Long-term Combination Therapy with Infliximab Plus Azathioprine Predicts Sustained Steroid-free Clinical Benefit in Steroid-dependent Ulcerative Colitis

Armuzzi, Alessandro; Pugliese, Daniela; Danese, Silvio; Rizzo, Gianluca; Felice, Carla; Marzo, Manuela; Andrisani, Gianluca; Fiorino, Gionata; Nardone, Olga Maria; Vitis, I. De; Papa, Alfredo; Rapaccini, Gian Lodovico; Guidi, L.

doi:10.1097/mib.0000000000000115

Cited by 62 publications

(45 citation statements)

References 22 publications

(38 reference statements)

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“…There is conflicting data on whether prior lack of response to thiopurines determines benefit with combination therapy. Some studies have suggested that the benefit of combination therapy is greater in the thiopurine naive setting 39 while others have demonstrated that prior non-response to thiopurines does not influence their benefit when used in combination with a biologic 40 . Jones et al , in a pooled analysis of randomized trials, demonstrated concomitant immunomodulator use to be associated with increased rates of clinical remission and response with infliximab therapy even in a population where the majority had previously failed thiopurine therapy 9 .…”

Section: Discussionmentioning

confidence: 99%

The benefit of combination therapy depends on disease phenotype and duration in Crohn's disease

Ananthakrishnan

Sakuraba

Barnes

et al. 2017

Aliment Pharmacol Ther

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Introduction The impact of combination therapy on disease-related morbidity in patients with established Crohn’s disease (CD) or ulcerative colitis (UC) remains to be well-defined. Aim To examine the effect of combination therapy on disease outcomes in CD and UC Methods Using a multi-center prospective cohort, we classified CD and UC patients as being on monotherapy with anti-TNF or on combination with an immunomodulator. The primary outcome was a composite of new IBD-related surgery, hospitalizations, penetrating complications, need for corticosteroids or new biologic at 1 year. Multivariable regression models adjusted for potential confounders. Results We included 707 patients with CD (45% combination therapy) and 164 with UC (38% combination therapy). Combination therapy was not associated with reduction in the composite outcome in either CD (OR 0.87, 95% CI 0.63 – 1.22) or UC (OR 1.45, 95% CI 0.63 – 3.38). However, while no difference was noted in those with non-stricturing, non-penetrating CD, a significant reduction in the likelihood of the outcome was seen in those with stricturing or penetrating CD (30% vs. 39%, OR 0.58, 95% CI 0.37 – 0.90). A stronger effect was also observed in those with disease duration < 5 years (OR 0.35, 95% CI 0.14 – 0.87) compared to those with a longer duration (OR 0.75, 95% CI 0.45 – 1.27). A similar reduction in occurrence of composite outcome was noted with infliximab and with other anti-TNF biologics. Conclusion The benefit of combination immunomodulator-biologic therapy is stronger in those with complicated Crohn’s disease, particularly early on in their disease course.

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Section: Discussionmentioning

confidence: 99%

The benefit of combination therapy depends on disease phenotype and duration in Crohn's disease

Ananthakrishnan

Sakuraba

Barnes

et al. 2017

Aliment Pharmacol Ther

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“…IMMs likely influence response to IFX in a dual manner. On the one hand, IMM-naïve patients have been shown to exhibit higher clinical remission rates with IFX at 8 weeks (13), with steroid-dependent subjects displaying a lower risk for colectomy (14). On the other hand, combined therapy has a number of benefits over monotherapy.…”

Section: In Ulcerative Colitismentioning

confidence: 99%

“…Ten of the 36 patients with shortened intervals were de-intensified after 12 months (IQR, [4][5][6][7][8][9][10][11][12][13][14][15][16], and 3 of these were again re-intensified. Two of the seven patients with increased doses were de-intensified after 2 and 4 months, respectively.…”

Section: De-intensificationmentioning

confidence: 99%

“…On the other hand, combined therapy has a number of benefits over monotherapy. IMMs, when associated with IFX, reduce infusion-related reactions and immunogenicity (15), increase sustained clinical response rates (14), and reduce steroid needs versus IFX monotherapy (16). Anti-infliximab antibodies develop within the initial 12 months of treatment with IFX (17), and the association of IMMs during this period may preclude their emergence.…”

