QuestionSBA
QuestionChoice
This is incorrect because p-ANCA (antibody against myeloperoxide (MPO)) is positive in microscopic polyangiitis and Churg-Strauss. p-ANCA stands for perinuclear anti-neutrophil cytoplasmic antibodies, whereas c-ANCA refers to cytoplasmic anti-neutrophil cytoplasmic antibodies. The terminology originates from the pattern of staining seen during immunoflouresence. Churg-Strauss is also known as eosinophilic granulomatosis with polyangiitis, and can present with a nephritic/rapidly progressive glomerulonephritis picture, as well as other clinical features such as eosinophilia and poorly controlled asthma. Microscopic polyangiitis has a less well defined constellation of clinical features, and may present non-specifically with virtually any organ system involved, as one would expect of a vasculitis disorder.
53293
b
p-ANCA
QuestionChoice
This is the correct answer because c-ANCA (antibody to proteinase-3 (PR-3)) is associated with granulomatosis with polyangiitis (GPA). This is a small-medium vessel vasculitis. This question stem describes the classic triad of upper and lower respiratory tract involvement (sinusitis and cough, often progressing to haemoptysis) and renal involvement (haematuria, which usually indicates a nephritic/crescentic presentation and a rapidly progressive deterioration in renal function.) c-ANCA is a highly specific antibody for Wegener's granulomatosis (the eponymous name, which has since been superseded by GPA), however its absence does not exclude the disease. Patients may develop a saddle-nose deformity due to collapse of the nasal cartilage.
53292
a
c-ANCA
QuestionChoice
Anti-dsDNA antibodies are specific to Systemic Lupus Erythematosus (SLE.) SLE is an autoimmune rheumatic condition which presents with systemic symptoms such as fever, myalgia and weight loss as well as joint and skin involvement. It is important to remember that ANA antibodies are sensitive but not specific as they can be found in many other rheumatological conditions.
53295
d
Anti-dsDNA
QuestionChoice
ANAs are not specific and may be present in many of the autoimmune rheumatic disorders, including SLE, systemic sclerosis, Sjogren's syndrome, polymyositis and dermatomyositis. They are a reasonably sensitive test for diagnosing Systemic Lupus Erythematosus (SLE.) This question stem points towards granulomatosis with polyangiitis, and though ANA may well be positive due to its reasonably non-specific character, the more specific test is c-ANCA.
53294
c
ANA
QuestionChoice
Anti-Scl70 antibodies are reasonably specific to diffuse cutaneous systemic sclerosis, which presents with widespread skin fibrosis and potential multi-organ involvement, most notably kidney and pulmonary. This is not associated with granulomatosis with polyangiitis, which is the diagnosis in this case as indicated by the classic triad of symptoms.
53296
e
Anti-Scl70
QuestionComment
lets be honest it was a 50/50 between PANCA and CANCA like always
29677
User
subscriber
Pudendal Syndrome
QuestionComment
W - Wegener's granulomatosis (now GPA)

E - Early respiratory symptoms (sinusitis, nasal ulcers, ear infections)

G - Glomerulonephritis (kidney involvement)

E - Elevated ANCA (anti-neutrophil cytoplasmic antibodies)

N - Nodules and granulomas (formation of small inflamed nodules)

E - Early diagnosis and treatment are essential

R - Respiratory and renal manifestations are common
44483
User
subscriber
Aristotle
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
410
Granulomatosis with polyangiitis (Wegener's Granulomatosis)
Topic
54
Rheumatology
10719
c-ANCA antibodies are highly specific for granulomatosis with polyangiitis, a condition characterised by respiratory and renal involvement.
Presentation
384
Muscle pain/ myalgia
UkmlaTopic
16
Musculoskeletal
A 43-year-old male presents to the GP with a 5-day history of cough on a background of lethargy and weight loss. He denies any recent unwell contacts. He is concerned as he saw blood in his urine for the first time this morning. He denies any regular medication but he says he has recently started to depend on nasal decongestants over-the-counter, due to chronic nasal congestion.

Given the most likely diagnosis, which of the following tests are most specific in this condition?
a