New Concepts in Inflammatory Bowel Disease and Colitis

[David in Seattle]

Inflammatory Bowel Disease and Colitis: New Concepts From the Bench and the Clinic

Séverine Vermeire; Gert Van Assche; Paul Rutgeerts

Curr Opin Gastroenterol. 2011;27(1):32-37. © 2011 Lippincott Williams & Wilkins

Abstract and Introduction
Abstract

Purpose of review The previous 18 months have shown important progress in unravelling the causes of inflammatory bowel disease (IBD) and in improving its management for the patients.
Recent findings More genome-wide association studies and meta-analyses of these have been published and have identified more than 100 confirmed genes for IBD, and highlighted a number of novel pathways. Two of the genes, NOD2/CARD15 and the autophagy gene ATG16L1 have recently been linked into one functional pathway of bacterial sensing, invasion and elimination. From the clinical side, the previous year has been dominated mainly by the results of the SONIC study, comparing efficacy and safety of azathioprine, infliximab and the combination of azathioprine and infliximab, in patients with active Crohn's disease, naive to these drugs. International consensus guidelines on infection prevention were released last year by the European Crohn's and Colitis Organisation.
Summary The recent findings in IBD include the increasing number of IBD susceptibility genes, the demonstration that NOD2 and ATG16L1 are linked in one functional pathway and the role of IL-33/ST2 in colitis. From the bedside, the novelties have been the results of SONIC and selecting the right patient for intensified treatment with immunomodulators and anti-tumor necrosis factor, and appropriate counselling regarding risk of infections and vaccinations.

Introduction

The successful integration of basic, translational and clinical research for several years already has resulted in major advances in understanding Crohn's disease and ulcerative colitis. The last 18 months have again been characterized by several landmark studies from both bench as well as bedside. We have selected a number of studies in this overview with respect to their relevance for the patient with IBD and the treating physician.

Inflammatory Bowel Disease Pathogenesis: Gene–Environment Interactions

Since 2006, the technique of genome-wide association scanning (GWAS) has been applied in the hunt for the genes underlying complex diseases such as rheumatoid arthritis, psoriasis, hypertension, Crohn's disease and ulcerative colitis. Besides the multiple GWAS published in adult inflammatory bowel disease (IBD), a GWAS in early-onset IBD was performed on 3426 children and 11 963 genetically matched controls recruited through international collaborations in Europe and North America.[1] At least five new regions were identified, including 16p11 near the cytokine gene IL27, but also 22q12, 10q22, 2q37 and 19q13.11. A large proportion of loci previously implicated in adult-onset Crohn's disease and ulcerative colitis were also identified in pediatric-onset IBD, highlighting the close pathogenetic relationship between early-onset and adult-onset IBD. Given the increasing amount of GWAS data, an updated meta-analysis of the Crohn's disease GWAS scans and an ulcerative colitis meta-analysis were performed by the analysts of the International IBD Genetics Consortium and have brought the total number of confirmed IBD loci to more than 100. The results will be published soon.

IBD genetics has highlighted a number of important pathways. The pathway of bacterial sensing with the pattern recognition receptor NOD2/CARD15 is most known without doubt but also the pathway of autophagy has received a lot of attention following the discovery of IRGM and ATG16L1. Autophagy is a physiological process important for cellular homeostasis but has also a role in the defence against intracellular bacteria. Given that both NOD2 and ATG16L1 are implicated in defence against bacteria, researchers hypothesized that both pathways could be linked. Two independent studies were able to demonstrate this. Travassos et al. [2] showed that Nod1 and Nod2 are critical for the autophagy response to invasive bacteria by recruiting ATG16L1 to the plasma membrane at the bacterial entry site. In cells that were homozygous for the Crohn's disease-associated NOD2 fs1001insC mutation, ATG16L1 could not be recruited to the plasma membrane and encapsulation of invading bacteria by autophagosomes was impaired. The NOD2-mediated autophagy is also required for generation of MHC class II antigen-specific CD4+ T cell responses in dendritic cells as shown by Cooney et al. [3] Dendritic cells from Crohn's disease patients with NOD2 or ATG16L1 risk alleles are defective in autophagy induction, bacterial trafficking and antigen presentation. Both studies have therefore linked these two Crohn's disease-associated susceptibility genes in a single functional pathway and show defects in dendritic cells that could lead to bacterial persistence via impaired autophagy.

