Tofacitinib: Janus Bifrons in Ulcerative Colitis Treatment

Abstract

Sandborn WJ, Ghosh S, Panes J, et al.; Study A3921063 Investigators. Tofacitinib, an oral Janus kinase inhibitor, in active ulcerative colitis. N Engl J Med 2012;367:616–624.Ulcerative colitis (UC) is a chronic and disabling condition. Our therapeutic armamentarium is still limited in patients with UC refractory to standard medications (Gut 2012;61:918–932). The advent of anti-tumor necrosis factor (TNF) agents (infliximab and adalimumab) has changed the way these patients are treated. However, less than one third of patients with UC who are administered infliximab or adalimumab will be in clinical remission at 1 year (Gastroenterology 2012;142:257–265), and secondary loss of response is relatively frequent with all anti-TNF agents. Hence, there is a need for more treatment options, especially for UC patients who have not responded to other treatments or for those who develop antibodies to current biologic treatments and have to discontinue use. Finally, available anti-TNF agents as large proteins are available only as parenteral agents, and a wider and prolonged use of these biologics may raise economic issues. Even though the UC drug pipeline now consists of multiple compounds, new biologics are still far from registration (Gut 2012;61:918–932).Most of biologics target 1 specific cytokine. The Janus Kinase (JAK) family of intracellular, nonreceptor protein tyrosine kinases, which includes JAK1, JAK2, JAK3 and tyrosine kinase 2 transduce signals from multiple type I and II cytokine receptors. Upon receptor activation, JAKs phosphorylate signal transducer and activator of transcription proteins that translocate to the nucleus and regulate the expression of numerous genes. This drives additional participation in the inflammatory response. They were initially named ”just another kinase” 1 and 2 (because they were just 2 of a large number of discoveries in a polymerase chain reaction-based screen of kinases). They were ultimately called “Janus Kinase” as 1 domain exhibits the kinase activity, whereas the other negatively regulates the kinase activity of the first. Tofacitinib (CP-690,550), formerly known as CP-690,550 and tasocitinib, is a selective oral inhibitor of JAK1 and JAK3 and, to a lesser extent, JAK2.In this paper, the results of an 8-week, randomized, controlled phase 2 trial of tofacitinib in moderately or severely active UC are reported (N Engl J Med 2012;367:616–624). This multicenter study was conducted from January 2009 through September 2010. Included patients were aged ≥18 years with a confirmed diagnosis of UC ≥3 months before enrollment, a score of 6–12 on the Mayo scale, and moderately or severely active disease on sigmoidoscopy. Patients were allowed oral mesalamine or oral prednisone at a stable dose of no more than 30 mg/d. The primary endpoint was clinical response at 8 weeks, defined as a decrease from baseline in the total Mayo score (an absolute decrease of ≥3 points and a relative decrease of ≥30% with an accompanying decrease in rectal bleeding subscore of ≥1 point or an absolute rectal bleeding subscore of 0 or 1). Patients were randomly assigned to oral tofacitinib 0.5 mg (n = 31), 3 mg (n = 33), 10 mg (n=33), 15 mg (n = 49), or placebo (n = 48), administered twice daily for 8 weeks, and were then followed for an additional 4 weeks.At 8 weeks, a clinical response occurred in 42% of patients receiving placebo (95% confidence interval [CI], 28–56) compared with 32% (95% CI, 16–66), 48% (95% CI, 31–66), 61% (95% CI, 44–77), and 78% (95% CI, 66–89) of patients receiving tofacitinib 0.5 mg, 3 mg, 10 mg, and 15 mg, respectively. The difference between placebo and tofacitinib was statistically significant for the 15-mg dose (P < .001). The study also analyzed several secondary endpoints. Clinical remission, defined as a total Mayo score of 0–2, with no individual subscore >1, was reported in 10% of those receiving placebo, compared with 13% receiving tofacitinib 0.5 mg, 33% receiving tofacitinib 3 mg (P = .01), 48% receiving tofacitinib 10 mg (P < .001) and 41% receiving tofacitinib 15 mg (P < .001). At 8 