Issue 03

Mentoring in IBD is an innovative and successful educational program for Canadian gastroenterologists that now includes an annual national meeting, regional satellites in both official languages, a website, an educational newsletter series, and regular electronic communications answering key clinical questions with new research. This issue is based on the presentation made by the issue editor, Dr Simon Travis, at the annual national meeting, Mentoring in IBD XV: The Master Class, held November 7, 2014 in Toronto, Ontario.

Introduction

Current guidelines recommend addition of an immunomodulator to tumour necrosis factor-α (TNF-α) inhibitor therapy in patients with inflammatory bowel disease (IBD) to prevent development of antidrug antibodies (ADAs). Although the clinical benefits of this approach are well established and some evidence guides the use of combination therapy, numerous questions still surround this strategy (Table 1).

Combination therapy in IBD

Combination therapy has been demonstrated to improve rates of corticosteroid-free clinical remission and mucosal healing. Sokol et al studied infliximab combination therapy with azathioprine or methotrexate in 121 patients with IBD.(1) They analyzed 6-month treatment semesters for disease activity and found that semesters including immunosuppressant therapy (n=265) were associated with fewer IBD flares (19.3% vs 32.0%, P=0.003), perianal complications (4.1% vs 11.8%, P=0.03) and switches to adalimumab (1.1% vs 5.3%, P=0.006) than semesters without immunosuppressive therapy (n=319). In addition, maximal C-reactive protein (CRP) levels and infliximab dose were lower in semesters that included immunosuppressive therapy. Combination therapy with azathioprine was more effective than with methotrexate. This study demonstrated that adding an immunosuppressant, even after initiation of infliximab, is beneficial.

Karmiris et al evaluated the benefit of adalimumab therapy after failure of infliximab in 168 patients and measured both trough serum concentration and ADAs to adalimumab.(2) Two-thirds of patients experienced a sustained clinical benefit during a median 2-year follow-up. Low drug trough levels, which were seen more often in patients positive for ADAs, were directly related to treatment discontinuation. Although combination therapy with an immunomodulator had no effect on overall treatment outcomes, it lengthened the time to dose escalation.

Combination therapy in Crohn’s disease

The Study of Immunomodulator Naive Patients in Crohn’s Disease (SONIC), a randomized, double-blind trial in 508 treatment-naïve adults with moderate-to-severe Crohn’s disease (CD), found a corticosteroid-free remission rate of 57% for the combination of infliximab plus azathioprine, compared with 44% for infliximab monotherapy, after 26 weeks of therapy (Figure 1).(3) In contrast, the Combination Of Maintenance Methotrexate-Infliximab Trial (COMMIT), a double-blind, placebo-controlled trial using prednisone induction in 126 adults with CD, found a 76% corticosteroid-free remission rate for infliximab plus methotrexate, compared with 78% for infliximab alone at 14 weeks (Figure 2).(4) Prednisone was discontinued no later than Week 14. It is important to note that 30% of patients did not have active disease at trial entry.

Dulai et al performed a meta-analysis of 11 randomized controlled trials (RCTs) comparing infliximab, adalimumab, or certolizumab pegol monotherapy with combination therapy including an immunosuppressive.(5) For patients with CD, the analysis showed combination therapy to be almost 80% more effective than monotherapy for infliximab (odds ratio [OR] 1.79; 95% confidence interval [CI] 1.06–3.01), but not adalimumab (OR 0.88; 95% CI 0.58–1.35), or certolizumab pegol (OR 0.93; 95% CI 0.65–1.34). Although infliximab therapy benefits from addition of thiopurines at any stage, a benefit was not demonstrated when adalimumab was combined with azathioprine.

Jones et al performed a meta-analysis of placebo-controlled TNF-α-inhibitor RCTs to evaluate the impact of combination therapy with an immunomodulator.(6) The study has yet to be published in full. The analysis found that the combination was not more effective overall than monotherapy for the endpoint 6-month remission, induction or maintenance of response, and partial or complete fistula closure. Subgroup analyses found combination therapy to be more effective than monotherapy for the endpoint 6-month remission for infliximab (OR 1.79; 95% CI 1.06–3.01), but not adalimumab (OR 0.88; 95% CI 0.58–1.35) or certolizumab pegol (OR 0.93; 95% CI 0.65–1.34). Infliximab combination therapy was also associated with fewer infusion reactions (OR 0.43; CI 0.19–0.97).

