Systematic Literature Review of Real-World Evidence on Dose Escalation and Treatment Switching in Ulcerative Colitis

Figures & data

Table 1 Regular Dosages for Drugs Administered in Patients with UC

Drug, Brand (Generic)	Class	Manufacturer	Mode of Administration	EU Dosage in UC	US Dosage in UC
Remicade (infliximab)	Anti-TNF therapy	Janssen Biotech	IV	5 mg/kg at 0, 2, and 6 weeks and every 8 weeks thereafter for the treatment of adult patients	5 mg/kg at 0, 2, and 6 weeks and every 8 weeks thereafter
Humira (adalimumab)		AbbVie	SC	160 mg at week 0 (given as four 40 mg injections in 1 day or as two 40 mg injections per day for 2 consecutive days) and 80 mg at week 2 (given as two 40 mg injections in 1 day) After induction treatment, the recommended dose is 40 mg every other week via SC injection	160 mg on day 1 (given in 1 day or split over 2 consecutive days), 80 mg on day 15 and 40 mg every other week starting on day 29. Discontinue in patients without evidence of clinical remission by 8 weeks (day 57)
Simponi (golimumab)		Janssen Biotech	SC	Patients with body weight <80 kg → initial dose of 200 mg, followed by 100 mg at week 2. Patients who have an adequate response should receive 50 mg at week 6 and every 4 weeks thereafter Patients with body weight ≥ 80 kg → initial dose of 200 mg, followed by 100 mg at week 2 and 100 mg every 4 weeks thereafter	200 mg initially administered by SC injection at week 0, followed by 100 mg at week 2 and 100 mg every 4 weeks thereafter
Entyvio (vedolizumab)	Integrin receptor antagonist	Takeda	IV	300 mg administered by IV infusion at 0, 2, and 6 weeks and every 8 weeks thereafter EU SmPC states that some patients who have experienced a decrease in their response may benefit from an increase in dosing frequency to IV vedolizumab 300 mg every 4 weeks	IV 300 mg infused over approximately 30 minutes at 0, 2, and 6 weeks and every 8 weeks thereafter
Xeljanz (tofacitinib)	JAK inhibitor	Pfizer	Oral	Induction: The recommended dose for induction treatment is 10 mg given orally twice daily for 8 weeks For patients who do not achieve adequate therapeutic benefit by week 8, the induction dose of 10 mg twice daily can be extended for an additional 8 weeks (16 weeks total), followed by 5 mg twice daily for maintenance Maintenance: The recommended dose for maintenance treatment is tofacitinib 5 mg orally given twice daily For patients with UC who are not at increased risk for venous thromboembolism, tofacitinib 10 mg orally twice daily may be considered if the patient experiences a decrease in response on tofacitinib 5 mg twice daily and failed to respond to alternative treatment options for UC such as anti-TNF therapy	Induction: Tofacitinib 10 mg twice daily or extended-release tofacitinib 22 mg once daily for 8 weeks; evaluate patients and transition to maintenance therapy depending on therapeutic response If needed, continue tofacitinib 10 mg twice daily or extended-release tofacitinib 22 mg once daily for a maximum of 16 weeks Discontinue tofacitinib 10 mg twice daily or extended-release tofacitinib 22 mg once daily after 16 weeks if adequate therapeutic response is not achieved Maintenance: Tofacitinib 5 mg twice daily or extended-release tofacitinib 11 mg once daily For patients with loss of response during maintenance treatment, tofacitinib 10 mg twice daily or extended-release tofacitinib 22 mg once daily may be considered and limited to the shortest duration, with careful consideration of the benefits and risks for the individual patient
Stelara (ustekinumab)	IL-12/ IL-23 antagonist	Janssen Biotech	IV and SC	A single IV, weight based: ≤55 kg: 260 mg (2 vials) 56–85 kg: 390 mg (3 vials) >85 kg: 520 mg (4 vials) The first SC dose should be given at week 8 following the IV dose. After this, dosing every 12 weeks is recommended	A single IV, weight based: ≤55 kg: 260 mg (2 vials) 56–85 kg: 390 mg (3 vials) >85 kg: 520 mg (4 vials) The SC maintenance dose is 90 mg 8 weeks after the first IV dose and every 8 weeks thereafter

Abbreviations: Anti-TNF, tumor necrosis factor inhibitor; IL, interleukin; JAK, Janus kinase; SmPC, summary of product characteristics; UC, ulcerative colitis.

