Corticosteroids Combined with Low-Dose Methotrexate in the Treatment of Pemphigus Vulgaris: A Retrospective Cohort Study

Rheumatology and Immunology Immunology Life Sciences Medicine
corticosteroids methotrexate pemphigus vulgaris efficacy safety

Academic Background

Pemphigus Vulgaris (PV) is a rare and severe autoimmune blistering disease characterized by a chronic course accompanied by multiple complications and side effects from medication. Currently, guidelines in many countries recognize systemic corticosteroids (CS) and rituximab (RTX) as first-line treatments for PV. However, due to the high cost of anti-CD20 monoclonal antibodies, patients in developing countries and regions find it difficult to access this therapy. Although several immunosuppressive agents (ISAs) have been proven effective in reducing corticosteroid use, their widespread application remains limited in many areas. For example, in China, mycophenolate mofetil (MMF) and intravenous immunoglobulin are not covered by national medical insurance, while the use of azathioprine (Aza) requires pre-screening of metabolic enzyme genes, a technology that is not yet widely available among physicians.

Methotrexate (MTX), as a classic immunosuppressant, has been used to treat PV for over half a century, but its efficacy and safety have been subjects of controversy. Previous studies have mostly been case reports or small-sample cohort studies, lacking large-scale randomized controlled trials. Therefore, this study aims to evaluate the short-term efficacy and safety of low-dose MTX combined with corticosteroids in the treatment of PV, providing an economical and effective treatment option for PV patients.

Source of the Paper

This paper was co-authored by Yan Chen, Jiaqi Li, Yuchen Tang, and others from the Department of Dermatology at Peking University First Hospital. It was published in 2025 in the Journal of Dermatology under the title Corticosteroids Combined with Low-Dose Methotrexate in the Treatment of Pemphigus Vulgaris: A Retrospective Cohort Study. The research was supported by the Peking University Health Science Center and the National Clinical Research Center for Skin and Immune Diseases.

Research Process and Key Findings

1. Study Subjects and Grouping

This study retrospectively screened PV patients who visited the Department of Dermatology at Peking University First Hospital between January 2010 and December 2021. Based on different treatment regimens, patients were automatically divided into two groups: corticosteroid monotherapy group (CS group) and corticosteroid combined with low-dose MTX group (CS-M group). The inclusion criteria were: 1) PV diagnosis based on guidelines; 2) patients receiving either CS monotherapy or CS combined with low-dose MTX (MTX dose not exceeding 15 mg/week with a minimum duration of 8 weeks); 3) patients followed up for at least 1 year. Exclusion criteria included: 1) use of other ISAs or biologics with therapeutic effects on pemphigus within 4 weeks before the first visit; 2) MTX use for less than 8 weeks; 3) lack of weight data.

Ultimately, 142 PV patients were eligible, with 100 in the CS group and 42 in the CS-M group.

2. Treatment Regimen

Initial corticosteroid doses were based on disease severity, categorized as mild (lesion area <10% body surface area, BSA), moderate (lesion area 10%-30% BSA), and severe (lesion area >30% BSA). Mild patients received prednisone ≤0.5 mg/kg/day, while moderate and severe patients received 0.5-1.0 mg/kg/day and >1.0 mg/kg/day, respectively. After disease control, corticosteroids were gradually tapered based on initial dose and treatment response.

The initiation and termination of MTX were determined by physicians based on clinical needs, with relatively low doses. The median initial MTX dose in the CS-M group was 10 mg/week, with a median treatment duration of 351.5 days and a median cumulative dose of 280 mg over one year.

3. Key Findings

3.1 Baseline Characteristics

There were no significant differences between the two groups in terms of sex, age of onset, disease duration, or disease subtype. However, the median anti-Dsg1 antibody titer in the CS-M group was significantly higher than in the CS group (126.61 vs. 54.36 RU/mL, p=0.006), while anti-Dsg3 antibody titers showed no significant difference.

3.2 Primary Outcome

Kaplan-Meier curves showed that the time to 50% corticosteroid reduction was significantly shorter in the CS-M group compared to the CS group (p=0.0132), especially in patients with initial doses >60 mg/day, where the difference was more pronounced (p=0.0009). During the 1-year follow-up, the median corticosteroid reduction proportion in the CS-M group was 55.0%, significantly higher than the 50.0% in the CS group (p=0.0118). However, there was no significant difference in the total cumulative corticosteroid dose between the groups.

3.3 Safety

In terms of adverse effects, the incidence of hyperlipidemia in the CS-M group was significantly lower than in the CS group (38.1% vs. 59.0%, p=0.028). Liver dysfunction showed no significant difference between the groups (11.9% vs. 14.0%, p=1.000). No severe adverse effects, such as bone marrow suppression or osteonecrosis of the femoral head, were observed. Notably, the CS-M group had 4 cases of bacterial infections, while the CS group had only 1; however, due to the complex circumstances of the infection cases, a direct correlation between MTX and increased infection risk could not be established.

Research Conclusion and Significance

This study demonstrates that low-dose MTX combined with corticosteroid therapy in PV patients significantly accelerates corticosteroid tapering, especially in patients with higher initial doses. Additionally, the use of MTX reduces the incidence of hyperlipidemia without significantly increasing the risk of other adverse effects. These findings provide an economical and effective treatment option for PV patients, particularly for those who cannot afford biologics or require a safer alternative.

Research Highlights

  1. Accelerated Corticosteroid Tapering: Low-dose MTX significantly shortens the time to 50% corticosteroid reduction, particularly in patients with higher initial doses.
  2. Reduced Hyperlipidemia Incidence: The inclusion of MTX significantly lowers the occurrence of hyperlipidemia, mitigating long-term corticosteroid side effects.
  3. Good Safety Profile: The addition of MTX does not significantly increase the risk of severe adverse effects, indicating its safety in PV treatment.

Other Valuable Information

  1. Mechanism of MTX: Although the exact mechanism of MTX is not entirely clear, studies suggest it may regulate cytokines through the JAK/STAT signaling pathway, thereby contributing to its efficacy in PV treatment.
  2. Long-Term Safety: Despite concerns about MTX’s long-term use potentially causing skin cancer and hepatic fibrosis, this study found no such evidence, suggesting its safety can be maintained with appropriate monitoring.

Summary

This retrospective cohort study demonstrates the short-term efficacy and safety of low-dose MTX in PV treatment, offering a viable alternative for patients unable to afford expensive biologics. Future research should further explore the long-term efficacy of MTX and optimize its use in PV treatment strategies.