Despite the progress in the field of genetics, it is clear that only a small proportion of individuals carrying disease susceptibility genes will effectively develop overt Crohn's disease or ulcerative colitis. Studies on gene–environment interactions have been limited so far. Cadwell et al. [4••] demonstrated in a recent issue of Cell that an interaction between murine norovirus (MNV) infection and a mutation in the Atg16L1 gene induces intestinal inflammation in mice. Noroviruses are RNA viruses responsible for the majority of epidemic nonbacterial gastroenteritis in humans. In their study, Atg16L1HM mice infected with MNV for 1 week prior to dextran sulfate sodium treatment showed ileocolonic inflammation and anorectal abnormalities with transmural inflammation and fibrosis as observed in human Crohn's disease. This study shows how an infection triggers Paneth cell abnormalities and leads to persistent infection in genetically predisposed mice, and for the first time in IBD, shows how multiple hits or triggers may induce disease in susceptible organisms.

 

[David in Seattle]

The IL-33/ST2 Pathway in Inflammatory Bowel Disease

IL-33 is a novel member of the IL-1 family and ligand for the IL-1 receptor-related protein, ST2. The IL-33/ST2 axis has been implicated in several autoimmune and inflammatory disorders (asthma, rheumatoid arthritis, lupus), but its role in IBD was unknown.[5] Data published in PNAS now show increased mucosal IL-33 in active ulcerative colitis patients, localized primarily to intestinal epithelial cells and colonic inflammatory infiltrates and elevated levels of cleaved IL-33 and soluble ST2 in IBD serum. IL-33 significantly increased and correlated with disease severity, and potently induced IL-5, IL-6, and IL-17 from mucosal immune cells in SAMP mice. Infliximab treatment of ulcerative colitis decreased circulating IL-33. Taken together, the IL-33/ST2 system plays an important role in IBD and experimental colitis. This pathway is modulated by anti-tumor necrosis factor (TNF) therapy and may represent a specific biomarker for active ulcerative colitis.

Translation from Bench to Clinic: Mechanisms of Action of Anti-tumor Necrosis Factor

Response to medical therapy is variable between patients. For anti-TNF, 30% of patients are considered primary nonresponders and fail to improve after induction. The reasons for this primary failure (in contrast to secondary failure which is mainly due to antibody formation and subsequent loss of response) are unknown. In an attempt to gain insights in the mechanisms underlying response or nonresponse, we studied mucosal gene expression in colonic biopsies from ulcerative colitis patients before and after their first IFX infusion.[6] Using two independent cohorts, the top five differentially expressed genes in a combined analysis were osteoprotegerin, stanniocalcin-1, prostaglandin-endoperoxide synthase 2, interleukin-13 receptor alpha 2 and interleukin-11. These markers separated responders from nonresponders with 95% sensitivity and 85% specificity. IL-13 receptor alpha 2 is of interest as blocking IL-13 signalling by sIL-13Ralpha2-Fc or IL-13Ralpha2 siRNA has shown to prevent onset of fibrosis in TNBS colitic mice.

More recently, a study from Nantes, France, studied 40 patients treated with IFX and associated response to IFX with a decrease of IL-15, and with increased serum levels of sIL-15Ralpha and the IL-15/sIL-15Ralpha complex.[7] IFX induced the release of IL-15Ralpha in vitro.

Translating clinical observations back to the bench is needed not only to understand why they occur, but also to hopefully identify alternative pathways which could be targeted in these patients.

 

[David in Seattle]

Medical Treatment of Crohn's Disease: Monotherapy or Combination Therapy?