Section: In Ulcerative Colitismentioning

confidence: 99%

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Frequency, predictors, and consequences of maintenance infliximab therapy intensification in ulcerative colitis

et al. 2015

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Introduction: Infliximab (IFX) therapy intensification in ulcerative colitis (UC) is more common than established in pivotal studies.Objectives: To establish the frequency and form of intensification for UC in clinical practice, as well as predictors, and to compare outcomes between intensified and non-intensified treatment.Methods: A retrospective study of 10 hospitals and 144 patients with response to infliximab (IFX) induction. Predictive variables for intensification were analyzed using a Cox regression analysis. Outcome, loss of response to IFX, and colectomy were compared between intensified and non-intensified therapy.Results: Follow-up time from induction to data collection: 38 months [interquartile range (IQR), 20-62]. Time on IFX therapy: 24 months (IQR, 10-44). In all, 37% of patients required intensification. Interval was shortened for 36 patients, dose was increased for 7, and 10 subjects received both. Concurrent thiopurine immunosuppressants (IMM) and IFX initiation was an independent predictor of intensification [Hazard ratio, 0.034; p, 0.006; CI,. In patients on intensified therapy IFX discontinuation for loss of response (30.4% vs. 10.2%; p, 0.002), steroid reintroduction (35% vs. 18%; p, 0.018), and colectomy (22% vs. 6.4%; p, 0.011) were more common. Of patients on intensification, 17% returned to receiving 5 mg/kg every 8 weeks.

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“…In a separate examination of the long-term effects of IFX on outcomes in patients with steroid-dependent UC, combination therapy with IFX and AZA was an independent predictor of sustained clinical response [12]. However, a more recent meta-analysis has indicated that when anti-TNF therapy is added to an existing immunosuppressive regimen for patients with CD, combination therapy is no more effective than anti-TNF monotherapy in inducing clinical remission at 6 months, inducing or maintaining a response, or inducing partial fistula closure [20].…”

Section: Introductionmentioning

confidence: 99%

Sequential Combination Therapy Versus Monotherapy: A Lack of Benefit in Time to Inflammatory Bowel Disease-Related Surgery

et al. 2016

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Background The benefits of combination therapy with infliximab and azathioprine have been demonstrated in clinical trials of patients with ulcerative colitis (UC) and Crohn's disease (CD). Concerns remain regarding the ideal duration and benefits of adding therapies in a sequential manner. Aims We aim to compare long-term outcomes among patients with inflammatory bowel disease (IBD) treated with sequentially added combination therapy or monother-apy strategies . Methods We performed a retrospective cohort study involving adult patients with UC and CD. One cohort included patients treated with infliximab, adalimumab, or a thiopurine as monotherapy. A second cohort included patients treated with sequentially added combination therapy including infliximab or adalimumab and a thiopurine. The primary outcome was the rate of IBD-related surgery. Results Among 462 patients, 181 (39 %) were treated with combination therapy. 12 % of patients treated with combination therapy underwent an IBD-related surgery compared to 18 % of patients treated with monotherapy (p = 0.091), with no overall difference in time to IBD-related surgery demonstrated (log-rank test, p = 0.063). When evaluating the subtypes of IBD, there was a significant benefit in time to IBD-related surgery among patients with CD treated with sequentially added combination therapy (HR 0.46, 95 % CI 0.25-0.85) but not UC (HR 0.82, 95 % CI 0.30-2.22). Conclusions The benefits of sequentially added combination therapy seem blunted when evaluating long-term clinical outcomes. This may be due to a decreased effectiveness of sequential combination therapy, a loss of benefit over time, or a differential effect between subtypes of IBD.

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Long-term Combination Therapy with Infliximab Plus Azathioprine Predicts Sustained Steroid-free Clinical Benefit in Steroid-dependent Ulcerative Colitis

Cited by 62 publications

References 22 publications

The benefit of combination therapy depends on disease phenotype and duration in Crohn's disease

The benefit of combination therapy depends on disease phenotype and duration in Crohn's disease

Frequency, predictors, and consequences of maintenance infliximab therapy intensification in ulcerative colitis

Sequential Combination Therapy Versus Monotherapy: A Lack of Benefit in Time to Inflammatory Bowel Disease-Related Surgery

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