In which cases of systemic sclerosis is injection cyclophosphamide (CYC) recommended, particularly in patients with significant organ involvement such as interstitial lung disease (ILD) or scleroderma renal crisis?

Cyclophosphamide in Systemic Sclerosis: Indications

Cyclophosphamide should be considered primarily for systemic sclerosis-related interstitial lung disease (SSc-ILD), where it has demonstrated improvement in lung function tests, dyspnea, and quality of life, though it is now considered one of several first-line options rather than the sole choice. 1

Primary Indication: SSc-Related Interstitial Lung Disease

Standard Progressive SSc-ILD

• Cyclophosphamide is conditionally recommended as a first-line treatment option for SSc-ILD, alongside mycophenolate, rituximab, and azathioprine 1
• The evidence base includes two high-quality randomized controlled trials (Jadad score 5) demonstrating efficacy in patients with active alveolitis 1
• Oral cyclophosphamide at 1-2 mg/kg/day for 12 months improved forced vital capacity (FVC) by 2.5% and total lung capacity by 4.1% compared to placebo (p<0.03 for both measures) 1
• Intravenous cyclophosphamide at 600 mg/m² monthly for 6 months showed a 4.2% improvement in FVC, though this narrowly missed statistical significance (p=0.08) 1
• Beyond lung function, cyclophosphamide improved dyspnea scores, HAQ disability index, and quality of life measures 1

Rapidly Progressive SSc-ILD

• For rapidly progressive ILD in systemic sclerosis, cyclophosphamide is conditionally recommended as one of 1-2 additional therapies alongside IV glucocorticoids 1
• In this setting, rituximab and cyclophosphamide are recommended over IVIG, though IVIG may be preferred if infection risk is high 1
• Critical caveat: In SSc patients with rapidly progressive ILD, there is no consensus on glucocorticoid use due to scleroderma renal crisis (SRC) risk; if glucocorticoids are used, close blood pressure monitoring is mandatory 1, 2
• Cyclophosphamide is not typically used in combination with other immunosuppressive therapies, whereas other agents may be combined 1

Secondary Indication: Skin Involvement

• Cyclophosphamide has been shown in RCTs to improve skin changes in SSc patients, though this is not its primary indication 1
• Other agents (mycophenolate mofetil, methotrexate, azathioprine) are more commonly used for skin involvement, as their efficacy for this manifestation has been studied more extensively 1, 3

Current Treatment Hierarchy

First-Line Options for SSc-ILD (2024 Guidelines)

The most recent ACR/CHEST guidelines position cyclophosphamide as one of several conditionally recommended first-line options 1:

• Mycophenolate is now preferred over cyclophosphamide due to similar efficacy with a more favorable adverse effect profile 1, 3
• Rituximab may be preferred when inflammatory arthritis, myositis, or Sjögren neuropathy coexist 1
• Cyclophosphamide remains an option particularly when other therapies have failed or are contraindicated 1

When to Choose Cyclophosphamide Over Alternatives

• Rapidly progressive disease requiring aggressive immunosuppression 1
• Failure of or contraindication to mycophenolate or rituximab 1
• Severe baseline disease with extensive lung involvement 3
• Mixed connective tissue disease (MCTD) with SSc features and ILD 1

Critical Safety Considerations

Scleroderma Renal Crisis Risk

• High-dose glucocorticoids (>15 mg/day prednisone) are strongly associated with triggering SRC and should be avoided 2
• Any SSc patient on glucocorticoids requires at least weekly blood pressure monitoring to detect SRC early 2
• If SRC develops during cyclophosphamide therapy, ACE inhibitors should be started immediately, even in hypotension, and plasma exchange may be beneficial 2, 4
• Once SRC is stabilized, mycophenolate, rituximab, or cyclophosphamide can be considered for SSc-ILD, but high-dose glucocorticoids must be avoided 2

Cyclophosphamide-Specific Toxicity

• Known toxicities include bone marrow suppression, hemorrhagic cystitis, infection risk, infertility, and malignancy risk 1
• Treatment duration is typically limited to 6-12 months due to cumulative toxicity 1
• Adequate hydration is essential to prevent hemorrhagic cystitis 5
• Regular complete blood count monitoring is mandatory during treatment 5

Dosing Protocols

Oral Regimen

• 1-2 mg/kg/day for 12 months 1, 3
• This was the regimen used in the landmark trial showing FVC improvement 1

Intravenous Regimen

• 600 mg/m² monthly for 6 months (induction phase) 1, 3
• Some protocols extend to 18 months with maintenance dosing at increasing intervals 6, 7
• May be followed by oral azathioprine 2.5 mg/kg/day for maintenance 1, 6

Monitoring Requirements

• Pulmonary function tests (FVC, DLCO) every 3-6 months to assess treatment response 2, 3
• Weekly blood pressure checks and renal function for the first month, then biweekly 2
• Complete blood counts regularly during treatment 5
• Assessment at 6 months to determine response; if inadequate, consider switching to alternative therapy 1, 3

Contraindications to Cyclophosphamide

• Active or recent scleroderma renal crisis (relative contraindication; mycophenolate or rituximab preferred) 2
• Active infection 1
• Severe bone marrow suppression 5
• Pregnancy or planned pregnancy 1