Influence of rheumatoid factor on serum drug levels of TNF inhibitors with different structures in rheumatoid arthritis.

OBJECTIVES: Certolizumab pegol (CZP), an Fc-free antibody fragment, has shown stable serum levels and steady efficacy in the treatment of RA patients, irrespective of RF levels at baseline. Here, we examine, in clinical practice, the effect of baseline RF and ACPA levels on serum drug levels of IFX, ADL and CZP an Fc-free antibody fragment. METHODS: This is a retrospective study performed in real-world patients. We assessed 170 patients with RA: 90 (53%) received IFX, 48 (28%) ADL and 32 (19%) CZP. Demographic and clinical variables, RF and ACPA levels were obtained at the baseline visit (T0), and patients were stratified based on negative, low, medium, or high levels. After 6 months (T6) serum drug levels and anti-drug antibodies (ADAb), were computed. RESULTS: While CZP serum levels did not differ across RF groups at T6, high baseline RF was linked to lower serum drug levels compared to RF negative status in treatment with complete monoclonal antibodies IFX and ADL. No differences in disease activity measured by DAS28 at baseline were observed across RF quartiles in patients treated with IFX or ADL. ADAb was observed in 26 patients with IFX, 3 with ADL and 1 with CZP, following 6 months of treatment. Patients with high baseline RF levels dropped out more frequently by secondary non-response in IFX or ADL than CZP (80% vs. 75% vs. 33%, p=0.002). CONCLUSIONS: In this real word data evaluation, CZP serum levels were independent of RF levels in patients however patients with high baseline RF levels who obtained IFX or ADL had lower serum drug levels at 6 months than baseline RF-negative patients. In addition, secondary non-response was more frequent in patients with high RF levels treated with IFX and ADL.

Certolizumab-induced sarcoidosis in a patient with psoriatic arthritis - a case report and review of literature.

Tumour necrosis factor-α (TNF- α) antagonists are considered a significant therapeutic option in the treatment of sarcoidosis. Nevertheless, their use can also paradoxically result in sarcoidosis-like reactions. Here, we present a case of a 56-year-old patient with psoriatic arthritis who after 3 months of certolizumab therapy developed pulmonary sarcoidosis. Therefore, certolizumab was discontinued and prednisone initiated. Subsequently, 4 months later a complete remission of interstitial lesions was observed. Due to insufficient control of psoriatic arthritis, upadacitinib and methotrexate were prescribed and despite initial improvement, a couple of months later a massive exacerbation of skin psoriasis occurred and the treatment was switched to secukinumab. As of today, no evidence of sarcoidosis recurrence has been noted. Drug-induced sarcoidosis-like reactions (DISR) appear to be less frequently associated with certolizumab rather than with other anti-TNF-α agents. However, specific mechanisms of this phenomenon remain unclear and require future investigation.

Characterization of anti-drug antibody dynamics using a bivariate mixed hidden-markov model by nonlinear-mixed effects approach.

Biological therapies may act as immunogenic triggers leading to the formation of anti-drug antibodies (ADAs). Population pharmacokinetic (PK) models can be used to characterize the relationship between ADA and drug disposition but often rely on the ADA bioassay results, which may not be sufficiently sensitive to inform on this characterization.In this work, a methodology that could help to further elucidate the underlying ADA production and impact on the drug disposition was explored. A mixed hidden-Markov model (MHMM) was developed to characterize the underlying (hidden) formation of ADA against the biologic, using certolizumab pegol (CZP), as a test drug. CZP is a PEGylated Fc free TNF-inhibitor used in the treatment of rheumatoid arthritis and other chronic inflammatory diseases.The bivariate MHMM used information from plasma drug concentrations and ADA measurements, from six clinical studies (n = 845), that were correlated through a bivariate Gaussian function to infer about two hidden states; production and no-production of ADA influencing PK. Estimation of inter-individual variability was not supported in this case. Parameters associated with the observed part of the model were reasonably well estimated while parameters associated with the hidden part were less precise. Individual state sequences obtained using a Viterbi algorithm suggested that the model was able to determine the start of ADA production for each individual, being a more assay-independent methodology than traditional population PK. The model serves as a basis for identification of covariates influencing the ADA formation, and thus has the potential to identify aspects that minimize its impact on PK and/or efficacy.

Long-term retention rates of anti-tumour necrosis factor and anti-interleukin-17 antibodies for patients with psoriatic arthritis.

