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					Section 6: Immunologic Disorders

Chapter 33: Cutaneous Vasculitis
Introduction
                                                      Pathogenesis of vasculitis
      Vasculitis is inflammation and necrosis
                                                      Introduction
of blood vessels, whether they be arteries,
                                                             Factors that play a role in the
veins or both. Vasculitis may be local or
                                                      pathogenesis of vasculitis include antigen-
systemic, and may be primary or secondary to
                                                      antibody related mechanisms (including
another disease process. Small vessels
                                                      autoantibodies     and     immune        complex
(capillaries, arterioles, venules), medium-sized
                                                      diseases), inflammatory cells and their
vessels (coronary, renal or hepatic arteries)
                                                      lysosomal content, complement, cytokines,
and large vessels (aorta and its great vessels)
                                                      chemokines, adhesion molecules, vascular and
may be affected. Many vasculitides have a
                                                      cellular growth factors, the fibrinolytic system,
cutaneous component and vasculitides may be
                                                      and direct vessel damage. It is apparent that
present without skin affection. Classic
                                                      none of these factors operates in isolation e.g.
cutaneous manifestations such as palpable
                                                      endothelial damage will cause expression of
purpura in dependent areas, typically the ankle
                                                      cell-surface adhesion molecules, producing
and lower legs, characterize small vessel
                                                      cytokines and influx of pro-inflammatory
involvement, whereas necrosing livedo
                                                      cells.      Histopathologically,       cutaneous
reticularis or multiple sites of peripheral
                                                      necrotizing vasculitis may be leukocytoclastic
gangrene characterize larger vessel vasculitis.
                                                      with a neutrophilic infiltrate and a presumed
Many vasculitides are triggered by various
                                                      immune complex pathogenesis, or may be
antigenic agents, such as infection or drugs, or
                                                      lymphomonocytic and pauci-immune.
are related to underlying disease such as
connective tissue, myelodysplastic or other           Role of antigens, immune complexes and
malignancies.                                         complement
                                                           Antigenic triggers of immunological
Classification
                                                      responses targeted at components of blood
     Vasculitis may be classified into
                                                      vessel walls elicit most vasculitides. The
cutaneous small vessel vasculitis, and
                                                      deposition of immune complexes in blood
systemic larger vessel vasculitides with skin
                                                      vessel walls is the best characterized
involvement.       Cutaneous       small    vessel
                                                      mechanism for the vascular injury associated
vasculitides include cutaneous small vessel
                                                      with vasculitis. This mechanism appears to be
vasculitis       (cutaneous       leukocytoclastic
                                                      particularly important in leukocytoclastic
vasculitis),      Henoch-Schönlein       purpura,
                                                      necrotizing cutaneous small vessel vasculitis.
essential        mixed         cryoglobulinaemia,
                                                      Potential antigens of relevance include
Waldenström's          hypergammaglobulinaemic
                                                      bacteria, viruses and drugs.
purpura, vasculitis associated with collagen
vascular      disease,    urticarial    vasculitis,   Role of infections
erythema elevatum diutinum, eosinophilic                    Infections appear to provoke some
vasculitis, rheumatoid nodules, reactive              vasculitides e.g. Henoch-Schönlein purpura,
leprosy and septic vasculitis. Systemic larger        acute haemorrhagic oedema of childhood,
vessel vasculitides with skin involvement             Kawasaki         disease      and     Wegener’
include polyarteritis nodosa (microscopic             granulomatosis. Several mechanisms may
polyarteritis, cutaneous form, systemic form),        occur e.g. immune complex reactions (e.g. in
granulomatous          vasculitis     (Wegener’s      the pustular vasculitis of gonococcal
granulomatosis, allergic granulomatosis of            infection), direct activation of complement by
Churge-Strauss, lymphomatoid granulomatosis),         infectious organisms (e.g. Gram-positive and
giant cell arteritis (temporal arteritis,             Gram-negative bacteria), direct activation of
Takayasu’s arteritis), large vessel vasculitis        other pro-inflammatory mechanisms (e.g.
with collagen vascular disease, and nodular           TNF-α        production     by     macrophages,
vasculitis.                                           production of IL-1 and IL-6 from endothelial


                                                  -381-
cells), superantigen hypothesis (superantigens      Role of antineutrophil cytoplasm antibodies
directly activate T cells without the need for      (ANCA)
antigen-presenting cells e.g. superantigens of           These antibodies have a diagnostic value
S. aureus in Kawasaki disease and Wegener’s         as well as an important role in the
granulomatosis), direct non-specific vessel         pathogenesis of systemic larger wall vasculitis
wall damage (by vasculotropic viruses such a        e.g. WG, MPA, necrotizing and crescentic
CMV and human herpes-virus 6), alteration of        GN, SLE, IBD, rheumatoid arthritis, and drug-
vessel wall components (in medium and large         induced systemic vasculitis.
vessel     vasculitides),   and    autoantigen
complementarity hypothesis (the microbial           Role of other cytokines and chemokines
immunogens induce production of antibodies                Numerous         cytokines   have      been
which react with the autoantigen, in ANCA-          implicated in vasculitis e.g. IL-1, IL-2, IL-6,
associated vasculitides).                           IL-8 and TNF-α. TNF-α is important for
                                                    priming endothelial cells to express E- and P-
Role of effector cells (T lymphocytes and           selectin, ICAM-1 and 2, and VCAM-1. TNF
PMN leukocytes)                                     receptors have been demonstrated in ANCA-
      T lymphocytes are found in the                positive vasculitides. IL-8 is a potent
inflammatory infiltrate in all vasculitis. A role   neutrophil chemoattractant that is expressed
for T lymphocytes (CD3+, CD4–, CD8–) has            by endothelial cells after stimulation by
been proposed in vasculitis. These cells are        ANCA. IL-6 appears to reflect disease activity
cytotoxic against various cells but they also       in giant cell arteritis and Takayasu’s arteritis.
secrete cytokines (IL-2, IL-4, GM-CSF, IFN-               Other chemokines that have enhanced
γ). They are found in significant number in the     tissue expression in vasculitis include
later stages of leukocytoclastic vasculitis, and    monocyte chemotactic protein-1 (MCP-1),
are especially associated with infective causes     macrophage inflammatory protein-1α and -1β
of vasculitis.                                      and RANTES.
      Neutrophils and eosinophils are the
predominant cells in many vasculitides,             Genetic factors
including most that are related to infections,           Familial clustering has been documented
drugs, foods, collagen vascular diseases, and       in some vasculitides (e.g. WG, Kawasaki
type II or III cryoglobulinaemias. They are         disease, H-S purpura), although this is
recruited in response to infection by               uncommon.
pathogenic processes such as vasculitis,            Pathogenesis of cutaneous small vessel
antibody and complement, mast cell release          vasculitis
and T-cell mediated neutrophil activation.                This is an immune complex disease.
Binding and activation of neutrophils or            There are circulating immune complexes and
eosinophils causes release of toxic enzymes         there is deposition of immune complexes in
and generation of reactive oxygen species,          blood vessel walls which cause the vascular
leading to tissue damage.                           injury associated with vasculitis. Antigens
Role of antiendothelial cell antibodies in          include bacteria, viruses and drugs. A theory
vessel wall injury                                  about the pathogenesis of cutaneous small
      Antiendothelial cell antibodies (AECA)        vessel vasculitis is as follows: the circulating
may be identified in patients with Takayasu's       immune complexes mediating vasculitis
arteritis, WG, microscopic PA, H-S purpura,         interact with the complement system to
hepatitis B-associated PN, Behcet’s disease,        generate C3a and C5a anaphylatoxins. These
and SLE-associated vasculitis. Mechanisms           stimulate the production of chemotactic
by which AECA might have a pathogenetic             factors and subsequent chemotaxis of
role in vasculitis include direct activation of     neutrophils, the release of vasoactive amines
endothelial cells (leading to up-regulation of      (such as histamine) by platelets and the release
adhesion molecules such as ICAM-1,                  of cytokines (e.g. IL-1, TNF-α) which induce
VCAM-1 and E-selectin), cytotoxicity,               the subsequent expression of adhesion
induction of coagulation, and induction of          molecules (such as P- and E-selectin) by
apoptosis.                                          endothelial cells. Vasoactive amines cause



