Treatment of severe ankylosing spondylitis with high-dose secukinumab: A retrospective study

doi:10.21203/rs.3.rs-2085501/v1

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Treatment of severe ankylosing spondylitis with high-dose secukinumab: A retrospective study

https://doi.org/10.21203/rs.3.rs-2085501/v1

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Background: Secukinumab is an effective biological agent for the treatment of ankylosing spondylitis(AS); however, some patients do not respond well to the administration of 150 mg every 4 weeks and require more effective management measures. This retrospective study evaluates the efficacy and safety of the administration of secukinumab (300 mg every 4 weeks) in patients with severe AS.

Methods: We reported 12 patients with severe ASand retrospectively reviewed their clinical records and follow-up data. These 12 patients were predominantly men (83.33%)with a mean age of 39.33 ± 13.01 years at the start of secukinumab treatment. Their mean body mass index was 27.48 ± 1.21kg/m2. The patients showed severe disease activity at baseline [Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score > 4]. The protocol of administration of subcutaneous loading doses of secukinumab every 5 weeks was instituted, followed by subcutaneous administration of secukinumab, 300 mg every 4 weeks or 150 mg every 3 weeks; the patients were advised against off-label use. The assessment of the patients’ conditions, including the Ankylosing Spondylitis Disease Activity Score (ASDAS), BASDAI, and Bath Ankylosing Spondylitis Functional Index (BASFI) was performed at weeks 12 and 24.

Results: All 12 patients had a reduction of more than 1.1 in the ASDAS at week 12, and the effect persisted through to week 22. The 50% BASDAIresponse rate was 58.3% at week 12 and 83.3% at week 24. No new safety findings were observed.

Conclusion: Subcutaneous administration of secukinumab, 300 mg every 4 weeks or 150 mg every 3 weeks, showed sustained efficacy of AS and a consistent safety profile after 24 weeks of treatment. This study is a retrospective study with a limited number of cases and a short observation period, which were the major limitations of the study. This retrospective study provides powerful evidence for the novel treatment strategy of refractory active AS switching to 300 mg secukinumab.

Ankylosing spondylitis

Secukinumab

High-dose

Severe disease activity

Ankylosing spondylitis (AS) is a chronic inflammatory disease closely related to human leukocyte antigen B27. The disease affects the sacroiliac joints, axial skeleton, peripheral joints, and enthesis, which causes chronic pain, disability, and reduced quality of life in patients [1]. Characteristic symptoms of AS include chronic inflammatory lower back pain, stiffness, progressive loss of spinal mobility, and hip lesions [2]. The primary goal of treating patients with AS is to control clinical symptoms and inflammation, prevent structural damage, normalize function and social participation, and improve the quality of life [3]. If not adequately treated, AS can lead to significant disability.

At present, the treatment of AS adopts step-by-step medication. Non-steroidal anti-inflammatory drugs (NSAIDs) can be used as first-line treatment for active AS [4]. Tumor necrosis factor (TNF) inhibitors are recommended for patients who experience pain after NSAID treatment; however, approximately 40% of patients with AS respond poorly to TNF inhibitors or develop secondary tolerance, and the efficacy of TNF inhibitors gradually weakens over time [5, 6]. Interleukin-17A (IL-17A) a member of the IL-17 superfamily of cytokines, plays an important role in the pathogenesis of AS in the processes of bone erosion and new bone formation [7, 8]. Secukinumab, a first-in-class fully human monoclonal antibody against IL-17A has demonstrated significant improvement in patients with AS, and offers an alternative therapeutic option for patients with AS. Subcutaneous administration of secukinumab at 150 mg once a week for 5 weeks, which has been changed to maintenance therapy of 150 mg every 4 weeks (Q4w) is the standard dosing regimen to achieve and maintain disease alleviation in the overall population of patients with moderate-to-severe AS in China.

