Inflammatory bowel disease (IBD) treatment has progressed significantly over the past decade with the advent of biologics. Anti-tumor necrosis factor (anti-TNF) agents are the most widely available biologics, but the optimal approach when using them remains unclear. In this review, we highlight the currently available evidence regarding the use of anti-TNF monotherapy versus combination therapy with an immunomodulator. We focus on those patients at greatest risk for adverse events and outline the clinical approach when considering the use of combination therapy. We review the available tools through which providers may efficiently communicate these data to patients in the clinical setting.
Key points
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The best available evidence in inflammatory bowel disease demonstrates that the use of infliximab in combination with azathioprine is superior to infliximab monotherapy in both Crohn disease and ulcerative colitis.
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Further direct comparative effectiveness studies are needed to establish the efficacy of combination therapy for anti–tumor necrosis factor (anti-TNF) agents other than infliximab.
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The efficacy of methotrexate as the concomitant immunomodulator agent remains unclear, but the clear impact on immunogenicity and potential reduction in risk for malignancy warrants consideration for use in certain clinical settings.
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In patients at higher risk for serious infection and malignancy, the use of combination therapy should be approached with caution.
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When possible, consideration may be given to transitioning to monotherapy with either an anti-TNF agent or an immunomodulator in patients at low risk for relapse.
Introduction
Anti–tumor necrosis factor (anti-TNF) therapy is an effective treatment option for inflammatory bowel disease (IBD), and the use of these biologics has risen substantially over the past decade. Despite the increased use and availability of biologics, the question of the most effective therapeutic strategy still remains. The most debated of these questions is whether anti-TNF therapy should be used alone or in combination with an immunomodulator. When considering the use of anti-TNF therapy in other inflammatory conditions, such as rheumatoid arthritis (RA), the combination of an anti-TNF agent with an immunomodulator is clearly superior to anti-TNF monotherapy, and the use of combination therapy is now considered standard of care.
In patients with IBD, anti-TNF therapy was initially used as salvage therapy, and combination therapy represented the addition of an anti-TNF in patients failing other therapeutic regimens, including immunomodulators. When the “top-down” approach demonstrated that the use of combination therapy earlier in the disease course was more effective than the traditional “step-up” approach, then combination therapy in patients who were naïve to both drugs was supported. Subsequently, randomized control trials (RCT) demonstrated that the combination of infliximab (IFX) and azathioprine (AZA) was superior to monotherapy with either agent, and this enhanced efficacy correlated with improved pharmacokinetics, similar to that seen in RA. Concerns arise, however, regarding the long-term efficacy of this approach in IBD, and the safety of combining 2 immunosuppressive drugs for an extended duration of time, especially in young men and the elderly (≥65 years) population with IBD. As we have learned more about which patients might be at higher risk for adverse events and for complications of their disease, recent efforts have focused on identifying the patients in whom combination therapy is thought to be most appropriate by taking into account the risk-benefit ratio of each strategy.
In this review, we discuss the currently available evidence regarding the efficacy of anti-TNF therapy in IBD when used as monotherapy versus in combination with an immunomodulator. We will further highlight those populations at greatest risk for adverse events and outline a clinical approach to the use of combination therapy in these patients. Finally, we discuss barriers to initiating therapy and identify tools through which providers may communicate these data to patients at the bedside.
Introduction
Anti–tumor necrosis factor (anti-TNF) therapy is an effective treatment option for inflammatory bowel disease (IBD), and the use of these biologics has risen substantially over the past decade. Despite the increased use and availability of biologics, the question of the most effective therapeutic strategy still remains. The most debated of these questions is whether anti-TNF therapy should be used alone or in combination with an immunomodulator. When considering the use of anti-TNF therapy in other inflammatory conditions, such as rheumatoid arthritis (RA), the combination of an anti-TNF agent with an immunomodulator is clearly superior to anti-TNF monotherapy, and the use of combination therapy is now considered standard of care.
In patients with IBD, anti-TNF therapy was initially used as salvage therapy, and combination therapy represented the addition of an anti-TNF in patients failing other therapeutic regimens, including immunomodulators. When the “top-down” approach demonstrated that the use of combination therapy earlier in the disease course was more effective than the traditional “step-up” approach, then combination therapy in patients who were naïve to both drugs was supported. Subsequently, randomized control trials (RCT) demonstrated that the combination of infliximab (IFX) and azathioprine (AZA) was superior to monotherapy with either agent, and this enhanced efficacy correlated with improved pharmacokinetics, similar to that seen in RA. Concerns arise, however, regarding the long-term efficacy of this approach in IBD, and the safety of combining 2 immunosuppressive drugs for an extended duration of time, especially in young men and the elderly (≥65 years) population with IBD. As we have learned more about which patients might be at higher risk for adverse events and for complications of their disease, recent efforts have focused on identifying the patients in whom combination therapy is thought to be most appropriate by taking into account the risk-benefit ratio of each strategy.