Infliximab has a well-established place in the treatment of Crohn's disease both as induction agent and to maintain remission long term. Its efficacy relative to that of azathioprine in this respect was unknown until earlier this year when the results of SONIC were published. SONIC was a double-blind randomized trial that evaluated the efficacy of infliximab monotherapy to azathioprine monotherapy and to both drugs combined in 508 adults with moderate-to-severe Crohn's disease who had not undergone previous immunosuppressive or biologic therapy.[8••] The corticosteroid-free clinical remission at week 26 (the primary end point) was 56.8% in the combination group, as compared with 44.4% in the infliximab monotherapy arm, and 30.0% in the azathioprine arm (P < 0.001 for the comparison with combination therapy and P = 0.006 for the comparison with infliximab). These results maintained through week 50 (see Fig. 1). Also the mucosal healing rates at this time point were highest in patients receiving combination therapy (43.9%), as compared with 30.1% in patients receiving infliximab and 16.5% in patients receiving azathioprine (P < 0.001 for the comparison with combination therapy and P = 0.02 for the comparison with infliximab). This landmark study advocates the use of combination therapy in Crohn's disease patients with active disease who are immunomodulator-naive.

Figure 1.
Corticosteroid-free remission at week 50 (SONIC study)

 

[David in Seattle]

Role of Mucosal Healing to Change the Disease Course?

The importance of mucosal healing in Crohn's disease has been debated for several years. With an increasing amount of data however which show healing leads to a reduction in bowel resections, clinical trials include healing more and more as primary endpoint. The Benelux step-up top-down study demonstrated that combined immunosuppression with azathioprine/MTX and anti-TNF is more effective than conventional step-up management for induction of remission and reduction of corticosteroid use in patients with a recent diagnosis of Crohn's disease. More patients in the combined treatment arm showed endoscopic healing at year 2, which led the authors to suggest that initiation of intensive treatment early in the disease could have a positive impact on the future disease course. Baert et al. [9] now published the 4-year outcome data of a subset of 49 patients from this initially randomized cohort who had an ileocolonoscopy performed after 2 years of therapy. The endoscopic findings at year 2 were correlated to the clinical outcome at year 4. The presence of complete mucosal healing, with absence of ulcers, predicted steroid-free remission 3 and 4 years after therapy. Seventy percent (17/24) of patients with healing at year 2 were in steroid-free remission at year 3 or 4 as compared to only 27.3% of patients (six of 22) who had still lesions detected at endoscopy (Fig. 2). The relative risk for sustained steroid-free remission in case of complete healing was 4.35 (95% confidence interval 1.10–17.220). These results add to the accumulating importance of achieving healing of the bowel in order to halt disease progression.

Figure 2.
Step-up versus top-down study: years 3–4 follow-up according to endoscopy at year 2

 

[David in Seattle]

Adalimumab and Fistula Healing

No data were available on the efficacy of adalimumab in active perianal Crohn's disease. The study by Present et al. [10] and ACCENT II[11] clearly demonstrated efficacy of infliximab on fistula healing but it was unclear if these data could be extrapolated also to adalimumab. This question has in part been answered by a subanalysis of CHARM where fistula healing was a predetermined secondary endpoint.[12] Of 854 patients enrolled in CHARM, 117 had draining fistulas at baseline. The mean number of draining fistulas per day decreased significantly in the adalimumab-treated patients compared with the placebo-treated patients during the double-blind treatment period. Of all the patients with healed fistulas at week 56 (both adalimumab and placebo), 90% (28/31) maintained healing when given open-label adalimumab therapy for 1 year. Although these results are promising and suggest also good healing of perianal fistulas with adalimumab, it needs to be stressed that this study was not powered for secondary endpoints and that still more experience with adalimumab on perianal fistulizing disease is needed.

Importance of Drug and Antibody Monitoring to Anti-tumor Necrosis Factor

Infliximab (chimeric, 25% murine) and adalimumab (human) are not free of immunogenicity. The occurrence of antibodies to these drugs is associated with low drug concentrations leading to loss of efficacy. The validity of measuring drug levels and/or antibodies in clinical practice still needs to be demonstrated. The study by Afif et al. [13] from the Mayo Clinic evaluated the clinical utility of measuring anti-infliximab antibodies (ATIs) and infliximab concentrations in 155 patients. More than two-thirds of patients had ATIs measured for reasons of loss of clinical efficacy. Not surprisingly, 23% of patients had ATIs detected and only 33% of patients had therapeutic infliximab concentrations. Correlating the drug and antibody levels to the long-term clinical outcome, in ATI-positive patients, change to another anti-TNF resulted in response in 92% of patients, whereas dose escalation had a response of only 17%. In patients with subtherapeutic infliximab concentrations (assuming no ATIs as IFX was still detectable), dose escalation led to regain of clinical response in 86% of patients whereas changing to another anti-TNF had a response of only 33%.

