Biologics: Anti-TNFs

Infliximab was the first anti-TNF licensed for Crohn’s disease, followed by adalimumab and certolizumab. Certolizumab is not licensed for use in Europe, except Switzerland.

Anti-TNFs are indicated for moderate and severe Crohn’s disease if :

  • Poor response to other therapies (e.g. steroid refractory or dependence despite immuno-modulator use)
  • Widespread active disease (raised inflammatory markers and/or mucosal lesions), particularly with adverse prognostic factors. Fibrotic disease including established fistulous tracts are unlikely to respond.

Also see the e-Guide algorithm for managing anti-TNF therapy.

Active disease

  • TNF-antagonists have similar efficacy and adverse effects.
  • Infliximab, Adalimumab, and Certolizumab have all been shown to induce response and remission.
  • Infliximab combined with azathioprine is more effective than infliximab and azathioprine alone to induce remission.
  • ACCENT II confirmed that infliximab was beneficial in perianal fistula: 69% responded at 14 weeks; of responders, 36% had complete closure (c.f. 19%) and 46% had >50% closure (c.f. 23%) at 1 year.
  • Rates of fistula remission following treatment for 1 y with adalimumab are similar, though velocity of closure may be slower than with infliximab (CARE study, CLASSIC 1 and GAIN – provide 4 week data; CHARM provides 56 week data 33% of adalimumab treated patients and 13% of placebo-treated patients).

Maintaining remission

  • Inlliximab, adalimumab and certolizumab have all been shown to maintain luminal remission.
  • Both infliximab and adalimumab are efficacious at maintaining remission, and should be provided for at least 1 year.
  • Anti-TNF reduces need for steroids; for example the early use of infliximab (top-down approach) reduced the need for steroid therapy.
  • Overall, rates of hospitalisation and surgery are reduced by ≈ 30%.

Prevention of post-surgical recurrence

To date, there are conflicting results regarding the effect of anti-TNF for post-operative Crohn’s disease prophylaxis.

Stopping therapy

  • Consider stopping anti-TNF in those with deep remission.
  • Factors have been defined predicting when it is safe to stop Infliximab (whilst continuing on an immunomodulator) in patients with luminal Crohn’s disease in remission for at least 6 months
  • It is not known but likely that similar factors apply to switching from Infliximab or other anti-TNFs to an immunomodulator
  • The STORI trial published in 2012 assessed the impact of stopping infliximab in 115 patients treated for > 1 y with combination therapy in steroid-free remission for > 6 months
    • 44% relapsed within the first year, only 2 thereafter.
    • Factors predicting relapse were male sex, the absence of surgical resection, leukocyte counts >6.0 × 109/L, hemoglobin ≤145 g/L, C-reactive protein ≥5.0 mg/L, and fecal calprotectin ≥300 μg/g.
    • 88% of patients regained remission on restarting therapy.
    • There were no adverse drug reactions on re-infusion.

Dosing, administration and monitoring

Before treatment

  • Conduct Opportunistic Infections checklist
  • Rule out:
    • Untreated TB or latent TB
    • Active infection (e.g. abdominal or perianal abscess)
    • Severe heart failure
    • History of demyelinating disease or optic neuritis
    • History of lymphoma
    • Possible non-hematopoietic cancer (discuss with oncologist)

Dosing

  • Infliximab
    • Three dose 5 mg/kg induction schedule (0, 2, 6 weeks) then every 8 weeks IVI.
    • Regular administration is superior to episodic (as required) therapy.
  • Adalimumab
    • Given as induction dose of 160 mg SC followed by 80 mg SC at 2 weeks then 40 mg SC every 2 weeks.

Follow-up

  • Only continue therapy beyond induction (i.e. 12 weeks) if there is a clear therapeutic response.
  • Plan objective (e.g. endoscopy and histology; ultrasonography, radiology; calprotectin) reassessment of therapeutic response at least annually to prevent providing anti-TNF to those in whom it is ineffective or not required.
  • In order to detect potential therapy related complications patients on anti-TNF therapy should be clearly instructed on when and whom to contact in case of symptoms.
  • Some services run "virtual biologic clinics" to ensure care is both appropriate and monitored.
  • Monitoring of anti-TNF drug levels and antibodies to anti-TNF can determine whether dose increases (pharmacokinetics generally support reducing the dose interval) or switching to a different class of agent are required.

