Safe and effective: anti-tumour necrosis factor therapy use in pregnant patients with Crohn disease and ulcerative colitis.

Biological therapy, particularly the anti-tumour necrosis factor (TNF) antibodies, infliximab and adalimumab, are used for the maintenance of remission for patients with inflammatory bowel diseases (IBD). We present 21 pregnancies in IBD patients exposed to anti-TNF agents between 2007 and 2014. Our study demonstrates that anti-TNF therapy is safe and effective in pregnancy. Rates of foetal complications are similar to IBD cohorts from the pre anti-TNF era.

Placental involvement by non-Hodgkin lymphoma in a Crohn disease patient on long-term thiopurine therapy.

We report the first published case of aggressive diffuse large B-cell (non-Hodgkin) lymphoma in a 35-year-old pregnant woman who had Crohn disease and was taking long-term thiopurine therapy: the patient developed placental insufficiency, and there was intrauterine fetal death.

Spondyloarthropathy in inflammatory bowel disease patients on TNF inhibitors.

BACKGROUND: Musculoskeletal symptoms are the most common extra-intestinal manifestation associated with inflammatory bowel disease (IBD). Spondyloarthritis (SpA) is an umbrella term applied to a group of rheumatic diseases with some features in common and others distinct from other inflammatory arthritides. AIM: To determine self-reported prevalence of SpA associated musculoskeletal manifestations in an IBD cohort on tumour necrosis factor (TNF) inhibitors using a questionnaire incorporating Assessment of SpondyloArthritis International Society (ASAS) criteria. METHODS: Consecutive IBD patients on TNF inhibitors attending a single IBD centre (May-September 2011) were asked to complete a SpA questionnaire. Data collected included SpA and IBD variables, demographics, concurrent medications, co-morbidities and autoimmune serology. RESULTS: The 140-patient cohort included 96 suffering from Crohn disease and 44 from ulcerative colitis. The mean age of disease onset was 29.3 years and 45% were men. Concurrent or past history of inflammatory back pain was reported by 29% subjects. Using the imaging and clinical arms of the ASAS criteria, 30% and 14% subjects respectively had axial SpA. Arthritis was reported by 34%, enthesitis 17%, dactylitis 4%, uveitis 6%, psoriasis 6% and a family history of SpA in 39%. Peripheral SpA was present in 41% by the ASAS criteria. There were no differences in these frequencies between Crohn disease and ulcerative colitis. A positive antinuclear antibodies (>1:80) was found in 19% before commencement of TNF inhibitor therapy and increased to 78% on therapy. Clinical drug-induced lupus erythematosus was uncommon (4%) and was characterised by new clinical signs and symptoms, including arthralgia, rash with elevated dsDNA titres and positive antinuclear antibodies. CONCLUSIONS: Inflammatory bowel disease patients on TNF inhibitors frequently reported musculoskeletal manifestations. Increased recognition of SpA occurred with use of an SpA self-reported questionnaire in IBD patients: this could alter management and improve patient outcomes. Clinical drug-induced lupus erythematosus was uncommon.

Infliximab reverses inflammatory muscle wasting (sarcopenia) in Crohn's disease.

BACKGROUND: Muscle wasting or sarcopenia arising from chronic inflammation is found in 60% of patients with Crohn's disease. Transcriptional protein NF-κB reduces muscle formation through MyoD transcription and increases muscle breakdown by proteolysis. AIM: As TNF is a potent activator of NF-κB, and anti-TNF agent infliximab (IFX) prevents NF-κB activation, to determine whether or not Crohn's patients treated with IFX gain muscle volume and strength. METHODS: We performed a prospective, repeated-measures cohort study in adult Crohn's disease patients with an acute disease flare. Patients were instructed not to vary diet or activity. Concomitant medications were kept stable. At week 1 (pre-treatment), week 16 (post-IFX induction) and week 25 (post-first IFX maintenance dose), we assessed (i) MRI volume of quadriceps femoris at anatomical mid-thigh; (ii) maximal concentric quadriceps contractions strength at three specific speeds of contraction; (iii) physical activity by validated instrument (IPAQ); (iv) Three-day food record of intake and composition (food-weighing method); (v) Serum levels of IL6. RESULTS: Nineteen patients (58% female; mean age 33.2 ± 10.7 years) were recruited. IFX increased muscle volume in both legs from baseline (right, 1505 cm(3) ) to week 25 (right, 1569 cm(3) ; P = 0.010). IFX also increased muscle strength in both legs from baseline (right 30°/s, 184.8 Nm) to week 25 (right 30°/s, 213.6 Nm; P = 0.002). Muscle volume gain correlated with male gender (P = 0.003). Significant gains in muscle volume and strength were unrelated to prednisolone use. Serum IL6 levels decreased by week 25 (P = 0.037). CONCLUSION: The anti-TNF agent infliximab reverses inflammatory sarcopenia in patients with Crohn's disease.

