Long-term cost and complications of surgery in patients with ulcerative colitis: a claims data analysis.

OBJECTIVES: Use claims data to assess healthcare resource utilization (HCRU) and cost for patients with ulcerative colitis (UC) who had surgery and patients who did not. METHODS: UC patients from a German health insurance were included between 01/01/2010-31/12/2017. Patients with proctocolectomy or colectomy between 01/07/2010 and 31/12/2014 were identified, and surgery date was set as index. For patients with IPAA, the last surgery in the 6 months was taken as index. Non-surgery patients received random index. After propensity score matching, UC-related HCRU and cost were observed for three years post-index. RESULTS: Of 21,392 UC patients, 85 underwent surgery and 2655 did not. After matching, 76 were included in the surgery group and 114 in the non-surgery group. Matched cohorts did not differ in baseline characteristics and mortality rates where high in both groups (21.1% and 29.0%, respectively). The percentage of patients with at least one hospitalization in the follow-up period was higher in the surgery (53.9%) compared to the non-surgery group (25.4%, p<0.001). In contrast, the number of outpatient prescriptions of UC-related drugs in the non-surgery group (11.2) was almost twice as large as in the surgery group (5.8, p<0.001). Hospitalization cost was 4.6 times higher in the surgery (1955.5€) than in the non-surgery group (419.6€, p<0.001). Medication cost was three times higher in the non-surgery group (6519€) compared to the surgery group (2151.7€, p<0.001). CONCLUSIONS: Based on hospitalizations, outpatient visits, and medical treatment, results show a considerable patient burden in UC from surgery complications or disease exacerbation in case of colectomy.

Indicators of active disease and steroid dependency in patients with inflammatory bowel diseases not treated with biologics in a German real-world-setting.

BACKGROUND AND AIMS: While a minority of inflammatory bowel disease (IBD) patients receives biologics in Germany, little is known about therapeutic needs of patients receiving non-biologic therapies. This study aimed to identify indicators of active disease/steroid dependency in patients with moderate to severe Crohn's disease (CD) and ulcerative colitis (UC) treated with conventional therapies and to describe health care resource use (HCRU)/cost. METHODS: CD/UC patients treated with immunosuppressants (IS) and/or systemic or locally acting oral corticosteroids (CS) were identified in German claims data (2013-2017) and followed for 12 months post-therapy start. Indicators of active disease/steroid dependency during follow-up period were (i) ≥ 2 prescriptions of CS (sensitivity ≥ 4) or (ii) ≥ 1 IBD-related surgery or (iii) > 7 days IBD-related hospitalization(s). RESULTS: Of 9871 included IBD patients (5170 CD, 4701 UC), 25.7%/19.9% (CD/UC) received ≥ 2 prescriptions of CS (sensitivity, 17.4%/15.7%) (i), 3.2% experienced IBD-related surgeries (ii), and 2.5% > 7 days of hospitalizations (iii). Altogether, 44.4% had indicators of active disease/steroid dependency (sensitivity, 23.9%). Among patients with active disease/steroid dependency, 78.0% received CS monotherapy at baseline. Of these, 89.6% received a CS monotherapy in the follow-up period, too. Proportionally, fewer patients with CS monotherapy (57.4%) than IS therapy (91.0%) visited a specialist. HCRU/cost per patient year was significantly higher in patients with than without active disease/steroid dependency. CONCLUSIONS: A substantial percentage of biologic-naïve IBD patients suffers from active disease/steroid dependency. The majority receives a monotherapy with systemic CS. Referral to gastroenterologists for treatment optimization is recommended, also because active disease/steroid dependency is associated with increased HCRU/cost.

Absence of specific alternatively spliced exon of CD44 in macrophages prevents colitis.

