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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.

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

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

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...

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.

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.

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.

This review article serves to assess the consistency of recommendations from guidelines on biologic agents for psoriasis, based on the quality evaluation of psoriasis Clinical Practice Guidelines (CPGs).We conducted a systematic literature search to identify CPGs that provide recommendations on diagnosis and treatment for psoriasis. Four reviewers performed a quality assessment of the included CPGs with the Appraisal of Guidelines Research and Evaluation II (AGREE II) Instrument.A total of 51 sets of CPGs from 22 medical societies or separate working groups fulfilled the inclusion criteria. The overall quality of the eligible sets of guidelines was moderate to high, with an overall average score of 55%. The highest domain scores were Score and Purpose (70%) and Clarity of Presentation (68%). A total of 95 biologic agent recommendations were extracted from the 18 recommended CPGs. Three biologic agents (Etanercept, Adalimumab, Ustekinumab) were recommended for pediatric patients. Three biologic agents (Adalimumab, Ustekinumab, Secukinumab) were recommended as first-line biologic agents for adults with psoriasis.The overall methodological quality of CPGs for psoriasis is medium to high. More attention should be paid to applicability in guideline development. The recommendations and the basis for them among various sets guidelines were almost consistent.

Background Patients with inflammatory bowel diseases (IBD), specifically those treated with anti-tumor-necrosis-factor (TNF)α biologics are at high risk for vaccine preventable infections. Their ability to mount adequate vaccine responses is unclear. Aim To assess serologic responses to mRNA-COVID-19 vaccine, and safety profile, in patients with IBD stratified according to therapy, compared to healthy controls (HC). Methods Prospective, controlled, multi-center Israeli study. Subjects enrolled received two BNT162b2 (Pfizer/BioNTech) doses. Anti-spike antibodies levels and functional activity, anti-TNFα levels and adverse events (AEs) were detected longitudinaly. Results Overall 258 subjects: 185 IBD (67 treated with anti-TNFα, 118 non-anti-TNFα), and 73 HC. After the first vaccine dose all HC were seropositive, while ∼7% of patients with IBD, regardless of treatment, remained seronegative. After the second dose all subjects were seropositive, however anti-spike levels were significantly lower in anti-TNFα treated compared to non-anti-TNFα treated patients, and HC (both P, Graphical abstract

Immunodeficiency-associated lymphoproliferative disorders are associated with latent infection by Epstein-Barr virus (EBV). Most cases of EBV-positive immunodeficiency-associated lymphoproliferative disorders arise from B cells, although some are of T-cell or natural killer origin. Cutaneous involvement is unusual and sporadically reported in the literature. We describe a rare case of an EBV-positive T-cell lymphoma presenting in the skin of a 32-year-old woman using adalimumab for neurosarcoidosis.

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.

Summary Background There is a growing armamentarium for the treatment of moderate-to-severe ulcerative colitis. We aimed to compare the relative efficacy and safety of biologics and small molecule drugs for the treatment of patients with moderate-to-severe ulcerative colitis. Methods In this systematic review and network meta-analysis, we searched MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials without language restrictions for articles published between Jan 1, 1990, and July 1, 2021. Major congresses' databases from Jan 1, 2018, to July 3, 2021, were reviewed manually. Phase 3, placebo-controlled or head-to-head randomised controlled trials (RCTs) assessing the efficacy and safety of biologics or small molecule drugs as induction or maintenance therapies for patients with moderate-to-severe ulcerative colitis were included. Phase 2 RCTs were excluded because of their small sample sizes and inclusion of doses not further explored in phase 3 RCTs. Summary data from intention-to-treat analyses were extracted from included reports by JSL and PAO. The primary outcome was the induction of clinical remission. A network meta-analysis was done under the frequentist framework, obtaining pairwise odds ratios (ORs) and 95% CIs. The surface under the cumulative ranking (SUCRA) was used to rank the included agents for each outcome. Higher SUCRA scores correlate with better efficacy, whereas lower SUCRA scores correlate with better safety. Maintenance data on efficacy for treat-straight-through and randomised responder trials are also presented. This study is registered with PROSPERO, CRD42021225329. Findings Our search yielded 5904 results, from which 29 studies (four being head-to-head RCTs) fulfilled our inclusion criteria and were included. Of these, 23 studies assessed induction therapy with either a biologic or small molecule drug, comprising 10 061 patients with ulcerative colitis. A risk of bias assessment showed a low risk of bias for most of the included studies. Upadacitinib was significantly superior to all other interventions for the induction of clinical remission (infliximab [OR 2·70, 95% CI 1·18–6·20], adalimumab [4·64, 2·47–8·71], golimumab [3·00, 1·32–6·82], vedolizumab [3·56, 1·84–6·91], ustekinumab [2·92, 1·31–6·51], etrolizumab [4·91, 2·59–9·31], tofacitinib [2·84, 1·28–6·31], filgotinib 100 mg [6·15, 2·98–12·72], filgotinib 200 mg [4·49, 2·18–9·24], and ozanimod (2·70, 1·18–6·20), and ranked highest for the induction of clinical remission (SUCRA 0·996). No differences between active interventions were observed when assessing adverse events and serious adverse events. Vedolizumab ranked lowest for both adverse events (SUCRA 0·184) and serious adverse events (0·139), whereas upadacitinib ranked highest for adverse events (0·843) and ozanimod ranked highest for serious adverse events (0·831). Interpretation Upadacitinib was the best performing agent for the induction of clinical remission (the primary outcome) but the worst performing agent in terms of adverse events in patients with moderate-to-severe ulcerative colitis. Vedolizumab was the best performing agent for safety outcomes. With the paucity of direct comparisons in the published literature, our results might help clinicians to position drugs in treatment algorithms. Funding None.

Optic neuritis (ON) is a rare complication of tumor necrosis factor (TNF)-α inhibitors. The autoantibody serostatus, treatment, and outcome of TNF-α inhibitor-associated ON remain unclear. We herein report a 50-year-old woman with ON following adalimumab therapy. The patient presented with decreasing visual acuity of the right eye, quickly diminishing to light perception. Anti-aquaporin-4 (anti-AQP4) and anti-myelin oligodendrocyte glycoprotein antibodies were negative. Adalimumab was discontinued, and intravenous methylprednisolone and intravenous immunoglobulin (IVIg) were administered. However, her visual acuity improved only up to counting fingers. IVIg may be ineffective depending on the pretreatment severity.

Nowadays, tumor necrosis factor-alpha (TNFα) inhibitors have revolutionised the treatment of inflammatory arthritides by demonstrating efficacy with an acceptable toxicity profile. However, autoimmune phenomena and clinical entities have been reported ranging from an isolated presence of autoantibodies to full-blown autoimmune diseases, including drug-induced lupus (DIL).Case Presentation:A 62-year-old woman with rheumatoid arthritis (RA) refractory to methotrexate and prednisone was treated with adalimumab (ADA). 4 months later, she presented acute cutaneous eruptions after sun exposure, positive ANA (1/640 fine speckled pattern), Ro (SSA) and anti- Smith (Sm) antibodies with no other clinical or laboratory abnormalities. The diagnosis of DIL was made, ADA was discontinued, and she was treated successfully with prednisone plus local calcineurin inhibitors.Conclusion:Thus, we review the literature for cases of DIL development in patients treated with TNFα inhibitors. Rheumatologists should be aware of the possible adverse events and the requirement of careful clinical evaluation and monitoring.

