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Raynaud phenomenon
Raynaud phenomenon is produced by an intermittent constriction of the small digital arteries and arterioles. The digits
have sequential pallor, cyanosis, and rubor. The involved
parts are affected in paroxysms by the attacks of ischemia,
which cause them to become pale, cold to the touch, and
numb. The phenomenon is more frequently observed in cold
weather. When exposed to cold, the digits become white
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Treatment
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Erythromelalgia
Erythromelalgia
Also called erythermalgia and acromelalgia, erythromelalgia
is a not uncommon condition. The population-based incidence
is 1.3 per 100 000 per year: 2.0 per 100 000 in women and
0.6 per 100 000 in men per year. Erythromelalgia is an easily
recognized clinical syndrome characterized by paroxysmal
vasodilation affecting the feet, with burning, localized pain,
redness, and high skin temperature. Infrequently, the hands
(Fig. 35-2), face, and ears may be involved. The burning paroxysms may last from a few minutes to several days, and are
usually triggered by an increase in environmental temperature
or exercise. The average patient has 12 attacks per week, but
in some patients, the attacks are much more frequent. Often,
relief can only be obtained by immersing the burning feet in
ice water. Over 20% of patients will have evidence of cold
injury, and more than 1% will suffer gangrene or undergo
amputation. Quality of life is severely impacted by this
condition.
Erythromelalgia can be considered primary, secondary, and
familial. For treatment purposes, secondary cases of erythro
melalgia should be carefully divided into those associated
with myeloproliferative diseases, often with elevated platelets,
and others. Myeloproliferative diseases complicated by
erythromelalgia include polycythemia vera, thrombotic
thrombocytopenic purpura, and various forms of thrombocythemia. Administration of romiplostim, a thrombopoiesisstimulating protein, has resulted in erythromelalgia. Low-dose
aspirin is effective therapy for erythromelalgia associated with
platelet abnormalities. If this fails, other methods to reduce the
platelet count should be considered.
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804
Fisher TZ, et al: A novel Nav1.7 mutation producing carbamazepineresponsive erythromelalgia. Ann Neurol 2009; 65:733.
Han C, et al: Early- and late-onset inherited erythromelalgia: genotypephenotype correlation. Brain 2009; 132:1711.
Iqbal J, et al: Experience with oral mexiletine in primary erythromelalgia
in children. Ann Saudi Med 2009; 29:316.
Jackson AL, Oates JA: A patient with adult erythermalgia: evidence
suggesting an autoimmune etiology. Am J Med Sci 2008; 335:320.
Kalgaard OM, et al: Prostacyclin reduces symptoms and sympathetic
dysfunction in erythromelalgia in a double-blind randomized pilot
study. Acta Derm Venereol 2003; 83:442.
Kluger N, et al: Romiplostim-induced erythromelalgia in a patient with
idiopathic thrombocytopenic purpura. Br J Dermatol 2009; 161:482.
Lampert A, et al: A pore-blocking hydrophobic motif at the cytoplasmic
aperture of the closed-state Nav1.7 channel is disrupted by the
erythromelalgia-associated F1449V mutation. J Biol Chem 2008;
283:24118.
Lampert A, et al: Erythromelalgia mutation L823R shifts activation and
inactivation of threshold sodium channel Nav1.7 to hyperpolarized
potentials. Biochem Biophy Res Commun 2009; 390:319.
Michiels JJ, et al: Platelet-mediated erythromelalgic, cerebral, ocular
and coronary microvascular ischemic and thrombotic manifestations in
patients with essential thrombocythemia and polycythemia vera: a
distinct aspirin-responsive and coumadin-resistant arterial
thrombophilia. Platelets 2006; 17:528.
Misery L, et al: Severe neurological complications of hereditary
erythermalgia. J Eur Acad Dermatol Venereol 2007; 21:1446.
Mork C, et al: The prostaglandin E1 analog misoprostol reduces
symptoms and microvascular arteriovenous shunting in
erythromelalgiaa double-blind, crossover, placebo-compared study.
J Invest Dermatol 2004; 122:587.
Nanayakkara PWB, et al: Verapamil-induced erythermalgia. Neth J Med
2007; 65:349.
Natkunarajah J, et al: Treatment with carbamazepine and gabapentin of
a patient with primary erythermalgia (erythromelalgia) identified to have
a mutation in the SCN9A gene, encoding a voltage-gated sodium
channel. Clin Exp Dermatol 2009 Jun 17 (Epub ahead of print).
Paticoff J, et al: Defining a treatable cause of erythromelalgia: acute
adolescent autoimmune small-fiber axonopathy. Anesth Analg 2007;
104:438.
Pipili C, Cholongitas E: Erythromelalgia in a diabetic patient managed
with gabapentin. Diabetes Res Clin Pract 2008; 79:e15.
Reed KB, Davis MDP: Incidence of erythromelalgia: a population-based
study in Olmsted County, Minnesota. J Eur Acad Dermatol Venereol
2009; 23:13.
Saviuc PF, et al: Erythromelalgia and mushroom poisoning. J Toxicol
Clin Toxicol 2001; 39:403.
Sheets PL, et al: A Nav1.7 channel mutation associated with hereditary
erythromelalgia contributes to neuronal hyperexcitability and displays
reduced lidocaine sensitivity. J Physiol 2007; 581:1019.
Thami GP, et al: Erythromelalgia induced by possible calcium channel
blockade by cyclosporin. BMJ 2003; 326:910.
Young FB: When adaptive processes go awry: gain-of-function in
SCN9A. Clin Genet 2008; 73:34.
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Cholesterol emboli
Cholesterol emboli resulting from severe atherosclerotic
disease, usually of the abdominal aorta, may cause unilateral
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Livedoid vasculopathy
Synonyms for livedoid vasculopathy include livedoid vasculitis, atrophie blanche, segmental hyalinizing vasculitis, livedo
reticularis with summer/winter ulceration, and PURPLE
(painful purpuric ulcers with reticular pattern of the lower
extremities). The vasculopathy is characterized clinically by
early focal, painful purpuric lesions of the lower extremities
that frequently ulcerate and heal slowly (Fig. 35-5). The ulcers
heal, with small, stellate and reticulated, white scars, referred
to as atrophie blanche (Fig. 35-6). The ulcers may be ringed by
telangiectasis and hemosiderin-induced hyperpigmentation.
Livedo racemosa may be present on the affected extremity or
be more widespread. About two-thirds to three-quarters of the
patients are female; the mean age of onset is 45 years. The
condition is bilateral in 80% of patients and ulceration occurs
in 70%.
Histologically, livedoid vasculopathy is characterized by
hyaline thrombi within small and at times medium vessels
in the dermis. Perivascular hemorrhage may be present.
Leukocytoclastic vasculitis is not found, and the biopsies can
be described as showing intravascular thrombosis without
inflammation. Focal lymphocytic intravascular and perivascular inflammation may be seen, but this is considered second-
Livedoid vasculopathy
and embolialter cutaneous blood flow and can be accompanied by livedo. If vessels lose competence they may leak, creating purpura, and if vasculitis, vasculopathy, or emboli are
severe enough or affect a large enough vessel, the viability of
the overlying skin is compromised, and necrosis and ulceration may occur. Complicating this situation is the fact that
patients may have both a vasculitis and a hypercoagulable
state, resulting in biopsies that, at times, are pathogenically
discordant. A patient with an inherited or acquired disorder
of coagulation and a drug-induced cutaneous vasculitis would
be a not uncommon example. The above discussion makes it
clear that this area of differential diagnosis is a difficult one
for even the most skilled dermatologist. Careful sampling of
early lesions, with large and deep biopsies if necessary, may
be required to find the primary vascular pathology. Since
vasculitis may be a focal process, step sections may be required
to find the diagnostic features. In addition, the diagnosis proposed must be interpreted in the context of other elements of
the patients medical condition, such as medications, infections, underlying diseases, and involvement of other organ
systems besides the skin.
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Calciphylaxis
Calciphylaxis is an increasingly reported syndrome that is
potentially fatal. It occurs most commonly in the setting of
chronic renal failure, often with type 2 diabetes, and obesity.
Women outnumber men 3:1 to 4:1. About 14% of patients
on hemodialysis and 4% of patients on peritoneal dialysis
develop calciphylaxis. About half of calciphylaxis patients are
diabetic and more than half have a body mass index (BMI) of
>30. Every gain in the BMI of 1 point over 30 increases the risk
for calciphylaxis by 10%. Calciphylaxis occurs on the background of extensive calcification of the media of mediumsized and small arterioles. Parathyroid hormone (PTH) levels
are often abnormal (either high or low), and calciphylaxis may
also be seen in the setting of primary hyperparathyroidism,
as well as secondary hyperparathyroidism of renal failure.
Tumors may also produce PTH-related proteins and be associated with calciphylaxis. In about 20% of calciphylaxis patients,
the Ca X PO4 product will be greater than 70, a sensitive but
not specific marker for calciphylaxis. The arteriolar calcification is a chronic process due to many metabolic factors and
signaling molecules that cause vascular smooth-muscle cells
to transform to an osteogenic phenotype. Thus the vascular
calcification in calciphylaxis and most cases of calcific uremic
arteriolopathy is due to local deposition of calcium in the
blood vessels by the vascular smooth muscles cells. It is not
metastatic or dystrophic calcification. Liver disease and systemic corticosteroid therapy increase the risk for development
of calciphylaxis by 23-fold.
Calciphylaxis begins as fixed livedo reticularis (livedo
racemosa). Areas within the livedo become increasingly
violaceous and eventually purpuric, bullous, and necrotic.
Subcutaneous nodules may herald the onset of the livedo and
be associated with it. Affected tissue in calciphylaxis has
reduced tissue oxygenation. Lesions affect the legs below the
knees in 90% of cases. More proximal lesions, and lesions of
the fatty areas of the thighs, buttocks, and abdomen occur in
about two-thirds of cases. Severe pain is a cardinal feature
of calciphylaxis, often requiring narcotic analgesia for
control. Ischemic myopathy may occur in severe cases,
and muscle pain may precede the appearance of the skin
lesions. Necrotic skin lesions are very resistant to healing and
infection of open wounds with septicemia is a common cause
of death. The 1-year survival of all calciphylaxis patients is
about 40%, and only 10% in patients with both proximal and
distal disease.
An optimum biopsy to confirm the diagnosis of calciphylaxis should be adjacent to the necrotic area where there is
erythema or early purpura. Ideally, it should be deep and large
enough to identify diagnostic features. This may require an
incisional rather than a simple punch biopsy. Since vascular
calcification is common in all patients with chronic renal
failure, this alone cannot confirm the diagnosis. In addition,
Purpura
there should be evidence of tissue damage (necrosis), extravascular calcification, and thrombosis in the arterioles of the
dermis and subcutaneous tissue.