CD44 is a transmembrane molecule appearing in numerous isoforms generated by insertions of alternatively spliced variant exons (CD44v) and having various binding partners. CD44v7 on T cells was proposed to promote colitis by preventing T-cell apoptosis. Here we demonstrate that Cd44v7-deficient T cells - like Cd44 wild-type (Cd44WT) T cells - provoked disease in two different colitis models: the model induced by CD4+CD45RBhigh T-cell transfer into Rag2-deficient mice and a new model based on ovalbumin (OVA)-specific T-cell transfer into Rag-sufficient, OVA-challenged mice. In contrast, CD44v7 absence on macrophages in recipient mice prevented colitis. Prevention was associated with the downregulation of signal transducer and activator of transcription 3 (STAT3)-activating and Foxp3-counteracting interleukin-6 (IL-6), lower numbers of phospho-STAT3-containing lymphocytes, and higher Foxp3+ T-cell counts in the colon. Consequently, the protected colons showed lower IL-12, IL-1ß expression, and decreased interferon-γ levels. Importantly, stimulation of T cells by Cd44v7-deficient macrophages induced upregulation of Foxp3 in vitro, while cotransfer of Cd44WT macrophages into Cd44v7-deficient mice reduced Foxp3+ T-cell counts and caused colitis. Accordingly, the CD44v7 ligand osteopontin, whose levels were elevated in Crohn's disease, specifically induced IL-6 in human monocytes, a cytokine also increased in these patients. We suggest macrophage-specific targeting of the CD44v7 pathway as a novel therapeutic option for Crohn's disease.

Patient Education in a 14-month Randomised Trial Fails to Improve Adherence in Ulcerative Colitis: Influence of Demographic and Clinical Parameters on Non-adherence.

BACKGROUND AND AIM: Recent observational studies document that non-adherence to mesalamine therapy during remission is frequent. We aimed to investigate patient impact of patient education using objective assessments of adherence. METHODS: A 14-month randomised, prospective clinical trial of adherence to mesalamine was conducted in 248 patients with ulcerative colitis [UC], Colitis Activity Index [CAI] ≤ 9, receiving standard care [n = 122] versus a standardised patient education programme [n = 126]. Primary endpoint was adherence at all visits (5-aminosalicylic acid [5-ASA] urine levels). Secondary endpoints included quality of life (inflammatory bowel disease questionnaise [IBDQ]), disease activity, partial adherence, and self-assessment of adherence. RESULTS: Patient allocation was well balanced. Baseline non-adherence was high in quiescent/mildly active UC [52.4%] without difference between the groups (52.4% of patients in the education group versus 52.5% in the standard care group [p = 0.99]). No difference between the intervention group and standard care was seen in IBDQ, partial adherence, self-assessment of adherence, or therapy satisfaction at all visits. We suggest a model in which individual risks for non-adherence are driven by patients with young age, short disease duration, and low education levels. CONCLUSIONS: Non-adherence is frequent in a population with quiescent/mildly active UC. Although more than 25% of the population was not in remission at the various time points, no relationship between disease activity and adherence was seen over the 14-month observation period. Physicians should maximise their efforts to motivate high-risk patients for adherence. Future trials should use objective exposure assessments to examine the impact of continuous education and consultations on the background of individual risks to develop non-adherence.

[Biosimilars in inflammatory bowel disease]. / Biosimilars in der Behandlung chronisch entzündlicher Darmerkrankungen.

After the expiry date of the patent protection for Infliximab in 2013, the biosimilar CT­P13 was approved for indications in Crohn's disease and ulcerative colitis in adults as well as in children. The approval has been based on two randomized clinical studies indicating equivalence for the biosimilar with regard to pharmacokinetics, efficacy, as well as side-effects. The clinical experience since, in addition to multiple non-randomized studies, indicate a comparable efficacy and immunogenicity of the Infliximab biosimilar CT-P13 in inflammatory bowel disease. Thus, the introduction of the biosimilar as primary therapy seems to be justified. Tight monitoring of the safety of biosimilars with regard to efficacy and side effects has to be ensured.

