Didia B. Cury

The impact of infliximab infusion reactions on long-term outcomes in patients with Crohn’s disease

Background  Little is known about long‐term outcomes in patients who experience infusion reactions while receiving infliximab.

Ocular manifestations in a community‐based cohort of patients with inflammatory bowel disease

Background: Ophthalmologic diseases in patients with inflammatory bowel disease (IBD) have been reported with varying frequency, mostly from tertiary referral centers. The aim was to describe the spectrum of ophthalmologic conditions in patients with IBD in a community setting and to compare it with a control non‐IBD cohort. Methods: A prospective cohort of patients with Crohns disease (CD), ulcerative colitis (UC), and non‐IBD controls underwent evaluation by an ophthalmologist, including visual acuity, slit‐lamp exam, and assessment of lacrimal output. Results: The ophthalmologic exam was completed in 112 subjects; 48 with CD, 40 with UC, and 24 controls. Active intestinal disease was present in 52/88 (59%) of the IBD patients, and 79/88 (89%) were taking 5‐aminosalicylates (5‐ASAs). The IBD and control populations had similar age and gender profiles. Patients with IBD were more likely to report ocular symptoms (odds ratio [OR] 5.6, 95% confidence interval [CI] 1.5–20), particularly dry eyes (OR 5.3, 95% CI 1.4–19), than the control population. On objective exam, 42% of IBD patients had evidence of dry eyes. In a univariate analysis, 5‐ASA use was associated with an increased risk of ocular symptoms (OR 7.4, 95% CI 0.9–64), and 5‐ASA use >3 g per day was associated with an increased odds ratio of dry eyes (OR 15, 95% CI 1.9–122). Active disease was not associated with eye symptoms or dry eyes. Other eye conditions such as episcleritis, uveitis, or cataracts were infrequent in this cohort. Conclusions: Patients with IBD in the community frequently have dry eyes. This is associated with 5‐ASA use, particularly doses >3 g per day. Whether this is a surrogate marker of disease severity is unclear. Inflamm Bowel Dis 2010

Impact of a patient-support program on mesalamine adherence in patients with ulcerative colitis--a prospective study.

BACKGROUND Patient adherence to medications, particularly mesalamine, is reported to be low in patients with ulcerative colitis. We sought to determine whether a nurse-delivered patient-support program could improve medication adherence in these patients. METHODS Patients prescribed mesalamine for ulcerative colitis prospectively received either a 23 week, nurse-delivered, patient support program (PSP) by phone, or standard care (SC). Medication adherence and quality of life were measured before and at 3 and 6 months after the program started. RESULTS Eighty-one patients completed the study; 60 who received standard care, and 21 who received the PSP. Patients were in remission (mean SCAI score 3) at enrollment. Mean % of prescribed mesalamine refilled was 71% and 74% in the SC and PSP groups at 3 months (p=0.7), and 73% and 84% at 6 months (p=0.4). The proportion of adherent patients at 3 months (39% vs 44%, p=0.7) and 6 months (50% vs 67%, p=0.3) were similar between the SC and PSP groups. There was no association between use of the PSP and adherence at 3 (OR 1.2, 95% CI 0.4 to 3.8) or 6 months (OR 2, 95% CI 0.6 to 7). The change from baseline in SIBDQ scores were similar between SC and PSP groups at 3 months (+0.3 vs +0.2, p=0.8), and 6 months (+0.6 vs +0.2, p=0.2). CONCLUSIONS This nurse-delivered patient-support program did not significantly improve medication adherence or quality-of-life beyond standard care at short and medium-term time-points. Simply discussing and measuring adherence improved mesalamine adherence in both groups in this study.

Serum calprotectin levels correlate with biochemical and histological markers of disease activity in TNBS colitis

BACKGROUND AND AIM Serum calprotectin is elevated in patients with inflammatory bowel disease (IBD). Whether it correlates other markers of disease activity is unknown. The aim of this study was to correlate serum calprotectin with biochemical and histological measures of intestinal inflammation. MATERIALS AND METHODS TNBS colitis was induced in wistar rats, and serial blood samples were collected at 0, 3, and 12 days. Animals were subsequently sacrificed for pathological evaluation at day 12. Serum calprotectin and cytokines were measured by ELISA. Pathologic changes were classified at the macroscopic and microscopic levels. RESULTS TNBS colitis induced elevated serum calprotectin, TNF and IL-6 within 24 h. Levels of serum calprotectin remained elevated in parallel to persistence of loose stool and weight loss to day 12. Serum calprotectin levels correlated with serum levels of TNF-α and IL6 (p < 0.001), but not CRP. Animals with liquid stool had significantly higher levels of serum calprotectin than control animals. There was a correlation between macroscopic colitis scores, and levels of serum calprotectin. CONCLUSION Serum calprotectin levels correlate with biochemical and histological markers of inflammation in TNBS colitis. This biomarker may have potential for diagnostic use in patients with IBD.

