Anti-tumor Necrosis Factor Antibody Research Articles

Infliximab in steroid-refractory immune-related hepatitis does not demonstrate hepatotoxicity and may shorten time on steroids

BackgroundImmune-related hepatitis (irHepatitis) is a relatively common immune-related adverse event (irAE) of checkpoint inhibitors. Often, it responds well to steroids; however, in refractory cases, further therapy is needed. Anti-tumor necrosis...

Treatment Discontinuation in Patients with Psoriasis Treated with Biologics: A Retrospective Analysis of German Health Claims Data.

Plaque psoriasis is a common, often debilitating, chronic autoimmune inflammatory skin disease. Moderate-to-severe forms of psoriasis can be treated with biologics such as anti-interleukin and anti-tumor necrosis factor antibodies. We aimed to investigate treatment discontinuation among patients with psoriasis who initiated biologic treatment. We conducted a retrospective, non-interventional cohort study based on anonymized claims data from the German statutory health insurance which covered the years from 2016 to 2021. We included adult patients with psoriasis who initiated biologic treatment in drug-specific cohorts. Over a 365-day follow-up period, we assessed the frequencies and the time until treatment discontinuation for different biologics. Differences in discontinuation rates were compared using a multivariate Cox proportional hazards model. A total of 2565 patients with psoriasis who initiated treatment with secukinumab (n = 612), adalimumab (n = 454), guselkumab (n = 354), ixekizumab (n = 259), ustekinumab (n = 241), tildrakizumab (n = 205), brodalumab (n = 166), risankizumab (n = 145), etanercept (n = 91), certolizumab (n = 29), and infliximab (n = 9) were included. A total of 1290 patients (50.29%) discontinued treatment during the follow-up period, ranging from 30.34% (risankizumab) to 69.23% (etanercept). Median time until discontinuation of treatment ranged from 102days (etanercept) to 208days (risankizumab). Once the biologic treatment was discontinued, 45.05% of patients restarted the treatment with the same agent, 23.10% of patients switched to another biologic, and 31.86% received no further biologic agent. Compared to patients treated with risankizumab, the treatment discontinuation rate was significantly higher (p < 0.05) in patients treated with the other biologics except ustekinumab (p = 0.12). Further research should explore reasons leading to treatment discontinuation in order to support treatment choices for patients with moderate-to-severe psoriasis.

#664 Childhood Takayasu arteritis: a multicentre retrospective study

Abstract Background and Aims Takayasu arteritis (TA) is a rare, large vessel vasculitis affecting mainly the aorta and its major branches. Data on paediatric TA (pTA) is very scarce. The aim of this study was to characterize clinical presentation, therapy and outcome of pTA in a global study population. Method We conducted an international multicentre retrospective observational study of children diagnosed with pTA. Inclusion criteria were an age of less than 18 years at initial presentation in the year 2000 or more recently. Clinical data were collected from patients’ charts by the treating paediatric rheumatologist or nephrologist; data were fully anonymised for analysis purposes. Follow-up data was collected up to 2 years after diagnosis. Results 198 patients from 20 countries were included (76% female). The median age at disease onset was 12 years. Arterial hypertension (67%), a difference in pulses between limbs (65%) and fatigue (66%) were the most common symptoms at presentation. The gastrointestinal system was the second most affected organ system. The median eGFR (estimated glomerular filtration rate) at baseline was 105 ml/min/1.73 m2. Renal artery stenosis was documented in 58% of all patients and in 37% there was need for an invasive renovascular procedure. In 25 of 32 (78%) patients who had either a positron emission tomography–magnetic resonance imaging (PET-MRI) or PET-computed tomography (CT) there was evidence of active inflammation mainly of the aorta. 67% of all patients showed thickened wall abnormalities and 31% had arterial dilatations in a major vessel on any one or more anatomical imaging modality such as ultrasound, CT or MRI. Immunosuppressive treatment was primarily steroids, cyclophosphamide and methotrexate, 37% of all patients were treated with monoclonal antibodies of which 65% received an anti-tumor necrosis factor (TNF) antibody, 31% an anti-Interleukin 6 (IL-6) antibody and 4% an anti-B-cell antibody. Dialysis was necessary in 7% and one patient underwent kidney transplantation. Seven patient deaths (4%) were documented at the most recent follow-up. The renal function after two years was median eGFR 102 ml/min/1.73 m2, with 67% showing normal function, 31% presenting with chronic kidney disease (CKD) stage 1, 1% with stage 2, 1% with stage 3 and no patients showed stages 4 and 5. A quarter of the patients (27%) were still symptomatic at the 2-year follow-up. The median systolic blood pressure was 117 (interquartile range 107–125) mmHg. 64% of all patients still had antihypertensive treatment, and 87% were still on immunosuppressive therapy. Conclusion Our study represents the largest paediatric cohort of children diagnosed with Takayasu arteritis. Several organ systems were involved at onset and the clinical spectrum was highly variable. We will in our further analyses in more detail describe the outcome in relation to presenting symptoms and treatment.

