Autoantibody profile during short-term infliximab treatment for Crohn's disease: a prospective cohort study

BACKGROUND: The potential clinical implications of autoimmunity during treatment with infliximab are unclear. AIM: To determine the frequency and correlation of autoantibody formation in patients with Crohn's disease treated with infliximab in a routine clinical setting. METHODS: Sixty-three patients with refractory/inflammatory (31) and/or fistulising Crohn's disease (32), received an infliximab infusion at a dose 5 mg/kg in weeks 0, 2 and 6, and were evaluated for the development of antinuclear, anti-double-stranded DNA, anti-Sm, anti-RNP, anti-SSA, anti-SSB and antihistone antibodies. The correlates with pharmacological treatments, the response to infliximab and adverse events were evaluated. RESULTS: Antinuclear antibodies were found in five of the 63 patients (8%) at baseline and in 26 (42%) after 10 weeks (P < 0.001). Of the 26 antinuclear antibody-positive patients who were further subtyped, nine of 63 (17%) had anti-double-stranded DNA (P = 0.003), and 1.5% were extractable nuclear antigen (ENA) and antihistone-positive. Five patients were initially positive for anticardiolipin antibodies and two more patients became positive during infliximab treatment. New autoantibody formation was more frequent in the patients with inflammatory/refractory disease than in those with fistulising disease (17 vs. 7; P = 0.02). One patient developed drug-induced lupus without major organ damage. CONCLUSIONS: Autoantibody formation occurs in 42% of patients (8% of these patients were positive before infliximab treatment) with Crohn's disease receiving induction treatment with infliximab, but the clinical significance of this remains to be determined.     

Polymorphism in IgG Fc receptor gene FCGR3A and response to infliximab in Crohn's disease: a subanalysis of the ACCENT I study

Recently, it has been shown that FCGR3A-158 gene polymorphism is associated with biological and possibly clinical response to infliximab in Crohn's disease. We further assessed this association in a subset of 344 patients from the large and well-defined cohort of 573 patients with Crohn's disease from the ACCENT I study. No association could be observed between FCGR3A-158 gene polymorphism and the clinical response to infliximab, which was primarily defined as a decrease of >or=70 points in the Crohn's disease activity index or clinical remission (Crohn's disease activity index <150). We did, however, confirm a trend towards a greater decrease in C-reactive protein after infliximab in V/V homozygotes as compared with V/F heterozygotes and F/F homozygotes (-79.4, -76.5, and -64.3%, respectively, at week 6; P=0.085; one-tailed P=0.043). This finding has no immediate clinical impact but may enhance the understanding of the complex mechanisms of action of anti-tumor necrosis factor agents in Crohn's disease.     

The TNF/ADAM 17 system: implication of an ADAM 17 haplotype in the clinical response to infliximab in Crohn's disease

Infliximab, a chimeric anti-tumour necrosis factor (TNF)-alpha antibody induces a clinical response in 70% of Crohn's disease patients and the response to infliximab therapy could be partially determined by genetic factors. The implication of both transmembrane and soluble forms of the TNF-alpha in the mechanism of action of infliximab has been demonstrated. The aim of our work was first to perform a complete study of TNF variants role in the response to infliximab in Crohn's disease. Secondly, considering the role of ADAM 17 in TNF-alpha shedding, the ADAM 17 locus was also studied. The response to infliximab was evaluated in 222 Caucasian Crohn's disease patients with a luminal (n=160) or fistulizing (n=62) form of the disease. Clinical and biological response evaluation was based on the Crohn's Disease Activity Index score and C-reactive protein level evolutions, respectively. The entire TNF gene was sequenced on the complete cohort. Twelve single nucleotide polymorphisms spanning the ADAM 17 locus were studied and haplotypes rebuilt. A clinical response was observed in 64% of the patients and biological response in 77.1% of patients. No association was found between the TNF gene and the response to infliximab. One haplotype in the ADAM 17 region was associated with a clinical response to infliximab in CD patients (adjusted P=0.045). In conclusion, our results exclude, with a reasonable power, an implication of the TNF gene in the response to infliximab in Crohn's disease, but reveal a potential role of the ADAM 17 gene in this response.     