In the Leuven cohort, patients who discontinued adalimumab throughout the follow-up period had significantly lower adalimumab serum concentrations as compared with patients who stayed on adalimumab (Fig.3).[14] Antibodies against adalimumab were present in 9.2% of the patients and clearly affected serum concentrations.

Figure 3.
Patients who needed to discontinue adalimumab by week 24 had lower adalimumab serum levels at all time points
Reproduced from Karmiris et al. [14].

 

[David in Seattle]

Safety Concerns of Medical Therapy and Infection Prevention

Patients receiving thiopurines are at increased risk for lymphoproliferative disorders as suggested from the literature including two meta-analyses. The CESAME study group assessed the risk for lymphomas prospectively in a nationwide cohort study of 19 486 IBD patients (60.3% Crohn's disease and 39.7% ulcerative colitis). The median follow-up was 35 months (interquartile range 29–40).[15•] Patients receiving thiopurines had a hazard ratio of 5.28 (2.01–13.9, P = 0.0007) for lymphoproliferative disorders, and this risk was observed in patients more than 65 years of male gender and with a longer duration of disease. Concluding from these important results, the absolute risk of a lymphoproliferative disorder in a young patient remains very low, but the situation seems different in elderly patients and should be included in the benefit/risk analysis.

Last year, our group reported on the long-term safety of anti-TNF therapy in the first 743 IBD patients who had received infliximab.[16•] The outcome of this cohort was compared to 666 nonanti-TNF treated IBD patients, also followed at our unit. With a follow-up as long as 14 years, there was no difference in mortality, cancer or infection risk between the anti-TNF and the control group. Concomitant steroid therapy was the only independent risk factor for infections in the infliximab group with a 2.69-fold (95% CI 1.18–6.12) increased risk in case of co-administration of corticosteroids together with infliximab (P = 0.018). The Edinburgh group also reported the long-term safety of their 202 IFX-treated IBD patients (no control group).[17] The median follow-up was 2.4 years (1.0–4.9) with a total of 620 patient-years follow-up. A total of 95 adverse events (36 serious) occurred in 28.7% of patients. The total mortality was 3.3% although only one death was less than 1 year postinfliximab (at day 72, from lung cancer). A total of six malignancies and six cases of suspected demyelination (three with confirmed neurological disease) were reported.

Taken together, anti-TNF agents are not free of side-effects, but seem safe, given that one knows the contra-indications (severe heart failure, demyelinating disorders, serious comorbidities, active TB, etc.) and that the benefit/risk analysis is carefully assessed and discussed prior to commencement of therapy.

The administration of immunomodulators and/or anti-TNF prevents patients from receiving live-attenuated vaccines. Also, immunomodulators and/or biological agents may attenuate the response to vaccination. The ECCO consensus on opportunistic infections in IBD therefore brought together 30 IBD and infectious disease specialists. Their guidelines recommend serology testing for specific viruses and a number of vaccinations shortly following diagnosis of IBD (;[18•,19] see Fig. 4). Besides the infectious serology, a baseline laboratory exam with neutrophil, eosinophil and lymphocyte blood count, C-reactive protein and HIV serology is also recommended. The experts taking part in the ECCO guidelines could not reach consensus regarding hepatitis C virus (HCV) screening, but recommended Hep B vaccination. A recent nationwide Spanish study on more than 2000 consecutively recruited IBD patients showed that the prevalence of hepatitis B virus (HBV) and HCV infection was similar to that of the general population.[20] This was also confirmed in a French study.[21] However, in case of infection, the frequency and severity of liver dysfunction appears significantly higher in HBV-infected patients than in HCV-infected patients. In the study from the Spanish GETECCU, Hep B infection in IBD patients resulted in liver dysfunction in more than one-third (36%) of patients including six cases of hepatic failure.[22] Liver dysfunction in HCV was less frequent (15.7%), and only one patient developed hepatic failure. The treatment with two or more immunosuppressants was an independent predictor of HBV reactivation (OR 8.75; 95% CI 1.16–65.66).