                                                -382-
endothelial cell retraction and deposition of      Histopathology
immune complexes in the vessel wall.                    In CSVV biopsy is best performed by
Neutrophils that are attracted to the site of      taking a punch biopsy of the lesions at the
immune complex deposition release lysosomal        appropriate stage, recognizing that lesions
enzymes in an attempt to engulf deposited          represent various chronological stages of the
immune complexes. They are activated in situ       disease process. Deeper elliptical incisional
through binding of the fragment crystallizable     biopsies should be performed for suspected
(Fc) portion of the antibody. This causes          larger vessel vasculitides.
degranulation and destruction of the               Systems examination for immune complex-
neutrophils     (visible     histologically as     mediated pathology
leukocytoclasis) and generation of reactive        • General: Myalgia, arthralgia, fever.
oxygen species and release of the proteolytic      • Renal: Proteinuria, haematuria.
enzymes collagenase and elastase, ultimately       • Nervous system: Central or peripheral,
resulting in inflammation and ‘bystander’          diffuse or localized findings.
fibrinoid necrosis of vessel walls.                • Musculoskeletal: Non-erosive polyarthritis.
Pathogenesis of systemic larger vessel             • GIT: Abdominal pain, GI bleeding.
vasculitides                                       • Pulmonary: Pleural effusion, pleuritis.
      Antineutrophil cytoplasmic antibodies        • Cardiac: Pericardial effusion.
(ANCA) have an important role in the               Laboratory investigations for the aetiology
pathogenesis. ANCA are classified, according       • Full blood count with differential white cell
to their indirect immunofluorescence pattern       count.
on ethanol-fixed neutrophils, into C-ANCA          • Markers of inflammation: ESR, CRP.
(granular cytoplasmic staining), P-ANCA            • Electrolytes, hepatic transaminases, glucose.
(perinuclear and/or nuclear staining) and          • Urinalysis for protein and blood.
atypical ANCA (diffuse cytoplasmic and             • Serology: ANA, ANCA, C3 and C4, ASO-
perinuclear staining). ANCA are usually of         titre, viral titres (HBV, HCV).
IgG type. In addition to systemic vasculitides,    • Cryoglobulins.
ANCA may be positive in infections (malaria,       • Chest radiograph.
HIV infection), connective tissue disorders
(SLE, rheumatoid arthritis), and GIT diseases      Cutaneous small vessel vasculitis
(inflammatory      bowel     syndrome      and     Introduction
autoimmune liver disease). ANCA have a                    This condition (CSVV, cutaneous
diagnostic value in these diseases. The C-         leukocytoclastic        vasculitis,      cutaneous
ANCA pattern occurs in Wegener’s                   necrotizing venulitis) affects the cutaneous
granulomatosis        (WG),       microscopic      post-capillary venules and is the most
polyangiitis (MPA) and SLE. The P-ANCA             common type of vasculitis in dermatology.
pattern occurs in HIV infection, drug induced      Features of CSVV include palpable purpura,
systemic vasculitis, MPA, WG, SLE and              urticaria or ulcers on the legs. It affects both
Churg-Strauss syndrome.                            children        and    adults.      Extracutaneous
      The role of ANCA in the pathogenesis of      manifestations are uncommon. The aetiology
vasculitis is multifactorial. ANCA cause           is idiopathic in 50% of cases and in other
activation of neutrophils primed by TNF-α          cases there is a history of drug exposure (10-
leading to production of reactive oxygen           15%), current infection, (15-20%), an
species. ANCA also cause neutrophil                associated collagen vascular disorder (15-
degranulation with release of the proteolytic      20%), or malignancy (5%). Circulating
enzymes collagenase and elastase. The major        immune complexes are present in a large
role of ANCA in vasculitis is caused by their      percentage of the patients.
effects on the neutrophil, thus leading to                The histology is that of leukocytoclastic
vessel wall damage.                                vasculitis with segmental inflammation in an
Evaluation of patients with suspected vasculitis   angiocentric pattern, showing swelling of the
Clinical patterns suggestive of vasculitis         endothelium, fibrinoid necrosis of vessel
     These include, in addition to overly          walls, extravasation of red blood cells, and an
vasculitic lesions, cutaneous livedo, cutaneous    infiltrate of neutrophils with karyorrhexis of
necrosis and non-specific purpura.                 nuclei (i.e. leukocytoclasis).


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Table 33.1 Therapeutic ladder for patients with CSVV.
Symptomatic relief
      Antihistamines, NSAIDs
Skin lesions alone
      Pentoxiphylline, colchicine, dapsone
Ulcerative skin lesions alone
      Thalidomide, prednisolone, low-dose weekly methotrexate
Systemic disease
      Prednisolone, azathioprine, cyclophosphamide, mycophenolate mofetil, ciclosporin, IFN-α (if HCV
associated), IVIG, extracorporeal immunomodulation, infliximab, rituximab
Table 32.2 Therapeutic ladder for patients with vasculitis.
Disease                 First line               Second line                  Third line
Cutaneous small vessel Discontinue drugs,        Colchicine, dapsone,         Azathioprine, methotrexate
vasculitis              treat infections,        steroids
                        NSAIDs,
                        antihistamines
Henoch-Schönlein        Supportive care          Dapsone, colchicine,         IVIG, plasmapheresis, factor
purpura                                          steroids (± azathioprine     XIII
                                                 or cyclosporine)
Acute haemorrhagic      Supportive care          Antihistamines               Steroids
edema of infancy
Urticarial vasculitis   Antihistamines,          Azathioprine,                Mycophenolate mofetil,
                        indomethacin, dapsone, colchicine                     rituximab
                        hydroxychloroquine
Erythema elevatum       NSAIDs, intralesional    Dapsone, colchicine,         Niacinamide,
diutinum                steroids                 chloroquine,                 plasmapheresis
                                                 tetracyclines
Cryoglobulinaemic       Low-antigen diet, IFN- Steroids + cyclosporine        IVIG, rituximab,
vasculitis              α+ ribavirin, steroids                                plasmapheresis
Cutaneous polyarteritis Treat underlying         Methotrexate, dapsone,       Pentoxifylline, colchicine,
nodosa                  infections, discontinue  IVIG                         azathioprine, anti-TNF
                        incriminated drugs,                                   agents
                        NSAIDs, steroids (oral,
                        IL, topical)
Classic polyarteritis   Steroids, steroids +     Steroids + cyclosporine      IVIG
nodosa                  plasmapheresis + IFN-
                        α
Microscopic             Steroids                 Steroids + cyclosporine      Azathioprine,
polyangiitis                                                                  mycophenolate mofetil,
                                                                              IVIG
Wegener’s                Steroids + cyclosporine    Co-trimoxazole            Mycophenolate mofetil,
granulomatosis           or methotrexate                                      IVIG, plasmapheresis,
                                                                              steroids + rituximab
Churg-Strauss            Steroids                   Steroids + cyclosporine   IVIG ± plasmapheresis
syndrome
                                                         to several centimeters, and may progress to
    In superficial dermal papillary vessels,
                                                         various lesions including papules, nodules,
IgM or C3 perivascular deposits are often
demonstrated in fresh lesions.                           vesicles, plaques, bullae or pustules, with
                                                         secondary findings of ulceration, necrosis and
Clinical features                                        post-inflammatory hyperpigmentation. Other
     The skin lesions of CSVV typically arise            cutaneous findings include livedo reticularis,
as a simultaneous single crop, resulting from            oedema and urticaria. Lesions typically occur
the exposure to an inciting stimulus, 7 to 10            on areas prone to stasis, commonly including
days after the exposure. They usually resolve            the ankles and lower legs.
within several weeks or months, although 10%                  Although      normally     asymptomatic,
of patients will have recurrent disease for              pruritus, pain or burning may be experienced,
years. The major skin feature of CSVV is                 as well as systemic symptoms of fever,
palpable purpura, ranging in size from 1 mm              arthralgia and myalgia. Extracutaneous