Hepatosplenic T-cell lymphoma, immunosuppressive agents and biologicals: what are the risks?

We present three cases of the rare hepatosplenic T-cell lymphoma (HSTCL); two patients suffering from Crohn disease who developed HSTCL on azathioprine without exposure to biologicals, and a third patient who had psoriasis treated using etanercept, cyclosporine and methotrexate. The evidence for an association between HSTCL and immunosuppressive drugs and biologicals is reviewed. We argue for improved pharmacovigilance processes to help determine the benefit to risk ratios for the use of these and other new agents.

Early predictors of colectomy and long-term maintenance of remission in ulcerative colitis patients treated using anti-tumour necrosis factor therapy.

BACKGROUND: Anti-tumour necrosis factor (TNF) agents are used as induction and maintenance therapy in ulcerative colitis (UC) refractory to standard therapy and as rescue therapy in acute severe UC (ASUC). AIMS: To determine long-term outcomes including colectomy rates, predictors of maintenance of response and remission, risk of serious adverse events by reviewing 12-year clinical experience from a single centre in Australia. METHODS: Seventy-one patients with moderate-severe UC (Mayo score ≥6) (n = 52) and ASUC (n = 19) treated with anti-TNF agents were included. Primary end-points were colectomy at 12 weeks and colectomy-free survival at last follow up. Secondary endpoints included clinical response (decrease in Mayo score of ≥3) and remission (Mayo score ≤2). RESULTS: Colectomy at 12 weeks was 1%, and colectomy-free survival was 69%. Using full Mayo score, at 3 months, 32/37 (87%) refractory and 9/12 (75%) ASUC patients responded to anti-TNF therapy; 19/37 (51%) refractory and 8/12 (67%) ASUC patients were in remission. Long-term response rates (mean follow up 37.4 months) were 24/44 (55%) and 11/15 (73%) in refractory and ASUC groups respectively. Long-term remission rates were 43% in refractory and 60% in ASUC patients. Twenty two of 71 (31%) underwent colectomy (mean time 50.4 months). Clinical non-response at 3 months was a predictor of colectomy (hazard ratio = 9.346; P = 0.001). ASUC predicted long-term maintenance of response (odds ratio 19.4; P = 0.013) and remission (odds ratio 6.13; P = 0.037). Two of 71 patients had serious infections. CONCLUSIONS: Anti-TNF therapy is effective in both refractory and ASUC. We argue that early anti-TNF therapy may improve outcome in UC.

Two rare cases of Epstein-Barr virus-associated lymphoproliferative disorders in inflammatory bowel disease patients on thiopurines and other immunosuppressive medications.

The setting of chronic immunosuppression in inflammatory bowel disease (IBD) may promote the proliferation of Epstein-Barr virus-positive neoplastic clones. We report two rare cases of Epstein-Barr virus-associated lymphoproliferative disorder in IBD patients: one resembled lymphomatoid granulomatosis, and the other was a lymphoma resembling Hodgkin lymphoma. There are currently no guidelines for the prevention of lymphoproliferative disorder in IBD patients on immunosuppressive therapy.

Glatiramer acetate induced hepatotoxicity.

