Inflammatory Bowel Disease (IBD), consisting of Crohn’s Disease (CD) or Ulcerative Colitis (UC), is an immune-mediated lifelong disease. In addition to biologics, 5-aminosalicylates, corticosteroids, antibiotics, immune modulators are used for the treatment of IBD. Biologics are necessary for refractory IBD to conventional therapy. In last decades, new biologics have been, and are being developed and explored rapidly in different target molecules, including Tumor Necrosis Factor alpha (TNFa). The aim of this mini-review is to summarize the biologics.

Tajima A (2014) Biologics for the Treatment of Inflammatory Bowel Disease (IBD). JSM Gastroenterol Hepatol 2(3): 1025.

Inflammatory Bowel Disease (IBD) , Crohn’s Disease (CD) , Ulcerative Colitis (UC) , Biologics

IBD: Inflammatory Bowel Disease; CD: Crohn’s Disease; UC: Ulcerative Colitis; TNFα: Tumor Necrosis Factor alpha; CDAI: Crohn’s Disease Activity Index; IL: Interleukin; JAK: Janus Kinase

Inflammatory Bowel Disease (IBD), consisting of Crohn’s Disease (CD) or Ulcerative Colitis (UC), is an immunemediated lifelong disease, and is refractory in some patients. Corticosteroids (prednisone, budesonide), immune modulators (azathioprine, mercaptopurine, and methotrexate), antibiotics (metronidazole, tinidazole, ciprofloxacin, and clarithromycin), 5-aminosalicylates (mesalamine, sulfasalazine, and olsalazine), in addition to biologics, are currently used for the treatment of IBD [1]. During last decades, new biologics have been, and are being developed and explored rapidly in different target molecules, including Tumor Necrosis Factor alpha (TNFα) [1-26]. Some of biologics can also be used for rheumatoid arthritis and psoriasis [27,28]. The aim of this mini-review is to summarize biologics in the treatment of IBD, using Pubmed with key words; Crohn’s disease, ulcerative colitis, biologics, infliximab, adalimumab, certolizumab, golimumab, natalizumab, MLN02, vedolizumab, ustekinumub, secukinumab, AMG 827, to facitinib, and abatacept. In this mini-review, adverse events of biologics were not highlighted.

Anti–Tumor Necrosis Factor Alpha Inhibitors

TNF α promotes the inflammatory response in various diseases including CD, UC, rheumatoid arthritis, ankylosing spondylitis, and psoriasis. Symptoms of these disorders improve upon therapy with TNFα inhibitors. Four anti-TNFα molecules are used currently to treat IBD: infliximab, adalimumab, certolizumab pegol, and golimumab (Table 1) [29]. For the treatment of CD, Hanauer SB et al concluded that patients with CD who respond to an initial dose of in fliximab are more likely to be in remission at weeks 30 and 54, to discontinue corticosteroids, and to maintain their response for a longer period of time, if in fliximab treatment is maintained every 8 weeks [2]. Patients with fistulizing CD who are responsive to infliximab induction therapy have an increased likelihood of a sustained response over a 54-week period if infliximab treatment is continued every 8 weeks [3]. Patients with moderate-to-severe CD who were treated with infliximab plus azathioprine or infliximab monotherapy were more likely to have a corticosteroid-free clinical remission than those receiving azathioprine monotherapy [4]. For the treatment of UC, Rutgeerts P et al concluded that patients with moderate-to-severe active UC treated with infliximab at weeks 0, 2, and 6 and every eight weeks thereafter were more likely to have a clinical response at weeks 8, 30, and 54 than were those receiving placebo [5]. A key question is whether we should use anti-TNFα with immunomodulator. Panaccione R et al addressed this point as follows; anti–TNFα– naïve patients with moderate to severe UC treated with infliximab plus azathioprine were more likely to achieve corticosteroid-free remission at 16 weeks than those receiving either monotherapy. Combination therapy led to significantly better mucosal healing than azathioprine monotherapy [30]. Another key question is whether we should use anti-TNFα as early treatment. Walters TD et al reported at this point, recently. In children newly diagnosed with comparably severe CD, early monotherapy with anti-TNFα produced better overall clinical and growth outcomes at 1 year than early monotherapy with an immunomodulator [31].

