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Vasculitis and other autoimmune conditions are known complications of tumour necrosis factor alpha (TNF-α) inhibitor use. By definition, TNF-α inhibitor induced vasculitis is a secondary systemic vasculitis. However, its phenotype is varied and can present as an isolated vasculitic neuropathy. This presents a diagnostic challenge as the gold standard for diagnosis of a vasculitic neuropathy is a peripheral nerve biopsy that meets predefined histopathological criteria. Given the poor sensitivity of the peripheral nerve biopsy, it is important that clinicians take a good history and maintain a high index of suspicion, as this is a treatable iatrogenic condition. Here we present a case of adalimumab-induced sensory vasculitic neuropathy, treated according to the Peripheral Nerve Society guideline for non-systemic vasculitic neuropathy, given her disease phenotype.

Uveitis is the most common extra-articular manifestation of juvenile idiopathic arthritis (JIA) and a potentially sight-threatening condition characterized by intraocular inflammation. Current treatment for JIA-associated uveitis (JIA-U) is largely based on physician experience, observational evidence and consensus guidelines, resulting in considerable variations in practice. OBJECTIVES: To evaluate the effectiveness and safety of tumor necrosis factor (TNF) inhibitors used for treatment of JIA-U.We searched the Cochrane Central Register of Controlled Trials (CENTRAL); Ovid MEDLINE; Embase.com; PubMed; Latin American and Caribbean Health Sciences Literature Database (LILACS); ClinicalTrials.gov, and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). We last searched the electronic databases on 3 February 2022.We included randomized controlled trials (RCTs) comparing TNF inhibitors with placebo in participants with a diagnosis of JIA and uveitis who were aged 2 to 18 years old.We used standard Cochrane methodology and graded the certainty of the body of evidence for seven outcomes using the GRADE classification.We included three RCTs with 134 participants. One study conducted in the USA randomized participants to etanercept or placebo (N = 12). Two studies, one conducted in the UK (N = 90) and one in France (N = 32), randomized participants to adalimumab or placebo. All studies were at low risk of bias. Initial pooled estimates suggested that TNF-inhibitors may result in little to no difference on treatment success defined as 0 to trace cells on Standardization of Uveitis Nomenclature (SUN)-grading; or two-step decrease in activity based on SUN grading (estimated risk ratio (RR) 0.66; 95% confidence interval (CI) 0.21 to 2.10; 2 studies; 43 participants; low-certainty evidence) or treatment failure defined as a two-step increase in activity based on SUN grading (RR 0.31; 95% CI 0.01 to 7.15; 1 study; 31 participants; low-certainty evidence). Further analysis using the individual trial definitions of treatment response and failure suggested a positive treatment effect of TNF inhibitors; a RR of treatment success of 2.60 (95% CI 1.30 to 5.20; 3 studies; 124 participants; low-certainty evidence), and RR of treatment failure of 0.23 (95% CI 0.11 to 0.50; 3 studies; 133 participants). Almost all the evidence was on adalimumab and the evidence on etanercept was very limited. For secondary outcomes, one study suggests that adalimumab may have little to no effect on risk of recurrence after induction of remission at three months (RR 2.50, 95% CI 0.31 to 20.45; 90 participants; very low-certainty evidence) and visual acuity, but the evidence is very uncertain; mean difference in longitudinal logMAR score change over six months was -0.01 (95% CI -0.06 to 0.03) and -0.02 (95% CI -0.07 to 0.03) using the best and worst logMAR measurement, respectively (low-certainty evidence). Low-certainty evidence from one study suggested that adalimumab treatment results in reduction of topical steroid doses at six months (hazard ratio 3.58; 95% CI 1.24 to 10.32; 74 participants who took one or more topical steroid per day at baseline). Adverse events, including injection site reactions and infections, were more common in the TNF inhibitor group. Serious adverse events were uncommon.Adalimumab appears to increase the likelihood of treatment success and decrease the likelihood of treatment failure when compared with placebo. The evidence was less conclusive about a positive treatment effect with etanercept. Adverse events from JIA-U trials are in keeping with the known side effect profile of TNF inhibitors. Standard validated JIA-U outcome measures are required to homogenize assessment and to allow for comparison and analysis of multiple datasets.

Induction of remission in biologic-experienced individuals with moderate to severe Crohn’s disease (CD) can be a challenge. We hereby present a case of CD with secondary non-response to infliximab. Adding methotrexate and switching to ustekinumab plus methotrexate did not stop the inflammatory process. Therefore, combination therapy with two classes of biologics consisting of ustekinumab and adalimumab plus methotrexate was initiated. He achieved clinical remission in 4 weeks and remained on triple therapy for 6 months which was subsequently tailored to adalimumab/methotrexate combination therapy due to insurance restriction on ustekinumab. He remained in remission for the duration of follow-up, 14 months after initiation of triple therapy and 8 months after switching to methotrexate/adalimumab biologic monotherapy. Triple therapy with anti-TNF, IL-12/23 inhibitor and methotrexate could potentially be an option for induction of remission in biologic-experienced individuals with good initial clinical response to anti-TNF agents.

Introduction and aims: The incidence of paediatric inflammatory bowel disease has increased in recent decades. The aim of the present study was to evaluate the role of proactive and serial monitoring of tumour necrosis factor (TNF) inhibitor levels to maintain clinical remission and mucosal healing in the follow-up of paediatric patients with Crohn disease (CD).Method: Prospective study that included all patients diagnosed with CD and treated with adali-mumab or infliximab between May 2015 and November 2020 who underwent serial and proactive monitoring of TNF inhibitor levels.Results: The study included 30 patients, 21 male (70%). The mean age at diagnosis was 11.3 years (SD, 2.0), the mean age at initiation of TNF inhibitors was 12.6 years (SD, 1.9) with a mean duration of follow-up of 27.1 +/- 9.1 months. Clinical remission was defined as a weighted Pediatric Crohn's Disease Activity Index (wPCDAI) of less than 12.5 and mucosal healing as a Mucosal Inflammation Non-invasive Index (MINI) of less than 8. During the follow-up, patients were in clinical remission in 87.1% of the visits, presented with mild disease in 11.4% and with moderate disease in 1.5%, and mucosal healing was assumed in 83% of the visits. The rates of clinical remission and mucosal healing at 1, 2, and 3 years of follow-up were 83.3%, 95.8%, 92.8%, and 86.7%, 87.5% and 85.7%, respectively. Conclusions: Proactive and serial monitoring of serum TNF inhibitor levels may make it possible for patients to maintain clinical remission and mucosal healing in the maintenance phase, with individualised optimization of the required dosage and minimization of secondary loss of response.(c) 2022 Asociacion Espanola de Pediatria. Published by Elsevier Espana, S.L.U. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Datos; Anticuerpos monoclonales biosimilares Dades; Anticossos monoclonals biosimilars Data; Biosimilar monoclonal antibodies Biosimilar monoclonal antibodies (mAbs) have been approved in the European Union since 2013 and have been demonstrated to reduce healthcare costs and to expand patient access. Biosimilarity is mainly established on the basis of demonstrated similarity of relevant quality attributes (QAs), determined by comprehensive physiochemical and functional analyses, and demonstration of bioequivalence. In addition, comparative efficacy/safety studies have been requested for all approved biosimilar mAbs so far, although the European Medicines Agency (EMA) Guidelines state that such confirmatory clinical trials may not be necessary in specific circumstances. In order to evaluate the degree of analytical similarity, how residual uncertainty regarding biosimilarity was resolved, and the value of clinical data, we analyzed the quality and clinical data packages for authorized adalimumab (7 products) and bevacizumab (5 products) biosimilars. The percentage of biosimilar batches meeting the similarity range for QAs, as defined by the biosimilar manufacturer based on a comprehensive characterization of the EU reference product (RP), was determined and clinical data were reviewed. Our analyses show that QAs of approved adalimumab and bevacizumab biosimilars have varying concordance with the EU-RP similarity range. In this study, we found that clinical efficacy data played a limited role in addressing quality concerns. Therefore, we encourage a regulatory review of the standards for clinical data requirements for mAb and fusion protein biosimilars. This study outlines a quality data driven approach for facilitating tailored clinical programs for biosimilars.

