Leflunomide Therapy for Adult Patients with Steroid-Dependent Minimal Change Disease or Primary Focal Segmental Glomerulosclerosis
Minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) are among the most common histological subtypes of nephrotic syndrome in both adults and children. Corticosteroids have long been established as the first-line treatment for these conditions. However, a significant subset of patients develops steroid-dependent nephrotic syndrome, requiring repeated steroid treatments that often lead to serious long-term adverse effects. Leflunomide, a competitive and reversible inhibitor of dihydroorotate dehydrogenase, has emerged as a potential therapeutic option due to its anti-inflammatory and antiproliferative effects, particularly in proliferating T cells and B cells. This article delves into a retrospective study investigating the efficacy and safety of leflunomide in adult patients with steroid-dependent MCD or primary FSGS.
Background and Study Design
The study was conducted at Peking University First Hospital, involving 49 adult patients diagnosed with steroid-dependent nephrotic syndrome due to biopsy-proven MCD or primary FSGS. Among these patients, 40 had MCD, and nine had FSGS. All participants had previously received corticosteroid monotherapy without any additional immunosuppressive drugs and exhibited steroid dependence, with a median threshold dose of prednisone at 30.0 mg/day (interquartile range [IQR], 20.0–40.0 mg/day). After experiencing a relapse, complete remission was induced using prednisone at a dose of 0.1–1.0 mg/kg/day, not exceeding 60 mg/day.
Following remission, 37 patients were treated with leflunomide, while 12 received cyclosporin. In the leflunomide group, 28 patients were administered a daily dose of 20 mg, and nine patients over 65 years old received 10 mg/day. The cyclosporin group included eight patients on 100 mg/day, three on 150 mg/day, and one on 200 mg/day, with a whole blood trough concentration of 117.6 ± 45.0 ng/mL. The two groups were comparable in terms of age, sex, and follow-up duration.
Efficacy of Leflunomide Therapy
The study’s primary focus was to evaluate the efficacy of leflunomide in maintaining clinical remission, reducing relapse rates, and enabling steroid withdrawal. In the leflunomide group, 65% (24/37) of patients maintained remission until the endpoint of follow-up, with a median duration of 18.9 months (IQR, 11.1–34.7 months). Among these patients, 42% (10/24) successfully discontinued steroid use for a median duration of 8.1 months (IQR, 4.3–27.6 months). For patients who continued steroid therapy, the median prednisone dose decreased significantly from 30.0 mg/day (IQR, 18.8–40.0 mg/day) to 4.4 mg/day (IQR, 2.5–10.0 mg/day).
However, 35% (13/37) of patients in the leflunomide group experienced a relapse during follow-up, with a median time to relapse of 10.8 months (IQR, 5.4–20.1 months). Before relapse, 31% (4/13) of these patients had discontinued steroid use for a median duration of 9.4 months (IQR, 5.2–20.3 months). Among those still on steroids at the time of relapse, the median prednisone dose was 15.0 mg/day (IQR, 6.3–18.8 mg/day). Notably, 14% (5/37) of patients in the leflunomide group discontinued both steroids and leflunomide after maintaining clinical remission for a median duration of 22.6 months (IQR, 19.3–27.6 months). Three of these patients remained in remission until the end of follow-up, with a median remission duration of 35.8 months. The other two patients relapsed after 31.0 and 32.3 months, respectively, but achieved complete remission again with re-initiation of steroids and leflunomide, maintaining remission for an additional 41.0 and 40.0 months, respectively.
Comparison with Cyclosporin Therapy
In contrast, the cyclosporin group demonstrated significantly lower efficacy. Only 16.7% (2/12) of patients maintained remission until the endpoint of follow-up, with durations of 18.9 months and 1.9 months, respectively. Both patients continued to receive prednisone at doses of 5.0 mg/day and 20.0 mg/day. The remaining 83.3% (10/12) of patients relapsed, with a median time to relapse of 3.5 months (IQR, 2.0–9.6 months). All patients in the cyclosporin group were still on prednisone at the time of relapse, with a median dose of 15.0 mg/day (IQR, 8.8–25.6 mg/day).
Statistical Analysis and Outcomes
Statistical analysis revealed that the rate of continuous clinical remission was significantly higher in the leflunomide group compared to the cyclosporin group (64.9% vs. 16.7%, P = 0.004). Although the median time to maintain clinical remission was longer in the leflunomide group (18.9 months vs. 10.4 months), the difference did not reach statistical significance (P = 0.345). The rate of steroid withdrawal was higher in the leflunomide group (41.7% vs. 0%), but this difference was not statistically significant (P = 0.508). For patients who continued steroid therapy, the median prednisone dose was comparable between the two groups (4.4 mg/day vs. 12.5 mg/day, P = 0.267).
In patients who experienced a relapse, the duration of clinical remission before relapse was significantly longer in the leflunomide group (10.8 months vs. 3.5 months, P = 0.021). Before relapse, 31% of patients in the leflunomide group had discontinued steroids, whereas none in the cyclosporin group had achieved steroid withdrawal (P = 0.081). The median prednisone dose at relapse was comparable between the two groups (15.0 mg/day vs. 15.0 mg/day, P = 0.661).
The overall remission rate without relapse was significantly higher in the leflunomide group compared to the cyclosporin group (P < 0.001). The estimated average duration of remission was also longer in the leflunomide group (45.9 months vs. 6.9 months, P < 0.001). Importantly, all patients maintained kidney function throughout the study. In the leflunomide group, the estimated glomerular filtration rate (eGFR) increased from 89.8 ± 26.4 mL/min/1.73 m² at the beginning of treatment to 94.1 ± 23.3 mL/min/1.73 m² at the endpoint (P = 0.114). In the cyclosporin group, the eGFR decreased from 103.0 ± 22.2 mL/min/1.73 m² to 91.6 ± 33.7 mL/min/1.73 m² (P = 0.293).
Safety Profile of Leflunomide
Leflunomide was generally well-tolerated, with adverse events reported in 13.5% (5/37) of patients. These included skin rash, diarrhea, and elevated blood pressure (<160/100 mmHg). One patient discontinued leflunomide due to a skin rash, but all adverse events resolved rapidly with supportive treatment.
Limitations and Future Directions
The study’s retrospective design and small sample size limit the generalizability of the findings. Further randomized controlled trials are warranted to compare the efficacy of leflunomide with other immunosuppressive agents, such as cyclophosphamide or cyclosporin, in treating steroid-dependent nephrotic syndrome.
Conclusion
This retrospective study highlights the potential of leflunomide as an effective and safe therapeutic option for adult patients with steroid-dependent MCD or primary FSGS. Leflunomide demonstrated superior efficacy in maintaining clinical remission, reducing relapse rates, and enabling steroid withdrawal compared to cyclosporin. Despite its limitations, the study provides valuable insights into the management of steroid-dependent nephrotic syndrome and underscores the need for further research in this area.
doi.org/10.1097/CM9.0000000000001855
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