|Ahead of print publication
Effectiveness and safety of secukinumab in axial spondyloarthritis and psoriatic arthritis: A retrospective analysis of its real-world usage from India
Sham Santhanam1, Hema Murugesan2, Thilagavthy Nambi3, Raja Natarajan4, Kavitha Mohanasundaram5
1 Department of Rheumatology, Consultant Rheumatologist, Gleneagles Global Hospitals, Chennai, India
2 Department of Rheumatology, Stanley Medical College, Chennai, India
3 Department of Rheumatology, Consultant Rheumatologist, SIMS Hospital, Chennai, India
4 Department of Rheumatology, Consultant Rheumatologist, Sri Narayani Hospital and Research Centre, Vellore, Tamil Nadu, India
5 Department of Rheumatology, Saveetha Medical College Hospital, Chennai, India
|Date of Submission||09-Apr-2020|
|Date of Acceptance||13-Jul-2020|
Department of Rheumatology, Saveetha Medical College and Hospital, Thandalam, Kancheepuram District, Tamilnadu
Source of Support: None, Conflict of Interest: None
Background: Although secukinumab has become available in India since mid-2016, there is no published data on its usage in axial spondyloarthritis (axial SpA) and psoriatic arthritis (PsA). In this study, we analyzed the real-world usage of this drug to assess the effectiveness and safety in axial SpA and PsA.
Methods: All patients with active axial SpA or PsA who had received secukinumab as a biological disease-modifying antirheumatic therapy either as a primary or as a secondary biological therapy covering the period between August 2017 and February 2020 from five Indian centers were included in the study. Whereas Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) 50 and Ankylosing Spondylitis Disease Activity Score (ASDAS) C-reactive protein (CRP) improvement were used to assess the treatment response in axial SpA, DAS 28ESR was used for PsA. The data were retrospectively analyzed.
Results: Out of 45 patients included in the study, 27 had axial SpA and 18 had PsA. Disease duration (median [interquartile range]) was 60 (96) months in axial SpA and 54 (108) in PsA. In axial SpA, out of 21 patients who had completed at least 6 months of therapy, 19 demonstrated a BASDAI 50 response and 20 reported good response as per ASDAS CRP (15, low disease activity and 5, inactive disease). In PsA, 14 patients had completed at least 6 months of therapy and 8 of them went in remission and another 4 achieved low disease activity. Adverse events were few (2, upper respiratory tract infection; 1 pneumonia; 3, uveitis; and leukocytoclastic vasculitis in 1) with no tuberculosis reported.
Conclusion: In its real-life usage to treat both active axial SpA and PsA, secukinumab was found to be effective and safe.
Keywords: Axial spondyloarthritis, effectiveness, psoriatic arthritis, safety, secukinumab
|How to cite this URL:|
Santhanam S, Murugesan H, Nambi T, Natarajan R, Mohanasundaram K. Effectiveness and safety of secukinumab in axial spondyloarthritis and psoriatic arthritis: A retrospective analysis of its real-world usage from India. Indian J Rheumatol [Epub ahead of print] [cited 2020 Oct 30]. Available from: https://www.indianjrheumatol.com/preprintarticle.asp?id=297406
| Introduction|| |
Secukinumab was the first fully human monoclonal antibody targeting interleukin (IL)-17A. IL-17A plays an important role in the pathogenesis of ankylosing spondylitis (AS) and psoriatic arthritis (PsA). Secukinumab has been approved by both the US Food and Drug Administration and the European Union for the Treatment of Skin Psoriasis, Psoriatic Arthritis, and Ankylosing Spondylitis., In axial spondyloarthritis (SpA), secukinumab was shown to be efficacious in comparison to placebo in both tumor necrosis factor (TNF)-naïve and TNF-inadequate responders (IR). As of now, it has been approved only for radiographic SpA (AS). However, based on the results of PREVENT study, its approval for nonradiographic SpA appears not too far. Similarly, its efficacy in PsA has been established in various clinical trials.
Although the introduction of TNFi has revolutionized the management of spondyloarthritides, there are patients who may not respond to TNFi, either as primary or secondary response failure. In this scenario, secukinumab is a useful alternative, considering its efficacy and good safety profile in clinical trials.
This biological agent became available in India in mid-2016. Since then, few Indian studies have studied its efficacy and safety in skin psoriasis.,, However, there is no published data from India on the usage of secukinumab in axial SpA and PsA. In this context, it is worth noting that in India, though the need for biological therapy is great, due to economic constraints, only few patients can afford long-term therapy and most rheumatologists are forced to use them either as a short-term therapy or as demand-based treatment. Second, tuberculosis is endemic in our country and anti-TNF usage poses a risk for its reactivation. Secukinumab provides a safer alternative in this regard.
