Simon Ghaly

Review article: consensus statements on therapeutic drug monitoring of anti-tumour necrosis factor therapy in inflammatory bowel diseases

Therapeutic drug monitoring (TDM) in inflammatory bowel disease (IBD) patients receiving anti‐tumour necrosis factor (TNF) agents can help optimise outcomes. Consensus statements based on current evidence will help the development of treatment guidelines.

The role of vitamin D in gastrointestinal inflammation

The emerging role of vitamin D as a regulator of both innate and adaptive immune responses has encouraged the investigation of its role in the pathogenesis of a variety of autoimmune conditions including the inflammatory bowel diseases (IBD), Crohn’s disease and ulcerative colitis. Animal models consistently demonstrate that vitamin D significantly impacts on the modulation of astrointestinal inflammation, while epidemiological and observational data show an inverse relationship between vitamin D status and the onset/progression of Crohn’s disease as well as the development of colorectal cancer. As vitamin D supplementation is readily available, at low cost, it is a very attractive potential therapeutic option. The biological plausibility for a role for vitamin D in inflammation modulation, the potential genetic links associated with vitamin D metabolism and the clinical aspects for it in IBD will be discussed.

Audit of endometrial biopsy at outpatient hysteroscopy

Background and aim:   Outpatient hysteroscopy (OPH) and endometrial biopsy (EMB) are less invasive alternatives to inpatient hysteroscopy and dilatation and curettage for assessment of the endometrium. Using local anaesthetic, the procedure is readily tolerated and can be completed in an ambulatory setting. This study aims to audit OPH and EMB conducted over three consecutive years with regard to the ability to complete the procedure and subsequent pathology.

High Vitamin D-Binding Protein Concentration, Low Albumin, and Mode of Remission Predict Relapse in Crohn's Disease

Background:Vitamin D (25(OH)D) deficiency occurs in active Crohns disease (CD) and may be secondary to reduced sunlight exposure and oral intake. Vitamin D–binding protein (VDBP) levels, however, fluctuate less with season and sunlight. The aim, therefore, was to examine patients with CD in remission and determine any associations between VDBP, serum 25(OH)D, and the calculated free 25(OH)D concentrations with the risk of disease flare. Methods:Subjects were identified from prospectively maintained inflammatory bowel disease databases at 3 teaching hospitals in Australia. Patients were in steroid-free clinical remission at the time of blood draw and were followed for at least 12 months. Total and epimer-25(OH)D3, VDBP concentrations, and genotypes were determined. Results:A total of 309 patients with CD (46% men) met the inclusion criteria. A disease flare occurred in 100 (32.4%). Serum 25(OH)D3 was deficient (<50 nmol/L) in 36 (12%) and insufficient (50–75 nmol/L) in 107 (35%) patients. Total, free, and epimer-25(OH)D3 serum levels did not predict disease flare. Higher VDBP concentrations, however, significantly correlated with increased risk of disease flare (hazard ratio 1.2, 95% CI, 1.0–1.5). On multivariate analysis, VDBP concentration, low albumin, and medication-induced remission were significantly more associated with disease flare. VDBP genotypes were significantly associated with 25(OH)D and VDBP concentrations but not disease flare. Conclusions:Vitamin D deficiency was uncommon in our patients with CD in remission, and serum 25(OH)D3 did not predict disease flare, whereas higher VDBP concentrations were significantly associated with disease flare. Further investigations to explore the possible mechanisms for this association are warranted.

High Dose Vitamin D supplementation alters faecal microbiome and predisposes mice to more severe colitis

Vitamin D has been suggested as a possible adjunctive treatment to ameliorate disease severity in human inflammatory bowel disease. In this study, the effects of diets containing high (D++, 10,000 IU/kg), moderate (D+, 2,280 IU/kg) or no vitamin D (D−) on the severity of dextran sodium sulphate (DSS) colitis in female C57Bl/6 mice were investigated. The group on high dose vitamin D (D++) developed the most severe colitis as measured by blinded endoscopic (p < 0.001) and histologic (p < 0.05) assessment, weight loss (p < 0.001), drop in serum albumin (p = 0.05) and increased expression of colonic TNF-α (p < 0.05). Microbiota analysis of faecal DNA showed that the microbial composition of D++ control mice was more similar to that of DSS mice. Serum 25(OH)D3 levels reduced by 63% in the D++ group and 23% in the D+ group after 6 days of DSS treatment. Thus, high dose vitamin D supplementation is associated with a shift to a more inflammatory faecal microbiome and increased susceptibility to colitis, with a fall in circulating vitamin D occurring as a secondary event in response to the inflammatory process.

