Immunogenicity and autoimmunity during anti-TNF therapy.

The introduction of anti-tumour necrosis factor (TNF) agents for the treatment of rheumatoid arthritis (RA), Crohn's disease (CD) or spondyloarthritis (SpA) has revolutionised the therapeutic approach to patients with active disease failing to respond to conventional therapy. However, some of the patients treated with selective TNF inhibitors may develop autoantibodies, such as antinuclear antibodies (ANAs) and anti-double-stranded DNA (anti-dsDNA) antibodies. Furthermore, anti-phospholipid antibodies, which are mainly detected by means of anti-cardiolipin assays, have been found in RA patients receiving TNF blockers. There have also been a number of reports of the development of anti-drug antibodies, of which those against infliximab can interfere with the drug's pharmacokinetics (and therefore its effects), and may also cause acute and delayed infusion and injection site reactions. The onset of autoimmune diseases during biological treatment is rare, but it needs to be promptly recognised in order to plan appropriate patient management. The addition of an immunosuppressive drug can reduce the induction of anti-TNF antibodies.

Immunomodulatory effects of 1,25-dihydroxyvitamin D3 on TH1/TH2 cytokines in inflammatory bowel disease: an in vitro study.

Crohn's disease (CD) is associated with a higher type-1-helper T cell (Th1) cytokine expression, whereas ulcerative colitis (UC) appears to express a modified Th2 response. In addition to its classic role in calcium homeostasis, calcitriol, the hormonal active form of vitamin D, exerts immunoregulatory effects such as modulation of Th1/Th2 cytokines. Therefore, calcitriol administration could modify immune dysfunction in CD and UC. Nine patients with UC (M/F: 5/4; mean age 47 years, remission(R)/active(A) disease: 7/2), 8 patients with CD (M/F: 2/6; mean age 36, R/A 5/3) and 6 healthy controls (HC) (M/F: 3/3, mean age 4) were enrolled. Peripheral blood was collected after a drug-washout of 15 days and peripheral blood mononuclear cells were stimulated with mitogens alone or in the presence of physiological concentrations of calcitriol (100 pg/ml). Type 1 (IL-2, TNF-alpha, IFN-gamma) and type 2 (IL-10) cytokine production was assayed on supernatants by ELISA. Compared to HC, TNF-alpha production was significantly higher both in UC (p=0.0002) and CD (p=0.0001) patients, at baseline and after incubation with calcitriol (UC p=0.0003, CD p=0.0009). The effects of calcitriol incubation were: 1) reduced IFN-gamma (p=0.024) and increased IL-10 (p=0.06) production in UC patients; 2) reduced TNF-alpha production in CD (p=0.032); 3) no significant effects in HC. Calcitriol increased, albeit not significantly, IL-10 production in UC compared to CD patients (p=0.09). These results suggest an important modulatory role of vitamin D in the Th1/Th2 immune response. The observation that the effect of this modulation was different in CD compared to UC patients provides an interesting area of research into the pathogenesis and treatment of these inflammatory conditions.

Use of colonoscopy in the management of patients with Crohn's disease: appropriateness and diagnostic yield.

INTRODUCTION: Colonoscopy is a necessary tool in the management of Crohn's disease, but the benefit achieved by the procedure is a matter of debate. In the present study we evaluate the clinical impact of performing colonoscopy in Crohn's disease patients. METHODS: Consecutive patients with Crohn's disease undergoing colonoscopy were considered. The following issues were considered: appropriateness of indications; relevant findings able to change the management of the patients; the endoscopist's management decisions based on patient's clinical picture, i.e. increased, maintained or decreased treatment, compared with those selected after performing endoscopy. RESULTS: 204 patients (116 male/88 female, mean age 41 years) were included. Colonoscopy was judged indicated in 52.9% cases, according to current guidelines. In 54% of patients, endoscopy revealed a significant lesion, and this rate was significantly lower for non-indicated procedures (25.9%, p<0.0001). The endoscopic findings were in disagreement with symptoms in about 25% of cases, but the impact of the endoscopic findings on the endoscopist's decision was likely to be very small without any differences between appropriate and inappropriate procedures. CONCLUSIONS: Endoscopy is a potent tool in the management of Crohn's disease, if correctly used, but in the majority of cases a correct therapeutic decision may be established simply on the basis of clinical picture and non-invasive markers, whilst relevant endoscopic findings have a relatively low impact on the medical treatment.

