Hyperhomocysteinemia in patients with Crohn’s disease

Background

Thromboembolic complications have been reported in patients with Crohn’s disease. Among the contributing factors, hyperhomocysteinemia has been described, although controversial data exist. The aim of our study was to assess the incidence of hyperhomocysteinemia in a nonselected group of patients with Crohn’s disease and to determine whether it might represent a risk marker for thrombosis in such patients.

Methods

Fifty consecutive patients were recruited, and clinical and laboratory variables were compared between those without and those with hyperhomocysteinemia. In the latter, gene mutations in N5-N10-methyltetrahydrofolate reductase were searched for, and clinical and laboratory variables were related to hyperhomocysteinemia. The presence/absence of thrombotic episodes in both groups was determined.

Results

Both groups had similar clinically active disease, with higher C-reactive protein values found in those with hyperhomocysteinemia. Hyperhomocysteinemia was found in 46 % of patients. Of these, 74 % had moderate, 13 % intermediate, and 13 % severe increase in serum homocysteine levels. No relationship was found between homocysteine levels, and age, vitamin B12 levels, folic acid levels, Crohn’s Disease Activity Index score, and CRP values. Gene mutations were found in 5 (22 %) patients, 2 homozygotes and 3 heterozygotes. None of the patients with or without hyperhomocysteinemia had episodes of venous or arterial thrombosis, or stroke.

Conclusions

Hyperhomocysteinemia is frequent in patients with Crohn’s disease, and it could be a cofactor for the pathogenesis of thrombotic episodes.     

Varicella zoster meningitis complicating combined anti-tumor necrosis factor and corticosteroid therapy in Crohn’s disease

Opportunistic viral infections are a well-recognized complication of anti-tumor necrosis factor (TNF) therapy for inflammatory bowel disease (IBD). Cases of severe or atypical varicella zoster virus infection, both primary and latent reactivation, have been described in association with immunosuppression of Crohn’s disease (CD) patients. However, central nervous system varicella zoster virus infections have been rarely described, and there are no previous reports of varicella zoster virus meningitis associated with anti-TNF therapy among the CD population. Here, we present the case of a 40-year-old male with severe ileocecal-CD who developed a reactivation of dermatomal herpes zoster after treatment with prednisone and adalimumab. The reactivation presented as debilitating varicella zoster virus meningitis, which was not completely resolved despite aggressive antiviral therapy with prolonged intravenous acyclovir and subsequent oral valacyclovir. This is the first reported case of opportunistic central nervous system varicella zoster infection complicating anti-TNF therapy in the CD population. This paper also reviews the literature on varicella zoster virus infections of immunosuppressed IBD patients and the importance of vaccination prior to initiation of anti-TNF therapy.     

Positive impact of blocking tumor necrosis factor α on the nutritional status in pediatric Crohn’s disease patients

Background  TNFα seems to contribute to inflammation and malnutrition in Crohn’s disease (CD) patients. In CD patients, the comparative effects on nutritional status of infliximab and traditional therapy have not yet been determined. The aim of our study was to assess the effects of infliximab as compared with those of standard therapy on nutritional status, disease activity, resting energy expenditure (REE), and food intake in CD children and adolescents. Methods  From September 1999 to September 2005, all CD patients treated with infliximab (group A) were reviewed and matched with CD patients treated with traditional therapy (mesalazine and azathioprine) (group B). Results  Fourteen CD patients from group A and 14 from group B were included; median interval before follow-up investigation was 10 months. Baseline and final values of weight, height, body mass index (BMI), pediatric CD activity index (pCDAI), REE, and food intake were studied. In treated patients, but not in control group, mean baseline weight (kg) and BMI values, 39.7 ± 13.1 and 17.9 ± 3.3, respectively, were significantly lower than their final values 42.6 ± 13.2 and 18.9 ± 3.1, and median pCDAI values 23.5 were significantly higher than their final values 10 (P < 0.05). Significant changes in height, REE, and food intake were not found in either group. Conclusions  In pediatric CD patients, infliximab seems to impact positively on the nutritional status as demonstrated by the improvement in weight and BMI, but not in linear growth; effects on nutritional status seem to be due to amelioration of disease activity, rather than to REE reduction or food intake increase.     