Compassionate access anti-tumour necrosis factor-α therapy for ulcerative colitis in Australia: the benefits to patients

The efficacy of infliximab has been demonstrated in patients with both acute severe and moderate‐severe ulcerative colitis (UC). However, there is a need for ‘real‐life data’ to ensure that conclusions from trial settings are applicable in usual care. We therefore examined the national experience of anti‐tumour necrosis factor‐α (TNF‐α) therapy in UC.

Dose tailoring of anti-tumour necrosis factor-alpha therapy delivers useful clinical efficacy in Crohn disease patients experiencing loss of response

‘Dose tailoring’ of anti‐tumour necrosis factor alpha (TNF‐α) therapy in Crohn disease (CD), by dose escalation, or shortening of dosing intervals, has been suggested to regain clinical response following a flare in a proportion of patients. However, reported outcome data are sparse and none exists from Australia.

Vitamin D C3-epimer levels are proportionally higher with oral vitamin D supplementation compared to ultraviolet irradiation of skin in mice but not humans

A proportion of circulating 25-hydroxy vitamin D3 (25(OH)D3)) undergoes epimerization to form C3-epi 25(OH)D3 and C3-epi 1,25(OH)2D3. These epimers have less calcaemic activity than non-epimerized metabolites and are not differentiated by many immunoassays when reporting total 25(OH)D3 levels. This study aimed to compare the effect of exposure to ultraviolet radiation (UVR) and oral vitamin D3 supplementation on vitamin D C3-epimer levels. C57Bl/6 female mice were fed either vitamin D-sufficient (vitamin D3 2000 IU/kg) or -deficient diets (no vitamin D3) for 4 weeks. Among the vitamin D-deficient group, the shaved backs of half were irradiated daily for 4 days with 1 kJ/m2 UVR, followed by twice weekly irradiation for 4 weeks. Despite similar 25(OH)D3 levels, the UV-irradiated group had a lower proportion of C3-epi 25(OH)D3 at week 7 (p < 0.05) and week 9 (p < 0.01). C3-epimer concentrations and %C3-epi 25(OH)D3 were also analysed in serum samples from two human clinical trials. These trials investigated the effect of high dose oral vitamin D3 supplementation and narrowband UVB phototherapy, respectively. Serum 25(OH)D3 and the %C3-epi 25(OH)D3 levels measured at 12 months after oral vitamin D3 supplementation were not significantly different to those measured at the time of maximal effect of phototherapy (2 months). Thus, the proportion of 25(OH)D3 that undergoes epimerization is greater with oral vitamin D3 supplementation than exposure to UVR in mice, but not in humans. This important difference between human and murine vitamin D metabolism warrants consideration when interpreting animal studies.

Ultraviolet Irradiation of Skin Alters the Faecal Microbiome Independently of Vitamin D in Mice

Reduced sunlight exposure has been associated with an increased incidence of Crohn’s disease and ulcerative colitis. The effect of ultraviolet radiation (UVR) on the faecal microbiome and susceptibility to colitis has not been explored. C57Bl/6 female mice were fed three different vitamin D-containing diets for 24 days before half of the mice in each group were UV-irradiated (1 kJ/m2) for each of four days, followed by twice-weekly irradiation of shaved dorsal skin for 35 days. Faecal DNA was extracted and high-throughput sequencing of the 16S RNA gene performed. UV irradiation of skin was associated with a significant change in the beta-diversity of faeces compared to nonirradiated mice, independently of vitamin D. Specifically, members of phylum Firmicutes, including Coprococcus, were enriched, whereas members of phylum Bacteroidetes, such as Bacteroidales, were depleted. Expression of colonic CYP27B1 increased by four-fold and IL1β decreased by five-fold, suggesting a UVR-induced anti-inflammatory effect. UV-irradiated mice, however, were not protected against colitis induced by dextran sodium sulfate (DSS), although distinct faecal microbiome differences were documented post-DSS between UV-irradiated and nonirradiated mice. Thus, skin exposure to UVR alters the faecal microbiome, and further investigations to explore the implications of this in health and disease are warranted.