                                                   -384-
manifestations of CSVV are uncommon and             microscopy shows deposition of IgA, C and
include involvement of the kidneys, joints,         fibrin in dermal blood vessels.
nervous system, lungs, GIT or pericardium.                The main skin lesion is palpable
The presence of symptoms affecting other            purpura. Urticaria, vesicles, bullae and
organ systems should raise the suspicion of         necrotic ulcers may occur. The condition
other vasculitides such as HSP, mixed               usually involves the limbs and buttocks, but
cryoglobulinaemia, or CSVV associated with          the trunk and face may be affected. Usually
PAN or with WG. CSVV may also be                    fading within 7 days, crops of lesions can
associated with other immune complex                recur for a few weeks or months and then
diseases including connective tissue vascular       subside, but the condition is chronic in 10% of
diseases, malignancy, inflammatory bowel            cases. Rarely involvement of GIT and arthritis
disease and chronic active hepatitis.               occur in the absence of skin disease. Renal
                                                    involvement occurs in 60% of cases, is usually
Diagnosis
                                                    mild and only 1% progress to renal failure.
    See evaluation for suspected vasculitis
                                                    GIT involvement occurs in 60% of cases and
Treatment                                           arthritis (knees, ankles) in 75%. IgA immune
      CSVV with skin lesions alone is treated       complexes are not specific for HSP but occur
with antihistamines, NSAIDs, colchicine and         also in dermatitis herpetiformis, SLE,
dapsone. When skin ulceration is present,           Sjögren’s syndrome and rheumatoid arthritis.
thalidomide, prednisone (30 – 80 mg once                  Classical HSP is treated with systemic
daily for 3 weeks), or low-dose methotrexate        steroids. Dapsone is effective for skin lesions.
(less than 25 mg/week) are used. CSVV               GIT lesions can benefit from factor VIII
associated with systemic disease is treated         replacement or ranitidine. Progressive renal
with     prednisone,    azathioprine,     cyclo-    disease can benefit from intravenous
phosphamide, cyclosporine, mycophenolate            immunoglobulin       or    high    dose     oral
mofetil, intravenous immunoglobulin or              corticosteroids, either alone, or with an
interferon-α (if associated with hepatitis C).      immunosuppressant such as azathioprine or
Treatment of cutaneous vasculitis is illustrated    cyclophosphamide.
in tables 33.1, 33.2.                               Urticarial vasculitis
Drug-induced vasculitis                                   This disease (UV) makes about 10% of
      Most drug-induced vasculitis is immune        cases of urticaria. It is a chronic condition,
complex mediated and accounts for 20% of            which presents as urticarial lesions that most
cases of CSVV. These drugs are discussed            often occur on the trunk or proximal limbs,
with drug-induced purpura. Larger vessel            frequently with associated angioedema.
systemic vasculitis is associated with ANCA         Lesions differ from those of simple urticaria in
                                                    that they are indurated weals, individual
and      include     hydralazine,    thiouracils,
                                                    lesions persist for greater than 24 h, often
penicillamine, allopurinol and minocycline.
                                                    demonstrate purpuric foci, leave post-
The clinical features of drug-induced CSVV
                                                    inflammatory pigmentation, and there is pain
and larger vessel vasculitis are similar to those
                                                    or burning rather than itching. Two types of
of their diseases. Stop of the offending drug is
                                                    UV are known: UV associated with
important and in cases with systemic features
                                                    hypocomplementaemia        and     UV      with
corticosteroids or immunosuppressive drugs          normocomplementaemia.
are used.                                                 Hypocomplementaemic UV is defined by
Henoch-Schönlein purpura                            the presence of anti-C1q precipitin and/or a
      This disease (IgA immune complex              decrease in the level of C1, and it occurs
vasculitis, HSP) is an immune complex               almost exclusively in females. Normo-
vasculitis affecting small blood vessels,           complementaemic UV patients have skin
involving deposition of IgA immune                  lesions only, white hypocomplementaemic UV
complexes and characteristically involves the       patients may have systemic features including
skin, GIT and kidney, with or without               fever,       myalgia,        lymphadenopathy,
arthralgia or arthritis. Most cases (75%) occur     hepatosplenomegaly, abdominal pain with
in children. The histopathology of purpuric         diarrhoea, chronic obstructive pulmonary
lesions shows leukocytoclastic vasculitis. DIF      disease, glomerulonephritis and conjunctivitis.


                                                -385-
UV is strongly associated with some                  necrosis, ulcerations and bullae. The disease
connective tissue diseases (SLE, Sjögren’s           usually has a chronic course. Extracutaneous
syndrome).     Other     associations   include      lesions include arthritis or arthralgias (70%),
physical urticarias, serum sickness, hepatitis C     peripheral     sensory     neuropathy    (40%),
or B, and colon cancer. UV is thought to be a        gastrointestinal disease or hepatitis (30%), and
type III hypersensitivity reaction, as               glomerulonephritis (25%).
circulating     immune        complexes      are           About 70% of patients have circulating
demonstrated in 75% of patients. Lesions of          rheumatoid factor activity, 20% have
UV show leukocytoclastic vasculitis on               antinuclear antibodies and 15% have a
biopsy. Hypocomplementaemic UV shows a               monoclonal       gammopathy.      Histologically,
large number of neutrophils, and may                 papular     lesions     show    leukocytoclastic
therefore be distinguished from normo-               vasculitis, while necrotic or ulcerated lesions
complementaemic UV.                                  may demonstrate medium-sized              vessel
      The majority of patients respond to            vasculitis. By DIF, granular deposits of IgM
systemic corticosteroids, which may be the           and C3 in a vascular pattern are observed in
only treatment effective in the hypo-                the papillary dermis.
complementaemic type. Systemic steroids may                Patients with HCV-associated mixed
be combined successfully with immuno-                cryoglobulinaemia are usually treated with
suppressants      as     azathioprine,   cyclo-      IFN-α plus ribavirin. This treatment should be
phosphamide and mycophenolate mofetil.               avoided if there is peripheral neuropathy as it
Methotrexate can be used on its own. Other           worsens it. Plasma exchange, as well as
effective drugs include dapsone, colchicine          cytotoxic agents such as cyclophosphamide
and hydroxychloroquine. Oral antihistamines          are often used for severe neurologic or renal
may be required to control angioedema and            involvement. IVIG is an effective therapy for
urticaria-like lesions. Rituximab may be a           cryoglobulinaemic vasculitis. Rituximab is
useful therapy for hypocomplementaemic               effective in refractory cases.
vasculitis.
                                                     Erythema elevatum diutinum
Cryoglobulinaemic vasculitis                               This chronic rare disease (EED) occurs in
      This occurs with mixed cryoglobulins           adults as fibrosing plaques with histological
(types II and III). About 15% of patients with       evidence of leukocytoclastic vasculitis.
circulating    mixed cryoglobulins        develop    Although it is thought to be an immune
cryoglobulinaemic vasculitis. This vasculitis is     complex disease, the exact aetiology is
associated with specific infections, autoimmune      unknown. It has been associated with
diseases (rheumatoid arthritis, SLE, Sjögren’s       autoimmune diseases          (e.g.    rheumatoid
syndrome,       systemic      sclerosis),     and    arthritis), infections (e.g. Streptococcus,
lymphoproliferative disorders (e.g. B-cell non-      hepatitis, HIV), hypergammaglobulinaemia
Hodgkin lymphoma, chronic lymphocytic                and IgA monoclonal gammopathies, and
leukaemia). HCV infection is the commonest
                                                     multiple myeloma. The histology of acute
cause of cryoglobulinaemic vasculitis and is
                                                     lesions shows leukocytoclastic vasculitis and
present in 70-90% of patients, while HBV
                                                     eosinophils may also be present. Chronic
infection causes only 5%. Although 50% of
                                                     lesions show fibrosis, capillary proliferation
patients     with     HCV      infection     have
cryoglobulinaemia, only 5% develop overt             and an infiltrate of macrophages, plasma cells
cryoglobulinaemic vasculitis. Cryoglobulinaemic      and lymphocytes. Cholesterol deposits may be
vasculitis occurs where immune complexes             present in older lesions.
form from circulating cryoglobulins and then               Skin lesions are symmetrical papules,
deposit (along with complement) within blood         nodules or plaques (red-violet or red brown)
vessel walls.                                        on the dorsa of the hands, the knees and
      Cryoglobulinaemic vasculitis especially        buttocks. They are initially soft but eventually
affects the skin, peripheral nervous system and      they fibrose and leave atrophic scars. Rarely,
kidneys. Skin lesions most commonly                  they are painful. Lesions usually last more
manifest as palpable purpura of the lower            than 5 years, with crops of new lesions
extremities.      Other      lesions      include    developing every few weeks or months. The
erythematous papules, ecchymoses and dermal          best drug is dapsone. Niacinamide, topical and
nodules and rarely, urticaria, livedo reticularis,   intralesional corticosteroids are also effective.

