João Santos-Antunes

Is it Possible to Change Phenotype Progression in Crohn's Disease in the Era of Immunomodulators? Predictive Factors of Phenotype Progression

OBJECTIVES:Crohns disease (CD) induces cumulative structural damage, initially characterized by a non-stenosing non-penetrating behavior (B1) with progression over time to a fibro-stenosing (B2) and/or penetrating phenotype (B3). Our aim was to assess the long-term evolution of disease behavior of CD and determine what factors predict phenotype progression.METHODS:This was a study based on prospectively collected data from a CD database in an inflammatory bowel disease outpatient clinic. B1 corresponds to a non-stenosing non-penetrating disease, B2 to a stenosing behavior, and B3 to a penetrating one.RESULTS:Seven hundred and thirty-six patients with CD (368 female) were followed up for 12.3 years (±8.4), with 87.0% of them exhibiting B1 phenotype at diagnosis. Of these patients, 28.5% progressed to B2 phenotype and 23.5% to B3. Fifty percent of the patients started azathioprine treatment before phenotype change and 13.9% started anti-tumor necrosis factor-α (anti-TNFα) treatment before phenotype change. Monotherapy with azathioprine before phenotype change as well as combination therapy with azathioprine/anti-TNFα before phenotype change delayed disease progression (B1–B2 or B3) in comparison with patients who did not receive treatment (P<0.001). The hazard ratio (HR) for disease progression was lower for both monotherapy with azathioprine (HR: 0.15, P<0.001) or combination therapy with anti-TNFα (HR: 0.33, P<0.001). Upper gastrointestinal tract involvement, male gender, and steroid use were associated with an early progression of phenotype from B1 to B2 or B3 (P<0.001). The HR for disease progression was higher in patients who used steroids without criteria of dependence or resistance (HR: 2.67, P<0.001) and was even higher in patients with criteria of dependence or resistance (HR: 6.44, P<0.001). Longer delays between CD diagnosis and beginning of therapy with azathioprine and/or anti-TNFα were associated with disease progression. The longer the duration of treatment, the less likely the disease progression.CONCLUSIONS:Monotherapy with azathioprine before behavior change as well as combination therapy with azathioprine and anti-TNFα before behavior change delays phenotype progression of CD, whereas upper gastrointestinal tract involvement, male gender, and steroid use with or without criteria of steroid dependence are associated with a higher risk for disease progression.

High C-reactive protein in Crohn's disease patients predicts nonresponse to infliximab treatment.

BACKGROUND Infliximab (IFX) is effective in treating Crohns disease (CD) and C-reactive protein (CRP) is a useful biomarker in assessing inflammatory activity. AIM Correlate CRP levels before beginning of IFX, at week 14 and CRP delta within the first year of IFX treatment. METHODS Retrospective study of CD patients undergoing treatment with IFX. Primary nonresponse (PNR) was defined as no symptomatic improvement and CRP persistently elevated; sustained response (SR) as symptomatic improvement for at least 1 year without therapeutic adjustment; response after therapeutic adjustment (RTA) as analytic and clinical response but requiring IFX dose/frequency adjustment or association with another drug. RESULTS Baseline CRP levels were higher in PNR compared with SR (26.2mg/L vs 9.6 mg/L, p=0.015) and RTA (26.2mg/L vs 7.6 mg/L, p=0.007). CRP levels greater than 15 mg/L at baseline predict PNR with 67% sensitivity and 65% specificity. Lower CRP levels at week 14 were more likely to predict SR relative to RTA (3.1mg/L vs 7.6 mg/L p=0.019) and PNR (3.1mg/L vs 9.1mg/L; p=0.013). CRP levels greater than 4.6 mg/L at week 14 predict PNR with 67% sensitivity and 62% specificity. A higher CRP delta between beginning of treatment and week 14 is more likely to predict SR relative to RTA (5.2mg/L vs 0.6 mg/L p=0.027). CONCLUSION CRP levels at week 14 were associated with SR in patients treated with IFX, independently of baseline CRP serum levels. High inflammatory burden at beginning of IFX treatment was correlated with a worse response.

Tuberculosis in anti-TNF-α treated patients remains a problem in countries with an intermediate incidence: Analysis of 25 patients matched with a control population

BACKGROUND AND AIMS An increased incidence of tuberculosis (TB) in patients under anti-TNF-α therapy has been reported, but outcome compared with TB in the general population are unknown. METHODS Patients who had active tuberculosis while taking anti-TNF-α drugs were studied and compared with a control group of community-acquired TB matched for sex, age and data of TB. RESULTS Twenty-five cases of TB were reported from a cohort of 765 patients under anti-TNF-α from 2001 to 2012. The incidence of TB per 100,000 patient-years was estimated to be 1337, 792 and 405 respectively for those on infliximab, adalimumab and etanercept. Twelve patients had inflammatory bowel disease, ten had rheumatologic diseases and three had psoriasis. From the 17 patients screened for latent TB before anti-TNF-α, three were treated with isoniazid. TB was diagnosed 1-108 months after starting anti-TNF-α, being the median time six, seven and 89 months respectively for those on infliximab, adalimumab and etanercept. Sixty per cent of the cases had extra-pulmonary TB. No deaths occurred in the case groups, while two died in control TB patients. Patients on anti-TNF-α drugs had more frequent extra-pulmonary TB, fever on presentation, higher mean C-reactive protein and lower positive rate of acid-fast bacilli. CONCLUSIONS TB may still occur in those with negative testing, some of them probably representing new infections instead of reactivations. Three out of 25 patients had TB in spite of previously treated LTB, although, the outcome of TB was not worse than in the general population.

