Effect of Ixekizumab on Enthesitis-related arthritis non-responsive to anti-TNF treatment, a case report

doi:10.21203/rs.3.rs-2725312/v1

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Effect of Ixekizumab on Enthesitis-related arthritis non-responsive to anti-TNF treatment, a case report

https://doi.org/10.21203/rs.3.rs-2725312/v1

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Background: To describe the effectiveness of Ixekizumab on a patient with ERA who was refractory to conventional treatment and TNF inhibitors.

Case presentation: A 15-year-old boy who manifested as swollen knees, bilateral ankle arthritis, sausage toes and low-grade fever was diagnosed as Enthesitis related arthritis. There was one episode of uveitis three years before the onset of joint symptoms. The patient had a high level of inflammation (ESR to 107 mm/hour, CRP to 248.77 mg/L) with increased level of serum IL-6 and VEGF. Combination therapy of NSAIDs with sulfasalazine, Adalimumab, Infliximab, low dose steroid, Golimumab and Tofacitinib were applied correspondingly. The systemic inflammation of this patient (not including swollen toes and enthesitis) got a little better with oral steroids, but intensified again when steroid was weaned. Ixekizumab (80mg, Q2W twice, then 80mg Q4W) combined with oral methotrexate were then applied for this patient. ESR and CRP decreased into normal level with quick alleviation of arthritis within the first month of treatment. A persistent clinical remission was achieved by using Ixekizumab in the following two years of therapy. Apart from slight redness and swelling at the injection site, no significant side effects were observed during follow up.

Conclusion: Ixekizumab can be a substitutive therapy for ERA patients who were unresponsive to traditional therapy or anti-TNF treatment.

Enthesitis-related arthritis

Effectiveness

Interleukin 17

Ixekizumab

Enthesitis-related arthritis (ERA) is characterized by the presence of enthesitis and/or arthritis with a strong association with human leukocyte antigen–B27 (HLA-B27)^[1]. ERA accounts for about 15% ~ 39.9% of juvenile idiopathic arthritis (JIA)^[2]. Although the clinical features of ERA are quite resemble as ankylosing spondylitis (AS), children with ERA are more prone to affect hips and peripheral joints and have higher frequency of disability than adults^[3]. Medications applied for ERA includes nonsteroidal antiinflammatory drugs (NSAIDs), disease modifying antirheumatic drugs (DMARDs), biological agents (esp. TNF inhibitors) and short-term therapy of glucocorticoids in the severely ill patients. Despite adequate use of DMARDs and/or combined therapy with TNF inhibitors, some patients may have persistent active disease or being intolerant of above conventional therapy^[4].

Except for TNF inhibitors, there are minimal pediatric data on other biologics applied in ERA. Interleukin (IL)-17A is a proinflammatory cytokine, involving in joint inflammation and joint erosion, mostly reported in the pathogenesis of psoriasis arthritis (PsA) and AS^[5]. Activation of IL-17/IL-23 axis was positively correlated with HLA-B27 and was found to be involved in the pathogenesis of enthesitis^{[6, 7]}. Ixekizumab is a fully humanized immunoglobulin G4 that selectively neutralizes IL-17A, which has been guideline approved for the treatment of PsA and AS, after TNF inhibitors failure in adults^[8]. Here we report a pediatric case who was refractory to conventional treatment and TNF inhibitors, but showed responsiveness to Ixekizumab.

The patient was admitted because of painful lower limbs and swollen right foot for 2 months in his 15 years of age. His weight was 39 kg, and his height was 150 cm. The joint symptom was accompanied by low-grade fever. He had morning stiffness lasted for about an hour each day. There was one episode of uveitis three years before the onset of joint symptoms. He had no family history of AS, inflammatory bowl disease, reactive arthritis or first-degree relative with psoriasis. Physical examination showed swollen knees, bilateral ankle arthritis (tender & pain on motion) and sausage toes (2,3,4,5) of right foot. He also had tenderness at the attachment points in both knees. He had positive Patrick sign and Schorber's sign (19cm). The HLA-B27 was tested positive and his serum inflammatory markers (c-reactive protein (CRP) & erythrocyte sedimentation (ESR)) were significant higher than normal (ESR to 107 mm/hour, CRP to 248.77 mg/L) .

The patient was diagnosed as ERA according to the ILAR criteria. Disease activity was evaluated using JADAS10 (AJC (8) + PGA (4) + VAS (5) + ESR (8.1) = 25.1) and JSpADA (score:4.5). He was commenced on combination therapy of NSAIDs with sulfasalazine (SASP). The dose of SASP was gradually increased to 1.5g/d (40mg/kg/d). His temperature was getting normal, but the painful and swollen joints and high inflammatory state were not alleviated after two weeks of treatment. Adalimumab was applied subsequently in the dose of 40mg by subcutaneous injection every two weeks. ESR and CRP was decreased to 45 mm/h and 82.65 mg/L, respectively. After 3 doses of Adalimumab, ESR was increased to 101mm/h without definite trigger. There was limit improvement of morning stiffness and arthritis. Adalimumab was substituted by Infliximab (200mg) with oral prednisolone (10mg/d). The level of ESR and CRP returned to normal levels in his second injection of Infliximab. Swollen knees and left ankle were relieved, but the sausage toes were not getting better. After 3 months treatment of Infliximab, the oral prednisolone was tapered off and his inflammation went up again. Afterwards, Golimumab and Tofacitinib was applied continuously, but little responds were getting from these medications.

