Urticaria and Angioedema

Definition

  • Urticaria is the oedema involving the superficial portion of the dermis
  • Angiooedema is localised oedema affecting the deeper layers of the skin including the subcutaneous tissue
  • Acute episodes are <6/52, otherwise, chronic

Classification by aetiology

  • IgE
    • Allergen
    • Physical
    • Autoimmune
  • Bradykinin
    • Hereditary angiodema
    • Acquired angioodema
    • ACE-I
  • Complement
    • Necrotising vasculitis
    • Serum sickness
    • Transfusion reaction
  • Non-immunological
    • Direct mast-cell releasing agents
    • Arachidonic acid pathway agents
  • Idiopathic

Pathophysiology

  • Mast cell
    • Mast cell degranulation > histamine > skin oedema
    • 40% of chronic patients have autoimmune causes
      • Auto anti-IgE
      • Auto anti-FcϵRI
      • Auto anti-peroxidase, anti-thyroglobulin
  • Bradykinin
    • C1INH blocks FXIIa, kallikrein, C1r/C1s
    • Defects = elevated bradykinin = angioodema
    • Hereditary angiodema
      • 85% Type I – C1INH deficiency
      • 15% Type II – C1INH dysfucntion
    • Acquired
      • Excessive consumption of C1INH due to
        • Autoantibody
        • Immune complex of anti-idiotypic antibody and monoclonal IgG presented by B cell lymphomas
    • ACE-I
      • ACE = kininase II
      • ACE-I = reduced bradykinin degradation

Diagnosis

  • IgE-mediated angioedema
    • Fever, leucocytosis and raised ESR are ABSENT
  • Hereditary angioedema
    • Implied by : angioedema WITHOUT pruitus or urticaria + recurrent colic + laryngeal involvement
    • C1INH number and function
    • C1 level normal
    • C2 + C4 (C1 substrates) depleted
  • Cutaneous necrotising vasculitis
    • Implied by : chronic urticaria persisting >72h + arthralgia + raised ESR +normo/hypocomplementaemia
    • Biopsy: cellular infiltration + nuclear debris + fibrinoid necrosis of venules

Treatment

  • Adrenaline if airway compromise (NOT helpful in bradykinin-mediated causes)
  • Antihistamines
  • Cyproheptadine / hydroxyzine if antihistamines fail
  • Montelukast as add on
  • Steroids with caution
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Sarcoidosis

Definition

  • Inflammatory disease of noncaseating granulomas frequently involving two or more organs
  • Löfgren’s syndrome is erythema nodosum, hilar adenopathy and uveitis

Pathophysiology

  • Macrophages present unknown antigen to CD-4 T cells > IL-2, IFN-gamma release from T cells + TNF release from macrophage > granuloma
  • Granulomas may either resolve (IL-10) or fibrose (TNF, IL-8, endothelin)

Presentation

  • Lung
    • Involved in >90%
    • Scadding stage
      • 1 – hilar adenopathy alone
      • 2 – adenopathy + infiltrates
      • 3 – infiltrates alone
      • 4 – fibrosis
    • Infiltrates predominantly upper lobe (diagnostically important as few other diseases have this preference)
    • 1/3 have obstructive picture, some may have restrictive picture
    • 5% have PAH
    • Chronic cough
    • Airways hyperreactivity
  • Skin
    • Erythema nodosum
    • Painless maculopapular lesions – most common skin presentation
    • Hyper/hypopigmentation
    • Keloid
    • Subcutaneous nodules
    • Lupus pernio
      • Inflammatory lesions of nose bridge, area under the eyes and cheeks
  • Eye
    • Ranges from 30% (Muricans) to 70% (East Asian) in prevalence
    • Uveitis (75% anterior)
    • Sicca complex
  • Liver
    • 30% have abnormal LFTs
    • 5% of all-comers will have symptomatic liver disease
    • Rarely progresses to need for transplant
  • Haematological
    • Lymphopaenia – from sequestration
    • Anemia in 1/5
    • Splenomegaly in 10% (but granulomas present in 60%) and can be massive
  • Metabolic
    • Hypercalcemia +/- hypercalciuria in 10%
    • Increased production of 1,25-dihydroxyvitamin D by granulomata
  • Renal disease
    • <5% of patients
    • Nephritis
    • May be as a result of hypercalcemia
  • CNS
    • 10% of patients
    • MRI with gadolinium enhancement for SOL
    • CSF – lymphocytic meningitis + mild elevated rotein
    • Typical involvement
      • Cranial nerves (presence of optic neuritis may lead to misdiagnosis of MS)
      • Basilar meninges
      • Myelopathy
      • Anterior hypothalamic disease + diabetes insipidus
  • Cardiac
    • 25% East Asian, 5% white
    • CCF
    • Arrythymias
  • MSK
    • Myalgia, arthralgia
    • Fatigue
    • Direct granulomatous bone/muscle lesions in 10%
  • Uncommon Areas
    • Involvement in the following are uncommon and should be biopsied
      • Breast
      • Testes
      • Ovaries
      • Stomach