Add-on multiple submucosal injections of the RNA oligonucleotide GUT-1 to anti-TNF antibody treatment in patients with moderate-to-severe ulcerative colitis: an open-label, proof-of concept study

BackgroundCarbohydrate sulfotransferase 15 (CHST15) is an enzyme biosynthesizing matrix glycosaminoglycan that modulates tissue remodeling. We evaluated the efficacy of add-on submucosal injections of GUT-1, the RNA oligonucleotide inhibitor of CHST15, to ongoing anti-tumor necrosis factor (TNF) antibody treatment in patients with moderate-to-severe ulcerative colitis (UC).MethodsThis was an open-label study of 250 nM of GUT-1 by endoscopic submucosal injections at weeks 0, 2, 4 in five UC patients who lost response during maintenance treatment to anti-TNF antibodies. The primary endpoint was the rate of endoscopic improvement at week 6 and secondary endpoints included the rates of clinical remission by modified Mayo Score (mMS). Patients received follow-up observation with continuous maintenance treatment by the same anti-TNF antibody till the time of clinical recurrence or for overall 52 weeks.ResultsAt week 6, rates of endoscopic improvement and clinical remission were 80% (n = 4/5) and 60% (n = 3/5), respectively. The mean Endoscopy Subscore was reduced from 2.4 (95%CI: 1.7 to 3.1) at baseline, to 1.0 (95%CI: 0.1 to 1.9) at week 6. The mean mMS was reduced from 7.8 (95%CI: 6.2 to 9.4) to 1.3 (95%CI: 2.9 to 4.3). GUT-1 was well tolerated. Three patients did not show clinical recurrence for 52 weeks. All three corticosteroid-dependent patients showed no corticosteroid exposure for at least 24 weeks after achieving clinical remission. Multiple dosing was also well tolerated.ConclusionsAdd-on multiple injections of GUT-1 to ongoing anti-TNF antibody was able to induce rapid and durable clinical responses in UC patients who lost response to anti-TNF therapy.Trial registrationClinical trial Registration Number (Japan): UMIN000020900.

Clinical Pharmacist Counselling Improves Long-term Medication Safety and Patient-reported Outcomes in Anti-TNF-treated Patients With Inflammatory Bowel Diseases: The Prospective, Randomized AdPhaNCED Trial.

Antitumor necrosis factor (anti-TNF) antibody treatment has led to marked improvements in the management of patients with inflammatory bowel diseases (IBDs). Nevertheless, anti-TNF therapy is associated with potential adverse drug reactions (ADRs). Our prospective, randomized trial investigated the effect of intensified clinical pharmacist counselling in a multidisciplinary team on medication safety in anti-TNF-treated IBD patients. Patients with IBD with ongoing anti-TNF treatment were enrolled in our tertiary center AdPhaNCED trial and randomized to either receive conventional standard of care (control group) or additional clinical pharmacist counselling (intervention group) over 12 months. The primary end point consisted of the number and severity of ADRs associated with anti-TNF therapy. Secondary end points included patient satisfaction with medication information and medication safety. One hundred twenty-seven IBD patients were included in this study. Anti-TNF-related ADRs were significantly lower in the intervention compared with the control group (0.20 vs 0.32 [mean] ADR/patient/month, P = .006) after 12 months. The risk of more severe ADRs (Common Terminology Criteria for Adverse Events [CTCAE] grade ≥2) was significantly higher in the control compared with the intervention group (hazard ratio, 0.34; P = .001). The probability of ADR resolution (hazard ratio, 2.02; P < .001) and patient satisfaction with medication information (14.82 vs 11.60; P < .001) were significantly higher in the intervention group compared with the control group. Our study results demonstrate that intensified pharmacist counselling significantly reduces the occurrence and severity of therapy-related ADRs and improves patient satisfaction. Clinical pharmacists should therefore be part of a holistic approach to IBD care delivered by a multidisciplinary team.