Reenaers et al conducted a retrospective study of 207 patients with CD to assess the benefits of adalimumab monotherapy or combination therapy with an immunomodulator in induction and maintenance.(7) The design was identical to the Sokol study on infliximab.(1) No significant between-group difference was seen in the success of induction, but combination therapy during the first 6 months of therapy was associated with a lower risk of treatment failure (5% vs 10%, P=0.04, OR 0.48) and combination therapy beyond 6 months was associated with fewer 6-month semesters with flares (14% vs 36%, P=0.02, OR 0.31).

Combination therapy in ulcerative colitis

The meta-analysis performed by Dulai et al included a single ulcerative colitis (UC) trial of combination therapy (UC-SUCCESS), which compared infliximab plus azathioprine to infliximab monotherapy in 239 patients with moderate-to-severe UC.(5) Combination therapy had a greater efficacy benefit in UC than in CD for corticosteroid-free remission (40%) compared with infliximab monotherapy (22%) at 16 weeks (P=0.017) and for mucosal healing (63% for the combination vs 55% for infliximab monotherapy, P=0.295). The trial was stopped early.

Risks of thiopurines in combination therapy

The meta-analysis performed by Jones et al also demonstrated that, compared with monotherapy, combination therapy was not associated with serious adverse events (serious infection, malignancy, or death) for the TNF-α-inhibitors studied in RCTs: adalimumab, infliximab, and certolizumab pegol.(6) Analysis of data on more than 3000 patients treated with infliximab or adalimumab found that the single greatest risk factor for serious infection or mortality was age >65 years.(8)

Serious infection

Deepak et al analyzed data from the Food and Drug Administration (FDA) Adverse Event Reporting System to identify any incremental risk of serious infection with TNF-α inhibitor and immunomodulator combination therapy over the risk seen with monotherapy with either drug.(9) The investigation found that combination therapy does not increase the odds of serious infection compared to monotherapy (Figure 3). However, it is important to note that this type of observational data is associated with substantial bias, as neither the denominator nor the follow-up duration is defined.

Malignancy

Deepak et al also examined the risk of T-cell non-Hodgkin lymphoma with TNF-α inhibitors in comparison with thiopurines in IBD using all cases reported to the FDA.(10) The review found TNF-α inhibitor plus thiopurine combination therapy (95% CI 4.98–354.09, P<0.0001) and thiopurine monotherapy (95% CI 8.32–945.38, P<0.0001) increased the risk of T-cell non-Hodgkin lymphoma, but TNF-α inhibitor monotherapy had no impact on risk (95% CI 0.13–10.61; P=1.00). Similar results were seen for hepatosplenic T-cell lymphoma.

Beaugerie et al performed a prospective observational cohort study with a median follow-up period of 35 months to evaluate the risk of lymphoproliferative disorders in patients receiving thiopurines for IBD.(11) The multivariate-adjusted hazard ratio for lymphoproliferative disorder for patients receiving thiopurines compared with those who had never received these agents was 5.28 (2.01–13.9, P=0.0007). The risk of hepatosplenic T-cell lymphoma appears to be related to a thiopurine therapy duration >2 years, and increasing age is the greatest risk factor for lymphoma. Risk decreases after thiopurine discontinuation.

Siegel et al performed a meta-analysis of trials of TNF-α inhibitor therapy in adults with CD to determine the rate of non-Hodgkin lymphoma. The derived rate was then compared with rates determined from the Surveillance Epidemiology & End Results database and a meta-analysis of patients with CD treated with immunomodulator therapy.(12) Compared with the general population, combination therapy may increase the risk of lymphoma (standardized incidence ratio [SIR] 3.2, 95% CI 1.5–6.9) to levels that are similar to those seen with immunomodulator monotherapy (SIR 1.7, 95% CI 0.5–7.1).

