Max Karner

Phosphatidylcholine for Steroid-Refractory Chronic Ulcerative Colitis: A Randomized Trial

Context Experts recommend immunosuppressant drugs, rather than long-term steroid therapy, for chronic active ulcerative colitis. Few options remain when immunosuppressant drugs fail or cause intolerable side effects. Contribution In this double-blind trial, 60 adults with chronic steroid-refractory ulcerative colitis in whom immunosuppressant drugs had failed or were poorly tolerated were randomly assigned to receive phosphatidylcholine or placebo for 12 weeks. More phosphatidylcholine recipients improved and achieved steroid withdrawal than placebo recipients (15 of 30 vs. 3 of 30, respectively). More patients reported bloating with phosphatidylcholine than placebo (11 vs. 6). Caution The study had a small sample size and was of short duration. Implication We need larger, long-term trials of phosphatidylcholine as a treatment for ulcerative colitis. The Editors Long-term steroid therapy is harmful and should be replaced by immunosuppressant drugs, such as azathioprine or 6-mercaptopurine, in chronic active ulcerative colitis. Treatment alternatives are lacking, however, when immunosuppressant drugs cause adverse events, fail, or are rejected by patients. In such cases, patients must endure long-term steroid therapy. A new therapeutic strategy with phosphatidylcholine supplementation in the colonic mucus has been developed. It is based on the pathogenetic concept of a mucosal barrier dysfunction in ulcerative colitis caused by a primary lack of the mucoprotective phosphatidylcholine in colonic mucus (14). Because ingestion of phosphatidylcholine leads to complete absorption in the upper intestine and topical rectal applications of phosphatidylcholine do not integrate into the mucus, phosphatidylcholine was encapsulated with Eudragit-S100 (Rhm Pharma, Darmstadt, Germany) to provide pH-dependent release in the distal intestine (5). A first proof-of-concept study in nonsteroid-treated ulcerative colitis showed that the lack of phosphatidylcholine in rectal mucus could be compensated and that patients benefited from treatment (5). We conducted the current study to see whether retarded-release phosphatidylcholine permits steroid withdrawal in chronic steroid-refractory ulcerative colitis. Methods Setting and Patients Patients with continuous clinical disease activity for at least 4 months despite steroid therapy were referred by their general practitioners to the Department of Gastroenterology at University Hospital Heidelberg, Heidelberg, Germany. The trial was announced by the German Crohn and Colitis Support Group and the press, and it attracted patients from throughout Germany. Steroid therapy was maintained at the lowest possible dose for at least 4 weeks before the study treatment started. Treatment with 5-aminosalicylates (3 to 4 g/d), Escherichia coli Nissle 1917 (200 mg/d), and azathioprine or 6-mercaptopurine (both at doses of 2 to 2.5 mg/kg for at least 6 months, respectively) at baseline was continued throughout the trial. Other immunosuppressant drugs or enemas or any changes in medication 4 weeks before the start of study treatment were not permitted. Inflammatory activity was defined during a screening phase of 10 to 14 days. Patients were naive to phosphatidylcholine treatment and were eligible if they had a moderate to high clinical activity index and endoscopic activity index (score 5 on both indexes) (6). Figure 1 shows further inclusion and exclusion criteria. The study was approved by the institutional ethics committee, and all patients signed consent forms. Figure 1. Study flow diagram. 6-MP= 6-mercaptopurine; AZT= azathioprine; CAI= clinical activity index; EAI= endoscopic activity index; ITT= intention to treat; PC= phosphatidylcholine; UC= ulcerative colitis. *Two patients in each group dropped out of the study. They were treated as nonresponders for categorical measurements and were excluded for the analyses of continuous end points. Randomization and Intervention A 33% phosphatidylcholine-enriched phospholipid preparation and a cellulose placebo version were encapsulated for retarded intestinal release with Eudragit-S100, an anionic copolymer based on methacrylic acid and methyl methacrylate. To ensure double-blinding, both study medications were prepared as indistinguishable granular matrix preparations. Patients received a numbered container of the study medication, which was computer randomized, in permuted blocks of 6 for the 12-week study period. The external manufacturer transferred the sealed randomization list to an independent study control, which forwarded the list to the statistician after database closure. Both the phospholipid preparation and placebo were taken orally 4 times daily, for a total phosphatidylcholine dosage of 2 g/d. During the study, patients completed diary sheets documenting bowel movements, blood in stool, abdominal pain, general well-being, fever, adverse events, and current medication. Physicians performed