Background/Purpose: Hydroxychloroquine (HCQ) is an antimalarial drug that interferes with dendritic cells and monocytes, acidifies endosomes, and modulates toll-like receptors, reducing autoimmune responses and cell proliferation through autophagy inhibition. HCQ is widely used in rheumatic diseases for its immunomodulatory properties and is often prescribed in systemic sclerosis (SSc), despite the lack of confirmation of its efficacy in randomized trials.The aim the study was to compare disease progression trajectories between HCQ-treated and -untreated SSc patients.

Methods: This retrospective, multicenter observational study included patients diagnosed with SSc according to the ACR/EULAR 2013 criteria, recruited from two Italian Rheumatology centers. Patients were grouped based on HCQ treatment. Demographic, clinical, serological, and capillaroscopic (NVC) data, as well as concomitant therapies, were recorded at baseline. At 6, 12-, 24-, 36-, and 60-months follow-up visits disease progression was determined according to validated criteria (Khanna D, 2016; Hoffmann-Vold AM, 2024) encompassing cutaneous, pulmonary, cardiac, and musculoskeletal domains, or the need to escalate immunosuppressive therapy. Progression-free survival was defined as the absence of worsening or new organ involvement. To test the study hypothesis Kaplan-Meier survival curves and Cox proportional hazards models were applied, stratifying the population by antibody profile (anticentromere, ACA+ or anti-topoisomerase I, Scl70+).

Results: A total of 301 patients with SSc were included (167 in the HCQ group and 134 in the non-HCQ group). Baseline characteristics were broadly similar between groups (Table 1), with no significant differences in age or disease duration. The HCQ group had a higher prevalence of ACA+ (50.8% vs 36.5%, p=0.036), and a lower prevalence of Scl70+ (25.7% vs 44.7%, p< 0.001) and interstitial lung disease (ILD, 13.1% vs 31.3%, p< 0.001). Mean mRSS was lower in the HCQ group (3±5 vs 5±7, p=0.004), while MMF use was more frequent in non-HCQ group (13.1% vs 6.0%, p=0.002). Kaplan-Meier curves demonstrated significant differences in progression-free survival between HCQ-treated patients in both ACA+ and Scl70+ (p< 0.001) subgroups (Figure 1). In multivariable Cox regression models, HCQ treatment was independently associated with a reduced hazard of progression in both ACA+ (n=134, events=16; HR=0.05, 95% CI 0.01–0.25) and Scl70+ (n=103, events=39; HR=0.14, 95% CI 0.06–0.34) subgroups. However, baseline imbalances and confounding by indication may partially explain these associations.Older age was also linked to reduced risk (HR=0.95, 95%CI 0.91–0.99) among ACA+ patients, while MMF showed a protective association (HR=0.37, 95%CI 0.15–0.88) in Scl70+ group.

Conclusion: In this retrospective study, HCQ use was associated with a lower risk of disease progression in patients with SSc, in both ACA+ and Scl70+ subgroups, over a 60 -months follow-up period. While the findings might suggest a potential protective role of HCQ, they must be interpreted with caution due to residual confounding. Prospective studies are warranted to validate these results.

Table 1. Comparison of demographical data and symptoms in SSc patients with or without treatment with hydroxychloroquine (HCQ).

ANA: anti-nuclear antibodies; lcSSc: limited cutaneous SSc; dcSSc: diffuse cutaneous SSc; ssSSc: SSc sine scleroderma

Figure 1. a. Kaplan-Meier curve showing the probability of remaining free from immunosuppressive therapy intensification in anti-Scl70 positive SSc patients, stratified by HCQ treatment. b. Forest plot illustrating the hazard ratios for progression in anti-Scl70 positive SSc patients. c. Kaplan-Meier curve showing the probability of remaining free from immunosuppressive therapy intensification in ACA-positive SSc patients, stratified by HCQ treatment. d. Forest plot illustrating the hazard ratios for progression in ACA-positive SSc patients.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/hydroxychloroquine-and-disease-progression-in-systemic-sclerosis-insights-from-antibody-stratified-survival-analyses/