Clinical effects of adalimumab treatment with concomitant azathioprine in Japanese Crohn’s disease patients

AIM:To assess adalimumab’s efficacy with concomitant azathioprine (AZA) for induction and maintenance of clinical remission in Japanese Crohn’s disease (CD) patients. METHODS:This retrospective, observational, singlecenter study enrolled 28 consecutive CD patients treated with adalimumab (ADA). Mean age and mean disease duration were 38.1 ± 11.8 years and 11.8 ± 10.1 years, respectively. The baseline mean Crohn’s disease activity index (CDAI) and C-reactive protein were 177.8 ± 82.0 and 0.70 ± 0.83 mg/dL, respectively. Twelve of these patients also received a concomitant stable dose of AZA. ADA was subcutaneously administered:160 mg at week 0, 80 mg at week 2, followed by 40 mg every other week. Clinical response and remission rates were assessed via CDAI and C-reactive protein for 24 wk. RESULTS:The mean CDAI at weeks 2, 4, 8, and 24 was 124.4, 120.2, 123.6, and 135.1, respectively. The CDAI was significantly decreased at weeks 2 and 4 with ADA and was significantly suppressed at 24 wk with ADA/AZA. Overall clinical remission rates at weeks 4 and 24 were 66.7% and 63.2%, respectively. Although no statistically significant difference in C-reactive protein was demonstrated, ADA with AZA resulted in a greater statistically significant improvement in CDAI at 24 wk, compared to ADA alone. CONCLUSION:Scheduled ADA with concomitant AZA may be more effective for clinical remission achievement at 24 wk in Japanese Crohn’s disease patients.     

Intestinal cancer in patients with Crohn’s disease

Background Surveillance of intestinal cancer in Crohn’s disease (CD) has often been advocated. To date, no clear evidence exists whether CD patients are at special risk for intestinal cancer. An increased incidence of small bowel adenocarcinoma is suggested. However, recent figures also suggest an increased risk of CD associated colorectal cancer. We report our experience with 10 cases of CD complicated by intestinal adenocarcinoma. Materials and methods Our institutional database included 330 patients treated for CD between 1988–2005. Data of patients that developed carcinoma within Crohn’s lesions of either small or large bowel were analyzed. Results Ten patients were diagnosed with CD complicated by carcinoma. In nine patients, cancer was present in the colorectum and in one, in Crohn’s ileitis. Tumors were in conjunction with fistulae in three and developed within strictures in five patients. Mean age at the time of diagnosis of CD was 43 years. Mean duration of CD until diagnosis of cancer was 14 years. Only five patients were diagnosed for cancer preoperatively. Staging revealed advanced tumors in almost all patients. Mean survival after surgery was 29 months (2–149 months). Conclusions Cancer risk in CD and especially in Crohn’s colitis may still be underestimated. Delayed diagnosis resulted in a poor prognosis. The value of colonoscopy as surveillance tool is questioned by the fact that in our patients, carcinoma was diagnosed in some patients preoperatively by routine colonoscopy. Therefore, additional markers should be identified to detect CD patients at risk.     

Severe cholestasis due to adalimumab in a Crohn’s disease patient

Elevation of liver biochemistry has been reported with anti-tumor necrosis factor agents, but overt liver failure rarely reported. Autoimmune hepatitis has been more commonly reported with infliximab than adalimumab(ADA). Our case, however, describes the first reported case of ADA-associated severe cholestatic injury. A 39-year-old female with Crohn’s disease developed severe jaundice after initiation of ADA. All serologic tests and imaging studies were normal. Liver biopsy showed prominent pericentral canalicular cholestasis,without features of steatosis or sclerosing cholangitis,consistent with drug-induced cholestasis. The serum total bilirubin peaked at 280 μmol/L, and improvement was seen after 5 wk with eventual normalization of liver enzymes at 10 wk. Our case describes the first reported case of ADA-associated severe cholestatic liver disease and the first histopathologic examination of this adverse drug effect. Clinicians need to be aware of this potential drug-induced liver injury when prescribing this commonly used biologic medication.     

