Real-world experience with filgotinib for rheumatoid arthritis in Germany : A retrospective chart review.

BACKGROUND: Real-world data for filgotinib, a Janus kinase (JAK)1 inhibitor, are limited in patients with rheumatoid arthritis (RA). OBJECTIVES: To explore real-world filgotinib use in patients with RA in Germany. MATERIALS AND METHODS: This retrospective chart review included patients aged ≥ 18 years with confirmed moderate to severe RA who initiated filgotinib before December 1, 2021, with ≥ 6 months of medical records available prior to filgotinib initiation or after initial diagnosis. Patient characteristics, prior treatments, reasons for initiating/discontinuing filgotinib, disease activity, dose adjustments and concomitant treatments were recorded. RESULTS: In total, 301 patients from 20 German rheumatology outpatient units were included. One-third were aged ≥ 65 years and almost half had ≥ 1 cardiovascular (CV) risk factor. Most patients initiated filgotinib as monotherapy (83.7%; 12.7% of whom with glucocorticoids) and at the 200 mg dose (84.7%); higher proportions of those initiating the 100 versus 200 mg dose were aged ≥ 65 years and had renal impairment or ≥ 1 CV risk factor. Oral administration (78.4%), fast onset of action (66.8%) and administration as monotherapy (65.4%) were the most common reasons for initiating filgotinib. At 12 months, 41 (18.4%) patients had discontinued filgotinib, most commonly due to lack of effectiveness. After 6­months of follow-up, 36.8% of patients had achieved Clinical Disease Activity Index (CDAI) remission and 45.6% had achieved CDAI low disease activity. CONCLUSIONS: In clinical practice in Germany, reasons for initiating filgotinib in patients with RA were related to dosing flexibility and general JAK inhibitor attributes. Filgotinib was used predominantly as monotherapy and was effective and generally well tolerated; however, longer-term data in larger, prospective cohorts are needed.

Real-world treatment persistence in patients with rheumatoid arthritis initiating DMARDs in Germany-a health insurance claims data analysis.

OBJECTIVE: To investigate treatment patterns in patients with rheumatoid arthritis (RA) in Germany who had previously received conventional synthetic (cs) or biologic (b) disease-modifying antirheumatic drugs (DMARDs). METHODS: Patients with RA who initiated treatment with a csDMARD, bDMARD, or Janus kinase (JAK) inhibitor between 2017 and 2018 and who had previously received csDMARD or bDMARD therapy were retrospectively selected from the Institute for Applied Health Research Berlin GmbH (InGef). Time on treatment and discontinuation risk were assessed using the Kaplan-Meier method. Cox regression identified variables associated with an increased discontinuation risk. RESULTS: A total of 990 patients had received prior csDMARD therapy; 375 had received prior bDMARD therapy. Tumor necrosis factor (TNF)-α inhibitors and JAK inhibitors were the most commonly prescribed DMARD class in those previously treated with a csDMARD or bDMARD, respectively. In both cohorts, more patients received DMARD monotherapy than combination therapy. In the prior csDMARD cohort, median time on treatment was 276, 252, and 148 days with JAK inhibitors, TNF­α inhibitors, and csDMARDs, respectively, and those treated with JAK or TNF­α inhibitors were less likely to discontinue treatment than those on csDMARDs (log-rank test p-value < 0.01 for both comparisons); no significant differences were found within the prior bDMARD cohort. CONCLUSION: This is among the first detailed analyses of RA treatment patterns in a real-world setting in Germany since the introduction of JAK inhibitors. TNF­α inhibitors were the most commonly prescribed DMARD after failure of an initial csDMARD, while JAK inhibitors were the most common among patients previously treated with a bDMARD. In both groups, monotherapy with bDMARD or targeted synthetic DMARD was common. In the prior csDMARD cohort, treatment duration was significantly longer with JAK or TNF­α inhibitors than with csDMARDs.

Persistence with Biologic Treatment in Patients with Inflammatory Bowel Disease: A German Claims Data Analysis.

