Jean-François Rahier

Second European evidence-based consensus on the prevention, diagnosis and management of opportunistic infections in inflammatory bowel disease

The treatment of inflammatory bowel disease (IBD) has been revolutionised over the past decade by the increasing use of immunomodulators, mainly azathioprine (AZA)/6-mercaptopurine (6-MP) and methotrexate (MTX), together with the advent of biological therapy. Immunomodulators are being used more often and earlier in the course of the disease.1 The introduction of biologic agents, especially inhibitors of the key proinflammatory cytokine, tumor necrosis factor alpha (TNF-α) initiated a new therapeutic era, whose use has grown continuously since their introduction in 1998.2 With such immunomodulation, the potential for opportunistic infection is a key safety concern for patients with IBD. Opportunistic infections pose particular problems for the clinician: they are often difficult to recognise and are associated with appreciable morbidity or mortality, because they are potentially serious and hard to treat effectively. Enhancing awareness and improving the knowledge of gastroenterologists about opportunistic infections are important elements to optimise patient outcomes through the development of preventive or early diagnostic strategies. A long list of opportunistic infections has been described in patients with IBD. Many questions remain unanswered, not only concerning the need for screening, preventive measures or the best diagnostic approach, but also on appropriate treatment and management of immunomodulator therapy once infection occurs. This led the European Crohns and Colitis Organisation (ECCO) to establish a Consensus meeting on opportunistic infections in IBD. The formal process of a Consensus meeting has been described,3 but the purpose is to quantify expert opinion in the context of a systematic review of existing evidence. To organise the work, infections were classified into six major topics (see plan). Specific questions were asked for each infectious agent. The different topics were distributed to working groups that comprised junior and senior gastroenterologists with infectious disease experts. Each group performed a systematic review of the literature and answered …

Severe Skin Lesions Cause Patients with Inflammatory Bowel Disease to Discontinue Anti-Tumor Necrosis Factor Therapy.

BACKGROUND & AIMS Psoriasiform and eczematiform lesions are associated with anti-tumor necrosis factor (TNF)-α therapies. We assessed clinical characteristics, risk factors, and outcomes of skin disease in patients with inflammatory bowel diseases that presented with psoriasiform and eczematiform lesions induced by anti-TNF-α agents. METHODS We studied 85 patients (69 with Crohns disease, 15 with ulcerative colitis, and 1 with indeterminate colitis; 62 women) with inflammatory skin lesions (62 psoriasiform and 23 eczematiform lesions). RESULTS Twenty-four patients had a history of inflammatory skin lesions and 15 had a familial history of inflammatory skin disease. Locations of eczematiform lesions varied whereas scalp and flexural varieties were mostly psoriasiform. Skin lesions emerged but inflammatory bowel disease was quiescent in 69 patients following treatment with any type of anti-TNF-α agent (60 with infliximab, 20 with adalimumab, and 5 with certolizumab). Topical therapy resulted in partial or total remission in 41 patients. Patients with psoriasiform lesions that were resistant to topical therapy and that changed anti-TNF-α therapies once or twice developed recurring lesions. Overall, uncontrolled skin lesions caused 29 patients to stop taking TNF-α inhibitors. CONCLUSIONS Inflammatory skin lesions following therapy with TNF-α inhibitors occurred most frequently among women and patients with a personal or familial history of inflammatory skin disease; lesions did not correlate with intestinal disease activity. Recurring and intense skin lesions caused 34% of patients in this study to discontinue use of anti-TNF-α agents.

Effects of infliximab therapy on transmural lesions as assessed by magnetic resonance enteroclysis in patients with ileal Crohn's disease☆ , ☆☆ , ★

BACKGROUND AND AIMS Anti TNF therapy induces mucosal healing in patients with Crohns disease, but the effects on transmural inflammation in the ileum are not well understood. Magnetic resonance-enteroclysis (MRE) offers excellent imaging of transmural and peri-enteric lesions in Crohns ileitis and we aimed to study its responsiveness to anti TNF therapy. METHODS In this multi-center prospective trial, anti TNF naïve patients with ileal Crohns disease and with increased CRP and contrast enhanced wall thickening received infliximab 5 mg/kg at weeks 0, 2 and 6, and q8 weeks maintenance MRE was performed at baseline, 2 weeks and 6 months and assessed based on a predefined MRE score of severity in ileal Crohns Disease. RESULTS Twenty patients were included; of those, 18 patients underwent MRE at week 2 and 15 patients at weeks 2 and 26 as scheduled. Inflammatory components of the MRE index decreased by ≥2 points and by ≥50% at week 26 (primary endpoint) in 40% and 32% of patients (per protocol and intention to treat analysis, respectively). The MRE index improved in 44% at week 2 and in 80% at week 26. Complete absence of inflammatory lesions was observed in 0/18 at week 2 and 13% (2/15) at week 26. The obstructive elements did not change. Clinical and CRP improvement occurred as early as wk 2, but only CDAI correlated with the MRE index. CONCLUSION Improvement of MRE occurs from 2 weeks after infliximab therapy onwards and correlates with clinical response but normalization of MRE is rare.

