Drug safety evaluation of ixekizumab for psoriasis: a review of the current knowledge.

INTRODUCTION: Since Anti-IL-17s availability, concerns about their safety have been raised due to the inhibition of physiological activities that IL-17A plays in the immune response against infections. Ixekizumab is a humanized monoclonal antibody specifically targeting IL-17A approved for the treatment of moderate-to-severe psoriasis. AREAS COVERED: The aim of this review is to evaluate the safety profile of ixekizumab in moderate-to-severe psoriasis patients. A compressive literature review has included articles since March 2022. EXPERT OPINION: In our analysis, most of the reported AEs were mild or moderate and rarely required treatment discontinuation. Among the class-specific AEs to consider during ixekizumab treatment, there are the risk of Candida infections and the risk of IBD, both of which were reported more frequently than placebo or other biologics (etanercept, ustekinumab, and guselkumab). However, the reported candidiasis resulted in mild-to-moderate and easily managed. The risk of IBD (both exacerbation and de novo diagnosis) represents a class effect of IL-17 inhibitors, which should be well evaluated before considering starting ixekizumab treatment. The most common AEs were represented by nasopharyngitis, upper respiratory tract infection, and injection-site reactions. The analyzed studies confirmed the favorable safety profile of ixekizumab even in more recently published studies.

Treatment adaptations and outcomes of patients experiencing inflammatory bowel disease flares during the early COVID-19 pandemic: the PREPARE-IBD multicentre cohort study.

BACKGROUND: The COVID-19 pandemic offered a unique opportunity to understand inflammatory bowel disease (IBD) management during unexpected disruption. This could help to guide practice overall. AIMS: To compare prescribing behaviour for IBD flares and outcomes during the early pandemic with pre-pandemic findings METHODS: We performed an observational cohort study comprising patients who contacted IBD teams for symptomatic flares between March and June 2020 in 60 National Health Service trusts in the United Kingdom. Data were compared with a pre-pandemic cohort after propensity-matching for age and physician global assessment of disease activity. RESULTS: We included 1864 patients in each of the pandemic and pre-pandemic cohorts. The principal findings were reduced systemic corticosteroid prescription during the pandemic in Crohn's disease (prednisolone: pandemic 26.5% vs. 37.1%; p < 0.001) and ulcerative colitis (UC) (prednisolone: pandemic 33.5% vs. 40.7%, p < 0.001), with increases in poorly bioavailable oral corticosteroids in Crohn's (pandemic 15.6% vs. 6.8%; p < 0.001) and UC (pandemic 11.8% vs. 5.2%; p < 0.001). Ustekinumab (Crohn's and UC) and vedolizumab (UC) treatment also significantly increased. Three-month steroid-free remission in each period was similar in Crohn's (pandemic 28.4% vs. 32.1%; p = 0.17) and UC (pandemic 36.4% vs. 40.2%; p = 0.095). Patients experiencing a flare and suspected COVID-19 were more likely to have moderately-to-severely active disease at 3 months than those with a flare alone. CONCLUSIONS: Despite treatment adaptations during the pandemic, steroid-free outcomes were comparable with pre-pandemic levels, although concurrent flare and suspected COVID-19 caused worse outcomes. These findings have implications for IBD management during future pandemics and for standard practice.

Impact of Immunotherapies on SARS-CoV-2-Infections and Other Respiratory Tract Infections during the COVID-19 Winter Season in IBD Patients.