Using adalimumab, four major studies were reported for the treatment of CD. Hanauer SB et al concluded that adalimumab was superior to placebo for induction of remission in patients with moderate to severe CD naïve to anti-TNFα therapy. The optimal induction dosing regimen for adalimumab was 160 mg at week 0 followed by 80 mg at week 2 [6]. Clinical remission induction and maintenance with adalimumab for moderate to severe CD without anti-TNFα was reported [7]. Adalimumab responsive patients had more clinical remission than placebo in CD with adalimumab [8]. Sandborn W et al concluded that adalimumab induces remissions more frequently than placebo in adult patients with CD who cannot tolerate infliximab or have symptoms despite receiving infliximab therapy [9]. Infliximab responsive pediatric patients were more likely to be in clinical response and remission when their maintenance therapy was given every 8 weeks rather than every 12 weeks [10]. More children who received high compared with low dose adalimumab were in remission at week 26, but the difference between dose groups was not statistically significant [11]. In terms of UC treatment, Feagan BG et al reported that in patients with moderate to severe UC, the addition of adalimumab to standard of care treatment reduced the number of hospitalizations for any cause, as well as for UC-related and UC- or drug-related complications, compared with placebo [12].

With certolizumab pegol, PRECISE-1 and PRECISE-2 were major studies [13,14]. In CD patients, induction and maintenance therapy with certolizumab pegol was associated with a modest improvement in response rates, but significant improvement in remission rates was not shown [13]. Certolizumab pegol responsive patients with CD were more likely to have a maintained response and a remission with continued certolizumab pegol treatment than with a switch to placebo [14].

In 2014, two studies using golimumab for the treatment of UC have been reported. Sandborn WJ et al concluded that treatment with subcutaneous golimumab induces clinical response, remission, and mucosal healing, and increases quality of life in larger percentages of patients with active UC than placebo [15]. Golimumab responsive patients with UC who received 100 mg golimumab had clinical remission and mucosal healing at weeks 30 and 54 [16].

Selective anti-adhesion molecules

Chronic inflammation could be decreased by the following mechanism; agents that block interactions between adhesion molecules on circulating immune cells and their endothelial cell receptors would be expected to decrease the migration of these cells through the endothelium [29]. Natalizumab, a humanized monoclonal antibody against α4 integrin, inhibits leukocyte adhesion and migration into inflamed tissue (Table 2) [1]. Induction therapy with natalizumab for CD showed only clinical response. Natalizumab responsive patients had significantly increased rates of sustained response and remission if natalizumab was continued every four weeks [1]. Targan SR et al concluded that natalizumab induced response and remission at week 8 through week 12. Response and remission rates for natalizumab were superior to those for placebo at weeks 4 through12, demonstrating the early and sustained efficacy of natalizumab as induction therapy in active CD [17]. Use of natalizumab in CD patients has been limited by the development of progressive multifocal leukoencephalopathy [18].

Vedolizumab, a humanized immunoglobulin G1 monoclonalantibody to α4 β7 integrin, modulates gut, but not brain, lymphocyte trafficking and therefore should theoretically be less likely to confer a predisposition to progressive multifocal leukoencephalopathy [18]. Sandborn WJ et al concluded that vedolizumab-treated patients with active CD were more likely than patients receiving placebo to have a remission, but not a Crohn’s Disease Activity index (CDAI)-100 response, at week 6; patients with a response to induction therapy who continued to receive vedolizumab (rather than switching to placebo) were more likely to be in remission at week 52 [18]. For UC, Feagan BG et al reported that vedolizumab was more effective than placebo as induction and maintenance therapy for UC [19].

MLN02, a humanized antibody to the α4 β7 integrin, was more effective than placebo for the induction of clinical and endoscopic remission in patients with active ulcerative colitis [20]. 

Anti-Interleukins

Interleukin (IL)-12 and IL-23 have been implicated in the pathogenesis of CD [29]. TNFα resistant patients with CD had an increased rate of response to induction with ustekinumab, a human monoclonal antibody against IL-12 and IL-23. Ustekinumab responsive patients had significantly increased rates of response and remission with ustekinumab as maintenance therapy (Table 3) [21]. Ustekinumab induced a clinical response in patients with moderate-to-severe CD, especially in patients previously given infliximab [22].

Data obtained in animal models of inflammatory bowel disease suggest involvement of IL-17 in CD pathogenesis, and overexpression of IL-17 was observed in intestinal tissue from patients with active CD [23]. However, blockade of IL-17A was ineffective compared with placebo for the treatment of active CD. [23].