However, individual responses to biologicals in patients with AS vary, and a subset of patients did not respond well to standard doses of secukinumab; thus, there may be a need to individualize treatment. Administration of 300 mg secukinumab provided sustained improvements in the signs and symptoms of active AS in the phase 3 MEASURE 3 study [13]. Therefore, this study investigates the efficacy and safety of an increased dose of secukinumab 300 mg Q3–4W or 150 mg Q3W in patients with moderate-to-severe chronic AS.

Twelve patients ≥ 18 years with moderate-to-severe AS at the Second Affiliated Hospital of Harbin Medical University (HMU) were enrolled in the study between January 2020 to January 2022. All the patients fulfilled the modified New York criteria with a score of four or higher on the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), despite treatment with the highest recommended doses of NSAIDs at baseline.

The exclusion criteria were as follows: (1) total spinal ankyloses, (2) evidence of malignancy, (3) active systemic infection within 2 weeks before baseline, (4) inflammatory bowel disease or uveitis, (5) hypersensitivity to any of the study drug constituents, and (6) pregnancy and lactation.

Clinical data collection

The medical records of the patients were carefully reviewed, including their demographic features, clinical symptoms, physical examinations, laboratory findings, treatment regimens, and follow-up data. Patients were evaluated with ASDAS, BASDAI, and BASFI score every 4 weeks using the scales of the Chinese Society of Rheumatology's APP. The overall safety and tolerability of secukinumab was reported.

A total of 12 patients were included in the analysis, 10 patients were men (83.33%), the average AS duration was 16.0 ± 8.98 years, and the mean age of the patients at the start of secukinumab treatment was 39.33 ± 13.01 years. The mean body mass index (BMI) of the patients was 27.48 ± 1.21 kg/m², and four patients (33.33%) were within the range of obesity with ≥ 28 kg/m². Secukinumab was administered as the first biological disease-modifying antirheumatic drugs (bDMARD) in three patients (25%). Table 1 shows a description of the demographic and disease characteristics, as well as the clinical and biological activities of the study population at the start of secukinumab treatment.

Table 1

Baseline characteristics of patients with AS treated by secukinumab
No.	Gender	Age (year)	Course (year)	BMI	Previous treatment	Joint involvement	CRP (mg/L)	ESR (mm/h)	BASDAI
1	Male	34	10	27.44	NSAIDs, infliximab	Sacroiliac joint, hip	18.2	25	5.4
2	Male	36	12	27.04	NSAIDs, infliximab	Sacroiliac joint, hip, cervical and lumbar spine	13.5	25	5.5
3	Male	42	16	27.43	NSAIDs, infliximab	Sacroiliac joint, hip, knee, chest rib joints	15.03	45	8.2
4	Female	73	40	27.34	NSAIDs	Sacroiliac joint, cervical and lumbar spine, chest rib joints	132.0	70	9.1
5	Male	32	14	29.41	NSAIDs, infliximab	Sacroiliac joint, lumbar spine, Achilles tendon	12.34	30	5.6
6	Male	41	16	28.34	NSAIDs, infliximab	Sacroiliac joint, cervical and lumbar spine	58.4	60	7.0
7	Male	36	8	28.44	NSAIDs, etanercept	Sacroiliac joint, hip, lumbar spine	16.4	30	5.1
8	Female	31	20	25.06	NSAIDs, etanercept, infliximab	Sacroiliac joint, hip, lumbar spine	21.4	40	5.7
9	Male	18	6	27.16	NSAIDs, adalimumab	Sacroiliac joint, hip, cervical and lumbar spine	20.6	30	6.17
10	Male	43	22	29.06	NSAIDs	Sacroiliac joint, hip, cervical and lumbar spine	10.6	30	6.0
11	Male	48	18	26.47	NSAIDs, golimumab	Sacroiliac joint, hip, cervical and lumbar spine	23.5	40	5.2
12	Male	38	10	26.51	NSAIDs	Sacroiliac joint, hip, cervical and lumbar spine	21.6	40	5.13
CRP, C-reactive protein; BMI, body mass index; ESR, Erythrocyte sedimentation rate; BASDAI, Bath Ankylosing Spondylitis Disease Activity Index