Extraintestinal manifestations of inflammatory bowel disease.

Inflammatory bowel disease (IBD) is associated with a variety of extraintestinal manifestations (EIMs) that may produce greater morbidity than the underlying intestinal disease and may even be the initial presenting symptoms of the IBD. As many as 36% of patients with IBD have at least one EIM. Some are more common related to active colitis (joint, skin, ocular, and oral manifestations). Others are especially seen with small bowel dysfunction (cholelithiasis, nephrolithiasis, and obstructive uropathy), and some are nonspecific disorders (osteoporosis, hepatobiliary disease, and amyloidosis). Patients with perianal Crohn's disease are at higher risk for developing EIMs than other IBD patients. Also the presence of one EIM appears to confer a higher likelihood of developing other manifestations than would be expected by chance alone. The identified pathogenetic autoimmune mechanisms include genetic susceptibility antigenic display of autoantigen, aberrant self-recognition, and immunopathogenetic autoantibodies against organ-specific cellular antigen(s) shared by colon and extra-colonic organs. Microbes may play an important role, probably by molecular mimicry. Early recognition of these extraintestinal manifestations should help guide therapy that will reduce overall morbidity in affected patients. This paper reviews the diagnosis, therapy and management of the more common EIMs.

Autologous haematopoietic stem cell transplantation without CD34+ cell selection in refractory Crohn's disease.

OBJECTIVES: Autologous haematopoietic stem cell transplantation (HSCT) with CD34(+) cell selection has recently been used in the treatment of refractory Crohn's disease, showing good safety and promising efficacy. We investigated the safety and efficacy of HSCT with unselected peripheral blood stem cells (PBSCs) in moderate-severe refractory Crohn's disease. PATIENTS: Four patients (three male, one female; age range 26-45 years) with active moderate-severe Crohn's disease (median Crohn's Disease Activity Index (CDAI) 319, range 272-345), refractory or intolerant to multiple drugs including infliximab, were enrolled. INTERVENTIONS: Unselected PBSCs were collected after mobilisation with cyclophosphamide (CTX) 1.5 g/m2 and granulocyte-colony stimulating factor (G-CSF) 10 microg/kg. The conditioning regimen included CTX 50 mg/kg on days -5 to -2 and rabbit anti-thymocyte globulin (ATG) 2.5 mg/kg on days -4 to -2. MAIN OUTCOME MEASURES: Primary endpoints were toxicity and clinical remission (CDAI<150) at 3 months. Secondary endpoints were clinical and endoscopic response at 3 months and toxicity, clinical and endoscopic remission at 12 months. RESULTS: No improvement or slight deterioration was observed following mobilisation (median CDAI 339, range 258-404). At the third month, the primary endpoint of clinical remission was achieved in all patients, with a median CDAI of 91 (range 56-102), and complete endoscopic remission was achieved in 2/3 patients. After a median follow-up of 16.5 months, 3/4 patients maintained both clinical and endoscopic remission, despite withdrawal of all drugs, and complete fistula closure was observed in all affected patients. No deaths or life-threatening infection occurred. Unexpected adverse events included a perianal abscess after mobilisation in one patient, pleural and pericardial effusions in another and BK virus-related macrohaematuria in another, all rapidly resolved with conservative treatment. CONCLUSION: Autologous HSCT with unselected PBSC appears to be safe and can induce and maintain remission in previously refractory Crohn's disease patients.

Review article: the management of steroid dependency in ulcerative colitis.

