Maintaining infliximab induced clinical remission with azathioprine and 5-aminosalicylates in acute severe steroid-refractory ulcerative colitis has lower cost and high efficacy (MIRACLE): a multicenter study

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Intest Res. 2022;20(1):64-71

Publication date (electronic) : 2021 February 3

doi : https://doi.org/10.5217/ir.2020.00100

Ramit Mahajan^1,*, Arshdeep Singh^1,*, Saurabh Kedia², Kirandeep Kaur³, Vandana Midha⁴, Pabitra Sahu², Varun Mehta¹, Dharmatma Singh⁵, Namita Bansal⁶, Khushdeep Dharni⁷, Sandeep Kaushal³, Vineet Ahuja^,2, Ajit Sood^,1

¹Department of Gastroenterology, Dayanand Medical College, Ludhiana, India

²Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India

³Department of Pharmacology, Dayanand Medical College, Ludhiana, India

⁴Department of Internal Medicine, Dayanand Medical College, Ludhiana, India

⁵Department of CRC, Research and Development Centre, Dayanand Medical College, Ludhiana, India

⁶Research and Development Centre, Dayanand Medical College, Ludhiana, India

⁷School of Business Studies, Punjab Agricultural University, Ludhiana, India

Correspondence to Ajit Sood, Department of Gastroenterology, Dayanand Medical College, Ludhiana 141001, Punjab, India. Tel: +91-9815-400-718, Fax: +91-161-2302620, E-mail: ajitsood10@gmail.com

Co-Correspondence to Vineet Ahuja, Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi 110023, India. Tel: +91-11-26593300, Fax: +91-11-2658663, E-mail: vineet.aiims@gmail.com

*These authors contributed equally to this study.

Received 2020 August 14; Revised 2020 October 23; Accepted 2020 November 29.

Abstract

INTRODUCTION

Ulcerative colitis (UC) is a chronic inflammatory disease of the colon with a relapsing remitting course [1]. Acute severe exacerbations of the disease develop in 15% to 20% of the patients, requiring hospitalization and treatment with intravenous (IV) corticosteroids [2]. Though corticosteroids are effective in a majority of patients with severe UC, they are not a panpharmacon. Up to one-third of patients with acute severe UC may fail to respond to therapy with IV corticosteroids and hence require rescue therapy with IV cyclosporin A (CsA)/infliximab (IFX) or colectomy [3-7]. In patients where IFX is used as rescue therapy, continuation of an 8 weekly dosing schedule has been recommended for maintenance of remission. However, up to 30% of patients may not be able to continue IFX in the long run due to adverse events or a secondary loss of response [8,9]. Furthermore, the continued use of biologics for maintenance of remission is not feasible in developing countries where the health insurance coverage is minimal, placing significant economic burden on the patients. To sustain clinical remission in these patients, alternative maintenance therapies need to be studied. We present a multicenter experience of use of combination therapy with azathioprine (AZA) and 5-aminosalicylates (5-ASA) for maintenance of clinical remission in patients with acute severe steroid-refractory UC who achieved clinical remission with IFX induction regimen and IFX was stopped thereafter.

METHODS

RESULTS

A total of 137 patients with acute severe UC were treated with IFX for inducing remission during the study period. Twenty-three patients (17.1%) did not respond to IFX and underwent colectomy, 5 (3.7%) had adverse events (tuberculosis: n=3; congestive heart failure: n=2) and 32 (23.4%) either had adverse events/poor compliance with AZA or were lost to follow-up. The 77 patients (56.2%) who achieved clinical remission were followed (median, follow up 4 years; range, 3 months–6 years) for disease course (Fig. 1). These patients were maintained on 5-ASA (median, 4.8 g/day; range, 3.6–4.8 g/day) and AZA (median, 100 mg/day; range, 50–150 mg/day). IFX was stopped after the induction regimen. The baseline characteristics of these patients are listed in Table 1.

Fig. 1.

Flowchart of the patients in the current study. IFX, infliximab; AZA, azathioprine.

Table 1.

Baseline Characteristics of the Patients

1. Corticosteroid-Free SCR

Seventy-seven patients (mean age, 34.81 ± 13.32 years; 68.83% of males, n=53) with acute severe steroid-refractory UC achieving clinical remission with IFX were followed up. The mean duration of corticosteroid-free SCR with 5-ASA and AZA was 2.70 ± 2.17 years (median, 1.5 years). The cumulative corticosteroid-free SCR at the end of follow-up (6 years) was 35%. The cumulative relapse-free survivals at 1, 2, and 4 years were 68%, 59%, and 42% respectively (Fig. 2).

