Continuing Education Activity

Tofacitinib is FDA approved for the treatment of moderate to severe rheumatoid arthritis (RA), psoriatic arthritis (PA), ulcerative colitis (UC), and polyarticular course juvenile idiopathic arthritis (pcJIA). It is a second-generation selective Janus kinase (JAK) inhibitor targeting the JAK1 enzyme. This activity will highlight the mechanism of action, adverse event profile, and other key factors pertinent to interprofessional team members in the management of patients with moderate to severe rheumatoid arthritis (RA), psoriatic arthritis (PA), ulcerative colitis (UC), and polyarticular course juvenile idiopathic arthritis (pcJIA) that is unresponsive to first-line therapy.

Objectives:

• Identify the mechanism of action of tofacitinib.
• Describe the potential adverse effects of tofacitinib
• Review the appropriate monitoring for patients receiving tofacitinib
• Summarize interprofessional team strategies for improving care coordination and communication to advance tofacitinib use in treating rheumatoid arthritis (RA), psoriatic arthritis (PA), ulcerative colitis (UC), and polyarticular course juvenile idiopathic arthritis (pcJIA) and improve outcomes.

Indications

Janus kinases are phosphotransferases, and receptor engagement by cytokines activates their enzymatic function. Janus kinase inhibitors represent a new strategy for the treatment of immune and inflammatory diseases. Tofacitinib is a targeted synthetic small molecule that is an oral inhibitor of Janus kinases (JAKs). It is (JAK) inhibitor FDA-approved in April 2012 and indicated for its use in the management of rheumatoid arthritis (RA), psoriatic arthritis (PA), ulcerative colitis (UC), polyarticular course juvenile idiopathic arthritis (pcJIA).[1] Tofacitinib's action on the nonreceptor tyrosine kinase JAK enzymes is more preferential to the JAK-1 and JAK-3 enzymes.[1] 

Tofacitinib's indications in rheumatoid arthritis are for adult patients unresponsive or developed intolerance to one or more disease-modifying rheumatoid drugs (DMARDs) with active moderate to severe disease course.[2] Tofacitinib can be used in sequence with first-line therapy methotrexate (MTX) or conventional DMARDS or can also be used as monotherapy for RA.[2] 

Tofacitinib's indication for active psoriatic arthritis received FDA approval following two phase III clinical trials, OPAL Broaden and OPAL Beyond.[3] The trials included subjects with psoriatic arthritis receiving tofacitinib treatment with a 5 mg dosage twice a day in sequence with MTX or other conventional synthetic DMARD therapy. Similar to RA, it is indicated for psoriatic arthritis in adult patients unresponsive or developed interlace to one or more disease-modifying rheumatoid drugs (DMARDs) with an active moderate to severe psoriatic disease course.

Tofacitinib's indication as a treatment for ulcerative colitis (UC) was approved by the FDA following three randomized phase III placebo-controlled clinical trials (OCTAVE Sustain trial, OCTAVE Induction 1, OCTAVE Induction 2), which were conducted following a promising phase 2 trial.[4] The agent is the first medication in the JAK inhibitors class of drugs to be approved in the UC management.[5] Similar to RA and PA, tofacitinib's indication in UC is for adult patients with active moderate or severe disease who have not demonstrated an adequate response to TNF blockers or intolerance to therapy.

Tofacitinib's indication as a treatment for polyarticular course juvenile idiopathic arthritis (pcJIA) is approved for subjects age two and older and available as an oral solution. The FDA approval was granted in September 2020 following a phase 3 clinical trial assessing its efficacy and safety in subjects aged 2 to 17 years.

FDA Approved Use

• Rheumatoid arthritis
• Psoriatic arthritis
• Ulcerative colitis
• Polyarticular course juvenile idiopathic arthritis

Mechanism of Action

Tofacitinib exerts its mechanism of action by inhibiting intracellular cytoplasmic nonreceptor tyrosine kinase JAK enzymes, which are involved in adaptive and innate immune reactions in the process of immune-mediated inflammatory diseases (IMIDs).[6] The Janus kinases are of four tyrosine kinase subtypes(JAK1, JAK2, JAK3, and TYK2).[6] Tofacitinib exhibits its inhibitory effects more selectively to the JAK1 and JAK3 enzymes, further restricting intracellular growth factor and cytokine-mediated signals to be transduced by the JAK-STAT pathway.[6] 

