Manuela Marzo

Dermatological adverse reactions during anti-TNF treatments: Focus on inflammatory bowel disease

The clinical introduction of tumour necrosis factor (TNF) inhibitors has deeply changed the treatment of inflammatory bowel diseases (IBD). It has demonstrated impressive efficacy as compared to alternative treatments, allowing for the chance to achieve near-remission and long-term improvement in function and quality of life and to alter the natural history of Crohns disease (CD) and ulcerative colitis (UC). As a consequence of longer follow-up periods the number of side effects which may be attributed to treatment with biologics is growing significantly. Cutaneous reactions are among the most common adverse reactions. These complications include injection site reactions, cutaneous infections, immune-mediated complications such as psoriasis and lupus-like syndrome and rarely skin cancers. We review the recent literature and draw attention to dermatological side effects of anti-TNF therapy of inflammatory bowel disease.

Infliximab in steroid-dependent ulcerative colitis: effectiveness and predictors of clinical and endoscopic remission.

Background:Up to 20% of patients with ulcerative colitis (UC) become steroid-dependent during their course. Thiopurines are recommended in steroid-dependent UC, but their efficacy is debated. Data exploring the use of infliximab in these patients are scarce. Aims of this study were to evaluate the effectiveness of infliximab in steroid-dependent UC and identify predictors of steroid-free remission, mucosal healing (MH), and colectomy. Methods:Steroid-dependent UC patients were enrolled and intentionally treated with infliximab. The prospectively designed analyses evaluated (1) steroid-free clinical remission at 6 and 12 months, (2) steroid-free clinical remission and MH at 12 months, and (3) colectomy within 12 months. Results:One hundred and twenty-six active steroid-dependent UC patients were studied. Of the 126 patients, 36 patients were retrospectively included and 90 patients prospectively enrolled. Steroid-free remission was 53% and 47% at 6 and 12 months, respectively. Predictors of steroid-free remission at 6 and 12 months were thiopurine-naive status (hazard ratio [HR], 2.5 and HR, 2.8, respectively) and combination therapy (HR, 2.1 and HR, 2.2, respectively). At 12 months, 32% were in steroid-free remission and MH. Thiopurine-naive status predicted steroid-free remission and MH (odds ratio, 3.6). C-reactive protein drop to normal after infliximab induction was predictive of steroid-free remission at 6 (HR, 5.9) and 12 months (HR, 4.6) and steroid-free remission and MH at 12 months (odds ratio, 6.0). Twelve patients underwent colectomy after a median of 4.7 months. Steroid sparing significantly reduced the risk of colectomy within 12 months (HR, 0.14). Conclusions:Infliximab seems effective in steroid-dependent UC. Thiopurine-naive status and combination therapy significantly increase the rate of steroid-free remission up to 12 months.

H1N1 vaccines in a large observational cohort of patients with inflammatory bowel disease treated with immunomodulators and biological therapy

Background Safety data are lacking on influenza vaccination in general and on A (H1N1)v vaccination in particular in patients with inflammatory bowel disease (IBD) receiving immmunomodulators and/or biological therapy. Aims and methods The authors conducted a multicentre observational cohort study to evaluate symptoms associated with influenza H1N1 adjuvanted (Pandemrix, Focetria, FluvalP) and non-adjuvanted (Celvapan) vaccines and to assess the risk of flare of IBD after vaccination. Patients with stable IBD treated with immunomodulators and/or biological therapy were recruited from November 2009 until March 2010 in 12 European countries. Harvey–Bradshaw Index and Partial Mayo Score were used to assess disease activity before and 4 weeks after vaccination in Crohns disease (CD) and ulcerative colitis (UC). Vaccination-related events up to 7 days after vaccination were recorded. Results Of 575 patients enrolled (407 CD, 159 UC and nine indeterminate colitis; 53.9% female; mean age 40.3 years, SD 13.9), local and systemic symptoms were reported by 34.6% and 15.5% of patients, respectively. The most common local and systemic reactions were pain in 32.8% and fatigue in 6.1% of subjects. Local symptoms were more common with adjuvanted (39.3%) than non-adjuvanted (3.9%) vaccines (p<0.0001), whereas rates of systemic symptoms were similar with both types (15.0% vs 18.4%, p=0.44). Among the adjuvanted group, Pandemrix more often induced local reactions than FluvalP and Focetria (51.2% vs 27.6% and 15.4%, p<0.0001). Solicited adverse events were not associated with any patient characteristics, specific immunomodulatory treatment, or biological therapy. Four weeks after vaccination, absence of flare was observed in 377 patients with CD (96.7%) and 151 with UC (95.6%). Conclusion Influenza A (H1N1)v vaccines are well tolerated in patients with IBD. Non-adjuvanted vaccines are associated with fewer local reactions. The risk of IBD flare is probably not increased after H1N1 vaccination.

