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Tofacitinib vs. glucocorticoids in mild-to-moderate systemic lupus erythematosus: A real-world study of the CSTAR cohort

Year: 2025

Type: article

Abstract: Systemic lupus erythematosus (SLE) is an autoimmune disease with an incidence rate of 47.61 per 100,000 individuals in China.[1] More than half of SLE patients experience cutaneous and musculoskeletal manifestations during the course of the disease. The standard treatment for active skin disease includes topical agents, antimalarials, and/or systemic glucocorticoids (GCs).[2] In clinical practice, for many patients who do not respond to topical agents and antimalarials, increasing the GC dosage on the basis of standard treatment is widely recognized as the most accepted therapeutic approach. However, the use of GCs poses risks, such as metabolic impairment, reduced bone density, and increased susceptibility to infections, highlighting the need for novel therapeutics.[3] Tofacitinib is a Janus kinase (JAK) inhibitor that can block the effects of several cytokines. We have previously conducted a meta-analysis of JAK inhibitors in SLE, suggesting that they have the potential to serve as viable treatment options for both systemic and cutaneous lupus erythematosus.[4] To further investigate this, we conducted a retrospective real-world cohort study to compare the efficacy of tofacitinib and GCs escalation in patients with mild-to-moderate SLE and poor responses to topical agents and antimalarials treatment, especially mucocutaneous and musculoskeletal involvement. Patients were recruited from the Chinese SLE Treatment and Research (CSTAR) registry. The inclusion criteria were (1) fulfillment of the 1997 American College of Rheumatology revised SLE classification criteria or the 2012 Systemic Lupus International Collaborating Clinics SLE classification criteria; (2) active disease activity in the mucocutaneous and/or musculoskeletal system, as evaluated by the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K); (3) receiving a stable therapeutic dose of hydroxychloroquine (HCQ), immunosuppressant (methotrexate, azathioprine, mycophenolate, tacrolimus, sirolimus, leflunomide), and/or GCs ≤15 mg/day prednisone (or equivalent); (4) initiation of tofacitinib treatment or an increase in GC dosage on the basis of Standard of Care (from ≤15 mg/day to ≥0.5 mg·kg−1·day−1 prednisone or equivalent, Supplementary Figure 1, https://links.lww.com/CM9/C396). The exclusion criteria were as follows: (1) simultaneous increases in the dosage of GCs and/or immunosuppressants at the time of tofacitinib initiation; (2) receiving cyclophosphamide during the follow-up process; (3) initiation of biological agents within four weeks prior to baseline; (4) severe disease activity at baseline, defined as major organ-threatening disease, severe lupus nephritis, thrombocytopenia with platelets <20 × 109/L, or SLEDAI-2K >12; and (5) incomplete data at baseline or lack of follow-up data for one year. This study was approved by the Medical Ethics Committee of the Peking Union Medical College Hospital (PUMCH), Chinese Academy of Medical Sciences (No. JS-2038). All patients provided informed consent. Quantitative variables were described using the mean (standard deviation) or median (interquartile range) and analyzed using Student’s t test or Mann–Whitney U test. Categorical variables were described using counts and percentages and analyzed using the χ2 test or Fisher’s exact test. A two-tailed P value less than 0.05 was considered statistically significant. Analyses were performed using GraphPad Prism (version 8.0 for Windows, GraphPad Software, Boston, Massachusetts, USA). Eighty-two patients who underwent GC escalation (GC group) and 40 patients who received tofacitinib (TOFA group) were enrolled in this study. The baseline demographic, disease, and therapeutic characteristics are summarized in Supplementary Table 1, https://links.lww.com/CM9/C396. The median age of the GC group was 29.5 years, the mean disease duration was 4.9 years, and 93.9% (77/82) were female. In the TOFA group, the mean age was 33.4 years, the mean disease duration was 5.2 years, and 95.0% (38/40) were female. The GC group exhibited a significantly higher median SLEDAI-2K score compared to the TOFA group (8 vs. 4, P <0.001). In the GC group, 26 (31.7%) patients had musculoskeletal involvement, 66 (80.5%) had mucocutaneous involvement, 16 (19.5%) had renal involvement, and 26 (31.7%) had hematological involvement. In the TOFA group, 10 (25.0%) patients had musculoskeletal involvement, 33 (82.5%) had mucocutaneous involvement, and 6 (15.0%) had hematological involvement. The mean prednisone dose in the GC group was 10.0 mg/day before increasing GCs, which increased to 40.0 mg/day at baseline. By three months, half of patients had reduced their prednisone dose to ≤15.0 mg/day, and by 12 months, half were taking ≤7.5 mg/day [Figure 1A]. In the TOFA group, 21 (52.5%) patients had a baseline prednisone dose of ≤5 mg/day, and 12 (30.0%) did not use GCs. After one year, 78.6% of patients were using ≤5 mg/day of prednisone, and 35.7% were not using GCs [Figure 1B]. Additionally, 76 (92.7%) patients in the GC group and 34 (85.0%) patients in the TOFA group were concomitantly using HCQ.Figure 1: Daily prednisone dose, resolution of