key: cord-0697711-8pvc8kgp
authors: Vijayan, Sooraj; Hwangbo, Kyungmin; Barkham, Nick
title: Real‐world evidence for subcutaneous infliximab (CT‐P13 SC) treatment in patients with ankylosing spondylitis during the coronavirus disease (COVID‐19) pandemic: A case series
date: 2022-01-13
journal: Clin Case Rep
DOI: 10.1002/ccr3.5233
sha: bb3190edf13d67db8c7c6f4c0fde824170f61058
doc_id: 697711
cord_uid: 8pvc8kgp

The COVID‐19 pandemic emphasized the utility of subcutaneous (SC) biologics for pressured healthcare systems. The first SC form of infliximab, CT‐P13 SC, provided safe and effective treatment for ankylosing spondylitis in our case series, with increased convenience relative to intravenous treatment benefitting patients both during the pandemic and beyond.

Infliximab holds an important role in treatment guidelines for ankylosing spondylitis (AS). [1] [2] [3] The intravenously (IV) administered infliximab biosimilar CT-P13 IV received regulatory approval from the European Medicines Agency in 2013, followed by United States Food and Drug Administration approval in 2016, for the same indications as reference infliximab. [4] [5] [6] [7] [8] Subsequently, the first and only subcutaneous (SC) infliximab, CT-P13 SC, has been developed; this offers potential benefits for patients and healthcare systems. 9 Comparable safety and noninferiority of CT-P13 SC to CT-P13 IV in terms of efficacy and pharmacokinetics were demonstrated in clinical trials in patients with rheumatoid arthritis (RA) 10 and inflammatory bowel disease (IBD), 11 respectively. In July 2020, the marketing authorisation for CT-P13 SC was extended to all of the adult IV formulation indications, including AS. 12 This extension was approved based on extrapolation rather than clinical trial experience in each indication, and to our knowledge, there are no published reports of CT-P13 SC treatment in patients with AS.

The coronavirus disease 2019 (COVID-19) pandemic has substantially impacted care and health behavior for patients with rheumatological conditions. [13] [14] [15] While moderate or high disease activity in patients with rheumatic diseases (including those with axial and peripheral spondyloarthritis) has been associated with an increased risk of COVID-19-related death, 16 biologic/tumor necrosis factor (TNF) inhibitor therapy has been associated with a reduced likelihood of hospitalization due to COVID-19. 17, 18 This highlighted the importance of continuing treatment during the pandemic to maintain effective disease control. At The Royal Wolverhampton Hospitals National Health Service (NHS) Trust, rheumatic disease therapies have been maintained throughout the pandemic (in patients without , as recommended by the European Alliance of Associations for Rheumatology. 19 In April 2020, National Institute for Health and Care Excellence (NICE) guidance recommended that patients with rheumatological autoimmune, inflammatory, and metabolic bone disorders who were receiving IV administered biologics should consider switching to an SC form of the same treatment or changing to a different SC administered biologic. 20 In this case series, 11 patients receiving CT-P13 IV treatment for AS switched to CT-P13 SC, helping to maximize patient and staff safety while optimizing healthcare system resource allocation. 20 This case series reports outcomes at up to 14.7 months of follow-up, providing a valuable perspective on CT-P13 SC therapy during the COVID-19 pandemic, offering insights into patient treatment decision-making and informing management approaches beyond the pandemic setting.

Eleven patients (seven male and four female) with diagnoses of AS were included in this case series (Table 1) . Patient age ranged from 28-70 years. Patients were receiving CT-P13 for the treatment of AS at The Royal Wolverhampton Hospitals NHS Trust, UK, in April 2020. Following a telephone discussion with their consultant, patients agreed to switch from CT-P13 IV (5 mg/kg every 8 weeks) to CT-P13 SC (120 mg every 2 weeks) in line with NICE guidance for the COVID-19 pandemic. 20 Switching aimed to minimize hospital attendance, reducing the risk of exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and allowed hospital resources to be redeployed as needed. Patients received a visit from a homecare nurse for training on CT-P13 SC administration, followed by telephone appointments with a physician (typically 3 months after CT-P13 SC initiation and then every 6 months). A telephone helpline was available to address any problems raised by patients in the interim. Patients could switch back to CT-P13 IV at any time if desired; all patients were followed up until June 2021. Patients completed a Self-Injection Assessment Questionnaire (SIAQ) at the end of follow-up, using a method adapted from Keininger and Coteur. 21 Patients scored the following domains on a 10-point scale (0 worst; 10 best): feelings about self-injection, self-confidence, self-image, satisfaction with self-injection, pain and skin reactions during or after injection, and ease of use of the self-injection device.

A total of 195 doses of CT-P13 SC were administered, with a median of 26 doses per patient ( Table 2 ). The total duration of follow-up while on CT-P13 SC was 94 months (median: 11).