OBJECTIVES: This study aimed to assess the real-world rates of treatment discontinuation and switching of biologic therapies in patients with inflammatory bowel disease (IBD). METHODS: A retrospective claims data analysis on all continuously insured adult IBD patients with initiation of a biologic therapy was conducted. Observation started with the date of the first prescription of index tumor necrosis factor α-inhibitors (anti-TNFα) or vedolizumab (VDZ) therapy and lasted 12 months. Non-persistence was assumed in case of a switch to another biologic or a treatment gap of >90 days. RESULTS: We included 1,248 IBD biologic treatment starters (502 adalimumab, 77 golimumab, 441 infliximab, 228 VDZ); 837/411 were biologic-naïve (bio-naïve)/ biologic-experienced (bio-experienced). Mean age of bio-naïve/bio-experienced anti-TNFα patients was 39.2/38.1 years (54.9%/56.7% female) and 42.6/37.8 years for VDZ patients (56.3%/54.9% female). Seven hundred and seventy-two patients (61.9%) were persistent with their index biologic therapy after 12 months (61.9%/61.8% bio-naïve/bio-experienced). Percentage of persistent patients was 69.7% for VDZ (65.6%/71.3%) and 60.1% for anti-TNFα (61.4%/55.5%). VDZ was associated with later non-persistence in a multivariable Cox regression analysis (hazard ratio 0.675; p = 0.003) compared to anti-TNFα. CONCLUSIONS: Only 60-70% of IBD -patients are still persistent with their biologic therapy after 12 months. VDZ therapy is associated with a higher persistence than anti-TNFα therapy in this analysis.

Real-world biologic treatment and associated cost in patients with inflammatory bowel disease.

OBJECTIVES: This study aimed to describe biologic treatment of German inflammatory bowel disease (IBD) patients, including biologics' dosage, health care resource use, and treatment-associated cost. METHODS: In this retrospective claims data analysis, all continuously insured adult IBD patients (Crohn's disease [CD] or ulcerative colitis [UC]) who started a new therapy with an anti-tumor necrosis factor alpha (anti-TNF-α) or vedolizumab (VDZ) were included. Observation started with the date of the first prescription of index biologic therapy and lasted 12 months. RESULTS: In the database, 1248 out of 57 296 IBD patients started a biologic treatment of interest (1020 anti-TNF-α, 228 VDZ), and 837 patients were bio-naïve (773 anti-TNF-α, 64 VDZ). The mean age of bio-naïve/bio-experienced anti-TNF-α patients was 39.2/38.1 years (54.9 %/56.7 % female) and 42.6/37.8 years for VDZ patients (56.3 %/54.9 % female). The proportion of patients receiving a maintenance dosage > 150 % compared to SmPC was 15.1 % for Adalimumab, 5.2-39.0 % for Golimumab, 14.7-34.5 % for Infliximab, and 19.7 % for VDZ patients. During the maintenance phase, up to 58.8 % of patients received at least 1 prescription of any CS, and 41.7 %/47.1 % (anti-TNF-α/VDZ) were treated in a hospital due to IBD. The mean IBD-related direct health care cost per patient year was €â€Š30 246 (anti-TNF-α)/ €â€Š28 227 (VDZ) for bio-naïve patients (p = 0.288) and €â€Š34 136 (anti-TNF-α)/ €â€Š32 112 (VDZ) for bio-experienced patients (p = 0.011). CONCLUSIONS: A substantial percentage of patients receive a high biologic dosage in the maintenance phase. Despite biologic therapy, 30-40 % receive a CS therapy and/or experience at least 1 IBD-associated hospitalization within a year, possibly indicating a remaining disease activity.

Flupirtine-induced liver injury--seven cases from the Berlin Case-control Surveillance Study and review of the German spontaneous adverse drug reaction reporting database.

