Axial spondylarthritis following COVID-19 infection.

Although SARS-CoV-2 syndrome primarily affects the lungs, systemic manifestations have been reported. New rheumatic immune-mediated inflammatory diseases have been reported following SARS-CoV-2 infection. We present a case of a woman in her mid-30s who developed inflammatory back pain due to bilateral sacroiliitis with erosions after contracting SARS-CoV-2 infection. Her inflammatory markers on presentation were normal. MRI of the sacroiliac joints demonstrated bone marrow oedema and erosive changes in both sacroiliac joints. As the patient was intolerant to non-steroidal anti-inflammatory drugs, adalimumab 40 mg subcutaneous (SC) injection was administered, which improved her symptoms in 8 weeks. However, due to the drug's side effects, SC adalimumab was switched to intravenous infliximab. The patient is currently tolerating her intravenous infliximab well and has experienced significant improvement in her symptoms. We reviewed the current literature on the prevalence of axial spondyloarthropathy after SARS-CoV-2 infection.

Evaluation of infliximab/tocilizumab versus tocilizumab among COVID-19 patients with cytokine storm syndrome.

Coronavirus Disease 2019 (COVID-19) continues to spread rapidly. Monoclonal antibodies as well as anti-tumor necrosis factor are considered promising treatments for COVID-19. A prospective cohort study in which patients are divided into three groups. Group 1: moderate and severe COVID-19 patients received standard treatment; Group 2: moderate and severe COVID-19 patients received tocilizumab; Group 3: moderate and severe COVID-19 patients received treatment with infliximab and tocilizumab. 153 patients were recruited in the study. 40 received standard treatment alone, 70 received tocilizumab with standard treatment, and 43 received tocilizumab/infliximab with standard treatment. There was a significant difference in length of hospital stay (10.3, 8.9, and 7.6 days respectively P = 0.03), need for a non-invasive mechanical ventilator (4, 5, and one patient; P = 1.2E-8), intensive care admission (32, 45, and 16 patients; P = 2.5E-5), the occurrence of sepsis (18, 12, and 10 patients; P = 0.005) and in death (42.5%, 14.2%, and 7%; P = 0.0008) which were significantly lower in tocilizumab/infliximab group compared to tocilizumab and standard of care groups. Our study showed that tocilizumab/ infliximab in addition to standard of care was considered a promising treatment for moderate and severe COVID-19 patients.Trial registration number: ClinicalTrials.gov NCT04734678; date of registration: 02/02/2021.

Multiple infliximab biosimilar switches appear to be safe and effective in a real-world inflammatory bowel disease cohort.

BACKGROUND: Switching from originator infliximab (IFX) to biosimilar IFX is effective and safe. However, data on multiple switching are scarce. The Edinburgh inflammatory bowel disease (IBD) unit has undertaken three switch programmes: (1) Remicade to CT-P13 (2016), (2) CT-P13 to SB2 (2020), and (3) SB2 to CT-P13 (2021). OBJECTIVE: The primary endpoint of this study was to assess CT-P13 persistence following switch from SB2. Secondary endpoints included persistence stratified by the number of biosimilar switches (single, double and triple), effectiveness and safety. METHODS: We performed a prospective, observational, cohort study. All adult IBD patients on IFX biosimilar SB2 underwent an elective switch to CT-P13. Patients were reviewed in a virtual biologic clinic with protocol driven collection of clinical disease activity, C-reactive protein (CRP), faecal calprotectin (FC), IFX trough/antibody levels, and drug survival. RESULTS: 297 patients (CD n = 196 [66%], ulcerative colitis/inflammatory bowel disease unclassified n = 101, [34%]) were switched (followed-up: 7.5 months [6.8-8.1]). This was the third, second and first IFX switch for 67/297 (22.5%), 138/297 (46.5%) and 92/297 (31%) of the cohort respectively. 90.6% of patients remained on IFX during follow-up. The number of switches was not independently associated with IFX persistence after adjusting for confounders. Clinical (p = 0.77), biochemical (CRP ≤5 mg/ml; p = 0.75) and faecal biomarker (FC<250 µg/g; p = 0.63) remission were comparable at baseline, week 12 and week 24. CONCLUSION: Multiple successive switches from IFX originator to biosimilars are effective and safe in patients with IBD, irrespective of the number of IFX switches.

90K/Mac-2 BP Is a New Predictive Biomarker of Response to Infliximab Therapy in IBD Patients.

Inflammatory bowel diseases (IBD), comprising Crohn's disease (CD) and Ulcerative Colitis (UC), are multifactorial disorders characterized by a chronic inflammatory status with the secretion of cytokines and immune mediators. Biologic drugs targeting pro-inflammatory cytokines, such as infliximab, are broadly used in the treatment of IBD patients, but some patients lose responsiveness after an initial success. The research into new biomarkers is crucial for advancing personalized therapies and monitoring the response to biologics. The aim of this single center, observational study is to analyze the relationship between serum levels of 90K/Mac-2 BP and the response to infliximab, in a cohort of 48 IBD patients (30 CD and 18 UC), enrolled from February 2017 to December 2018. In our IBD cohort, high 90K serum levels were found at baseline in patients who then developed anti-infliximab antibodies at the fifth infusion (22 weeks after the first), becoming non-responders (9.76 ± 4.65 µg/mL compared to 6.53 ± 3.29 µg/mL in responder patients, p = 0.005). This difference was significant in the total cohort and in CD, but not significant in UC. We then analyzed the relationship between serum levels of 90K, C-reactive protein (CRP), and Fecal calprotectin. A significant positive correlation was found at baseline between 90K and CRP, the most common serum inflammation marker (R = 0.42, p = 0.0032). We concluded that circulating 90K could be considered a new non-invasive biomarker for monitoring the response to infliximab. Furthermore, 90K serum level determination, before the first infliximab infusion, in association with other inflammatory markers such as CRP, could assist in the choice of biologics for the treatment of IBD patients, thereby obviating the need for a drug switch due to loss of response, and so improving clinical practice and patient care.