The pathogenesis of calciphylaxis is still being elucidated. In
most cases, it occurs on the background of extensive calcification of arterioles of the skin. The calcification triggers intimal
proliferation and narrows the arterioles. Gradually or rather
suddenly, the patient will develop areas of livedo and necrosis. This heralds the onset of vascular thrombosis. The mechanism that triggers this thrombotic phase of calciphylaxis and
the appearance of the skin lesions is unclear. Some of these
may be prothrombotic states, such as female gender, warfarin
administration, trauma, the presence of cancer, edema, and
anatomic location. The skin overlying fatty areas, such as the
medial thighs, abdomen, and breasts of women, is particularly
susceptible to thrombotic diseases such as diffuse dermal angiomatosis and warfarin and heparin necrosis. This may be
caused by low blood flow or the reduced circulation due to
tethering and kinking of vessels due to gravity. In some
patients, low protein C levels are identified. Human immunodeficiency virus (HIV) infection and cryofibrinogenemia have
also been associated. A useful model to consider pathogenically is that calciphylaxis is analogous to atherosclerotic myocardial disease. There is a gradual and progressive abnormality
of the vasculature, with narrowing of the vessel lumen (by
plaque in the case of atherosclerosis and by intimal calcification in the case of calciphylaxis). The acute symptomatology
is triggered by thrombosis of the narrowed vessel, leading to
occlusion of the vessel and downstream anoxia and necrosis.
As in atherosclerotic disease, treatment for calciphylaxis
should be directed at early prevention of intimal calcification.
Unlike atherosclerosis, however, it is unclear how to prevent
intimal calcification in the setting of renal disease.
Penile calciphylaxis is a particularly painful variant. The
glans penis develops a deep necrotic ischemic ulceration. The
risk factors are diabetes and renal failure. Penectomy is often
required for pain management. One case resembled temporal
arteritis.
Much of the treatment for calciphylaxis is directed at altering abnormal calcium metabolism. Low calcium dialysis, oral
phosphate binders, cinacalcet, bisphosphonates, and intra
venous sodium thiosulfate have all been used with some
success. Once the ulcerations are present, gentle debridement
is associated with healing and increased survival. Painful
ulcers may also respond to hyperbaric oxygen therapy.
Parathyroidectomy is best reserved for cases refractory to the
above regimens and a marked elevation of PTH.
Purpura
Purpura is the term used to describe extravasation of blood
into the skin or a mucous membrane. It presents as distinctive
brownish-red or purplish macules a few millimeters to many
centimeters in diameter. Several terms are used to describe
various clinical manifestations of purpura.
Petechiae are superficial, pinhead-sized (<3mm), round,
hemorrhagic macules, bright red at first, then brownish or
rust-colored. They are most commonly seen in the dependent
areas, are evanescent, occur in crops, regress over a period of
days, and most often imply a disorder of platelets rather than
a coagulation factor disorder. These disorders typically give
rise to ecchymoses or hematomas rather than petechiae.
Petechiae may also be a sign of vasculitis.
Ecchymoses are better known as bruises or black and blue
marks. These extravasations signify a deeper and more extensive interstitial hemorrhage, which forms a flat, irregularly
shaped, bluish-purplish patch. Such patches gradually turn
yellowish and finally fade away. They are characteristic of
scurvy.
Vibices (singular, vibex) are linear purpuric lesions.
Hematoma designates a pool-like collection of extravasated
blood in a dead space in tissue that, if of sufficient size, produces a swelling that fluctuates on palpation. Hematomas are
usually walled off by tissue planes.
Pathogenesis
Purpura may result from hyper- and hypocoagulable states,
vascular dysfunction, and extravascular causes, including idio
pathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura, disseminated intravascular coagulation (DIC),
drug-induced thrombocytopenia, bone marrow failure, congenital or inherited platelet function defects, acquired platelet
function defects (aspirin, renal or hepatic disease, or gammopathy), and thrombocytosis secondary to myeloproliferable
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diseases. Most of these disorders produce findings of nonpalpable purpura. Ecchymosis predominates in procoagulant
defects, such as hemophilia, anticoagulants, vitamin K deficiency, and hepatic disease resulting in poor procoagulant
synthesis. There is often a component of trauma. Increased
frequency of ecchymotic skin can be the result of poor dermal
support of blood vessels, most often localized to the area of
trauma, and may result from actinic (senile) purpura, topical or
systemic corticosteroid therapy, scurvy, systemic amyloidosis,
EhlersDanlos syndrome, or pseudoxanthoma elasticum.
Primarily prothrombotic disorders form characteristic retiform purpura or purpura associated with livedo reticularis.
These include disorders in which fibrin, cryoglobulin, or
other material occludes vessels. Representative causes include
monoclonal cryoglobulinemia, cryofibrinogenemia, DIC,
purpura fulminans, protein C/S deficiency, warfarin-induced
necrosis, heparin necrosis, cholesterol emboli, oxalate crystal
occlusion, and antiphospholipid syndrome.
Evaluation
A history and physical examination are often all that is necessary. A family history of bleeding or thrombotic disorders,
duration of symptoms, use of drugs and medications that
might affect platelet function and coagulation, as well as a
review of medical conditions that may result in altered coagulation, should be documented. Physical examination should
stress the size, type, and distribution of purpura; a search for
telangiectases; a joint examination; and an evaluation of skin
elasticity, unusual scars, and unusual body habitus. Correlation
of purpura morphology with pathogenesis allows for a more
focused approach.
A complete blood cell count and differential can be used to
assess for microangiopathic anemia, screen for myeloproliferative disorders, and assess the number and morphology of
platelets. A bleeding time is the preferred method of assessing
platelet function. The partial thromboplastin time (PTT) and
the prothrombin time (PT) are tests to evaluate abnormal coagulation states.
Thrombocytopenic purpura
Thrombocytopenic purpura may be classified into two large
categories: states resulting from accelerated platelet destruction and states resulting from deficient platelet production.
Accelerated platelet destruction may be immunologic or nonimmunologic. The former may be due to antibodies (auto
immune or drug-induced thrombocytopenia), isoantibodies
(congenital or post-transfusion), immune complex disease, or
other immunologic processes, such as erythroblastosis fetalis,
neonatal lupus, scleroderma, other connective tissue diseases,
or acquired immunodeficiency syndrome (AIDS). The group
of thrombocytopenias with accelerated platelet destruction
includes thrombotic thrombocytopenic purpura and DIC.
Deficient platelet production may be related to diseases such
as aplastic anemia and leukemia.
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Drug-induced thrombocytopenia
Thrombocytopenic purpura resulting from drug-induced
antiplatelet antibodies may be caused by drugs such as
heparin, sulfonamides (antibiotics and hydrochlorthiazide),
digoxin, quinine, quinidine, chlorothiazides, penicillin,
cephalosporins, minocycline, acetaminophen, nonsteroidal
anti-inflammatory drugs (NSAIDs), statins, fluconazole,
protease inhibitors, H2 blockers, antiplatelet agents, rifampin,
and lidocaine.
Heparin-induced thrombocytopenia (HIT) is associated
with life-threatening arterial and venous thrombosis and, to a
lesser extent, hemorrhagic complications. The platelet count
Thrombotic microangiopathy
Blackmer AB, et al: Fondaparinux and the management of heparininduced thrombocytopenia: the journey continues. Ann Pharmacother
2009; 43:1636.
Chong BH, Isaacs A: Heparin-induced thrombocytopenia: what clinicians
need to know. Thromb Haemost 2009; 101:279.
Grossjohann B, et al: Ceftriaxone causes drug-induced immune
thrombocytopenia and hemolytic anemia: characterization of targets
on platelets and red blood cells. Transfusion 2004; 44:1033.
Picker SM, et al: Pathophysiology, epidemiology, diagnosis and
treatment of heparin-induced thrombocytopenia (HIT). Eur J Med Res
2004; 9:180.
Russell KN, et al: Acute profound thrombocytopenia associated with
readministration of eptifibatide: case report and review of the literature.
Pharmacotherapy 2009; 29:867.
Selleng K, et al: Heparin-induced thrombocytopenia in intensive care
patients. Semin Thromb Hemost 2008; 34:425.
Shantsila E, et al: Heparin-induced thrombocytopenia: a contemporary
clinical approach to diagnosis and management. Chest 2009; 135:1652.
Syed S, Reilly RF: Heparin-induced thrombocytopenia: a renal
perspective. Nat Rev Nephrol 2009; 5:501.
Wirth SM, et al: Evaluation of a clinical scoring scale to direct early
appropriate therapy in heparin-induced thrombocytopenia. J Oncol
Pharm Pract 2009 Aug 19 (Epub ahead of print).
Zondor SD, et al: Treatment of drug-induced thrombocytopenia. Expert
Opin Drug Saf 2002; 1:173.
Thrombotic microangiopathy
The diagnosis of a thrombotic microangiopathy is made in the
presence of a microangiopathic hemolytic anemia and thrombo
cytopenia in the absence of another plausible explanation.
Thrombotic thrombocytopenic purpura and hemolytic uremic
syndrome are the two major diseases in this group. Certain
drugs, such as cyclosporine, quinine, ticlopidine, clopidogrel,
mitomycin C, docetaxel, trastuzumab, and bleomycin, have
been associated with a thrombotic microangiopathy.
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Nonthrombocytopenic purpura
(dysproteinemic purpura)
Cryoglobulinemia and cryofibrinogenemia
The term cryoglobulinemia refers to the presence in the serum
of proteins that precipitate at temperatures below 37C and
redissolve on rewarming. These tend to be chronic conditions,
unless the underlying disease process is treated. Abnormal
serum proteins behaving as cryoglobulins and cryofibrinogens
may be IgG, IgM, or both. Type I cryoglobulinemia occurs
most frequently in multiple myeloma and macroglobulinemia,
and is of a monoclonal IgM, IgG, or Bence Jones cryoglobulin
form. Type II cryoglobulins are monoclonal and have rheumatoid factor-like activity. They are autoantibodies to the constant region of IgG. They occur in many connective tissue
diseases and may also be due to the B-cell proliferation seen
in hepatitis C virus (HCV) infection. Mixed cryoglobulinemia
(type III), in which the cryoglobulins are of various classes, are
associated with HCV infection in more than 90% of cases.
Purpura is most apt to occur on exposed surfaces after cold
exposure. It may be of sudden onset and may clear rapidly
once the patient is kept warm. Marked brown hyperpigmentation of the dorsal feet, at times in a livedoid pattern, may
suggest this diagnosis. Cryoglobulinemia can be the cause of
chronic leg ulcers (Fig. 35-8). An unusual clinical presentation
of type I cryoglobulinemia in association with multiple
myeloma is follicular hyperkeratosis of the central face, especially the nose.