weekly telephone interviews with each patient to check the data from his or her diary and assess the possibility of steroid reduction. Interview data were submitted to 3 specialists (expert panel) who collectively made a decision, which was then communicated to the patient with a separate phone call. Two weeks after the start of the study, the steroid dose was reduced stepwise if possible. Steroid reduction followed a standard tapering protocol; the definite steroid dose, however, was decided by the expert panel. If symptoms deteriorated, steroid reduction was paused and, if necessary, rescue therapy with 50 mg of prednisolone or prednisone for 3 days was initiated. Adherence was controlled by assessing the intake of the study medication during telephone interviews and by collecting used medication boxes at the end of the trial. Outcomes and Follow-up The primary end point was assessed after 12 weeks. It was defined as steroid withdrawal with either a low clinical activity index (3) or a reduction in the clinical activity index of 50% or more. Secondary end points (clinical activity index and endoscopic activity index, disease extent, histologic findings, and life quality index evaluated by using the German version of the Inflammatory Bowel Disease Questionnaire [IBDQ]) were defined a priori and were compared between groups. Response patients were subdivided into patients who achieved a clinically or endoscopically inactive state (clinical activity or endoscopic index 3) and those who had improvement of 50% or more (5). An improvement of 25% or more was used as a discriminate value for histologic findings and life quality indexes. In addition, absolute changes of disease indexes were reported. The clinical activity index comprises measurements for stool frequency, blood in stool, abdominal pain, extraintestinal manifestations, fever, physicians global assessment, and laboratory results (erythrocyte sedimentation rate and hemoglobin levels). The clinical activity index is based on a 0- to 29-point scale; the higher the score, the worse the disease activity (6). The endoscopic activity index consists of 4 variables: granulation, vulnerability, ulcerations of the mucosa, and vascular patterns (0 to 12 points) (6). The rectal biopsies were evaluated by an independent pathologist who was blinded to randomization and clinical information. Inflammation was scored as follows: 0= none, 1= inactive, 2= mild, 3= moderate, 4= severe (5, 7). Life quality was evaluated by using the German version of the IBDQ, which includes systemic, bowel, emotional, and social functions (8, 9) (scale of 32 to 224 points; the lower the score, the worse the life quality). Adverse events were assessed during the study by using a self-administered questionnaire that included open-ended questions and a checklist. In addition, a study physician interviewed patients at the end of the trial about the occurrence and details of adverse events and rated them as plausibly, possibly, or not related to the study medication. Formal, safety-related stopping criteria were preplanned and comprised acute disease exacerbation (2-fold increase of clinical activity index, fever >39 C on 5 consecutive days), complications (toxic megacolon, abscesses, and need for surgical interventions) or persistence of unexplainable laboratory results. Leukocyte count; hemoglobin levels; platelet count; erythrocyte sedimentation rate; and C-reactive protein, creatinine, urea, alanine and aspartate aminotransferase, -glutamyltransferase, and total bilirubin levels were obtained at the start and end of the study. A study physician documented the source data and transferred them to the case report form and electronic data sheets. A second study physician compared the case report forms with the source data after each patients visit and checked the data for plausibility. In addition, a study nurse controlled the electronic data sheets with the case report forms. The external statistician checked the electronic data sheets again for plausibility before database closure. Statistical Analysis Results from 60 patients were calculated to be sufficient to demonstrate a significant treatment effect with a 2-sided significance level of 5% and a power of 85%. This is based on the 10% placebo response rate of our earlier study (5) and correlates to reported rates in the literature (1012). A 45% response rate was assumed for the phosphatidylcholine group, which is similar to the findings of our earlier study (5) and compares with reported rates achieved by immunosuppressant drugs (12). After database closure, the external statistician received the electronic data sheets from the investigators and the randomization list from the external study control. Analyses were done in an unblinded manner by the predefined intention-to-treat analyses (SAS software, version 9.1.3; SAS, Cary, North Carolina). The Fisher exact test was used for categorical variables of differences in demographic data and for the primary outcome measure and response

