The Systemic Vasculitides — DCE Clinical Case

Long Case — Granulomatosis with polyangiitis with pulmonary-renal syndrome

Patient scenario

Mr David Chen is a 56-year-old mechanical engineer who presents to the emergency department with a three-month history of progressive symptoms. ^[1]

History of presenting complaint: ^[1]

• Three months ago: onset of nasal crusting and bloody nasal discharge, initially attributed to dry air. Over the following weeks he developed bilateral conductive hearing loss from Eustachian tube dysfunction and recurrent epistaxis.
• Two months ago: he noticed arthralgia in the wrists and ankles, fatigue, and a 5 kg weight loss.
• Two weeks ago: he developed a productive cough with haemoptysis (approximately a teaspoon of blood daily), dyspnoea on exertion, and noticed his urine was dark and frothy.
• His general practitioner checked bloods and found creatinine 340 micromol per litre (baseline 80 three years ago on a routine check), and referred him urgently. ^[1]

Past medical history: Hypertension (well-controlled on ramipril 5 mg daily). No previous autoimmune disease. No asthma or atopy. ^[1]

Medications: Ramipril 5 mg daily. No over-the-counter or herbal medications. No recent new drugs. ^[1]

Family history: Father with type 2 diabetes. No family history of autoimmune or renal disease. ^[1]

Social history: Married with two teenage children. Works as a mechanical engineer. Non-smoker, minimal alcohol. No illicit drug use. No recent overseas travel. ^[1]

Examination findings: ^[1]

• Afebrile, heart rate 92, blood pressure 156/92, respiratory rate 18, oxygen saturation 94 per cent on room air.
• ENT: Nasal crusting with serosanguinous discharge. Saddling of the nasal bridge (early). Oral ulceration on the buccal mucosa. Bilateral conductive hearing loss on tuning-fork testing (negative Rinne bilaterally, Weber lateralising to the worse-hearing ear).
• Respiratory: Bilateral inspiratory crackles in the lower zones. No wheeze.
• Cardiovascular: Normal heart sounds, no murmur. No peripheral oedema.
• Abdomen: Soft, non-tender. No organomegaly. No bruits.
• Neurological: Intact. No mononeuritis multiplex.
• Skin: Palpable purpura on the lower limbs. ^[1]

Investigations: ^[1]

Candidate's opening statement (model answer — SASPOP format)

"Mr David Chen is a 56-year-old engineer presenting with a three-month history of progressive granulomatosis with polyangiitis — initially upper airway disease with nasal crusting, epistaxis and conductive hearing loss, now complicated by a pulmonary-renal syndrome with haemoptysis from cavitating pulmonary nodules and alveolar haemorrhage, and rapidly progressive pauci-immune crescentic glomerulonephritis with a creatinine of 340 and 60 per cent crescents. ^[1]

He is c-ANCA strongly positive with anti-PR3 specificity. Anti-GBM antibody is negative, blood cultures and echocardiogram have excluded endocarditis and myxoma, and hepatitis and HIV serology are negative. ^[1]

My problem list is: (1) granulomatosis with polyangiitis with pulmonary-renal syndrome — an organ- and life-threatening presentation requiring immediate immunosuppression; (2) rapidly progressive glomerulonephritis with 60 per cent crescents and a creatinine of 340; (3) pulmonary involvement with cavitating nodules and alveolar haemorrhage; (4) upper airway disease with nasal crusting, early saddle-nose deformity and conductive hearing loss; (5) normocytic anaemia and constitutional features; (6) treatment-related risks including infection, rituximab-related hypogammaglobulinaemia, and glucocorticoid side effects; and (7) the psychosocial impact of a new diagnosis of a serious chronic illness on a working man with a family. ^[1]

This is a medical emergency. My immediate management is admission and same-day initiation of intravenous methylprednisolone and rituximab, with concurrent involvement of nephrology, respiratory and rheumatology." ^[1]

Integrated management plan

1. Granulomatosis with polyangiitis with pulmonary-renal syndrome (organ- and life-threatening) ^[1]

• Immediate induction therapy:
  • IV methylprednisolone 1 g daily for 3 days, followed by oral prednisolone 1 mg/kg daily (approximately 70 mg), with a planned taper to 5 mg daily by 4 to 5 months ^[7].
  • Rituximab 375 mg per square metre weekly for 4 weeks (RAVE regimen) or 1 g on days 1 and 15 (RITUXVAS regimen) ^[3][4].
  • Consider a reduced-dose glucocorticoid regimen (per PEXIVAS) to reduce serious infection risk — discuss with the team ^[6].