Workup

  • CXR +/- CT
  • PET
  • Serum ACE levels may be helpful but sensitivity and specificity is low
  • Biopsy

Treatment

  • Most self-resolve but some go on to develop chronic disease
  • Steroids are the mainstay of treatment
  • Infliximab is of benefit

Sjoegren’s Syndrome

Definition

  • Chronic, progressive lymphocytic infiltration of exocrine glands
  • Primary and secondary (to other autoimmune disease) forms

Pathology

  • Lymphocytic infiltration of the exocrine glands
    • T cell dominance in milder lesions, B cell dominance in more severe lesions
    • Marchophages and dendritic cells contribute as well
      • IL-18+ macrophages  = parotid enlargement + hypoC4aemia = higher chance of lymphoma
    • Infiltrating lymphocytes promote epithelial apoptosis while themselves resistant to apoptosis
    • Ductal + acinar cells
      • Possible epitopes for lymphocyte activation
      • Abnormal cytokine and chemokine secretion
      • Expression of receptors of innate immunity (TLR 3, 7, 9)
  • B lymphocyte hyperreactivity
    • Antibodies against non-organ targets such as
      • Rheumatoid factors
      • Ro/SSA
      • La/SSB
      • Alpha-fodrin
      • Muscarinin receptor 3 (M3R)

Presentation

  • Slow course in most
  • Salivary glands
    • Salivary gland enlargement (indicates primary disease)
    • Xerostomia
  • Keratoconjunctivitis sicca
    • Schirmer’s test
    • Tear break-up time
    • Tear lysozyme content
    • Punctuate corneal ulceration on rose Bengal stain
  • Other
    • Respiratory tree dryness
    • Atrophic gastritis
    • Subclinical pancreatitis
    • Esophageal muscle atrophy
    • Dyspareunia
  • Extraglandular
    • Fatigue, fever
    • Raynaud’s
    • Myalgias, arthralgias
    • Interstitial nephritis
      • Hyposthenuria
      • Renal tubular disease +/- acidosis
    • Rarely glomerulonephritis in overlap syndromes
    • Small-medium vessel vasculitis
    • Sensorinueral haering loss (assoc. anticardiolipin)
  • Lymphoma

Labs

  • FBC – Mild normochromic normocytic anaemia
  • ESR – Elevated in 70%
  • Hep C serology – clinicla picture almost identical
  • Immunological panel
  • Labial biopsy if uncertain clinical picture

Treatment

  • Xerostomia – water
  • Tears – artifical tears,
  • Vaginal dryness – propionic acid
  • Secretion stimulation – pilocarpine / cevemeline
  • Arthralgia – hydroxychloroquine
  • RTA – bicarb
  • Vasculitis – glucocorticoids, anti-CD20
  • Lymphoma – CHOP + anti-CD20

Systemic Sclerosis / Scleroderma

Definition

  • Chronic, progressive, connective tissue disorder of unknown origin
  • Three main forms
    • Diffuse cutaneous form (dcSSc)
    • Limited cutaneous form (lcSSc)
    • Systemic sclerosis sine scleroderma (SScSD)

