Area Editoriale

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
· 1mg/kg/day i.v. over a period of 1 week
· STEROID-DEPENDENT UC: inability to stop steroids within 3 months of starting therapy, without clinical relapse, or relapse within 3 months after steroid weaning
 

3. Activity indexes to be monitored

IG-IBD Statement 3A
Clinical activity should be monitored during induction and maintenance therapy with Anti-TNF_ 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]

IG-IBD Statement 3B
The Perianal Disease Activity Index is a validated index for measuring treatment outcomes in perianal CD, [EL 1b, RG B]
but it should be integrated with examination under anaesthesia [EL 2b, RG C], trans-anal ultrasonography [EL 1b, RG B]
and/or magnetic resonance imaging [EL 1b, RG B] performed by experienced specialists where these services are available

IG-IBD Statement 3C
Efficacy of treatment in modifying patients' Quality of Life should be measured [EL 1b, RG B]
Patient reported general well being can be assessed simply by using a Visual Analogical Scale [EL 1a, RG A]

IG-IBD Statement 3D
CRP can be used to monitor patients, especially in CD, mainly because of its cheapness, wide availability and immediacy. If available, hs-CRP or wr-CRP should be preferred [EL 1b, RG B]

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

IG-IBD Statement 4A
Anti-TNF_ agents are a valuable option (infliximab [EL 1b, RG A], adalimumab [EL 1b, RG B]) in moderate-to-severe steroidrefractory 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]

4.1. Maintenance of remission in luminal CD

IG-IBD Statement 4B
Anti-TNF_ agents (infliximab and adalimumab) are effective for maintenance of remission up to 1 year in patients with
clinical response to induction therapy [EL 1a, RG A] Anti-TNF_ agents should be the treatment of choice for
patients who have failed maintenance strategies with immunosuppressants [EL 1b, RG B]
IG-IBD Statement 4C
Open experiences have reported long-term effectiveness and safety of anti-TNF_ agents; however, the duration of the therapy over 1 year should be carefully evaluated on a case-by-case
basis [EL 4, RG C]

4.2. Early treatment in CD

IG-IBD Statement 4D
Early use of Biologics may improve patient outcomes in active CD [EL 2b, RG B]. However, a widespread use of a “top down” approach in all CD patients cannot be recommended Clinical factors at diagnosis may predict poor outcome in CD and should be taken into account when determining the initial therapeutic approach [EL 2b, RG C]. However, the benefit of early treatment with biologics in this patient subgroup is not proven

5. Management of perianal fistulae

5.1. Diagnosis and anatomical classification

IG-IBD Statement 5A
Pelvic MRI should be the initial procedure complementing EUA because it is accurate and non-invasive, although it is not
needed routinely in simple fistulae [EL 2b, RG B] EUA is considered the gold standard only in the hands of an experienced surgeon [EL 5, RG D]
EUS requires expertise, but can be equivalent to MRI in complementing EUA if rectal stenosis has been excluded [EL 2b, RG B]
Fistulography is not recommended [EL 3, RG C]
As the presence of concomitant rectosigmoid inflammation has prognostic and therapeutic relevance, proctosigmoidoscopy should be used routinely in the initial evaluation [EL 2b, RG B]

5.2. Treatment

IG-IBD Statement 5B
The presence of a perianal abscess should be ruled out and if present should be drained as a matter of urgency [EL 5, RG D]
IG-IBD Statement 5C
Simple perianal fistulas should be treated either with fistulotomy (in extra or intersphincteric tract) or with placement
of loose seton [EL 3, RG D]. Antibiotics, metronidazole (750-1500mg/day), and/or ciprofloxacin (1000 mg/day), could
be added in the presence of sepsis [EL 3, RG D]. Biological therapy is not indicated
5.2.2. Anti-TNF agents
IG-IBD Statement 5D
Complex fistulas:
“Cone-like” fistulectomy of each fistula tract should firstly be performed with sparing of sphincteric structures [EL 4, RG D]. Seton placement should be recommended [EL 4, RG D], the timing of removal depending on subsequent therapy. Anti-TNF_ agents should be used as the first choice of medical therapy for complex perianal CD [infliximab EL1b, RG A; adalimumab EL1b, RG B]. Combination with surgical therapy is recommended despite a lack of clinical trials [EL 4, RG D]. Antibiotics and/or azathioprine/6-mercaptopurine should be used as a second line medical treatment, despite a lack of clinical trials [EL 4 RG D]
IG-IBD Statement 5E
In evaluating the response to medical and/or surgical treatment in routine practice, combined medical and surgical
clinical assessment in combination with MRI is now considered mandatory [EL 2b, RG D]
IG-IBD Statement 5F
Maintenance therapy after successful anti-TNF_ agents induction is mandatory. Infliximab [EL 1b, RG A], adalimumab [EL 1b, RG B], or AZA/6-MP [EL 2b, RG C], with drained sepsis [EL 4, RG B], should be used as maintenance therapy. All the maintenance therapy should be used for at least 1 year [EL 1b, RG A]; adalimumab could be used up to 3 years [EL 2, RG B]
IG-IBD Statement 5G
In the event of infliximab secondary failure the use of adalimumab is recommended [EL 2, RG B]. In case of anti-TNF_
agents failure, azathioprine/6-mercaptopurine or methotrexate [EL 5, RG D] or tacrolimus [EL 1b, RG B], with antibiotics
as adjunctive treatment, is another therapeutic choice. Depending on the severity of the disease, a diverting ostomy
can be performed later, or proctectomy as the last resort [EL 5, RG D]

