PROF. MARCUS MAURER
with Chronic Spontaneous Urticaria (CSU)
Prof. Marcus Maurer
with Chronic Inducible Urticaria (CIndU)
Prof. Marcus Maurer
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This diagnostic algorithm is aimed at
patients presenting with wheals, angioedema, or both
for longer than 6 weeks.
If a patient presents with both wheals and angioedema, follow the algorithm through twice,
clicking a different starting option and following through each time to confirm the correct
diagnosis.
With Prof. Marcus Maurer
WHEALS
ARE CHARACTERIZED BY:
A sharply circumscribed superficial
central swelling of variable size and shape, almost invariably surrounded by reflex
erythema.
An itching or sometimes burning sensation.
A fleeting nature, with the skin returning to its normal appearance, usually within 0.5–24
hours.
ANGIOEDEMA
IS CHARACTERIZED BY:
A sudden, pronounced erythematous or
skin-colored deep swelling in the lower dermis and subcutis or mucous
membranes.
Tingling, burning, tightness, and sometimes pain rather than itch.
Resolution within 72h.
Patients who present with wheals should be asked whether they have experienced RECURRENT UNEXPLAINED FEVER, JOINT/BONE PAIN, OR MALAISE.
A finding of recurrent unexplained fever, joint/bone pain, or malaise should trigger investigations for potential acquired or hereditary AUTOINFLAMMATORY DISEASE.
If there is no history of recurrent unexplained fever, joint/bone pain or malaise, the next step is to determine if the AVERAGE WHEAL DURATION EXCEEDS 24 HOURS.
If there is no presence of acquired or hereditary inflammatory disease, the next step is to determine if the AVERAGE WHEAL DURATION EXCEEDS 24 HOURS.
If wheals persist >24 hours, a LESIONAL SKIN BIOPSY should be undertaken to INVESTIGATE SIGNS OF VASCULITIS.
If average wheal duration is
NOT >24h ,
the next step is to determine
ARE SYMPTOMS INDUCIBLE?
Urticaria symptoms may arise due to specific TRIGGERS that are often noticed by the patient.
Patients should be asked if there are any triggers that provoke their symptoms.
If a patient recognizes a particular trigger for their symptoms, VALIDATED PROVOCATION TESTS may be used to investigate suspected triggers.
If a patient recognizes a particular trigger for their symptoms, VALIDATED PROVOCATION TESTS may be used to investigate suspected triggers.
Patients who present with angioedema should be asked if they are being treated with ANGIOTENSIN-CONVERTING ENZYME (ACE) INHIBITORS.
Angioedema can also be a symptom of conditions such as
HEREDITARY ANGIOEDEMA (HAE) OR
ACQUIRED ANGIOEDEMA (AAE).
These conditions can be ruled out through laboratory diagnostic testing.
Urticaria symptoms may arise due to specific TRIGGERS that are often noticed by the patient.
Patients should be asked if there are any triggers that provoke their symptoms.
If a patient recognizes a particular trigger for their symptoms, VALIDATED PROVOCATION TESTS may be used to investigate suspected triggers.
If the patient is on medication such as ACE-inhibitor treatments that may induce angioedema, treatment should be stopped in a safe way. The patient should then be monitored for REMISSION OF SYMPTOMS OF ANGIOEDEMA.
Angioedema can also be a symptom of conditions such as
HEREDITARY ANGIOEDEMA (HAE) OR
ACQUIRED ANGIOEDEMA (AAE).
These conditions can be ruled out through laboratory diagnostic testing.
Urticaria symptoms may arise due to specific TRIGGERS that are often noticed by the patient.
Patients should be asked if there are any triggers that provoke their symptoms.
If a patient recognizes a particular trigger for their symptoms, VALIDATED PROVOCATION TESTS may be used to investigate suspected triggers.
- Evaluating potential autoinflammatory disease requires investigating family history and age of disease onset.
- Additional tests may include tests for:1
- Elevated inflammation markers such as C-reactive protein and erythrocyte sedimentation rate
- Paraproteinemia
- Signs of neutrophil-rich infiltrates in skin biopsy
- Gene mutation analysis may be indicated if
hereditary
periodic fever syndromes are strongly suspected.
References
1. Zuberbier T, et al.
Allergy. 2022;77(3):734-766.
- Wheals usually disappear within 0.5–24 hours.1
- Wheals lasting >24 hours could be indicative of urticarial
vasculitis.
A skin biopsy of lesional skin would show vessel-wall necrosis, a hallmark of urticarial vasculitis, but does not occur in urticaria.1 - In urticarial vasculitis, wheals may leave behind a dark hyperpigmentation once they disappear after ≥24 hours.2
References
1. Zuberbier T, et al.
Allergy. 2022;77(3):734-766.
2. Gu SL, et al. Int J Womens
Dermatol. 2021;7(3):290-297.