Ileal Crohn Disease: Mural Microvascularity Quantified with Contrast-enhanced US Correlates with Disease Activity

PURPOSE To quantitatively assess microvascular activation in the thickened ileal walls of patients with Crohn disease (CD) by using contrast-enhanced ultrasonography (US) and evaluate its correlation with widely used indexes of CD activity. MATERIALS AND METHODS This prospective study was approved by the ethics committee, and written informed consent was obtained from all patients. The authors examined 54 consecutively enrolled patients (mean age, 35.29 years; age range, 18-69 years; 39 men, 15 women) with endoscopically confirmed CD of the terminal ileum. Ileal wall segments thicker than 3 mm were examined with low-mechanical-index contrast-enhanced US and a second-generation US contrast agent. The authors analyzed software-plotted time-enhancement intensity curves to determine the maximum peak intensity (MPI) and wash-in slope coefficient (β) and evaluated their correlation with (a) the composite index of CD activity (CICDA), (b) the CD activity index (CDAI), and (c) the simplified endoscopic score for CD (SES-CD, evaluated in 37 patients) for the terminal ileum. Statistical analysis was performed with the Mann-Whitney test, Spearman rank test, and receiver operating characteristic (ROC) analysis. RESULTS MPI and β coefficients were significantly increased in the 36 patients with a CICDA indicative of active disease (P<.0001 for both), the 33 patients with a CDAI of at least 150 (P<.032 and P<.0074, respectively), and the 26 patients with an SES-CD of at least 1 (P<.0001 and P<.002, respectively). ROC analysis revealed accurate identification (compared with CICDA) of active CD with an MPI threshold of 24 video intensity (VI) (sensitivity, 97%; specificity, 83%) and a β coefficient of 4.5 VI/sec (sensitivity, 86%; specificity, 83%). CONCLUSION Contrast-enhanced US of the ileal wall is a promising method for objective, reproducible assessment of disease activity in patients with ileal CD.

Long-term combination therapy with infliximab plus azathioprine predicts sustained steroid-free clinical benefit in steroid-dependent ulcerative colitis.

Background:Infliximab (IFX) has demonstrated effectiveness for inducing 12-month steroid-free clinical remission in patients with steroid-dependent ulcerative colitis (UC), but long-term data are lacking. The aim of the study was to describe the long-term outcome of IFX treatment in steroid-dependent UC and investigate if predictors of sustained clinical response and colectomy could be identified. Methods:Consecutive patients with steroid-dependent UC treated with IFX were studied. The coprimary prespecified outcomes were sustained clinical response in patients who achieved clinical remission or response after IFX induction and colectomy-free survival. Secondary analyses were addressed to look for predictors of sustained clinical response and colectomy. Results:After induction, 76% (96/126) of patients achieved clinical benefit. The median duration of follow-up on IFX maintenance therapy was 41.5 months (interquartile range, 26–45). Sixty-four percent (46/96) of patients had sustained clinical response at median follow-up. Colectomy-free survival was 77% at median follow-up. Combination therapy of IFX with thiopurines was an independent predictor of sustained clinical response (P < 0.0001; hazard ratio [HR], 3.98; 95% confidence interval [CI], 1.73–9.14). Independent predictors of colectomy were Mayo endoscopic subscore of 3 at baseline (P = 0.04; HR, 2.77; 95% CI, 1.09–7.05) and high C-reactive protein after induction (P = 0.001; HR, 5.65; 95% CI, 2.03–15.7). Thiopurine naive status (P = 0.025; HR, 0.34; 95% CI, 0.13–0.87) was protective from colectomy. Conclusions:Long-term IFX treatment is effective in inducing sustained clinical response in patients with steroid-dependent UC. Combination therapy is predictive of sustained clinical response in the long-term. Patients with more severe endoscopic lesions at baseline and high C-reactive protein after induction are at higher risk of colectomy. Conversely, thiopurine naive status is protective from colectomy.

Prevalence and natural history of hepatitis B and C infections in a large population of IBD patients treated with anti-tumor necrosis factor-α agents☆

BACKGROUND The prevalence rates of hepatitis B virus (HBV) and hepatitis C virus (HCV) in patients with inflammatory bowel disease (IBD) have been reported to be higher than rates of infection among the general population. Although several cases of HBV infection reactivation in IBD patients treated with anti-TNF-α agents have been described, no evidence exists that anti-TNF-α therapy exacerbates the course of HCV. The aims of this study were to assess the prevalence of HBV and HCV and the rate of HBV vaccination in a population of IBD patients; and to investigate the long-term effects of anti-TNF-α therapy in the subgroup with HBV or HCV infections. METHODS 301 patients were studied. Prior to the initiation of anti-TNF-α therapy, serum samples were tested for HBsAg and anti-HBc, anti-HBs and anti-HCV antibodies. During the follow-up, HBsAg and anti-HBc positive patients underwent periodic blood testing for viral markers, HBV-DNA and liver function; anti-HCV positive patients were assessed for liver function and HCV-RNA. RESULTS One patient was HBsAg positive (0.3%), and 22 (7.3%) tested positive for anti-HBc. Seventy-two patients (23.9%) had been vaccinated for HBV. Four patients tested positive for anti-HCV (1.3%). During anti-TNF-α therapy, none of the patients experienced HBV or HCV reactivation. CONCLUSIONS HBV and HCV infection rates were similar to infection rates among the general population. Less than one quarter of the patients had been vaccinated against HBV. Anti-TNF-α agents appear to be safe for patients with HBV infection; more data are needed for patients with HCV infection.