Nephrolithiasis in patients with inflammatory bowel disease in the community

Background Inflammatory bowel disease (IBD) has been associated with renal stone formation. The objective of this study was to determine prospectively the prevalence of nephrolithiasis in a community-based population of patients with IBD and to analyze factors associated with renal calculus formation. Methods Screening renal ultrasound was performed in a well characterized cohort of patients seen between 2009 and 2012 at an IBD clinic. We enrolled 168 patients, including 93 with Crohn’s disease and 75 with ulcerative colitis. Clinical and phenotypic variables associated with asymptomatic nephrolithiasis were determined. Results Nephrolithiasis was detected in 36 patients with Crohn’s disease and in 28 patients with ulcerative colitis (38% for both). Although none of the patients had been previously hospitalized for symptomatic nephrolithiasis, nine with Crohn’s disease and five with ulcerative colitis had recurrent urinary tract infections or hydronephrosis. In patients with Crohn’s disease, ileocolonic (L3) disease was associated with a greater risk of nephrolithiasis than was ileal (L1) or colonic (L2) disease (odds ratio [OR] 2.3, 95% confidence interval [CI] 1.8–7). Active ulcerative colitis (regardless of severity) represented a significant risk factor for formation of renal calculi (OR 4.2, 95% CI 1.1–15, P = 0.02). Conclusion In surgery-naïve patients with IBD in the community, asymptomatic nephrolithiasis is common and should be considered when renal dysfunction or infection is detected.

Adalimumab for cutaneous metastatic Crohn's disease

To the Editor: Cutaneous manifestations are a common extraintestinal feature of inflammatory bowel disease (IBD). In fact, it has been demonstrated that these may occur in up to 34% of patients. Rarely, cutaneous inflammatory changes can occur, which are often referred to as ‘‘metastatic’’ Crohn’s disease (CD). Such manifestations may be refractory to conventional clinical treatment. We present a case of a patient with colonic and metastatic cutaneous CD who was treated with adalimumab (Humira, Abbott, Abbott Park, IL). The patient experienced complete remission from his cutaneous and colonic lesions with this therapy. A Caucasian 21-year-old male with CD for 11 years was referred to our facility in 2007 for management. He had active intestinal disease, with 8 episodes of diarrhea per day, abdominal pain, poor appetite, and weight loss (Crohn’s Disease Activity Index [CDAI] score >250). In addition, he had generalized arthralgias and cutaneous lesions that looked like severe acne (Fig. 1A). These lesions were spread across his face, neck, and thorax, and their severity mirrored his intestinal symptoms. The dermatological diagnosis was initially hydradenitis suppurativa and later labeled severe acne, which was refractory to conventional therapy. Colonoscopy demonstrated active CD in the transverse, descending, and sigmoid colon (Fig. 1B), and histology confirmed this process. Despite initial trials of therapy with prednisone (60 mg), and azathioprine (2 mg/kg), the cutaneous lesions progressed. A skin biopsy showed noncaseating granulomas, consistent with metastatic CD. Adalimumab was begun and the patient was treated with induction and maintenance injections (40 mg) every other week. Within 6 weeks the patient reported a clinical improvement in symptoms. At 6 months, both cutaneous and endoscopic improvement were apparent (Fig. 2A,B). The patient remains in remission on this regimen (CDAI <150). CD may be associated with skin manifestations such as erythema nodosum, erythema multiforme, pyoderma gangrenosum, and aphthoid ulcers. However, metastatic cutaneous CD is a rare condition, and in some cases can be difficult to distinguish from sarcoidosis. In this case both sarcoidosis and tuberculosis were excluded by additional testing and the clinical and histologic picture was consistent with metastatic CD. Previous studies have reported that this CD manifestation is unrelated to intestinal disease geography or activity. The conventional therapy of extraintestinal manifestations such as erythema nodosum and pyoderma gangrenosum is steroids. When this treatment fails, alternative regimens include agents such as dapsone or thalidomide,

Adherence to Rectal Mesalamine in Patients with Ulcerative Colitis.

Background:Rectal mesalamine is an effective induction and maintenance therapy for ulcerative colitis. Little is known about the adherence rates to rectal mesalamine or barriers to its use. The aim was to quantify the prevalence of nonadherence to rectal mesalamine and to identify patient-reported barriers to adherence. Methods:A cohort of patients with ulcerative colitis was prospectively enrolled in this observational study and followed for 12 months. Adherence was assessed by tracking pharmacy refills (medication possession ratio). Individual interviews were undertaken in a subset of subjects. Transcripts from the focus groups and interviews were analyzed to identify themes and links between these themes using qualitative data software (MaxQDA). Results:Seventy patients prescribed rectal mesalamine were prospectively enrolled in the study. At enrollment, 39 of 70 subjects (55%) self-reported “occasional nonadherence” to rectal mesalamine. Over the 12-month follow-up period, only 20 subjects (26%) completed 3 or more refills. Males, or subjects prescribed a once-a-day suppository, were significantly more likely to refill than females (odds ratio = 3.3, 95% confidence interval, 1.1–10.9) or those prescribed suppositories more than once a day (odds ratio = 1.3, 95% confidence interval, 1.1–1.7). By medication possession ratio criteria, 71% of all subjects were nonadherent with their prescribed regimen (medication possession ratio <0.6). Nonadherers were significantly older than adherent subjects: mean age 48 years in nonadherers, versus 37 in adherers, P = 0.04. Patients who were nonadherent to rectal mesalamine frequently cited the mode of administration (65%) and busy lifestyle (40%) as reasons for nonadherence. Conclusions:Intentional nonadherence is common in patients who have been prescribed rectal mesalamine. Gender, age, frequency of dosing, and lifestyle factors may impact adherence.

