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Background: HLA-Cw6 is the strongest genetic marker associated with psoriasis susceptibility, but its role in psoriatic arthritis (PsA) remains unclear. Studies have suggested that HLA-Cw6 may influence specific disease domains, age of onset, and treatment response, but findings are inconsistent across populations. Understanding its phenotypic and therapeutic implications may improve PsA stratification and personalized management.
Objectives: To evaluate the association between HLA-Cw6 status and clinical characteristics, comorbidities, and therapeutic outcomes in PsA patients.
Methods: A retrospective observational study was conducted in 426 PsA patients fulfilling CASPAR criteria and with documented HLA-Cw6 typing. Demographic, clinical, analytical, and therapeutic data were extracted from electronic medical records. Descriptive, bivariate (Student’s t , Mann–Whitney U , χ 2 ) and multivariate logistic regression analyses were performed, adjusting for potential confounders. Odds ratios (OR) and 95% confidence intervals (CI) were calculated. P < 0.05 was considered statistically significant. The study was approved by the local Ethics Committee (ref. 110/25).
Results: HLA-Cw6 was positive in 24.6% of patients. Women were more frequent among HLA-Cw6–positive cases (65.7% vs. 46.1%; p = 0.001). Psoriasis onset occurred earlier (28.0 ± 15.7 vs. 35.3 ± 17.3 years; p = 0.009), with a longer psoriasis–PsA latency (17 vs. 9 years; p = 0.024). Dactylitis was less common (25.7% vs. 38.0%; p = 0.022), whereas no significant differences were found in PsA pattern, nail disease, CRP, DAPSA, or PsAID scores. HLA-Cw6–positive patients received more ts/bDMARD targets (1.8 ± 0.9 vs. 1.5 ± 0.8; p = 0.014) and had shorter TNFi persistence (17 vs. 36 months; p = 0.044). IL-12/23 inhibitors showed longer persistence in HLA-Cw6–positive patients (72 vs. 36 months), although this difference was not significant. In multivariable analysis, HLA-Cw6 positivity was independently associated with female sex (OR 4.11; p = 0.003), lower prevalence of dactylitis (OR 0.33; p = 0.020), and higher odds of belonging to the EULAR-defined difficult-to-manage (OR 12.53; p < 0.001) and treatment-refractory PsA groups (OR 15.39; p < 0.001). No significant differences were observed in methotrexate intolerance or major comorbidities. See Tables 1 and 2.
Conclusions: HLA-Cw6 identifies a PsA subset with distinct clinical and therapeutic features, including earlier psoriasis onset, longer cutaneous-articular latency, lower dactylitis frequency, and greater therapeutic complexity, with higher ts/bDMARD exposure and shorter TNFi persistence. IL-12/23 inhibitors may offer a relative advantage in this subgroup. These findings support the role of HLA-Cw6 as a potential biomarker for disease characterization and personalized treatment stratification in PsA.
Bivariate descriptive analysis of characteristics of the patients related to HLA-CW6 status
| HLA-Cw6 positive
| HLA-Cw6 negative
| p value | |
|---|---|---|---|
| Female sex (%) | 65.7 | 46.1 | 0.001 |
| BMI 1 | 26.9 ± 5.5 | 28.5 ± 5.3 | 0.059 |
| PsO age of onset (years) 1 | 28.0 ± 15.7 | 35.3 ± 17.3 | 0.009 |
| PsA age of onset (years) 1 | 48.2 ± 12.3 | 48.8 ± 12.8 | 0.643 |
