High Dose Tofacitinib (Xeljanz) for Alopecia Areata: What do we need to tell our patients?

Tofacitinib Topping Twenty: Things to Think about when we go above 20 mg

Xeljanz (tofacitinib) is FDA approved for the treatment of adults with moderate to severe rheumatoid arthritis, active psoriatic arthritis, and moderate to severe ulcerative colitis. It is sometimes used by dermatologists as an off label treatment for alopecia areata. The typical doses in alopecia areata are 5 mg twice daily. For those patients who are only partial responders to the drug, a decision is sometimes made to increase doses to 15 and 20 mg and sometimes even higher (25 mg). Nowadays, with concerns about blood clots are 20 mg doses, it’s not common for physicians to go above 10 mg. Dosing to 15 mg is done on a case by case basis.

As with any drug, the potential for side effects often increases with higher doses of a medication.

Tofacitinib Side effects that may be greater at 20 mg than 10 mg

The following side effects of tofacitinib seem dose dependent - meaning that a greater proporiton of people using the drug are expected to experience these side effects at the higher doses compared to the lower doses.

1. Elevation in Cholesterol

2. Elevation in Creatinine

3. Herpes Zoster Infections

4. Serious Infections

5. Non-melanoma skin cancer

6. Blood clots

7. Reductions in circulating NK cells

Pulmonary Embolism (Blood Clots in the Lung): A Dose Dependent Side Effect

This week, the company Pfizer made an announcement that patients with rheumatoid arthritis who use higher doses of tofacitinib with their methotrexate may be at increased risk for pulmonary embolism (blood clots in the lungs).

READ REPORT: PFIZER ANNOUNCES HIGH DOSE TOFACITINIB CONCERNS

Pfizer reported an update from their study known as “ A392133” which is a study that allows surveillance of potential side effects in the years after the drug is launched to the public.

Study A3921133 was designed to evaluate the safety of tofacitinib at two doses (5 mg twice daily and 10 mg twice daily) and compare side effects to patients using a tumor necrosis factor inhibitor (TNFi). This study was designed to assess the risk of cardiovascular (CV) events. In this particular study, patients were required to be at least 50 years of age and have at least one CV risk factor to be eligible for participation in this study. All patients entered the study on stable doses of the immunosuppressive drug methotrexate.

The data safety monitoring board that oversees that study observed that patients treated with tofacitinib 10 mg twice daily had a statistically and clinically important difference in the occurrence of pulmonary embolism, compared with patients in this study who were treated with a TNFi. The DSMB also noted an increase in overall mortality in the 10 mg twice daily treatment group compared to the tofacitinib 5 mg twice daily and TNFi treatment arms.

As a result of this study, Pfizer took steps move rheumatoid arthritis study patients who were on tofacitinib 10 mg twice daily down to tofacitinib 5 mg twice daily.

High Dose Tofacitinib in Alopecia Areata

This update from the A3921133 study is important because it reminds us that as we increase the dose of any drug, we need to let patients know what side effects might be experienced on these higher doses compared to staying on the lower doses.

The patients in the A3921133 study were slightly older and had heart disease to begin with and were using methotrexate. When faced with a patient with alopecia areata who is older than 50 and has heart disease and is using methotrexate, it is most certainly apppropriate to advise them that increasing their tofacitinib dose from 10 mg to 20 mg might increase their chances of having a blood clot in the lung.

What we don’t know now is whether the typical patient with alopecia areata (who is generally very healthy) is at increased risk for a blood clot with higher doses of tofacitinib. Is that 21 year old very healthy college student who failed nearly every other drug we tried but who is doing amazing well now on 20 mg of tofacitinib placing themselves at increased risk for a blood clot? That we simply don’t know. Nevertheless, it is important that good studies and monitoring specifically in patients with alopecia areata be done. For now, it would at least be appropriate to keep this side effect on our radar.