Patient preferences and current practice for adults with steroid-resistant ulcerative colitis: POPSTER mixed-methods study.

BACKGROUND: Corticosteroids are a mainstay of the treatment of moderately severe relapses of ulcerative colitis, yet almost 50% of patients do not respond fully to these and risk prolonged steroid use and side effects. There is a lack of clarity about the definitions of steroid resistance, the optimum choice of treatment, and patient and health-care professional treatment preferences. OBJECTIVES: The overall aim of this research was to understand how steroid-resistant ulcerative colitis is managed in adult secondary care and how current practice compares with patient and health-care professional preferences. DESIGN: A mixed-methods study, including an online survey, qualitative interviews and discrete choice experiments. SETTING: NHS inflammatory bowel disease services in the UK. PARTICIPANTS: Adults with ulcerative colitis and health-care professionals treating inflammatory bowel disease. RESULTS: We carried out a survey of health-care professionals (n = 168), qualitative interviews with health-care professionals (n = 20) and patients (n = 33), discrete choice experiments with health-care professionals (n = 116) and patients (n = 115), and a multistakeholder workshop (n = 9). The interviews with and survey of health-care professionals showed that most health-care professionals define steroid resistance as an incomplete response to 40 mg per day of prednisolone after 2 weeks. The survey also found that anti-tumour necrosis factor drugs (particularly infliximab) are the most frequently offered drugs across most steroid-resistant (and steroid-dependent) patient scenarios, but they are less frequently offered to thiopurine-naive patients. Patient interviews identified several factors influencing their treatment choices, including effectiveness of treatment, recommendations from health-care professionals, route of administration and side effects. Over time, depending on the severity and duration of symptoms and, crucially, as medical treatment options become exhausted, patients are willing to try alternative treatments and, eventually, to undergo surgery. The discrete choice experiments found that the probability of remission and of side effects strongly influences the treatment choices of both patients and health-care professionals. Patients are less likely to choose a treatment that takes longer to improve symptoms. Health-care professionals are willing to make difficult compromises by tolerating greater safety risks in exchange for therapeutic benefits. The treatments ranked most positively by patients were infliximab and tofacitinib (each preferred by 38% of patients), and the predicted probability of uptake by health-care professionals was greatest for infliximab (62%). LIMITATIONS: The survey and the discrete choice experiments with patients and health-care professionals are limited by their relatively small sample sizes. The qualitative studies are subject to selection bias. The timing of the different substudies, both before and during the COVID-19 pandemic, is a potential limitation. CONCLUSIONS: We have identified factors influencing treatment decisions for steroid-resistant ulcerative colitis and the characteristics to consider when choosing treatments to evaluate in future randomised controlled trials. The findings may be used to improve discussions between patients and health-care professionals when they review treatment options for steroid-resistant ulcerative colitis. FUTURE WORK: This research highlights the need for consensus work to establish an agreed definition of steroid resistance in ulcerative colitis and a greater understanding of the optimal use of tofacitinib and surgery for this patient group. A randomised controlled trial comparing infliximab with tofacitinib is also recommended. FUNDING: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 41. See the NIHR Journals Library website for further project information.

Steroids are one of the main treatments for ulcerative colitis; however, steroids work well for only about 50% of people who take them. There are many other treatments that can be given when steroids do not work, but evidence is limited about how these treatments are best used. To carry out better research about the best treatment options and to improve clinical practice in the future, this study aimed to find out how adults with steroid-resistant ulcerative colitis are managed in hospital and why patients and health-care professionals prefer different treatments. The study combined various methods of research, including an online survey of health-care professionals (n = 168), interviews with health-care professionals (n = 20) and patients (n = 33), a survey of health-care professionals (n = 116) and patients (n = 115) to ask them about treatment preferences, and a multistakeholder workshop (n = 9). The interviews with and survey of health-care professionals found that most health-care professionals define steroid resistance as an incomplete response to 40 mg per day of prednisolone after 2 weeks. The survey also found that the most frequently offered drugs are anti-tumour necrosis factor drugs (particularly infliximab). Patient interviews found that several factors influenced treatment choices, including effectiveness of treament, guidance from health-care professionals, route of administration and side effects. Patients were willing to try alternative treatments and surgery over time. The survey found that a higher level of remission and a lower chance of side effects strongly influenced treatment choices. Patients are less likely to choose a treatment that takes longer to improve symptoms. Health-care professionals are willing to make difficult compromises by tolerating greater safety risks in exchange for therapeutic benefits. Infliximab and tofacitinib were ranked most positively by patients, and the predicted uptake by health-care professionals was greatest for infliximab. The results of this study help improve understanding of why people choose certain treatments, improve decision-making in partnership and inform the design of future research.