Due to the refractory arthritis and a high level of inflammation, Ixekizumab (80mg, Q2W twice, then 80mg Q4W) combined with oral methotrexate (MTX) were applied for this patient with informed consent getting from both patient and his parents. Amazingly, the ESR and CRP decreased into normal level with quick alleviation of arthritis within the first month of Ixekizumab therapy (Fig. 1). The patient achieved clinical remission (according to Wallace criteria) on medication after 6 months of Ixekizumab therapy (JADAS 10 (score: 0); JSpADA (score: 0)). Abnormal changes of both ultrasound and MRI were gradually improved after one year treatment of Ixekizumab (Fig. 2). The serum cytokines including Interleukin (IL)-17A, IL-1β, IL-2, IL-5, IL-6, TNF, interferon (IFN)-γ, vascular endothelial growth factor (VEGF) and transforming growth factor (TGF)-β1 were tested before Ixekizumab therapy, and 6 months as well as 12 months after Ixekizumab treatment (Table 1). The patient had a high level of IL-6, which was consistent with his systemic manifestation as fever and high level inflammatory state. After 6 months of treatment with Ixekizumab, the level of IL-6 returned to normal (69.93 ± 5.71 v.s 5.37 ± 0.44, p༜0.05). VEGF was also elevated in the active state of arthritis (454.21 ± 90.07 v.s 168.28 ± 21.07, p༜0.05). But, target of this medicine (IL-17A) was kept at normal level, whether it was before or after treatment. Apart from slight redness and swelling at the injection site, no significant side effects were observed during the two years’ follow up.

Table 1

Level of different cytokines before and after anti- IL−17A treatment
Cytokine (pg/ml)	0M	6M	12M	Reference range
IL−17A	2.74	2.44	2.61	0 ~ 15
IL−1β	2.97	2.79	2.77	0 ~ 15
IL−2	4.06	4.40	4.04	0 ~ 20
IL−5	3.05	3.41	3.10	0 ~ 12
IL−6	69.93	5.37	11.20	0 ~ 15
TNF	10.05	11.80	12.80	0 ~ 15
IFN-γ	3.95	2.76	3.19	0 ~ 12
VEGF	454.21	168.28	246.92	0 ~ 40
TGF-β1	9628.10	9679.00	10698.46	0 ~ 33000

Criteria and disease activity measurement: ERA was diagnosed according to the International League Against Rheumatism (ILAR) criteria, which is defined as follows^[1]: 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 older than 6 years. JADAS10^[9] and the Juvenile Spondyloarthritis Disease Activity Index (JSpADA)^[10] were used to evaluate response.

Different subtypes of JIA have different predominant effector cells and therefore different cytokines involved in the pathogenesis. Th17 cells, γδT-cells and macrophages are considered as predominant effector cells in ERA^[11]. Researchers found that inflammatory T cells mostly CD8⁺ and CD14⁺ cells were infiltrated at sites of synovium and enthesitis, which indicated a T cell predominant inflammation in ERA^{[12, 13]}. TNF-α, IL-17 and IL-23 are the principal proinflammatory cytokines involved in the pathogenesis of ERA. Blocking of TNF-α has been the main treatment target in ERA. Although anti-TNF therapy has been verified useful based on the data from retrospective studies, only one third of ERA patients who received TNFi were able to achieve non-active disease status^{[14, 15]}. The reason for treatment discrepancies among different patients was unclear. Different genetic background with variety inflammatory pathways involved in the synovial biology may contribute to different treatment responses.

Besides of TNF-α, IL-17A was another crucial inflammatory cytokine taking a pathogenic role in enthesitis and arthritis. Th17 cells and its related IL-23/IL-17 axis play a central role in PsA and axial spondyloarthritis (SpA)^{[16, 17]}. IL-17A inhibitors were demonstrated to be effective in entheseal inflammation in adult’s PsA and SpA. In a phase 3b clinical trial, greater improvements with secukinumab (a fully human monoclonal antibody that directly inhibits IL-17A) were observed in heel enthesitis and global assessment of disease activity^[7]. At present, there are few data about the efficacy and safety of inhibition IL-17A for the treatment of pediatric enthesitis and ERA. A retrospective study which included 17 ERA patients who were unresponsive to anti-TNF treatment, verified a good effectiveness under treatment of Secukinumab during a 2-years’ follow up^[18]. Recently, a double-blind, randomized and placebo controlled phase 3 study demonstrated efficacy and safety of Secukinumab in children with active ERA and JPsA^[19].