Background and Aims: Objective monitoring and effective early treatment using a treat-to-target approach are key to improving therapeutic outcomes in IBD patients. This study aimed to assess adherence to objective monitoring (clinical, biomarkers, and endoscopy) and its impact on clinical outcomes. Methods: A prospective, multicenter study included consecutive IBD patients starting on adalimumab therapy between January 2019 and December 2020. Disease activity, assessed by the Harvey-Bradshaw index (HBI), partial Mayo, C-reactive protein (CRP), fecal calprotectin (FCAL), and endoscopy were evaluated at adalimumab initiation and 3, 6, 9 and 12 months. Therapeutic drug monitoring, changes in treatment, drug sustainability, and clinical outcomes were assessed. Results: 104 IBD patients were enrolled (78.8% CD, median age 34.3 years, disease duration 9 years). During the 12 months follow-up, high adherence to clinical activity assessment was observed in both CD (81.3%- 87.7%) and UC patients (76.5-90.9%). CRP measurement decreased over time in both CD (37.3%-54.9%) and UC (29.4%-50.0%). The adherence to serial FCAL monitoring was low in CD (22.7-31.3%) and UC patients (17.6-56.0%). UC patients had higher adherence to early endoscopic assessment (

Ultrasound is valuable in tight control algorithms for Crohn's disease (CD). However, the correlation between ultrasonographic response and anti-tumor necrosis factor (TNF) drug levels remains unknown. Elucidating this correlation would be helpful in optimizing the use of anti-TNF drugs. Thus, the authors aimed to investigate this correlation.Between June 2020 and June 2021, all patients with CD who completed anti-TNF induction therapy were retrospectively included. Ultrasound was performed at week 0 and week 14, and proactive therapeutic drug monitoring of anti-TNF drugs was performed at week 14. The receiver operating characteristic (ROC) curve was used in the correlation analysis.Ninety-two patients (60 treated with infliximab and 32 with adalimumab) were included. At week 14, an ultrasonographic response was detected in 43 patients. Patients with ultrasonographic response had significantly higher median drug levels (5.9 mcg/mL for infliximab; 18.2 mcg/mL for adalimumab) than those without (0.9 mcg/mL for infliximab, P0.001; 4.8 mcg/mL for adalimumab, P0.001). The ROC curve showed a significant correlation between ultrasonographic response and anti-TNF drug levels (area under the curve = 0.79 for infliximab, P0.001; area under the curve = 0.86 for adalimumab, P0.001). The optimal cut-off values for infliximab and adalimumab correlated with ultrasonographic response were 5.0 and 10.5 mcg/mL, respectively. An incremental increase was observed in ultrasonographic response with higher anti-TNF drug levels.Higher anti-TNF drug levels are associated with an increased likelihood of ultrasonographic response in patients with CD.

Ustekinumab (UST), an antibody against the p40 subunit of interleukin-12/23, has been proven to be effective in patients with Crohn's disease (CD). However, large, long-term comparative studies of UST against anti--tumor necrosis factor (TNF) agents are lacking. We compared the effectiveness of anti-TNF agents and UST in CD patients without prior use of biologics.We used a large nationwide anonymized Japanese database containing administrative medical claims data and various related patient data. In a propensity score-matched cohort with similar clinical characteristics, 2-year effectiveness was compared between patients treated with infliximab or adalimumab (anti-TNF group) and those treated with UST (UST group). Primary outcomes were cumulative rates of hospitalization, surgery, and persistence.Among 53 540 CD patients, 7047 were extracted for eligibility, of which 5665 were treated with an anti-TNF agent and 1382 with UST. After propensity score matching, the cumulative hospitalization rates were comparable between anti-TNF and UST groups (P = 0.85; 25.3% vs 26.5% at 1 year, 33.8% vs 39.8% at 2 years). The cumulative surgery rates were also comparable between these groups (P = 0.46; 5.5% vs 5.1% at 1 year, 8.3% vs 8.4% at 2 years). The persistence rate at 1 year was higher in UST group (90.8% vs 92.5%), and that at 2 years was higher in anti-TNF group (81.2% and 74.6%); however, there was no significant difference in the cumulative persistence rate (P = 0.55).Anti-TNF agents and UST appear to have comparable effectiveness for CD patients without prior use of biologics.

Biologic therapy resulted in a significant positive impact on the management of inflammatory bowel disease (IBD) however data on the efficacy and side effects of these therapies in the elderly is scant.To evaluate retrospectively the drug sustainability, effectiveness, and safety of the biologic therapies in the elderly IBD population.Consecutive elderly (≥ 60 years old) IBD patients, treated with biologics [infliximab (IFX), adalimumab (ADAL), vedolizumab (VDZ), ustekinumab (UST)] followed at the McGill University Inflammatory Bowel Diseases Center were included between January 2000 and 2020. Efficacy was measured by clinical scores at 3, 6-9 and 12-18 mo after initiation of the biologic therapy. Patients completing induction therapy were included. Adverse events (AEs) or serious AE were collected during and within three months of stopping of the biologic therapy.We identified a total of 147 elderly patients with IBD treated with biologicals during the study period, including 109 with Crohn's disease and 38 with ulcerative colitis. Patients received the following biologicals: IFX (28.5%), ADAL (38.7%), VDZ (15.6%), UST (17%). The mean duration of biologic treatment was 157.5 (SD = 148) wk. Parallel steroid therapy was given in 34% at baseline, 19% at 3 mo, 16.3% at 6-9 mo and 6.5% at 12-18 mo. The remission rates at 3, 6-9 and 12-18 mo were not significantly different among biological therapies. Kaplan-Meyer analysis did not show statistical difference for drug sustainability (Current biologics were not different regarding drug sustainability, effectiveness, and safety in the elderly IBD population. Therefore, we are not able to suggest a preferred sequencing order among biologicals.

Bevezetés: A gyermekkori uveitisek kezelésében 2016 óta van lehetőség biológiai terápia alkalmazására. Szemészeti indikáció esetén adalimumabbal indítható terápia, mely egy tumornekrózisfaktor-ellenes monoklonális antitest. Célkitűzés: Klinikánk uveitisambulanciáján a gyermekkori uveitis miatt kezelt betegek adatainak retrospektív feldolgozása alapján a nem fertőzéses eredetű uveitis esetén alkalmazott adalimumabkezelésről szerzett tapasztalataink összefoglalása. Betegek és módszerek: Restrospektív módon elemeztük a Szegedi Tudományegyetem Szemészeti Klinikáján 2017. 01. 01. és 2021. 05. 31. között uveitis miatt gondozott gyermekek adatait. Eredmények: 2017 és 2021 között 46 uveitises gyermeket vizsgáltunk klinikánkon. A 23 lány és 23 fiúgyermek átlagéletkora 11 év volt. Közülük 21 gyermek szenvedett juvenilis idiopathiás arthritisben, 14 gyermeknél igazolódott infekció, 3 gyermeknél hematológiai betegség okozta az elváltozást, 8 gyermeknél idiopathiás eredetű volt a gyulladás. Krónikus, súlyos uveitis miatt 11 gyermeknél indítottunk biológiai terápiát az Európai Gyógyszerügynökség engedélye alapján. 3 fiúgyermek és 8 lánygyermek részesült adalimumabkezelésben, átlagéletkoruk 10 év volt. 6 gyermeknél anterior, 5 gyermeknél panuveitis indikálta a kezelést. Az adalimumab alkalmazási leirata szerint 2 évnél idősebb gyermekeknél a krónikus, nem fertőzéses eredetű szemgyulladás kezelésére alkalmazható, amikor a gyulladás a szem elülső részét érinti. Panuveitises betegeink esetén gyermekreumatológus segítségét kértük a biológiai terápia engedélyezéséhez. Következtetés: A gyermekkori uveitisek és azok terápiájának jelentősége kiemelkedő. A szemészeti kezelés célja a gyermekek látásélességének megőrzése és a szemészeti szövődmények megelőzése mellett a betegek megfelelő életminőségének biztosítása. Kiemelkedő fontosságú a korai diagnózis, a megfelelő terápia, a rendszeres kontrollvizsgálat. Az adalimumab hatékonyságát mutatja, hogy a kezelt gyermekek jelentős százalékánál sikerült a teljes látásélességet elérni, valamint a kezelés mellett újabb szemészeti szövődmény nem alakult ki. Orv Hetil. 2022; 163(35): 1402–1408.

Therapeutic Abs directed toward TNF-α display significant immunogenicity in humans, frequently leading to lower serum concentrations of the Ab that are associated with lower treatment efficacy. The enhanced incidence of immunogenicity observed with this class of therapeutics may be mediated by the expression of TNF-α as a homotrimer, both as a soluble serum protein and as a membrane-associated protein (mTNF-α) on the surface of dendritic cells. The TNF-α homotrimer enables the formation of polyvalent Ab–TNF-α immune complexes (ICs) that enhance binding to FcR and neonatal FcR. Polyvalent ICs and Ab bound to mTNF-α on the surface of dendritic cells can internalize, traffic to the lysosomes, and be processed for presentation by MHC molecules. To diminish immunogenicity caused by trafficking of ICs and mTNF-α to the lysosomes, we engineered a monovalent format of adalimumab with pH-sensitive binding to TNF-α. The engineered variant, termed AF-M2637, did not cross-link TNF-α trimers and consequently formed small, nonprecipitating ICs only. AF-M2637 bound TNF-α with high affinity at pH 7.4 (EC50 = 1.1 nM) and displayed a significantly faster dissociation rate than adalimumab at pH 6.0. No immune response to AF-M2637 was detected in mice following a single i.v. dose. In contrast, rapid immunization was detected following the injection of a single i.v. dose of adalimumab, monovalent adalimumab, or the bivalent form of the pH-sensitive variant. These data suggest that ICs and mTNF-α both contribute to the immunogenicity of adalimumab in mice and provide a general strategy for engineering less immunogenic therapeutic TNF-α Abs.