Internet use among inflammatory bowel disease patients : an Italian multicenter survey

Background The internet has been increasingly used as a resource for accessing health-related information. A recent US survey found that approximately half of inflammatory bowel disease (IBD) patients in an IBD clinic use the internet to gather IBD-specific information. Aim The aim of this study was to evaluate the use of the internet among Italian IBD patients. Methods The study was performed in seven Italian IBD referral centers by using a 28-item anonymous questionnaire. Results In all, 495 questionnaires were returned for analysis, in which 305 of 495 patients (61.6%) indicated that they are able to access the internet. A large proportion used the internet to gather health-related information (180 of 305, 59.1%) and IBD-related information (226 of 305, 74.2%). The use of the internet increased significantly with level of education (P<0.0001) and household income (P<0.0001). In addition, the use of the internet to gather IBD-related information increased significantly with the increase of disease activity and severity. Conclusion Approximately half of the patients in Italian IBD referral centers used the internet to gather IBD-related information. This use positively correlated with disease activity and severity. The great majority of patients indicated that it was very important for IBD referral centers to have their own IBD-dedicated website.

Immune response to influenza A/H1N1 vaccine in inflammatory bowel disease patients treated with anti TNF-α agents: Effects of combined therapy with immunosuppressants

BACKGROUND AND AIMS Our first objective was to evaluate the immune response to the adjuvanted 2009 A/H1N1 pandemic (pH1N1) vaccine in inflammatory bowel disease (IBD) patients treated with anti-TNF-α alone or combined with immunosuppressants (IS). Second and third aims were the safety of pH1N1 vaccine and the effects on IBD clinical activity. METHODS 36 patients with Crohns disease (CD) and 26 with ulcerative colitis (UC) and thirty-one healthy control (HC) subjects were enrolled. 47 patients were on anti TNF-α maintenance monotherapy and 15 on anti TNF-α combined with IS. Sera were collected at baseline (T0) and 4 weeks after the vaccination (T1) for antibody determination by hemagglutination inhibition (HAI). Disease activity was monitored at T0 and T1. RESULTS Seroprotective titers (≥1:40) in patients were comparable to HC. Seroconvertion rate (≥4 fold increase in HAI titer) was lower than HC in IBD patients (p=0.009), either on anti TNF-α monotherapy (p=0.034) or combined with IS (p=0.011). Geometric mean titer (GMT) of antibodies at T1 was significantly lower in patients on combined therapy versus those on monotherapy (p=0.0017) and versus HC (p=0.011). The factor increase of GMT at T1 versus T0 was significantly lower in IBD patients versus HC (p=0.042), and in those on combined immunosuppression, both versus monotherapy (p=0.0048) and HC (p=0.0015). None of the patients experienced a disease flare. CONCLUSION Our study has shown a suboptimal response to pH1N1 vaccine in IBD patients on therapy with anti TNF-α and IS compared to those on anti-TNF-α monotherapy and HC.

Combined therapy with infliximab and seton drainage for perianal fistulizing Crohn’s disease with anal endosonographic monitoring: a single-centre experience

During infliximab treatment of perianal Crohn’s disease (CD), the healing of the skin opening precedes fistula tract healing and this contributes to abscess formation and fistula recurrence. The aims of this study were to evaluate the efficacy of combined treatment with infliximab and setons for complex perianal fistulas in CD and to define the optimal time for seton removal by anal endosonography (AE). Nine consecutive patients with CD were studied. Perianal sepsis was eradicated when necessary and setons were placed before infliximab therapy. Setons were removed after AE evidence of fistulous tracts healing. Patients received a mean of 10±2.3 infliximab infusions. At week 6 all patients showed a reduction in mean CD activity index (p<0.005) and perianal disease activity index (p<0.0001). Complete fistula response was achieved in eight of nine patients. In six patients after a mean of 9.2 infusions, infliximab treatment was discontinued. Clinical and AE response persisted at 19.4±8.8 months (range 3–28 months) in five of these patients. One patient had fistula recurrence 20 weeks after infliximab discontinuation and responded rapidly to retreatment. At the time of this report, two patients were still on infliximab and in remission after a mean follow-up of 25±5 months. Combined therapy with infliximab and setons with AE monitoring of the response showed high efficacy in the management of patients with CD with complex perianal fistulas.

Management of perianal fistulas in Crohn's disease: An up- to-date review

Perianal disease is one of the most disabling manifestations of Crohns disease. A multidisciplinary approach of gastroenterologist, colorectal surgeon and radiologist is necessary for its management. A correct diagnosis, based on endoscopy, magnetic resonance imaging, endoanal ultrasound and examination under anesthesia, is crucial for perianal fistula treatment. Available medical and surgical therapies are discussed in this review, including new local treatment modalities that are under investigation.