Pathogenesis

  • Three main features
    • Vasculopathy
    • Autoimmune activation of cellular and humoral systems
    • Progressive multiorgan vascular and tissue fibrosis
  • Vasculopathy
    • Altered ANS/ PNS > impaired neuropeptide sysnthesis + heightened alpha-2 receptor sensitivity > functional vasospasm
    • Immune response to multiple stimuli (eg viruses, ROS, cytokines, immune complexes) > endothelial cell injury > altered endothelial nitric oxide + prostacyclin synthesis + increased adhesion molecule expression > vasospasm
    • Endothelial cell injury > increased micorvessel permeability + leuckocyte diapedesis (facilitated by adhesion molecules) + coagulation and fibrolytic cascade activation with platelet activation + myointimal cell proliferation + thickened basement membrane > adventitial fibrosis > reduced luminal flow > increased profibrotic factors
    • Luminal obstruction + endothelial cell damage + adventitial fibrosis > self-propagating vasculopathy
    • Revascularisation mechanism defective despite high levels of VEGF > capillary malformation + obliterative vasculopathy of small-medium aa
  • Autoimmune activation
    • Activated T cells + macrophages accumulate in lesions
    • Circulating CD4+ cells bind to endothelium and fibroblasts
    • Leukocyte diapedesis facilitated by increased expression of adhesion molecules
    • TH2 response
      • T cell and macrophages show TH2 polarisation with IL-4 and IL-13 secretion (i.e. induction of TGF-beta, collagen sysnthesis, profibrotic signalling)
      • TGF-beta > auto/paracrine loop > sustained fibroblast activation
      • Deficiency in Tregs in SSc = lack of control over fibrotic process
    • Humoral activation
      • ANA occurs in almost all SSc patients
      • Antibodies to fibroblasys, endothelial cells, MMPs etc. have been described but the direct role is still inclear
  • Fibrosis
    • Follows autoimmunity and vascular damage
    • Tissue-resident fibrblasts, endothelial to fibroblast transformation and circulating mesenchymal progenitor cells from bone marrow contribute to process

Pathology

  • Classic
    • Widespread capillary loss
    • Obliterative vasculopathy of small arteries and arterioles
    • Skin and visceral fibrosis
  • Vasculature
    • Intimal proliferation in small to medium aa > luminal narrowing
  • Skin
    • Dermal expansion
    • Obliteration of hair follicles, sweat glands etc.
    • Invasion of adipose layer by fibrosis
    • Atropic epidermis with effaced rete pegs
  • Lungs
    • Alveolar wall inflitration with T cells, macrophages and eosinophils
    • Interstitial fibrosis + vascular damage
    • Progressive septal thickening > airspace obliteration + honeycombing + loss of pulmonary vasculature > impaired gas exchange + pulmonary hypertension
  • GIT
    • Most collonly lower esophageal involvement
    • Replacement of normal tract = reduced peristalsis + reflux +SBO + dysmotility
  • Renal
    • Commonly vascular lesions of interlobular and arcuate arteries
      • Elastic lamina duplication
      • Intimal proliferation
      • Thrombosis + microangiopathic haemolysis
    • Glomerulonephritis rare
    • Chronic ischaemia > shrunken glomeruli
  • Heart
    • Coronary arteriolar concentric intimal hypertrophy + luminal narrowin _ contraction band necrosis (=ischaemia-reperfusion injury)
    • Patchy mycocardial fibrosis > conduction defects
  • MSK
    • Fibrotic synovium and tendon sheaths

Classification

  • dcSSc
    • Prominent and early visceral involvement
    • Development of internal organ injury often weeks to months after first episode of Raynaud’s phenomenon
    • Soft tissue swelling + pruritus = early inflammatory ‘oedematous’ stage
      • Distal limbs and face
      • Diffuse hyperpigmentation
      • Carpal tunnel syndrome
      • Arthralgias and reduced mobility
    • Oedematous stage evolves into fibrotic stage
      • Skin induration
        • Loss of body hair
        • Loss of skin oils
        • Loss of sweating
      • Joints
        • Flexion contratures of fingers
        • Stiff joints due to supporting structure fibrosis
      • Evolving internal organ injury
  • lcSSc
    • Long-standing Raynaud’s, indolent skin changes and limited organ involvement
    • Subsets
      • CREST syndrome – calcinosis cutis, Raynaud’s, esophageal dysmotility, slcerodactyly and telangiectasia
      • 15% develop severe pulmonary arterial hypertension without interstitial lung disease
  • SScSS
    • Systemic features of systemic sclerosis without scleroderma