Phosphatidylcholine as a constituent in the colonic mucosal barrier--physiological and clinical relevance.

Phosphatidylcholine (PC) is an important constituent of the gastrointestinal tract. PC molecules are not only important in intestinal cell membranes but also receiving increasing attention as protective agents in the gastrointestinal barrier. They are largely responsible for establishing the hydrophobic surface of the colon. Decreased phospholipids in colonic mucus could be linked to the pathogenesis of ulcerative colitis, a chronic inflammatory bowel disease. Clinical studies revealed that therapeutic addition of PC to the colonic mucus of these patients alleviated the inflammatory activity. This positive role is still elusive, however, we hypothesized that luminal PC has two possible functions: first, it is essential for surface hydrophobicity, and second, it is integrated into the plasma membrane of enterocytes and it modulates the signaling state of the mucosa. The membrane structure and lipid composition of cells is a regulatory component of the inflammatory signaling pathways. In this perspective, we will shortly summarize what is known about the localization and protective properties of PC in the colonic mucosa before turning to its evident medical importance. We will discuss how PC contributes to our understanding of the pathogenesis of ulcerative colitis and how reinforcing the luminal phospholipid monolayer can be used as a therapeutic concept in humans.

First Multicenter Study of Modified Release Phosphatidylcholine “LT-02” in Ulcerative Colitis: A Randomized, Placebo-Controlled Trial in Mesalazine-Refractory Courses

OBJECTIVES:Phosphatidylcholine is a key component of the mucosal barrier. Treatment with modified release phosphatidylcholine aims to improve the impaired barrier function. The primary objective is to evaluate the efficacy of LT-02, a newly designed modified release phosphatidylcholine formula, in a multicenter setting.METHODS:This is a double-blinded, randomized, placebo-controlled, superiority study conducted in 24 ambulatory referral centers in Germany, Lithuania, and Romania. A total of 156 patients with an inadequate response to mesalazine, a disease activity score (Simple Clinical Colitis Activity Index (SCCAI)) of ≥5, and bloody diarrhea underwent treatment with 0, 0.8, 1.6, or 3.2 g LT-02. The primary end point was defined a priori as changes in SCCAI from baseline to the end of treatment. The primary statistical model was a general linear least-squares model. The study was funded by the sponsor Lipid Therapeutics, Heidelberg, Germany, and registered at http://clinicaltrials.gov/show/NCT01011322.RESULTS:Baseline characteristics and dropouts were well balanced between all groups. The primary analyses revealed an SCCAI drop of 33.3% in the placebo group (from 9.0 to 6.0 points) compared with 44.3% in the 0.8 g LT-02 (from 8.8 to 4.9, P>0.05) and 40.7% in the 1.6 g groups (from 8.6 to 5.1, P>0.05). The 3.2 g group improved 51.7% from 8.5 to 4.1 (P=0.030 in comparison with placebo). The remission rate was 15% (6/40) in the placebo group compared with 31.4% (11/35) in the highest LT-02 dose group (P=0.089). Mucosal healing was achieved in 32.5% of placebo patients compared with 47.4% of LT-02 patients (P=0.098); the rates for histologic remission were 20% compared with 40.5%, respectively (P=0.016). There were 17 (48.6%) treatment-emergent adverse events in the highest dose group (and 0 serious adverse events (SAEs)) compared with 22 (55%) in the placebo group (4 SAEs).CONCLUSIONS:The primary end point analysis showed a statistically significant improvement in disease activity during LT-02 treatment in comparison with placebo. The drug was found to be very safe.

