Human type 1 innate lymphoid cells accumulate in inflamed mucosal tissues.

Innate lymphoid cells (ILCs) are effectors of innate immunity and regulators of tissue modeling. Recently identified ILC populations have a cytokine expression pattern that resembles that of the helper T cell subsets T(H)2, T(H)17 and T(H)22. Here we describe a distinct ILC subset similar to T(H)1 cells, which we call 'ILC1'. ILC1 cells expressed the transcription factor T-bet and responded to interleukin 12 (IL-12) by producing interferon-γ (IFN-γ). ILC1 cells were distinct from natural killer (NK) cells as they lacked perforin, granzyme B and the NK cell markers CD56, CD16 and CD94, and could develop from RORγt(+) ILC3 under the influence of IL-12. The frequency of the ILC1 subset was much higher in inflamed intestine of people with Crohn's disease, which indicated a role for these IFN-γ-producing ILC1 cells in the pathogenesis of gut mucosal inflammation.

Differences in STI/HIV Burden and Sexual Health Care-Seeking Behavior Among First- and Second-Generation Migrant and Western-Born Male Sex Workers Who Have Sex With Men in the Netherlands: A Retrospective Cohort Study.

BACKGROUND: Globally, migrant sex workers have a higher burden of sexually transmitted infections (STI)/human immunodeficiency virus (HIV). This large study aimed to assess demographics, STI/HIV burden, and sexual health care-seeking behavior of first-generation migrant and second-generation migrant male sex workers who have sex with men (MSW-MSM) versus Western-born MSW-MSM. METHODS: Coded STI clinic consultations (n = 6970) from 3116 individual MSW-MSM attending any Dutch STI clinic between 2016 and 2021 were included. First-generation migrant: born outside of northern/central/southern/western Europe/North America/Oceania. Second-generation migrant: ≥1parent born outside of northern/central/southern/western Europe/North America/Oceania. Multivariable logistic regression analysis assessed associations between MSW-MSM groups and STI in first consultation in the data. A Cox proportional hazard regression compared the incidence of a first repeat consultation between migration groups, stratified by STI in first consultation. All analyses were adjusted for age and urbanity of STI clinic region. RESULTS: First-generation migrant MSW-MSM (n = 1085) were mostly born in Latin America (50%), whereas second-generation migrant MSW-MSM (n = 368) mostly originated from North Africa (30.4%). The proportion of STI diagnoses differed (33.2%, 29.3%, 23.3%; P < 0.001) between the first-generation migrant, second-generation migrant, and Western-born MSW-MSM. First-generation migrant MSW-MSM versus Western-born had an adjusted odds ratio of 1.6 (95% confidence interval, 1.3-1.9) of STI diagnosis in the first consultation. First-generation migrant MSW-MSM versus Western-born had an adjusted hazard ratio of 1.5 (95% confidence interval, 1.3-1.8) of having a first repeat consultation at any time, when stratified for no STI in the first consultation. CONCLUSIONS: The STI/HIV burden is high among all 3 MSW-MSM groups. First-generation migrants have higher odds of STI, but retention in care seems similar. Results highlight the importance of low-threshold STI testing and care for (migrant) MSW-MSM.

Human IL-25- and IL-33-responsive type 2 innate lymphoid cells are defined by expression of CRTH2 and CD161.

Innate lymphoid cells (ILCs) are emerging as a family of effectors and regulators of innate immunity and tissue remodeling. Interleukin 22 (IL-22)- and IL-17-producing ILCs, which depend on the transcription factor RORγt, express CD127 (IL-7 receptor α-chain) and the natural killer cell marker CD161. Here we describe another lineage-negative CD127(+)CD161(+) ILC population found in humans that expressed the chemoattractant receptor CRTH2. These cells responded in vitro to IL-2 plus IL-25 and IL-33 by producing IL-13. CRTH2(+) ILCs were present in fetal and adult lung and gut. In fetal gut, these cells expressed IL-13 but not IL-17 or IL-22. There was enrichment for CRTH2(+) ILCs in nasal polyps of chronic rhinosinusitis, a typical type 2 inflammatory disease. Our data identify a unique type of human ILC that provides an innate source of T helper type 2 (T(H)2) cytokines.

