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Immunomodulators with Anti–Tumor Necrosis Factor Agents: One Size does not Fit All

Immunomodulators with Anti–Tumor Necrosis Factor Agents: One Size does not Fit All

Gil Y. Melmed; Brennan M. Spiegel; Brian Bressler; Adam S. Cheifetz; Shane M. Devlin; Laura E. Harrell; Peter M. Irving; Jennifer Jones; Gilaad G. Kaplan; Patricia L. Kozuch; Fernando S. Velayos; Leonard Baidoo; Miles P. Sparrow; Corey A. Siegel

Posted: 09/07/2010; Clin Gastroenterol Hepatol. 2010;8(8):655-659. © 2010 AGA Institute

Abstract and Introduction

Background & Aims: There is no consensus on the appropriateness of concomitant immunomodulators with anti– tumor necrosis factor (TNF) therapy for Crohn's disease. Some patients benefit from concomitant immunomodulators, but concerns related to infections and lymphoma risk have dampened enthusiasm for this approach. We applied the RAND/University of California Los Angeles Appropriateness Method toward establishing appropriateness of concomitant immunomodulators and anti-TNF therapies for Crohn's disease.
Methods: A literature review was conducted regarding efficacy and safety of concomitant immunomodulators in the setting of anti-TNF therapy for Crohn's disease and presented to the Building Research in Inflammatory Bowel Disease Globally group, a globally diverse panel of 13 gastroenterologists clinically experienced in inflammatory bowel disease. A total of 134 scenarios were constructed using several clinical variables. Panelists used a modified Delphi method to rate the appropriateness of concomitant immunomodulators, and met to discuss and re-rate appropriateness. Disagreement was assessed using a validated index.
Results: Concomitant immunomodulators were generally rated appropriate for 63 scenarios, uncertain for 60 scenarios, and inappropriate for 11 scenarios. In general, concomitant immunomodulators were appropriate for those with extensive disease, shorter duration of disease, perianal involvement, prior surgery, females, and older patients (>26 y). Concomitant immunomodulators were generally rated inappropriate for young males, and in some scenarios involving uncomplicated disease. Smoking and the particular anti-TNF medication did not influence ratings. Disagreement was observed in 6 of 134 scenarios.
Conclusions: The appropriateness of concomitant immunomodulators with anti-TNF therapy for Crohn's disease was determined through a modified Delphi panel approach based on expert interpretation of the available literature. Clinicians should consider multiple factors when considering concomitant immunomodulators with anti-TNF treatment.

The treatment of Crohn's disease was revolutionized in the late 1990s with the introduction of infliximab, an anti–tumor necrosis factor (TNF) monoclonal antibody. Since then, clinicians have faced uncertainty regarding the optimization of efficacy and safety of anti-TNF therapy. The use of immunomodulators such as 6-mercaptopurine, azathioprine, and methotrexate concurrently with anti-TNF therapy may increase response rates by decreasing immunogenicity against the anti-TNF compounds or through synergy by administering 2 effective medications.[1–3] The Study of Biologic and Immunomodulator Naive Patients in Crohn's Disease (SONIC) trial found that in immunomodulator-naive patients induced and maintained with infliximab, concomitant azathioprine allowed for significantly more patients to achieve remission at 6 months, as compared with those treated with either infliximab alone or azathioprine alone.[4] In contrast, the Combination of Maintenance Methotrexate-Infliximab Trial (COMMIT) did not show a difference in treatment success among patients induced with prednisone and infliximab, randomized to receive methotrexate or placebo. Thus, the efficacy of combination therapy is unclear. Furthermore, serious adverse events may occur more often when prescribing 2 immune-suppressant medications, including serious infections, non-Hodgkin's lymphoma,[5–7] and hepatosplenic T-cell lymphoma.[8,9] However, it remains unknown whether exposure to an immunomodulator in addition to anti-TNF therapy increases these risks relative to those treated with anti-TNF or immunomodulators alone.[6]

Given the potential for improved efficacy but increased risk from concomitant immunomodulators, clinicians prescribing anti-TNF agents carefully must evaluate the pros and cons of combination therapy for the individual patient. We used the RAND appropriateness methodology, an evidence-based process, to assess the appropriateness of concomitant immunosuppressive therapy with anti-TNF use in a range of patients with moderate-to-severe Crohn's disease.