Epstein-Barr virus in inflammatory bowel disease-correlation with different therapeutic regimens.

Background: Inflammatory bowel disease (IBD) is associated with a higher prevalence of opportunistic infections. Epstein–Barr virus (EBV) is a ubiquitous virus related to several malignancies, namely lymphoma; its prevalence in patients with IBD and its relation with different therapeutic regimens are not well studied. Methods: Patients followed in our IBD outpatient clinic were consecutively enrolled for participation in a prospective study, and healthy volunteers were recruited as controls. EBV DNA was measured at least 1 time in each patient. Results: Three hundred and seventy-nine individuals were enrolled in the study (93 treated with 5-aminosalicylates, 91 with azathioprine, 70 with infliximab, 43 with combined treatment with infliximab and azathioprine, and 82 controls). More than 90% of the patients had previous EBV exposure. EBV DNA was found in 132 samples (35%); its prevalence was significantly higher in every group of patients with IBD, comparing to controls. Among patients with IBD, infliximab with or without azathioprine was related to higher prevalence of EBV comparing to azathioprine alone or 5-aminosalicylates (P < 0.05). Age above 60 years was related to EBV DNA positivity with a specificity of 92%. Concerning treated groups, ulcerative colitis was the only risk factor identified for high levels of EBV DNA (>1000 and 2500 copies per milliliter). No relationship was found between EBV and C-reactive protein. Conclusions: IBD is a risk factor for the presence of EBV DNA in blood, particularly in older patients and in those taking infliximab. C-reactive protein was not related to EBV DNA prevalence.

Disseminated cutaneous herpes simplex infection in a patient with Crohn's disease under azathioprine and steroids: First case report and literature review

Immunosuppressive treatments used in the management of Inflammatory Bowel Disease, namely steroids, thiopurines and anti-TNF drugs, raise the risk of acquiring opportunistic infections. However, most of these infections are mild and self-limited, not requiring specific therapy or suspension of the immunosuppressors. We report a case of disseminated cutaneous herpes simplex infection in a patient with Crohns disease under steroids and azathioprine.

Treatment with infliximab or azathioprine negatively impact the efficacy of hepatitis B vaccine in inflammatory bowel disease patients

Immunization against hepatitis B virus (HBV) infection is recommended in patients with inflammatory bowel disease (IBD), particularly in those under immunosuppressive therapy. Limited data are available about IBD patients response to HBV vaccination. We assessed the response rate to HBV vaccination in IBD patients and evaluated the impact of different factors on the efficacy of HBV vaccination.

Crohn's disease outcome in patients under azathioprine: A tertiary referral center experience

BACKGROUND AND AIMS Azathioprine is of major importance in the treatment of Crohns disease; its efficacy has been showed in several works, but real-life data regarding its use is scarce. Our aim was to address the outcome of patients with Crohns disease under azathioprine in the real-life setting. METHODS Crohns disease patients followed at an Inflammatory Bowel Disease Outpatient Clinic under azathioprine were consecutively enrolled, being allocated in one of four groups. Two groups included patients on treatment with this drug, regarding its two major indications - prevention of post-operative recurrence and steroid-dependent disease; a third group included patients who needed infliximab in addition to azathioprine and a fourth group comprised patients who did not tolerate azathioprine. RESULTS A total of 221 patients were enrolled, 180 on azathioprine due to steroid-dependency (64 needing additional treatment with infliximab) and 41 for prevention of post-operative recurrence. Steroid-free remission was obtained in 48%. Immunosuppression decreased the number of hospitalized patients (64% vs 36%; p<0.001), but not the surgery rates per person per year. Azathioprine as a post-operative drug was effective in decreasing hospitalizations. The addition of infliximab decreased the number of patients hospitalized (p=0.009) and hospitalization rates per person per year (p<0.001), but had no effect in the surgery rates per person per year. Sixty patients (23%) experienced adverse effects with AZA, 39 requiring discontinuation of the drug. CONCLUSIONS In this real-life study, azathioprine had a long-term steroid sparing effect and reduced hospitalizations. Combination with infliximab reduced hospitalizations but did not decrease the surgery rate.