Five patients switched from existing CT-P13 IV treatment to CT-P13 SC and were continuing CT-P13 SC at their last follow-up. Figure 1 shows the distribution of patients who decided to continue CT-P13 SC, by age, weight, and Creactive protein (CRP) level.

Patient 1 was diagnosed with both AS and rheumatoid factor (RF)-positive RA before 2006 (Table 1) . Syndesmophytes were identified on X-ray in 2015, and the patient had undergone spinal fixation surgery. He had received 13 years of prior infliximab treatment with concomitant methotrexate (MTX)-approximately 9 years of reference infliximab and 4 years of CT-P13 IV-but had not received any other prior biologic medications for his AS. Before switching to CT-P13 SC, he reported back pain, peripheral joint involvement, and iritis. While receiving CT-P13 SC, his CRP level remained consistent at 1.0-1.1 mg/L, and disease activity measures were maintained. The patient preferred to continue CT-P13 SC long term to save time and avoid travel to the hospital and payment of parking charges. He also noted that the time required for treatment was much shorter with CT-P13 SC, taking <2 min to administer compared with half a day for CT-P13 IV infusion. Patient 2 had human leukocyte antigen (HLA)-B27positive AS with sacroiliitis (Table 1) maintained. The patient experienced minor bruising at injection sites but reported no other issues. Patient 3 had AS with fused sacroiliac joints, significant spinal fusion, and no cervical spine movement prior to switching to CT-P13 SC ( Table 1) . The patient had received 15 years of prior infliximab treatment as monotherapy (approximately 11 years of reference infliximab and 4 years of CT-P13 IV). The symptomatic response to CT-P13 IV was suboptimal, although inflammatory markers were normal. While receiving CT-P13 SC, disease activity scores improved, although CRP levels increased. Patient 4 had HLA-B27-positive AS diagnosed in 2017 (Table 1) , following a history of back pain (since 2015), sacroiliac joint erosions on pelvis X-ray (2016), and sacroiliitis and thoracic spine marrow edema on magnetic resonance imaging (MRI) (2017). The patient had previously received adalimumab (discontinued because of lack of efficacy) and secukinumab (discontinued as no response was observed), before a treatment break when the patient was not in the UK. He received approximately 4 months of CT-P13 IV treatment before switching to CT-P13 SC. With CT-P13 SC, the patient's disease activity scores improved, although CRP levels increased. The patient reported problems with drug deliveries but decided to continue CT-P13 SC long term as treatment was convenient for his work schedule.

Patient 5 was diagnosed with HLA-B27-positive AS with a history of back pain and scalp psoriasis prior to CT-P13 SC treatment ( Table 1) . The patient had previously received adalimumab, which was discontinued because of local injection-site reactions (ISRs), before approximately 2 years of CT-P13 IV monotherapy. During CT-P13 SC treatment, CRP levels were normal. The patient was needle phobic and expressed a desire to change to a treatment administered via a different route; however, the patient's friend assumed responsibility for administering the injections without any further issues. Patients 1-5 completed the SIAQ at the end of the follow-up period (while remaining on CT-P13 SC). Mean scores were at least 6.60 for all domains other than selfconfidence ( Table 3) . The lower mean self-confidence domain score (4.60) was skewed by two patients who scored 0; this may have been related to the needle phobia experienced by Patient 5 and generally low self-confidence affecting patients as a result of pandemic-related restrictions.

Six patients in this case series switched from ongoing CT-P13 IV treatment to CT-P13 SC and later decided to switch back to CT-P13 IV. The distribution of patients who decided to switch back to CT-P13 IV, by age, weight, and CRP level, is shown in Figure 1 . (Table 1) . He had received just over 1 year of prior CT-P13 IV treatment with concomitant MTX, hydroxychloroquine, and prednisolone. No clinical assessments were conducted during CT-P13 SC treatment; however, the patient reported that the treatment was less effective than CT-P13 IV. Prior to switching, the patient's CRP level was 1 mg/L; this was 2 mg/L during CT-P13 SC treatment and returned to 1 mg/L after the patient restarted CT-P13 IV.