Figure 4.
Serology and vaccination to be performed in IBD patients before starting immunomodulators and/or biological therapy as recommended by the ECCO consensus guidelines



In contrast to the severe but infrequent opportunistic infections, benign infections such as common colds, bronchitis, warts and herpes are more frequently reported by patients.[23] In a prospective cohort study with a follow-up of 207 patient-years, no difference in upper respiratory tract infections was found between azathioprine-taking patients and those not on purine analogues. In contrast, the incidence of herpes flares and warts was significantly increased in IBD patients on azathioprine. Stopping therapy may be necessary if these flares are too frequent and/or severe. However, in case therapy needs to be continued to maintain disease remission, daily oral acyclovir (400 mg bid) can prevent frequent recurrences of herpes simplex disease.

 

[David in Seattle]

Conclusion

The recent findings regarding IBD pathogenesis include the increasing number of IBD susceptibility genes, reaching more than 100 genes at the moment, the demonstration that NOD2 and ATG16L1 are linked in one functional pathway and the role of IL-33/ST2 in colitis.

From the bedside, the focus has been on selecting the right patient for intensified treatment with immunomodulators and anti-TNF, and on a careful risk/benefit analysis for each patient, including appropriate counselling regarding risk of infections and vaccinations.

References

1. Imielinski M, Baldassano RN, Griffiths A. Common variants at five new loci associated with early-onset inflammatory bowel disease. Nat Genet 2009; 41:1335–1340.
2. Travassos LH, Carneiro LA, Ramjeet M, et al. Nod1 and Nod2 direct autophagy by recruiting ATG16L1 to the plasma membrane at the site of bacterial entry. Nat Immunol 2010; 11:55–62.
3. Cooney R, Baker J, Brain O, et al. Simmons ANOD2 stimulation induces autophagy in dendritic cells influencing bacterial handling and antigen presentation. Nat Med 2010; 16:90–97.
4. Cadwell K, Patel KK, Maloney NS, et al. Virus-plus-susceptibility gene interaction determines Crohn's disease gene Atg16L1 phenotypes in intestine. Cell 2010; 141:1135–1145.
•• This study shows evidence for a multihit model in IBD with specific interaction between enteric infection, the microbiota and a genetic susceptibility.
5. Pastorelli L, Garg RR, Hoang SB, et al. Epithelial-derived IL-33 and its receptor ST2 are dysregulated in ulcerative colitis and in experimental Th1/Th2 driven enteritis. Proc Natl Acad Sci U S A 2010; 107:8017–8022.
6. Arijs I, Li K, Toedter G, et al. Mucosal gene signatures to predict response to infliximab in patients with ulcerative colitis. Gut 2009; 58:1612–1619.
7. Bouchaud G, Mortier E, Flamant M, et al. Interleukin-15 and its soluble receptor mediate the response to infliximab in patients with Crohn's disease. Gastroenterology 2010; 138:2378–2387.
8. Colombel JF, Sandborn WJ, Reinisch W, et al, SONIC Study Group. Infliximab, azathioprine, or combination therapy for Crohn's disease. N Engl J Med 2010; 362:1383–1395.
•• This is the first double-blind randomized trial ever comparing efficacy, safety and mucosal healing of azathioprine, infliximab, and the combination of azathioprine with infliximab.
9. Baert F, Moortgat L, Van Assche G, et al, Belgian Inflammatory Bowel Disease Research Group. North-Holland Gut ClubMucosal healing predicts sustained clinical remission in patients with early-stage Crohn's disease. Gastroenterology 2010; 138:463–468.
10. Present DH, Rutgeerts P, Targan S, et al. Infliximab for the treatment of fistulas in patients with Crohn's disease. N Engl J Med 1999; 340:1398–1405.
11. Sands BE, Anderson FH, Bernstein CN, et al. Infliximab maintenance therapy for fistulizing Crohn's disease. N Engl J Med 2004; 350:876–885.
