Current, experimental, and future treatments in inflammatory bowel disease: a clinical review.

Inflammatory bowel diseases (IBDs) may result from dysregulated mucosal immune responses directed toward the resident intestinal microbiota. This review describes the hallmark immunobiology of Crohn's disease and ulcerative colitis as well as therapeutic targets and mechanisms of action for current, experimental, and future treatments in IBD. Conventional therapies include 5-aminosalicylic acid, glucocorticosteroids, thiopurines, and methotrexate. Since 1997, monoclonal antibodies have gained widespread use. These consist of antibodies directed against pro-inflammatory cytokines such as tumor necrosis factor α, interleukin (IL)-12, and IL-23, or anti-homing antibodies directed against α4ß7 integrin. Emerging oral therapies include modulators of intracellular signal transduction such as Janus kinase inhibitors. Vitamin D may help to regulate innate and adaptive immune responses. Modulation of the intestinal microbiota, using live microorganisms (probiotics), substrates for the colonic microbiota (prebiotics), or fecal microbiota transplantation (FMT), is in development. Dietary supplements are in widespread use, but providing evidence for their benefit is challenging. Stem cell treatment and nervous stimulation are promising future treatments.

Casein glycomacropeptide for active distal ulcerative colitis: a randomized pilot study.

BACKGROUND: In ulcerative colitis (UC), dietary supplements may have anti-inflammatory properties and improve disease course. We investigated the effects of casein glycomacropeptide (CGMP), a fraction of bovine whey protein, in active UC. MATERIALS AND METHODS: In a randomized open-label intervention study, 24 patients with active UC involving 10-40 cm of the distal colon were randomized in a 2 : 1 ratio into two groups. The first group was administered their usual treatment plus a daily supplement of CGMP 30 g, and the second group was administered a dose escalation to 4800 mg oral mesalamine daily (standard treatment) for 4 weeks. Clinical, endoscopic, mucosal and circulating disease activity markers were monitored. Acceptance of and adherence to CGMP up to 8 weeks were documented. RESULTS: After 4 weeks of treatment, 10 of 16 (63%) patients who received CGMP had an unchanged or decreased Simple Clinical Colitis Activity Index (SCCAI), which was similar to the four of eight (50%) (P = 0·67) patients on the standard treatment. The number of patients in which SCCAI decreased by three or more did not differ between the two groups: nine of 16 (56%) in the CGMP group vs. four of eight (50%) in the standard treatment group (P = 0·77). Changes in disease extent and severity were similar between the two groups. CGMP was well tolerated and accepted by the patients. CONCLUSIONS: The addition of CGMP as a nutritional therapy to standard treatment was safe and accepted by patients with active distal UC. The disease-modifying effect of CGMP was similar to that of the mesalamine dose escalation.

Administration of Panobinostat Is Associated with Increased IL-17A mRNA in the Intestinal Epithelium of HIV-1 Patients.

Intestinal CD4(+) T cell depletion is rapid and profound during early HIV-1 infection. This leads to a compromised mucosal barrier that prompts chronic systemic inflammation. The preferential loss of intestinal T helper 17 (Th17) cells in HIV-1 disease is a driver of the damage within the mucosal barrier and of disease progression. Thus, understanding the effects of new therapeutic strategies in the intestines has high priority. Histone deacetylase (HDAC) inhibitors (e.g., panobinostat) are actively under investigation as potential latency reversing agents in HIV eradication studies. These drugs have broad effects that go beyond reactivating virus, including modulation of immune pathways. We examined colonic biopsies from ART suppressed HIV-1 infected individuals (clinicaltrials.gov: NCT01680094) for the effects of panobinostat on intestinal T cell activation and on inflammatory cytokine production. We compared biopsy samples that were collected before and during oral panobinostat treatment and observed that panobinostat had a clear biological impact in this anatomical compartment. Specifically, we observed a decrease in CD69(+) intestinal lamina propria T cell frequency and increased IL-17A mRNA expression in the intestinal epithelium. These results suggest that panobinostat therapy may influence the restoration of mucosal barrier function in these patients.

Oral vitamin D3 supplementation reduces monocyte-derived dendritic cell maturation and cytokine production in Crohn's disease patients.