[Put to Test: Medical Inpatient Rehabilitation of Inflammatory Bowel Diseases]. / Auf dem Prüfstand: stationäre medizinische Rehabilitation bei chronisch entzündlichen Darmerkrankungen.

BACKGROUND: Many CED-patients struggle with complex problem profiles and may be offered and profit from multidisciplinary multimodal rehabilitation. It is still unclear by whom and with what effects this option is used. METHODS: We compared the results of an observational cohort study of 199 CED-inpatients of a single rehab clinic with those of 310 gastroenterological outpatients using propensity score matching. RESULTS: Rehabilitands show more complex problem profiles than CED-outpatients. After 6 months of follow up direct and indirect change measures show generally small positive changes - however comparable in quality and size with that of matched outpatients. CONCLUSION: Complex rehab is mainly used by CED-patients with several bio-psycho-social problems. Our preliminary data do not suggest a marked additional benefit of inpatient rehab compared to specialised outpatient care. Stricter controlled trials are urgently needed.

Ferric maltol therapy for iron deficiency anaemia in patients with inflammatory bowel disease: long-term extension data from a Phase 3 study.

BACKGROUND: Ferric maltol was effective and well-tolerated in iron deficiency anaemia patients with inflammatory bowel disease during a 12-week placebo-controlled trial. AIM: To perform a Phase 3 extension study evaluating long-term efficacy and safety with ferric maltol in inflammatory bowel disease patients in whom oral ferrous therapies had failed to correct iron deficiency anaemia. METHODS: After 12 weeks of randomised, double-blind treatment, patients with iron deficiency anaemia and mild-to-moderate ulcerative colitis or Crohn's disease received open-label ferric maltol 30 mg b.d. for 52 weeks. RESULTS: 111 patients completed randomised treatment and 97 entered the open-label ferric maltol extension. In patients randomised to ferric maltol ('continued'; n = 50), mean ± s.d. haemoglobin increased by 3.07 ± 1.46 g/dL between baseline and Week 64. In patients randomised to placebo ('switch'; n = 47), haemoglobin increased by 2.19 ± 1.61 g/dL. Normal haemoglobin was achieved in high proportions of both continued and switch patients (89% and 83% at Week 64, respectively). Serum ferritin increased from 8.9 µg/L (baseline) to 26.0 µg/L (Week 12) in ferric maltol-treated patients, and to 57.4 µg/L amongst all patients at Week 64. In total, 80% of patients reported ≥1 adverse event by Week 64. Adverse events considered related to ferric maltol were recorded in 27/111 (24%) patients: 8/18 discontinuations due to adverse events were treatment-related. One patient was withdrawn due to increased ulcerative colitis activity. CONCLUSIONS: Normal haemoglobin was observed in ≥80% of patients from weeks 20-64 of long-term ferric maltol treatment, with concomitant increases in iron storage parameters. Ferric maltol was well-tolerated throughout this 64-week study.

Vedolizumab induction therapy for inflammatory bowel disease in clinical practice--a nationwide consecutive German cohort study.

BACKGROUND: Vedolizumab (VDZ) is a humanised monoclonal IgG1 antibody targeting α4 ß7 integrin. AIM: To investigate the real-world efficacy of vedolizumab for the treatment of Crohn's disease (CD) and ulcerative colitis (UC). METHODS: A consecutive cohort of 212 adult IBD patients with active disease (HBI >7/partial Mayo >4) newly receiving VDZ was prospectively recruited from 7 academic and 17 community centres. The primary endpoint was clinical remission (CRM) (CD HBI ≤4, UC pMayo ≤1) in week 14. Secondary endpoints included steroid-free remission (SFCRM), clinical response (CRS) (HBI/pMayo score drop ≥3), vedolizumab impact on CRP, calprotectin and haemoglobin. RESULTS: Data of 97 CD (71.1% female, HBI 11) and 115 UC (42.6% female, pMayo 6) patients were analysed. Only 5.2% CD and 24.3% UC were anti-TNFα naïve. Most had extensive mucosal involvement (Montreal L3 69.1%/E3 53.9%). At week 14, 23.7% vs. 23.5% of CD vs. UC patients achieved CRM, 19.6% vs. 19.1% SFCRM and 60.8% vs. 57.4% CRS, respectively (all based on NRI). Week 14 CRM in CD was significantly associated with no history of extraintestinal manifestations (P = 0.019), no prior adalimumab use (P = 0.011), no hospitalisation in the past 12 months (P = 0.015) and low HBI score (P = 0.02) and in UC with active or previous smoking (P = 0.044/0.028) and no anti-TNFα (P = 0.023) use. Low HBI (P = 0.019) and no hospitalisation in the past 12 months (P = 0.01) predict CD CRM. The three most common AE were joint pain, acne and nasopharyngitis. CONCLUSION: Vedolizumab is effective in routine use.

