Mycophenolate mofetil (MMF, CellCept) was effective in halting rapidly progressive diffuse cutaneous systemic sclerosis (SSc), but a substantial percentage of patients experienced recurrences when the treatment was stopped, a small open-label study found.
Five out of 19 patients (26.3%) who discontinued or decreased the dose of mycophenolate after almost 23 months of treatment had recurrences of the skin manifestations, with a 35.9% increase in their modified Rodnan skin scores from 7.8 to 10.6, according to Fabian A. Mendoza, MD, and colleagues from Thomas Jefferson University in Philadelphia.
Two of those patients also had new-onset respiratory symptoms, the researchers reported online in .
Patients with rapidly progressive diffuse SSc are at risk for developing serious internal organ involvement and have an increased risk of death, so prompt intervention is necessary for this complex systemic autoimmune disease, which is characterized by vasculopathy and fibrosis of the skin and organs.
Mycophenolate mofetil has been widely used to prevent rejection in patients undergoing lung or kidney transplants, and also as an immunosuppressive for systemic lupus erythematosus.
"It has been postulated that mycophenolate mofetil may also exert antifibrotic effects by inhibiting the differentiation of fibroblasts into myofibroblasts, and therefore decreasing the production and exaggerated accumulation of collagen and other extracellular matrix proteins in affected SSc tissues," Mendoza and colleagues explained.
Previous have demonstrated benefits with mycophenolate in patients with rapidly progressing diffuse cutaneous SSc, and found similar efficacy and better tolerability than cyclophosphamide for the interstitial lung disease that is the most common cause of death in SSc.
However, in those earlier studies the duration of treatment averaged 1.5 to 2 years, and the optimal length of treatment has not been established.
"Based on the natural history of SSc, it [could] be inferred that immunosuppression of limited duration would be sufficient to control progressive skin disease since skin involvement is usually self-limited over time as demonstrated by historical cohorts of untreated SSc patients," the researchers wrote.
Therefore, to see whether 2 years would suffice, the researchers followed a group of patients with rapidly progressive SSc for 5 years after discontinuing treatment or reducing the dosage of mycophenolate mofetil to less than 1,000 mg/day. This extension phase of an open-label trial included 19 of the initial 25 patients, with the remainder having been lost to follow-up.
At the time of enrollment into the open-label study, patients had less than 24 months' disease duration, and none showed clinical or imaging evidence of pulmonary involvement.
During the extension phase, patients were seen every 3 to 6 months as they discontinued or tapered the drug. Any increase of 20% or more in the Rodnan skin score or a 15% reduction in forced vital capacity (FVC) or diffusing capacity for carbon monoxide (DLCO) was followed by a re-introduction of mycophenolate mofetil in full dosages of 2,000 mg/day.
This low threshold for resumption of therapy was considered necessary because of the potential for severe and rapid disease progression.
Patients' mean age was 50, and most were white women. Mean Rodnan skin score at baseline was 22.36, all had Raynaud's phenomenon, and all were positive for antinuclear antibodies. Significantly more patients who relapsed had digital ulcers (80% vs 21%, P=0.038), and the average daily dose before withdrawal or taper of mycophenolate was higher among relapsers, at 2,600 mg compared with 2,000 mg. There were no other differences between relapsers and nonrelapsers, including on measures of more active disease such as erythrocyte sedimentation rate.
The five patients in whom treatment was re-instituted had relapsed after a mean of 6.9 months.
The two patients who developed respiratory symptoms after withdrawal had declines in both FVC and DLCO, and high-resolution computed tomography revealed interstitial lung disease in one and reticulo-nodular infiltrates in the other. Another patient showed a decline in DLCO but had no echocardiographic evidence of pulmonary arterial hypertension.
After mycophenolate was restarted, skin manifestations stabilized in all five affected patients and pulmonary abnormalities showed improvements but did not return to baseline levels. For instance, in one of the two patients with new-onset pulmonary manifestations, FVC was 75% of predicted at baseline, falling to 48% at the time of restarting mycophenolate, and only 52% with retreatment.
The observation that patients with digital ulcers were significantly more likely to relapse will need to be confirmed in other cohorts, and it "raises the important question of whether the extent and/or severity of SSc vascular involvement responsible for the occurrence of digital ulcers in these patients may also be indicative of a higher risk for a prompt recurrence of the cutaneous fibrotic process following effective mycophenolate mofetil therapy," the authors noted.
They concluded that mycophenolate treatment should extend beyond 2 years for patients with rapidly progressing diffuse cutaneous SSc, and that even slow downward dose titration should be accompanied by close follow-up including quantification of Rodnan skin scores and serial pulmonary function tests.
A limitation of the study, the team said, was the small number of patients included.
Disclosures
The authors reported no conflicts of interest.
Primary Source
Seminars in Arthritis & Rheumatism
Mendoza F, et al "Recurrence of progressive skin involvement following discontinuation or dose reduction of mycophenolate mofetil treatment in patients with diffuse systemic sclerosis" Semin Arthritis Rheum 2019; doi:10.1016/j.semarthrit.2019.06.012.