Mast cell activation disorders: chronic urticaria

Mast cell activation disorders: chronic
urticaria, mastocytosis, monoclonal mast
cell activation syndrome (MMAS) and
mast cell activation syndrome (MCAS)
Clive Grattan, MA, MD, FRCP (UK)
Consultant Dermatologist and Honorary Senior Lecturer
Norfolk and Norwich University Hospital, UK
&
St John’s Institute of Dermatology, London
The cutaneous mast cell
Mast cell ultrastructure
The mast cell is more than a bunch of
histamine-rich granules
allergen
anti-IgE
Opiates
Neuropeptides
anti-FcεRI
Cytokines
KIT
Mutations described in
mastocytosis
Extracellular
(23-520)
Transmembrane
(521-43)
Juxtamembrane
Del D419
K5091
F22C, A533D
V559I, V560G
(544-581)
TK1
(582-684)
TK2
(762-937)
Activating
loop
mutations
e.g. D816V
Mast Cell Activation Disorders
(MCAD)
•  Primary (clonal)
–  Anaphylaxis associated with systemic mastocytosis (SM)
–  Monoclonal Mast cell Activation Syndrome (MMAS):
mediator-related symptoms but no skin lesions, BM
biopsy not diagnostic of SM but 1-2 minor criteria present
e.g. KIT D816V+ and/or CD25+
•  Secondary to a known cause (non-clonal)
–  Allergic disorders, autoimmune (& physical) urticarias
•  Idiopathic (unknown cause, non-clonal)
–  Anaphylaxis, angio-oedema, urticaria, ‘Mast Cell
Activation Syndrome’ (MCAS)
Akin et al. Mast cell activation syndrome: proposed diagnostic criteria J Allergy Clin Immunol 2010; 126:1099-104
Proposed criteria for the diagnosis
of MCAS (1)
1.  Episodic symptoms consistent with mast cell
mediator release affecting ≥ 2 organ systems
1.  Skin: weals, angio-oedema or flushing
2.  Gastrointestinal: nausea, vomiting, abdominal
cramping, diarrhoea
3.  Cardiovascular: fainting, collapse, tachycardia
4.  Respiratory: wheezing
5.  Naso-ocular: conjunctival redness, itch, nasal
stuffiness
Akin et al. Mast cell activation syndrome: proposed diagnostic criteria J Allergy Clin Immunol 2010; 126:1099-104
Proposed criteria for the diagnosis
of MCAS (2)
•  Decrease in frequency or severity of mediator
symptoms with anti-mediator therapies (e.g. H1
and H2 antihistamines, antileukotrienes, mast
cell stabilizers)
•  Evidence of increase of a validated serum or
urinary marker of mast cell activation during
symptoms (e.g. tryptase, N-methyl histamine) on
≥ 2 occasions
•  Exclude primary and secondary causes of mast
cell activation
Akin et al. Mast cell activation syndrome: proposed diagnostic criteria J Allergy Clin Immunol 2010; 126:1099-104
Consensus classification of chronic
urticaria
Chronic urticaria (CU)
Chronic spontaneous urticaria
(CSU)
CSU due to unknown causes
Chronic inducible urticaria
(CINDU)
Physical urticarias
Symptomatic dermographism
Cold urticaria
CSU due to known causes
Delayed pressure urticaria
Solar urticaria
Heat urticaria
Vibratory angioedema
Cholinergic urticaria
Contact urticaria
Aquagenic urticaria
Maurer M et al. Chronic idiopathic urticaria (CIU) is no longer idiopathic. Time for an update! Br J Dermatol. 2012 Jul 27. doi:
10.1111/j.1365-2133.2012.11171.x.