[Current position on Vedolizumab for ulcerative colitis and Crohn's disease]. / Vedolizumab bei Colitis ulcerosa und Morbus Crohn: eine Standortbestimmung.

Vedolizumab, the first drug in the class of anti-integrin molecules, is newly approved for ulcerative colitis and Crohn's disease and can be prescribed in Germany since mid-2014. By a specific receptor binding a relatively gut-selective mode of action was achieved without the known side effects of the systemic immunosuppression of the anti-TNF-alpha antibodies. According to the present data the safety profile of Vedolizumab appears to be more favorable than that of the anti-TNF- alpha therapy. Vedolizumab is suitable for induction therapy in patients with ulcerative colitis and Crohn's disease, however the kinetic of response compared with the anti-TNF-alpha antibodies seems to be slower. For maintenance therapy the Vedolizumab data show a deep and sustained remission in patients initially responding to induction therapy with a lower loss of efficacy in the long-term treatment known from the anti-TNF-alpha therapy. On the basis of currently available data the efficacy of Vedolizumab in ulcerative colitis appears to be slightly better than in Crohn's disease.

[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.

[Evolution of biologicals in inflammation medicine--biosimilars in gastroenterology, rheumatology and dermatology]. / Evolution der Biologika in der Entzündungsmedizin--Biosimilars in Gastroenterologie, Rheumatologie und Dermatologie.

Biologicals revolutionized the therapy of chronic inflammatory diseases in gastroenterology, rheumatology and dermatology in the last decade. The first generation biologicals mainly targeted against the pro-inflammatory cytokine TNF-α. The evolution of these therapies in the last years led to the development of new antibodies and to the admission of first generation "generic" biologics - the biosimilars. Biosimilars are not a fundamental new pharmacological development for existing substances, however they have the potential to lead to enormous cost savings in healthcare without reducing the level of care for patients. Biosimilars are not identical with the originator, but in an extensive biosimilarity exercise including analytical, preclinical and comparative clinical studies it was shown that the biosimilars could demonstrate comparability in all relevant aspects with the originator.In September 2013, the Infliximab biosimilars (Inflectra(®), Remsina(®)) were the first biosimilars for monoclonal antibodies to be authorized by the EMA for use in the European Union. By demonstrating the therapeutic similarity only in one indication (rheumatoid arthritis) the EMA agreed with an extrapolation also to all approved indications of the originator. This could be a relevant problem in clinical practice. Therefore, comparative studies with the originator are required in all approved indications.After expiration of the national patent protection in beginning of 2015, the infliximab biosimilars will be launched on the market in Germany and will be part of the therapeutic arsenal in gastroenterology, rheumatology and dermatology. Interchangeability (Switching) of biosimilars with the originator will be subject of an important discussion with the health care providers. Regardless of the biosimilars EMA-approval, several potential problems (efficacy, extrapolation, switching, long-term safety) should be the topic of intensive long-term registries in the future.

Clinical status, psychosocial impairments, medical treatment and health care costs for patients with inflammatory bowel disease (IBD) in Germany: an online IBD registry.