Sexual (Risk) Behavior and Risk-Reduction Strategies of Home-Based Male Sex Workers Who Have Sex with Men (MSW-MSM) in The Netherlands: A Qualitative Study.

An understanding of sexual (risk) behavior is necessary to successfully develop prevention and care strategies for the sexually transmitted infections (STI) high-risk group of male sex workers who have sex with men (MSW-MSM). However, limited scientific knowledge is available on sexual (risk) behavior of (home-based) MSW-MSM. This study aimed to gain an understanding of sexual (risk) behavior, factors influencing sexual (risk) behavior, and applied risk-reduction strategies of home-based MSW-MSM. For this qualitative study, semi-structured individual interviews were conducted with 20 home-based MSW-MSM in the Netherlands. The interviews' recordings were transcribed verbatim and thematically analyzed with Atlas.ti 8. Condom use was reported to be high during anal sex, but low during oral sex and mostly determined by STI risk perception, trust in clients, and sexual pleasure. Many experienced condom failure, while few knew what to do after condom failure and were aware of post-exposure prophylaxis (PEP). Many MSW-MSM had chemsex in the past 6 months in order to loosen up and enhance sexual pleasure. Some were not vaccinated against hepatitis B virus (HBV), mainly due to the lack of information and awareness of HBV vaccination and low risk perception of HBV. The results of this study can be used to tailor future STI/HIV risk-reduction strategies for home-based MSW-MSM and to increase awareness and uptake of available STI/HIV prevention strategies such as P(r)EP and HBV vaccination.

Using a theoretical framework of Intervention Mapping to inform public health communication messages designed to increase vaccination uptake; the example of mpox in the Netherlands.

INTRODUCTION: During an infectious disease outbreak, primary preventive pre-exposure vaccination (PPV) could substantially increase the potential for its control, if uptake is sufficiently high. An important tool to increase PPV uptake, are communication strategies, with tailored messages targeted to modify determinants for PPV uptake. Here, we take the example of the 2022 mpox multicountry outbreak, as we inform the development of communication strategies by applying a theoretical framework for selecting effective communication strategies. METHODS: The theoretical framework Intervention Mapping (IM) was applied during the outbreak to inform communications [program]. Steps included: 1. Creating a logic model of the problem [not accepting PPV] by reviewing available literature, conducting an online survey among people at risk of mpox exposure, and consulting community-members, healthcare-and communication professionals; 2. Creating a matrix of change [from lower to higher PPV acceptance]; and 3. Selecting theory-based methods and practical applications for communication messages to achieve the intended behaviour change (getting vaccinated). RESULTS: The program objective was to promote PPV uptake in people at risk of mpox exposure. Important changeable determinants identified included perceived risk and severity of mpox, importance to protect against mpox [attitude], experienced effectiveness of vaccination and side-effects [response efficacy], and social norm. Theory-based communication methods for optimizing these determinants include provision of facts [increasing knowledge], personalized risk and scenario-based risk information [addressing risk perception/severity], elaboration, arguments [stimulating a positive attitude], gain framing [increasing perceived response efficacy], guided practice [increasing skills/self-efficacy in overcoming barriers] and social norm approach [demonstrating positive norm]. Other key important factors include that communication delivery is uniform (across channels), clear, accessible, and with stigma-free messaging, and that is well-timed and repeated. CONCLUSION: IM provided a valuable tool in selecting communication methods to promote mpox vaccination uptake. These methods can be used to (more quickly) produce and implement a communication program in the context of possible future, vaccine-preventable, infectious disease outbreaks.

Quality of Surveillance Impacts the Colitis-Associated Advanced Neoplasia Risk: A Multicenter Case-Control Study.