| Delay between PsO and PsA onset (years) 2 | 17.0 [0 – 62.0] | 9.0 [0 – 59.0] | 0.024 |
| PsA pattern | |||
| Peripheral (%) | 88.6 | 91.0 | 0.470 |
| Axial (%) | 25.7 | 24.6 | 0.820 |
| Mixed (%) | 14.3 | 15.9 | 0.694 |
| Nail involvement (%) | 32.4 | 31.5 | 0.861 |
| Clinical enthesitis (%) | 18.1 | 19.3 | 0.782 |
| Dactylitis (%) | 25.7 | 38.0 | 0.022 |
| CRP (mg/L) 2 | 2.9 [0.2 – 30.2] | 3.4 [0.2 – 84.6] | 0.163 |
| DAPSA 2 | 6.1 [0.1 – 31.1] | 4.4 [0.0 – 44.0] | 0.816 |
| PSAID-12 2 | 3.3 [0.1 – 8.8] | 3.1 [0.2 – 9.0] | 0.632 |
| PSAID-9 2 | 3.7 [0.1 – 9.4] | 3.3 [0.2 – 9.0] | 0.836 |
| Treatment received 1 | |||
| Number of csDMARDs | 1.2 ± 0.8 | 1.2 ± 0.7 | 0.667 |
| Number of ts/bDMARDs | 1.0 ± 1.4 | 0.8 ± 1.1 | 0.139 |
| Number of ts/bDMARDs targets | 1.8 ± 0.9 | 1.5 ± 0.8 | 0.014 |
| ts/b DMARDs persistence (months ) 2 | |||
| TNFi | 17 [2 – 168] | 36 [2 – 228] | 0.044 |
| IL-12/23i | 72 [3 – 144] | 36 [6 – 144] | 0.479 |
| IL-23i | 12 [1 – 36] | 22 [3 – 48] | 0.196 |
| IL-17i | 12 [3 – 96] | 22 [3 – 96] | 0.115 |
| Apremilast | 6 [3 – 12] | 18 [1 – 84] | 0.087 |
| JAKi | 9 [6 – 12] | 24 [6 – 60] | 0.178 |
| Abatacept | NA | 3 [3 – 3] | NA |
| Methotrexate | |||
| Methotrexate intolerance (%) | 32.9 | 24.7 | 0.143 |
| Methotrexate-related hepatotoxicity (%) | 9.8 | 10.4 | 0.862 |
| EULAR definition D2M/TR PsA * | |||
| Difficult to manage PsA (%) | 8.6 | 6.2 | 0.001 |
| Treatment refractory PsA (%) | 4.8 | 3.8 | 0.002 |
| Comorbidities | |||
| AHT (%) | 24.8 | 32.1 | 0.156 |
| Dyslipidaemia (%) | 31.4 | 33.6 | 0.675 |
| Diabetes mellitus (%) | 9.5 | 14.6 | 0.181 |
| Uric acid levels ≥7 mg/dl (%) | 23.8 | 30.7 | 0.176 |
BMI body mass index. PsO psoriasis. PsA psoriatic arthritis. IBD inflammatory bowel disease. csDMARDs conventional synthetic DMARDs. Ts/bDMARDs targeted/biologic DMARDs. AHT arterial hypertension. NA non applicable. * Data were available for 208 patients. 1 Mean ± SD. 2 Median (mean rank). p -values <0.05 are shown in bold.
Multivariable logistic regression analysis for HLA-Cw6 positivity
| Variable | OR (95% CI) | p value |
|---|---|---|
| Female sex (ref. men) | 4.11 (1.63 – 10.32) | 0.003 |
| Age at PsA onset (per year) | 1.01 (0.97 – 1.05) | 0.788 |
| Dactylitis (ref. no) | 0.33 (0.13 – 0.84) | 0.020 |
| MTX intolerance (ref. no) | 1.69 (0.72 – 3.94) | 0.226 |
| Difficult to manage PsA (ref. no) | 12.53 (4.15 – 37.80) | <0.001 |
| Treatment refractory PsA (ref. no) | 15.39 (4.02 – 58.88) | <0.001 |
| AHT (ref. no) | 0.86 (0.32 – 2.34) | 0.772 |
| Diabetes mellitus (ref. no) | 0.22 (0.04 – 1.40) | 0.109 |
| Uric acid ≥7 mg/dL (ref. no) | 1.78 (0.71 – 4.51) | 0.222 |
Multivariable model adjusted for all included covariates. BMI body mass index. PsO psoriasis. PsA psoriatic arthritis. IBD inflammatory bowel disease. csDMARDs conventional synthetic DMARDs. Ts/bDMARDs targeted/biologic DMARDs. AHT arterial hypertension. p -values <0.05 are shown in bold.
REFERENCES: [1] Queiro R, Alvarez P et al. Clin Exp Rheumatol 2025;43:889–96.
[2] Queiro R, Braña I et al. J Clin Med 2024;13:845.
[3] Dand N, Duckworth M et al. J Allergy Clin Immunol 2019;143:2120–6.
[4] Marzo-Ortega H, Harrison SR et al. Ann Rheum Dis 2025;84(Suppl):S0003-4967.
Acknowledgments: NIL.
Disclosure of Interests: None declared.