BACKGROUND: The aim of this cross-sectional study was to establish an online inflammatory bowel disease (IBD) registry for a first picture of the situation of IBD outpatients' treatment in Germany. METHODS: Between March 2006 and July 2007 IBD outpatients from 24 gastroenterological specialist practices and two hospitals in Germany were enrolled in an Internet-based registry to evaluate the outpatients' clinical status, psychological impairments, provided health care, as well as medical treatment and medication costs. RESULTS: 1032 IBD patients (ulcerative colitis/UC: 519; Crohn's disease/CD: 511; indeterminate colitis: 2) were enrolled in the study (age: 43 ± 14 years/M ± SD). Disease duration of all patients averaged 10 ± 8.5 years. In 519 UC-patients (49% male; 33% pancolitis), 66% were in remission as were 55% of CD patients (37 % male; 41 % active smokers). Associated with higher rates of disease activity (CDAI ≥ 150; CAI>4) were corticosteroids (CD, UC), topical medication (UC), relevant reported depressive symptoms (15%; 6-31%) and impairments in sexuality (21%; 9-42%). Relevant medication groups prescribed were oral aminosalicylates (UC: 70%; CD: 47%); immunosuppressive therapy - mostly azathioprine/6 MP (CD: 47%; UC: 26%), and Infliximab (CD: 8%; UC: 3%). Strongly associated with their clinical disease activity in UC as well as CD patients, 15% (6-31%) reported relevant depressive symptoms and 21% (9-42%) relevant impairments in sexuality. CONCLUSIONS: The registry constitutes a large complemental database for the patient population in Germany. About one third of the IBD patients were not in clinical remission (CDAI ≥150/CAI >4) (CD: 45%; UC: 27%), although high rates of immunosuppressive drugs (CD: 47%; UC 26%) were administered. This study shows a large burden of active disease associated with an unexpectedly high (co)morbidity and high psychosocial impairments, indicating a reduced health state in IBD patients.

Predictive factors for an uncomplicated long-term course of Crohn's disease: a retrospective analysis.

BACKGROUND: Predictive factors for a mild course of Crohn's disease (CD) may have therapeutic consequences, but as yet have not been identified. AIMS: To identify baseline factors that predict mild CD and design a predictive scoring system. METHODS: A retrospective, multicenter study of newly diagnosed CD patients allocated to mild CD (no therapy, mesalazine only, or mesalazine with a single initial short course of low-dose prednisone) or moderate CD (all other patients including resected patients). RESULTS: 162 patients (median follow-up 43 months) were analyzed: 47 mild CD and 115 moderate CD. For mild CD versus moderate CD, mean age at first diagnosis was higher (41.1 versus 33.9 years, p=0.02), mean C-reactive protein (CRP) concentration was lower (1.6 versus 3.6 mg/L, p<0.01), and perianal lesions were less frequent (0% versus 10.4%, p=0.02). The combined incidence of complications (stenosis, any type of fistula, extraintestinal complications or fever) was 21.3% in mild CD versus 35.7% in moderate CD (p=0.07). A scoring system based on age, CRP, endoscopic severity (adapted Rutgeert's score), perianal lesions and combined incidence of complications was developed which can predict a mild prognosis at the initial diagnosis, giving patients the chance of simplified therapy and accelerated step-up in the event of treatment failure. CONCLUSIONS: Approximately a third of CD patients experience a mild disease course and require only basic therapy. A possible scoring system to predict mild CD which may avoid overtreatment and unnecessary risks for the patient and costs is suggested.

[Epidemiology and clinical characteristics of patients with chronic hepatitis B (CHB) in Germany - results of a nationwide cross-sectional study]. / Epidemiologie und Klinik von Patienten mit chronischer Hepatitis B (CHB) in Deutschland - Ergebnisse einer bundesweiten Querschnittstudie.