OBJECTIVE: While biologics have been used for the patients with psoriatic arthritis, there remains to be unknown concerning long-term retention rates. This study aims to present real-world data about long-term retention rates of biologics for the patients with psoriatic arthritis, and to undertake an analysis of the contributing factors. METHODS: We examined retention rates and the reasons for discontinuation for biologics (adalimumab, certolizumab pegol, secukinumab, and ixekizumab) in 146 prescriptions (of which, 109 prescriptions were as naive) at our hospital since March 2010. RESULTS: Throughout the entire course of the study, the 10-year retention rates were approximately 70% for adalimumab, 50% for ixekizumab, and 40% for secukinumab. When evaluating retention rates in the biologic-naïve subgroups, the 10-year retention rates were all approximately 70%. Regarding certolizumab pegol, the 3-year retention rate was approximately 75%. For adalimumab, a higher degree of arthritis at the initiation of treatment was found to correlate with an increased likelihood of secondary inefficacy. The main reason for discontinuation was secondary inefficacy, except for ixekizumab. CONCLUSIONS: Each biologic exhibited a favourable long-term retention rate. The main reason for discontinuation was secondary inefficacy. Regarding adalimumab, secondary inefficacy was linked to the extent of arthritis upon treatment initiation.

Efficacy of Biologic Drugs in Short-Duration Versus Long-Duration Inflammatory Bowel Disease: A Systematic Review and an Individual-Patient Data Meta-Analysis of Randomized Controlled Trials.

BACKGROUND AND AIMS: Starting biologic treatment early in the course of inflammatory bowel disease (IBD) may be associated with higher efficacy, especially in Crohn's disease (CD). METHODS: This was a systematic review and individual-patient data meta-analysis of all placebo-controlled trials of biologics approved for IBD at study inception (October 2015), using Vivli data-sharing platform. The primary outcome was the proportional biologic/placebo treatment effect on induction of remission in patients with short-duration (≤18 months) vs long-duration disease (>18 months) analyzed separately for CD and ulcerative colitis (UC). We used meta-regression to examine the impact of patients' characteristics on the primary outcome. RESULTS: We included 25 trials, testing infliximab, adalimumab, certolizumab, golimumab, natalizumab, or vedolizumab (6168 patients with CD and 3227 patients with UC). In CD, remission induction rates were higher in pooled placebo and patients in active arms with short-duration disease of ≤18 months (41.4% [244 of 589]) compared with disease duration of >18 months (29.8% [852 of 2857], meta-analytically estimated odds ratio, 1.33; 95% confidence interval, 1.09-1.64). The primary outcome, proportional biologic/placebo treatment effect on induction of remission, was not different in short-duration disease of ≤18 months (n = 589, odds ratio, 1.47; 95% confidence interval, 1.01-2.15) compared with longer disease duration (n = 2857, odds ratio, 1.43; 95% confidence interval, 1.19-1.72). In UC trials, both the proportional biologic/placebo remission-induction effect and the pooled biologic-placebo effect were stable, regardless of disease duration. Primary outcome results remained unchanged when tested using alternative temporal cutoffs and when modeled for individual patient's covariates, including prior anti-tumor necrosis factor exposure. CONCLUSIONS: There are higher rates of induction of remission with biologics and with placebo in early CD, resulting in a treatment to placebo effect ratio that is similar across disease durations. No such relationships between disease duration and outcomes was found in UC. PROSPERO registration: CRD42018041961.

Efficacy and safety of biological DMARDs: a systematic literature review informing the 2022 update of the ASAS-EULAR recommendations for the management of axial spondyloarthritis.

OBJECTIVE: To update the evidence on efficacy and safety of biological disease-modifying antirheumatic drugs (bDMARDs) in patients with axial spondyloarthritis (axSpA) to inform the 2022 update of the Assessment of SpondyloArthritis international Society/European Alliance of Associations for Rheumatology (ASAS-EULAR) recommendations for the management of axSpA. METHODS: Systematic literature review (2016-2021) on efficacy and safety of bDMARDs in axSpA (radiographic axSpA (r-axSpA)/non-radiographic axSpA (nr-axSpA)). Eligible study designs included randomised controlled trials (RCTs), strategy trials and observational studies (the latter only for safety and extra-musculoskeletal manifestations). All relevant efficacy/safety outcomes were included. RESULTS: In total, 148 publications were included. Efficacy of golimumab and certolizumab was confirmed. Tumour necrosis factor inhibitor (TNFi) biosimilar-originator equivalence was demonstrated. RCT (n=15) data on efficacy of interleukin-17 inhibitors (IL-17i) demonstrated clinically relevant effects (risk ratio vs placebo to achieve ASAS40 response 1.3-15.3 (r-axSpA, n=9), 1.4-2.1 (nr-axSpA, n=2)). Efficacy of secukinumab/ixekizumab was demonstrated in TNFi-naïve and TNFi-inadequate responders. IL-23 and IL-12/23 inhibitors (risankizumab/ustekinumab) failed to show relevant benefits. Tapering of TNFi by spacing was non-inferior to standard-dose treatment. The first axSpA treat-to-target trial did not meet its primary endpoint, but showed improvements in secondary outcomes. No new risks were identified with TNFi use in observational studies (data lacking for IL-17i). Secukinumab (n=1) and etanercept (n=2) were associated with increased risk of uveitis in observational studies compared to monoclonal TNFi. CONCLUSIONS: New evidence supports the efficacy and safety of TNFi (originators/biosimilars) and IL-17i in r-axSpA and nr-axSpA, while IL-23i failed to show relevant effects. Observational studies are needed to confirm long-term IL-17i safety. PROSPERO REGISTRATION NUMBER: CRD42021257588.