After 5 weeks of secukinumab treatment, the ASDAS (4.10 ± 0.72 vs 3.32 ± 0.37, p < 0.01), BASDAI (5.92 ± 0.90 vs 4.70 ± 0.50, p < 0.005) and BASFI scores (6.11 ± 1.18 vs 5.05 ± 1.13, p < 0.05) decreased significantly. (Fig. 1a–c). The ASDAS improved to less than 1.1, and the BASFI was still > 4, indicating that the patients were still in a state of disease activity. Therefore, the dose of secukinumab was changed to 300 mg every 4 weeks from week 8 until week 24 (patient no. 5 received 150 mg every 3 weeks). At 12 weeks, all patients improved by 1.1 on the ASDAS; these improvements continued through week 24; the 50% BASDAI response rate was 58.3% at week 12 and 83.3% at week 24. (Fig. 1a–c). Positron emission tomography-computed tomography (PET-CT) of patient no. 4 showed cervical vertebral facet joint inflammation; the standardized uptake value was significantly increased (Fig. 1d). Magnetic resonance imaging (MRI) showed the formation of a bone bridge at the anterior border of the cervical vertebral body, uneven signal, and vertebral endplate inflammation (Fig. 1e). No adverse events were reported during the 24 weeks.

Secukinumab is a fully human monoclonal antibody targeting IL-17A and has indications for AS, psoriasis, and psoriatic arthritis [8, 14]. Secukinumab is a systemic therapy for the treatment of adults with moderate-to-severe AS, and the efficacy of subcutaneous secukinumab for the treatment of AS has been assessed in multicenter phase III trials and real-world settings [9, 10, 12, 13].

In this study, we explored the efficacy and safety of high-dose secukinumab in patients with moderate-to-severe AS. We reviewed 12 patients (Table 1) fulfilling the criteria for moderate-to-severe AS, and most of these patients had a long medical history. Nine of them received TNF inhibitors, including etanercept and/or infliximab and golimumab, and the other three patients had received only NSAIDs. The patients developed lower back pain, limited spinal movement, and increased C-reactive protein (CRP) and erythrocyte sedimentation rate. Additionally, bone bridge formation can be detected on CT or MRI. Considering the patient's disease activity, secukinumab may be a better option than other types of TNF when changing the treatment regimens. Ten of the patients subcutaneously received 150 mg of secukinumab every week for 5 weeks, and two patients (no. 4 and 6) received secukinumab 300 mg once a week for 5 weeks; the pain was relieved to a certain extent; however, they were still in a state of high disease activity (BASFAI > 4), which affected their life and work. Therefore, they requested more effective treatments. In view of the patient's high disease activity and weight (BMI 27.48 ± 1.21 kg/m²), after consultation with the patient, the secukinumab dose was increased to 300 mg subcutaneously every 4 weeks, except in patient no. 5, who received secukinumab 150 mg every 3 weeks. At weeks 12 and 24, the patients showed significant improvement, and the ASDAS were 2.21 ± 0.25 at week 12 and 1.77 ± 0.21 at week 24; an improvement of more than 1.1 was observed as compared to that with baseline. The BASDAI was reduced to 2.95 ± 0.56 and 2.30 ± 0.55 at weeks 12 and 24, respectively, indicating that the patients responded well to secukinumab treatment. Additionally, there was a significant decrease in the BASFI, but it was still greater than 2 at weeks 12 and 24, indicating active disease. This is likely because these patients already had bone bridge formation and spinal rigidity with limited spinal function, despite receiving secukinumab treatment, these patients cannot completely improve spinal function, suggesting that patients with AS should be treated effectively early in the morning.