Background/Aims: Current literature is lacking in studies comparing the incidence of adverse events (AEs) in patients with inflammatory bowel diseases (IBD) treated with adalimumab (ADA) or vedolizumab (VDZ) in a real-life scenario. Therefore, our primary aim was to compare the AEs occurring in patients taking ADA to those of patients taking VDZ. Methods: In this single center study, data on AEs from IBD patients who underwent treatment with ADA and VDZ were retrospectively collected. AE rates per 100 person-years were calculated. A Cox regression model was used to estimate the hazard ratios of the AEs between the 2 drugs. Results: A total of 16 ADA patients (17.2%) and 11 VDZ patients (7.6%) had AEs causing drug interruption during the study period (P=0.02). Most of the AEs were noninfectious extraintestinal events (50% in ADA and 54.5% in VDZ) while infections accounted for 31.2% of the AEs in patients treated with ADA and 27.3% in those treated with VDZ. The incidence rate of AEs causing withdrawal of therapy was 13.2 per 100 person-years for ADA and 5.3 per 100 person-years for VDZ, corresponding to a 76% lower risk in patients in VDZ. Considering the first year of treatment, we observed 34 subjects treated with ADA (36.5%) having at least 1 AEs and 57 (39.3%) among those taking VDZ (P=0.67). Conclusions: VDZ has a lower incidence rate of AEs causing withdrawal of treatment compared to ADA but a similar risk of AEs not causing drug interruption. Real-life head-to-head studies are still necessary to further explore the safety profile of these drugs.

Background & Aims Infliximab has been associated with drug-induced liver injury (DILI), particularly drug-induced autoimmune hepatitis (DIAIH). DIAIH is commonly treated with corticosteroids, but there is limited data on the efficacy of corticosteroids in infliximab-induced DILI. Methods Patients were included for assessment if they had been treated with infliximab between 2009-2020 in Iceland and had developed elevated liver tests. Other specific etiologies of liver enzyme elevations were excluded. Patients treated with corticosteroids were compared to patients not receiving corticosteroids. Results A total of 36 patients with infliximab-induced DILI were identified: median age was 46 years (IQR 32-54) and 28 (78%) were female. Type of liver injury was predominantly hepatocellular (64%). Median peak liver enzymes were: alanine aminotransferase (ALT) 393 (328-695) U/L, aspartate aminotransferase 283 (158-564) U/L, alkaline phosphatase 116 (83-205) U/L, and bilirubin (10-20) 13 μmol/L. A total of 25 (69%) were positive for anti-nuclear antibody and/or had elevated IgG. Corticosteroids were initiated in 17 (47%). Median time from onset of liver injury to peak ALT value was longer in patients treated with corticosteroids, 22 (12-59) vs. 0 (0-3) days (p = 0.001). Time from peak ALT to normalization of liver enzymes was 45 days in the corticosteroid group vs. 77 days in others (p = 0.062). Corticosteroids were tapered in all patients, with no cases of relapse during the follow-up period of 1,245 (820-2,698) days. Overall 75% received another biologic, mostly adalimumab, without evidence of liver injury. Conclusion Approximately half of patients with infliximab-induced liver injury had slow improvement in ALT despite cessation of therapy and were treated with corticosteroids. Treatment response was good with prompt resolution of liver test abnormalities. Relapse of liver injury was not observed after tapering of corticosteroids despite prolonged follow-up and no patients developed DILI due to a second biologic. Lay summary A rare side effect of infliximab, a biologic medicine used to treat multiple inflammatory diseases, is liver injury and liver inflammation. Steroid treatment has been used in some patients with liver injury caused by infliximab, but there have been few studies supporting this treatment. In this study of 36 patients with infliximab-induced liver injury, approximately half of patients were treated with steroids and the results suggest that patients receiving steroids recover more quickly.

Tumor necrosis factor (TNF) α inhibitors are widely used to treat inflammatory bowel disease (IBD); however, some patients have unexpected inflammatory episodes during anti-TNF therapy. The objective of our research was to highlight a paradoxical case of anti-TNF-agent-induced Sweet syndrome compared with Sweet syndrome treated by anti-TNF agents. We describe a 62-year-old male with a history of ulcerative colitis presenting with multiple polymorphic indurated skin macules and plaques after 2 months of adalimumab therapy. Neutrophilic dermatosis was diagnosed based on the clinical presentation and skin biopsy and may have resulted from extraintestinal manifestations of a flare-up of IBD or been induced by adalimumab therapy. We conclude that when facing this dilemma, adalimumab should be discontinued, and the dose of prednisolone should be increased before determining the definitive cause. Based on drug hypersensitivity syndrome (DHS) risk assessment in the 10-D assessment system, this case was classified as grade 1 (no risk). Finally, we review the molecular and cellular mechanisms connecting cytokine dysregulation to Sweet syndrome.

OBJECTIVES To examine concurrent validity and discrimination of modified minimal disease activity (mMDA) criteria in peripheral spondyloarthritis (pSpA) following OMERACT filter principles and determine predictors of mMDA response. METHODS Four mMDA versions were derived in the ABILITY-2 study using the SPondyloArthritis Research Consortium of Canada (SPARCC) or Leeds Enthesitis Index (LEI) but excluding psoriasis. To assess concurrent validity, mMDA versions were correlated with Peripheral SpondyloArthritis Response Criteria (PSpARC) remission, Ankylosing Spondylitis Disease Activity Score for inactive disease (ASDAS ID), and physician global. Treatment discrimination was assessed between adalimumab and placebo at week 12. Multiple logistic regression was used to determine baseline predictors of long-term mMDA responses and sustained mMDA. RESULTS The four mMDA versions showed a stronger positive correlation with PSpARC remission (rtet >0.95) versus ASDAS ID (rtet >0.75) at week 12 and years 1-3 and were able to show discrimination (p

Objective B cells can become activated in germinal center (GC) reactions in secondary lymphoid tissue and ectopic GCs in synovium in RA that may be TNF and lymphotoxin (LT) dependent. Here we characterized the peripheral B cell compartment longitudinally during anti-TNF therapy in RA. Methods Participants were randomized in a 2:1 ratio to receive standard dosing regimens of etanercept (n=43) or adalimumab (n=20) for 24 weeks. Eligible participants met the 1987 ACR criteria for RA, clinically active (DAS28>4.4), and on stable doses of methotrexate. The primary mechanistic endpoint was the change in switched memory B cell fraction from baseline to week 12 in each treatment group. Results B cell subsets remained surprisingly stable over the course of the study regardless of treatment group, with no significant change in memory B cells. Blockade of TNF and LT with etanercept compared to TNF blockade alone with adalimumab did not translate into significant differences in clinical response. Multiple activated B cell populations including CD21- double negative memory and activated naive were higher in RA non-responders (NR) at all time points, and CD95+ activated B cells increased with anti-TNF in the NR group. In contrast, transitional B cells- a putative regulatory subset- were lower in the NRs. Conclusions Overall, our results support that peripheral blood B cell subsets are remarkably stable in RA and not differentially impacted by dual blockade of TNF and LT with etanercept or single blockade of TNF with adalimumab. Activated B cells do associate with a less robust response.