Certolizumab pegol, abatacept, tocilizumab or active conventional treatment in early rheumatoid arthritis: 48-week clinical and radiographic results of the investigator-initiated randomised controlled NORD-STAR trial.

BACKGROUND: The optimal first-line treatment in early rheumatoid arthritis (RA) is debated. We compared clinical and radiographic outcomes of active conventional therapy with each of three biological treatments with different modes of action. METHODS: Investigator-initiated, randomised, blinded-assessor study. Patients with treatment-naïve early RA with moderate-severe disease activity were randomised 1:1:1:1 to methotrexate combined with (1) active conventional therapy: oral prednisolone (tapered quickly, discontinued at week 36) or sulfasalazine, hydroxychloroquine and intra-articular glucocorticoid injections in swollen joints; (2) certolizumab pegol; (3) abatacept or (4) tocilizumab. Coprimary endpoints were week 48 Clinical Disease Activity Index (CDAI) remission (CDAI ≤2.8) and change in radiographic van der Heijde-modified Sharp Score, estimated using logistic regression and analysis of covariance, adjusted for sex, anticitrullinated protein antibody status and country. Bonferroni's and Dunnet's procedures adjusted for multiple testing (significance level: 0.025). RESULTS: Eight hundred and twelve patients were randomised. Adjusted CDAI remission rates at week 48 were: 59.3% (abatacept), 52.3% (certolizumab), 51.9% (tocilizumab) and 39.2% (active conventional therapy). Compared with active conventional therapy, CDAI remission rates were significantly higher for abatacept (adjusted difference +20.1%, p<0.001) and certolizumab (+13.1%, p=0.021), but not for tocilizumab (+12.7%, p=0.030). Key secondary clinical outcomes were consistently better in biological groups. Radiographic progression was low, without group differences.The proportions of patients with serious adverse events were abatacept, 8.3%; certolizumab, 12.4%; tocilizumab, 9.2%; and active conventional therapy, 10.7%. CONCLUSIONS: Compared with active conventional therapy, clinical remission rates were superior for abatacept and certolizumab pegol, but not for tocilizumab. Radiographic progression was low and similar between treatments. TRIAL REGISTRATION NUMBER: NCT01491815.

Non-trough adalimumab and certolizumab drug levels associated with a therapeutic EULAR response in adherent patients with rheumatoid arthritis.

OBJECTIVES: Interventions aimed at increasing TNF-α inhibitor serum drug levels (SDLs) may improve treatment response; however, previous studies suggesting SDL cut-offs have not accounted for treatment adherence. The aim of this study was to establish the relationship between adalimumab/certolizumab SDLs and EULAR good vs non-/moderate response and to define SDL cut-offs associated with good response in fully adherent patients. METHODS: In a prospective observational study, 475 patients with RA were treated with certolizumab (n = 192) or adalimumab (n = 283). At baseline and 3, 6 and 12 months, patients had 28-joint DAS, self-reported treatment adherence and SDLs measured. Fully adherent patients were analysed as a subgroup. Follow-up data at 3, 6 and 12 months were analysed separately. Median SDLs were compared in good vs non-/moderate response patients and receiver operating characteristics (ROC) curves were used to establish cut-off SDLs. RESULTS: Fully adherent good responders had significantly higher median adalimumab/certolizumab SDLs compared with non-/moderate responders (P = 0.04 and P = 0.0005, respectively). ROC analysis reported 3 month non-trough adalimumab SDLs discriminated good vs non-/moderate response with an area under the curve (AUC) of 0.63 (95% CI 0.52, 0.75), with a cut-off of 7.5 mg/l being 39.1% specific and 80.9% sensitive. Similarly, 3 month non-trough certolizumab SDLs discriminated good vs non-/moderate response with an AUC of 0.65 (95% CI 0.51, 0.78), with a cut-off of 26.0 mg/l being 43.9% specific and 77.8% sensitive. CONCLUSION: In fully adherent patients, higher SDLs are detected in good responders, suggesting that interventions to improve SDLs, such as encouraging adherence, could improve treatment response. The 3 month non-trough SDL cut-offs of 7.5 mg/l for adalimumab and 26.0 mg/l for certolizumab may be useful in clinical practice.