In monoclonal disease, the biopsy reveals amorphous, jellylike, eosinophilic material in the vessel lumen. In types II and
III cryoglobulinaemia, a skin biopsy reveals classic leukocytoclastic vasculitis, and less commonly features of polyarteritis
nodosa.
Treatment of type I cryoglobulinemia is to address the associated myeloproliferative disorder. Thalidomide was beneficial in one patient with a type I cryoglobulin, retiform purpura
and clonal plasma cell expansion. For cryoglobulinemia associated with HCV or connective tissue disease, options include
plasmapheresis, IVIG, systemic steroids, immunosuppressors,
and colchicine. Simple plasma exchange can be helpful, but
cryofiltration apheresis is the best method to remove cryoproteins in the treatment of cryoprecipitate-induced diseases.
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814
patients. Antithyroglobulins, increased erythrocyte sedimentation rate (ESR), leukopenia, antinuclear factors, and proteinuria may be found. Almost 80% of patients with
hypergammaglobulinemic purpura of Waldenstrm have
antibodies to Ro/SSA.
Hyperglobulinemic purpura occurs most commonly in
women and is frequently seen with Sjgren syndrome and
rheumatoid arthritis. Adverse fetal outcomes in these women
may be associated with the associated autoantibodies (SSA/
SSB). Hyperglobulinemic purpura may also be a primary
chronic benign illness. When it is associated with hepatitis C,
it has a predilection for men, and has manifestations that
usually last longer than those associated with Sjgren
syndrome.
In about one-third of patients, leukocytoclastic vasculitis is
present. Patients with leukocytoclastic vasculitis have a higher
prevalence of articular involvement, peripheral neuropathy,
Raynaud phenomenon, renal involvement, ANA, rheumatoid
factor, and anti-Ro/SSA antibodies. The course of the disease
is essentially benign, but chronic. Rare deaths are related to
associated cryoglobulin disease. Hyperglobulinemic purpura
may be a manifestation or harbinger of connective tissue or
hematopoietic diseases, and rarely, progression to myeloma
has been reported.
Patients often improve with support stockings. Steroids
should be reserved for severe disease. Indomethacin and
hydroxychloroquine may be of value in the treatment of
milder disease, especially in patients who have connective
tissue disease or are SSA/B (Ro/La)-positive. Aspirin and colchicine have been used with some success.
Al-Mayouf SM, et al: Hypergammaglobulinaemic purpura associated
with IgG subclass imbalance and recurrent infection. Clin Rheumatol
2000; 19:499.
Jolly EC, et al: Benign hypergammaglobulinemic purpura is not
benign in pregnancy. Clin Rheumatol 2009; 28:S11.
Maeda-Tanaka M, et al: Juvenile-onset hypergammaglobulinemic
purpura and fetal congenital heart block. J Dermatol 2006; 33:714.
Malaviya AN, et al: Hypergammaglobulinemic purpura of Waldenstrm:
report of 3 cases with a short review. Clin Exp Rheumatol 2000; 18:518.
Ramos-Casals M, et al: Cutaneous vasculitis in primary Sjgren
syndrome: classification and clinical significance of 52 patients.
Medicine (Baltimore) 2004; 83:96.
Waldenstrm macroglobulinemia
Waldenstrm macroglobulinemia (WM) is a lymphoplasmacytic lymphoma of B lymphocytes, with proliferation of monoclonal lymphocytes in bone marrow, lymph nodes, and spleen.
Lymphadenopathy, hepatosplenomegaly, and anemia are
characteristic. Elevated levels of IgM in the circulation define
this unique and rare lymphoproliferative disease, and the IgM
is responsible for some of the skin manifestations of this disorder. Elderly men are predominately affected, and there is a
strong familial predisposition. The cutaneous manifestations
of WM can be divided into two categories: nonspecific and
specific. Nonspecific manifestations are related to the hyperviscosity syndrome created by the circulating IgM, and include
purpura of the skin and mucous membranes. The purpura
may be surmounted by giant tense bullae. Bleeding of the
gums and epistaxis can occur. The IgM may behave as a cryo
globulin, resulting in purpura, livedo, cutaneous ulcerations,
and vasculitis. Urticaria (some patients satisfying the diagnostic criteria for Schnitzlers syndrome), disseminated xanthoma,
and amyloid deposition can be seen. Specific skin lesions are
of two types: specific skin deposits of aggregates of the IgM
(IgM storage lesions), and cutaneous infiltrates with neoplastic
lymphoid cells. The specific skin lesions usually occur once the
diagnosis of WM is already known, but uncommonly the skin
lesions are the first clue to the diagnosis. The specific IgM
deposits present clinically as subepidermal blisters (clinically
and histologically resembling bullous amyloidosis) or translucent 13mm papules. They are found most commonly on the
lower extremity, even on the sole. Slight hyperkeratosis may
be seen over the papules. Histologically, the papules are composed of dermal nodular homogenous and fissured pink
deposits with a tendency to involve newly formed vessels.
They are periodic acid-Schiff (PAS)-positive, but negative for
Congo red. Direct immunofluorescence will identify the
dermal globules as being composed of IgM and is a useful
diagnostic approach. When WM results in specific cutaneous
lymphoid aggregates, the presentation is very nonspecific.
Small redbrown to violaceous macules, papules, nodules, or
plaques may be present, usually on the face. Rosacea is often
initially entertained as a diagnosis. Widespread skin involvement with a deck-chair sign (sparing the abdominal skin
folds) has been reported.
The natural history of WM is that of an indolent myelodysplasia. Treatment is directed at reducing the volume of neoplastic cells and should be managed by an oncologist. Most
indolent and asymptomatic patients are followed or treated
only when clinical disease occurs. Given the risk of secondary
neoplasms, fludarabine is avoided, unless other options are
not possible. Combinations of cyclophosphamide, systemic
steroids, and rituximab or bortezomib, systemic steroids and
rituximab are initial therapeutic options. Plasmapheresis can
be effective in controlling acute symptoms of hyperviscosity
syndrome. Rituximab is not used as a monotherapy in WM
patients with hyperviscosity, as they may experience a flare of
their disease. Soluble CD27 can be used as a marker to determine response to therapy.
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Purpura fulminans
Also known as purpura gangrenosa, this is a severe, rapidly
fatal reaction. There are three forms of the disease:
1. that associated with infection and DIC
2. hereditary deficiency of protein C or S
3. that which follows a febrile illness that leads to an
acquired protein S deficiency.
The most common form is that which is associated with an
infectious illness, usually bacterial septicemia, but sometimes
a viral infection (varicella). Asplenic patients, who are at risk
for pneumococcal or meningococcal sepsis, are also predisposed to purpura fulminans. Neonates with homozygous
protein C or protein S deficiencies may suffer purpura fulminans (Fig. 35-10). Some patients develop transient deficiencies
of proteins C and S in response to infection. A number of cases
of purpura fulminans associated with infections and factor V
Leiden mutation, with normal protein C and protein S levels,
have been reported. Meningococcemia, streptococcal sepsis,
Capnocytophaga sepsis (from dog bite), staphylococcal septicemia, and urosepsis are the most common causes. Rickettsial
disease and malaria may present as purpura fulminans. Active
HHV-6 replication with acquired protein S deficiency and
purpura fulminans has been described. Purpura fulminans
presents as the sudden appearance of large ecchymotic areas,
especially prominent over the extremities, progressing to acral
hemorrhagic skin necrosis. (Fig. 35-11). The term symmetrical
peripheral gangrene is used to describe cases when acral
gangrene is present. Fever, shock, and DIC usually accompany
the skin lesions, which on biopsy show noninflammatory
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Superficial thrombophlebitis
Mondors disease
Painful induration with erythema, often in a linear or branching configuration forming cords, is the classic presentation of
Postcardiotomy syndrome
Between 2 and 3 weeks after pericardiotomy, fever, pleuritis,
pericarditis, or arthritis may appear, together with petechiae
on the skin and palate. This syndrome may be confused with
infectious mononucleosis and bacterial endocarditis.
Fig. 35-15 Child abuse, purpura of the face from the sole of a shoe.
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35
In most cases of pigmented purpuric dermatosis, the etiology is unknown. Patients with stasis dermatitis and venous
insufficiency may develop lesions that bear a superficial clinical resemblance to Schambergs disease. Their lesions are more
diffuse and do not form well-circumscribed macules. Oral
medications can induce eruptions that closely resemble
DucasKapetanakis purpura. These include acetaminophen,
aspirin, glipizide, IFN-, and medroxyprogesterone injections.
Stopping the offending medication will lead to resolution of
the eruption. Pigmented purpuric contact dermatitis may simulate a PPE. Inciting allergens include nickel sulfate, fragrance
mix, and Disperse Blue dyes. Patch testing on the back may be
negative, but a positive response may be seen when the offending allergen is applied to a lesion. As with pigmenting drug
eruptions, pigmented purpuric contact dermatitis should be
suspected when the lesions are more widespread (sites other
than the legs) and especially if they have an eczematous
character.
Anecdotal reports of benefit from topical steroids make a
therapeutic trial for 46 weeks reasonable. Oral rutoside,
50mg twice a day, and ascorbic acid, 500mg twice a day, have
cleared a few patients. PUVA and narrow-band ultraviolet
(UV) B have demonstrated efficacy and should be considered
when the above modalities fail. Immunosuppressive therapy
with cyclosporine and methotrexate has also been effective,
but is usually not warranted in such a pauci-symptomatic
disorder. If immunosuppression is considered, CTCL (cutaneous T-cell lymphoma) must be excluded, and patch testing and
drug withdrawal should have been undertaken.
Abe M, et al: Transitory pigmented purpuric dermatoses in a young
Japanese female. J Dermatol 2008; 35:525.
Bell HK, et al: Localized morphoea preceded by a pigmented purpuric
dermatosis. Clin Exp Dermatol 2003; 28:369.
Engin B, et al: Patch test results in patients with progressive pigmented
purpuric dermatosis. J Eur Acad Dermatol Venereol 2009; 23:209.
Georgala S, et al: Persistent pigmented purpuric eruption associated
with mycosis fungoides: a case report and review of the literature. J
Eur Acad Dermatol Venereol 2001; 15:62.
Gupta G, et al: Capillaritis associated with interferon-alfa treatment of
chronic hepatitis C infection. J Am Acad Dermatol 2000; 43(5 Pt
2):937.
Hamada T, et al: A case of zosteriform pigmented purpuric dermatosis.
Arch Dermatol 2007; 143:1599.
Hoesly FJ, et al: Purpura annularis telangiectodes of Majocchi: case
report and review of the literature. Int J Dermatol 2009; 48:1129.
Komericki P, et al: Pigmented purpuric contact dermatitis from Disperse
Blue 106 and 124 dyes. J Am Acad Dermatol 2001; 45:456
Lin W-L, et al: Granulomatous variant of chronic pigmented purpuric
dermatoses: report of four new cases and an association with
hyperlipidaemia. Clin Exp Dermatol 2007; 32:513.
