Comprehensive Clinical Report: Tofacitinib

Introduction and Pharmacological Profile

Overview of Tofacitinib as a Targeted Synthetic DMARD

Tofacitinib is an oral medication representing a significant advancement in the management of several immune-mediated inflammatory diseases (IMIDs). It is classified as a targeted synthetic disease-modifying antirheumatic drug (tsDMARD) and is the first agent in the class of Janus kinase (JAK) inhibitors to receive widespread regulatory approval.[1] Developed and marketed by Pfizer, it is available under the brand names Xeljanz® for its immediate-release (IR) tablets and oral solution, and Xeljanz XR® for its extended-release (XR) formulation.[4] As an orally administered small molecule, tofacitinib offers a distinct alternative to the injectable biologic DMARDs that have long been mainstays in the treatment of these conditions.[1]

Regulatory History and Evolution of Clinical Use

The regulatory journey of tofacitinib provides a critical case study in modern pharmacovigilance and the evolving understanding of a novel drug class's risk-benefit profile. Tofacitinib was first approved by the U.S. Food and Drug Administration (FDA) on November 6, 2012, for the treatment of adult patients with moderately to severely active rheumatoid arthritis (RA).[1] At the time of its initial approval for RA, the indication was for patients who had an inadequate response or intolerance to methotrexate, positioning it as a major new oral option relatively early in the treatment algorithm.[4]

Following its initial approval, the indications for tofacitinib were progressively expanded based on further clinical trials. These expansions included:

• Active psoriatic arthritis (PsA) in 2017.[7]
• Moderately to severely active ulcerative colitis (UC) in 2018.[7]
• Active polyarticular course juvenile idiopathic arthritis (pcJIA) in patients aged 2 years and older in 2020.[7]
• Active ankylosing spondylitis (AS) in 2021.[7]

However, the accumulation of long-term post-marketing safety data, particularly from the pivotal ORAL Surveillance study, prompted significant revisions to the drug's labeling and its recommended place in therapy.[13] The findings from this study, which revealed increased risks of major adverse cardiovascular events (MACE), malignancy, and thrombosis compared to tumor necrosis factor (TNF) inhibitors, led regulatory agencies to narrow the drug's approved use. Consequently, the indications for RA, PsA, AS, and pcJIA were revised to specify use in patients who have had an inadequate response or intolerance to one or more TNF blockers.[3] This fundamental shift repositioned tofacitinib from a broad second-line agent to a more specific, later-line therapy for most of its rheumatologic indications, demonstrating how long-term safety data can redefine a drug's clinical utility years after its initial market entry.

Chemical Structure and Physicochemical Properties

Tofacitinib is a small molecule belonging to the pyrrolopyrimidine class of compounds. Its chemical name is (3R,4R)-4-methyl-3-(methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl-amino)-β-oxopiperidine-1-propanenitrile, and it is formulated as a citrate salt for clinical use.[4] It presents as a white crystalline solid with a melting point between 199-206 °C.[4] As a small molecule, its chemical structure allows for oral bioavailability and the ability to penetrate the cell membrane to reach its intracellular targets, the JAK enzymes.[1]

Mechanism of Action: The JAK-STAT Signaling Pathway

The Role of Janus Kinases in Immune-Mediated Inflammatory Diseases

The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway is a crucial intracellular signaling cascade responsible for mediating the effects of a wide array of cytokines, growth factors, and hormones.[1] In the context of IMIDs such as rheumatoid arthritis, the JAK-STAT pathway is pathologically dysregulated. This leads to the overproduction of pro-inflammatory cytokines, the activation and infiltration of immune cells into target tissues like the synovium, and the subsequent chronic inflammation and structural damage that characterize these diseases.[19] The pathway is composed of four non-receptor tyrosine kinase subtypes: JAK1, JAK2, JAK3, and Tyrosine Kinase 2 (TYK2).[1] These kinases exist as pairs associated with the intracellular domains of cytokine receptors. Upon cytokine binding, the JAKs are brought into proximity, leading to their autophosphorylation and activation.[20]

Tofacitinib's Selective Inhibition of JAKs

Tofacitinib functions as a partial and reversible inhibitor of JAK enzymes.[22] In biochemical kinase assays, it demonstrates inhibitory activity against JAK1, JAK2, and JAK3.[23] However, in cellular settings where JAKs signal in pairs, tofacitinib exhibits functional selectivity, preferentially inhibiting signaling mediated by heterodimeric receptors associated with JAK1 and/or JAK3 over receptors that signal through pairs of JAK2.[1] This preferential inhibition of JAK1 and JAK3 is central to its therapeutic efficacy in autoimmune diseases, as these specific kinases are paired with the receptors for numerous key pro-inflammatory cytokines, including interleukin-2 (IL-2), IL-4, IL-6, IL-7, IL-9, IL-15, IL-21, and interferons (IFNs).[20]

Downstream Effects on Cytokine Signaling and Immune Cell Function

By binding to the ATP-binding site of the JAK enzymes, tofacitinib blocks their ability to phosphorylate themselves and their associated cytokine receptors. This, in turn, prevents the recruitment, phosphorylation, and subsequent activation of STAT proteins.[1] The activated STATs would normally dimerize, translocate to the nucleus, and bind to DNA to regulate the transcription of target genes involved in immune cell function and hematopoiesis.[1] By interrupting this cascade, tofacitinib effectively dampens the cellular response to pro-inflammatory cytokine signals, leading to a broad modulation of both the innate and adaptive immune systems. The clinical result is a reduction in the signs and symptoms of inflammation, including joint pain, swelling, and stiffness.[4]

The specific JAK selectivity profile of tofacitinib provides a clear mechanistic basis for both its therapeutic effects and its characteristic adverse event profile. The potent inhibition of JAK1 and JAK3 directly targets the signaling of cytokines central to the pathogenesis of RA and other IMIDs, explaining its clinical efficacy.[25] Concurrently, JAK2 plays a critical role in hematopoiesis by mediating signals from erythropoietin (essential for red blood cell production) and thrombopoietin (essential for platelet production).[1] Although tofacitinib is functionally selective for JAK1/3, it retains inhibitory activity against JAK2.[23] This off-target inhibition of JAK2 provides a direct causal link to the dose-dependent hematologic adverse events observed with tofacitinib, such as anemia and neutropenia, which are key risks requiring routine laboratory monitoring.[1] Therefore, the drug's safety profile is not a random occurrence but a predictable consequence of its specific kinase inhibition pattern. This understanding has also driven the development of second-generation, more selective JAK inhibitors (e.g., JAK1-selective agents) with the aim of potentially mitigating some of these hematologic effects.[27]

Pharmacokinetics and Pharmacodynamics

Absorption, Distribution, Metabolism, and Excretion (ADME)

The pharmacokinetic profile of tofacitinib is characterized by rapid absorption and elimination, which supports its oral dosing regimen.

