Withdrawal of Long-Term Maintenance Treatment with Azathioprine Tends to Increase Relapse Risk in Patients with Crohn’s Disease

Wenzl, H; Primas, Christian; Novacek, Gottfried; Teml, Alexander; Öfferlbauer-Ernst, Anna; Högenauer, Christoph; Vogelsang, Harald; Petritsch, Wolfgang; Reinisch, Walter

doi:10.1007/s10620-014-3419-5

Cited by 36 publications

(37 citation statements)

References 45 publications

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“…These comprised 5 RCTs 8-12 and 13 retrospective cohort studies [13][14][15][16][17][18][19][20][21][22][23][24][25] (one of which 20 was an extension study from a previous RCT 8 ). Eleven studies reported on immunomodulator withdrawal in CD [8][9][10][11]14,15,17,20,[23][24][25] and 8 in UC. 12,13,[17][18][19]21,22,24 One study by Fraser et al reported on long-term outcomes of patients treated with methotrexate and presented relapse rates for IBD with no distinction between CD and UC.…”

Section: De-escalation Of Immunomodulator Monotherapymentioning

confidence: 99%

“…All 4 RCTs in CD reported higher relapse rates after stopping the immunomodulator compared with continuing the drug. [8][9][10][11] All RCTs focused on azathioprine exclusively and the longest follow-up was for 2 years after withdrawal. 10 The study by Lemann et al was designed as a noninferiority study, and the investigators concluded that they could not reject the hypothesis that placebo was inferior to continuing azathioprine.…”

Section: De-escalation Of Immunomodulator Monotherapymentioning

confidence: 99%

“…[8][9][10][11] All RCTs focused on azathioprine exclusively and the longest follow-up was for 2 years after withdrawal. 10 The study by Lemann et al was designed as a noninferiority study, and the investigators concluded that they could not reject the hypothesis that placebo was inferior to continuing azathioprine. 8 The other 3 RCTs showed higher relapse rates in the drug withdrawal arm compared with the drug continuation arm (P < .05), but statistical significance was lost in one study at longer follow-up.…”

Section: De-escalation Of Immunomodulator Monotherapymentioning

confidence: 99%

“…8 The other 3 RCTs showed higher relapse rates in the drug withdrawal arm compared with the drug continuation arm (P < .05), but statistical significance was lost in one study at longer follow-up. 10 Of the RCTs, Treton et al 20 reported the highest relapse rates at 12 months but was the only one that was not placebo controlled. Relapse rates after drug withdrawal in RCTs ranged from 8% to 25% at 6 months, 16.5% to 53% at 12 months, 21.3% to 31% at 18 months, and 31% at 24 months.…”

Section: De-escalation Of Immunomodulator Monotherapymentioning

confidence: 99%

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Systematic Review of Effects of Withdrawal of Immunomodulators or Biologic Agents From Patients With Inflammatory Bowel Disease

et al. 2015

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Little is known about the optimal duration of therapy with an anti-tumor necrosis factor (TNF) agent and/or an immunomodulator for patients with inflammatory bowel disease (IBD). We performed a systematic search of the literature to identify studies reporting after de-escalation (drug cessation or dose reduction) of anti-TNF agents and/or immunomodulators in patients in remission from IBD. Studies were reviewed according to the type of IBD and drug. Rates of relapse, factors associated with relapse, and response to re-treatment were determined. Our search yielded 6315 unique citations; we analyzed findings from 69 studies (18 on de-escalation [drug cessation or dose reduction] of immunomodulator monotherapy, 8 on immunomodulator de-escalation from combination therapy, and 43 on de-escalation of anti-TNF agents, including 3 during pregnancy) comprising 4672 patients. Stopping immunomodulator monotherapy after a period of remission was associated with high rates of relapse in patients with Crohn's disease or ulcerative colitis (approximately 75% of patients experienced a relapse within 5 years after therapy was stopped). Most studies of patients with Crohn's disease who discontinued an immunomodulator after combination therapy found that rates of relapse did not differ from those of patients who continued taking the drug (55%-60% had disease relapse 24 months after they stopped taking the immunomodulator). The only study in patients with ulcerative colitis supported continued immunomodulator use. Approximately 50% of patients who discontinued anti-TNF agents after combination therapy maintained remission 24 months later, but the proportion in remission decreased with time. Markers of disease activity, poor prognostic factors, and complicated or relapsing disease course were associated with future relapse. In conclusion, based on a systematic review, 50% or more of patients with IBD who cease therapy have a disease relapse. Further studies are required to accurately identify subgroups of patients who are good candidates for discontinuation of treatment. The decision to withdraw a drug should be made for each individual based on patient preference, disease markers, consequences of relapse, safety, and cost.Keywords : Crohn's Disease ; Ulcerative Colitis ; Patient Management ; Cessation.Abbreviations used in this paper : anti-TNF, anti-tumor necrosis factor therapy ; CD, Crohn's disease ; CRP, C-reactive protein ; FC, fecal calprotectin ; IBD, inflammatory bowel disease ; PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses ; RCT, randomized controlled trial ; TNF, tumor necrosis factor ; UC, ulcerative colitis.Therapeutic strategies in inflammatory bowel disease (IBD) have evolved considerably in the past few decades. The acknowledgment that subclinical and undertreated inflammation can lead to poor outcomes has underpinned a shift in treatment goals from symptomatic control to sustained clinical and endoscopic remission.1 Treatment strategies have changed accordingly, including the ear...