Background: COVID-19 represents one of the most significant medical problems of our time. Aims: This study is focused on the question whether patients with inflammatory bowel disease (IBD) who receive immunotherapies are more vulnerable to respiratory tract infections and SARS-CoV-2 infections in comparison to medical staff, as a cohort with an increased infection risk, and to the general population in a COVID-19 hotspot. Methods: We analysed data regarding respiratory tract infections that were collected in our IBD registry and compared them with corresponding data from medical employees in our associated Isarklinikum hospital and from the healthy general population in Munich, Germany, over the same time frame in April and June 2020. Patients were tested for SARS-CoV-2 immunoglobulins (Ig). Results: Symptoms of respiratory tract infections occurred equally frequent in IBD patients with immunotherapies as compared to those without. Older age (>49 years), TNF-inhibitor, and ustekinumab treatment showed a significantly protective role in preventing respiratory tract symptomatic COVID-19 infections that occurred in 0.45% of all our 1.091 IBD patients. Of those, 1.8% were positive for SARS-CoV-2 Ig, identically to the general population of Munich with also 1.8% positivity. Whilst more than 3% of all COVID-19 subjects of the general population died during the first wave, none of our IBD patients died or needed referral to the ICU or oxygen treatment. Conclusions: In our study, IBD patients are as susceptible to respiratory tract infections or SARS-CoV-2 as the normal population. There is no evidence of an association between IBD therapies and increased risk of COVID-19. Interestingly, a reduced rate of COVID-19 deaths in IBD patients, the majority on immunomodulator therapy, was observed, compared to the general population. Therefore, no evidence was found to suggest that IBD medication should be withheld, and adherence should be encouraged to prevent flares. In addition to older age (>49 years), TNF inhibitors and ustekinumab show a protective role in preventing respiratory tract infections. In addition, these results add to the growing evidence that supports further investigation of TNF inhibitors as a possible treatment in the early course of severe COVID-19.

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.

Italian adaptation of EuroGuiDerm guideline on the systemic treatment of chronic plaque psoriasis.

SIDeMaST (Società Italiana di Dermatologia Medica, Chirurgica, Estetica e delle Malattie Sessualmente Trasmesse) contributed to the development of the present guideline on the systemic treatment of chronic plaque psoriasis. With the permission of EuroGuiDerm, SIDeMaST adapted the guideline to the Italian healthcare context to supply a reliable and affordable tool to Italian physicians who take care of patients affected by moderate to severe plaque psoriasis. The content of the guideline includes general information on the scope and purpose, health questions covered, target users and strength/limitations of the guideline, suggestions for disease severity grading and treatment goals. It presents the general treatment recommendations as well as detailed management and monitoring recommendations for the individual drugs including acitretin, cyclosporine, fumarates, methotrexate, adalimumab, apremilast, brodalumab, certolizumab pegol, etanercept, guselkumab, infliximab, ixekizumab, risankizumab, secukinumab, tildrakizumab and ustekinumab. Moreover, the guideline provides guidance for specific clinical situations such as patient with concomitant psoriatic arthritis, inflammatory bowel disease, a history of malignancies, a history of depression, diabetes, viral hepatitis, disease affecting the heart or the kidneys as well as concomitant neurological disease. Advice on how to screen for tuberculosis and recommendations on how to manage patients with a positive tuberculosis test result are given. It further covers treatment for pregnant women or those with childbearing potential. Information on vaccination, immunogenicity and systemic treatment during the COVID-19 pandemic is also provided.

Safety evaluation of ustekinumab for moderate-to-severe ulcerative colitis.

INTRODUCTION: Ustekinumab is a human IgG1 kappa monoclonal antibody that targets the p40 subunit of interleukin (IL)-12 and IL-23 and blocks the binding of these cytokines to the IL-12Rß1 chain of their receptors. Ustekinumab is approved for treating moderate-to-severe ulcerative colitis (UC). AREAS COVERED: We reviewed the mechanism of action, pharmacokinetics, efficacy, and safety of ustekinumab. Future challenges for optimizing UC treatment with ustekinumab are discussed. EXPERT OPINION: Ustekinumab has favorable clinical efficacy and safety profiles for moderately-to-severely active UC. Ustekinumab is the first biologic for targeting IL-12/IL-23 pathways. Therefore, ustekinumab can be a therapeutic option following the failure of other biologics, including anti-tumor necrosis factor-α antagonists and anti-α4ß7 integrin antagonists. However, the positioning of ustekinumab in the therapeutic strategy for UC remains unclear. The efficacy of combinations of ustekinumab and immunomodulators over ustekinumab monotherapy has not been supported in studies. Ustekinumab is a human immunoglobulin G monoclonal antibody with low immunogenicity. Therefore, ustekinumab monotherapy, which should be safe, could be sufficient for treating UC. Further studies are required to understand the efficacy and safety of ustekinumab in patients with UC, particularly in special situations, and to optimize UC treatment with ustekinumab.