Presentaiton

  • Raynaud’s phenomenon
    • Episodic vasocontriction of fingers/toes
    • Triggers include
      • Cold
      • Emotional stress
      • Vibration
    • Pallor (vasoconstriction) followed by cyanosis (ischaemia) resolving with erythema (reperfusion)
    • Distorted nailfold capillaries under oil-immersion microscopy
  • Skin
    • Skin thickening
      • Symmetrical and bilateral
      • Starts int he fingers, advancing distal to proximal
      • Loss of dorsal creases of the fingers
    • Colour changes
      • diffuse tanning or vitiligo-type hypopigmentation
      • pigment loss spares perifolliuclar areas > salt and pepper appearance
    • Obliteration of appendages = dry skin, hair loss, no sweating
    • Reduced mobility
      • Flexion contractures of fingers
      • Contractures
      • Masukopf facies
        • Taut, shiny skin
        • Loss of wrinkles
        • Expersionless facies
        • Thinning of lips with accentuation of incisors and radial furrowing around the mouth
        • Beak-like nose
    • Micostomia
    • Telangiectasia
    • Chronic ulceration
      • Extensior surfaces of the PIPJ, volar pads of fingers and bony prominences (elbows, malleoli)
      • Healing leaves pits
      • Loss of fingertip soft tissue may result in acro-osteolysis
    • Calcium deposition
      • Calcium hydroxyapatite crystals
      • Finger pads, palms, extensor surface of forarm, olecranon bursa, prepatellar bursa
      • Persistent firm, non-tender subcut lumps
  • Lungs
    • ILD
      • HRCT
        • Ground-glass opacification seen in 50%
        • Mediastinal lymphadenopathy, traction bronchiectasis, honeycombing etc.
      • BAL
        • Elevated neutrophils (2%) / eosinophils (3%) = worse disease
    • PAH
      • Exertional dyspnoea
      • Reduced exercise capacity
      • Angina
      • Right-sided ehart failure
      • Echo for screen, confirm with right heart catheterisation
      • BNP correlates to prognosis
    • Aspiration penominitis complicating reflux
    • Endobronchial telangiectasia leading to pulmonary haemorrhage
    • Obliterative bronchiolitis
    • Cheast wall fibrosis
  • GIT
    • Oral Cavity
      • Xerostomia, microstomia
      • Periodontal diase
      • Mandibular condylar resoption
    • Upper GI
      • GORD
        • Reduced lower esophaageal sphincter
        • Dysmotility in distal 2/3 leading to reduced clearance
        • Reduced gastric clearance
        • CT – dilated esophagus with intraluminal air
      • Gastroparesis
        • Early satiety
        • Distension
        • Aggravated reflux
        • Gastric antral vascular ectasia may lead to recurrent bleeding
      • Rarely, primary biliary sclerosis
    • Lower GI
      • Impaired motility
      • Malabsorption
      • Diarrhoea from bacterial overgrowth syndrome
      • Pseudoobstruction
      • Wide mouth sacculations / diverticula > perforation
      • Pneumatosis cystoides intestinalis (air trapping in bowel wall > risk of rupture)
  • Renal
    • Sclerodermal renal crisis occurs in 15%, usually within 4 years
    • Obliterative vasculopathy + luminal obstruction > reduction in renal flow > juxtaglomerular hyperplasia > increased renin > AT activation > vicious cycle of renal vasoconstriction
    • Presents with accelerated HTN + fulminant renal insufficiency
    • Mild proteinuria, granular casts, microscopic haematuria
    • MAHA + thrombocytopaenia
  • Cardiac involvement
    • Generally silent, clinically evident disease = poor prognosis
    • Pericardial effusions
    • Dysrythymia
    • Valvular regurgitation
    • Hyerptrophy
    • Heart failure
    • BNP is prognostic
  • MSK
    • Carpal tunnel
    • Arthralgia and stiffness
    • Contractures
    • Rendon rubs
    • Inflammatory myositis
  • Others
    • Sicca complex (dry eyes, dry mouth)
    • Hypothyroidism
    • Sensory trigeminal neuropathy
    • Pregnancy adverse outcomes
    • Erectile dysfunction