- If vasculitis is present a biopsy may reveal damage to small vessels in the papillary or reticular dermis, and/or fibrinoid deposits in perivascular and interstitial locations.1
References
1. Zuberbier T, et al.
Allergy. 2021 Sep 18. doi: 10.1111/all.15090.
- Wheals usually disappear within 0.5–24 hours.1
- Wheals lasting >24 hours could be indicative of urticarial vasculitis. A skin biopsy of lesional skin would show vessel-wall necrosis, a hallmark of urticarial vasculitis, but does not occur in urticaria.1
- In urticarial vasculitis, wheals may leave behind a dark hyperpigmentation once they disappear after ≥24 hours.2
References
1. Zuberbier T, et al.
Allergy. 2022;77(3):734-766.
2. Gu SL, et al. Int J Womens
Dermatol. 2021;7(3):290-297.
- If vasculitis is present a biopsy may reveal damage to small vessels in the papillary or reticular dermis, and/or fibrinoid deposits in perivascular and interstitial locations.1
References
1. Zuberbier T, et al.
Allergy. 2022;77(3):734-766.
- The identification of specific triggers may help in differentiating between different types of urticaria.
- A patient may report more than one trigger for urticaria symptoms.
- Examples of urticaria triggers include exposure to cold, constant pressure, sunlight, heat, vibration, rubbing, friction, and sweat.
References
1. Zuberbier T, et al.
Allergy. 2022;77(3):734-766.
Examples of validated provocation tests include:1
- Peltier element-based provocation device (TempTest®) for cold and heat urticaria2
- Dermographometers (e.g., Dermographic Tester, FricTest) for symptomatic dermographism3,4
- Dermographic Tester for delayed pressure urticaria3
- Graded provocation test (e.g., pulse-controlled ergometry) for cholinergic urticaria5,6
- Cutaneous provocation tests for contact urticaria or aquagenic urticaria7
References
1. Zuberbier T, et al. Allergy.
2022;77(3):734-766.
2. Magerl M, et al. J Eur Acad
Dermatol Venereol. 2015;29(10):2043-2045.
3. Schoepke N, et al. Clin Exp
Dermatol. 2015;40(4):399-403.
4. Mlynek A, et al. Clin Exp
Dermatol. 2013;38(4):360-366; quiz 366.
5. Altrichter S, et al. J
Dermatol Sci. 2014;75(2):88-93.
6. Koch K, et al. J Allergy Clin
Immunol. 2016;138(5):1483-1485.
7. Magerl M, et al. J Allergy
2016;71(6):780-802.
- The identification of specific triggers may help in differentiating between different types of urticaria.
- A patient may report more than one trigger for urticaria symptoms.
- Examples of urticaria triggers include exposure to cold, constant pressure, sunlight, heat, vibration, rubbing, friction, and sweat.
References
1. Zuberbier T, et al.
Allergy. 2022;77(3):734-766.
- ACE inhibitors can cause angioedema by inhibition of bradykinin and substance P degradation by ACE.1,2
- Other drugs that can induce angioedema include:1
- angiotensin II type 1 receptor blockers (e.g., sartans)
- dipeptidyl peptidase IV inhibitors (e.g., gliptins)
- neprilysin inhibitors
ACE, angiotensin-converting enzyme.
References
1. Zuberbier T, et al.
Allergy. 2022;77(3):734-766.
2. Kostis WJ, et al. Curr
Hypertens Rep. 2018;20(7):55.
acquired angioedema (AAE)?
- Test for Complement C4, C1-INH levels and function
- In addition, if AAE is suspected test for C1q and C1-INH antibodies; do gene mutation analysis if former tests are unremarkable but patient’s history suggests HAE.1
AAE,
acquired angioedema; C1, complement component 1; C1q, complement component 1q;
C4, complement component 4;
HAE, hereditary angioedema;
INH, inhibitor.
References
1. Zuberbier T, et al.
Allergy. 2022;77(3):734-766.
- The identification of specific triggers may help in differentiating between different types of urticaria.
- A patient may report more than one trigger for urticaria symptoms.
- Examples of urticaria triggers include exposure to cold, constant pressure, sunlight, heat, vibration, rubbing, friction, and sweat.
References
1. Zuberbier T, et al.
Allergy. 2022;77(3):734-766.
Examples of validated provocation tests include:1
- Peltier element-based provocation device (TempTest®) for cold and heat urticaria2
- Dermographometers (e.g., Dermographic Tester, FricTest) for symptomatic dermographism3,4
- Dermographic Tester for delayed pressure urticaria3
- Graded provocation test (e.g., pulse-controlled ergometry) for cholinergic urticaria5,6
- Cutaneous provocation tests for contact urticaria or aquagenic urticaria7
References
1. Zuberbier T, et al. Allergy.
2022;77(3):734-766.
2. Magerl M, et al. J Eur Acad
Dermatol Venereol. 2015;29(10):2043-2045.