Focus on Anti-Tumour Necrosis Factor (TNF)-α-Related Autoimmune Diseases.

Anti-tumour necrosis factor (TNF)-α agents have been increasingly used to treat patients affected by inflammatory bowel disease and dermatological and rheumatologic inflammatory disorders. However, the widening use of biologics is related to a new class of adverse events called paradoxical reactions. Its pathogenesis remains unclear, but it is suggested that cytokine remodulation in predisposed individuals can lead to the inflammatory process. Here, we dissect the clinical aspects and overall outcomes of autoimmune diseases caused by anti-TNF-α therapies.

Safety and effectiveness of certolizumab pegol in Japanese patients with rheumatoid arthritis: Results from a 24-week post-marketing surveillance study.

OBJECTIVES: To report 24-week safety and effectiveness of certolizumab pegol (CZP) in Japanese patients with rheumatoid arthritis from a post-marketing surveillance study. METHODS: Enrolled patients were newly receiving CZP. All adverse events (AEs) and adverse drug reactions (ADRs) were recorded for patients who received ≥1 CZP dose. Effectiveness outcomes included: 28-joint Disease Activity Score with erythrocyte sedimentation rate (DAS28-ESR) and European Alliance of Associations for Rheumatology (EULAR) response. Missing data were imputed using the last observation carried forward. RESULTS: 3727 patients were enrolled; safety and effectiveness were evaluated in 3586 and 1794 patients, respectively. 24.9% of patients reported AEs (893/3586), 14.7% reported ADRs (528/3586), 8.3% (298/3586) reported serious AEs and 5.3% (190/3586) reported serious ADRs. Selected serious ADRs of interest: infections (110; 3.1%), tuberculosis (6; 0.2%), interstitial pneumonia (15; 0.4%), malignancy (8; 0.2%), and hepatic function disorder (7; 0.2%). No allergic reactions, autoimmune disease, cardiac failure, demyelinating diseases, or pancytopenia were reported. Mean DAS28-ESR reduced from 4.8 (baseline) to 3.4 (final evaluation). At final evaluation, 34.7% of patients achieved EULAR good response. CONCLUSIONS: These real-world safety and effectiveness results were consistent with previously reported data, with no new safety signals identified. Long-term, real-world CZP safety and effectiveness data are needed.

Comparative analysis of low-field magnetic resonance imaging in patients with rheumatoid arthritis treated with certolizumab pegol or infliximab.

OBJECTIVES: The aim is to clarify the differences in magnetic resonance imaging (MRI) findings between rheumatoid arthritis (RA) patients treated with certolizumab pegol (CZP) and infliximab (IFX). METHODS: The study included RA patients who received CZP or IFX and were examined with low-field MRI (compacTscan; compact magnetic resonance imaging) at the beginning and again within 6 months of treatment initiation. Comparisons were made regarding background, clinical course, and differences in MRI findings following initiation of tumour necrosis factor inhibitors between the CZP and IFX treatment groups. MRI findings were evaluated by scoring erosion, bone marrow oedema (BME), and synovitis. RESULTS: Ten cases in CZP and 18 cases in IFX group were compared. The biologic disease-modifying antirheumatic drug-naïve rate in the IFX group was significantly higher than that in the CZP group. After 6 months, disease activities were significantly decreased from baseline in both groups. Erosion score did not change significantly in both groups after 6 months. BME score was significantly decreased in the CZP group after 6 months, whereas in the IFX group, there was no significant change. Synovitis score was significantly decreased in both groups after 6 months. CONCLUSIONS: The findings of our study suggest that, in patients with RA, CZP might improve BME more effectively than IFX.

[Overview and therapy update Crohn's disease].