Labs

  • FBC
    • Normocytic/microcytic anaemia of chronic inflammation
    • Iron deficiency may occurs from GAVE / chronic esophagitis bleeding
    • Macrocytic anaemia from malabsorption / bacterial overgrowth / therapy
    • MAHA from traumatic passage of vessles through fibrin/platelet thrombi coated vessles implies scleroderma renal crisis
    • Thrombocytopaenia / leukopaenia usually therapy effect
  • ESR generally normal
  • Antibodies
    • ANA sensitive but not specific
    • Anti-topoisomerase-1 (anti-Scl-70) and centromere are mutually exclusive specific anitbodies for SSc
      • Anti-topoisomerase
        • 31% of dcSSc and 13% of lcSSc
        • Negative prognostic marker
      • Anti-centromere
        • 40% of lcSSc and 2% dcSSc
        • Associated with PAH but rare with ILD, cardiac or renal disease
        • Positive prognostic marker
      • Nuceloar immunofluorescence pattern implies anti-U3-RNP (fibrillarin), Th/To or PM/Scl
      • Speckled IF pattern impliies anti-RNA polmerase III
      • Anti-Beta2GPI associated with increased ischaemic risk

Treatment

  • No treatment alters the course but treatments slow progression and provide symptomatic relief
  • Immunosupressives
    • Glucocorticoids of limited benefit for stiffness but do not affect skin or visceral involvement and may contribute to scleroderma renal crisis – use should be avoided
    • Cyclophosphamide of beenfit in ILD
    • Methotrexate and mycophenolate mofetil of modest benefit for skin disease
  • Anti-fibrotics
    • No strong prospective evidence for D-penicillamine, minocycline, relaxine, IFN-gamma or TNF inhibitors
    • Some retrospective evidence for D-penicillamine use
  • Vascular
    • Dress warm / move to somewhere warm with coconuts and beaches
    • Moderate benefit with calcium channel blockers
    • alpha1-blockersm 5-PDE inhibitors, SSRI, topical nitroglycerine, IV PGs may help Raynaud’s
    • Low dose aspirin may be of benefit
    • Bosentan, an endothelin-1 receptor antagonist reduces new ulcers
  • GIT
    • Treat reflux – PPI at high doses
    • Photocoagulation for GAVE
    • Short courses of metronidazole / erythromycin / tetracyclin for bacterial overgrowth
    • Octreotide may be trialled for small bowel hypermotility
  • PAH
    • Bosentan of PDE inhibitor
    • Diruesism anticoagulation and digoxin as needed
    • Suplemental oxygen if documented hypoxemia
    • Prostacyclin analogues may be of benefit
  • Renal crisis
    • Aggresive treatment with ACE-I
    • Early use of dialysis
  • Skin
    • Skin disease stabilises with time
    • Hydrophilic ointments
    • Bath oils
    • Regular massage
    • No effective therapy for calcinosis

Related Diseases

  • Mixed Connective Tissue Disease
    • lcSSc coexisting with symptoms of SLE, polymyositis, RA is suggestive of MCTD
    • Associated with high titres of anti-U1-RNP
    • SSc-specific antibodies not found
    • Elevated ESR and hypergammaglobulinemia
    • Good response to glucocorticoids
  • Eosinophilic fasciitis
    • Coarse peau d’orange skin
    • Rare visceral involvement
    • Raynaud’s absent
    • SSc-specific antibodies absent
    • Peripheral eosinophilia may be present acutely
    • Biopsy of skin generally neded for diagnosis
    • Responsive to glucocorticoids