3. Schoepke N, et al. Clin Exp
Dermatol. 2015;40(4):399-403.
4. Mlynek A, et al. Clin Exp
Dermatol. 2013;38(4):360-366; quiz 366.
5. Altrichter S, et al. J
Dermatol Sci. 2014;75(2):88-93.
6. Koch K, et al. J Allergy Clin
Immunol. 2016;138(5):1483-1485.
7. Magerl M, et al. J Allergy
2016;71(6):780-802.
Acquired AIDs
- Schnitzler’s syndrome
- Systemic-onset juvenile idiopathic arthritis (sJIA)
- Adult-onset Still’s disease (AOSD)
Hereditary AIDs
- Cryopyrin-associated periodic syndromes (CAPS)
- Familial cold autoinflammatory syndromes (FCAS)
- Muckle-Wells syndrome (MWS)
- Neonatal onset multisystem inflammatory disease (NOMID)
- Hyper-IgD syndrome (HIDS)
- Tumor necrosis factor receptor alpha-associated periodic syndrome (TRAPS)
References
1. Zuberbier T, et al.
Allergy. 2022;77(3):734-766.
observed in a skin biopsy,
URTICARIAL VASCULITIS is a
likely diagnosis.1
- Urticarial vasculitis
(UV)
is a rare immune complex-driven cutaneous vasculitis of
small vessels.2 - UV is characterized by
recurrent episodes of wheal-like lesions that last >24 hours and can
heal with residual ecchymotic
post-inflammatory hyperpigmentation.2
References
1. Zuberbier T, et al.
Allergy. 2022;77(3):734-766.
2. Marzano AV, et al.
J Allergy Clin Immunol. 2022;149(4):1137-1149.
observed in a skin biopsy,
URTICARIAL VASCULITIS is a
likely diagnosis.1
- Urticarial vasculitis
(UV)
is a rare immune complex-driven cutaneous vasculitis of
small vessels.2 - UV is characterized by
recurrent episodes of wheal-like lesions that last >24 hours and can
heal with residual ecchymotic
post-inflammatory hyperpigmentation.2
References
1. Zuberbier T, et al.
Allergy. 2022;77(3):734-766.
2. Marzano AV, et al.
J Allergy Clin Immunol. 2022;149(4):1137-1149.
References
1. Zuberbier T, et al.
Allergy. 2022;77(3):734-766.
Key steps to be taken in the diagnosis of patients with Chronic Spontaneous Urticaria (CSU)
References
1. Zuberbier T, et al.
Allergy. 2022;77(3):734-766.
Variants of CIndU include:1
- Symptomatic dermographism
- Cold urticaria
- Delayed pressure urticaria
- Heat urticaria
- Vibratory
angioedema
(chronic physical urticaria) - Cholinergic (solar) urticaria
- Contact urticaria
- Aquagenic urticaria
Key steps to be taken in the diagnosis of patients with Chronic Inducible Urticaria (CIndU)
References
1. Zuberbier T, et al.
Allergy.
2021 Sep 18. doi: 10.1111/all.15090.
References
1. Zuberbier T, et al.
Allergy. 2022;77(3):734-766.
Variants of CIndU include:1
- Symptomatic dermographism
- Cold urticaria
- Delayed pressure urticaria
- Heat urticaria
- Vibratory
angioedema
(chronic physical urticaria) - Cholinergic (solar) urticaria
- Contact urticaria
- Aquagenic urticaria
Key steps to be taken in the diagnosis of patients with Chronic Inducible Urticaria (CIndU)
References
1. Zuberbier T, et al.
Allergy.
2022;77(3):734-766.
There are three subtypes of HAE1
- HAE-1: caused by C1-Inhibitor deficiency
- HAE-2: caused by C1-Inhibitor dysfunction
- HAE with normal C1-inhibitor (nC1-INH) levels caused by mutations in other genes:
- FXII (factor 12)
- ANGPT1 (angiopoietin-1)
- PLG (plasminogen)
- KNG1 (kininogen)
- MYOF (myoferlin)
- HS3ST6 (Heparan Sulfate-Glucosamine 3-Sulfotransferase 6)
- Unknown genes
AAE is due to either consumption
(type
1)
or inactivation (type 2) of C1-INH.2
AAE, acquired angioedema; HAE, hereditary angioedema; nC1-INH, normal C1-Inhibitor levels.
References
1. Zuberbier T, et al.
Allergy. 2022;77(3):734-766.
2. Patel G, et al. Allergy
Asthma Proc. 2019;1;40(6):441-445.
Angioedema occurs when ACE inhibitors block the ACE-mediated degradation of bradykinin and substance P.2
ACE, angiotensin-converting enzyme.
References
1. Zuberbier T, et al.
Allergy.
2022;77(3):734-766.
2. Kostis WJ, et al. Curr
Hypertens Rep. 2018;20(7):55.
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