BI 695501 is an FDA-approved biosimilar to adalimumab reference product (RP). VOLTAIRE-X was a randomized clinical trial to assess outcomes with a biosimilar monoclonal antibody in line with the FDA requirements for designation as an 'interchangeable' biosimilar.The aim of this study was to assess whether multiple switches between adalimumab RP and BI 695501 lead to equivalent pharmacokinetics and a similar safety and immunogenicity profile compared with continuous adalimumab RP.We conducted a phase III, double-blind, randomized controlled trial between July 19, 2017, and April 16, 2019. There were 49 investigational sites across Europe and North America. Of 323 screened patients with moderate-to-severe chronic plaque psoriasis, 259 were treated with adalimumab RP during the run-in period. Of these, 118 and 120 were randomized to the continuous or switching arms, respectively. Interventions consisted of a run-in period with adalimumab RP 80 mg subcutaneously (SC) on Day 1, then 40 mg SC every other week (EOW) Weeks 2-12. Patients were then randomized to receive adalimumab RP 40 mg EOW Weeks 14-48 (continuous arm) or BI 695501 40 mg Weeks 14 and 16, adalimumab RP 40 mg Weeks 18 and 20, and BI 695501 40 mg EOW Weeks 22 to 48 (switching arm); all interventions were given SC. Primary endpoints were pharmacokinetics parameters, area under the plasma concentration-time curve (AUC238 patients (mean [standard deviation] age 44.9 [13.8]; 66.0% male) were treated in the switching (n = 118) or continuous arms (n = 120). Adjusted mean CPharmacokinetic equivalence was demonstrated, with highly similar efficacy and immunogenicity, and comparable safety observed in patients with chronic plaque psoriasis who received either adalimumab RP continuously or who switched between adalimumab RP and BI 695501.ClinicalTrials.gov: NCT03210259 (registered July 2017); Eudract.ema.europa.eu: 2016-002254-20.

Psoriasis is often treated with biologic therapies. While many patients see improvement in their symptoms with treatment, some achieve only partial success. In this post-hoc analysis we assess Psoriasis Area Severity Index (PASI) and Dermatology Life Quality Index (DLQI) results from patients who switched to RZB due to suboptimal results that originally received ADA (N = 53, IMMvent NCT02694523) or UST (N = 172, UltIMMa-1 [NCT02684370], UltIMMa-2 [NCT02684357]). For patients originally treated with ADA, after three doses of RZB, 83.3% of PASI 50 to

Background/Aims: This study assessed the efficacy and safety of adalimumab (ADA) and explored predictors of response in Korean patients with ulcerative colitis (UC).Methods: A prospective, observational, multicenter study was conducted over 56 weeks in adult patients with moderately to severely active UC who received ADA. Clinical response, remission, and mucosal healing were assessed using the Mayo score.Results: A total of 146 patients were enrolled from 17 academic hospitals. Clinical response rates were 52.1% and 37.7% and clinical remission rates were 24.0% and 22.0% at weeks 8 and 56, respectively. Mucosal healing rates were 39.0% and 30.1% at weeks 8 and 56, respectively. Prior use of anti-tumor necrosis factor-α (anti-TNF-α) did not affect clinical and endoscopic responses. The ADA drug level was significantly higher in patients with better outcomes at week 8 (P

An association between tumor necrosis factor (TNF)-α inhibitors and hypoglycemia has been detected in a few case reports and small case series; however, no relevant pharmacovigilance data have been published yet.The objective of this study was to detect and characterize relevant safety signals between hypoglycemia and TNF-α inhibitor use.Indication-focused disproportionality analysis was conducted to detect increased reporting of TNF-α-associated hypoglycemia compared with all other reports with the same indication during the same time period. Reporting odds ratios (RORs) with 95% confidence intervals (CIs) were calculated to determine disproportionality. To reduce potential confounding factors, adjusted RORs were further calculated by logistic regression to control for age, sex, diabetes status, and concomitant drugs that potentially affect blood glucose levels.In all, 1086 adverse drug reactions related to TNF-α inhibitors were reported as 'hypoglycemia'. There were no disproportionality signals of hypoglycemia in TNF-α inhibitor users with indication of inflammatory bowel disease. When TNF-α inhibitors were considered as a class, disproportion for hypoglycemia only emerged in indication of psoriasis (n = 267, ROR 1.20, 95% CI 1.02-1.41). In further analyses of specific TNF-α inhibitor type, significant RORs for hypoglycemia were found in indication of rheumatic disease, including adalimumab in ankylosing spondylitis (n = 37, ROR 1.97, 95% CI 1.28-3.04), psoriasis (n = 160, ROR 1.64, 95% CI 1.37-1.97), and rheumatoid arthritis (n = 230, ROR 1.35, 95% CI 1.16-1.56) and infliximab in psoriasis (n = 18, ROR 2.14, 95% CI 1.33-3.42). After adjusting for confounding factors, only the signals of adalimumab were stable.Our study identified some potential pharmacovigilance signals between hypoglycemia and TNF-α inhibitors, which warrants further validation.

Limited data are currently available regarding anti-tumor necrosis factor (TNF) use and outcomes in very early onset inflammatory bowel disease (VEOIBD) patients. We aimed to assess the long-term outcomes and time to progression to anti-TNF treatment in VEOIBD patients.We retrospectively reviewed IBD patients diagnosed under 6 years of age, between January 2005 and December 2019, from the British-Columbia (BC) Pediatric IBD database. Demographic data, disease characteristics, disease location and severity were documented. Data on anti-TNF treatment at initiation and during follow up including type of biologic, dosing, and response were collected. Kaplan-Meier curves were used to assess the number of years to progression to anti-TNF treatment and the parameters influencing commencement.Eighty-nine patients with VEOIBD were diagnosed during the study period. Median age at diagnosis was 3.8 years [interquartile range (IQR) 2.6-5.1], 45.3% had Crohn disease (CD) and 62.8% were males. Median duration of follow up was 6.39 years (IQR 3.71-10.55). Anti-TNF treatment was started on 39.5% of patients and 7.0% underwent surgery. Rapid progression to biologic treatment was associated with Perianal fistulizing disease or stricturing disease in CD patients ( P = 0.026, P = 0.033, respectively), and disease severity ( P = 0.017) in ulcerative colitis(UC) patients. The median dose of infliximab at 1 year was 10 mg/kg (IQR 7.5-11) and a median dose interval of 4.5 weeks (IQR 4-6). Clinical remission was reported in 61.8% of patients on their first biologic agent.The response rate was higher than previously reported and might be due to higher infliximab dosing with shorter infusion intervals than standard dosing.

Since the expiry of the patents on originator anti-TNF agents in Europe, France has authorized the sale of biosimilars. The penetration rate of anti-TNF agents and their biosimilars, and the cost savings driven by the introduction of biosimilars appears to vary widely. This study aimed to describe the market share of anti-TNFs and their biosimilars, and the cost savings generated by the introduction of biosimilars in French hospitals 5 years ago.The pharmaceutical component of the French national uniform hospital discharge data set database (PMSI) was used to study sales of infliximab, etanercept and adalimumab originators and biosimilars, and to estimate cost savings generated by the introduction of biosimilars onto the market, using the historical tariffs of the originators.The penetration rate of anti-TNF biosimilars in France in 76% for infliximab, 74% for etanercept and 77% for adalimumab. In 2020, Inflectra® (41%) was the Remicade® biosimilar with the highest sales volume, while Erelzi® (57%) and Amgevita® (64%) were the most widely sold biosimilars of Enbrel® and Humira® respectively. In terms of cost savings since the launch of biosimilars, overall, for all biosimilars taken together, over the 5-year period, a total of 824 million Euro was saved, in relation to the historical tariffs of the originators.This study shows firstly that the penetration rate of anti-TNF biosimilars in France 5 years after their launch is close to 80%. Secondly, we show that the cost savings generated by the use of biosimilars to anti-TNF agents exceed 820 million Euro over 5 years.