Anti-SARS-CoV-2 Vaccination and Antibody Response in Patients With Inflammatory Bowel Disease on Immune-modifying Therapy: Prospective Single-Tertiary Study.

BACKGROUND: Patients with inflammatory bowel disease (IBD) on immune-modifying treatment could be at an increased risk for severe coronavirus disease 2019 (COVID-19); thus, data on the efficacy and safety of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) vaccines are essential. We conducted a prospective study of IBD patients vaccinated with BNT162b2, CX-024414, and ChAdOx1 nCoV-19 vaccines. The aim was to evaluate the rate and magnitude of seroconversion, assess the effect of different immune-modifying treatment modalities on the magnitude of anti-SARS-CoV-2 IgG antibody levels, and analyze the impact of anti-SARS-CoV-2 vaccination on the inflammatory biomarkers of IBD. METHODS: The study included 602 IBD patients and 168 immunocompetent health care workers serving as controls. Serum anti-SARS-CoV-2 IgG antibodies were measured by chemiluminescent microparticle immunoassay before the vaccination and 8 weeks after the vaccination. RESULTS: Of IBD patients, 82.2% were receiving biological treatment: most of them were treated with antitumor necrosis factor (TNF)-α inhibitors (48.5%), and just under half of them were treated with concomitant thiopurines or methotrexate, followed by vedolizumab (18.6%) and ustekinumab (15.1%). Only 8.1% of patients were on 5-aminosalicylates, and a minority (2.2%) were treatment-free. The postvaccine seropositivity rate among IBD patients and controls was 97.8% vs 100%. Median anti-SARS-CoV-2 IgG levels were lower among IBD recipients of ChAdOx1 nCoV-19 compared with 2 other vaccines (P < .0001) and control ChAdOx1 nCoV-19 recipients (P = .01). No correlation was found between serum trough levels and anti-SARS-CoV-2 IgG concentrations for any of the biological drugs used. The TNF-α inhibitors with concomitant immunosuppressive treatment but no other treatment modalities were associated with a lower postvaccination antibody response (P < .0001). When evaluating the laboratory activity of IBD by C-reactive protein and fecal calprotectin levels, no significant differences were found before the vaccination and 8 weeks after its completion. CONCLUSIONS: Our findings warrant particular attention to the anti-SARS-CoV-2 vaccination of IBD patients treated with TNF-α inhibitors with concomitant immunomodulators and show the priority of mRNA vaccines in this specific group of patients.

Effectiveness and Safety of Ustekinumab in Ulcerative Colitis: Real-world Evidence from the ENEIDA Registry.

BACKGROUND AND AIMS: The development programm UNIFI has shown promising results of ustekinumab in ulcerative colitis [UC] treatment which should be confirmed in clinical practice. We aimed to evaluate the durability, effectiveness, and safety of ustekinumab in UC in real life. METHODS: Patients included in the prospectively maintained ENEIDA registry, who received at least one intravenous dose of ustekinumab due to active UC [Partial Mayo Score [PMS]>2], were included. Clinical activity and effectiveness were defined based on PMS. Short-term response was assessed at Week 16. RESULTS: A total of 95 patients were included. At Week 16, 53% of patients had response [including 35% of patients in remission]. In the multivariate analysis, elevated serum C-reactive protein was the only variable significantly associated with lower likelihood of achieving remission. Remission was achieved in 39% and 33% of patients at Weeks 24 and 52, respectively; 36% of patients discontinued the treatment with ustekinumab during a median follow-up of 31 weeks. The probability of maintaining ustekinumab treatment was 87% at Week 16, 63% at Week 56, and 59% at Week 72; primary failure was the main reason for ustekinumab discontinuation. No variable was associated with risk of discontinuation. Three patients reported adverse events; one of them had a fatal severe SARS-CoV-2 infection. CONCLUSIONS: Ustekinumab is effective in both the short and the long term in real life, even in a highly refractory cohort. Higher inflammatory burden at baseline correlated with lower probability of achieving remission. Safety was consistent with the known profile of ustekinumab.