In this review, we discuss the currently available evidence regarding the efficacy of anti-TNF therapy in IBD when used as monotherapy versus in combination with an immunomodulator. We will further highlight those populations at greatest risk for adverse events and outline a clinical approach to the use of combination therapy in these patients. Finally, we discuss barriers to initiating therapy and identify tools through which providers may communicate these data to patients at the bedside.
Clinical efficacy and pharmacokinetics
The debate surrounding efficacy and the use of anti-TNF therapy in combination with an immunomodulator stems largely from the impact that immunomodulators have on the rate of antidrug antibody formation and subsequent drug concentrations. Episodic use of anti-TNF therapy was initially very common, but it quickly became apparent that episodic therapy was associated with impaired anti-TNF pharmacokinetics (specifically the presence of antidrug antibodies and low drug concentrations), which in turn significantly impacted treatment outcomes. Although episodic use of anti-TNFs is no longer considered a reasonable treatment approach, it taught us that the use of a concomitant immunomodulator reduced the formation of anti-TNF antibodies and allowed for more consistent drug concentrations, thereby resulting in enhanced treatment efficacy. Evidence for the impact of combination therapy on antibody formation, drug concentrations, and treatment efficacy, when following scheduled anti-TNF treatments, is more inconsistent.
Observational Studies
Several observational studies have attempted to address this question with variable findings ( Table 1 ). Sokol and colleagues divided IFX treatment periods for a cohort of patients with IBD and subsequently analyzed these data according to whether patients had been treated with IFX monotherapy (n = 319 semesters) or IFX combination therapy (n = 265 semesters). This study demonstrated that the concomitant use of an immunomodulator decreased the risk for an IBD flare (odds ratio [OR] 0.50, 95% confidence interval [CI] 0.32–0.77), and when considering the need for abdominal surgery or switching to adalimumab (ADA), cotreatment with an immunomodulator was again demonstrated to significantly reduce the risk of these events (OR 0.18, 95% CI 0.05–0.63). Given the impact immunomodulator therapy has on pharmacokinetics when using episodic anti-TNF therapy, Ungar and colleagues later assessed the correlation between antidrug antibody formation and clinical response in patients receiving concomitant immunomodulator therapy while undergoing scheduled maintenance therapy. They demonstrated that the use of combination therapy resulted in longer antibody-free survival ( P = .003), and survival free of loss of response was significantly longer among patients with no antidrug antibodies ( P <.01).
| Anti-TNF | Impact of Combination Therapy | |
|---|---|---|
| Sokol et al, 2010 | IFX | Decreased risk of clinical flare, need for abdominal surgery or switching to ADA therapy during follow-up. Flares and complications were less frequently observed when AZA was used as the concomitant immunomodulator as compared with MTX. |
| Bouguen et al, 2013 | IFX | Concomitant immunosuppressive therapy increased the likelihood of fistula closure, and this impact was more pronounced for first fistula closure in patients who were naïve to immunosuppressants. Combination therapy had no impact on fistula or abscess recurrence. |
| Ungar et al, 2013 | IFX | Increased duration of clinical response, but effect was blunted when only patients who were scheduled for maintenance therapy were analyzed. |
| Maser et al, 2006 | IFX | Scheduled maintenance therapy, but not concomitant IM therapy, improved complete interval remission, normalization of CRP, and endoscopic improvement. |
| Seow et al, 2010 | IFX | No impact on antidrug antibody formation, IFX levels, clinical remission, or rate of colectomy. |
| Baert et al, 2014 | IFX | The use of an IM at reinitiation of IFX improved short-term response. Although the overall trough level of IFX was similar between anti-TNF mono and combo groups, within the subgroup having the lowest quartile of trough levels, combo therapy resulted in significantly higher levels. Median ATI was also lower on combo therapy. The presence of ATI was a negative predictor for response, and absence of ATI was a positive predictor for safely restarting IFX therapy. |
| Bortlik et al, 2013 | IFX | Combo therapy resulted in lower ATI levels and higher IFX trough concentrations, and higher trough concentrations (>3 μg/mL) were associated with a decreased risk of treatment failure, but concomitant IM therapy had no direct measurable impact on sustained response to IFX. |