Fig. 2.

Kaplan-Meier cumulative survival curve for corticosteroid-free sustained clinical remission (SCR).

2. Rates and Patterns of Relapse

Thirty-three patients (42.85%) suffered a total of 67 relapses over the entire follow-up period. Twelve (36.36%) of these 33 patients suffered > 1 relapses. Majority of the patients (n=27, 81.81%) relapsed within first 2 years of follow-up. Of the total 67 relapses, 64 (95.52%) were managed successfully with repeat courses of corticosteroids whereas 2 needed re-induction with IFX and 1 needed colectomy (Table 2). The factors that influenced corticosteroid-free SCR were evaluated. No significant effects of age, sex, disease duration, disease severity (Mayo score), disease extent, previous exposure to AZA and inflammatory markers (ESR, C-reactive protein, and albumin) were observed (Table 3).

Table 2.

Patterns of Disease Relapse and Treatment

Table 3.

Factors Influencing the Maintenance of Corticosteroid-Free Sustained Clinical Remission

4. Cost-Benefit Analysis

Cost-benefit analysis was performed by comparing the therapeutic benefits (including the proportion of patients maintaining corticosteroid-free SCR and frequency of relapses) and costs incurred on the therapy. Comparisons were made for IFX used as maintenance therapy versus IFX used only for inducing remission and maintaining with 5-ASA and AZA. The relapse rates with IFX maintenance were derived from the existing literature reporting long-term efficacy of IFX. Annual costs were calculated based on absolute compliance to therapy, the number of relapses observed/expected and costs incurred on management of relapses. Maintenance therapy per capita per annum was cheaper by US$ 4,526 with 5-ASA and AZA as compared to maintaining remission with IFX (Table 4).

Table 4.

Cost-Benefit Analysis (Annual) (n=77)

DISCUSSION

In acute severe UC, corticosteroids are the initially recommended drugs. However, a subset of patients is refractory to corticosteroids and need rescue therapy with IFX. Both ECCO (European Crohn’s and Colitis Organisation) and ACG (American College of Gastroenterology) guidelines recommend that remission achieved with IFX should be maintained with the same, either alone or in combination with thiopurines [13,14]. However, maintenance of remission with IFX every 8 weeks is difficult in real world settings in resource-limited countries like India. Apart from cost, there are safety concerns as the use of IFX in areas with high prevalence of tuberculosis carries a risk of reactivation, even in the absence of latent tuberculosis [15]. The present study highlights the role of combination therapy with AZA and 5-ASA as effective maintenance therapy for patients with severe steroid-refractory UC who required IFX as a rescue induction therapy. Cumulative corticosteroid-free SCR was achieved in 35% of patients at 6 years. A total of 67 relapses were observed in 33 patients. Majority of the relapses (45/67, 67.16%) occurred within first 2 years of follow-up. Two relapses were managed with re-induction with IFX, 1 required colectomy, whereas all other responded to repeat course(s) of corticosteroids.

Thiopurines are immunosuppressive agents with proven clinical efficacy and long-term safety in patients with IBD [16,17]. However, the primary obstacle to their use in an acute flare is their delayed onset of action. Therefore, IFX was used in the current study only to induce remission and rapidly decrease tumor necrosis factor (TNF)-α secretion; thereby normalizing dysregulated immunity, reducing intestinal inflammation, and restoring mucosal immune homeostasis [18-21]. The clinical remission achieved by IFX was subsequently maintained on AZA in combination with 5-ASA. A secondary loss of response is reported in nearly 30%–50% receiving maintenance therapy with IFX [22-24]. The ACT1 and ACT2 extension studies found that nearly 45% of patients had active disease at week 152 of follow-up [8]. Similarly, the cumulative rates of maintenance of remission with IFX monotherapy in single center studies from Belgium and Japan were also 68% at 3 years and 56.1% at 5 years, respectively [11,23].

