Long-term Outcomes in Steroid-refractory Ulcerative Colitis Treated with Tacrolimus Alone or in Combination with Purine Analogues.

BACKGROUND AND AIMS: Tacrolimus is recommended for the treatment of steroid-refractory ulcerative colitis (UC). Concomitantly started purine analogues (PAs) are used for the maintenance of remission, though their therapeutic relevance remains uncertain. Here we studied the role of PAs in the long-term outcome of steroid-refractory UC after tacrolimus treatment. METHODS: In five centres, charts of tacrolimus-treated UC patients with a steroid-refractory moderate to severe course were reviewed. Long-term efficacy was determined by colectomy rates and clinical remission in cases of colectomy-free survival for 3 months. RESULTS: We identified 156 patients (median age 34 years) with a median Lichtiger score of 12 (4-17) and pancolitis (E3) in 65% (101). The Kaplan-Meier curve for colectomy-free survival after month 3 showed a benefit in the PA group (p = 0.02). In patients treated with PA clinical remission was achieved in 82% (65/79) vs 67% (39/58) in those not treated with PA (p = 0.02). Time to colectomy was 2 years (median, 0.7-5.8) in the PA group and 0.8 years (0.3-4.7) in the group not treated with PAs (p = 0.02). Time to relapse was 1.2 years (median, 0.3-6.2) in patients with PA treatment and 0.5 years (0.3-3.9) in those without PA treatment (p = 0.05). Overall, clinical remission was achieved in 67% (104/156) of patients. Colectomy was performed in 29% (45/156) 0.5 years (median, 0.04-5.79) after initiation of tacrolimus. Ten (6%) patients had to stop tacrolimus due to adverse events and two (without PA treatment) died. CONCLUSIONS: Our study supports the efficacy of tacrolimus in steroid-refractory UC. Purine analogues appear to be beneficial for the long-term outcome of these patients.

[Azathioprine in Crohn's disease therapy--guidance against the background of recent studies]. / Azathioprin in der Therapie des Morbus Crohn--eine Standortbestimmung vor dem Hintergrund aktueller Studien.

Thiopurines (azathioprine and 6-mercaptopurine) are the most frequently used drugs in the treatment of patients with Crohn's disease. In current guidelines published by the German Society of Gastroenterology, Nutritional and Metabolic Diseases (DGVS) in 2014 and by the European Crohn´s and Colitis Organisation (ECCO) in 2010 different indications have been suggested. However, efficacy of azathioprine has been substantially questioned by recent publications in adults as well as in children examining the efficacy of early initiation of this treatment. These articles were published after release of the aforementioned guidelines. Therefore, in this survey recently published data are discussed on the background of our knowledge on the efficacy of azathioprine and 6-mercaptopurine developed in many years, and suggestions for the future use of these substances in the treatment of patients with Crohn's disease will be provided.

[Therapy of chronic inflammatory bowel diseases. Standards, controversies and perspectives]. / Therapie chronisch-entzündlicher Darmerkrankungen. Standards, Kontroversen und Perspektiven.

Crohn's disease and ulcerative colitis are the most common forms of chronic inflammatory bowel disease. The therapeutic algorithm is complex and individualized especially in complicated courses of the disease. This article gives a comprehensive overview on the typical courses of disease and the standard therapy of both diseases. Furthermore, ongoing controversies will be highlighted including early immunosuppression and immunomodulation as well as new therapeutic goals, such as mucosal healing. Finally, a perspective on future therapeutic options is given focusing especially on vedolizumab, the new antibody against the bowel-specific α4ß7-integrin.

Short-term efficacy of tacrolimus in steroid-refractory ulcerative colitis - experience in 130 patients.

BACKGROUND: Steroid-refractory ulcerative colitis (UC) remains a challenging condition warranting surgery upon failure of pharmacological treatment. Calcineurin inhibitors or infliximab are alternatives in this situation. Data on the efficacy and safety of tacrolimus in this setting are limited. AIM: To study the short-term efficacy and safety of tacrolimus in moderate-to-severe steroid-refractory UC. The role of thiopurines in this situation and predictors of colectomy were evaluated. METHODS: In three centers, all charts from tacrolimus-treated patients with steroid-refractory UC were reviewed. Efficacy was assessed by colectomy-free survival and clinical remission at 3 months. RESULTS: We identified 130 patients with pancolitis in 75 (59%), left-sided disease in 35 (27%) and proctitis in 18 patients (14%) (disease localisation not obtainable in two patients). The median age was 40 (range: 18-81). Clinical activity according to the median Lichtiger score decreased from 13 (range: 4-17) at baseline to 3 (0-14) at week 12. Eighteen patients underwent colectomy within the first 3 months of treatment with tacrolimus (14%). Clinical remission was achieved in 94 patients (72%) in this period. Thiopurines given in parallel to tacrolimus tended to limit colectomy and significantly increased remission (P = 0.002) in the short-term. No other predictors of colectomy or remission were identified. Side effects were noticed in 53% of patients and no severe events occurred. CONCLUSION: This large survey confirms the efficacy and safety of tacrolimus in patients with steroid-refractory ulcerative colitis.

