Antonio López-Sanromán

Ciclosporin versus infliximab in patients with severe ulcerative colitis refractory to intravenous steroids: a parallel, open-label randomised controlled trial

BACKGROUND Ciclosporin and infliximab are potential rescue treatments to avoid colectomy in patients with acute severe ulcerative colitis refractory to intravenous corticosteroids. We compared the efficacy and safety of these drugs for this indication. METHODS In this parallel, open-label, randomised controlled trial, patients were aged at least 18 years, had an acute severe flare of ulcerative colitis defined by a Lichtiger score greater than 10 points, and had been given an unsuccessful course of high-dose intravenous steroids. None of the patients had previously received ciclosporin or infliximab. Between June 1, 2007, and Aug 31, 2010, patients at 27 European centres were randomly assigned (via computer-derived permutation tables; 1:1) to receive either intravenous ciclosporin (2 mg/kg per day for 1 week, followed by oral drug until day 98) or infliximab (5 mg/kg on days 0, 14, and 42). In both groups, azathioprine was started at day 7 in patients with a clinical response. Neither patients nor investigators were masked to study treatment. The primary efficacy outcome was treatment failure defined by absence of a clinical response at day 7, a relapse between day 7 and day 98, absence of steroid-free remission at day 98, a severe adverse event leading to treatment interruption, colectomy, or death. Analysis was by intention to treat. This trial is registered with EudraCT (2006-005299-42) and ClinicalTrials.gov (NCT00542152). FINDINGS 115 patients were randomly assigned; 58 patients were allocated to receive ciclosporin and 57 to receive infliximab. Treatment failure occurred in 35 (60%) patients given ciclosporin and 31 (54%) given infliximab (absolute risk difference 6%; 95% CI -7 to 19; p=0·52). Nine (16%) patients in the ciclosporin group and 14 (25%) in the infliximab group had severe adverse events. INTERPRETATION Ciclosporin was not more effective than infliximab in patients with acute severe ulcerative colitis refractory to intravenous steroids. In clinical practice, treatment choice should be guided by physician and centre experience. FUNDING Association François Aupetit, Société Nationale Française de Gastroentérologie, and the International Organization for the study of Inflammatory Bowel Disease.

Acute pancreatitis in inflammatory bowel disease, with special reference to azathioprine-induced pancreatitis

Background  Pancreatitis is a potentially severe condition. Patients with inflammatory bowel disease (IBD) seem to be at increased risk for acute pancreatitis.

Thiopurine methyl-transferase activity and azathioprine metabolite concentrations do not predict clinical outcome in thiopurine-treated inflammatory bowel disease patients

Aliment Pharmacol Ther 2011; 34: 544–554

Induction of psoriasis with anti-TNF agents in patients with inflammatory bowel disease: A report of 21 cases

AIM Anti-tumor necrosis factor (TNF)-alpha agents are widely used for the treatment of both inflammatory bowel disease (IBD) and psoriasis. Psoriatic skin lesions induced by anti-TNF have been described in patients with IBD. We report a case series of psoriasis induced by anti-TNF agents in IBD patients. METHODS Systematic analysis of cases of psoriasis induced by anti-TNF in an IBD patient cohort in tertiary hospitals of Madrid. RESULTS A total of 21 of 1294 patients with IBD treated with anti-TNF-alpha agents developed drug-induced psoriasis (cumulative incidence 1.62%; 95% CI 1.06%-2.47%): 14 patients with infliximab and 7 with adalimumab; seventeen with Crohns disease, 4 with ulcerative colitis. The onset of skin lesions varied in a wide range of time (after a mean 13±8 doses). The most frequent site of skin lesions was the limbs (62%) followed by the trunk (48%) and the scalp (43%). The psoriasis phenotypes were plaque psoriasis (57%), scalp (14%), palmoplantar pustulosis (14%), pustular generalized psoriasis (5%), guttate (5%) and inverse (5%). Four patients interrupted the anti-TNF treatment, and that led to the complete regression of lesions in 1 of them. The other 17 patients were maintained on anti-TNF therapy and managed with topical steroids. CONCLUSION Psoriatic lesions can be induced by anti-TNF drugs. Plaque psoriasis on the extremities and trunk were the most frequent presentations in our series. Topical steroid treatment is effective in most patients. Anti-TNF discontinuance may be reserved for patients with severe psoriasis or patients without response to topical therapy.