                                                 -386-
Table 33.3 Differential diagnosis of eosinophilic dermatoses.
Disease                      Clinical clues
Immunologic diseases
Atopic dermatitis            History of atopy, pruritus, flexural and extremity accentuation
Allergic contact dermatitis  History of exposure, suggestive distribution, positive patch test
Discoid eczema               Discrete round eczematous plaques on the extremities, pruritic
Bullous                      Initial phase may be urticarial, flexural
Pemphigoid                   sites and legs favored, elderly patients
Pemphigus variants           Flaccid vesicles and crusted erosions, distribution depends on subtype
Pemphigoid gestationis       Pregnant patient, periumbilical lesions, urticarial plaques and bullae
Urticaria                    Pruritic, migratory, transient (lasting less than 24h) wheals
Urticarial vasculitis        Lesions burn rather than itchy, persist more than 24h, associated with auto-
                             immune disease and decrease in complement
Churg-Strauss syndrome       Palpable purpura and papulonodules on the extremities or scalp, asthma and
                             eosinophilia, peripheral neuropathy, glomerulonephritis
Drug eruption                History of new drug within previous 2 weeks
Eosinophilic fasciitis       Sudden onset of symmetrical induration of the skin and subcutaneous tissues
                             of the limbs
Eosinophilic vasculitis      Pruritic urticarial and purpuric papules, angioedema
Infections
Parasitic infestations       e.g. filariasis, schistosomiasis
Scabies                      Marked nocturnal itching, involvement of web space, umbilicus and groin
Seabather’s eruption         Pruritic papules in distribution of swimsuits, occurs after ocean swimming
Pruritic papular eruption of Pruritic non-follicular papules in symmetric distribution, HIV infection
HIV disease
Tumours
Angiolymphoid hyperplasia Single or multiple nodules on the face, scalp and ears, histologically shows
with eosinophils             prominent vascular channels and endothelial cells with vacuolization and
                             ‘hobnail’ appearance in addition to eosinophils
Mastocytosis                 Pink-to-red-brown macules, papules and plaques that urticate on stroking
MF and Hodgkin’s disease     Patches, plaques or nodules, lymphadenopathy
Pseudolymphoma               Association with arthropod bite or drug intake (especially phenytoin)
Infantile disorders
Eosinophilic pustular        Follicular pustules on the scalp of an infant
folliculitis
Erythema toxicum             Newborn with erythematous macules, papules and pustules on the trunk
neonatorum
Incontinentia pigmenti       Vesicles and bullae along Blaschko’s lines in neonate (stage I), blood
                             eosinophilia
Juvenile xanthogranuloma     Yellow to red-brown papules or nodules on the head and neck, upper trunk
                             or proximal extremities
Langerhans cell              Disseminated pink and yellow-brown papules (often with crusts) to nodulo-
histiocytosis                ulcerative periorificial lesions
Other disorders
Papuloerythroderma of        Widespread erythematous, flat-tapped papules with striking sparing of the
Ofugi                        body folds
PUPPP                        Usually primigravida in the third trimester, urticarial papules and plaques,
                             especially in striae
Well’s syndrome              Itchy erythematous plaques resembling both urticaria and cellulitis
(eosinophilic cellulitis)
Hypereosinophilic            Systemic features (fever, affection of internal organs), skin affected in 50%
syndrome                     of cases with eruption resembling atopic dermatitis or urticaria, intense blood
                             eosinophilia
Eosinophilic pustular        Ofuji type, immunodeficiency type
folliculitis of adults
Eosinophilic vasculitis                                   especially the head and neck, with angio-
      This is a rare disease consisting of                oedema of the face, and occurring at any age,
recurrent pruritic purpuric papules and                   with a long and recurrent course. It is
urticarial lesions occurring at any site,                 characterized by blood eosinophilia and an

                                                  -387-
eosinophilic necrotizing vasculitis of small       lobular panniculitis with septal vasculitis
vessels. The cause is unknown, but as in other     affecting the subcutaneous arteries and veins,
eosinophilic disorders, eosinophil cytokines       with subsequent ischaemia of subcutaneous
are present in serum, and toxic eosinophil         tissue which results in clinical suppuration and
granule proteins are present in tissues. The       ulceration. The pathogenesis may be similar to
histology shows fibrinoid deposition and           that of CSVV and the causes include
necrosis of small dermal vessels with an           infections (tuberculosis, Streptococci) and
infiltrate of eosinophils and absent or minimal    drugs. The histology shows early changes of
leukocytoclasis.      Treatment    with     oral   leukocytoclastic vasculitis of vessels in the
corticosteroids is effective. Table 33.3           subcutaneous tissue leading to ischaemic
illustrates the differential diagnosis of          necrosis of fat lobules which become encircled
eosinophilic       dermatoses     which      are   by foamy histiocytes. The skin lesions occur
characterized histologically by presence of        usually in middle-aged females, who are often
eosinophils in the inflammatory infiltrate.        obese, as tender, dusky, suppurative nodules
                                                   or plaques on the legs, which may progress to
Granuloma faciale
                                                   ulceration and heal leaving atrophic scars. The
       This immune complex mediated disease
                                                   condition may be unilateral and the course is
is considered to be a histological variant of
                                                   chronic and relapsing over several years.
leukocytoclastic vasculitis with a prominent
                                                   Cases with tuberculous aetiology are treated
eosinophilic infiltrate. Histology shows a
                                                   with triple-agent antituberculous therapy for a
mixed infiltrate predominantly of neutrophils
                                                   minimum of 9 months. Non-tuberculous cases
and eosinophils in the upper half of the
                                                   are treated with systemic corticosteroids and
dermis. A band of normal collagen (Grenz
                                                   potassium iodide. Other treatments used for
zone) typically separates the inflammatory
                                                   CSVV may be used.
infiltrate from the epidermis. Skin lesions are
asymptomatic, smooth, soft, usually single and     Polyarteritis nodosa
less often multiple, brown-red nodules on the            This disease (PAN) is a systemic
face, with prominent follicular orifices and       segmental vasculitis affecting medium-sized
telangiectatic surface. GF usually follows a       vessels leading to skin affection in 60%
chronic course with intermittent acute flares,     together with multiple organ systems.
and is often refractory to treatment. Several      Ischaemia, infarcts and haemorrhage result
lines of therapy exist, including intralesional    from the vasculitis and lead to end-organ
or systemic corticosteroids, cryosurgery,          damage. The incidence is 5 per million per
clofazimine, antimalarials, dapsone, surgery or    year and men are more commonly affected.
laser.                                             There is susceptibility of endothelial cells at
                                                   arterial branch points to inflammatory activity.
Acute haemorrhagic oedema of childhood
                                                   The condition may be associated with hepatitis
      This condition occurs in children under 2
                                                   B infection in 10% of cases and may also be
years old who often have recently had an
                                                   associated with other diseases e.g. SLE,
upper respiratory infection and/or have been
                                                   familial     Mediterranean     fever.   Immune
treated with antibiotics. The condition may be
                                                   complexes are most commonly implicated in
variant of childhood CSVV. The pathology
                                                   development of PN. Histology shows focal
shows leukocytoclastic vasculitis. It starts by
                                                   necrotizing obliterative arteritis with focal
facial    oedema      followed    by     sudden
                                                   panniculitis, and the vessels show nodose
development of tender petechiae and
                                                   swellings and aneurysms. Rupture at the weak
ecchymoses on the head and distal extremities,
                                                   points leads to luminal thrombosis and
as well as large annular, coin-shaped or
                                                   obliteration which cause distal ischaemia and
targetoid lesions that may later develop into
                                                   necrosis.
bullae or necrotizing lesions. Lesions start
                                                         The skin lesions are a nodule or group of
distally and spread proximally. Spontaneous
                                                   nodules along the course of a blood vessel
resolution occurs after 1-3 weeks. Treatment is
                                                   around the knee, anterior lower leg or dorsum
only supportive.
                                                   of the foot. Lesions are tender, pulsatile or
Nodular vasculitis                                 ulcerated. Other skin lesions include livedo
    This condition (erythema induratum of          reticularis, digital gangrene and ‘punched-out’
Bazin and of Whitfield) is a chronic relapsing     ulcers. Systemic features include fever, loss of


