Vasculitis and Hypersensitivity



Vasculitis and Hypersensitivity


Cathleen Case



A hypersensitivity reaction is an exaggerated and pathologic response by the immune system to a self- or foreign antigen. Hypersensitivity reactions differ in the mediators involved, mechanisms, timing, and clinical manifestations; however, there may be similar morphologic appearances making clinical diagnosis a challenge. There are four types of hypersensitivity reactions: Type I is immediate, anaphylactic; mediated by IgE, histamine, leukotrienes; and includes urticaria and angioedema. Type II is cytotoxic; mediated by IgM or IgG, complement; and includes some drug reactions and transfusion reaction. Type III is mediated by IgG or IgM antibodies in immune complexes; includes serum sickness, arthus reaction, vasculitis, or systemic lupus erythematosus. Type IV is delayed/cell mediated; activates reactions with antigen-specific T cells, such as poison ivy, allergic contact dermatitis, tuberculin reaction.

The hypersensitivity reactions addressed in this chapter include vasculitis, urticaria and angioedema, erythema multiforme (EM), and erythema nodosum (EN). These reactions range in severity from mild to life-threatening and can be triggered by drugs, infectious agents, foods, environmental allergens, malignancies, autoimmune disorders, other systemic illness, or unknown etiologies.


VASCULITIS

Vasculitis is an inflammatory process which involves the walls of any size or type of vessel causing damage that results in tissue necrosis. Cutaneous vasculitis may be limited to the skin only, may be a primary cutaneous vasculitis with secondary systemic involvement; or a cutaneous manifestation of a systemic vasculitis. All categories of vessels can be affected, including small, medium-sized, and large vessels of the arterial and/or venous systems. Small vessels include arterioles, capillaries, and postcapillary venules that are found in the superficial and mid-dermis of the skin (Table 16-1). Medium-sized vessels refer to the main visceral arteries and veins, and the small arteries and veins within the deep dermis or subcutaneous tissue (Table 16-2). Large vessels are the aorta, its major branches and corresponding veins, and other named arteries such as pulmonary or temporal artery. Cutaneous involvement occurs almost always with vasculitis of small and medium-size vessels and therefore the large-vessel vasculitides will only be briefly mentioned in this chapter.

The clinical spectrum of vasculitis presents a diagnostic challenge even for the experienced dermatology or rheumatology provider. In an attempt to classify the vasculitides, several schemes have been proposed; historically the classification was based on vessel size. Other criteria have been developed based on clinical signs and symptoms, histopathology, historical data, and the presence or absence of internal organ involvement. Most recently, The International Chapel Hill Consensus Conference on the Nomenclature of Systemic Vasculitides (CHCC2012) updated their original work of 1994. This is neither a classification system nor a diagnostic system, but rather it defines the nomenclature that should be used for a specifically defined disease process (Figure 16-1). For example, if a vasculitis is caused by direct invasion of pathogens, then the vasculitis should be specified as such (i.e., rickettsial vasculitis or syphilitic aortitis) rather than “infectious vasculitis.” Although there are differences among these criteria, a shared defining feature of vasculitis is an inflammation of blood vessel walls at some time during the course of the disease.

Furthermore, CCHC has renamed the vasculitis previously known as cutaneous leukocytoclastic vasculitis and is now referred to as cutaneous small-vessel vasculitis (CSVV). By definition, CSVV has the histologic findings associated with leukocytoclastic vasculitis but the involvement is limited to the small blood vessels of the skin, and no other organ system is involved. This may also be referred to as single-organ vasculitis. The following section will focus on the CSVV that is more commonly seen in the primary care setting, the importance of screening for systemic organ involvement, differential diagnoses, diagnostics, and prompt management.



Clinical Presentation

The importance of a detailed physical examination that accurately identifies the morphology of the presenting lesions cannot be overemphasized. Clinical presentation is critical in developing a differential diagnoses for vasculitis. It is absolutely essential that clinicians evaluate the patient for systemic involvement, which may present as fever, cough, myalgia, hemoptysis, abdominal pain, melena, weight loss, nausea/vomiting, diarrhea, hypertension, headache, visual disturbances, and renal insufficiency (urine sediment with protein and red and white cells).

