Progress Report
The Italian Society of Gastroenterology (SIGE) and the Italian Group for the study of Inflammatory Bowel Disease (IG-IBD) Clinical Practice Guidelines: The use of tumor necrosis factor-alpha antagonist therapy in Inflammatory Bowel Disease

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Abstract

Biological therapies are an important step in the management of Inflammatory Bowel Diseases. In consideration of high cost and safety issues there is the need to have clear recommendations for their use. Despite the American Gastroenterological Association and the European Crohn's and Colitis Organisation have published exhaustive Inflammatory Bowel Disease guidelines, national guidelines may be necessary as cultural values, economical and legal issues may differ between countries. For these reasons the Italian Society of Gastroenterology and the Italian Group for the study of Inflammatory Bowel Disease have decided to elaborate the Italian guidelines on the use of biologics in Inflammatory Bowel Disease. The following items have been chosen: definitions of active, inactive, steroid dependent and resistant disease; measures of activity; anti-tumor necrosis factor alpha therapy use in active steroid dependent and refractory luminal Crohn's Disease, in fistulising Crohn's Disease, in steroid dependent and resistant active Ulcerative Colitis; risk of cancer; risk of infections during anti-tumor necrosis factor alpha therapy; special situations. These guidelines are based on evidence from relevant medical literature and clinical experience of a national working group.

Introduction

During the last 15 years biological therapy has been an important step forward in the treatment of Inflammatory Bowel Disease (IBD). Several Randomised Controlled Trials (RCTs) have allowed the role of these therapies to be defined. National guidelines have been published in order to provide homogeneous indications to their use [1], [2], [3], [4]. In Europe the European Crohn's and Colitis Organisation (ECCO) have recently published the guidelines for the diagnosis and treatment of Crohn's disease (CD) and Ulcerative Colitis (UC) [5], [6]. In these guidelines, as far as biological treatment is concerned, anti-tumor necrosis factor alpha (anti-TNFα) therapies are mainly considered because these are the only biologics which have been approved by the European Medicine Agency (EMEA) and more than 40% of the statements are based on the recommendations of experts. Up to today, no guidelines regarding the use of biologics in adult patients with IBD have been published in Italy. The only biologics approved are infliximab in CD and UC and adalimumab in CD. National guidelines may be necessary as cultural values, economical and legal issues may differ between countries [7]. For this reason the Italian Society of Gastroenterology (SIGE) and the Italian Group for the study of Inflammatory Bowel Disease (IG-IBD) have decided to elaborate the Italian guidelines on the use of biologics in IBD.

Fifteen experts of Italian IBD referral centers belonging to the IG-IBD had been invited to join a meeting where the main issues of TNFα antagonist therapy have been identified. The following items have been chosen: definitions of active, inactive, steroid dependent and resistant disease; measures of activity; anti-TNFα therapy use in active steroid dependent and refractory luminal CD, in fistulising CD, in steroid dependent and resistant active UC; risk of cancer; risk of infections during anti-TNFα therapy; special situations. Each expert was invited to formulate provisional statements on one of these topics and to justify the statements according to current scientific evidence. The Oxford methodology was used to establish levels of evidence and degree of recommendations (Table 1) [8]. A complete research thorough Pub Med, Embase, Cochrane database was done by each expert in order to formulate recommendations. After statement elaboration, a further 14 Italian experts belonging to the IG-IBD (from the referral gastroenterological centers and non-referral gastroenterological centers) together with a national representative of the association of patients with IBD (Associazione Malattie Infiammatorie Croniche Intestinali: AMICI) were invited to participate to 3 consensus conferences (one in Bologna and 2 in Rome) in which the provisional statements were discussed with the 15 experts and an agreement on the statements was reached. If there was a disagreement amongst the 30 partecipants an agreement on the statements was reached by vote (51% of partecipants).

With respect to the definitions of IBD, the participants have tried to reach an overall agreement about commonly used terms. Although some of the used definitions are arbitrary, they reflect the every day practice of clinical decision-making.

IG-IBD Statement 1

RESPONSE: ΔCDAI > 100 points or Δ HBI  3

REMISSION: CDAI < 150 or a HBI < 4, without steroids

RELAPSE: A flare of symptoms with a CDAI > 150 or a HBI > 4 in a patient in clinical remission

RECURRENCE: The appearance of new CD lesions after curative resection of macroscopic disease, usually in the neo-terminal ileum and/or at the anastomotic level, detected by endoscopy, radiology, or surgery

STEROID-REFRACTORY CD: Active disease in spite of an adequate dose and duration of prednisone (0.75–1 mg/kg/day for at least 2 weeks)

STEROID-DEPENDENT CD: inability to stop systemic steroids within 3 months or budesonide within 6–9 months, without clinical relapse or relapse within 3 months after steroid weaning

Clinical disease activity is classified into mild, moderate, and severe according to the CD activity (CDAI) or the Harvey–Bradshaw (HBI) indexes [9], [10]. Mild disease is defined with a CDAI value between 150 and 220 or with a HBI value between 5 and 7. Moderate disease is defined with a CDAI value between 220 and 450 or with a HBI value between 8 and 16. Severe disease is defined with a CDAI value > 450 or with a HBI value > 16 [11]. In clinical practice, however, the evaluation of disease activity is subjected to the overall clinical condition, together with laboratory, endoscopy and imaging findings.