| Baert et al, 2010 | IFX | Combo therapy resulted in lower ATI formation and higher IFX concentrations, but it had no overall impact on the duration of response to IFX. |
| Paul et al, 2013 | IFX | No impact on ATI formation, IFX trough concentrations, or clinical remission. |
| Pariente et al, 2012 | IFX | Trend toward lower incidence of ATI formation, but no impact on IFX trough levels or clinical outcomes. |
| Imaeda et al, 2014 | IFX | No impact on IFX trough levels or ATI formation, both of which were predictors of achieving mucosal healing. |
| Karmiris et al, 2009 | ADA | Increased ADA dose, but not concomitant IM therapy, reduced antibody formation, increased trough concentrations, improved initial response to therapy, and improved the likelihood of maintaining a sustained clinical response. |
| Lofberg et al, 2012 | ADA | Increased likelihood of achieving clinical remission after induction therapy (4 wk) and during follow-up (20 wk). |
| Reenaers et al, 2012 | ADA | No overall impact on risk for disease flares or ADA failure, but early use (first 6 mo of ADA) of combination therapy was associated with lower ADA failure rates, and prolonged use (beyond 6 mo) was associated with fewer semesters with flares. |
| Cohen et al, 2012 | ADA | No impact on the need for ADA dose escalation. |
| Chaparro et al, 2012 | ADA | No impact on likelihood of maintaining response to ADA. |
| Allez et al, 2010 | ADA, CZP | When initiating ADA or CZP as the third anti-TNF agent, the use of combo therapy had no impact on the probability of remaining on anti-TNF therapy. |
| De Silva et al, 2012 | Multiple | No impact on clinical response to third anti-TNF agent after failing 2 previous agents. |
| Bougen et al, 2014 | Multiple | No impact on likelihood of achieving mucosal healing when following a treat-to-target approach |
Other observational studies evaluating the correlation between IFX pharmacokinetics and clinical outcomes, however, have found no such correlation among combination therapy, pharmacokinetics, and enhanced efficacy. Maser and colleagues demonstrated that the concurrent use of an immunomodulator did not alter the proportion of patients who achieved complete interval remission ( P = .49), a normal C-reactive protein ( P = .16), and endoscopic improvement ( P = .59). Although this study demonstrated a correlation between IFX concentrations and improved outcomes, it was the use of scheduled maintenance therapy and not concomitant immunomodulator therapy that impacted antibody formation and IFX levels. Seow and colleagues similarly demonstrated that IFX trough levels were associated with increased rates of clinical remission (OR 12.5, 95% CI 4.6–33.9) and endoscopic improvement (OR 7.3, 95% CI 2.9–18.4), but the use of combination therapy had no impact on antidrug antibody formation ( P = .88), IFX trough levels ( P = .46), clinical remission (OR 1.16, 95% CI 0.47–2.88), or the rate of colectomy (OR 1.13, 95% CI 0.46–2.75). Data regarding the impact of concomitant immunomodulator therapy has similarly been conflicting when considering ADA, certolizumab pegol (CZP), or golimumab, but observational data evaluating the correlation among combination therapy, pharmacokinetics, and clinical efficacy for these anti-TNF agents are limited.
RCTs
Several investigators have suggested that these observational studies more closely represent the real-life experience with these drugs, but the differences in baseline characteristics across studies, variability, and inconsistency in outcome measurements, and method of analysis (subanalyses) significantly limit the conclusions that can be made from these data. RCTs in contrast represent the best-available evidence with regard to treatment efficacy given the rigorous nature of these studies and more consistent measurement of key clinical end points. Subanalyses of anti-TNF RCTs stratified according to baseline immunomodulator use have demonstrated that, despite a clear association between combination therapy and pharmacokinetics, the use of combination therapy appears to have no impact on clinical outcomes ( Table 2 ).
| Agent | Clinical Remission (%) | Antidrug Antibody (%) | |||
|---|---|---|---|---|---|
| Mono | Combo | Mono | Combo | ||
| ACT 1 | IFX | 36 | 34 | 12 | 3.5 |
| ACT 2 | IFX | 27 | 36 | 15.5 | 2.5 |
| ACCENT I | IFX | 32 | 37 | 9.5 | 5.6 |
| ACCENT II a | IFX | 38 | 32 | 18.1 | 2.4 |
| PRECISE 2 b | CZP | 64 | 61 | 12 | 2 |
| CLASSIC II | ADA | 45 | 48 | 3.8 | 0 |
| PURSUIT a | GOL | 50 | 44 | 3.8 | 1.1 |
a Complete fistula closure used for clinical remission in ACCENT II and clinical response used for clinical remission in PURSUIT.
b Week 26 response used in place of clinical remission and data from maintenance group used for antidrug antibody levels.