Study Overview

The RAND/University of California Los Angeles appropriateness method uses a modified Delphi panel approach, which is a widely used, iterative, evidence-based process that combines the best available evidence with the expert opinion of the available literature to determine the appropriateness of processes of care in medicine.[10]
Literature Review

We conducted a systematic literature search in September 2008 to identify controlled trials that evaluated the longterm safety and/or efficacy of concomitant immunomodulator therapy in patients with Crohn's disease treated with anti-TNF therapy. We also conducted reviews for the following topics: (1) summary and analysis of the SONIC[4] and COMMIT[11] trials; (2) pharmacokinetics of anti-TNF therapy and concomitant immunomodulators; (3) predictors of response to anti-TNF therapy; (4) efficacy and safety of concomitant immunomodulators in the rheumatology literature; and (5) lymphoma risk with immunomodulators and anti-TNF therapy. The summary document was distributed to all panelists for review before the first round of ratings (Supplementary Material).
Clinical Scenarios and Definitions

We created clinical scenarios using variables that might influence the decision to use immunomodulators with anti-TNF therapy, and sought input from opinion leaders for additional variables. Scenarios were arranged in 5 chapters, as follows: Chapter 1: Steroid and immunomodulator-naive, starting an anti-TNF (similar to the SONIC[4] population); Chapter 2: Steroid-induced, starting an anti-TNF concurrently for maintenance (similar to the COMMIT[11] population); Chapter 3: Failing immunomodulators and starting anti-TNF therapy (similar to many subjects enrolled in anti-TNF pivotal trials);[12–16] Chapter 4: Clinical attenuation to monotherapy with anti-TNF therapy, switching to a second anti-TNF; and Chapter 5: In remission for 6 months or longer on anti-TNF therapy with a concomitant immunomodulator (similar to the population in the report by Van Assche et al[17]).

Within each chapter, scenarios were constructed using the following variables: sex, age, disease duration, disease extent, presence or absence of perianal involvement, and surgical history. A total of 134 scenarios were created. Definitions of terms used to construct the scenarios are listed in Supplementary Table 1.

Appropriateness was rated on a scale of 1 to 9 for each scenario (1–3, inappropriate; 4–6, uncertain; and 7–9, appropriate[10]). An immunomodulator was considered appropriate when the expected benefits exceeded the expected negative consequences by a sufficiently wide margin to justify prescribing the immunomodulator. Additional questions were posed, as follows. First, is the decision to use concomitant immunomodulator therapy influenced by specific anti-TNF medications? Second, does active smoking status increase the likelihood of prescribing an immunomodulator? Third, in an older patient, does gender influence the likelihood of prescribing an immunomodulator? Fourth, is the decision to use an immunomodulator influenced by a patient being older than 60 years old?
Appropriateness Panel

The panel consisted of 13 members of the Building Research in Inflammatory Bowel Disease (IBD) Globally (BRIDGe) group, composed of gastroenterologists engaged in IBD research (www.BRIDGeIBD.com). The group is diverse, with representation from the United States, Canada, Australia, and the United Kingdom, and from both university and private practice settings. After receiving the literature summary, panelists confidentially rated the scenarios and convened 2 weeks later at a moderated in-person meeting (January 2009, Dallas, TX). During this meeting scenarios were discussed in detail, after which panelists confidentially re-rated each scenario; agreement was not required.

Median scores were calculated and rounded up, so that a median score of 3.5 was rated as uncertain whereas a median score of 6.5 was rated as appropriate. To quantify the level of agreement, a RAND/UCLA disagreement index was calculated.[16] A disagreement index greater than 1.0 indicates extreme variation whereas disagreement index values less than 1.0 reflect increasing agreement. The disagreement index is calculated using a standard published equation.[8,16]
Overall Results

Overall, the panelists rated concomitant immunomodulator therapy as appropriate in 63 of 134 total scenarios, uncertain in 60 scenarios, and inappropriate for 11 scenarios. There was a high degree of agreement among the panelists, with only 6 of 134 scenarios showing disagreement. Scenarios with common ratings and agreement were collapsed into 58 scenarios divided into 5 chapter headings. Table 1 shows examples of ratings within each chapter; for complete ratings of all 134 scenarios, see Supplementary Table 2 or visit www.BRIDGeIBD.com.
Chapter 1: Immunomodulator-naive