Neutralising antibody potency against SARS-CoV-2 wild-type and omicron BA.1 and BA.4/5 variants in patients with inflammatory bowel disease treated with infliximab and vedolizumab after three doses of COVID-19 vaccine (CLARITY IBD): an analysis of a prospective multicentre cohort study.

BACKGROUND: Anti-TNF drugs, such as infliximab, are associated with attenuated antibody responses after SARS-CoV-2 vaccination. We aimed to determine how the anti-TNF drug infliximab and the anti-integrin drug vedolizumab affect vaccine-induced neutralising antibodies against highly transmissible omicron (B.1.1.529) BA.1, and BA.4 and BA.5 (hereafter BA.4/5) SARS-CoV-2 variants, which possess the ability to evade host immunity and, together with emerging sublineages, are now the dominating variants causing current waves of infection. METHODS: CLARITY IBD is a prospective, multicentre, observational cohort study investigating the effect of infliximab and vedolizumab on SARS-CoV-2 infection and vaccination in patients with inflammatory bowel disease (IBD). Patients aged 5 years and older with a diagnosis of IBD and being treated with infliximab or vedolizumab for 6 weeks or longer were recruited from infusion units at 92 hospitals in the UK. In this analysis, we included participants who had received uninterrupted biological therapy since recruitment and without a previous SARS-CoV-2 infection. The primary outcome was neutralising antibody responses against SARS-CoV-2 wild-type and omicron subvariants BA.1 and BA.4/5 after three doses of SARS-CoV-2 vaccine. We constructed Cox proportional hazards models to investigate the risk of breakthrough infection in relation to neutralising antibody titres. The study is registered with the ISRCTN registry, ISRCTN45176516, and is closed to accrual. FINDINGS: Between Sept 22 and Dec 23, 2020, 7224 patients with IBD were recruited to the CLARITY IBD study, of whom 1288 had no previous SARS-CoV-2 infection after three doses of SARS-CoV-2 vaccine and were established on either infliximab (n=871) or vedolizumab (n=417) and included in this study (median age was 46·1 years [IQR 33·6-58·2], 610 [47·4%] were female, 671 [52·1%] were male, 1209 [93·9%] were White, and 46 [3·6%] were Asian). After three doses of SARS-CoV-2 vaccine, 50% neutralising titres (NT50s) were significantly lower in patients treated with infliximab than in those treated with vedolizumab, against wild-type (geometric mean 2062 [95% CI 1720-2473] vs 3440 [2939-4026]; p<0·0001), BA.1 (107·3 [86·40-133·2] vs 648·9 [523·5-804·5]; p<0·0001), and BA.4/5 (40·63 [31·99-51·60] vs 223·0 [183·1-271·4]; p<0·0001) variants. Breakthrough infection was significantly more frequent in patients treated with infliximab (119 [13·7%; 95% CI 11·5-16·2] of 871) than in those treated with vedolizumab (29 [7·0% [4·8-10·0] of 417; p=0·00040). Cox proportional hazards models of time to breakthrough infection after the third dose of vaccine showed infliximab treatment to be associated with a higher hazard risk than treatment with vedolizumab (hazard ratio [HR] 1·71 [95% CI 1·08-2·71]; p=0·022). Among participants who had a breakthrough infection, we found that higher neutralising antibody titres against BA.4/5 were associated with a lower hazard risk and, hence, a longer time to breakthrough infection (HR 0·87 [0·79-0·95]; p=0·0028). INTERPRETATION: Our findings underline the importance of continued SARS-CoV-2 vaccination programmes, including second-generation bivalent vaccines, especially in patient subgroups where vaccine immunogenicity and efficacy might be reduced, such as those on anti-TNF therapies. FUNDING: Royal Devon University Healthcare NHS Foundation Trust; Hull University Teaching Hospital NHS Trust; NIHR Imperial Biomedical Research Centre; Crohn's and Colitis UK; Guts UK; National Core Studies Immunity Programme, UK Research and Innovation; and unrestricted educational grants from F Hoffmann-La Roche, Biogen, Celltrion Healthcare, Takeda, and Galapagos.

Evaluation of the frequency and intensity of COVID-19 in patients with ankylosing spondylitis under anti-TNF therapy.

