In December 2021, the US Food and Drug Administration (FDA) approved upadacitinib (Rinvoq® [AbbVie, Inc.]), a Janus kinase (JAK) inhibitor, for the treatment of adults with active psoriatic arthritis with an inadequate response or who demonstrate intolerance to at least 1 tumor necrosis factor (TNF) blocker.
Upadacitinib acts by inhibiting intracellular JAK enzymes, which transmit signals arising from cytokine or growth factor-receptor interactions on the cellular membrane to influence cellular processes of hematopoiesis and immune cell function. Within the signaling pathway, phosphorylation of JAKs promotes the activation of signal transducers and activators of transcription (STATs), which influence intracellular activity, including gene expression. By preventing the phosphorylation of JAKs, upadacitinib inhibits the activation of STATs and modulates the signaling pathway.
Additional indications for Rinvoq include the treatment of adults with moderately to severely active rheumatoid arthritis with an inadequate response or who demonstrate intolerance to at least 1 TNF blocker and the treatment of patients at least 12 years of age with refractory, moderate to severe atopic dermatitis that is not adequately controlled with other systemic drug products, including biologics, or when use of those therapies is inadvisable.
Coadministration of Rinvoq with other JAK inhibitors, biologic disease-modifying antirheumatic drugs (DMARDs), or other potent immunosuppressants is not recommended.
The approval of Rinvoq for psoriatic arthritis was based on the results of 2 clinical trials — SELECT-PsA 1 (ClinicalTrials.gov Identifier: NCT03104400) and SELECT-PsA 2 (ClinicalTrials.gov Identifier: NCT03104374) — that evaluated the safety and efficacy of the drug in patients with moderately to severely active psoriatic arthritis.
The studies were randomized, double-blind, multicenter, placebo-controlled, phase 3 clinical trials. Study participants were required to be at least 18 years old with active psoriatic arthritis for at least 6 months according to the Classification Criteria for Psoriatic Arthritis (CASPAR), with at least 3 tender joints and at least 3 swollen joints, and either current or a history of active plaque psoriasis. Both studies included patients with moderate to severe, active psoriatic arthritis with inadequate response to or who were intolerant of at least 1 therapy (nonbiologic DMARDs for SELECT-PsA 1 and biologic DMARDs for SELECT-PsA 2).
SELECT-PsA 1 included 1704 patients who received upadacitinib 15 mg or 30 mg orally once daily, subcutaneous adalimumab, or placebo, either alone or combined with nonbiologic DMARDs. In a blinded manner, all patients who were randomly assigned to placebo initiated treatment with upadacitinib 15 mg or 30 mg once daily at week 24. The primary endpoint of SELECT-PsA 1 was the proportion of patients who attained an American College of Rheumatology ≥20% (ACR20) response at week 12.
SELECT-PsA 2 included 642 patients who received upadacitinib 15 mg, upadacitinib 30 mg once daily, or placebo, either alone or combined with nonbiologic DMARDs. In a blinded manner, all patients who were randomly assigned to placebo initiated upadacitinib 15 mg or 30 mg once daily at week 24. The primary endpoint of SELECT PsA-II was the proportion of patients who attained an ACR20 response at week 12.
Efficacy findings revealed significantly higher ACR20, ACR50, and ACR70 response rates in patients who received upadacitinib 15 mg compared with placebo at week 12 (Table 1). At the primary efficacy time point, improvements in the ACR components were also observed in patients who received treatment with upadacitinib 15 mg compared with placebo (Table 2).
Treatment with upadacitinib 15 mg was also found to be associated with improvement in dactylitis and enthesitis in patients with these conditions, as well as improvement in skin manifestations in patients with psoriatic arthritis.
Results obtained from both clinical trials also revealed significant improvement in physical function from baseline in patients who received upadacitinib 15 mg compared with placebo. At week 12, the mean difference from placebo in the Health Assessment Questionnaire-Disability Index (HAQ-DI) change from baseline was reported to be -0.28 (95% CI, -0.35 to -0.22) in SELECT-PsA 1 and -0.21 (95% CI, -0.30 to -0.12) in SELECT-PsA 2.
Additionally, findings obtained from SELECT-PsA 1 revealed the proportion of HAQ-DI responders (defined as those experiencing a ≥0.35 improvement in HAQ-DI score from baseline) to be 58% for the upadacitinib group compared with 33% for the placebo group at week 12. Results obtained from Study PsA-II showed 45% of the treatment group to be HAQ-DI responders at week 12 compared with 27% of the placebo group.