Magro CM, et al: Pigmented purpuric dermatosis. Am J Clin Pathol
2007; 128:218.
Rose RF, et al: Pigmented purpuric dermatosis as a delayed reaction to
medroxyprogesterone acetate. J Eur Acad Dermatol Venereol 2008;
22:1150.
Sardana K, et al: Pigmented purpuric dermatoses: an overview. Int J
Dermatol 2004; 43:482.
Ugajin T, et al: Mycosis fungoides presenting as pigmented purpuric
eruption. Eur J Dermatol 2005; 15:489.
VASCULITIS
Vasculitis is a clinicopathologic process characterized by
inflammation and necrosis of blood vessels. Since the clinical
morphology correlates with the size of the affected blood
vessel(s), these disorders are classified by the blood vessel(s)
affected. Diseases may involve vessels of overlapping size. In
general, small-vessel disease (affecting postcapillary venules)
causes urticarial lesions and palpable purpura; small-artery
disease manifests as subcutaneous nodules; medium-sized
arteries with necrosis of major organs, livedo, purpura, and
mononeuritis multiplex; and large-vessel disease with symptoms of claudication and necrosis.
Classification
Numerous classification schemes have been proposed, all of
which have limitations. It is important to remember that infectious and thrombotic conditions, which classically show
thrombosis of vessels histologically, may also at times show
true leukocytoclastic vasculitis. Hence, infectious, embolic,
and thrombotic causes of vessel damage must always be considered before unequivocally diagnosing a case as an inflammatory vasculitis. Leukocytoclastic vasculitis is also
commonly seen adjacent to suppurative folliculitis and at the
base of chronic ulcers. The discovery of the association of some
forms of small- and medium-vessel vasculitides with positive
ANCAs has made their diagnosis and classification much
easier (Box 35-1).
Carlson JA, Chen KR: Cutaneous vasculitis update: small vessel
neutrophilic vasculitis syndromes. Am J Dermatopathol 2006; 28:486.
Fiorentino DF: Cutaneous vasculitis. J Am Acad Dermatol 2003; 48:311.
Grzeszkiewicz TM, Fiorentino DF: Update on cutaneous vasculitis. Semin
Cutan Med Surg 2006; 25:221.
Sunderkotter C, Sindrilaru A: Clinical classification of vasculitis. Eur J
Dermatol 2006; 16:114.
Small-vessel vasculitis
Cutaneous small-vessel vasculitis (cutaneous
leukocytoclastic vasculitis)
The vast majority of cases of cutaneous leukocytoclastic vasculitis (LCV) follow an acute infection or exposure to a new
medication. Palpable purpura is the hallmark of this disease,
with lesions ranging from pinpoint to several centimeters in
diameter (Fig. 35-18). Annular, vesicular, bullous, or pustular
lesions may develop. Small ulcerations may develop, but
when ulceration is prominent, one must suspect either a vasculitis of larger vessels (small to medium arterioles) or the
presence of both a vasculitis and a hypercoagulable state.
Lesions of LCV predominate on the ankles and lower legs,
affecting mainly dependent areas or areas under local pressure. Edema, especially of the ankles, is usually noted. In the
hospitalized or bedridden patient, the buttocks and posterior
Small-vessel vasculitis
A.
B.
C.
D.
E.
F.
G.
H.
II. Medium-vessel
A. Polyarteritis nodosa
1. Benign cutaneous forms
2. Systemic form
Histology
There is angiocentric segmental inflammation of the postcapillary venule, with expansion of the vessel wall, fibrin deposition, and infiltration by neutrophils that show fragmentation
of their nuclei (karyorrhexis or leukocytoclasia). Endothelial
cell swelling is common, but endothelial necrosis suggests
more serious illness (including septic vasculitis, ANCAassociated vasculitis). Vascular thrombosis may be present.
The presence of tissue eosinophilia favors a medication as the
cause. Immunofluorescence and ultrastructural studies have
shown the presence of immunoglobulins, complement components, and fibrin deposits within postcapillary venule walls if
the biopsy is taken within the first 24h. Later, fibrin is prominent, but immunoglobulin deposits may have been destroyed.
An important exception is HenochSchnlein purpura, which
Pathogenesis
Cutaneous small-vessel vasculitis is felt to be caused by circulating immune complexes. These complexes lodge in vessel
walls and activate complement. Various inflammatory mediators are produced, contributing to endothelial injury. Cocaine
use may cause or exacerbate small-vessel vasculitis.
Etiology
Most cases of cutaneous LCV are post-infectious or druginduced. Drugs in virtually every class have been reported as
causing LCV, and the time from when the medication was
started to the onset of the eruption may be hours to years,
making any ingested agent a possible cause. A host of infectious agents, such as -hemolytic Streptococcus group A,
Mycoplasma, and rarely Mycobacterium tuberculosis may cause
palpable purpura. Patients with lymphoproliferative neoplasms, as well as solid tumors (lung, colon, genitourinary,
and breast cancer) may experience cutaneous small-vessel vasculitis at some time during the course of their disease. A recurrence of the LCV may mark the return of a treated malignancy.
Cutaneous LCV may be the initial manifestation of a medium
or mixed-vessel vasculitis.
Clinical evaluation
The clinical evaluation is critical in separating those cases of
benign cutaneous vasculitis (usually following an infection or
induced by a medication) from those cases associated with
more serious underlying disease or which have significant
systemic involvement. It may not be possible on initial physical examination to separate the more benign-behaving cases
from those associated with more serious disease. The history
823
35
Treatment
The initial treatment of most cases of leukocytoclastic vasculitis in patients who are clinically well and have a normal urin
alysis should be nonaggressive, since the majority of cases
are acute and self-limited, affect only the skin, and do not
threaten progressive deterioration of internal organs. Rest and
elevation of the legs is likely to be helpful. Analgesics and
avoidance of trauma and cold are prudent general measures.
An identified antigen or drug should, of course, be eliminated
and any identified infectious, connective tissue, or neoplastic
disease treated.
A variety of systemic treatments may be required for severe,
intractable, or recurrent disease, especially if significant organ
involvement is present. For disease limited to the skin, NSAIDs
can be considered for the arthralgias. Colchicine, 0.6mg 23
times a day, or dapsone, 50200mg/day, as trials of 23 weeks
each, may be useful for chronic vasculitis. Low doses of colchicine and dapsone may be combined, if either medication
alone is unsuccessful or effective doses of either drug cannot
be reached. Although one controlled trial suggested that colchicine was ineffective in LCV, even in that trial a portion of
the patients did respond and flared when the drug was
stopped. Oral antihistamines, by blocking the vasodilation
induced by histamine, may reduce immune complex trapping
and improve LCV. Systemic corticosteroids, in doses ranging
from 60 to 80mg/day, are recommended for patients with
serious systemic manifestations or necrotic lesions. Usually, a
brief course leads to resolution, and chronic treatment is rarely
required. In refractory patients immunosuppressive agents,
such as mycophenolate mofetil, 23g/day; methotrexate,
525mg/week; or azathioprine, 50200mg/day (23.5mg/
kg/day), may be considered. Azathioprine dosing is based on
thiopurine methyltransferase levels. In more difficult cases,
cyclophosphamide, monthly intravenous pulses of steroids or
cyclophosphamide, or cyclosporine, 35mg/kg/day, may be
effective. The tumor necrosis factor (TNF)-blockers, especially
infliximab and to a lesser degree etanercept, may be effective
in cutaneous small-vessel vasculitis. These agents may also
cause vasculitis. Rituximab has been effective in refractory
cases.
824
Small-vessel vasculitis
825
35
Urticarial vasculitis
A significant percentage of patients (reported as high as 510%,
but probably less) with fixed urticarial lesions will have vasculitis histologically. This is termed urticarial vasculitis (Fig.
35-21). This urticarial morphology is maintained throughout
the course of the illness. Microscopic hemorrhage into the
urticarial plaques may occur, resulting in a bruise-like appearance as the lesions fade. Determination of the serum complement levels (CH50, C3, C4, and anti-C1q precipitins) is critical
in the evaluation of urticarial vasculitis. Patients with normal
complement levels usually have a leukocytoclastic vasculitis,
which is idiopathic, limited to the skin, self-resolving, and best
considered a subset of cutaneous small-vessel vasculitis.
Hypocomplementemic urticarial vasculitis is a distinctive syndrome seen virtually always in women. Clinical features
include arthritis (50%), arthralgias, angioedema, eye symptoms, asthma and obstructive pulmonary disease (20%), and
gastrointestinal symptoms (20%). Glomerulonephritis may be
present. A rare subset of patients with hypocomplementemic
urticarial vasculitis has Jaccouds arthropathy and serious valvular heart disease.
Underlying diseases associated with all forms of urticarial
vasculitis include gammopathies (IgG and IgM gammopathy),
SLE, Sjgren syndrome, serum sickness, and viral infections,
especially hepatitis C. Patients with hypocomplementemic
urticarial vasculitis can have anti-C1q antibodies directed
against the collagen-like region of that molecule, a feature used
to define this disease. Patients with SLE may also have these
autoantibodies. Many patients with hypocomplementemic
urticarial vasculitis will have positive ANAs, and up to onequarter will have positive anti-dsDNA antibodies. The vast
majority (96%) will have a positive lupus band test. Over
time, more than 50% will meet the criteria for the diagnosis of
SLE. For this reason, some consider hypocomplementemic
urticarial vasculitis a form of SLE. Patients with HCV infection
may develop hypocomplementemic or normocomplementic
urticarial vasculitis without a detectable cryoglobulin.
Three clinical features distinguish the skin lesions of urticarial vasculitis from true urticaria:
1. The lesions are often painful, rather than pruritic.
2. The lesions last longer than 24h and are fixed, rather
than migrating.
826
Cryoglobulinemic vasculitis
About 15% of patients with a circulating cryoprecipitable
protein are symptomatic and have cryoglobulinemic vasculitis. They typically have mixed cryoglobulinemia. Mixed cryo
globulinemia follows a benign course in half of cases, but in
about one-third liver or renal failure occurs. Fifteen percent of
cases develop malignancy, usually B-cell lymphoma, and less
frequently hepatocellular or thyroid cancer. By far the most
common cause of cryoglobulinemic vasculitis is HCV infection, but autoimmune diseases and lymphoproliferative disorders can also be associated with cryoglobulinemic vasculitis.
Cryoglobulinemic vasculitis usually presents with macular or
palpable purpura, typically confined to the lower extremities.