The increased lymphoma risk seen in patients receiving combination therapy appears to be driven by thiopurines, as an increased risk of lymphoma has not been reported in patients receiving TNF-α inhibitor monotherapy in any study.

Withdrawal of immunosuppression

Definitive data on withdrawal of immunosuppression in patients in remission do not exist. Van Assche et al performed an open, randomized, controlled trial to compare the clinical impact of continuing or discontinuing immunosuppressive therapy in patients in remission after 6 months of infliximab combination therapy.(13) At 2-year follow-up, no significant between-group difference was seen in the presence of mucosal ulceration, the need for an increased infliximab dose, or infliximab discontinuation. Continued combination therapy, however, was associated with higher median infliximab trough levels and lower CRP levels.

Louis et al assessed the clinical outcome after discontinuing infliximab in a prospective study of 115 patients with CD who had been in corticosteroid-free remission for >6 months and had been treated for >1 year with infliximab combination therapy.(14) After a median 28-month follow-up, 52 patients relapsed. Multivariable analysis found risk factors for relapse to be male sex, the absence of surgical resection, white blood cell counts >6.0 × 10⁹/L, hemoglobin ≤145 g/L, CRP ≥5.0 mg/L, and fecal calprotectin ≥300 μg/g. A 15% risk of relapse within 1 year was seen in patients with ≤2 risk factors. Infliximab retreatment upon relapse was successful in 88% of patients, but long-term outcomes were not reported.

Conclusions

In most patients the benefit of combination therapy outweighs the risk, as the addition of an immunomodulator to therapy increases the effect and extends the durability of treatment with a TNF-α inhibitor. This is certainly true for infliximab and appears to apply to treatment initiation with adalimumab. At this point, it can only be assumed that treatment with a biosimilar should be managed in the same way. Although combination therapy does not increase the risk of infection or malignancy compared with monotherapy, even monotherapy with a TNF-α inhibitor or an immunomodulator increases risk, especially in elderly patients. In young males, methotrexate may be preferred over azathioprine. Optimizing management includes discussion and explanation, early introduction of combination therapy, maintenance therapy, monitoring drug levels and (probably) TNF-α inhibitor monotherapy after 1 to 2 years of combination therapy.

Clinical case

Case presentation

A 37-year-old female presents to you for consultation. She has a diagnosis of Crohn’s disease (CD) that involves 25 cm of terminal ileum, most of the sigmoid colon, and several patches in the duodenum. In addition, a simple perianal fistula has been documented. She was initially diagnosed in 2010, and after treatment with prednisone and 6-mercaptopurine had failed, she progressed within 18 months via an accelerated step-up program to tumour necrosis factor-α (TNF-α) inhibitor monotherapy. After induction she rapidly entered clinical remission and has remained well for 3 years.

Commentary

Had this patient been started on infliximab or adalimumab now, she would likely have received combination therapy. It is difficult to justify combination therapy without a formal assessment, as she is clinically well. Combination therapy is, however, a recommended option to protect the clinical response, especially as several features of high-risk disease are present. Azathioprine at 2.5 mg/kg/day is an appropriate choice for combination therapy with a TNF-α inhibitor. It is important to discuss the benefits and risks of combination therapy with her, and the fact that she is of childbearing age is a relevant part of the discussion (hence, a higher threshold exists for using methotrexate). Objective assessment is also recommended to supplement the clinical evaluation, including C-reactive protein (CRP), fecal calprotectin, hemoglobin (Hb), small bowel imaging, and endoscopy.

Case evolution

During the consultation, she describes loss of response characterized by increasing diarrhea up to 4 times per day, loss of well-being, and mild abdominal pain for a short time before the TNF-α inhibitor dose. She feels better fairly quickly after the TNF-α inhibitor dose. Physical examination revels tenderness in the right and left lower quadrants but no masses.

