Tofacitinib

• Rheumatoid Arthritis
• Psoriatic Arthritis
• Ulcerative Colitis
• Ankylosing Spondylitis

Tofacitinib (brand names Xeljanz and Xeljanz XR) is an oral Janus kinase (JAK) inhibitor used to treat moderate-to-severe rheumatoid arthritis, psoriatic arthritis, ulcerative colitis, ankylosing spondylitis, and polyarticular course juvenile idiopathic arthritis. As a small molecule given by mouth, it offers an alternative to injectable biologics for patients who have not responded to conventional disease-modifying agents, although it carries a series of FDA boxed warnings that shape its current place in therapy. Since the publication of the ORAL Surveillance trial in 2022, JAK inhibitors as a class have moved later in many treatment algorithms, particularly in older patients with cardiovascular risk factors.

Mechanism of Action

Tofacitinib selectively inhibits Janus kinases, primarily JAK1 and JAK3 with some activity at JAK2 and TYK2. JAKs phosphorylate STAT proteins downstream of cytokine receptors that lack intrinsic kinase activity, including receptors for IL-2, IL-4, IL-6, IL-7, IL-9, IL-15, IL-21, granulocyte-macrophage colony-stimulating factor (GM-CSF), and several interferons. By blocking this signaling cascade, tofacitinib dampens T-cell, B-cell, natural killer cell, and innate immune responses central to autoimmune inflammation. The breadth of this immunomodulation accounts for both clinical effectiveness across multiple diseases and the spectrum of class-related risks: serious infections including herpes zoster reactivation (significantly elevated risk), lipid elevations driven by IL-6 pathway inhibition, cytopenias including neutropenia and lymphopenia, and changes in lymphocyte subsets that may carry long-term implications. The FDA safety communication on JAK inhibitors summarizes class-wide concerns identified in the ORAL Surveillance study and subsequent analyses.

Clinical Use

Following the ORAL Surveillance trial, which randomized rheumatoid arthritis patients aged 50 or older with at least one cardiovascular risk factor to tofacitinib versus a TNF inhibitor, tofacitinib carries boxed warnings for major adverse cardiovascular events, malignancy (including lymphoma and lung cancer), thrombosis (deep venous thrombosis and pulmonary embolism), and all-cause mortality compared with TNF inhibitors in this higher-risk population. Current guidance generally reserves tofacitinib and other JAK inhibitors for patients who have failed or cannot tolerate at least one TNF inhibitor such as adalimumab, etanercept, infliximab, certolizumab, or golimumab, particularly in patients over 65 or with cardiovascular risk factors. For ulcerative colitis, it remains an effective oral option after biologic failure and was the first JAK inhibitor approved for IBD. Within the JAK class, baricitinib and upadacitinib are also available, with similar warnings as a class effect. The American College of Rheumatology guidelines detail current placement.

How to Take It

Immediate-release tofacitinib is dosed twice daily; the extended-release tablet is once daily and must be swallowed whole, never crushed, split, or chewed because the controlled-release matrix may release the dose too rapidly. The medication can be taken with or without food. If a dose is missed, take it as soon as remembered unless the next dose is within 6 hours (IR) or 14 hours (XR), in which case skip the missed dose and resume the regular schedule rather than doubling. Many patients note improvement in joint pain and morning stiffness within two to four weeks, with continued benefit accruing over three to six months for joint symptoms and analogous time courses for skin and gastrointestinal symptoms in psoriatic arthritis and ulcerative colitis. Live vaccines are contraindicated during therapy, so vaccination status (including herpes zoster recombinant vaccine, pneumococcal vaccines, and others) should be brought up to date before starting if possible. Storage is at room temperature in the original container.