Delayed release phosphatidylcholine in chronic-active ulcerative colitis: a randomized, double-blinded, dose finding study.

Background In 2 preceding studies, delayed release phosphatidylcholine (rPC) was found to (a) improve disease activity and (b) withdraw steroids in patients with chronic-active ulcerative colitis. Goal Objective of the study was to determine the most effective rPC dose with least adverse events. Study A randomized, dose-controlled, double-blinded study. Four groups of 10 patients each with nonsteroid-treated, chronic-active ulcerative pancolitis with a clinical activity index (CAI) and endoscopic activity index (EAI) ≥7. Patients were treated with oral rPC at doses of 0.5, 1, 3, and 4 g daily over 12 weeks. Results The CAI changes from baseline to the end of the study were 2.5 (0.5 g), 7.0 (1 g), 5.5 (3 g), and 6.0 (4 g dose arm). Significant improvement of the CAI was registered between the lowest rPC dose of 0.5 g (control group) and all higher doses of 1.0, 3.0, and 4.0-g rPC (P≤0.05). Remission (CAI ≤3) was reached in 5/10 and 6/10 patients in the 3 and 4-g dose groups compared with no patients in the 0.5-g arm (P=0.033). In the 1-g dose group only 3/10 patients reached remission (P=0.21). The rates of clinical response (≥50% CAI improvement) were 70% in all of the effective dose groups (1 to 4 g, P=0.003). This was paralleled by the EAI improvement and by the rates of mucosal healing. Median time to clinical response was 5 (IQR 2 to 8) weeks. Bloating was registered in 40% of the patients irrespective of the treatment dose. Three of the 10 patients in the 4 g dose group reported nausea. Conclusion We found a saturable dose response of rPC in the treatment of chronic-active ulcerative colitis with effective doses ≥1 g per day; doses of 3 and 4 g seem to be superior in achieving remission.

Phosphatidylcholine (lecithin) and the mucus layer: Evidence of therapeutic efficacy in ulcerative colitis?

Colonic mucus protects against attacks from bacteria in stool. One component of mucus is phosphatidylcholine (PC) which is thought to be arranged as continuous lamellar layer in the apical mucus and to be responsible for establishing a protective hydrophobic surface. This ‘intestinal surfactant’ plays a key role in mucosal defense. Thus, a defective PC layer contributes to the development of inflammation. Analysis of rectoscopically acquired mucus aliquots revealed a 70% decrease in PC content in ulcerative colitis (UC) compared to Crohn´s disease (CD) and healthy controls – independent of disease activity. Accordingly, we propose that lack of mucus PC is a key pathogenetic factor in UC. In clinical studies a delayed-release oral PC preparation (rPC) was found to substitute the lack of PC in rectal mucus. Indeed, in non-steroid-treated active UC, 53% of rPC patients reached remission [clinical activity index (CAI) ≤3] compared to 10% of placebo patients (p ≤ 0.001). Endoscopic and histologic findings improved concomitantly. A second trial with 60 chronic-active, steroid-dependent UC patients was conducted to test for steroid-sparing effects. Complete steroid withdrawal with a concomitant achievement of remission (CAI ≤3) or clinical response (≧50% CAI improvement) was reached in 15 PC-treated patients (50%) but only in 3 (10%) placebo patients (p = 0.002). In conclusion, intrinsic reduction of PC (lecithin) in colonic mucus may be a key pathogenetic feature of UC. Topical supplement of PC by a delayed-released oral PC preparation is effective in resolving inflammatory activity of UC and may develop to a first-choice therapy for this disease.