An anti-TNF-glucocorticoid receptor modulator antibody-drug conjugate is efficacious against immune-mediated inflammatory diseases.

Glucocorticoids (GCs) are efficacious drugs used for treating many inflammatory diseases, but the dose and duration of administration are limited because of severe side effects. We therefore sought to identify an approach to selectively target GCs to inflamed tissue. Previous work identified that anti-tumor necrosis factor (TNF) antibodies that bind to transmembrane TNF undergo internalization; therefore, an anti-TNF antibody-drug conjugate (ADC) would be mechanistically similar, where lysosomal catabolism could release a GC receptor modulator (GRM) payload to dampen immune cell activity. Consequently, we have generated an anti-TNF-GRM ADC with the aim of inhibiting pro-inflammatory cytokine production from stimulated human immune cells. In an acute mouse model of contact hypersensitivity, a murine surrogate anti-TNF-GRM ADC inhibited inflammatory responses with minimal effect on systemic GC biomarkers. In addition, in a mouse model of collagen-induced arthritis, single-dose administration of the ADC, delivered at disease onset, was able to completely inhibit arthritis for greater than 30 days, whereas an anti-TNF monoclonal antibody only partially inhibited disease. ADC treatment at the peak of disease was also able to attenuate the arthritic phenotype. Clinical data for a human anti-TNF-GRM ADC (ABBV-3373) from a single ascending dose phase 1 study in healthy volunteers demonstrated antibody-like pharmacokinetic profiles and a lack of impact on serum cortisol concentrations at predicted therapeutic doses. These data suggest that an anti-TNF-GRM ADC may provide improved efficacy beyond anti-TNF alone in immune mediated diseases while minimizing systemic side effects associated with standard GC treatment.

Treatment of autoimmune hepatitis-First-line, second-line and third-line treatment

Autoimmune hepatitis (AIH) is a rare autoimmune inflammation of the liver mostly with a chronic course, which can also be acutely manifested up to acute liver failure. It affects women 3-4 times more frequently than men and can be diagnosed in all age groups. In one third of the patients a liver cirrhosis is present at the time of diagnosis. It is characterized by a hepatic inflammation pattern, a polyclonal hypergammaglobulinemia of immunoglobulin G and the detection of autoantibodies. A liver biopsy is necessary to make the diagnosis. The AIH is histologically characterized in particular by a lymphoplasmacytic infiltrate in the portal fields. In cases with a relevant disease activity, AIH is typically treated by immunosuppression. The immunosuppressive treatment is associated with a prevention of disease progression to liver cirrhosis and a better survival. The success of treatment is measured by achieving biochemical remission, i.e., normalization of the transaminase and immunoglobulin G levels as a good noninvasive predictor of a histological remission. Another treatment target is an improvement of the symptoms of the patient. The first-line treatment consists of a glucocorticoid, mostly prednisolone or in cases without advanced fibrosis budesonide, and azothioprine. For reduction of steroid-specific treatment side effects the maintenance treatment should be carried out steroid-free whenever possible. In cases of insufficient response to azothioprine or side effects a treatment attempt using antimetabolites, such as 6‑mercaptopurine or mycophenolate mofetil is primarily carried out as second-line treatment. For patients who do not achieve biochemical remission through first-line or second-line treatment, a variety of medications are available for third-line treatment, e.g., rituximab, calcineurin inhibitors or antitumor necrosis factor (anti-TNF) antibodies. Third-line treatment should be carried out in expert centers and registered in the European Reference Network for Rare Liver Diseases in order to improve the currently sparse database for these forms of treatment in the future.

