FULL-2225 - IDD1 - Vasculitis, Diagnostic Strategies

12/10/22, 12:07 PM FULL-Mod1-IDD1 | In-depth Discussion 1: Vasculitis, Diagnostic Strategies
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In-depth Discussion 1: Vasculitis,

Diagnostic Strategies
Back to course
Clinical case
A 45-year-old man is admitted to your

department. His history is: « I´m visiting you
because of a rash on my legs which I noticed
just yesterday. I have been unwell for about 3
weeks. I have pain all over, and I have also felt
sweaty at night and have lost 2 or 3 kg. I do not
feel right and am very tired. »
Clinical examination and laboratory results

show a palpable rash on his legs (See Figure).
His blood pressure is 195/100 mmHg,
temperature 37.8°C, and he has diffusely tender
muscles. Urine dipstick shows 1+ of protein.
Lab reveals mild normocytic and
normochromic anaemia and a CRP of 85 mg/L
(normal <5 mg/L).
https://esor.eular.org/mod/scorm/player.php?a=2548&currentorg=adapt_scorm&scoid=5096 1/13
Try to formulate a one-sentence representation defining the case in abstract

terms
A 45-year-old Caucasian male with a systemic syndrome consisting of B-symptom
Submit
EULAR model answers and explanation
The one-sentence representation can be as follows:
A 45-year-old Caucasian male with a systemic syndrome consisting of B-

symptoms for 3 weeks and a non-itching palpable purpuric rash suggestive of
leukocytoclastic vasculitis. He has hypertension and proteinuria which might
point to possible involvement of his kidneys.
Could it be an Infectious disease?
yes, it could be the short duration of symptoms an infectious process. An increase
Submit
Answer: Yes – it could be – the relatively short duration of symptoms and low-
grade fever might point to an infectious process such as parvovirus B19, HCV,
HBV or SBE. A vasculitic rash and an increased CRP could be a manifestation of
these diseases as could kidney involvement. Serological studies and cultures

should be performed.
In addition to ruling out infection, how should we classify this cluster of

symptoms?
hhhhh
Answer: a systemic clinical picture for which the main differential diagnosis is
vasculitis. However, another DD should among others include SLE, PM/DM,
MCTD.
Diagnostic approach
Step one: When to suspect vasculitis?
Vasculitis is an inflammation of blood vessel walls. It is a highly heterogeneous

group and can affect vessels of all sizes in any organ. The clinical picture of
vasculitis can vary from a benign loco-regionally restricted processes to systemic
necrotising vasculitis leading to life-threatening conditions.
The presenting symptoms (Table 1) varies. They include such constitutional

symptoms as fatigue, weight loss, night sweats and low grade fever (the B-
symptoms) and also more specific symptoms derived from tissue and organ
ischemia, such as claudication, angina, stroke, cutaneous ischemia, and
mesenteric ischemia depending on the vessels involved. Several organs may be
affected. Ischemia is especially suggestive when it affects a young person
without atherosclerosis. Also, multiple organ dysfunctions in a systemically ill

patient should raise the possibility of vasculitis.
 You have to suspect vasculitis when a patient presents with:
Unexplained systemic illness

Symptoms of organ system ischaemia
Nephritic syndrome
We have now given you the first step of your two-step approach to diagnose
vasculitis: when to suspect vasculitis.
Now reaching step two you must be aware that several other conditions can
mimic vasculitis or initiate a secondary vasculitis. These conditions need to be
considered and excluded before you finally decide on the specific type of primary
vasculitis. A structured diagnostic approach is indispensable.
Step two: The diagnostic strategy
Having considered the possibility of primary vasculitis we suggest you try to

answer the following questions in succession:
Is this a condition that could mimic the presentation of vasculitis?