Radiographic response was also assessed in SELECT-PsA 1 at week 24. This was expressed as the change from baseline in modified Total Sharp Score (mTSS) and its components, the erosion score, and the joint space narrowing score. At week 24, structural joint damage progression was found to be inhibited in patients who received treatment with upadacitinib 15 mg, with the estimated difference in mTSS between treatment vs placebo reported to be -0.25 (95% CI, -0.41 to -0.09). Consistent results were observed when analyzing erosion and joint space narrowing scores. Additionally, at week 24, no radiographic progression (mTSS change ≤0) occurred in 93% of patients who received therapy with upadacitinib compared with 89% of those who received placebo.
In both clinical trials, the 36-Item Short Form Health Survey Physical Component Summary (SF-36) was used to assess health-related quality of life outcomes. Findings obtained from both studies showed a significantly greater improvement in the Physical Component Summary score from baseline in patients who received upadacitinib 15 mg compared with placebo at week 12. Improvement in the Mental Component Summary score, as well as in all domains of SF-36, in patients treated with upadacitinib was also observed compared with placebo. Additionally, both studies showed a greater improvement in fatigue from baseline, as measured by the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) score, among patients who received upadacitinib 15 mg compared with those who received placebo at week 12.
The safety population included 1827 patients with psoriatic arthritis who received upadacitinib during the clinical studies. This population represented 1639.2 patient-years of exposure, and 722 patients were exposed to upadacitinib for at least 1 year. A total of 907 patients received at least 1 dose of upadacitinib 15 mg during the clinical studies; 359 of these patients were exposed to the drug for at least 1 year.
To evaluate the safety of Rinvoq, the 2 clinical studies were integrated and included 640 patients who received upadacitinib 15 mg once daily and 635 patients who received placebo. Safety findings revealed the frequencies of herpes zoster and herpes simplex were 1.1% and 1.4%, respectively, in patients who received upadacitinib compared with 0.8% and 1.3%, respectively, in those who received placebo during the 24-week period. Treatment with upadacitinib was also found to be associated with a higher incidence of acne and bronchitis (1.3% and 3.9%, respectively) compared with placebo (0.3% and 2.7%, respectively).
Dosage and Administration
Rinvoq is supplied as 15-mg and 30-mg extended-release tablets. The recommended dosage of Rinvoq for the treatment of psoriatic arthritis is 15 mg once daily orally with or without food. In addition to verifying immunization status, certain evaluations should be considered prior to initiating treatment (Figure 1).
Treatment with Rinvoq should be interrupted in patients who develop a serious infection until the infection is controlled.
Rinvoq dosing should be interrupted in patients presenting with any of the following laboratory abnormalities: absolute neutrophil count (ANC) <1000 cells/mm3, absolute lymphocyte count (ALC) <500 cells/mm3, or hemoglobin (Hb) level <8 g/dL. Treatment can resume once the values are in the normal range.
If drug-induced liver injury is suspected due to abnormal levels of hepatic transaminases, Rinvoq should be interrupted until this diagnosis is excluded.
Contraindications, Warnings, Precautions, and Adverse Reactions
Rinvoq is contraindicated in patients with a hypersensitivity to upadacitinib or any of its components.
The prescribing information for Rinvoq includes a Boxed Warning regarding the risk of serious and sometimes fatal infections. The most frequent serious infections reported with Rinvoq use were pneumonia and cellulitis. Opportunistic infections have also been reported with Rinvoq use. These include tuberculosis (TB), multidermatomal herpes zoster, oral/esophageal candidiasis, and cryptococcosis.
Rinvoq should be avoided in patients with active serious infections, including localized infections. Prior to initiation, the risks and benefits of treatment with Rinvoq must be considered in patients with chronic or recurrent infections, underlying conditions that predispose them to infection, a past exposure to tuberculosis, or history of a serious or an opportunistic infection.
Additionally, treatment risks and benefits should be considered in patients who have resided in or traveled to areas of endemic tuberculosis or mycoses.
Patients should be monitored for signs and symptoms of an infection during and after treatment with Rinvoq. Development of a serious or opportunistic infection requires the interruption of Rinvoq.
