Dose escalation and switching of biologics in ulcerative colitis: a systematic literature review in real-world evidence

Figures & data

Figure 1. PRISMA chart for the review on dose escalation and treatment switching in UC.

Table 1. Characteristics of identified studies.

Authors, year	Country	Full text or abstract	Study design	Study period	Methods of data collection	UC sample size (n)	Females/ males (n)	Age (mean or median y)
Afif et al. 2009^16	USA	Full text	Uncontrolled trial	8 November 2006–17 September 2007	Medical records	20	8/12	38
Alzafiri et al. 2011^17	Canada	Full text	Retrospective study	2000–2008	Database	26	14/12	38.4
Amiot et al. 2016^18	France	Full text	Multicenter, prospective study	June–December 2014	41 French centers	121	54/67	42.8
Angelison et al. 2014^19	Sweden	Abstract	Retrospective study	November 2004–December 2011	Local registries at 9 Swedish IBD centers	243	98/145	26.3
Armuzzi et al. 2013^20	Italy	Full text	Open-label retrospective study	April 2006–July 2011	22 Italian referral centers	88	53/35	27.7
Armuzzi et al. 2013^21	Italy	Abstract	Prospective study	NR	NR	40	24/16	37
Baert et al. 2014^22	Belgium	Full text	Retrospective study	July 2005–December 2012	Electronic charts of the patients	73	31/42	28.1
Baki et al. 2015^23	Germany	Full text	Uncontrolled, open-label retrospective	January 2011–February 2014	Electronic patient charts and medical records	72	39/33	33
Black et al. 2016^24	England	Full text	Retrospective study	1 January 2010–31 March 2014	Hospital Treatment Insights database/NHS Hospital Episode Statistics data	191	109/82	41
Bressler et al. 2016^25	Canada	Abstract	Retrospective study	August 2012–August 2015	Patient support program (PSP), BioAdvance	136	67/69	44.4
Cappello et al. 2013^26	Italy	Abstract	Retrospective multicenter study	January 2008–June 2012	Clinical records in 9 referral centers from Southern Italy	257	107/150	35.7
Cappello et al. 2014^27	Italy	Abstract	Retrospective multicenter study	January 2008–June 2012	11 centers from Southern Italy	160	61/99	35.5
Cesarini et al. 2014^28	Europe	Full text	Retrospective multicenter study	2009–2012	Database from participating institutions	41	11/30	46.6
Christensen et al. 2015^29	Denmark	Full text	Retrospective, observational study	Patients on ADL until February 2014	Danish inflammatory bowel disease center (Department of Gastroenterology, Herlev Hospital)	33	21/12	37
Daperno et al. 2016^30	Italy	Abstract	Prospective observational study	NR	Three institutions in Italy	54	NR	38.7
Dumitrescu et al. 2015^31	France	Full text	Retrospective study	January 2006–May 2013	Personal database and/or a standardized hospital in-patient diagnostic data set	157	73/84	37.6
Echarri et al. 2015^32	Spain	Abstract	Retrospective observational study	January 2011–April 2014	NR	21	NR	NR
Fernández-Salazar et al. 2015^33	Spain	Abstract	Observational study, retrospective	2003–2014	NR	144	NR	NR
Fernández-Salazar et al. 2014^34	Spain	Abstract	Multicentric and retrospective study	June 2003–September 2013	Four Spanish hospitals	88	37/51	35
