LIMA, Camila Cunha Gonzaga; QUEIROZ, Natália Sousa Freitas; SOBRADO, Carlos Walter; SILVA, Gustavo Luís Rodela; NAHAS, Sérgio Carlos

doi:10.1590/S0004-2803.202000000-59

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ORIGINAL ARTICLE • Arq. Gastroenterol. 57 (03) • Jul-Sep 2020 • https://doi.org/10.1590/S0004-2803.202000000-59 copiar

Análise crítica do uso dos anti-TNF na era dos novos agentes biológicos na doença inflamatória intestinal

Autoria SCIMAGO INSTITUTIONS RANKINGS

RESUMO

CONTEXTO:

As doenças inflamatórias intestinais (DII), tanto a doença de Crohn (DC) como a retocolite ulcerativa (RCU), são doenças crônicas imunomediadas que se apresentam com períodos de surto e remissão e requerem terapia a longo prazo. A terapia com anti-fator de necrose tumoral (anti-TNF) tem mudado o manejo da doença reduzindo a necessidade de hospitalizações, cirurgias e melhorando a qualidade de vida dos pacientes.

OBJETIVO:

O objetivo do presente trabalho é apresentar uma revisão sobre a importância dos agentes anti-TNF no contexto da DII, levando em consideração situações em que essas drogas são usadas como terapia de primeira linha.

MÉTODOS:

Revisão narrativa baseada nas melhores evidências disponíveis na literatura através de buscas feitas nas bases de dados MedLine e PubMed até abril de 2020, utilizando as seguintes palavras chaves: “doença inflamatória intestinal’’, “agentes anti-TNF” e “terapia biológica”.

CONCLUSÃO:

A terapia biológica permanece sendo fundamental no tratamento da DII. Na ausência de estudos “head-to-head’’ comparando os biológicos entre si, a escolha do agente biológico pode ser um desafio na prática clínica e múltiplas variáveis devem ser levadas em consideração. Os agentes anti-TNF devem ser considerados terapia de primeira linha em situações específicas como na colite ulcerativa aguda grave, na doença de Crohn fistulizante e nas manifestações extra-intestinais da doença inflamatória intestinal, uma vez que há evidências científicas robustas que sustentam a sua eficácia e segurança nessas situações.

DESCRITORES:
Doenças inflamatórias intestinais; Fator de necrose tumoral alfa, antagonistas & inibidores; Terapia biológica; Doença de Crohn, tratamento farmacológico; Colite ulcerativa, tratamento farmacológico

Trial (year)	Design; n	Population	Primary outcome	Follow-up duration	Medication	Results
Targan et al.⁵5. Targan SR, Hanauer SB, Deventer SJV, Mayer L, Present DH, Braakman T, et al. A Short-Term Study of Chimeric Monoclonal Antibody cA2 to Tumor Necrosis Factor α for Crohns Disease. N Engl J Med. 1997;337:1029-36. (1997)	Multicenter, double-blind, placebo-controlled RCT. n=108	Patients with moderate to severe CD refractory to 5-ASA and steroids.	Reduction of CDAI ≥70 points after 4 weeks of single induction dose.	12 weeks		Clinical response (week 4)
					Placebo (n=25)	17%
					IFX 5 mg/kg (n=27)	81%
					IFX 10 mg/kg (n=28)	50%
					IFX 20 mg/kg (n=28)	64%

CLASSIC I⁶6. Hanauer SB, Sandborn WJ, Rutgeerts P, Fedorak RN, Lukas M, Macintosh D, et al. Human Anti-Tumor Necrosis Factor Monoclonal Antibody (Adalimumab) in Crohn’s Disease: the CLASSIC-I Trial. Gastroenterology. 2006;130:323-33. (2006)	Multicenter, double-blind, placebo-controlled RCT. n=299	Patients with moderate to severe CD naive to anti-TNF therapy.	Clinical remission (CDAI <150) at week 4 after initial induction therapy.	4 weeks		Clinical remission (week 4)
					Placebo (n=74)	12%
					ADA 40 mg/ 20 mg (n=74)	18%
					ADA 80 mg/ 40 mg (n=75)	24%
					ADA 160 mg/ 80 mg (n=76)	36%

ACCENT I⁷7. Hanauer SB, Feagan BG, Lichtenstein GR, Mayer LF, Schreiber S, Colombel JF, et al. Maintenance infliximab for Crohns disease: the ACCENT I randomised trial. The Lancet. 2002;359:1541-9. (2002)	Multicenter, double-blind, randomized controlled RCT. n=335	Patients with luminal CD that responded to a single infusion of IFX within 2 weeks.	Clinical remission (defined as a CDAI score <150) at week 30.	54 weeks		Clinical remission (week 30)
					Placebo (n=110)	21%
					IFX 5 mg/kg (n=113)	39%
					IFX 10 mg/kg (n=112)	45%