                                               -388-
weight, arthralgia, congestive heart failure,      subcutaneous nodules, most common on the
hypertension, orchitis, abdominal pain and         lower legs and may extend proximally to the
mononeuritis multiplex. Diagnosis of PAN is        thighs and buttocks. The nodules may be
best made from muscle or sural nerve biopsy.       tender, may ulcerate, or are associated with
Also by angiography which demonstrate              necrotizing livedo reticularis. Gangrene of the
pathognomonic aneurysmal dilatations of            digits may occur in children. Treatment of C-
vessel walls. The P-ANCA is positive in 20%        PAN is with penicillin, especially in children
of cases of PAN. The 5-year survival without       for streptococcal infection, NSAIDs, systemic
treatment is 10%.                                  steroids, dapsone, or low dose (7.5-20
      Plasma exchange combined with IFN-α          mg/week) methotrexate. Chronic leg ulcers
and/or the antiviral drug vidarabine is an         not responding to high-dose steroids are
effective treatment for PAN associated with        recently successfully treated with GM-CSF.
hepatitis B infection. Prednisolone 1-2            Wegener’s granulomatosis
mg/kg/day is used for other patients and has             This disease (WG) is a triad of systemic
increased the 5-year survival rate to 50%.         small       vessel      vasculitis,     necrotizing
Microscopic polyangiitis                           granulomatous inflammation of both the upper
      This     disease   (MPA,      microscopic    and       lower     respiratory      tracts,     and
polyarteritis nodosa) is a systemic vasculitis     glomerulonephritis. The incidence is 10 per
affecting blood vessels ranging in size from       million per year and if not treated it can lead
capillaries to medium-sized arteries. It affects   to death. It is an immune response to an
the kidneys (necrotizing glomerulonephritis in     antigen stimulus such as an infection. One
80%), lungs (50%) and skin (in 50% of cases,       theory regarding the pathogenesis of WG is
appearing as palpable purpura). The                that neutrophils are activated via cytokines
incidence is 6 per million per year. P-ANCA        leading to release of harmful oxygen radicals
may have a role in the pathogenesis by             and this enables ANCA to bind cytoplasmic
activating neutrophils and monocytes leading       antigens and damage vascular endothelium.
to direct injury to the vessel endothelium by      Leukocytoclastic           vasculitis         and/or
their       products.     Histology      shows     granulomatous inflammation may be present
leukocytoclastic vasculitis with segmental         in 50% of skin biopsy specimens.
vascular necrosis. Neutrophils and monocytes             Approximately 80% of patients will
permeate         vessel     walls,      causing    develop upper respiratory tract manifestations
leukocytoclasia, accumulation of fibrin and        (otitis, epistaxis, rhinorrhoea, sinusitis, saddle-
haemorrhage. Positive P-ANCA is present in         nose deformity), 50% develop pulmonary
50% of the patients. MPA is treated with high-     lesions (cough, dyspnoea, chest pain,
dose       systemic     corticosteroids     and    haemoptysis),              80%               develop
cyclophosphamide is used as a steroid-sparing      glomerulonephritis (proteinuria, haematuria),
agent. Other useful treatments include plasma      and 40% develop skin lesions. The most
exchange, IVIG, and gabexalate mesilate.           common skin lesion is palpable purpura
Cutaneous polyarteritis nodosa                     followed by oral ulcers and pathognomonic
      This condition (C-PAN) is a benign           gingival hyperplasia. Other skin features
relapsing variant of PAN that is limited to the    include tender subcutaneous nodules, papules,
skin. The aetiology is unknown and the             vesicles, petechiae, pyoderma gangrenosum-
condition is associated with infections such as    like lesions and papulonecrotic lesions. The
Streptococcus (particularly in children),          differential diagnosis is CSS. Laboratory
parvovirus B19, and hepatitis B virus.             findings include positive C-ANCA in 80% of
Histology shows an early predominantly             cases, elevated ESR and C-reactive protein,
neutrophilic infiltrate in the walls of the        anaemia, leukocytosis and positive rheumatoid
medium-sized arteries and arterioles of septae     factor. Survival of untreated WG is only 5
in the upper portions of the subcutaneous fat.     months.
Vessels      classically    demonstrate      an          A combination therapy of corticosteroids
eosinophilic ring of fibrinoid necrosis. Later,    and cyclophosphamide causes remission in
the infiltrate becomes less neutrophilic,          75% and raises the survival rate. Long term
consisting predominantly of lymphocytes and        treatment with co-trimoxazole has been
histiocytes. Skin lesions are dermal or            documented to reduce the incidence of

                                               -389-
relapses as it decreases respiratory infections.           The histopathology shows a chronic
Refractory WG can be treated with infliximab         granulomatous inflammatory disease that
or etanercept, and rituximab.                        typically affects the tunica media of medium
                                                     or large arteries. The non-specific infiltrate
Churg-Strauss syndrome
                                                     includes histiocytes, lymphocytes, monocytes,
      This rare allergic disease (CSS, allergic
                                                     giant cells and sometime eosinophils.
granulomatosis) is characterized by asthma,
                                                           Cutaneous involvement is uncommon
peripheral blood eosinophilia and necrotizing
                                                     and the most common finding is painful
vasculitis with extravascular granulomas. The
                                                     nodules over involved superficial arteries. The
aetiology is unknown. Both eosinophils and
                                                     classic sign of giant cell arteritis is a tender,
neutrophils are involved in the pathogenesis.
                                                     swollen, nodular, pulseless, indurated temporal
Serum levels of eosinophil cationic protein,
                                                     artery. Extracutaneous manifestations include
which is a marker of eosinophil activation
                                                     headache, earache, sore throat, jaw
often correspond with disease activity and
                                                     claudication, and blindness. Many patients
may be used to predict relapse. CSS is
                                                     also have pain and morning stiffness involving
characterized histopathologically by 3 key
                                                     the neck, shoulders and pelvic girdles.
features: eosinophilic infiltration of tissue,
                                                     Involvement of the aorta or its main branches
formation of extravascular granulomas of the
                                                     is common. The disease is very responsive to
viscera and skin, and necrotizing vasculitis
                                                     corticosteroids and methotrexate is a useful
involving both arteries and veins.
                                                     corticosteroid-sparing agent.
      Three clinical phases of CSS have been
described. The first phase, which may                Takayasu’s arteritis
continue for years, consists of allergic rhinitis,         This is a rare chronic inflammatory
nasal polyps, asthma and peripheral blood            vasculitis involving the aorta and great
eosinophilia. The second phase is vasculitis         vessels, occurring mainly in women aged 15-
affecting almost all body organ systems              30 years. The exact pathogenesis is unknown
including the skin (heart, lungs, kidneys,           but infective (tuberculosis, viral infections),
joints, GIT and nervous system). The third           autoimmune (a role for natural killer cells,
stage is characterized by allergic rhinitis,         CD4+ an CD8+ in the vasculitis) and genetic
asthma,     hypertension       and    peripheral     factors have been implicated.
neuropathies, and there is typically complete              Histopathologically, the skin lesions
resolution of damage to other organ systems.         consist of a necrotizing vasculitis with PMN
Nearly 50% of patients in all phases of the          leucocytes, fibrinoid necrosis within the vessel
disease will have skin lesions. Most common          walls, a granulomatous vasculitis with PMN
lesions are palpable purpura and infiltrated         leukocytes, eosinophils, foreign body type
nodules on the scalp or limbs, but other lesions     giant cells, and fibrinoid necrosis that may
may occur (livedo reticularis, Raynaud’s             also be associated with lobular panniculitis
phenomenon,            aseptic         pustules).    with fat necrosis and septal panniculitis.
Corticosteroids and cytotoxic agents are                   Clinically, there are 2 phases: an early
effective treatment, leading to clinical             prepulseless phase (fever, weight loss,
remission in 90% of the patients.                    myalgia, arthralgia) and a later pulseless phase
Giant cell arteritis                                 (bruits, blood pressure irregularity between the
      This disease (temporal arteritis) occurs in    arms or actual loss of pulse, hypertension,
persons over 50 years of age and is a                headache, angina, seizures and retinopathy).
granulomatous panarteritis affecting medium          Skin lesions occur in 20% of patients in the
or large arteries of the head and neck and is        early phase as erythema nodosum-like nodules
much commoner in females (4 : 1). The                or nodules of erythema induratum, and in the
pathogenesis involves the production of IFN-γ        later phase as pyoderma-gangrenosum-like
by       lymphocytes      which        stimulates    lesions.
multinucleated giant cells and macrophages to              Treatment       is     with       systemic
produce factors that stimulate the production        corticosteroids and cyclophosphamide for a
of myofibroblasts which proliferate to produce       period of 6 months to 2 years to induce
intimal hyperplasia and subsequent occlusion         remission, followed by a maintenance dose of
of arterial lumen.                                   10 mg once daily of corticosteroids. Stenotic


