Summary for Clinicians: Lymphangioleiomyomatosis Diagnosis and Management Clinical Practice Guideline

Summary of: McCormack FX, Gupta N, Finlay GR, Young LR, Taveira-DaSilva AM, Glasgow CG, Steagall WK, Johnson SR, Sahn SA, Ryu JH, and colleagues for the ATS Committee on Lymphangioleiomyomatosis. Official American Thoracic Society and Japanese Respiratory Society Clinical Practice Guidelines: Lymphangioleiomyomatosis Diagnosis and Management. Am J Respir Crit Care Med 2016;194:748–761. (2)

The American Thoracic Society (ATS) and Japanese Respiratory Society (JRS) collaborated to create recommendations addressing the use of vascular endothelial growth factor D (VEGF-D) as a diagnostic test and the therapeutic role of sirolimus, doxycycline and hormonal manipulation in patients with lymphangioleiomyomatosis (LAM). Using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach, the interdisciplinary ATS/JRS panel performed a systematic evidence synthesis and rated the quality of the evidence to indicate their certainty about the estimated effects (1). The panel used discussion and consensus to formulate “strong” or “conditional” recommendations in favor of, or against, specific interventions.

The resulting guidelines, published in 2016 in the American Journal of Respiratory and Critical Care Medicine (2) are complementary to the previous European Respiratory Society (ERS) guidelines for the diagnosis and management of LAM (3). This summary is prepared for practicing clinicians.

The ATS/JRS LAM recommendations are intended to guide clinical decision-making, but do not establish a “standard of care” and cannot take into account all conditions that should be considered for a particular individual. Clinicians and patients should interpret these recommendations in the setting of patient values and preferences, and adapt them appropriately to each clinical situation.

Lymphangioleiomyomatosis

Lymphangioleiomyomatosis (LAM) is a rare, neoplastic disease affecting primarily women that is associated with progressive cystic lung destruction, chylous pleural effusions and/or ascites, renal angiomyolipomas and lymphangioleiomyomas (2). LAM occurs sporadically or in patients with tuberous sclerosis complex (TSC). Neoplastic cells circulating in the blood, circulating in the lymphatic fluids, and infiltrating the lung originate from an unknown source, but have characteristics of smooth muscle and histologically appear benign.

Sirolimus

• •“For patients with LAM with abnormal/declining lung function, we recommend treatment with sirolimus rather than observation (strong recommendation based on moderate-quality evidence).”

Patients with LAM have inactivating mutations in TSC genes that ultimately result in disruption of cell development, motility and survival through activation of the mechanistic target of rapamycin (mTOR) signaling pathway. Sirolimus inhibits this mTOR pathway to restore homeostasis to cells with TSC deficiency.

The strongest evidence to support the use of sirolimus for patients with LAM and abnormal lung function comes from the Multicenter International LAM Efficacy of Sirolimus (MILES) trial, a double-blind, randomized, parallel group trial of 89 patients with LAM and an FEV₁ < 70% predicted (4). Participants were randomly assigned to receive one year of treatment with sirolimus or placebo, followed by an additional year of observation after medication withdrawal.

Treatment with sirolimus reduced lung function decline as measured by a change in the FEV₁ (1 ± 2 ml/month versus −12 ± 2 ml/month for placebo) and a change in the FVC (8 ± 3 ml/month versus −11 ± 3 ml/month for placebo), with a P value <0.001 for both comparisons. In addition, patients treated with sirolimus reported improved quality of life and functional performance. Following medication discontinuation, participants previously receiving sirolimus experienced a decline in their lung function at a rate similar to those in the placebo group.

Mild adverse events that commonly occurred in patients treated with sirolimus included mucositis, diarrhea, nausea, elevated cholesterol, acneiform rash and lower extremity edema. Serious adverse events occurred similarly in participants assigned to sirolimus or placebo. Additional research is needed to optimize patient selection, mTOR inhibitor selection (sirolimus or everolimus), indications for initiation, dosing, and duration of treatment.

• •“For selected patients with LAM with problematic chylous effusions, we suggest treatment with sirolimus before invasive management (conditional recommendation based on very low-quality evidence).”

Evidence to support the use of sirolimus for patients with chylous fluid collections comes from multiple case series and one small, uncontrolled open-label trial (2). In this study of twelve LAM patients with chylous pleural effusions or ascites treated with sirolimus, all patients had significant improvement or complete resolution of their fluid collections. Although side effects of sirolimus were common, most were mild and no patients in the trial discontinued the drug. Patients may take several months to respond to sirolimus, and discontinuation of the medication may result in recurrence of fluid accumulations. Alternative management options for chylous fluid accumulations include observation and invasive interventions such as intermittent percutaneous drainage or placement of an indwelling drainage system.

Doxycycline

• •“We suggest NOT using doxycycline as treatment for LAM (conditional recommendation based on low-quality evidence).”