The risk of post-operative complications associated with infliximab therapy for Crohn's disease: a controlled cohort study

BACKGROUND: By temporarily suppressing the immune response, the anti-tumour necrosis factor agent, infliximab, may increase the risk of peri-operative complications. AIM: To test this hypothesis for intestinal resection in a cohort of 313 Crohn's disease patients treated with infliximab. Forty received one or more infusions prior to intestinal resection (31/40 within 12 weeks). METHODS: The post-operative events of these patients were compared with those of a control group (infliximab naive) of 39 patients adjusted for age, gender and surgical procedure. Early (10 days) and late (3 months) major or minor complications were identified. RESULTS: The incidence of early minor (15.0% vs. 12.8%) and major (12.5% vs. 7.7%) and late minor (2.5% vs. 5.1%) and major (17.5% vs. 12.8%) complications and the mean hospital stay after surgery (10.3 +/- 4.0 days vs. 9.9 +/- 5.5 days) were similar in both groups. A trend towards an increased early infection rate was found in infliximab pre-treated patients (6 vs. 1; P = 0.10), but more patients in this group received corticosteroids and/or immunosuppressives (29 vs. 16 patients; P < 0.05). CONCLUSION: The use of infliximab before intestinal resection does not prolong the hospital stay and does not increase the rate of post-operative complications.     

Basic fibroblast growth factor as a response parameter to infliximab in fistulizing Crohn's disease

BACKGROUND: Fibroblast growth factors play an important role in (patho)physiological processes such as wound healing and tissue repair. We previously showed that basic fibroblast growth factor is actively involved in inflammatory bowel disease processes. In the present retrospective study, we assessed whether serum basic fibroblast growth factor levels in Crohn's disease patients reflect the response to anti-tumour necrosis factor-alpha antibody infliximab treatment. AIM AND METHODS: Serum samples, biopsies and patient data from a subgroup of patients included in two placebo-controlled trials were used. Fistulizing Crohn's disease patients (n = 42) were administered placebo or infliximab intravenously three times and evaluated for response up to 18 weeks. Biopsies from a subgroup of patients were stained for basic fibroblast growth factor using indirect immunohistochemistry. In the active Crohn's disease trial, patients (n = 24) received either placebo or infliximab once, and disease activity and serum basic fibroblast growth factor were assessed at weeks 0 and 4. RESULTS: Basic fibroblast growth factor levels at inclusion were comparable in the fistulizing Crohn's disease patients regardless of whether the fistulas did or did not respond or completely heal (median range: 9.3-10.6 pg/mL). At the end of follow-up basic fibroblast growth factor levels were lower in patients who responded (9.2 pg/mL, P = 0.06) or who were completely healed (8.9 pg/mL, P = 0.009) when compared with patients did not respond/heal (14.5 pg/mL), the latter not significantly increased from baseline. Decreases in the perianal disease activity index and open fistula scores at the end of the follow-up were significantly correlated with the decrease in basic fibroblast growth factor (R = 0.41; P = 0.012 and R = 0.35; P =0.027, respectively). Immunohistological evaluation also showed a trend towards decreased basic fibroblast growth factor expression in intestinal biopsies of these patients. Patients with active disease, i.e. a Crohn's disease activity index > or = 220 combined from the two studies, were found to have significantly (P = 0.0046) lower baseline serum basic fibroblast growth factors levels than those with inactive disease (5.3 vs. 10.3 pg/mL, respectively). Treatment of the active disease patients did not affect the serum basic fibroblast growth factor level, although a general decrease in disease activity was observed with infliximab treatment. CONCLUSIONS: Healing of fistulizing/perianal Crohn's disease seems to be reflected by a decrease in high serum basic fibroblast growth factor. Basic fibroblast growth factor levels do not relate with response in active Crohn's disease patients.     

Adalimumab maintenance therapy for Crohn's disease with intolerance or lost response to infliximab: an open-label study

BACKGROUND: Adalimumab is effective in inducing remission in patients with active Crohn's disease who had secondary failure to infliximab therapy. AIM: To evaluate the efficacy and safety of adalimumab maintenance therapy in Crohn's disease patients who previously responded to infliximab and then lost response or became intolerant. METHODS: Twenty-four patients with Crohn's disease were enrolled in a 52-week open-label trial. The patients received a loading dose of adalimumab 80-mg at week 0, and then 40 mg every other week starting at week 2. The primary efficacy measure was clinical remission defined as Crohn's Disease Activity Index score < 150 at week 52. RESULTS: Five patients lost response to adalimumab. None of the patients experienced intolerance to adalimumab. Clinical remission rates were higher at weeks 4 (16/24, 67%) and 52 (14/24, 58%) compared with baseline (8/24, 35%) (P=0.043 at week 52). This was accompanied by a decrease in mean C-reactive protein concentration from 31.8 mg/mL at baseline to 9.7 mg/mL at week 52, and 3/4 (75%) patients achieved steroid-free remission. No serious toxicities occurred in the study. CONCLUSIONS: Adalimumab is well tolerated and appears to be effective in maintaining clinical remission in patients with Crohn's disease and lost response or intolerance to infliximab.     