Infliximab treatment for Crohn’s disease in a patient with IgA nephropathy

We describe herein a case of IgA nephropathy in a 34-year-old woman with Crohn’s disease (CD) treated with infliximab. CD first appeared at the age of 15 years. An elemental diet was started for remission maintenance. Ten years later, the patient suffered from a recto-vaginal fistula and subtotal colectomy with stoma formation was performed. At the age of 33 years, the patient was investigated for painless macroscopic hematuria and proteinuria. Renal biopsy revealed IgA nephropathy. Mizoribine was started but proteinuria persisted. Due to diarrhea she was admitted to our hospital, and scheduled maintenance therapy with infliximab was initiated. After the first infliximab infusion, the patient presented significant clinical improvement in both diarrhea and proteinuria with concomitant decrease of C-reactive protein to normal levels and proteinuria ~1 g/day. This represents the first report of infliximab treatment in a patient with IgA nephropathy associated with CD and clarifies the importance of tumor necrosis factor-alpha (TNFα) in immunity to renal disease. Further studies are needed to draw firm conclusions for the safety of infliximab in patients with IgA nephropathy.     

Efficacy of early treatment with infliximab in pediatric Crohn’s disease

AIM: To investigate the effectiveness of early infliximab use for induction and maintenance therapy in pediatric Crohn’s disease. METHODS: We performed a retrospective chart review of 36 patients with Crohn’s disease. Ten patients (group A) were treated with mesalamine after induction therapy with oral prednisolone, and 13 patients (group B) were treated with azathioprine after induction therapy with oral prednisolone. Thirteen patients (group C) received infliximab and azathioprine for induction and mainte...     

Correlations between skin lesions induced by anti-tumor necrosis factor-α and selected cytokines in Crohn’s disease patients

AIM:To investigate the correlation between the appearance of skin lesions and concentration of interleukin(IL)-17A,IL-23 and interferon-γ(IFN-γ)in Crohn’s disease(CD)patients during anti-tumor necrosis factor-α(TNF-α)therapy METHODS:A prospective study included 30 adult patients with CD of Caucasian origin(19 men and 11women;mean age±SD 32.0±8.6 years)during biological therapy with anti-TNF-αantibodies from January2012 to March 2013.Eighteen patients were treated with infliximab,seven with adalimumab and five withcertolizumab.Inclusion criteria were exacerbation of the underlying disease,Crohn’s Disease Activity Index over 300 and the ineffectiveness of previously used non-biological therapies.Patients with a history of psoriasis,atopic dermatitis and other autoimmune skin lesions were excluded from the study.The control group consisted of 12 healthy subjects.A diagnostic survey was carried out,blood tests and careful skin examination were performed,and the serum levels of IL-17,IL-23 and IFN-γwere measured using an enzyme-linked immunosorbent assays technique.Dermatoses that have developed in the course of biological therapy in patients who had no pre-existing skin lesions of similar character were qualified as skin lesions induced by antiTNF-αtherapy.RESULTS:Skin manifestations occurred in 18 of CD patients during the anti-TNF-αtherapy(60%),in the average time of 10.16±3.42 mo following the beginning of the 52-wk treatment cycle.Skin lesions observed in CD patients during biological therapy included psoriasiform lesions(44.4%),and eczema forms lesions(22.2%).In CD patients with drug induced skin lesions significantly higher levels of hemoglobin(13.3±1.5 g/dL vs 10.8±1.9 g/dL,P=0.018)and hematocrit(39.9%±4.5%vs 34.3%±5.4%,P=0.01),as well as a significantly lower level of platelets(268±62×103/μL vs 408±239×103/μL,P=0.046)was observed compared with CD patients without skin manifestations.The concentrations of IL-17A and IL-23in CD patients with skin lesions developed under antiTNF-αtherapy were significantly higher compared to those in patients without lesions(IL-17A:39.01±7.03pg/mL vs 25.71±4.90 pg/mL,P=0.00004;IL-23:408.78±94.13 pg/mL vs 312.15±76.24 pg/mL,P=0.00556).CONCLUSION:Skin lesions in CD patients during bio-logical therapy may result from significantly increased concentrations of IL-17A and IL-23,which are strongly associated with TNF-α/Th1 immune pathways.     

