The ‘Hit Hard and Early’ randomized controlled trial published to investigate the efficacy of methylprednisolone in very early systemic sclerosis (SSc) found no significant benefit in preventing disease progression. The study aimed to determine whether glucocorticoids could induce remission by inhibiting early inflammatory processes that drive disease development.
The trial enrolled adults with puffy fingers for less than three years, presence of specific autoantibodies, and meeting the Very Early Diagnosis of Systemic Sclerosis (VEDOSS) criteria. Participants were randomly assigned in a 2:1 ratio to receive either methylprednisolone 1000 mg intravenously for three consecutive days, repeated monthly for three cycles, or a placebo. Between February 2017 and February 2021, 87 patients were screened, and 30 were randomized (70% female, median age 52.9 years, median disease duration 11.4 months). No significant difference in nailfold capillary density at 12 weeks was observed between the treatment and placebo groups. Similarly, secondary outcomes showed no meaningful benefit. Over one year, 37% of participants exhibited disease progression, while 23% experienced a decline in pulmonary function. No serious adverse events were reported.
Glucocorticoids (GCs) possess potent anti-inflammatory and immunosuppressive properties. However, their use in SSc remains controversial due to limited supporting evidence and concerns about potential adverse effects. Some studies have suggested that pulsed intravenous methylprednisolone (MP pulse) may be an effective treatment option for active SSc. Nevertheless, repeated courses of MP pulse therapy have been associated with an increased risk of adverse events.
A retrospective study by Chenge et al. assessed 46 SSc patients with interstitial lung disease over 10 years. All received high-dose intravenous methylprednisolone (MP-Pulse); 21 also received long-term low-dose oral glucocorticoids (LTLD-GC). The combination group showed significantly greater and sustained improvements in skin thickening and lung function compared to MP-Pulse alone. No serious adverse events were reported. The findings suggested that MP-Pulse followed by LTLD-GC was a safe and effective long-term treatment for SSc with ILD.
Furthermore, a study utilizing data from the European Scleroderma Trials and Research Group emulated a target trial comparing low-dose oral glucocorticoids combined with immunosuppressive therapy to immunosuppression alone in early diffuse cutaneous SSc patients. The results indicated no significant difference in the modified Rodnan skin score (mRSS) between the two groups after 12 months. Additionally, there was no observed increase in the incidence of scleroderma renal crisis among patients receiving glucocorticoids.
These findings suggest that while short-term methylprednisolone does not provide clinically relevant benefits in very early SSc, its combination with long-term low-dose glucocorticoids may offer advantages in patients with SSc-associated ILD. The notable proportion of patients experiencing disease progression underscores the need for alternative therapeutic strategies to address early-stage disease more effectively. Future research should prioritize confirming these findings and exploring other immunomodulatory treatments to prevent the progression of SSc.
References
- Kersten BE, Lemmers JMJ, Vanhaecke A, Velauthapillai A, van den Hombergh WMT, van den Hoogen FHJ, van den Ende CHM, Smith V, Vonk MC. Efficacy of methylprednisolone in very early systemic sclerosis: results of the ‘Hit Hard and Early’ randomized controlled trial. Rheumatology (Oxford). 2025 Mar 1;64(3):1261-1269.
- Cheng H, Yu Z, Yan CL, Yang HD, Gao C, Wen HY. Long-Term Efficacy and Low Adverse Events of Methylprednisolone Pulses Combined to Low-Dose Glucocorticoids for Systemic Sclerosis: A Retrospective Clinical Study of 10 Years’ Follow-Up. J Inflamm Res. 2022 Aug 4;15:4421-4433.
- Mongin D, Matucci-Cerinic M, Walker UA, et al. Oral Glucocorticoids for Skin Fibrosis in Early Diffuse Systemic Sclerosis: A Target Trial Emulation Study From the European Scleroderma Trials and Research Group Database. Arthritis Care Res (Hoboken). 2024 Nov 14. doi: 10.1002/acr.25469