BACKGROUND AND AIMS: Although colorectal cancer (CRC) surveillance is embedded in clinical inflammatory bowel disease (IBD) practice, a subset of patients still develops advanced neoplasia (AN) (high-grade dysplasia [HGD] and/or CRC). We aimed to assess the impact of surveillance quality on AN risk in IBD. METHODS: In this multicenter case-control study, we searched the Dutch nationwide pathology databank to identify IBD cases with AN and controls with indefinite or low-grade dysplasia. The surveillance colonoscopy preceding the index lesion (first indefinite for dysplasia [IND]/low-grade dysplasia [LGD] or AN) was used to assess the impact of surveillance quality. We assessed intervals, bowel preparation, cecal intubation, and absence of inflammation as primary quality indicators. In addition, we assessed chromoendoscopy, endoscopist expertise, hospital setting, and biopsy strategy. Associations of quality indicators with AN risk were determined with multivariable logistic regression analyses with Firth's correction. RESULTS: We included 137 cases and 138 controls. Delayed intervals (58.2% vs 39.6%) and active inflammation (65.3% vs 41.8%) were frequently present in cases and controls and were associated with AN (delayed interval: adjusted odds ratio [aOR], 2.00; 95% confidence interval [CI], 1.07-3.81; P = .03; active inflammation: aOR, 2.46; 95% CI, 1.33-4.61; P < .01). Surveillance compliant with primary quality indicators was associated with a reduced AN risk (aOR, 0.43; 95% CI, 0.22-0.91; P = .03), similar to chromoendoscopy (OR, 0.11; 95% CI, 0.01-0.89; P = .01). Other indicators were not significantly associated with AN. CONCLUSIONS: Surveillance compliant with primary quality indicators is associated with a reduced colitis-associated AN risk. Delayed surveillance intervals and active inflammation were associated with an increased AN risk. This underlines the importance of procedural quality, including endoscopic remission to optimize the effectiveness of endoscopic surveillance.

Barriers and facilitators to utilisation of public sexual healthcare services for male sex workers who have sex with men (MSW-MSM) in The Netherlands: a qualitative study.

BACKGROUND: Male sex workers who have sex with men (MSW-MSM) are a high-risk group for sexually transmitted infections (STI) including human immunodeficiency virus (HIV). Provision of sexual services by MSW-MSM has shifted to the internet. Consequently, MSW-MSM have become hidden to care for providers of sexual healthcare services (SHS). The aim of this study was to 1) assess characteristics of the MSW-MSM population and 2) assess MSW-MSM's perceived barriers and facilitators to utilise SHS provided free and anonymously by the public health STI clinic in The Netherlands. METHODS: For this qualitative study, semi-structured individual in-depth interviews were conducted with 20 MSW-MSM who worked home-based in the Dutch province of Limburg. Participants were recruited from November 2018 to June 2019 by purposive sampling until saturation was reached via 1) five websites and smartphone applications commonly used by MSW-MSM, 2) STI clinic, 3) two gay saunas. A theory-informed interview guide was developed including themes such as sexuality, sex work, SHS and barriers and facilitators to SHS utilisation. The interviews' recordings were transcribed verbatim and thematically analysed by inductive and deductive coding with Atlas.ti 8. RESULTS: The interviewed MSW-MSM were diverse in age (range: 18 - 66; median: 39.5) and mostly western European (85%). Identified barriers to SHS utilisation were lack of self-identification as homosexual and sex worker, perceived stigma on sex work and MSM, the lack of awareness of SHS and a low STI risk perception. Identified facilitators were trust in and positive attitude towards SHS, awareness of SHS's anonymous, confidential and free-of-charge nature, high STI risk perception and knowledgeable about STI/HIV. MSW-MSM-identified implications for SHS-providers were promotion of SHS on online MSW-MSM and general platforms (e.g. Facebook), offering one-on-one online and informal communication with an SHS-provider (e.g. STI clinic nurse) and providing STI (testing) information. CONCLUSION: The MSW-MSM population's diversity and identified barriers, facilitators and implications should be taken into account to optimize accessibility and utilisation of SHS for MSW-MSM in Western Europe. SHS-providers could facilitate sex work disclosure by personally asking patients about sex in exchange for money or goods in a non-judgmental manner and explaining the medical relevance of disclosure.

The transcription factor GATA3 is essential for the function of human type 2 innate lymphoid cells.