Association between polymorphism in IgG Fc receptor IIIa coding gene and biological response to infliximab in Crohn's disease

AIM: To test the hypothesis of an association between polymorphism in FCGR3A (the gene coding for FcgammaRIIIa, which is expressed on macrophages and natural killer cells, is involved in antibody-dependent cell-mediated cytotoxicity and has recently been associated with a positive response to rituximab, a recombinant immunoglobulin G1 antibody used in non-Hodgkin's lymphomas) and response to infliximab in Crohn's disease. METHODS: FCGR3A-158 polymorphism was determined using an allele-specific polymerase chain reaction assay in 200 Crohn's disease patients who had received infliximab for either refractory luminal (n = 142) or fistulizing (n = 58) Crohn's disease. Clinical and biological responses (according to C-reactive protein levels) were assessed in 200 and 145 patients, respectively. RESULTS: There were 82.9% clinical responders in V/V patients vs. 72.7% in V/F and F/F patients (N.S.). Globally, the decrease in C-reactive protein was significantly higher in V/V patients than in F carriers (P = 0.0078). A biological response was observed in 100% of V/V patients, compared with 69.8% of F carriers (P = 0.0002; relative risk, 1.43; 95% confidence interval, 1.27-1.61). In the sub-group of patients with elevated C-reactive protein before treatment, the multivariate analysis selected the use of immunosuppressive drugs and FCGR3A genotype as independent factors influencing the clinical response to infliximab (P = 0.003). CONCLUSION: Crohn's disease patients with FCGR3A-158 V/V genotype have a better biological and, possibly, clinical response to infliximab.     

Managing immunogenic responses to infliximab: treatment implications for patients with Crohn's disease

Infliximab is a tumour necrosis factor (TNF)-alpha antagonist that has revolutionised the treatment of Crohn's disease and rheumatoid arthritis. However, infliximab therapy can be complicated by a variety of adverse reactions. Acute infusion reactions occur during or shortly after infusion and typically consist of fever, chills, nausea, dyspnoea and headaches. Delayed reactions, characterised by myalgias, arthralgias, fever, rash, pruritus, facial, hand or lip oedema, dysphagia, urticaria, sore throat and headache may occur 3-12 days after infusion. Although the mechanisms of these reactions are not yet clearly defined, emerging evidence indicates that these reactions may be associated with the immune response against infliximab and the development of antibodies to infliximab.A number of studies have identified protective factors that may minimise adverse reactions, presumably related to the immune response against infliximab. Factors that may be protective by helping to establish immune tolerance for the foreign infliximab protein include concomitant administration of immunomodulators or corticosteroids, starting infliximab therapy with a 0, 2, 6-week induction regimen, maintenance dose administration with infusions every 8 weeks or less, and avoiding long periods between infusions.Infliximab therapy also may have other immunological consequences. There is evidence that infliximab may impede the appropriate immune response to a number of pathogens, prohibiting its use in patients with active infections. In addition, patients should be screened and appropriately treated for tuberculosis before initiating infliximab therapy. The development of autoantibodies, such as antinuclear antibody or anti-ds-DNA, has also been described with infliximab therapy, although the development of clinical lupus-like syndrome is rare. While there is a theoretical risk of increased rate of malignancies due to antagonism of TNFalpha, to date there is no clear evidence of such an effect. In addition, cardiac and neurological adverse events associated with infliximab therapy have been described. The mechanism for these adverse events is unclear.In summary, infliximab therapy can be an effective treatment for Crohn's disease; however, a number of immunological consequences and adverse events may complicate the infusion of this agent. Appropriate prophylaxis and therapy of these adverse reactions will allow infliximab to be used safely in the vast majority of patients.     

Adalimumab for Crohn's disease with intolerance or lost response to infliximab: a 3-year single-centre experience

Background  Adalimumab is effective in inducing clinical remission in patients with Crohn's disease who lost response or became intolerant to infliximab.
Aim  To evaluate long-term efficacy and safety of adalimumab as a second line therapy in luminal and fistulizing Crohn's disease.
Methods  We report our single-centre experience in 53 patients. We evaluated maintenance of clinical response defined as the absence of adverse events leading to drug withdrawal, no major abdominal surgery and no loss of clinical response in initial responders. Major abdominal surgery, steroid sparing, complete fistula closure and safety were also assessed.
Results  The probability of maintaining clinical response was 77.2%, 67.8% and 50.8% at 26, 52 and 130 weeks respectively. The probability of remaining major abdominal surgery-free was 82.3% at 26, 52 and 130 weeks. Complete fistula closure occurred in six of 10 patients, and eight of 10 patients were able to taper steroid therapy. Adverse events occurred in 31 patients (58.5%) leading to adalimumab withdrawal in nine patients (17%).
Conclusion  Adalimumab therapy may be effective in the long term in both luminal and fistulizing Crohn's disease in infliximab-failure patients, half of patients maintaining clinical response and potentially avoiding major abdominal surgery in 80% of cases.     