The primary objective of our study was therefore to evaluate the effectiveness of secukinumab in its long-term real-life usage and also appraise its safety.
| Methods|| |
This was a multicenter retrospective analysis of data from five Indian centers over 2.5 years (from August 2017 to February 2020). We included all patients (the axial SpA, satisfying the 2010 ASAS classification criteria for axial SpA; and PsA, satisfying the CASPAR classification criteria) who were treated with secukinumab with a dosing schedule comprising a loading dose of 150 mg at weeks 0, 1, 2, and 3, followed by maintenance dose of 150 mg once in 4 weeks.
Using a structured pro forma, data were retrieved from patient's medical records of the participating centers. This included clinical history, baseline characteristics, disease activity at baseline and at periodic intervals after initiation of treatment, screening for latent tuberculosis, and all drug-related adverse effects. Imaging and laboratory investigations (including those done for screening prior to biological therapy) were also recorded.
Assessment of disease activity
The disease activity in axial SpA was assessed by the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and Ankylosing Spondylitis Disease Activity Score (ASDAS) C-reactive protein (CRP) and in PsA by DAS 28 ESR for peripheral arthritis. The response criteria used in axial SpA were BASDAI 50 (defined as improvement by at least 50% in the score or a change of 2 units in BASDAI scores) and ASDAS CRP (defined as major improvement, change in score by ≥2 units; clinically important improvement, change in score by ≥1.1; inactive disease, ASDAS CRP <1.3; and low disease activity, ASDAS CRP <2.1). The response criteria used in PsA were DAS 28ESR (defined as remission, <2.6; and low disease activity, ≥2.6 to ≤3.2). In both the groups, other manifestations such as enthesitis, dactylitis, and skin and nail psoriasis were assessed clinically.
The data were analyzed for effectiveness and safety for patients who had a minimum of 10 doses of secukinumab by 24 weeks. For follow-up, those patients who had completed 52 weeks were analyzed. The data for patients who completed only 12 weeks and continued treatment with secukinumab were also analyzed separately.
For discrete data, proportion was computed and the mean (standard deviation) and median (interquartile range) was computed for the continuous data. The data were managed and analyzed using IBM SPSS statistics for Windows (version 25, Armonk, Newyork).
Due approval from the Institutional Ethical Committees of the participating centers was obtained.
| Results|| |
A total of 45 patients (27 with axial SpA and 18 with PsA) were enrolled. [Figure 1] depicts the participants' flow in this study. In the axial SpA and PsA groups, 21 and 14 patients completed 24 weeks of follow-up, respectively. The baseline disease characteristics of both the groups are discussed in [Table 1]. Secukinumab was the first biological agent in 36/45 (19 in axial SpA and 17 in PsA) patients and all had high baseline disease activity [Table 1].
|Figure 1: Flowchart depicting the number of patients analyzed in the study based on the disease and follow-up duration|
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|Table 1: Demographics, clinical features, and disease activity at baseline of the study population|
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In the remaining 9 patients where secukinumab was the secondary biologic, these included 7 with axial SpA who were IR to anti-TNF (3 to infliximab, 2 to infliximab followed by adalimumab, and 2 to adalimumab). Out of the remaining two, one patient with axial SpA had developed pulmonary tuberculosis on infliximab and was later switched to etanercept and then to secukinumab and the other patient with PsA had failed on both etanercept and infliximab.
Among the total 45 patients, 4 patients (3 with axial SpA and 1 with PsA) reported no relief in symptoms after the loading dose and then lost to follow-up.
Six patients were yet to complete the 10 doses, but had completed 12 weeks of follow-up. Three of those had axial SpA and 3 PsA. All three with axial SpA reported BASDAI 50 improvement, 2 major ASDAS improvement, and 1 clinically important ASDAS improvement at 12 weeks. One achieved inactive disease status and 2 low disease activity as per ASDAS CRP. Among the 3 PsA patients, 2 had low disease activity and 1 attained remission by DAS 28 ESR.
[Table 2] and [Table 3] detail the analyses of remaining 35 patients who had all scheduled 10 doses by 24 weeks (21 with axial SpA and 14 with PsA). In axial SpA, 19/21 patients had BASDAI 50 improvement and 16/21 had major improvement by ASDAS. In PsA, 8/14 patients had remission and 4/14 had low disease activity by DAS 28 ESR.
