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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.
2.1 Consensus process for guidelines development
- –Setting 1: Induction of remission in adults with moderate to severe UC. This setting was divided into four sub-settings:
- –1A: Biologics or tofacitinib vs. no treatment in biologic-naïve patients
- –1B: Comparisons among drugs in biologic-naïve patients
- –1C: Biologics or tofacitinib vs. no treatment in biologic-experienced patients
- –1D: Comparisons among drugs in biologic-experienced patients.
- –Setting 2: Anti-TNF-based combination therapy for the induction of remission in adults with moderate to severe UC
- –Setting 3: Acute severe UC refractory to intravenous steroids
- –Setting 4: Maintenance of remission induced by biologics or tofacitinib
- –Setting 5: Optimization strategies and de-escalation of anti-TNF-based treatments.
2.2 Grading of the evidence and strength of recommendations
|Quality of evidence||Interpretation|
|High||We are very confident that the true effect lies close to the estimate of the effect.|
|Moderate||We are moderately confident in the effect estimate. The true effect is likely to be close to the estimate of effect (even if it is possible that the true effect is different).|
|Low||Our confidence in the effect estimate is limited. The true effect may be substantially different from the estimate of effect.|
|Very low||We have very little confidence in the effect estimate. The true effect is likely to be different from the estimate of effect.|
|Knowledge gap||There is insufficient evidence to determine the true effect.|
|Strength of recommendation||For patients||For clinicians|
|Most individuals in this situation would want the recommended course and only a small proportion would not.||Most individuals should receive the recommended course of action.|
|The majority of individuals in this situation would want the suggested course, but many would not.||Different choices will be appropriate for different patients.|
“IG-IBD makes no recommendation”
|–||The confidence in the effect estimate is so low that any effect estimate is speculative.|
2.3 Setting 1: induction of remission in adults with moderate to severe UC
2.3.1 1A: biologics or tofacitinib vs. no treatment in biologic-naïve patients
2.3.2 1B: comparisons among drugs in biologic-naïve patients
2.3.3 1C: biologics or tofacitinib vs. no treatment in biologic-experienced patients
2.3.4 1D: comparisons among drugs in biologic-experienced patients
2.4 Setting 2: anti-TNF-based combination therapy for the induction of remission in adults with moderate to severe UC
2.5 Setting 3: acute severe UC refractory to intravenous steroids
2.6 Setting 4: maintenance of remission induced by biologics or tofacitinib
2.7 Setting 5: optimization strategies and de-escalation of anti-TNF-based treatments
|Statements||Quality of evidence||Agreement rate||Panel comment beyond GRADE|
|1. For adults with moderate to severe UC refractory to conventional therapy who are naïve to biologics, IG-IBD recommends using infliximab, adalimumab, golimumab, vedolizumab, ustekinumab or tofacitinib over no treatment to induce remission.||High-quality for infliximab and adalimumab; moderate-quality for vedolizumab and tofacitinib; low-quality for golimumab and ustekinumab||100%||The availability of low-cost biosimilars of infliximab and adalimumab – with proven, equivalent efficacy and safety to the originator products – reinforces the strength of the recommendation for these two biologics.|
|2. For adults with moderate to severe, active UC refractory to conventional therapy who are naïve to biologics, IG-IBD suggests using infliximab over adalimumab and golimumab for the induction of remission.||Very low-quality||100%|
|3. For adults with moderate to severe UC refractory to conventional therapy who are naïve to biologics, IG-IBD suggests using vedolizumab over adalimumab due to vedolizumab's superiority in maintaining remission.||Low-quality for induction of remission; moderate-quality for maintenance of remission||82%||The superiority of vedolizumab over adalimumab for maintaining remission was also found in a recent observational study.|
|4. For adults with moderate to severe UC refractory to conventional therapy who are naïve to biologics, IG-IBD makes no recommendation on the use of:|
- infliximab over vedolizumab, ustekinumab, or tofacitinib;
- adalimumab over golimumab, ustekinumab, or tofacitinib;
- golimumab over vedolizumab, ustekinumab, or tofacitinib;
- vedolizumab over ustekinumab or tofacitinib;
- ustekinumab over tofacinitib.
|Low- or very low-quality||86%||The lack of a recommendation regarding the choice between infliximab and tofacitinib is based on data at induction only. However, the reported superiority of tofacitinib for the maintenance of remission should be interpreted with caution, as it is derived from an indirect comparison, and the real-world experience with tofacitinib is currently limited.|
The lack of a recommendation on the choice between ustekinumab and tofacitinib is based on data at induction only. However, the superiority of ustekinumab over tofacitinib for the maintenance of remission should be interpreted with caution.