BACKGROUND: Dear Editor, After the coronavirus disease 2019 (COVID-19) pandemic affected the whole world, rheumatologists began to think about how COVID-19 will progress in patients with inflammatory conditions. High cytokine levels play a role in the pathophysiology of COVID-19 infection. Tumor necrosis factor alpha (TNF-α) is a proinflammatory cytokine known to have a key role in the pathogenesis of chronic immune-mediated diseases. AntiTNF therapy may cause an increase in active tuberculosis, other granulomatous diseases, and serious infections [1]. According to many studies, rheumatological diseases have not been identified as a risk factor for severe COVID-19 infection [2]. Should significantly increased cytokine levels during COVID-19 infection make us consider anticytokine therapies that may be used in the treatment of patients with COVID-19 a risk? We aimed to explore whether the frequency of COVID-19 infection increased, the effect of comorbidities on the frequency of infection, and whether the severity of the disease and need for intensive care support increased in patients who used anti-TNF agents. We performed a retrospective case-control study between March and December 2020 in Sakarya University Training and Research Hospital. Retrospectively, we evaluated whether there was a difference in the frequency and severity of COVID-19 in our patients diagnosed with ankylosing spondylitis (AS), 77 of whom were using anti-TNF and 49 of whom didn't use anti-TNF. Hospitalization and intensive care unit (ICU) requirements were evaluated as endpoints. In the anti-TNF group, patients used adalimumab, etanercept, certolizumab, infliximab, and golimumab. Patients were questioned at an outpatient clinic in person or by phone. Seventy-seven patients with AS using anti-TNF agents (58 males, 19 females) and 49 patients with AS (38 males, 11 females) not using anti-TNF agents were included in the study (p = 0.943). Mean age of patients using antiTNF agents was 41.53 ± 10.38, and mean age of patients not using anti-TNF agents was 42.94 ± 10.86 (p = 0.468). Thirty-three (42.9%) patients were smokers in the antiTNF group, while 23 (46.9%) patients were smokers in the group not using TNFi (p = 0.791). There was 12 pack-year smoking in the anti-TNF group, and 14 pack-year smoking in not using TNFi (p = 0.623). The frequency of diabetes mellitus (DM), hypertension (HT), amiloidosis, familial mediterranean fever (FMF), coronary artery disease (CAD), chronic obstructive pulmonary disease (COPD) was similar in both groups (p = 0.403, p = 0.999, p = 0.521, p = 0.999, p = 0.999, respectively). Six patients using TNFi and 3 patients not using TNFi recovered from COVID-19 infection. However, this result was not statistically significant (p = 0.999). One patient using anti-TNF was hospitalized but with no need for admission to the ICU (p = 0.999). All 9 patients recovering from COVID-19 were male (p = 0.113). There were 2 (22.2%) smokers in the SARS-CoV-2 positive group and 54 (46.2%) smokers in SARS-CoV-2 negative group (p = 0.297). There was 37.5 pack-year smoking in SARS-CoV-2 positive group, and 12 pack-year smoking in SARS-CoV-2 negative group (p = 0.151). Nobody has comorbidities (DM, HT, amiloidosis, FMF, CAD, COPD) in SARS-CoV-2 positive group. There were patients with DM (5.1%), HT (15.4%), amiloidosis (1.7%), FMF (1.7%), CAD (0.9%) and COPD (0.9%) in SARS-CoV-2 negative group (p = 0.999, p = 0.356, p = 0.999, p = 0.999, p = 0.999, p = 0.999, respectively). Having comorbidities was not detected to be associated with frequency of COVID-19. 31 (40.3%) patients were using adalimumab, 25 (32.5%) patients were using etanercept, 13 patients were using (16.9%) certolizumab, 6 (7.8%) patients were using golimumab, and 2 patients (2.6%) were using infliximab in TNF group. Six patients using anti-TNF (2 adalimumab, 1 etanercept, 1 golimumab,2 infliximab) and 3 nonuser patients recovered from COVID-19 (p = 0.999). No statistically significant difference was found between SARS-CoV-2 positive and negative patients in terms of the types of anti TNF they used. Patients were called in March 2020, and they were advised to terminate their anti-TNF therapy, when the COVID-19 pandemic began. Among those who used antiTNF, 2 (33.3%) people who had COVID-19 and 38 (53.5%) people who did not have COVID-19 interrupted treatment (p = 0.419). Anti-TNF users who did not have COVID-19 stopped taking the treatment for an average of 3 months (min 2-max 4 months) starting from March 2020, and the patients who had COVID-19 (p = 0.102) stopped taking the treatment for 1.5 months (min 1-max 2 months). Duration of interrupting TNFi was not significant for the risk of COVID-19. Comorbidities, older age, and the presence of active disease have been associated with worse outcomes in previous studies [3]. In our study, the anti-TNF using and the nonuser groups were similar according to age, sex, and comorbidities. Although comorbidities in COVID-19 are associated with severe disease in the literature, we did not find a significant difference in our study. This result is probably related to our insufficient number of patients. As a result, we found that the use of anti-TNF did not increase the frequency and severity of COVID-19. In a recently published multicenter study, it was stated that the use of biological DMARDs in patients with inflammatory rheumatic diseases was not significantly associated with a worse outcome of COVID-19. But unlike our study, having no comorbidities was associated with a decreased risk of a worse outcome [4]. There are currently studies investigating the therapeutic utility of infliximab and adalimumab in hospitalized COVID-19 patients [5]. The results of these studies are very important. The usability of TNFi in treatment and at which stage of the disease anti-TNF agents can be used are wondered. We will see the course of the disease all over the world after the administration of the COVID-19 vaccines, but we still need more information about effective and safe treatment. RESULTS: The authors declare that there is no conflict of interest. DISCUSSION: The authors did not receive support from any organization for this work.

COVID-19 vaccine-induced antibody and T-cell responses in immunosuppressed patients with inflammatory bowel disease after the third vaccine dose (VIP): a multicentre, prospective, case-control study.