Objective Real-world data of adalimumab (ADA) in the treatment of ulcerative colitis (UC) are scarce. We aimed to study the ADA response rates and predictors of response in UC treatment. Methods This observational, prospective and multi-center study assessed the clinical outcome of refractory UC patients treated with ADA who previously had an inadequate response to either conventional therapies or other anti-TNF antibodies or tacrolimus. The primary endpoint was the proportion of UC patients achieving a clinical response and remission at 8 and 52 weeks. We also evaluated the parameters which were associated with a clinical response at 8 and 52 weeks. Results A total of 35 patients were enrolled from 11 centers. The clinical responses at 8 and 52 weeks were 60.0% and 51.4%, respectively. The clinical remission rates at 8 and 52 weeks were 45.7% and 48.6%, respectively. Positive predictors for week 52 response were combination of ADA with immunomodulator (IM) (OR: 27.229; 95% CI; 1.897-390.76; p=0.015) and a week 8 lower partial Mayo score (OR: 0.406; 95% CI; 0.204-0.809; p=0.010). A receiver operation characteristic curve analysis revealed the optimal week 8 partial Mayo score to be 2.5, therefore a partial Mayo score of ≤2 was a positive predictor for the continuation of ADA. No malignancy or death occurred during this study. Conclusion ADA was effective for inducing and maintaining both a clinical response and remission in patients with refractory UC. It remains possible that the concomitant use of IM and a week 8 partial Mayo score of ≤2 may predict the long-term response of ADA.

Background Biologics are a good therapeutic option for severe, chronic plaque psoriasis; however, they come with significant cost to the health care system. Objective To conduct a cost-utility analysis of outpatient biologics (adalimumab, etanercept, guselkumab, ixekizumab, risankizumab, secukinumab, tildrakizumab, and ustekinumab) available to adults with severe, chronic plaque psoriasis from the perspective of the Australian health care system. Methods A Markov cohort model was constructed to estimate the quality-adjusted life years (QALYs) and costs accrued for treatment pathways commencing with different first-line biologics, over a 96-week time horizon. The model adhered to the Australian Pharmaceutical Benefits Scheme eligibility criteria and guidelines. Results A biologic treatment pathway commencing on tildrakizumab was the most cost-effective first-line treatment (Australian dollar 39,930; total utility of 1.57 QALYs over 96 weeks). First-line secukinumab and risankizumab had incremental cost-utility ratios of Australian dollar 194,524/QALY and Australian dollar 479,834/QALY, respectively, when compared with first-line tildrakizumab. Limitations The efficacy and utility input parameters were derived from international randomized control trials and patients from the United Kingdom, respectively. Findings from this study cannot be generalized beyond Australia. Conclusion Tildrakizumab may be considered as first-line treatment for adult patients with severe, chronic plaque psoriasis embarking on biologic therapy, from the economic perspective of the Australian health care system.

Objectives: In this study, we aimed to describe the demographic and clinical findings of children with uveitis at a tertiary pediatric rheumatology and ophthalmology center. Materials and Methods: A retrospective cross-sectional study was conducted with 46 patients who were diagnosed with uveitis before the age of 16 years and were followed regularly for at least 6 months between January 2013 and June 2019. Demographic data, uveitis characteristics, underlying diseases, systemic treatment modalities, drug side effects, complications, and surgical intervention were evaluated. Results: Eighty-three eyes of 46 patients were included in the study. The mean age at diagnosis of uveitis was 9.2 +/- 4.5 (1.6-15.6) years, and the mean uveitis follow-up period was 54 +/- 41 (6-191) months. Twenty-one patients (45.7%) had uveitis associated with rheumatologic diseases. Juvenile idiopathic arthritis was the most common disease (23.9%). Visual acuity was categorized as moderately impaired in 6 eyes (7.2%), severely impaired in 4 eyes ( 4.8%), and blindness in 1 eye (1.2%). Methotrexate (87%) was the most frequently used systemic immunosuppressive agent in treatment. Adalimumab (73.9%) was added to treatment in resistant cases. Thirty-five patients (76.1%) had complications in at least 1 eye secondary to uveitis or uveitis treatment. Posterior synechiae (11 eyes, 13.2%) was the most common complication during treatment. Conclusion: In order to preserve visual acuity, pediatric uveitis should be recognized early and especially persistent/chronic cases should be started on effective systemic treatment immediately.

Objectives Only few observational studies have investigated the actual effectiveness of switching to biosimilars in daily clinical practice in unselected patients. The objective of this study was to examine the maintenance of effect and safety after a hospital-wide switch for economic reasons from adalimumab originator Humira® to biosimilar Amgevita® in real-world rheumatoid arthritis (RA) patients and patient satisfaction with the switch. Methods A single centre retrospective observational study of RA patients on the course of their disease activity (DAS28, ESR and CRP), health-related quality of life (SF-36) and functional disability (HAQ-DI) before and up to one year after the switch, supplemented with a cross-sectional survey on satisfaction and experienced side effects approximately 18 months after the switch. Treatment outcomes were analysed with linear mixed modelling and generalized estimation equations. Results On November 1st 2018, 239 rheumatology patients switched to the adalimumab biosimilar. Of 52 RA patients who met the inclusion criteria sufficient data were available. Disease activity levels, the proportion of patients in remission (DAS28

Introduction. Rheumatoid arthritis (RA) is a chronic progressive inflammatory disease that causes joint destruction. The condition imposes a significant economic burden on patients and societies. The present study is aimed at evaluating the cost-effectiveness of Infliximab, Adalimumab, and Etanercept in treating rheumatoid arthritis in Iran. Methods. This is a cost-effectiveness study of economic evaluation in which the Markov model was used. The study was carried out on 154 patients with rheumatoid arthritis in Fars province taking Infliximab, Adalimumab, and Etanercept. The patients were selected through sampling. In this study, the cost data were collected from a community perspective, and the outcomes were the mean reductions in DAS-28 and QALY. The cost data collection form and the EQ-5D questionnaire were also used to collect the required data. The results were presented in the form of an incremental cost-effectiveness ratio, and the sensitivity analysis was used to measure the robustness of the study results. The TreeAge Pro and Excel softwares were used to analyze the collected data. Results. The results showed that the mean costs and the QALY rates in the Infliximab, Adalimumab, and Etanercept arms were $ 79,518.33 and 12.34, $ 91,695.59 and 13.25, and $ 87,440.92 and 11.79, respectively. The one-way sensitivity analysis confirmed the robustness of the results. In addition, the results of the probabilistic sensitivity analysis (PSA) indicated that on the cost-effectiveness acceptability curve, Infliximab was in the acceptance area and below the threshold in 77% of simulations. The scatter plot was in the mentioned area in 81% and 91% of simulations compared with Adalimumab and Etanercept, respectively, implying lower costs and higher effectiveness than the other two alternatives. Therefore, the strategy was more cost-effective. Conclusion. According to the results of this study, Infliximab was more cost-effective than the other two medications. Therefore, it is recommended that physicians use this medication as the priority in treating rheumatoid arthritis. It is also suggested that health policymakers consider the present study results in preparing treatment guidelines for RA.

