Pierluigi Ballabeni

Frequency and risk factors for extraintestinal manifestations in the Swiss inflammatory bowel disease cohort.

OBJECTIVES:Data on the frequency of extraintestinal manifestations (EIMs) in Crohns disease (CD) and ulcerative colitis (UC) and analyses of their risk factors are scarce. We evaluated their prevalence and risk factors in a large nationwide cohort of inflammatory bowel disease (IBD) patients.METHODS:IBD patients from an adult clinical cohort in Switzerland (Swiss IBD cohort study) were prospectively included. Data from validated physician enrolment questionnaires were analyzed.RESULTS:A total of 950 patients were included, 580 (61%) with CD (mean age 41 years) and 370 (39%) with UC (mean age 42 years). Of these, 249 (43%) of CD and 113 (31%) of UC patients had one to five EIMs. The following EIMs were found: arthritis (CD 33%, UC 21%), aphthous stomatitis (CD 10%, UC 4%), uveitis (CD 6%, UC 4%), erythema nodosum (CD 6%, UC 3%), ankylosing spondylitis (CD 6%, UC 2%), psoriasis (CD 2%, UC 1%), pyoderma gangrenosum (CD and UC each 2%), and primary sclerosing cholangitis (CD 1%, UC 4%). Multiple logistic regression identified the following risk factors for ongoing EIM in CD: active disease (odds ratio (OR)=1.95, 95% confidence interval (CI)=1.17–3.23, P=0.01), and positive IBD family history (OR=1.77, 95% CI=1.07–2.92, P=0.025). No risk factors were identified in UC patients.CONCLUSIONS:EIMs are a frequent problem in CD and UC patients. Active disease and positive IBD family history are associated with ongoing EIM in CD patients. Identification of EIM prevalence and associated risk factors may result in increased awareness for this problem and thereby facilitating their diagnosis and therapeutic management.

Ipilimumab-dependent cell-mediated cytotoxicity of regulatory T cells ex vivo by nonclassical monocytes in melanoma patients.

Significance mAbs directed to inhibitory immune receptors represent a very promising class of immunotherapeutics. This study suggests a potential mechanism of action of ipilimumab (a fully human anti–cytotoxic T lymphocyte–associated antigen 4), by which FcγRIIIA (CD16)-expressing nonclassical monocytes kill regulatory T cells ex vivo via antibody-dependent cell-mediated cytotoxicity. Notably, at baseline, responder patients display significantly higher peripheral frequencies of nonclassical monocytes and a selective enrichment in tumor-infiltrating CD68+CD16+ macrophages compared with nonresponder patients. If further confirmed, these findings may contribute to the generation of predictive biomarker panels, antibody design, and the development of rational combination therapies to promote antitumor immunity. Enhancing immune responses with immune-modulatory monoclonal antibodies directed to inhibitory immune receptors is a promising modality in cancer therapy. Clinical efficacy has been demonstrated with antibodies blocking inhibitory immune checkpoints such as cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) or PD-1/PD-L1. Treatment with ipilimumab, a fully human CTLA-4–specific mAb, showed durable clinical efficacy in metastatic melanoma; its mechanism of action is, however, only partially understood. This is a study of 29 patients with advanced cutaneous melanoma treated with ipilimumab. We analyzed peripheral blood mononuclear cells (PBMCs) and matched melanoma metastases from 15 patients responding and 14 not responding to ipilimumab by multicolor flow cytometry, antibody-dependent cell-mediated cytotoxicity (ADCC) assay, and immunohistochemistry. PBMCs and matched tumor biopsies were collected 24 h before (i.e., baseline) and up to 4 wk after ipilimumab. Our findings show, to our knowledge for the first time, that ipilimumab can engage ex vivo FcγRIIIA (CD16)-expressing, nonclassical monocytes resulting in ADCC-mediated lysis of regulatory T cells (Tregs). In contrast, classical CD14++CD16− monocytes are unable to do so. Moreover, we show that patients responding to ipilimumab display significantly higher baseline peripheral frequencies of nonclassical monocytes compared with nonresponder patients. In the tumor microenvironment, responders have higher CD68+/CD163+ macrophage ratios at baseline and show decreased Treg infiltration after treatment. Together, our results suggest that anti–CTLA-4 therapy may target Tregs in vivo. Larger translational studies are, however, warranted to substantiate this mechanism of action of ipilimumab in patients.