BACKGROUND: Approximately 20% of patients with ulcerative colitis have a chronic active disease often requiring several courses of systemic steroids in order to achieve remission, but followed by relapse of symptoms during steroid tapering or soon after their discontinuation. Although short term control of symptoms can be achieved with steroid treatment, this pattern of drug response, known as steroid-dependency, leads to important complications of the treatment, while a significant proportion of patients requires colectomy. AIM: To review the studies currently available specifically evaluating the management of steroid-dependent ulcerative colitis. RESULTS: The clinical and biological mechanisms of steroid-dependency are not well understood compared with those determining steroid-refractoriness. Very few evidence-based data are available concerning the management of patients with steroid-dependent ulcerative colitis. The therapeutic role of aminosalicylates, thiopurines, methotrexate, infliximab, leukocyte apheresis and other drugs in the treatment of steroid-dependent ulcerative colitis are evaluated. CONCLUSIONS: Outcomes of studies in steroid-refractory patients may not be applicable to steroid-dependency. Trials are needed to define the correct approaches and new strategies to ameliorate the therapy of steroid-dependent ulcerative colitis.

Imaging of perianal Crohn's disease.

Perianal fistulas and abscesses are common complications of Crohn's disease, affecting up to 50% of patients during their disease course. Accurate diagnosis and classification of perianal disease is crucial before and during treatment to plan an adequate approach for each patient and to avoid irreversible functional consequences. Although examination under anaesthesia has been considered the gold standard for diagnosis and classification of Crohn's disease perianal fistulas, taken alone it does not have perfect accuracy, stressing the need for concomitant or alternative, non-invasive, methods of evaluation. In this context, imaging modalities assessed for diagnosis, classification and monitoring of Crohn's disease perianal fistulas include pelvic magnetic resonance imaging, anorectal endoscopic ultrasonography, transcutaneous perianal ultrasound, fistulography and computed tomography. In particular, magnetic resonance imaging and endoscopic ultrasonography findings have shown the best accuracy, and the ability to influence therapeutic management of these patients. For transcutaneous perianal ultrasound too, good preliminary data have been reported. This paper reviews the available data on imaging methods for the management of perianal Crohn's disease.

Multidrug resistance 1 gene polymorphism and susceptibility to inflammatory bowel disease.

BACKGROUND: Several studies have evaluated the role of the multidrug resistance 1 gene (MDR1) polymorphism, which encodes the membrane-bound efflux transporter P-glycoprotein 170, in determining susceptibility to and disease behavior in inflammatory bowel disease (IBD), but with conflicting results. METHODS: A total of 211 patients with Crohn's disease (CD), 97 patients with ulcerative colitis (UC), and 212 control subjects were investigated for the presence of MDR1 G2677T/A and C3435T polymorphisms. Genotype frequencies of CD and UC patients were compared to those observed in a control population. Genotype-phenotype correlations with major clinical features were also established and estimated risks (odds ratio [OR] with 95% confidence interval [CI]) for the mutations were calculated by a logistic regression analysis and multiple correspondent analysis. RESULTS: No significant difference was observed for genotype frequencies for both MDR1 G2677T/A and C3435T polymorphisms on overall disease susceptibility for either CD or UC patients compared with control subjects. A significant association was found between the MDR1 C3435T polymorphism and patients with ileo-colonic CD (OR = 3.34; 95% CI: 1.34-8.27). Interestingly, a negative association was found between MDR1 C3435T polymorphism in patients with a positive family history for IBD (OR = 0.44; 95% CI: 0.20-0.95) and articular manifestations (OR = 0.29; 95% CI: 0.13-0.68). Both susceptible and protective effects were identified. No significant association between G2677T/A polymorphism and any specific subphenotypes was found, nor was there any association with subphenotypic categories of UC and both single nucleotide polymorphisms. CONCLUSIONS: The results of our study suggest that MDR1 gene polymorphism could have a role in determining susceptibility to IBD. The variability of this possible effect in the several studies reported so far may be the indirect expression of the complex role played by the MDR1 gene and its product, P-glycoprotein 170, in the regulation of host-bacteria interactions and in the pathogenesis of IBD.