Matteo Megna, Luigi Fornaro, Luca Potestio, Maria Antonietta Luciano, Mariateresa Nocerino, Mario Delfino, Maria Guarino, Gabriella Fabbrocini, Elisa Camela Section of Dermatology - Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, NA, ItalyCorrespondence: Elisa Camela, Section of Dermatology - Department of Clinical Medicine and Surgery, University of Naples Federico II, Via Pansini 5, Naples, NA, 80131, Italy, Tel +39 - 081 – 7462457, Fax +39 - 081 – 7462442, Email elisacamela@gmail.comPurpose: To determine the efficacy and safety of adalimumab (ADA) and etanercept (ETA) biosimilars in elderly and children with psoriasis.Methods: A real-life retrospective observational study was conducted on pediatric (< 18 years) and geriatric (≥ 65 years) psoriasis patients treated with anti-TNF biosimilar agents referring to the Psoriasis Unit of the University of Naples Federico II, Italy, from January 2018 to January 2022. At baseline, demographic characteristics (age and sex), data on psoriasis duration and severity (measured by Psoriasis Area Severity Index [PASI] and body surface area [BSA]), presence of psoriatic arthritis if applicable, comorbidities, and previous psoriasis treatments were recorded. Patients were monitored by regular follow-ups (week 12, 24, 48 and 72) through clinical and haematological assessments and adverse events (AEs) were registered.Results: A total of 11 children and 23 elderly psoriasis patients were enrolled. Concerning children, 6 (54.5%) were under ADA biosimilar and 5 (45.5%) under ETA biosimilar. ETA and ADA biosimilars were equally effective and safe for up to 72 weeks (mean PASI and BSA < 3). No significant AEs were reported, and none discontinued treatment. In the elderly, 15 (65.2%) were treated with ADA biosimilar and 8 (34.8%) with ETA biosimilar. ETA and ADA biosimilars were equally effective up to 72 weeks (mean PASI < 4 and mean BSA < 5%). AEs (mainly mild) were registered in 9 subjects (39.1%). Also, 4 (17.4%) patients discontinued biologicals for secondary lack of efficacy (3, 75%) or AEs (1, 25%).Conclusion: Our study found that ADA and ETA biosimilars are effective and safe for the treatment of moderate-to-severe psoriasis in children and the elderly. No statistically significant efficacy and safety differences were found between ADA and ETA biosimilars in both children and the elderly. Geriatric patients displayed a higher discontinuation rate and side effects than the pediatric counterpart even if without approaching statistical significance.Keywords: psoriasis, etanercept, adalimumab, biosimilar, treatment

Background: Rheumatoid arthritis (RA) represents the most frequent form of inflammatory arthritis, affecting approximately 1% of the population worldwide. The introduction of novel therapeutic strategies targeting proinflammatory cytokines (TNF-α and interleukin-6) revolutionized the treatment of RA. This kind of treatment, although effective in a substantial portion of patients, may potentially cause many side effects. Among them, cardiovascular safety is one of the main concerns. Objectives: In the present study, we investigated the impact of treatment with anti-TNF-α and anti-IL-6 agents on heart function and levels of heart function biomarkers. Methods: To measure this, we used cardiac function biomarkers, such as NT-pro Brain Natriuretic Peptide, mid regional pro-Atrial Natriuretic Peptide, Galectin-3, and Heart-Type Fatty Acid-Binding Protein and compared them to patients treated with methotrexate as well as healthy controls. Results: Patients treated with biologics were characterized by low disease activity or were in remission. The disease activity in these groups was significantly lower than in the methotrexate group. All patients recruited for the study were characterized by normal heart function measured using echocardiography (EF>50%). With the exception of MR-proANP between tocilizumab and adalimumab (median: 1.01 vs. 0.49 nmol/L, p Conclusion: As this biomarker reflects potential heart injury, we suggest that heart damage proceeds in a continuous manner in RA patients despite effective treatment and attainment of remission/low disease activity. This finding, however, should be verified in a larger cohort of RA patients to ascertain if the routine assessment of H-FABP may be useful for the detection of patients with RA who are at risk of development of heart damage.

A 45-year-old woman presented to the emergency department (ED) with severe pain in the left lower abdomen, which was characterised as sharp, cramping, non-radiating and precipitated by food intake. She had experienced constipation for 3 days, which she treated with over-the-counter laxatives. She

IMPORTANCE: There is a need for observational studies to supplement evidence from clinical trials, and the target trial emulation (TTE) framework can help avoid biases that can be introduced when treatments are compared crudely using observational data by applying design principles for randomized clinical trials. Adalimumab (ADA) and tofacitinib (TOF) were shown to be equivalent in patients with rheumatoid arthritis (RA) in a randomized clinical trial, but to our knowledge, these drugs have not been compared head-to-head using routinely collected clinical data and the TTE framework. OBJECTIVE: To emulate a randomized clinical trial comparing ADA vs TOF in patients with RA who were new users of a biologic or targeted synthetic disease-modifying antirheumatic drug (b/tsDMARD). DESIGN, SETTING, AND PARTICIPANTS: This comparative effectiveness study emulating a randomized clinical trial of ADA vs TOF included Australian adults aged 18 years or older with RA in the Optimising Patient Outcomes in Australian Rheumatology (OPAL) data set. Patients were included if they initiated ADA or TOF between October 1, 2015, and April 1, 2021; were new b/tsDMARD users; and had at least 1 component of the disease activity score in 28 joints using C-reactive protein (DAS28-CRP) recorded at baseline or during follow-up. INTERVENTION: Treatment with either ADA (40 mg every 14 days) or TOF (10 mg daily). MAIN OUTCOMES AND MEASURES: The main outcome was the estimated average treatment effect, defined as the difference in mean DAS28-CRP among patients receiving TOF compared with those receiving ADA at 3 and 9 months after initiating treatment. Missing DAS28-CRP data were multiply imputed. Stable balancing weights were used to account for nonrandomized treatment assignment. RESULTS: A total of 842 patients were identified, including 569 treated with ADA (387 [68.0%] female; median age, 56 years [IQR, 47-66 years]) and 273 treated with TOF (201 [73.6%] female; median age, 59 years [IQR, 51-68 years]). After applying stable balancing weights, mean DAS28-CRP in the ADA group was 5.3 (95% CI, 5.2-5.4) at baseline, 2.6 (95% CI, 2.5-2.7) at 3 months, and 2.3 (95% CI, 2.2-2.4) at 9 months; in the TOF group, it was 5.3 (95% CI, 5.2-5.4) at baseline, 2.4 (95% CI, 2.2-2.5) at 3 months, and 2.3 (95% CI, 2.1-2.4) at 9 months. The estimated average treatment effect was -0.2 (95% CI, -0.4 to -0.03; P = .02) at 3 months and -0.03 (95% CI, -0.2 to 0.1; P = .60) at 9 months. CONCLUSIONS AND RELEVANCE: In this study, there was a modest but statistically significant reduction in DAS28-CRP at 3 months for patients receiving TOF compared with those receiving ADA and no difference between treatment groups at 9 months. Three months of treatment with either drug led to clinically relevant average reductions in mean DAS28-CRP, consistent with remission.

Every physician who cares for patients with non-infectious uveitis or other immune-mediated diseases seeks to recommend therapy by finding the optimal balance between likelihood of therapeutic bene...

INTRODUCTION: Dose escalation is one of the treatment approaches studied and suggested in advanced therapies for Crohn's disease (CD) and ulcerative colitis (UC). This study aimed to identify and characterize the dosing escalation patterns of advanced therapies in CD and UC. METHODS: Two systematic literature reviews (SLRs) were conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. MEDLINE®, Embase®, and Cochrane Library were searched for articles published between January 2011 and October 2021 and limited to non-interventional studies in English language. Congress and bibliographic searches were also conducted. Articles were screened by two independent researchers. Dose escalation patterns were described and summarized considering the regional regulatory label recommendation (in North America [NA] or outside of North America [ONA]). RESULTS: Among 3190 CD and 2116 UC articles identified in the Ovid searches, 100 CD and 54 UC studies were included in the SLR, with more studies conducted ONA. Most studies reported an initial maintenance dose pattern aligned with the lower starting dose per local regulatory label; however, several ONA studies (n = 13 out of 14) reported ustekinumab every 8 weeks as starting maintenance pattern in CD. In ONA studies, the median within-guideline escalation rates in CD and UC were 43% in ustekinumab (CD only), 33% and 32% for vedolizumab; 29% and 39% for adalimumab; and 14% and 10% for infliximab. Evidence regarding dose escalation patterns for tofacitinib, certolizumab pegol, and golimumab was limited. Some dose escalation patterns outside of label recommendations were observed including ustekinumab every 8 weeks to every 4 weeks and vedolizumab every 8 weeks to every 6 weeks. CONCLUSION: Dose escalation strategies are widely documented in the literature. The reported dose escalation patterns and escalation rates vary by region and by CD and UC. Most escalation patterns reported were aligned with regulatory recommendations while some reported more diverse or aggressive dose escalation. PROSPERO REGISTRATION: CRD42021289251.