Commentary

Appropriate investigations at this time include imaging with magnetic resonance (MR) or computed tomography (CT) enterography. Although the risks associated with CT are difficult to quantify, they appear to be significantly overstated. In addition, today’s ultralow-dose CTs use only 10% of the standard radiation dose. CT enterography is the preferred imaging modality, as contrast-enhanced ultrasound is subject to considerable interoperator variation. MR enterography may allow better visualization of some lesions. The choice of imaging modality also depends on local availability and expertise. It is however, important to use the same modality for routine monitoring. Additional investigations should assess the presence of inflammation and anemia. Obtaining a ferritin level is important, as it provides information about iron stores, which is more useful than serum iron levels. To use an analogy, serum iron reflects the amount of loose change in your pocket, while ferritin reflects the amount of money in your bank.

Case evolution

–  The results of your investigations are as follows:

–  Hb:112 g/L (125–140 g/L)

–  Mean cell volume: 75 fL (80–90 fL)

–  Platelet count: 578 x 10⁹/L (120–400 x 10⁹/L)

–  CRP: 2 mg/L (0–8 mg/L)

–  Ferritin: 4 pmol/L (22–561 pmol/L)

–  Iron: 2 μmol/L (11–32 μmol/L)

–  CT enterography: Active disease in 30-cm segment of distal ileum and 5-cm segment of distal jejunum

Commentary

Many clinicians would use a course of prednisone at this point, depending on how ill the patient is. It is also appropriate to add azathioprine to her therapy. Although dose intensification using a shortened dosing interval may be an option, it would be important to measure trough drug levels and antibody levels first.

Case evolution

You choose to administer a tapering course of prednisone and add azathioprine 2.5 mg/kg/day to her current TNF-α inhibitor therapy. Clinical remission is rapidly restored. However, after the corticosteroid is tapered off, she begins to exhibit similar symptoms again despite combination therapy.

Commentary

It is important to first determine whether she is adhering to azathioprine therapy, and metabolite testing can provide useful information. Therapeutic drug monitoring and antibody levels may also be helpful.

Case evolution

You have just returned from Mentoring in IBD XV, where you learned about the utility of measuring drug levels. You therefore request TNF-α inhibitor trough levels and 6-thioguanine (6-TG) and 6-methylmercaptopurine (6-MMP) levels. TNF-α inhibitor levels are returned because the blood clotted. Metabolite levels are as follows:

–  6-TG: 123 pmol/8 x 10⁸ red blood cells (RBC)

–  6-MMP: 4234 pmol/8 x 10⁸ RBC

Commentary

Measurement of 6-TG and 6-MMP is useful in patients in whom thiopurine therapy has failed and corticosteroid-free remission cannot be achieved despite an appropriate dose and duration of thiopurine therapy. A complete blood count should also be performed. Markedly low levels of both 6-TG and 6-MMP suggest nonadherence. 6-TG levels between 235 and 400 pmol/8 x 10⁸ RBC may be correlated with response and remission and levels >400 pmol/8 x 10⁸ RBC may correlate with bone marrow suppression. 6-MMP levels <5700 pmol/8 x 10⁸ RBC would be expected with a therapeutic azathioprine dose, and levels >5700 pmol/8 x 10⁸ RBC may correlate with hepatotoxicity.

Case evolution

You call the patient back to your office and discuss the need to increase the azathioprine dose. Because her herbalist told her that azathioprine causes brain cancer, she stopped the medication and refuses to entertain using it again.

Commentary

In treating patients with IBD who lose response, it is essential to optimize both drugs in the combination. In the current situation, it is appropriate to switch her to methotrexate at ≥12.5 mg/week, as doses above this threshold are more effective in maintaining clinical remission than lower doses. However, methotrexate 25 mg/week is no more effective than 12.5 mg/week.