INTRODUCTION: Crohn's disease (CD) is a chronic inflammatory bowel disease that can affect the entire gastrointestinal tract. The pathophysiology of CD includes a disrupted interplay of intestinal bacteria, the intestinal immune system and the intestinal surface in genetically susceptible individuals, which remains incompletely understood. Conventional therapies include steroids, but numerous advanced therapies are also available. Three tumor necrosis factor (TNF) inhibitors (infliximab, adalimumab and certolizumab pegol (Switzerland)) have been approved for MC. Additional treatment options include the interleukin (IL)-12/23 inhibitors ustekinumab and the integrin inhibitors vedolizumab. With risankizumab, a first selective IL-23 inhibitor for CD has been approved by the EMA in 2022. Moreover, the Janus kinase-1 inhibitor upadacitinib has been available for the treatment of CD in the EU since 2023. For localized CD, elective surgical resection also remains a valid option with good long-term outcomes. Perianal and fistulizing CD are difficult to treat and require a close interdisciplinary collaboration between gastroenterologists and colorectal surgeons. Surgical fistula treatment with curative intent should only be performed in well-controlled CD. The recent increase in therapeutic options in CD is encouraging, since more safe and effective therapies are now available to patients. Nevertheless, CD remains an incurable disease and so far, for all existing treatments only a fraction of patients responds to the therapy. Therefore, the development of new therapies should continue.

Analysing cord blood levels of TNF inhibitors to validate the EULAR points to consider for TNF inhibitor use during pregnancy.

BACKGROUND: To minimise placental transfer of tumour necrosis factor inhibitors (TNFi), the European League Against Rheumatism (EULAR) created points to consider (PtC) for the use of TNFi during pregnancy. We are the first to validate the EULAR-PtC by analysing TNFi concentrations in cord blood. METHODS: Patients were derived from the Preconceptional Counselling in Active Rheumatoid Arthritis Study. TNFi was stopped at the time points recommended by the EULAR. Maternal blood and cord blood were collected and analysed for the concentration of TNFi. RESULTS: 111 patients were eligible for the analysis. Median stop time points were gestational age (GA) 37.0 weeks for certolizumab pegol, GA 25.0 weeks for etanercept, GA 19.0 weeks for adalimumab and GA 18.4 weeks for infliximab. Certolizumab pegol (n=68) was detectable in 5.9% of cord blood samples, with a median concentration of 0.3 µg/mL (IQR: 0.2-1.3) and a median cord/maternal concentration ratio of 0.010. Etanercept (n=30) was not detected in any cord blood samples. Adalimumab (n=25) was detectable in 48.0% of cord blood samples, with a median concentration of 0.5 µg/mL (IQR: 0.2-0.7) and a median concentration ratio of 0.062 (IQR: 0.018-0.15). Infliximab (n=14) was detectable in 57.1% of cord blood samples, with a median concentration of 0.4 µg/mL (IQR: 0.1-1.2) and a median concentration ratio of 0.012 (IQR: 0.006-0.081). CONCLUSION: Compliance with the EULAR-PtC results in absence or low levels of TNFi in cord blood.

Certolizumab pegol treatment in axial spondyloarthritis mitigates fat lesion development: 4-year post-hoc MRI results from a phase 3 study.

OBJECTIVES: Fat lesions (FLs) on MRI T1 sequences are considered to be early indicators of structural spinal progression in axial spondyloarthritis (axSpA) patients. In this post-hoc analysis from RAPID-axSpA, we assess whether tumour necrosis factor inhibitor (TNFi) treatment over 4 years impacts FLs in spinal vertebral edges (VEs) of patients with axSpA. METHODS: In RAPID-axSpA (NCT01087762), a 4-year, phase 3 randomized trial, participants were randomized to certolizumab pegol (CZP; 400 mg loading dose at Weeks 0/2/4 then 200/400 mg every 2/4 weeks) or placebo (PBO) at baseline; PBO-randomized participants switched to CZP at Week 16/24 (denoted PBO-randomized/CZP). Spinal MRI scans were taken at Weeks 0, 12, 48, 96 and 204. Changes in proportions of VEs with FLs are reported as odds ratios (ORs) between time points. RESULTS: Overall, 136 participants (CZP: 89, PBO-randomized/CZP: 47) had a baseline and ≥1 post-baseline MRI. The OR (95% confidence interval) vs baseline of FLs was higher in PBO-randomized/CZP vs CZP-randomized participants at Weeks 48 [3.35 (2.16-5.19) vs 1.45 (1.07-1.97)], 96 [2.62 (1.77-3.88) vs 1.84 (1.36-2.48)] and 204 [2.55 (1.59-4.06) vs 1.71 (1.23-2.37)]. Across 204 weeks, FLs increased more in VEs with baseline inflammation [Week 204 OR: 4.84 (2.56-9.18)] than those without [OR: 1.15 (0.78-1.71)]. VEs in which inflammation was resolved by Week 12 had lower FL prevalence at Weeks 48, 96 and 204 compared with VEs with unresolved inflammation. CONCLUSIONS: Early and sustained suppression of inflammation mitigates the risk of long-term FL development in the spine in study participants with axSpA evaluated over 4 years. TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov, NCT01087762.

