A few recent articles provide a lot of practical information regarding implementation of tofacitinib into treatment regimens for ulcerative colitis (UC).
- S Danese et al. Inflamm Bowel Dis 2018; 24: 2106–12. Review article on Tofacitinib.
- J-F Colombel. Inflamm Bowel Dis 2018; 24: 2173–80. Review article on Herpes Zoster due to JAK Inhibitors (eg Tofacitinib).
- KL Winthrop et al. Inflamm Bowel Dis 2018; 24: 2258-65. Clinical study detailing the risk of Herpes Zoster in patients with UC receiving Tofacitinib.
The first of these articles reviews the mechanism of action of tofacitinib (TFB) and the relevant studies showing efficacy for UC. A summary of the results are listed in Table 1. Some of the reported results –with TFB dosed at 10 mg BID:
- In 2012, Sandborn et al: clinical response in 61% at wk 8 and clinical remission of 48% at wk 8.
- In 2017 (OCTAVE Induction 1): clinical response in 18.5% at wk 8 and clinical remission of 31.3% at wk 8.
- In 2017 (OCTAVE Induction 2): clinical response in 16.6% at wk 8 and clinical remission of 28.4% at wk 8.
- In 2017 (OCTAVE Sustain):clinical response in 40.6% at wk 8 and clinical remission of 45.7% at wk 8.
- In all of these studies, TFB outperformed the placebo arm and has had a good safety profile
Most common adverse effects had similar rates in the placebo arm:
Other adverse effects have included pneumonia, herpes zoster (HZ) infection, and increased lipid levels (more common than with placebo group). Trials in patients with rheumatoid arthritis have indicated an increased incidence of nonmelanoma skin cancer, lymphoma, breast cancer, lung cancer, and gastric cancers.
Preclinical studies have shown that TFB could cause fetal malformations when given at much higher doses. Though, clinical experience in humans have not found teratogenic effects; this is based on one study with 9815 RA/psoriasis patients and 47 women who became pregnant.
Role for tofacitinib:
- “Tofacitinib could be used in patients suffering mild, moderate and severe UC…after aminosalicylates (5-ASA)…and as second-line therapy in patients who have been treated with TNF inhibitors.”
Advantages of tofacitinib:
- Oral administration with rapid absorption
- Short serum half-life
- Good experience in large number of patients with rheumatoid arthritis
- No immunogenicity.
- Effective in patients who have had previous anti-TNF agents
More on Herpes Zoster Infection:
- The other two references detail the risk of Herpes Zoster infections with TFB usage.
- Winthrop et al identified 65 (5.6%) of patients developed HZ among phase II/III open-label, long-term extension trials.
- The review by Colombel notes that patients with UC have “an increased risk of HZ compared with the general population, and this risk can be increase by the use of immunosuppressive therapy. JAK inhibitors, including tofacitinib, have been associated with HZ risk…The majority of HZ casees are noncomplicated.”
- In this review, Colombel details an algorithm for treatment of HZ cases and indicates that adults receiving TFB should consider vaccination to lower the risk of HZ.
My take: A significant portion of patients with UC either do not respond to anit-TNF agents or lose response. Tofacitinib provides an alternative treatment with a different mechanism of action. Given the few other non-surgical treatment options, I expect it will be rapidly incorporated into treatment algorithms.
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