Cyst formation in LAM may involve extracellular matrix destruction by matrix metalloproteinases. Doxycycline inhibits both the production and enzymatic activity of several matrix metalloproteinases implicated in LAM pathogenesis. In two uncontrolled open-label trials, doxycycline decreased matrix metalloproteinases concentrations in patients with LAM (2). However, a single-center, double-blind randomized trial of doxycycline versus placebo in 23 women with moderate pulmonary function impairment due to LAM found no benefit in the rate of FEV₁ decline, diffusion capacity, shuttle walk distance, or quality of life after two years of doxycycline treatment (5). Adverse effects, including gastrointestinal upset and photosensitivity were more common in the doxycycline group.

Thus, doxycycline has not been shown to improve clinical outcomes, but it may increase adverse effects. The effect of doxycycline combined with other treatments for LAM (such as mTOR inhibitors or hormonal therapy) has not been evaluated.

Hormonal Therapy

• •“We suggest NOT using hormonal therapy as treatment for LAM (conditional recommendation based on very low-quality evidence).”

Studies exploring hormonal manipulation as a possible therapeutic option in LAM arise from a number of observations, including its occurrence almost exclusively in females and expression of estrogen and progesterone receptors by LAM cells. In addition, the disease process may worsen after exposure to estrogen containing medications, pregnancy and during the menstrual cycle but stabilize in the post-menopausal period (2).

The literature evaluating oophorectomy, serum estrogen response modulators (e.g., tamoxifen), gonadotropin releasing hormone agonists, or combination therapies has consisted of small case series demonstrating inconsistent results, ranging from improvement to deterioration (2). Two controlled observational studies of progesterone also showed variable results. One retrospective cohort study showed that rates of decline of diffusion capacity were higher among patients with LAM receiving progesterone compared with those who were not, with no difference found in annual decline in FEV₁ between groups (6). In contrast, a smaller retrospective cohort study demonstrated a potential benefit in rates of decline of FEV₁ as well as diffusion capacity among premenopausal women with LAM receiving progesterone (7).

Overall, though there have been sporadic reports of success, the current body of evidence is of very low quality and does not support the use of hormonal therapy in patients with LAM. Among patients with LAM already receiving hormonal therapy for non-pulmonary reasons, the recommendation is to discontinue estrogen-containing products. Current evidence does not contraindicate the use of gonadotropin releasing hormone agonists or progestins for other therapeutic indications or progestin containing intrauterine devices. In addition to the cost burden, patients receiving hormonal therapies are also subject to the usual adverse effects of such therapy. Randomized controlled trials of hormonal agents are required to interpret the significance of their effects on the clinical course of patients with LAM.

Vascular Endothelial Growth Factor-D Diagnostic Testing

• •“For patients whose computed tomography scan shows cystic abnormalities characteristic of LAM, but who have no other confirmatory clinical or extrapulmonary radiologic features of LAM, we recommend vascular endothelial growth factor D testing to establish the diagnosis of LAM before consideration of proceeding to diagnostic lung biopsy (strong recommendation based on moderate-quality evidence).”

A clinical diagnosis of LAM requires the presence of characteristic cystic changes in the lung on high-resolution CT (HRCT) along with one or more of the following: TSC, renal angiomyolipoma, lymphangioleiomyoma, or a chylous pleural effusion. In cases where the diagnosis is unclear or certainty is necessary, biopsy of the lung is often obtained. Vascular endothelial growth factor-D, a serum biomarker elevated in 70% of LAM patients, has the potential for non-invasive diagnostic confirmation in cases of clinical uncertainty (2).

Three diagnostic accuracy studies of vascular endothelial growth factor-D all showed favorable test characteristics exceeding a priori thresholds for sensitivity (>70%) and specificity (>90%) set by the guideline panel, particularly when using a cutoff of 800 pg/ml (2). The panel predicted that out of 1,000 patients tested using vascular endothelial growth factor-D, 219 patients with LAM will be spared invasive testing (“true positive”), 81 patients with LAM will proceed to lung biopsy (“false negative”) and 10 patients without LAM will be incorrectly diagnosed (“false positive”).

Among patients with cystic lung disease on HRCT who lack other confirmatory clinical findings of LAM, a positive test can therefore eliminate the need for an invasive lung biopsy. However, among similar patients, a negative test does not exclude a diagnosis of LAM. Although uncommon, false-positive results do occur with vascular endothelial growth factor-D testing and may lead to missed opportunities to treat the correct disease.

Conclusions and Future Directions

In the setting of significant recent advances, guidelines have been developed against the use of doxycycline and anti-hormonal agents for the treatment of LAM. Vascular endothelial growth factor-D has been proposed as a useful diagnostic test, while sirolimus has proven to be an effective therapy (2).

Studies are still required to establish the long-term safety and efficacy of mTOR inhibitors, and to evaluate possible benefits for low-dose prophylactic therapy in patients with normal lung function. Additional studies of the role of vascular endothelial growth factor-D as a biomarker for improvement in lung function over time are warranted, while research continues on possible hormonal therapeutic approaches.