Adverse effects

  • Local or systemic reactions
    • Acute Infusion reaction within 2 h administration of infliximab, usually within the first few minutes.
    • Painful injection site reactions with SC administration (Adalimumab or Certolizumab).
    • Delayed infusion reactions (joint pain, stiffness, fever, malaise).
  • Opportunistic infections (see ECCO 5L beneath)
  • Malignancy
    • Increased risk of hepatosplenic T-cell lymphoma in young patients taking anti-TNF and an immunomodulator
    • Increased risk of B-cell lymphoma, similar to thiopurine users
    • Potentially increased risk for melanoma development.
  • National Formulary should be consulted to review adverse drug reactions and drug interactions.
ECCO statement 5K (CD 2016)

Particular care should be taken to consider serious infections as a complication of immunosuppressive therapy, including anti-TNF [EL3]

Special situations

Pregnancy

  • Infliximab (and likely aalimumab) cross the placenta from about 24 weeks. Therefore to avoid fetal exposure, consider withholding infusions in the 3rd trimester.
  • Use beyond this time throughout pregnancy does not appear to harm the foetus/baby, though live vaccination should be withheld for 6 months.

Breastfeeding

  • Infliximab and adalimumab are probably safe during lactation.

Surgery

  • There is no consensus as to when surgery can be performed after anti-TNF therapy.
  • Some experts believe inter-current anti-TNF does not increase post-operative complications, while others recommend operating at least one month, or longer after drug administration
  • Anti-TNF may increase the risk of infections about two-fold up to 30 days following surgery in UC
ECCO Statement 7I (CD 2016)

Patients with a (unsuspected) diagnosis of Crohn’s disease after IPAA present markedly higher complication and failure rates. An IPAA may be discussed in highly selected and motivated patients with Crohn’s colitis, pending proof of absent small bowel disease and no existing or previous evidence of perineal involvement. Intensive combined management by IBD physicians is mandatory to maintain an acceptable pouch function in those patients [EL4]

Paediatrics

  • B-cell and hepatosplenic T-cell lymphoma are increased in those treated with anti-TNF and azathioprine.
  • In those non-immune to EBV, and in young males, some experts preferentially consider using Adalimumab therapy alone rather than Infliximab with azathioprine, so as to reduce the risk of post-mononucleosis lymphoproliferation or hepato-splenic T-cell lymphoma, which may both be associated with thiopurine use.

Elderly

  • Anti-TNF therapy in the elderly is associated with an increased risk of opportunistic infections compared to younger patients.

Active disease

Infliximab

The ACT 1 & 2 trials evaluated the efficacy of infliximab in moderate UC refractory to 5-ASA and/or corticosteroids at week 8, with response in 65-70%, remission in 34-39%, and mucosal healing in the majority. After 1 year, colectomy rates reduced from 17% to 10%.

Acute severe colitis

Infliximab is an effective 2nd-line therapy in acute severe UC; 85% respond by day 7. Colectomy-free survival is improved (e.g. 50% c.f. 76% @ 3 years comparing infliximab and placebo). Broadly, the adverse events are similar to ciclosporin. There is no trial evidence to support the preferential use of anti-TNF or ciclosporin as 2nd-line therapy. Infliximab has been assessed as a 3rd-line therapy following failure to respond to steroids and then ciclosporin; the colectomy free survival at 3, 12, 36 months was 60%, 40% & 30%, with remission in only 30%.

Adalimumab

160/80 mg induction dose has also been shown to be superior to placebo, with remission in 18.5% patients at week 8 (placebo 10%). A separate trial demonstrated superior responses in anti-TNF naïve patients at the same time point (21% vs 9%). It is not appropriate to compare the results between trials of different agents, with increasingly robust endpoints being required to define remission.

Golimumab

200/100 mg also induces clinical remission, with 19% vs. 6% in clinical remission at week 6.

Maintaining remission

In ACT 1 & ACT 2, sustained clinical remission at all assessed time points over 1 yr was 20% (7% placebo); with steroid-free remission in the subset receiving corticosteroids of 24% (10% placebo). These results improve with concomitant thiopurine therapy (UC-SUCCESS trial - corticosteroid-free remission at week 16 was achieved by 39.7% (31 of 78) of patients receiving infliximab/azathioprine, compared with 22.1% (17 of 77) receiving infliximab alone (P = .017) and 23.7% (18 of 76) receiving azathioprine alone (P = .032)).

Broadly, 2/3 of patients respond of whom 2/3 have a sustained clinical response. Remission rates are similar with adalimumab. Follow-up of responders to IFX over 2 years demonstrated moderate disease in < 10%.