Is this a secondary vasculitis?
How do I confirm the diagnosis of vasculitis and what is the extent of the
disease?
What specific type of vasculitis is this? Is this a large-vessel, medium-vessel,
or small-vessel vasculitis?
Consider mimics of vasculitis
Mimics of vasculitis:
Infections
Embolic disorders
Malignancy
Drugs
Vasculitis mimics, frequently entitled pseudo-vasculitis or vasculitis-like

syndromes, should be excluded first. Infections deserve careful attention, as they
are major mimics of vasculitis and would be aggravated by medication aimed to
suppress vascular inflammation. Infective endocarditis should always be
considered. Although the endocardium is the primary site of infection, it often
results in multisystem manifestations, involving several organs. Bacteraemia and
peripheral embolic events are common. Circulating immune complexes may lead
to immune responses most often affecting the skin, the kidney, and the central
nervous system.
Differential diagnosis is not always simple.
An embolism from an atrial myxoma or cholesterol emboli from an atheroma are

examples of embolic diseases that can mimic vasculitis. Thrombotic disorders
such as antiphospholipid syndrome, thrombotic thrombocytopenic purpura and
sickle cell disease can cause thrombosis and thus mimic vasculitis. Amyloid
angiopathy and fibromuscular dysplasia are non-inflammatory vessel wall
disorders causing ischaemic organ damage. Some conditions like end-stage
renal failure and hyperparathyroidism can be associated with a livedo reticularis-
like rash which can be mistaken as a sign of vasculitis.
Drugs can induce

vasoconstriction and
ischaemia. These include
ergots, cocaine, and
phenylpropanolamine. Some
drugs can cause coagulopathy
and, in this way, mimic the
vasculitis e.g. Warfarin.
Malignancy will often have B-

symptoms and basic
laboratory findings such as
normocytic normochromic
anaemia, lymphocytosis,
thrombocytosis, elevated ESR
and raised CRP. Radiological
findings of multi nodular lung
shadows due to metastasis
can suggest GPA.
Consider secondary vasculitis
Conditions that may cause secondary vasculitis
Infections
Drugs
Malignancy
Infections
Many infections can result in secondary vasculitis; the majority are viral.
Hepatitis B and C, Parvovirus B19, Human immunodeficiency virus (HIV),
Cytomegalovirus (CMV), and Epstein-Barr virus (EBV) are examples of viral
conditions which are known to cause secondary vasculitis. Cryoglobulins
can be found in many of primary or secondary vasculitis.
Infections with Salmonella, Streptococcus pneumoniae, Clostridium

septicum, Chlamydia pneumoniae and Mycobacterium tuberculosis can also
result in vasculitis. Even parasites (e.g. Ascaris) and fungi (e.g. Aspergillus)
have been associated with secondary vasculitis.
Many clues suggest the hypotheses that infections may be the cause of true
primary vasculitis, but we will leave this discussion to the modules on
vasculitis.
Drugs
Drugs from almost every pharmacological class have been mentioned as the
cause of secondary vasculitis. Some have been shown in large clinical trials;
others just in case reports. Hydralazine, propylthiouracil, minocycline and
related agents are well described ANCA-associated drugs, while leukotriene
inhibitors, sulfasalazine, D-penicillamine, ciprofloxacin, phenytoin, clozapine,
allopurinol, and several others are suspected of causing secondary vasculitis
without ANCA association. Intoxication (drug abuse) with cocaine, morphine
and others can also result in secondary vasculitis.
The clinical presentations are highly variable, from small vessel

hypersensitivity vasculitis and leukocytoclastic vasculitis to conditions
resembling granulomatosis with polyangiitis (GPA), polyarteritis nodosa

(PAN) and eosinophilic granulomatosis with polyangiitis (eGPA). However,
cutaneous manifestations, such as palpable purpura and maculopapular
rash, are the most common manifestations of drug induced vasculitis. The
lesions more frequently affect the lower part of the legs and are almost
always synchronous with respect to the time of onset and rate of
progression, as opposed to primary vasculitis where lesions occur at
different times and progress independently. Musculoskeletal symptoms are
common, and involvement of the kidneys, liver, CNS, and other organs can
occur.
Diagnosing a drug induced vasculitis might be very difficult. A

comprehensive drug history should be obtained for all patients with
vasculitic manifestations.
Malignant diseases such as solid tumours, myeloproliferative and

lymphoproliferative disorders can be associated with secondary vasculitis.
Connective tissue diseases, especially SLE and primary Sjögren’s syndrome, as