In 2017 the first Janus kinase (JAK) inhibitors were approved for the treatment of rheumatoid arthritis in Germany. The mode of action of JAK inhibitors differs from biologicals, as multiple cytokines are inhibited. In comparison with the treatment with biologicals, JAK inhibitors have the advantage of oral application, three of the four currently approved JAK inhibitors were superior to adalimumab in at least some of the endpoints in randomized controlled trials, they have a short half-life and have a particular efficacy in the control of pain. On the other hand, the rate of malignancies and major cardiovascular events was increased in the Oral Surveillance trial in comparison with tofacitinib and tumor necrosis factor (TNF) inhibitors but not in the CorEvitas registry and not in the phase III approval trials. The clarification of these safety discussions and the evaluation of further registry data will decide the position of JAK inhibitors in the therapeutic algorithm for rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic autoimmune disease requiring long-term treatment. Upadacitinib (UPA), a Janus kinase (JAK) inhibitor, is a new treatment for RA. The benefit–risk profile of a medication is best understood by evaluating the number needed to treat (NNT) and the number needed to harm (NNH). This analysis evaluated the comparative risk–benefit of UPA versus adalimumab (ADA). Post-hoc analyses were performed using data from the SELECT-COMPARE trial of UPA versus placebo (PBO) and UPA versus ADA among patients with active RA who remained on stable methotrexate (MTX) treatment and had an inadequate response; patients who failed to achieve response were rescued by predefined criteria—PBO or ADA switch to UPA, and UPA switch to ADA (all patients on PBO were switched to UPA at week 26). This analysis assessed efficacy and adverse events of special interest (AESIs) at week 26, 48, and 156 (3 years). NNT and NNH (95% confidence intervals) values were calculated between UPA versus ADA for all time points, and between UPA versus PBO for week 26. NNT and NNH values were applied to a hypothetical cohort of 100 patients to estimate the comparative efficacy and safety profiles. UPA consistently showed greater efficacy than ADA, as evidenced by NNT values

Background/aims Although anti-tumor necrosis factor (TNF) agents have been widely used to treat ulcerative colitis (UC), the real-world incidence of suboptimal response to anti-TNF agents has not been thoroughly investigated, especially among Asians. Methods Using the Korean National Health Insurance database, we collected data on UC patients who initiated anti-TNF agents between July 1, 2014, and June 30, 2017. We assessed suboptimal responses, including anti-TNF discontinuation or dose escalation, switching to other biologics, augmentation with a non-biologic therapy, and the requirement for colectomy. Results A total of 1,268 patients were included as new anti-TNF users (infliximab 713, adalimumab 433, golimumab 122). The proportion of patients who experienced at least one suboptimal response within 1 year among all patients was 63.5%, including 59.1%, 69.5%, and 68.0% of patients treated with infliximab, adalimumab, and golimumab, respectively. The cumulative incidences of at least one suboptimal response over time were 41.5%, 63.7%, 80.5%, and 87.1% at 6, 12, 24, and 36 months, respectively. Cox proportional hazards modeling revealed that adalimumab was associated with a higher risk of at least one suboptimal response (hazard ratio [HR], 1.29; 95% confidence interval [CI], 1.13 to 1.48), dose escalation (HR, 4.35; 95% CI, 2.97 to 6.38) and discontinuation (HR, 1.25; 95% CI, 1.03 to 1.52) than infliximab. Golimumab was associated with a higher risk of switching to other biologics than infliximab (HR, 1.78; 95% CI, 1.21 to 2.60). Conclusions More than half of Korean UC patients had suboptimal responses to anti-TNF agents within 1 year. UC patients treated with infliximab might be less prone to suboptimal responses than those treated with adalimumab or golimumab.

Purpose Anti-TNF-α-induced lupus (ATIL) is a rare condition considered as a drug-induced lupus (DIL) in patients under anti-TNF-α therapies. Nowadays it is still unclear if ATIL is a classical DIL or represent a distinct syndrome. Some characteristics of DIL have been described specifically associated with patients with lupus-like syndrome receiving anti-TNF-α therapy: the severity of the disease, incidence/prevalence of dsDNA antibodies (anti-dsDNA) and hypocomplementaemia. The objective of this study is to describe the development of ATIL in patients with non-infectious uveitis in a single tertiary center. Methods Retrospective description of a case series. Results We describe three patients with noninfectious uveitis (NIU) of different etiologies who developed antinuclear antibody (ANA) and anti-dsDNA antibody positivity, arthritis and, in one case, skin lesions under adalimumab treatment. The condition resolved in all of them after adalimumab withdrawal. Corticosteroids were required in one patient, non-steroidal anti-inflammatory drugs in two patients, and hydroxychloroquine in one of them. None required another immunosuppressive drug. A subsequent control of the NIU could continue to be carried out without anti-TNF-α therapy in two patients and in the remaining a switch was made to another anti-TNF-α (golimumab). Conclusion The current report describes three cases of ATIL in patients with different types of NIU which share some common features: ANA positivity, articular symptoms, and a temporal relationship between symptoms onset and anti-TNF-α treatment. A review of the literature and comparison with the few previous reported ATIL cases was conducted as well.

Aim Inflammatory signals in the sacroiliac (SI) joints and the aorta of patients with axial spondyloarthritis (axSpA) were graded by positron emission tomography/computed tomography (PET/CT) imaging before and after treatment with sulfasalazine (SSZ) or adalimumab (ADA). Methods Patients with axSpA, Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) ≥ 4, were recruited. Disease‐modifying antirheumatic drug‐naïve patients started SSZ for 12 weeks, whereas those with prestudy treatment with or contraindication to SSZ commenced ADA for 16 weeks. In addition, those patients in the SSZ group with insufficient response commenced ADA for 16 weeks. 18F‐fluorodeoxyglucose PET/CT was performed after inclusion and after treatment with SSZ and ADA. Maximum standardized uptake value (SUVmax) was assessed for the aorta and the SI joints, and maximal target‐to‐blood‐pool ratio (TBRmax) only for the aorta. Results Among five SSZ patients, mean ± SD BASDAI was 4.7 ± 1.6 before and 3.5 ± 1.4 after treatment (p = .101). In 13 ADA patients, the BASDAI decreased from 5.4 ± 1.6 to 2.8 ± 2.2 (p, We launched this small open‐label study to test the hypothesis that axial spondyloarthritis (axSpA) induces positron emission tomography (PET)‐detectable inflammation in the sacroiliac (SI) joints and cardiovascular tissues and that the effects of treatment with sulfasalazine and adalimumab (ADA) for axSpA can be visualized and confirmed by PET. Our results imply that sulfasalazine may reduce PET‐computed tomography‐detectable inflammation in the SI joints, with a trend towards a reduction in the aorta. In the ADA group, however, we did not observe any change in the PET signals in the SI joints nor in the aorta.

A growing number of studies support a bidirectional relationship between inflammation and bipolar disorders. Tumor necrosis factor-α (TNF-α) inhibitors have recently attracted interest as potential therapeutic compounds for treating depressive symptoms, but the risk for triggering mood switches in patients with or without bipolar disorders remains controversial. Thus, we conducted a systematic review to study the anti-TNF-α medication-induced manic or hypomanic episodes. PubMed, Scopus, Medline, and Embase databases were screened for a comprehensive literature search from inception until November 2020, using The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Out of the initial 75 references, the screening resulted in the inclusion of four case reports (each describing one patient) and a cohort study (in which 40 patients out of 7600-0.53% - experienced elated mood episodes after infliximab administration). Of these 44 patients, 97.7% experienced a manic episode and 2.3% hypomania. 93.2% of patients had no history of psychiatric disorder or psychotropic treatment. Only 6.8% had a history of psychiatric disorders with the affective spectrum (4.6% dysthymia and 2.3% bipolar disorder). The time of onset of manic or hypomanic symptoms varied across TNF-α inhibitors with an early onset for Infliximab and a later onset for Adalimumab and Etanercept. These findings suggest that medications targeting the TNF-α pathway may trigger a manic episode in patients with or without affective disorders. However, prospective studies are needed to evaluate the relative risk of such side effects and identify the population susceptible to secondary mania.