The morphology of the cutaneous findings in any vasculitis will depend on the size of the vessels primarily affected and will provide clues to the type of vasculitis. Clinicians should understand the terminology frequently used in discussing these dermatoses (Table 16-4). Small-vessel vasculitis (SVV) results in petechia, purpura, erythematous macules, papules, and pustules (Figure 16-3). Palpable purpura occurs when vasculitis is present
in postcapillary venules and is the hallmark of cutaneous vasculitis (Figures 16-4, 16-5 and 16-6). Lesions typically evolve within 7 to 10 days of a causative exposure, and erupt in crops lasting about 1 to 4 weeks. The size of SVV lesions can range from 1 mm to several centimeters and may be asymptomatic, itchy, or painful. Edema may develop if nephritis is present. Painful nodules, pustules, and necrotic ulcers can present in specific types of SVV like granulomatosis with polyangiitis (GPA). The unusual distribution of lesions in GPA found in the oral and nasal mucosa should heighten the clinician’s index of suspicion. Yet most SVV lesions favor dependent sites such as legs and feet, or areas affected by trauma and tight-fitting clothing. The buttocks or back of a bedridden patient may be involved and reflects the influence of venous pressure due to gravity.








TABLE 16-2 Medium- and Large-Vessel Vasculitides (Other Than Small Vessel)










































NOMENCLATURE


DESCRIPTION


Large-Vessel Vasculitis


Large arteries and aorta


Takayasu arteritis


Arteritis, often granulomatous, usually patients <50 years


Giant cell arteritis


Arteritis, often granulomatous, usually patients >50 years. Predominantly the carotid and vertebral arteries; most commonly the temporal artery


Medium-Vessel Vasculitis


Any size artery, especially medium-sized artery like main visceral arteries & branches


Polyarteritis nodosa


Necrotizing arteritis without glomerulonephritis (of medium-sized or small arteries), or vasculitis not associated with ANCAs (arterioles, capillaries, or venules)


Kawasaki disease


Arteritis associated with mucocutaneous lymph node syndrome (small, medium-sized, large arteries, and aorta)


Coronary artery involvement usually seen in young children and infants


Variable Vessel Vasculitis


No predominant size or type of vessel


Behçet disease, Cogan syndrome


Primary categories of vasculitis because of the frequency of vasculitis in these conditions


Single-Organ Vasculitis


Any size artery and in a single organ


Named according to the affected organ or vessel


Distribution may be unifocal or diffuse within an organ/system Examples: cutaneous small-vessel vasculitis; testicular vasculitis; or central nervous system vasculitis


Vasculitis Associated with Systemic Disease


Caused by or associated with a systemic disease


Named according to disease-related etiology


Sometimes considered secondary vasculitis


Examples: rheumatoid vasculitis; lupus vasculitis; or sarcoidosis vasculitis


Vasculitis Associated with Probable Etiology


Based on specific etiology


Named according to etiology


Sometimes considered a secondary vasculitis Examples: Hydralazine-associated microscopic polyangiitis; hepatitis B virus-associated vasculitis; syphilis-associated aortitis; or cancer-associated vasculitis


Medium-vessel vasculitis occurs predominately in medium-size and small arteries (i.e., visceral arteries and branches). Polyarteritis nodosa (PAN) is a necrotizing medium-vessel vasculitis presenting as nodules (similar to EN), palpable purpura, and vesicles/bullae. Livedo reticularis may progress to ulcerations usually located on the lower extremities. The lesions are painful and may be accompanied by edema. Patients with PAN often have systemic symptoms.

Kawasaki disease (KD) is also a vasculitis of medium-size arteries, including coronary arteries and aorta. Although it is rare and self-limiting, recognition of the clinical presentation is important to avoid cardiac sequelae. It is more common in childhood and is discussed under Childhood Vasculitis.

Large-vessel vasculitis involving the aorta and large arteries means that affected patients have systemic involvement and appear much sicker. Ulcerations and sometimes gangrenous digits are seen with large-vessel involvement. Giant cell arteritis (GCA) occurs in patients over 50 years, who report constitutional symptoms along with temporal artery tenderness, visual loss, polymyalgia rheumatica, headache, jaw claudication, and temporal enlargement with absent pulse is common. Clinicians should assess the patient for aortic involvement, including signs and symptoms of aneurysm. In contrast, Takayasu arteritis is more prevalent in females younger than 50 years and affects the aorta and major branches. Granulomatous inflammation affects any or all of the organs, resulting in significant morbidity and mortality.





