Figure 1 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram for publication screening and selection. ^aEMBASE + Medline.

Figure 2 Proportion of patients treated with dose escalation due to loss of response^{31,44,46,63,66–68,75,76} or any reason.^{22–29,32,34,35,37,38,40–42,45,47–52,55,57–62,64,65,69,71,72,74} Studies originating in multiple countries and including multiple anti-TNF therapies were counted more than once, giving a total number of references higher than the 48 publications found.

Abbreviations: ADA, adalimumab; GOL, golimumab; IFX, infliximab; TOF, tofacitinib; UST, ustekinumab; VDZ, vedolizumab.

Figure 3 (A) Rates of clinical response^{31,32,40,44,55,61,62,66–69} and (B) clinical remission^{31,32,34,55,59,61,62,66,67,69,75} after dose escalation. ^a20% of patients were in clinical remission at time of dose escalation. ^bPartial remission; only 20 observed cases for partial remission at 12 months (ie, data missing for 21 of the original 41 patients). ^c10% of patients were in clinical remission at the time of dose escalation, with such patients who violated protocol being treated with dose escalation at the discretion of the treating physician. ^dData reported for a subpopulation of patients treated with dose escalation (n=20/40) for whom 16-week follow-up data were available.

Abbreviations: ADA, adalimumab; GOL, golimumab; IFX, infliximab; NR, not reported; TOF, tofacitinib; UC, ulcerative colitis; UST, ustekinumab; VDZ, vedolizumab.

Table 2 Clinical Remission and Clinical Response Following Treatment Switch

Study	Treatment Switch	Patients with UC, n (%)	Patients Who Switched Treatment, n (%)	Time of Assessment	Switched Patients Achieving Clinical Remission, n (%)	Switched Patients Achieving Clinical Response, n (%)
Studies reporting on switching within treatment class^a
Baert et al (2014)^Citation25	IFX>ADA	73 (100)	73 (100)	12 weeks	—	55 (75.3)
Baert et al (2014)^Citation25	IFX>ADA	73 (100)	73 (100)	12 months (52 weeks)	—	38 (52.1)
Baki et al (2015)^Citation26	IFX>ADAADA>IFX	72 (100)	72 (100)	—	2 (2.8)	—
Christensen et al (2015)^Citation33	IFX>ADA	33 (100)	33 (100)	12 weeks	6 (18.2)	15 (45.5)
Christensen et al (2015)^Citation33	IFX>ADA	33 (100)	33 (100)	12 months (52 weeks)	6 (18.2)	8 (24.2)
Peyrin-Biroulet et al (2007)^Citation56	IFX>ADA	10 (100)	10 (100)	—	1 (10)	3 (30)
Taxonera et al (2011)^Citation64	IFX>ADA	30 (100)	30 (100)	4 weeks	3 (10)	16 (53.3)
Taxonera et al (2011)^Citation64	IFX>ADA	30 (100)	30 (100)	12 weeks	8 (26.7)	18 (60)
Taxonera et al (2017)^Citation68	IFX/ADA>GOL	142 (100)	85 (59.9)	8 weeks	45 (52.9)	92 (64.7)
Taxonera et al (2017)^Citation68	IFX/ADA>GOL	142 (100)	85 (59.9)	12 months	50 (58.8)	—
Tursi et al (2014)^Citation71	IFX>ADA	15 (100)	15 (100)	24 weeks	11 (73.3)	—
Tursi et al (2014)^Citation71	IFX>ADA	15 (100)	15 (100)	54 weeks	15 (100)	—
Viola et al (2019)^Citation73	ADA/GOL>IFX	76 (100)	76 (100)	3 months	29 (38.2)	24 (31.6)
Viola et al (2019)^Citation73	ADA/GOL>IFX	76 (100)	76 (100)	6 months	29 (38.2)	14 (18.4)
Viola et al (2019)^Citation73	ADA/GOL>IFX	76 (100)	76 (100)	12 months	26 (34.2)	7 (9.2)
Stefanovic et al (2021)^Citation63	GOL>IFX	30 (100)	11 (36.7)	13 months (57 weeks)	9 (81.8)	—
Studies reporting on switching treatment MOA^b
Stefanovic et al (2021)^Citation63	GOL>VDZ	30 (100)	3 (10)	13 months (57 weeks)	3 (100)	—
Wang et al (2019)^Citation74	Anti-TNF>VDZ	5 (12.2)	5 (100)	6 months	5 (100)	—
Wang et al (2019)^Citation74	Anti-TNF>VDZ	5 (12.2)	5 (100)	12 months	5 (100)	—