• Absorption: Following oral administration, tofacitinib is rapidly and well-absorbed, reaching peak plasma concentrations (Tmax​) within 0.5 to 1 hour. The absolute oral bioavailability is high at 74%.[22] Administration with a high-fat, high-calorie meal does not significantly alter the overall exposure (Area Under the Curve, AUC) but does reduce the peak concentration ( Cmax​) by 32%. This effect is not considered clinically significant, allowing tofacitinib to be taken with or without food.[19]
• Distribution: Tofacitinib has a volume of distribution (Vd​) of 87 L following intravenous administration. Its binding to plasma proteins is low (40%), primarily to albumin. The drug distributes equally between red blood cells and plasma.[22]
• Metabolism: Tofacitinib is extensively cleared through hepatic metabolism, which accounts for approximately 70% of its total clearance. The primary enzyme responsible for its metabolism is Cytochrome P450 3A4 (CYP3A4), with a minor contribution from CYP2C19. All identified metabolites of tofacitinib are inactive, meaning they do not contribute to the drug's therapeutic or toxic effects.[1]
• Excretion: The remaining 30% of the drug is cleared via renal excretion of the unchanged parent drug. Following a radiolabeled dose, approximately 94% of the total radioactivity is recovered, with 80% in the urine (primarily as metabolites) and about 14% in the feces.[1] The terminal elimination half-life ( t1/2​) is approximately 3 hours for the immediate-release (IR) formulation and around 6 hours for the extended-release (XR) formulation.[1]

The pharmacokinetic properties of tofacitinib, particularly its reliance on dual metabolic pathways (CYP3A4 and CYP2C19) and a significant component of renal clearance, create a triad of potential variability. This necessitates careful patient assessment prior to and during therapy. The heavy reliance on CYP3A4 metabolism creates a high potential for clinically significant drug-drug interactions with strong inhibitors (e.g., ketoconazole) or inducers (e.g., rifampin) of this enzyme, requiring dose adjustments as specified in the prescribing information.[32] Furthermore, the 30% renal clearance is substantial enough that patients with moderate to severe renal impairment will experience reduced drug elimination, leading to accumulation and increased risk of toxicity. Similarly, moderate hepatic impairment will compromise the primary metabolic clearance route. Consequently, dosage adjustments are mandatory for patients with moderate-to-severe renal impairment or moderate hepatic impairment, making a thorough evaluation of concomitant medications, renal function, and hepatic function an essential step before prescribing.[19]

Impact of Formulations (IR vs. XR)

Tofacitinib is available in two main oral formulations to accommodate different dosing preferences. The immediate-release (IR) tablet, with its short 3-hour half-life, requires twice-daily (BID) dosing to maintain therapeutic drug concentrations throughout the day.[1] The extended-release (XR) tablet was developed as a convenience formulation, allowing for once-daily (QD) administration.[5] It is critical to note that these formulations are not interchangeable on a milligram-for-milligram basis. For example, the standard 5 mg BID IR dose corresponds to an 11 mg QD XR dose. Any switch between formulations must be made under the direction of a healthcare provider to ensure proper dosing.[35]

Pharmacodynamic Response

The pharmacodynamic effects of tofacitinib are observed rapidly following administration. Treatment leads to a dose-dependent and swift reduction in levels of C-reactive protein (CRP), a key biomarker of systemic inflammation. This effect can be seen within two weeks of initiating therapy and suggests that the drug's biological activity may persist longer than its short pharmacokinetic half-life would imply.[22] In addition to its effect on CRP, tofacitinib treatment also results in dose-dependent decreases in circulating natural killer (NK) cell counts and dose-dependent increases in B cell counts.[22]

FDA-Approved Indications and Clinical Use

Tofacitinib is approved by the U.S. FDA for the treatment of five distinct immune-mediated inflammatory diseases. A common theme across most of these indications, following label updates based on long-term safety data, is the stipulation that the drug be used in patients who have had an inadequate response or are intolerant to one or more TNF blockers.

1. Rheumatoid Arthritis (RA): Tofacitinib is indicated for the treatment of adult patients with moderately to severely active RA who have had an inadequate response or intolerance to one or more TNF blockers.[18]
2. Psoriatic Arthritis (PsA): Tofacitinib is indicated for the treatment of adult patients with active PsA who have had an inadequate response or intolerance to one or more TNF blockers.[18]
3. Ankylosing Spondylitis (AS): Tofacitinib is indicated for the treatment of adult patients with active AS who have had an inadequate response or intolerance to one or more TNF blockers.[12]
4. Ulcerative Colitis (UC): Tofacitinib is indicated for the treatment of adult patients with moderately to severely active UC who have had an inadequate response or intolerance to one or more TNF blockers.[10]
5. Polyarticular Course Juvenile Idiopathic Arthritis (pcJIA): Tofacitinib is indicated for the treatment of active pcJIA in patients 2 years of age and older who have had an inadequate response or intolerance to one or more TNF blockers.[11]

The evolution of these indications to a near-universal "post-TNF blocker" status reflects a significant shift in the drug's perceived risk-benefit profile. Initially approved for RA after methotrexate failure, tofacitinib was positioned as a direct competitor to TNF inhibitors.[8] However, the ORAL Surveillance study provided head-to-head safety data against TNF blockers in a high-risk RA population, revealing a higher rate of MACE, malignancies, and mortality with tofacitinib.[14] This evidence provided a clear rationale for regulatory bodies to re-evaluate its place in therapy. The FDA's subsequent actions, including strengthening warnings and revising the indications, effectively moved tofacitinib from a potential alternative to a subsequent option for most patients, fundamentally altering its role in established treatment algorithms.[16]

Universal Limitation of Use

For all approved indications, the prescribing information includes a critical limitation of use: Tofacitinib is not recommended for use in combination with biologic DMARDs (e.g., TNF blockers, IL-6 receptor antagonists) or with potent immunosuppressants such as azathioprine and cyclosporine. This recommendation is based on the potential for additive immunosuppression, which would significantly increase the risk of serious and opportunistic infections.[17]

Dosage and Administration

The dosing of tofacitinib is complex and varies significantly based on the indication, patient age, body weight (for pediatric use), renal and hepatic function, and concomitant medications. Formulations are not interchangeable, and adherence to specific administration instructions is crucial for safety and efficacy.

Table V-1 provides a summary of the recommended dosing regimens.

Table V-1: Tofacitinib Dosing Regimens by Indication and Formulation

Indication	Patient Population	Formulation	Induction Dose & Duration	Maintenance Dose	Key Considerations & Adjustments
Rheumatoid Arthritis (RA)	Adults	IR Tablet	N/A	5 mg BID	Dose reduction to 5 mg QD for moderate/severe renal or moderate hepatic impairment. 10 mg BID dose is not recommended. 34
		XR Tablet	N/A	11 mg QD
Psoriatic Arthritis (PsA)	Adults	IR Tablet	N/A	5 mg BID	Dose reduction to 5 mg QD for moderate/severe renal or moderate hepatic impairment. 10 mg BID dose is not recommended. 34
		XR Tablet	N/A	11 mg QD
Ankylosing Spondylitis (AS)	Adults	IR Tablet	N/A	5 mg BID	Dose reduction to 5 mg QD for moderate/severe renal or moderate hepatic impairment. 34
		XR Tablet	N/A	11 mg QD
Ulcerative Colitis (UC)	Adults	IR Tablet	10 mg BID for 8-16 weeks	5 mg BID (may increase to 10 mg BID for shortest duration if loss of response)	Dose is halved for moderate/severe renal or moderate hepatic impairment (e.g., 10 mg BID becomes 5 mg BID). 2
		XR Tablet	22 mg QD for 8-16 weeks	11 mg QD (may increase to 22 mg QD for shortest duration if loss of response)
Polyarticular Course JIA (pcJIA)	Children ≥2 yrs	Oral Solution (1 mg/mL)	N/A	Weight-based BID: • 10 to <20 kg: 3.2 mg (3.2 mL) • 20 to <40 kg: 4 mg (4 mL) • ≥40 kg: 5 mg (5 mL)	Dose reduced to QD for moderate/severe renal or moderate hepatic impairment. 1
		IR Tablet	N/A	Weight-based BID: • ≥40 kg: 5 mg

Induction and Maintenance Dosing Strategies

A key difference in dosing exists between rheumatologic conditions and ulcerative colitis.