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Section: De-escalation Of Immunomodulator Monotherapymentioning

confidence: 99%

Section: De-escalation Of Immunomodulator Monotherapymentioning

confidence: 99%

Section: De-escalation Of Immunomodulator Monotherapymentioning

confidence: 99%

Section: De-escalation Of Immunomodulator Monotherapymentioning

confidence: 99%

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Systematic Review of Effects of Withdrawal of Immunomodulators or Biologic Agents From Patients With Inflammatory Bowel Disease

et al. 2015

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“…7 15 NS NR 8 of 15 (Vilien, et al, 2004) (Gross, et al, 1998) 13 1 NS Less than 1 year 0 of 1 (Lennard-Jones, 1977) 14a 11 C 3 months to 2 years 6 of 11 (Prantera, et al, 1992) 14b 18 IC 3 months to 2 years 9 of 18 (Prantera, et al, 1992) 14c 32 I 3 months to 2 years 17 of 32 (Prantera, et al, 1992) (Gendre, et al, 1993) 21b #48 NS 3 months to 2 years 22% 42% (Gendre, et al, 1993) 22 101, 57 NS 1 -2 years or less 36 of 101 34 of 57 (Summers, et al, 1979) 23a 7 C 12 months or more 0 of 7 (Wenzl, et al, 2015) 23b 14 IC 12 months or more 7 of 14 (Wenzl, et al, 2015) 23c 5 I 12 months or more 1 of 5 (Wenzl, et al, 2015) 24 § § § § ~ 65% (Malchow, et al, 1984) 25 #10 NS NR 50% (Nyman, et al, 1985) (Steenholdt, et al, 2012) 9 100 95 4% 7% 12% 20% 27% 48% NR (Papamichael, et al, 2015) …”

mentioning

confidence: 99%

Bovine lactoferrin and Crohn’s disease: a case study

Alexander

Iigo

Abdelgied

et al. 2017

Biochem. Cell Biol.

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A 22-year-old male suffering from abdominal pain, repeated diarrhea, and weight loss visited the Digestive Disease Department of Nagoya City University Hospital on 19 December 2011. He was hospitalized and diagnosed with Crohn’s colitis. His Crohn’s Disease Activity Index (CDAI) was 415. Treatment by granulocyte apheresis, mesalazine, and adalimumab was started. His CDAI was 314 on 30 December and 215 on 5 January. A colonoscopic examination on 19 January showed almost complete remission in the transverse colon and marked remission in the rectum. Mesalazine therapy was stopped on 28 February, and the patient was instructed to self-inject 40 mg of adalimumab every other week. His CDAI was 50 on 10 April, indicating clinical remission. His last self-injection of adalimumab was on 24 April 2012, and he started taking 1 g of bovine lactoferrin (bLF) daily. His CDAI was 35 on 8 January 2013. He continued taking 1 g of bLF daily without any other treatment for Crohn’s disease. Laboratory blood tests on 7 September 2015 showed no sign of disease recurrence, and a colonoscopic examination on 23 October 2015 showed almost complete mucosal healing. This case indicates that ingestion of bLF to maintain Crohn’s disease in a remissive state should be further explored.

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Withdrawal of immunosuppressant or biologic therapy for patients with quiescent Crohn's disease

Boyapati

Torres

Palmela

et al. 2018

Cochrane Database of Systematic Reviews

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The effects of withdrawal of immunosuppressant therapy in people with quiescent Crohn's disease are uncertain. Low quality evidence suggests that continuing azathioprine monotherapy may be superior to withdrawal for avoiding clinical relapse, while very low quality evidence suggests that there may be no difference in clinical relapse rates between discontinuing azathioprine from a combination therapy regimen, compared to continuing combination therapy. It is unclear whether withdrawal of azathioprine, initially administered alone or in combination, impacts on the development of CD-related complications, adverse events, serious adverse events or withdrawal due to adverse events. Further high-quality research is needed in this area, particularly double-blind RCTs in which biologic therapy or an immunosuppressant other than azathioprine is withdrawn.

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Withdrawal of Long-Term Maintenance Treatment with Azathioprine Tends to Increase Relapse Risk in Patients with Crohn’s Disease

Abstract: AZA withdrawal resulted in a significantly increased relapse risk after 1 year and a nonstatistically significant trend for relapse after 2 years. Our results are in line with previous observations.

Cited by 36 publications

References 45 publications

Systematic Review of Effects of Withdrawal of Immunomodulators or Biologic Agents From Patients With Inflammatory Bowel Disease

Systematic Review of Effects of Withdrawal of Immunomodulators or Biologic Agents From Patients With Inflammatory Bowel Disease

Bovine lactoferrin and Crohn’s disease: a case study

Withdrawal of immunosuppressant or biologic therapy for patients with quiescent Crohn's disease

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