BACKGROUND: COVID-19 vaccine-induced antibody responses are reduced in patients with inflammatory bowel disease (IBD) taking anti-TNF or tofacitinib after two vaccine doses. We sought to assess whether immunosuppressive treatments were associated with reduced antibody and T-cell responses in patients with IBD after a third vaccine dose. METHODS: VIP was a multicentre, prospective, case-control study done in nine centres in the UK. We recruited immunosuppressed patients with IBD and non-immunosuppressed healthy individuals. All participants were aged 18 years or older. The healthy control group had no diagnosis of IBD and no current treatment with systemic immunosuppressive therapy for any other indication. The immunosuppressed patients with IBD had an established diagnosis of Crohn's disease, ulcerative colitis, or unclassified IBD using standard definitions of IBD, and were receiving established treatment with one of six immunosuppressive regimens for at least 12 weeks at the time of first dose of SARS-CoV-2 vaccination. All participants had to have received three doses of an approved COVID-19 vaccine. SARS-CoV-2 spike antibody binding and T-cell responses were measured in all participant groups. The primary outcome was anti-SARS-CoV-2 spike (S1 receptor binding domain [RBD]) antibody concentration 28-49 days after the third vaccine dose, adjusted by age, homologous versus heterologous vaccine schedule, and previous SARS-CoV-2 infection. The primary outcome was assessed in all participants with available data. FINDINGS: Between Oct 18, 2021, and March 29, 2022, 352 participants were included in the study (thiopurine n=65, infliximab n=46, thiopurine plus infliximab combination therapy n=49, ustekinumab n=44, vedolizumab n=50, tofacitinib n=26, and healthy controls n=72). Geometric mean anti-SARS-CoV-2 S1 RBD antibody concentrations increased in all groups following a third vaccine dose, but were significantly lower in patients treated with infliximab (2736·8 U/mL [geometric SD 4·3]; p<0·0001), infliximab plus thiopurine (1818·3 U/mL [6·7]; p<0·0001), and tofacitinib (8071·5 U/mL [3·1]; p=0·0018) compared with the healthy control group (16 774·2 U/mL [2·6]). There were no significant differences in anti-SARS-CoV-2 S1 RBD antibody concentrations between the healthy control group and patients treated with thiopurine (12 019·7 U/mL [2·2]; p=0·099), ustekinumab (11 089·3 U/mL [2·8]; p=0·060), or vedolizumab (13 564·9 U/mL [2·4]; p=0·27). In multivariable modelling, lower anti-SARS-CoV-2 S1 RBD antibody concentrations were independently associated with infliximab (geometric mean ratio 0·15 [95% CI 0·11-0·21]; p<0·0001), tofacitinib (0·52 [CI 0·31-0·87]; p=0·012), and thiopurine (0·69 [0·51-0·95]; p=0·021), but not with ustekinumab (0·64 [0·39-1·06]; p=0·083), or vedolizumab (0·84 [0·54-1·30]; p=0·43). Previous SARS-CoV-2 infection (1·58 [1·22-2·05]; p=0·0006) was independently associated with higher anti-SARS-CoV-2 S1 RBD antibody concentrations and older age (0·88 [0·80-0·97]; p=0·0073) was independently associated with lower anti-SARS-CoV-2 S1 RBD antibody concentrations. Antigen-specific T-cell responses were similar in all groups, except for recipients of tofacitinib without evidence of previous infection, where T-cell responses were significantly reduced relative to healthy controls (p=0·021). INTERPRETATION: A third dose of COVID-19 vaccine induced a boost in antibody binding in immunosuppressed patients with IBD, but these responses were reduced in patients taking infliximab, infliximab plus thiopurine, and tofacitinib. Tofacitinib was also associated with reduced T-cell responses. These findings support continued prioritisation of immunosuppressed groups for further vaccine booster dosing, particularly patients on anti-TNF and JAK inhibitors. FUNDING: Pfizer.

Re-Routing Infliximab Therapy: Subcutaneous Infliximab Opens a Path Towards Greater Convenience and Clinical Benefit.

Subcutaneous infliximab recently received approval for the treatment of various immune-mediated inflammatory diseases in Europe, following pivotal clinical trials in patients with rheumatoid arthritis and inflammatory bowel disease. Subcutaneous infliximab demonstrated an improved pharmacokinetic profile compared with intravenous infliximab: the more stable exposure and increased systemic drug concentrations mean it has been cited as a biobetter. Alongside the pharmacokinetic advantages, potential benefits for efficacy, immunogenicity, and health-related quality-of-life outcomes have been suggested with subcutaneous infliximab. During the coronavirus disease 2019 pandemic, the benefits of subcutaneous over intravenous therapies became apparent: switching from intravenous to subcutaneous infliximab reduced the hospital visit-related healthcare resource burden and potential viral transmission. Clinical advantages observed in pivotal trials are also being seen in the real world. Accumulating experience from four European countries (the UK, Spain, France, and Germany) in patients with rheumatic diseases and inflammatory bowel disease supports clinical trial findings that subcutaneous infliximab is well tolerated, increases serum drug concentrations, and offers maintained or improved efficacy outcomes for patients switching from intravenous infliximab. Initial evidence is emerging with subcutaneous infliximab treatment after intravenous infliximab failure. High patient satisfaction and pharmacoeconomic benefits have also been reported with subcutaneous infliximab. Treatments aligned with patient preferences for the flexibility and convenience of at-home subcutaneous administration could boost adherence and treatment outcomes. Altogether, findings suggest that switching from intravenous to subcutaneous infliximab could be advantageous, and healthcare professionals should be prepared to discuss supporting data as part of shared decision making during patient consultations.