The Relevance of Vitamin D and Antinuclear Antibodies in Patients with Inflammatory Bowel Disease Under Anti-TNF Treatment: A Prospective Study

Background:The importance of vitamin D in inflammatory bowel disease (IBD) has been analyzed in former studies, namely concerning the severity of the disease and the efficacy of anti–tumor necrosis factor (TNF) medications. In several inflammatory conditions, biologics have been associated with an autoimmune response with formation of antinuclear antibodies (ANA). In addition, an inverse relationship between vitamin D levels and ANA has been documented. We aimed to evaluate the clinical importance of the link between vitamin D, ANA, and anti-TNF in patients with IBD. Methods:Prospective study including patients with IBD with indication to start anti-TNF, between 2009 and 2014. Deficiency and extreme deficiency of vitamin D were defined as levels of 25-hydroxyvitamin D below 20 and 4 ng/mL, respectively. ANA titers were considered positive if higher or equal to 1/100. Results:Among 68 patients (56 with Crohns Disease, 12 with ulcerative colitis), vitamin D deficiency was detected in 93%. Pretreatment positivity for ANA was related to higher failure rates of anti-TNF treatment (P = 0.008). Pretreatment positivity for ANA and extreme vitamin D deficiency were significant risk factors for adverse events associated with anti-TNF therapy. A significant link was found between extreme deficiency of vitamin D and the presence of ANA. Conclusions:Our study highlights the association between vitamin D deficiency and pretreatment positivity for ANA with the risk for anti-TNF failure and adverse events, and the inverse relationship between vitamin D levels and ANA. Due to the high prevalence of vitamin D deficiency in IBD and the immune-mediated nature of the disease, these elements should be evaluated before starting biologics.

CA 19-9 as a Marker of Survival and a Predictor of Metastization in Cholangiocarcinoma

Background: Cholangiocarcinoma is the second most frequent primitive liver malignancy and is responsible for 3% of the malignant gastrointestinal neoplasms. The aims of this study were to determine the association of serum levels of CA 19-9 at diagnosis with other clinical data and serum liver function tests and to identify possible factors that influence the survival rates during follow-up. Methods: Retrospective observational study of 89 patients with a diagnosis of cholangiocarcinoma followed at the Department of Gastroenterology during 5 years. Statistical analyses were performed using SPSS version 20.0. Results: Patients were followed up for a median time of 127 days (IQR: 48-564), and the median age at diagnosis was 71.0 years (IQR: 62.0-77.5). The median survival rate was 14.0 months (IQR: 4.3-23.7), and the mortality rate was 79%. Patients with CA 19-9 levels ≥103 U/L had lower albumin levels and higher levels of alanine aminotransferase and γ-glutamyltransferase. CA 19-9 levels ≥103 U/L were associated with a higher probability of metastization (p = 0.001) and lower rates of treatment with curative intent (p = 0.024). In a multivariate analysis, CA 19-9 levels <103 U/L and surgery were independent predictors of survival. Conclusion: Predictive factors for overall survival were identified, namely presence of metastasis, surgery, and chemotherapy. CA 19-9 levels ≥103 U/L were predictive factors for survival and metastization.

Response to Targownik

To the Editor: In the June 2014 issue of the American Journal of Gastroenterology , Magro et al. ( 1 ) reported on the results of a study where a cohort of persons with Crohn’s disease were followed to evaluate whether the use of immunomodulator medications and/or biologics was associated with a decreased risk of progression from an infl ammatory phenotype to either a fi brostenosing or a penetrating phenotype. In this study, the use of immunomodulatory agents like azathioprine was associated with an 85% reduction in the hazard of developing phenotype progression compared with those who did not use these medications. However, any time a survival analysis demonstrates a particularly strong association between exposure to a medication and the subsequent prevention of an adverse outcome, one must consider whether these fi ndings may have been erroneously generated owing to the failure to account for immortal person time ( 2 ). Th is issue tends to arise when (1) the initial exposure (immunomodulator exposure) occurs at a later time than the point at which follow-up begins for both the exposed and the unexposed; (2) follow-up ends before the event of interest (development of fi brostenosing or penetrating disease); and (3) the person time accrued between the beginning of follow-up and the time of the initial exposure (unexposed person time) is misattributed to the exposed group. Th is unexposed person time is considered “immortal”, for under no circumstance could the event of interest that occurred during this time have been counted as an exposure-related event. Failure to account for this bias leads to an inappropriate increase in exposed person time, which in turn decreases the exposure-related incidence. In order to properly address this issue, the authors should have followed exposed subjects from the date of the receipt of an immunomodulator (instead of from diagnosis) and matched the data with those of unexposed subjects who had survived an equivalent duration without developing progression. Alternatively, exposure to immunomodulators could have been modeled as a timevariable covariate. Given the magnitude of the association, these results may inappropriately both aff ect clinical practice and provide support to future guidelines on the use of immunomodulators and biologics in the management of Crohn’s disease. I strongly recommend to the authors of this study that they repeat these analyses using a methodology that allows for the proper attribution of exposed and unexposed person time.