Diffuse alveolar hemorrhage associated with ustekinumab treatment.

PURPOSE: A case of diffuse alveolar hemorrhage (DAH) occurring as a reaction to ustekinumab therapy is reported. SUMMARY: After starting ustekinumab for treatment of psoriatric arthritis, a 46-year-old female presented with flu-like symptoms and cough with blood-tinged sputum that had begun 1 week previously. Her initial computed tomography scan of the chest demonstrated bilateral ground-glass opacities. On bronchoscopy, the bronchoalveolar lavage (BAL) return became bloodier from sample 1 to samples 2 and 3. Her BAL fluid was more than 90% hemosiderin-laden macrophages, a finding consistent with DAH. We ruled out infectious etiologies and other common vasculitis conditions that can cause DAH. A diagnosis of ustekinumab-induced DAH was made due to a temporal relationship between initiation of the drug and the patient's presentation and the absence of infection and other alternate diagnosis. Prior case reports including ustekinumab-induced pneumonitis, interstitial lung disease with a granulomatous component, and lupus syndrome have been reported, with this being the first case of DAH in a patient undergoing treatment of psoriatic arthritis. CONCLUSION: A 46-year-old woman developed DAH during ustekinumab treatment. Symptoms abated after drug discontinuation and supportive treament. Clinicians must remain mindful of this rare complication of ustekinumab use in order to avoid potential delays in appropriate DAH treatment.

Management of Crohn's disease in an immunosuppressed COVID-19-positive patient: safety-driven prioritisation of nutritional therapy as a bridge to restarting immunosuppression.

Active inflammatory bowel disease (IBD), combined immunosuppression and corticosteroid therapy have all been identified as risk factors for a poor outcome in COVID-19 infection. The management of patients with both COVID-19 infection and active IBD is therefore complex. We present the case of a 31-year-old patient with Crohn's disease, on dual immunosuppression with infliximab and mercaptopurine presenting with inflammatory small bowel obstruction and COVID-19 infection. The case highlights the use of nutritional therapy, which remains underused in the management of adults with IBD, to manage his flare acutely. Following negative SARS-CoV-2 PCR testing and SARS-CoV-2 IgG testing confirming an antibody response, ustekinumab (anti-interleukin 12/23) was prescribed for long-term maintenance.

Impact of the COVID-19 outbreak and the serum prevalence of SARS-CoV-2 antibodies in patients with inflammatory bowel disease treated with biologic drugs.

BACKGROUND: Patients receiving biologic therapies are at risk for viral infections. This study investigated the impact of the SARS-CoV-2 infection and the serum prevalence of SARS-CoV-2 antibodies in patients with inflammatory bowel disease (IBD) treated with biologic drugs. METHODS: Information on demography, co-morbidities, clinical data regarding IBD, symptoms suggestive of the SARS-CoV-2 infection, close contacts with SARS-CoV-2 positive patients, hospitalization, and therapies administered for COVID-19 was collected for all patients who were being treated with biologic drugs. All patients underwent SARS-CoV-2 antibody testing. RESULTS: Two hundred and fifty-nine patients (27 children) with a mean age of 42.2 ±â€¯16.7 years (range 9 - 88) and a mean duration of disease of 13.4 ±â€¯10 years (range 0.2 - 49) were enrolled. One hundred four patients (40.2%) had ulcerative colitis, and 155 (59.8%) had Crohn's disease. About the therapy: 62 patients were receiving infliximab, 89 adalimumab, 20 golimumab, 57 vedolizumab, 27 ustekinumab, 1 thalidomide, and 3 an experimental compound. The mean Charlson Comorbidity Index was 2. Thirty-two patients (12.3%) reported respiratory symptoms, and 2 of them were hospitalized (0.77%). Two patients resulted positive for IgG against SARS-CoV-2 (0.77%). CONCLUSIONS: In patients with IBD, treatment with biologic drug does not represent a risk factor for the SARS-CoV-2 infection.