Comparison of a selective STAT3 inhibitor with a dual STAT3/STAT1 inhibitor using a dextran sulfate sodium murine colitis model: new insight into the debate on selectivity.

Recent advances in the treatment of inflammatory bowel disease include antitumor necrosis factor antibodies and the Janus kinase inhibitor tofacitinib, approved for ulcerative colitis. Janus kinase recruits signal transducers and activators of transcriptions (STAT), which are promising targets in inflammatory bowel diseases. However few inhibitors have been evaluated, and their selectivity with respect to STAT1 and STAT3 remains controversial. Here, we investigated the therapeutic potential of a selective inhibitor vs. a non-selective, closely related compound, in a dextran sulfate sodium (DSS) murine colitis model. Thirty Swiss/CD-1 male mice were used in this study. They were divided into a healthy control group, a colitis-DSS control group, a compound (cpd) 23-treated group, a cpd 46-treated group and an icariin-treated group. For the coadministration experiment with rutin, the cpd 46-treated group and the icariin-treated group were replaced by the oral rutin-treated group and the coadministration rutin/cpd 23-treated group. The effect of the tested inhibitors was also assessed by quantification of proinflammatory markers. The selective inhibitor had a significantly greater effect than the dual inhibitor on the disease activity index. We also noticed in curative treatment a significant decrease in the most abundant proinflammatory biomarker present in neutrophilic granulocytes, myeloperoxidase and on proinflammatory cytokines, including tumor necrosis factor-α, interferon-γ, interleukins -6 and -23, with a mild synergy with rutin, the glycoside of quercetin. The current study shows how STAT3 selective inhibitors can exert a significant therapeutic effect in the treatment of experimental DSS-colitis.

Review of Adalimumab Biosimilar SB5 in Immune-Mediated Inflammatory Diseases.

SB5 is an approved biosimilar of adalimumab, a recombinant monoclonal anti-tumor necrosis factor (TNF) antibody. The approval of SB5 was based on the comparison with reference adalimumab in analytical studies, pharmacokinetic (PK) and immunogenicity assessments, and randomized controlled trials. Efficacy data was primarily obtained in patients with rheumatoid arthritis, and extended to include additional indications such as psoriasis, Crohn's disease, or ulcerative colitis by extrapolation. Following its approval, additional post-marketing data have been collected comparing SB5 with reference adalimumab. This review summarizes the clinical data on SB5 from randomized controlled trials and provides a comprehensive overview of the available post-approval data. In "real-world" settings, SB5 was as effective as its reference product across different indications and countries, treatment persistence was well maintained throughout studies, and no new safety concerns were identified. In both controlled and "real-world" settings, switching from reference adalimumab to SB5 was not associated with altered efficacy or clinical complications. In post-approval studies, the quality of SB5 was consistent over time, independent of the batch and process changes, and the SB5 autoinjector was preferred over other autoinjectors by both healthcare professionals and patients. Taken together, these data support the use of SB5 whenever reference adalimumab is appropriate and demonstrate that switching from reference adalimumab to SB5 is feasible.

Amnion responses to intrauterine inflammation and effects of inhibition of TNF signaling in preterm Rhesus macaque

Intrauterine infection/inflammation (IUI) is a frequent complication of pregnancy leading to preterm labor and fetal inflammation. How inflammation is modulated at the maternal-fetal interface is unresolved. We compared transcriptomics of amnion (a fetal tissue in contact with amniotic fluid) in a preterm Rhesus macaque model of IUI induced by lipopolysaccharide with human cohorts of chorioamnionitis. Bulk RNA sequencing (RNA-seq) amnion transcriptomic profiles were remarkably similar in both Rhesus and human subjects and revealed that induction of key labor-mediating genes such as IL1 and IL6 was dependent on nuclear factor κB (NF-κB) signaling and reversed by the anti-tumor necrosis factor (TNF) antibody Adalimumab. Inhibition of collagen biosynthesis by IUI was partially restored by Adalimumab. Interestingly, single-cell transcriptomics, flow cytometry, and immunohistology demonstrated that a subset of amnion mesenchymal cells (AMCs) increase CD14 and other myeloid cell markers during IUI both in the human and Rhesus macaque. Our data suggest that CD14+ AMCs represent activated AMCs at the maternal-fetal interface.

