What is the treatment for Raynaud's (Raynaud's disease) syndrome with cyanosis, glomerulonephritis, pleuritis, and vasculitis?

Treatment of Raynaud Syndrome with Systemic Vasculitis and Glomerulonephritis

This clinical presentation—Raynaud syndrome with cyanosis, glomerulonephritis, pleuritis, and vasculitis—represents ANCA-associated vasculitis (AAV) and requires immediate aggressive immunosuppression with glucocorticoids plus either rituximab or cyclophosphamide for remission induction. 1

Immediate Diagnostic and Treatment Approach

Urgent Evaluation Before Treatment Delay

• Do not wait for kidney biopsy results to initiate treatment if the clinical presentation is compatible with small-vessel vasculitis and ANCA serology (MPO-ANCA or PR3-ANCA) is positive 1
• Exclude infection with as much certainty as possible before starting significant immunosuppression 1
• Obtain autoimmune serologies immediately: ANCA, ANA, anti-GBM antibodies, complement levels 1
• Perform kidney biopsy when feasible for diagnostic confirmation and prognostic information, but this should not delay treatment 1

Remission Induction Therapy (First-Line)

For organ-threatening or life-threatening AAV (which this presentation represents), use:

• Glucocorticoids PLUS either rituximab OR cyclophosphamide 1
• Both rituximab and cyclophosphamide have Level 1A evidence for GPA/MPA 1

Choosing between rituximab and cyclophosphamide:

• Rituximab is preferred for maintenance therapy and increasingly for induction 1
• Cyclophosphamide may be preferred when severe GN is present (serum creatinine >4 mg/dL or 354 μmol/L), where combination of two intravenous pulses of cyclophosphamide with rituximab can be considered 1
• Consider cyclophosphamide for PR3-ANCA positive patients or those with more extensive disease 1
• Rituximab is preferred for patients with prior cyclophosphamide exposure, childbearing potential, or concerns about cumulative cyclophosphamide toxicity 1

Plasma Exchange Consideration

• Plasma exchange should be considered for patients with serum creatinine ≥500 μmol/L (5.7 mg/dL) due to rapidly progressive glomerulonephritis 1
• Plasma exchange can also be considered for severe diffuse alveolar hemorrhage 1
• However, the 2021 KDIGO guideline suggests plasma exchange not be used routinely in AAV, though it remains an option for severe presentations 1

Maintenance Therapy

After achieving remission, continue with:

• Low-dose glucocorticoids PLUS either rituximab (preferred), azathioprine, methotrexate, or mycophenolate mofetil 1
• Rituximab is the preferred maintenance agent 1
• Continue maintenance therapy for at least 18-24 months following induction of sustained remission 1

Factors favoring rituximab for maintenance:

• History of relapse 1
• PR3-ANCA subgroup 1
• Diagnosis of granulomatosis with polyangiitis 1
• ANCA positive at end of induction 1

Management of Raynaud Phenomenon Component

The Raynaud phenomenon in this context is secondary to systemic vasculitis and will improve with treatment of the underlying AAV:

• Primary treatment is immunosuppression for the vasculitis, not vasodilators 1
• Conservative measures: avoid cold exposure, smoking cessation 2, 3
• If Raynaud symptoms persist despite vasculitis control, calcium channel blockers (nifedipine) can be added 3, 4
• Note that isolated new-onset Raynaud phenomenon is rarely reported with checkpoint inhibitor-associated vasculitis, but this presentation suggests true AAV 1

Critical Monitoring and Supportive Care

Infection Prophylaxis

• Prophylactic trimethoprim-sulfamethoxazole (TMP-SMX) should be considered with high-dose prednisone, rituximab, or cyclophosphamide 1
• Screen for tuberculosis, hepatitis B, hepatitis C, HIV prior to immunosuppression 1
• Consider Strongyloides screening in patients from endemic areas 1

Monitoring During Treatment

• Structured clinical assessment rather than ANCA testing should inform treatment decisions 1
• Monitor serum immunoglobulin levels prior to each rituximab course and in patients with recurrent infection 1
• Assess cardiovascular risk periodically 1
• Investigate persistent unexplained hematuria in patients with prior cyclophosphamide exposure 1

Refractory Disease Management

If disease is refractory to initial induction therapy:

• Switch from cyclophosphamide to rituximab or vice versa 1, 5
• Manage in close conjunction with or refer to an expert center for evaluation and potential clinical trial enrollment 1

Important Caveats

• This multi-organ presentation (glomerulonephritis, pleuritis, vasculitis with Raynaud) strongly suggests AAV rather than lupus, despite lupus being theoretically possible with PD-1 deficiency 1
• Autoantibodies (RF, ACPA, ANA, ANCA) are often absent in checkpoint inhibitor-associated rheumatic irAEs, but this appears to be true AAV based on the constellation of findings 1
• Patients should be managed at or in close collaboration with centers of expertise that have experience with these treatment modalities and their complications 1