What are the new treatment options for sarcoidosis beyond traditional corticosteroids?

New Treatment Era in Sarcoidosis: Beyond Traditional Corticosteroids

Primary Recommendation

The European Respiratory Society (ERS) 2021 guidelines establish a clear treatment escalation pathway: methotrexate as the preferred second-line agent for steroid-resistant disease, followed by infliximab for refractory cases, marking a significant shift toward evidence-based glucocorticoid-sparing strategies that reduce long-term toxicity while maintaining disease control. 1

Treatment Algorithm for Pulmonary Sarcoidosis

First-Line Therapy

• Glucocorticoids remain the initial treatment for symptomatic disease requiring systemic therapy, but the goal is minimizing duration and dose to prevent substantial morbidity from prolonged use 1
• Recent evidence suggests similar efficacy between high and low glucocorticoid doses, with increased side effects at higher doses 2

Second-Line: Methotrexate

• Methotrexate is the ERS-recommended first alternative for patients with inadequate steroid response, steroid toxicity, or those at high risk for mortality/permanent disability 1, 3
• Oral administration is generally favored over subcutaneous routes 3
• Allow 3-6 months to assess therapeutic response before escalating treatment 3
• Folic acid supplementation may reduce side effects 3
• Evidence shows methotrexate is steroid-sparing and associated with improved lung function, though one randomized trial showed no significant FVC improvement in the first 6 months 1

Third-Line: Anti-TNF Biologics

• Infliximab is the preferred biologic agent with the strongest evidence base for patients failing glucocorticoids and methotrexate 1, 3
• Two phase III randomized trials demonstrated infliximab significantly improved FVC compared to prednisone in chronic respiratory symptoms, though absolute changes were small 1
• Recommended dosing: 5 mg/kg at weeks 0,2, and 6, then maintenance therapy 3
• Combining infliximab with low-dose methotrexate may reduce autoantibody formation risk 3
• Mandatory tuberculosis screening before initiating anti-TNF therapy 3

Alternative Second-Line Agents

• Azathioprine is as effective as methotrexate for pulmonary sarcoidosis 1
• Leflunomide and mycophenolate mofetil show effectiveness in prospective and retrospective studies 1, 2
• Adalimumab demonstrated efficacy in prospective open-label trials for pulmonary disease 1
• Hydroxychloroquine/chloroquine shows mild benefit, particularly effective for cutaneous manifestations 1, 3

Emerging Therapies Under Investigation

• Repository corticotropin injection (RCI) has shown steroid-sparing effects in two retrospective and one prospective study, though cost remains prohibitive 1, 4
• Rituximab shows promise in some studies for refractory cases 1
• JAK inhibitors and anti-interleukin-6 therapy reported in small retrospective series 1
• The CLEAR antibiotic regimen (levofloxacin, ethambutol, azithromycin, rifampin) failed to show benefit over placebo in a recent double-blind trial 1, 5

Organ-Specific Considerations

Cardiac Sarcoidosis

• Strong recommendation for glucocorticoids (with or without other immunosuppressives) for patients with functional cardiac abnormalities including heart block, dysrhythmias, or cardiomyopathy 1
• More aggressive treatment approach warranted due to high mortality risk 1

Neurosarcoidosis

• Glucocorticoids strongly recommended as first-line therapy 1
• Methotrexate suggested for continued disease despite glucocorticoids 1
• Infliximab suggested for patients failing glucocorticoids and second-line agents (methotrexate, azathioprine, mycophenolate) 1, 3
• Aggressive treatment justified given high morbidity from neurological involvement 3

Cutaneous Sarcoidosis

• Infliximab suggested for cosmetically important active skin lesions failing glucocorticoids and other immunosuppressives 1, 3
• Hydroxychloroquine particularly effective for skin manifestations 3

Sarcoidosis-Associated Fatigue

• Pulmonary rehabilitation and/or inspiratory muscle strength training for 6-12 weeks conditionally recommended 1
• D-methylphenidate or armodafinil for 8 weeks suggested for troublesome fatigue not related to disease activity, after consideration of exercise programs 1

Treatment Duration and Monitoring

Duration Guidelines

• Minimum 1 year of treatment recommended unless no improvement after 3 months 6
• For biologics like infliximab, consider continuation for 2-3 years in responders 3
• Consider discontinuation after demonstrating disease stability for at least 2-3 years 3
• Continued low-dose prednisone (10-15 mg daily) helps prevent relapses, with periodic tapering attempts justified 6

Monitoring Requirements

• Regular monitoring for drug toxicity essential 3
• Pneumocystis pneumonia prophylaxis for patients on multiple immunosuppressive agents 3
• Ensure pneumococcal and influenza vaccination 3

Critical Pitfalls to Avoid

Common Errors

• Avoid prolonged corticosteroid monotherapy - fails to adequately address disease progression and causes significant toxicity 3
• Do not escalate treatment prematurely; allow sufficient time (3-6 months) to assess response before changing therapy 3
• Recognize that randomized trials showed no benefit for cyclosporine A, golimumab, or ustekinumab - these should only be considered case-by-case 1

Special Considerations

• Inhaled corticosteroids may provide symptomatic relief for cough and asthma-like symptoms but should be discontinued if ineffective 3
• Non-inflammatory effects (pulmonary hypertension, bronchiectasis) may contribute to symptoms and require alternative treatment strategies 5
• Consider lung transplantation for severe disease unresponsive to therapy, worsening pulmonary function, or pulmonary hypertension 3

Treatment Decision Framework

The ERS guidelines emphasize that treatment decisions require assessment of three factors: organ involvement, risk for significant morbidity/mortality, and impact on quality of life 1. Approximately 5% of patients die from sarcoidosis, with pulmonary and cardiac disease being the most common causes 1. Features associated with increased death risk include pulmonary hypertension, reduced lung function, and pulmonary fibrosis 1.