The intracellular Janus kinases' natural role is to phosphorylate the signal transducers and activators of transcription (STATs) enzymes which further influence gene expression and impact hematopoiesis and immune cell function.[6] The JAK-STAT signaling pathway plays a major role in the pathogenesis of autoimmune diseases, such as RA. Similar to other JAK inhibitors, tofacitinib blocks the phosphorylation and intracellular activation of signal transducers and activators of transcription, further diminishing their inflammatory effects.[6]

Administration

Tofacitinib is available in tablet form in 5 mg and 10 mg dosages and extended-release (XR) 11 mg dosage for oral consumption for adults. Tofacitinib is also available as a 1 mg/mL oral solution for children 2 years of age or older.

Rheumatoid Arthritis

The recommended dose of tofacitinib in rheumatoid arthritis treatment is 5 mg twice daily or extended-release (XR) 11 mg once a day.

• Subjects with moderate to severe renal impairment or moderate hepatic impairment are recommended 5 mg once daily.

Psoriatic Arthritis

The recommended dose of tofacitinib in the psoriatic arthritis treatment is 5 mg twice daily or extended-release (XR) 11 mg once a day.

• Subjects with moderate to severe renal impairment or moderate hepatic impairment are recommended 5 mg once daily.

Ulcerative Colitis

The recommended dose of tofacitinib in the ulcerative colitis treatment is 10 mg twice daily for a duration of eight weeks initially, then decreased to 5 mg twice a day.

Important to note that tofacitinib 10 mg twice daily is only FDA approved for ulcerative colitis treatment. Tofacitinib treatment should be discontinued if an adequate therapeutic response is not achieved by 16 weeks of therapy at the 10 mg twice a day dosage. Subjects with moderate to severe renal impairment or moderate hepatic impairment are recommended half of the daily dosage of subjects receiving treatment within the normal renal and hepatic function range.

Polyarticular Course Juvenile Idiopathic Arthritis

The recommended dose of tofacitinib in the polyarticular course juvenile idiopathic arthritis treatment is 5 mg twice daily (oral Solution) or weight-based equivalent twice daily.

Bodyweight greater than or equal to 10 kg and less than 20 kg: 3.2 mg (3.2 mL oral solution) twice daily

Bodyweight greater than or equal to 20 kg and less than 40 kg: 4 mg (4 mL oral solution) twice daily

Bodyweight greater than 40 kg: 5 mg (one 5 mg tablet or 5 mL oral solution ) twice daily

• Subjects with moderate to severe renal impairment or moderate hepatic impairment are recommended dosing modifications.

Adverse Effects

Some of the reported adverse effects includes[4][7]

• Upper respiratory tract infection (4% to 6%)
• Nasopharyngitis (4% to 14%)
• Diarrhea (2% to 5%)
• Gastroenteritis (4%)
• Nausea (1% to 4%)
• Headache (4% to 9%)
• Elevated cholesterol levels (5% to 9%)
• Increased blood creatine phosphokinase (3% to 7%)
• Rash (3% to 6%)
• Hypertension (2% to 9%)
• Anemia (4%)
• Herpes zoster (1% to 5%)

Tofacitinib treatment may also increase the risk for new primary malignancy and opportunistic infections. Severe adverse events include serious infections such as cytomegalovirus (CMV), Epstein Barr Virus (EBV), BK virus(BKV), and tuberculosis(TB), malignancy, lymphoproliferative disorder, and abnormal lab changes(anemia and leukopenia).[8] Hence, it has thus far not been used with potent immunosuppressants or biological DMARDs. Upper respiratory tract infections and urinary tract infections represent the most common infections.

Tofacitinib can cause hyperlipidemia. Dose-dependent increases in the levels of low-density lipoprotein (LDL), high-density lipoprotein (HDL), and total cholesterol have been reported in patients receiving tofacitinib. Long-term safety data showed higher rates of pulmonary embolism and death when using higher-dose tofacitinib (10 mg bid) in RA patients compared to those treated with a TNF inhibitor.

Contraindications

Tofacitinib is not recommended for combination use with strong immunosuppressants (cyclosporine, azathioprine, tacrolimus) or biologic DMARDs (infliximab, etanercept, rituximab, abatacept, adalimumab).[9] The administration of live vaccinations soon before or concurrently with tofacitinib is not recommended.

