Highlights
- Five years of treat-to-target urate-lowering therapy (T2T-ULT) significantly reduces serum uric acid (sUA) levels and ultrasonographically detected monosodium urate crystal deposits in gout patients.
- Complete dissolution of ultrasound-detected double contour and tophi occurs in the majority of patients, with assessment of first metatarsophalangeal joints proving most informative.
- Long-term therapy substantially reduces clinical gout flares, with residual flares associated with higher sUA and crystal burden.
- Gout remission rates increase markedly over 5 years using various remission criteria, correlating with improved quality of life and structural improvements.
- High medication adherence over 5 years is critical for urate target achievement and flare prevention; younger age, non-European origin, and lower mental health scores predict non-adherence.
Background
Gout is a prevalent inflammatory arthritis characterized by monosodium urate (MSU) crystal deposition in joints, leading to acute flares and chronic joint damage. Management centers on lowering serum uric acid (sUA) to prevent crystal formation and promote dissolution. Clinical guidelines advocate treat-to-target urate-lowering therapy (T2T-ULT) aimed at maintaining sUA below 360 μmol/L to prevent flares and joint damage. Yet, data on the long-term impact of maintaining low sUA on MSU crystal burden as detected by musculoskeletal ultrasound and clinical outcomes remains limited. The NOR-Gout study addresses this gap by evaluating sustained T2T-ULT over 5 years with serial ultrasound monitoring, flare recording, remission assessments, and adherence evaluation.
Key Content
Study Design and Patient Population
The 5-year observational NOR-Gout study enrolled 209 patients with recent gout flares (mean age 56.4 years, mean disease duration 7.9 years). Patients initiated T2T-ULT with sUA targets set below 360 μmol/L and were followed systematically at baseline, 1, 2, and 5 years. Year 1 outpatient rheumatology clinic visits transitioned to general practitioner follow-up for years 2–5. Assessments included sUA measurements, detailed musculoskeletal ultrasound of crystal depositions (double contour sign, tophi, aggregates) in bilateral hands, elbows, knees, ankles, and feet, and recording of gout flares in the preceding year.
Reduction and Dissolution of Crystal Depositions
At 5 years, 163 patients completed follow-up with significant reduction in mean sUA from 500 to 337 μmol/L (P < .001). The proportion achieving target sUA (<360 μmol/L) was 71.2%. Ultrasound evaluations showed statistically significant decreases in all categories of crystal deposition (P < .001). Notably, complete dissolution was observed in 83.4% for the double contour sign and 63.2% for tophi. Evaluating only the first metatarsophalangeal (MTP1) joints identified the majority of these patients, emphasizing its clinical utility as a sentinel joint in gout management monitoring. These findings document that intensive T2T-ULT leads to not merely reduction but often full resolution of pathologic crystal deposits over extended treatment.
Clinical Flare Dynamics and Predictors
Flares remained frequent during the initial treatment year, particularly months 3–6, with 81% experiencing at least one flare. However, flare rates declined sharply to 26% during year 2 and further to 16% by year 5. Patients who experienced flares during the last year of follow-up had significantly higher sUA and persistent crystal depositions (P-values ranging from .035 to .006). Baseline ultrasound- and DECT-detected crystal burden independently predicted flares both within the first year and at 2 years, alongside baseline subcutaneous tophi and prior colchicine use, which increased flare risk during months 9–12. Self-efficacy for pain was protective, highlighting psychosocial factors in flare occurrence.
Remission Rates and Quality of Life Outcomes
Using three distinct gout remission definitions (preliminary, modified preliminary, and simplified), remission frequency rose substantially from around 5% at 1 year to 43–59% by 5 years (p < 0.001). The simplified definition consistently identified more patients in remission at 2 and 5 years. All definitions correlated well with patient-reported outcomes such as SF-36 mental and physical component scores and structural changes detected by DECT imaging, underscoring clinical and quality of life improvements linked to remission status.
