Safety and efficacy of transitioning inflammatory bowel disease patients from intravenous to subcutaneous infliximab: a single-center real-world experience.

Background: A new subcutaneous (SC) formulation exists for infliximab (CT-P13 SC). The aim of this study was to assess the durability of clinical and endoscopic responses after a switch from intravenous (IV) to SC infliximab. Methods: Patients were transitioned on maintenance infliximab, including those with dose-optimized therapy. The primary outcome was clinical, biochemical and overall remission at 6 months, as defined by a Harvey-Bradshaw Index <5 for Crohn's disease or a partial Mayo score <3 for ulcerative colitis, C-reactive protein less than 10 mg/L, and fecal calprotectin less than 100 µg/g. Results: Forty patients were switched from IV to SC infliximab. Twenty-seven (68%) had a diagnosis of Crohn's disease and 13 (33%) had ulcerative colitis. Twenty-three (58%) were on 5 mg/kg of IV infliximab every 8 weeks and 15 (38%) 5 mg/kg every 6 weeks. There were 2 patients (4%) on 10 mg/kg every 6 weeks. At the time of their switch, 37 (93%) patients were in clinical remission, 25 (76%) were in biochemical remission, and 25 (76%) were in both biochemical and clinical remission. At 6 months the proportion of patients in clinical remission decreased from 93% to 82%, with an overall relapse rate of 11%. Treatment persistence at 6 months was 77.5%. Conclusion: Switching patients from IV infliximab to 120 mg fortnightly SC injections is a safe and effective option for the treatment of inflammatory bowel disease, including for those patients on dose-escalated infliximab or with active disease at the time of switch.

Combination therapy is not associated with improved rates of clinical or endoscopic remission in patients with inflammatory bowel disease treated with ustekinumab or vedolizumab: a retrospective study.

Background: Management of inflammatory bowel disease (IBD) involves biological agents, often in combination with thiopurines or methotrexate. The aim of our study was to compare clinical and endoscopic outcomes in IBD patients treated with vedolizumab or ustekinumab, as monotherapy or in combination with thiopurines or methotrexate. Methods: We conducted a retrospective cohort study of all patients aged ≥18 years with a diagnosis of ulcerative colitis or Crohn's disease, commenced on vedolizumab or ustekinumab between October 2015 and March 2022. Primary outcome was clinical remission or response calculated by partial Mayo score (remission: <3; response: improvement >1) for ulcerative colitis or Harvey-Bradshaw index (<5, >2 respectively) for Crohn's disease over 1 year. Secondary endpoints were treatment failure, relapse, endoscopic remission at 1 year. Statistical analysis was done using 2-sample Student's t and chi-square tests. Results: A total of 159 IBD patients were included in the study, 85 (53%) on vedolizumab and 74 (47%) on ustekinumab. For those on vedolizumab, 61 (72%) patients had ulcerative colitis, and 24 (28%) has Crohn's disease. All patients on ustekinumab had Crohn's disease. Mean disease duration in was 9.4 and 13.5 years respectively. There was no difference in clinical response or remission for vedolizumab or ustekinumab monotherapy compared to combination therapy at 1 year. There was also no difference in treatment failure, relapse or endoscopic remission. Conclusion: Combining vedolizumab or ustekinumab with an immunomodulator is not superior to monotherapy in terms of clinical response or endoscopic remission up to 1 year in IBD.

Peripheral parenteral nutrition: An evaluation of its use, safety and cost implications in a tertiary hospital setting.