INTRODUCTION: Glatiramer acetate (Copaxone), a polypeptide has been approved for treating patients with active relapsing-remitting multiple sclerosis. CASE PRESENTATION: We report the first case of severe acute hepatitis after commencing treatment for multiple sclerosis with glatiramer acetate. A 31-year-old female with multiple sclerosis presented with anorexia, lethargy and jaundice five weeks after commencing glatiramer acetate. She had never received beta-interferon treatment. Investigations revealed a bilirubin of 0.109 mmol/L (0.002-0.02 mmoL/L) and prothrombin time of 21 secs (9-15 secs). Her liver function tests were normal before commencing glatiramer acetate. A liver biopsy performed approximately 6 weeks after commencement of glatiramer acetate showed predominantly centrilobular hepatocyte necrosis with portal-venous bridging, along with mild portal and interface hepatitis. The necrosis was not accompanied by an acute inflammatory or chronic inflammatory infiltrate. The features were not suggestive of autoimmune hepatitis but consistent with drug toxicity. The liver tests returned to normal within 2 months after cessation of glatiramer acetate. CONCLUSION: Physicians should be aware that glatiramer acetate can be associated with uncommon but yet significantly severe liver toxicity.

Advances in the management of inflammatory bowel disease.

Our understanding of inflammatory bowel diseases (IBD) is constantly evolving, and many new treatment options have emerged recently. This review critically examines the evidence for these new developments and aims to provide an overview for medical professionals involved in the care of patients with IBD. Proposed changes in the use of aminosalicylates, immunosuppressants and biological agents are described, and the evidence for several promising novel agents is reviewed.

Aspiration in the context of upper gastrointestinal endoscopy.

BACKGROUND: Pulmonary aspiration is a life-threatening complication of upper gastrointestinal endoscopy, the incidence of which has not been determined. Endoscopy-related aspiration has not been studied in procedures in which patients swallow a radiolabelled potential aspirate immediately before endoscopy and undergo nuclear scanning postprocedure. METHODS: A pilot study was conducted in which 200 MBq of nonabsorbable technetium-99m phytate in 10 mL of water was administered orally to 50 patients who were about to undergo endoscopy. Gamma camera images were obtained to ensure that there had been no aspiration before endoscopy. After endoscopy, a repeat scan was performed. Fluid aspirated through the endoscope was also collected and analyzed for radioactivity using a hand-held radiation monitor. RESULTS: No evidence of pulmonary aspiration was found in any of the patients studied. The mean estimated percentage of the initially administered radioactivity aspirated through the endoscope was 2.66% (range 0% to 10.3%). CONCLUSION: The present pilot study confirms earlier observations that clinically significant aspiration in the context of upper gastrointestinal endoscopy is uncommon. The incidence of aspiration may, however, be different in acutely bleeding patients undergoing endoscopy. For logistic reasons, this group could not be studied.

Perioperative acute upper gastrointestinal haemorrhage in older patients with hip fracture: incidence, risk factors and prevention.

BACKGROUND: No specific preventive strategy exists for acute gastrointestinal haemorrhage in hip fracture patients. AIMS: To determine the effectiveness of prophylactic use of proton pump inhibitors in patients with risk factors for acute gastrointestinal haemorrhage. METHODS: Prospective two-stage study of 822 consecutive older (> or =60 years) hip fracture patients. RESULTS: Acute gastrointestinal haemorrhage occurred in 16 (3.9%) of 407 patients and was associated with increased length of hospital stay (28.7 vs. 15.9; P = 0.0027) and mortality (18.8% vs. 4.3%; P = 0.043). Multiple analysis identified five independent risk factors for acute gastrointestinal haemorrhage: pre-existing peptic ulcer (OR 4.3; P = 0.043), current smoking (OR 3.1; P = 0.023), post-operative use of an antiplatelet agent (OR 6.5; P = 0.046), post-operative use of non-steroidal anti-inflammatory drug/cyclo-oxygenase-2 inhibitor (OR 4.9; P = 0.06) and blood group O (OR 1.7; P = 0.046). These risk factors were highly sensitive and had a negative predictive value of 99.8%. Prophylactic use of proton pump inhibitors in patients with risk factor for acute gastrointestinal haemorrhage significantly reduced the incidence of this complication (0.72% in treated patients vs. 13.4% in untreated; P < 0.001); the number needed to treat was 7.9. Conclusions In older hip fracture patients perioperative acute gastrointestinal haemorrhage occurs in 3.9% and is associated with poor outcome. Preventive proton pump inhibitor therapy in patients at risk of acute gastrointestinal haemorrhage is effective and safe.

The IBD international genetics consortium provides further evidence for linkage to IBD4 and shows gene-environment interaction.