Transcript levels of different cytokines and chemokines correlate with clinical and endoscopic activity in ulcerative colitis

BackgroundA definition of disease activity in ulcerative colitis (UC) is difficult. The clinical activity index (CAI) is only an indirect assessment tool of bowel inflammation and the endoscopic activity index (EAI) sometimes cannot reflect the severity of disease to the full extent. Therefore, there is a need for an objective means to quantify inflammatory activity in mucosal biopsies. In our study, we wanted to examine the correlation between transcript levels of interleukin 8 (CXCL8), interferon γ inducible protein 10 (CXCL10), myeloid-related protein 14 (calgranulin B), macrophage inflammatory protein 2 α (CXCL2) with CAI and EAI in UC.MethodsCytokine and chemokine transcripts were quantified using real-time PCR in 49 mucosal biopsies from 27 different patients with UC. Cytokine transcript levels were correlated with CAI and EAI.ResultsThere was a statistically significant positive correlation between CXCL8 (r = 0.30; p < 0.05), CXCL10 (r = 0.40; p < 0.02), calgranulin B (r = 0.36; p < 0.03), CXCL2 (r = 0.31; p < 0.05) and CAI. Concerning EAI significant positive correlations for CXCL8 (r = 0.37; p < 0.02), CXCL10 (r = 0.33; p < 0.04), calgranulin B (r = 0.31; p < 0.05) and CXCL2 (r = 0.44; p < 0.05) were found. Low clinical and endoscopic activity was accompanied by low cytokine levels whereas high CAI and EAI were associated with high cytokine levels.ConclusionFrom our data, we conclude that real-time PCR quantification of CXCL8, CXCL10, calgranulin B and CXCL2 in colonic biopsies is a simple and objective method for grading inflammation of intestinal mucosa in UC. CXCL8, CXCL10, calgranulin B and CXCL2 might be used as biomarkers and thus as an objective tool especially in clinical trials to evaluate anti-inflammatory and immunomodulatory regimens.

Mucosal Protection by Phosphatidylcholine

The colonic mucus serves a first barrier towards invasion of commensal bacteria in stools to prevent inflammation. One essential component of intestinal mucus is phosphatidylcholine (PC) which represents more than 90% of the phospholipids in mucus indicative for a selective transport of PC into this compartment. It is arranged in lamellar structures as surfactant-like particles which provide a hydrophobic surface on top of the hydrated mucus gel to prevent the invasion of bacteria from intestinal lumen. In ulcerative colitis (UC), the mucus PC content is reduced by 70%, irrespective of the state of inflammation. Thus, it could represent an intrinsic primary pathogenetic condition predisposing to bacterial invasion and the precipitation of inflammation. Since PC was shown to be mainly secreted by the ileal mucosa from where it is assumed to move distally to the colon, the PC content along the colonic wall towards the rectum gradually thins, with the least PC content in the rectum. This explains the start of the clinical manifestation of UC in the rectum and the expansion from there to the upper parts of the colon. In three clinical trials, when missing mucus PC in UC was supplemented by an oral, delayed release PC preparation, the inflammation improved and even resolved after a 3-month treatment course. The data indicate the essential role of the mucus PC content for protection against inflammation in colon.

Objectifying specific and nonspecific effects of acupuncture: a double-blinded randomised trial in osteoarthritis of the knee.