well as rheumatoid arthritis (RA) are known to cause secondary vasculitis. An
important clue is that the vasculitis usually appears late in the disease, which
makes the diagnosis easier.
Inflammatory bowel diseases can also originate secondary vasculitis.
Confirming the diagnosis of vasculitis and assessing the

extent of the disease
We have now discussed different diseases that mimic vasculitis or result in a

secondary vasculitis looking at many similarities, but how do we exclude the
mimics and secondary vasculitis from primary vasculitis? And how do we
separate isolated cutaneous manifestations from multisystem involvement?
Let us revert to our initial case:
A 45-year-old Caucasian male with a 3-week history of B-symptoms and a non-

itching rash on the lower part of the legs looking like a leukocytoclastic
vasculitis. He has possible involvement of his kidney and CRP is raised at 85
mg/l.
 How will you continue the assessment of this patient?
The secret to the diagnosis is to systematically ask and look for symptoms
or signs of the skin, muscle, nervous system, or vital organ impairment
pointing to local ischemia, arterial and venous thrombosis, arterial
hypertension, bloody nose discharge, sight loss, mononeuropathy,
pulmonary infiltration. Be aware that what might look like an isolated
cutaneous vasculitis can be complicated by life threatening internal organ
involvement and the need for immediate aggressive systemic treatment.
In the early stage of vasculitis, the diagnosis is especially difficult while late
manifestations are often more specific.
Our patient could have a mimic of vasculitis, secondary vasculitis as well as

primary vasculitis. To get closer to the diagnosis, you first must exclude
mimics and secondary vasculitis:
• Expand the history taken
- Travel history
- Drug history
• Full clinical examination
• Urine protein: creatinine ratio and urine microscopy
• Chest x-ray
• Basic blood screening (complete blood cell count, liver enzymes, CRP, ESR,
creatinine)
• Electrocardiogram
Laboratory testing is only occasionally helpful in classifying vasculitis, but it

is most important in excluding other diseases and determining organ
involvement. Here you must have all the former conditions in mind and
undertake laboratory testing based on the history and clinical examination.
You may consider:
• Blood cultures
• Hepatitis B and C screening, CMV and Parvovirus B19
• HIV test
• Relevant testing for bacteria, fungi, or parasites
• Serological tests
- ANA, anti-double stranded DNA, rheumatoid factor, ACPA, glomerular

basement membrane antibody, creatine phosphokinase, complement
factors (C3, C4)
- ANCA (PR3/MPO)
- Antiphospholipid antibodies & Lupus anticoagulan
- Cryoglobulins
• Echocardiogram
Consider how you can confirm the diagnosis of primary vasculitis, once you
have excluded mimics and secondary vasculitis
Confirming the diagnosis of primary vasculitis

The diagnosis of vasculitis is based on a combination of clinical, serologic,

histological, and angiographic parameters.
Histological confirmation of vasculitis should be sought in most cases by

undertaking a tissue biopsy. The site of biopsy is guided by clinical
manifestations and by the likelihood of the results affecting treatment decisions.
If there is an indication of kidney involvement (proteinuria), a kidney biopsy will
be preferred. Other favoured sites are skin, temporal artery, muscle, nasal
mucosa, lung, sural nerve, and testis. Although pathological proof of vasculitis
should be looked for, it is not mandatory for the final diagnosis. In the context of
a clinical picture suggestive of GCA, a negative temporal artery biopsy does not
rule out GCA. Likewise, a full-blown picture of ANCA associated vasculitis does
not necessarily require pathological confirmation.
In patients with large or medium vessel vasculitis, there are commonly great
difficulties verifying the biopsy and an angiography, computed tomography
angiography (CTA), magnetic resonance angiography (MRA) or even positron
emission tomography scan (PET scan) should be considered. For example, MRA
of the thoracic aorta may show stenosis, occlusion, or aneurysm formation in
patients with large vessel vasculitis such as Takayasu´s arteritis.
Which specific type of vasculitis is this?
A in depth approach to this question is better served by the modules on