Janus kinases

Tofacitinib (CP-690,550) is a selective oral inhibitor of the Janus Kinase (JAK) family of kinases, including JAK1 and JAK3, a tyrosine kinase that mediates signal-transduction activity involving the common gamma chain of the surface receptors for multiple cytokines, including ILs 2, 4, 7, 9, 15, and 21. These cytokines are integral to lymphocyte activation, function, and proliferation (Table 4) [24]. Tofacitinib had no significant treatment effect within 4 weeks on clinical endpoints measured by CDAI in patients with active CD [25]. Patients with moderately to severely active UC treated with tofacitinib were more likely to have clinical response and remission than those receiving placebo [24].

Co stimulation modulator

T cells are believed to play a role in the pathogenesis of CD and UC; thus, therapies targeting T cells are highlighted. T-cell activation requires co-stimulatory signaling via T cell CD28 and CD80 or CD86 on the antigen-presenting cell. Abatacept is a recombinant fusion protein comprising a fragment of the Fc domain of human IgG1 and the extracellular domain of human cytotoxic T-lymphocyte antigen 4 (Table 5) [26]. Sand born WJ et al reported the studies using abatacept for CD and UC. The studies showed that abatacept is not efficacious for the treatment of moderate-to-severe CD or UC [26].

Table 1: Anti–tumor necrosis factor alpha inhibitors.

Biologics are necessary for refractory IBD to conventional therapy. In last decades, new biologics have been, and are being developed and explored rapidly in different target molecules, including TNFα. Unfortunately, some of new biologics did not work well. In this mini-review, biologics for the treatment of IBD were summarized. Further studies upon the efficacy of other biologics are waiting. The treatment of IBD is still challenging.

1. Sandborn WJ, Colombel JF, Enns R, Feagan BG, Hanauer SB, Lawrance IC, et al. Natalizumab induction and maintenance therapy for Crohn’s disease. N Engl J Med. 2005; 353: 1912-1925.

2. Hanauer SB, Feagan BG, Lichtenstein GR, Mayer LF, Schreiber S, Colombel JF, et al. Maintenance infliximab for Crohn’s disease: the ACCENT I randomised trial. Lancet. 2002; 359: 1541-1549.

3. Sands BE, Anderson FH, Bernstein CN, Chey WY, Feagan BG, Fedorak RN, et al. Infliximab maintenance therapy for fistulizing Crohn’s disease. N Engl J Med. 2004; 350: 876-885.

4. Colombel JF, Sandborn WJ, Reinisch W, Mantzaris GJ, Kornbluth A, Rachmilewitz D, et al. Infliximab, azathioprine, or combination therapy for Crohn’s disease. N Engl J Med. 2010; 362: 1383-1395.

5. 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: 2462-2476.

6. 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: 323-333.

7. Sandborn WJ, Hanauer SB, Rutgeerts P, Fedorak RN, Lukas M, MacIntosh DG, et al. Adalimumab for maintenance treatment of Crohn’s disease: results of the CLASSIC II trial. Gut. 2007; 56: 1232- 1239.

8. 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.

9. Sandborn WJ, Rutgeerts P, Enns R, Hanauer SB, Colombel JF, Panaccione R, et al. Adalimumab induction therapy for Crohn disease previously treated with infliximab: a randomized trial. Ann Intern Med. 2007; 146: 829-838.

10. Hyams J, Crandall W, Kugathasan S, Griffiths A, Olson A, Johanns J, et al. Induction and maintenance infliximab therapy for the treatment of moderate-to-severe Crohn’s disease in children. Gastroenterology. 2007; 132: 863-873.

11. Hyams JS, Griffiths A, Markowitz J, Baldassano RN, Faubion WA Jr, Colletti RB, et al. Safety and efficacy of adalimumab for moderate to severe Crohn’s disease in children. Gastroenterology. 2012; 143: 365- 374.

12. Feagan BG, Sandborn WJ, Lazar A, Thakkar RB, Huang B, Reilly N, et al. Adalimumab therapy is associated with reduced risk of hospitalization in patients with ulcerative colitis. Gastroenterology. 2014; 146: 110- 118.