Cohort Profile: The Swiss Inflammatory Bowel Disease Cohort Study (SIBDCS)

Background Crohn’s disease, ulcerative colitis and indeterminate colitis are the three subtypes of disease collectively known as inflammatory bowel diseases: relapsing and remitting conditions characterized by chronic inflammation which is limited to the colon in ulcerative colitis, whereas it can involve various sites in the gastrointestinal tract in Crohn’s disease. The pathogenesis of inflammatory bowel disease is currently still unclear, although humoral and cell-mediated immune system, as well as environmental [hygiene, smoking, nonsteroidal anti-inflammatory drugs (NSAIDs) use, geographic location] and genetic factors are known to be involved in the occurrence of these diseases. Patients often require continuous medication as well as one or more intestinal resections. The care of these patients is evolving rapidly with the introduction of novel therapies and treatment plans. Some of these new treatments are expensive and their efficacy is usually limited to 30–50% of patients. In the absence of markers able to predict response to specific therapies, all eligible patients currently receive several of these drugs. They are thus exposed to side-effects which contribute to the high overall cost of these therapies—half the average medical costs associated with the disease,—while only a fraction of those treated will benefit at each stage. Impact on patient quality of life is often considerable, especially because disease onset can occur already in the first or second decade of life, while patients are either in full-time education or just entering the workforce. The negative impact on social life or ability to achieve, either scholastically or professionally, can severely affect professional as well as family life. Indeed, 450% of patients with Crohn’s disease indicate that their disease has an influence on their professional and personal life. The course of the disease is often characterized by progressive worsening of the patient’s condition, with increasing frequency of hospitalization and considerable indirect costs through absenteeism and disability allowances. Disease activity is known to be influenced by psychological factors.

Parent perceived quality of life is age-dependent in children with food allergy

To cite this article: Wassenberg J, Cochard M‐M, DunnGalvin A, Ballabeni P, Flokstra‐de Blok BMJ, Newman CJ, Hofer M, Eigenmann PA. Parent perceived quality of life is age‐dependent in children with food allergy. Pediatr Allergy Immunol 2012: 23: 412–419.

Prevalence of anaemia in inflammatory bowel disease in Switzerland: A cross-sectional study in patients from private practices and university hospitals

BACKGROUND Anaemia represents a common complication of inflammatory bowel disease (IBD). Most studies on anaemia in IBD patients have been performed in tertiary referral centres (RC) and data from gastroenterologic practices (GP) are lacking. We investigated the frequency and severity of anaemia in IBD patients from tertiary referral centres and gastroenterologic practices compared to the general population. METHODS Data were acquired from patients included in the Swiss IBD Cohort Study. IBD activity was evaluated by CDAI and modified Truelove and Witts severity index (MTWSI). Anaemia was defined as haemoglobin ≤120g/L in women and ≤130g/L in men. RESULTS 125 patients from RC (66 with Crohns disease (CD) and 59 with ulcerative colitis (UC)) and 116 patients from GP (71 CD and 45 UC) were included and compared to 6074 blood donors. Anaemia was found in 21.2% (51/241) of the IBD patients and more frequently in patients from RC as compared to GP and healthy controls (28.8% vs. 12.9% vs. 3.4%; P<0.01). IBD patients from RC suffered more frequently from active disease compared to IBD patients in GP (36% vs. 23%, P=0.032). Supplementation therapy (iron, vitamin B12, folic acid) was performed in 40% of anaemic IBD patients in GP as compared to 43% in RC. CONCLUSIONS Anaemia is a common complication in patients with IBD and significantly more prevalent in patients from referral centres as compared to patients from gastroenterologic practices. Physicians treating IBD patients should pay attention to the presence of anaemia and ensure sufficient supplementation therapy.

Manual therapy followed by specific active exercises versus a placebo followed by specific active exercises on the improvement of functional disability in patients with chronic non specific low back pain: a randomized controlled trial.