BACKGROUND AND AIMS: Malnutrition is a common challenge among hospitalised patients and its associatiation with poor patient health-related outcomes places a significant financial burden on the healthcare system. Total parenteral nutrition (TPN) is the primary means for providing nutrition to individuals in whom enteral feeding is not possible but is costly and requires invasive central venous access. Peripheral parenteral nutrition (PPN) provides a suitable option for early nutrition provision in select patients; however, its routine use has been limited by safety and tolerability concerns, with high rates of phlebitis reported in previous studies. The objectives of this study were to review the use, safety, and costs of PPN in an Australian tertiary hospital. METHODS: A single-site, prospective observational study was conducted over 15 months in a tertiary hospital. 139 participants (87 male and 52 female) were enrolled in the study. Data collected assessed the indication for PPN initiation, compliance with the hospital's protocols for PPN, total fasting days, the proportion of the patient's total energy and protein requirements provided by PPN, the incidence of phlebitis and potential cost implications associated with the use of PPN. RESULTS: 139 patients (62.6% male), median age 62 years (IQR (interquartile range) 48-74) were enrolled. Most patients had an emergency admission (80.6%) under a general surgical team (84.2%). Forty-eight patients (34.5%) were malnourished, as assessed by the Subjective Global Assessment tool (SGA). Patients fasted for a median of 3 days (IQR 2-5) before PPN commencement, with a median duration of PPN use of 3 days (IQR 2-4). PPN provided an average of 61.6% of the patients' required caloric intake and 46.4% of protein requirements. Progression to TPN was observed in 34.5% of patients. There were low rates of complications with phlebitis observed in 3.7%, extravasation in 1.1%, and no patients developed septicaemia, despite suboptimal compliance with the recommended cannula management guidelines for PPN (66.4% compliant). The cost of PPN was estimated to be AUD$187 per patient day. CONCLUSION: PPN is an effective short-term nutrient delivery solution to facilitate early feeding with small numbers of patients requiring transition to TPN. PPN was safe with low rates of cannula complications. Costs were favourable, with potentially significant cost savings as compared with TPN.

Infliximab-induced optic neuritis.

Antitumour necrosis factor alpha agents are important treatments in many inflammatory conditions including rheumatoid arthritis, psoriatic arthritis and the inflammatory bowel diseases. However, there have been case reports of optic neuritis and other demyelinating diseases as complications of these agents. This case report presents a patient with ulcerative colitis on infliximab who presented with sudden onset mono-ocular visual field loss and highlights the diagnosis and management of infliximab-induced optic neuritis.

Anti-TNF-induced lupus in patients with inflammatory bowel disease.

BACKGROUND AND AIMS: Anti-Tumor Necrosis Factor (TNF)-induced lupus (ATIL) is a distinct clinical entity, increasingly recognized in patients with inflammatory bowel disease treated with anti-TNF therapy. Our aims were to evaluate the incidence and clinical and serological markers of ATIL in this population. METHODS: This observational cohort study reviewed 454 patient treatment courses with anti-TNF therapy (300 infliximab and 154 adalimumab). A diagnosis of ATIL was based on the most widely accepted diagnostic criteria: (i) a temporal relationship between symptoms and anti-TNF therapy and resolution of symptoms following cessation of the offending medication; (ii) at least one serologic American College of Rheumatology (ACR) criterion of Systemic Lupus Erythematosus (SLE); and (iii) at least one nonserological criterion such as arthritis, serositis, or rash. Clinical, demographic, and serological predictors were evaluated. RESULTS: The incidence rate of ATIL was 5.7% for infliximab and 0.6% for adalimumab, which are much higher than previously reported postmarketing estimates. The median duration to diagnosis following commencement of anti-TNF therapy was 15 months (3-62 months). ATIL occurs more commonly patients that commence therapy at an older age (46.47 years ± 13.79 years vs. 38.85 years ± 14.75 years, P = 0.033). CONCLUSIONS: ATIL is a significant complication of anti-TNF therapy, affecting 1 in every 20 patients who commence infliximab. A panel of serological markers is useful to confirm the diagnosis and exclude other conditions that may mimic ATIL. Clinicians using anti-TNF medications should counsel patients about this potential risk and monitor for clinical manifestations of lupus during routine follow up.

Association of Genetic Variants in NUDT15 With Thiopurine-Induced Myelosuppression in Patients With Inflammatory Bowel Disease.

