QuestionSBA
QuestionChoice
Meningococcal septicaemia can present with a purpuric rash, similar to that seen in small vessel vasculitis. However, the absence of any infective symptoms, normal observations and chronicity of the history favour a diagnosis of vasculitis
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Blood cultures
QuestionChoice
This is an important test to look for any evidence of proteinuria (especially in a patient who is likely to have significant renal disease) but a simple urine dipstick should be done in the first instance
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Urine Protein Creatinine ratio
QuestionChoice
CRP levels are indicative of infective and inflammatory states and therefore are likely to be raised in vasculitis. However, it is a non-specific test. A urine dipstick is preferable as an initial test to exclude potentially life-threatening renal vasculitis
32317
e
Measure C-reactive protein (CRP) levels
QuestionChoice
Tryptase levels are increased in anaphylaxis. The rash in anaphylaxis is typically an urticarial rash, characterised by itchy weals and surrounding erythema. Also, there are no other signs or symptoms of anaphylaxis described
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d
Serum tryptase levels
QuestionChoice
The rash combined with systemic symptoms and recurrent sinusitis is suggestive of small vessel vasculitis. In this context, recurrent sinusitis, in particular, is indicative of granulomatosis with polyangiitis (GPA). Vasculitis, in general, is commonly associated with renal disease, which can manifest with proteinuria and haematuria. Therefore, it is important to do a urine dipstick in all patients with this presentation to exclude significant renal complications
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a
Urine dipstick
QuestionComment
nothing in the quesbook about a rash in this condition 
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QuestionComment
vascultis diseases tend to present with purpuric rash
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Hematoma Hereditary
User
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Dermis Cystic
QuestionComment
Features
upper respiratory tract: epistaxis, sinusitis, nasal crusting
lower respiratory tract: dyspnoea, haemoptysis
rapidly progressive glomerulonephritis ('pauci-immune', 80% of patients)
saddle-shape nose deformity
also: vasculitic rash, eye involvement (e.g. proptosis), cranial nerve lesions
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Intravenous Prone
Concept
Chapter
# Summary

Granulomatosis with polyangiitis (GPA), previously known as Wegener's granulomatosis, is an ANCA associated vasculitis affecting small and medium sized vessels. The classic triad of manifestations is of upper respiratory tract involvement, lower respiratory tract involvement, and pauci-immune glomerulonephritis. Additional organs may be involved, including the skin, the eyes and the peripheral nerves. Key investigations are blood tests including ANCA (c-ANCA is usually positive), chest X-ray or CT showing nodules +/- cavitation and biopsy (showing necrotising granulomas with associated vasculitis). Acute management is usually with steroids with another immunosuppressive agent, the choice of which is dependent on the severity of disease. Steroids should be tapered once remission is achieved whilst another immunosuppressant is continued.

# Definition

Granulomatosis with polyangiitis (GPA), formerly known as Wegener's granulomatosis, is a chronic granulomatous ANCA-associated vasculitis that primarily involves the upper and lower respiratory tracts and the kidneys. 

# Epidemiology

- GPA is a rare disease with an annual incidence of 8.4 per million
- Men are slightly more likely to be affected
- Onset peaks between the ages of 35 to 55
- There is a higher incidence of cases seen in the winter, suggesting that environmental exposures such as infections may trigger GPA
- There is also a slightly increased risk in first degree relatives of people with GPA, indicating a genetic predisposition

# Signs and Symptoms

The classic triad involved in GPA is as follows:

- **Upper respiratory tract** 
- Chronic sinusitis with nasal obstruction and facial pain
- Rhinorrhoea which is often bloody
- Epistaxis
- Ulceration and crusting in and around the nose
- Destruction of nasal cartilage leading to a saddle-nose deformity 
- Subglottis stenosis may present with hoarseness, stridor or airway obstruction
- Otitis media causing ear pain and fullness
- Hearing loss
- **Lower respiratory tract**
- Cough
- Haemoptysis due to pulmonary haemorrhage
- Dyspnoea
- Pleuritic chest pain
- Wheeze
- **Necrotising glomerulonephritis**
- Haematuria
- Frothy urine due to proteinuria
- Oliguria

**Systemic signs and symptoms** are common:

- Fatigue
- Malaise
- Fevers
- Night sweats
- Anorexia
- Weight loss
- Arthralgia or arthritis

Other organs may also be affected, for example:

- **Skin**
- Palpable purpura
- Nodular, papular or vesicular rashes
- Ulcers
- **Eyes**
- Granulomatous disease may cause an inflammatory mass in the orbit leading to proptosis 
- The optic nerve may also be compressed
- Vasculitis may cause conjunctivitis, episcleritis, scleritis, uveitis, retinitis or optic neuritis
- Eye pain, redness and visual loss may occur
- **Peripheral nerves**
- Mononeuritis multiple is the usual pattern seen
- Sensory and motor deficits are seen in the distribution of particular peripheral nerves
- Pain and paraesthesias of affected areas are common
- **Central nervous system**
- Granulomatous lesions
- Vasculitis causing infarction
- Intracranial haemorrhage
- Symptoms include headaches, cranial nerve lesions, seizures, focal neurological deficits and altered consciousness
- **Gastrointestinal (GI) tract**
- Mouth ulcers
- Strawberry gums (hyperplastic gingival lesions)
- Ulceration elsewhere in the GI tract leading to bleeding or perforation
- Ischaemic bowel disease
- Symptoms include abdominal pain, vomiting and diarrhoea
- **Heart**
- Pericarditis or myocarditis
- Coronary arteritis
- Valvular disease
- Conduction deficits
- Symptoms include chest pain, dyspnoea, palpitations and dizziness

# Differential Diagnosis

- **Eosinophilic granulomatosis with polyangiitis** is another ANCA-associated systemic vasculitis which may share features of sinusitis, lung and renal involvement however almost all patients have asthma and eosinophilia
- **Microscopic polyangiitis** is also an ANCA-associated systemic vasculitis which classically involves the lungs and kidneys, as well as the eyes, peripheral nerves, GI tract and skin, however features of sinusitis are not present
- **Anti-GBM disease** (also known as Goodpasture's syndrome) causes diffuse pulmonary alveolar haemorrhage and rapidly progressive glomerulonephritis; antibodies against the glomerular basement membrane (GBM) are the key differentiating investigation; ANCA may also be positive
- **Polyarteritis nodosa** also causes systemic symptoms and commonly involves the kidneys, however pulmonary involvement is very rare unlike in GPA
- **IgA vasculitis** is an immune complex-mediated small vessel vasculitis that typically affects children; palpable purpura on the legs, abdominal pain and renal involvement are all shared features
- **Infective endocarditis** causes similar systemic symptoms (e.g. fevers, malaise, weight loss) and septic emboli can affect the lungs and kidneys as well as the central nervous system
- **Malignancy** may cause similar systemic symptoms of weight loss, fatigue, malaise and low-grade fevers, and specific malignancies may cause symptoms that mimic GPA (e.g. haemoptysis due to lung cancer, haematuria due to urological malignancies)

# Investigations

**Bedside tests:**

- **Urine dip** for blood and protein
- **Urinary protein:creatine ratio** if proteinuria present on urinalysis
- **Urine microscopy** may show red blood cell casts

**Blood tests:**

- **Full blood count** which may show a normocytic anaemia and thrombocytosis due to chronic inflammation, or a microcytic anaemia due to alveolar haemorrhage or GI bleeding
- **U&Es** looking for renal impairment due to glomerulonephritis
- **LFTs** may show hypoalbuminemia due to inflammation or proteinuria
- **CRP** and **ESR** are raised due to systemic inflammation
- **Bone profile** is typically normal, hypercalcaemia should raise suspicion of malignancy as an important differential
- **ANCA** is usually positive - anti-PR3 or c-ANCA is most commonly seen but a small proportion of people are anti-MPO or p-ANCA positive

**Imaging tests:**

- **Chest X-ray**
- The most common finding is multiple nodules of various sizes throughout both lung fields
- These may cavitate
- Pulmonary haemorrhage may also be seen with patchy or diffuse opacification
- Focal areas of alveolar consolidation may occur and can also cavitate
- Pleural effusions may be seen secondary to cardiac or renal GPA
- **CT chest** is more sensitive for the above findings and may also show:
- Micronodules due to bronchial wall involvement or retained blood in the distal airways
- Mild bronchiectasis
- Ground glass changes secondary to haemorrhage
- Tracheobronchial wall thickening
- **CT of the sinuses** may show:
- Mucosal thickening
- Soft tissues nodules
- Erosions +/- perforation of the cartilage and bones
- Sclerosis and calcification may also be present
- **CT** or **MRI** of the head and orbits may show central nervous system involvement or granulomatous disease of the orbits
- **CT** of the kidneys typically shows a hypovascular mass
- **FDG-PET CT** can be used to identify occult sites of disease and investigate for differentials such as chronic infection or malignancy

