Upadacitinib

Upadacitinib is a selective and reversible JAK inhibitor. In adult patients, upadacitinib has been approved since December 2019 for the treatment of moderate to severe active rheumatoid arthritis and active psoriatic arthritis who have had an inadequate response to or are intolerant to one or more disease-modifying antirheumatic drugs(DMARDs). Upadacitinib can be used as monotherapy or in combination with methotrexate. It is also approved for the treatment of moderate to severe atopic dermatitis in adults and adolescents aged 12 years and older who are eligible for systemic therapy*. Furthermore, the preparation can be used to treat active ankylosing spondylitis in adult patients who have responded inadequately to conventional therapy.

There are individual reports of positive effects of upadacitinib in erosive lichen planus and recurrent erythema multiforme (Balestri R et al. 2022/Murphy MJ et al. 2021).

Upadacitinib is a selective and reversible JAK inhibitor. In human cell-based assays, upadacitinib preferentially inhibits JAK1 or JAK1/3 signaling pathways compared to other cytokine signaling pathways mediated through JAK2 pairs. This results in inhibition of STAT3 phosphorylation induced by IL-6 and STAT5 phosphorylation induced by IL-7. Maximal inhibition was observed one hour after ingestion and fell back to near initial levels by the end of the application interval. The mean terminal elimination half-life is 9 to 14 hours; this allows for once-daily (oral) administration.

In the clinical trials, patients treated with upadacitinib achieved significant improvements in patient-reported quality of life as measured by the physical domain of the short-form-36 health questionnaire (SF-36) compared to placebo and MTX. In addition, patients treated with upadacitinib reported significant improvement in fatigue as measured by the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) compared to patients treated with placebo.

Psoriatic arthritis: The efficacy and safety of upadacitinib 15 mg once daily were evaluated in two randomized, double-blind, multicenter, placebo-controlled Phase III studies in patients 18 years of age and older with moderate-to-severe active psoriatic arthritis. Significant improvement in psoriatic arthritis (classified according to CASPAR Classification Criteria for Psoriatic Arthritis - at least 3 tender joints and at least 3 swollen joints, plus active plaque psoriasis or a history of plaque psoriasis) was also demonstrated in these patients.

SELECT-PsA 1 was a 24-week study of 1,705 patients with inadequate response to or intolerance to at least one nonbiologic DMARD. Upadacitinib monotherapy showed statistically significant improvements in clinical and functional outcomes compared with methotrexate continuation (Smolen JS et al 2019).

The recommended dose of upadacitinib is 15 mg or 30 mg orally once daily. In patients with ankylosing spondylitis who do not show a clinical response after 16 weeks of treatment, discontinuation of treatment should be considered. Some patients with an initial partial response may improve over the course of continued treatment beyond 16 weeks. Treatment shouldnot be started in patients with an absolute lymphocyte count (ALC) < 500 ^cells/mm3, an absolute neutrophil count (ANC) of < 1,000 ^cells/mm3 or a hemoglobin level of < 8 g/dl In elderly patients No dose adjustment is required in patients aged 65 years and over.

Renal insufficiency: No dose adjustment is required in patients with mild or moderate renal insufficiency. Upadacitinib should be used with caution in patients with severe renal insufficiency.

Hepatic insufficiency: No dose adjustment is required in patients with mild(Child-Pugh A) or moderate (Child-Pugh B) hepatic insufficiency. Upadacitinib must not be used in patients with severe hepatic insufficiency (Child-Pugh C).

Children and adolescents: The safety and efficacy of upadacitinib in children and adolescents aged 0 to under 18 years have not yet been established. No data are available.

Route of administration: Upadacitinib is to be taken orally once daily with or without a meal at any time.

