Long-term safety and efficacy of upadacitinib compared with adalimumab in patients with rheumatoid arthritis: 7-year data from the SELECT-COMPARE study.

TL;DR

In a 7-year trial, the JAK inhibitor upadacitinib maintained disease control comparable to adalimumab (a TNF inhibitor) in rheumatoid arthritis patients, with similar overall safety profiles but numerically higher rates of herpes zoster and skin cancer.

What the Study Found

The SELECT-COMPARE trial represents one of the longest head-to-head comparisons of a JAK inhibitor against a conventional biologic in rheumatoid arthritis. Researchers tracked 651 RA patients inadequately controlled on methotrexate alone, randomizing them to either upadacitinib (15 mg daily), adalimumab (40 mg every two weeks), or placebo, all on a methotrexate background. The primary comparison ran for 48 weeks, but patients who responded were eligible to continue into a 10-year extension phase, allowing assessment of long-term outcomes.

By week 372 (approximately 7 years), disease remission rates were substantial in patients who remained on continuous therapy. Using as-observed analysis (patients still in the study and on their original assigned therapy), 63% of upadacitinib recipients achieved remission by Clinical Disease Activity Index versus 53.5% on adalimumab. When examining a stricter remission definition based on the 28-joint Disease Activity Score and C-reactive protein levels, 83.2% of upadacitinib patients versus 72.8% on adalimumab achieved remission. These response rates held steady over the full 7-year period, suggesting both therapies maintained their anti-inflammatory effects without evidence of waning efficacy or "loss of response" over time.

Safety signals require careful interpretation. Overall treatment-emergent adverse event rates were numerically comparable between groups, but upadacitinib showed a higher frequency of several specific complications: herpes zoster reactivation, elevations in creatine phosphokinase (a muscle enzyme), non-melanoma skin cancer, lymphopenia (low white blood cell counts), and hepatic (liver) abnormalities. None of these reached dramatic difference levels in the reported data, but the consistent pattern across multiple organ systems aligns with known JAK inhibitor biology. JAK inhibitors suppress immune signaling more broadly than TNF inhibitors, which theoretically increases infection risk and may alter immune surveillance against malignancy. The trial found no new safety signals emerging in years 5-7, indicating the risk profile did not deteriorate with extended exposure.

Patients who initially failed their assigned therapy (randomized to placebo or showing inadequate response to monotherapy) were eligible for "rescue" switching to the alternate drug. Among these switchers, those moved to upadacitinib showed clinical improvement that persisted through week 336 post-switch without additional safety complications. This finding suggests JAK inhibition remained effective even in patients previously unresponsive to TNF blockade, a clinically relevant observation since treatment sequencing remains a key decision in RA management.

What This Means for You

If you have rheumatoid arthritis already on methotrexate, this trial provides the longest direct safety and efficacy comparison available for upadacitinib versus adalimumab. Both therapies achieved meaningful disease remission in the majority of patients over 7 years. The choice between them should incorporate individual risk factors: upadacitinib may carry a slightly elevated baseline risk for shingles and skin cancer, whereas TNF inhibitors have different infection and malignancy profiles. Neither approach guarantees remission, and approximately 1 in 3-4 patients on upadacitinib failed to achieve remission even in this trial, underscoring that RA remains heterogeneous and difficult to control in some individuals.

The practical takeaway is that extended JAK inhibitor use appears safe through at least 7 years in this population, without evidence of accumulated toxicity or loss of efficacy. However, these benefits assume adequate monitoring for blood counts, liver function, and screening for infections and skin changes. If you are considering either therapy, discuss your personal risk profile for zoster (vaccination status), prior skin cancers, and any susceptibility to serious infections with your rheumatologist. The rescue data also suggests trying the other class may help if your current biologic has plateaued.

Study Details

Sources

SELECT-COMPARE 7-year data - PubMed