weeks, an endoscopic response (defined as a decrease from baseline in the endoscopy subscore by ≥1) occurred in 46% of patients receiving placebo, compared with 52% receiving tofacitinib 0.5 mg, 58% receiving tofacitinib 3 mg, 67% receiving tofacitinib 10 mg, and 78% receiving tofacitinib 15 mg (P = .001). Endoscopic remission at 8 weeks (defined as an endoscopy subscore of 0) occurred in 2% receiving placebo, compared with 10% receiving tofacitinib 0.5 mg, 18% receiving tofacitinib 0.5 mg (P = .01), 30% receiving tofacitinib 10 mg (P < .001), and 27% receiving tofacitinib 15 mg (P < .001).The most commonly reported adverse events related to infection were influenza and nasopharyngitis (in 6 patients each). Among patients receiving the 10-mg dose of tofacitinib, there were 2 serious infection-related adverse events: One a postoperative abscess and the other an anal abscess. Notably, there was a dose-dependent increase in both low-density and high-density lipoprotein cholesterol concentrations at 8 weeks with tofacitinib, which resolved after study drug discontinuation. Three patients receiving tofacitinib (one in the 10-mg group and 2 in the 15-mg group) had absolute neutrophil counts <1500 cells/m3; all were >1000 cells/m3. Tofacitinib was also associated with reductions in C-reactive protein and fecal calprotectin concentrations as well as improvements in the Inflammatory Bowel Disease Questionnaire score.Overall, tofacitinib 15 mg twice daily was associated with significant improvements in induction of a clinical response, as well as in clinical remission, endoscopic response and endoscopic remission. In conclusion, patients with moderately or severely active UC treated with tofacitinib had a clinical response and clinical remission more frequently than those receiving placebo.CommentRenal transplant clinical trials in humans have demonstrated tofacitinib to be noninferior to cyclosporine in terms of rejection rates and graft survival (Am J Transplant 2012;12:2446-2456). More recently, treatment with tofacitinib in clinical trials has demonstrated efficacy in autoimmune disorders such as psoriasis and rheumatoid arthritis (J Invest Dermatol 2009;129:2299-2302; Br J Dermatol 2012;167:668-677; N Engl J Med 2012;367:508-519; N Engl J Med 2012;367:495-507). Recently, the US Food and Drug Administration (FDA)-approved tofacitinib for treating adults with moderate to severe rheumatoid arthritis who experienced inadequate response to or cannot tolerate methotrexate. Tofacitinib, which is manufactured by Pfizer, has been given the brand name Xeljanz. It is the first FDA-approved Janus kinase inhibitor. The present clinical data strongly support the use of tofacitinib to produce sufficient immunosuppression to treat UC.Mechanisms of action of tofacitinib are partially understood. JAK3 is a tyrosine kinase mediating signal transduction activity involving the common gamma chain of the surface receptors for multiple cytokines (J Med Chem 2010;53:8468-8484). These cytokines are important for lymphocyte activation, function, and proliferation. Recently, tofacitinib has been shown to inhibit interleukin-2–dependent differentiation of type 2 and type 17 helper T cells, as well as lipopolysaccharide-induced innate immune responses in vitro (J Immunol 2011;186:4234-4243).Importantly, tofacitinib is not a biological agent but a conventional immunosuppressive drug. The benefits of available biologics are countered by some side effects, especially when used in combination with an immunomodulator (Am J Gastroenterol 2012;107:1051-1063). These side effects are caused mainly by the ubiquitous distribution of the target molecules of these treatments such as TNF. Tofacitinib is expected to overcome these limitations by targeting JAK, which are expressed only in immune cells.In a phase 1, randomized, dose escalation, double-blind study, enrolling 59 patients with psoriasis, each of the 6 CP-690,550 dosage cohorts (oral administration of 5, 10, 20, 30, and 50 mg 2 times daily [BID] and 60 mg once daily) had a concurrent, parallel, placebo control (J Invest Dermatol 2009;129:2299-2302). Total cholesterol in the 30- and 50-mg