Patient 7 had HLA-B27-positive AS with a fused dorsolumbar spine and uveitis (Table 1) . He had previously received secukinumab (discontinued because of longterm failure of efficacy), adalimumab (discontinued because of anti-drug antibody formation), and etanercept (discontinued because of long-term failure of efficacy), before beginning CT-P13 IV in February 2020. No clinical assessments were conducted during CT-P13 SC treatment, but the patient reported that the therapy was less effective than CT-P13 IV. The patient's CRP level was 2 mg/L before switching to CT-P13 SC, 4 mg/L while receiving CT-P13 SC, and 8 mg/L after switching back to CT-P13 IV. Patient 8 had AS and Crohn's disease ( Table 1 ). The patient had received 17 years of prior infliximab treatment (approximately 13 years of reference infliximab and 4 years of CT-P13 IV) as monotherapy. Initiation of CT-P13 SC was delayed because of late drug delivery due to the pandemic situation. No clinical assessments were conducted while the patient was receiving CT-P13 SC, but he reported that the therapy was less effective than CT-P13 IV. The CRP level while receiving CT-P13 SC was 5 mg/L; after the patient decided to switch back to CT-P13 IV, this was 7 mg/L. Patient 9 had HLA-B27-positive AS with sacroiliitis, having reported back and hip pain at presentation ( Table 1) . She had received etanercept (discontinued because of ISR) and golimumab (discontinued because of ineffectiveness) before initiating CT-P13 IV. One hour following her first injection of CT-P13 SC, she experienced a localized ISR consisting of simple erythema of 2 cm in diameter. This resolved after 48 h without pain or itch, but as a consequence, the patient preferred to switch back to CT-P13 IV. After switching back to CT-P13 IV, her CRP level was 3 mg/L. Patient 10 was diagnosed with both AS and seronegative RA in 2009, with the AS diagnosis following squaring of vertebrae, ankylosis, and Romanus lesions identified by MRI ( Table 1) . The patient had received 10 years of prior infliximab treatment as monotherapy (approximately 6 years of reference infliximab and 4 years of CT-P13 IV). Throughout CT-P13 SC treatment, CRP levels remained normal, but the patient decided to switch back to CT-P13 IV because of a perceived reduction in effectiveness. After switching back to CT-P13 IV, the CRP level was <0.2 mg/L. Patient 11 had diagnoses of AS, uveitis, and Crohn's disease ( Table 1) . The patient had received etanercept and adalimumab prior to initiating infliximab and went on to receive 13 years of infliximab as monotherapy (approximately 9 years of reference infliximab and 4 years of CT-P13 IV). No clinical assessments were conducted during CT-P13 SC treatment, but the patient reported that the effect of the medication was not lasting 2 weeks. While receiving CT-P13 SC, the patient's CRP levels were 57 mg/L, 12 mg/L, and 14 mg/L. After switching back to CT-P13 IV, the CRP level was 20 mg/L. Patients 6-11 completed the SIAQ at the end of the follow-up period (after they had switched back to CT-P13 IV). Mean scores were at least 7.33 for all domains other than satisfaction with self-injection, which was slightly lower at 6.33 (Table 3 ).

In our case series, of the 11 patients who switched from CT-P13 IV to CT-P13 SC, 5 (45.5%) decided to continue CT-P13 SC long term, while 6 (54.5%) decided to switch back to CT-P13 IV. Two of the patients who decided to continue CT-P13 SC long term noted increased convenience, with reduced time and travel requirements for treatment, as a reason for their choice. These findings are in keeping with those from a study of patient preferences in AS, in which patients receiving SC administered TNF inhibitors cited flexibility, convenience, and shortened administration time as benefits. 22 Similarly, the duration of infusion, need to travel, and appointment scheduling were the most frequent perceived disadvantages of IV therapy listed by patients with immunemediated inflammatory diseases (IMIDs) receiving IV administered biologics. 23 In this case series, five of the six patients who decided to switch back to CT-P13 IV reported that CT-P13 SC was not as effective as CT-P13 IV. However, it is important to note that few clinical assessments were conducted in these patients because of the pandemic. Persistence with CT-P13 SC did not seem to be related to patient age, weight, or CRP level. Since decisions about whether to persist with CT-P13 SC treatment did not seem to correlate with objective findings in terms of CRP level, this suggests that factors including the nocebo effect might underpin subjective perceptions of reduced effectiveness in these patients. 24 Clinical trials evaluating CT-P13 SC in patients with RA and IBD found that efficacy was maintained following a switch from CT-P13 IV, 10, 11 and this is supported by clinical experience in the IBD setting as patients have switched to CT-P13 SC during the pandemic. 25, 26 In this case series, mean SIAQ scores for self-image and satisfaction with self-injection were higher for patients continuing CT-P13 SC compared with those who decided to switch back to CT-P13 IV. One of the patients in this case series, who ultimately decided to continue CT-P13 SC, reported needle phobia, requiring a friend to assume responsibility for administering the treatment. Dislikes of selfinjection/needles or lack of comfort with self-injection was the most frequent reason given by patients with IMIDs who preferred IV over SC biologic therapy in a previous analysis, 23 indicating the potential influence of this concern on treatment decision-making. One patient highlighted problems or delays with receiving deliveries of CT-P13 SC, which may have adversely affected their treatment experience. Such issues are more likely to have been prevalent during the pandemic owing to the impact of staff shortages or redeployment; thus, any potential impact on CT-P13 SC-treated patients should be reduced in the future.