Importance: Use of thiopurines may be limited by myelosuppression. TPMT pharmacogenetic testing identifies only 25% of at-risk patients of European ancestry. Among patients of East Asian ancestry, NUDT15 variants are associated with thiopurine-induced myelosuppression (TIM). Objective: To identify genetic variants associated with TIM among patients of European ancestry with inflammatory bowel disease (IBD). Design, Setting, and Participants: Case-control study of 491 patients affected by TIM and 679 thiopurine-tolerant unaffected patients who were recruited from 89 international sites between March 2012 and November 2015. Genome-wide association studies (GWAS) and exome-wide association studies (EWAS) were conducted in patients of European ancestry. The replication cohort comprised 73 patients affected by TIM and 840 thiopurine-tolerant unaffected patients. Exposures: Genetic variants associated with TIM. Main Outcomes and Measures: Thiopurine-induced myelosuppression, defined as a decline in absolute white blood cell count to 2.5 × 109/L or less or a decline in absolute neutrophil cell count to 1.0 × 109/L or less leading to a dose reduction or drug withdrawal. Results: Among 1077 patients (398 affected and 679 unaffected; median age at IBD diagnosis, 31.0 years [interquartile range, 21.2 to 44.1 years]; 540 [50%] women; 602 [56%] diagnosed as having Crohn disease), 919 (311 affected and 608 unaffected) were included in the GWAS analysis and 961 (328 affected and 633 unaffected) in the EWAS analysis. The GWAS analysis confirmed association of TPMT (chromosome 6, rs11969064) with TIM (30.5% [95/311] affected vs 16.4% [100/608] unaffected patients; odds ratio [OR], 2.3 [95% CI, 1.7 to 3.1], P = 5.2 × 10-9). The EWAS analysis demonstrated an association with an in-frame deletion in NUDT15 (chromosome 13, rs746071566) and TIM (5.8% [19/328] affected vs 0.2% [1/633] unaffected patients; OR, 38.2 [95% CI, 5.1 to 286.1], P = 1.3 × 10-8), which was replicated in a different cohort (2.7% [2/73] affected vs 0.2% [2/840] unaffected patients; OR, 11.8 [95% CI, 1.6 to 85.0], P = .03). Carriage of any of 3 coding NUDT15 variants was associated with an increased risk (OR, 27.3 [95% CI, 9.3 to 116.7], P = 1.1 × 10-7) of TIM, independent of TPMT genotype and thiopurine dose. Conclusions and Relevance: Among patients of European ancestry with IBD, variants in NUDT15 were associated with increased risk of TIM. These findings suggest that NUDT15 genotyping may be considered prior to initiation of thiopurine therapy; however, further study including additional validation in independent cohorts is required.

Vedolizumab-induced acute pancreatitis: the first reported clinical case.

Drug-induced acute pancreatitis (DIAP) is a rare, but clinically significant diagnosis. Vedolizumab, an α4ß7 integrin inhibitor, which was approved in 2015 for treatment of moderate to severe inflammatory bowel disease, is a well-tolerated medication with a favourable safety profile and minimal serious adverse events in premarketing clinical trials. We present the first reported case of acute pancreatitis directly attributable to vedolizumab.

Gastroduodenal Artery Psuedoaneurysm Bleed through a Spontaneous Pancreaticoduodenal Fistula as a Result of Acute Necrotizing Pancreatitis.

Spontaneous pancreaticoduodenal fistulization and arterial psuedoaneurysm formation are both complications of acute pancreatitis. We present a 27-year-old man with hematemesis who was found to be bleeding from a gastroduodenal artery psuedoaneurysm through a spontaneous pancreaticoduodenal fistula as a result of severe alcohol-related necrotizing pancreatitis. This is the first reported case in the literature to describe this occurrence.

Clinical Features and HLA Association of 5-Aminosalicylate (5-ASA)-induced Nephrotoxicity in Inflammatory Bowel Disease.

BACKGROUND AND AIMS: Nephrotoxicity is a rare idiosyncratic reaction to 5-aminosalicylate (5-ASA) therapies. The aims of this study were to describe the clinical features of this complication and identify clinically useful genetic markers so that these drugs can be avoided or so that monitoring can be intensified in high-risk patients. METHODS: Inflammatory bowel disease patients were recruited from 89 sites around the world. Inclusion criteria included normal renal function prior to commencing 5-ASA, ≥50% rise in creatinine any time after starting 5-ASA, and physician opinion implicating 5-ASA strong enough to justify drug withdrawal. An adjudication panel identified definite and probable cases from structured case report forms. A genome-wide association study was then undertaken with these cases and 4109 disease controls. RESULTS: After adjudication, 151 cases of 5-ASA-induced nephrotoxicity were identified. Sixty-eight percent of cases were males, with nephrotoxicity occurring at a median age of 39.4 years (range 6-79 years). The median time for development of renal injury after commencing 5-ASA was 3.0 years (95% confidence interval [CI] 2.3-3.7). Only 30% of cases recovered completely after drug withdrawal, with 15 patients requiring permanent renal replacement therapy. A genome-wide association study identified a suggestive association in the HLA region (p = 1×10(-7)) with 5-ASA-induced nephrotoxicity. A sub-group analysis of patients who had a renal biopsy demonstrating interstitial nephritis (n = 55) significantly strengthened this association (p = 4×10(-9), odds ratio 3.1). CONCLUSIONS: This is the largest and most detailed study of 5-ASA-induced nephrotoxicity to date. It highlights the morbidity associated with this condition and identifies for the first time a significant genetic predisposition to drug-induced renal injury.