2. Rapidly progressive glomerulonephritis ^[1]

• Nephrology involvement for ongoing renal management.
• Consider plasma exchange given the severity (creatinine 340, 60 per cent crescents) — the MEPEX trial showed short-term renal recovery benefit, though PEXIVAS did not show benefit on the composite of death or ESKD; the decision should be individualised in discussion with nephrology and the patient ^[5][6][7].
• Dialysis if required for uraemia, fluid overload or hyperkalaemia.
• Monitor renal function, urinalysis and urine microscopy daily during induction.

3. Pulmonary involvement ^[1]

• Respiratory involvement and ICU input for alveolar haemorrhage with hypoxaemia.
• Oxygen therapy; mechanical ventilation if respiratory failure develops.
• Serial chest X-rays and repeat chest CT as needed.
• Plasma exchange may be considered for severe diffuse alveolar haemorrhage. ^[1]

4. Upper airway disease ^[1]

• ENT involvement for management of nasal crusting and conductive hearing loss.
• Nasal saline irrigations and topical steroids for symptomatic relief.
• Monitor for subglottic stenosis (stridor is an emergency). ^[1]

5. Normocytic anaemia and constitutional features ^[1]

• Iron studies to exclude iron deficiency contributing to anaemia.
• Blood transfusion if symptomatic or haemoglobin below 70 g/L.
• Nutritional support for weight loss. ^[1]

6. Treatment-related risks ^[1]

• Co-trimoxazole 480 mg daily (or 960 mg three times weekly) for pneumocystis prophylaxis during induction.
• Bone protection: calcium 1000 mg daily, vitamin D 1000 IU daily, and a bisphosphonate (alendronate 70 mg weekly) — baseline DEXA scan.
• Gastric protection: proton pump inhibitor (pantoprazole 40 mg daily) during high-dose steroids.
• Monitor full blood count, immunoglobulins and liver function during rituximab therapy.
• Vaccination (influenza, pneumococcal, hepatitis B, COVID-19) before or between immunosuppressive cycles — avoid live vaccines during rituximab. ^[1]

7. Psychosocial support ^[1]

• Clinical psychology referral for adjustment to a new serious diagnosis.
• Social work for practical support (time off work, financial assistance).
• Connect with Vasculitis Foundation or patient support group.
• Clear communication with the patient and family about the diagnosis, prognosis and treatment plan. ^[1]

Maintenance strategy

After 3 to 6 months of successful induction: ^[1]

• Rituximab maintenance — 1 g every 4 months for 24 to 36 months. Preferred for PR3-ANCA disease (highest relapse risk) ^[7].
• Continue low-dose prednisolone (5 mg daily or less) for the first 4 to 6 months, then taper if possible.
• Monitoring — ANCA titre, inflammatory markers, renal function and urinalysis every 3 months; full blood count and immunoglobulins; bone density and cardiovascular risk assessment.
• Total maintenance duration — typically 18 to 24 months after sustained remission, then cautious withdrawal with relapse monitoring.

Communication and shared decision-making

• Frame GPA as a serious but treatable chronic relapsing disease — sustained remission is achievable with modern therapy.
• Discuss the treatment burden honestly — immunosuppression carries infection risk, rituximab can cause hypogammaglobulinaemia, and prolonged steroids cause osteoporosis, diabetes, cataracts and mood effects.
• Address fertility if relevant — cyclophosphamide affects fertility more than rituximab, which is one reason rituximab is preferred.
• Set up a relapse-monitoring contract — regular ANCA titres, inflammatory markers, urinalysis and renal function; early reporting of new symptoms.
• Discuss vaccination timing — give vaccines before immunosuppression; avoid live vaccines during rituximab.
• Address the psychosocial impact — time off work, financial pressure, anxiety, and the practicalities of a multisystem chronic illness on family life. ^[1]

Probing questions and model answers

Examiner: Why rituximab over cyclophosphamide for this patient? ^[1]