Treatment of pediatric refractory Crohn’s disease with thalidomide

AIM: To assess the efficacy and tolerability of thalidomide in pediatric Crohn’s disease (CD). METHODS: Six patients with refractory CD received thalidomide at an initial dose of 2 mg/kg per day for one month, then increased to 3 mg/kg per day or decreased to 1 mg/kg per day, and again further reduced to 0.5 mg/kg per day, according to the individual patient’s response to the drug. RESULTS: Remission was achieved within three months. Dramatic clinical improvement was demonstrated after thalidomide treatment...     

Adalimumab dose escalation is effective and well tolerated in Crohn’s disease patients with secondary loss of response to adalimumab

BackgroundAlthough adalimumab is effective in Crohn’s disease, most patients experience a loss of response over time. The aim of the present study was to evaluate efficacy and safety of adalimumab dose escalation and identify predictors of a clinical response in Crohn’s disease patients with a secondary loss of response.MethodsWe performed a retrospective and observational study including all Crohn’s disease patients who underwent dose escalation of adalimumab after a secondary loss of response from 2007 to 2015.ResultsA clinical response was observed in 99/124 (79%) patients at 3 months and in 62/107 (61%) patients at 12 months. The predictive factors of response to ADA dose escalation at 12 months on multivariate analysis were: maintenance therapy of 40 mg every week rather than 80 mg every other week (OR 3.64, 95% CI: 1.28–10.37) and a CRP level ≤ 5 mg/L at adalimumab dose escalation (OR 6.64, 95% CI: 1.40–27.53). Adalimumab was withdrawn in 4 patients due to side effects.ConclusionsAdalimumab dose escalation is an effective and well-tolerated therapeutic option in patients with secondary loss of response. A 40 mg every week optimized regimen was predictive of a response to ADA dose escalation.     

Usefulness of a rapid faecal calprotectin test to predict relapse in Crohn’s disease patients on maintenance treatment with adalimumab

Background and aim Predicting relapse in Crohn’s disease (CD) patients by measuring non-invasive biomarkers could allow for early changes of treatment. Data are scarce regarding the utility of monitoring calprotectin to predict relapse. The aim of the study was to evaluate the predictive value of a rapid test of faecal calprotectin (FC) to predict for flares in CD patients on maintenance treatment with adalimumab (ADA). Methods A prospective, observational cohort study was designed. Inclusion criteria were CD patients in clinical remission on a standard dose of ADA therapy. Fresh FC was measured using a rapid test. Results Thirty patients were included (median age 38 years, 56.7% female). After the 4 months follow-up, 70.0% patients remained in clinical remission and 30.0% had a relapse. FC concentration at inclusion was significantly higher in those patients who relapsed during the follow-up (625?μg/g) compared to those who stayed in remission (45?μg/g). The optimal cut-off for FC to predict relapse was 204?μg/g. The area under the receiver-operating characteristic curve was 0.968. Sensitivity, specificity, positive, and negative predictive value of FC to predict relapse were 100%, 85.7%, 74.1%, and 100%, respectively. Conclusion In CD patients on ADA maintenance therapy, FC levels measured with a rapid test allow relapse over the following months to be predicted with high accuracy. Low FC levels exclude relapse within at least 4 months after testing, whereas high levels are associated with relapse in three out of every four patients.     

How should immunomodulators be optimized when used as combination therapy with anti-tumor necrosis factor agents in the management of inflammatory bowel disease?