• RA, PsA, and AS: For these conditions, treatment is initiated directly at the maintenance dose of 5 mg IR BID or 11 mg XR QD.[2] The higher 10 mg BID (or 22 mg XR QD) dose is explicitly not recommended for the treatment of RA or PsA due to the unfavorable safety profile observed in clinical trials.[14]
• UC: This indication employs a distinct induction and maintenance strategy to achieve rapid control of inflammation. Treatment begins with a higher induction dose of 10 mg IR BID or 22 mg XR QD for at least 8 weeks. After this period, patients are evaluated for therapeutic response. If an adequate response is achieved, the dose is reduced to the maintenance level of 5 mg IR BID or 11 mg XR QD. The induction dose may be continued for a maximum of 16 weeks if necessary to achieve a response. For patients who experience a loss of response during maintenance therapy, re-escalation to the 10 mg BID (or 22 mg XR QD) dose may be considered, but it should be limited to the shortest possible duration, with careful consideration of the risks and benefits.[2]

Dose Adjustments for Special Populations

• Renal and Hepatic Impairment: Dose adjustments are mandatory for patients with impaired kidney or liver function. For patients with moderate to severe renal impairment (including those undergoing hemodialysis) or moderate hepatic impairment, the dose for RA, PsA, and AS is reduced to 5 mg once daily. For UC, the total daily dose is halved (e.g., 10 mg BID is reduced to 5 mg BID). Tofacitinib is not recommended for patients with severe hepatic impairment.[1]
• Concomitant CYP Inhibitors: Tofacitinib exposure is significantly increased when co-administered with drugs that inhibit its metabolism. A dose reduction is required when used with strong inhibitors of CYP3A4 (e.g., ketoconazole) or with a combination of a moderate CYP3A4 inhibitor and a strong CYP2C19 inhibitor (e.g., fluconazole). Specific dose reductions are outlined in the full prescribing information.[32]

Administration Instructions

To ensure proper delivery and absorption, specific administration instructions must be followed. The extended-release (XR) tablets must be swallowed whole and should not be crushed, split, or chewed.[2] Patients should be counseled that a portion of the inert XR tablet matrix may be visible in their stool; this is normal and does not indicate a lack of efficacy.[2] The oral solution, used primarily in pediatric patients, must be measured accurately using the oral dosing syringe provided with the medication.[2]

The Black Box Warning: A Detailed Analysis of Major Risks

The FDA has mandated a boxed warning, its most serious level of warning, for tofacitinib. This warning highlights a constellation of significant risks that fundamentally define the drug's safety profile and guide its clinical use. These risks were largely identified or confirmed through the ORAL Surveillance post-marketing safety study.

1. Serious Infections

• Risk Profile: Patients treated with tofacitinib are at an increased risk for developing serious infections that may lead to hospitalization or death. These include bacterial infections (e.g., pneumonia, cellulitis), invasive fungal infections (e.g., cryptococcosis, pneumocystosis), viral infections, most notably Herpes Zoster (shingles), and other opportunistic pathogens.[8] The risk is further elevated in patients receiving concomitant immunosuppressants like corticosteroids or methotrexate.[11] For ulcerative colitis, the higher 10 mg BID induction dose is associated with a greater risk of serious infections and shingles compared to the 5 mg BID maintenance dose.[11]
• Screening and Management: Treatment should not be initiated in patients with an active, serious infection. A critical prerequisite to therapy is screening for latent tuberculosis (TB). If latent TB is detected, appropriate treatment must be initiated before starting tofacitinib. Patients should be monitored for signs of active TB during therapy, even if the initial screening was negative. Screening for viral hepatitis B and C is also recommended prior to initiation.[19]

2. Mortality

• Risk Profile: The ORAL Surveillance study, a large, randomized trial in RA patients aged 50 years or older with at least one cardiovascular (CV) risk factor, identified a higher rate of all-cause mortality, including sudden cardiovascular death, in patients treated with tofacitinib (both 5 mg and 10 mg twice daily) compared to those treated with TNF blockers.[14]
• Clinical Implication: This finding was a primary driver for the recommendation against using the 10 mg twice-daily dose for the treatment of RA and PsA.[14]

3. Malignancy

• Risk Profile: Tofacitinib may increase the risk of malignancies by modulating the immune system. Cases of lymphoma and other cancers, including solid tumors and non-melanoma skin cancer (NMSC), have been observed.[14] The ORAL Surveillance study demonstrated a statistically significant higher rate of malignancies (excluding NMSC) in RA patients treated with tofacitinib compared to TNF blockers. The most common malignancies with an increased risk were lung cancer and lymphoma.[14] Patients who are current or past smokers are at an additional increased risk for these malignancies.[14]

4. Major Adverse Cardiovascular Events (MACE)

• Risk Profile: The ORAL Surveillance study also showed a higher rate of MACE, defined as a composite of cardiovascular death, non-fatal myocardial infarction (MI), and non-fatal stroke. This increased risk was observed in RA patients aged 50 or older with at least one pre-existing CV risk factor who were treated with tofacitinib, compared to those treated with TNF blockers.[2] As with malignancy, current or past smokers are at an additional increased risk.[14]
• Management: The prescribing information advises that tofacitinib should be discontinued in patients who experience a myocardial infarction or stroke.[14]

5. Thrombosis

• Risk Profile: An increased risk of thrombosis, including deep vein thrombosis (DVT), pulmonary embolism (PE), and arterial thrombosis, has been observed in patients treated with tofacitinib. Some of these events have been serious and, in some cases, fatal.[14] This risk was particularly evident in the ORAL Surveillance study, where an increased incidence of PE and death in the 10 mg twice-daily arm led the Data Safety Monitoring Board to halt that portion of the trial prematurely.[15]
• Management: Tofacitinib should be avoided in patients who are determined to be at an increased risk for thrombosis. If a patient develops signs or symptoms of a thrombotic event, treatment should be discontinued promptly, and the patient should be evaluated immediately.[14]

The constellation of risks detailed in the Black Box Warning is not uniform across all patient populations. The data from ORAL Surveillance clearly indicate that these risks—MACE, malignancy, and mortality—are significantly magnified in a specific and identifiable patient phenotype: older individuals (aged ≥50-65), current or past smokers, and those with pre-existing cardiovascular risk factors or established atherosclerotic cardiovascular disease.[44] This understanding transforms clinical practice from a passive communication of warnings to an active, mandatory process of risk stratification. The clinician must assess a patient's age, smoking history, and detailed cardiovascular status to quantify these risks. This stratified risk assessment is fundamental to the shared decision-making process and is critical for determining whether tofacitinib is an appropriate choice, especially when compared to alternatives like TNF inhibitors, for which these specific risk signals were not observed in head-to-head comparison.

Comprehensive Safety Profile and Adverse Events

Beyond the Black Box Warning, tofacitinib is associated with a broad range of potential adverse events and requires careful consideration of contraindications and drug interactions.