mucocutaneous involvement, rash, and arthritis, and BICLA response at 1 month, 3 months, 6 months, and 12 months of follow-up. (A) Change in prednisone dose in the GC group. (B) Change in prednisone dose in the TOFA group. (C) The proportion of patients with resolution of mucocutaneous involvement (including rash, alopecia, and mucosal ulcers) assessed by SLEDAI-2K. (D) The proportion of patients with resolution of rash assessed by SLEDAI-2K. (E) The proportion of patients with resolution of arthritis assessed by SLEDAI-2K. (F) The proportion of patients achieving BICLA response. BICLA: British Isles Lupus Assessment Group-based Composite Lupus Assessment; GC: Glucocorticoids; ns: No statistically significant difference; SLEDAI-2K: Systemic Lupus Erythematosus Disease Activity Index 2000; TOFA: Tofacitinib.Tofacitinib demonstrated non-inferior efficacy compared to GCs in treating mucocutaneous and musculoskeletal involvement in mild-to-moderate SLE patients who had a poor response to topical agents and antimalarials treatment. At 3 months, 6 months, and 12 months, the GC and TOFA groups exhibited comparable efficacy in resolving mucocutaneous involvement, including rash, alopecia, and oral ulceration, as evaluated by SLEDAI-2K (3 months: 80.4% vs. 77.3%, P = 0.758; 6 months: 88.1% vs. 77.8%, P = 0.431; 12 months: 100% vs. 77.8%, P = 0.095; Figure 1C). Separately, the GC group and the TOFA group showed no significant difference in the percentage of patients with resolution of rash (1 month: 82.6% vs. 60.0%, P = 0.150; 3 months: 83.9% vs. 83.3%, P >0.999; 6 months: 85.7% vs. 76.9%, P = 0.659; 12 months: 100% vs. 80.0%, P = 0.333; Figure 1D) and alopecia (1 month: 70.0% vs. 55.6%, P = 0.650; 3 months: 83.9% vs. 83.3%, P >0.999; 6 months: 92.3% vs. 88.9%, P >0.999; 12 months: 100% vs. 100%, P >0.999) at any of the follow-up time points. Similarly, no differences were observed in arthritis resolution between the two groups at any of the follow-up time points (1 month: 87.5% vs. 50.0%, P = 0.162; 3 months: 73.3% vs. 100%, P = 0.281; 6 months: 100% vs. 100%, P >0.999; 12 months: 90.9% vs. 100%, P >0.999; Figure 1E). The disease activity was reduced in both group. No significant difference was observed in the proportion of patients achieving a British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) response between the GC and TOFA groups (1 month: 72.7% vs. 56.0%, P = 0.189; 3 months: 69.1% vs. 66.7%, P = 0.813; 6 months: 85.4% vs. 70.8%, P = 0.206; 12 months: 96.0% vs. 85.7%, P = 0.289, Figure 1F). Both groups demonstrated significant reductions in SLEDAI-2K and physician global assessment scores. In the TOFA group, three patients reduced their GC dose from ≥10 mg/day to ≤5 mg/day, and four patients discontinued GCs entirely. However, tofacitinib showed limited efficacy in improving serological activity compared to GCs, with no changes observed in C3, C4, or anti-double stranded DNA (dsDNA) levels. A subgroup analysis was performed on patients without baseline renal involvement, as 19.5% (16/82) of patients in the GC group had renal involvement compared to none in the TOFA group. Among the 66 patients in the GC group and 40 patients in the TOFA group, baseline clinical SLEDAI-2K scores showed no significant differences. At 3 months, 6 months, and 12 months, the proportions of patients achieving resolution of mucocutaneous involvement, arthritis, and a BICLA response were comparable between the GC and TOFA groups [Supplementary Figure 2, https://links.lww.com/CM9/C396]. During the one-year follow-up, two patients in the TOFA group reported adverse events: one developed herpes zoster six months after starting tofacitinib, and another experienced leukopenia. In the GC group, one patient developed an infection, and another showed abnormalities in liver function [Supplementary Table 2, https://links.lww.com/CM9/C396]. This study had some limitations. First, this was a real-world, retrospective cohort study, and some data were missing at certain follow-up time points. Second, the sample size was relatively small, which introduces uncertainty regarding the statistical reliability. Third, the follow-up duration may not be sufficient to fully assess the safety of tofacitinib. Further observational studies with larger sample sizes and randomized controlled trials are needed to validate the efficacy and safety of tofacitinib in SLE patients. In conclusion, our results demonstrated that tofacitinib and GCs may have comparable effects in treating mild-to-moderate mucocutaneous and musculoskeletal diseases in SLE patients. We anticipate that tofacitinib can help reduce dependence on GCs and has potential as an alternative to GCs in these patient groups. Acknowledgments The authors would like to thank all the CSTAR centers for data collection and the Health Cloud as the system provider. Funding This study was supported by the Chinese National Key Technology R&D Program, Ministry of Science and Technology (No. 2021YFC2501300), and Beijing Municipal Science & Technology Commission (Nos. Z201100005520022, 23, and 25-27), CAMS Innovation Fund for Medical Sciences (CIFMS) (No. 2021-I2M-1-005), and National High-Level Hospital Clinical Research Funding (No. 2022-PUMCH-B-013, C-002, and D-009). Conflicts of interest None.

Source: Chinese Medical Journal

DOI: 10.1097/cm9.0000000000003571