PURPOSE: The hepatotoxic potential of the analgesic flupirtine has attracted increased attention over the past years. Recently, risk minimisation measures such as maximum treatment duration of 2 weeks have been requested by the European Medicines Agency (EMA). This study was conducted to further elucidate the clinical pattern of flupirtine-induced liver injury (FILI). METHODS: Seven FILI patients were ascertained in all Berlin hospitals in the Berlin Case-control Surveillance Study (FAKOS) between 2002 and 2011. Furthermore, we reviewed the severe cases of flupirtine-associated hepatotoxicity included in the adverse drug reaction database of the Federal Institute for Drugs and Medical Devices (BfArM) in Germany from between 1991 and 2012. RESULTS: All seven FILI patients of FAKOS were hospitalised. Six of them were female, mean age was 58 [corrected] years, and the most common symptoms were fatigue and jaundice. Three patients developed acute liver failure (ALF). Discontinuation of flupirtine invariably led to clinical and laboratory improvement. Review of the BfArM cases (n = 248) showed female sex predominance and high prevalence of jaundice and ALF. Time to onset of symptoms was less than 2 weeks in 9 % of the patients with respective data. CONCLUSIONS: Our results corroborate previous findings on FILI's clinical pattern and on its potentially severe course. Although the hepatotoxic risk might be higher after the first 2 weeks of treatment, earlier onset of severe FILI cannot be ruled out. Postauthorisation safety studies are needed to evaluate EMA's risk minimisation measures and to quantify flupirtine's risk according to its duration of use.

Effect of Filgotinib on Body Mass Index (BMI) and Effect of Baseline BMI on the Efficacy and Safety of Filgotinib in Rheumatoid Arthritis.

INTRODUCTION: This post hoc analysis of the phase 3 rheumatoid arthritis (RA) filgotinib clinical trial program assessed the effect of filgotinib on body mass index (BMI) in patients with RA and the impact of BMI on the efficacy and safety of filgotinib. METHODS: FINCH 1-3 were randomized, double-blind, active- or placebo-controlled phase 3 trials of filgotinib 100 and 200 mg in patients with RA (N = 3452). BMI assessments included the mean change from baseline in BMI and the proportion of patients whose BMI increased by incremental thresholds. Efficacy measures included American College of Rheumatology (ACR) 20/50/70 response and low disease activity/remission according to Disease Activity Score 28 using C-reactive protein. The exposure-adjusted incident rate (EAIR) of adverse events (AEs) was assessed by baseline BMI, using integrated data from the FINCH 1-4 and the phase 2 DARWIN 1-3 studies (total filgotinib exposure = 8085 patient-years). RESULTS: Mean change from baseline in BMI over time was similar across treatment arms. In most patients, BMI increased by ≤ 1 or 2 kg/m2 at both weeks 12 and 24, regardless of treatment group or baseline BMI; few patients had increases of ≥ 4 kg/m2. For most efficacy measures, filgotinib 200 mg was more efficacious than filgotinib 100 mg or active comparators or placebo across BMI subgroups. For the higher filgotinib dose, the EAIR of serious treatment-emergent AEs, venous thrombotic and embolic events, and major adverse cardiovascular events increased with increasing BMI. CONCLUSIONS: Filgotinib did not lead to substantial changes in BMI, and BMI did not appear to affect the efficacy of filgotinib. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT02889796, NCT02873936, NCT02886728, NCT03025308, NCT01888874, NCT01894516, NCT02065700.