References

1. Sokol H, Seksik P, Carrat F, et al. Usefulness of co-treatment with immunomodulators in patients with inflammatory bowel disease treated with scheduled infliximab maintenance therapy. Gut. 2010;59(10):1363–8.
2. 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(5):1628–40.
3. 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(15):1383–95.
4. Feagan BG, McDonald JW, Panaccione R, et al. Methotrexate in combination with infliximab is no more effective than infliximab alone in patients with Crohn’s disease. Gastroenterology. 2014;146(3):681–8.
5. Dulai PS, Siegel CA, Colombel JF, et al. Systematic review: monotherapy with antitumour necrosis factor α agents versus combination therapy with an immunosuppressive for IBD. Gut 2014;63(12):1843–53.
6. Jones J, Kaplan GG, Peyrin-Biroulet L, et al. Impact of concomitant immunomodulator treatment on efficacy and safety of anti-TNF therapy in Crohn’s disease: a meta-analysis of placebo controlled trials with individual patient-level data. Gastroenterology. 2013;144:S-179.
7. Reenaers C, Louis E, Belaiche J, et al. Does co-treatment with immunosuppressors improve outcome in patients with Crohn’s disease treated with adalimumab? Aliment Pharmacol Ther. 2012;36(11–12):1040–8.
8. Cottone M, Kohn A, Daperno M, et al. Advanced age is an independent risk factor for severe infections and mortality in patients given anti-tumor necrosis factor therapy for inflammatory bowel disease. Clin Gastroenterol Hepatol. 2011;9(1):30–5.
9. Deepak P, Stobaugh DJ, Ehrenpreis ED. Infectious complications of TNF-α inhibitor monotherapy versus combination therapy with immunomodulators in inflammatory bowel disease: analysis of the Food and Drug Administration Adverse Event Reporting System. J Gastrointestin Liver Dis. 2013;22(3):269–76.
10. Deepak P, Sifuentes H, Sherid M, et al. T-cell non-Hodgkin’s lymphomas reported to the FDA AERS with tumor necrosis factor-alpha (TNF-α) inhibitors: results of the REFURBISH study. Am J Gastroenterol. 2013;108(1):99–105.
11. 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(9701):1617–25.
12. Siegel CA, Marden SM, Persing SM, et al. Risk of lymphoma associated with combination anti-tumor necrosis factor and immunomodulator therapy for the treatment of Crohn’s disease: a meta-analysis. Clin Gastroenterol Hepatol. 2009;7(8):874–81.
13. Van Assche G, Magdelaine-Beuzelin C, D’Haens G, et al. Withdrawal of immunosuppression in Crohn’s disease treated with scheduled infliximab maintenance: a randomized trial. Gastroenterology. 2008;134(7):1861–8.
14. Louis E, Mary JY, Vernier-Massouille G, et al; Groupe D’etudes Thérapeutiques Des Affections Inflammatoires Digestives. Maintenance of remission among patients with Crohn’s disease on antimetabolite therapy after infliximab therapy is stopped. Gastroenterology. 2012;142(1):63–70.e5; quiz e31.

Editor-in-Chief

John K. Marshall, MD MSc FRCPC AGAF, Chief of Gastroenterology Clinical Service, Hamilton Health Sciences; Professor of Medicine, Division of Gastroenterology, McMaster University , Hamilton, ON

Co-Editor-in-Chief

Richard N. Fedorak, MD FRCPC FRCP (London) FRCS, Dean, Faculty of Medicine & Dentistry; Professor of Medicine, Division of Gastroenterology, University of Alberta, Edmonton, AB

Issue Editor

Simon PL Travis, DPhil FRCP, Consultant Gastroenterologist, Translational Gastroenterology Unit, Nuffield Department of Experimental Medicine, Oxford University Hospital Trust, Oxford, UK

Mentoring in IBD Curriculum Steering Committee

 Alain Bitton, MD FRCPC, McGill University, Montreal, QC
Brian Bressler, MD MS FRCPC, University of British Columbia, Vancouver, BC
Anne M. Griffiths, MC FRCPC, University of Toronto, Toronto, ON
Steven E. Gruchy, MD MSc FRCPC, Dalhousie University, Halifax, ON
Remo Panaccione, MD FRCPC, University of Calgary, Calgary, AB
Craig Render, MD FRPCP, University of British Columbia, University of Alberta, Kelowna, BC
Hillary Steinhart, MD MSc FRCPC, University of Toronto, Toronto, ON
Jennifer Stretton, ACNP MN BScN, St. Joseph’s Healthcare, Hamilton, ON

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