Medication Adherence and Its Impact on Outcomes
At 5 years, 95.1% of patients reported ongoing ULT use with high adherence scores based on the Medication Adherence Report Scale (MARS-5), median 24/25. Patients in the lowest adherence quartile had significantly more flares (33.3% vs. 9.5%, P=0.004) and less frequently reached sUA targets (45.2% vs. 87.5%, P<0.001) compared to the highest quartile. Predictors of non-adherence included younger age, non-European ethnicity, lower mental health scores, and less joint pain during the last flare, highlighting population subsets requiring targeted adherence support.
Expert Commentary
The NOR-Gout study offers robust longitudinal evidence affirming that sustained T2T-ULT not only lowers serum urate but promotes progressive resolution of urate crystal depositions observable by ultrasound, consistent with clinical remission and reduced flare frequency. This supports emerging consensus that tight urate control is disease-modifying rather than simply symptom-controlling.
The study’s integration of imaging biomarkers and patient-centered outcomes enhances clinical understanding of gout pathophysiology and treatment goals. The demonstrated high remission rates at 5 years challenge previous notions of gout as an invariably chronic, recurring disease, suggesting that with consistent therapy and adherence, disease remission is attainable.
However, the persistent flare risk in some patients underscores the heterogeneity of disease biology and the need for individualized management, including adherence strategies, psychosocial support, and early treatment initiation. The study also underscores the clinical utility of ultrasound, particularly at MTP1 joints, as a non-invasive, accessible tool for monitoring urate crystal burden and therapeutic response.
Despite its strengths, the study population predominantly male and European limits generalizability. The observational design, while pragmatic, may be affected by adherence-related selection biases. Nonetheless, findings align with guideline recommendations advocating early and sustained urate lowering. Future studies could explore mechanistic pathways underlying residual flares and crystal persistence despite urate control.
Conclusion
The 5-year NOR-Gout study demonstrates that treat-to-target urate-lowering therapy effectively achieves sustained low serum urate, continuous reduction and dissolution of ultrasound-detected crystal deposits, and substantial flare reduction. Remission in gout is achievable and correlates with structural and quality of life improvements. High medication adherence is crucial to optimize outcomes. These findings reinforce the paradigm of gout as a treatable and potentially reversible crystal arthropathy, emphasizing the importance of sustained urate control and monitoring in clinical practice.
References
- Hammer HB, Karoliussen L, Terslev L, Haavardsholm EA, Uhlig T. Ultrasound-detected crystal depositions and clinical flares dissolve during successful urate-lowering therapy: 5-year follow-up results from the treat-to-target NOR-Gout study. Ann Rheum Dis. 2025 Nov 20:S0003-4967(25)04517-0. doi: 10.1016/j.ard.2025.10.029. Epub ahead of print. PMID: 41271521.
- Uhlig T, Karoliussen LF, Sexton J, Provan SA, Haavardsholm EA, Dalbeth N, Hammer HB. Non-adherence to urate lowering therapy in gout after 5 years is related to poor outcomes: results from the NOR-Gout study. Rheumatology (Oxford). 2025 Apr 1;64(4):1799-1806. doi: 10.1093/rheumatology/keae514. PMID: 39292608; PMCID: PMC11962959.
- Uhlig T, Karoliussen LF, Sexton J, Kvien TK, Haavardsholm EA, Perez-Ruiz F, Hammer HB. One- and 2-year flare rates after treat-to-target and tight-control therapy of gout: results from the NOR-Gout study. Arthritis Res Ther. 2022 Apr 20;24(1):88. doi: 10.1186/s13075-022-02772-3. PMID: 35443675; PMCID: PMC9020166.
- Uhlig T, Stjärne J, Karoliussen LF, Sexton J, Eskild T, Provan SA, Haavardsholm EA, Hammer HB. Remission in gout is possible: 5-year follow-up in the NOR-Gout study. Semin Arthritis Rheum. 2025 Jun;72:152698. doi: 10.1016/j.semarthrit.2025.152698. Epub 2025 Feb 27. PMID: 40056480.