Efficacy, safety and tolerability of vidofludimus in patients with inflammatory bowel disease: the ENTRANCE study.

BACKGROUND: Vidofludimus (SC12267) is a novel oral immunomodulator inhibiting dihydroorotate dehydrogenase (DHODH) and the expression of proinflammatory cytokines including interleukin-17 (IL17A and IL17F) and interferon-gamma. The objective of the study was to explore the efficacy, safety and tolerability of vidofludimus in steroid-dependent inflammatory bowel disease (IBD). METHODS: The open label uncontrolled ENTRANCE study (ClinicalTrials.gov NCT00820365) has been conducted at 13 study centers in Germany, Bulgaria and Romania. Thirty-four steroid-dependent patients with a confirmed diagnosis of Crohn's disease (CD) or ulcerative colitis (UC) were treated with a once daily 35mg oral dose of vidofludimus over 12weeks. Steroids were tapered during the first 8weeks followed by a steroid-free treatment period of 4weeks. Complete response was defined as steroid-free clinical remission at week 12; partial response was defined as being in remission at steroid dose equal or lower than the individual patient's threshold dose for relapse. RESULTS: Of the thirty-four patients enrolled in this trial 26 were evaluable for primary efficacy assessment. After completion of the 12weeks treatment phase 8 out of 14 (57.1%) patients with CD and 6 out of 12 (50.0%) patients with UC were in steroid-free remission (complete responders). Another 4 (28.6%) patients in CD and 5 (41.7%) patients in UC were partial responders. Vidofludimus was well tolerated, no drug-related serious adverse events were observed. CONCLUSIONS: This trial provides first evidence of clinical efficacy of vidofludimus in IBD. Although the safety and tolerability profile seems favorable, long-term controlled studies are needed to further investigate its potential as novel IBD therapy.

[Histoplasmosis: uncommon opportunistic infection in a patient with HIV infection]. / Histoplasmose: seltene opportunistische Infektion bei HIV-Infektion.

HISTORY AND ADMISSION FINDINGS: A 19-year-old HIV-positive man was admitted with fever of unknown origin and poor general condition. Antiretroviral therapy had been stopped by the patient eight months prior to admission. INVESTIGATIONS: Laboratory tests revealed pancytopenia, high viral load and low count of T-helper cells (13/µl). Computer tomography of the thorax showed small patchy infiltrations. Extensive examinations (microbiology, laboratory tests, multiple investigations) revealed no pathogen. Liver biopsy proved disseminated histoplasmosis. TREATMENT AND COURSE: Liposomal amphotericin B was started and switched to oral itraconazole after 14 days with itraconazole. With this treatment the patient condition improved and fever stopped. T-helper cells increased and the patient was discharged. CONCLUSION: Disseminated histoplasmosis as an AIDS-defining opportunistic infection is uncommon (particularly as the patient had not been abroad in the last four years) and can be a life-threatening complication. Diagnosis must be confirmed by invasive methods especially in patients with compromised immune status and rapid clinical progression.

ABCB1 single-nucleotide polymorphisms determine tacrolimus response in patients with ulcerative colitis.

Tacrolimus (Tac) is effective in the treatment of steroid-refractory ulcerative colitis (UC); however, nonresponse and unpredictable side effects are major limitations. Because Tac response in patients who have undergone solid-organ transplantation has been associated with the presence of variants in CYP3A and ABCB1, we elucidated the contributions of CYP3A4*1B and CYP3A5*3 and of ABCB1 1236C>T, 2677G>T,A, and 3435C>T polymorphisms to Tac response in 89 patients with UC. Short-term remission and response were achieved in 61 and 14% of the patients, respectively, and were associated with colectomy-free survival. In a linear logistic regression model, patients with homozygous variants for one of the three ABCB1 alleles showed significantly higher short-term remission rates as compared with those of other genotypes. The effects held true after multivariate analysis including multiple comparisons and were more pronounced after correction for dose-adjusted Tac blood trough levels. We suggest that ABCB1, but not CYP3A5, may predict short-term remission of Tac in steroid-refractory UC.