For patients with Crohn's disease naive to all immunosuppressive medications, concomitant immunomodulators were considered inappropriate for young men with limited disease, no perianal involvement, and a longer (>2 y) duration of disease. All other scenarios were considered uncertain or appropriate. In this chapter there was agreement for all but 2 scenarios, which involved males with a short duration of disease and females with a longer duration of disease.
Chapter 2: Steroid Induction with Anti–Tumor Necrosis Factor Maintenance

In patients induced with steroids and started on an anti-TNF for maintenance therapy, concomitant immunomodulator use was considered appropriate in all cases in which a patient already had a surgical resection, and in all those with extensive/complicated disease; all other scenarios were rated as uncertain. None of the scenarios in this chapter was rated as inappropriate, and no disagreement was noted.
Chapter 3: Starting Anti–Tumor Necrosis Factor Therapy after Failing Immunomodulators

For patients starting anti-TNF treatment after failing immunomodulators, continuation of the immunomodulator was considered inappropriate or uncertain in most scenarios, and appropriate in older patients and younger women with extensive/complicated disease who had undergone extensive/multiple surgical resections.
Chapter 4: Switching to a Second Anti–Tumor Necrosis Factor Agent

For patients failing monotherapy with an anti-TNFα and switching to a second anti-TNF, the addition of an immunomodulator was considered appropriate for most scenarios, and uncertain in the remaining scenarios; no scenarios were rated inappropriate. However, in 3 scenarios that were rated appropriate, disagreement was noted when younger patients were involved.
Chapter 5: Immunomodulator Withdrawal

Finally, for patients doing well on an anti-TNF and immunomodulator for 6 months, scenarios were rated for the appropriateness of discontinuation of the immunomodulator. In this chapter, panelists rated most scenarios as uncertain but believed that discontinuation was more appropriate in cases of limited disease and no prior resections.
Results of Additional Questions

Panelists believed that smoking status was somewhat important in their decision to use an immunomodulator, and were more likely to prescribe an immunomodulator in this setting. No panelists believed that sex influenced the use of concomitant immunomodulators in older patients (age, >25 years). However, for patients older than 60 years, most panelists were less likely to start an immunomodulator. Finally, immunomodulators were considered slightly more appropriate for patients receiving infliximab than for those receiving adalimumab or certolizumab (Supplementary Table 3).

Since the approval of anti-TNF agents for Crohn's disease, the appropriateness of concomitant immunomodulators has been uncertain. The difficulty in establishing appropriateness is in part owing to seemingly conflicting evidence gleaned from heterogeneous study populations across clinical trials, and rare but serious adverse events including infection and lymphoma.

Our study had several important findings. First, the appropriateness of concomitant immunomodulators was influenced significantly by prior medication history, disease phenotype, and patient demographics. Specifically, immunomodulators were considered more appropriate in the presence of more aggressive disease (eg, perianal involvement, more extensive involvement, and in those with prior surgical resections), presumably owing to the need to maximize medical treatment in the setting of disease that likely will require surgery. In most cases, young males were regarded as the group for whom concomitant immunomodulators were considered least appropriate, likely owing to the increased risk of hepatosplenic T-cell lymphoma in this demographic group. Second, appropriateness was not uniform across all scenarios, reinforcing the concept that each patient requires an individualized decision. Finally, although the RAND methodology does not require agreement, there was consensus among panelists for the majority (96%) of scenarios. Although geographic practice variation might be postulated, disagreement did not correlate with geographic origin of the panelists.

Although many scenarios were rated as appropriate, several scenarios were rated as uncertain, which suggests that for those scenarios data are lacking to drive a decision, and therefore both the use or non-use of concomitant immunomodulators is acceptable.

Concomitant therapy with immunomodulators was rated overall least appropriate for chapter 3 (patients failing immunomodulators who are initiating their first anti-TNF). This is arguably the most common clinical scenario for which an anti-TNF currently is prescribed. Only 2 scenarios within this chapter were rated appropriate (young females with extensive resections, and older patients with extensive resections), owing to the lack of data supporting efficacy of combination therapy in this setting.