Schnitzler et al.⁸8. Schnitzler F, Fidder H, Ferrante M, Noman M, Arijs I, Assche GV, et al. Long-term outcome of treatment with infliximab in 614 patients with Crohns disease: results from a single-centre cohort. Gut. 2008;58:492-500. (2009)	Single centre, real-life cohort. n=614	CD patients (treated for luminal, perianal or extraintestinal manifestations).	Assess the patients with initial response to IFX who had sustained clinical benefit at the end of follow-up.	55 months		Clinical response (week 10)
					IFX 5 mg/kg - single dose (n=432)	87.7%
					IFX 5 mg/kg 0, 2 and 6 (n=182)	92.3%

Present et al.¹⁰10. Present DH, Rutgeerts P, Targan S, Hanauer SB, Mayer L, Hogezand RV, et al. Infliximab for the Treatment of Fistulas in Patients with Crohns Disease. N Engl J Med . 1999;340:1398-405. (1999)	Randomized, multicenter, double-blind, placebo-controlled RCT. n=94	Patients who had draining abdominal or perianal fistulas of at least three months’ duration.	Reduction of ≥50% from base line in the number of draining fistulas.	18 weeks		Achieved primary endpoint
					Placebo (n=31)	26%
					IFX 5 mg/kg (n=31)	68%
					IFX 10 mg/kg (n=32)	56%

ACCENT II¹¹11. Sands BE, Anderson FH, Bernstein CN, Chey WY, Feagan BG, Fedorak RN, et al. Infliximab Maintenance Therapy for Fistulizing Crohns Disease. N Engl J Med . 2004;350:876-85. (2004)	Multicenter, double-blind, randomized, placebo-controlled. n=306	Patients with CD and one or more fistulas, with active drainage, abdominal or perianal, of at least three months duration.	Time to loss of response during follow-up among patients who had a response at week 14 and were randomized.	54 weeks		Absence of draining fistulas (week 54)
					Placebo	19%
					IFX 5 mg/kg	36%
						Median time to loss of response
					Placebo	14 weeks
					IFX 5 mg/kg	>40 weeks

CHARM¹²12. Colombel JF, Sandborn WJ, Rutgeerts P, Enns R, Hanauer SB, Panaccione R, et al. Adalimumab for Maintenance of Clinical Response and Remission in Patients With Crohn’s Disease: The CHARM Trial. Gastroenterology. 2007;132:52-65. (2007)	Multicenter, randomized, double-blind, placebo-controlled. n=854	Patients with moderate to severe luminal and fistulizing CD for at least 4 months.	Percentage of randomized responders who achieved clinical remission (CDAI <150) at weeks 26 and 56.	56 weeks		Clinical remission at week
						26	56
					Placebo (n=170)	17%	12%
					ADA 40mg w (n=157)	47%	41%
					ADA 40mg eow (n=172)	40%	36%
						Complete fistula closure at week
						26	56
					Placebo (n=47)	13%	13%
					ADA-treated patients (n=70)	30%	33%

Regueiro et al.¹³13. Swoger JM, Regueiro M. Preventive therapy in postoperative Crohn’s disease. Current Opinion in Gastroenterology. 2010;26:337-43. (2009)	Randomized, double-blind, placebo-controlled RCT. n=24	Patients with CD who had undergone ileocolonic resection and were allocated to receive intravenous IFX or placebo administered within 4 weeks of surgery and continued for 1 year.	Proportion of patients with endoscopic recurrence at 1 year after surgery.	1 year		Endoscopic recurrence (1 year)
					Placebo (n=13)	84.6%
					IFX 5 mg/kg (n=11)	9.1%

PREVENT¹⁷17. Regueiro M, Feagan BG, Zou B., Johanns J, Blank MA, Chevrier M, et al. Infliximab reduces endoscopic, but not clinical, recurrence of Crohn’s disease after ileocolonic resection. Gastroenterology. 2016;150(7). (2016)	Multicenter, randomized, double-blind, placebo-controlled RCT. n=297	Patients with CD which had undergone ileocolonic resection within 45 days before randomization.	Clinical recurrence prior to or at week 76 and evidence of endoscopic recurrence.	76 weeks		Endoscopic recurrence (≤76 weeks)
					Placebo (n=150)	60.0%
					IFX 5 mg/kg (n=147)	30.6%