Prediction of Crohn's disease relapse with faecal calprotectin in infliximab responders: a prospective study

Aliment Pharmacol Ther 2011; 34: 462–469

Summary

Background Faecal calprotectin is a reliable tool for predicting Crohn’s disease (CD) relapse in patients with sustained remission. Prediction of relapse with faecal calprotectin has been less studied in patients with severe CD treated with anti‐TNF. Aim To identify an association between faecal calprotectin concentration and CD clinical relapse in patients achieving remission with infliximab (IFX). Methods From February 2007 to October 2008, consecutive patients with refractory luminal CD were prospectively included when they received three IFX infusions (5 mg/kg at weeks 0, 2 and 6) followed by maintenance with an immunomodulator alone. Faecal calprotectin and C‐reactive protein (CRP) were measured at entry and at week 14 (w14). Results Sixty‐five patients (43W; median age: 30.4 years) were included, and 50 (77%) were in clinical remission off steroids at w14; twenty‐three of fifty (46%) experienced CD clinical relapse during the first year of follow‐up. Median faecal calprotectin level at w14 was similar in patients with and without CD clinical relapse (200 and 150 μg/g respectively). When considering two suggested faecal calprotectin cut‐offs to predict CD relapse, sensitivities and specificities were 61% and 48% for 130 μg/g, respectively, and 43% and 57% for 250 μg/g. Neither faecal calprotectin nor CRP at baseline and at w14 could predict relapse even when CD location subgroup analysis was considered. Conclusion In patients responding to an infliximab induction regimen, faecal calprotectin measurement at w14 cannot predict Crohn’s disease clinical relapse at 1 year.     

Resource use in patients with Crohn's disease treated with infliximab

Aim To estimate the impact of infliximab (IFX) on hospital resources for patients with Crohn’s disease. Methods Resource use data for at least 1 year before (B‐IFX) and after (A‐IFX) infliximab administration were retrospectively collected for all patients treated with IFX at the Hospital Cabueñes (Spain). Direct costs calculated were: hospital‐stays, surgeries, out‐patient visits, diagnostic and laboratory tests, pharmacological treatments, and day‐care hospitalization for IFX administration. Results Patients (n = 34; mean age at treatment: 43.6 years) with 9.8 and 4.3 years (B‐IFX and A‐IFX, respectively) had their costs estimated. Partial or complete response was achieved in 82% of patients. Total annual B‐IFX costs per patient were €4464, of which 62.4% was for hospitalization, 3.1% for surgery, 8.7% for consultation visits, 16.2% for diagnostic and laboratory tests, and 9.6% for other treatments. Total annual A‐IFX costs per patient were €10 594; of which 6.4% was for hospitalization, 0.8% for surgery, 4.2% for consultation visits, 7.6% for diagnostic and laboratory tests, 5.5% for other treatments, and 75.5% for IFX and its administration. The primary cost item was hospitalization (€2783) during the B‐IFX period as opposed to IFX itself (€7996) during the subsequent A‐IFX period. Conclusions In routine practice, IFX appears to be an effective treatment by reducing hospital‐stays, but increases overall budgetary cost for patients with Crohn’s disease.     

Response to infliximab is related to disease duration in paediatric Crohn's disease

BACKGROUND: Infliximab is an effective therapy in adult patients with refractory and fistulizing Crohn's disease. Experience in children is still limited. AIM: : To evaluate the experience in 22 children and adolescents treated with infliximab with refractory and/or fistulizing Crohn's disease, and to compare duration of response in children between early Crohn's disease and late Crohn's disease. METHODS: The experience in 22 children and adolescents treated with a total of 73 infusions was evaluated retrospectively. Treatment indication was refractory Crohn's disease in 9/22 patients, fistulizing Crohn's disease in 7/22 patients and both these conditions in 6/22. All patients with refractory Crohn's disease had late Crohn's disease (> 1 year), whereas 6/13 patients with fistulas had early disease (< 1 year). RESULTS: Mean Paediatric Crohn's Disease Activity Index (PCDAI) decreased from 41.2 to 16.2 at 4 weeks (P < 0.01), and to 15.4 at 18 weeks (P < 0.01). Mean PCDAI at 18 weeks in children with early Crohn's disease and late Crohn's disease was 5.5 and 18.1, respectively (P < 0.05). Complete closure of fistulas was obtained in 5/6 children with early Crohn's disease and in 2/7 children with late Crohn's disease. Immediate adverse reactions were observed in two children. CONCLUSIONS: Infliximab is a highly effective treatment in children and adolescents with both severe refractory or fistulizing Crohn's disease. Children with early Crohn's disease have a higher chance of prolonged response to infliximab than children with late Crohn's disease.     