BACKGROUND AND AIMS: The inflammatory bowel diseases (IBDs) Crohn's disease (CD) and ulcerative colitis are complex disorders with an important genetic determinant. One gene associated with CD has been identified: NOD2/CARD15. Two independent genome-wide scans found significant evidence (logarithm of odds [LOD] 3.6) and suggestive evidence (LOD 2.8) for linkage on locus 14q11-12, also known as the IBD4 locus. To further characterize this locus, we assessed gene-environment interaction (IBD4 x smoking) and phenotypic heterogeneity in a large cohort of IBD-affected sibling pairs as part of an ongoing international collaborative effort. PATIENTS AND METHODS: A total of 733 IBD families, comprising 892 affected sibling pairs, were genotyped for microsatellites D14S261, D14S283, D14S972, and D14S275, spanning the IBD4 locus. Information on gender, ethnicity, age at onset, smoking at diagnosis, extraintestinal manifestations, and disease location was available. RESULTS: A significant distortion in the mean allele sharing (MAS) between affected siblings was observed for CD patients only at each of the four markers (54.6%, 52.8%, 50.4%, and 53.3%, respectively). Maximum linkage for CD was observed at marker D14S261 (multipoint nonparametric linkage score 2.36; P

CARD15/NOD2 risk alleles in the development of Crohn's disease in the Australian population.

We have previously reported strong evidence for linkage between IBD1 and Crohn's disease (CD) in Australian Crohn's disease families. Three risk alleles for Crohn's disease, (Arg702Trp (C/T), Gly908Arg (G/C) and 980fs981 (-/C), were recently identified in the CARD15/NOD2 gene on chromosome 16, implicating this as the IBD1 locus. Using a novel diagnostic PCR-RFLP, we have examined the frequency of these alleles in 205 multiplex IBD families, 107 sporadic Crohn's disease cases and 409 normal individuals. We demonstrate that the three risk alleles are more frequent in Crohn's disease, than in controls, with allelic frequencies of 0.11, 0.02 and 0.07 respectively. Heterozygosity for individual variants conferred a three-fold increase in risk for Crohn's disease while substantially higher risks were associated with being homozygous or compound heterozygous. Despite a significantly lower population allele frequency for the frameshift mutation than reported by other groups, we see a similar contribution by this allele to the risk of developing Crohn's disease. While the three risk alleles influence susceptibility to Crohn's disease in Australia, we show that these alleles do not fully explain the linkage evidence and suggest that there are very likely additional IBD1 susceptibility alleles yet to be described in Australian CD at the NOD2 locus. We also show a second linkage peak in Australian CD that provides some support for a second disease susceptibility locus on chromosome 16.

Dextran sulphate sodium-induced colitis is ameliorated in interleukin 4 deficient mice.

The importance of IL-4 and its effects in inflammatory bowel disease (IBD) was studied using the dextran sulphate sodium-induced model of experimental colitis. The model resembles ulcerative colitis in humans. IL-4 deficient mice and IL-4+/+ littermates were used to induce colitis. Activity of disease, extent of tissue damage, immunoglobulin isotypes, IFNgamma and IL-10 production was assessed. Both disease activity index (DAI) and histological scores were consistently lower in the IL-4 deficient mice than in the IL-4+/+ littermates. Furthermore, the lower histological scores reflected the milder inflammatory lesions and decreased ulceration found in the IL-4 deficient mice. Analysis of immunoglobulin subtypes showed that IgG1 was almost absent in the sera of IL-4 deficient mice. IFNgamma contents was much higher in colonic tissues from IL-4 deficient mice. Dextran sulphate sodium-induced colitis is ameliorated in IL-4 deficient mice. IL-4 either directly or through its effects on T and B cells influences its severity. It is unclear if the higher immunoglobulin-producing cells in the colonic tissues of IL-4 deficient mice before colitis was induced could have influenced the outcome of the disease. The high IFNgamma contents in colonic tissues of IL-4 deficient mice argue against the role of this cytokine as a crucial mediator of tissue damage during the acute phase of colitis.

Murine intestinal dendritic cell isolation.

This chapter describes techniques for the isolation of dendritic cell-enriched single-cell suspensions from the lamina propria (LP) of both small and large intestine and from Peyer's patches (PP). This technique can also be used to obtain intestinal macrophage-enriched populations. The characterization of an assay system, the allogeneic mixed leukocyte reaction (MLR), is also described.