Hatoum et al. 2014^35	US	Abstract	Retrospective cohort study	2005–2012	US Clinformatics administrative health claims database	587	283/304	42.8
Hudis et al. 2009^36	NR	Abstract	Retrospective study	NR	Tertiary referral center and an affiliated VA hospital	9	5/9	NR
Hussey et al. 2016^37	Ireland	Full text	Retrospective cross-sectional study	2007	IBD databases from two Trinity College Dublin affiliated hospitals centers	52	18/34	45
Iborra et al. 2016^38	Spain	Full text	Retrospective cohort study	1 year	The Spanish National Inflammatory Bowel Disease Study of Genetic and Environmental Factors database ENEIDA	263	Cohort 1 (TNF naive): 29/87	Cohort 1 (TNF naïve): 5/7
							Cohort 2 (non TNF naive): 75/176	Cohort 2 (non-TNF naïve): 7/2
Lindsay et al. 2016^39	Europe	Abstract	Retrospective, multicenter study	June 2009–June 2013	NR	538	253/285	42
Ladd et al. 2016^40	Liechtenstein	Abstract	Retrospective study	June 2014–August 2015	Medical records	15	Cohort 1 (VDZ 300 mg q4w): 5/7	Cohort 1 (VDZ 300 mg q4w): 38
							Cohort 2 (VDZ 300 mg q6w): 7/2	Cohort 2 (VDZ 300 mg q6w): 36
Naymagon et al. 2013^41	NR	Abstract	NR	1 January 2010–31 March 2013	Institutional database	58	NR	NR
Null et al. 2017^42	USA	Full text	Retrospective study	1 January 2007–31 December 2014	Humana Research Database (Louisville, KY)	295	149/146	50.9
Oussalah et al. 2010^43	NR	Abstract	Retrospective, multicenter study	January 2000–August 2009	NR	191	NR	NR
Patel et al. 2017^44	USA	Full text	Retrospective study	1 January 2005–31 December 2013	US commercial claims database	1699	866/833	47.5
Rostholder et al. 2012^45	USA	Full text	Retrospective study	2000–2009	EMR	56	26/30	41
Rubin et al. 2012^46	USA	Abstract	Retrospective study	2006–2010	US commercial claims database	21,371	NR	40–46
Salomonsson et al. 2015^47	Sweden	Abstract	Longitudinal, retrospective study	January 2010–April 2014	National Drug Registry and the National Patient Registry	587	NR	NR
Sandborn et al. 2015^48	USA	Full text	Retrospective study	October 2012–April 2014	Patient chart reviews	804	Cohort 1 (ADA): 162/218	Cohort 1 (ADA): 39
							Cohort 2 (IFX): 183/241	Cohort 2 (IFX): 39.3
Takada et al. 2016^49	Japan	Abstract	NR	June 2010–July 2015	NR	72	34/38	NR
Taxonera et al. 2017^50	Spain	Full text	Retrospective multicenter study	January 2013–September 2015	Data generated in routine clinical practice	142	70/72	46
Taxonera et al. 2014^51	Spain	Full text	Prospective, observational study	July 2008–January 2010	Data from the bowel disease unit	38	22/16	41.9
Taxonera et al. 2015^52	NR	Full text	Multicenter, retrospective study	October 2008–January 2012	14 IBD referral centers	79	38/41	46
Taxonera et al. 2017^53	Spain	Full text	Retrospective multicenter study	October 2011–January 2014	15 inflammatory bowel diseases (IBD) referral centers	184	NR	NR
Weil et al. 2016^54	Israel	Abstract	Retrospective cohort study	January 2010–December 2014	Maccabi Healthcare Services (MHS) database	204	110/94	36.1
Yamada et al. 2014^55	Japan	Full text	Retrospective study	January 2003–June 2013	Kyoto University Hospital medical records	33	13/20	43.2
Yoshimura et al. 2016^56	Japan	Abstract	Retrospective study	NR	NR	111	NR	NR