Ixekizumab is another humanized IgG monoclonal antibody that can selectively bind and neutralize interleukin IL-17A^[20]. Ixekizumab was reported as benefiting on entheseal inflammation in a randomized-controlled trial which contained of 204 active PsA or axial SpA with heel enthesitis^[21]. We reported a case who had a high level of inflammation with swollen toes in the early stage of the disease, who were refractory to DMARDs and TNFi, but showed responsiveness to Ixekizumab. For our case, Ixekizumab was injected subcutaneously (80mg/dose) once a month. Symptoms were improved significantly after the first injection of Ixekizumab and the patient was achieved clinical remission after 6 months of combined therapy with MTX. Until now, this patient had been treated with Ixekizumab for two years without flares. Except for slight redness and swelling at the injection place, there was no significant side effect observed in this patient.

The levels of different cytokines were analyzed before and after application of Ixekizumab in this patient. Levels of IL-6 and VEGF were found fairly higher at baseline, which were consistent with the clinical presentation of this patient (fever with a high level of inflammatory markers). TGF-β1 was in a relatively high level in the remission period. There were no difference in the levels of TNF-α and IL-17A at different time points of Ixekizumab treatment, which indicated a limited value of measuring serum cytokine level in assessing disease activity. The reason for the minor detection difference might be that IL-17A exerts its biological function in the targeted tissue (such as synovium or attachment points) with a relatively low concentration.

The network between IL-17 family members and other cytokines was complex. Up to now, there are six subsets of IL-17 family members identified based on amino acid sequence homology^[22]. IL-17A promotes the secretion of proinflammatory cytokines and chemokines from a variety of target cells to activate inflammation and neutrophil aggregation. IL-17C interacted with IL-17RA/IL-17RE triggering THP-1 producing TNF-α and TGF-β^[23]. IL-17A works synergistically with TNF-α inducing differentiation of mesenchymal stem cells into osteoblasts and promoting aberrant new bone formation in SPA patients^[24]. IL-17D can stimulate endothelial cells to secrete IL-6, IL-8 and GM-CSF^[25]. It was reported that the IL-6/sIL-6R complex can induce VEGF synthesis of mesothelial cells through JAK/STAT3 pathway^[26]. VEGF is a proangiogenic factor playing a role in synovial angiogenesis and vascular permeability^[27]. In this case, a a remarkable high levels of IL-6 and VEGF were found when the disease was in an active state. Whether different cytokine profiles with diversified clinical spectrum reflect different treatment effects needs more studies to confirm.

ERA: enthesitis-related arthritis;

HLA-B27: human leukocyte antigen–B27;

JIA: juvenile idiopathic arthritis;

AS: ankylosing spondylitis;

NSAIDs: nonsteroidal antiinflammatory drugs;

DMARDs: disease modifying antirheumatic drugs;

IL-17: interleukin 17;

PsA: psoriasis arthritis;

ILAR: International League Against Rheumatism;

JADAS10: 10-joint juvenile arthritis disease activity score;

JSpADA: juvenile spondyloarthritis disease activity index;

CRP: c-reactive protein;

ESR: erythrocyte sedimentation;

AJC: active joint count;

PGA: physician global assessment;

VAS: parent/patient visual analogue scale;

SASP: sulfasalazine;

VEGF: vascular endothelial growth factor;

TGF-β1: transforming growth factor-β1;

TNFi: tumor necrosis factor inhibitor;

SpA: spondyloarthritis;

GM-CSF: granulocyte-macrophage colony-stimulating factor;

JAK: janus kinase;

STAT3: signal transducer and activator of transcription 3.

Ethics approval and consent to participate

Formal ethics approval was obtained from research ethnic board at the Children’s Hospital of Zhejiang University School of Medicine.

Consent for publication

The patient and his parents provided written informed consent for the data to be used in analyses and reported.

Availability of data and materials

All important data are within the paper. The datasets generated and/or

analyzed during the current study are not publicly available for privacy

reasons, as well as ethical reasons.

Competing interests

The authors declare that they have no competing interests.

Funding

This work was supported by National Natural Science Foundation of China (No.82070027) and National Key Research and Development Program of China (No. 2021YFC2702000).

Authors’ contributions

QZ analyzed and interpreted the patient data and was a major contributor in writing the manuscript; XHM: images collection and interpreted the patient data, QZ and XHM contributed equally to this work; MMZ & YZ were responsible for collection and analysis of the clinical data; MPL: critical review and modification of the final article. All authors read and approved the final manuscript.

Acknowledgements

We want to thank participating patient and his family for their support.

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Effect of Ixekizumab on Enthesitis-related arthritis non-responsive to anti-TNF treatment, a case report

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