13. Sandborn WJ, Feagan BG, Stoinov S, Honiball PJ, Rutgeerts P, Mason D, et al. Certolizumab pegol for the treatment of Crohn’s disease. N Engl J Med. 2007; 357: 228-238.

14. Schreiber S, Khaliq-Kareemi M, Lawrance IC, Thomsen OØ, Hanauer SB, McColm J, et al. Maintenance therapy with certolizumab pegol for Crohn’s disease. N Engl J Med. 2007; 357: 239-250.

15. Sandborn WJ, Feagan BG, Marano C, Zhang H, Strauss R, Johanns J, et al. Subcutaneous golimumab induces clinical response and remission in patients with moderate-to-severe ulcerative colitis. Gastroenterology. 2014; 146: 85-95.

16. 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: 96-109.

17. Targan SR, Feagan BG, Fedorak RN, Lashner BA, Panaccione R, Present DH, et al. Natalizumab for the treatment of active Crohn’s disease: results of the ENCORE Trial. Gastroenterology. 2007; 132: 1672-1683.

18. Sandborn WJ, Feagan BG, Rutgeerts P, Hanauer S, Colombel JF, Sands BE, et al. Vedolizumab as induction and maintenance therapy for Crohn’s disease. N Engl J Med. 2013; 369: 711-721.

19. Feagan BG, Rutgeerts P, Sands BE, Hanauer S, Colombel JF, Sandborn WJ, et al. Vedolizumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2013; 369: 699-710.

20. Feagan BG, Greenberg GR, Wild G, Fedorak RN, Paré P, McDonald JW, et al. Treatment of ulcerative colitis with a humanized antibody to the alpha4beta7 integrin. N Engl J Med. 2005; 352: 2499-2507.

21. Sandborn WJ, Gasink C, Gao LL, Blank MA, Johanns J, Guzzo C, et al. Ustekinumab induction and maintenance therapy in refractory Crohn’s disease. N Engl J Med. 2012; 367: 1519-1528.

22. Sandborn WJ, Feagan BG, Fedorak RN, Scherl E, Fleisher MR, Katz S, et al. A randomized trial of Ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with moderate-to-severe Crohn’s disease. Gastroenterology. 2008; 135: 1130-1141.

23. Hueber W, Sands BE, Lewitzky S, Vandemeulebroecke M, Reinisch W, Higgins PD, et al. Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn’s disease: unexpected results of a randomised, double-blind placebo-controlled trial. Gut. 2012; 61: 1693-1700.

24. Sandborn WJ, Ghosh S, Panes J, Vranic I, Su C, Rousell S, et al. Study A3921063 Investigators. Tofacitinib, an oral Janus kinase inhibitor, in active ulcerative colitis. N Engl J Med. 2012; 367: 616-624.

25. Sandborn WJ, Ghosh S, Panes J, Vranic I, Spanton J, Niezychowski W. Phase 2 Randomized Study of CP-690,550, an Oral Janus Kinase Inhibitor, in Active Crohn’s Disease. Gastroenterology. 2011; 140: S124.

26. Sandborn WJ, Colombel JF, Sands BE, Rutgeerts P, Targan SR, Panaccione R, et al. Abatacept for Crohn’s disease and ulcerative colitis. Gastroenterology. 2012; 143: 62-69.

27. Lipsky PE, van der Heijde DM, St Clair EW, Furst DE, Breedveld FC, Kalden JR, et al. Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group. N Engl J Med. 2000; 343: 1594-1602.

28. Griffiths CE, Strober BE, van de Kerkhof P, Ho V, Fidelus-Gort R, Yeilding N, et al. Comparison of ustekinumab and etanercept for moderate-to-severe psoriasis. N Engl J Med. 2010; 362: 118-128. 29.Rutgeerts P, Vermeire S, Van Assche G. Biological therapies for inflammatory bowel diseases. Gastroenterology. 2009; 136: 1182- 1197.

30. Panaccione R, Ghosh S, Middleton S, Márquez JR, Scott BB, Flint L, et al. Combination therapy with infliximab and azathioprine is superior to monotherapy with either agent in ulcerative colitis. Gastroenterology. 2014; 146: 392-400.

31. Walters TD, Kim MO, Denson LA, Griffiths AM, Dubinsky M, Markowitz J, et al. Increased effectiveness of early therapy with anti-tumor necrosis factor-α vs an immunomodulator in children with Crohn’s disease. Gastroenterology. 2014; 146: 383-391.