Treatment of Crohn's disease in pregnant women: drug and multidisciplinary approaches.

Inflammatory bowel disease affects a substantial number of women in their reproductive years. Pregnancy presents a number of challenges for clinicians and patients; the health of the baby needs to be balanced with the need to maintain remission in the mother. Historically, treatments for Crohns disease (CD) were often discontinued during the pregnancy, or nursing period, due to concerns about teratogenicity. Fortunately, observational data has reported the relative safety of many agents used to treat CD, including 5-aminosalicylic acid, thiopurines, and tumor necrosis factor. Data on the long-term development outcomes of children exposed to these therapies in utero are still limited. It is most important that physicians educate the patient regarding the optimal time to conceive, discuss the possible risks, and together decide on the best management strategy.

Comparative study of intravenous and topical administration of mesenchymal stem cells in experimental colitis

Adult marrow-derived mesenchymal stem cells (MSCs) have anti-inflammatory properties in patients with Inflammatory Bowel Disease (IBD), but systemic delivery is associated with safety concerns. Whether topical delivery of MSCs would provide similar efficacy to systemic administration is unknown. To compare topicallydelivered MSCs to systemic asministration, and non-MSC therapy, in animal model of colitis. Trinitrobenzenesulfonic acid (TNBS) colitis was induced in Wistar rats. Topical MSCs were compared to intravenous MSCs, adalimumab, infliximab and control in this model. Serial measurements of clinical criteria were used (i.e., weight, stool characteristics), and serum interleukin 6 (IL-6) and TNF measurements and macroscopic and microscopic scores were used to evaluate treatment efficacy. Topical and intravenous stem cell treatments, significantly prevented weight loss in TNBS mice on day 3 of colitis. There was greater evidence of a difference mainly on the third day (p<0.001). IV or PR stem cells also reduced serum IL-6 and TNF levels to similar levels to those of anti-TNF treated animals. In the intestinal tract, stem-cell treatment ameliorated the microscopic and macroscopic damage caused by TNBS. Rectal-delivered stem cells produced similar results to IV-delivered cells. This study demonstrates that rectal stem cells can treat colitis in an animal model to a similar extent to IV stem cells and systemic anti-TNF therapies. The mechanisms of this effect warrants further study. Introduction Inflammatory bowel diseases have pathophysiologies based on genetic inheritance associated with environmental factors related either to the intestinal lumen or not, and produce an exacerbated inflammatory response, resulting in intestinal or extraintestinal clinical manifestations [1-4]. In recent years, experimental models have significantly contributed to the understanding of these diseases, allowing the development of drugs with high specificity that act directly on target inflammatory mediators, such as Tumor Necrosis Factor alpha (TNF-alpha) and adhesion molecules, among others.This advancement has enabled treatment providers to change the natural history of these diseases, increasing the quality of life of affected patients and decreasing hospitalization and surgical intervention rates [5]. Although these drugs have modified the treatment scenario, primary drug failure due to loss of response has been observed over the years [6]. Primary failure has corresponded to more than 40% of cases [7], and serial clinical studies indicate a primary failure rate of 10 to 20%. During one year, this loss of response may vary between 23 to 43% of cases [6]. Genetic factors, disease duration, smoking and even the production of antidrug antibodies have been associated with primary failure [6,8]. Conversely, recent studies indicate the possibility of treatment using an immune path (cell therapy) different from drug therapy in patients who are intolerant to conventional drug treatments or when such treatments fail [9]. Cell therapy could represent the optimization of intestinal factors produced by mesenchymal stem cells, which have demonstrated the capacity to inhibit TNF-alpha and Interleukin 6 (IL-6) by regulating the incorrectly exacerbated immune response and inducing intestinal homeostasis, producing an important clinical response for healing the colonic mucosa in both experimental models and humans [9-11]. One of the limiting factors of this treatment is associated with opportunistic infections and uncontrolled cell development, which lead to neoplasms [12,13]. In addition to these data, these cells have the capacity to migrate to the lesion site, even when applied far from the lesion [1,14]. Such lines of evidence have encouraged the studies regarding the topical application of these cells in the colon, which has potential as a new drug strategy and may decrease the side effects of this therapy [1]. Objectives This study aims to assess the applicability and the results of mesenchymal stem cell implantation in animals submitted to Correspondence to: Didia Bismara Cury, Director, Center of Inflammatory Bowel Disease, Clínica Scope, Campo Grande, MS 79002212, Brazil, Tel: +55673-3256040 Fax: +55-673-3256040; E-mail: didia_cury@uol.com.br