What are the latest guidelines for managing Lymphangioleiomyomatosis (LAM)?

Latest Guidelines for Lymphangioleiomyomatosis (LAM)

The 2016 ATS/JRS guidelines represent the most current evidence-based recommendations for LAM management, with sirolimus now established as the standard treatment for patients with abnormal or declining lung function (FEV1 <70% predicted), marking a significant shift from the 2010 European guidelines that recommended against routine use. 1

Medical Treatment

Sirolimus (mTOR Inhibitor) - Primary Therapy

For patients with LAM and FEV1 <70% predicted or declining lung function, sirolimus is strongly recommended over observation. 1 The goals are to stabilize lung function, improve functional performance, and enhance quality of life.

Dosing strategy:

• Target serum trough levels: 5-15 ng/mL (standard dosing from MILES trial) 1
• Emerging evidence suggests low-dose sirolimus (trough <5 ng/mL) may also be effective 1, 2
• Monitor lung function at 3-month intervals to assess treatment response 1

Common adverse effects include:

• Mucositis, diarrhea, nausea 1
• Hypercholesterolemia, acneiform rash, lower extremity swelling 1
• Ovarian cyst formation, dysmenorrhea, proteinuria 1
• Drug-induced pneumonitis and infection risk due to immunosuppression 1

Critical caveat: Sirolimus must be discontinued once patients are listed for active lung transplantation due to increased perioperative complications. 1

Therapies NOT Recommended

Doxycycline should NOT be used for LAM treatment (conditional recommendation), as no beneficial effects on respiratory impairment have been confirmed despite its theoretical MMP-inhibiting properties. 1

Hormonal therapies should NOT be used for LAM treatment (conditional recommendation), including: 1

• Progesterone (oral or intramuscular) 1
• GnRH agonists
• Selective estrogen receptor modulators (e.g., tamoxifen)
• Oophorectomy

The 2010 European guidelines allowed consideration of intramuscular progesterone in rapidly declining patients 1, but the 2016 ATS/JRS guidelines explicitly recommend against all hormonal therapies based on lack of proven benefit. 1

Management of Extrapulmonary Manifestations

Chylous Effusions

For symptomatic chylous fluid accumulations (pleural effusions or ascites), sirolimus is suggested before invasive management (conditional recommendation). 1

Important considerations:

• Chylous effusions may require several months to respond to mTOR inhibitors 1
• Can recur after treatment cessation 1
• Fat-free diet with medium-chain triglyceride supplementation may be used adjunctively 1

Renal Angiomyolipomas

Sirolimus should NOT be first-line therapy for renal angiomyolipomas. 1 It may be considered on an individual basis for symptomatic angiomyolipomas not amenable to embolization or conservative surgery in experienced centers. 1

Management of Pneumothorax

Pneumothorax management requires joint care by chest physician and thoracic surgeon. 1

Treatment algorithm:

• First pneumothorax: Chemical pleurodesis may be performed; if unsuccessful, proceed to appropriate surgical procedure 1
• Second pneumothorax: Appropriate surgical procedure should be performed according to clinical condition and local expertise 1

Transplantation considerations:

• History of pleurodesis or pleurectomy is NOT a contraindication to lung transplantation 1
• However, patients must be informed of increased risk of perioperative pleural bleeding 1
• Refer to transplant centers with LAM experience to anticipate pleural complications 1

Diagnostic Recommendations

For patients with characteristic cystic abnormalities on CT but no confirmatory clinical or extrapulmonary features, VEGF-D testing is strongly recommended before proceeding to diagnostic lung biopsy. 1 Confirmatory features include tuberous sclerosis complex, angiomyolipomas, chylous effusions/ascites, and lymphangioleiomyomas.

Key Differences Between 2010 and 2016 Guidelines

The evolution in LAM management reflects the impact of the MILES trial and subsequent evidence:

• 2010 European guidelines: Sirolimus should NOT be prescribed routinely outside clinical trials 1
• 2016 ATS/JRS guidelines: Sirolimus is STRONGLY RECOMMENDED for patients with abnormal/declining lung function 1

This represents a fundamental shift from experimental therapy to standard of care based on moderate-quality evidence demonstrating stabilization of lung function and improvement in quality of life. 1