BID groups, low-density lipoprotein cholesterol in the 30-mg BID group, and triglycerides in the 50-mg BID group were elevated relative to placebo. All were mild except for moderate worsening psoriasis in 1 patient (J Invest Dermatol 2009;129:2299-2302). In a phase 2b, randomized, placebo-controlled, dose-ranging study enrolling 197 patients with psoriasis, the most frequently reported adverse events were infections and infestations, but at a similar rate than in the placebo arm (Br J Dermatol 2012;167:668-677). Dose-dependent increases from baseline in mean serum high-density lipoprotein, low-density lipoprotein, and total cholesterol, and decreases in hemoglobin and neutrophils were also observed (Br J Dermatol 2012;167:668-677).Two phase 3 trials enrolled a total of 1328 patients with rheumatoid arthritis (N Engl J Med 2012;367:508-519; N Engl J Med 2012;367:495-507). Similar to clinical trials in psoriasis, the most common serious tofacitinib-related adverse events were infection events (upper respiratory tract infections, herpes zoster, pulmonary tuberculosis). Tofacitinib was also associated an increase in both low-density and high-density cholesterol levels and with reductions in neutrophil counts (N Engl J Med 2012;367:508-519; N Engl J Med 2012;367:495-507).Overall, tofacitinib had a manageable safety profile and the majority of adverse events reported in clinical trials were mild to moderate in nature. Most patients could continue taking tofacitinib. However, because the drug may be associated with an increased risk of serious infections, including opportunistic infections, tuberculosis, cancers, and lymphoma, it carries a boxed warning regarding these safety risks. The FDA approved the drug with a Risk Evaluation and Mitigation Strategy, which consists of a Medication Guide advising patients about important safety information and a communication plan to inform health care providers about the serious risks associated with tofacitinib. The FDA also required a postmarketing study that will evaluate 2 doses of tofacitinib and include a group of patients on another approved treatment to serve as a comparison. In most of the trials, the rate of serious infections increased in the 10-mg groups compared with the 5-mg groups. Therefore, the recommended dosage of tofacitinib is 5 mg taken twice daily in rheumatoid arthritis. The effects of tofacitinib on lipid profiles are still not completely understood, whereas the infectious events might be explained by cytopenia and the effects on immune cells related to JAK inhibition.Since the introduction of biologic therapies into the treatment paradigm of UC, there has been hope that oral small molecule immune modulators would be developed that would have a risk:benefit profile at least similar to biologic therapies, be more convenient for the patient and, hopefully, be less expensive.Tofacitinib could become the Janus bifrons of UC treatment. Janus Bifrons was a Roman god with 2 faces, one looking at the past and one looking at the future. Similarly, tofacitinib could be the transition from the past targeting 1 single cytokine, to the future, blocking multiple cytokines at the same time, JAK-3 acting as a hub for multiple inflammatory cytokine-signaling pathways. Whether tofacitinib could herald the beginning of a new generation of safe and effective drugs in UC awaits confirmation in phase 3 trials. Sandborn WJ, Ghosh S, Panes J, et al.; Study A3921063 Investigators. Tofacitinib, an oral Janus kinase inhibitor, in active ulcerative colitis. N Engl J Med 2012;367:616–624. Ulcerative colitis (UC) is a chronic and disabling condition. Our therapeutic armamentarium is still limited in patients with UC refractory to standard medications (Gut 2012;61:918–932). The advent of anti-tumor necrosis factor (TNF) agents (infliximab and adalimumab) has changed the way these patients are treated. However, less than one third of patients with UC who are administered infliximab or adalimumab will be in clinical remission at 1 year (Gastroenterology 2012;142:257–265), and secondary loss of response is relatively frequent with all anti-TNF agents. Hence, there is a need