Two cases of fatal Pneumocystis jirovecii pneumonia as a complication of tacrolimus therapy in ulcerative colitis--a need for prophylaxis.

Here we report 2 cases of fatal Pneumocystis jirovecii pneumonia in patients with severe ulcerative colitis receiving combination immunosuppression including tacrolimus. We discuss the necessity of a P. jirovecii prophylaxis especially in elderly patients according to the European evidence-based consensus on the prevention and management of opportunistic infections in inflammatory bowel disease.

[Classification and management of upper gastrointestinal bleeding]. / Einteilung und Management der oberen gastrointestinalen Blutung.

The upper gastrointestinal bleeding remains the most frequent emergency in gastroenterology. Due to the different therapeutic approach a distinction between the variceal and the non-variceal bleeding has been established. A risk assessment for the individual patient is crucial for timing of the endoscopic procedure as well as for the estimation of prognosis. This review gives an overview on modern therapeutic techniques for both, variceal and non-variceal bleeding highlighting on success rates but also on potential complications of the different therapeutic interventions.

[New therapeutic approaches to special diseases of the small intestine]. / Neue therapeutische Ansätze bei speziellen Erkrankungen des Dünndarms.

Numerous reports on fundamental research and clinical studies have appeared in the past 1-2 decades which have contributed decisively to understanding inflammatory diseases of the small intestine. Illustrated by the examples of Crohn's disease, celiac disease, refractory sprue, and Whipple's disease, the rationale and evidence for treatment approaches are presented that are based on these pathophysiological findings. Emphasis is placed on modulation of the intestinal flora with antibiotics and probiotics as well as immunomodulatory/immunosuppressive measures with so-called biological agents. Future treatment options that directly intervene in the disease process are discussed.

Infliximab as rescue medication for patients with severe ulcerative/indeterminate colitis refractory to tacrolimus.

BACKGROUND: The calcineurin inhibitor tacrolimus and the anti-TNF-antibody infliximab are established options in steroid-refractory ulcerative colitis (UC). AIM: To evaluate the efficacy of infliximab-salvage therapy in patients with refractory UC failing to respond to tacrolimus. METHODS: Twenty-four patients were enrolled in this evaluation. Reasons for tacrolimus therapy were steroid-refractory disease in 19 patients and steroid-dependency in five patients. All patients receiving infliximab had tacrolimus-refractory active disease (Lichtiger score >10) and were treated with 5 mg/kg at weeks 0, 2 and 6 and every 8 weeks thereafter, if tolerated. RESULTS: Six of 24 patients (25%) achieved remission following infliximab infusion and four of 24 (17%) had an initial response only, but underwent proctocolectomy later because of loss of response (3) or development of a delayed hypersensitivity reaction (1). Fourteen patients (58%) completely failed to respond with 10 undergoing colectomy. Eight patients experienced side effects under infliximab, including two infectious complications (herpes zoster and herpes pneumonia). CONCLUSIONS: Infliximab offers a therapeutic option as rescue therapy in about a quarter of patients with active UC after failing to respond to tacrolimus. This benefit has to be weighed against the risks of infectious complications.

[Updated German S3-guideline regarding the diagnosis of Crohn's disease--implementation of radiological modalities]. / Aktualisierte S 3-Leitlinie zur Diagnostik des Morbus Crohn--radiologische Untersuchungstechniken.

The recently updated German S 3-guideline regarding the diagnosis and treatment of Crohn's disease incorporates several changes concerning the radiological approach compared to the former guideline. This article focuses on guideline-based radiological imaging techniques for patients with Crohn's disease. The new guideline is also compared to former European and German guidelines in the context of recently published radiological literature.

[Chronic inflammatory intestinal diseases. Pathophysiology and therapy]. / Chronisch entzündliche Darmerkrankungen. Pathophysiologie und Therapie.

The pathogenesis and therapy of chronic inflammatory intestinal diseases are characterized by an obvious discrepancy. There is extensive agreement that the pathogenesis is substantially based on a disruption of the barrier of the intestinal mucous membrane against luminal bacteria. This has been demonstrated in recent years by evidence from various disciplines, in particular from genetics, microbiology, morphology and innate immunology. However, there is also the evidence-based therapy which, as in the past, is aimed against the effectors of the adaptive immune system. In this case the therapy with biologicals is more aggressive and takes the risk of a series of undesired side-effects. This dichotomy of pathological knowledge and therapeutic innovation is not only medically unsatisfactory but also makes it difficult to present a consistent picture of these symptoms. Despite this an attempt will be made to bridge these inconsistencies and to demonstrate possible future developments which will lead to a final causal therapy. An extended version of this article appears in our newly published book "Colitis ulcerosa und Morbus Crohn".