Lucía Marquez

Safety of thiopurine therapy in inflammatory bowel disease: long-term follow-up study of 3931 patients.

Background:To evaluate the safety of thiopurines in patients with inflammatory bowel disease. To identify predictive factors associated with the development of thiopurine-induced adverse events. Methods:Long-term incidence of adverse events was estimated in patients from a prospectively maintained Spanish nationwide database using Kaplan–Meier analysis. Cox regression analysis was performed to identify potential predictive factors of adverse events. Results:Three thousand nine hundred and thirty-one patients were included. Ninety-five percent of patients were on azathioprine. The median follow-up with thiopurines was 44 months (range, 0–420). Adverse events occurred at a median of 1 month after starting treatment. The cumulative incidence of adverse events was 26%, with an annual risk of 7% per patient-year of treatment. Most frequent adverse events were nausea (8%), hepatotoxicity (4%), myelotoxicity (4%), and pancreatitis (4%). Four patients had lymphoma. Female and Crohns disease increased the risk of having nausea. The risk of hepatotoxicity was lower in females and higher in Crohns disease. The risk of myelotoxicity was significantly higher in patients treated with mercaptopurine and in females. The risk of pancreatitis was higher in Crohns disease. Overall, 17% of patients discontinued thiopurine treatment due to adverse events. Thirty-seven percent of these patients started thiopurines again and 40% of them had adverse events again. Conclusions:As many as 1 of 4 patients on thiopurine therapy had adverse events during follow-up. A relatively high proportion of patients (17%) had to discontinue the treatment with thiopurines due to adverse events. However, more than half of patients that restarted thiopurine treatment after its discontinuation due to adverse events tolerated it. Several predictive factors for some adverse events have been identified.

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.

Thiopurine Therapy Reduces the Incidence of Colorectal Neoplasia in Patients with Ulcerative Colitis. Data from the ENEIDA Registry

BACKGROUND AND AIMS Patients with ulcerative colitis (UC) are at increased risk of developing colorectal cancer (CRC), but recent studies suggest a lower risk than previously reported. The aim was to evaluate the incidence of dysplasia, CRC and related risk factors in UC patients from a Spanish nationwide database. METHODS All UC patients were identified and retrospectively reviewed. Clinical-epidemiological data and the finding of dysplasia and/or CRC were collected. RESULTS A total of 831 UC patients were included. Twenty-six cases of CRC in 26 patients and 29 cases of high-grade dysplasia (HGD) in 24 patients were found, accounting for 55 diagnoses of advanced neoplasia (AN = CRC and/or HGD) in 45 patients (33% of them within the first 8 years after UC diagnosis). The cumulative risk of AN was 2, 5.3 and 14.7% at 10, 20 and 30 years, respectively. Concomitant primary sclerosing cholangitis (odds ratio [OR] 10.90; 95% confidence interval [CI] 3.75-31.76, p < 0.001), extensive UC (OR 2.10, 95% CI 1.01-4.38, p = 0.048), UC diagnosis at an older age (OR 2.23, 95% CI 1.03-4.83, p = 0.043) and appendectomy prior to UC diagnosis (OR 2.66, 95% CI 1.06-6.71, p = 0.038) were independent risk factors for AN. Use of thiopurines (OR 0.21, 95% CI 0.06-0.74, p = 0.015) and being in a surveillance colonoscopy programme (OR 0.33; 95% CI 0.16-0.67; p = 0.002) were independent protective factors for AN. CONCLUSIONS The risk of AN among UC patients is lower than previously reported but steadily increases from the time of UC diagnosis. The widespread use of thiopurines may have influenced this reduced incidence of UC-related neoplasias.

A genome-wide association study identifies a novel locus at 6q22.1 associated with ulcerative colitis

The genetic analysis of ulcerative colitis (UC) has provided new insights into the etiology of this prevalent inflammatory bowel disease. However, most of the heritability of UC (>70%) has still not been characterized. To identify new risk loci for UC we have performed the first genome-wide association study (GWAS) in a Southern European population and undertaken a meta-analysis study combining the newly genotyped 825 UC patients and 1525 healthy controls from Spain with the six previously published GWAS comprising 6687 cases and 19 718 controls from Northern-European ancestry. We identified a novel locus with genome-wide significance at 6q22.1 [rs2858829, P = 8.97 × 10(-9), odds ratio (OR) (95% confidence interval, CI] = 1.12 (1.08-1.16)] that was validated with genotype data from a replication cohort of the same Southern European ancestry consisting in 1073 cases and 1279 controls [combined P = 7.59 × 10(-10), OR (95% CI) = 1.12 (1.08-1.16)]. Furthermore, we confirmed the association of 33 reported associations with UC and we nominally validated the GWAS results of nine new risk loci (P < 0.05, same direction of effect). SNP rs2858829 lies in an intergenic region and is a strong cis-eQTL for FAM26F gene, a gene that is shown to be selectively upregulated in UC colonic mucosa with active inflammation. Our results provide new insight into the genetic risk background of UC, confirming that there is a genetic risk component that differentiates from Crohns Disease, the other major form of inflammatory bowel disease.