for more treatment options, especially for UC patients who have not responded to other treatments or for those who develop antibodies to current biologic treatments and have to discontinue use. Finally, available anti-TNF agents as large proteins are available only as parenteral agents, and a wider and prolonged use of these biologics may raise economic issues. Even though the UC drug pipeline now consists of multiple compounds, new biologics are still far from registration (Gut 2012;61:918–932). Most of biologics target 1 specific cytokine. The Janus Kinase (JAK) family of intracellular, nonreceptor protein tyrosine kinases, which includes JAK1, JAK2, JAK3 and tyrosine kinase 2 transduce signals from multiple type I and II cytokine receptors. Upon receptor activation, JAKs phosphorylate signal transducer and activator of transcription proteins that translocate to the nucleus and regulate the expression of numerous genes. This drives additional participation in the inflammatory response. They were initially named ”just another kinase” 1 and 2 (because they were just 2 of a large number of discoveries in a polymerase chain reaction-based screen of kinases). They were ultimately called “Janus Kinase” as 1 domain exhibits the kinase activity, whereas the other negatively regulates the kinase activity of the first. Tofacitinib (CP-690,550), formerly known as CP-690,550 and tasocitinib, is a selective oral inhibitor of JAK1 and JAK3 and, to a lesser extent, JAK2. In this paper, the results of an 8-week, randomized, controlled phase 2 trial of tofacitinib in moderately or severely active UC are reported (N Engl J Med 2012;367:616–624). This multicenter study was conducted from January 2009 through September 2010. Included patients were aged ≥18 years with a confirmed diagnosis of UC ≥3 months before enrollment, a score of 6–12 on the Mayo scale, and moderately or severely active disease on sigmoidoscopy. Patients were allowed oral mesalamine or oral prednisone at a stable dose of no more than 30 mg/d. The primary endpoint was clinical response at 8 weeks, defined as a decrease from baseline in the total Mayo score (an absolute decrease of ≥3 points and a relative decrease of ≥30% with an accompanying decrease in rectal bleeding subscore of ≥1 point or an absolute rectal bleeding subscore of 0 or 1). Patients were randomly assigned to oral tofacitinib 0.5 mg (n = 31), 3 mg (n = 33), 10 mg (n=33), 15 mg (n = 49), or placebo (n = 48), administered twice daily for 8 weeks, and were then followed for an additional 4 weeks. At 8 weeks, a clinical response occurred in 42% of patients receiving placebo (95% confidence interval [CI], 28–56) compared with 32% (95% CI, 16–66), 48% (95% CI, 31–66), 61% (95% CI, 44–77), and 78% (95% CI, 66–89) of patients receiving tofacitinib 0.5 mg, 3 mg, 10 mg, and 15 mg, respectively. The difference between placebo and tofacitinib was statistically significant for the 15-mg dose (P < .001). The study also analyzed several secondary endpoints. Clinical remission, defined as a total Mayo score of 0–2, with no individual subscore >1, was reported in 10% of those receiving placebo, compared with 13% receiving tofacitinib 0.5 mg, 33% receiving tofacitinib 3 mg (P = .01), 48% receiving tofacitinib 10 mg (P < .001) and 41% receiving tofacitinib 15 mg (P < .001). At 8 weeks, an endoscopic response (defined as a decrease from baseline in the endoscopy subscore by ≥1) occurred in 46% of patients receiving placebo, compared with 52% receiving tofacitinib 0.5 mg, 58% receiving tofacitinib 3 mg, 67% receiving tofacitinib 10 mg, and 78% receiving tofacitinib 15 mg (P = .001). Endoscopic remission at 8 weeks (defined as an endoscopy subscore of 0) occurred in 2% receiving placebo, compared with 10% receiving tofacitinib 0.5 mg, 18% receiving tofacitinib 0.5 mg (P = .01), 30% receiving tofacitinib 10 mg (P < .001), and 27% receiving tofacitinib 15 mg (P < .001). The most commonly reported adverse events related to infection were influenza and nasopharyngitis (in 6 patients each). Among patients receiving the 10-mg dose of tofacitinib, there were 2 serious infection-related adverse events: One a