Most of the anti-TNF pivotal trials and a pooled post hoc analysis of infliximab studies did not show a significant benefit for those on immunomodulators.[18] The SONIC trial showed that in naive patients concomitant infliximab and azathioprine allowed for 57% of patients to achieve corticosteroid-free remission at 6 months, as compared with 44% on infliximab alone and 31% on azathioprine alone.[4] In contrast, the COMMIT study did not show a difference in treatment success among patients induced with prednisone and infliximab, randomized to receive methotrexate or placebo.[11] Importantly, patients enrolled in COMMIT were induced with both corticosteroids and infliximab, whereas SONIC participants were induced with infliximab alone and all were naive to immunomodulators. In addition, the average disease duration among SONIC subjects was 2 years compared with 10 years among COMMIT patients. Finally, there may be differences between azathioprine and methotrexate that account for differences seen between SONIC and COMMIT.

The RAND methodology previously has been applied toward Crohn's disease management,[19] including the question of concomitant immunomodulators. However, only 2 variables were considered. For the present study, we incorporated more than 10 variables for this complex decision.

Our study had several limitations. First, the recommendations were subjective because they relied on panelists' interpretations of the best available evidence and their individual clinical experience. Second, not every possible clinical scenario could be rated because of the need to limit panelist burden. For example, some panelists use low-dose immunomodulators (eg, 7.5 mg oral methotrexate, dosed weekly[20]), which were not included as a variable. Third, panelists were instructed not to consider cost when rating appropriateness, to avoid cost bias. However, in the real world, cost can and does influence therapeutic decisions. Finally, our results were time-bound to the current understanding of the comparative effectiveness of these strategies.

Despite these limitations, our study presents a practical, evidence-based guide for the use of concomitant immunomodulator treatment for patients with Crohn's disease receiving anti-TNF therapies using a modified Delphi panel approach based on expert interpretation of the available literature. Our results can be accessed readily for decision making at the point of care; at www.BRIDGeIBD.com, patient characteristics can be entered to yield a recommendation for any particular scenario. These recommendations should not replace clinical judgment but might clarify factors to consider in making this decision. It thus behooves the practitioner to consider each individual case, rather than maintain a one-size-fits-all approach, in the decision to prescribe concomitant immunomodulators in the setting of anti-TNF therapy.

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2. Baert F, Noman F, Vermeire S, et al. Influence of immunogenicity on the long-term efficacy of infliximab in Crohn's disease. N Engl J Med 2003;348:601–608.
3. Hanauer SB, Wagner CL, Bala M, et al. Incidence and importance of antibody responses to infliximab after maintenance or episodic treatment in Crohn's disease. Clin Gastroenterol Hepatol 2004;2:542–553.
4. Colombel JF, Sandborn WJ, Reinisch W, et al. Infliximab, azathioprine, or combination therapy for Crohn's disease. N Engl J Med 2010;362:1383–1395.
5. Ljung T, Karlén P, Schmidt D, et al. Infliximab in inflammatory bowel disease: clinical outcome in a population based cohort from Stockholm County. Gut 2004;53:849–853.
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7. Toruner M, Loftus EV Jr, Harmsen WS, et al. Risk factors for opportunistic infections in patients with inflammatory bowel disease. Gastroenterology 2008;134:929–936.
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10. Brook RH. The RAND/UCLA appropriateness method. Clinical practice guideline development: methodology perspectives. Rockville, MD: Public Health Service, AHCR, 1994.
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To save time...Ask Dusty!
Ok, that was hard but after reading through 3 times, I finally began to understand what concomitant and immunomodulater-naive meant!! As always, glad you are doing this David!! My head would explode!!!
slow read...

Hi David,
I have been reading your posts for quite a while.(before I reg'd)
I found this one interesting and relevant, as I am on combo therapy.

There is a YouTube clip on this by the Doc who did the paper.
I was told that 1 + 1 = 3.
There is a beneficial synergy when these bigdog drugs are used together.

Also, the immunomodulator may minimize antibodies rendering the biologic ineffective over time.
I've been on Metho jabs and Remi for some time, along with 200mg Pred premed at infusions.
Fingers crossed for a better tomorrow, but that is alot of scary drugs!

Thanks for sharing,
be well

ps. my GI is on the list of references cited, cool