Type 2 innate lymphoid cells (ILC2s) are part of a large family of ILCs that are important effectors in innate immunity, lymphoid organogenesis, and tissue remodeling. ILC2s mediate parasite expulsion but also contribute to airway inflammation, emphasizing the functional similarity between these cells and Th2 cells. Consistent with this, we report that the transcription factor GATA3 was highly expressed by human ILC2s. CRTH2(+) ILC2s were enriched in nasal polyps of patients with chronic rhinosinusitis, a typical type 2-mediated disease. Nasal polyp epithelial cells expressed TSLP, which enhanced STAT5 activation, GATA3 expression, and type 2 cytokine production in ILC2s. Ectopic expression of GATA3 in Lin(-)CD127(+)CRTH2(-) cells resulted in induction of CRTH2 and the capacity to produce high amounts of type 2 cytokines in response to TSLP plus IL-33. Hence, we identify GATA3, potently regulated by TSLP, as an essential transcription factor for the function of human ILC2s.

Transcriptional control of innate lymphoid cells.

Cells that belong to the family of innate lymphoid cells (ILCs) not only form a first line of defense against invading microbes, but also play essential roles in tissue remodeling and immune pathology. Rorγt(+) ILCs, producing the cytokines IL-22 and IL-17, include lymphoid tissue inducer (LTi) cells which are critical for the formation of lymphoid structures. Recently another ILC subset has been identified, which is dependent on RORα for its development and is dedicated to the production of the Th2 cytokines IL-5 and IL-13. These ILCs have been termed type 2 ILCs. All ILC subets are considered to belong to the same family that also includes natural killer cells because they all rely on the common γ-chain (γc) of the IL-2 receptor for their development and function, share a lymphoid morphology and depend on the transcriptional repressor Id2 for their development. Other transcription factors, including Notch, and the aryl hydrocarbon receptor (AhR) in RORγt(+) ILCs and GATA3 in type 2 ILCs, also play roles in the development, survival, and function of these ILC subpopulations. Here we review the current knowledge with regard to the transcription factors involved in the development and functions of ILCs.

Endoscopic and surgical treatment outcomes of colitis-associated advanced colorectal neoplasia: a multicenter cohort study.

BACKGROUND: Inflammatory bowel disease (IBD) patients are at increased risk of advanced neoplasia (high-grade dysplasia or colorectal cancer). The authors aimed to (1) assess synchronous and metachronous neoplasia following (sub)total or proctocolectomy, partial colectomy or endoscopic resection for advanced neoplasia in IBD, and (2) identify factors associated with treatment choice. MATERIAL AND METHODS: In this retrospective multicenter cohort study, the authors used the Dutch nationwide pathology databank (PALGA) to identify patients diagnosed with IBD and colonic advanced neoplasia (AN) between 1991 and 2020 in seven hospitals in the Netherlands. Logistic and Fine & Gray's subdistribution hazard models were used to assess adjusted subdistribution hazard ratios for metachronous neoplasia and associations with treatment choice. RESULTS: The authors included 189 patients (high-grade dysplasia n =81; colorectal cancer n =108). Patients were treated with proctocolectomy ( n =33), (sub)total colectomy ( n =45), partial colectomy ( n =56) and endoscopic resection ( n =38). Partial colectomy was more frequently performed in patients with limited disease and older age, with similar patient characteristics between Crohn's disease and ulcerative colitis. Synchronous neoplasia was found in 43 patients (25.0%; (sub)total or proctocolectomy n =22, partial colectomy n =8, endoscopic resection n =13). The authors found a metachronous neoplasia rate of 6.1, 11.5 and 13.7 per 100 patient-years after (sub)total colectomy, partial colectomy and endoscopic resection, respectively. Endoscopic resection, but not partial colectomy, was associated with an increased metachronous neoplasia risk (adjusted subdistribution hazard ratios 4.16, 95% CI 1.64-10.54, P <0.01) compared with (sub)total colectomy. CONCLUSION: After confounder adjustment, partial colectomy yielded a similar metachronous neoplasia risk compared to (sub)total colectomy. High metachronous neoplasia rates after endoscopic resection underline the importance of strict subsequent endoscopic surveillance.