Blood PD-1+TFh and CTLA-4+CD4+ T cells predict remission after CTLA-4Ig treatment in early rheumatoid arthritis.

OBJECTIVE: Treatment with CTLA-4Ig blocks T-cell activation and is clinically effective in RA. However, it is unknown if specific CD4+ T-cell subsets in blood at baseline predict remission after CTLA-4Ig, or other biological treatments with different modes of action, and how treatment affects CD4+ T cells in patients with untreated early RA (eRA). METHODS: This study included 60 patients with untreated eRA from a larger randomized trial. They were treated with methotrexate combined with CTLA-4Ig (abatacept, n = 17), anti-IL6 receptor (tocilizumab, n = 21) or anti-TNF (certolizumab-pegol, n = 22). Disease activity was assessed by clinical disease activity index (CDAI), DAS28, swollen joint counts, tender joint counts, CRP and ESR. The primary outcome was CDAI remission (CDAI ≤ 2.8) at week 24. Proportions of 12 CD4+ T-cell subsets were measured by flow cytometry at baseline and after 4, 12 and 24 weeks of treatment. RESULTS: In patients treated with CTLA-4Ig, the proportions of PD-1+TFh and CTLA-4+ conventional CD4+ T cells at baseline predicted CDAI remission at week 24. CD4+ T-cell subset proportions could not predict remission after treatment with anti-IL6R or anti-TNF. The percentage of regulatory T cells (Tregs) expressing CTLA-4 decreased in all treatment arms by 24 weeks, but only CTLA-4Ig treatment significantly reduced the proportions of Tregs and PD-1+T follicular helper (TFh) cells. CONCLUSION: These findings indicate that circulating proportions PD-1+TFh and CTLA-4+ conventional CD4+ T cells at baseline may serve as predictive biomarkers for remission in early RA after CTLA-4Ig treatment.

Reported congenital malformations after exposure to non-tumour necrosis factor inhibitor biologics: A retrospective comparative study in EudraVigilance.

AIMS: To evaluate the number and nature of reported congenital malformations (CMs) after intrauterine exposure to non-tumour necrosis factor inhibitor biologics (non-TNFi biologics) compared to certolizumab pegol (CZP). METHODS: A retrospective comparative study was conducted in the EudraVigilance (EV) database. A safe biologic (CZP) was considered as the reference group. Odds ratios (ORs) for CMs were calculated for each non-TNFi biologic (including abatacept, anakinra, belimumab, ixekizumab, rituximab, secukinumab, tocilizumab, ustekinumab and vedolizumab), versus CZP (quantitative assessment). Then, CM patterns were reviewed in consultation with a clinical geneticist (qualitative assessment). RESULTS: ORs were not statistically significant except for belimumab and vedolizumab (similar in magnitude). Except for vedolizumab, no specific CM patterns were observed for the included non-TNFi biologics. Three cases of corpus callosum agenesis (CCA) were identified for vedolizumab (versus none in CZP and other investigated non-TNFi biologics). Two of the CCA cases were associated with other neurological CMs (one cerebral ventriculomegaly with microcephaly and one polymicrogyria). This may indicate that these CCAs are related to undiagnosed genetic alterations or are associated with the underlying maternal disease, although a definite relationship with vedolizumab exposure cannot be ruled out. CONCLUSION: No special safety signal was identified regarding the occurrence of CMs after exposure to abatacept (n = 64), anakinra (n = 20), belimumab (n = 93), ixekizumab (n = 29), rituximab (n = 57), secukinumab (n = 128), tocilizumab (n = 124) and ustekinumab (n = 215). Regarding observed CCAs in the vedolizumab group (n = 113), no firm conclusions can be made based on available information.

Pharmacological Management of Inflammatory Bowel Disease: a Century of Expert Opinions in Cecil Textbook of Medicine.