Patient no. 4 was a 72-year-old woman with a history of AS for more than 30 years. The patient had only received NSAIDs in the past and had an ankylosing spine. The patient developed neck pain 2 months before admission, which was evident at the time of admission. The head was fixed, CRP was 132 mg/L, and PET-CT showed inflammation of the spine, sternoclavicular joint, shoulder joint, and other parts. Patient no. 6 was a patient with AS weighing 100 kg (BMI: 28.34 kg/m²), who had been treated with infliximab for 8 years. In the past 2 years, the disease had relapsed. In the previous 6 months, the patient received infliximab at 500 mg every 6 weeks. However, the patient still had severe pain in the spine, and the cervical spinal movement was significantly limited. MRI revealed formation of a bone bridge at the anterior border of the cervical vertebral body, uneven signal, and vertebral endplate inflammation with a CRP of 58.4 mg/L. These two patients were administered secukinumab at 300 mg every week, and the CRP reduced to 20 and 29.1 mg/L at week 5, followed by 300 mg every 4 weeks with CRP of 3.12 and 8.31 mg/L at week 12 and 3.1 and 5.42 mg/L at week 24. The patients’ cervical spine pain and activity limitations significantly improved. Patient no. 6 reduced their body weight to 85 kg, and the facial acne significantly improved.

We observed significant improvements in pain, inflammation, and spinal function after secukinumab treatment in patients with AS with severe disease activity. Body weight may be a potential factor affecting the therapeutic effect of secukinumab. If the therapeutic effect of secukinumab at a dose of 150 mg is not satisfactory, adjusting the dose to 300 mg may achieve good clinical effects. Our findings are consistent with the long-term 3-year efficacy and safety data from MEASURE 3, which showed that secukinumab at 300 mg every week had numerically higher responses than at 150 mg every week through week 156 across the majority of efficacy endpoints [10]. Although the 300 mg dose is not currently approved for the treatment of AS, our findings suggest that some patients may benefit from this higher dose.

The safety of 300 mg secukinumab in this study was good, and no adverse events or side effects were observed.

Limitations

Our study had several limitations. This study is a retrospective study with a limited number of cases and a short observation period, and it is difficult to analyze the potential factors affecting secukinumab response. Moreover, we did not observe imaging changes. Therefore, more cases and well-designed studies are required.

In conclusion, high dose of secukinumab (300 mg) provided improvements in the signs and symptoms of active AS, which can be administered as a treatment conversion option for patients with AS who did not improve with 150 mg secukinumab or TNF inhibitor therapy.

AS, ankylosing spondylitis; ASDAS, Ankylosing Spondylitis Disease Activity Score; BASDAI, Bath Ankylosing Spondylitis Disease Activity Index; BASFI, Bath Ankylosing Spondylitis Functional Index; BMI, body mass index; CRP, C-reactive protein; BMI, body mass index; bDMARD, biologic disease-modifying antirheumatic drugs; ESR, Erythrocyte sedimentation rate;IL-17A, interleukin-17A; NSAIDs, Non-steroidal anti-inflammatory drugs; PET-CT, Positron emission tomography-computed tomography; SUV, standardized uptake value; TNF, Tumor necrosis factor.

Ethics approval and consent to participate

The study was performed in accordance with the Helsinki Declaration and approved by the local ethics committee of the Second Affiliated Hospital of Harbin Medical University.

Consent for publication

Not applicable.

Availability of data and materials

The datasets of this study are available from the corresponding author on reasonable request.

Competing interests

None declared.

Funding

This work was partly supported by Heilongjiang Medical Development Foundation.

Authors' contributions

Lei HW wrote the main manuscript text and Lei HW, Huang H, Ma CX and Li YN collected and organizing data. Lei HW and Huang H were responsible for statistical supervision. Li YN supervise the clinical aspect of the study. All authors reviewed the manuscript. The authors read and approved the final manuscript.

Acknowledgments

We would like tothank the patients, and colleagues of the department of Rheumatology and Immunology of the Second Affiliated Hospital of Harbin Medical University (HMU). We also present our gratitude to editage (https://app.editage.com) for the English language review.

Authors' information

¹Department of Rheumatology and Immunology, The Second Affiliated Hospital of Harbin Medical University, Harbin 150001, PR China

* Corresponding author at: No. 148 Baojian Road, Nangang District, Harbin City, Heilongjiang Province, China. E-mail address: [email protected] (YN Li)

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No competing interests reported.

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Treatment of severe ankylosing spondylitis with high-dose secukinumab: A retrospective study

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