All nine patients who were IR to TNF blockers responded well to secukinumab. Patients with poor response and lost to follow-up were biological naïve and had long-standing disease with structural deformities.
Of the 35 patients who had completed a minimum of 10 doses, 28 (16 with axial SpA and 12 with PsA) completed 52 weeks of follow-up. In those with axial SpA (n = 16), 3 were on continuous treatment with secukinumab and remained in low disease activity status. Of the remaining 13 who discontinued secukinumab by 24 weeks, 7 were able to sustain their low disease activity, 3 were able to sustain inactive disease status, and 3 had a flare. Of the 3 who were able to sustain inactive disease status, 2 were non radiographic axial SpA. All these 16 patients including those 3 patients who continued on secukinumab were on sulfasalazine ± methotrexate, except one.
In those with PsA (n = 12), 4 patients were on continuous treatment with secukinumab and remained in sustained remission. Of the remaining 8 patients who discontinued treatment with secukinumab by 24 weeks, 4 achieved low disease activity and 4 remained in remission. Among the 4 patients who had low disease activity, 2 had skin flare. All patients were on background treatment with methotrexate/leflunomide/apremilast/sulfasalazine as either monotherapy or in combination.
For skin and nail psoriasis, the treatment response was assessed clinically based on observation by the treating rheumatologist with inputs from the dermatologist. Among the 18 patients with PsA, 4 had severe skin psoriasis. One responded well with no flare after stopping treatment. One patient had mild flare when the drug was discontinued; therefore, it was continued for over 2 years with sustained good results. The remaining two patients had severe skin flare on stopping secukinumab despite being on background synthetic DMARDs. They had to be switched to TNF blockers in view of patient's preference.
All patients on secukinumab showed resolution of dactylitis and enthesitis.
Overall, only few adverse events were noted in this study of 45 patients. Two patients developed upper respiratory tract infection during the course of loading doses. For both, injection of secukinumab was delayed by 1 week, and once the infection settled, it was continued as per the schedule. A 67-year-old patient with PsA developed pneumonia after the 6th dose, needing hospitalization. After it resolved, treatment with secukinumab was continued.
On screening, 6 patients were positive for latent tuberculosis infections (4 with axial SpA and 2 with PsA). They were treated with isoniazid and rifampicin for 4 months. Secukinumab was started after 2 months of starting treatment for latent TB. Two patients (1 each with axial Spa and PsA) had a history of pulmonary TB. They had relevant investigations including computed tomography scan of the chest to rule out an active infection before starting them on secukinumab. None of these patients had any new infection or reactivation.
One patient had hepatitis B core antibody positivity with no evidence of active infection. Considering his carrier state, he was started on empirical treatment with efavirenz and continued for 6 months after stopping secukinumab.
There were 5 patients with a history of uveitis and four of them were HLA B27 positive. Of these 5 patients, 1 had relapse of uveitis during the course of treatment and another 1 after stopping secukinumab. One HLA B27-negative patient without a history of uveitis developed uveitis during the treatment.
One of the patients with axial SpA developed purpuric lesions (skin biopsy-confirmed leukocytoclastic vasculitis [LCV]) after 8 doses of secukinumab. He was treated with colchicine, and once this condition settled, secukinumab was continued. One patient with PsA had preexisting interstitial lung disease (ILD). This patient was treated with both secukinumab and mycophenolate mofetil (MMF) and no worsening of ILD on CT chest was noted.
None of our patients had any new onset diarrhea or any feature suggestive of inflammatory bowel disease after treatment. We did not have any patients with neutropenia, cardiac ailments, or malignancies during the course of treatment or on follow-up.
| Discussion|| |
Ours was a retrospective analysis of the effectiveness and safety of secukinumab in axial SpA and PsA. At 24 weeks, among patients with axial SpA, 90% (19/21) attained BASDAI 50 improvement and 76% (16/21) ASDAS improvement. In those patients with PsA, 57% (8/14) attained remission and 28.6% (4/14) had low disease activity by DAS 28 ESR at 24 weeks. In our study, all the nine patients who were TNF IR responded well to secukinumab.
The MEASURE 4 study had a similar study design, evaluating the efficacy and safety of secukinumab (150 mg with and without loading dose) in AS. The ASAS 20, 40 response rates were similar in both arms, which was consistent with previous studies. There was a high retention rate, with 84% of patients enrolled at baseline remained till 104 weeks. The treatment response was sustained or improved form week 16 to week 104 irrespective of usage of prior TNF inhibitor therapy.