Polymorphisms in apoptosis genes predict response to infliximab therapy in luminal and fistulizing Crohn's disease

BACKGROUND: Infliximab treatment is effective in 70-80% of patients with refractory luminal and fistulizing Crohn's disease. The effect of infliximab is ascribed to induction of apoptosis. AIM: To study whether polymorphisms in apoptosis genes predict the response to infliximab and whether they interact with clinical predictors. METHODS: Cohort of 287 consecutive patients treated with infliximab for refractory luminal (n = 204) or fistulizing (n = 83) Crohn's disease was genotyped for 21 polymorphisms in apoptosis genes. Short-term clinical response was assessed at week 4 (luminal Crohn's disease) or 10 (fistulizing Crohn's disease) after the first infliximab infusion. RESULTS: The response rate was 69% in luminal and 80% in fistulizing Crohn's disease. In luminal Crohn's disease, two genetic predictors were identified: (i) patients with the Fas ligand -843 CC/CT genotype (n = 135) responded in 75%, with the TT genotype (n = 21) in 38% only (P = 0.002; OR = 0.11; 95% CI: 0.08-0.56). (ii) Patients with the caspase-9 93 TT (n = 9) genotype all responded, in contrast with 67% (n = 147) with the CC and CT genotype (P = 0.04; OR = 1.50; 95% CI: 1.34-1.68). Concomitant azathioprine/mercaptopurine therapy overcame the effect of unfavourable genotypes. In the fistulizing Crohn's disease cohort, the same Fas ligand -843 CC/CT genotype was the only predictor of response (P = 0.002; OR = 1.66; 95% CI: 1.21-2.29), interacting with caspase-9 93 polymorphism but not with azathioprine/mercaptopurine. CONCLUSION: We observed that polymorphisms in FasL/Fas system and caspase-9 influence the response to infliximab in luminal and fistulizing Crohn's disease. The strongest association was seen between the Fas ligand -843 TT genotype and non-response. Concomitant mercaptopurine/azathioprine therapy, however, was able to overcome the effect of unfavourable genotypes in luminal disease.     

Exposure to hookworms in patients with Crohn's disease: a case-control study

Aliment Pharmacol Ther 2011; 34: 923–930

Summary

Background Helminths have been used to inhibit intestinal inflammation in patients with Crohn’s disease. Aim This study was undertaken to determine if there is a protective association of prior hookworm infection with Crohn’s disease, in a region where there is epidemiological transition from parasitic and infectious diseases to increased auto‐inflammatory diseases. Methods Hookworm exposure was assessed by peripheral blood mononuclear cell (PBMC) activation by hookworm antigens in 78 patients with Crohn’s disease and 75 healthy control participants. The change in proportion of T cells exhibiting CD69 after exposure to crude hookworm antigens was measured. Interferon‐γ ELISPOT response to a panel of six recombinant hookworm antigens was analysed. Results Patients with Crohn’s disease were more often from an urban background (P = 0.005) compared to controls, while their socioeconomic status was not significantly different. T cell activation (increase in CD3⁺CD69⁺ population) by hookworm antigen was significantly higher in controls compared to Crohn’s disease patients (P = 0.017), while activation by the nonspecific mitogen phytohemagglutinin was similar in both groups. Circulating T memory cells (CD3⁺CD45RO⁺) after exposure to hookworm antigens were not significantly different between the two groups. Mirroring these changes, interferon‐γ ELISPOT responses to hookworm antigens were seen in 36 of 75 controls compared to 20 of 78 Crohn’s disease patients (Fisher’s exact P = 0.005). Multivariate analysis indicated that CD3CD69 shifts (P = 0.019), ELISPOT reactivity (P = 0.039) and place of residence (P = 0.024) were all independently associated with Crohn’s disease. Conclusion The inverse association between Crohn’s disease and hookworm antigen reactivity is consistent with the hygiene hypothesis, but requires further exploration.