Can an individual with the MS alpha-1 (alpha-1 antitrypsin) phenotype receive alpha-1 replacement therapy?

Alpha-1 Antitrypsin Replacement Therapy for MS Phenotype

Individuals with the MS alpha-1 antitrypsin phenotype do not qualify for alpha-1 antitrypsin replacement therapy based on current guidelines and evidence. 1

Understanding the MS Phenotype and Alpha-1 Antitrypsin Levels

• The MS phenotype represents a heterozygous state with one normal M allele and one S allele, resulting in only moderately decreased alpha-1 antitrypsin (A1AT) levels compared to normal (MM) phenotype 1
• Meta-analysis data shows that MS phenotype individuals have A1AT serum levels approximately 24.82 mg/dL lower than MM individuals, which is not considered severe deficiency 1
• MS phenotype typically maintains A1AT levels above the protective threshold of 11 μmol/L (0.57 g/L), which is the cutoff for defining severe deficiency 1

Current Eligibility Criteria for Replacement Therapy

The Canadian Blood Services criteria for A1AT augmentation therapy, which align with evidence-based recommendations, require:

• Confirmed diagnosis of severe A1AT deficiency with serum A1AT levels <11 μmol/L (0.57 g/L) 1
• Clinical evidence of COPD with associated emphysema (FEV1 <80%) 1
• No smoking for at least 6 months 1
• No previous lung transplant 1

Why MS Phenotype Doesn't Qualify

• MS phenotype individuals maintain significantly higher A1AT levels than the severe deficiency threshold required for therapy 1
• The FDA-approved indication for A1AT products like GLASSIA specifically states it is for "clinically evident emphysema due to severe hereditary deficiency of Alpha1-PI" 2
• The MS phenotype is not associated with the same risk of emphysema development as severe deficiency phenotypes like ZZ, SZ, or null variants 1
• Current guidelines recommend augmentation therapy only for individuals with impaired FEV1 <80%, presence of emphysema, AND severe A1AT deficiency 1

Clinical Implications and Management

• Individuals with MS phenotype should still receive optimal pharmacological and non-pharmacological therapies for any existing COPD or respiratory symptoms 1
• Regular monitoring of lung function may be appropriate, but replacement therapy is not indicated 1
• Smoking cessation is particularly important for individuals with any A1AT variant, as smoking accelerates lung function decline 1, 3
• Genetic counseling may be appropriate for family planning purposes 1

Evidence Limitations and Future Directions

• Current research focuses primarily on severe deficiency states (ZZ, SZ, null variants) rather than intermediate deficiency states like MS 1, 4
• The SPARTA trial and other ongoing research may provide more insights into appropriate treatment thresholds, but current evidence does not support therapy for MS phenotype 1
• Novel approaches to A1AT therapy beyond augmentation are being explored, including targeting protein misfolding, increasing autophagy, RNA interference, and gene transfer 1, 5

In conclusion, while MS phenotype represents a mild deficiency of alpha-1 antitrypsin, it does not meet the established criteria for replacement therapy, which is reserved for individuals with severe deficiency (<11 μmol/L or 0.57 g/L) and clinical evidence of emphysema with reduced lung function.