Abbreviations. NR, Not reported; n, Sample size; y, Years.

Table 2. Dose escalation outcomes in daily practice.

Authors, year	Drug	Sample (N)	DE patients (% or Indexed at DE)	Population included in the proportion of DE	Initial regime	Escalated regime	Follow-up period (y)	Time to escalation (mo or y)
Afif et al. 2009^16	ADA	20	35%	Everyone included at induction	40 mg q2w	40 mg q1w	tot time 0.46y	TDE 1.84 mo–3.68 mo
Amiot et al. 2016^18^,^57^,^a	VDZ	121	9.9%	Induction responders	300 mg q8w	300 mg q4w	tot time 1 y	TOA 1.4 mo
Amiot et al. 2016^18	VDZ	121	29.8%	Induction responders	300 mg q8w	300 mg q4w	tot time 1 y	TOA 3.2 mo
Amiot et al. 2016^18	VDZ	121	43%	Induction responders	300 mg q8w	300 mg q4w	tot time 1 y	TOA 5 mo
Amiot et al. 2016^18	VDZ	121	47.1%	Induction responders	300 mg q8w	300 mg q4w	tot time 1 y	TOA 6.9 mo
Amiot et al. 2016^18	VDZ	121	47.1%	Induction responders	300 mg q8w	300 mg q4w	tot time 1 y	TOA 1 y
Armuzzi et al. 2013^20	ADA	88	35.2%	Everyone included at induction	80 or 40 mg at wk2	80/40 mg q1w	Median 1.29 y	TOA Median 1.29 y
Armuzzi et al. 2013^21	IFX	40	15%	Patients in mucosal healing at maintenance	NR	NR	NR	TOA within y2
Baert et al. 2014^22	ADA	73	30.1%	Everyone included at induction	40 mg q1w	NR	Median 1.69 y	TDE Median 2.7 mo
Baki et al. 2015^23^,^b	IFX	54	48.1%	Everyone included at induction	NR	NR	Median 2.25 y	TDE Median 4 mo
Baki et al. 2015^23	ADA	37	45.9%	Everyone included at induction	NR	NR	Median 2.25 y	TDE Median 5 mo
Black et al. 2016^24	ADA	191	43.5%	Induction responders	NR	NR	NR	TDE Median 4.57 mo
Bressler et al. 2016^25	GOL	136	3.6%	Induction responders	100 mg q4w	NR	3 y	TOA 3 y
Cappello et al. 2013^26	IFX	257	15.2%	Induction responders	5 mg/kg	NR	Median 2.17 y	NR
Cappello et al. 2014^27	IFX	160	21.0%	Induction responders	5 mg/kg	NR	Median 2.33 y	NR
Cesarini et al. 2014^28	IFX	15	Indexed at DE	Patients with 2^nd LoR	5 mg/kg q8w	10 mg/kg q8w	tot time 1 y	NR
Cesarini et al. 2014^28	IFX	26	Indexed at DE	Patients with 2^nd LoR	5 mg/kg q8w	5 mg/kg q4–q6w	tot time 1 y	NR
Christensen et al. 2015^29	ADA	33	21.2%	Everyone included at induction	160–80–40 mg, or 80–40 mg q1w	40 mg q1w–q10 d or 80 mg q1w	Median 0.62 y	TOA Median 0.62 y
Daperno et al. 2016^30	ADA	54	50%	Everyone included at induction	5 mg/kg q8w	NR	Median 0.67 y	TOA Median 0.67 y
Dumitrescu et al. 2015^31	IFX	157	Indexed at DE	Patients with a 1st or 2nd LoR	5 mg/kg q6-7w	10 mg/kg q6–7w	Median 1.8 y (1.0–3.1)	TDE Median 6 mo
Echarri et al. 2015^32	IFX	21	71.4%	NR	NR	NR	NR	TOA 1 y
Fernández-Salazar et al. 2015^33	IFX	144	36.8%	Patients in response or remission at induction	NR	5 mg/kg q6w or 10mg/kg q8w	Median 3.17 y	TDE Mean 9 mo
Fernández-Salazar et al. 2015^33	IFX	144	25%	Patients in response or remission at induction	NR	5 mg/kg q6w	Median 3.17 y	TDE Mean 9.5 mo
Fernández-Salazar et al. 2015^33	IFX	144	5%	Patients in response or remission at induction	NR	10 mg/kg q8w	Median 3.17 y	TDE Mean 9mo
Fernández-Salazar et al. 2015^33	IFX	144	7%	Patients in response or remission at induction	NR	10 mg/kg q6w	Median 3.17 y	TDE Mean 6 mo
Fernández-Salazar et al. 2014^34	IFX	88	39.8%	Everyone included at induction	5 mg/kg q8w	10 mg/kg q8w and/or 5 mg/kg q4w	tot time 3.5 y	TOA 2.08 y
Hatoum et al. 2014^35	ADA	58	46.6%	Induction responders	NR	NR	Mean 2.75 y	TOA Mean 2.75 y
Hatoum et al. 2014^35	IFX	280	51.4%	Induction responders	NR	NR	Mean 2.75 y	TOA Mean 2.75 y