Accumulation of bioactive lipids during storage of blood products is not cell but plasma derived and temperature dependent.

BACKGROUND: Bioactive lipids (lysophosphatidylcholines [lysoPCs]) accumulating during storage of cell-containing blood products are thought to be causative in onset of transfusion-related acute lung injury through activation of neutrophils. LysoPCs are thought to be derived from cell membrane degradation products such as phosphatidylcholines (PC) by partial hydrolysis of PC, a process that is catalyzed by phospholipase A(2) (PLA(2) ). STUDY DESIGN AND METHODS: We investigated the underlying mechanisms of lysoPC generation and its contribution to in vitro neutrophil-priming capacity during storage of red blood cells (RBCs), platelet (PLTs) concentrates, and cell-free plasma. Blood from healthy volunteers was drawn, processed, and stored according to Sanquin Blood Bank protocols. RESULTS: Storage of RBCs in saline-adenine-glucose-mannitol (SAGM) did not result in accumulation of lysoPCs or neutrophil-priming capacity. Replacement of SAGM by plasma as RBC storage medium caused elevated lysoPC levels on Day 0, which did not further increase during storage. Cell-free plasma stored at 22°C showed accumulation of lysoPCs during storage, which was not present at 4°C. Addition of a soluble PLA(2) or cytosolic PLA(2) inhibitor did not prevent accumulation of lysoPCs in plasma. In PLTs, lysoPC accumulation during storage was plasma dependent, but lysoPCs did not explain the observed neutrophil-priming effect as preventing accumulation of lysoPCs by removing the plasma fraction did not prevent the neutrophil-priming capacity. CONCLUSION: Accumulation of lysoPCs during storage is not cell but plasma derived and storage temperature dependent and does not explain the neutrophil-priming effect of aged products.

[Acute liver failure due to food supplements]. / Acuut leverfalen na gebruik van voedingssupplementen.

BACKGROUND: Acute liver failure resulting from the use of food supplements is rare. However, due to the rapid rise in the use of food supplements, the incidence of liver damage is increasing. CASE DESCRIPTION: We describe the cases of two women with menopausal symptoms who developed liver failure shortly after starting to take food supplements containing plant extracts. Both women consequently underwent a liver transplant. CONCLUSION: Food supplements are not regarded as medicines, but fall under regulations pertaining to foodstuffs. This means they can be put on the market without their safety having first been checked. The old Dutch saying 'if it doesn't do any good, it won't do any harm' is certainly not applicable here. Is it time for a new law?

TNF-anti-TNF Immune Complexes Inhibit IL-12/IL-23 Secretion by Inflammatory Macrophages via an Fc-dependent Mechanism.

BACKGROUND AND AIMS: We have recently shown that the mode of action of IgG1 anti-tumour necrosis factor [TNF] antibodies in inflammatory bowel disease [IBD] requires Fcγ-receptor [FcγR] engagement on macrophages. Here we examine the effect of Fcγ-receptor signalling by anti-TNF on macrophage IL-12/IL-23 secretion. METHODS: Cytokine production by human inflammatory macrophages was assessed at the level of RNA and protein. TNF-anti-TNF immune complex formation was determined by size-exclusion chromatography and signalling visualized by immunofluorescence. IL-12/IL-23p40 was measured in CD14+ lamina propria cells from IBD patients. RESULTS: Infliximab and adalimumab potently suppressed IL-12/IL-23 production by inflammatory macrophages, but Fab' fragment certolizumab did not. IL-12/IL-23 suppression depended on Syk activity and was mediated at the level of IL-12/IL-23p40 mRNA. Etanercept, a soluble TNF receptor fused to an Fc-region, did not inhibit IL-12/L-23 secretion, suggesting that the presence of an Fc-region was not sufficient. Infliximab and adalimumab formed immune complexes with soluble TNF whereas etanercept did not, suggesting that FcγR-mediated suppression of IL-12/IL-23 required the formation of immune complexes. Indeed, non-specific IgG1 immune complexes, but not uncomplexed IgG1, similarly suppressed IL-12/IL-23 secretion. Finally, infliximab significantly decreased IL-12/IL-23p40 production in myeloid cells isolated from the lamina propria of IBD patients. CONCLUSIONS: TNF-anti-TNF antibody immune complexes potently inhibit IL-12/IL-23 expression by inflammatory macrophages. Our data suggest that anti-TNFs and antibodies against IL-12/IL-23 may therefore have partially overlapping modes of action in patients with IBD.

