Combination Therapy with Steroids, Tacrolimus, and Rituximab

Introduction to Combination Therapy

The American College of Physicians and other medical societies recommend that steroids, tacrolimus, and rituximab can be given together, but dose reduction of the immunosuppressants should be strongly considered to minimize infection risk and other adverse effects from cumulative immunosuppression 1

In pemphigus vulgaris, rituximab has been successfully used with concomitant corticosteroids and immunosuppressants (including tacrolimus) in 79-97% of cases, with NHS England approving rituximab for pemphigus that has failed steroids plus adjuvant immunosuppressants like azathioprine or mycophenolate 2, 3

When combining these agents, adjuvant immunosuppressive drugs should be continued but dose reduction is strongly recommended to decrease infection risk, according to the American College of Physicians 1

Tacrolimus doses should be reduced to 2-3 mg/day (targeting trough levels of 6 ng/mL) when adding rituximab, rather than standard doses of 4-6 mg/day, as recommended by the European Association for the Study of the Liver 4

Patients with advanced age, diabetes, or other comorbidities that impair immune function require more aggressive dose reduction or closer monitoring, according to the American Geriatrics Society and the American Diabetes Association 1
Patients with impaired renal function require dose reduction or avoidance of tacrolimus to minimize toxicity risk, as recommended by the National Kidney Foundation 1
Patients with a history of recurrent infections require more aggressive dose reduction or closer monitoring, according to the Infectious Diseases Society of America 1

Complete blood count should be performed every 2-4 weeks initially after starting rituximab, and liver and renal function tests should be performed regularly, as recommended by the American College of Physicians 1
Tacrolimus trough levels should be monitored (target 6 ng/mL when combined with rituximab), according to the European Association for the Study of the Liver 4
Hepatitis B screening should be performed before rituximab initiation, as reactivation can be fatal, as recommended by the Centers for Disease Control and Prevention 5

The combination of rituximab and tacrolimus dramatically increases infection risk beyond any single agent alone, and vaccinations should be completed before starting rituximab whenever possible, according to the American College of Physicians and the Centers for Disease Control and Prevention 1
Tacrolimus should be temporarily discontinued if serious infection develops requiring antibiotics, as continuing immunosuppression during active infection increases mortality risk, as recommended by the Infectious Diseases Society of America 1
Consider Pneumocystis prophylaxis when using triple immunosuppression, particularly in patients with additional risk factors, according to the Centers for Disease Control and Prevention 5

This combination is particularly justified in refractory autoimmune disease that has failed conventional dual therapy (steroids plus one immunosuppressant), as recommended by the British Society for Rheumatology and the American College of Rheumatology 2, 3