Azathioprine in hidradenitis suppurativa with inflammatory phenotype: a case series of 11 patients.

Hidradenitis suppurativa (HS) is a chronic inflammatory disease that negatively impacts the quality of life of patients. It presents as deep-seated nodules, abscesses, fistulae, sinus tracts, and scars in the axilla, inguinal area, submammary folds, and perianal area. Recently, two phenotypes have been described: a follicular phenotype and an inflammatory phenotype. Numerous medical treatments are available for hidradenitis suppurativa, with particular importance of antitumor necrosis factor antibodies. Due to the association of HS with other conditions with a pro-inflammatory state, particularly Crohn's disease, it has been suggested that azathioprine may have a role in the treatment of HS. To assess the effectiveness of azathioprine monotherapy in patients with moderate-severe HS. We retrospectively studied patients with HS treated with azathioprine in monotherapy. We performed both clinical and ultrasound evaluation at baseline as well as in the follow-up visits. Their baseline score on the iHS4 and DLQI scales and 12-16 weeks after starting the treatment were compared. We also registered the number of patients who achieved HiSCR. Six patients presented significant improvement, reducing their score in iHS4 and DLQI scales and achieving HiSCR. Another patient had clinical improvement, meaning reduction in iHS4 and DLQI, but without achieving HiSCR. Two patients stopped the treatment before week 12 because of adverse events. The remaining two patients presented no improvement. The median (Q3-Q1) baseline iHS4 score was 6 (12-6), and follow-up iHS4 score, 4 (6-2), being these differences statistically significant (P = 0.006). Median (Q3-Q1) baseline DLQI scores and 12-16 weeks after treatment were 17 (23-11) and 14 (18-9), although statistically nonsignificant (P = 0.099). We present a case series of 11 patients treated with azathioprine with good clinical and ultrasonographic response. We suggest that azathioprine may benefit a certain patient profile with the inflammatory phenotype.

Discovery of ABBV-3373, an Anti-TNF Glucocorticoid Receptor Modulator Immunology Antibody Drug Conjugate.

Using a convergent synthetic route to enable multiple points of diversity, a series of glucocorticoid receptor modulators (GRM) were profiled for potency, selectivity, and drug-like properties in vitro. Despite covering a large range of diversity, profiling the nonconjugated small molecule was suboptimal and they were conjugated to a mouse antitumor necrosis factor (TNF) antibody using the MP-Ala-Ala linker. Screening of the resulting antibody drug conjugates (ADCs) provided a better assessment of efficacy and physical properties, reinforcing the need to conduct structure-activity relationship studies on the complete ADC. DAR4 ADCs were screened in an acute mouse contact hypersensitivity model measuring biomarkers to ensure a sufficient therapeutic window. In a chronic mouse arthritis model, mouse anti-TNF GRM ADCs were efficacious after a single dose of 10 mg/kg i.p. for over 30 days. Data on the unconjugated payloads and mouse surrogate anti-TNF ADCs identified payload 17 which was conjugated to a human anti-TNF antibody and advanced to the clinic as ABBV-3373.

A critical review of adalimumab for the treatment of moderate-to-severe active ulcerative colitis in children

Introduction Anti-TNF antibodies play a major role in treating IBD, both in adult and paediatric patients. While there is a large number of studies on efficacy and safety of infliximab in treating children and adolescents with UC, data on adalimumab (ADA) are scarce. Areas covered Here, we review published case reports, cohort and real time data as well as the first randomized trial, ENVISION I, using ADA for treating paediatric UC. Available evidence confirms good efficacy inducing and maintaining remission in children and adolescents with UC, with even higher response rates compared to adult UC. ENVISION I showed that in UC patients responding to ADA induction therapy almost half of the patients remained in remission after 52 weeks of therapy on high-dosing ADA (weekly administration). As already well experienced with other biologics, dosing schemes are different between paediatric and adult patients, with children often requiring higher dosing. Expert opinion: Further data are required to better understand how to optimize ADA therapy. The present and still growing evidence places sc. anti-TNF-medication as alternative first line therapy also for paediatric UC. This is also reflected by the preference for sc. medication of adolescent patients allowing less frequent and autonomous drug administration.