BACKGROUND: Advances in drug therapy for inflammatory bowel disease (IBD) [Crohn disease and ulcerative colitis (UC)] have contributed to a decrease in the severity of these chronic and disabling conditions. STUDY QUESTION: What are the milestones of the changes in the expert approach to the pharmacological management of IBD in the past century? STUDY DESIGN: To determine the changes in the experts' approach to the management of regional ileitis and UC, as presented in a widely used textbook in the United States. DATA SOURCES: The chapters presenting the management of IBD in the 26 editions of Cecil Textbook of Medicine published from 1927 through 2020. RESULTS: No specific interventions existed from 1927 through 1942. The pharmacological management of IBD has had 3 slightly overlapping eras starting in 1943. During the first period (1943-1951), the medical management relied on antibiotics, primarily sulfonamides and chloramphenicol. In the second (1955-75), experts recommended the use of adrenocorticotropic hormone or corticosteroids and 5-aminosalicylate. In the third era, which commenced in 1979 and is continuing to date, the pharmacological interventions have been expanded and refined to include 5 main drug classes, 5-aminosalicylates (sulfasalazine, mesalamine, and olsalazine), corticosteroids (prednisone and budesonide), immunomodulators (azathioprine, 6-mercaptopurine, cyclosporine, and tofacitinib), biologics (infliximab adalimumab certolizumab pegol, and natalizumab), and antibiotics (metronidazole and ciprofloxacin). A consensus exists that the monoclonal antibodies again tumor necrosis factor alpha are cost-effective for induction and maintenance of clinical remission in both UC (golimumab) and Crohn disease (certolizumab pegol). The newer agents ustekinumab (a monoclonal antibody to the interleukin p40 subunit) and vedolizumab (a monoclonal antibody to the homing receptor integrin complex) have also performed well. CONCLUSIONS: The pharmacological management of IBD has been the focus of intense research and development in the past 60 years. The pillars of drug treatment have been 5-aminosalicylates and corticosteroids. Recent pharmacological innovations (immunomodulators and biologicals) constitute an encouraging paradigm shift in the treatment of UC and Crohn disease.

Certolizumab pegol in the treatment of severe hidradenitis suppurativa after adalimumab failure: A real-life experience.

There exists an unmet need to treat hidradenitis suppurativa (HS) despite several approved therapeutic agents for its treatment. We sought to investigate the role of certolizumab pegol in severe, recalcitrant HS patients unresponsive to adalimumab. This retrospective cohort includes HS patients over 18 years of age who had a history of unresponsiveness to adalimumab and whose treatments were switched to certolizumab pegol with dosing similar to psoriasis (400 mg every 2 weeks). For subjects who achieved a hidradenitis suppurativa clinical response (HiSCR) following 12 and 24 weeks of treatment, dermatological life quality index (DLQI), abscess, inflammatory nodule count (AN count), and International Hidradenitis Suppurativa Severity Score System (IHS4) were evaluated as outcome measures. Eleven severe, recalcitrant HS patients with Hurley stage III HS were enrolled for this study. All patients were male and had a history of prior adalimumab exposure. Only three (27.2%) patients also had a history of using biologic agents other than adalimumab for HS. Six of 11 patients (54.5%) achieved HiSCR at week 12. However, two among these six responders lost response at week 24 despite continued therapy (HiSCR at week 24: 33.3%). The decrease in DLQI (p: 0.017 and 0.021) and IHS4 (p: 0.008 and 0.007) scores of the patients at weeks 12 and 24 showed a significant difference compared to the baseline. Certolizumab pegol is a promising treatment option for severe, recalcitrant HS patients who are unresponsive to adalimumab.

Certolizumab pegol for maintenance of medically induced remission in Crohn's disease.