The prevalence of the chronic inflammatory bowel diseases (CIBD) Crohn's disease (CD) and ulcerative colitis (UC) is on the rise worldwide. In Germany CIBDs are also a significant healthcare problem. The pathogenesis is complex and involves genetic factors, environmental aspects and changes in the immunological constitution. Furthermore, the gut microbiota plays a role in the maintenance of intestinal inflammation. Fortunately, several new drugs, in particular biologicals, have been approved for the treatment of CIBDs. The treatment of UC is mainly based on 5‑aminosalicylic acid formulations, preferably as a topical form for distal colitis and proctitis as well as local budesonide formulations. In the case of extensive spread, high disease activity and refractory disease antibodies (biologicals) are successfully used, similar to CD. In addition to anti-tumor necrosis factor antibodies (infliximab, adalimumab, golimumab), vedolizumab, an anti-integrin antibody and the interleukin 12/23 antibody ustekinumab can be successfully used. The intravenous and also subcutaneous administration of antibodies are increasing in importance and are now available for all forms. Furthermore, the Janus kinase inhibitor tofacitinib is an orally administered option for UC. Clinical scores, endoscopy, ultrasound, laboratory parameters and calprotectin determination in stool are employed to evaluate treatment response (treat to target approach). Ultimately, the long-term goal is mucosal healing. Despite advances in the pharmaceutical treatment, a significant number of patients with CIBD still suffer from treatment refractory courses and need surgery at some time during the disease.Die Prävalenzen der chronisch-entzündlichen Darmerkrankungen (CED) Morbus Crohn (MC) und Colitis ulcerosa (CU) steigen weltweit an. Auch in Deutschland stellen die CED ein großes gesundheitspolitisches Problem dar. Die Pathogenese ist komplex und involviert genetische Faktoren, Umweltaspekte und Veränderungen in der immunologischen Konstitution. Weiterhin spielt das Darmmikrobiom eine Rolle bei der Aufrechterhaltung der Entzündung. In den letzten Jahren sind erfreulicherweise weitere Medikamente für die Behandlung der CED zugelassen worden, vor allem Biologika. Die Therapie der CU stützt sich hauptsächlich auf 5‑Aminosalicylsäure-Präparate, bevorzugt auch in topischer Form bei distaler Kolitis und Proktitis, sowie lokale Budesonidformulierungen. Bei ausgedehntem Befall, hoher Krankheitsaktivität oder refraktärem Verlauf kommen ähnlich wie beim MC auch Antikörper (Biologika) mit gutem Erfolg zum Einsatz. Neben Anti-Tumor-Nekrose-Faktor-Antikörpern (Infliximab, Adalimumab, Golimumab) werden der Integrinantikörper Vedolizumab sowie der Interleukin-12/23-Antikörper Ustekinumab erfolgreich verwendet. Einen zunehmenden Stellenwert erhält neben der intravenösen auch die subkutane Anwendung der Antikörpertherapien, die mittlerweile für alle Präparate zur Verfügung steht. Des Weiteren ist bei CU der Januskinaseinhibitor Tofacitinib eine orale Option. Der Therapieerfolg wird multimodal anhand von Endoskopie, Sonographie, Laborparametern, Calprotectinbestimmung im Stuhl und klinischen Scores beurteilt („treat-to-target approach“). Langfristig gilt das Ziel einer mukosalen Heilung. Trotz der Fortschritte in der medikamentösen Therapie leidet immer noch ein signifikanter Teil der Patienten mit CED unter therapierefraktären Verläufen und benötigt im Verlauf eine chirurgische Therapie.

Background. There is a need to study genetically engineered biological therapy (GEBT) survivability and identify any significant risk factors for its ineffectiveness due to the increasing prevalence of psoriasis among children and the spreading GEBT administration. Such information has practical importance, it can be used to predict treatment outcomes and to develop individual therapeutic approaches.Objective. Our aim was to study biological therapy survivability and to identify risk factors for its ineffectiveness in children with moderate and severe forms of psoriasis.Methods. The study included data from 4-17 years old patients with moderate and severe forms of psoriasis vulgaris. Groups were formed according to the biological medication used. Statistical analyses were performed via SPSS Statistics. Biologic therapy survivability was determined via Kaplan-Meier method with the assessment of differences significance using log-rank test. Significant factors affecting cumulative risk growth were determined by Cox multiple regression method.Results. The study analysed data from the medical records of 105 patients. The average survivability of ustekinumab was 28.7 months, etanercept — 23.1, and adalimumab — 18.4. In the group of bio-naive patients, the survivability was higher: 30.8 months for ustekinumab and 24.4 months for ethanercept, while in the group of patients administrated previously with biological medication the survivability was 24.2 and 8.3 months, respectively. No statistically significant difference was revealed for adalimumab therapy. Significant risk factors for therapy ineffectiveness were the following: high body mass index (BMI) at the time of GEBT onset, aggravated family history, and prior use of one or several subsequent GEBT lines.Conclusion. The therapy survivability is inevitably declining over time. The best results were noted in bio-naive patients treated with ustekinumab that allows us to recommend it as the first-line drug in children with severe and moderate forms of psoriasis.

Axial spondyloarthritis (axSpA) is an inflammatory rheumatic disorder that causes chronic pain, primarily in the spine and sacroiliac joints. It is characterized by the presence of type 1 major histocompatibility complex HLA-B27 genetic marker, arthritis in peripheral joints, enthesitis and/or dactylitis and extra-articular manifestations. Current guidelines recommend biological therapy when first-line therapy is not sufficiently effective. The finding that the interleukin (IL)-17 axis is vital for the pathogenesis of axSpA propelled the development of secukinumab, a fully human monoclonal antibody directed against IL-17A. The present review provides evidence on the efficacy and safety of secukinumab in the treatment of radiographic and non-radiographic axSpA from nine randomized controlled phase III trials, as well as evidence from real-world observational analyses. The primary endpoint in six clinical trials was the proportion of patients meeting the Assessment of SpondyloArthritis international Society criteria for either 20% or 40% improvement (ASAS20, ASAS40) at week 16. Significantly more patients achieved the primary endpoint with secukinumab compared with placebo in all the studies except MEASURE 4. Both clinical trials and real-world studies showed significant improvements in the secondary endpoints of disease activity, quality of life, and pain and fatigue relative to placebo. The benefits of secukinumab were generally sustained during longer-term (up to 5 years) treatment. Overall, secukinumab was well tolerated with a low frequency of adverse events and treatment persistence was high in the real-world setting. Although indirect comparisons suggest that secukinumab and adalimumab have comparable efficacy and safety, they are being directly compared in the ongoing SURPASS study. During the current coronavirus disease 2019 (COVID-19) pandemic, it is advisable to continue biological therapy in patients who do not have severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection, but interrupt treatment during an infection, reinitiating once the patient has recovered from the infection. In conclusion, secukinumab is a largely safe and effective treatment for radiographic and non-radiographic axSpA.

Background Several Canadian provinces have introduced reimbursement policies mandating substitution of innovator biologics with lower-cost biosimilars. We estimated the number of patients affected and cost implications if such policy changes were to be implemented in Ontario, Canada. Methods We conducted a cross-sectional time series analysis of Ontarians dispensed publicly funded biologics indicated for inflammatory diseases (rheumatic conditions, inflammatory bowel disease: infliximab, etanercept, adalimumab) between January 2018 and December 2019, and forecasted trends to Dec. 31, 2020. The primary source of data was pharmacy claims data for all biologics reimbursed by the public drug program. We modelled the number of patients affected and government expenditures (in nominal Canadian dollars) of several biosimilar policy options, including mandatory nonmedical biosimilar substitution, substitution in new users, introduction of a biosimilar for adalimumab, and price negotiations. In a secondary analysis, we included insulin glargine. Results In 2018, 14 089 individuals were prescribed a publicly funded biologic for inflammatory diseases. A mandatory nonmedical biosimilar substitution would potentially have affected 7209 patients and saved $238.6 million from 2018 to 2020. A new-user substitution would have affected 757 patients and saved $34.2 million. If an adalimumab biosimilar were to become available, 12 928 patients would be affected by a mandatory nonmedical substitution and the 3-year savings would increase to $645.9 million (all biosimilars priced at 25% of innovator biologics). Finally, an expanded nonmedical substitution policy including insulin glargine would affect 115 895 patients and save $288.7 million (not including adalimumab). Interpretation Policies designed to curb rising costs of biologics can have substantially different effects on patients and government expenditures. Such analyses warrant careful consideration of the balance between cost savings and effects on patients.