BACKGROUND: Low serum vitamin D levels may provoke or aggravate Crohn's disease (CrD). Vitamin D3 is a well-known immune modulator that affects immune functions in vitro and may prevent CrD flares. Dendritic cells (DC) are key mediators of vitamin D3 effects. In this study, we describe changes in monocyte-derived DC (mo-DC) maturation marker expression and cytokine production following 26 weeks of oral vitamin D3 supplementation in CrD patients. METHODS: Ten CrD patients who had increased serum 25-hydroxy vitamin D levels after oral vitamin D3 and calcium treatment and ten seasonally matched placebo-treated patients were selected for this study. Mo-DC were generated before and after the 26 weeks and induced to mature upon lipopolysaccharide (LPS) stimulation. Maturation marker expression and cytokine production were analysed. Mo-DC function was analysed in a mixed leucocyte reaction (MLR). RESULTS: Compared with baseline values, LPS-matured mo-DC exhibited reduced expression of CD80 and reduced production of the cytokines IL-10, IL-1ß, and IL-6 following 26 weeks of oral vitamin D3 supplementation. Mo-DC performance in an allogeneic MLR was unchanged after vitamin D3 supplementation. Treatment with the placebo did not affect maturation markers, cytokine production, or the MLR. CONCLUSIONS: Vitamin D3 treatment in CrD patients led to hypo-responsive LPS-stimulated mo-DC. This finding indicates that vitamin D3 levels have an impact on the monocytic precursors of mo-DC in vivo and may explain the positive effects of vitamin D3 supplementation on CrD patients. Alternatively, CrD patients with high serum vitamin D3 levels may represent a subgroup with low disease activity.

Acute pancreatitis in an ulcerative colitis patient treated with vedolizumab and budesonide.

Acute pancreatitis (AP) is a sudden inflammation of the pancreas which often manifests as a mild disease but can be associated with high morbidity and mortality. Drug-induced AP is rare and most likely underdiagnosed. Vedolizumab is a human monoclonal antibody with gut-selective integrin antagonist effect, and it is used for treatment of inflammatory bowel disease (IBD). Budesonid is a glucocorticoid which is released in the colon and it is also used in IBD treatment. This is a case report where vedolizumab or budesonide caused acute pancreatitis in a young man with ulcerative colitis.

25-Hydroxy vitamin D3 modulates dendritic cell phenotype and function in Crohn's disease.

BACKGROUND: In Crohn's disease (CrD), vitamin D may help to balance an exaggerated immune response and thereby improve the disease course. The immunomodulating effects depend on the activation of 25-hydroxy vitamin D3 (25-D3), into 1,25-dihydroxy vitamin D3 (1,25-D3). This activation has previously been shown to take place in dendritic cells (DC) from healthy individuals. We hypothesised that DC from CrD patients are able to regulate and control inflammatory responses through 25-D3 activation. METHODS: During differentiation, monocyte-derived DC from 20 CrD patients were cultured with either 25-D3 or 1,25-D3 and matured with lipopolysaccharide (LPS). We examined DC surface marker expression, cytokine production, and the ability to induce cell proliferation in an allogeneic mixed leukocyte reaction. RESULTS: Following stimulation with LPS, DC exposed to either 25-D3 or 1,25-D3 exhibited lower expression levels of CD80, CD83, CD86, and HLA-DR and diminished TNF-α production compared with DC cultured with LPS alone. In contrast, CD14 expression and IL-6 production were higher following 25-D3 or 1,25-D3 treatment. Compared with LPS alone, both forms of vitamin D3 reduced the ability of DC to activate lymphocytes. CONCLUSIONS: Following stimulation with 25-D3, DC from CrD patients displayed a reduced response to LPS with a diminished capability to activate T cells compared with DC stimulated with LPS alone. These data indicate that intrinsic activation of 25-D3 occurs in DC from CrD patients and show that 25-D3 can modulate DC function in CrD. Our data suggest that vitamin D deficiency may contribute to the uncontrolled inflammatory process seen in CrD.

Fecal Supernatants from Patients with Crohn's Disease Induce Inflammatory Alterations in M2 Macrophages and Fibroblasts.

Intestinal macrophages and fibroblasts act as microenvironmental sentinels mediating inflammation and disease progression in Crohn's disease (CD). We aimed to establish the effects of fecal supernatants (FSs) from patients with CD on macrophage and fibroblast phenotype and function. FS were obtained by ultracentrifugation, and the metabolites were analyzed. Monocyte-derived M2 macrophages and fibroblasts were conditioned with FS, and secreted proteins, surface proteins and gene expression were analyzed. M2 macrophage efferocytosis was evaluated. Patients with CD (n = 15) had a skewed fecal metabolite profile compared to healthy subjects (HS, n = 10). FS from CD patients (CD-FS) induced an anti-inflammatory response in M2 macrophages with higher expression of IL-10, IL1RA and CD206 as compared to healthy FS (HS-FS) while the efferocytotic capacity was unaltered. CD-FS did not affect extracellular matrix production from fibroblasts, but increased expression of the pro-inflammatory proteins IL-6 and MCP-1. Conditioned media from M2 macrophages treated with CD-FS modulated gene expression in fibroblasts for TGFß superfamily members and reduced IL-4 expression compared to HS-FS. We show that M2 macrophages and fibroblasts react abnormally to the fecal microenvironment of CD patients, resulting in altered protein expression related to inflammation but not fibrosis. This implies that the gut microbiota and its metabolites have an important role in the generation and/or perpetuation of inflammation in CD.