The influence of oral contraceptives on athletic performance in female athletes.

It is now estimated that the prevalence of oral contraceptive use in athletic women matches that of women in the general population. The oral contraceptive pill (OCP) reduces cycle-length variability and provides a consistent 28-day cycle by controlling concentrations of endogenous sex hormones. The OCP is administered in three different forms that differ widely in chemical constitution and concomitant effects on the human body. As fluctuation in sex steroids are believed to be a possible causal factor in performance and exercise capacity, it is imperative to understand the effect of administering the various types of OCP on women. However, the research into oral contraceptives and exercise performance is not consistent. The type of OCP administered (monophasic, biphasic or triphasic), as well as the type and dose of estrogen and progestogen within, will have varying effects on exercise. To date, research in the area of oral contraceptives and exercise capacity is sparse and much has been plagued by poor research design, methodology and small sample size. It is clear from the research to date that more randomised clinical trials are urgently required to assess the array of OCP formulations currently available to women and their concomitant effect on health and exercise capacity. Therefore, the purpose of this article is to critically appraise the literature to date and to provide a current review of the physiological scientific knowledge base in relation to the OCP and exercise performance. In addition, methodological control, design and conduct will be considered with future areas of research highlighted.

Androgenicity of the progestin in oral contraceptives does not affect maximal leg strength.

PURPOSE: This study was conducted to examine androgenicity of the progestin in oral contraceptive pills and its effect on maximal leg strength in females. METHODS: Twelve participants who were using a monophasic pill containing 30 microg ethinylestradiol plus either 150 microg levonorgestrel (LEV) or 250 microg norgestimate (NOR) for at least the last 6 months were recruited (mean+/-SEM; LEV: age, 19.8+/-0.3 years; stature, 1.67+/-0.17 m; mass, 65.9+/-1.9 kg; NOR: age, 20.6+/-0.2 years; stature, 1.65+/-0.17 m; mass, 64.6+/-2.4 kg). Three maximal isokinetic extension and flexion tests were performed on three occasions (Days 3-6, 11-14 and 18-21 of the pill cycle) to assess peak extension and peak flexion torque (in Newton meters). RESULTS: No significant (p>.05) differences were found in the LEV and NOR groups in peak extension torque (F=0.719; p=.416) or peak flexion torque (F=0.291, p=.601) throughout the pill cycle and between groups. CONCLUSION: In this small study, the androgenicity of the progestin in the contraceptive pill had no significant association with maximal strength in these female athletes.

ATG16L1 and NOD2 polymorphisms enhance phagocytosis in monocytes of Crohn's disease patients.

AIM: To investigate if the presence of relevant genetic polymorphisms has effect on the effectual clearance of bacteria by monocytes and granulocytes in patients with Crohn's disease (CD). METHODS: In this study, we assessed the differential responses in phagocytosis by measuring the phagocytic activity and the percentage of active phagocytic monocytes and granulocytes in inflammatory bowel disease patients as well as healthy controls. As both autophagy related like 1 (ATG16L1) and immunity-related guanosine triphosphatase gene are autophagy genes associated with CD and more recently nucleotide-binding ligomerization domain-containing protein 2 (NOD2) has been identified as a potent inducer of autophagy we genotyped the patients for these variants and correlated this to the phagocytic reaction. The genotyping was done with restriction fragment length polymorphisms analysis and the phagocytosis was determined with the pHrodo™ Escherichia coli Bioparticles Phagocytosis kit for flowcytometry. RESULTS: In this study, we demonstrate that analysis of the monocyte and granulocyte populations of patients with CD and ulcerative colitis showed a comparable phagocytic activity (ratio of mean fluorescence intensity) between the patient groups and the healthy controls. CD patients show a significantly higher phagocytic capacity (ratio mean percentage of phagocytic cells) compared to healthy controls (51.91% ± 2.85% vs 37.67% ± 7.06%, P = 0.05). The extend of disease was not of influence. However, variants of ATG16L1 (WT: 2.03 ± 0.19 vs homozygoot variant: 4.38 ± 0.37, P < 0.009) as well as NOD2 (C-ins) (heterozygous variant: 42.08 ± 2.94 vs homozygous variant: 75.58 ± 4.34 (P = 0.05) are associated with the phagocytic activity in patients with CD. CONCLUSION: Monocytes of CD patients show enhanced phagocytosis associated with the presence of ATG16L1 and NOD2 variants. This could be part of the pathophysiological mechanism resulting in the disease.