Although the number of patients included in this case series is limited, the safety profile of CT-P13 SC was consistent with data included within the EU product information, 4 with no new or unexpected safety findings. Two patients experienced mild ISRs, consistent with those described in the EU product information. 4 The remaining patients did not report any adverse reactions. These safety findings are in keeping with reports for patients with IBD switching from IV to SC infliximab during the pandemic. [25] [26] [27] [28] There were no reported cases of SARS-CoV-2 infection in our case series. Of the limited published data regarding SARS-CoV-2 infection in patients with AS or spondyloarthritis treated with TNF inhibitors, most reports found that the clinical course of COVID-19 was not severe in this population. [29] [30] [31] [32] [33] [34] [35] In addition, a survey found that TNF inhibitor treatment did not impact subjective scores ascribed by patients with spondyloarthritis to the severity of their COVID-19. 36 Subcutaneous biologic therapy offers several potential benefits for healthcare systems and patients, including increased convenience and flexibility (including at-home administration) for patients, and reduced preparation, drug delivery time, and resource requirements for healthcare providers. 9 Indeed, benefits including enhanced control and improved convenience for patients, alongside reduced pressure on infusion units, have been reported in the IBD context as patients have switched from IV to SC infliximab treatment during the COVID-19 pandemic. 25, 27, 28 An analysis of 88 patients with IBD found that 85.2% of patients were happier receiving CT-P13 SC than infliximab IV, and 92.0% felt that CT-P13 SC was easy to use. 26 Given these potential benefits of CT-P13 SC, our findings suggest that it may be appropriate to offer patients currently receiving infliximab IV the opportunity to switch to CT-P13 SC; however, additional studies may be needed to confirm the efficacy and safety of making such a switch. In addition, it might be beneficial for patients with indications for infliximab therapy to initiate treatment with CT-P13 SC (after the required IV loading dose 4 ).

Our results reflect 11 cases from a single center and, because of the low number of patients included, may not be fully generalizable to the wider AS patient population. However, since patients with AS are often of working age and may experience work instability as a result of the disease, 37 the benefit of increased convenience of CT-P13 SC treatment reported by some of the patients in this case series may be attractive to many individuals with AS, relative to the demands of frequent hospital visits for IV infusions. Our conclusions are limited by the observational nature of case reports, meaning that clinical and laboratory assessments were not collected consistently for all patients. Because of the pandemic situation, such assessments were made less regularly than usual, with reductions in both face-to-face and blood monitoring appointments further restricting data collection possibilities. However, an advantage of this management approach, offering patients a switch to CT-P13 SC, was the potential reduction in nosocomial exposure to SARS-CoV-2. Experience with online collection of outcome measures also suggests a model for patient management that is less dependent on face-to-face appointments and could be implemented post pandemic. Acknowledging the limitations of the case series, our findings make a valuable contribution to the available information about the efficacy and safety of CT-P13 SC in patients with AS. While these data were collected during the COVID-19 pandemic, we believe that our patient preference findings will be transferable to a postpandemic setting.

In summary, our case series suggests that CT-P13 SC can provide safe and effective treatment for patients with AS. The convenience of CT-P13 SC may be a benefit for patients both during and beyond the COVID-19 pandemic.

Medical writing support, including development of a draft outline, and subsequent drafts in consultation with the authors, collating author comments, copyediting, fact checking, and referencing, was provided by Beatrice Tyrrell, DPhil, at Aspire Scientific Limited (Bollington, UK). Funding for medical writing support for this article was provided by Celltrion Healthcare Co., Ltd (Incheon, Republic of Korea).

Sooraj Vijayan has no potential conflicts of interest to declare. Kyungmin Hwangbo is an employee of Celltrion Healthcare Co., Ltd. Nick Barkham has received honoraria and speaker fees from Celltrion Healthcare.

Sooraj Vijayan and Nick Barkham collected data, contributed to analysis and interpretation, and drafted and critically revised the article. Kyungmin Hwangbo contributed to analysis and interpretation, and drafted and critically revised the article. All authors take responsibility for the integrity of the work as a whole and have given their approval for this version to be published.

The treatment described in this case series arose from a service development due to the COVID-19 pandemic and in response to NICE guidance, which is mandatory in the UK. Since the treatment was not part of a clinical trial, formal ethical submission was not required. All patients had a telephone call with their consultant to discuss the potential risks and benefits prior to the change of treatment and all agreed to it; approval was provided by the NHS Trust (treatment provider) and the Clinical Commissioning Group (payer authority). The patients provided written informed consent for their cases to be included in this article.

All data generated or analyzed during this study are included in this published article.

Nick Barkham https://orcid.org/0000-0001-7754-6931

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