to have active sacroiliitis on adalimumab weekly (confirmed on MRI) and was transitioned to secukinumab (2019). Subsequently, her joint symptoms significantly improved and repeat MRI in 12/2020 showed no active sacroiliitis. However, patient was found to have a flare of uveitis on routine screening examination in 5/2020, and she was re-started on subcutaneous methotrexate with subsequent improvement in uveitis.
Patient 5
A 19-year-old man was diagnosed at 10 years of age with HLA-B27-positive spondyloarthritis. He presented with a 5-year history of back pain and joint stiffness, as well as bilateral knee pain. He previously was treated with sulfasalazine (4/2016-8/2016), etanercept (2013-2014), and adalimumab (7/2015, increased to weekly 10/2015 due to ongoing disease activity). He underwent bilateral knee intra-articular steroid injections in 2015. Adalimumab was discontinued from 12/2017 to 4/2018 due to loss to follow-up with resultant flare of enthesitis. He was subsequently re-started on weekly adalimumab with sulfasalazine due to inability to obtain insurance approval for secukinumab in 4/2018, with continued enthesitis. He was ultimately transitioned in 2019 to secukinumab with marked improvement in his joint/back pain as well as a decline in his joint stiffness.
Patient 6
A 13-year-old girl was diagnosed at 8 years of age with spondyloarthritis. She presented with low back pain and MRI (2016) showed sacroiliitis, leading to initiation of Humira as well as 2-week prednisone taper for ongoing pain. She responded well to Humira; however, due to development of lower extremity paresthesia and family history of Guillain Barre syndrome, she was transitioned to secukinumab in 11/2017 with resolution of neuropathic symptoms. She was able to taper off secukinumab in 4/2018 due to improvement in arthritis.
Patient 7
A 22-year-old woman was diagnosed at 17 years of age with HLA-B27-positive spondyloarthritis. She presented with chronic hip pain, along with prior history of knee and elbow pain and swelling. Magnetic resonance imaging obtained 2/2016 revealed bilateral sacroiliitis for which she was started on etanercept, celecoxib, and tramadol. She underwent bilateral SI injections in 2016 with minimal relief. Due to persistent hip and low back pain, she was transitioned to adalimumab in 6/2016. Due to persistent pain, she was changed to secukinumab in 7/2016 along with prednisone taper with decrease in her stiffness and joint complaints. Magnetic resonance imaging 11/2016 showed resolution of sacroiliitis with persistent enthesitis with hip effusions bilaterally. The patient subsequently underwent right hip steroid injection 12/2016 for residual pain. Bilateral hip ultrasound in 12/2016 showed resolution of effusions.
Patient 8
A 13-year-old girl with Type 1 Diabetes and Celiac Disease presented at 8 years of age with ankle and wrist arthritis, ultimately diagnosed with RF and Antinuclear antibody (ANA)-positive polyarticular JIA. She was started on subcutaneous methotrexate and etanercept was later added due to continued active arthritis. However, patient developed an allergic reaction to etanercept (4/2017), as well as to adalimumab (9/2017), and to abatacept (3/2018), requiring medication discontinuation. She underwent left knee intra-articular steroid injection (5/2018) and was started on tocilizumab (10/2018). Due to persistently active arthritis, she was switched to tofacitinib (3/2019) and underwent intra-articular steroid injection of multiple proximal interphalangeal (PIP) joints (6/2019, 2/2020). Despite this therapy, MRI obtained 3/2020 revealed active foot arthritis and she was transitioned to secukinumab (5/2020). Repeat MRI in 8/2020 showed improved but persistent foot synovitis while on secukinumab, and given her history of positive autoantibodies, she was transitioned to rituximab (10/2020) and leflunomide added (12/2020), with subsequent improvement in arthritis symptoms (no repeat MRI yet obtained).