Although tumor necrosis factor inhibitors (TNFi) have favorably altered the treatment landscape for patients with axial spondyloarthritis (axSpA), there is limited data regarding TNFi persistence and reasons for discontinuation. This is an observational time-to-event study utilizing data collected for a prospective multiple-disease registry of US Veterans with axSpA treated with TNFi therapies and recruited over a 10 year period. Clinical, serological, and comorbid parameters were collected. Corporate Data Warehouse Pharmacy files provided courses of the 5 TNFi agents, and response to treatment was documented. Individual TNFi persistence was established utilizing univariate and multivariate Cox proportional models, and reasons for discontinuation were obtained by physician chart review. Two-hundred and fifty-five axSpA patients received 731 TNFi courses. A majority of patients (84.3%) had TNFi persistence at 12 months; 63.5% and 47.1% at 24 and 36 months, respectively. Compared to adalimumab, infliximab demonstrated greater persistence, certolizumab the least. Age, smoking status, BMI, comorbidity burden, inflammatory markers and HLA-B27 did not predict TNFi persistence or discontinuation. Stroke and peripheral arterial disease increased the probability of TNFi discontinuation. Secondary non-response (SNR) was the most common reason for discontinuation (46% of all courses); non-adherence (6%) and clinical remission (2%) were uncommon. Pain score at enrollment, myocardial infarction, African American race and inflammatory bowel disease (IBD) predicted TNFi response. While initial persistence of TNFi treatment was high, a large proportion of the patients discontinued initial TNFi therapy by 3 years, primarily due to loss of efficacy. While further research identifying potential predictors of TNFi discontinuation in axSpA is warranted, access to alternate disease-modifying therapies is needed.

Objective: The management of inflammatory bowel disease (IBD) patients on complex medications such as biologic disease-modifying anti-rheumatic drugs (DMARD) requires close supervision. At East Sussex NHS Healthcare Trust (ESHT), the multi-disciplinary team (MDT) already looking after these patients could benefit from the additional knowledge and support from a specialist pharmacist (SP). Methods: To assess if the MDT could benefit from an SP, all IBD patients on the DMARD adalimumab were identified. The patient records were screened for patient demographic data, clinical assessment and investigations, treatment, and follow-up clinics. Results: 162 patients at ESHT were identified as being on adalimumab treatment for either Crohn’s Disease (77%) or Ulcerative Colitis (23%). Disease activity scores, a clinical measure of IBD severity, were infrequently recorded (1%) on patient letters. Evidence of a biologic screen, a series of investigations to ensure safety in a biologic treatment, was only evident in one-third of patients. Clinic review of patients recently started on adalimumab and annual review of stable patients occurred 43% and 26% respectively. Conclusion: The results indicate that there is a need for an additional member to support the IBD MDT in managing this cohort of patients. An SP is uniquely positioned to fill this gap. They have extensive knowledge in drug indication, therapeutic drug monitoring, and side-effect profiles. Similar studies have been identified that support SP in this role.

Background The safety and effectiveness of live virus vaccines, such as the varicella-zoster vaccine, are unknown in patients with inflammatory diseases receiving immunomodulatory therapy such as tumor necrosis factor inhibitors (TNFis). Objective To evaluate the safety and immunogenicity of the live attenuated zoster vaccine (ZVL) in patients receiving TNFis. Design Randomized, blinded, placebo-controlled trial. (ClinicalTrials.gov: NCT02538341). Setting Academic and community-based rheumatology, gastroenterology, and dermatology practices. Patients Adults aged 50 years or older receiving TNFis for any indication. Intervention Random assignment to ZVL versus placebo. Measurements Glycoprotein enzyme-linked immunosorbent assay (gpELISA) and enzyme-linked immunosorbent spot (ELISpot) from serum and peripheral blood mononuclear cells measured at baseline and 6 weeks after vaccination. Suspected varicella infection or herpes zoster was clinically assessed using digital photographs and polymerase chain reaction on vesicular fluid. Results Between March 2015 and December 2018, 617 participants were randomly assigned in a 1:1 ratio to receive ZVL (n = 310) or placebo (n = 307) at 33 centers. Mean age was 62.7 years (SD, 7.5); 66.1% of participants were female, 90% were White, 8.2% were Black, and 5.9% were Hispanic. The most common TNFi indications were rheumatoid arthritis (57.6%) and psoriatic arthritis (24.1%); TNFi medications were adalimumab (32.7%), infliximab (31.3%), etanercept (21.2%), golimumab (9.1%), and certolizumab (5.7%). Concomitant therapies included methotrexate (48.0%) and oral glucocorticoids (10.5%). Through week 6, no cases of confirmed varicella infection were found; cumulative incidence of varicella infection or shingles was 0.0% (95% CI, 0.0% to 1.2%). At 6 weeks, compared with baseline, the mean increases in geometric mean fold rise as measured by gpELISA and ELISpot were 1.33 percentage points (CI, 1.17 to 1.51 percentage points) and 1.39 percentage points (CI, 1.07 to 1.82 percentage points), respectively. Limitation Potentially limited generalizability to patients receiving other types of immunomodulators. Conclusion This trial informs safety concerns related to use of live virus vaccines in patients receiving biologics. Primary funding source The National Institute of Arthritis and Musculoskeletal and Skin Diseases and the American College of Rheumatology.

Objectives To assess the efficiency of secukinumab compared to adalimumab as first biologic treatment for psoriatic arthritis (PsA) from the Spanish National Health System (SNHS) perspective. Methods A cost-consequence analysis of the cost and clinical response of two treatment strategies was conducted over a 2-year time horizon. A hypothetical cohort of 10 patients with PsA initiated treatment with secukinumab 150 mg (cohort A) or adalimumab 40 mg (cohort B), respectively. Patients achieving clinical response (ACR20/50/70) at week 24 continued the initial treatment, while patients with inadequate response switched to secukinumab 300 mg. Pharmacological costs were calculated based on SmPC (notified ex-factory price). The lowest cost of adalimumab biosimilar was considered. Data on clinical response were extracted from the two matching-adjusted indirect comparison (MAIC) published comparing secukinumab vs adalimumab. Results were expressed as the cost difference between the two cohorts (€, 2019) and were calculated for each clinical response criteria (ACR20/50/70) and for each MAIC. Sensitivity analysis assessed the impact of potential discounts on the cost of adalimumab while maintaining the cost of secukinumab unchanged. Results Depending on the MAIC used, the cost of initiating biologic treatment for PsA with secukinumab 150 mg was 18–33% lower than the one estimated for adalimumab 40 mg, for ACR20, 18–28% for ACR50, and 16–23% for ACR70 response rate. Sensitivity analysis showed that it would be necessary a discount of 40–60%, 40–65% and 50–75% over the adalimumab cost to compensate for the differences in efficacy observed for ACR20/50/70, respectively, depending on the MAIC used. Conclusion In patients with PsA, secukinumab could be considered a more efficient first-line biologic treatment compared to adalimumab, from the SNHS perspective.