Serum cytokine/chemokine levels in a patient with perifolliculitis capitis abscedens et suffodiens (dissecting cellulitis) successfully treated with the tumour necrosis factor α inhibitor adalimumab

AbstractPerifolliculitis capitis abscedens et suffodiens (PCAS), also called dissecting cellulitis, is a refractory disease characterized by deep follicular occlusion, ruptures and infections. Here, we present a case of PCAS in a young man whose scalp showed subcutaneous nodules with purulent secretions, and geographic hair loss from the occipital region. Since the PCAS was refractory to treatment by incision, drainage and systemic antibiotics, we administered adalimumab, an antitumour necrosis factor (TNF) antibody. After 4 months of treatment with adalimumab, the PCAS improved markedly, with flattening of the scalp lesions and hair regrowth. We examined the serum levels of cytokines/chemokines using a Magnetic Bead Panel Plate Assay to compare levels before and at 3 months post‐adalimumab treatment. The results showed a slight decrease in TNF‐α levels and a significant reduction in the expression of cytokines or chemokines that promote macrophage and neutrophil migration, suggesting that these factors might contribute to the pathogenesis of PCAS.

A Randomized Pharmacokinetic Study in Healthy Male Subjects Comparing a High-concentration, Citrate-free SB5 Formulation (40mg/0.4ml) and Prior SB5 (Adalimumab Biosimilar).

IntroductionSB5 is an approved biosimilar of adalimumab, a monoclonal anti-tumor necrosis factor (anti-TNF) antibody. This study compared pharmacokinetics (PK), safety, tolerability, and immunogenicity between a new high-concentration, low-volume, and citrate-free formulation (40 mg/0.4 ml, SB5-HC) and the current low-concentration formulation with higher volume (40 mg/0.8 ml, SB5-LC) to evaluate the bioequivalence of the two formulations.MethodsThis study was a randomized, single-blind, two-arm, parallel-group, single-dose study in healthy male subjects. Subjects were randomized to receive either SB5-HC or SB5-LC via subcutaneous injection using a pre-filled syringe. Primary endpoints were the area under the curve of the concentration–time curve from zero to infinity (AUCinf) and maximum serum concentration (Cmax). Bioequivalence was achieved if the 90% confidence intervals (CIs) for the ratios of the geometric least squares mean (LSMean) of primary endpoints were within the pre-defined bioequivalence margins of 0.80–1.25. Secondary endpoints included safety, tolerability, and immunogenicity.ResultsSubjects (n = 188) were randomized to SB5-HC (n = 94) or SB5-LC (n = 94). Baseline characteristics were comparable between the two treatment groups. The mean values for AUCinf and Cmax were similar between the SB5-HC and SB5-LC groups. For the primary endpoints, the geometric LSMean ratios (90% CI) for AUCinf and Cmax were 0.920 (0.8262–1.0239) and 0.984 (0.9126–1.0604), respectively, placing the corresponding 90% CIs well within the pre-defined bioequivalence margin of 0.80–1.25. All treatment-emergent adverse events (TEAEs) were considered mild to moderate and were reported for 44.7% and 51.1% of subjects in the SB5-HC and SB5-LC groups, respectively. Immunogenicity assessed by frequency of occurrence of anti-drug antibodies (ADAs) and neutralizing antibodies (NAbs) was comparable between groups.ConclusionsThis bridging study demonstrated PK equivalence and comparable safety and tolerability of subcutaneous injection of SB5 via SB5-HC or SB5-LC.Clinicaltrials.gov identifierhttps://clinicaltrials.gov/ct2/show/NCT04514796.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40744-022-00471-8.