5.3. Surgical procedures for perianal CD

IG-IBD Statement 5H
Surgical treatment is mandatory both for simple and complex fistulas. It includes abscess drainage, fistulotomy, fistulectomy, and loose seton placement.
A diverting ostomy or proctectomy may be necessary for severe disease refractory to medical therapy. Complete fistulectomy should not be performed because of the risk of incontinence. A more complex surgical procedure such as an
endoanal advancement flap should be an attractive option in absence of rectal disease and a single source is easily identified [EL 4a, RG D]

6. 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 option [EL 5, RG D]. The duration of the therapy over 1 year should be carefully evaluated on a case-by-case basis [EL 4, RG C]. Maintenance therapy with infliximab that achieves only response should be carefully evaluated in the face of a colectomy [EL 5, RG D]

7. 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 against opportunistic infections is suggested [EL 5, RG D]

8. Anti-TNF_ and malignancies

IG-IBD Statement 8A
The overall risk of malignancies appears not to be increased in patients treated with anti-TNF_ agents [EL 1a]. Their use
increases the risk of lymphoma in CD patients with concomitant immunomodulators, although the absolute risk is low [EL
1a]. Combined maintenance treatment with anti-TNF_ agents and conventional immunosuppressors is best avoided particularly in young patients because of the risk of hepatosplenic T cell lymphoma (HSTCL) [EL 4, RG C]. Whether a previous history of cancer is a controindication for anti-TNF_ therapy is controversial and should be considered on a case-by-case basis [EL 5, RG D]. Conventional screening programs are advisable before the use of anti-TNF_ agents [EL 5, RG D]
IG-IBD Statement 8B
Recommendations reported for anti-TNF_ agents and malignancies in CD, are also suggested for UC, although the number and follow-up of treated patients are significantly lower than for CD [EL 4, RG C]

10. Infections

IG-IBD Statement 10A
The risk of infections is increased in patients treated with anti-TNF_ 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]

10.1. Tuberculosis

IG-IBD Statement 10B
Before starting anti-TNF_ agents, screening for tuberculosis is mandatory. Appropriate screening includes a full medical
history, physical examination, TST or IGRA and a chest X-ray. The IGRA can also be used to distinguish a true positive TST from a false positive TST caused by BCG sensitisation [EL 1, RG A]
IG-IBD Statement 10C
All patients who have a TST result of ≥ 5 mm induration or a positive IGRA and planning to receive anti-TNF

°° agents, should undergo TB chemoprophylaxis [EL 5, RG D]. Patients with a negative TST (< 5 mm) or IGRA should also be treated for LTBI if there is any evidence, on a chest X-ray, of a remote TB disease or if there is positive history of prior TB exposure [EL 5, RG D]. Patients with a latent TB infection must receive standard therapy with isoniazid for 9 months [EL 3b, RG B]. If active TB is diagnosed , anti-TNF °° therapy must be stopped and can be resumed only after TB treatment and specialist consultation [EL 4, RG D]

10.2. Bacterial and fungal infections

IG-IBD Statement 10D
Anti-TNF_therapy should be temporarily stopped until the resolution of the active bacterial infection [EL 5,RGD]. Clostridium difficile infection must be ruled out before starting anti-TNF_ therapy [EL 2, RG B]. Patients on immunomodulator therapy have a higher risk of pneumococcal infection [EL 4]. Pneumococcal vaccination is recommended in elderly patients, whereas it is a valuable option in the other age groups on anti-TNF_ therapy [EL 5, RG D]
IG-IBD Statement 10E
Consider Pneumocystis jiroveci (P. carinii) pneumonia prophylaxis in patients treated with anti-TNF_ agents who are also
receiving other immunosuppressive medications, particularly high-doses of glucocorticoids [EL 4, RG D]

10.3. Hepatitis B virus (HBV) infection

IG-IBD Statement 10F
During anti-TNF_ therapy there is an increased risk of reactivation in patients with previous and occult HBV infections
[EL 4]. Before starting anti-TNF_ agents screening for HBV is mandatory [EL 5, RG D]. Appropriate screening includes
transaminases, HBsAg and Anti-HBc. If Anti-HBc is positive HBvDna is required [EL 5, RG D]. HBsAg positive patients
should be treated with nucleoside analogues [EL 1, RG B]. HBsAg negative patients with positive anti-HBc (+/-anti-HBs)
should be carefully monitored during anti-TNF_ therapy and nucleos(t)ide analogues started at the appearance of HBsAg
and/or HBvDna [EL 4, RG C]