The tumor necrosis factor inhibitor infliximab is one treatment option that may be appropriate for patients with immune-mediated inflammatory diseases. Patients may prefer tumor necrosis factor inhibitors administered via the subcutaneous (SC) or intravenous (IV) route, with preferences influencing treatment satisfaction and outcomes. In 2019, CT-P13 SC became the first SC infliximab product to receive regulatory approval in Europe, based on pivotal clinical studies that compared SC infliximab to IV infliximab in patients with rheumatoid arthritis and inflammatory bowel disease. Subcutaneous infliximab is now approved in Europe for the treatment of adults with rheumatoid arthritis, Crohn's disease, ulcerative colitis, ankylosing spondylitis, psoriatic arthritis, and psoriasis. Patients began to switch from IV to SC infliximab outside clinical trials in March 2020, during the coronavirus disease 2019 pandemic. Switching from IV to SC infliximab allowed patients to self-administer treatment at home rather than attend hospital for infusions, reducing potential hospital-acquired infections and lessening the strain on healthcare systems during the pandemic. Clinical trial evidence and growing real-world experience demonstrate that SC infliximab offers clinical advantages in terms of an improved pharmacokinetic profile and potential efficacy, immunogenicity, and health-related quality-of-life benefits compared with IV infliximab. Patients have also reported increased satisfaction with SC infliximab after switching from IV infliximab. Together with the long-standing flexibility and convenience benefits of SC administration, the clinical advantages of SC infliximab make it a valid therapeutic option for rheumatoid arthritis and inflammatory bowel disease. This warrants discussion with appropriate patients as part of shared treatment decision making.

Artesunate, imatinib, and infliximab in COVID-19: A rapid review and meta-analysis of current evidence.

BACKGROUND AND OBJECTIVE: Despite the pervasive vaccination program against coronavirus disease 2019 (COVID-19), fully vaccinated people are still being infected by severe acute respiratory syndrome coronavirus 2, making an effective and safe therapeutic intervention a crucial need for the patients' survival. The purpose of the present study is to seek available evidence for the efficacy and safety of three promising medications artesunate, imatinib, and infliximab against COVID-19. METHODS: A literature search was conducted in PubMed, Cochrane Library, medRxive, and Google Scholar up to January 2022. Furthermore, the clinical trial databases were screened to find more citations. The Cochrane Collaboration tool and Newcastle-Ottawa scale were used to assess the included studies. Meta-analysis was performed using RevMan 5.4.1. RESULTS: Five published studies were identified as eligible. Meta-analysis showed that there was no significant difference between the infliximab and control groups in terms of mortality rate (risk ratio [RR]: 0.65; 95% confidence interval [CI]: 0.40-1.07; p = 0.09). However, a significant difference was observed between the two groups for the hospital discharge (RR: 1.37; 95% CI: 1.04-1.80; p = 0.03). No remarkable clinical benefit was observed in favor of using imatinib for COVID-19 patients. Artesunate showed significant improvement in patients with COVID-19. CONCLUSION: In the present, limited evidence exists for the efficacy and safety of artesunate, imatinib, and infliximab in patients with COVID-19. The findings of WHO's Solidarity international trial will provide further information regarding these therapeutic interventions.

Preserved SARS-CoV-2 Vaccine Cell-Mediated Immunogenicity in Patients With Inflammatory Bowel Disease on Immune-Modulating Therapies.

Immune-modulating medications for inflammatory bowel diseases (IBDs) have been associated with suboptimal vaccine responses. There are conflicting data with SARS-CoV-2 vaccination. We therefore assessed SARS-CoV-2 vaccine immunogenicity at 2 weeks after second mRNA vaccination in 29 patients with IBD compared with 12 normal healthy donors. We observed reduced humoral immunity in patients with IBD on infliximab. However, we observed no difference in humoral and cell-mediated immunity in patients with IBD on infliximab with a thiopurine or vedolizumab compared with normal healthy donors. This is the first study to demonstrate comparable cell-mediated immunity with SARS-CoV-2 vaccination in patients with IBD treated with different immune-modulating medications.

Kawasaki Disease with Peripheral and Facial Gangrene: A Case report and review of literature.

With the onset of the SARS-CoV-2 pandemic, Kawasaki Disease (KD) has come to the fore with its many atypical manifestations. Atypical clinical neurological, ophthalmological, musculoskeletal, gastrointestinal and pulmonary manifestations in a febrile child with raised markers should prompt the clinician to think of Kawasaki disease. Peripheral gangrene is a rare atypical manifestation of KD reported in infancy. We present a three-and-a-half-year-old boy with extensive gangrene all four limbs and face along with purpura fulminans. He was successfully treated with two doses of intravenous immunoglobulin (IVIG) and infliximab, with no residual gangrene. This case highlights that very severe forms of Kawasaki disease require IVIG, pulse steroids as well as infliximab for adequate control and complete resolution of the disease.

Antibody decay, T cell immunity and breakthrough infections following two SARS-CoV-2 vaccine doses in inflammatory bowel disease patients treated with infliximab and vedolizumab.