Notes: ^aSwitching between anti-TNF agents. ^bSwitching between drugs with different mechanisms of action.

Abbreviations: Anti-TNF, tumor necrosis factor inhibitor; ADA, adalimumab; GOL, golimumab; IFX, infliximab; MOA, mechanism of action; UC, ulcerative colitis; VDZ, vedolizumab.

Cesarini M, Katsanos K, Papamichael K, et al. Dose optimization is effective in ulcerative colitis patients losing response to infliximab: a collaborative multicentre retrospective study. Dig Liver Dis. 2014;46(2):135–139. doi:10.1016/j.dld.2013.10.007

 PubMedGoogle Scholar

Kopylov U, Avni-Biron I, Ron Y, et al. Effectiveness and safety of vedolizumab for maintenance treatment in inflammatory bowel disease-The Israeli real world experience. Dig Liver Dis. 2019;51(1):68–74. doi:10.1016/j.dld.2018.07.040

 PubMedGoogle Scholar

Ma C, Huang V, Fedorak DK, et al. Outpatient ulcerative colitis primary anti-TNF responders receiving adalimumab or infliximab maintenance therapy have similar rates of secondary loss of response. J Clin Gastroenterol. 2015;49(8):675–682. doi:10.1097/MCG.0000000000000265

 PubMed Web of Science ®Google Scholar

Stefanovic S, Detrez I, Compernolle G, et al. Endoscopic remission can be predicted by golimumab concentrations in patients with ulcerative colitis treated with the changed label. Eur J Gastroenterol Hepatol. 2021;33(1):54–61. doi:10.1097/MEG.0000000000001843

 PubMed Web of Science ®Google Scholar

Yamada S, Yoshino T, Matsuura M, et al. Long-term efficacy of infliximab for refractory ulcerative colitis: results from a single center experience. BMC Gastroenterol. 2014;14:80. doi:10.1186/1471-230X-14-80

 PubMed Web of Science ®Google Scholar

Yamamoto-Furusho JK, Al Harbi O, Armuzzi A, et al. Incidence of suboptimal response to tumor necrosis factor antagonist therapy in inflammatory bowel disease in newly industrialised countries: the EXPLORE study. Dig Liver Dis. 2020;52(8):869–877. doi:10.1016/j.dld.2020.05.031

 PubMedGoogle Scholar

Chan W, Lynch N, Bampton P, et al. Entyvio lengthen dose-interval study: lengthening vedolizumab dose interval and the risk of clinical relapse in inflammatory bowel disease. Eur J Gastroenterol Hepatol. 2018;30(7):735–740. doi:10.1097/MEG.0000000000001150

 PubMed Web of Science ®Google Scholar

Danese S, Panaccione R, Peyrin-Biroulet L, et al. Dose adjustment in patients with moderate-to-severe ulcerative colitis: results from the UNIFI maintenance study long-term extension [abstract P448]. J Crohns Colitis. 2020;14(Suppl 1):S403. doi:10.1093/ecco-jcc/jjz203.577