Seven Weeks of High-Dose Vitamin D Treatment Reduces the Need for Infliximab Dose-Escalation and Decreases Inflammatory Markers in Crohn's Disease during One-Year Follow-Up.

BACKGROUND: Seven weeks of high-dose vitamin D treatment decreases intestinal IL17A and IFN-γ mRNA expression in active Crohn's disease (CD). In this follow-up study, we investigated whether seven-week vitamin D treatment affected the infliximab response in the following 45 weeks compared to placebo. METHODS: CD patients (n = 40) were initially randomised into four groups: infliximab + vitamin-D; infliximab + placebo-vitamin-D; placebo-infliximab + vitamin-D; and placebo-infliximab + placebo-vitamin-D. Infliximab (5 mg/kg) or placebo-infliximab was administered at weeks 0, 2 and 6. Vitamin D (5 mg bolus followed by 0.5 mg/day for 7 weeks) or placebo-vitamin D was handed out. After the 7-week vitamin D period, all patients received infliximab during follow-up. Results are reported for Group D+ (infliximab + vitamin-D and placebo-infliximab + vitamin-D) and Group D- (infliximab + placebo-vitamin-D and placebo-infliximab + placebo-vitamin-D). RESULTS: Group D- patients had greater needs for infliximab dose escalation during follow-up compared to group D+ (p = 0.05). Group D+ had lower median calprotectin levels week 15 (p = 0.02) and week 23 (p = 0.04) compared to group D-. Throughout follow-up, group D+ had 2.2 times (95% CI: 1.1-4.3) (p = 0.02) lower median CRP levels compared with group D-. CONCLUSIONS: Seven weeks high-dose vitamin D treatment reduces the need for later infliximab dose-escalation and reduces inflammatory markers. EudraCT no. 2013-000971-34.

Decrease in Mucosal IL17A, IFNγ and IL10 Expressions in Active Crohn's Disease Patients Treated with High-Dose Vitamin Alone or Combined with Infliximab.

BACKGROUND: Vitamin D treatment may reduce Crohn's disease (CD) activity by modulating the mucosal immune function. We investigated if high-dose vitamin D +/- infliximab modulated the mucosal cytokine expression in active CD. METHODS: Forty CD patients were randomized into: infliximab + vitamin D; infliximab + placebo-vitamin D; placebo-infliximab + vitamin D or placebo-infliximab + placebo-vitamin D. Infliximab (5 mg/kg) and placebo-infliximab were administered at weeks 0, 2 and 6. Oral vitamin D was administered as bolus 200,000 international units (IU) per week 0 followed by 20,000 IU/day for 7 weeks or placebo. Endoscopy with biopsies was performed at weeks 0 and 7 where endoscopic activity was measured and mucosal mRNA cytokine expression was examined. C-reactive protein (CRP), fecal calprotectin and Harvey-Bradshaw Index (HBI) were measured at weeks 0, 2 and 6. RESULTS: High-dose vitamin D treatment alone and combined with infliximab decreased the IL17A, IFNγ and IL10 expression. High-dose vitamin D alone did not significantly decrease the disease activity, CRP or calprotectin. Combined infliximab and vitamin D treatment was not clinically significantly superior to monotherapy with infliximab. CONCLUSIONS: High-dose vitamin D as monotherapy and combined with infliximab decreases IL17A, IFNγ and IL-10 expression in mucosa within treatment groups. This did not induce a statistically significant decreased disease activity. EudraCT no.2013-000971-34.

Vitamin D increases programmed death receptor-1 expression in Crohn's disease.

BACKGROUND: Vitamin D modulates inflammation in Crohn's disease (CD). Programmed death (PD)-1 receptor contributes to the maintenance of immune tolerance. Vitamin D might modulate PD-1 signalling in CD. AIM: To investigate PD-1 expression on T cell subsets in CD patients treated with vitamin D or placebo. METHODS: We included 40 CD patients who received 1200 IU vitamin D3 for 26 weeks or placebo and eight healthy controls. Peripheral blood mononuclear cells (PBMCs) and plasma were isolated at baseline and week 26. The expressions of PD-1, PD-L1, and surface activation markers were analysed by flow cytometry. Soluble PD-1 plasma levels were measured by ELISA. RESULTS: PD-1 expression upon T cell stimulation was increased in CD4+CD25+int T cells in vitamin D treated CD patients from 19% (range 10 - 39%) to 29% (11 - 79%)(p = 0.03) compared with placebo-treated patients. Vitamin D treatment, but not placebo, decreased the expression of the T cell activation marker CD69 from 42% (31 - 62%) to 33% (19 - 54%)(p = 0.01). Soluble PD-1 levels were not influenced by vitamin D treatment. CONCLUSIONS: Vitamin D treatment increases CD4+CD25+int T cells ability to up-regulate PD-1 in response to activation and reduces the CD69 expression in CD patients.