DIFFERENTIAL DIAGNOSIS Vasculitis


MORPHOLOGIC PRESENTATION


DIFFERENTIAL DIAGNOSIS


Palpable purpuric papules/plaques (raised)


Arthropod bite


Erythema multiforme


Morbilliform drug eruption with hemorrhage


Infectious emboli


Cellulitis


Purpuric macules/patches (flat)


Hemorrhage


Trauma, solar/actinic purpura, medication-related (e.g., aspirin), thrombocytopenia, viral exanthem, scurvy


Thrombosis


Hypercoagulable state, purpura fulminans (e.g., DIC or sepsis), heparin or warfarin necrosis, livedoid vasculopathy


Emboli


Cholesterol, cardiac, fat, air


Inflammation


Pigmented purpura/capillaritis


Urticarial lesions


Urticaria


Arthropod bites


Papular urticaria


Serum sickness-like reaction


Erythema multiforme


Viral exanthem


Sweet syndrome


Urticarial phase of bullous pemphigoid


Ulcers


Venous or arterial disease


Pyoderma gangrenosum


Livedoid vasculopathy


Hypercoagulable state


Calciphylaxis


Infections (e.g., bacterial, mycobacterial, fungal)


Nodules


Panniculitis


Superficial migratory thrombophlebitis


Dermal neoplasms


Infections (e.g., bacterial, mycobacterial, fungal)


Systemic vasculitides



Diagnostics

The general approach for any patient with vasculitis should be to rule out other diseases that may mimic vasculitis; look for any underlying or secondary cause (disease, infection, drug, or malignancy); perform diagnostics to confirm the presence of a vasculitis; and conduct additional tests to identify the type and severity of the vasculitis.

A detailed history, review of systems, and clinical presentation will be invaluable in guiding the clinician’s development of a differential diagnosis or suspicion for secondary causes (Table 16-5). The initial diagnostic test should be a punch or excisional biopsy, the gold standard for evaluation of vasculitis, which should be taken from the center of a new lesion (preferably 24-48 hours old), making sure to collect some of the subcutaneous tissue if evaluating deeper, larger vessels. The histopathologic features of the biopsy can aid in identifying the type of vasculitis as well as other features which may indicate other systemic disease (i.e., interface dermatitis suggestive of connective tissue disease). Additional punch biopsy for direct immunofluorescence (preserved in Michel’s medium) may be helpful in identifying the deposition of immunoglobulins and complements in the blood vessels (i.e., Henoch-Schönlein purpura [HSP]).

A complete blood count with differential should be part of the initial workup. Patients with a primary vasculitis rarely have leukocytosis or thrombocytopenia, which, if present, should prompt further evaluation for an underlying disease, malignancy, or infection. Eosinophilia is seen in Churg-Strauss syndrome. Anemia could signify underlying lupus erythematosus or malignancy. A C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) are usually elevated but are nonspecific markers of systemic inflammation. Blood urea nitrogen, creatinine, and electrolyte abnormalities may reflect kidney involvement. Abnormal liver function tests may be associated with underlying liver disease or malignancy. A stool guaiac will help assess for vasculitis of the bowel in patients with abdominal pain. Urinalysis with microscopy that is positive for red blood cell casts is suggestive of glomerulonephritis, while proteinuria is common in lupus nephritis. A chest x-ray may be recommended if the patient’s review of symptoms or clinical presentation suggests pulmonary involvement and may reveal pulmonary infiltrates, nodules, patchy consolidation, pleural effusion, and cardiomegaly.


Management

Treatment of vasculitis should be based on type and severity, as well as the presence of organ involvement. Management of primary CSVV seen in primary care will be the focus of this section. Medium- and large-vessel vasculitis are beyond the scope of this text and should be managed by dermatologists or appropriate specialists.

Most primary CSVV is mild and self-limiting. If an offending antigen like a drug is identified, then removing the source is the obvious first step. Underlying infection or disease should be treated at the outset. Treatment of CSVV (without systemic involvement) should proceed with supportive care, including leg elevation, rest, and gentle compression of legs for comfort. However, tight restrictive clothing may aggravate susceptible skin regions and should be avoided. Pain and inflammation can be treated with nonsteroidal anti-inflammatory drugs (NSAIDs), and pruritus may be attenuated with antihistamines such as hydroxyzine or diphenhydramine. Class I topical corticosteroid (TCS) ointment may also be helpful for adult patients, most of whom will not require systemic measures.