Table VII-1: Common and Serious Adverse Events Associated with Tofacitinib

System Organ Class	Adverse Event	Frequency	Clinical Considerations
Infections and Infestations	Upper respiratory tract infection (nasopharyngitis)	Common (>10%)	Most frequent AE. Monitor for signs of infection. 1
	Herpes Zoster (Shingles)	Common (1-5%)	Risk is dose-dependent. Non-live zoster vaccine recommended pre-treatment. 1
	Serious Infections (Pneumonia, Cellulitis, UTI)	Uncommon	See Black Box Warning. Interrupt therapy if serious infection occurs. 11
	Tuberculosis, Opportunistic Fungal Infections	Rare	See Black Box Warning. Requires pre-screening and monitoring. 14
Gastrointestinal Disorders	Diarrhea	Common (2-5%)	Usually mild to moderate. 1
	Nausea	Common (1-4%)	Can be taken with or without food to mitigate. 1
	Gastrointestinal Perforation	Rare	Increased risk in patients with history of diverticulitis. 5
Nervous System Disorders	Headache	Common (4-9%)	Generally mild and manageable. 1
Metabolism and Nutrition Disorders	Hyperlipidemia (Increased LDL, HDL, Total Cholesterol)	Common (5-9%)	Occurs within 4-8 weeks. Requires lipid monitoring. 1
Hepatobiliary Disorders	Elevated Liver Enzymes	Common	Requires routine monitoring of LFTs. 1
Blood and Lymphatic System Disorders	Anemia	Common (4%)	Requires baseline and follow-up CBC monitoring. 1
	Neutropenia	Uncommon	Requires CBC monitoring; may require dose interruption. 28
	Lymphopenia	Uncommon	Requires CBC monitoring; may require dose interruption. 28
Skin and Subcutaneous Tissue Disorders	Rash, Acne	Common (3-6%)	Generally mild. 1
	Angioedema, Urticaria	Postmarketing	Signs of serious allergic reaction; discontinue immediately. 29
Vascular Disorders	Hypertension	Common (2-9%)	Monitor blood pressure. 1
	Thrombosis (DVT, PE)	Uncommon	See Black Box Warning. 14
Neoplasms Benign, Malignant	Malignancy (Lymphoma, Lung Cancer), NMSC	Uncommon	See Black Box Warning. 14
Cardiac Disorders	Major Adverse Cardiovascular Events (MACE)	Uncommon	See Black Box Warning. 14

Contraindications and Significant Drug Interactions

• Contraindications: While few absolute contraindications are listed in the US prescribing information, treatment should not be initiated in patients with an active serious infection, severe hepatic impairment, or clinically significant hematologic abnormalities (Absolute Neutrophil Count [ANC] <1000 cells/mm³, Absolute Lymphocyte Count [ALC] <500 cells/mm³, or hemoglobin <9 g/dL).[8] European guidelines also list pregnancy and breastfeeding as contraindications.[47]
• Drug-Drug Interactions: Tofacitinib has a high potential for drug-drug interactions, with over 600 identified, many of which are classified as major or moderate in severity.[48] Key interactions include:
• Other Immunosuppressants: Co-administration with biologic DMARDs (e.g., adalimumab, infliximab, abatacept) or potent non-biologic immunosuppressants (e.g., azathioprine, cyclosporine, tacrolimus) is not recommended. The combination significantly increases the risk of additive immunosuppression and serious infections.[17]
• CYP450 Enzyme Modulators: Because tofacitinib is metabolized by CYP3A4 and CYP2C19, its plasma concentration is highly susceptible to modulation by other drugs:
• Strong CYP3A4 Inhibitors (e.g., ketoconazole, itraconazole) and combined Moderate CYP3A4/Strong CYP2C19 Inhibitors (e.g., fluconazole) can significantly increase tofacitinib levels, necessitating a dose reduction.[32]
• Strong CYP3A4 Inducers (e.g., rifampin, carbamazepine, phenytoin, St. John's Wort) can significantly decrease tofacitinib levels, potentially leading to a loss of efficacy. Co-administration with these agents should generally be avoided.[2]
• Live Vaccines: Patients receiving tofacitinib should not be administered live attenuated vaccines (e.g., measles, mumps, rubella; intranasal influenza; rotavirus; yellow fever; live zoster vaccine [Zostavax]). The suppressed immune response increases the risk of developing a disseminated infection from the vaccine virus. Inactivated vaccines can be administered.[5]

Clinical and Laboratory Monitoring Recommendations

To mitigate the known risks associated with tofacitinib therapy, a structured and rigorous monitoring plan is essential. This includes comprehensive baseline assessments and regular follow-up laboratory tests.

Table VIII-1: Recommended Monitoring Schedule for Patients on Tofacitinib

Parameter	Baseline Assessment	Follow-up Schedule	Action Threshold / Key Consideration
Tuberculosis (TB)	Test for latent TB infection.	Monitor for signs/symptoms of active TB during therapy.	Treat latent TB prior to initiating tofacitinib. 19
Viral Hepatitis	Screen for Hepatitis B and C.	Monitor for signs of reactivation during therapy.	Use with caution in carriers; monitor closely. 19
Complete Blood Count (CBC) with Differential	Obtain baseline values.	4-8 weeks after initiation, then every 3 months.	Do not initiate if: ANC <1000 cells/mm³, ALC <500 cells/mm³, or Hemoglobin <9 g/dL.Interrupt dose if: ANC <1000, ALC <500, or significant drop in Hemoglobin. 1
Lipid Panel	Obtain baseline values.	4-8 weeks after initiation.	Manage hyperlipidemia according to standard clinical guidelines. 1
Liver Function Tests (LFTs)	Obtain baseline values.	Routinely monitor during therapy.	Investigate significant elevations. Dose adjustment needed for moderate hepatic impairment; avoid in severe impairment. 1
Vaccination Status	Assess and update as needed.	N/A	Administer necessary vaccines, especially non-live zoster and pneumococcal, prior to starting therapy. Avoid live vaccines during treatment. 5
Skin Examination	N/A	Periodically, especially in patients with risk factors for skin cancer.	Monitor for new or changing skin lesions. 39

Baseline Assessments

Before a patient begins treatment with tofacitinib, a thorough baseline evaluation must be performed to establish safety and identify potential risks. This includes screening for infections (latent TB, hepatitis B and C), obtaining a complete blood count (CBC) with differential, a lipid panel, and liver function tests (LFTs). Treatment should not be initiated if baseline hematologic parameters are below the specified safety thresholds.[1] It is also the ideal time to ensure the patient's vaccinations are up-to-date, particularly with inactivated vaccines for shingles and pneumococcus.[5]

Ongoing Monitoring

Once therapy is initiated, regular laboratory monitoring is non-negotiable. A CBC should be repeated 4 to 8 weeks after starting and then every 3 months thereafter to monitor for neutropenia, lymphopenia, and anemia.[1] A lipid panel should be checked 4 to 8 weeks after initiation to assess for drug-induced hyperlipidemia, which should then be managed according to standard clinical guidelines.[1] LFTs should be monitored routinely throughout treatment.[1] In addition to laboratory tests, clinicians must remain vigilant for the signs and symptoms of infection at every patient encounter.[12] For patients at higher risk of skin cancer, periodic skin examinations are also recommended.[39]

Efficacy and Safety in Pivotal Clinical Trials

The efficacy and safety of tofacitinib have been established through extensive clinical development programs across its approved indications. These pivotal trials demonstrated its superiority over placebo and, in some cases, provided comparative data against active comparators.

Rheumatoid Arthritis (ORAL Program)

The RA clinical program included multiple Phase 3 trials that established tofacitinib's efficacy as both monotherapy and in combination with conventional synthetic DMARDs (csDMARDs) like methotrexate (MTX).