Monitoring

Before initiating treatment with tofacitinib, the patient should be tested for active or latent TB. In the case of a positive active or latent TB test, patients should be treated accordingly prior to receiving treatment with tofacitinib. While on therapy with tofacitinib, patients should also be monitored for TB routinely throughout. A baseline complete blood count (CBC) should be done before starting tofacitinib and 1 to 2 months following initiation, and every 12 weeks after that. Subjects with hemoglobin (Hb) levels below 9 g/dL, absolute lymphocyte count below 500 cells/mm^3, and absolute neutrophil count below 1000 cells/mm^3 should not be started on therapy.

Baseline lipid levels should be obtained and monitored 4 to 8 weeks after initiation of treatment. Dose-dependent increases in total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol may occur. Patients receiving treatment should be routinely monitored for the development of any severe infections. Treatment should be halted if any bacterial, viral, fungal, or opportunistic infections ensue. Liver function tests should also be monitored routinely as tofacitinib may cause hepatotoxicity. If hepatic injury from tofacitinib is suspected, treatment should be interrupted. Use in severe hepatic impairment is not recommended.

Toxicity

Like other JAK inhibitors, tofacitinib is metabolized by the hepatic cytochrome P450 (CYP) system, mainly the CYP3A4 enzyme, in the liver (70%) and eliminated by renal clearance (30%).[10] Tofacitinib has a drug half-life of 3 hours, and Tofacitinib XR has a drug half-life of 6 hours.[10] Its use in combination with moderate to strong CYP3A4 inhibitors (ketoconazole, fluconazole) and CYP3A4 inducers(rifampin) should be used cautiously and is not recommended as interruptions to drug pharmacokinetics may occur, moreover raising or lowering drug plasma concentration.[11] 

Tofacitinib therapy in females of reproductive age may cause a possible risk to a developing fetus during pregnancy and may also impair infertility in women of reproductive potential. Females who are lactating and receiving treatment are advised not to breastfeed 18 to 36 hours following the last dosage.

US Boxed Warnings: Serious infections such as tuberculosis, bacterial, fungal, viral, and opportunistic diseases, which may lead to hospitalization or mortality.[8] Malignancy and lymphomas have been reported. Renal transplant subjects receiving tofacitinib alongside immunosuppressive therapy are at increased risk of Epstein Barr virus (EBV) associated post-transplant lymphoproliferative disorder.[8]

Enhancing Healthcare Team Outcomes

Tofacitinib is a Janus kinase (JAK) inhibitor FDA-approved in April 2012 indicated for its use in the management of rheumatoid arthritis (RA), psoriatic arthritis (PA), ulcerative colitis (UC), and polyarticular course juvenile idiopathic arthritis (pcJIA). Patients suffering from such ailments require oversight from an interprofessional team of healthcare professionals. The interprofessional team can include a primary care physician (PCP), a rheumatologist, gastroenterologist, mid-level practitioners, nurses, a physical therapist (PT), and a pharmacist. Efficient interprofessional care from the healthcare team of patients suffering from RA, PA, or UC can lead to clinical and symptomatic improvements and a better quality of life. [Level 5]

Continuous communication between the interprofessional team, primarily the PCP and specialist, and their patients is imperative, and thorough education on treatment and disease should be provided. Updates on the latest guidelines on disease management using tofacitinib should be routinely reviewed. The patients should also be advised about the potential adverse effects while receiving treatment and the increased risk of severe infections. The patients should be advised to report any new-onset clinical manifestations. Period follow-ups visits with the PCP and specialist are essential to prevent complications, hospitalization, and mortality.

The interprofessional team should initiate a baseline laboratory workup prior to starting tofacitinib therapy. Patients considering tofacitinib treatment should be checked for active or latent TB, CBC, LFT, and lipid panel primarily and routinely after that. Women of reproductive potential should be counseled on the risk of possible infertility from tofacitinib, and treatment during pregnancy may increase potential risk to the fetus and discontinue breastfeeding as tofacitinib may be excreted in breastmilk. Regular communications and follow-ups between patients and their health providers build reliance and rapport, strengthening medication compliance, further reducing the progression of ailments while enhancing the quality of life.