Anti tumour necrosis factor (anti-TNF) drugs increase the risk of serious respiratory infection and impair protective immunity following pneumococcal and influenza vaccination. Here we report SARS-CoV-2 vaccine-induced immune responses and breakthrough infections in patients with inflammatory bowel disease, who are treated either with the anti-TNF antibody, infliximab, or with vedolizumab targeting a gut-specific anti-integrin that does not impair systemic immunity. Geometric mean [SD] anti-S RBD antibody concentrations are lower and half-lives shorter in patients treated with infliximab than vedolizumab, following two doses of BNT162b2 (566.7 U/mL [6.2] vs 4555.3 U/mL [5.4], p <0.0001; 26.8 days [95% CI 26.2 - 27.5] vs 47.6 days [45.5 - 49.8], p <0.0001); similar results are also observed with ChAdOx1 nCoV-19 vaccination (184.7 U/mL [5.0] vs 784.0 U/mL [3.5], p <0.0001; 35.9 days [34.9 - 36.8] vs 58.0 days [55.0 - 61.3], p value < 0.0001). One fifth of patients fail to mount a T cell response in both treatment groups. Breakthrough SARS-CoV-2 infections are more frequent (5.8% (201/3441) vs 3.9% (66/1682), p = 0.0039) in patients treated with infliximab than vedolizumab, and the risk of breakthrough SARS-CoV-2 infection is predicted by peak anti-S RBD antibody concentration after two vaccine doses. Irrespective of the treatments, higher, more sustained antibody levels are observed in patients with a history of SARS-CoV-2 infection prior to vaccination. Our results thus suggest that adapted vaccination schedules may be required to induce immunity in at-risk, anti-TNF-treated patients.

Infliximab treatment for refractory COVID-19-associated multisystem inflammatory syndrome in a Japanese child.

Patients with multisystem inflammatory syndrome in children (MIS-C) can develop clinical features resembling Kawasaki disease (KD). A full picture of MIS-C in East Asia which has higher incidence of KD than other regions remains unclear. We report on a 15-year-old Japanese boy with refractory MIS-C who was successfully treated with infliximab. A Japanese boy who was diagnosed with coronavirus disease 2019 (COVID-19) before a month developed MIS-C with fulfilling six principal symptoms of KD. Laboratory data showed extreme hyperferritinemia (11,404 ng/mL), besides lymphopenia and thrombocytopenia. The patient was refractory to initial therapy with intravenous immunoglobulin (IVIG; 2 g/kg), aspirin, and prednisolone. He was therefore administered a second IVIG (2 g/kg) and infliximab (5 mg/kg) on days 7 and 8 from the onset of fever, respectively, which resulted in an improvement of clinical symptoms. Only four Japanese cases with MIS-C were reported and all of them were responsive to IVIG. The hyperferritinemia in this case was distinctive from previously reported MIS-C cases in Japan and other cohorts and may be associated with refractoriness to IVIG therapy. Marked elevation of circulating ferritin levels is known to be induced by tumor necrosis factor-α, which plays a key role in the pathogenesis of both KD and MIS-C. Thus, for MIS-C patients with hyperferritinemia, early intervention with adjunctive infliximab may induce a more rapid resolution of inflammation and improve outcome. Because MIS-C may be heterogeneous with respect to immunopathology, genetic background, clinical phenotypes and response to therapies, optimized treatment strategies according to immunopathogenesis are required.

Nationwide cross-sectional survey of patients with relapsing polychondritis in 2019 demonstrates reduction of airway involvement compared with that in 2009.

We conducted retrospective cohort studies of patients with relapsing polychondritis (RP) twice in 2009 and 2019, using a physician questionnaire. We compared the patients' clinical statuses between the years. Age and gender were comparable between the two surveys. Mean disease duration was longer in 2019 survey (8.3 years) than that in 2009 survey (4.8 years, P < 0.001). The mortality rate declined in 2019 survey compared with those in 2009 survey (from 9.2 to 1.6%, P < 0.001). Incidence of airway involvement decreased in 2019 survey compared with that in 2009 survey (from 49 to 37%, P = 0.012). In 2019 survey, we found more frequent use of biological agents and immunosuppressants in patients with airway involvement. When we focused on RP patients with airway involvement, physicians in 2019 chose methotrexate and calcineurin inhibitors preferentially, compared with azathioprine and cyclophosphamide. Of note is that increased use of infliximab was observed in RP patients with airway involvement, but not in those without. Reduction of airway involvement and mortality in patients with RP was observed in 2019 survey. The reduction may associate with the frequent use of biologics including infliximab in RP patients with airway involvement.

Perspectives on Subcutaneous Infliximab for Rheumatic Diseases and Inflammatory Bowel Disease: Before, During, and After the COVID-19 Era.

The coronavirus disease 2019 (COVID-19) pandemic has prompted significant changes in patient care in rheumatology and gastroenterology, with clinical guidance issued to manage ongoing therapy while minimising the risk of nosocomial infection for patients and healthcare professionals (HCPs). Subcutaneous (SC) formulations of biologics enable patients to self-administer treatments at home; however, switching between agents may be undesirable. CT-P13 SC is the first SC formulation of infliximab that received regulatory approval and may be termed a biobetter as it offers significant clinical advantages over intravenous (IV) infliximab, including improved pharmacokinetics and a convenient mode of delivery. Potential benefits in terms of reduced immunogenicity have also been suggested. With a new SC formulation, infliximab provides an additional option for dual formulation, which enables patients to transition from IV to SC administration route without changing agent. Before COVID-19, clinical trials supported the efficacy and safety of switching from IV to SC infliximab for patients with rheumatoid arthritis and inflammatory bowel disease (IBD), and SC infliximab may have been selected on the basis of patient and HCP preferences for SC agents. During the pandemic, patients with rheumatic diseases and IBD have successfully switched from IV to SC infliximab, with some clinical benefits and high levels of patient satisfaction. As patients switched to SC therapeutics, the reduction in resource requirements for IV infusion services may have been particularly welcome given the pandemic, facilitating reorganisation and redeployment in overstretched healthcare systems, alongside pharmacoeconomic benefits and a reduction in exposure to nosocomial infection. Telemedicine and contactless healthcare have been pushed to the forefront during the pandemic, and a lasting shift towards remote patient management and community/home-based drug administration is anticipated. SC infliximab supports the implementation of this paradigm for future improvements of healthcare value delivered. The accumulation of real-world data during the pandemic supports the high level of confidence, with patients, physicians, and healthcare systems benefitting from its uptake.

