John Keohane

Irritable Bowel Syndrome–Type Symptoms in Patients With Inflammatory Bowel Disease: A Real Association or Reflection of Occult Inflammation?

OBJECTIVES:Do gastrointestinal symptoms in patients with inflammatory bowel disease (IBD) in apparent remission reflect the coexistence of irritable bowel syndrome (IBS) or subclinical inflammation? The aims of this study were as follows: (i) to prospectively determine the prevalence of IBS symptoms in IBD patients in remission; and (ii) to determine whether IBS symptoms correlate with levels of fecal calprotectin.METHODS:Remission was defined by physician assessment: Crohns disease (CD) activity index ≤150 and ulcerative colitis disease activity index ≤3, and serum C-reactive protein <10, while off corticosteroids or biologics. Quality of life (QOL) (by inflammatory bowel disease questionnaire), the hospital anxiety and depression scale (HAD), and fecal calprotectin were measured.RESULTS:Rome II criteria for IBS were fulfilled in 37/62 (59.7%) of CD patients and by 17/44 (38.6%) of those with ulcerative colitis (UC). However, fecal calprotectin was significantly elevated above the upper limit of normal in both IBD patient groups, indicating the presence of occult inflammation. Furthermore, calprotectin levels were significantly higher in CD and UC patients with criteria for IBS than in those without IBS-type symptoms. QOL scores were lower and HAD scores higher among UC patients with IBS symptoms in comparison to those who did not have IBS symptoms.CONCLUSIONS:IBS-like symptoms are common in patients with IBD who are thought to be in clinical remission, but abnormal calprotectin levels suggest that the mechanism in most cases is likely to be occult inflammation rather than coexistent IBS.

Plasma cytokine profiles in females with irritable bowel syndrome and extra-intestinal co-morbidity.

OBJECTIVES:Irritable bowel syndrome (IBS) is a functional disorder that is associated with a number of extra-intestinal co-morbidities and a pro-inflammatory profile. This study was designed to examine the cytokine profile among a group of IBS patients with the extra-intestinal co-morbidities fibromyalgia, premenstrual dysmorphic disorder, and chronic fatigue syndrome.METHODS:In all, 100 female IBS patients with these co-morbidities, 21 IBS subjects without co-morbidity (“pure” IBS; Rome II), and 54 age-matched female controls took part in the study. Blood was drawn for measurement of the plasma cytokines interleukin (IL)-1β, IL-6, IL-8, IL-10, IL-12p70, IL-13, tumor necrosis factor (TNF)α, and interferon γ. The presence of the selected extra-intestinal manifestations was assessed using standard international criteria.RESULTS:Patients with IBS have increased plasma levels of IL-6 and IL-8; those with these extra-intestinal co-morbidities were found to have, in addition, increased levels of IL-1β and TNFα. No associations were evident between cytokine profiles and the nature of the co-morbidity or number of extra-intestinal co-morbidities present.CONCLUSIONS:Although IBS is characterized by a pro-inflammatory profile featuring the pro-inflammatory cytokines IL-6 and IL-8, IBS patients with certain extra-intestinal co-morbid conditions are distinguished by additional elevations in IL-1β and TNFα.

Mycobacterium avium subsp. Paratuberculosis (MAP) as a modifying factor in Crohn's disease

Background: Crohns disease (CD) is a multifactorial syndrome with genetic and environmental contributions. Mycobacterium avium subspecies paratuberculosis (MAP) has been frequently isolated from mucosal tissues of patients with CD but the cellular immune response to this bacterium has been poorly described. Our aim was to examine the influence of MAP on T‐cell proliferation and cytokine responses in patients with inflammatory bowel disease (IBD). Methods: Peripheral blood mononuclear cells (PBMCs) and mesenteric lymph node cells (MLNCs) were obtained from IBD patients and non‐IBD controls. PBMC T‐cell proliferation in response to MAP was determined using CFSE labeling and flow cytometry. The specificity of cytokine responses to MAP was controlled by parallel exposure to Listeria monocytogenes (LM) or Salmonella typhimurium (ST). Results: Coincubation of PBMCs with MAP induced significantly more T‐cell proliferation (P < 0.0001) in PBMCs isolated from CD patients compared to PBMCs obtained from ulcerative colitis (UC) patients or healthy volunteers. In addition, PBMCs from CD patients secreted significantly higher (P < 0.05) levels of tumor necrosis factor‐alpha (TNF‐&agr;; 2302 ± 230 pg/mL) and interleukin (IL)‐10 (299 ± 48 pg/mL) in response to MAP compared to UC patients (TNF‐&agr;: 1219 ± 411 pg/mL; IL‐10: 125 ± 19 pg/mL) and controls (TNF‐&agr;: 1447 ± 173 pg/mL; IL‐10: 127 ± 12 pg/mL). No difference in cytokine responses was observed in response to LM or ST. MLNCs from both CD and UC patients secreted significantly more TNF‐&agr; and IL‐8 in response to MAP compared to MLNCs from non‐IBD control patients. Conclusions: Increased proliferation of T cells and an altered cytokine response suggest that prior exposure to MAP and engagement of the immune system is common in patients with CD. This does not imply causation but does support further examination of this bacterium as an environmental modifying factor. (Inflamm Bowel Dis 2009)