"Rituximab is now the preferred induction agent for most organ-threatening ANCA-associated vasculitis, based on the RAVE and RITUXVAS trials. The RAVE trial showed rituximab was non-inferior to cyclophosphamide for remission induction at 6 months, and superior in relapsing disease. The RITUXVAS trial confirmed this in renal-limited AAV. Rituximab has several advantages over cyclophosphamide: it does not cause haemorrhagic cystitis, it has less impact on fertility, it has a lower cumulative malignancy risk, and it is more convenient (4 weekly infusions rather than 3 to 6 months of daily oral or pulsed IV cyclophosphamide). Cyclophosphamide is still used when rituximab is contraindicated, in specific clinical contexts, or in some centres as first-line, but rituximab is the evidence-based preference ^[3][4][7]."

Examiner: What is the role of plasma exchange in this patient? ^[1]

"Plasma exchange is considered for three indications in AAV: anti-GBM overlap, dialysis-dependent renal disease, and severe diffuse alveolar haemorrhage. This patient does not have anti-GBM overlap (antibody negative), but his creatinine is 340 with 60 per cent crescents, placing him in the severe renal category. ^[1]

The evidence is mixed. The MEPEX trial showed that plasma exchange increased the rate of dialysis independence at 3 months in patients with severe renal vasculitis (creatinine above 500 micromol per litre or dialysis-dependent), though the long-term survival benefit was not sustained. However, the much larger PEXIVAS trial (704 patients) did not show a significant benefit of plasma exchange on the composite of death or end-stage kidney disease. The 2022 EULAR update states that plasma exchange may be considered in patients with rapidly progressive glomerulonephritis or other severe organ-threatening conditions ^[5][6][7].

My approach would be to discuss this with the nephrology team and with the patient, weighing the potential renal benefit against the procedural risks (central line infection, bleeding from immunosuppression-related thrombocytopenia) and the uncertain long-term benefit." ^[1]

Examiner: What mimics did you specifically exclude, and why are they important? ^[1]

"I excluded four critical mimics before committing to immunosuppression: ^[1]

First, anti-GBM disease (Goodpasture syndrome) — also causes a pulmonary-renal syndrome with rapidly progressive GN and alveolar haemorrhage, but requires mandatory plasma exchange to remove the pathogenic antibody. Missing it is fatal. Mr Chen's anti-GBM antibody is negative. ^[1]

Second, infective endocarditis — can be ANCA-positive and causes pulmonary-renal syndrome from septic emboli. Treating endocarditis with rituximab instead of antibiotics would be catastrophic. Mr Chen's blood cultures are negative and echocardiogram shows no vegetations. ^[1]

Third, atrial myxoma — causes systemic emboli with constitutional features and can mimic vasculitis. An echocardiogram is part of the workup. Mr Chen's echocardiogram is normal. ^[1]

Fourth, lupus nephritis — causes rapidly progressive GN but is immune complex (not pauci-immune), and management differs. Mr Chen's ANA is negative and complement was not low, and the biopsy showed a pauci-immune pattern. ^[1]

These four mimics are the most dangerous because treating them with immunosuppression (rather than their specific therapy) would be harmful or fatal. Excluding them is non-negotiable before starting rituximab or cyclophosphamide." ^[1]

Examiner: What is the long-term outlook for this patient? ^[1]

"With modern therapy, the five-year survival in AAV is approximately 75 to 85 per cent, but mortality remains higher than the general population, driven by cardiovascular disease, infection and malignancy. The renal outcome depends on the response to induction — with a creatinine of 340 and 60 per cent crescents, there is a real risk of chronic kidney disease. If he achieves remission, his creatinine may improve but may not return to baseline. ^[1]

Relapse is common in PR3-ANCA disease, which relapses at roughly twice the rate of MPO-ANCA disease. He will need lifelong monitoring — ANCA titre, inflammatory markers, renal function and urinalysis every 3 months during maintenance, then at least annually after withdrawal. ^[1]

Cardiovascular risk is significantly elevated in AAV, so aggressive management of traditional risk factors (blood pressure, lipids, smoking, diabetes from steroids) is essential. Treatment-related malignancy risk (from cyclophosphamide and to a lesser extent rituximab) requires age-appropriate cancer screening." ^[1]