Some rheumatoid arthritis treatments cause patients to gain weight or are less effective in patients with obesity than in patients without obesity. Also, obesity can make rheumatoid arthritis worse. Filgotinib is a rheumatoid arthritis treatment that was evaluated in seven randomized clinical studies (FINCH 1­4 and DARWIN 1­3). We investigated whether filgotinib causes changes in weight and whether body mass index (BMI) affects the efficacy or safety of filgotinib. We analyzed how the BMI of patients who participated in FINCH 1, 2, or 3 changed over time. Most patients had a small increase in BMI (around 1­2 kg/m²) after 24 weeks of filgotinib treatment. This change in BMI was not affected by patients' BMI at baseline. Baseline BMI did not impact the efficacy of filgotinib, which was assessed using standard measures of disease activity. Filgotinib was more effective than other rheumatoid arthritis treatments and placebo in all patients, regardless of BMI subgroup. Using safety data from all seven clinical studies (FINCH 1­4 and DARWIN 1­3), we found that some adverse events occurred more often in patients with obesity (a BMI of ≥ 30 kg/m²) than in those without obesity. The increased adverse events included venous thrombotic and embolic events and major adverse cardiovascular events, for which obesity is a known risk factor. These results show that filgotinib did not substantially change BMI (which increased by around 1­2 kg/m² in most patients), and that baseline BMI did not affect the efficacy of filgotinib.

The extracellular regulated kinase-1 (ERK1) controls regulated alpha-secretase-mediated processing, promoter transactivation, and mRNA levels of the cellular prion protein.

The α-secretases A disintegrin and metalloprotease 10 (ADAM10) and ADAM17 trigger constitutive and regulated processing of the cellular prion protein (PrP(c)) yielding N1 fragment. The latter depends on protein kinase C (PKC)-coupled M1/M3 muscarinic receptor activation and subsequent phosphorylation of ADAM17 on its intracytoplasmic threonine 735. Here we show that regulated PrP(c) processing and ADAM17 phosphorylation and activation are controlled by the extracellular-regulated kinase-1/MAP-ERK kinase (ERK1/MEK) cascade. Thus, reductions of ERK1 or MEK activities by dominant-negative analogs, pharmacological inhibition, or genetic ablation all impair N1 secretion, whereas constitutively active proteins increase N1 recovery in the conditioned medium. Interestingly, we also observed an ERK1-mediated enhanced expression of PrP(c). We demonstrate that the ERK1-associated increase in PrP(c) promoter transactivation and mRNA levels involve transcription factor AP-1 as a downstream effector. Altogether, our data identify ERK1 as an important regulator of PrP(c) cellular homeostasis and indicate that this kinase exerts a dual control of PrP(c) levels through transcriptional and post-transcriptional mechanisms.

S3 - Guidelines on the treatment of psoriasis vulgaris (English version). Update.

Psoriasis vulgaris is a common and often chronic inflammatory skin disease. The incidence of psoriasis in Western industrialized countries ranges from 1.5% to 2%. Patients afflicted with severe psoriasis vulgaris may experience a significant reduction in quality of life. Despite the large variety of treatment options available, surveys have shown that patients still do not received optimal treatments. To optimize the treatment of psoriasis in Germany, the Deutsche Dermatologi sche Gesellschaft (DDG) and the Berufsverband Deutscher Dermatologen (BVDD) have initiated a project to develop evidence-based guidelines for the management of psoriasis. They were first published in 2006 and updated in 2011. The Guidelines focus on induction therapy in cases of mild, moderate and severe plaque-type psoriasis in adults including systemic therapy, UV therapy and topical therapies. The therapeutic recommendations were developed based on the results of a systematic literature search and were finalized during a consensus meeting using structured consensus methods (nominal group process).

p53-Dependent transcriptional control of cellular prion by presenilins.

The presenilin-dependent gamma-secretase processing of the beta-amyloid precursor protein (betaAPP) conditions the length of the amyloid beta peptides (Abeta) that accumulate in the senile plaques of Alzheimer's disease-affected brains. This, together with an additional presenilin-mediated epsilon-secretase cleavage, generates intracellular betaAPP-derived fragments named amyloid intracellular domains (AICDs) that regulate the transcription of several genes. We establish that presenilins control the transcription of cellular prion protein (PrP(c)) by a gamma-secretase inhibitor-sensitive and AICD-mediated process. We demonstrate that AICD-dependent control of PrP(c) involves the tumor suppressor p53. Thus, p53-deficiency abolishes the AICD-mediated control of PrP(c) transcription. Furthermore, we show that p53 directly binds to the PrP(c) promoter and increases its transactivation. Overall, our study unravels a transcriptional regulation of PrP(c) by the oncogene p53 that is directly driven by presenilin-dependent formation of AICD. Furthermore, it adds support to previous reports linking secretase activities involved in betaAPP metabolism to the physiology of PrP(c).