Are Patients with IBD Knowledgeable About the Risks of Their Medications

Patient education is an important determinant of the effectiveness of the doctor–patient relationship, and should perhaps be viewed as an outcome modifier in patients with chronic disease.1 Incorporation of patients’ perspectives into treatment plans, with increased involvement in disease management, has been advocated by several clinicians.2 Adherence to drug regimens is likely to be enhanced when patients are included in clinical decision-making, and when they are required to take some degree of responsibility for their own management (albeit under guidance from their doctor). Poor adherence is common, and is frequently underestimated by the prescribing clinician.3 A diversity of reasons may account for nonadherence, and these include asymptomatic disease (e.g., maintenance of remission in inflammatory bowel disease [IBD]), prolonged therapy, complicated regimens, and most important, fear of the unknown and concern about side effects of medications. In the latest National Health and Nutrition Examination Survey (NHANES-III), only about half of hypertensive patients in the US were being treated and only 34% of those being treated had well-controlled blood pressure.4 One of the major reasons for this is poor adherence or compliance. Although most drugs prescribed today have extensive patient information leaflets and include the commonly encountered side effects, patient confidence has been undermined by recent high-profile examples of pharmaceutical agents withdrawn because of side effects that were unpredictable or unforeseen. As with most chronic disorders, the drug therapy of IBD is complex, with several classes and subclasses of drugs involved. Patient knowledge of the side effects of their prescribed medications is generally disappointing and physician perceptions regarding patient knowledge is often overestimated. Calkins et al5 studied 99 patients and their physicians and enquired about their understanding of the side effects of the patient’s medications. Of the physicians questioned, 89% believed that their patients understood the side effects, in contrast to only 57% of the patients who reported that they understood the side effects. Other studies have confirmed that patients not only do not know the side effects of their drugs, but often are not aware of the identity of the drugs they are consuming.6,7 It is noteworthy that the peak incidence of IBD occurs in an age group (15 and 25 years) that may need special attention to education and the importance of adherence. In a study of adolescents, a very poor understanding of the potential hazards of over-the-counter medications was found.8 The Crohn’s and Colitis Knowledge Score (CCKNOW) was developed by Eaden et al12 to quantify patient knowledge. This showed the variable level of basic disease understanding among patients, and that the level of knowledge was independent of disease duration. Of 354 respondents to the questionnaire, only 60% understood the role of immunosuppressive drugs. A similar proportion understood the role of sulphasalazine in the reduction of relapse, but only 26% knew that it can reversibly reduce male fertility. More important, 56% of patients believed that side effects from steroids occur immediately even after a small dose, and that the side effects disappeared promptly on discontinuing the steroid. Others have confirmed the confusion among patients regarding their medications and the concerns surrounding toxicity.10,11 It is this confusion and lack of knowledge of medications that results in noncompliance and patients turning to alternative remedies. Hilsden et al9 surveyed 2847 members of the Crohn’s and Colitis Foundation of Canada and found that over 23% of them were actively using complementary and alternative medicines. Efforts to improve this knowledge gap by membership in patient advocacy groups including Crohn’s & Colitis societies, and use of information leaflets, have led to improved knowledge scores.13 A predischarge interview improves patient knowledge and reduces the risk of stopping a medication.14 However, as in other spheres, educational strategies for patients with IBD need continual reinforcement. Indeed, for some patients with Crohn’s disease, there is a curiously ambiguous response to information about drugs. It is not uncommon for patients to express concern about the longterm side effects of a prescribed medication, yet blissfully consume a nonprescribed drug (cigarette smoking) which they know damages their general health and aggravates the clinical course of their disease! This paradox needs to be directly addressed repeatedly by the attending clinician, beFrom the Department of Medicine and Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland. Copyright

Response to Sprakes et al.

To the Editor: Sprakes et al. (1) raise some valid questions, and a subtle but important point emerges in relation to our study (2) on irritable bowel syndrome (IBS)-type symptoms in patients with inflammatory bowel disease (IBD). First, we included two control groups, IBS and healthy controls, and although the latter were not matched to the IBD group, neither age nor gender is likely to have a substantial impact on the results or their interpretation. The healthy controls were included for the calprotectin assay, which consistently yielded negative results (<50 mg/kg stool) in subjects without intestinal inflammation. Second, calprotectin levels were not normally distributed in IBD patients; hence, a non-parametric test of significance was applied. The final comments by Sprakes et al. raise a critical point that is important for clinicians to understand. Fecal calprotectin levels are, indeed, elevated in most patients with IBD, including those considered to be in clinical remission by pre-defined, conventional criteria. However, for both ulcerative colitis and Crohns disease, those patients with IBS-like symptoms had the highest calprotectin levels, which were on average twice those of patients without IBS-like symptoms. Therefore, we are not proposing calprotectin as a diagnostic marker (regardless of the threshold) to distinguish active IBD from IBS co-existing with IBD in any given patient, but rather, that IBS-like symptoms in patients with IBD are associated with greater inflammatory activity than in those without IBS-like symptoms. The message from the collective data using calprotectin suggests that caution should be applied to any diagnosis of IBS in patients with IBD, but the data should not be extrapolated to a proposal for use of calprotectin as a diagnostic marker in an individual patient.