Risk of colectomy in patients with ulcerative colitis under thiopurine treatment

BACKGROUND AND AIMS Little is known about the risk factors of colectomy in patients with ulcerative colitis (UC) under thiopurine treatment. The aim of the study was to determine the prevalence and the predictive risk factors of colectomy in an extensive cohort of patients with UC treated with thiopurines in Spain. METHODS Among 5753 UC patients, we identified those diagnosed between 1980 and 2009 and treated with azathioprine or mercaptopurine (AZA/MP). We analyzed the age at diagnosis, familial history of IBD, extraintestinal manifestations (EIMs), disease extent, smoking status and treatment requirements (AZA/MP, cyclosporine (CsA) or anti-TNFα). Colectomies for dysplasia or cancer were excluded. Survival analysis and Cox proportional hazard regression were performed. Results were reported as hazard ratios (HR) with 95% CI. RESULTS Among the 1334 cases included, 119 patients (8.9%) required colectomy after a median time of 26 months (IQR 12-42) after AZA/MP initiation. Independent predictors of colectomy were: Extensive UC (HR 1.7, 95% CI: 1.1-2.6), EIMs (HR 1.5, 95% CI: 1.0-2.4), need for antiTNFα (HR 2.3, 95% CI: 1.5-3.4) and need for CsA (HR 2.4, 95% CI: 1.6-3.7). Patients requiring early introduction of AZA/MP had an increased risk of colectomy with a HR of 4.9 (95% CI: 3.2-7.8) when AZA/MP started in the first 33 months after UC diagnosis. CONCLUSIONS Nearly one-tenth of patients with UC under thiopurines require colectomy. Extensive UC, EIMs, need for CsA or anti-TNFα ever and an early need for AZA/MP treatment were associated with a higher risk of colectomy. These risk factors of colectomy could help to stratify risk in further controlled studies in UC.

Erratum to: Effectiveness of adalimumab for the treatment of ulcerative colitis in clinical practice: comparison between anti-tumour necrosis factor-naïve and non-naïve patients

Background Ulcerative colitis (UC) treatment is focused to achieve mucosal healing, avoiding disease progression. The study aimed to evaluate the real-world effectiveness of adalimumab (ADA) in UC and to identify predictors of remission to ADA.

Disease severity in familial cases of IBD

BACKGROUND Phenotypic traits of familial IBD relative to sporadic cases are controversial, probably related to limited statistical power of published evidence. AIM To know if there are phenotype differences between familial and sporadic IBD, evaluating the prospective Spanish registry (ENEIDA) with 11,983 cases. METHODS 5783 patients (48.3%) had ulcerative colitis (UC) and 6200 (51.7%) Crohns disease (CD). Cases with one or more 1st, 2nd or 3rd degree relatives affected by UC/CD were defined as familial case. RESULTS In UC and CD, familial cases compared with sporadic cases had an earlier disease onset (UC: 33 years [IQR 25-44] vs 37 years [IQR 27-49]; p<0.0001); (CD: 27 years [IQR 21-35] vs 29 years [IQR 22-40]; p<0.0001), higher prevalence of extraintestinal immune-related manifestations (EIMs) (UC: 17.2% vs 14%; p=0.04); (CD: 30.1% vs 23.6%; p<0.0001). Familial CD had higher percentage of ileocolic location (42.7% vs 51.8%; p=0.0001), penetrating behavior (21% vs 17.6%; p=0.01) and perianal disease (32% vs 27.1%; p=0.003). Differences are not influenced by degree of consanguinity. CONCLUSION When a sufficiently powered cohort is evaluated, familial aggregation in IBD is associated to an earlier disease onset, more EIMs and more severe phenotype in CD. This feature should be taken into account at establishing predictors of disease course.