Hudis et al. 2009^36	ADA	7	42.9%	Everyone included at induction	NR	ADA 40mg q1w	NR	NR
Hussey et al. 2016^37	ADA	52	25%	Everyone included at induction	40 mg q2w	NR	tot time 1 y	TOA 12 mo
Iborra et al. 2016^38	ADA	263	35.4%	Everyone included at induction	NR	NR	tot time >1 y	TDE Mean 4.73 mo
Iborra et al. 2016^38	ADA	87	24%	Everyone included at induction	NR	NR	tot time >1 y	TDE Mean 4.73 mo
Iborra et al. 2016^38	ADA	176	41%	Everyone included at induction	NR	NR	tot time >1 y	TDE Mean 4.73 mo
Lindsay et al. 2016^39	anti-TNF	538	26%	Everyone included at induction	NR	NR	tot time 2 y	TOA 2 y
Ladd et al. 2016^40	VDZ	15	20%^c	Patients in response or remission at maintenance	300 mg q8w	300 mg q4w	NR	NR
Naymagon et al. 2013^41	IFX	58	13.8%	Everyone included at induction	NR	NR	tot time 3.25 y	TOA 0.46 mo
Oussalah et al. 2010^43	IFX	191	45%	Induction responders	NR	NR	NR	NR
Patel et al. 2017^44^,^d	anti-TNF	1699	1) 16%	Everyone included at induction	NR	NR	tot time 3 y	TOA 6 mo
Patel et al. 2017^44	anti-TNF	1699	2) 28%	Everyone included at induction	NR	NR	tot time 3 y	TOA 12 mo
Patel et al. 2017^44	anti-TNF	1699	3) 40%	Everyone included at induction	NR	NR	tot time 3 y	TOA 24 mo
Patel et al. 2017^44	anti-TNF	1699	4) 44%	Everyone included at induction	NR	NR	tot time 3 y	TOA 36 mo
Rostholder et al. 2012^45	IFX	50	54%	Induction responders	5 mg/kg q8w	10 mg/kg q8 w or 5 mg/kg q4–6 w	Mean 3.17 y	TDE Mean 0.92 y
Rubin et al. 2012^46	IFX	128	11.2%	Everyone included at induction	NR	NR	tot time 1 y	TOA 12 mo
Salomonsson et al. 2015^47	ADA	587	46.5%	Induction responders	NR	ADA 40qw	tot time 1 y	TDE Median 2.76 mo
Salomonsson et al. 2015^47	ADA	587	32.5%	Everyone included at induction	NR	≥50 mg	tot time 1 y	NR
Sandborn et al. 2015^48^,^e	ADA	380	5%	Everyone included at induction	NR	NR	tot time 1.5 y	TOA 6 mo
Sandborn et al. 2015^48	ADA	380	8%	Everyone included at induction	NR	NR	tot time 1.5 y	TOA 12 mo
Sandborn et al. 2015^48	ADA	380	13%	Everyone included at induction	NR	NR	tot time 1.5 y	TOA 18 mo
Sandborn et al. 2015^48	IFX	424	6%	Everyone included at induction	NR	NR	tot time 1.5 y	TOA 6 mo
Sandborn et al. 2015^48	IFX	424	11%	Everyone included at induction	NR	NR	tot time 1.5 y	TOA 12 mo
Sandborn et al. 2015^48	IFX	424	11%	Everyone included at induction	NR	NR	tot time 1.5 y	TOA 18 mo
Taxonera et al. 2014^51	IFX	38	42.1%	Induction responders	NR	NR	NR	TDE Median 6.6 mo
Taxonera et al. 2015^52	IFX	79	Indexed at DE	Patients with 2nd LoR	NR	NR	Median 1.25 y	TDE Median 9.2 mo
Taxonera et al. 2015^52	IFX	30	Indexed at DE	Patients with 2nd LoR	NR	10 mg/kg/q8w	Median 1.25 y	TDE Median 9.2 mo
Taxonera et al. 2015^52	IFX	21	Indexed at DE	Patients with 2nd LoR	NR	5 mg/kg/q4w	Median 1.25 y	TDE Median 9.2 mo
Taxonera et al. 2015^52	IFX	28	Indexed at DE	Patients with 2nd LoR	NR	5 mg/kg/q6w	Median 1.25 y	TDE Median 9.2 mo
Taxonera et al. 2017^53	ADA	184	41%	Induction responders	NR	NR	Median 1.91 y	TDE Median 4 mo
Taxonera et al. 2017^53	ADA	116	55.2%	Induction responders	ADA	NR	Median 1.91 y	TDE Median 5 mo
Taxonera et al. 2017^53	ADA	68	17.2%	Induction responders	ADA	NR	Median 1.91 y	TDE Median 6 mo
Taxonera et al. 2017^50	GOL	142	22%	Everyone included at induction	50/100 mg q4wk	100/200 mg q4wk	Median 1 y	TDE Median 5 mo
Weil et al. 2016^54	anti-TNF	204	8%	Everyone included at induction	NR	NR	tot time 1 y	NR
Yamada et al. 2014^55	IFX	24	70.8%	Induction responders	5 mg/kg q8w	10 mg/kg q8w or 5 mg/kg q4–6w	Median 3 y	TOA 8w