BackgroundRecent clinical recommendations still propose active exercises (AE) for CNSLBP. However, acceptance of exercises by patients may be limited by pain-related manifestations. Current evidences suggest that manual therapy (MT) induces an immediate analgesic effect through neurophysiologic mechanisms at peripheral, spinal and cortical levels. The aim of this pilot study was first, to assess whether MT has an immediate analgesic effect, and second, to compare the lasting effect on functional disability of MT plus AE to sham therapy (ST) plus AE.MethodsForty-two CNSLBP patients without co-morbidities, randomly distributed into 2 treatment groups, received either spinal manipulation/mobilization (first intervention) plus AE (MT group; n = 22), or detuned ultrasound (first intervention) plus AE (ST group; n = 20). Eight therapeutic sessions were delivered over 4 to 8 weeks. Immediate analgesic effect was obtained by measuring pain intensity (Visual Analogue Scale) before and immediately after the first intervention of each therapeutic session. Pain intensity, disability (Oswestry Disability Index), fear-avoidance beliefs (Fear-Avoidance Beliefs Questionnaire), erector spinae and abdominal muscles endurance (Sorensen and Shirado tests) were assessed before treatment, after the 8th therapeutic session, and at 3- and 6-month follow-ups.ResultsThirty-seven subjects completed the study. MT intervention induced a better immediate analgesic effect that was independent from the therapeutic session (VAS mean difference between interventions: -0.8; 95% CI: -1.2 to −0.3). Independently from time after treatment, MT + AE induced lower disability (ODI mean group difference: -7.1; 95% CI: -12.8 to −1.5) and a trend to lower pain (VAS mean group difference: -1.2; 95% CI: -2.4 to −0.30). Six months after treatment, Shirado test was better for the ST group (Shirado mean group difference: -61.6; 95% CI: -117.5 to −5.7). Insufficient evidence for group differences was found in remaining outcomes.ConclusionsThis study confirmed the immediate analgesic effect of MT over ST. Followed by specific active exercises, it reduces significantly functional disability and tends to induce a larger decrease in pain intensity, compared to a control group. These results confirm the clinical relevance of MT as an appropriate treatment for CNSLBP. Its neurophysiologic mechanisms at cortical level should be investigated more thoroughly.Trial registrationTrial registration number: NCT01496144

Predictors of Nonresponse in a Questionnaire-Based Outcome Study of Vocational Rehabilitation Patients

OBJECTIVE To identify predictors of nonresponse to a self-report study of patients with orthopedic trauma hospitalized for vocational rehabilitation between November 15, 2003, and December 31, 2005. The role of biopsychosocial complexity, assessed using the INTERMED, was of particular interest. DESIGN Cohort study. Questionnaires with quality of life, sociodemographic, and job-related questions were given to patients at hospitalization and 1 year after discharge. Sociodemographic data, biopsychosocial complexity, and presence of comorbidity were available at hospitalization (baseline) for all eligible patients. Logistic regression models were used to test a number of baseline variables as potential predictors of nonresponse to the questionnaires at each of the 2 time points. SETTING Rehabilitation clinic. PARTICIPANTS Patients (N=990) hospitalized for vocational rehabilitation over a period of 2 years. INTERVENTIONS Not applicable. MAIN OUTCOME MEASURE Nonresponse to the questionnaires was the binary dependent variable. RESULTS Patients with high biopsychosocial complexity, foreign native language, or low educational level were less likely to respond at both time points. Younger patients were less likely to respond at 1 year. Those living in a stable partnership were less likely than singles to respond at hospitalization. Sex, psychiatric, and somatic comorbidity and alcoholism were never associated with nonresponse. CONCLUSIONS We stress the importance of assessing biopsychosocial complexity to predict nonresponse. Furthermore, the factors we found to be predictive of nonresponse are also known to influence treatment outcome and vocational rehabilitation. Therefore, it is important to increase the response rate of the groups of concern in order to reduce selection bias in epidemiologic investigations.

Epidemiology of inflammatory bowel disease: Is there a shift towards onset at a younger age?