H1N1 vaccines in a large observational cohort of patients with inflammatory bowel disease treated with immunomodulators and biological therapy

Background Safety data are lacking on influenza vaccination in general and on A (H1N1)v vaccination in particular in patients with inflammatory bowel disease (IBD) receiving immmunomodulators and/or biological therapy. Aims and methods The authors conducted a multicentre observational cohort study to evaluate symptoms associated with influenza H1N1 adjuvanted (Pandemrix, Focetria, FluvalP) and non-adjuvanted (Celvapan) vaccines and to assess the risk of flare of IBD after vaccination. Patients with stable IBD treated with immunomodulators and/or biological therapy were recruited from November 2009 until March 2010 in 12 European countries. Harvey–Bradshaw Index and Partial Mayo Score were used to assess disease activity before and 4 weeks after vaccination in Crohns disease (CD) and ulcerative colitis (UC). Vaccination-related events up to 7 days after vaccination were recorded. Results Of 575 patients enrolled (407 CD, 159 UC and nine indeterminate colitis; 53.9% female; mean age 40.3 years, SD 13.9), local and systemic symptoms were reported by 34.6% and 15.5% of patients, respectively. The most common local and systemic reactions were pain in 32.8% and fatigue in 6.1% of subjects. Local symptoms were more common with adjuvanted (39.3%) than non-adjuvanted (3.9%) vaccines (p<0.0001), whereas rates of systemic symptoms were similar with both types (15.0% vs 18.4%, p=0.44). Among the adjuvanted group, Pandemrix more often induced local reactions than FluvalP and Focetria (51.2% vs 27.6% and 15.4%, p<0.0001). Solicited adverse events were not associated with any patient characteristics, specific immunomodulatory treatment, or biological therapy. Four weeks after vaccination, absence of flare was observed in 377 patients with CD (96.7%) and 151 with UC (95.6%). Conclusion Influenza A (H1N1)v vaccines are well tolerated in patients with IBD. Non-adjuvanted vaccines are associated with fewer local reactions. The risk of IBD flare is probably not increased after H1N1 vaccination.

Risk of infection and prevention in pediatric patients with IBD: ESPGHAN IBD Porto Group commentary.

ABSTRACT Combined immunosuppression by immunomodulators and biological therapy has become standard in the medical management of moderate-to-severe inflammatory bowel disease (IBD) because of clearly demonstrated efficacy. Clinical studies, registries, and case reports warn of the increased risk of infections, particularly opportunistic infections; however, already in the steroid monotherapy era, patients are at risk because it is accepted that a patient should be considered immunosuppressed when receiving a daily dose of 20 mg of prednisone for 2 weeks. Prescriptions increasingly involve azathioprine, methotrexate, and various biological agents. The TREAT registry evaluated safety in >6000 adult patients, half of them treated with infliximab (IFX) for about 1.9 years. IFX-treated patients had an increased risk of infections and this was associated with disease severity and concomitant prednisone use. The REACH study, evaluating the efficacy of IFX in children with moderate-to-severe Crohn disease, refractory to immunomodulatory treatment, reports serious infections as the major adverse events and their frequency is higher with shorter treatment intervals. The combination of immunosuppressive medications is a risk factor for opportunistic infections. Exhaustive guidelines on prophylaxis, diagnosis, and management of opportunistic infections in adult patients with IBD have been published by a European Crohns and Colitis Organization working group, including clear evidence-based statements. We have reviewed the literature on infections in pediatric IBD as well as the European Crohns and Colitis Organization guidelines to present a commentary on infection prophylaxis for the pediatric age group.

Cancer Immunotherapy with Anti-CTLA-4 Monoclonal Antibodies Induces an Inflammatory Bowel Disease

BACKGROUND Therapeutic monoclonal anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) antibodies are associated with immune-mediated enterocolitis. The aim of this study was to provide a detailed description of this entity. METHODS We included patients with endoscopic signs of inflammation after anti-CTLA-4 infusions for cancer treatment. Other causes of enterocolitis were excluded. Clinical, biological and endoscopic data were recorded. A single pathologist reviewed endoscopic biopsies and colectomy specimens from 27 patients. Patients with and without enterocolitis after ipilimumab-treated melanoma were compared, to identify clinical factors associated with enterocolitis. RESULTS Thirty-nine patients with anti-CTLA-4 enterocolitis were included (ipilimumab n = 37; tremelimumab n = 2). The most frequent symptom was diarrhoea. Ten patients had extra-intestinal manifestations. Most colonoscopies showed ulcerations involving the rectum and sigmoid, 66% of patients had extensive colitis, 55% had patchy distribution and 20% had ileal inflammation. Endoscopic colonic biopsies showed acute colitis in most patients, while half of the patients had chronic duodenitis. Thirty-five patients received steroids that led to complete clinical remission in 13 patients (37%). Twelve patients required infliximab, of whom 10 (83%) responded. Six patients underwent colectomy (perforation n = 5; toxic megacolon n = 1); one of them died postoperatively. Four patients had a persistent enterocolitis at follow-up colonoscopy. Patients with enterocolitis were more frequently prescribed NSAIDs compared with patients without enterocolitis (31 vs 5%, p = 0.003). CONCLUSIONS Ipilimumab and tremelimumab may induce a severe and extensive form of inflammatory bowel disease. Rapid escalation to infliximab should be advocated in patients who do not respond to steroids. Patients treated with anti-CTLA-4 should be advised to avoid NSAIDs.