The FUTURE 4 studied the efficacy and safety of secukinumab (150 mg with and without loading dose) in patients with active PsA. The short-term efficacy was assessed at week 16 and the long-term efficacy at weeks 52 and 104. Both the arms showed significant and sustained improvement in comparison to placebo. However, the loading dose arm had earlier and numerically higher responses for stringent endpoints such as ACR 50, 70. The treatment response was better in TNF-naïve patients in comparison to TNF IR, similar to previous secukinumab studies.,
In our study, of the 13 patients with axial SpA who discontinued secukinumab after 10 doses, 3/13 (23%) had inactive disease, 7/13 (53.8%) had low disease activity, and only 3/13 (23%) had a flare at 52 weeks. Similarly, 8 patients with PsA had discontinued secukinumab after 10 doses; all had a sustained LDA or remission at 52 weeks. These data appear encouraging in the Indian context, as a sizable number of patients in both disease groups maintained their low disease activity/remission even after stoppage of secukinumab at 24 weeks when continuing on the background treatment with synthetic DMARDs.
AQUILA is an ongoing multicenter trial evaluating the real-word experience of secukinumab in AS (n = 187) and PsA (n = 385). Once results on efficacy and safety are available, we hope that it will add to our present Indian experience.
Deodhar et al. have assessed the long-term safety by pooling the data from clinical trials of psoriasis, AS, and PsA. The most common infections were upper respiratory tract infections, followed by mucocutaneous candidiasis with no systemic infections. There were no cases of reactivation of tuberculosis. Other side effects such as neutropenia, new-onset inflammatory bowel disease, major cardiovascular events, and antidrug antibodies were minimal. In our study, therapy with secukinumab resulted in no serious side effects.
Among the Indian subjects of FIXTURE trial, common side effects noted were diarrhea, pyrexia, headache, nasopharyngitis, and decreased appetite. In an Indian study of secukinumab use in cutaneous psoriasis, there were reports of injection site reaction, tinea corporis, vulvovaginal candidiasis, and exacerbation of eczema. Our patients did not report any injection site reactions or fungal infections during the course the study.
One of the patients with PsA had ILD, prior to starting secukinumab. Although there are case reports of secukinumab worsening ILD, this patient had improvement of pulmonary function test with secukinumab. However, this patient was also on treatment with MMF Whether secukinumab is a safe option for PsA, patients with preexisting ILD need further study.
One patient with axial SpA developed biopsy-proven cutaneous LCV. Few cases of secukinumab causing LCV in isolation or in association with gastrointestinal vasculitis have been reported. The pathogenesis is not clear, though it may be similar to TNF blocker-induced cutaneous vasculitis.
Overall, secukinumab was well tolerated and appears to be a safe molecule; our study has few limitations. First, being a retrospective study, we were not able to assess the functional status or the spinal mobility in axial SpA. Second, in PsA, we did not assess cutaneous psoriasis and other components of PsA such as dactylitis and enthesitis objectively with disease activity indices. Third, we had some missing data, but as those variables were not included for analyses, we could not assess risk factors such as smoking, body mass index, and coexisting comorbidities. Further, though several of our patients completed 52 weeks of follow-up, majority took treatment for 24 weeks only. Finally, we used DAS 28 ESR for assessing PsA. PsA is a multifaceted disease with extra articular features such as enthesitis, dactylitis, and skin and nail psoriasis. Although there are better composite disease activity measures specific for PsA such as psoriatic arthritis disease activity score or composite psoriatic disease activity index, we were unable to use them as a standard due to a paucity of time in our routine clinical practice. However, we cannot completely discredit the use of DAS 28 in PsA. DAS 28 has performed well in clinical trials involving biologics, including all major secukinumab trials (FUTURE 1 to 4) in PsA. In addition, it has been deemed an acceptable disease activity measure in polyarticular PsA (similar to our cohort) and appears to be more responsive and discriminates better between drug and placebo.,
To the best of our knowledge, ours is the first Indian study to capture the real-world data on secukinumab usage in axial SpA and PsA. In Indian setting, most patients are not able to continue biologics for prolonged duration and this was also found true in our study. This study also alludes to the fact that a good proportion of patients at 1 year continue to be in remission or low disease activity state after 6 months (10 doses) of secukinumab. However, a long-term follow-up of such patients would be needed to derive any meaningful conclusion.
| Conclusion|| |
The present study found that secukinumab in the Indian setting is an effective and safe therapy for the management of both axial SpA and PsA in both biological naïve and TNF IR.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3]