Lesions may be limited or severe. Two-thirds of patients show
confluent areas of hemosiderosis of the feet and lower legs,
characteristic of prior episodes of purpura. While only 30% of
patients report an exacerbation with cold exposure, up to 50%
will have Raynaud phenomenon and cold-induced acrocyanosis of the ears. Other morphologies include ecchymoses, livedo
reticularis, urticaria, and ulcerations. Widespread systemic
vasculitis occurs in about 10% of patients. Neuropathy and
other neurologic complications occur in 40% of patients.
Arthralgias, xerostomia, and xerophthalmia are frequent complaints. Laboratory evaluation will reveal a cryoglobulin,
hypocomplementemia (90%), and a positive rheumatoid factor
(70%). ANCAs are rarely positive. A skin biopsy will show
LCV.
The treatment of cryoglobulinemic vasculitis is the treatment of the underlying disease if possible. In the case of HCV
infection, this usually is IFN- plus ribavirin. Cryoglobulinemic
vasculitis associated with HCV may also be flared by IFN
treatment. Colchicine, dapsone, IVIG, infliximab, and rituximab (an anti-CD20 monoclonal antibody) can be attempted. In
severe cases plasmapheresis may be beneficial.
Batisse D, et al: Sustained exacerbation of cryoglobulinaemia-related
vasculitis following treatment of hepatitis C with peginterferon alfa. Eur
J Gastroenterol Hepatol 2004; 16:701.
Cacoub P, et al: Anti-CD20 monoclonal antibody (rituximab) treatment
for cryoglobulinemic vasculitis: where do we stand? Ann Rheum Dis
2008; 67:283.
Chandesris MO, et al: Infliximab in the treatment of refractory vasculitis
secondary to hepatitis C-associated mixed cryoglobulinaemia.
Rheumatology 2004; 43:532.
De Blasi T, et al: Cryoglobulinemia-related vasculitis during effective
anti-HCV treatment with PEG-interferon alfa-2b. Infection 2008; 36:285.
Enomoto M, et al: Entecavir to treat hepatitis B-associated
cryoglobulinemic vasculitis. Ann Intern Med 2008; 149:912.
Farri C, et al: Mixed cryoglobulinemia: demographic, clinical, and
serologic features and survival in 231 patients. Semin Arthritis Rheum
2004; 33:355.
Kawakami T, et al: Remission of hepatitis B virus-related
cryoglobulinemic vasculitis with entecavir. Ann Intern Med 2008;
149:911.
Nemni R, et al: Peripheral neuropathy in hepatitis C virus infections with
and without cryoglobulinaemia. J Neurol Neurosurg Psychiatry 2003;
74:1267.
Roccatello D, et al: Long-term effects of anti-CD20 monoclonal antibody
treatment of cryoglobulinaemic glomerulonephritis. Nephrol Dial
Transplant 2004; 19:3054.
Small-vessel vasculitis
827
35
828
Granuloma faciale
Characterized by brownish-red, infiltrated papules, plaques
(Fig. 35-23), and nodules, granuloma faciale involves the facial
areas, particularly the nose. Healthy, middle-aged (mean
53 years) white men (male to female ratio, 5:1) are most typically affected. Childhood cases have been reported. Extrafacial
disease occurs in up to 20% of cases, usually affecting the
upper trunk and extremities.
The pathology of granuloma faciale is similar to that of EED,
with focal leukocytoclastic vasculitis, diffuse dermal neutrophilia with leukocytoclasia, tissue eosinophilia, and perivascular fibrosis.
A variety of treatment options are available. Intralesional
corticosteroids are the recommended first approach.
Cryotherapy in combination with intralesional corticosteroids
has been shown to be very effective. Topical corticosteroids
may also be useful. Although controlled clinical trials are
lacking, dapsone, colchicine, or antimalarials could be considered if the patient remains unresponsive. Laser treatment with
pulsed dye and argon lasers has been effective in multiple
cases, making it a reasonable consideration as first-line
treatment.
Polyarteritis nodosa
Polyarteritis nodosa
Polyarteritis nodosa (PAN) is characterized by necrotizing
vasculitis affecting primarily the small to medium-sized arteries. There are two major forms, the benign cutaneous and the
systemic, although even long-standing benign cutaneous PAN
can evolve into systemic disease. There are ten diagnostic criteria for systemic PAN:
1. livedo racemosa
2. polymorphonuclear arteritis
3. leg pain/myopathy/weakness
4. mono-/polyneuropathy
5. positive hepatitis B virus (HBV) serology
6. weight loss >4kg
7. testicular pain/tenderness
8. diastolic blood pressure >90mmHg
9. elevated BUN/creatinine
10. arteriographic abnormality.
Separating systemic PAN from microscopic polyangiitis
(MPA) can be difficult, and the skin manifestations clinically
and histologically are of no benefit in this regard.
PAN is 24 times more common in men than in women and
the mean age of presentation is 4550 years. A cutaneous vasculitis identical to PAN has been seen in intravenous drug
abusers (see below) and in association with SLE, inflammatory
bowel disease, hairy cell leukemia, familial Mediterranean
fever, and Cogan syndrome (nonsyphilitic interstitial keratitis
and vestibulo-auditory symptoms). Infectious associations
include hepatitis B, hepatitis C, and antecedent streptococcal
infections. Vascular-based tuberculids (erythema induratum,
nodular tuberculid) may have histology identical to PAN. The
proportion of PAN cases associated with HBV is currently
about 57% of cases overall, but this percentage is falling
with HBV immunization. The identification of associated
hepatitis virus infection has therapeutic and prognostic
implications.
The skin is involved in up to 50% of patients with the systemic form of PAN, with wide-ranging findings. The most
striking and diagnostic lesions (15% of patients) are 510mm
subcutaneous nodules occurring singly or in groups, distributed along the course of the blood vessels, above which the
skin is normal or slightly erythematous (macular arteritis).
These nodules are often painful and may pulsate and, in time,
ulcerate (Fig. 35-24). Common sites are the lower extremities,
especially below the knee. Ecchymoses and peripheral gangrene of the fingers and toes may also be present. Livedo
reticularis in combination with subcutaneous nodules strongly
suggests the diagnosis of PAN. Palpable purpura with histologic features of cutaneous LCV may be seen in PAN in 20%
of patients. Urticaria is present in 6% of cases of PAN. HBVassociated PAN is associated with cutaneous findings in only
30% of cases.
35
Treatment
Untreated classic PAN can be fatal, death usually being due
to renal failure or cardiovascular or gastrointestinal complications. Death generally occurs early in the course of the disease.
Patients with HBV- or HCV-associated PAN should be given
IFN and other antiviral treatments as their initial therapy.
For PAN not associated with HBV or HCV, treatment with
corticosteroids and cytotoxic agents has increased the 5-year
survival rate to more than 75%. Corticosteroids in the range of
1mg/kg/day are given initially. Once the disease remits, the
dose should be reduced. After an average of 36 months, with
the patient in remission, the steroids are slowly tapered to
discontinuation.
Cyclophosphamide is given with steroids or sometimes as a
single agent. Initially, 2mg/kg/day as a single dose is recommended. Twice this amount may be required for severely ill
patients. The oral dose is then adjusted to maintain the white
blood cell count between 3000 and 3500/mm3 and the neutrophil count above 1500 cells/mm3. When the disease has
been quiescent for at least 1 year, the cyclophosphamide may
be tapered and stopped. On average, 1824 months of therapy
are required. Pulsed intravenous cyclophosphamide is associated with a lower incidence of toxicity, especially the longterm risk of malignancy. Plasma exchange may be used for
acute crises or treatment failures with corticosteroids and
cyclophosphamide. Ulcerations in PAN can be very painful
due to the associated neuropathy. They should be managed
like nonhealing leg ulcers.
Microscopic polyangiitis
With the advent of ANCA serologies and clarification of the
features of microscopic polyangiitis (MPA), this diagnosis is
becoming increasingly more common. There is a northsouth
gradient in incidence, with southern European countries
having 34 times as many cases. Most patients with MPA have
systemic symptoms, such as fever, weight loss, myalgias, and
arthralgias, which can present with an acute flu-like illness or
can evolve for months to years before a more explosive phase
of their disease. These cases have been termed slowly progressive MPA. Most patients with MPA will have or develop
segmental necrotizing and crescentic glomerulonephritis
(8090%), with pulmonary involvement in 2565% of cases.
Pulmonary capillaritis, which can be complicated by hemorrhage, occurs in 1229% of MPA patients. The skin is involved
in 44% of cases of MPA. Purpura as papules, macules, or
ecchymoses (retiform purpura) is present in 26% of cases and
cutaneous ulceration may result. Urticarial lesions occur in 1%
of cases. Patients with MPA may present with skin lesions as
their initial clinical findings. Livedo is seen in two-thirds of
such patients. Skin biopsies of macules, papules, petechiae, or
sites adjacent to ecchymoses may reveal a necrotizing LCV in
the reticular dermis. Palisading and neutrophilic granulomatous dermatitis was found on a skin biopsy of the elbow of an
MPA patient.
Vasculitic neuropathy is common (58%) and eye disease
may occur. Eosinophilia and asthma are not seen. ANCAs are
positive in 70% of cases, p-ANCA more frequently than
c-ANCA. MPA is separated from PAN by the presence of
glomerulonephritis, pulmonary symptoms, and the absence of
hypertension and microaneurysms. ANCAs are less frequently
positive in PAN.
MPA is managed like other forms of ANCA-SVV, with systemic corticosteroids and often cytotoxic agents from the
disease onset. If the disease is localized, sulfamethoxazole/
trimethoprim with corticosteroids may be considered. In generalized but non-organ-threatening disease, methotrexate may
be added to the corticosteroids. Cyclophosphamide is usually
used in the early induction phase of treatment (612 months)
as monthly pulses (as opposed to daily treatment). Lowertoxicity immunosuppressives (methotrexate, azathioprine,
mycophenolate mofetil) may be used as maintenance or in
milder cases. IVIG and anti-TNF agents (infliximab) may be
considered in refractory cases. Relapses are frequent; the
5-year survival is about 75% and 7-year survival is 62%.
Bosch X, et al: Treatment of antineutrophil cytoplasmic antibodyassociated vasculitis: a systematic review. JAMA 2007; 298:655.
Greenfield JR, et al: ANCA-positive vasculitis induced by thioridazine:
confirmed by rechallenge. Br J Dermatol 2002; 147:1265.
Guilleven L, et al: Microscopic polyangiitis: clinical and laboratory
findings in eighty-five patients. Arthritis Rheum 1999; 42:421.
Irvine AD, et al: Microscopic polyangiitis. Arch Dermatol 1997; 133:474.
Jacobs-Kosmin D, et al: Pantoprazole and perinuclear antineutrophil
cytoplasmic antibody-associated vasculitis. J Rheumatol 2006; 33:629.
Kawakami T, et al: Cutaneous manifestations in patients with
microscopic polyangiitis: two case reports and a minireview. Acta
Derm Venereol 2006; 86:144.
