Correspondence

Doxycycline Treatment for Lymphangioleiomyomatosis with Urinary Monitoring for MMPs

N Engl J Med 2006; 354:2621-2622June 15, 2006

Article

To the Editor:

Lymphangioleiomyomatosis, a rare lung disease typically affecting women of reproductive age, is characterized by an abnormal proliferation of smooth-muscle cells and the progressive loss of pulmonary function due to destruction of lung parenchyma.1 Long-term survival is rare; in patients with lymphangioleiomyomatosis, respiratory failure often develops within 10 years after diagnosis. Currently, there is no standard-of-care therapy for this disease, although limited success has been reported with hormone therapy or lung transplantation.

The destruction of lung parenchyma has been attributed to an environment conducive to proteolysis resulting from increased expression and activity of matrix metalloproteinases (MMPs). MMP-2, in particular, is substantially up-regulated in the pulmonary tissues of patients with lymphangioleiomyomatosis.2 We have treated patients with pulmonary-capillary hemangiomatosis3 with the antibiotic doxycycline, an MMP inhibitor.4 We hypothesized that doxycycline would inhibit MMP-induced tissue degradation in patients with lymphangioleiomyomatosis, thereby providing clinical benefit. Having reported that the presence of MMPs in the urine is a predictor of disease status in patients with diseases that are characterized by dysregulated extracellular-matrix degradation such as cancer5 and hemangiomatosis,3 we analyzed urinary profiles for MMPs to monitor the therapeutic efficacy of doxycycline in a patient with lymphangioleiomyomatosis. The patient had substantial and rapid clinical improvement after receiving doxycycline therapy.

A 66-year-old woman was diagnosed with lymphangioleiomyomatosis in 1975 after having undergone a partial nephrectomy for angiomyolipoma. Since the diagnosis, the disease had progressed, with continuing deterioration of pulmonary function. In February 2005, her forced expiratory volume in one second (FEV₁) was 0.48 liter (21 percent of the predicted value), and she was placed on the list for lung transplantation. Before treatment with doxycycline, several species of MMP were found to be markedly elevated in her urine, including MMP-2, MMP-9, and a complex of MMP-9 and neutrophil gelatinase–associated lipocalin (Figure 1AFigure 1Treatment of Lymphangioleiomyomatosis with Doxycycline.). On the basis of the elevated MMP levels, doxycycline was initiated at an initial dose of 20 mg per day. Dose escalation (up to 100 mg per day) was based on the results of monthly urinary MMP profiling (Figure 1A) and on the patient's tolerance of the drug. The patient's lung capacity (as measured on September 30, 2005) was increased (FEV₁, 0.91 liter; 35 percent of the predicted value), and enhanced oxygen saturation was observed (Figure 1B). Telegraphic speech, which had been present, resolved. The patient has had a clear improvement in the quality of life and has been taken off the waiting list for a lung transplant — an outcome that was predicted by the decreasing urinary levels of MMPs (Figure 1A).

This case supports the hypothesis that doxycycline may represent a promising therapy for lymphangioleiomyomatosis and appears to be a potential means to ameliorate this disease, as guided by the biomarker of urinary levels of MMPs.

Marsha A. Moses, Ph.D.
Jay Harper, Ph.D.
Judah Folkman, M.D.
Children's Hospital Boston, Boston, MA 02115

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