Objectives: Increasing numbers of paediatric and adolescent patients with Crohn disease (CD) and ulcerative colitis (UC) are reported. To determine whether this observation is a consequence of a shift towards onset at a younger age, we analysed retrospective data from patients enrolled in the Swiss IBD Cohort Study (SIBDCS). Patients and Methods: The SIBDCS is a disease-based cohort in Switzerland, which collects retrospective and prospective data on a large sample of patients with inflammatory bowel disease (IBD). Patients, diagnosed from 1980, were stratified according to diagnosis of CD and UC. Age at disease onset (age at first symptoms and age at diagnosis) was analysed in relation to calendar year of disease onset. Data were extracted from physician and patient questionnaires. Linear regressions of age at disease onset by calendar year of disease onset adjusted by sex, country of birth, and education were performed. Results: Adjusted regression coefficients for CD and UC were significantly positive, that is, age at disease onset has increased with time. Male sex was associated with an increase in age at disease onset, and birth in Switzerland with a decrease. These associations were statistically significant. Conclusions: The results from the SIBDCS do not support the hypothesis that disease onset of both CD and UC occur today at a younger age. On the contrary, our results show that there is a significant trend for age at disease onset occurring at an older age today as compared with recent decades. We conclude that the observation of increasing numbers of paediatric and adolescent patients with IBD is not caused by a trend towards disease onset at a younger age, but that this may rather be a consequence of the overall increasing incidence of these conditions.

Retinal Thickening in HLA-B27-Associated Acute Anterior Uveitis: Evolution with Time and Association with Severity of Inflammatory Activity

PURPOSE To describe the evolution of retinal thickness in eyes affected with acute anterior uveitis (AAU) in the course of follow-up and to assess its correlation with severity of inflammatory activity in the anterior chamber. METHODS 72 eyes (affected and fellow eyes) of 36 patients presenting with HLA-B27-related acute anterior uveitis were included in a prospective, institutional, cohort study. Patients were followed daily until beginning of resolution of inflammatory activity and weekly thereafter. Optical coherence tomography and laser flare photometry were performed at each visit. Treatment consisted of topical corticosteroids. Main outcome measures were retinal thickness of affected eyes, difference in retinal thickness between affected and fellow eyes and their evolution in time, association between maximal retinal thickness, and initial laser flare photometry. RESULTS Difference in retinal thickness between affected and fellow eyes became significant on average 7 days from baseline and remained so throughout follow-up (P < 0.001). There was a steep increase in retinal thickness of affected eyes, followed by a progressive decrease after reaching a peak value. Maximal difference in retinal thickness between affected and fellow eyes was observed between 17 and 25 days from baseline and exhibited a strong, positive correlation with initial laser flare photometry values (P = 0.015). CONCLUSIONS Retinal thickness in eyes affected with AAU presents a steep increase over 3 to 4 weeks and then gradually decreases. Severity of inflammation at baseline predicts the amount of retinal thickening in affected eyes. A characteristic pattern of temporal response of retinal anatomy to inflammatory stimuli seems to arise.

Evidence for validity and reliability of a french version of the FAAM

BackgroundThe Foot and Ankle Ability Measure (FAAM) is a self reported questionnaire for patients with foot and ankle disorders available in English, German, and Persian. This study plans to translate the FAAM from English to French (FAAM-F) and assess the validity and reliability of this new version.MethodsThe FAAM-F Activities of Daily Living (ADL) and sports subscales were completed by 105 French-speaking patients (average age 50.5 years) presenting various chronic foot and ankle disorders. Convergent and divergent validity was assessed by Pearsons correlation coefficients between the FAAM-F subscales and the SF-36 scales: Physical Functioning (PF), Physical Component Summary (PCS), Mental Health (MH) and Mental Component Summary (MCS). Internal consistency was calculated by Cronbachs Alpha (CA). To assess test re-test reliability, 22 patients filled out the questionnaire a second time to estimate minimal detectable changes (MDC) and intraclass correlation coefficients (ICC).ResultsCorrelations for FAAM-F ADL subscale were 0.85 with PF, 0.81 with PCS, 0.26 with MH, 0.37 with MCS. Correlations for FAAM-F Sports subscale were 0.72 with PF, 0.72 with PCS, 0.21 with MH, 0.29 with MCS. CA estimates were 0.97 for both subscales. Respectively for the ADL and Sports subscales, ICC were 0.97 and 0.94, errors for a single measure were 8 and 10 points at 95% confidence and the MDC values at 95% confidence were 7 and 18 points.ConclusionThe FAAM-F is valid and reliable for the self-assessment of physical function in French-speaking patients with a wide range of chronic foot and ankle disorders.