Background: Factors like the number of biosimilar competitors and competitive pricing strategies from originator companies may influence price competition and biosimilar uptake.Objective: The aim of this study was to analyze multiple facets of biosimilar competition of TNF-alpha inhibitors in Europe by exploring the existence of a biosimilar first-mover advantage, pricing strategies of originator companies, and the evolution in patient access.Methods: Sales and volume data on biosimilar and originator infliximab, etanercept, and adalimumab between 2008 and 2020 were provided by IQVIA. Countries included 24 European Union Member States, Norway, Switzerland, United Kingdom, Serbia, and Bosnia and Herzegovina. Sales value was expressed as ex-manufacturer price per defined daily dose (DDD), and volume data were transformed into the number of DDDs per 1,000 inhabitants per day. Descriptive analyses were conducted based on the evolution in price per DDD, trends in biosimilar and originator market shares and utilization trends.Results: Market entry of the first biosimilars of infliximab and adalimumab resulted in a decrease of the volume-weighted average price (VWAP) per DDD by 13.6% and 0.9% on average, whilst the second biosimilars resulted in a decrease by 26.4% and 27.3%, respectively. The first and second etanercept biosimilars generated a similar decrease in the VWAP per DDD by 9.3% and 9.1% on average, respectively. Average market share captured by the first biosimilars was at least twice as large as the second biosimilars for all molecules. In addition, sharp reductions in price per DDD of Humira® in most countries indicated a pricing strategy resulting in low uptake of adalimumab biosimilars. Lastly, utilization of infliximab, etanercept, and adalimumab following biosimilar entry increased by an average of 88.9%, 14.6%, and 22.4%, respectively. However, introduction of (multiple) biosimilar competitors did not necessarily translate into increase in treatment access for all three molecules across some European countries indicating a shift in utilization from one molecule towards the other(s).Conclusion: Overall, this study revealed that biosimilar entry results in increased utilization and price reduction, although at a heterogenous rate among TNF-alpha inhibitors. Observed trends in market shares indicate a biosimilar first-mover advantage whereas pricing strategies considered to be anti-competitive can limit market uptake.

Background The objective of this post-hoc analysis was to assess the efficacy and safety of upadacitinib in psoriatic arthritis (PsA) patients with axial involvement. Methods Post-hoc analysis of SELECT-PsA 1 and SELECT-PsA 2 in patients randomized to upadacitinib 15 mg (UPA15), placebo (switched to UPA15 at week 24), or adalimumab 40 mg (ADA; SELECT-PsA 1 only). Axial involvement was determined by investigator judgement (yes or no; based on the totality of available clinical information, such as duration and characteristics of back pain, age of onset, and previous lab investigations and imaging, if available) alone, or investigator judgement and patient-reported outcome (PRO)-based criteria (Bath Ankylosing Spondylitis Disease Activity Index [BASDAI] ≥ 4 and BASDAI Q2 ≥ 4). Efficacy outcomes that describe axial disease activity, including BASDAI endpoints, such as change from baseline in the overall BASDAI score or proportion of patients achieving BASDAI50 (≥ 50% improvement from baseline), as well as Ankylosing Spondylitis Disease Activity Score (ASDAS) endpoints, such as mean change from baseline in overall ASDAS or proportion of patients achieving ASDAS inactive disease or low disease activity, were evaluated at weeks 12, 24, and 56, with nominal P-values shown. Treatment-emergent adverse events (TEAEs) are summarized through week 56. Results 30.9% of patients in SELECT-PsA 1 and 35.7% in SELECT-PsA 2 had axial involvement by investigator judgement alone; 22.6% (SELECT-PsA 1) and 28.6% (SELECT-PsA 2) had axial involvement by investigator judgement and PRO-based criteria. Greater proportions of patients achieved BASDAI50 with UPA15 versus placebo using either criterion, and versus ADA using investigator judgement alone, at week 24 in SELECT-PsA 1 (investigator alone: UPA15, 59.0%, placebo, 26.9%, P P = 0.015; investigator and PRO-based: UPA15, 60.4%, placebo, 29.3%, P P = 0.074), with comparable findings in SELECT-PsA 2. Similar results were observed with UPA15 for additional BASDAI and ASDAS endpoints at weeks 12 and 24, with improvements maintained at week 56. Rates of TEAEs were generally similar across sub-groups irrespective of axial involvement status. Conclusions PsA patients with axial involvement determined by predefined criteria showed greater BASDAI and ASDAS responses with UPA15 versus placebo, and numerically similar/greater responses versus ADA. Safety results were generally comparable between patients with or without axial involvement. Trial registration ClinicalTrials.gov: SELECT-PsA 1, NCT03104400; SELECT-PsA 2, NCT0310437.

This ALK-positive anaplastic large cell lymphoma (ALCL) case highlights the importance of considering ALCL in the setting of iatrogenic immunosuppression in hidradenitis suppurativa patients. Diagnosis of ALCL can be challenging in situations with very low viability/cellularity, negative CD3 and/or other T-cell markers, and immunosuppression.

This study explores the potential of gene polymorphisms in the canonical and noncanonical NF-kB signaling pathway as a prediction biomarker of anti-tumor necrosis factor (TNF)α response in Crohn's patients.A total of 109 Greek patients with Crohn's disease (CD) were recruited, and the genotype of TLR2 rs3804099, LTA rs909253, TLR4 rs5030728, and MAP3K14/NIK rs7222094 single nucleotide polymorphisms was investigated for association with response to anti-TNFα therapy. Patient's response to therapy was based on the Crohn's Disease Activity Index, depicting the maximum response within 24 months after initiation of treatment.Seventy-three patients (66.7%) were classified as responders while 36 as nonresponders (33.3%). Comparing allelic frequencies between responders and nonresponders, the presence of TLR2 rs3804099 T allele was associated with nonresponse (P = 0.003), even after stratification by anti-TNFα drugs (infliximab: P = 0.032, adalimumab: P = 0.026). No other association was identified for the rest of the polymorphisms under study. Haplotype analysis further enhanced the association of rs3804099 T allele with loss of response, even though the results were NS (P = 0.073).Our results suggest that polymorphisms in the canonical NF-kB pathway genes could potentially act as a predictive biomarker of anti-TNFα response in CD.

Psoriasis is a chronic systemic inflammatory disease, and hyperuricemia is a common comorbidity in patients with psoriasis. However, there are limited reports on the relationship between serum uric acid levels and biological treatment efficacy. The purposes of this study were to compare the differences in serum uric acid levels between patients with psoriasis and healthy controls and analyze the risk of hyperuricemia.A total of 196 patients with psoriasis and 191 age- and sex-matched healthy controls were enrolled in this retrospective cohort study. One hundred and twenty-seven patients with severe psoriasis were treated with biologics. Sixty-eight patients received adalimumab, and 59 patients received secukinumab. Serum uric acid levels were measured at baseline, week 24, and week 48 of treatment.Patients with psoriasis had higher serum uric acid levels than healthy controls (6.4 ± 1.7 mg/dL vs. 5.7 ± 1.5 mg/dL, P 0.001). Hyperuricemia was found in 33.7% (66/196) of patients with psoriasis, which was significantly higher than that in healthy controls (13.1% [25/191], P 0.001). Serum uric acid levels and hyperuricemia were not related to the severity of psoriasis ( P 0.05). No significant changes in serum uric acid levels and hyperuricemia were observed following adalimumab treatment ( P 0.05). The serum uric acid level in patients treated with secukinumab was 6.7 ± 1.6 mg/dL at week 24, which was not statistically different from that at baseline (6.6 ± 1.4 mg/dL, P = 0.885). Serum uric acid levels were significantly decreased at week 48 (6.3 ± 1.5 mg/dL vs. 6.6 ± 1.4 mg/dL, P = 0.007) in patients treated with secukinumab. Secukinumab had no significant effect on hyperuricemia either ( P 0.05).The serum uric acid levels and prevalence of hyperuricemia in patients with psoriasis were significantly higher than those in healthy controls. Secukinumab treatment for 48 weeks successfully decreased serum uric acid levels in patients with psoriasis, whereas adalimumab had no significant effect on serum uric acid levels.