Evidence-based (S3) guidelines for the treatment of psoriasis vulgaris.

Psoriasis vulgaris is a common and often chronic inflammatory skin disease. The incidence of psoriasis in Western industrialized countries ranges from 1 to 2%. Patients afflicted with severe psoriasis vulgaris may experience a significant reduction in quality of life. Despite the large variety of treatment options available, patient surveys have revealed lack of satisfaction with the efficacy of available treatments and a high rate of non-compliance. To optimize the treatment of psoriasis in Germany, the Deutsche Dermatologische Gesellschaft (DDG) and the Berufsverband Deutscher Dermatologen (BVDD) initiated a project to develop evidence-based guidelines for the management of psoriasis. These resulting Guidelines focus on induction therapy in cases of mild, moderate, and severe plaquetype psoriasis in adults. The Guidelines include evidence-based evaluation of the efficacy of all currently available therapeutic options in Germany. In addition, they offer detailed information on how best to administer the various treatments and give information on contraindications, adverse drug reactions, and drug interactions as well as estimates of practicability and cost. The Guidelines were developed following the recommendations of the Arbeitsgemeinschaft wissenschaftlicher medizinischer Fachgesellschaften (AWMF). The therapeutic recommendations were developed by an expert group and finalized during interdisciplinary consensus conferences.

Genomic organisation of the mouse gene encoding endothelin-converting enzyme-1 (ECE-1) and mRNA expression of ECE-1 isoforms in murine tissues.

Mouse knockout-models have previously revealed important biological functions of endothelin-converting enzyme-1 (ECE-1) in normal cardiac and craniofacial development. Since human ECE-1 is expressed in various isoforms, termed a, b, c, and d, expression of which is controlled by alternative promoters, we postulated that corresponding isoforms may also be transcribed from the murine Ece1 gene. By comparative sequence analysis using exon-specific sequences of human and rat ECE-1 we have resolved the complete exon-intron structure of the murine Ece1 locus on chromosome 4. The murine Ece1 gene comprises 23 exons distributed over 100 kb of genomic DNA and was found to be structurally highly conserved when compared to the human ECE1 gene. As with the human gene, the exons containing isoform-specific sequences were localised in the 5' terminal region of the murine Ece1 gene. Using specific sense primers, isoform-specific expression of murine ECE-1 mRNA in various mouse tissues was confirmed by RT-PCR. Using real-time PCR we demonstrated that ECE-1c was the most abundantly expressed isoform in most tissues, except for heart and aorta displaying a more even isoform distribution. We detected an additional isoform-specific exon, designated c2, which was apparently constitutively spliced and expressed only as minor fraction of ECE-1c transcripts. Our results provide evidence of structural conservation of mammalian genes encoding ECE-1 and will facilitate a more refined analysis of ECE-1 mRNA expression in the mouse model organism.

Blockade of the intermediate-conductance calcium-activated potassium channel as a new therapeutic strategy for restenosis.