Causes of spontaneous urticaria
Allergens
Functional autoantibodies: anti-IgE
and anti-FcεRI
Drugs
? dietary
pseudoallergens
? infection
Idiopathic
10
Cause vs. aggravating vs. trigger factors
Spontaneous urticaria
•  Allergy
•  Autoimmune
•  Pseudoallergy
(drug & diet)
•  Infection
•  Heat
•  Tight clothes
•  Pseudoallergy
(drug and diet)
•  Infection
•  Stress
Inducible urticarias
•  Thermal
•  Cold or heat
contact
•  Overheating or
chilling
•  Mechanical
•  Pressure
•  Stroking
•  Vibration
•  Others e.g.
•  Sun, water
What is mastocytosis?
•  Too many clonal mast cells
–  Most affected adults have a mutation of the gene
(KIT) for stem cell factor receptors on MCs resulting in
sustained signalling of the kit pathway
–  Increased mast cell load but NOT intrinsic
releasability
•  The clonal mast cells generally behave normally
–  Symptoms of mastocytosis are mainly due to induced
rather than spontaneous degranulation
•  Mast cells generally look normal in skin biopsies
(but may be atypical)
Classification of mastocytosis
•  Cutaneous versus systemic disease
•  BUT is this meaningful? Most adults with skin
mastocytosis will have systemic disease on full
evaluation
•  ‘Mastocytosis in the skin’ (MIS) proposed until a
final diagnosis of Cutaneous OR Systemic can
be made
Valent et al, Eur J Clin Invest 2007, 435-53
An overlapping clinical entity
Mastocytoma
DCM
TMEP
URTICARIA
PIGMENTOSA
Systemic
SM-AHNMD>ASM>MC leukaemia
Classification of Systemic
Mastocytosis (WHO, 2001)
•  Indolent (ISM)
•  Systemic mastocytosis with an
associated clonal, haematological
non-mast cell disease (SM-AHNMD)
•  Aggressive systemic mastocytosis (ASM)
•  Mast cell leukaemia (MCL)
• 
Mast cell sarcoma
• 
Extracutaneous mastocytoma
Valent et al. Leukaemia Res 2001; 25:603-25
WHO criteria for SM diagnosis
Defined by: 1 major + 1 minor, OR 3 minor criteria
1.  Major: multifocal aggregates of at least 15 MC
in bone marrow or other organ (not skin)
2.  Minor:
a)  > 25% of MC in infiltrates are spindle-shaped in
bone marrow biopsy or other tissue, OR > 25% of
MC in bone marrow aspirate smears are immature
or atypical
b)  Activating mutations in KIT (e.g. codon 816) in bone
marrow, blood or other tissue (not skin)
c)  Co-expression of CD117 with CD2 and/or CD25 in
bone marrow MC, blood or other tissue (not skin)
d)  Serum tryptase >20 ng/ml (unless associated clonal
myeloid disorder)
Valent et al. Leukaemia Res 2001; 25:603-25
Subclassification of SM
B-findings
C-findings
(organ abnormalities)
Defines SMOULDERING ISM
(impaired organ function)
Defines AGGRESSIVE SM
1. High mast cell load:
1.  BM: cytopenia
2.  Liver: ascites, abnormal
LFT
3.  Spleen: hypersplenism
4.  GI tract: malabsorption,
weight loss
5.  Bones: osteolysis with
pathological #
> 30% atypical MC on BM
& tryptase > 200 ng/ml
2. Dysmyelopoiesis
3. Organomegally (LN,
Spleen, liver)
Lim et al. Systemic mastocytois in 342 consecutive adults: survival studies and prognostic factors. Blood 2009; 113:5727-36
Mastocytosis in the skin
1) 
2) 
3) 
4) 
UK
Urticaria pigmentosa
(UP)
Mastocytoma
Diffuse cutaneous
mastocytosis (DCM)
Telangiectasia
macularis eruptiva
perstans (TMEP)
WHO, 2001
•  Maculopapular
cutaneous
mastocytosis (MPCM)
•  Mastocytoma
•  Diffuse cutaneous
mastocytosis (DCM)
Mastocytosis in the skin
UP
TMEP
DCM
Mastocytoma
Mastocytosis presentation by
medical specialty
Allergy
Dermatology
How may systemic mastocytosis
present clinically?