• ORAL Solo: This monotherapy trial enrolled patients with an inadequate response to one or more csDMARDs or biologic DMARDs. At 3 months, a significantly higher proportion of patients receiving tofacitinib 5 mg BID achieved an American College of Rheumatology 20% improvement (ACR20) response compared to placebo (59% vs. 25%). Tofacitinib also demonstrated statistically significant improvements in physical function, as measured by the Health Assessment Questionnaire-Disability Index (HAQ-DI).[52]
• ORAL Scan: This study evaluated patients with an inadequate response to MTX, with tofacitinib or placebo added to their background MTX therapy. A key endpoint was the inhibition of structural joint damage. At 6 months, patients treated with tofacitinib plus MTX showed significantly less radiographic progression, as measured by the modified Total Sharp Score (mTSS), compared to those receiving placebo plus MTX. At 6 months, 84% of patients in the tofacitinib 5 mg BID group experienced no radiographic progression versus 74% in the placebo group.[52]
• ORAL Strategy: This Phase 3b/4 head-to-head trial compared three treatment arms: tofacitinib 5 mg BID monotherapy, tofacitinib 5 mg BID plus MTX, and the TNF inhibitor adalimumab 40 mg every other week plus MTX. The study found that the tofacitinib plus MTX combination provided similar ACR50 response rates to the adalimumab plus MTX combination (46% vs. 43.8%, respectively). However, tofacitinib monotherapy did not demonstrate non-inferiority to either of the combination therapy arms, affirming the clinical benefit of using tofacitinib in combination with MTX for many patients.[53]

Psoriatic Arthritis (OPAL Program)

The OPAL (Oral Psoriatic Arthritis TriaL) program demonstrated tofacitinib's efficacy in patients with PsA, including both those who were naïve to biologic therapy and those who had previously failed TNF inhibitors.

• OPAL Broaden: This trial enrolled TNFi-naïve patients with an inadequate response to at least one csDMARD. At 3 months, 50% of patients treated with tofacitinib 5 mg BID achieved an ACR20 response, compared to 33% of patients receiving placebo. Tofacitinib also showed rapid onset of action, with separation from placebo as early as 2 weeks. Furthermore, it demonstrated significant improvements in skin manifestations of psoriasis (measured by PASI75), enthesitis (inflammation of tendon/ligament insertions), and dactylitis ("sausage digits").[54]
• OPAL Beyond: This study focused on a more treatment-resistant population: patients with an inadequate response to at least one TNF inhibitor. Tofacitinib again demonstrated significant efficacy, with 50% of patients in the 5 mg BID group achieving an ACR20 response at 3 months, compared to just 24% in the placebo group. This result established tofacitinib as a viable treatment option for patients after TNF blocker failure.[54]

Ulcerative Colitis (OCTAVE Program)

The OCTAVE (Oral Clinical Trials for Tofacitinib in Ulcerative Colitis) program established the efficacy of tofacitinib for both inducing and maintaining remission in patients with moderately to severely active UC.

• OCTAVE Induction 1 & 2: These were two identical, 8-week, placebo-controlled induction trials. The primary endpoint was clinical remission at Week 8, defined by a stringent composite Mayo score. In these trials, 17-18% of patients receiving the induction dose of tofacitinib 10 mg BID achieved remission, compared to 4-8% of patients on placebo.[10] Significant improvements in rectal bleeding and stool frequency were observed in as little as 3 days.[58]
• OCTAVE Sustain: This 52-week maintenance trial enrolled patients who had achieved a clinical response in the induction studies. Patients were re-randomized to receive tofacitinib 5 mg BID, 10 mg BID, or placebo. At 1 year, remission was maintained in a significantly higher proportion of patients on tofacitinib (34% for 5 mg BID and 41% for 10 mg BID) compared to placebo (11%). The study also demonstrated a significant steroid-sparing effect, with a large proportion of patients who were in remission at the start of the trial able to achieve sustained, steroid-free remission at one year.[10]

The ORAL Surveillance Study: A Paradigm Shift in Safety Assessment

The ORAL Surveillance study (NCT02092467) was a landmark post-authorization safety trial that fundamentally reshaped the clinical understanding and regulatory landscape for tofacitinib and the entire JAK inhibitor class.

Study Design

ORAL Surveillance was a large-scale (N=4362), randomized, open-label, non-inferiority, safety endpoint trial. Its primary purpose was to compare the long-term safety of tofacitinib with that of TNF inhibitors. The study specifically enrolled a population at elevated cardiovascular risk: patients with RA aged 50 years or older who had at least one additional cardiovascular risk factor (e.g., smoking, hypertension, high cholesterol, diabetes, family history of premature coronary artery disease).[37] Patients were randomized 1:1:1 to receive either tofacitinib 5 mg BID, tofacitinib 10 mg BID, or a subcutaneous TNF inhibitor (adalimumab in North America, etanercept elsewhere).[43]

Primary Endpoints

The study had two co-primary endpoints, both assessed for non-inferiority against the TNF inhibitor arm using a pre-specified hazard ratio (HR) margin of 1.8. These endpoints were:

1. Adjudicated Major Adverse Cardiovascular Events (MACE), a composite of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke.
2. Adjudicated malignancies, excluding non-melanoma skin cancer (NMSC).[43]

Key Findings

The results of ORAL Surveillance were profound and led to significant regulatory actions.

• Failure to Meet Non-Inferiority: Tofacitinib failed to demonstrate non-inferiority to TNF inhibitors for both co-primary endpoints.
• For MACE, the HR for the combined tofacitinib doses versus TNF inhibitors was 1.33 (95% Confidence Interval [CI] 0.91–1.94). The upper bound of the CI exceeded the non-inferiority margin of 1.8, and the point estimate suggested a 33% higher risk.[37]
• For malignancies, the HR was 1.48 (95% CI 1.04–2.09). The lower bound of the CI was above 1.0, indicating a statistically significant increased risk of cancer with tofacitinib compared to TNF inhibitors.[37]
• Other Critical Safety Signals: The study also confirmed higher rates of serious infections and Herpes Zoster with tofacitinib. Most notably, the Data Safety Monitoring Board recommended halting the 10 mg BID arm prematurely due to an observed increased risk of pulmonary embolism and all-cause mortality compared to the other two arms.[37]

Post-Hoc Analysis: The Critical Role of ASCVD History

A crucial post-hoc analysis of the ORAL Surveillance data provided critical nuance by stratifying patients based on whether they had a history of atherosclerotic cardiovascular disease (ASCVD) at baseline.[46] This analysis revealed that the increased MACE risk was not uniform across the study population.

• In patients with a history of ASCVD, the risk of MACE was substantially and significantly higher with tofacitinib compared to TNF inhibitors (HR for combined tofacitinib doses vs. TNFi was 1.98).[46]
• In patients without a history of ASCVD (but who still had other CV risk factors), the MACE risk did not appear to be different between tofacitinib 5 mg BID and TNF inhibitors (HR 1.03).[46]

Clinical Implications

The ORAL Surveillance study was a paradigm shift. It provided direct, head-to-head evidence that in a population of RA patients with elevated cardiovascular risk, tofacitinib carries a greater risk of MACE and malignancy than the established TNF inhibitor class. The post-hoc analysis was instrumental in refining this finding, strongly suggesting that this excess risk is primarily driven by patients with pre-existing ASCVD. This has made cardiovascular risk stratification an absolute necessity in clinical practice before prescribing tofacitinib or other JAK inhibitors, as clinicians must now weigh the drug's efficacy against a clearly defined and quantifiable increase in cardiovascular and malignancy risk in certain patient populations.