Life-threatening bowel complications following anti-tumor necrosis factor antibody therapy for patients with inflammatory bowel disease

Incidence of inflammatory bowel disease (IBD) in Taiwan and the experience of the management of serious complications is much lower than in Western countries. The authors just want to alert readers that anti-tumor necrosis factor (TNF) is not without life-threatening complications. Three serious complications were described, including surgical management and outcomes following the application of anti-TNF monoclonal antibody therapy for IBD. Case 1 involved a 25-year-old man treated with five doses of adalimumab for moderate control of Crohn's disease (CD). Six months later, he experienced severe intestinal obstruction, which necessitated right hemicolectomy with ileocolic anastomosis. He recovered postsurgery. Case 2 involved a 54-year-old man treated with adalimumab for intractable ulcerative colitis. Ten days after the second dose of adalimumab, an emergent subtotal colectomy with ileostomy was performed for a transverse colon perforation with peritonitis. The patient underwent an ileal pouch operation a year later. Case 3 was based on a 16-year-old male patient treated with six doses of an infliximab biosimilar for CD; thereafter, an emergent subtotal colectomy with ileostomy and Hartmann's pouch was performed for peritonitis with the presence of a perforated gastrocolic fistula tract. He had no serious complications following an uneventful recovery period. Creating awareness of serious complications associated with biologic treatments and offering appropriate patient management, including surgical treatment, is beneficial to patients.

Immunomodulatory Agents for Treatment of Patients with Inflammatory Bowel Disease (Review safety of anti-TNF, Anti-Integrin, Anti IL-12/23, JAK Inhibition, Sphingosine 1-Phosphate Receptor Modulator, Azathioprine / 6-MP and Methotrexate).

As treatment options for Inflammatory Bowel Disease (IBD) expand each class of medication will have specific safety concerns and side-effect profiles that need to be considered for optimal treatment of patients. We will review the most recent safety data for the newly approved immunomodulator therapies for the treatment of IBD. There are a growing number of publications outlining safety concerns for medications used to treat IBD. We reviewed safety profile of anti-tumor necrosis factor antibodies (TNF) with specific attention to combination therapy (anti-TNF plus immunomodulator). Recent publications have demonstrated increased risk of serious infection and malignancy (lymphoma and overall cancer rates) in patients receiving anti-TNF combination therapy when compared with patients receiving anti-TNF monotherapy or immunomodulator monotherapy. Recent publications on Janus Kinase Inhibitors indicate an increased risk of infection, specifically Herpes Zoster, and increased risk of major cardiovascular events and venous thromboembolic events resulting in a black box warning for the medication. In contrast, anti-interleukin 12/23 agents and gut selective anti-integrin antibody agents have demonstrated a favorable side-effect profile with low rates of infection and malignancy. The latest class of medications to be approved, sphingosine 1-phosphate (S1P) receptor modulators, have cardiac and infectious precautions. The field of IBD treatment is rapidly evolving with several mechanistic classes of medications now available. While corticosteroids continue to be associated with the greatest, overall, safety risks, each of the newer mechanistic classes have unique safety concerns. In the future, as we gain more experience with these agents, we will need to continue to evaluate the safety profile of our therapies used alone or in combination to make informed treatment decisions with our patients.

What is confirmed in the treatment of chronic inflammatory bowel diseases

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.

S2391 Concomitant Treatment of Secondary Lymphocytic Hypophysitis and Crohn’s Disease With Adalimumab