10.4. Hepatitis C virus (HCV) infection

IG-IBD Statement 10G
Anti-TNF_ agents are safe in patients with HCV infection, although there is little data available [EL 4, RG D]. Active HCV
infection should be treated according to a standard therapy practice without stopping biological treatment [EL 5, RG D]

10.5. Cytomegalovirus (CMV) infection

IG-IBD Statement 10H
Screening for a latent or subclinical CMV infection is not necessary before starting anti-TNF_ therapy [EL 2, RG B]. Systemic CMV infection is a contraindication for anti-TNF_ therapy; if a systemic infection appears, anti-TNF_ must be discontinued and an antiviral therapy should be started [EL 2, RG B]. Before starting treatment or during immunomodulator therapy, in the case of severe colitis with CMV detected in the mucosa and not in the blood, anti-TNF_ therapy is not contraindicated [EL 4, RG C]

10.6. Varicella zoster virus (VZV) infection

IG-IBD Statement 10I
A previous VZV infection is not a contraindication to anti-TNF_therapy, but biologics should not be started during an active infection with chickenpox or herpes zoster [EL 4, RG D]. In the event of a VZV infection during anti-TNF_ therapy, an antiviral treatment should be started [EL 1, RG B] and anti-TNF_ agents should be discontinued [EL 5, RG D]. Reintroduction of anti- TNF_ therapy is possible after vesicles and fever have been resolved [EL 5, RG D]

10.7. Epstein Barr virus (EBV) infection

IG-IBD Statement 10L
Screening for an EBV infection or antiviral prophylaxis before starting anti-TNF_ therapy is not justified [EL 2a, RG B]. In the case of a severe EBV infection during biologic therapy, treatment should be interrupted and an antiviral therapy promptly initiated [EL 4, RG D]

10.8. Influenza virus infection

IG-IBD Statement 10M
Influenza vaccination with inactivated vaccine is an effective strategy before and during anti-TNF_ therapy [EL 2, RG B].
The live attenuated vaccine is a contraindication. Early antiviral treatment is recommended when the influenza infection
appears during biological therapy [EL 5, RG D].

11. Autoimmunity

IG-IBD Statement 11A
In patients with a lupus like syndrome anti-TNF_ therapy should be discontinued [EL 4, RG C]

12. 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 [EL 5, RG D]

13. Miscellaneous complications

13.1. Neurologic disorders

IG-IBD Statement 13A
Patients with symptoms of sensory or motor neuropathy should be carefully evaluated and anti-TNF_ agents should be
stopped if a patient develops demyelinating-like disorders [EL 5, RG D]. Anti-TNF_ agents should be used with caution in
patients with family histories of multiple sclerosis [EL 5, RG D].

13.2. Congestive heart failure

IG-IBD Statement 13B
Infliximab or Adalimumab are formally contraindicated in NYHA III-IV patients [EL 1, RG A]. Anti-TNF_ agents should
be used with caution in patients with congestive heart failure or decreased left ventricular function (NYHA I-II patients) and therapy should be discontinued if new or worsening symptoms of HF appear [EL 2, RG B]

13.3. Liver disorders

IG-IBD Statement 13C
If jaundice or ALT elevations >5 times the upper limit appear, anti-TNF_ agents should be discontinued [EL 5, RG D]

13.4. Surgery after anti-TNF

IG-IBD Statement 13D
Whether there is an increased risk of peri or post-operative infections during or after the use of anti-TNF_ agents remains
controversial [EL 4]. Anti-TNF_ agents should be used with caution when surgery is a possible option [EL 5, RG D]

14. Special situations

14.1. 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

14.2. Extra-intestinal manifestations (EIMs)

IG-IBD Statement 14B
In axial and/or peripheral arthritis, in the case of failure of a standard treatment, the use of anti-TNF_ agents is suggested
[EL 2a, RG B]. Anti-TNF_ agents are the treatment of choice in patients with ankylosing spondylitis [EL 1 a RG A]
IG-IBD Statement 14C
An early use of Infliximab [EL 2b] or Adalimumab [EL 4] in Pyoderma Gangrenosum is a valuable option [RG C]
IG-IBD Statement 14D
Anti-TNF_ agents (infliximab and adalimumab) can be considered in resistant cases of uveitis [EL 4, RG C]

14.3. Refractory pouchitis

IG-IBD Statement 14E
Use of infliximab or adalimumab is an option for refractory pouchitis [EL 4, RG C]

15. Anti-TNF_ therapy and pregnancy

IG-IBD Statement 15A
Women of child-bearing age should be advised to avoid becoming pregnant during anti-TNF_ therapy [EL 5, RG D].
If anti-TNF_ therapy is necessary to control disease activity during pregnancy, the benefits of treatment outweigh the risks particularly during the first two trimesters of pregnancy [EL 4, RG C]