Comparative Analysis and Off-Label Use

Tofacitinib in the Context of Other JAK Inhibitors

Following the approval of tofacitinib, other JAK inhibitors with varying selectivity profiles, such as baricitinib (JAK1/2), upadacitinib (JAK1-selective), and filgotinib (JAK1-selective), have entered the market. The absence of large head-to-head trials has led to the use of network meta-analyses and indirect comparisons to evaluate their relative efficacy and safety.[62]

• Efficacy: These analyses have yielded mixed but informative results. Some studies suggest that the more JAK1-selective agents, particularly upadacitinib, may offer numerically higher efficacy in terms of ACR response rates and clinical remission compared to tofacitinib, although these differences often do not reach statistical significance.[62] One analysis also found peficitinib to have the highest ACR20 response rate among monotherapies.[65]
• Safety: The safety profiles also appear to differ, potentially related to their varying selectivity. One analysis found baricitinib to be associated with the highest rates of serious adverse events and herpes zoster.[62] Spontaneous adverse event reporting data suggested tofacitinib had the highest proportion of reported cardiovascular and thrombotic events among the class.[66] The greater JAK1 selectivity of agents like filgotinib may translate to less inhibition of JAK2-dependent pathways, which could theoretically result in a more favorable hematologic safety profile, though this requires confirmation in long-term studies.[27]

Emerging Evidence for Off-Label Applications

The central role of the JAK-STAT pathway in a wide range of immune-mediated conditions has prompted significant investigation into the off-label use of tofacitinib.

• Dermatology: Tofacitinib is being increasingly used for dermatological conditions refractory to standard therapies. There is strong evidence from randomized controlled trials supporting its efficacy in treating alopecia areata, atopic dermatitis, and plaque psoriasis.[67] Case reports and series suggest potential benefit in a variety of other skin disorders.
• Other Rheumatic Diseases: There is emerging evidence from case reports and small pilot studies suggesting that tofacitinib may be a valuable therapeutic option for patients with other severe, refractory systemic rheumatic diseases. This includes conditions such as dermatomyositis and SAPHO (Synovitis, Acne, Pustulosis, Hyperostosis, and Osteitis) syndrome, particularly in patients who have failed conventional therapies and biologic agents.[24]

Patient-Reported Experiences and Real-World Evidence

Synthesis of Patient-Reported Outcomes

Patient reviews and forums reveal a highly polarized experience with tofacitinib. This dichotomy reflects the drug's potent efficacy on one hand and its significant side effect burden on the other.

• Positive Experiences: Many patients describe the drug as "life-changing" or a "miracle." These reviews often come from individuals with severe, long-standing RA or UC who have failed multiple previous therapies. They report dramatic and rapid improvements in pain, joint swelling, fatigue, and overall quality of life, allowing them to resume activities they had previously given up.[71]
• Negative Experiences: Conversely, a substantial number of negative reviews focus on the high burden of adverse events. Common themes include the development of frequent or severe infections, significant gastrointestinal distress, debilitating fatigue, persistent headaches, weight gain, and in some cases, the development of skin cancers.[71] For some patients, the side effects were perceived as being worse than the underlying disease itself, leading to treatment discontinuation.

Analysis of Drug Retention and Real-World Data

Real-world evidence (RWE) studies, which analyze data from routine clinical practice, provide a valuable complement to the controlled environment of RCTs.

• Drug Retention: RWE studies generally show reasonable long-term persistence with tofacitinib. One study in patients with RA found a 5-year drug retention rate of 54%.[74] Another real-world analysis of UC patients found that the majority of individuals who initiated tofacitinib remained on therapy at the 12-month mark.[75]
• Clinical Effectiveness: These studies confirm the effectiveness of tofacitinib outside of trial settings. Long-term extension studies of RA trials have shown that remission rates can be maintained for up to 8 years in a subset of patients.[74] A key finding from RWE in UC is the significant reduction in the use of oral corticosteroids (OCS), a major therapeutic goal associated with reducing long-term toxicity. One study found that 40% of UC patients on OCS at baseline were able to discontinue them within 12 months of starting tofacitinib.[75]

Conclusion and Clinical Recommendations

Summary of the Risk-Benefit Profile

Tofacitinib is a potent and effective oral targeted synthetic DMARD that has secured a definitive place in the treatment of several challenging immune-mediated inflammatory diseases. Its novel mechanism of action, the inhibition of the JAK-STAT signaling pathway, provides rapid and substantial clinical benefit for many patients, including those who are refractory to both conventional and biologic therapies. This profound efficacy, however, is counterbalanced by a significant and complex safety profile. This profile is headlined by a comprehensive Black Box Warning detailing increased risks of serious and opportunistic infections, malignancy, major adverse cardiovascular events, thrombosis, and all-cause mortality, particularly in specific high-risk populations.

Recommendations for Patient Selection and Risk Mitigation

The safe and effective use of tofacitinib hinges on a clinical strategy of meticulous patient selection and proactive risk mitigation. The evidence from pivotal trials, and especially from the ORAL Surveillance study, allows for the delineation of patient profiles to guide this process.

• Favorable Candidate Profile: The risk-benefit profile for tofacitinib is most favorable in a younger patient (e.g., <65 years old), who is a non-smoker, has no history of atherosclerotic cardiovascular disease, and possesses few or no additional cardiovascular risk factors. For such a patient who has experienced an inadequate response or intolerance to one or more TNF blockers, tofacitinib represents a valuable oral treatment option.
• High-Risk Candidate Profile (Use with Caution or Avoid): The risk-benefit profile becomes considerably less favorable in patients with one or more of the following characteristics: age 65 years or older, a current or past history of smoking, a personal history of ASCVD (e.g., previous myocardial infarction or stroke), a history of thrombosis (DVT/PE), or a prior malignancy. In these individuals, the absolute risks of MACE, malignancy, and thrombosis associated with tofacitinib are elevated. For these patients, treatment with an agent from a different drug class, such as a TNF inhibitor, should be strongly considered as a preferential option.
• Essential Risk Mitigation Strategies: For any patient being considered for or treated with tofacitinib, strict adherence to recommended screening and monitoring guidelines is non-negotiable. This includes:
• Comprehensive baseline screening for latent TB, viral hepatitis, and hematologic abnormalities.
• Regular laboratory monitoring of blood counts, liver enzymes, and lipid levels.
• Thorough patient education on the signs and symptoms of infection, thrombosis, and MACE, with clear instructions to seek immediate medical attention if they occur.
• Ongoing assessment of the patient's overall risk profile and a willingness to re-evaluate the appropriateness of therapy over time.

Future Directions

The development of tofacitinib, the first-in-class oral JAK inhibitor, has paved the way for a new era in the treatment of IMIDs. Its journey has provided invaluable lessons in pharmacovigilance and risk stratification. Future research will continue to focus on the development of next-generation JAK inhibitors with greater selectivity, with the goal of uncoupling the profound efficacy of JAK inhibition from its significant safety concerns. Furthermore, long-term comparative effectiveness and safety trials will be essential to more precisely position each of the available JAK inhibitors within increasingly complex and personalized treatment algorithms.