BACKGROUND: Crohn's disease (CD) is a disease with an impaired immune response characterized by chronic, relapsing-remitting, and progressive inflammation mainly affecting the gastrointestinal tract. Certolizumab pegol (CZP) is a biological agent that regulates the impaired immune response by controlling tumour necrosis factor-α (TNFα). However, the efficacy and safety of long-term administration of CZP for people with CD with inflammation under control are not well understood. OBJECTIVES: To assess the efficacy and safety of CZP for maintenance of remission in people with CD. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, ClinicalTrials.gov, WHO ICTRP, and conference abstracts from inception to 23 March 2022. We contacted pharmaceutical companies involved with the production of CZP for further relevant information. SELECTION CRITERIA: We included randomized controlled trials (RCTs) comparing CZP with placebo in adults with CD. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies and extracted data. The main outcomes were failure to maintain clinical remission at week 26, failure to maintain clinical response at week 26, and serious adverse events. We planned to perform meta-analyses including all available studies if similar enough for pooling to be appropriate and calculated risk ratios (RRs) with 95% confidence intervals (CIs) for dichotomous outcomes and mean differences with 95% CIs for continuous outcomes. We analyzed the number needed to treat for an additional beneficial outcome (NNTB) and the number needed to treat for an additional harmful outcome (NNTH) to indicate the magnitude of treatment effects. The same two review authors independently evaluated the risk of bias by using the Cochrane RoB 2 tool and evaluated the certainty of evidence using the GRADE framework. MAIN RESULTS: We identified one study meeting our prespecified eligibility criteria. The included study enrolled 428 adults with CD who responded to induction therapy with CZP 400 mg at weeks 0, 2, and 4. The study evaluated long-term efficacy and safety of CZP administered subcutaneously every four weeks compared with placebo. The proportion of participants who failed to maintain clinical remission at week 26 was 52.3% (113/216) in the CZP group compared to 71.7% (152/212) in the placebo group. Treatment of CZP probably results in a large reduction in failure to maintain clinical remission at week 26 (RR 0.73, 95% CI 0.63 to 0.85). The NNTB was 5 (95% CI 4 to 9). We judged this outcome at low risk of bias. Using the GRADE assessment, we judged the certainty of evidence as moderate due to the low number of events occurred. The proportion of participants who failed to maintain clinical response at week 26 was 37.5% (81/216) in the CZP group compared to 64.2% (136/212) in the placebo group. Treatment of CZP probably results in a large reduction in failure to maintain clinical response at week 26 (RR 0.58, 95% CI 0.48 to 0.71). The NNTB was 4 (95% CI 3 to 5). We judged this outcome at low risk of bias. Using the GRADE assessment, we judged the certainty of evidence as moderate due to the low number of events occurred. The proportion of participants who developed serious adverse events was 5.6% (12/216) in the CZP group compared to 6.6% (14/212) in the placebo group. Treatment of CZP may lead to no difference in serious adverse events compared to placebo when used as a remission maintenance treatment (RR 0.84, 95% CI 0.40 to 1.78). The NNTB was 95 (95% CI NNTH 19 to NNTB 25). We evaluated the risk of bias for this outcome as low. We evaluated the certainty of evidence as low due to the low number of events occurred and the CIs were not sufficiently narrow. AUTHORS' CONCLUSIONS: CZP probably results in a large reduction in failure to maintain clinical remission and response at week 26 in people with CD. The evidence suggests that CZP may lead to no difference in serious adverse events compared to placebo when used as a remission maintenance treatment. However, the current studies are limited to 26 weeks of follow-up and only included adults. Therefore, these conclusions cannot be used to guide longer term treatment or for treatment in children at present.

Infection risk in psoriatic patients receiving tumour necrosis factor inhibitors: a 20-year systematic review and meta-analysis of randomized controlled trials.

Tumour necrosis factor inhibitors (TNFis) are commonly used for treating psoriatic diseases; however, the risk of infection while receiving TNFis remains uncertain. The aim of this study was to investigate the infection risk in patients with psoriatic disease receiving TNFis. A prospectively registered systematic literature search was conducted in Medline (PubMed), Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE and the ClinicalTrials.gov databases from inception to December 31, 2021. We included double-blind randomized controlled trials that compared TNFis or other biologics with placebo in adults with psoriasis or psoriatic arthritis. The primary outcomes included overall and serious infection risks, and secondary outcomes included upper respiratory infections and nasopharyngitis risks. The risk ratio of the dichotomous outcome was calculated using the Mantel-Haenszel method with random effects, and heterogeneity was assessed using Cochran's Q statistic and quantified using the I-squared statistic. A total of 48 studies with 15 464 patients with psoriatic diseases were included. The meta-analysis demonstrated a slightly increased overall infection risk (risk ratio = 1.09; 95% confidence interval, 1.02-1.15) but not serious infection risk (risk ratio = 0.95; 95% confidence interval, 0.61-1.49) among patients receiving TNFis. There were also no increased risks of upper respiratory infections (risk ratio = 1.10; 95% confidence interval, 0.94-1.28) or nasopharyngitis (risk ratio = 1.14; 95% confidence interval, 1.00-1.30). In subgroup analyses using the fixed effects model, only etanercept and certolizumab pegol were, respectively, associated with an increased risk of overall infection (RR = 1.14, 95% CI, 1.03-1.27) and upper respiratory infections (RR = 1.42, 95% CI, 1.02-1.98). In conclusion, evidence to date suggests an increased overall infection risk that is generally tolerable in patients with psoriatic diseases receiving TNFis. There are no increased risks of serious infections, upper respiratory infections or nasopharyngitis.