 Google Scholar

Dignass A, Waller J, Cappelleri JC, et al. Living with ulcerative colitis in Germany: a retrospective analysis of dose escalation, concomitant treatment use and healthcare costs. J Med Econ. 2020;23(4):415–427. doi:10.1080/13696998.2019.1707210

 PubMed Web of Science ®Google Scholar

Fernández-Salazar L, Muñoz F, Barrio J, et al. Infliximab in ulcerative colitis: real-life analysis of factors predicting treatment discontinuation due to lack of response or colectomy: ECIA (ACAD Colitis and Infliximab Study). Scand J Gastroenterol. 2016;51(2):186–195. doi:10.3109/00365521.2015.1070900

 PubMed Web of Science ®Google Scholar

Harper JW, Sinanan MN, Zisman TL. Increased body mass index is associated with earlier time to loss of response to infliximab in patients with inflammatory bowel disease. Inflamm Bowel Dis. 2013;19(10):2118–2124. doi:10.1097/MIB.0b013e31829cf401

 PubMed Web of Science ®Google Scholar

Lindsay JO, Armuzzi A, Gisbert JP, et al. Indicators of suboptimal tumor necrosis factor antagonist therapy in inflammatory bowel disease. Dig Liver Dis. 2017;49(10):1086–1091. doi:10.1016/j.dld.2017.07.010

 PubMedGoogle Scholar

Perry C, Fischer K, Elmoursi A, et al. Vedolizumab dose escalation improves therapeutic response in a subset of patients with ulcerative colitis. Dig Dis Sci. 2021;66(6):2051–2058. doi:10.1007/s10620-020-06486-x

 PubMed Web of Science ®Google Scholar

Taxonera C, Estellés J, Fernández-Blanco I, et al. Adalimumab induction and maintenance therapy for patients with ulcerative colitis previously treated with infliximab. Aliment Pharmacol Ther. 2011;33(3):340–348. doi:10.1111/j.1365-2036.2010.04531.x

 PubMed Web of Science ®Google Scholar

Taxonera C, Olivares D, Mendoza JL, Díaz-Rubio M, Rey E. Need for infliximab dose intensification in Crohn’s disease and ulcerative colitis. World J Gastroenterol. 2014;20(27):9170–9177. doi:10.3748/wjg.v20.i27.9170

 PubMed Web of Science ®Google Scholar

Taxonera C, Iborra M, Bosca-Watts MM, et al. Early dose optimization of golimumab induces late response and long-term clinical benefit in moderately to severely active ulcerative colitis. Curr Med Res Opin. 2019;35(7):1297–1304. doi:10.1080/03007995.2019.1579557

 PubMed Web of Science ®Google Scholar

Tursi A, Elisei W, Picchio M, et al. Effectiveness of adalimumab for ambulatory ulcerative colitis patients after failure of infliximab treatment: a first “real-life” experience in primary gastroenterology centers in Italy. Ann Gastroenterol. 2014;27(4):369–373.

 PubMedGoogle Scholar

Tursi A, Elisei W, Faggiani R, et al. Effectiveness and safety of adalimumab to treat outpatient ulcerative colitis: a real-life multicenter, observational study in primary inflammatory bowel disease centers. Medicine. 2018;97(34):e11897. doi:10.1097/MD.0000000000011897

 PubMed Web of Science ®Google Scholar

Wang Y, Wang J, Pekow J, et al. Outcome of elective switching to vedolizumab in inflammatory bowel disease patients under tumor necrosis factor antagonist-maintained clinical remission. J Gastroenterol Hepatol. 2019;34(12):2090–2095. doi:10.1111/jgh.14751

 PubMed Web of Science ®Google Scholar

Honap S, Chee D, Chapman TP, et al. Real-world effectiveness of tofacitinib for moderate to severe ulcerative colitis: a multicentre UK experience. J Crohns Colitis. 2020;14(10):1385–1393. doi:10.1093/ecco-jcc/jjaa075