What is in our treasure chest? Australian pharmaceutical benefits scheme availability and criteria for prescribing biologics: Prescribing biologics for IBD in Australia

The development of biological agents has been the single greatest advance in the management of the inflammatory bowel diseases (IBD) over the last 20 years. They improve patient quality of life, reduce the need for surgery, and importantly are cost-effective. In 2014, it was estimated that 80 000 individuals suffered IBD in Australia; during the same year, a total of 7000 patients were on biological agents for Crohn’s disease. Despite this, there are many patients who would benefit from biological therapies but are not started on them for a variety of reasons including poor access to health care, fear of toxicity, and physician reluctance to prescribe them. One major obstacle in Australia is the cumbersome application and re-application process required by the Pharmaceutical Benefits Scheme (PBS) to gain approval for and continue all biological medications. Biological therapies can be accessed on the PBS for the indications of severe refractory luminal Crohn’s disease, complex refractory fistulising Crohn’s disease, moderate–severe ulcerative colitis, and acute severe ulcerative colitis. For the indication of severe refractory luminal Crohn’s disease, there are four agents now approved: infliximab, adalimumab, vedolizumab, and ustekinumab. For patients who qualify for therapy, any of these agents can be used first-line. Prior to qualifying, patients need to have failed to achieve adequate response with a tapered course of corticosteroids, at a dose of at least 40 mg prednisone over a 6-week period, failed to achieve adequate response to appropriately dosed azathioprine, 6-mercaptopurine, or methotrexate for 3 months, and have a Crohn’s Disease Activity Index greater than or equal to 300 (or 220 in the case of extensive small bowel disease or have short gut syndrome). To continue therapy, patients must demonstrate a response to treatment with a Crohn’s Disease Activity Index < 150 assessed at week 12 or appropriate radiological and biochemical response in the case of extensive small bowel Crohn’s disease. Therapy can be changed due to treatment failure (primary non-response, secondary loss of response, or adverse effects), but a maximum of three lines of treatment are allowed within a 5-year cycle. Since the September 1, 2017, all previous “strikes” were canceled to allow patients the opportunity to trial newly available therapies. For a variety of reasons, such as preferred route of administration, patients responding to therapy can swap to an alternative biologic. This is not counted as a “strike” as long as the PBS application for continuation clearly states the patient is responding to therapy. Patients cannot swap to a therapy they have previously failed within the same 5-year cycle. Finally, patients are allowed a medical break and can re-start therapy within the 5-year cycle without having to requalify again for therapy. Infliximab and adalimumab are approved for the treatment of complex refractory fistulising Crohn’s disease. Patients need to have an externally draining enterocutaneous or rectovaginal fistula and a completed fistula assessment form. Treatment response is assessed up to 12 weeks after the first dose of treatment. Rules regarding treatment changes and recommencement are similar to other schemes. For the indication of moderate–severe ulcerative colitis, there are three biologicals approved: infliximab, adalimumab, and vedolizumab. All prior treatment “strikes” were canceled as of December 1, 2016. To qualify for treatment, patients must have failed to achieve adequate response to appropriately dosed 5-aminosalicylate therapy for three or more months; and appropriately dosed azathioprine or 6-mercaptopurine for three or more months; and have a Mayo Clinic score ≥ 6 or partial Mayo clinical score ≥ 6, provided the rectal bleeding and stool frequency sub-scores are both ≥ 2. Response is demonstrated by partial Mayo Clinic score ≤ 2, with no sub-score greater than 1. Patients with acute severe ulcerative colitis, as defined by the Truelove–Witts criteria, and not responding to 72 h of IV corticosteroids according the Oxford days 3 and 7 criteria are eligible to access treatment with infliximab. The initial dose is not funded by the PBS; however, if the patient responds, the subsequent two induction doses can be accessed by streamlined authority. There continues to be confusion among prescribers about ongoing PBS funding of infliximab in those responding to induction infliximab therapy. Patients not previously on a thiopurine do not qualify for maintenance infliximab on the moderate–severe scheme as they have not demonstrated failure to thiopurines. It is therefore important to start the thiopurine as early as possible during the first hospital admission, such that if symptoms relapse after 3 months, they will qualify for maintenance infliximab. Patients suffering acute severe ulcerative colitis while already on an appropriately dosed thiopurine for 3 months or more qualify for maintenance infliximab on the moderate–severe scheme. A number of PBS changes are expected in the next 12–24 months. Firstly, the subcutaneous anti-TNF golimumab (Simponi), received a positive recommendation from the Pharmaceutical Benefits Advisory Committee in November 2017 for moderate–severe ulcerative colitis and is expected to be PBS-listed during 2018. Several biosimilar agents are now marketed in Australia for indications in rheumatology, dermatology, and gastroenterology. The etanercept biosimilar, Brenzys, has been approved for streamlined authority after the first continuation doi:10.1111/jgh.14420