postoperative abscess and the other an anal abscess. Notably, there was a dose-dependent increase in both low-density and high-density lipoprotein cholesterol concentrations at 8 weeks with tofacitinib, which resolved after study drug discontinuation. Three patients receiving tofacitinib (one in the 10-mg group and 2 in the 15-mg group) had absolute neutrophil counts <1500 cells/m3; all were >1000 cells/m3. Tofacitinib was also associated with reductions in C-reactive protein and fecal calprotectin concentrations as well as improvements in the Inflammatory Bowel Disease Questionnaire score. Overall, tofacitinib 15 mg twice daily was associated with significant improvements in induction of a clinical response, as well as in clinical remission, endoscopic response and endoscopic remission. In conclusion, patients with moderately or severely active UC treated with tofacitinib had a clinical response and clinical remission more frequently than those receiving placebo. CommentRenal transplant clinical trials in humans have demonstrated tofacitinib to be noninferior to cyclosporine in terms of rejection rates and graft survival (Am J Transplant 2012;12:2446-2456). More recently, treatment with tofacitinib in clinical trials has demonstrated efficacy in autoimmune disorders such as psoriasis and rheumatoid arthritis (J Invest Dermatol 2009;129:2299-2302; Br J Dermatol 2012;167:668-677; N Engl J Med 2012;367:508-519; N Engl J Med 2012;367:495-507). Recently, the US Food and Drug Administration (FDA)-approved tofacitinib for treating adults with moderate to severe rheumatoid arthritis who experienced inadequate response to or cannot tolerate methotrexate. Tofacitinib, which is manufactured by Pfizer, has been given the brand name Xeljanz. It is the first FDA-approved Janus kinase inhibitor. The present clinical data strongly support the use of tofacitinib to produce sufficient immunosuppression to treat UC.Mechanisms of action of tofacitinib are partially understood. JAK3 is a tyrosine kinase mediating signal transduction activity involving the common gamma chain of the surface receptors for multiple cytokines (J Med Chem 2010;53:8468-8484). These cytokines are important for lymphocyte activation, function, and proliferation. Recently, tofacitinib has been shown to inhibit interleukin-2–dependent differentiation of type 2 and type 17 helper T cells, as well as lipopolysaccharide-induced innate immune responses in vitro (J Immunol 2011;186:4234-4243).Importantly, tofacitinib is not a biological agent but a conventional immunosuppressive drug. The benefits of available biologics are countered by some side effects, especially when used in combination with an immunomodulator (Am J Gastroenterol 2012;107:1051-1063). These side effects are caused mainly by the ubiquitous distribution of the target molecules of these treatments such as TNF. Tofacitinib is expected to overcome these limitations by targeting JAK, which are expressed only in immune cells.In a phase 1, randomized, dose escalation, double-blind study, enrolling 59 patients with psoriasis, each of the 6 CP-690,550 dosage cohorts (oral administration of 5, 10, 20, 30, and 50 mg 2 times daily [BID] and 60 mg once daily) had a concurrent, parallel, placebo control (J Invest Dermatol 2009;129:2299-2302). Total cholesterol in the 30- and 50-mg BID groups, low-density lipoprotein cholesterol in the 30-mg BID group, and triglycerides in the 50-mg BID group were elevated relative to placebo. All were mild except for moderate worsening psoriasis in 1 patient (J Invest Dermatol 2009;129:2299-2302). In a phase 2b, randomized, placebo-controlled, dose-ranging study enrolling 197 patients with psoriasis, the most frequently reported adverse events were infections and infestations, but at a similar rate than in the placebo arm (Br J Dermatol 2012;167:668-677). Dose-dependent increases from baseline in mean serum high-density lipoprotein, low-density lipoprotein, and total cholesterol, and decreases in hemoglobin and neutrophils were also observed (Br J Dermatol 2012;167:668-677).Two phase 3 trials enrolled a total of 1328 patients with rheumatoid arthritis (N Engl J