Background: Adalimumab (ADA), certolizumab pegol (CER), etanercept (ETA), guselkumab (GUS), ixekizumab (IXE), secukinumab (SEC), and ustekinumab (UST) are biologic medications approved in the USA for the treatment of moderate to severe psoriasis. We examined drug adherence and persistence of patients with moderate to severe psoriasis who initiated these seven biologic medications. Methods: Adult patients with ≥1 pharmacy/medical claim for any of the seven psoriasis medications and ≥1 diagnosis of psoriasis in the previous 6 months between July 1, 2014 and June 30, 2019 were selected from the IBM MarketScan® Commercial Claims and Encounters Database. The index date was defined as the date of the first prescription fill. Patients were required to have continuous health plan enrollment during the 6 months prior to their index date and ≥9 months after. Patients were grouped into seven study cohorts based upon their index biologic medication. Adherence was measured using the proportion of days covered (PDC) and defined by a PDC ≥80%. Adherence and persistence with index biologic medications were examined during fixed follow-up periods of 3, 6, and 9 months, with a subpopulation analysis carried out among patients with 12 months of follow-up. Results: Among psoriasis patients with ≥9 months of continuous enrollment included in the study population, the number of those who initiated each biologic medication was 10,324 for ADA, 431 for CER, 3,092 for ETA, 821 for GUS, 1,766 for IXE, 4,132 for SEC, and 5,441 for UST. The mean age at the time of initiating biologic treatment was 46.9 years. During the 9-month follow-up period, the proportions of adherent patients (i.e., PDC ≥80%) were numerically higher among those treated with UST (59.9%) and GUS (56.9%), followed by those treated with SEC (46.1%), IXE (45.5%), ADA (44.7%), ETA (33.9%), and CER (22.0%). The proportions of patients who were persistent with their index biologic medication during the 9-month follow-up period were numerically higher among those treated with UST (70.1%) and GUS (67.8%), followed by those treated with IXE (47.3%), SEC (46.9%), ADA (28.7%), CER (14.8%), and ETA (10.7%). Conclusions: In this large healthcare claims database analysis of psoriasis patients treated with seven different biologic medications, adherence was numerically higher among those treated with UST or GUS. UST and GUS were also associated with numerically greater persistence.

BACKGROUND Traditional methods of developing predictive models in inflammatory bowel diseases (IBD) rely on using statistical regression approaches to deriving clinical scores such as the Crohn's disease (CD) activity index. However, traditional approaches are unable to take advantage of more complex data structures such as repeated measurements. Deep learning methods have the potential ability to automatically find and learn complex, hidden relationships between predictive markers and outcomes, but their application to clinical prediction in CD and IBD has not been explored previously. AIM To determine and compare the utility of deep learning with conventional algorithms in predicting response to anti-tumor necrosis factor (anti-TNF) therapy in CD. METHODS This was a retrospective single-center cohort study of all CD patients who commenced anti-TNF therapy (either adalimumab or infliximab) from January 1, 2010 to December 31, 2015. Remission was defined as a C-reactive protein (CRP) < 5 mg/L at 12 mo after anti-TNF commencement. Three supervised learning algorithms were compared: (1) A conventional statistical learning algorithm using multivariable logistic regression on baseline data only; (2) A deep learning algorithm using a feed-forward artificial neural network on baseline data only; and (3) A deep learning algorithm using a recurrent neural network on repeated data. Predictive performance was assessed using area under the receiver operator characteristic curve (AUC) after 10× repeated 5-fold cross-validation. RESULTS A total of 146 patients were included (median age 36 years, 48% male). Concomitant therapy at anti-TNF commencement included thiopurines (68%), methotrexate (18%), corticosteroids (44%) and aminosalicylates (33%). After 12 mo, 64% had CRP < 5 mg/L. The conventional learning algorithm selected the following baseline variables for the predictive model: Complex disease behavior, albumin, monocytes, lymphocytes, mean corpuscular hemoglobin concentration and gamma-glutamyl transferase, and had a cross-validated AUC of 0.659, 95% confidence interval (CI): 0.562-0.756. A feed-forward artificial neural network using only baseline data demonstrated an AUC of 0.710 (95%CI: 0.622-0.799; P = 0.25 vs conventional). A recurrent neural network using repeated biomarker measurements demonstrated significantly higher AUC compared to the conventional algorithm (0.754, 95%CI: 0.674-0.834; P = 0.036). CONCLUSION Deep learning methods are feasible and have the potential for stronger predictive performance compared to conventional model building methods when applied to predicting remission after anti-TNF therapy in CD.

Background Biological drugs have improved the management of immune-mediated inflammatory diseases (IMIDs) despite being associated with important safety issues such as immunogenicity, infections, and malignancies in real-world settings. Objective The aim of this study was to explore the potential of a large Italian multi-database distributed network for use in the postmarketing surveillance of biological drugs, including biosimilars, in patients with IMID. Methods A retrospective cohort study was conducted using 13 Italian regional claims databases during 2010–2019. A tailor-made R-based tool developed for distributed analysis of claims data using a study-specific common data model was customized for this study. We measured the yearly prevalence of biological drug users and the frequency of switches between originator and biosimilars for infliximab, etanercept, and adalimumab separately and stratified them by calendar year and region. We then calculated the cumulative number of users and person-years (PYs) of exposure to individual biological drugs approved for IMIDs. For a number of safety outcomes (e.g., severe acute respiratory syndrome coronavirus 2 [SARS-COV-2] infection), we conducted a sample power calculation to estimate the PYs of exposure required to investigate their association with individual biological drugs approved for IMIDs, considering different strengths of association. Results From a total underlying population of almost 50 million inhabitants from 13 Italian regions, we identified 143,602 (0.3%) biological drug users, with a cumulative exposure of 507,745 PYs during the entire follow-up. The mean age ± standard deviation of biological drug users was 49.3 ± 16.3, with a female-to-male ratio of 1.2. The age-adjusted yearly prevalence of biological drug users increased threefold from 0.7 per 1000 in 2010 to 2.1 per 1000 in 2019. Overall, we identified 40,996 users of biosimilars of tumor necrosis factor (TNF)-α inhibitors (i.e., etanercept, adalimumab, and infliximab) in the years 2015–2019. Of these, 46% (N = 18,845) switched at any time between originator and biosimilars or vice versa. To investigate a moderate association (incidence rate ratio 2) between biological drugs approved for IMIDs and safety events of interest, such as optic neuritis (lowest background incidence rate 10.4/100,000 PYs) or severe infection (highest background incidence rate 4312/100,000 PYs), a total of 43,311 PYs and 104 PYs of exposure to individual biological drugs, respectively, would be required. As such, using this network, of 15 individual biological drugs approved for IMIDs, the association with those adverse events could be investigated for four (27%) and 14 (93%), respectively. Conclusion The VALORE project multi-database network has access to data on more than 140,000 biological drug users (and > 0.5 million PYs) from 13 Italian regions during the years 2010–2019, which will be further expanded with the inclusion of data from other regions and more recent calendar years. Overall, the cumulated amount of person-time of exposure to biological drugs approved for IMIDs provides enough statistical power to investigate weak/moderate associations of almost all individual compounds and the most relevant safety outcomes. Moreover, this network may offer the opportunity to investigate the interchangeability of originator and biosimilars of several TNFα inhibitors in different therapeutic areas in real-world settings. Supplementary Information The online version contains supplementary material available at 10.1007/s40259-021-00498-3.