More recently, a systematic review pooled RCT data for 3 anti-TNF therapies (IFX, ADA, CZP) in Crohn disease (CD) and demonstrated that although there was no overall impact on outcomes (response, remission, fistula closure), the use of combination therapy was more efficacious than monotherapy for 6-month remission rates in IFX-treated patients specifically (OR 1.79, 95% CI 1.06–3.01), but not ADA-treated (OR 0.88, 95% CI 0.58–1.35) or CZP-treated (OR 0.93; 95% CI 0.65–1.34) patients. When attempting to interpret these data, clinicians should be reminded that the ADA and CZP RCTs enrolled a significant proportion of patients who had failed IFX therapy, and the use of combination therapy in these studies actually represented the continuation of an immunomodulator in patients switching anti-TNF agents. Furthermore, this meta-analysis excluded patients who were naïve to immunomodulator therapy, and this cohort more closely resembles the classic “step-up” approach to combination therapy, as opposed to the more efficacious “top-down” strategy. As there was no assessment of the impact of combination therapy on pharmacokinetics in this meta-analysis, it is unclear if this benefit for IFX but not ADA and CZP is secondary to a reduction in immunogenicity and improved pharmacokinetics, or variations in study populations and analysis.
An even more recent meta-analysis, pooling data from 6 RCT and 12 observational studies for ADA, demonstrated that the use of ADA in combination with an immunomodulator was superior to ADA monotherapy with regard to induction of remission at 12 weeks (OR 0.78, 95% CI 0.64–0.95), but not for induction of response (OR 0.68, 95% CI 0.37–1.25) or need for ADA dose escalation to achieve a clinical response (OR, 1.24; 95% CI, 0.70–2.20). Similar to the previous meta-analysis by Jones and colleagues, there was again no difference between ADA monotherapy or combination therapy with regard to long-term (52 week) maintenance of response (OR 1.21, 95% CI 0.74–1.99) or remission (OR 1.08, 95% CI 0.87–1.33). Given the variability and inherit limitations of these data with regard to patient populations, previous drug exposure, and outcome assessment, perhaps the most robust assessment of whether combination therapy improves outcomes will come from comparative effectiveness studies directly comparing these 2 strategies in a randomized cohort of patients with IBD.
The Study of Biologic and Immunomodulator Naïve Patients in Crohn’s Disease (SONIC) trial randomized patients with moderate-to-severe CD to AZA monotherapy (n = 170), IFX monotherapy (n = 169), or IFX and AZA combination therapy (n = 169), and demonstrated that the combination therapy group had a higher rate of corticosteroid-free remission ( P = .02) and mucosal healing ( P = .06) at week 26, with a similar trend being seen at week 50 ( Table 3 ). The Combination of Maintenance Methotrexate-Infliximab Trial (COMMIT), which randomized patients with moderate-to-severe CD to IFX monotherapy (n = 63) or IFX and methotrexate (MTX) combination therapy (n = 63), found no significant difference with regard to achieving week 14 steroid-free remission or maintaining this remission out to week 50 ( P = .63). When considering ulcerative colitis (UC), the UC-SUCCESS trial randomized patients with moderate-to-severe UC to receive AZA monotherapy (n = 76), IFX monotherapy (n = 77), or IFX and AZA combination therapy (n = 78), and, similar to the SONIC trial, demonstrated that the use of IFX in combination with AZA achieved higher rates of steroid-free remission ( P = .02). Although the overall mucosal healing rate (Mayo endoscopic subscore of 0 or 1) was similar between the 2 groups ( P = .3), the complete mucosal healing rate (Mayo score of 0) was significantly higher in the combination group (30% vs 12%, P = .006).
Related posts:
Anti–Tumor Necrosis Factor-α Monotherapy Versus Combination Therapy with an Immunomodulator in IBD
Update on Anti-Tumor Necrosis Factor Agents in Crohn Disease
Pharmacokinetics of Biologics and the Role of Therapeutic Monitoring
Biologics of IBD
The Use of Biologic Agents in Pregnancy and Breastfeeding
Update on Janus Kinase Antagonists in Inflammatory Bowel Disease
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