Works cited

1. Tofacitinib - StatPearls - NCBI Bookshelf, accessed August 4, 2025, https://www.ncbi.nlm.nih.gov/books/NBK572148/
2. Tofacitinib (oral route) - Side effects & dosage - Mayo Clinic, accessed August 4, 2025, https://www.mayoclinic.org/drugs-supplements/tofacitinib-oral-route/description/drg-20075863
3. Home Page | XELJANZ® (tofacitinib) | Safety Info, accessed August 4, 2025, https://www.xeljanz.com/
4. Tofacitinib | C16H20N6O | CID 9926791 - PubChem, accessed August 4, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/Tofacitinib
5. Tofacitinib (Xeljanz®/XeljanzXR®) - Johns Hopkins Arthritis Center, accessed August 4, 2025, https://www.hopkinsarthritis.org/patient-corner/drug-information/tofacitinib-xeljanzxeljanzxr/
6. XELJANZ® | Pfizer, accessed August 4, 2025, https://www.pfizer.com/products/product-detail/xeljanz
7. Xeljanz (tofacitinib) FDA Approval History - Drugs.com, accessed August 4, 2025, https://www.drugs.com/history/xeljanz.html
8. XELJANZ (tofacitinib) - accessdata.fda.gov, accessed August 4, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/203214s018lbl.pdf
9. Impact of tofacitinib on patient outcomes in rheumatoid arthritis – review of clinical studies, accessed August 4, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC4716749/
10. Xeljanz (Tofacitinib) Receives Expanded Indication, Becoming the First Oral JAK Inhibitor Approved for Ulcerative Colitis - American Health & Drug Benefits, accessed August 4, 2025, https://www.ahdbonline.com/issues/2019/march-2019-vol-12-tenth-annual-payers-guide/xeljanz-tofacitinib-receives-expanded-indication-becoming-the-first-oral-jak-inhibitor-approved-for-ulcerative-colitis
11. U.S. FDA Approves Pfizer's XELJANZ® (tofacitinib) for the Treatment of Active Polyarticular Course Juvenile Idiopathic Arthritis, accessed August 4, 2025, https://www.pfizer.com/news/press-release/press-release-detail/us-fda-approves-pfizers-xeljanzr-tofacitinib-treatment
12. U.S. FDA Approves Pfizer's XELJANZ® (tofacitinib) for the Treatment of Active Ankylosing Spondylitis, accessed August 4, 2025, https://www.pfizer.com/news/press-release/press-release-detail/us-fda-approves-pfizers-xeljanzr-tofacitinib-treatment-0
13. Studies Raise Questions About JAK Inhibitor Risks - Arthritis Foundation, accessed August 4, 2025, https://www.arthritis.org/drug-guide/medication-topics/jak-inhibitor-safety
14. XELJANZ / XELJANZ XR® (tofacitinib) Boxed Warning | Pfizer ..., accessed August 4, 2025, https://www.pfizermedical.com/xeljanz/boxed-warning
15. FDA approves Boxed Warning about increased risk of blood clots and death with higher dose of arthritis and ulcerative colitis medicine tofacitinib (Xeljanz, Xeljanz XR) | FDA, accessed August 4, 2025, https://www.fda.gov/drugs/fda-drug-safety-podcasts/fda-approves-boxed-warning-about-increased-risk-blood-clots-and-death-higher-dose-arthritis-and
16. XELJANZ® (tofacitinib) | Safety Info, accessed August 4, 2025, https://xeljanz.pfizerpro.com/
17. XELJANZ / XELJANZ XR® (tofacitinib) | Pfizer Medical - US, accessed August 4, 2025, https://www.pfizermedical.com/xeljanz
18. XELJANZ / XELJANZ XR® (tofacitinib) Indications and Usage ..., accessed August 4, 2025, https://www.pfizermedical.com/xeljanz/indications-usage
19. Tofacitinib Citrate (Xeljanz) - American College of Rheumatology, accessed August 4, 2025, https://rheumatology.org/patients/tofacitinib-citrate-xeljanz
20. The mechanism of action of tofacitinib - an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis - PubMed, accessed August 4, 2025, https://pubmed.ncbi.nlm.nih.gov/26966791/
21. JAK (Janus Kinase Pathway) Inhibitor Tofacitinib - pharmacology, mechanism of action, side effects - YouTube, accessed August 4, 2025, https://m.youtube.com/watch?v=oB68zQzJRfA&pp=ygUMI2phbnVza2luYXNl
22. Tofacitinib: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed August 4, 2025, https://go.drugbank.com/drugs/DB08895
23. The Pharmacokinetics, Metabolism, and Clearance Mechanisms of Tofacitinib, a Janus Kinase Inhibitor, in Humans - ResearchGate, accessed August 4, 2025, https://www.researchgate.net/publication/259919422_The_Pharmacokinetics_Metabolism_and_Clearance_Mechanisms_of_Tofacitinib_a_Janus_Kinase_Inhibitor_in_Humans
24. The off-label uses profile of tofacitinib in systemic rheumatic diseases, accessed August 4, 2025, https://pubmed.ncbi.nlm.nih.gov/32283509/
25. Tofacitinib in the management of active psoriatic arthritis: patient ..., accessed August 4, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC6717840/
26. Population Pharmacokinetics of Tofacitinib in Patients With Moderate to Severe Ulcerative Colitis - PMC - PubMed Central, accessed August 4, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC7986169/
27. JAK selectivity and the implications for clinical inhibition of pharmacodynamic cytokine signalling by filgotinib, upadacitinib, tofacitinib and baricitinib | Annals of the Rheumatic Diseases, accessed August 4, 2025, https://ard.bmj.com/content/80/7/865
28. Considering a Different Treatment For Your Child's Active Polyarticular Course Juvenile Idiopathic Arthritis (pcJIA)? - Xeljanz, accessed August 4, 2025, https://www.xeljanz.com/pcjia/
29. Tofacitinib Side Effects: Common, Severe, Long Term - Drugs.com, accessed August 4, 2025, https://www.drugs.com/sfx/tofacitinib-side-effects.html
30. Upadacitinib Appears Safe, Effective In Older Adults With UC - Gastroenterology & Endoscopy News, accessed August 4, 2025, https://www.gastroendonews.com/Inflammatory-Bowel-Disease/Article/07-25/Upadacitinib-Safe-Older-Adults/77665
31. The pharmacokinetics, metabolism, and clearance mechanisms of tofacitinib, a janus kinase inhibitor, in humans - PubMed, accessed August 4, 2025, https://pubmed.ncbi.nlm.nih.gov/24464803/
32. Xeljanz, Xeljanz XR (tofacitinib) dosing, indications, interactions, adverse effects, and more - Medscape Reference, accessed August 4, 2025, https://reference.medscape.com/drug/xeljanz-xeljanz-xr-tofacitinib-999789
33. 9 Xeljanz Interactions You Need to Know - GoodRx, accessed August 4, 2025, https://www.goodrx.com/xeljanz/interactions
34. Xeljanz - This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda, accessed August 4, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/203214s028,208246s013,213082s003lbl.pdf
35. Tofacitinib Dosage Guide + Max Dose, Adjustments - Drugs.com, accessed August 4, 2025, https://www.drugs.com/dosage/tofacitinib.html
36. highlights of prescribing information - Pfizer, accessed August 4, 2025, https://labeling.pfizer.com/showlabeling.aspx?id=959
37. Oral Rheumatoid Arthritis Trial - American College of Cardiology, accessed August 4, 2025, https://www.acc.org/Latest-in-Cardiology/Clinical-Trials/2022/02/01/15/21/ORAL-Surveillance
38. Xeljanz Blood Clots and Death Cases - Lieff Cabraser, accessed August 4, 2025, https://www.lieffcabraser.com/injury/drugs/xeljanz/
39. Dosing & Monitoring | XELJANZ® (tofacitinib) | Safety Info, accessed August 4, 2025, https://xeljanz.pfizerpro.com/r/dosing-and-monitoring