Efficacy and safety of thiopurinic immunomodulators (azathioprine and mercaptopurine) in steroid‐dependent ulcerative colitis

Background : The efficacy of azathioprine in the management of steroid‐dependent ulcerative colitis is taken for granted. However, study populations frequently include together steroid‐dependent and refractory patients.

Efficacy of different therapeutic options for spontaneous abdominal abscesses in Crohn's disease: are antibiotics enough?

Background: Management of abdominal abscesses (AA) in Crohns disease (CD) always includes antibiotics, and some type of drainage is added according to the response and other considerations. Our aim was to assess the efficacy of different therapeutic approaches to spontaneous AA in CD. Methods: All cases of AA in CD were identified from the databases of five university hospitals. Postoperative cases were excluded. Therapeutic success was defined as abscess resolution and nonreappearance within 1 year of follow‐up. Results: We identified 128 cases in 2236 patients (cumulative incidence 5.7%). Initial therapy included medical therapy with antibiotics alone (42.2%), antibiotics plus percutaneous drainage (23.4%), and antibiotics plus surgical drainage (34.4%). The highest final efficacy corresponded to surgery (91%) as compared with antibiotic therapy alone (63%) or percutaneous drainage (30%). Failure of initial therapy was predicted by immunomodulators at diagnosis (odds ratio [OR] 8.45; 95% confidence interval [CI] 1.16–61.5; P = 0.03), fistula detectable in imaging techniques (OR 5.43; 95% CI 1.18–24.8; P = 0.02), and abscess size (OR 1.65; 95% CI 1.07–2.54; P = 0.02) only for patients treated with antibiotic therapy alone. Percutaneous drainage was associated with 19% of complications (enterocutaneous fistulas 13%); surgery was associated with 13% of postoperative complications (enterocutaneous fistulas 7.7%). Following abscess resolution, 60% of patients were started on thiopurines, 9% on biologics, and in 31% baseline therapy was not modified. Conclusions: Management of spontaneous AA in CD with antibiotics alone seems to be a good option for small abscesses, especially those without associated fistula and appearing in immunomodulator‐naïve patients. Surgery offers better results in the remaining clinical settings, although percutaneous drainage can avoid operative treatment in some cases. (Inflamm Bowel Dis 2012)

Infliximab induces clinical, endoscopic and histological responses in refractory ulcerative colitis

BACKGROUND infliximab is a monoclonal antiTNF-ct antibody that has repeatedly shown to be effective in the management of Crohns disease. However, data are scarce about its efficacy in ulcerative colitis. AIM to describe the joint experience of three Spanish hospitals in the use of infliximab in patients with active refractory ulcerative colitis. PATIENTS AND METHODS we present seven cases of ulcerative colitis (6 with chronic active disease despite immunosuppressive therapy, and one with acute steroid-refractory ulcerative colitis) treated with infliximab 5 mg/kg of body weight. Clinical response was evaluated by means of the Clinical Activity Index at 2, 4 and 8 weeks after initial infusion. Biochemical (erythrocyte sedimentation rate and C-reactive protein), endoscopic, and histological changes were also assessed. RESULTS mean age of patients was 45.8 +/- 17 years (range 23-77); 4 were female. No adverse effects were recorded. Inflammatory activity diminished significantly in 6 of 7 patients (85.7%; CI 95%: 42-99%) both from a clinical (p = 0.01) and biochemical (p <0.05) point of view. Five out of six patients (83.3%; 36-99%) with corticosteroid-dependent disease could be successfully weaned off these drugs. Five patients were endoscopicly controlled both before and after therapy, and a positive endoscopic and histological response could be recorded in all of them. CONCLUSION infliximab may be an effective and safe therapy for some patients with ulcerative colitis refractory to other forms of therapy, although controlled studies are needed to assess its role in the general management of this disease.