Response is defined by a decrease of CDAI of at least 100 points (ΔCDAI  100) [6]. In the past years, some studies, including those initially evaluating the effectiveness of infliximab, considered a softer endpoint of response with a reduction in CDAI > 70 points or more from the baseline value and at least a 25% reduction in the total score [12], [13], [14]. It has been recently reported that a decrease in the HBI index  3 points closely correlates with a ΔCDAI  100, thus allowing a simpler Crohn's disease activity assessment [15].

Most of the clinical trials, including studies on the efficacy of biologics in CD, have adopted the definition of disease in clinical remission when the CDAI is <150 [11]. It has recently been reported that a HBI index < 4 points closely correlates with a CDAI < 150 points, thus allowing a simpler Crohn's disease activity assessment [15].

A flare-up of symptoms with a CDAI > 150 or a HBI > 4 in a patient with an established CD who is in clinical remission. Other definitions have been proposed for the purposes of clinical trials, but there is a disagreement about this issue [16]. In clinical practice, however, the evaluation of a disease relapse is subjected to the overall clinical condition, laboratory, endoscopy and imaging. Early relapse is defined as a clinical relapse within 3 months after achieving remission with a previous therapy.

The term recurrence is best used to define the reappearance of disease after curative surgical resection. Recurrence is commonly classified as clinical and morphological. Clinical recurrence is defined as the appearance of symptoms after surgical resection, provided that recurrence of lesions is confirmed [17]. Morphological recurrence is defined as the appearance of new lesions after curative surgical resection, even in the absence of overt symptoms, usually located at the neo-terminal ileum and/or anastomosis. The severity of morphological recurrence is commonly graded endoscopically using the Rutgeerts score [18]. Other diagnostic techniques (ultrasound, computed tomography, magnetic resonance imaging) proposed to assess morphological recurrence have not yet been widely accepted.

Steroid-refractory CD is defined as an active disease in spite of an adequate dose and duration of prednisone therapy (0.75–1 mg/kg/day or equivalent for at least 2 weeks).

This definition is slightly different from the ECCO guidelines [16]. There was a complete agreement amongst participants about the duration of steroid therapy, since the timing of biologic therapy is continually changing.

Steroid-dependent CD is defined as (1) the inability to stop systemic steroids within 3 months or budesonide within 6–9 months of starting therapy, without clinical relapse, or as (2) a relapse within 3 months after steroid weaning. Many definitions have been proposed, mainly based on clinical experience and not on physiopathologic evidence [16], [19]. Despite these limitations, an arbitrary definition of steroid dependency is useful as guidance for clinical practice.

Section snippets

Definitions of Ulcerative Colitis

IG-IBD Statement 2

RESPONSE: Clinical and endoscopic improvement according to the activity index used

REMISSION: Stool frequency  3/day with no bleeding or urgency

RELAPSE: Flare of symptoms in a patient who is in clinical remission

ORAL STEROID-REFRACTORY UC: Active disease in spite of an adequate dose and duration of prednisone therapy (0.75–1 mg/kg/day or equivalent for at least 2 weeks)

I.V. STEROID-REFRACTORY UC: Persistent active disease or worsening despite equivalent methylprednisolone 1 

Activity indexes to be monitored

IG-IBD Statement 3A

Clinical activity should be monitored during induction and maintenance therapy with Anti-TNFα to support the efficacy of treatment: the Harvey–Bradshaw Index (HBI) could be the best choice in clinical practice for CD [EL 1b, RG B], the Modified Truelove & Witts Severity Index (MTWSI) for UC [EL 3b, RG C]

The best clinical outcome in the treatment of IBD patients is steroid-free remission. In the real clinical setting, however, clinical response could be an acceptable endpoint

Induction and maintenance of remission in moderate-to-severe steroid-refractory or dependent Crohn's disease

IG-IBD Statement 4A

Anti-TNFα agents are a valuable option (infliximab [EL 1b, RG A], adalimumab [EL 1b, RG B]) in moderate-to-severe steroid-refractory or dependent CD

Thiopurines could be added in naïve patients [EL 1b, RG B]

Adalimumab can be used as a second line treatment in patients with primary failures to infliximab [EL 4, RG C] or with loss of response or intolerance to infliximab [EL 1b, RG B]

Anti-TNFα therapy has been evaluated as an induction and maintenance therapy in CD in several

Management of perianal fistulae

The advent of biologics has dramatically changed the therapeutic approach to perianal fistulising disease. Moreover the introduction of new image technics such as Magnetic Resonance Imaging (RNI) and Endoscopic Ultrasound (EUS) has provided new insights into the anatomical definition of perianal fistulas. For this reason in this section we have considered the global approach to perianal disease including diagnostic work-up, pharmacological strategies and surgical approach.