BACKGROUND AND AIMS: Knowledge about the epidemiology, demography and social status of patients with replicative chronic hepatitis B (CHB) in Germany is still scarce. This cross-sectional study evaluated in patients with chronic hepatitis B infection, with a serum HBV-DNA concentration of at least 10,000 copies/mL (> 2000 IU/mL) at documentation visit, the epidemiology, socio-demographics, time of diagnosis, history of disease, prior therapies as well the therapeutic decision. METHODS: 74 German centres with predominately hepatologic focus, recorded in an online-survey the pseudonymised data of patients with chronic HBV-infection with a serum HBV-DNA-concentration of at least 10,000 copies/mL (n = 35). RESULTS: 65 % of the patients were male. The mean age was 40 ± 14 years. 63 % were immigrants (i. e., country of birth not being Germany). 37 % were HBeAg-positive. Mean ALT value 114 ± 183 IU/mL in males and 77 ± 176 IU/mL in females. ALT was above the upper limit of normal (ULN) in 59 % and 9 % of the patients were cirrhotic. The large immigrant groups, Turks (22 %), people from the former USSR (11 %) or from Southeast Asia (10 %) differed in terms of age, sex, HBeAg-status and clinical parameters clearly from each other as well as from German patients. 55 % of the patients from SE-Asia were female and overall considerably younger than German patients. 69 % of the patients with HBV-DNA > 10,000 copies/mL combined with ALT-levels above ULN, and 87 % with advanced fibrosis recieved antiviral treatment. CONCLUSIONS: This database currently contains the largest collection of epidemiological data of CHB patients in Germany. It therefore allows a representative overview on the disease in Germany. In Germany CHB epidemiology is triggered by migration from countries with higher CHB prevalence. However, the high proportion of patients coming from states of the former USSR is likely to be a historical peculiarity of Germany. The sometimes weak German language skills as well as the cultural specifics in the different immigrant groups are still a challenge for health-care providers. The high proportion of viraemic patients, already being treated, could indicate a suboptimal efficacy of the available therapeutic options at the time documentation.

[Pharmacotherapy in patients with ulcerative colitis]. / Medikamentöse Versorgung von Patienten mit Colitis ulcerosa.

BACKGROUND: Patients with ulcerative colitis experience various impairments. The pharmacological treatment of the disease comprises 5-aminosalicylic acid, corticosteroids as well as immunomodulatory and biological agents. Little self-reported data exist on the prescription of these drugs. METHODS: This cross-sectional study was conducted in 2005 as a postal survey in different regions of Germany [Kiel/Lübeck, Halle (Saale), Minden, Regensburg]. Patients with ulcerative colitis (UC) were recruited from specialised gastroenterological practices, university outpatient clinics, and the member registry of a prominent patient organisation (DCCV). Participants returned a questionnaire including established items and scales on physical and psychosocial well-being as well as the self-reported current medication. RESULTS: A total of 444 patients with ulcerative colitis returned the questionnaires. Most of the participants were female, had a high level of school education and were currently employed. Twenty-eight percent of the participants reported to receive corticosteroids and 71 % reported a current treatment with 5-aminosalicylic acid. Approximately one quarter of our study population reported a treatment with immunomodulatory agents. Analgesics were reported to be prescribed only in 15 % of the patients, primarily in patients with depressive symptoms. Patients recruited from specialised gastroenterological practices and university outpatient clinics were more likely to report the prescription of 5-aminosalicylic acid and immunomodulatory drugs than members of the patient organisation. Only 7 % of our patients received loperamide, however, probiotics (12 %) and complementary agents (36 %) seem to have an important role with regard to prevalence of intake. About 40 % of women but only 28 % of the men reported to use complementary agents. Persons with a duration of illness of less than 11 years (median split) were almost twice as likely to take corticosteroids than persons with a longer duration of ulcerative colitis. DISCUSSION: Our results suggest an estimation of prescription rates in ulcerative colitis. However, they raise new questions, for example, concerning a potential underuse of immunomodulatory agents in this patient population. With regard to the identified differences in prescription rates according to psychosocial characteristics further studies are needed to examine these relationships.