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  1. 1. SONIC HTTP://TRIALGURU.ORG Colombel JF, et al. "Infliximab, azathioprine, or combination therapy for Crohn's disease". The New England Journal of Medicine. 2010. 362(15):1383- 1395.
  2. 2. 2010 Study of Biologic and Immunomodulator Naive Patients in Crohn Disease (SONIC)
  3. 3. BACKGROUND  Infliximab (anti-TNF-α monoclonal antibody) as maintenance therapy for Crohn disease has been established  However, studying infliximab as an induction agent has not been done
  4. 4. CLINICAL QUESTION Among patients with moderate to severe Crohn disease without prior treatment with immunosuppressive therapies or biologics, does azathioprine, infliximab, or a combination of both therapies improve rates of steroid-free remission?
  5. 5. DESIGN  Analysis: Intention-to-treat  Multicenter, randomized, double blind, comparative trial  N=508 patients with Crohn disease  Azathioprine (n=170)  Infliximab (n=169)  Combination therapy (N=169)  Setting: 92 centers in multiple continents  Enrollment: 2005-2008  Follow-up: 26 weeks  Primary outcome: Corticosteroid-free clinical remission at week 26
  6. 6. POPULATION Inclusion Criteria  Age ≥21 years  Crohn's disease for ≥6 weeks  Crohn's disease activity Index (CDAI) score 220-450 off corticosteroids  Out of a total score of 600, remission <150 and severe >450  One of the following:  On steroids for disease control  May need 2nd course of steroids in 1 year  No response to ≥4 weeks of Exclusion Criteria  Treatment with 6MP, MTX, or anti-TNF biologic  Short gut, Ostomy, Symptomatic stricture  Abscess, Abdominal surgery in prior 6 months  Granulomatous infection including TB  HIV, Hep B, Hep C  Multiple sclerosis  Cancer  Mutant thiopurine methyltransferase phenotype
  7. 7. INTERVENTIONS  Randomized to a group with stratification by center, disease duration, and baseline prednisone equivalent dosing:  Infliximab - Infliximab 5 mg/kg IV at weeks 0, 2, 6, then q8 weeks, plus placebo tablets  Azathioprine - Azathioprine 2.5 mg/kg qday, plus placebo infusions  Combination - Infliximab plus azathioprine as above  Oral mesalamine was continued at a stable dosing  Corticosteroids and Budesonide continued, but at adjusted dosing  Colonoscopy at baseline, repeated at week 26 for those with mucosal ulcers at baseline  Groups were followed until week 30  Participants had the option of continuing on their assigned therapies in a blinded fashion until week 50 as part of an extension trial, though these results are out of the scope of this review
  8. 8. RESULTS Fig. 2A  At week 26, a total of 96 of the 169 patients (56.8%) receiving combination therapy, 75 of the 169 patients (44.4%) receiving infliximab, and 51 of the 170 patients (30.0%) receiving azathioprine were in corticosteroid- clinical remission  P=0.006 for the comparison of infliximab vs.  P<0.001 for the comparison of combination therapy vs. azathioprine  P=0.02 for the comparison of combination therapy vs. infliximab
  9. 9. RESULTS Fig. 2B  At week 26, mucosal healing had occurred in 47 of 107 patients (43.9%) receiving combination therapy, in 28 of 93 patients (30.1%) receiving infliximab, and in 18 of 109 patients (16.5%) receiving azathioprine  P=0.02 for infliximab vs. azathioprine  P<0.001 for combination therapy vs. azathioprine  P=0.06 for combination therapy vs. infliximab
  10. 10. BOTTOM LINE Patients with moderate to severe Crohn disease who has NOT previously been treated with immunosuppressives or biologics, a combination of azathioprine and infliximab resulted in a higher rate of steroid-free remission at week 26 than either drug alone. Infliximab monotherapy showed longer steroid free remission than azathioprine monotherapy.
  11. 11. CRITICISMS  Low rate of mucosal ulceration, which may be more likely attributable to IBS rather than IBD  Induction therapy only given to group getting Infliximab  Azathioprine takes up to 6 month so trial not a fair comparison between azathioprine and infliximab  Unclear efficacy in patients with longer disease duration  No cost analysis  Funding for study:  Centocor Ortho Biotech (now Janssen Biotech, sellers of Remicade in the US, the brand name of infliximab)  Schering-Plough (now owned by Merck, sellers of Remicade outside of the US)
  12. 12. DISCUSSION QUESTIONS  What did the SONIC trial show?  For patients with Crohn’s disease, should a patient be given anti-TNF induction therapy?  According to the SONIC trial, are anti-TNF better or worse than Azathioprine at achieving steroid free remission?
  13. 13. DISCUSSION QUESTIONS/ANSWERS  What did the SONIC trial show?  ANSWER: It showed that a combination of azathioprine and infliximab resulted in a higher rate of steroid-free remission  For patients with Crohn’s disease in the SONIC trial, should a patient be given anti-TNF induction therapy?  ANSWER: Yes, anti-TNF induction should be given  According to the SONIC trial, are anti-TNF better or worse than Azathioprine at achieving steroid free remission?  ANSWER: Anti-TNF (especially Infliximab which was the study drug) was better at achieving steroid free remission
  14. 14. BOARD-LIKE QUESTION 71yo women with history of Crohn disease presents with B symptoms of fatigue, unintentional weight loss, fever, night sweats. Only medication is Infliximab Physical exam: T 37.9, HR 107, BP 108/61, RR 14. BMI 20. Gen: NAD, thin Diffuse lymphadenopathy, no hepatosplenomegaly Radiographs: CT scan shows extensive lymphadenopathy at cervical, axillary, abdominal, pelvis Adapted from MKSAP 17 QUESTION What is the most likely diagnosis? A. Non-Hodgkin lymphoma B. Sarcoidosis C. Testicular cancer D. Tuberculosis
  15. 15. BOARD-LIKE QUESTION ANSWER What is the most likely diagnosis? A. Non-Hodgkin lymphoma B. Sarcoidosis C. Testicular cancer D. Tuberculosis Educational Objective: Immunosuppression can lead to non- Hodgkin lymphoma Key Point: - This patient has received long term immunosuppression with Infliximab. Now with B-symptoms, likely from NHL - Viral infections (eg EBV, HIV, HTLV, Hep B/C) can also drive transformation of lymphoid tissue to lymphoma or contribute indirectly by cause immunodeficiency (risk for development of lymphoma)
  16. 16. REFERENCES  Thursz MR, et al. "Prednisolone or pentoxifylline for alcoholic hepatitis". The New England Journal of Medicine. 2015. 372(17):1619-1628.  LLC PeripheralBrain. https://www.wikijournalclub.org/wiki/SO NIC

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