Short-term oral corticosteroids (prednisone) may be considered in patients with chronic (active disease that persists for more than 4 weeks) or recurring CSVV if hemorrhagic blisters and ulcerations are present. The dose and duration of treatment are dependent on the severity. A dosage of 0.5 mg/kg/day can be prescribed for 1 to 2 weeks or until new lesions cease to erupt. A taper over 2 to 4 weeks may be necessary and usually meets with complete resolution. Chronic forms of CSVV, or those with more severe cutaneous
disease, may require higher doses of prednisone dosed 1 mg/kg/day to control symptoms. Since long-term use of corticosteroids has the risk of significant side effects, transitioning the patient to a steroid-sparing agent (i.e., colchicine, dapsone) is important. Patients on dapsone need G6PD testing prior to initiating therapy and careful monitoring for hemolytic anemia during therapy. Pentoxifylline has been effective when the CSVV is resistant. Recalcitrant CSVV or SVV with systemic involvement often requires management by dermatology specialists with azathioprine, methotrexate, cyclophosphamide, intravenous immunoglobulin, mycophenolate mofetil, rituximab, or plasmapheresis.






FIG. 16-1. Diagram of vasculitis showing vessel size, morphology, and related conditions.









TABLE 16-3 Cutaneous Vasculitis: Causes and Precipitating Agents




























CAUSE


AGENT


Infection


Bacterial


β-hemolytic Streptococcus group A


Staphylococcus aureus


Mycobacterium leprae


Mycobacterium tuberculosis


Viral


Hepatitis A, B, C (including vaccines)


HSV


HIV


Parvovirus B19


Fungal


Candida albicans


Protozoan


Plasmodium malariae


Helminthic infections


Schistosoma haematobium


Schistosoma mansoni


Chronic disease state


Systemic lupus erythematosis


Sjogren syndrome


Rheumatoid arthritis


Inflammatory bowel disease


Behcet disease


Cystic fibrosis


Cryoglobulinemia


Bowel bypass syndrome


Drug exposure


Common


Anti-TNF agents


COX-2 inhibitors


Granulocyte colony-stimulating factor


Hydralazine


Leukotriene inhibitors


Minocycline


NSAIDs


Penicillins


Quinolones


Streptokinase


Occasional


ACE inhibitors


Allopurinol


β-blockers


Coumarins


Furosemide


Interferons


Macrolide antibiotics


Phenytoin


Retinoids


Sulfonylureas


Thiazides


Trimethoprim-sulfamethoxazole


Vancomycin


Rare


Aspirin


Atypical antipsychotics


Cocaine/levamisole contaminated


Gabapentin


Insulin


Metformin


Rituximab


Selective serotonin-reuptake inhibitors


Vitamins


Neoplasm


Lymphoproliferative disorders


Hodgkin disease


Mycosis fungoides


Myeloproliferative disorders


Lymphosarcoma


Multiple myeloma


Solid organ tumors


Adult T-cell leukemia


Other


Chemicals


Insecticides


Petroleum products


Food stuff allergens


Milk proteins


Gluten


HSV, herpes simplex virus; COX, cyclooxygenase; NSAIDs, nonsteroidal anti-inflammatory drugs; TNF, tumor necrosis factor. Adapted from Chung, L., Kea, B., & Fiorentino, D. F. (2008). Cutaneous vasculitis. In J. L. Bolognia, J. L. Jorizzo, & R. P. Rapini (Eds.), Dermatology (2nd ed., pp. 347-367). Spain: Mosby Elsevier.







FIG. 16-2. Characteristic purpura associated with levamisole (common contaminate in cocaine) induced small-vessel vasculitis on the ear (A) and arms (B).









TABLE 16-4 Terminology



























Purpura


Lesions caused by extravasated red blood cells into skin, appearing red-brown or purple, flat (macule or patch)


Palpable purpura


Papules or plaques (raised) which are blanchable erythema or nonblanchable component of visible hemorrhage. Diascopy can help distinguish between the two (below).