                                                 -390-
lesions may require treatment with angioplasty        Pityriasis lichenoides
or stenting.                                                There are 2 forms of this disease.
Lymphocytic vasculitis                                Pityriasis lichenoides chronica (PLC) is the
     Lymphocytic vasculitis, with a predominant       more common and occurs in young adults with
infiltrate of lymphocytes, occurs only in some        a male predominance (2 : 1). The acute form,
of the patients of several diseases showing           pityriasis lichenoides et varioliformis acuta
vasculitis (Table 33.4). The benefits of anti-        (PLEVA, Mucha-Habermann disease), is less
TNF-α agents (e.g. infliximab) and                    common, usually occurs in childhood and has
antilymphocyte antibodies (e.g. rituximab)            an equal sex incidence. However, some
point to an important role of both T and B            patients may have simultaneous lesions of
lymphocytes. A histopathological classification       both types, or may have transitional lesions
of lymphocytic vasculitis includes the                from PLEVA to PLC or vice versa. A subset
following:                                            of PLEVA with an aggressive course is termed
1. Lichenoid lymphocytic vasculitis: The              febrile ulcerative Mucha-Habermann disease
most common pattern and may occur in viral            (FUMHD).
infections,     drug    reactions,     erythema             The older name of pityriasis lichenoides
multiforme, SLE, graft-versus-host disease,           was guttate parapsoriasis because of its
pityriasis lichenoides et varioliformis acuta,        overlap with lymphomatoid papulosis
lymphomatoid papulosis, lichenoid mycosis             clinically and possible development of T-cell
fungoides and Degos’ disease.                         lymphoma. However, an overlap with
2. Angiodestructive lymphocytic vasculitis:           vasculitis is suggested since PLEVA causes
This is rare and occurs in lymphoma and               necrosis and extravasation of RBCs and most
lymphomatoid granulomatosis.                          cases follow a benign but prolonged course.
3. Lymphocytic endovasculitis: This affects                 The aetiology is unknown. One theory is
medium sized vessels causing intimal                  that the vascular injury is a hypersensitivity
hyperplasia and vessel wall mucinosis, and            reaction      to   infections     (Streptococcus,
causes segmental hyalinization of small               toxoplasmosis, parvovirus, cytomegalovirus).
vessels with thrombosis. Examples include             The occurrence of CD8+ clonality with IgM
chronic graft-versus-host disease, scleroderma        and C3 deposition in the vessels, suggests a
profunda, LE profundus and Degos’ disease.            form of chronic antigen stimulation with
                                                      resulting immune complex deposition.
Table 33.4 Diseases in which lymphocytic              Paraneoplastic pityriasis lichenoides have also
vasculitis may occur in some patients.                been reported.
Type of           Examples
                                                            Histopathologically, PLEVA shows an
process
Autoimmune        SLE,      rheumatoid     disease,
                                                      infiltrate of predominantly lymphocytes which
disorders         morphoea               profunda,    surrounds and involves the walls of dilated
                  dermatomyositis,       Sjögren’s    dermal capillaries. The epidermis is
                  syndrome, lichen sclerosus          oedematous with some necrotic keratinocytes.
Vasculitides      Older lesions of several            Intraepidermal and perivascular extravasation
                  leukocytoclastic     vasculitides   of erythrocytes is typical. In PLC, a
                  (e.g. granuloma faciale, EED),      parakeratotic     scale     forms,     containing
                  PN (classic and cutaneous           lymphocytic pseudo-Munro abscesses. In
                  types),    nodular    vasculitis,   FUMHD, there is marked fibrinoid necrosis of
                  Behcet’s disease, pyoderma          deep      vessels    with     intimal thrombi.
                  gangrenosum, Degos’ disease,
                  Buerger’s disease, PL et V
                                                      Immunofluorescence         studies     commonly
                  acuta,     pigmented     pruritic   demonstrate IgM, C3 and fibrin in vessel walls
                  dermatosis, Kawasaki disease        of fresh lesions.
Viral infections EBV, CMV, VZV                              In PLEVA, the eruption occurs in crops
Drugs             Anti-TNF           monoclonals,     and consequently appears polymorphic. The
                  interferon, bortezomib, topical     initial lesion is an asymptomatic oedematous
                  NSAIDs, imiquimod                   papule that undergoes central vesiculation and
Malignancy        Chronic lymphatic leukaemia,        haemorrhagic necrosis. The trunk, thighs and
                  lymphoma                            upper arms are chiefly affected. Erythematous
Miscellaneous     Perniosis,     graft-versus-host    or necrotic lesions may occur or mucous
                  disease, some arthropod bites
                                                      membranes. Lesions heal with scarring, which

                                                  -391-
may be varioliform. In FUMHD, there is high         Table 33.6 Aetiological classification of
fever with large ulcero-necrotic lesions with a     neutrophilic dermatoses.
fulminating course that may be fatal. About         Leukocytoclastic vasculitis
50% of cases occur in children, and new crops       CSVV, EED, Behcet’s disease
of lesions may develop over many months.            Neutrophilic vascular reactions (leukocytoclasia
                                                    without vasculitis)
Raised ESR and lymphadenopathy may occur.           Pyoderma gangrenosum, Sweet’s syndrome,
      In PLC, the lesion is a reddish brown         Behcet’s syndrome, bowel-associated dermatitis
small firm lichenoid papule, 3-10 mm in             arthritis syndrome
diameter. An adherent mica-like scale can be        Other neutrophilic dermatoses
detached by scrapping to reveal a shining           SAPHO syndrome, relapsing polychondritis,
brown surface (a diagnostic feature). Over the      erythema nodosum, neutrophilic eccrine adenitis,
course of 4 weeks the papule flatters and the       familial Mediterranean fever, hyper-IgD syndrome
scale separates spontaneously to leave a            Neutrophilic vascular reactions
pigmented macule which gradually fades.                 These are dermatoses characterized by
Temporary post-inflammatory hypopigmentation        neutrophilic infiltrates in the dermis and
may occur.                                          changes in the dermal blood vessels. The
      The course of pityriasis lichenoides is       vessel damage responsible for these
variable. In PLEVA, new crops may cease to          dermatoses is thought to be a result of immune
develop after few months or may continue to         complex deposition as well as to neutrophil
erupt for years or become PLC. PLC may be           induced injury. The neutrophilic dermatoses,
chronic from the start and new crops develop        being composed of dermal infiltrates and
from time to time over years and uncommonly         associated with changes in blood vessels, are a
PLEVA occurs on top of PLC. Prognosis is            characteristic group of cutaneous neutrophilic
better with PLEVA. The differential diagnosis       disorders, which include also the following:
of PLEVA includes varicella, vasculitis,            • Infective conditions.
necrotic skin infections and lymphomatoid           • Sterile epidermal neutrophilic infiltrates e.g.
papulosis. PLC is differentiated from guttate         subcorneal pustular dermatosis, pustular
psoriasis, lichen planus, and Gianotti-Crosti         psoriasis, infantile acropustulosis, and drug-
syndrome.                                             induced pustular eruptions.
      Therapeutic options include antibiotics         An aetiological classification of the
(tetracycline, erythromycin) and phototherapy       neutrophilic dermatoses is presented in table
(natural sunlight, UVB and PUVA). Topical           33.6.
steroids may improve healing of lesions but do
                                                    Sweet’s syndrome
not alter the course of the disease. In FUMHD,      Aetiology
treatment includes oral steroids, methotrexate,          Sweet syndrome (SS, acute febrile
dapsone,      ciclosporin     and     intravenous   neutrophilic dermatosis) is characterized by
immunoglobulin.                                     fever, peripheral neutrophil leukocytosis,
Infections and vasculitis                           acute onset of painful erythematous papules,
     Several infections are implicated in the       nodules or plaques and histological findings of
pathogenesis of vasculitides (Table 33.5).          a dense neutrophilic infiltrate without
                                                    evidence of primary vasculitis. The syndrome
Table 33.5 Infections causing vasculitis.           is subdivided into 3 groups: classical or
Organism            Diseases                        idiopathic, malignancy-associated and drug-
Streptococci        HSP, Kawasaki disease
                                                    induced. SS is associated with underlying
Staphylococcus      WG, Kawasaki disease
aureus
                                                    disease in 50% of cases. Classical SS affects
Hepatitis C virus   Mixed cryoglobulinaemic         middle-aged women and may be associated
                    vasculitis                      with infection (streptococcal upper respiratory
Hepatitis B virus   PAN                             infection and yersinial gastrointestinal
HIV                 HSP, EED, C-PAN, CSS,           infection), IBD (ulcerative colitis and Crohn’s
                    eosinophilic vasculitis         disease) and pregnancy. About 25% of cases
Influenza vaccine CSVV, MPA                         of SS have an associated malignancy (acute
Hepatitis B         CSVV, Kawasaki disease,         myelogenous leukemia or solid tumors in
vaccine             HSP, CSS and Takayasu’s         breast, GUT or GIT) and may be its first
                    arteritis                       manifestation and SS may be recurrent in

