What is the treatment for anti-synthetase syndrome?

Treatment of Anti-Synthetase Syndrome

The first-line treatment for anti-synthetase syndrome consists of high-dose corticosteroids combined with immunosuppressive agents such as mycophenolate mofetil (MMF) or cyclophosphamide, with rituximab showing superior long-term outcomes for interstitial lung disease (ILD) manifestations.

Understanding Anti-Synthetase Syndrome

Anti-synthetase syndrome (ASS) is an autoimmune disorder characterized by:

• Antibodies against aminoacyl-tRNA synthetases (most commonly anti-Jo-1)
• Interstitial lung disease (ILD)
• Inflammatory myositis
• Non-erosive polyarthritis
• Raynaud's phenomenon
• Mechanic's hands
• Fever

The syndrome is associated with significant morbidity and mortality, particularly when ILD is present, which occurs in approximately one-third of patients 1.

Treatment Algorithm

First-Line Treatment:

1. High-dose corticosteroids:

   • Prednisolone 1 mg/kg/day initially
   • Gradually tapered over 6 months 1
   • For severe disease: IV pulse methylprednisolone may be used initially

2. Combined with immunosuppressive agent:

   • Mycophenolate mofetil (MMF): First-line for ILD component
   • Methotrexate: Alternative first-line, particularly for predominant skin/muscle disease

For Moderate to Severe Disease or Refractory Cases:

1. Rituximab:

   • Superior 2-year progression-free survival compared to cyclophosphamide for ILD (HR 0.263,95% CI 0.094-0.732) 2
   • Typically administered as initial infusions on days 1 and 15, followed by maintenance every 6 months

2. Cyclophosphamide:

   • Option for severe or rapidly progressive ILD
   • Intravenous administration preferred over oral route 1
   • Usually given as monthly pulses for 6-12 months

3. Calcineurin inhibitors (CNIs):

   • Tacrolimus or cyclosporine
   • Particularly beneficial in refractory IIM-ILD, especially in anti-synthetase syndrome 1

For Refractory Disease:

1. Therapeutic plasma exchange (TPE):

   • Consider in severe ILD associated with ASS refractory to standard immunosuppressive therapy 3, 4
   • Has shown promising results in reducing antibody levels and improving respiratory status

2. IVIG:

   • Conditionally recommended for IIM-ILD and MCTD-ILD progression despite first-line treatment 1
   • Lower infection risk, particularly important in critically ill patients

Monitoring and Follow-up

• Pulmonary function tests (PFTs) with diffusion capacity (DLCO)
• High-resolution CT scans of the chest
• Creatine kinase (CK) levels
• Anti-Jo-1 and other anti-synthetase antibody levels
• Regular assessment for medication side effects

Special Considerations

Poor Prognostic Factors:

• Lower DLCO at baseline is independently predictive of poor 2-year progression-free survival 2
• Rapidly progressive ILD requires more aggressive initial therapy

Maintenance Therapy:

• Long-term immunosuppression is typically required
• After achieving remission, consider gradual taper of corticosteroids while maintaining immunosuppressive agents

Pitfalls and Caveats

1. Delayed diagnosis: ASS can present with variable symptoms, leading to delayed diagnosis and treatment. Early recognition is crucial for preventing irreversible lung damage.

2. Undertreatment: Given the aggressive nature of ILD in ASS, inadequate immunosuppression can lead to rapid progression and poor outcomes.

3. Infection risk: Aggressive immunosuppression increases infection risk. Consider Pneumocystis jirovecii pneumonia prophylaxis with trimethoprim-sulfamethoxazole 1.

4. Medication toxicity: Monitor for side effects of immunosuppressive agents, particularly with cyclophosphamide (hemorrhagic cystitis, infertility) and calcineurin inhibitors (nephrotoxicity).

5. Malignancy screening: Patients with inflammatory myopathies have increased cancer risk; appropriate screening is warranted.

The evidence strongly supports early aggressive immunosuppressive therapy for ASS, particularly when ILD is present, as this manifestation is the primary driver of morbidity and mortality. Rituximab has emerged as a particularly effective agent for long-term control of ILD in ASS patients 2.