Kawakami T, et al: Clinical and histopathologic features of 8 patients
with microscopic polyangiitis including two with a slowly progressive
clinical course. J Am Acad Dermatol 2007; 57:840.
Kluger N, et al: Comparison of cutaneous manifestations in systemic
polyarteritis nodosa and microscopic polyangiitis. Br J Dermatol 2008;
159:615.
Maejima H, et al: Microscopic polyangiitis presenting urticarial erythema
and HenochSchnlein purpura: two case reports. J Dermatol 2004;
31:655.
Niiyama S, et al: Dermatological manifestations associated with
microscopic polyangiitis. Rheumatol Int 2008; 28:593.
Penas PF, et al: Microscopic polyangiitis: a systemic vasculitis with a
positive p-ANCA. Br J Dermatol 1996; 134:542.
Watz H, et al: Bronchioloalveolar carcinoma of the lung associated with
a highly positive pANCA-titer and clinical signs of microscopic
polyangiitis. Pneumologie 2004; 58:493.
Wegener granulomatosis
Wegener granulomatosis is a syndrome consisting of necrotizing granulomas of the upper and lower respiratory tract, generalized necrotizing angiitis affecting the medium-sized blood
vessels, and focal necrotizing glomerulitis. By far the most
common initial manifestation, present in 90% of patients, is the
occurrence of rhinorrhea, severe sinusitis, and nasal mucosal
ulcerations, with one or several nodules in the nose, larynx,
trachea, or bronchi. Fever, weight loss, and malaise occur in
these patients, who are usually 4050 years of age and more
often male than female (1.3:1). Obstruction in the nose may
also block the sinuses. The nodules in the nose frequently
ulcerate and bleed. The parenchymal involvement of the lungs
produces cough, dyspnea, and chest pain. Granulomas may
occur in the ear and mouth, where the alveolar ridge becomes
necrotic, and ulceration of the tongue and perforated ulcers of
the palate develop. The combination of nasal and palatal
involvement may lead to saddle-nose deformity. The strawberry gums appearance of hypertrophic gingivitis is characteristic, and biopsy from these lesions may be diagnostic (Fig.
35-25).
Cutaneous findings occur in 45% of patients. Nodules may
appear in crops, especially along the extensor surfaces of the
extremities. The firm, slightly tender, flesh-colored or violaceous nodules may later ulcerate. These may be mistaken
for ulcerating rheumatoid nodules. The necrotizing angiitis
of the skin may present as a palpable purpura, petechial or
831
35
ChurgStrauss syndrome
ChurgStrauss syndrome (CSS) occurs in three phases. The
initial phase, often lasting many years, consists of allergic
rhinitis, nasal polyps, and asthma. The average age of onset of
the asthma is 35 years in CSS (as opposed to allergic asthma,
which often presents in childhood). After 2 to 12 years, a
debilitated asthmatic begins to experience attacks of fever and
eosinophilia (2090%), with pneumonia and gastroenteritis
(second phase). After a few more months or years, but on
average 3 years after the initial symptoms, a diffuse angiitis
involves the lungs, heart, liver, spleen, kidneys, intestines, and
pancreas. Mononeuritis multiplex is common. Triggers of this
third phase have included vaccination, desensitization, leukotriene inhibitors, azithromycin, inhaled fluticasone, or rapid
discontinuation of corticosteroids. Renal involvement is less
common than in Wegener granulomatosis or microscopic
polyangiitis. A fatal outcome is likely in most untreated
patients, with congestive heart failure resulting from granulomatous inflammation of the myocardium being the most frequent cause of death. Increased rates of arterial and venous
thrombosis are seen in CSS, perhaps related to the dense infiltrates of eosinophils.
Cutaneous lesions are present in two-thirds of patients.
Palpable purpura is seen in nearly 50% of patients. Subcutaneous
nodules on the extensor surfaces of the extremities and on the
scalp are seen in 30%. Firm, nontender papules may be present
on the fingertips. These may resemble lesions seen with septic
emboli or atrial myxoma, but show vasculitis on biopsy.
Urticaria, solar urticaria, and livedo reticularis can occur in
CSS. Plaques with the histologic features of eosinophilic cellulitis (Well syndrome) can be seen.
Laboratory studies are significant for a peripheral eosino
philia, which correlates with disease severity. ANCAs are
frequently positive (5570%), most commonly for antimyeloperoxidase (p-ANCA) and less frequently for anti-PR3
(c-ANCA), and tend to correlate with disease severity.
Histologically, a small-vessel vasculitis is present that
involves not only superficial venules, but also larger and
deeper vessels. The tissue is often diffusely infiltrated with
eosinophils, and granulomas may be present. Palisaded granulomas differ from those in Wegener granulomatosis in that
Cocaine-associated vasculitis
There are numerous reports of various forms of cutaneous
vasculitis associated with the intravenous or intranasal use of
cocaine. Skin lesions have included typical LCV, as well as
larger-vessel vasculitis resembling PAN. Localized nasal
lesions with vasculitis resembling Wegener granulomatosis
have been observed in patients using inhaled cocaine. This has
been termed cocaine-induced pseudovasculitis or cocaineinduced midline destructive lesions to try to distinguish it
from true Wegener granulomatosis. In addition, patients using
cocaine may develop more widespread cutaneous and sys-
temic vasculitis affecting kidneys, lungs, and testes. The cutaneous lesions resemble LCV, but ecchymotic lesions and skin
necrosis were more prominent in these patients than in the
typical LCV patient. Purpura and necrosis of the earlobe were
especially common and characteristic. Agranulocytosis, not a
typical feature of ANCA-positive vasculitis, was also found.
These patients have an elevated c-ANCA (PR3-ANCA), similar
to patients with true Wegener granulomatosis. However, the
c-ANCA in patients with cocaine-induced vasculitis reacts
with human neutrophil elastase (HNE-ANCA). Patients with
Wegener granulomatosis and microscopic polyangiitis are
negative for HNE-ANCA.
Street cocaine is commonly contaminated with pharmaceutical agents. Surprisingly, levamisole has been found in the
cocaine seized by law enforcement in up to 30% of cases in the
US and 100% in Italy. Levamisole therapy is associated with
ecchymotic purpura and necrosis, with a predilection for the
ears. It also causes agranulocytosis and c-ANCA positivity. It
is therefore unclear whether the vasculitic lesions seen in recreational cocaine users are due to the cocaine or to the levamisole excipient or both. In every patient presenting with a
cutaneous or systemic vasculitis, a detailed history of recreational drug use must be obtained, and toxicology screening
should be considered in any patient with vasculitis having the
features outlined above, especially agranulocytosis or cutaneous necrosis, or failure to respond to appropriate therapy. In
these patients, stopping of the drug may lead to a gradual
improvement of the vasculitis, although initial immunosuppressive therapy may be required. Treatment to eradicate
nasal S. aureus should be considered if there are prominent
nasal findings.
35
Cutaneous Vascular Diseases
834
Takayasu arteritis
Known also as aortic arch syndrome and pulseless disease,
Takayasu arteritis is a thrombo-obliterative process of the
great vessels stemming from the aortic arch, occurring generally in young women (female to male ratio, 9:1) in the second
or third decade of life. It is more common in Japan, Southeast
Asia, India, and South America. Radial and carotid pulses are
typically obliterated. Most skin changes are due to the disturbed circulation. There may be loss of hair and atrophy
of the skin and its appendages, with underlying muscle
atrophy. Occasional patients with cutaneous necrotizing or
granulomatous vasculitis of small vessels have been reported.
Erythematous nodules with or without livedo, simulating erythema nodosum or erythema induratum, may rarely occur.
Pyoderma gangrenosum-like ulcerations are well described in
Japan. Pyoderma gangrenosum lesions precede the diagnosis
of the arteritis by an average of 3 years. These lesions are more
commonly generalized and in three-quarters of cases occur on
the upper extremities.
Treatment of Takayasu arteritis with prednisone, 1mg/kg/
day tapered in 812 weeks to 20mg/day or less, is recommended. Methotrexate may be used for its steroid-sparing
effects. With active medical and surgical intervention, the
aggressive course of this disease can be modified. The
pyoderma gangrenosum-like lesions are also treated with
systemic steroids, but azathioprine, cyclophosphamide, mycophenolate mofetil, cyclosporine, and tacrolimus have also been
effective.
Ohta Y, et al: Inflammatory diseases associated with Takayasus
arteritis. Angiology 2003; 54:339.
Pascual-Lopez M, et al: Takayasus disease with cutaneous involvement.
Dermatology 2004; 208:10.
Skaria AM, et al: Takayasu arteritis and cutaneous necrotizing vasculitis.
Dermatology 2000; 200:139.
Ujiie H, et al: Pyoderma gangrenosum associated with Takayasus
arteritis. Clin Exp Dermatol 2004; 29:357.
Thromboangiitis obliterans
mucosa. Palms, soles, and face are spared, but the penis may
be involved. Over days to weeks, the lesions become umbilicated, with a central depression, which enlarges. The center
becomes distinctively porcelain-white, while the periphery
becomes livid red and telangiectatic. Central atrophy occurs
eventually. The eruption proceeds by crops in which only a
few new lesions appear at any one time. One patient was
reported to develop panniculitis. Lesions characteristic of
Degos disease may be seen in patients with lupus erythematosus, dermatomyositis, scleroderma, and Wegener
granulomatosis.
Systemically, ischemic infarcts involve the intestines, producing acute abdominal symptoms, which include epigastric
pain, fever, and hematemesis. Death is usually due to fulminating peritonitis caused by multiple perforations of the intestine. Less commonly, death occurs from cerebral infarctions.
Wedge-shaped necroses brought on by the occlusion of arterioles and small arteries account for the clinical lesions.
Proliferation of the intima and thrombosis constitute the
typical histologic picture. The thrombosing process is usually
pauci-inflammatory, although neutrophils or lymphocytes
may be found associated with the thrombosis. The overlying
dermis, which is infarcted, contains abundant mucin, especially early in the lesions evolution. Adnexae are typically
necrotic and the depressed central portion may be noted
histologically.
The etiology of this disease is unknown, but based on the
infarctive nature of the lesions and the universal presence of
arteriolar thrombosis, a hyperthrombotic state or endothelial
abnormality is suggested. While most patients have not had
abnormalities identified, abnormal platelet aggregation and
abnormal coagulation have been identified in some cases.
Antiphospholipid antibodies and anticardiolipin antibodies
have been present in some patients, and a Leiden factor V
mutation in one patient. Parvovirus B19 infection was associated with a fatal case in an adult.
Administration of immunosuppressives has not been beneficial. IVIG has been of therapeutic benefit in one case, but failed
in another. Ingestion of low-dose acetylsalicylic acid alone or
in combination with dipyridamole (Persantine) has been effective in some patients. Heparin, as described by Degos, has
been helpful, and should be considered if antiplatelet therapy
is ineffective. Nicotine patches, 5mg/day, were effective in
one case. In severe crises, fibrinolytic therapy should be considered. The prognosis is guarded in patients with systemic
involvement.