|5. For adults with moderate to severe, active UC refractory to at least one anti-TNF agent, IG-IBD makes no recommendation in favor of or against using infliximab or golimumab to induce remission.||Knowledge gap||68%||The 15-year clinical experience with infliximab and demonstration of this drug's efficacy in observational studies suggest that it may also be effective in patients in whom previous treatment with a different anti-TNF agent was unsuccessful. Clinical experience with golimumab is more limited, but there is evidence from observational studies of a clinical benefit in this setting.|
|6. For adults with moderate to severe UC refractory to at least one anti-TNF agent, IG-IBD suggests against using adalimumab or vedolizumab to induce remission.||Low-quality||45%||There is a clinical perception and evidence from observational studies that a substantial proportion of patients previously found to be unresponsive to an anti-TNF drug have a clinical benefit with vedolizumab as a second-line agent. Similar considerations can be made for adalimumab as a second-line agent.|
|7. For adults with moderate to severe UC refractory to at least one biologic, IG-IBD recommends using tofacitinib or ustekinumab for the induction of remission.||Moderate-quality for tofacitinib; low-quality for ustekinumab||91%||Robust real-world studies are needed to confirm the data from randomized controlled trials. In addition, the profiles of the ideal patient to be treated differ for the two drugs: tofacitinib should not be used in patients with thrombotic or cardiovascular risk factors, while ustekinumab is also indicated for frail patients due its safety profile.|
|8. For adults with moderate to severe UC refractory to therapy with at least one biologic, IG-IBD makes no recommendation on the use of:|
- infliximab over adalimumab, golimumab, vedolizumab, tofacitinib or ustekinumab;
- adalimumab over golimumab;
- golimumab over vedolizumab, tofacitinib, or ustekinumab.
|9. For adults with moderate to severe UC refractory to therapy with at least one biologic, IG-IBD makes no recommendation on the use of adalimumab over vedolizumab or on the use of tofacitinib over ustekinumab.||Very low-quality||91%|
|10. For adults with moderate to severe UC refractory to at least one biologic, IG-IBD suggests using tofacitinib or ustekinumab over adalimumab or vedolizumab.||Very low-quality||55%|
|11. For adults with moderate to severe UC refractory to conventional therapy, IG-IBD suggests using combination therapy with infliximab plus an immunosuppressant rather than infliximab monotherapy for the induction of remission.||Low-quality||55%||This recommendation arises from only one study. It should be noted that the primary endpoint of the study was set at 16 weeks. Therefore, the period of observation is limited, and there are safety concerns regarding prolonged combination therapy|
|12. For adults with moderate to severe UC refractory to conventional therapy, IG-IBD makes no recommendation on using combination therapy with adalimumab plus an immunosuppressant vs. adalimumab monotherapy for the induction of remission.||Knowledge gap||95%|
|13. For adults with acute severe UC refractory to intravenous steroids, IG-IBD makes no recommendation on using infliximab vs. cyclosporine.||Very low-quality||95%||Only one rescue therapy line (with infliximab or cyclosporine) should be attempted. A second rescue therapy poses significant safety problems with a higher mortality risk and is generally not recommended. However, it may be occasionally considered in selected cases at tertiary referral centers.|
|14. For adults with UC who achieved remission with infliximab, adalimumab, vedolizumab, ustekinumab or tofacitinib, IG-IBD recommends using the same drug as maintenance treatment.||High-quality for infliximab; moderate-quality for adalimumab, vedolizumab, ustekinumab, and tofacitinib||100%|
|15. For adults with UC who achieved remission with golimumab, IG-IBD makes no recommendation on using golimumab as maintenance therapy.||Low-quality||55%||The failure to recommend golimumab as maintenance therapy resulted from the strict critical outcomes used to assess efficacy. However, it is reasonable to continue golimumab as a maintenance treatment in those cases of successful induction with golimumab.|
|16. For adults with moderate to severe UC, IG-IBD makes no recommendation on using an anti-TNF agent plus an immunosuppressant vs. anti-TNF monotherapy as maintenance treatment.||Very low-quality evidence for infliximab; knowledge gap for adalimumab and golimumab||86%|
|17. For adults with moderate to severe UC, IG-IBD makes no recommendation on using an anti-TNF agent plus an immunosuppressant vs. immunosuppressant monotherapy as maintenance treatment.||Knowledge gap||82%|
|18. For adults with UC who lost the response to anti-TNF agents, IG-IBD makes no recommendation on using therapeutic drug monitoring or a standard symptom-based approach of dose optimization.||Knowledge gap||86%|
|19. For adults with UC who lost the response to anti-TNF agents and do not respond to dose escalation, IG-IBD makes no recommendation on using an anti-TNF agent plus an immunosuppressant or making a therapeutic change.||Knowledge gap||82%||Therapeutic drug monitoring, when available, can be considered a useful tool to drive therapeutic choices in case of non-response or loss of response with anti-TNF agents.|
|20. For adults with UC who achieved long-term deep remission, IG-IBD makes no recommendation about the withdrawal of anti-TNF treatment.||Very low-quality||100%||This possibility should be assessed on a case-by-case basis and discussed with the patient. In case of withdrawal, remission can be maintained with 5-aminosalicylates or thiopurines. However, the higher rate of clinical remission in patients who continue anti-TNF treatment and the risk of relapse in cases of discontinuation should always be considered.|
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Edited by Roberto de Franchis.
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