Several therapies for psoriasis have been described as triggers of biologic-induced bullous pemphigoid (BIBP). The real incidence of BIBP in psoriatic patients is still unknown. Hence, we compilated and analyzed current literature to identify the frequency and burden of this adverse event for psoriasis patients treated with biologics.We systematically searched literature records involving psoriatic patients developing BIBP. Electronic searches were conducted in Pubmed, EMBASE and Scopus in April 2021. To assess the causal relationship between BP and the biologic drug, we applied the Naranjo adverse reaction probability scale and the Karch-Lasagna algorithm.Our systematic review identified 586 records through the three electronic databases. We identified 15 case reports of BIBP. These cases implicated two cases induced by adalimumab, three by efalizumab, three by etanercept, six by ustekinumab, and one case by secukinumab. Mean period of latency until the BIBP developed was time 5.12 ± 3.44 weeks for TNF-α blockers, and 28.66 ± 26.27 weeks for ustekinumab (This work presents an accurate estimation on the frequency and burden of BIBP. Ustekinumab presents with the largest evidence of BIBP, especially in patients with previous failure to TNF-α agents. Distinct patterns in the cytokinic pathways and clinical course exist between the BP induced by TNF-α blockers and ustekinumab. A close monitoring of skin condition is highly advisable in patients receiving biologic therapies for psoriasis. Knowledge of BIBP is of great importance to determine the preventive measures and select optimal treatment options.What's already known about this topic?The widespread use of biologic drugs has led dermatologists to encounter increasing situations of biologic-induced BP (BIBP).A lack of data exists on the real incidence of BIBP in psoriatic patients.BIBP is an important adverse event to know when managing patients with psoriasis using biologics.What does this study add?This work presents an accurate estimation on the raised burden of BIBP.Ustekinumab presents with the largest evidence of BIBP, especially in patients with previous failure to TNF-α agents.Mean period of latency until the BIBP developed was time 5.12 ± 3.44 weeks for TNF-α blockers, and 28.66 ± 26.27 weeks for ustekinumab.Distinct patterns in the cytokine pathways and clinical course exist between the BP induced by TNF-α blockers and ustekinumab.A careful screening of previous history of bullous diseases and a baseline immunologic study in psoriatic patients should be advisable prior to commencing any biologic therapy.A close monitoring of skin condition is highly advisable in patients receiving biologic therapies for psoriasis.

BACKGROUND & AIMS: SERENE UC (Study of a Novel Approach to Induction and Maintenance Dosing With Adalimumab in Patients With Moderate to Severe Ulcerative Colitis) evaluated the efficacy of higher adalimumab induction and maintenance dose regimens in patients with ulcerative colitis. METHODS: This phase 3, double-blind, randomized trial included induction and maintenance studies, with a main study (ex-Japan) and Japan substudy. Eligible patients (18-75 years, full Mayo score 6-12, centrally read endoscopy subscore 2-3) were randomized 3:2 to higher induction regimen (adalimumab 160 mg at weeks 0, 1, 2, and 3) or standard induction regimen (160 mg at week 0 and 80 mg at week 2); all received 40 mg at weeks 4 and 6. At week 8, all patients were rerandomized 2:2:1 (main study) to 40 mg every week (ew), 40 mg every other week (eow), or exploratory therapeutic drug monitoring; or 1:1 (Japan substudy) to 40 mg ew or 40 mg eow maintenance regimens. RESULTS: In the main study, 13.3% vs 10.9% of patients receiving the higher induction regimen vs standard induction regimen achieved clinical remission (full Mayo score ≤2 with no subscore >1) at week 8 (induction primary end point; P = .265); among week-8 responders, 39.5% vs 29.0% receiving 40 mg ew vs 40 mg eow achieved clinical remission at week 52 (maintenance primary end point; P = .069). In the integrated (main + Japan) population, 41.1% vs 30.1% of week-8 responders receiving 40 mg ew vs 40 mg eow achieved clinical remission at week 52 (nominal P = .045). Safety profiles were comparable between dosing regimens. CONCLUSION: Although primary end points were not met, a >10% absolute difference in clinical remission was demonstrated with higher adalimumab maintenance dosing. Higher dosing regimens were generally well tolerated and consistent with the known safety profile of adalimumab in ulcerative colitis. CLINICALTRIALS: gov, Number: NCT002209456. ispartof: GASTROENTEROLOGY vol:162 issue:7 pages:1891-1910 ispartof: location:United States status: published

This real-world study evaluated biologic treatment patterns in patients with moderate-to-severe ulcerative colitis (UC).IQVIA PharMetrics, IBM MarketScan, and Optum Clinformatics were pooled to identify UC patients with ≥1 claim for UC and ≥1 claim for adalimumab (ADA), golimumab (GOL), infliximab (IFX), or vedolizumab (VDZ). The index date for each biologic was the first claim for that biologic. Patients could be included in1 cohort if they switched biologics during the identification period. Continuous eligibility for medical/pharmacy benefits was required for 12 months before (baseline) and after (follow-up) the index date. Patients lacking claims for any biologic during baseline were categorized as bio-naïve; those with any biologic claim were categorized as bio-experienced. Persistence was defined as the proportion of patients that remained on the index biologic without a gap between claims of28 days for ADA,56 days for GOL, and112 days for IFX and VDZ. Dose titration was assessed among patients with ≥2 maintenance doses during follow-up among ADA, GOL, and VDZ patients.In total, 6,106 bio-naïve UC patients and 1,027 bio-experienced UC patients were identified. Patients treated with VDZ and IFX had the highest persistence followed by ADA and GOL patients for bio-naïve and bio-experienced, respectively. ADA patients had a numerically higher proportion of patients with 50% dose escalation, followed by VDZ and GOL; 50% dose reduction was observed in ≤1% patients.In this descriptive study of UC patients without confounder adjustment, VDZ persistence was numerically highest followed by IFX, GOL, and ADA across both populations.

Limited real-world data are available comparing multiple biologics on their adherence, persistence, and the use of concomitant biologics in the treatment of moderate-to-severe psoriasis in clinical practice. The objective was to compare persistence of and adherence to ixekizumab (IXE) treatment, as monotherapy or with concomitant medication, versus patients receiving other commonly prescribed biologics.Patients who newly initiated IXE, adalimumab (ADA), etanercept (ETN), secukinumab (SEC), or ustekinumab (UST) in IBM MarketScanA higher proportion of patients receiving IXE had had previous biologic therapies (50.3%) versus other biologics (ADA: 9.1%, ETN: 10.9%, SEC: 33.9%, UST: 19.7%). Patients treated with IXE showed statistically (p 0.001) greater persistence than patients treated with SEC, ADA, UST, or ETN at both 1-year follow-up and up to 3 years of follow-up. Adherence for patients treated with IXE was significantly (p 0.001) higher compared to ADA, ETN, and UST at both 1-year follow-up and up to 3 years of follow-up. There was no significantly higher adherence in patients treated with IXE compared to those treated with SEC at 1-year follow-up, but IXE had higher adherence than SEC (p 0.05) at 1-3 year follow-up. IXE showed longer time on monotherapy than ADA (p 0.001), ETN (p 0.001), SEC (p 0.05), and UST (p 0.001) for both 1-year and 1-3 year follow-up. Sensitivity analyses on persistence, adherence, and monotherapy with further model adjustments after IPTW confirmed the findings.Patients treated with IXE were more persistent on and adherent to treatment and remained on monotherapy longer compared to those on all other commonly prescribed biologics combined or with individual biologics.

Background: PYRAMID was an international post-marketing registry that aimed to collect data on the long-term safety and effectiveness of adalimumab treatment per local standard of care in patients with moderately to severely active Crohn's disease (CD). Here, we present post hoc analyses of observational data from patients who became pregnant while participating in this registry and receiving adalimumab. Methods: From the subpopulation of patients receiving adalimumab who became pregnant while taking part in PYRAMID, data on patient characteristics, pregnancy outcomes, and complications of pregnancy were analysed retrospectively. Results: Across the PYRAMID registry, 293 pregnancies occurred in patients who had gestational adalimumab exposure (average disease duration at last menstrual period: 8.6 years), resulting in 300 pregnancy outcomes. A total of 197 pregnancies (67.2%) were exposed to adalimumab in all trimesters per physician's decision. Of the known reported outcomes (96.3%), 81.7% (236/289) were live births, 10.4% (30/289) were spontaneous abortions, 4.8% (14/289) elective terminations, 2.8% (8/289) ectopic pregnancies, and 0.3% (1/289) was a stillbirth. Congenital malformations (pulmonary valve stenosis and tricuspid valve incompetence) were reported in one infant. In addition to the pregnancy outcomes described above, 23 complications of pregnancy were reported in 20 patients. Conclusions: This analysis showed that adalimumab treatment in patients with CD, who became pregnant whilst participating in the PYRAMID registry, contributed no additional adverse effects during the pregnancy course or on pregnancy outcomes.