835
Arteriosclerosis obliterans
35
836
Pathogenesis
A viral or infectious pathogenesis is attractive for the following reasons:
1. Cases were rare before 1950.
2. KD affects children older than 3 months but younger
than 8 years.
3. Seasonal peaks occur in the winter and spring.
4. Focal epidemics have been reported.
5. Oligoclonal IgA immune responses are found, suggesting
a respiratory portal of entry of an infectious agent.
There are increased superantigens in the stool of children
with KD. A KD-like illness has been described with group
A meningococcal septicemia. An infectious pathogenesis,
therefore, remains the most plausible etiologic hypothesis.
It has long been suspected that there is a genetic basis for
KD. The disease is 1020 times more common in persons from
Northeast Asia (Japan and Korea), where rates of up to 1 per
150 children are reported. When these Asians move to the US,
they still have this high rate of increased susceptibility. The
risk of a sibling developing KD is increased tenfold. Children
of parents who had KD in childhood have a twofold increased
risk of developing KD. A recent genome-wide search of almost
1000KD cases and family members found strong linkage to
five genes, three of which form a single functional network.
The central gene of this network is CAMK2D, which encodes
a serine/threonine kinase expressed in cardiomyocytes and
vascular endothelial cells. These genes are already known to
be involved in cardiac and inflammatory pathways. The transcripts of these genes were also markedly suppressed during
KD. The previously reported genetic associations for KD were
not found in this study, including the ITPKC gene mutation.
Coronary arterial disease occurs after day 10 of the illness
(subacute phase), in combination with thrombocythemia (up
to 1 million). This combination of an altered endovascular
surface and too many platelets, plus abnormal blood flow in
837
35
Treatment
IVIG is the cornerstone of therapy, given in a single dose of
2g/kg infused over 1012h. Response to treatment is best if
given during the first 56 days of the illness; however, children
with persistent fever beyond this period may benefit from later
treatment. Aspirin is used to reduce inflammation and platelet
aggregation. The dose is 80100mg/kg/day in four divided
doses. Once the child has been afebrile for 37 days, the aspirin
dose is decreased to a single daily dose of 35mg/kg. If the
child remains febrile, a second 2g/kg dose of IVIG should be
given. A single dose of infliximab, 5mg/kg, has been reported
to be effective in refractory cases, but response, as with other
treatments, is not universal. If there is no response to the
second IVIG dose, systemic steroid therapy is commonly
given. Angioplasty, thrombolytic therapy, or coronary artery
bypass surgery may be required for patients with coronary
disease.
Ahn SY, et al: Treatment of intravenous immunoglobulin-resistant
Kawasaki disease with methotrexate. Scand J Rheumatol 2005;
34:136.
Ayusawa M, et al: Revision of diagnostic guidelines from Kawasaki
disease (the 5th revised edition). Pediatr Int 2005; 47:232.
Burgner D, et al: A genome-wide association study identifies novel and
functionally related susceptibility loci for Kawasaki disease. PLoS
Genet 2009; 5:e1000319.
Burns JC, Glod MP: Kawasaki syndrome. Lancet 2004; 364:533.
Burns JC, et al: Infliximab treatment for refractory Kawasaki syndrome. J
Pediatr 2005; 146:662.
Fretzayas A, et al: Meningococcal group A sepsis associated with rare
manifestations and complicated by Kawasaki-like disease. Pediatr
Emerg Care 2009; 25:190.
Garty B, et al: Guttate psoriasis following Kawasaki disease. Pediatr
Dermatol 2001; 18:507.
Harnden A, et al: Kawasaki disease. BMJ 2009; 338:1133.
Larralde M, et al: Kawasaki disease with facial nerve paralysis. Pediatr
Dermatol 2003; 20:511.
Miura M, et al: Coronary risk factors in Kawasaki disease treated with
additional gammaglobulin. Arch Dis Child 2004; 89:776.
Muta H, et al: Early intravenous gamma-globulin treatment for Kawasaki
disease: the nationwide surveys in Japan. J Pediatr 2004; 144:496.
Pannaraj PS, et al: Failure to diagnose Kawasaki disease at the
extremes of the pediatric age range. Pediatr Infect Dis J 2004; 23:789.
Thapa R, et al: Neonatal Kawasaki disease with multiple coronary
aneurysms and thrombocytopenia. Pediatr Dermatol 2007; 24:662.
Yamauchi H, et al: Optimal time of surgical treatment for Kawasaki
coronary artery disease. J Nippon Med Sch 2004; 71:279.
Yoon SY, et al: Plaque type psoriasiform eruption following Kawasaki
disease. Pediatr Dermatol 2007; 24:336.
Telangiectasia
Telangiectasia are fine linear vessels coursing on the surface
of the skin; the name given to them collectively is telangiectasia. Telangiectasia may occur in normal skin at any age, in both
sexes, and anywhere on the skin and mucous membranes. Fine
telangiectases may be seen on the alae nasi of most adults.
They are prominent in areas of chronic actinic damage. In
addition, persons long exposed to wind, cold, or heat are
subject to telangiectasia. Calcium channel-blockers may lead
to telangiectatic lesions in a generalized or photodistribution
and contribute to the appearance of photoaging. Telangiectasias
may also be found on the legs as a result of heredity, varicosities, pregnancy, and birth control pill use.
Telangiectases can be found in conditions such as radio
dermatitis, xeroderma pigmentosum, lupus erythematosus,
scleroderma and the CREST syndrome, rosacea, pregnancy,
838
cirrhosis of the liver, AIDS, poikiloderma, basal cell carcinoma, necrobiosis lipoidica diabeticorum, lichen sclerosus et
atrophicus, sarcoid, lupus vulgaris, keloid, adenoma sebaceum,
Kaposiform hemangioendothelioma, angioma serpiginosum,
angiokeratoma corporis diffusum, hereditary benign telangiectasia, Cockayne syndrome, ataxia-telangiectasia, and
Bloom syndrome.
Altered capillary patterns on the finger nailfolds (cuticular
telangiectases) are indicative of collagen vascular disease, such
as lupus erythematosus, scleroderma, or dermatomyositis.
They may infrequently be present in rheumatoid arthritis.
These disorders are reviewed in Chapter 8.
Beaubien ER, et al: Kaposiform hemangioendothelioma. J Am Acad
Dermatol 1998; 38:799.
Cooper SM, Wojnaraowska F: Photo-damage in Northern European renal
transplant recipients is associated with the use of calcium channel
blockers. Clin Exp Dermatol 2003; 28:588.
Grabczynska SA, Cowley N: Amlodipine-induced photosensitivity
presenting as telangiectasia. Br J Dermatol 2000; 142:1255.
Huh J, et al: Localized facial telangiectasias following frostbite injury.
Cutis 1996; 57:97.
Ioulios P, et al: The spectrum of cutaneous reactions associated with
calcium antagonists: a review of the literature and the possible
etiopathogenic mechanisms. Dermatol Online J 2003; 9:6.
Kanekura T, et al: Lichen sclerosus et atrophicus with prominent
telangiectasia. J Dermatol 1994; 21:447.
Silvestre JF, et al: Photodistributed felodipine-induced facial
telangiectasia. J Am Acad Dermatol 2001; 45:323.
35
VEGF with thalidomide (or more effectively with lenalidomide) can reduce gastrointestinal bleeding and transfusion
dependence. Bevacizumab, a monoclonal inhibitor of VEGF,
has dramatically improved some severely ill HHT patients,
reducing the size and flow of their hepatic AVMs, reversing
heart and liver failure, and reducing transfusion
requirement.
Abdalla SA, et al: Visceral manifestations in hereditary haemorrhagic
telangiectasia type 2. J Med Genet 2003; 40:494.
Al-Saleh S, et al: Screening for pulmonary and cerebral arteriovenous
malformations in children with hereditary haemorrhagic telangiectasia.
Eur Respir J 2009; 34:875.
Bose P, et al: Bevacizumab in hereditary hemorrhagic telangiectasia. N
Engl J Med 2009; 360:2143.
Bowcock SJ, Patrick HE: Lenalidomide to control gastrointestinal
bleeding in hereditary haemorrhagic telangiectasia: potential
implications for angiodysplasias? Br J Haematol 2009; 146:220.
Faughnan ME, et al: International Guidelines for the Diagnosis and
Management of Hereditary Hemorrhagic Telangiectasia. J Med Genet
2009 Jun 29 (Epub ahead of print).
Fernandez-Fernandez FJ: Hereditary haemorrhagic telangiectasia: from
symptomatic management to pathogenesis based treatment. Eur J
Hum Genet 2009 Nov 4 (Epub ahead of print).
Flieger D, et al: Dramatic improvement in hereditary hemorrhagic
telangiectasia after treatment with the vascular endothelial growth
factor (VEGF) antagonist bevacizumab. Ann Hematol 2006; 85:631.
Fuchizaki U, et al: Hereditary haemorrhagic telangiectasia (Rendu
OslerWeber disease). Lancet 2003; 362:1490.
Gallione CJ, et al: A combined syndrome of juvenile polyposis and
hereditary haemorrhagic telangiectasia associated with mutations in
MADH4 (SMAD4). Lancet 2004; 363:852.
Garcia-Tsao G, et al: Liver disease in patients with hereditary
hemorrhagic telangiectasia. N Engl J Med 2000; 343:931.
Goussous T, et al: Hereditary hemorrhagic telangiectasia presenting as
high output cardiac failure during pregnancy. Cardiol Res Pract 2009;
2009:437237.
Haneen S, et al: Mutation analysis of Endoglin and Activin receptorlike kinase genes in German patients with hereditary hemorrhagic
telangiectasia and the value of rapid genotyping using an allelespecific PCR-technique. BMC Med Genet 2009; 10:53.
Kanna B, Das B: Hemorrhagic pericardial effusion causing pericardial
tamponade in hereditary hemorrhagic telangiectasia. Am J Med Sci
2004; 327:149.
Khalid SK, et al: Worsening of nose bleeding heralds high cardiac
output state in hereditary hemorrhagic telangiectasia. Am J Med 2009;
122:779.e1.
Klepfish A, et al: Intranasal tranexamic acid treatment for severe
epistaxis in hereditary hemorrhagic telangiectasia. Arch Intern Med
2001; 161:767.
Lee JB, et al: The diagnostic quandary of hereditary haemorrhagic
telangiectasia vs. CREST syndrome. Br J Dermatol 2001; 145:646.
Mager JJ, Westermann CJJ: Value of capillary microscopy in the
diagnosis of hereditary hemorrhagic telangiectasia. Arch Dermatol
2000; 136:732.