vasculitis. Here, we will just give a short introduction.
The group of vaskulitis is very heterogeneous and there is considerable clinical

overlap in their manifestations. One of the most accepted attempts to classify
vaskulitis is the Chapel Hill classification from 2012. It builds on microscopic
findings, but also considers the size of vessels involved, and immunological
markers (e.g. ANCA in GPA), and immunohistological findings (e.g. IgA-dominant
immune deposit in Henoch-Schönlein purpura). Many other manifestations help
with diagnosing the type of vasculitis such as demographic associations, clinical
features, and histological findings (Table 13).
In-depth Discussion 1: Vasculitis, Diagnostic Strategies :

Take time for a brief reflection
Insert your take aways from this chapter
Notes
or even positron emission tomography scan (PET scan) should be
considered. For example, MRA of the thoracic aorta may show stenosis,
occlusion, or aneurysm formation in patients with large vessel vasculitis
such as Takayasu´s arteritis.
ne of the most accepted attempts to classify vaskulitis is the Chapel Hill
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12/10/22, 12:07 PM FULL-Mod1-IDD1 | In-depth Discussion 1: Vasculitis, Diagnostic Strategies

In-depth Discussion 1: Vasculitis,

A 45-year-old man is admitted to your

Clinical examination and laboratory results

Try to formulate a one-sentence representation defining the case in abstract

A 45-year-old Caucasian male with a systemic syndrome consisting of B-symptom

EULAR model answers and explanation

The one-sentence representation can be as follows:

A 45-year-old Caucasian male with a systemic syndrome consisting of B-

Could it be an Infectious disease?

yes, it could be the short duration of symptoms an infectious process. An increase

EULAR model answers and explanation

these diseases as could kidney involvement. Serological studies and cultures

In addition to ruling out infection, how should we classify this cluster of

EULAR model answers and explanation

Vasculitis is an inflammation of blood vessel walls. It is a highly heterogeneous

The presenting symptoms (Table 1) varies. They include such constitutional

without atherosclerosis. Also, multiple organ dysfunctions in a systemically ill

 You have to suspect vasculitis when a patient presents with:

Unexplained systemic illness

Step two: The diagnostic strategy

Having considered the possibility of primary vasculitis we suggest you try to

Is this a condition that could mimic the presentation of vasculitis?

Consider mimics of vasculitis

Vasculitis mimics, frequently entitled pseudo-vasculitis or vasculitis-like

Differential diagnosis is not always simple.

An embolism from an atrial myxoma or cholesterol emboli from an atheroma are

Drugs can induce

Malignancy will often have B-

Consider secondary vasculitis

Conditions that may cause secondary vasculitis

Infections with Salmonella, Streptococcus pneumoniae, Clostridium

The clinical presentations are highly variable, from small vessel

resembling granulomatosis with polyangiitis (GPA), polyarteritis nodosa

Diagnosing a drug induced vasculitis might be very difficult. A

Malignant diseases such as solid tumours, myeloproliferative and

Connective tissue diseases, especially SLE and primary Sjögren’s syndrome, as

Inflammatory bowel diseases can also originate secondary vasculitis.

Confirming the diagnosis of vasculitis and assessing the

We have now discussed different diseases that mimic vasculitis or result in a

Let us revert to our initial case:

A 45-year-old Caucasian male with a 3-week history of B-symptoms and a non-

 How will you continue the assessment of this patient?

Our patient could have a mimic of vasculitis, secondary vasculitis as well as

• Expand the history taken

• Full clinical examination

• Urine protein: creatinine ratio and urine microscopy

Laboratory testing is only occasionally helpful in classifying vasculitis, but it

You may consider:

• Hepatitis B and C screening, CMV and Parvovirus B19

• Relevant testing for bacteria, fungi, or parasites

- ANA, anti-double stranded DNA, rheumatoid factor, ACPA, glomerular

- Antiphospholipid antibodies & Lupus anticoagulan

Confirming the diagnosis of primary vasculitis

The diagnosis of vasculitis is based on a combination of clinical, serologic,

Histological confirmation of vasculitis should be sought in most cases by

Which specific type of vasculitis is this?