Effects of infliximab retreatment after consecutive discontinuation of infliximab and adalimumab in refractory Crohn's disease.

BACKGROUND: Switches between anti-tumor necrosis factor agents in the treatment of Crohn's disease (CD) occur in case of treatment failure, intolerance, or patient preference. No data are currently available on the usefulness of a second infliximab treatment after earlier discontinuation and previous switch to an alternative anti-tumor necrosis factor agent. In this study, we evaluated the clinical benefit of infliximab retreatment in patients with CD after sequential use of both infliximab and adalimumab. METHODS: Twenty-nine patients with CD who had received earlier treatments with sequential infliximab and adalimumab and were then restarted on infliximab were retrieved from a multicenter registry designed for the follow-up of adalimumab treatment for CD. Short-term and sustained effects of infliximab retreatment were evaluated retrospectively by reviewing clinical records. Follow-up was 18 months for all patients. RESULTS: In 13/29 (45%) patients, infliximab was reintroduced at intensified dosing schedule (>5 mg/kg or <8 wk) for 23/29 (79%) of patients similar to the schedule who were on at time of previous discontinuation. During the second infliximab treatment course, dosing was further intensified in 11 out of 29 (38%) patients. After 18 months 18/29 (62%), patients were still on continued therapy of their second infliximab treatment. Infliximab was discontinued (after a median of 7 mo) in 11 out of 29 patients for loss of response (n = 7 [24%]), intolerance (n = 3 [10%]), or non-compliance (n = 1 [3%]). Use of induction schedule or concomitant immunomodulators were not significantly associated with treatment benefit. CONCLUSIONS: The majority of patients with CD benefit from a second treatment with infliximab after previous treatment with infliximab and adalimumab, which offer a meaningful therapeutic option in often highly refractory patients.

Adalimumab for Crohn's disease: long-term sustained benefit in a population-based cohort of 438 patients.

BACKGROUND AND AIMS: Adalimumab is an effective therapy for induction and maintenance of Crohn's disease. However, results in clinical trials don't necessarily reflect daily clinical practice. Therefore, we assessed real-life long-term clinical response to adalimumab in a large population-based cohort and identified clinical parameters affecting response METHODS: All consecutive patients in North-Holland that started adalimumab between 2003 and 2011 were included, of which medical charts were reviewed. Response to induction therapy was assessed after 3months. Sustained benefit of maintenance therapy was calculated from Kaplan-Meier survival tables depicting ongoing adalimumab treatment. Regression analyses were performed to identify factors predicting response to adalimumab therapy. RESULTS: In total 438 Crohn's patients started adalimumab with 92.5% response to the induction phase. After 1year 83.3% showed sustained benefit of maintenance treatment, followed by 74.0% after 2years. Nevertheless, one third of patients were in steroid-free remission at the end of their follow-up. Response to induction was negatively affected by longer disease duration (OR 1.05; p<0.01) and strictures (OR 3.73; p=0.04). Increased CRP levels predicted higher rates of initial response (OR 0.31; p<0.01). Concomitant thiopurines in the first 6months of adalimumab treatment decreased the risk to fail maintenance therapy (HR 0.69, p=0.05). Previous infliximab therapy did not affect response to adalimumab, however dose escalation was more often deemed necessary (p<0.01). CONCLUSION: Adalimumab was successful in the majority of patients, with 10% loss of response per subsequent year. Concomitant thiopurines might improve adalimumab maintenance treatment.