Abbreviations. Anti-TNF, Tumor necrosis factor antagonist; DE, Dose escalation; mo, Months; n, Sample size; LoR, Loss of response; NR, Not reported; qw, Every week; TDE, Time to dose escalation; TOA, Time of assessment; w, Week; y, Year; ADA, Adalimumab; GOL, Golimumab; IFX, Infliximab; VDZ, Vedolizumab; tot, Total time.

Studies by the same author mentioned more than once refer to different cohorts or subgroup analysis of patients who escalated at different times.

^a Rates of dose escalation were obtained from the updated study by Amiot et al. published in 2017⁵⁷.

^b Number of enrolled patients was 72: 35 patients received IFX, 17 underwent treatment with ADA, and 20 patients were on both medications consecutively (15 IFX first, 5 ADA first). Among patients receiving IFX therapy, information on dose escalation was missing for one patient.

^c Five out of 15 patients who responded to VDZ 300 mg q8w at week 14 had lost response and dose escalated which would explain the low rate of dose escalation.

^d The majority of patients were under anti-TNF with infliximab (68.4%), adalimumab (29.3%), golimumab (0.4%) and certolizumab (1.5%). The remaining non-anti-TNF agent used was natalizumab (0.4%).

^e The probabilities of dose escalation for ADA and IFX patients over time were obtained from unadjusted time-to-event analyses of dose escalation; however, a significant number of patients over 1 year discontinued treatment or were lost to follow up.

Figure 2. Percentage of patients with clinical response after dose escalation. Taxonera 2017 (ADA)⁵³, Taxonera 2017 (GOL)⁵⁰ , Cesarini 2014 (IFX)²⁸, Dumitrescu 2015 (IFX)³¹, Taxonera 2015 (IFX)⁵², Ladd 2016 (VDZ)⁴⁰.

Figure 3. Percentage of patients in clinical remission after dose escalation. Taxonera 2017 (ADA)⁵³, Cesarini 2014 (IFX)²⁸, Dumitrescu 2015 (IFX)³¹, Taxonera 2015 (IFX)⁵², Rostholder 2012 (IFX)⁴⁵, Yamada 2014 (IFX)⁵⁵.

Table 3. Treatment switching in daily clinical practice.

Authors, year	Sample (N)	Treatment sequence	Treatment switching (%)	Time at switch (y)
Alzafiri et al. 2011^17	26	IFX → ADA	3.8%	Median 5.16 y
Angelison et al. 2014^19	98	IFX → ADA	25.5%	Mean 3.3 y
Baki et al. 2015^23	72	IFX → ADA	21%	Median 2.25 y
Baki et al. 2015^23	21	ADA → IFX	7%	Median 2.25 y
Christensen et al. 2015^29	33	IFX → ADA	100%	At baseline
Hatoum et al. 2014^35	280	IFX → anti-TNF	15%	Mean 2.75 y
Hatoum et al. 2014^35	58	ADA → anti-TNF	7%	Mean 2.75 y
Lindsay et al. 2016^39	538	anti-TNF → anti-TNF	26%	2 y
Null et al. 2017^42	245	IFX → anti-TNF	4.5%	1 y
Patel et al. 2017^44	1699	anti-TNF → anti-TNF	2%	0.5 y
			6%	1 y
			10%	2 y
			11%	3 y
Sandborn et al. 2015^48	424	IFX → anti-TNF	3.3%, 58.2%, 100%	0.5 y, 1 y, 1.5 y
Sandborn et al. 2015^48	380	ADA → anti-TNF	3.6%	0.5 y
			63%	1 y
			100%	1.5 y
Takada et al. 2016^49	72	IFX → ADA	8.3%	0.17 y
Weil et al. 2016^54	204	anti-TNF → anti-TNF or VDZ	14%	1 y
Yoshimura et al. 2016^56	35	anti-TNF → ADA	40%	1 y
Yoshimura et al. 2016^56	76	anti-TNF → IFX	16%	1 y

Abbreviations. Anti-TNF, Tumor necrosis factor antagonist; n, Sample size; y, Year, ADA, Adlimumab; IFX, Infliximab; VDZ, Vedolizumab.

Figure 4. Percentage of patients with clinical response after switching Christensen 2015²⁹, Yoshimura 2016⁵⁶.

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