                                                -392-
these cases. Drug-induced SS is caused by G-        yellowish discoloration producing a targetoid
CSF therapy, all-trans-retinoic acid, co-           appearance. Healing occurs without scarring.
trimoxazole, minocycline, hydralazine and           Arthralgia, myalgia and arthritis are frequent.
oral contraceptives.
                                                    Diagnosis
      As with other neutrophilic dermatoses,
                                                          Diagnosis of SS is based on the presence
the pathogenesis of SS is unknown, but it is
                                                    of 2 major criteria and 2 out of 4 minor
thought     to    be     related     to   altered
                                                    criteria. Major criteria include acute onset of
immunological reactivity. A hypersensitivity
                                                    typical skin lesions and presence of typical
reaction to bacterial , viral or tumour antigens
                                                    histopathological findings. Minor criteria
has been suggested as a possible aetiology.
                                                    include fever > 38ºC, association with a cause
This theory is supported by the frequent
                                                    (infection, malignancy, pregnancy), excellent
association of SS with infection, drugs or
                                                    response to systemic corticosteroids or
malignancy.      Circulating      autoantibodies,
                                                    potassium iodide, and laboratory findings
immune complexes and cytokines have also
                                                    (raised ESR, positive C-reactive protein,
been proposed to play a part in the
                                                    leukocytes > 8000, neutrophils > 70%). Drug-
pathogenesis of SS. Th1 cytokines (IL-2 and
                                                    induced SS is diagnosed by occurrence of the
IFN-γ) are the proposed mediators, which            clinical features on drug intake and their
may stimulate the cytokine cascade leading to       resolution after stop of the drug.
activation of neutrophils and release of toxic
metabolites which may have a role in                Treatment
secondary vessel wall injury. Moreover, there             Systemic corticosteroids, potassium
are elevated levels of G-CSF and this caused        iodide and colchicine cause rapid regression of
reduced neutrophil apoptosis which would            lesions and symptoms. Other effective drugs
account for accumulation of neutrophils             include dapsone, ciclosporin, topical and
which are the hallmark of Sweet’s syndrome.         intralesional steroids, acitretin and IFN-α.
                                                    Thalidomide, cyclophosphamide and IVIG
Pathology
                                                    have also been used.
      Histologically, there is a dense, diffuse,
superficial neutrophilic infiltrate showing         Pyoderma gangrenosum
neutrophil karyorrhexis, with papillary dermal      Aetiology
oedema. The epidermis may be normal or                   This disease (PG) is a rare non-infectious
show spongiosis or subcorneal pustules.             neutrophilic dermatosis commonly associated
Formerly considered not to be a vasculitis, SS      with underlying systemic disease. Diagnosis is
is thought later to be a leukocytoclastic           based on typical clinical features and
vasculitis as evidenced by presence of              exclusion of other cutaneous ulcerating
fibrinoid necrosis, inflammatory cells within       diseases. Several clinical variants exist
vessel walls, extravasated RBCs and                 including ulcerative, pustular, bullous and
intraluminal thrombi. However, due to               vegetative forms. The pathogenesis is not clear
absence of IF findings of immune complex            and an immune-mediated process is thought to
mediated injury, SS is thought now to be a          have an important role. About 50% of patients
secondary vessel damage (by toxic metabolites       have an associated systemic disease including
released by activated neutrophils) rather than a    inflammatory bowel disease (IBD), arthritis,
primary vasculitis.                                 haematological malignancies and monoclonal
Clinical features                                   gammopathies. PG occurs in immuno-
     The patient typically appears ill with high    compromized       patients     secondary     to
fever, neutrophilia and elevated ESR. Skin          accompanying disease, infection or therapy.
lesion are tender, erythematous or violaceous       Both humoural (e.g. autoantibodies against
papules or nodules that form irregular plaques      skin and bowel) and cell-mediated (e.g.
on the arms, face and neck or anywhere.             cutaneous anergy to Candida) abnormalities
Lesions may be single or multiple, or               have been associated with PG. There is also
widespread in malignancy-associated cases           decreased neutrophil chemotaxis and impaired
which may be afebrile or recurrent. Lesions         monocyte phagocytosis in PG and these
may appear pseudovesicular or studded with          leukocyte abnormalities may contribute to the
minute pustules and may develop a central           pathergic phenomenon that occurs in 50% of


                                                -393-
cases, whereby new lesions can be induced at        • PG of specific sites:
sites of minor trauma as venepuncture or             - PG of the face, lips, orbital adnexae or
vaccination.                                          upper trunk.
                                                     - PG of the genitalia.
Pathology
                                                     - PG of the breast.
      Typical      histopathological    findings
                                                     - PG of oral, pharyngeal, nasal, respiratory
include central necrosis and ulceration of the
                                                      tract and ocular mucosae.
epidermis and dermis, surrounded by an
                                                     - Systemic PG (affecting lung, bones, etc.)
intense acute inflammatory cell infiltrate, with
                                                     Criteria have been proposed for diagnosis of
a more peripheral chronic inflammatory cell
                                                    classical ulcerative PG and these include:
infiltrate. In the ulcerative variant there is
massive       dermal-epidermal       neutrophilic   Major criteria (both required)
infiltrate with abscess formation. In pustular      1. Rapid (usually > 1 cm/day) progression of
PG, there is a perifollicular neutrophilic          painful necrolytic ulceration with an irregular,
infiltrate with subcorneal pustule formation.       undermined, violaceous border, usually with a
The bullous variant shows a neutrophilic            preceding papule, pustule or bulla, and pain
infiltrate    with     intraepidermal     vesicle   out of proportion to the size of the ulcerated
formation. In vegetating PG, there is a             area.
granulomatous reaction with peripheral              2. Exclusion of other causes of ulceration.
palisading histiocytes and giant cells.             Minor criteria (at least 2 required)
Clinical features                                   1. (a) history of pathergy, or (b) presence of
      PG can have a variety of clinical             cribriform scarring.
presentations. The classical type shows             2. Presence of a disease known to be
presentation with the ulcerative variant which      associated with PG (IBD, polyarthritis,
begins with tender papules or pustules that         myelodysplasia,      leukaemia,     monoclonal
evolve into painful ulcers with characteristic      gammopathy).
violaceous undermined edge, and a base that         3. Appropriate histopathological findings.
shows granulations tissue, necrosis or purulent     4. Rapid response to oral corticosteroid
exudate. Lesions may be solitary or multiple        therapy (usually interpreted as at least 50%
and healing occurs with an atrophic cribriform      reduction in size using 1-2 mg/kg/day).
scar. Lesions occur on the legs or trunk or at      Differential diagnosis
any site. It is usually associated with IBD,             This is illustrated in table 33.7.
arthritis or monoclonal gammopathy. Pustular
PG occurs during acute exacerbations of IBD         Treatment
and resolve with its control. Lesions are                For early or mild cases of PG, wet
discrete painful pustules with a surrounding        compresses, antimicrobial agents, topical
halo of erythema, occurring on the extensor         tacrolimus or intralesional steroids are
aspects of the limbs, and may evolve into           effective.
typical ulcerations of PG. The bullous variant      Table 33.7 Differential diagnosis of PG.
is associated with myeloproliferative disease       Category          Examples
and occurs as haemorrhagic bullae on the arms       Infection         Ecthyma, tuberculous ulcer,
which ulcerate and heal with scarring. The                            gummatous ulcer,
vegetating variant is not associated with                             blastomycosis, sporotrichosis,
systemic disease and appears as a solitary,                           amoebiasis
slowly progressive, superficial, non-painful,       Vascular          Arterial ulcer, venous ulcer,
granulomatous ulcer lacking the violaceous          disease           microvascular occlusion (e.g.
undermined border.                                                    cryogelling, antiphospholipid
    Recently, PG has been classified, for                             syndrome, sickle cell anaemia)
                                                    Vasculitis        WG, PAN, CSVV, mixed
reasons of diagnosis or disease association or
                                                                      cryoglobulinaemia, Takayasu's
therapy into the following types:
                                                                      arteritis
• Classical (ulcerative) PG: Commonest and          Neoplasia         Lymphoma, leukaemia
best recognized variant.                            Drugs             Bromoderma
• Atypical forms: Include pustular PG and           Tissue injury     Factitious ulcer, cocaine ulcer
bullous PG                                          Other disorders   Ulcerative colitis, Crohn’s
• Superficial (vegetative) PG.                                        disease, necrobiosis lipoidica