Petechiae


Small pinpoint (<4 mm) purpuric macules, initially bright red that turn brown or rust-colored, and can be seen in thrombocytopenic states, as shown in Figure 16-3


Livedo


Macular violaceous netlike patterned erythema of the skin; may indicate vasculopathy


Retiform purpura


Angulated or branched configuration of purpura reflecting the vascular architecture in the skin; vasculopathy diagnosis should be favored


Ecchymosis


Large (>1 cm) blue-purple areas of interstitial hemorrhage


Infarct


Areas of cutaneous necrosis secondary to occlusion of blood vessels. Lesions are dusky red and gray irregular macules surrounded by pink hyperemia and eventually turning black. It can be present in vasculitis, vasculopathy, or embolic disorders.


Diascopy


Application of pressure using a glass slide on a red lesion to distinguish vascular dilatation (erythema) which blanches compared to redness due to extravasated red blood cells (purpura), which does not blanch.







FIG. 16-3. A: Tiny skin hemorrhages (petechiae) in a child with thrombocytopenia. B: Petechiae on the foot and sole of a child with HSP with palpable purpura.






FIG. 16-4. Purpura in a patient with small-vessel vasculitis on the lower legs.






FIG. 16-5. Purpura with a bulla on the lower leg.







FIG. 16-6. Nonpalpable purpura of leukocytoclastic vasculitis, also called single-organ vasculitis, on man with an allergy to shellfish.








TABLE 16-5 Assessment of the Patient with Cutaneous Vasculitis












History


Timing, lesions develop 7-10 days after inciting agent. Special focus on history of malignancy, infections, connective tissue disorder, and recent drug administration or ingestion, including illicit drug use


Review of systems


Critical for assessment of systemic involvement: cardiovascular, pulmonary, abdominal, and neurologic symptoms


Physical examination


Detailed: For the initial evaluation, assess patient for signs of systemic involvement. Special attention should be paid to dependent areas, body areas affected by trauma or tight clothing


Constitutional: fever, weight loss, chills, night sweats, and fatigue


Weight loss, myalgia, arthralgia


Positive findings: diplopia, headache, eye or ear pain, cough, shortness of breath, hemoptysis, nausea, vomiting, diarrhea, abdominal pain, blood in stool, weakness, neuropathy, myalgia, arthralgia, hair loss, sicca symptoms, sinus tenderness, oral or nasal inflammation, otitis media, keratitis, hepatosplenomegaly, and lymphadenopathy



Referral and Consultation

The initial presentation and evaluation of vasculitis may begin in the primary care office, and patients with localized or early vasculitis can be managed symptomatically with removal of an offending antigen. Most patients are referred to a dermatology provider when there is extensive cutaneous involvement, threatened organ involvement, and relapse or disease progression despite treatment. A number of specialists should be consulted based on findings, including a nephrologist, pulmonologist, cardiologist, and otolaryngologist. Surgical consult may be necessary if necrotizing or ulcerative lesions are present.


Prognosis and Complications

If a drug or infection is the cause, there may only be one episode with spontaneous resolution; however, if SVV is associated with a systemic disease, such as hepatitis C infection or rheumatoid arthritis, treatment considerations will be different. Ultimately, the best indicator of prognosis in any vasculitis with systemic involvement depends on the size of the vessel and organ involved. Long-term implications include the possibility of multiple episodes with recurrent crops of vasculitic lesions appearing for months or years.


Patient Education and Follow-up

Patients receiving short-term corticosteroids should be advised of possible adverse effects, including hypertension, glucose intolerance, sleep disturbance, hirsutism, weight gain, and avascular necrosis of the hip. Patients on prednisone for extended periods of time should have baseline bone mineral density testing and receive education about corticosteroid-induced osteoporosis, including weight-bearing exercise, smoking and alcohol cessation, and fall prevention in the elderly. Consider calcium with vitamin D supplementation and bisphosphonates for high-risk individuals. Blood pressure and serum glucose should be monitored. Patients of childbearing age should always be counseled regarding adequate birth control measures, especially if treated with teratogenic medications. Close follow-up of patients with systemic vasculitis by multiple providers may be required to halt disease progression, evaluate response to therapy, and prevention of complications.

May 25, 2016 | Posted by in Dermatology | Comments Off on Vasculitis and Hypersensitivity

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