Introduction: Lymphocytic hypophysitis (LH) results from atrophy and fibrosis of pituitary cells secondary to lymphocyte infiltration. Patients initially present with headaches, visual changes and endocrine dysfunction. Magnetic resonance imaging (MRI) and biopsy are the gold-standards of diagnosis. LH is typically treated with high-dose glucocorticoids. Secondary LH can occur in association with systemic inflammatory disorders such as inflammatory bowel disease. We describe an unusual case of LH presenting during treatment revision of Crohn’s disease (CD) and successful treatment of both conditions with the anti-tumor necrosis factor antibody, adalimumab. Case description/methods: A 37-year-old female was diagnosed with inflammatory Crohn’s ileitis and achieved rapid remission with infliximab. Nine years later, she became a secondary nonresponder, having developed active disease with high antibody levels, and was switched to vedolizumab. Within a month, she developed diabetes insipidus and bitemporal hemianopsia with no prior neurological symptoms or headaches. An MRI with and without contrast revealed abnormal T2 enhancement involving the hypothalamus and optic tracts extending to the optic chiasm (Figure 1A). A pituitary biopsy was consistent with LH and she was treated with dexamethasone with symptom resolution in three months. She was tapered off steroids, but one month later she developed visual changes, headaches, and lactation. A repeat MRI showed new/increased T2 hyperintensities along the infundibulum, hypothalamus, optic chiasm, optic nerves and optic tract/subcortical white matter (Figure 1B). With the goal of treating both LH and CD with a single nonsteroidal therapy, vedolizumab was discontinued and she was started on a adalimumab and dexamethasone taper during induction. Five months later, she remained neurologically and digestively asymptomatic on adalimumab monotherapy and an MRI showed no abnormal enhancement of the chiasmal or hypophyseal region (Figure 1C). Discussion: Lymphocytic hypophysitis can be a primary or secondary disorder. This case highlights the importance of considering treatment options that reduce steroid burden when LH is associated with other systemic disorders. In this case, we postulate that switching treatment of CD with vedolizumab, which does not cross the blood-brain barrier, may have unmasked the development of LH. Switching to an anti-inflammatory agent such as adalimumab that does penetrate into the central nervous system lead to effective therapy of both disorders.Figure 1.: A. T1 pre-contrast and T2 post-contrast coronal MRI demonstrates abnormal T2 signal involving the hypothalamus and optic tracts extending to the optic chiasm (arrow), right greater than left, with patchy enhancement. B. Repeat T1 pre-contrast and post-contrast sagittal MRI demonstrates enlargement of the pituitary gland and infundibular stalk (arrow) with abnormal contrast enhancement. C. Five months later, post- adalimumab treatment, T1 pre-contrast and post-contrast sagittal MRI demonstrates normal physiologic contrast uptake of the hypophysis with a normal appearing infundibulum.

Symptoms, diagnostic and therapy of perianal disease in patients with inflammatory bowel diseases

Symptoms, diagnostic and therapy of perianal disease in patients with inflammatory bowel diseases Abstract. Inflammatory bowel diseases (IBD) frequently affect the perianal region. Due to the great functional importance of the anorectum, this frequently results in a significant burden of disease for the patient. For assessment of perianal IBD symptoms, the clinical history is of great importance. Often, anorectal symptoms are not reported spontaneously by patients, and a respectful direct conversation remains crucial. More than 30 % of patients with Crohn's disease (CD) will develop perianal fistulas. Perianal fistulas can be further characterized by endoscopic ultrasound, MRI, and investigation under anesthesia. These investigations provide complementary information. Fistula therapy is based on symptoms; the short-term goal is improvement of pain and secretion; the long-term goal of treatment remains fistula closure. However, preservation of the anal sphincter is of utmost importance and incontinence needs to be avoided. Antibiotics and/ or seton drainage are the mainstay for acute fistula treatment. The anti-tumor necrosis factor antibody infliximab can improve fistula symptoms, as demonstrated in a randomized controlled study. Surgical fistula closure is only possible in a clinically stable situation without rectal inflammation or other symptoms of active CD. Several surgical strategies exist including 1) fistulotomy, 2) disconnection of the fistula, 3) filling of the fistula tract and 4) fistula ablation. The optimal strategy needs to be decided on an individual basis. Intraoperative application of mesenchymal donor stem cells into the fistula tract and surrounding tissue is possibly the most effective fistula therapy. Due to the significant logistic effort, this therapy is only available in a few selected centers. Currently, stem cell therapy for CD fistulas is limited to patients with no more than two external fistula openings. The therapy of fissures and hemorrhoids in IBD patients is similar to patients without intestinal inflammation; however, due to a high rate of complications, surgery should be avoided whenever possible in CD patients. Incontinence is a frequent problem in IBD patients leading to highly relevant restrictions in daily life. Therapy is directed against intestinal inflammation but also comprises measures for normalization of stool consistency and intestinal motility. However, there are no IBD-specific concepts for the treatment of incontinence. Functional intestinal diseases are frequent in IBD patients and can contribute to urge and incontinence. Some IBD patients might benefit from anorectal physiotherapy. IBD patients have an increased risk for colorectal carcinoma, fistula carcinoma and possibly also anal carcinoma. Therefore, malignancy needs to be excluded at reasonable intervals.