 PubMed Web of Science ®Google Scholar

Rubin DT, Dubinsky MC, Panés J, et al. Efficacy of tofacitinib dose escalation to 10 mg BID in patients with UC after completing maintenance therapy in remission and losing response: data from OCTAVE open-label, long-term extension study [abstract DOP75]. J Crohns Colitis. 2020;14(Suppl 1):S112–S113. doi:10.1093/ecco-jcc/jjz203.114

 Google Scholar

Sands BE, Moss AC, Armuzzi A, et al. Efficacy and safety of escalation to tofacitinib 10 mg Bid for patients with UC following loss of response on 5 mg BID maintenance therapy: results from OCTAVE open-label, long-term extension study [abstract DOP73]. J Crohns Colitis. 2020;14(Suppl 1):S110–S111. doi:10.1093/ecco-jcc/jjz203.112

 PubMedGoogle Scholar

Rostholder E, Ahmed A, Cheifetz AS, Moss AC. Outcomes after escalation of infliximab therapy in ambulatory patients with moderately active ulcerative colitis. Aliment Pharmacol Ther. 2012;35(5):562–567. doi:10.1111/j.1365-2036.2011.04986.x

 PubMed Web of Science ®Google Scholar

Taxonera C, Barreiro-de Acosta M, Calvo M, et al. Infliximab dose escalation as an effective strategy for managing secondary loss of response in ulcerative colitis. Dig Dis Sci. 2015;60(10):3075–3084. doi:10.1007/s10620-015-3735-4

 PubMed Web of Science ®Google Scholar

Taxonera C, Iglesias E, Muñoz F, et al. Adalimumab maintenance treatment in ulcerative colitis: outcomes by prior anti-TNF use and efficacy of dose escalation. Dig Dis Sci. 2017;62(2):481–490. doi:10.1007/s10620-016-4398-5

 PubMed Web of Science ®Google Scholar

Baert F, Vande Casteele N, Tops S, et al. Prior response to infliximab and early serum drug concentrations predict effects of adalimumab in ulcerative colitis. Aliment Pharmacol Ther. 2014;40(11–12):1324–1332. doi:10.1111/apt.12968

 PubMed Web of Science ®Google Scholar

Baki E, Zwickel P, Zawierucha A, et al. Real-life outcome of anti-tumor necrosis factor α in the ambulatory treatment of ulcerative colitis. World J Gastroenterol. 2015;21(11):3282–3290. doi:10.3748/wjg.v21.i11.3282

 PubMed Web of Science ®Google Scholar

Christensen KR, Steenholdt C, Brynskov J. Clinical outcome of adalimumab therapy in patients with ulcerative colitis previously treated with infliximab: a Danish single-center cohort study. Scand J Gastroenterol. 2015;50(8):1018–1024. doi:10.3109/00365521.2015.1019558

 PubMed Web of Science ®Google Scholar

Peyrin-Biroulet L, Laclotte C, Roblin X, Bigard MA. Adalimumab induction therapy for ulcerative colitis with intolerance or lost response to infliximab: an open-label study. World J Gastroenterol. 2007;13(16):2328–2332. doi:10.3748/wjg.v13.i16.2328

 PubMed Web of Science ®Google Scholar

Taxonera C, Rodríguez C, Bertoletti F, et al. Clinical outcomes of golimumab as first, second or third anti-TNF agent in patients with moderate-to-severe ulcerative colitis. Inflamm Bowel Dis. 2017;23(8):1394–1402. doi:10.1097/MIB.0000000000001144

 PubMed Web of Science ®Google Scholar

Viola A, Pugliese D, Renna S, et al. Outcome in ulcerative colitis after switch from adalimumab/golimumab to infliximab: a multicenter retrospective study. Dig Liver Dis. 2019;51(4):510–515. doi:10.1016/j.dld.2018.10.013

 PubMedGoogle Scholar