Namilumab or infliximab compared with standard of care in hospitalised patients with COVID-19 (CATALYST): a randomised, multicentre, multi-arm, multistage, open-label, adaptive, phase 2, proof-of-concept trial.

BACKGROUND: Dysregulated inflammation is associated with poor outcomes in COVID-19. We aimed to assess the efficacy of namilumab (a granulocyte-macrophage colony stimulating factor inhibitor) and infliximab (a tumour necrosis factor inhibitor) in hospitalised patients with COVID-19, to prioritise agents for phase 3 trials. METHODS: In this randomised, multicentre, multi-arm, multistage, parallel-group, open-label, adaptive, phase 2, proof-of-concept trial (CATALYST), we recruited patients (aged ≥16 years) admitted to hospital with COVID-19 pneumonia and C-reactive protein (CRP) concentrations of 40 mg/L or greater, at nine hospitals in the UK. Participants were randomly assigned with equal probability to usual care or usual care plus a single intravenous dose of namilumab (150 mg) or infliximab (5 mg/kg). Randomisation was stratified by care location within the hospital (ward vs intensive care unit [ICU]). Patients and investigators were not masked to treatment allocation. The primary endpoint was improvement in inflammation, measured by CRP concentration over time, analysed using Bayesian multilevel models. This trial is now complete and is registered with ISRCTN, 40580903. FINDINGS: Between June 15, 2020, and Feb 18, 2021, we screened 299 patients and 146 were enrolled and randomly assigned to usual care (n=54), namilumab (n=57), or infliximab (n=35). For the primary outcome, 45 patients in the usual care group were compared with 52 in the namilumab group, and 29 in the usual care group were compared with 28 in the infliximab group. The probabilities that the interventions were superior to usual care alone in reducing CRP concentration over time were 97% for namilumab and 15% for infliximab; the point estimates for treatment-time interactions were -0·09 (95% CI -0·19 to 0·00) for namilumab and 0·06 (-0·05 to 0·17) for infliximab. 134 adverse events occurred in 30 (55%) of 55 patients in the namilumab group compared with 145 in 29 (54%) of 54 in the usual care group. 102 adverse events occurred in 20 (69%) of 29 patients in the infliximab group compared with 112 in 17 (50%) of 34 in the usual care group. Death occurred in six (11%) patients in the namilumab group compared with ten (19%) in the usual care group, and in four (14%) in the infliximab group compared with five (15%) in the usual care group. INTERPRETATION: Namilumab, but not infliximab, showed proof-of-concept evidence for reduction in inflammation-as measured by CRP concentration-in hospitalised patients with COVID-19 pneumonia. Namilumab should be prioritised for further investigation in COVID-19. FUNDING: Medical Research Council.

Impairment of CD4+ T and Memory B Cell Responses but Normal Memory CD8+T-Cell Activation on Crohn's Disease after COVID-19 Vaccination: A Twin Case.

Vaccines to prevent the impact of SARS-CoV-2 are now available, including for patients with autoimmune diseases. However, there is no information about how inflammatory bowel disease (IBD) treatment could impact the cellular and humoral immune responses. This study evaluated SARS-CoV-2-specific humoral and cellular responses after vaccination with a two-dose schedule in a Crohn's disease patient treated with Infliximab (10 mg/kg); we included comparisons with a monozygotic twin. The results showed that the Crohn's disease's twin (twin 2) had no antibody detection and reduced activation of CD4+ T cell responses, unlike the twin without the autoimmune disease (twin 1). Twin 2 developed antigen-specific central memory CD8+ T-cells and IFNγ production after the second dose of COVID-19 vaccination, similar to twin 1. These findings elucidated the role of T-cell immunity after COVID-19 immunization on IBD patients despite the lack of antibody production. Finally, our observation supports the consensus recommendation for IBD patients to receive COVID-19 vaccines.

Harnessing autophagy to fight SARS-CoV-2: An update in view of recent drug development efforts.

Drug repurposing is an attractive option for identifying new treatment strategies, in particular in extraordinary situations of urgent need such as the current coronavirus disease 2019 (Covid-19) pandemic. Recently, the World Health Organization announced testing of three drugs as potential Covid-19 therapeutics that are known for their dampening effect on the immune system. Thus, the underlying concept of selecting these drugs is to temper the potentially life-threatening overshooting of the immune system reacting to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. This viewpoint discusses the possibility that the impact of these and other drugs on autophagy contributes to their therapeutic effect by hampering the SARS-CoV-2 life cycle.