                                                -394-
      The main therapy for more severe cases       Clinical features
are oral corticosteroids and if there is                 EN typically manifests by the sudden
resistance to them, other drugs are effective      onset of painful erythematous warm nodules
including pulsed intravenous corticosteroid        and plaques on the shins, knees and ankles.
therapy, immunosuppressants (azathioprine,         The lesions are more easily palpated than
ciclosporin, methotrexate, mycophenolate           visualized, are bilateral and symmetrical, 1-5
mofetil, cyclophosphamide) or biological           cm in diameter. After several days, the
TNF-α inhibitors (infliximab, etanercept).         erythematous nodules flatten, become
      Other drugs effective in PG include          ecchymotic, finally taking a yellow-green
dapsone,       clofazimine,       minocycline,     appearance, referred to as erythema
thalidomide and intravenous immunoglobulin.        contusiformis. Lesions of EN never ulcerate,
Split-skin grafts and cultured keratinocyte        atrophy or scar. Lesions erupt and are usually
autografting are also effective.                   present for 3-6 weeks. Systemic symptoms
                                                   may be present including fever, arthralgia,
Erythema nodosum
                                                   gastrointestinal upset or conjunctivitis. In the
Aetiology
      This disease (EN) is characterized by        chronic EN variant (subacute nodular
painful erythematous, and sometimes                migratory panniculitis) lesions may be
ecchymotic nodules on the anterior surface of      solitary or few, on the lateral part of the lower
the legs. The condition may be idiopathic (30      leg. They are initially nodular but later
– 50% of cases) or secondary to various            become broader and flatten, and last several
                                                   months.
causes including infections (group Aβ-
haemolytic       streptococci,     tuberculosis,   Diagnosis
Chlamydia, Yersinia, leprosy, bacterial                 A chest X-ray, tuberculin skin test and
gastroenteritis as Salmonella, Shigella,           ASO titre may be done in some patients to
Campylobacter), or fungus infections               exclude causes such as sarcoidosis,
(dermatophytes, coccidioidomycosis, histo-         tuberculosis or streptococcal infection.
plasmosis, blastomycosis), drugs (sulphonamides,
                                                   Treatment
bromides, oral contraceptives), sarcoidosis,
                                                         EN typically resolves without treatment.
IBD,      malignancy,       pregnancy,      and
                                                   However, effective treatments are available
rheumatological and immune disease. The
                                                   and include NSAIDs, potassium iodide (300-
exact pathogenesis of EN is unknown,
                                                   900      mg/day),     colchicine,     dapsone,
although it is thought that it may be the result
                                                   hydroxychloroquine,       thalidomide     and
of deposition of immune complexes in the
venules of the septae of subcutaneous fat.         prednisolone. Potassium iodide is supplied as
The triggering factors are antigens usually        a saturated solution (1000 mg/ml). Each 0.1
associated with infections or drugs.               ml contains 100 mg and 0.3 ml (300 mg)
                                                   equal 10 drops. It may work through
Pathology                                          inhibition of cell-mediated immunity, as well
      Histopathologically, EN is a septal          as through inhibition of neutrophil
panniculitis and early lesions show septal         chemotaxis and suppression of neutrophil-
oedema, a lymphohistiocytic infiltrate with an     generated oxygen intermediates. It should be
admixture of neutrophils and eosinophils, with     added to water or juice to minimize the bitter
inflammation spreading to surrounding fat          taste. Acute side effects include nausea,
lobules. Miescher’s radial nodules which are       excessive salivation and urticaria and chronic
clusters of macrophages around small vessels,      side effects include enlargement of salivary
are characteristic of EN. Older lesions            and lacrimal glands, iododerma and
demonstrate widened septae with peripheral         hypothyroidism.
fibrosis, a shift from primarily neutrophilic
infiltrate to one of primarily lipid-rich          Behcet’s disease
macrophages with a ‘foam cell’ appearance.              Behcet’s disease histopathology shows
Macrophages without phagocytosed lipid             leukocytoclastic vasculitis or a neutrophilic
surround multinucleated giant cells, forming       vascular reaction. This disease is discussed in
granulomas.                                        chapter 54.



                                               -395-
Bowel-associated dermatitis-arthritis              SAPHO syndrome
syndrome (BADAS)                                        See chapter 45.
      This disease is defined by the presence of   Neutrophilic eccrine hidradenitis
pustular vasculitic skin lesions following               This is characterized by a neutrophilic
bowel bypass surgery or in patients having         infiltrate that is centered and extends into the
IBD. Blood vessel damage secondary to bowel        eccrine coils. Typically, the eccrine apparatus
flora antigen-associated circulating immune        shows vacuolar degeneration or necrosis.
complexes is thought to be the pathogenesis of     Chemotherapeutic agents are the cause in
skin lesions. The histopathology shows dermal      90% of cases, especially drugs used for acute
oedema with dilated dermal venules and             myeloid leukaemia. Other causes include
capillaries with a marked perivascular             malignant diseases (e.g. lymphomas, lung
neutrophilic infiltrate. Skin lesions are          cancer) and drugs used for their treatment (e.g.
pustules on a purpuric base, most often on the     bleomycin,       chlorambucil,    5-fluorouracil,
arms and other areas of the upper body. These      vincristine), other drugs (e.g. paracetamol,
pustules measure 0.5 - 1.5 cm in diameter and      amoxicillin), and infections (e.g. S. aureus,
occur in crops, each lasting up to 2 weeks, and    hepatitis C, HIV).
recurring at intervals of several months. The            Lesions may be plaques, papules,
skin lesions may be preceeded by fever,            nodules,       erythema-multiforme-like,      or
gastrointestinal upset or arthritis of the hands   urticated, and may be grouped. Lesions affect
and wrists. Treatment of cases secondary to        predominantly the head, neck and upper trunk.
previous bowel surgery is surgical correction      Pathergic phenomenon is positive. An
of bowel anatomy. Treatment of cases not           associated      fever    is   common.      Most
secondary surgery or having or incorrectable       chemotherapy-related cases occur about 2
surgery is oral antibiotics to reduce bacterial    weeks after starting treatment, and resolve
overgrowth for 4-8 weeks (tetracycline,            spontaneously after 2-3 weeks.
doxycycline, clindamycin, metronidazole) and             Treatment options include topical and
aseptic neutrophilic inhibitory drugs for 4-8      systemic steroids, NSAIDs, dapsone and
weeks (colchicine, dapsone, thalidomide).          colchicine.




                                               -396-

				
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