Anaphylaxis:
e.g. stings,
foods, drugs
General: poor
concentration, mood
changes, hypotension
depression, irritability,
fatigue
Gut: pain, acid &
diarrhoea, bowel
frequency
Skin: lesions,
itch & flushing
Systemic
mastocytosis
Bone: osteoporosis,
bone pain & fracture
Blood: disorders
Bladder: frequency of
micturition, dysuria
Management of mastocytosis
• 
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Correct diagnosis
Re-assurance where possible
Accurate information
Self-help groups (e.g. UK Mastocytosis Society)
Avoid aggravating and trigger factors
Optimize anti-mediator therapies
Multidisciplinary approach
Lifetime review for adults
Networks, national registries and research
Treatments of mastocytosis
Mast cell-derived mediator antagonists
• H1 antihistamines
• H2 antihistamines
• Antileukotrienes
Mast cell stabilizing
drugs
Mast cell inhibitors
• Chromones
• Lipid raft modulators
• Steroids
• Ultraviolet radiation
• Interferon alpha
• Tyrosine kinase inhibitors
Vascular ablation (lasers)
Antihistamines & antileukotrienes
1
2
Histamine
Eicosanoids
PAF
Mast cell stabilizing drugs
Cromones
Ca2+
Vieira dos Santos et al. Br J Dermatol 2010; 162:674-6
Mast cell inhibitors
Steroids
S
T
E
M
C
E
L
L
F
A
C
T
O
R
Finotto et al. J Clin Invest 1997; 99:1721-8
Mast cell inhibitors
Ultraviolet (B, UVA-1 and PUVA)
Anti-IgE
Guhl et al. J Invest Dermatol 2005; 124:543-6
Organ-based management
SKIN
GUT
SKELETON
Skin
•  Topical corticosteroids
•  Phototherapy
•  Lasers
Clobetasol propionate for UP
Skin - ultraviolet
•  PUVA (320-400 nm)1,2
•  NB-UVB (311 nm)3
•  UVA1 (340-400 nm)4,5
1 Kolde et al. J Invest Dermatol 1984; 83:175-8
2 Vella Briffa et al. Br J Dermatol 1983; 109:67-75
3 Prignano et a. Clin Exp Dermatol 2010
4 Stege et al. Lancet 1996; 347:64
5 Gobello et al. J Am Acad Dermatol 2003; 49:679-84
Cutaneous microvascular ablation
with lasers
•  585 flashlamp
pumped dye laser for
TMEP1
•  Q-switch Nd:YAG
laser for UP2
1 Bedlow et al. J Cutaneous Laser Therapy 2000; 2:45-7
2 Ellis. Dermatol Surg 1996; 22:33-7
Laser for UP
Gastrointestinal tract
•  H2 antihistamines
•  Proton pump inhibitors
•  Sodium cromoglicate
Bone
•  Lifestyle measures
•  Calcium and vitamin D supplementation
•  Osteoclast inhibitors
Cytoreductive therapies
• 
• 
• 
• 
Oral corticosteroids
Interferon-α
Cladribine
Kit tyrosine kinase inhibitors
–  Imatinib (Glivec®) – not effective for D816V
–  Midostaurin (PKC 412) –phase II study for
ASM and MC leukaemia completed
–  Masitinib (AB1010) – ongoing phase III study
for CM, ISM and SSM with handicap
Kim et al. Am J Haematol 2009; 84:790-4
Prognosis of mastocytosis
•  Cutaneous: excellent
–  Children: ? spontaneous resolution by puberty
–  Adults: excellent but may progress to systemic disease
•  Indolent systemic: excellent, except problems
from complications
–  SM-AHNMD (? 10-20% lifetime risk)
–  Allergies
–  Osteopathy
•  Aggressive systemic and mast cell leukaemia:
poor, better Rx’s needed