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 •  •  •  •  •  •  •  •  • 

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