The hypothesis of the study was that polymorphisms in promoter regions -238 and -308 of TNF-α could be associated with different clinical outcomes in inflammatory bowel diseases (IBD) and immune- mediated rheumatic diseases (IMRD). The aim was to examine the possible association of both polymorphisms with concentration of C-reactive protein (CRP) and fecal calprotectin (fCAL), onset of the remission and development of the ADA in patients on therapy with anti-TNF inhibitors. The prospective study was done in patients with IBD and IMRD on infliximab (IFX) or adalimumab (ADM). Patients were genotyped for TNF-α -238 and -308 polymorphisms. The concentration of CRP, fCAL, IFX or ADM and antibodies to drugs were measured according to manufacturer’s instructions and followed-up for 6 or 12 months. Out of all patients (N = 112), number of patients in remission did not differ according to genotypes (for IBD patients P = 0.509 vs 0.223 ; for IMRD patients P = 0.541 vs 0.132 for TNF-α -238 and -308, respectively). Initial CRP concentration was higher in IBD patients with TNF-α -308 GG than GA/AA genotypes in patients who failed to achieve remission [11.8 (4.4–39.6) vs 3.1 (1.5–6.5), P = 0.033]. In IBD patients with remission, fCAL concentration after at least 6 months of therapy was higher in TNF-α-308 GG than in GA genotype [52 (25–552) vs 20 (20–20) µg/g, P = 0.041]. Our results showed the association of TNF-α -308 GG genotype with a higher concentration of CRP and fecal calprotectin in patients with inflammatory bowel diseases on IFX or ADM therapy. Clinical remission and development of antibodies to anti- TNF drugs were not associated with TNF-α -238 and -308 polymorphisms.

CT-P17 (Celltrion, Inc., Incheon, Republic of Korea) is a biosimilar of reference adalimumab (Humira®; AbbVie Inc., North Chicago, IL, USA), which has recently received regulatory approval from the European Medicines Agency. This analysis was designed to evaluate the stability profile of CT-P17 compared with reference adalimumab and the currently licensed adalimumab biosimilars ABP 501 (Amjevita®/Amgevita®; Amgen Inc., Thousand Oaks, CA, USA) and SB5 (Imraldi®; Biogen Inc., Cambridge, MA, USA) when stored at low temperature (5 °C) or room temperature (25 °C) with 60% relative humidity for up to 28 days. Multiple orthogonal and complementary tests demonstrated that CT-P17 was stable for 28 days under all tested conditions, as well as for protein concentrations tested (50 vs 100 mg/mL), type of delivery device (autoinjector vs prefilled syringe), and manufacturing date (recently manufactured vs aged for 17 months). There were slight differences among products in terms of charge variants, oxidation level, purity, and number of subvisible particles; however, overall, the quality of each product was maintained over 28 days. Our data suggest that CT-P17 may be used without any significant loss of stability when stored at 5 °C or 25 °C with 60% relative humidity for up to 28 days, and was not impacted by protein concentration tested and delivery device. Comparative stability data suggest that the appropriate maximum storage period for CT-P17 may be up to 28 days at room temperature with 60% relative humidity.

Psoriasis is one of the most common autoimmune dermatoses with a chronic relapsing course. Biologic therapy should be initiated for patients with moderate to severe psoriasis when conventional systemic therapy and phototherapy are ineffective, or their use is limited due to comorbidities. In Latvia, adalimumab is the first choice of biologic drugs for treatment of psoriasis. The correlation between changes in cellular and humoral immunological parameters and clinical signs based on immunological data from psoriasis patients are evaluated in the publication.

Localized Listeria infection predominantly occurs in the prosthetic and hip joints. We herein report a case of Listeria monocytogenes ankle osteomyelitis in a 73-year-old man receiving adalimumab who was transferred to our hospital because of suspected rheumatoid arthritis (RA) flare. He reported a four-month history of left ankle swelling. A surgical biopsy revealed L. monocytogenes osteomyelitis in the left tibia and talus bones. The patient was successfully treated with antibiotics and surgical debridement. Thus, infection due to L. monocytogenes can present as ankle osteomyelitis in immunocompromised patients and may mimic an RA flare.

Introduction and aims: The primary aim was to explore the epidemiologic trend of pediatric inflammatory bowel disease in Latin America, and the secondary aims were to obtain an overview of the diagnostic/therapeutic focus of the members of the LASPGHAN and examine the relation of case frequency to year, during the study period. Materials and methods: Latin American pediatric gastroenterologists participated in an online survey, conducted through the SurveyMonkey platform, that investigated the yearly frequency of new inflammatory bowel disease patients within the time frame of 2005–2016, their disease variety, the gastrointestinal segments affected, and the diagnostic and treatment methods utilized. The correlation of new case frequency with each study year was evaluated. Results: A total of 607 patients were studied. The diagnoses were ulcerative colitis in 475 (78.3%) cases, Crohn’s disease in 104 (17.1%), and inflammatory bowel disease D unclassified in 28 (4.6%). The trend in ulcerative colitis was a lineal increase in the frequency of new cases related to each study year, with a significant correlation coefficient. Pancolitis was found in 67.6% of the patients. The diagnostic methods included clinical data, endoscopy, and biopsies in more than 99% of the cases, and imaging studies were indicated selectively. Drug regimens were limited to 5-aminosalicylic acid derivatives, azathioprine, 6-mercaptopurine, infliximab, and adalimumab. Conclusions: Pediatric inflammatory bowel disease in Latin America appears to have increased during the years included in the study period, with a predominance of moderate or severe ulcerative colitis. That lineal trend suggests the predictive likelihood of a gradual increase in the coming years, with possible epidemiologic and clinical implications. Resumen: Introducción y objetivos: El objetivo primario fue explorar la tendencia epidemiológica de la enfermedad intestinal inflamatoria pediátrica en América Latina; los secundarios, obtener una visión general del enfoque diagnóstico/terapéutico de miembros de la SLAGHNP y explorar la relación entre la frecuencia de casos y los años del período evaluado. Material y métodos: Se realizó una encuesta en línea a pediatras gastroenterólogos de América Latina con la plataforma SurveyMonkey. Se preguntó la frecuencia anual de pacientes nuevos de 2005 a 2016, su variedad, los segmentos del tubo digestivo afectados, los métodos de diagnóstico y el tratamiento utilizado. Se evaluó la correlación entre la frecuencia anual y los años de estudio. Resultados: Se estudió a 607 pacientes; el diagnóstico de colitis ulcerativa se realizó en 475 (78.3%), de enfermedad de Crohn en 104 (17.1%) y de enfermedad intestinal inflamatoria no clasificable en 28 (4.6%). La tendencia de colitis ulcerativa tuvo un incremento lineal con coeficiente de correlación significativo entre la frecuencia de casos nuevos y el año de estudio; 67.6% tuvieron pancolitis. Los métodos de diagnóstico incluyeron datos clínicos, endoscopia y biopsias en más del 99% de los casos; los estudios de imagen se indicaron de manera selectiva. Los esquemas farmacológicos se circunscribieron a derivados del ácido 5-aminosalicílico, azatioprina, 6-mercaptopurina, infliximab y adalimumab. Conclusiones: La enfermedad intestinal inflamatoria pediátrica en América Latina parece incrementarse en el período estudiado con predominio de formas moderadas o graves de colitis ulcerativa; esta tendencia lineal puede indicar la posibilidad predictiva de incremento gradual en la próxima década, lo que es probable que tenga implicaciones epidemiológicas y clínicas.