Infliximab in the treatment of Crohn's disease: predictors of response in an Italian multicentric open study.

BACKGROUND: Almost 20% of patients with active Crohn's disease are refractory to conventional therapy. Infliximab is a treatment of proven efficacy in this group of patients and it is not clear which variables predict a good response. AIMS.: To evaluate the role of infliximab looking at the predictors of response in a large series of patients with Crohn's disease. PATIENTS AND METHODS: Five hundred and seventy-three patients with luminal refractory Crohn's disease (Crohn's Disease Activity Index (CDAI)>220-400) (312 patients) or with fistulising disease (190 patients) or both of them (71 patients) were treated with a dose of 5 mg/kg in 12 Italian referral centres. The primary endpoints of the study were clinical response and clinical remission for luminal refractory and fistulising disease. We evaluated at univariable and multivariable analysis the following variables: number of infusions, sex, age at diagnosis, smoking habit, site of disease, previous surgery, extraintestinal manifestations and concomitant therapies, and type of fistulas. RESULTS: Patients with luminal refractory disease: 322 patients (84.1%) had a clinical response and 228 (59.5%) reached clinical remission. Patients with fistulising disease: 187 patients (72%) had a reduction of 50% of the number of fistulas and in 107 (41%) a total closure of fistulas was observed. For luminal disease, single infusion (OR 0.49, 95% CI 0.28-0.86) and previous surgery (OR 0.53, 95% CI 0.30-0.93) predicted a worse response for fistulising disease. Other fistulas responded worse than perianal fistulas (OR 0.57, 95% CI 0.303-1.097). CONCLUSION: In Crohn's disease infliximab is effective in luminal refractory and in fistulising disease. A single infusion and previous surgery predicted a worse response in luminal disease whereas perianal fistulas predicted a better response than other type of fistulas.

Prevalence, detection rate and outcome of cytomegalovirus infection in ulcerative colitis patients requiring colonic resection.

OBJECTIVE: To determine the prevalence of cytomegalovirus infection in patients with steroid-refractory ulcerative colitis who required colonic resection, and to assess its possible association with the use of immunosuppressive and steroid treatment and outcome after colectomy. PATIENTS AND METHODS: The study included surgical specimens and related pre-operative endoscopic biopsy specimens of 77 consecutive ulcerative colitis patients (34 females) who underwent colectomy because of intractable steroid-refractory ulcerative colitis (55 patients), toxic megacolon (6 patients), dysplasia or cancer (7 patients) or loss of function of the colon (9 patients). Clinical features and current and past treatments were analysed. Haematoxylin and eosin and specific immunohistochemical staining for cytomegalovirus were used to detect inclusion bodies in all specimens. RESULTS: Cytomegalovirus infection was found in 15 of 55 steroid-refractory ulcerative colitis patients (27.3%) and in 2 of 22 non-refractory patients (9.1%) (p=0.123). Only six patients had positive staining for cytomegalovirus in pre-operative endoscopic biopsy specimens. Detection of cytomegalovirus inclusion in biopsy specimens was not related to the number of biopsies or to time that had elapsed since colonoscopy and index surgery. Cytomegalovirus-positive patients were more likely to be on systemic corticosteroids (p=0.03). In contrast, current use and duration of immunosuppressive treatment, number of steroid cycles since diagnosis and in the last year, as well as chronic use of steroid in the last year were not significantly related to cytomegalovirus infection. Cytomegalovirus-positive patients did not receive antiviral therapy following proctocolectomy but did not show endoscopic or histological cytomegalovirus reactivation in the ileo-anal pouch and in the remaining bowel. CONCLUSIONS: Cytomegalovirus infection is frequently found in surgical specimens of patients with steroid-refractory ulcerative colitis and is more likely in patients on corticosteroid treatment. Cytomegalovirus infection is frequently unrecognised in pre-operative biopsy specimens, thus raising concerns about the accuracy of the available diagnostic tools. Unrecognised and untreated cytomegalovirus infection does not affect the outcome of ulcerative colitis patients following proctocolectomy.