Med 2012;367:508-519; N Engl J Med 2012;367:495-507). Similar to clinical trials in psoriasis, the most common serious tofacitinib-related adverse events were infection events (upper respiratory tract infections, herpes zoster, pulmonary tuberculosis). Tofacitinib was also associated an increase in both low-density and high-density cholesterol levels and with reductions in neutrophil counts (N Engl J Med 2012;367:508-519; N Engl J Med 2012;367:495-507).Overall, tofacitinib had a manageable safety profile and the majority of adverse events reported in clinical trials were mild to moderate in nature. Most patients could continue taking tofacitinib. However, because the drug may be associated with an increased risk of serious infections, including opportunistic infections, tuberculosis, cancers, and lymphoma, it carries a boxed warning regarding these safety risks. The FDA approved the drug with a Risk Evaluation and Mitigation Strategy, which consists of a Medication Guide advising patients about important safety information and a communication plan to inform health care providers about the serious risks associated with tofacitinib. The FDA also required a postmarketing study that will evaluate 2 doses of tofacitinib and include a group of patients on another approved treatment to serve as a comparison. In most of the trials, the rate of serious infections increased in the 10-mg groups compared with the 5-mg groups. Therefore, the recommended dosage of tofacitinib is 5 mg taken twice daily in rheumatoid arthritis. The effects of tofacitinib on lipid profiles are still not completely understood, whereas the infectious events might be explained by cytopenia and the effects on immune cells related to JAK inhibition.Since the introduction of biologic therapies into the treatment paradigm of UC, there has been hope that oral small molecule immune modulators would be developed that would have a risk:benefit profile at least similar to biologic therapies, be more convenient for the patient and, hopefully, be less expensive.Tofacitinib could become the Janus bifrons of UC treatment. Janus Bifrons was a Roman god with 2 faces, one looking at the past and one looking at the future. Similarly, tofacitinib could be the transition from the past targeting 1 single cytokine, to the future, blocking multiple cytokines at the same time, JAK-3 acting as a hub for multiple inflammatory cytokine-signaling pathways. Whether tofacitinib could herald the beginning of a new generation of safe and effective drugs in UC awaits confirmation in phase 3 trials. Renal transplant clinical trials in humans have demonstrated tofacitinib to be noninferior to cyclosporine in terms of rejection rates and graft survival (Am J Transplant 2012;12:2446-2456). More recently, treatment with tofacitinib in clinical trials has demonstrated efficacy in autoimmune disorders such as psoriasis and rheumatoid arthritis (J Invest Dermatol 2009;129:2299-2302; Br J Dermatol 2012;167:668-677; N Engl J Med 2012;367:508-519; N Engl J Med 2012;367:495-507). Recently, the US Food and Drug Administration (FDA)-approved tofacitinib for treating adults with moderate to severe rheumatoid arthritis who experienced inadequate response to or cannot tolerate methotrexate. Tofacitinib, which is manufactured by Pfizer, has been given the brand name Xeljanz. It is the first FDA-approved Janus kinase inhibitor. The present clinical data strongly support the use of tofacitinib to produce sufficient immunosuppression to treat UC. Mechanisms of action of tofacitinib are partially understood. JAK3 is a tyrosine kinase mediating signal transduction activity involving the common gamma chain of the surface receptors for multiple cytokines (J Med Chem 2010;53:8468-8484). These cytokines are important for lymphocyte activation, function, and proliferation. Recently, tofacitinib has been shown to inhibit interleukin-2–dependent differentiation of type 2 and type 17 helper T cells, as well as lipopolysaccharide-induced innate immune responses in vitro (J Immunol 2011;186:4234-4243). Importantly, tofacitinib is not a biological agent but a conventional immunosuppressive drug. The