Nonadherence to medication is common in patients with inflammatory bowel disease (IBD) and can result in disease complications, therapy escalation, and the need for corticosteroids. The aim of this study was to assess the adherence to self-administered subcutaneous biologic medications prescribed for IBD and to identify the risk factors for nonadherence.A retrospective cohort study on IBD patients initiated on subcutaneous biologic therapy between January 2016 and July 2019 was performed. Medical records were retrospectively reviewed for collection of demographic and IBD data. Medication possession ratios (mMPRs) during the first 12 months of treatment and at the end of the follow-up period (global, 42 months) were calculated. Nonadherence was defined as an mMPR of90%. Multiple regression analysis was performed to assess the risk factors for nonadherence to therapy.A total of 154 patients (84 male and 70 female; mean age at biologic treatment initiation, 36±14 years; Crohn's disease, n=118; ulcerative colitis, n=31; indeterminate colitis, n=5) were included; 121 received adalimumab (ADA) and 33 received ustekinumab (UST); 63% were naive to anti-TNF therapy, while 16.9% previously received more than two biologic treatments. Mean time from IBD diagnosis to subcutaneous biological agent use was 16±10 months. Mean duration of subcutaneous agent use was 17.6 (SD, 11.0) and 17.08 (SD, 6.8) months for ADA and UST, respectively. Global nonadherence (mMPR≤90%) rate was 6.6% for all patients receiving subcutaneous treatment, 6.3% for ADA, and 6.5% for UST. Nonadherence during the first 12 months of treatment (n=98) was 6.1% for all patients, 2.7% for ADA, and 16% for UST. In the multivariate analysis, UST use was independently associated with higher nonadherence only within the first 12 months (OR, 6.7; 95% CI, 1.1-39.5).High global adherence to self-administered subcutaneous biologic treatment was shown in our study, with higher rates of adherence to ADA than to UST within the first 12 months.

Pharmacoeconomic studies comparing the cost of adalimumab biosimilars versus the originator and conventional drugs in psoriasis are lacking.To assess the cost per responder of adalimumab biosimilars versus the originator and methotrexate for psoriasis treatment. A cost per responder analysis comparing adalimumab biosimilars MSB11022 (Idacio®) and ABP 501 (Amgevita®), and methotrexate to the originator (Humira®) was performed. The incremental cost per responder was calculated by multiplying the cost of treatment based on the perspective of the National Healthcare System and number needed to treat for each therapy.Considering the PASI75 response rate at 16 weeks, the cost per responder for MSB11022 and ABP 501 compared to the originator was € 500 versus 1,831 and € 968 versus 1,949, respectively. For the same endpoint, the cost per responder for subcutaneous or oral methotrexate was € 543 or 34 compared to 2,117 for adalimumab originator. At an indirect comparison among methotrexate, MSB11022 and ABP 501, the costs per PASI75 responder at week 16 were 2%, 26%, 27% and 50% of that of the originator, respectively.The use of biosimilars was confirmed as a valuable pharmacoeconomic strategy to lower healthcare cost in patients with psoriasis.

Biologic therapies are effective at inducing and maintaining remission in people with inflammatory bowel disease (IBD). Previous studies have associated TNF-a inhibitors with weight gain, however, it is unclear if this is a class-specific effect or a manifestation of good disease control. To clarify this issue, a retrospective study was undertaken to examine weight changes over time during therapy with different biologic agents.Adult patients with IBD who received any biological therapy for at least 12 months, between 2008 and 2020, were identified at two specialised IBD services. Demographic, disease, and therapy-related data were examined. Weight change and patterns thereof were examined for each specific therapy and relationships amongst weight outcomes and various predictive factors explored.Of 294 patients (156 females), 165 received Infliximab (IFX), 68 Adalimumab (ADA), 36 Vedolizumab (VDZ) and 25 Ustekinumab (UST). There was a statistically significant weight gain over time in the IFX and VDZ groups and more weight gain in the IFX vs ADA and VDZ vs ADA at most time points. Three weight trajectories were identified: around 95% of patients had small weight loss or a modest weight gain but 5% of patients, most of whom were on IFX had marked weight gain (24.3 kg). Having a baseline high BMI, being female, having an initiation CRP ≤ 5 or albumin 35 reduced the odds of major weight gain.Weight gain in biologic treated IBD patients appears to be associated with clinical factors (male gender, high CRP, low albumin) and therapy-specific factors.

Guselkumab effectively treats moderate-to-severe psoriasis.To evaluate the cumulative safety experience of guselkumab using pooled data from the VOYAGE 1 and 2 studies through 5 years.Patients were randomized to guselkumab, placebo with crossover to guselkumab at week 16, or adalimumab. The studies were identical through week 24. VOYAGE 1 evaluated continuous guselkumab treatment (adalimumab-crossover-to-guselkumab at week 52), while VOYAGE 2 assessed randomized withdrawal/retreatment (weeks 28-76). Open-label guselkumab treatment was administered starting at week 52 in VOYAGE 1 and week 76 in VOYAGE 2 and continued through week 252. Pooled safety data were adjusted by exposure and analyzed in the guselkumab groups, including placebo-crossover-to-guselkumab (n = 1221) and adalimumab-crossover-to-guselkumab (n = 500), through week 264.Patients were followed for a total of 7166 patient-years (PY). Overall, 1349 of 1721 guselkumab-treated patients (78.4%) continued treatment through week 252. The rates of adverse and serious adverse events were 149/100 PY and 5.01/100 PY, respectively. Rates of adverse events of interest were low: serious infections (0.85/100 PY), nonmelanoma skin cancer (0.34/100 PY), malignancies other than nonmelanoma skin cancer (0.45/100 PY), and major adverse cardiovascular events (0.29/100 PY). Year-to-year variability was evident, but no increasing trend was observed.No direct treatment comparisons were possible after week 52.The safety profile remained consistent and favorable during 5 years of continuous guselkumab treatment of psoriasis.

The characterization of a biosimilar drug HS016, the reference product adalimumab (Humira), and their biosimilarities were determined using physical chemistry and functional similarity tests. The primary and higher order structures, size and charge variants, glycosylation profiles, and in vitro potency of both antibodies were characterized both for unstressed and stability samples. Slight differences were observed in the relative levels of methionine oxidation, low molecular weight components, terminal lysine variant, high mannoses and galactosylated glycans between HS016 and Humira. However, no differences in antigen binding activity, Fc receptor affinity, antibody-dependent cell-mediated cytotoxicity or complemented-dependent cytotoxicity were found. The primary and higher order structures, physicochemical properties, and biological activity of HS016 and adalimumab were similar.

Pharmacoeconomic studies examining the cost-effectiveness of adalimumab biosimilars versus methotrexate in real-life settings are limited. To assess the cost per responder from the perspective of the National Health System of adalimumab biosimilars versus methotrexate for psoriasis treatment in a real-life setting. A cost-per responder analysis comparing adalimumab biosimilars MSB11022 (Idacio®) and ABP 501 (Amgevita) versus subcutaneous methotrexate was performed. The incremental cost per responder was calculated by multiplying the cost of treatment (including the discounts, as published in the framework agreement of the Veneto region) and the number needed to treat each therapy. The clinical efficacy measures were defined as being on treatment (i.e., retention rate) at weeks 24 and 52. A total of 712 adult patients with moderate-to-severe chronic plaque psoriasis consecutively admitted to the outpatient clinic from January 2021 to December 2022 were included; 160 were treated with ABP 501 (Amgevita), 250 with MSB11022 (Idacio) and 302 with methotrexate. The retention rates of Amgevita, Idacio and methotrexate at week 24 were 86%, 90% and 78%, and 81%, 82% and 63% at week 52, respectively. The cost per responder at week 24 was €674 for Amgevita, €366 for Idacio and €264 for methotrexate, respectively; at week 52, was €1430 for Amgevita® €799 for Idacio® and €652 for methotrexate, respectively. The real-life cost-effectiveness of biosimilar drugs is largely influenced by discount rates. The week 52 cost-effectiveness of Idacio is comparable to subcutaneous methotrexate. The lowering of the cost of biosimilar drugs makes them a more accessible therapeutic option and they also can be introduced earlier in the treatment of moderate-to-severe psoriasis.

This is a Rapid Review Protocol.

In this case series, ustekinumab therapy demonstrated efficacy in some patients with severe hidradenitis suppurativa previously treated with adalimumab and/or infliximab. Larger prospective studies are needed to evaluate ustekinumab as a treatment option for recalcitrant hidradenitis suppurativa.

Verrucous psoriasis (VP) is a rare histologic variant of psoriasis. To date, fewer than 40 cases have been reported, with pediatric cases representing an exceedingly small fraction. Treatment options are limited, and the disease is often refractory to conventional methods. Herein, we report a case of VP in an adolescent male which previously failed biologic and systemic therapy with adalimumab and acitretin, respectively, ultimately responding with great success to ixekizumab in combination with topical corticosteroids. J Drugs Dermatol. 2022;21(8):891-893. doi:10.36849/JDD.6626R1.