Monitoring of the following laboratory parameters is recommended:

• Absolute neutrophil count (ANC): Treatment should be discontinued if ANC is < 1,000 ^cells/mm3 and restarted after ANC rises above this level.
• Absolute lymphocyte count (ALC): Treatment should be interrupted at an ALC of < 500 cells/mm3 and restarted after the ALC rises above this value. Hemoglobin (Hb): Treatment should be interrupted at an Hb level of < 8 g/dl and may only be restarted after Hb rises above this level.
• Liver transaminases: If drug-induced liver damage is suspected, treatment should be temporarily interrupted.
• Lipids: Patients should be treated according to international clinical guidelines for hyperlipidemia.

Opportunistic infections. Observed during upadacitinib treatment were tuberculosis, multidermatomal herpes zoster, oral/esophageal candidiasis, and cryptococcosis. Neutropenia, hypercholesterolemia, increase in liver transaminases are common. Increase in creatine kinase and weight gain.

Serious Infections: Ser ious infections, including those with fatal outcomes, have been reported in patients receiving upadacitinib. The most commonly reported serious infections reported with upadacitinib included pneumonia and cellulitis (erysipelas).

Viral reactivation: Viral reactivations, including cases of reactivation of herpes viruses (e.g., herpes zoster), have been reported in clinical trials.

Non-melanoma skin cancer: NMSCs have been reported in patients treated with upadacitinib. Regular skin examination is recommended in patients at increased risk for skin cancer.

Hypersensitivity to the active substance.

Active tuberculosis (TB) or active serious other infections.

Severe hepatic insufficiency.

Pregnancy

Rinvoq®

Combination with other potent immunosuppressants such as azathioprine, ciclosporin, tacrolimus and biological DMARDs or other Janus kinase (JAK) inhibitors has not been studied in clinical trials and is not recommended because the risk of additional immunosuppressive effects cannot be excluded. In patients with active serious infection, including local infections, treatment with upadacitinib must not be started.

Vaccinations: No data are available on the response to vaccination with live or inactivated vaccines in patients receiving upadacitinib treatment. The use of live attenuated vaccines during or immediately prior to treatment with upadacitinib is not recommended.

Prior to initiation of therapy with upadacitinib, it is recommended that patients' vaccination status be reviewed according to current vaccination guidelines and that all required vaccinations be obtained; this includes prophylactic vaccination against herpes zoster.

Tuberculosis: Tuberculosis (TB) screening should be performed prior to initiation of therapy with upadacitinib. In patients with untreated latent TB or in patients with risk factors for TB infection, consider anti-TB therapy prior to initiation of treatment with upadacitinib.

1. Balestri R et al. (2022) Treatment of Oral Erosive Lichen Planus With Upadacitinib. JAMA Dermatol 158: 457-458.

2. Fleischmann R et al. (2019) Upadacitinib Versus Placebo or Adalimumab in Patients With Rheumatoid Arthritis and an Inadequate Response to Methotrexate: Results of a Phase III, Double-Blind, Randomized Controlled Trial. Arthritis Rheumatol 71:1788-1800.
3. Guttman-Yassky E et al. (2019) Upadacitinib in adults with moderate to severe atopic dermatitis: 16-week results from a randomized, placebo-controlled trial. J Allergy Clin Immunol 145:877-884.

4. Murphy MJ et al. (2021) Treatment of Persistent Erythema Multiforme With Janus Kinase Inhibition and the Role of Interferon Gamma and Interleukin 15 in Its Pathogenesis. JAMA Dermatol 157:1477-1482.

5. Rubbert-Roth A et al. (2020) Trial of Upadacitinib or Abatacept in Rheumatoid Arthritis. N Engl J Med. 383:1511-1521.
6. Serhal L et al. (2019) Upadacitinib for the treatment of rheumatoid arthritis.Expert Rev Clin Immunol 15:13-25.
7. Smolen JS et al. (2019) Upadacitinib as monotherapy in patients with active rheumatoid arthritis and inadequate response to methotrexate (SELECT-MONOTHERAPY): a randomized, placebo-controlled, double-blind phase 3 study. Lancet 393:2303-2311.