In patients who develop a new infection while being treated with Rinvoq, immediate and complete diagnostic testing that is appropriate for an immunocompromised patient should be completed. Antimicrobial therapy should be initiated, and Rinvoq should be interrupted if the patient is not responding appropriately. Once the infection is controlled, Rinvoq may be resumed.
Prior to initiation of Rinvoq, patients should be evaluated and tested for both latent as well as active TB infection. Rinvoq should be avoided in patients with active TB, and treatment initiation should be delayed in patients with latent TB until standard antimycobacterial therapy is complete. Prior to initiating Rinvoq, anti-TB therapy should be considered in patients with previously untreated latent or active TB in whom an adequate course of treatment cannot be confirmed and in those with a negative test for latent TB but who are at risk for infection. A physician specializing in TB treatment should be consulted to determine whether anti-TB therapy is appropriate. Patients should be monitored for signs and symptoms of TB during treatment with Rinvoq.
During clinical trials, Rinvoq was found to cause viral reactivation, including herpes virus reactivation as well as hepatitis B reactivation. Rinvoq should be temporarily discontinued in patients who develop herpes zoster until the episode resolves. Prior to initiation of and during therapy with Rinvoq, viral hepatitis screenings and monitoring for reactivation should be completed according to clinical guidelines.
Clinical trials excluded patients who were positive for hepatitis C antibody, hepatitis C virus RNA, hepatitis B surface antigen, and hepatitis B virus DNA. Cases of hepatitis B reactivation were still reported in clinical trials assessing Rinvoq. A liver specialist should be consulted if detection of hepatitis B virus DNA occurs during treatment with Rinvoq.
The prescribing information for Rinvoq includes a Boxed Warning regarding the increased risk of all-cause mortality. Findings of a postmarketing safety study in patients with rheumatoid arthritis revealed another JAK inhibitor to be associated with a higher rate of all-cause mortality, including sudden cardiovascular death, compared with TNF blockers. The risks and benefits of treatment with Rinvoq should be considered for each individual patient.
Malignancy and Lymphoproliferative Disorders
The prescribing information for Rinvoq includes a Boxed Warning regarding the incidence of malignancies, including lymphomas, observed during clinical trials in patients treated with Rinvoq. A postmarketing safety study observed an increased rate of malignancies (excluding nonmelanoma skin cancer [NMSC]) in patients with rheumatoid arthritis who received treatment with another JAK inhibitor compared with patients who received TNF blockers. Similarly, the rate of lung cancers was found to be higher among patients who smoked or had a history of smoking who were treated with a JAK inhibitor compared with those who received TNF blockers. Findings of this study also observed an additional increased risk of overall malignancies in current or past smokers.
The risks and benefits of treatment with Rinvoq should be considered for each individual patient, especially in patients with a known malignancy (excluding cases of NMSC that are effectively managed), in patients who develop a malignancy during treatment, and in patients who smoke or have a history of smoking.
There have been reports of cases of NMSC in patients receiving Rinvoq. For patients with an increased skin cancer risk, periodic skin examinations are recommended. Protective clothing and broad-spectrum sunscreen should be utilized to limit exposure to sunlight and ultraviolet (UV) light.
Major Adverse Cardiovascular Events
The prescribing information for Rinvoq includes a Boxed Warning regarding the increased risk of major adverse cardiovascular events (MACE), which is defined as cardiovascular death, nonfatal myocardial infarction (MI), and nonfatal stroke. A large postmarketing safety study observed an increased risk of MACE associated with the use of another JAK inhibitor in patients with rheumatoid arthritis who were 50 years of age and older with at least 1 cardiovascular risk factor compared with those who received TNF blockers. An additional increased risk was observed in current or past smokers.
The risks and benefits of treatment with Rinvoq should be considered for each individual patient, especially in those with cardiovascular risk factors and those who smoke or have a history of smoking. Patients should be counseled on the symptoms and management of serious cardiovascular events. Rinvoq should be discontinued in patients who have experienced an MI or stroke.
The prescribing information for Rinvoq includes a Boxed Warning regarding the increased risk of thrombosis. Cases of thrombosis (deep venous thrombosis [DVT], pulmonary embolism [PE], and arterial thrombosis) have been reported in patients who received JAK inhibitors for the treatment of inflammatory conditions. A large number of these cases were considered to be serious, with some resulting in death.