Mei-Zahav M, et al: Symptomatic children with hereditary hemorrhagic
telangiectasia: a pediatric center experience. Arch Pediatr Adolesc
Med 2006; 160:596.
Mitchell A, et al: Bevacizumab reverses need for liver transplantation in
hereditary hemorrhagic telangiectasia. Liver Transpl 2008; 14:210.
Leg ulcers
Leg ulcers are a common medical condition, affecting 35% of
the population over the age of 65. The cause of chronic leg
ulceration is venous insufficiency alone in 4560% of cases,
arterial insufficiency in 1020%, diabetes mellitus in 1525%,
or combinations in 1015%. Smoking and obesity increase the
risk for ulcer development and persistence, independent of the
underlying cause. Defining the cause of the leg ulceration is
important in treating the leg ulcer.
The wound healing response is complex, involving intricate
interactions between different cell types, structural proteins,
840
growth factors, and proteinases. Normal wound repair consists of three phasesinflammation, proliferation, and
remodelingthat occur in a predictable sequence.
841
35
Neuropathic ulcers
Foot ulcers in diabetics are usually related to sensory neuropathy. Offloading the ulcer is the primary principle of manage842
will separate the two entities if the diagnosis cannot be confirmed on a clinical basis.
Types
Lymphedema is classified by clinical type (Box 35-2). Primary
types include congenital, and early- and late-onset types.
Other primary types of lymphedema are associated with characteristic features or syndromes. Some cutaneous disorders
are associated with or are a complication of primary lymphedema. Secondary lymphedema can occur from numerous
causes, including neoplasia and its treatment, infections, and
physical factors.
Lymphedema
LYMPHEDEMA
Lymphedema praecox
Lymphedema praecox develops in females between the ages
of 9 and 25. Swelling appears around the ankle and then
extends upward to involve the entire leg. With the passage of
time, the leg becomes painful, with a dull, heavy sensation.
Once this stage has been reached, the swollen limb remains
swollen, as fibrosis has occurred. Primary lymphedema is
caused by a defect in the lymphatic system. Lymphangiography
demonstrates hypoplastic lymphatics in 87%, aplasia in
approximately 5%, and hyperplasia with varicose dilation of
the lymphatic vessels in 8%.
Yellow nails
Hemangiomas
Xanthomatosis and chylous lymphedema
Congenital absence of nails
Secondary lymphedema
Postmastectomy lymphedema
Melphalan isolated limb perfusion
Malignant occlusion with obstruction
Extrinsic pressure
Factitial lymphedema
Postradiation therapy
Following recurrent lymphangitis/cellulitis
Lymphedema of upper limb in recurrent eczema
Granulomatous disease
Rosaceous lymphedema
Primary amyloidosis
Complications of lymphedema
Cellulitis of lymphedema
Elephantiasis nostra verrucosa
Ulceration
Lymphangiosarcoma
843
35
Lymphedemadistichiasis syndrome
The association of distichiasis (double row of eyelashes) and
late-onset lymphedema is a form of hereditary lymphedema
called lymphedema-distichiasis syndrome, or Meige syndrome. It is an autosomal-dominant syndrome with the
appearance of bilateral lymphedema, beginning between the
ages of 8 and 10 in affected boys, and 13 and 30 in affected
girls. Lymphatic vessels are increased (not hypoplastic or
absent, as in other forms of congenital lymphedema) in the
affected legs. Associated findings are varicose veins in 50% by
age 64; congenital ptosis (31%); and congenital heart disease
(6.8%), cleft palate (4%), scoliosis, and renal abnormalities.
There may be phenotypic heterogeneity in this syndrome,
as different types of mutation may lead to slightly different
phenotypes, especially with regard to the ancillary features
associated with the syndrome. This syndrome is due to a
mutation in the FOXC2 transcription factor. This factor is
expressed in developing eyelids, lymphatics, lymphatic valves,
and other tissues with abnormalities in this syndrome.
Emberger syndrome
Emberger syndrome is primary lymphedema associated with
myelodysplasia. This genetic syndrome presents with lymphedema of one or both lower limbs and often the genitalia
between infancy and puberty. Myelodysplastic syndrome
and/or acute myeloid leukemia developing in adolescence or
childhood are preceded by pancytopenia with a high incidence of monosomy 7 in the bone marrow. Associated features
include mild skeletal abnormalities, deafness, and multiple
warts.
Hypotrichosis-telangiectasia-lymphedema syndrome
Lymphedema appears in childhood. Vascular dilations and
telangiectasias appear on the palms and soles. Both autosomal
recessive and autosomal dominant patterns of inheritance
occur, but both forms are due to mutations in the SOX18 gene.
Secondary lymphedema
In some malignant diseases, involvement of the axillary or
pelvic lymph nodes will produce blockage and lymphedema.
Malignant disease of the breast, uterus, prostate, skin, bones,
or other tissues may cause such changes. Hodgkin disease and,
especially, Kaposi sarcoma (KS) may be accompanied by significant lymphedema well beyond the amount expected from
the degree of skin involvement by the KS. Such patients
require chemotherapy, as this is the hallmark of lymphatic
involvement by the KS. Chronic lymphedema is frequently
seen after mastectomy and the removal of the axillary nodes;
it may occur after varying lengths of time.
844
Postmastectomy lymphangiosarcoma
(StewartTreves syndrome)
This type of vascular malignancy usually arises in chronic
postmastectomy lymphedema. The lesions are bluish or
reddish nodules arising on the arm. Similarly, primary or secondary lymphedema of the lower extremity may be complicated by angiosarcoma. Angiosarcoma arising in a
lymphedematous extremity often presents with multiple
lesions. Metastasis and death commonly result. Early aggressive surgical treatment with amputation may be life-saving.
The treatment of breast cancer with lumpectomy and local
radiation therapy may be complicated by angiosarcoma of the
breast with minimal or no associated lymphedema. This is
called cutaneous postradiation angiosarcoma of the breast.
This form of angiosarcoma also frequently results in metastasis and death.
Postinflammatory lymphedema
The lymphedematous extremity may be caused by and worsened by repeated bacterial cellulitis/lymphangitis. It is these
recurrent infectious episodes, when they complicate filariasis,
that cause the elephantiasis. Streptococcal cellulitis following
venectomy in patients who had undergone coronary bypass
surgery is a well-documented cause. However, almost any
chronic or recurrent infection can cause this. Chronic antibiotic
therapy can halt the progression by preventing the attacks of
bacterial cellulitis.
Bullous lymphedema
Commonly misdiagnosed as an immunobullous disease,
bullous lymphedema usually occurs with poorly controlled
edema related to heart failure and fluid overload. Compression
results in healing.
Factitial lymphedema
Also known as hysterical edema, lymphedema can be produced by wrapping an elastic bandage, cord, or shirt around
an extremity, and/or holding the extremity in a dependent
and immobile state. Self-inflicted causes of lymphedema are
usually difficult to prove and may occur in settings of known
causes of lymphedema, such as postphlebitic syndrome or
surgical injury to the brachial plexus. Factitial lymphedema
caused by blunt trauma localized to the dorsum of the hand
or forearm is referred to as Secretan syndrome or loedme
bleu, respectively. It often is unilateral and there may be significant purpura. Effective care of such patients requires psychiatric intervention. Occupational causes must be excluded.
Podoconiosis
Podoconiosis, or mossy foot, is a non-infectious form of lymphedema. It is restricted to tropical regions in Central Africa,
Central America, and North India. It occurs in persons walking
barefoot in soil of volcanic origin. This soil has high concentrations of aluminum, silicon, beryllium, zirconium, magnesium,
and iron. Apparently, colloid-sized particles of the dust penetrate the sole, and migrate to lymph nodes ingested in macro
phages. Lymphatic drainage is impaired by fibrosis of
lymphatic channels, induced by the microscopic deposits of
the substances. Males and females are equally affected, and in
endemic areas up to 5% of the population can develop the
disease. Moving into an endemic area from a non-endemic
area can lead to the condition appearing over the next 5 years.
Podoconiosis begins in childhood or adolescence with mild
swelling of the feet. Burning of the feet occurs at night. The
dorsal surface of the foot itches, and is rubbed and lichenified.
Increased skin markings and finally marked hyperkeratosis
due to repeated infections result. This closely resembles
Other causes
Occupational persistent hand edema in divers, related to the
constrictive action of the divers suits and pricks from sea
urchin spines, can occur.
Evaluation
The diagnosis is usually based on a classic presentation;
however, in the early stages the disease may require further
investigation. Considerations include isotopic lymphoscintigraphy, indirect and direct lymphography, MRI, computed
tomography, and ultrasonography.
Treatment
Most cases are treated conservatively by means of various
forms of compression therapy, complex physical therapy,
pneumatic pumps, and compressive garments. Chronic antibiotic treatment may be beneficial in patients suffering
repeated episodes of erysipelas or cellulitis. In diabetics with
insensate feet, the frequency of infection can be reduced by
wearing properly fitting shoes. Volume-reducing surgery and
lymphatic microsurgery are rarely performed, although a few
centers consistently report favorable results. It is best to refer
these patients to a center versed in the treatment of these
complicated conditions, to optimize patient compliance and
customize therapy to the patients lifestyle.
Allen PJ, et al: Lower extremity lymphedema caused by acquired
immune deficient syndrome-related Kaposis sarcoma. J Vasc Surg
1995; 22:178.
Ameen M, et al: Clinicopathological case 2: lymphoedemadistichiasis
syndrome. Clin Exp Dermatol 2003; 28:463.
Angelini G, et al: Occupational traumatic lymphedema of the hands.
Dermatol Clin 1990; 8:205.
Badger C, et al: Physical therapies for reducing and controlling
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4:CD003141.
Bastien MR, et al: Treatment of lymphedema with a multicompartmental
pneumatic compression device. J Am Acad Dermatol 1989; 20:853.
Billings SD, et al: Cutaneous angiosarcoma following breast-conserving
surgery and radiation. Am J Surg Pathol 2004; 28:781.
Campisi C, Boccardo F: Microsurgical techniques for lymphedema
treatment: derivative lymphatic-venous microsurgery. World J Surg
2004; 28:609.
Cerri A, et al: Lymphangiosarcoma of the pubic region: a rare
complication arising in congenital non-hereditary lymphedema. Eur J
Dermatol 1998; 8:511.
Downes M, et al: Vascular defects in a mouse model of hypotrichosislymphedoma-telangiectasia syndrome indicate a role for SOX18 in
blood vessel maturation. Hum Mol Genet 2009; 18:2839.
Neuropathic ulcers
elephantiasis verrucosa cutis. The condition is usually asymmetrical. Podoconiosis is prevented by wearing shoes.
Elevation, compression, and local wound care all aid in this
condition. Extensive surgery, as done for filariasis, has had
disappointing results.
845