Outcome in obscure gastrointestinal bleeding after capsule endoscopy

AIM To investigate the clinical impact of capsule endoscopy (CE) after an obscure gastrointestinal bleeding (OGIB) episode, focusing on diagnostic work-up, follow-up and predictive factors of rebleeding. METHODS Patients who were referred to Hospital del Mar (Barcelona, Spain) between 2007 and 2009 for OGIB who underwent a CE were retrospectively analyzed. Demographic data, current treatment with non-steroid anti-inflammtory drugs or anticoagulant drugs, hemoglobin levels, transfusion requirements, previous diagnostic tests for the bleeding episode, as well as CE findings (significant or non-significant), work-up and patient outcomes were analyzed from electronic charts. Variables were compared by χ (2) analysis and Student t test. Risk factors of rebleeding were assessed by Log-rank test, Kaplan-Meier curves and Cox regression model. RESULTS There were 105 patients [45.7% women, median age of 72 years old (interquartile range 56-79)] and a median follow-up of 326 d (interquartile range 123-641) included in this study. The overall diagnostic yield of CE was 58.1% (55.2% and 63.2%, for patients with occult OGIB and overt OGIB, respectively). In 73 patients (69.5%), OGIB was resolved. Multivariate analysis showed that hemoglobin levels lower than 8 g/dL at diagnosis [hazard ratios (HR) = 2.7, 95%CI: 1.9-6.3], patients aged 70 years and above (HR = 2.1, 95%CI: 1.2-6.1) and significant findings in CE (HR = 2.4, 95%CI: 1.1-5.8) were independent predictors of rebleeding. CONCLUSION One third of the patients presented with rebleeding after CE; risk factors were hemoglobin levels < 8 g/dL, age ≥ 70 years or the presence of significant lesions.

Tocilizumab in Amyloidosis-Associated Kidney Disease Secondary to Inflammatory Bowel Diseases

We read with interest the article by Sattianayagam et al. [1] about inflammatory bowel diseases (IBD) and AA amyloidosis with amyloidosis-associated kidney disease. The authors concluded that suppression of inflammatory activity may improve systemic amyloidosis prognosis and that patients undergoing renal transplantation have an excellent outcome. There is some evidence of the efficacy of the humanized anti-interleukin-6 receptor antibody tocilizumab (TCZ) on renal failure associated with AA amyloidosis improvement. TCZ has been reported to be effective in secondary AA amyloidosis related to rheumatologic diseases [2], in amyloidosis in the GI tract [3], and in renal amyloidosis [4], despite the scarcity of controlled evidence. In support of the effect of TCZ, we report the case of a 45-year-old patient with ulcerative colitis and grade III sacroileitis (HLA-B27 negative), followed in another center. After an acute flare, refractory to corticosteroids and cyclosporine, the patient underwent a proctocolectomy with an ileoanal pouch. Ten years later he was referred to our unit with elevated inflammatory markers, diarrhea, and abdominal pain. He had suffered from mild to moderate symptoms for at least the two previous years. Endoscopy revealed extensive ulceration of the pouch, jejunum, and ileum. Crohn’s disease was therefore diagnosed, and, because of persistent clinical activity, he was treated sequentially with adalimumab, infliximab, and methotrexate, without clinical response. Concurrently, the patient developed progressive chronic kidney disease with non-nephrotic range proteinuria reaching CKD stage IV (glomerular filtration rate \15 ml/min/m). After exclusion of other potential causes of renal dysfunction in IBD (5-ASA treatment, hypercalcemia renal oxalate stones), AA amyloidosis secondary to chronic inflammation related to IBD was diagnosed on the basis of amyloid A deposits in subcutaneous fat biopsy and duodenum, ileum, and colon biopsies (Congo redstained positive). Because of the clinical activity and the diagnosis of AA amyloidosis, we decided to start TCZ 8 mg/kg monthly. Tolerance of the treatment was excellent and the patient improved progressively and achieved clinical remission at week 52. At week 64, an ileoscopy, through the ileostomy, and a capsule endoscopy were performed; these showed mucosal healing was complete. In addition, renal function improved progressively and remained stable for two years (Cr 2.4 mg/dl, GFR 32 ml/min/1.73 m). Ileal biopsies performed two years after the onset of treatment showed no AA deposits. This clinical case and the literature published so far emphasize the importance of TCZ in controlling inflammatory activity in IBD and in reducing AA deposits, leading to improvement of renal function. It may therefore be considered as an alternative treatment or as bridge therapy before renal replacement therapy.

Phenotype and natural history of elderly onset inflammatory bowel disease: a multicentre, case-control study

Onset during old age has been reported in upto 10% of total cases of inflammatory bowel disease (IBD).