benefits of available biologics are countered by some side effects, especially when used in combination with an immunomodulator (Am J Gastroenterol 2012;107:1051-1063). These side effects are caused mainly by the ubiquitous distribution of the target molecules of these treatments such as TNF. Tofacitinib is expected to overcome these limitations by targeting JAK, which are expressed only in immune cells. In a phase 1, randomized, dose escalation, double-blind study, enrolling 59 patients with psoriasis, each of the 6 CP-690,550 dosage cohorts (oral administration of 5, 10, 20, 30, and 50 mg 2 times daily [BID] and 60 mg once daily) had a concurrent, parallel, placebo control (J Invest Dermatol 2009;129:2299-2302). Total cholesterol in the 30- and 50-mg BID groups, low-density lipoprotein cholesterol in the 30-mg BID group, and triglycerides in the 50-mg BID group were elevated relative to placebo. All were mild except for moderate worsening psoriasis in 1 patient (J Invest Dermatol 2009;129:2299-2302). In a phase 2b, randomized, placebo-controlled, dose-ranging study enrolling 197 patients with psoriasis, the most frequently reported adverse events were infections and infestations, but at a similar rate than in the placebo arm (Br J Dermatol 2012;167:668-677). Dose-dependent increases from baseline in mean serum high-density lipoprotein, low-density lipoprotein, and total cholesterol, and decreases in hemoglobin and neutrophils were also observed (Br J Dermatol 2012;167:668-677). Two phase 3 trials enrolled a total of 1328 patients with rheumatoid arthritis (N Engl J Med 2012;367:508-519; N Engl J Med 2012;367:495-507). Similar to clinical trials in psoriasis, the most common serious tofacitinib-related adverse events were infection events (upper respiratory tract infections, herpes zoster, pulmonary tuberculosis). Tofacitinib was also associated an increase in both low-density and high-density cholesterol levels and with reductions in neutrophil counts (N Engl J Med 2012;367:508-519; N Engl J Med 2012;367:495-507). Overall, tofacitinib had a manageable safety profile and the majority of adverse events reported in clinical trials were mild to moderate in nature. Most patients could continue taking tofacitinib. However, because the drug may be associated with an increased risk of serious infections, including opportunistic infections, tuberculosis, cancers, and lymphoma, it carries a boxed warning regarding these safety risks. The FDA approved the drug with a Risk Evaluation and Mitigation Strategy, which consists of a Medication Guide advising patients about important safety information and a communication plan to inform health care providers about the serious risks associated with tofacitinib. The FDA also required a postmarketing study that will evaluate 2 doses of tofacitinib and include a group of patients on another approved treatment to serve as a comparison. In most of the trials, the rate of serious infections increased in the 10-mg groups compared with the 5-mg groups. Therefore, the recommended dosage of tofacitinib is 5 mg taken twice daily in rheumatoid arthritis. The effects of tofacitinib on lipid profiles are still not completely understood, whereas the infectious events might be explained by cytopenia and the effects on immune cells related to JAK inhibition. Since the introduction of biologic therapies into the treatment paradigm of UC, there has been hope that oral small molecule immune modulators would be developed that would have a risk:benefit profile at least similar to biologic therapies, be more convenient for the patient and, hopefully, be less expensive. Tofacitinib could become the Janus bifrons of UC treatment. Janus Bifrons was a Roman god with 2 faces, one looking at the past and one looking at the future. Similarly, tofacitinib could be the transition from the past targeting 1 single cytokine, to the future, blocking multiple cytokines at the same time, JAK-3 acting as a hub for multiple inflammatory cytokine-signaling pathways. Whether tofacitinib could herald the beginning of a new generation of safe and effective drugs in UC awaits confirmation in phase 3 trials.