ObjectiveTo evaluate the long-term safety profile for upadacitinib across rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS) and atopic dermatitis (AD).MethodsSafety data from clinical trials of upadacitinib 15 mg and upadacitinib 30 mg (AD only) for treating RA, PsA, AS and AD as of 30 June 2021 were analysed; some RA and PsA studies included adalimumab and methotrexate as active comparators. Treatment-emergent adverse events (TEAEs) were presented by disease as exposure-adjusted event rates per 100 patient years (E/100 PY).ResultsThe analysis included 6991 patients (RA, n=3209; PsA, n=907; AS, n=182; AD, n=2693) who received at least one dose of upadacitinib, representing 15 425 PY of exposure (maximum duration 2.75–5.45 years) across diseases. Rates (E/100 PY) of any TEAE (205.5–278.1) and TEAE leading to discontinuation (4.5–5.4) were similar across diseases; serious TEAEs were numerically higher in patients with RA and PsA. Rates of herpes zoster (1.6–3.6), non-melanoma skin cancer (0–0.8) and elevations in creatine phosphokinase levels (4.4–7.9) were higher with upadacitinib than with active comparators in the RA and PsA populations. Deaths (0–0.8), serious infections (0–3.9), major adverse cardiovascular events (0–0.4), venous thromboembolism (<0.1–0.4) and malignancies (0.3–1.4) were observed, with rates generally lowest in AS and AD. Increased rates of acne were observed in patients with AD only.ConclusionsFindings from this analysis demonstrate that upadacitinib is generally well tolerated with observed differences in safety profiles likely reflective of varying patient characteristics across RA, PsA, AS and AD populations.Trial registration numbersNCT02675426,NCT02706951,NCT02706847,NCT02629159,NCT02706873,NCT03086343,NCT03104374,NCT03104400,NCT03178487,NCT03569293,NCT03568318andNCT03607422.