POCER¹⁸18. Cruz PD, Kamm MA, Hamilton AL, Ritchie KJ, Krejany EO, Gorelik A, et al. Crohns disease management after intestinal resection: a randomised trial. The Lancet . 2015;385:1406-17. (2015)	Part of multicenter, randomized, double-blind, placebo-controlled RCT. n=101	Patients with CD undergoing intestinal resection of all macroscopic disease, with an endoscopically accessible anastomosis.	Presence and severity of endoscopic recurrence 6 months after surgery.	6 months	Colonoscopy at 6 month post-operatively	Endoscopic recurrence
					Thiopurine (n=62)	39%
					ADA 160/80 (followed by 40 mg eow) (n=24)	13%

Savarino et al.¹⁹19. Savarino E, Bodini G, Dulbecco P, Assandri L, Bruzzone L, Mazza F, et al. Adalimumab Is More Effective Than Azathioprine and Mesalamine at Preventing Postoperative Recurrence of Crohn’s Disease: A Randomized Controlled Trial. Am J Gastroenterol. 2013;108:1731-42. (2013)	Randomized, prospective, three-armed, unblended. n=51	Patients with ileal or ileocolonic CD undergoing resection to receive after 2 weeks from surgery ADA, AZA or Mesalamine.	Proportion of patients with endoscopic and clinical recurrence at 2 years after surgery.	2 years		Endoscopic recurrence
					ADA 160/80 mg (followed by 40 mg eow) (n=16)	6.3%
					AZA 2 mg/kg/day (n=17)	64.7%
					Mesalamine 3g/day (n=18)	83.3%

Trial (year)	Design; n	Population	Primary outcome	Follow-up duration	Medication	Results
ACT 1²⁰20. Rutgeerts P, Sandborn WJ, Feagan BG, Reinisch W, Olson A, Johanns J, et al. Infliximab for Induction and Maintenance Therapy for Ulcerative Colitis. N Engl J Med . 2005;353:2462-76. (2005)	Multicenter, randomized,	Patients with moderate-to-severe active ulcerative colitis despite treatment with concurrent medications.	Clinical response at week 8 and secondarily, clinical response or remission and mucosal healing at weeks 8, 30, and 54.	54 weeks		Clinical response at week
						8	54
					Placebo (n=121)	37.2%	19.8%
					IFX 5 mg/kg (n=121)	69.4 %	45.5%
					IFX 10 mg/kg (n=122)	61.5 %	44.3%

ACT 2²⁰20. Rutgeerts P, Sandborn WJ, Feagan BG, Reinisch W, Olson A, Johanns J, et al. Infliximab for Induction and Maintenance Therapy for Ulcerative Colitis. N Engl J Med . 2005;353:2462-76. (2005)	Multicenter, randomized, double-blind, placebo- controlled RCT. n=364	Patients with moderate-to-severe active ulcerative colitis despite treatment with concurrent medications.	Clinical response at week 8 and secondarily, clinical response or remission and mucosal healing at weeks 8 and 30.	30 weeks		Clinical response at week
						8	30
					Placebo (n=123)	29.3%	26.0%
					IFX 5 mg/kg (n=121)	64.5 %	47.1%
					IFX 10 mg/kg (n=120)	69.2 %	60.0%

ULTRA I²¹21. Reinisch W, Sandborn WJ, Hommes DW, Dhaens G, Hanauer S, Schreiber S, et al. Adalimumab for induction of clinical remission in moderately to severely active ulcerative colitis: results of a randomised controlled trial. Gut. 2011;60:780-7. (2011)	Multicenter, randomized, double-blind, placebo-controlled RCT. n=390	Anti-TNF naıve patients with moderate-to-severe active ulcerative colitis.	Clinical remission at week 8 after initial induction therapy.	8 weeks		Clinical response (week 8)
					Placebo (n=130)	9.2%
					ADA 80/40 (followed by 40 mg EOW) (n=130)	10.0%
					ADA 160/80 (followed by 40 mg EOW ) (n=130)	18.5%

SERENE- UC²²22. Colombel JF, Panés J, D’Haens G, Schreiber S, Panaccione R, Peyrin-Biroulet L, et al. OP01 Higher vs. standard adalimumab maintenance regimens in patients with moderately to severely active ulcerative colitis: Results from the SERENE-UC maintenance study. J Crohns Colitis. 2020; 14(Suppl 1):S001-S001. (2019)	Multicenter, randomized, double-blind. n=852	Patients with moderate-to-severe active ulcerative colitis.	Clinical remission at week 8.	8 weeks		Clinical remission (week 8)
					ADA 160 mg at week 0, 80 mg at week 2 (followed by 40 mg eow) (n=340)	10.9%
					ADA 160 mg at weeks 0, 1, 2, and 3 (followed by 40 mg EOW) (n=512)	13.3%