Introduction The aim of this nationwide, prospective post-marketing surveillance was to assess the safety and effectiveness of up to 52 weeks of adalimumab treatment in patients with noninfectious intermediate, posterior, or panuveitis in Japanese clinical practice. Methods This post-marketing surveillance was conducted at 60 medical facilities in Japan from October 2016 to June 2020. Patients with noninfectious intermediate, posterior, or panuveitis who were administered adalimumab (Humira(R), AbbVie Inc.) for the first time were eligible. Subcutaneous adalimumab was initially administered at 80 mg, followed by 40 mg 1 week later, then 40 mg every 2 weeks. Safety measures included the incidence of adverse events (AEs) and adverse drug reactions (ADRs; primary endpoint). Effectiveness measures included visual acuity, anterior chamber cell grade, vitreous haze, macular edema, foveal retinal thickness, uveitis recurrence rate, and oral corticosteroid dose. Health-related quality of life was evaluated using the 25-item National Eye Institute Visual Function Questionnaire (VFQ-25). Results During 52 weeks of surveillance, AEs and ADRs occurred in 70 (27.9%) and 47 (18.7%) of 251 patients, respectively. The most common ADR was infection (21/251 patients; 8.4%), including serious infections in eight (3.2%) patients. ADRs were more frequent in patients >= 65 years of age, those with concurrent diseases, and those with past medical history. Four patients developed tuberculosis. The uveitis recurrence rate was 24.8% (61/246 patients). All effectiveness measures tended to improve from baseline to week 52, and mean corticosteroid doses decreased. Clinically meaningful changes were observed for most VFQ-25 subscales. Conclusions The safety profile of adalimumab was generally consistent with previous reports, and no new safety concerns were identified.

Pyoderma gangrenosum (PG) is a rare chronic skin disease characterised by painful skin ulcers. There are no treatment guidelines for PG, but systemic treatments including biologics are often used. Recently, adalimumab (ADA), a fully human monoclonal antibody against tumour necrosis factor, was approved for refractory PG treatment in Japan. Herein, we report a case of rheumatoid arthritis with refractory PG 2 months after orthopaedic surgery of the foot during treatment with low-dose etanercept and methotrexate. Although adding a moderate dose of glucocorticoid did not improve her PG, the patient showed a remarkable response after switching from etanercept to ADA in a higher dose than that used to treat rheumatoid arthritis. This higher dose of ADA may be effective for the treatment of refractory PG after the failure of other tumour necrosis factor inhibitors.

Rheumatoid factor (RF) binds to the fragment crystallizable (Fc) portion of immunoglobulin. It could bind to the Fc portion of anti-TNF inhibitors (TNFi) and attenuate the clinical efficacy. We tried to determine whether the therapeutic efficacy of TNFi with Fc might be lower than that of TNFi without Fc in rheumatoid arthritis (RA) patients with high titres of RF. The Kansai Consortium for Well-being of Rheumatic Disease Patients (ANSWER) cohort is an observational multi-center registry of patients with RA in the Kansai district of Japan. RA patients treated with TNFi were included and divided into two groups based on the structural characteristics between TNFi with Fc (infliximab, adalimumab, golimumab, and etanercept) and TNFi without Fc (certolizumab pegol). Patients were classified into 4 groups according to RF titre quartiles. The sequential disease activity score in 28 joints using erythrocyte sedimentation rate (DAS28-ESR) was compared by Mann-Whitney U test between TNFi with and without Fc in each RF titre group. Multiple linear regression analysis was used to analyze the effect of TNFi without Fc for the change of DAS28-ESR adjusted after potential confounders. A total of 705 RA patients were classified into four groups (RF

Objectives Biologics are new treatment alternatives in Takayasu arteritis (TA), although data in childhood are limited. The aim of this study was to share our experience in seven childhood-onset TA patients who received a TNF-α inhibitor (adalimumab) or an IL-6 receptor inhibitor (tocilizumab) and the effect of switching therapy. Methods We retrospectively evaluated the medical treatment records of seven patients with TA, followed between August 2005 and January 2021 at the Pediatric Rheumatology Department of Hacettepe University Faculty of Medicine. Results The median age of patients was 14 (IQR 4) years, and six were female. All of the patients had severe disease and high acute-phase reactants. The patients initially received only steroids or steroids+CYC. Prednisone was decreased, and biologic agents were started once the acute phase reactants decreased, and the Indian Takayasu Activity Score (ITAS) returned to normal. Initially, four patients received tocilizumab (TCZ) [median 25.5 (IQR 41) months] and three patients received adalimumab (ADA) [median 13 (IQR 31) months]. However, due to the progression of MR angiography findings or persistent elevation in acute-phase reactants, the biologic agents were switched from TCZ to ADA in four patients and from ADA to TCZ in three patients. The patients' median follow-up time after changing was 50 (IQR 77) months, and median ITAS was evaluated as ‘0’ after 2 (IQR 4) months. Conclusions In conclusion, both TNF-α and IL-6 inhibitors are effective alternatives in treating patients with childhood-onset TA. However, prospective randomized controlled trials are needed for the comparison of their effectiveness.

This study aimed to investigate the efficacy and safety of antitumor necrosis factor-alpha (TNF-α) therapy using adalimumab in patients with chronic schizophrenia. This is a randomized, double-blind, placebo-controlled clinical trial carried out at Roozbeh Hospital (Tehran, Iran) from June 2020 to October 2021. The patients were randomly divided into two parallel adalimumab + risperidone and placebo + risperidone groups. Participants in the intervention group received adalimumab subcutaneous injection (40 mg) by pen-injector at weeks 0 and 4. Using the Positive and Negative Symptoms Scale (PANSS), patients' positive and negative symptoms were assessed at weeks 0, 4, and 8. Forty patients (20 in each group) were included. PANSS total (t = 4.43, df = 38, P0.001), negative (t = 2.88, df = 38, P = 0.006), and general psychopathology (t = 4.06, df = 38, P0.001) scores demonstrated a significantly greater decline in adalimumab compared with the placebo group from baseline study endpoint. However, improvement of PANSS positive subscale scores showed no significant difference from the baseline study endpoint. There was no significant between-group difference regarding levels of C-reactive protein, interleukin (IL)-1β, TNF-α, IL-6, and IL-8 at baseline and also at the week 8 visit (P0.05 for all). The current study found adalimumab adjunctive therapy effective in treating schizophrenia, particularly its negative and general psychopathology symptoms, with no side effects.

In this 52-week, phase 3 open-label study, efficacy and safety of adalimumab were evaluated in Japanese patients with active ulcers due to pyoderma gangrenosum (PG) during a 26-week treatment period and another 26-week extension period. Patients received adalimumab 160 mg at week 0, 80 mg at week 2, and 40 mg every week from week 4. At week 26, 12 of 22 patients (54.5%, p 0.001) achieved the primary efficacy endpoint of PG area reduction 100 (PGAR 100, complete skin re-epithelialization) for the target ulcer. Nine patients with Physician's Global Assessment (PGA) score of 1, 2, or 3, including four patients achieving PGAR 100, continued into the extension period. During the extension period, six of nine patients (66.7%) achieved PGAR 100 for the target PG ulcer at 52 weeks; one patient who achieved PGAR 100 before week 26 experienced a relapse 162 days after achieving this endpoint. Six patients achieved PGA 0 by week 52, and one patient reported new ulcers at day 57 of the extension period. Continued improvements from study baseline to week 52 were observed in pain (mean [95% CI] -4.0 [-6.5 to -1.5] numeric rating scale) and Dermatology Life Quality Index (-7.3 [-15.1 to 0.4]). In addition to the adverse events (AE) reported in 18 patients (including four serious AE) through week 26 (most commonly infections [n = 11]), there was one 1 additional AE (infection) during the extension period. These results suggest that adalimumab is effective and generally well tolerated in Japanese patients with active PG ulcers.

No studies evaluating the rapidity of response to biological therapies are available for Crohn's disease (CD). The aim of this study was to evaluate rapidity of onset of clinical response and impact on quality of life (QoL) of adalimumab therapy in adult anti-TNF-naïve patients with moderately-to-severely active CD.RAPIDA was an open-label, single-arm, prospective, multicenter clinical trial. Adult patients with moderately-to-severely active luminal CD, anti-TNF-naïve, and unresponsive to conventional therapy were treated with adalimumab. Clinical disease activity, QoL and inflammatory biomarkers were measured at day 4, and weeks 1, 2, 4, and 12 after treatment initiation.Eighty-six patients were included in the intention-to-treat (ITT) analyses. Clinical disease activity was reduced from a median of 9.0 points to 6.0 points at day 4. Clinical response (≥ 3-point reduction in the Harvey-Bradshaw Index, HBI) was achieved by 61.6% (d4) and 75.6% (w1) of patients in the ITT population (median 2.5 days) and with non-responder imputation (NRI), by 55.8% and 53.4%, respectively. The proportion of patients in clinical remission (HBI5) at weeks 2 and 4 in the ITT population was 54.7% and 62.8%, respectively (median 7.0 days), and 38.4% and 45.3% in the NRI population. All QoL scores significantly improved and inflammatory biomarkers significantly decreased from day 4 onwards (p0.0001).Rapid clinical response and remission, improvement in QoL and fatigue, and a reduction of inflammatory biomarkers were achieved with adalimumab as early as day 4 in adult anti-TNF-naïve patients with moderately-to-severely active CD.