40. Tofacitinib: Uses, Dosage, Side Effects, Warnings - Drugs.com, accessed August 4, 2025, https://www.drugs.com/tofacitinib.html
41. Safety And Side Effects | XELJANZ® (tofacitinib) | Safety Info, accessed August 4, 2025, https://www.xeljanz.com/safety-side-effects/
42. UC Home Page | XELJANZ® (tofacitinib) | Safety Info - Pfizer For Professionals, accessed August 4, 2025, https://xeljanz.pfizerpro.com/uc/home
43. Malignancy risk with tofacitinib versus TNF inhibitors in rheumatoid ..., accessed August 4, 2025, https://ard.bmj.com/content/82/3/331
44. Analysis Offers Insight into Patients Most Likely to Derive Benefit from Tofacitinib - HCPLive, accessed August 4, 2025, https://www.hcplive.com/view/analysis-offers-insight-into-patients-most-likely-to-derive-benefit-from-tofacitinib
45. Identification of two tofacitinib subpopulations with different relative risk versus TNF inhibitors: an analysis of the open label, randomised controlled study ORAL Surveillance | Annals of the Rheumatic Diseases, accessed August 4, 2025, https://ard.bmj.com/content/82/7/901
46. Risk of major adverse cardiovascular events with tofacitinib versus ..., accessed August 4, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC9811099/
47. Xeljanz | European Medicines Agency (EMA), accessed August 4, 2025, https://www.ema.europa.eu/en/medicines/human/EPAR/xeljanz
48. Xeljanz Interactions Checker - Drugs.com, accessed August 4, 2025, https://www.drugs.com/drug-interactions/tofacitinib,xeljanz.html
49. Tofacitinib Interactions Checker - Drugs.com, accessed August 4, 2025, https://www.drugs.com/drug-interactions/tofacitinib.html
50. Xeljanz interactions: Other drugs, alcohol, and more - Medical News Today, accessed August 4, 2025, https://www.medicalnewstoday.com/articles/drugs-xeljanz-interactions
51. UC Dosing & Monitoring | XELJANZ® (tofacitinib) | Safety Info, accessed August 4, 2025, https://xeljanz.pfizerpro.com/uc/dosing-monitoring
52. Clinical Trials | XELJANZ® (tofacitinib) For RA | Safety Info, accessed August 4, 2025, https://www.xeljanz.com/ra/clinical-trials
53. Trial Data Further Supports Xeljanz Plus Methotrexate Combination in Rheumatoid Arthritis, accessed August 4, 2025, https://www.pharmacytimes.com/view/trial-data-further-supports-xeljanz-plus-methotrexate-combination-in-rheumatoid-arthritis
54. Clinical Trials | XELJANZ® (tofacitinib) For PsA | Safety Info, accessed August 4, 2025, https://www.xeljanz.com/psa/clinical-trials
55. Pfizer Announces Positive Top-Line Results from the First Phase 3 Trial of Investigational Tofacitinib in Adults with Psoriatic Arthritis, accessed August 4, 2025, https://www.pfizer.com/news/press-release/press-release-detail/pfizer_announces_positive_top_line_results_from_the_first_phase_3_trial_of_investigational_tofacitinib_in_adults_with_psoriatic_arthritis
56. Efficacy of Tofacitinib for the Treatment of Psoriatic Arthritis: Pooled Analysis of Two Phase 3 Studies - PMC, accessed August 4, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC6251851/
57. Tofacitinib In Psoriatic Arthritis Subjects With Inadequate Response to TNF Inhibitors (OPAL BEYOND) - ClinicalTrials.gov, accessed August 4, 2025, https://clinicaltrials.gov/study/NCT01882439
58. Tofacitinib in the treatment of ulcerative colitis: efficacy and safety from clinical trials to real-world experience, accessed August 4, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC6535722/
59. Pfizer Announces Positive Top-Line Results from Two Phase 3 Trials of Oral Tofacitinib in Adults with Moderate-to-Severe Ulcerative Colitis | Fierce Pharma, accessed August 4, 2025, https://www.fiercepharma.com/pharma/pfizer-announces-positive-top-line-results-from-two-phase-3-trials-of-oral-tofacitinib
60. Clinical Trials | XELJANZ® (tofacitinib) For UC | Safety Info, accessed August 4, 2025, https://www.xeljanz.com/uc/clinical-trials
61. ORAL Surveillance Study | XELJANZ® (tofacitinib) | Safety Info, accessed August 4, 2025, https://xeljanz.pfizerpro.com/r/efficacy-safety/oral-surveillance-pooled-safety-analysis-ra
62. Relative Efficacy and Safety of Tofacitinib, Baricitinib, Upadacitinib ..., accessed August 4, 2025, https://imidforum.com/publications/297/relative-efficacy-and-safety-of-tofacitinib-baricitinib-upadacitinib-and-filgotinib-in-comparison-to-adalimumab-in-patients-with-active-rheumatoid-arthritis
63. Are all JAK inhibitors for the treatment of rheumatoid arthritis equivalent? An adjusted indirect comparison of the efficacy of tofacitinib, baricitinib, upadacitinib, and filgotinib - PubMed, accessed August 4, 2025, https://pubmed.ncbi.nlm.nih.gov/37831336/
64. Comparative Efficacy of JAK Inhibitors for Moderate-To-Severe Rheumatoid Arthritis: A Network Meta-Analysis, accessed August 4, 2025, https://www.analysisgroup.com/Insights/publishing/comparative-efficacy-of-jak-inhibitors-for-moderate-to-severe-rheumatoid-arthritis-a-network-meta-analysis/
65. Tofacitinib, Baricitinib, Upadacitinib, Filgotinib or Peficitinib? Study Compares Five Rheumatoid Arthritis Monotherapies - Docwire News, accessed August 4, 2025, https://www.docwirenews.com/post/tofacitinib-baricitinib-upadacitinib-filgotinib-or-peficitinib-study-compares-five-rheumatoid-arthritis-monotherapies
66. Characteristics of adverse event reporting of Xeljanz/Xeljanz XR, accessed August 4, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC10372959/
67. Off-label studies on tofacitinib in dermatology: a review - Northwestern Scholars, accessed August 4, 2025, https://www.scholars.northwestern.edu/en/publications/off-label-studies-on-tofacitinib-in-dermatology-a-review
68. Off-label studies on tofacitinib in dermatology: a review - PubMed, accessed August 4, 2025, https://pubmed.ncbi.nlm.nih.gov/31581859/
69. Off-label use of tofacitinib: a potential treatment option for SAPHO syndrome - Annals of the Rheumatic Diseases, accessed August 4, 2025, https://ard.bmj.com/content/annrheumdis/early/2020/06/11/annrheumdis-2020-217854.full.pdf
70. Off-label use of tofacitinib: a potential treatment option for SAPHO syndrome | Annals of the Rheumatic Diseases, accessed August 4, 2025, https://ard.bmj.com/content/81/6/e91
71. Xeljanz (tofacitinib) Reviews and User Ratings: Effectiveness, Ease ..., accessed August 4, 2025, https://reviews.webmd.com/drugs/drugreview-162865-xeljanz-oral
72. Tofacitinib Reviews & Ratings - Drugs.com, accessed August 4, 2025, https://www.drugs.com/comments/tofacitinib/
73. Lisa's Story | Rx XELJANZ® (tofacitinib) | Safety Info, accessed August 4, 2025, https://www.xeljanz.com/patients-in-focus/lisa
74. Real-life experience of tofacitinib in patients with treatment-resistant rheumatoid arthritis: A 5-year follow-up, accessed August 4, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC9514069/
75. Experience with Tofacitinib in Patients with Ulcerative Colitis: Data from a United States Claims Database - PubMed, accessed August 4, 2025, https://pubmed.ncbi.nlm.nih.gov/37639057/