Infliximab and adalimumab are stable in whole blood clotted samples for seven days at room temperature.

INTRODUCTION: The biologic anti-tumour necrosis factor alpha (anti-TNFα) agents infliximab and adalimumab are monoclonal antibodies with binding specificity to TNFα, which are used for the treatment of Crohn's disease. Clinical response is varied from complete with mucosal healing, to primary non-response, loss of response and adverse drug reactions. Measuring trough blood levels of infliximab and adalimumab may guide clinical management. The sample handling requirements for infliximab and adalimumab were previously unknown. AIM: The aim of this study was to determine the in vitro stability of infliximab and adalimumab in samples stored for up to seven days at room temperature. METHODS: Samples were stored as clotted whole blood or serum at room temperature for up to seven days, before being frozen (-20℃) and analysed as a batch for either infliximab or adalimumab. RESULTS: No significant difference between the concentration of infliximab and adalimumab measured in samples stored as serum or whole blood for seven days at room temperature, as compared to baseline was found (t-test; infliximab: P = .35 [serum], P = .38 [whole blood]; adalimumab: P = .12 [serum], P = .49 [whole blood]). CONCLUSION: The stability of infliximab and adalimumab at room temperature for seven days allows samples to be posted direct from clinics and research centres to the analysing laboratory.

HLA-DQA1-HLA-DRB1 variants confer susceptibility to pancreatitis induced by thiopurine immunosuppressants.

Pancreatitis occurs in approximately 4% of patients treated with the thiopurines azathioprine or mercaptopurine. Its development is unpredictable and almost always leads to drug withdrawal. We identified patients with inflammatory bowel disease (IBD) who had developed pancreatitis within 3 months of starting these drugs from 168 sites around the world. After detailed case adjudication, we performed a genome-wide association study on 172 cases and 2,035 controls with IBD. We identified strong evidence of association within the class II HLA region, with the most significant association identified at rs2647087 (odds ratio 2.59, 95% confidence interval 2.07-3.26, P = 2 × 10(-16)). We replicated these findings in an independent set of 78 cases and 472 controls with IBD matched for drug exposure. Fine mapping of the HLA region identified association with the HLA-DQA1*02:01-HLA-DRB1*07:01 haplotype. Patients heterozygous at rs2647087 have a 9% risk of developing pancreatitis after administration of a thiopurine, whereas homozygotes have a 17% risk.

Papillary carcinoma arising in thyroglossal duct cyst in the lateral neck.

The patient presented here, a 74-year-old female, had a 3-year history of a gradually enlarging painless nodule in the right submental lateral region of the neck. A neck CT scan showed a well-demarcated cystic lesion, measuring 25mm in diameter, but without any definite evidence of neoplastic foci in the lymph nodes, thyroid gland, or lung. Clinicians first interpreted it as branchial cleft cyst, and a cystectomy was performed. Gross examination revealed a unilocular cystic lesion filled with yellowish clear fluids, containing a markedly thinned fibrous wall with smooth inner surface, partly coexisting with tiny solid and papillary-like components. On microscopic examination, the cystic tumor was lined by mono-layered ciliated columnar or metaplastic stratified squamous epithelium with underlying ectopic thyroid follicles or lymphocytic infiltrate, reminiscent of thyroglossal duct cyst (TDC), partly adjacent to the compressed lymph node tissue. Its solid parts were composed of a proliferation of atypical cuboidal to columnar epithelial cells with occasional nuclear grooves or intranuclear inclusions, arranged in a papillary growth pattern with supporting delicate fibrovascular cores. Immunohistochemically, these atypical cells were positive for thyroid transcription factor 1, thyroglobulin, and cytokeratin 19. Therefore, we finally made a diagnosis of papillary carcinoma (PC) arising in TDC in the lateral neck. Although metastatic thyroid PC of cervical lymph node was an important differential diagnosis owing to various overlapping clinicopathological features, coexistent benign lining epithelium or thyroid follicles, a histological hallmark of TDC, were present in the current case.