In the last 15 years the management of inflammatory bowel disease has evolved greatly,largely through the increased use of immunomodulators and,especially,anti-tumor necrosis factor(anti-TNF) biologic agents. Within this time period,confidence in the use of anti-TNFs has increased,whilst,especially in recent years,the efficacy and safety of thiopurines has been questioned. Yet despite recent concerns regarding the risk: benefit profile of thiopurines,combination therapy with an immunomodulator and an anti-TNF has emerged as the recommended treatment strategy for the majority of patients with moderate-severe disease,especially those who are recently diagnosed. Concurrently,therapeutic drug monitoring has emerged as a means of optimizing the dosage of both immunomodulators and antiTNFs. However the recommended therapeutic target levels for both drug classes were largely derived from studies of monotherapy with either agent,or studies underpowered to analyze outcomes in combination therapy patients. It has been assumed that these target levels are applicable to patients on combination therapy also,however there are few data to support this. Similarly,the timing and duration of treatment with immunomodulators when used in combination therapy remains unknown. Recent attention,including post hoc analyses of the pivotal registration trials,has focused on the optimization of anti-TNF agents,when used as either monotherapy or combination therapy. This review will instead focus on how best to optimize immunomodulators when used in combination therapy,including an evaluation of recent data addressing unanswered questions regarding the optimal timing,dosage and duration of immunomodulator therapy in combination therapy patients.     

Cross-sectional evaluation of transmural healing in patients with Crohn’s disease on maintenance treatment with anti-TNF alpha agents

BackgroundTransmural healing (TH) of Crohn’s disease (CD) is a still unexplored and interesting outcome correlated to concept of deep remission.AimTo assess the rate of TH in CD patients treated with anti-TNF alpha agents using two cross-sectional procedures: bowel sonography (BS) and magnetic resonance enterography (MRE).MethodsWe performed a 2-year observational longitudinal study, evaluating steroid-free clinical remission (CR), mucosal healing (MH), and TH in CD patients who would complete a 2-year treatment period with anti-TNFs. All patients underwent endoscopy, BS, and MRE before and after 2 years of treatment.ResultsForty out of 80 CD patients were treated with anti-TNFs for 2 years. CR was achieved in 24 patients (60%) while MH in 14 (35%). Using BS, TH was observed in 10 patients (25%), while using MRE, TH was observed in 9 patients (23%) (k = 0.90; P < 0.01). A good agreement was observed between MH and TH, both using BS (k = 0.63; P < 0.01) and MRE (k = 0.64; P < 0.01). A poor agreement was found between CR and TH, with both BS and MRE (k = 0.27 and 0.29, respectively; P < 0.01); even though all patients with TH had achieved CR.ConclusionsTH can be achieved in about 25% of CD patients treated with anti-TNFs, as shown by BS and MRE. BS could be used as the first cross-sectional procedure to detect TH.     

Epstein–Barr virus-positive mucocutaneous ulcer in Crohn’s disease. A condition to consider in immunosuppressed IBD patients

Epstein–Barr virus-positive mucocutaneous ulcer (EBVMCU) is a little known entity that can affect the oropharyngeal mucosa, the gastrointestinal tract and the skin. The main risk factor for the development of this lesion is immunosuppression. Because its features are similar to other Epstein–Barr virus-associated lymphoproliferative disorders, a differential diagnosis can sometimes prove challenging. Here, we report the case of a man diagnosed with Crohn’s disease and treated with azathioprine and infliximab who developed ulceration at the rectum that was refractory to conventional medical treatment. Although the histological characteristics were suggestive of an EBVMCU, lymphoproliferative disease could not be ruled out. The patient did not improve after discontinuation of the treatment, a proctectomy was performed and the diagnosis of this disease was confirmed. Although very few cases of EBVMCU affecting the colon have been reported, its diagnosis should be always considered in refractory cases of inflammatory bowel disease with patients undergoing immunosuppressive treatment.