A large postmarketing safety study observed an increased risk of thrombosis, DVT, and PE associated with the use of another JAK inhibitor in patients with rheumatoid arthritis who were 50 years of age and older with at least 1 cardiovascular risk factor compared with those who received TNF blockers.
Rinvoq should be avoided in patients at increased risk for thrombosis. Discontinuation of Rinvoq as well as prompt evaluation and treatment are recommended in patients who present with symptoms of thrombosis.
In clinical trials, cases of serious hypersensitivity reactions, including anaphylaxis and angioedema, have occurred in patients receiving Rinvoq. Rinvoq should be discontinued in patients who experience a clinically significant hypersensitivity reaction, and appropriate therapy should be initiated.
In clinical trials, cases of gastrointestinal perforations were reported in patients receiving Rinvoq. In these trials, a large number of patients were receiving nonsteroidal antiinflammatory drugs (NSAIDs) as background therapy. Patients receiving Rinvoq who are at increased risk for gastrointestinal perforation should be monitored closely and evaluated immediately if new-onset abdominal pain occurs.
Laboratory abnormalities have been observed in patients receiving Rinvoq (Figure 2).
Based on findings from animal studies, Rinvoq has the potential to cause fetal harm if administered to a pregnant woman. Increases in fetal malformations were observed when upadacitinib was administered to rats and rabbits during organogenesis.
The pregnancy status of patients of reproductive potential should be verified prior to the initiation of Rinvoq. Female patients of reproductive potential should be advised on the potential risk to the fetus and the importance of using effective contraception during Rinvoq treatment, as well as for 4 weeks following the last dose.
Use of live vaccines should be avoided immediately prior to as well as during Rinvoq therapy. It is recommended that patients be brought up to date on all immunizations prior to initiating therapy.
The metabolism of Rinvoq is mainly mediated by cytochrome P450 3A4 (CYP3A4).
Strong CYP3A4 Inhibitors
Co-administration of Rinvoq with a strong CYP3A4 inhibitor increases drug exposure as well as the risk of adverse events. Although no dose modification is required, patients should be monitored closely for adverse events during coadministration of Rinvoq 15 mg with a strong CYP3A4 inhibitor. It is recommended that coadministration of Rinvoq 30 mg with a strong CYP3A4 inhibitor be avoided.
Strong CYP3A4 Inducers
Co-administration of Rinvoq with a strong CYP3A4 inducer decreases drug exposure and reduces its therapeutic effect. It is recommended to avoid coadministration of Rinvoq with strong CYP3A4 inducers.
Considerations for Specific Populations
There is insufficient data on the risk associated with the use of Rinvoq during pregnancy. Based on animal study findings, use of Rinvoq has the potential to cause harm to a developing fetus.
No data currently exist on the presence of Rinvoq in breast milk, its effect in a breastfed child, or its effect on milk production/excretion. Based on animal study data, Rinvoq is excreted in milk. Due to its potential for excretion into human milk and its risk of harm to an infant, patients should be advised to avoid breastfeeding during treatment with Rinvoq and for 6 days following the last dose.
The efficacy and safety of Rinvoq have not been established in pediatric patients with psoriatic arthritis.
Findings of the 2 phase 3 psoriatic arthritis clinical trials showed no difference in treatment efficacy in patients with increasing age when analyzing patients 65 years of age and older. Results of these studies did find, however, a higher rate of overall adverse events, including serious infections, in older patients.
For patients with psoriatic arthritis, no dose adjustment is recommended with mild, moderate, or severe renal impairment.
No dose adjustment is recommended for patients with mild (Child Pugh A) or moderate (Child Pugh B) hepatic impairment. Rinvoq is not recommended in patients with severe hepatic impairment (Child Pugh C) as it has not been studied in this population.
- Rinvoq is approved for the treatment of active psoriatic arthritis in patients who have demonstrated an inadequate response or who are intolerant of at least 1 TNF inhibitor.
- The recommended dosage of Rinvoq for psoriatic arthritis is 15 mg once daily.
- Prior to initiating treatment, evaluate for TB, screen for viral hepatitis, obtain a complete blood count (CBC), evaluate baseline hepatic function, verify pregnancy status, and update immunizations.
Rinvoq. Package insert. AbbVie, Inc.; 2021. Accessed January 25, 2022. https://www.rxabbvie.com/pdf/rinvoq_pi.pdf
Posted by Haymarket’s Clinical Content Hub. The editorial staff of MPR had no role in this content’s preparation.
Reviewed March 2022