Stopping therapy

  • Consider stopping anti-TNF in those with deep remission.
  • In patients on double immunosuppression stopping one of the two should be considered after 3-6 month in stable remission.
  • The STORI trial published in 2012 assessed the impact of stopping infliximab in 115 patients treated for > 1 y with combination therapy in steroid-free remission for > 6 months
    • 44% relapsed within the first year, only 2 thereafter.
    • Factors predicting relapse were male sex, the absence of surgical resection, leukocyte counts >6.0 × 109/L, hemoglobin ≤145 g/L, C-reactive protein ≥5.0 mg/L, and fecal calprotectin ≥300 μg/g.
    • 88% of patients regained remission on restarting therapy.
    • There were no adverse drug reactions on re-infusion.

Dosing, administration and monitoring

Before treatment

  • Conduct Opportunistic Infections checklist
  • Rule out:
    • Untreated TB or latent TB
    • Untreated or latent Hepatitis B
    • Active infection (e.g. abdominal or perianal abscess)
    • Severe heart failure
    • History of demyelinating disease or optic neuritis
    • History of lymphoma
    • Possible non-hematopoietic cancer (discuss with oncologist)

Dosing

  • Infliximab
    • Three dose 5 mg/kg induction schedule (0, 2, 6 weeks) then every 8 weeks IVI.
    • Regular administration is superior to episodic (as required) therapy.
  • Adalimumab
    • Given as induction dose of 160 mg SC followed by 80 mg SC at 2 weeks then 40 mg SC every 2 weeks.
  • Golimumab
    • Induction 200 mg SC followed by 100 mg SC at week 2, then 50 mg SC every 4 weeks in those < 80 kg and 100 mg SC in those > 80 kg

Follow-up

  • Only continue therapy beyond induction (i.e. 12 weeks) if there is a clear therapeutic response.
  • Plan objective (e.g. endoscopy and histology; ultrasonography, radiology; calprotectin) reassessment of therapeutic response at least annually to prevent providing anti-TNF to those in whom it is ineffective or not required.
  • In order to detect potential therapy-related complications patients on anti-TNF therapy should be clearly instructed on when and whom to contact in case of symptoms.
  • Some services run "virtual biologic clinics" to ensure care is both appropriate and monitored.
  • Monitoring of anti-TNF drug levels and antibodies to anti-TNF can determine whether dose increases (pharmacokinetics generally support reducing the dose interval) or switching to a different class of agent are required.

Adverse effects

  • Local or systemic reactions
    • Infusion reaction within 2 h administration of infliximab, usually within the first few minutes.
    • Painful injection site reactions with SC administration (Adalimumab or Certolizumab).
    • Delayed infusion reactions (joint pain, stiffness, fever, malaise).
  • Opportunistic infections (see ECCO 5L beneath)
  • Malignancy
    • Increased risk of hepatosplenic T-cell lymphoma in young patients taking anti-TNF with an immunomodulator
    • Possibly increased risk of B-cell lymphoma (the data is conflicting)
    • Potentially increased risk for non-melanoma skin cancer development; all patients should use sun-protection
  • National Formulary should be consulted to review adverse drug reactions and drug interactions.
ECCO statement 5K (CD 2016)

Particular care should be taken to consider serious infections as a complication of immunosuppressive therapy, including anti-TNF [EL3]

Special situations

Pregnancy

  • Infliximab (and likely aalimumab) cross the placenta from about 24 weeks. Therefore to avoid fetal exposure, consider withholding infusions beyond 16 weeks.
  • Use beyond this time throughout pregnancy does not appear to harm the foetus/baby, though live vaccination should be withheld for 6 months.

Breastfeeding

  • Infliximab and adalimumab are probably safe during lactation.

Surgery

  • There is no consensus as to when surgery can be performed after anti-TNF therapy.
  • Some experts believe inter-current anti-TNF does not increase post-operative complications, while others recommend operating at least one month, or longer after drug administration
  • Anti-TNF may increase the risk of infections about two-fold up to 30 days following surgery in UC

Paediatrics

  • B-cell and hepatosplenic T-cell lymphoma are increased in those treated with anti-TNF and azathioprine.
  • In those non-immune to EBV, and in young males, some experts preferentially consider using Adalimumab therapy alone rather than Infliximab with azathioprine, so as to reduce the risk of post-mononucleosis lymphoproliferation or hepato-splenic T-cell lymphoma, which may both be associated with thiopurine use.

Elderly

  • Anti-TNF therapy in the elderly is associated with an increased risk of opportunistic infections compared to younger patients.

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