**Special tests include:**

- **Renal biopsy** shows crescentic and necrotising glomerular lesions with no or few immune deposits (pauci-immune)
- Other affected sites may also be amenable to biopsy, including skin, nasal mucosa and lung tissues 
- **Flexible nasendoscopy** may be done to look for features such as ulceration, septal perforation, crusting and subglottic stenosis
- **Lung function testing** with **flow-volume loops** may show evidence of fixed upper airway obstruction in subglottic stenosis
- **Nerve conduction studies** and **electromyography** may be useful in the investigation of mononeuritis multiplex
- **Endoscopy** may be required in GPA associated with gastrointestinal bleeding
- **Bronchoalveolar lavage** may be indicated in evaluating pulmonary infiltrates e.g. alveolar haemorrhage

# Management

- Organ or life-threatening GPA should be treated with high dose steroids (usually 1mg/kg prednisolone or equivalent) with either rituximab or cyclophosphamide
- Avacopan (an oral C5a-receptor antagonist) may be substituted for steroids in severe GPA
- Plasma exchange is another option that may be used for salvage therapy, especially in severe renal impairment due to rapidly progressive glomerulonephritis
- Patients may require supportive treatment e.g. intensive care admission with intubation and ventilation and/or renal replacement therapy
- If GPA is not organ or life-threatening, steroids and rituximab (in some cases methotrexate or mycophenolate mofetil may be used instead of rituximab) are recommended
- Prednisolone should be tapered over several months
- Options for maintenance treatment once remission is achieved include rituximab, azathioprine or methotrexate 
- Maintenance immunosuppressive treatment is usually continued for 2 to 4 years (longer in relapsing disease)
- Patients should be counselled on the risks of immunosuppressive treatments, and prophylactic co-trimoxazole given to patients on rituximab, cyclophosphamide or high-dose steroids
- In some cases, surgical treatment is required e.g. reconstructive surgery for nasal deformities or for subglottic stenosis
- Long-term renal replacement therapy (haemodialysis or transplant) may be required for patients who develop end-stage renal disease

# Complications

- Renal failure due to rapidly progressive glomerulonephritis 
- Respiratory failure due to diffuse pulmonary haemorrhage
- Hearing loss
- Vision loss
- Septal perforation or saddle nose deformity
- Increased cardiovascular risk due to chronic inflammation
- Increased risk of bladder cancer in patients treatment with cyclophosphamide - patients should have regular urinalysis as part of follow up
- Side effects of immunosuppression e.g. osteoporosis, diabetes, peptic ulceration with prolonged steroid courses
- Psychological distress and negative impacts on quality of life due to the burden of disease and its treatments

# Prognosis

- Without treatment, GPA is usually fatal
- Patients with both renal and respiratory tract involvement have an increased risk of early death
- Mortality with effective treatment is 14% at 1 year
- The majority of patients respond to treatment although relapses are frequent (50% at 8 years)

# References

[EULAR recommendations for the management of ANCA-associated vasculitis](https://ard.bmj.com/content/83/1/30)

[Radiopaedia - Granulomatosis with polyangiitis](https://radiopaedia.org/articles/granulomatosis-with-polyangiitis?lang=gb)

[Patient UK - Granulomatosis with polyangiitis](https://patient.info/doctor/granulomatosis-with-polyangiitis-wegeners-granulomatosis-pro)

[DermNet - Granulomatosis with polyangiitis](https://dermnetnz.org/topics/granulomatosis-with-polyangiitis)

[StatPearls - Granulomatosis with polyangiitis](https://www.ncbi.nlm.nih.gov/books/NBK557827/)
2030
2654
Granulomatosis with polyangiitis (Wegener's Granulomatosis)
Topic
4
Dermatology
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Recurrent sinusitis and a purpuric rash could suggest granulomatosis with polyangiitis, making urine dipstick testing important to evaluate potential renal involvement.
A 34-year-old man presents with a two-week history of a purple coloured rash on his lower limbs. He also reports approximately 5kg weight loss in the last two months. He is otherwise well, and his only significant past medical history is of recurrent episodes of sinusitis in the past year.

On examination, there is a widespread palpable purpuric rash on the anterior aspects of both legs. Examination and observations are otherwise normal.

Which of the following is the next best step in management?
a