The European (ECCO) Consensus on infection in IBD: what does it change for the clinician?

Gastroenterologists are pausing to reflect on the risks of immunomodulation and reassess the benefits of biological tratment for inflammatory bowel disease (IBD). This is constructive. Every experienced gastroenterologist can recall a case of disseminated varicella zoster, Pneumocystis spp pneumonia or severe sepsis from an otherwise unheard of opportunistic pathogen in a patient with IBD on immunomodulators that they put down to, well, experience. A near disaster skilfully managed, perhaps, but a catastrophe for the patient—especially if such infection was preventable in the first place. So it is indeed constructive that IBD specialists who have long advocated early or increasing use of immunomodulators are sufficiently confident to appraise the risks of infection inherent to immunosuppression. This is precisely what the European Crohn’s and Colitis Organisation (ECCO) has set out to do with their new Consensus on opportunistic infections in IBD.1 It answers the call for a Consensus made in a review of the prevention and diagnosis of opportunistic infections, published in Gut last year.2 It is aimed at specialist gastroenterologists making the diagnosis of and managing patients with IBD. Although the practical implications of the ECCO Consensus for general gastroenterologists are substantial, they are worth the candle. Vaccination and chemoprevention of infection in healthy visitors to exotic locations is accepted by travellers and the community alike, although the absolute risk of infection is generally very much less than the risk of opportunistic infection faced by patients with IBD taking immunomodulators or biological treatment. So what is the absolute risk of infection in patients with IBD? Inevitably this is difficult to quantify, since there has been no systematic study. The best data come from the carefully controlled trials of biological treatment. In a recent report on adverse events in the global trials of adalimumab for rheumatoid arthritis (RA) and Crohn’s …

Factors associated with pregnancy outcome in anti-TNF treated women with inflammatory bowel disease

The safety of anti‐tumour necrosis factor (TNF) agents during pregnancy is a major concern for child‐bearing women and physicians.

Review article: influenza A (H1N1) virus in patients with inflammatory bowel disease.

Background  Infection with influenza A (H1N1)v (swine flu) has caused widespread anxiety, among patients who are potentially immunocompromised, such as those being treated for inflammatory bowel disease.

Small Bowel Adenocarcinomas Complicating Crohn's Disease Are Associated With Dysplasia: A Pathological and Molecular Study.

Background:Crohns disease (CD) is associated with an increased risk of small bowel adenocarcinoma (SBA). However, there are no guidelines for the screening and early diagnosis of SBA. Colorectal cancer associated with chronic colitis arises from dysplasia. High-risk patients benefit from surveillance colonoscopies aimed to detect dysplasia. The dysplasia–carcinoma sequence remains poorly documented in CD-associated SBA. Moreover, molecular data about SBA complicating CD and associated dysplasia are very limited. We therefore assessed dysplasia and several key molecular markers of carcinogenesis in SBA and dysplasia developed in patients with CD. Methods:Forty-five SBA complicating CD and 4 specimens with dysplasia without SBA were screened. In SBA, we looked for dysplasia and determined their pathological characteristics (type, grade, distribution). We also stained for mismatch repair proteins (MLH1, MSH2, MSH6, PMS2), p53, &bgr;-catenin, and p16 and looked for KRAS, BRAF and PIK3CA mutations. Results:All neoplastic lesions, except 1 lesion, were found in inflamed mucosal areas. Dysplasia was found in 20 of 41 patients with SBA (49%). Dysplasia was flat or raised, low grade or high grade, and adjacent or distant to concomitant SBA. Molecular markers of SBA carcinogenesis complicating CD were similar to those observed in chronic colitis-related colorectal cancer (KRAS, BRAF, p53, MSI), although differences were observed for &bgr;-catenin and p16. No PIK3CA mutations were observed. Conclusions:These results suggest that there is an inflammation–dysplasia–adenocarcinoma sequence in at least half of CD-related SBA, similar to what is observed in chronic colitis-related colorectal cancer and may have implications for the prevention and treatment of this cancer.