12. Colombel JF, Schwartz DA, Sandborn WJ, et al. Adalimumab for the treatment of fistulas in patients with Crohn's disease. Gut 2009; 58:940–948.
13. Afif W, Loftus EV Jr, Faubion WA, et al. Clinical utility of measuring infliximab and human antichimeric antibody concentrations in patients with inflammatory bowel disease. Am J Gastroenterol 2010; 105:1133–1139.
14. Karmiris K, Paintaud G, Noman M, et al. Influence of trough serum levels and immunogenicity on long-term outcome of adalimumab therapy in Crohn's disease. Gastroenterology 2009; 137:1628–1640.
15. Beaugerie L, Brousse N, Bouvier AM, et al, CESAME Study Group. Lymphoproliferative disorders in patients receiving thiopurines for inflammatory bowel disease: a prospective observational cohort study. Lancet 2009; 374:1617–1625.
• This is the largest prospective study to date assessing the risk of lymphoproliferative disorders in patients with IBD and the effect of medical therapy on this risk.
16. Fidder H, Schnitzler F, Ferrante M, et al. Long-term safety of infliximab for the treatment of inflammatory bowel disease: a single-centre cohort study. Gut 2009; 58:501–508.
• This is a large controlled cohort study on the long-term safety of infliximab in patients with IBD.
17. Lees CW, Ali AI, Thompson AI, et al. The safety profile of antitumour necrosis factor therapy in inflammatory bowel disease in clinical practice: analysis of 620 patient-years follow-up. Aliment Pharmacol Ther 2009; 29:286–297.
18. Rahier JF, Ben-Horin S, Chowers Y, et al. European evidence-based consensus on the prevention, diagnosis and management of opportunistic infections in inflammatory bowel disease. J Crohn's Colitis 2009; 3:47–91.
• This is the very first guidelines on prevention and management of (opportunistic) infections in IBD.
19. Rahier JF, Yazdanpanah Y, Colombel JF, Travis S. The European (ECCO) Consensus on infection in IBD: what does it change for the clinician? Gut 2009; 58:1313–1315.
20. Loras C, Saro C, Gonzalez-Huix F, GETECCu (Grupo Español de Enfermedades de Crohn y Colitis Ulcerosa). Prevalence and factors related to hepatitis B and C in inflammatory bowel disease patients in Spain: a nationwide, multicenter study. Am J Gastroenterol 2009; 104:57–63.
21. Chevaux JB, Nani A, Oussalah A, et al. Prevalence of hepatitis B and C and risk factors for nonvaccination in inflammatory bowel disease patients in Northeast France. Inflamm Bowel Dis 2010; 16:916–924.
22. Loras C, Gisbert JP, Mínguez M, for the REPENTINA study; GETECCU (Grupo Español de Enfermedades de Crohn y Colitis Ulcerosa) Group. Liver dysfunction related to hepatitis B and C in patients with inflammatory bowel disease treated with immunosuppressive therapy. Gut 2010; 59:1340–1346.
23. Seksik P, Cosnes J, Sokol H, et al. Incidence of benign upper respiratory tract infections, HSV and HPV cutaneous infections in inflammatory bowel disease patients treated with azathioprine. Aliment Pharmacol Ther 2009; 29:1106–1113.

Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 86–88).

 

[DustyKat]

Very interesting, thanks David!

Dusty.

 

[troydanielbecker]

nothing like some light weekday reading material.

 

[troydanielbecker]

or weekend rather!

 

[PeninsulaLil]

Thanks David. Very interesting. Always cheering to see actual research that can have immediate impact.

Lilly

 

[David in Seattle]

Dusty & Lilly - Glad you found the article interesting. I think it's a very good review of some of the latest developments in IBD research.

Troy - Sorry you found the material boring, but it really wasn't written for entertainment purposes. Medical research may not be your thing, particularly if you're not sure what day of the week it is...

 

[troydanielbecker]

tout au contraire...

 

[Trysha]

Most interesting reading David.
Thank you for caring and sharing
trysha

 

[David in Seattle]

You're very welcome, Trysha!