IFX withdrawal after achieving remission has been attempted in patients with Crohn’s disease (CD), though not in UC [25,26]. In a retrospective analysis of patients with CD where IFX was withdrawn, 52% of patients remained in SCR after a median period of approximately 10 years [27]. The cumulative relapse-free survivals in our study, though in patients with UC, were 68%, 59%, 42%, and 35% patients at 1, 2, 4, and 6 years respectively.

The majority of episodes of relapse were seen in the first 2 years after initiation of 5-ASA and AZA. Most patients experiencing multiple relapses were also seen in the initial 2 years (Table 2, Fig. 2). A systematic review assessing relapse rates after discontinuation of anti-TNF treatment revealed a similar number of relapses at the end of 1 year (21.1%–39%), but relapse rates were much higher (37%–55.7%) at the end of 2 years [28]. Animal models of colitis have demonstrated that AZA induces production of interleukin 10 (IL-10) by T cells in cultures that are primed for > 6 days and not in early primed (< 2 days) cultures despite increasing concentrations of the drug [29]. AZA thus tilts the balance towards prominence of anti-inflammatory cytokines (decreased serum IL-6, IL-8, IL-17, TNF-α levels and increased IL-10, transforming growth factor β), after a lag period, and the frequency of relapses decreases with time. This could explain greater number of relapses in initial 2 years of follow-up. 5-ASA and AZA combination was well tolerated and only 6 patients, who were intolerant to AZA, had to stop thiopurines.

Patients who experienced relapses during long-term follow up in the current study rarely required a re-induction with IFX and could be managed with repeat course(s) of corticosteroids, suggesting that initial steroid refractoriness is not permanent. Even though a proportion of patients suffered repeated relapses over the period of follow-up (Table 2), majority of these subsequent relapses were also responsive to corticosteroids. Corticosteroids have both immunologic and anti-inflammatory properties, including inhibitory effects on nuclear factor-κB and activating protein-1 [30]. Resistance to corticosteroids is mediated by altered expression of transcription factors and/or cytokines. IL-2 has been shown to promote resistance to corticosteroids by reducing the nuclear translocation of glucocorticoid receptor. T cells from steroid-resistant individuals have been demonstrated to produce more IL-2 than T cells from steroid-sensitive individuals. Blocking IL-2 (via anti-IL-2 [basiliximab] or Janus kinase inhibitors [JAK1 and JAK3]) has been demonstrated to restore steroid sensitivity in vitro [31,32]. Thiopurines, especially AZA, have anti-proliferative effects that are mediated by direct inhibition of IL-2 and hence could help in re-establishment of response to corticosteroids [33]. AZA, along with 5-ASA, in the current study therefore may have resulted steroid responsiveness of the relapses occurring during follow up. The colectomy rate in our study was very low. However, colectomy could not be excluded in patients who were lost to follow-up.

The cost of AZA+5-ASA maintenance therapy (including the costs for management of relapses) was approximately INR 53,535 (US$ 733) per capita per year while maintenance with IFX alone would cost approximately INR 383,906 (US$ 5,259) per capita per year, which is nearly seven times higher. In a similar cost analysis of contemporary immunomodulatory and biologic strategies in CD, AZA monotherapy was found to be more cost effective than maintenance with IFX alone or IFX+AZA combination and it yielded similar quality-adjusted life years and rates of surgery [34].

This is the first study where IFX has been withdrawn after inducing remission in patients with UC. This is also the first study to document sustained benefit with use of combination of 5-ASA and AZA in maintaining remission achieved by IFX over a long time (up to 6 years). The limitations of our study include the lack of control group, retrospective analysis, high rates of attrition due to loss of follow-up (relapse and/or colectomy cannot be excluded in patients lost to follow-up) and use of clinical parameters to assess efficacy rather than a more precise end point like mucosal healing (endoscopy/biomarkers like fecal calprotectin). However, the present study documents AZA+5-ASA combination as an effective, safe and cost-beneficial alternative to maintain remission induced by IFX in acute severe steroid-refractory UC. Larger, prospective studies using the proposed regime are however needed.

To conclude, treatment strategies in resource constrained countries cannot match those followed in developed countries as the health care policies in these countries differ significantly. Induction of remission with IFX and subsequent maintenance with AZA and 5-ASA in patients with acute severe steroid-refractory UC seems to be an effective strategy, sustaining clinical remission over long term. Relapses occur on combination therapy of 5-ASA and AZA but vast majority of these relapses can be managed with repeat course(s) of corticosteroids.

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