Introduction. Acupuncture was recently shown to be effective in the treatment of knee osteoarthritis. However, controversy persists whether the observed effects are specific to acupuncture or merely nonspecific consequences of needling. Therefore, the objective of this study is to determine the efficacy of different acupuncture treatment modalities. Materials and Methods. We compared between three different forms of acupuncture in a prospective randomised trial with a novel double-blinded study design. One-hundred and sixteen patients aged from 35 to 82 with osteoarthritis of the knee were enrolled in three study centres. Interventions were individualised classical/ modern semistandardised acupuncture and non-specific needling. Blinded outcome assessment comprised knee flexibility and changes in pain according to the WOMAC score. Results and Discussion. Improvement in knee flexibility was significantly higher after classical Chinese acupuncture (10.3 degrees; 95% CI 8.9 to 11.7) as compared to modern acupuncture (4.7 degrees; 3.6 to 5.8). All methods achieved pain relief, with a patient response rate of 48 percent for non-specific needling, 64 percent for modern acupuncture, and 73 percent for classical acupuncture. Conclusion. This trial establishes a novel study design enabling double blinding in acupuncture studies. The data suggest a specific effect of acupuncture in knee mobility and both non-specific and specific effects of needling in pain relief.

Delayed release phosphatidylcholine as new therapeutic drug for ulcerative colitis – a review of three clinical trials

Importance of the field: As the pathogenesis of ulcerative colitis (UC) is unknown, a causative therapy is lacking. Therefore, some UC patients suffer from disease activity despite symptomatic anti-inflammatory treatment strategies. We claim that reduction of phosphatidylcholine (PC) in colonic mucus impairs the mucosal barrier and, thus, causes attacks of the commensal bacterial flora to induce colitis. Thus, mucus PC substitution could provide a causal therapy for UC. Areas covered in this review: A delayed released oral PC preparation (rPC) was found to substitute for the lack of PC in rectal mucus. In non-steroid-treated active UC, 53% of rPC-treated patients reached remission compared with 10% of placebo patients (p < 0.001). In a second trial with chronic-active, steroid-dependent UC patients, steroid withdrawal with a concomitant achievement of remission (CAI ≤ 3) or clinical response (≥ 50% CAI improvement) was reached in 15 rPC-treated patients (50%) but only in 3 (10%) placebo patients (p = 0.002). What the reader will gain: The concept that missing PC in colonic mucus is the main pathogenetic factor for development of UC. PC can be substituted by rPC, which cures the disease in the majority of patients. Take home message: rPC is, to our knowledge, the first causative therapeutic option for patients with UC.

Dealing with Our ‘In-Vironment’: New Aspects of Inflammatory Bowel Disease Pathogenesis and Therapy

making it more proinflammatory or aggressive. Other factors may directly act on the intestinal barrier function. Our therapeutic approaches still mainly focus on regulating adaptive immunity. Only recently have the barrier function of the gut mucosa and the defense function of the innate immune system come into focus. A recent FALK meeting entitled ‘Dealing with our ‘In-vironment’: New Aspects in IBD Pathogenesis and Therapy’ was, therefore, centered around recent discoveries that may change future treatment strategies. In a 2-day meeting, genetic risk factors in IBD, antibacterial defense mechanisms, the epithelial barrier as a border to the in-vironment, environmental factors in pathogenesis, disease markers, new therapeutic approaches and future therapeutic direction were discussed. The articles summarized here cover the most important aspects of the meeting and highlight the role of the in-vironment in IBD pathogenesis. Gerhard Rogler , Zürich Our understanding of the pathogenesis of inflammatory bowel disease (IBD) has dramatically changed during recent years. The focus of research has shifted from adaptive immunity to genetic risk factors and now to disturbances in innate immunity and the interactions of the mucosal immune system with the content of the gut – our ‘in-vironment’. The in-vironment is a term introduced by Michael Mayerfeld Bell in his book ‘An Invitation to Environmental Sociology’. He describes it as the ‘human body, which is continuously interacting with the environment’. He points to the fact that eating and drinking are particular ways for humans to interact with their environment. The groundbreaking insights gained in the last years indicate that the genetic factors only contribute 50% to the risk of developing IBD and that environmental factors may trigger or even cause the disease. These factors mediate their effects via uptake into the human body. They may change the composition of our microbiome