BACKGROUND: Angioplasty stimulates proliferation and migration of vascular smooth muscle cells (VSMC), leading to neointimal thickening and vascular restenosis. In a rat model of balloon catheter injury (BCI), we investigated whether alterations in expression of Ca2+-activated K+ channels (KCa) contribute to intimal hyperplasia and vascular restenosis. METHODS AND RESULTS: Function and expression of KCa in mature medial and neointimal VSMC were characterized in situ by combined single-cell RT-PCR and patch-clamp analysis. Mature medial VSMC exclusively expressed large-conductance KCa (BKCa) channels. Two weeks after BCI, expression of BKCa was significantly reduced in neointimal VSMC, whereas expression of intermediate-conductance KCa (IKCa1) channels was upregulated. In the aortic VSMC cell line, A7r5 epidermal growth factor (EGF) induced IKCa1 upregulation and EGF-stimulated proliferation was suppressed by the selective IKCa1 blocker TRAM-34. Daily in vivo administration of TRAM-34 to rats significantly reduced intimal hyperplasia by approximately 40% at 1, 2, and 6 weeks after BCI. Two weeks of treatment with the related compound clotrimazole was equally effective. Reduction of intimal hyperplasia was accompanied by decreased neointimal cell content, with no change in the rate of apoptosis or collagen content. CONCLUSIONS: The switch toward IKCa1 expression may promote excessive neointimal VSMC proliferation. Blockade of IKCa1 could therefore represent a new therapeutic strategy to prevent restenosis after angioplasty.

Differential regulation of in vivo angiogenesis by angiotensin II receptors.

Angiotensin II (ANG II), a key regulator of blood pressure and body fluid homeostasis, exerts mitogenic effects on endothelial cells. We therefore hypothesized that ANG II could be a mediator between homeostatic changes within the vascular perfusion bed and growth factor-driven angiogenesis. In the present study, we applied the alginate implant angiogenesis model in mice with normal ANG II levels, elevated ANG II levels by transgenic overexpression of angiotensinogen (AOGEN), or in AT2 receptor-deficient mice. We demonstrate that a decrease in the amount of circulating ANG II by the angiotensin-converting enzyme (ACE) inhibitor enalapril or the AT1 receptor antagonist losartan induced a stimulation of in vivo angiogenesis implying an inhibitory function of ANG II through the AT1 receptor. However, the strong increase of angiogenesis in AOGEN-transgenic mice compared with mice with normal ANG II levels suggests additional stimulatory activity. We showed that the ANG II-induced stimulation of angiogenesis is linked to the AT2 receptor as an impaired induction of angiogenesis was obtained in AT2 receptor knockout mice. These findings provide the first evidence that the AT2 receptor mediates a stimulation of in vivo angiogenesis and indicate that ANG II is a humoral regulator of peripheral angiogenesis involving two receptor subtypes with opposing actions.

Regulation of the major isoform of human endothelin-converting enzyme-1 by a strong housekeeping promoter modulated by polymorphic microsatellites.

BACKGROUND: Human endothelin-converting enzyme (ECE)-1, the key enzyme in endothelin biosynthesis, shows broad cell and tissue expression within the cardiovascular system. Expression of ECE-1c, which represents the major ECE-1 isoform, is directed by an alternative promoter, but the mechanisms of ECE-1c promoter regulation are largely unknown. As ECE-1c transcription is initiated from several start sites, we hypothesized that the ECE-1c promoter functions as a housekeeping promoter. OBJECTIVE: To investigate the putative housekeeping function of the ECE-1c promoter in vascular endothelial cells, which represent a main site of its expression. RESULTS: Using promoter reporter assays, gel shift and supershift assays, we have demonstrated, in human endothelial EA.hy926 cells, functionality of cis-acting elements for binding of the CAAT-box binding protein NF-YB, GATA-2) E2F-2, and a GC-box binding factor, which are spatially associated with transcriptional start sites of ECE-1c. In the more upstream promoter region we have identified three highly polymorphic dinucleotide repeats, 5'-(CA)n, (CG)n and 3'-(CA)n, which strongly affected promoter function in endothelial EA.hy926 cells (2.7-fold activation comparing the most active to the least active allele) and, in a similar manner, in human neuronal KELLY cells. Finally, by in-vitro methylation, we were able to achieve strong suppression of the ECE-1c promoter activity in endothelial cells. CONCLUSION: Our results provide a molecular explanation for constitutive expression of ECE-1c mRNA. Modulation by genetic and epigenetic mechanisms as revealed in our study may account for interindividual variation of the constitutive endothelin system activity in humans and thus influence individual predisposition to cardiovascular disease.