Suppurative granulomatous inflammation in the ileo-anal pouch.

Restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) is commonly performed for medically refractory ulcerative colitis (UC), however with multiple possible complications, most notably pouchitis, cuffitis, Crohn's disease of the pouch and irritable pouch syndrome. We present a unique case of suppurative granulomatous inflammation in the ileal pouch mucosa, most likely infective in nature, that is unrelated to recognised causes of such pathology, especially yersiniosis.

Thyroid papillary carcinoma with solid sclerosing change in IgG4-related sclerosing disease.

IgG4-related sclerosing disease (IgG4-RSD) is an inflammatory and fibrosing disorder characterized by lymphoplasmacytic inflammation with infiltration of various organs, including the pancreas, bile ducts, lung, kidney, and retroperitoneum. As for malignancy in IgG4-RSD, only limited literature is available. We report here a case of thyroid papillary carcinoma showing unique morphology in IgG4-RSD. Solid tumor nests were surrounded by dense IgG4-positive plasma cells and fibrosis at both the primary site and metastatic lymph nodes. In contrast the background thyroid showed focal lymphocytic thyroiditis. IgG4-related sclerosing sialadenitis and autoimmune pancreatitis were also diagnosed, and prednisolone treatment improved symptoms and serum IgG4 abnormality. To the best of our knowledge, this is the first documentation of a malignancy of the thyroid gland occurring in a background of IgG4-RSD. A brief review of the literature on the relationship between IgG4 and malignancy is included.

Late-onset carbamoyl phosphate synthetase 1 deficiency in an adult cured by liver transplantation.

Urea cycle disorders (UCDs) are rare causes of hyperammonemic encephalopathy in adults. Most UCDs present in childhood and, if unrecognized, are rapidly fatal. Affected individuals who survive to adulthood may remain undiagnosed because of clinicians' unawareness of the condition or atypical presentations. We describe the case of a 49-year-old man who initially presented with a stroke and developed hyperammonemic encephalopathy over a period of 8 months. A diagnosis of carbamoyl phosphate synthetase type 1 deficiency was made, and the patient was referred for liver transplantation. One year after liver transplantation, the patient had normal plasma ammonia concentrations and had returned to work.

Effects of oxygen concentration on the proliferation and differentiation of mouse neural stem cells in vitro.

BACKGROUND AND PURPOSE: Cerebral ischemia is known to elicit the activation of neural stem cells (NSCs); however its mechanism is not fully determined. Although oxygen concentration is known to mediate many ischemic actions, there has been little attention given to the role of pathological oxygen changes under cerebral ischemia on the activation of NSCs. We investigated the effects of various oxygen concentrations on mouse neural stem cells in vitro. METHODS: NSCs were cultured from the ganglionic eminence of fetal ICR mice on embryonic day 15.5 using a neurosphere method. The effects of oxygen concentrations on proliferation, differentiation, and cell death of NSCs were evaluated by bromodeoxyuridine (BrdU) incorporation, immunocytochemistry, and TUNEL assay, respectively. RESULTS: The highest proliferation and the neuronal differentiation of the NSCs were observed in 2% oxygen, which yielded significantly higher proportions of both BrdU-labeled cells and Tuj1-positive cells when compared with 20% and 4% oxygen. On the other hand, the differentiation to the astrocytes was not affected by oxygen concentrations, except in the case of anoxia (0% oxygen). The cell death of the NSCs increased in lower oxygen conditions and peaked at anoxia. Furthermore, the switching of the neuronal subtype differentiation from GABA-positive to glutamate-positive neurons was observed in lower oxygen conditions. CONCLUSIONS: These findings raise the possibility that reduced oxygen levels occurring with cerebral ischemia enhance NSC proliferation and neural differentiation, and that mild hypoxia (2% oxygen), which is known to occur in the ischemic penumbra, is suitable for abundant neuronal differentiation.