Monitoring and Follow-Up

Before starting, screen for latent tuberculosis with an interferon-gamma release assay or PPD, and review hepatitis B and C status; reactivation of latent infections has been reported. Obtain baseline CBC with differential, comprehensive metabolic panel, and lipid profile. Repeat CBC and lipids at four to eight weeks, then every three months; the lab panels overview explains common values and what changes mean. Interrupt therapy for absolute neutrophil count below 1000, lymphocyte count below 500, hemoglobin below 8, or any serious infection. Monitor blood pressure, weight, and signs or symptoms of thrombosis, cardiovascular events, or skin malignancy at every visit. Annual full skin examinations are reasonable given an increased risk of nonmelanoma skin cancer. Pregnancy testing before starting is appropriate in women of reproductive potential. Cardiovascular risk should be assessed annually and modifiable factors (lipid management, blood pressure control, smoking cessation) addressed aggressively.

Special Populations

In moderate to severe renal impairment, reduce the dose to once daily for the immediate-release formulation. In moderate hepatic impairment, also reduce the dose; severe hepatic impairment is a contraindication. In older adults (age 65 and over), use only when adequate alternatives are unavailable, given the elevated cardiovascular and malignancy risks identified in postmarketing studies, particularly the ORAL Surveillance findings. Pregnancy data suggest possible risk based on animal studies showing teratogenicity at clinically relevant exposures, and effective contraception is recommended during therapy and for several weeks after discontinuation. Lactation is not recommended because tofacitinib is excreted into milk in animal studies and may pose risk to the nursing infant. Pediatric use is limited to polyarticular course juvenile idiopathic arthritis at age 2 and older, with weight-based dosing of the oral solution. Patients with a history of lymphoma or other malignancies require especially careful risk-benefit discussion before initiation.

Vaccinations, Surgery, and Drug Interactions

Vaccination planning is essential before starting tofacitinib. The recombinant herpes zoster vaccine (Shingrix), which is non-live and effective in immunocompromised patients, should be administered to all patients age 50 and older before initiation, ideally completing both doses several weeks before the first tofacitinib dose. Pneumococcal vaccination per current adult schedules, hepatitis B vaccination if not immune, and annual inactivated influenza vaccine are all indicated. Live vaccines (MMR, varicella, yellow fever, oral typhoid, intranasal influenza) are contraindicated during therapy and require either administration before starting or a washout of several months after stopping. Surgical planning typically involves holding tofacitinib for one to two weeks before major elective surgery and resuming once wound healing is established and infection risk has passed, generally one to two weeks postoperatively for clean procedures. Drug interactions are clinically significant: strong CYP3A4 inhibitors such as ketoconazole or clarithromycin require dose reduction; strong CYP3A4 inducers such as rifampin or carbamazepine substantially reduce efficacy and should be avoided; and the combination of moderate CYP3A4 inhibitors with strong CYP2C19 inhibitors (for example, fluconazole) also warrants dose reduction. Tofacitinib should not be combined with biologic DMARDs, other JAK inhibitors, or potent immunosuppressants such as cyclosporine or azathioprine outside specialized regimens because of additive immunosuppression. Concurrent low-dose methotrexate is acceptable and may enhance response in rheumatoid arthritis. Patients should inform all healthcare providers of tofacitinib use, particularly when seeking care for new symptoms or considering new medications. A wallet card identifying immunosuppressant use is sensible for emergencies. Smoking cessation, blood pressure control, lipid management, and cardiovascular risk reduction should all be optimized given the boxed warnings; our understanding cholesterol article covers lipid management basics.

When to Contact Your Doctor

Call promptly for fever, persistent cough, or other infection symptoms; chest pain, shortness of breath, or unilateral leg swelling that could suggest pulmonary embolism or deep vein thrombosis; new or changing skin lesions warranting dermatologic evaluation; severe abdominal pain (bowel perforation has been reported, particularly in patients with ulcerative colitis); or signs of an allergic reaction. Severe headache, vision changes, focal neurologic symptoms, or features of stroke warrant urgent evaluation given the increased cardiovascular risk. Notify your physician about any planned surgery, since therapy is typically held perioperatively to reduce infection and thrombosis risk, and about any new prescriptions, since strong CYP3A4 inhibitors and inducers significantly affect tofacitinib levels. Painful skin rash with blisters may suggest herpes zoster reactivation, which can be severe in JAK inhibitor users.

To discuss whether a JAK inhibitor fits your inflammatory disease management plan, contact us or schedule a visit.