The main aspects to be

Induction and maintenance of response/remission in moderate-to-severe steroid-refractory or steroid-dependent Ulcerative Colitis

IG-IBD Statement 6A

Infliximab induction regimen can be used in patients with moderate-to-severe UC who are refractory to systemic corticosteroids [EL 1b, RG A] and in corticosteroid-dependent patients who are intolerant/refractory to thiopurines [EL 2b, RG C]

IG-IBD Statement 6B

One year scheduled treatment with Infliximab can be used in patients who have responded to infliximab induction [EL 1b, RG A]. In patients who are thiopurine-naïve, maintenance therapy with thiopurines alone is a valuable

Induction and maintenance of response/remission in severe steroids refractory Ulcerative Colitis

IG-IBD Statement 7A

Infliximab reduces colectomy rate within 3 months in steroid-refractory severe UC [EL 1b, RG A]. A colectomy is recommended if there is no improvement within 5 days [EL 5, RG D]. Infliximab should be avoided in patients with a complicated disease [EL 5, RG D]. Re-infusions seem more effective than one single infusion to prevent early colectomy [EL 4, RG C], but there is insufficient evidence to provide recommendations on the ideal dosing schedule. Antibiotic prophylaxis

Anti-TNFα and malignancies

The widespread use of the highly effective immunomodulatory drugs, including the anti-TNFα biologic therapies, is raising concerns about cancer risk, in relation to the physiological role of TNF in cancer suppression. The evidence on the cancer risk associated with the use of anti-TNFα agents in IBD since 1995 has been obtained from the results of clinical trials, meta-analysis, retrospective analysis, case reports, and post-marketing surveillance reports.

IG-IBD Statement 8A

The overall risk of

Anti-TNFα infections and adverse drug events

The nature and prevalence of adverse drug reactions associated with biologics, reflects the difficulties inherent to the determination of adverse drug events (ADEs). In addition, significant differences in the sources of available safety data limit any detailed comparison. ADE data sources, such as placebo-controlled randomised clinical trials, meta-analysis, case reports, open series, post-approval databases, registries supported by pharmaceutical companies, vary in relation to their

Infections

IG-IBD Statement 10A

The risk of infections is increased in patients treated with anti-TNFα agents [EL 1]. It is not clear whether this risk is related to biologics or to steroids use, severity of disease and narcotic drugs [EL 3b]. The risk of severe infections is not usually increased [EL 1] but it seems higher in elderly patients [EL 3]. Biologics should not be started during infections [EL 5, RG D]

Autoimmunity

IG-IBD Statement 11A

In patients with a lupus like syndrome anti-TNFα therapy should be discontinued [EL 4, RG C]

The appearance of autoantibodies (antinuclear antibodies and autoantibodies to double-stranded DNA: anti-dsDNA) is frequent in patients undergoing anti-TNFα therapy. The reported rates of autoimmunity range from <5% at 6 months amongst certolizumab pegol-treated patients to >50% amongst infliximab-treated patients [3], [141], [142]. The clinical relevance of autoantibodies is unclear.

Infusion and injection site reactions

IG-IBD Statement 12A

Three-dose induction of infliximab and 8 weeks maintenance dosing reduce drug reactions [EL 1, RG A]. Premedication, 90 minutes before infliximab infusion, may be advisable using diphenildramine (25 to 50 mg), acetaminophen (1 g) and/or steroids [EL 5, RG D]

IG-IBD Statement 12B

Injection site reactions can occur during the first month of adalimumab treatment and can last for 3 to 5 days, but rarely lead to discontinuation of the medication [EL 1]. No premedication is indicated

Neurologic disorders

IG-IBD Statement 13A

Patients with symptoms of sensory or motor neuropathy should be carefully evaluated and anti-TNFα agents should be stopped if a patient develops demyelinating-like disorders [EL 5, RG D]. Anti-TNFα agents should be used with caution in patients with family histories of multiple sclerosis [EL 5, RG D]

Different neurologic disorders such as optic neuritis, seizure, and new onset or exacerbation of demyelinating disorders, including multiple sclerosis, have been reported with

Prevention of post-operative recurrence of CD

IG-IBD Statement 14A

Infliximab can be considered in selected high risk patients [EL 2b, RG B] for prevention of post-operative recurrence

CD almost inevitably recurs after surgical resection. The risk of severe endoscopic recurrence is 51% within 1 year, with approximately 7–25% a year risk of symptomatic recurrence and a likelihood of 50% for recurrent symptoms within 5 years after surgery [18], [180]. Factors contributing to recurrence include fistulising vs nonfistulising disease, site of

Anti-TNFα therapy and pregnancy

IBD occurs frequently during the peak reproductive years. An understanding of the safest management strategies of IBD during pregnancy and breastfeeding is crucial to the health of both the mother and child. Unfortunately, data on the safety of medications in these clinical settings is limited and often the information is contradictory. The United States Food and Drug Administration (FDA) classification of drugs offers a guide to the use of medications during pregnancy [209]. The

Conflict of interest

None declared.

Acknowledgments

The authors thank Mrs. Jacquelyn Pitts Matranga for help in translating and Dr. Carla Felice, Filippo Mocciaro and Sara Renna for help in editing the manuscript.

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    See Appendix A for the list of experts.

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