Patient 9
A 16-year-old girl was diagnosed with sacroiliitis at 13 years of age. Magnetic resonance imaging obtained at diagnosis revealed bilateral sacroiliitis with erosive changes as well as bilateral hip synovitis. She was started on adalimumab (11/2018). Due to worsening gait dysfunction, she was started on secukinumab (3/2019) and continued therapy for approximately 2 months along with scheduled indomethacin prior to discontinuation due to worsening bilateral hip synovitis and bilateral sacroiliitis on MRI (6/2019). She was transitioned to etanercept (6/2019-11/2019) and underwent bilateral hip and SI joint steroid injections (7/2019) with subsequent improved yet persistent hip arthritis and sacroiliitis on MRI (11/2019). She was then started on infliximab with methotrexate (12/2019). She underwent right hip replacement (5/2020) and later left hip replacement (7/2020). She was transitioned to tofacitinib (4/2021) due to insurance difficulties with infliximab, but has not yet had repeat MRI on tofacitinib.
Patient 10
A 17-year-old boy presented at 11 years of age with tenosynovitis and polyarthritis, initially believed to have post-infectious arthritis, later diagnosed with HLA-B27-positive ERA. On initial diagnosis, he was started on scheduled naproxen (5/2015) before escalation to methotrexate due to worsening joint symptoms (6/2015). He was lost to follow-up from June 2015 to September 2016 prior to starting leflunomide (9/2016) upon presentation to clinic in the setting of active arthritis. Given persistent active arthritis, he was transitioned to secukinumab (4/2017) with improvement in his arthritis (decreased pain, decreased active joint count) noted after 3 months of treatment, but subsequently lost to follow-up again.
Discussion and Conclusions
Secukinumab recently received FDA approval for children and adolescents with ERA and juvenile PsA, with a reported significantly longer time to flare and sustained improvement of signs and symptoms in treated patients. 9 In this case series of 10 patients with resistant JIA, treatment with secukinumab was both efficacious and well tolerated. For a majority of patients, there was improvement in symptoms, physical examination, and objective MRI findings (Table 1). Furthermore, all of our patients had failed at least one previous therapy prior to initiation of secukinumab, highlighting the importance of availability of this medication as an efficacious alternative therapy for refractory patients who have exhausted their therapeutic options. The single polyarticular JIA patient included in this case series experienced some improvement in arthritis but did not achieve good disease control and did later respond to rituximab, highlighting the difference in pathophysiology in poly JIA compared with SpA. It is important to note that one patient developed a flare of her uveitis while on secukinumab, perhaps indicating lack of effectiveness in the treatment of uveitis as opposed to its efficacy with musculoskeletal disease. Due to the paucity of literature reporting secukinumab use in the pediatric population particularly with respect to refractory disease, this report will add greatly to the knowledge of utilization of this medication in JIA.
The primary limitation of our study pertains to the small number of patients involved. This is in part due to only recent FDA approval of secukinumab in pediatric ERA and PsA patients with associated difficulty in obtaining insurance approval, even in refractory cases. Additional limitations of this study are due to constraints of a retrospective chart review which is limited to the data recorded in the electronic medical record. We did not have adequate information in all patients to relay clinimetric data routinely, such as Juvenile Arthritis Disease Activity Score (JADAS). It is our hope that this report will further substantiate the use of secukinumab in PsA and ERA JIA patients and serve as an impetus for further assessment as to its clinical efficacy in particularly refractory patients in this vulnerable patient population.
Supplemental Material
sj-docx-1-hic-10.1177_23247096231200403 – Supplemental material for Secukinumab Therapy in Refractory Juvenile Idiopathic Arthritis
Supplemental material, sj-docx-1-hic-10.1177_23247096231200403 for Secukinumab Therapy in Refractory Juvenile Idiopathic Arthritis by Meghan Corrigan Nelson and Cynthia K. Manos in Journal of Investigative Medicine High Impact Case Reports
Footnotes
Acknowledgements
Not applicable.
Author Contributions
M.C.N. and C.K.M. analyzed and interpreted the patient data, and both M.C.N. and C.K.M. were major contributors in writing the manuscript. All authors read and approved the final manuscript.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.
Ethics Approval and Consent to Participate
This study was not considered Human Research by the Children’s Healthcare of Atlanta Institutional Review Board and no ethics board approval was required in accordance with the policy of our institution. Informed consent was obtained from all participants prior to the publication of any patient related information.
Consent for Publication
Written consent was obtained from case series parents and participants prior to publication.
Availability of Data and Materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Supplemental Material
Supplemental material for this article is available online.
References
Supplementary Material
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