ULTRA 2²³23. Sandborn WJ, Assche GV, Reinisch W, Colombel JF, Dhaens G, Wolf DC, et al. Adalimumab Induces and Maintains Clinical Remission in Patients With Moderate-to-Severe Ulcerative Colitis. Gastroenterology. 2012;142(2). (2012)	Multicenter, randomized, double-blind, placebo-controlled RCT. n=494	Patients with moderate-to-severe ulcerative colitis who received concurrent treatment with oral corticosteroids or immunosuppressants.	Clinical remission at week 8 and week 52 after initial induction therapy.	52 weeks		Clinical remission at week
						8	52
					Placebo (n=246)	9.3%	8.5%
					ADA160/80 (followed by 40 mg EOW) (n=248)	16.5 %	17.3%

Tursi et al.²⁴24. Tursi A, Elisei W, Faggiani R, Allegretta L, Valle ND, Forti G, et al. Effectiveness and safety of adalimumab to treat outpatient ulcerative colitis. Medicine. 2018;97(34). (2018)	Real-life, multicenter, retrospective, observational. n=107	Patients with ulcerative colitis unresponsive to standard treatments and treated with ADA.	Induction and maintenance of remission in UC, defined as Mayo score ≤2.	24 months		Clinical remission (at 3-month)
					ADA160/80 (followed by 40 mg EOW)	54.9%

PURSUIT-M²⁵25. Sandborn WJ, Feagan BG, Marano C, Zhang H, Strauss R, Johanns J, et al. Subcutaneous Golimumab Maintains Clinical Response in Patients With Moderate-to-Severe Ulcerative Colitis. Gastroenterology. 2014;146(1). (2014)	Multicenter, randomized, double-blind, placebo-controlled RCT. n=464	Patients with moderate-to-severe ulcerative colitis who responded to induction therapy with GOL.	Clinical response maintained through week 54.	54 weeks		Clinical remission (week 54)
					Placebo (n=156)	31.2%
					GOL 50 mg every 4 weeks (n=154)	47.0%
					GOL 100 mg every 4 weeks (n=154)	49.7%

Sands et al.²⁷27. Sands BE, Tremaine WJ, Sandborn WJ, Rutgeerts PJ, Hanauer SB, Mayer L, et al. Infliximab in the Treatment of Severe, Steroid-Refractory Ulcerative Colitis: A Pilot Study. Inflammatory Bowel Diseases. 2001;7:83-8. (2001)	Randomized, double-blind, placebo-controlled RCT. n=11	Severe ulcerative colitis for at least 2 weeks and receiving at least 5 days of intravenous corticosteroids.	Treatment failure at 2 weeks after infusion.	10 weeks		Treatment success (week 2)
					Placebo (n=3)	0%
					IFX 5 mg/kg (n=3)	66.7%
					IFX 10mg/kg (n=3)	33.3%
					IFX 20mg/kg (n=2)	50.0%

Järnerot et al.²⁸28. Järnerot G, Hertervig E, Friis-Liby I, Blomquist L, Karlén P, Grännö C, et al. Infliximab as Rescue Therapy in Severe to Moderately Severe Ulcerative Colitis: A Randomized, Placebo-Controlled Study. Gastroenterology. 2005;128:1805-11. (2005)	Randomized, double-blind, placebo-controlled RCT. n=45	Patients with an acute severe or moderately severe ulcerative colitis that did not respond quickly to intravenous corticosteroids.	Colectomy or death 3 months after randomization.	6 months		Colectomy rates (90 days after)
					Placebo (n=21)	67%
					IFX 5 mg/kg (n=24)	29%

Gustavsson et al.²⁹29. Gustavsson A, Järnerot G, Hertervig E, Friis-Liby I, Blomquist L, Karlén P, et al. Clinical trial: colectomy after rescue therapy in ulcerative colitis - 3-year follow-up of the Swedish-Danish controlled infliximab study. Aliment Pharmacol Ther . 2010;32:984-9. (2010)	Randomized, double-blind, placebo-controlled RCT. n=45	patients with an acute severe or moderately severe ulcerative colitis that did not respond quickly to intravenous corticosteroids.	Determine the number of patients escaping a colectomy at follow-up.	3 years		Colectomy rates (3 years after)
					Placebo (n=21)	76%
					IFX 5 mg/kg (n=24)	50%

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[1] Corresponding author: Camila Cunha Gonzaga Lima. E-mail: cacunhag@gmail.com