Incidence, Clinical Characteristics, and Management of Psoriasis Induced by Anti-TNF Therapy in Patients with Inflammatory Bowel Disease: A Nationwide Cohort Study

Background:Psoriasis induced by anti–tumor necrosis factor-&agr; (TNF) therapy has been described as a paradoxical side effect. Aim:To determine the incidence, clinical characteristics, and management of psoriasis induced by anti-TNF therapy in a large nationwide cohort of inflammatory bowel disease patients. Methods:Patients with inflammatory bowel disease were identified from the Spanish prospectively maintained Estudio Nacional en Enfermedad Inflamatoria Intestinal sobre Determinantes genéticos y Ambientales registry of Grupo Español de Trabajo en Enfermedad de Croh y Colitis Ulcerosa. Patients who developed psoriasis by anti-TNF drugs were the cases, whereas patients treated with anti-TNFs without psoriasis were controls. Cox regression analysis was performed to identify predictive factors. Results:Anti-TNF–induced psoriasis was reported in 125 of 7415 patients treated with anti-TNFs (1.7%; 95% CI, 1.4–2). The incidence rate of psoriasis is 0.5% (95% CI, 0.4–0.6) per patient-year. In the multivariate analysis, the female sex (HR 1.9; 95% CI, 1.3–2.9) and being a smoker/former smoker (HR 2.1; 95% CI, 1.4–3.3) were associated with an increased risk of psoriasis. The age at start of anti-TNF therapy, type of inflammatory bowel disease, Montreal Classification, and first anti-TNF drug used were not associated with the risk of psoriasis. Topical steroids were the most frequent treatment (70%), achieving clinical response in 78% of patients. Patients switching to another anti-TNF agent resulted in 60% presenting recurrence of psoriasis. In 45 patients (37%), the anti-TNF therapy had to be definitely withdrawn. Conclusions:The incidence rate of psoriasis induced by anti-TNF therapy is higher in women and in smokers/former smokers. In most patients, skin lesions were controlled with topical steroids. More than half of patients switching to another anti-TNF agent had recurrence of psoriasis. In most patients, the anti-TNF therapy could be maintained.

Genital fistulas in female Crohn's disease patients.: clinical characteristics and response to therapy.

BACKGROUND Genital fistulas (GF) can arise in the course of Crohns disease (CD), are difficult to manage and determine a significant alteration of the quality of life. AIMS To review the joint experience of the Inflammatory Bowel Disease Units in six University Hospitals in the management of GF in Crohns disease on female patients. RESULTS A total of 47 patients with GF were identified, affecting 3.8% of women with CD treated in our centers. A 47.5% of patients were smokers. The median of time from the diagnosis of CD reached 102 months. According to anatomical type, GF were classified as rectovaginal (74.5%), anovaginal/anovulvar (21.3%) and enterovaginal (4.3%). Main symptoms were vaginal discharge of fecal material (55.3%), vaginal passage of gas (40.4%), or both. Fistulas were treated with antibiotics in 59.6% of patients, without any lasting success. Thiopurines were used in 80.9% of cases, with 13.2% of complete and 23.7% of partial responses. Anti TNF-alpha therapy was applied in 63.8%, with a 16.7% of complete and a 30% of partial responses (all responding patients received infliximab). Surgery was indicated in 38.3% of patients, with a 22% of complete responses after a first operation and 38.8% after reintervention. In all, definitive closure after one or more of these therapies was achieved in only 31.9% of cases. CONCLUSION Genital fistulas are a significant problem in female Crohns disease patients. Therapy is not well defined and only partially effective (one in three cases). Surgical therapy stands out as the most effective treatment.

Role of TNFRSF1B polymorphisms in the response of Crohn's disease patients to infliximab.

Infliximab (IFX) is a valid treatment for Crohns disease (CD), but a relevant percentage of patients do not benefit from this therapy. In the Japanese population, the response to IFX was associated with markers in the TNF receptor superfamily 1A (TNFRSF1A) and 1B (TNFRSF1B) genes. We aimed to replicate the association previously described in the Japanese population and to ascertain the role of TNF receptors as modulators of the response to IFX. We studied 297 white Spanish CD patients with a known response to IFX: 238 responders and 59 primary nonresponders. Four single nucleotide polymorphisms (SNPs) were analyzed: rs767455 in TNFRSF1A and rs1061622, rs1061624, and rs3397 in TNFRSF1B. Comparisons between groups were performed with chi-square tests or the Fishers exact test. Different features (sex, age, disease duration, smoking among others) were evaluated as possible confounding factors. No significant association was found between the studied TNFRSF1A polymorphisms and response to IFX. In the TNFRSF1B gene, the haplotype rs1061624_A-rs3397_T was significantly increased in nonresponders: p = 0.015, OR = 1.78, 95% CI 1.09-2.90; and an increased frequency of rs1061622_G carriers was observed in patients with remission: p = 0.033 vs nonresponders and p = 0.023 vs patients with a partial response. Our results support a role of TNFRSF1B gene variants in the response to IFX in CD patients.