You are in: eMedicine Specialties > Dermatology > DISEASES OF THE VESSELS Urticarial VasculitisArticle Last Updated: Mar 16, 2007AUTHOR AND EDITOR INFORMATIONSection 1 of 11
  Author: Darius Mehregan, MD, Associate Professor, Hermann Pinkus Chairman of Dermatology, Department of Dermatology, Wayne State University of Michigan; Clinical Associate Professor of Pathology, University of Toledo; Dermatopathologist, Pinkus Laboratory; Consulting Staff, J Dingell Veterans Affairs Medical Center Darius Mehregan is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, American Society of Dermatopathology, International Society of Dermatology, International Society of Dermatopathology, Phi Beta Kappa, and Society for Investigative Dermatology Coauthor(s): Iltefat Hamzavi, MD, Staff Physician, Department of Dermatology, Wayne State University School of Medicine, Michigan Editors: Gregory J Raugi, MD, PhD, Professor, Department of Internal Medicine, Division of Dermatology, University of Washington at Seattle; Chief, Dermatology Section, Primary and Specialty Care Service, Veterans Administration Medical Center of Seattle; Richard P Vinson, MD, Assistant Clinical Professor, Department of Dermatology, Texas Tech University School of Medicine; Consulting Staff, Mountain View Dermatology, PA; Jeffrey P Callen, MD, Professor of Medicine, Chief, Division of Dermatology, University of Louisville School of Medicine; Joel M Gelfand, MD, MSCE, Medical Director, Clinical Studies Unit, Assistant Professor, Department of Dermatology, Associate Scholar, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania; Dirk M Elston, MD, Director, Department of Dermatology, Geisinger Medical Center Author and Editor Disclosure Synonyms and related keywords: normocomplementemic urticarial vasculitis, hypocomplementemic urticarial vasculitis, wheals, hives, allergic reaction, hypersensitivity reaction, systemic lupus erythematosus, SLE, connective tissue disease, connective-tissue disease, vasculitis INTRODUCTIONSection 2 of 11
  BackgroundUrticarial vasculitis is an eruption of erythematous wheals that clinically resemble urticaria but histologically show changes of leukocytoclastic vasculitis. Urticarial vasculitis may be divided into normocomplementemic and hypocomplementemic variants. Both subsets can be associated with systemic symptoms (eg, angioedema, arthralgias, abdominal or chest pain, fever, pulmonary disease, renal disease, episcleritis, uveitis). The hypocomplementemic form more often is associated with systemic symptoms and has been linked to connective-tissue disease (ie, systemic lupus erythematosus [SLE]).1 PathophysiologyThe pathophysiology of urticarial vasculitis is similar to other forms of cutaneous small vessel leukocytoclastic vasculitis. Urticarial vasculitis is a type III hypersensitivity reaction in which antigen-antibody complexes are deposited in the vascular lumina. This reaction results in complement activation and chemotaxis of neutrophils. These cells release various proteolytic enzymes, such as collagenase and elastase, resulting in damage to the vascular lumina. Some authors have speculated that eosinophils may be involved in the early stages of the vasculitic lesions. Patients with hypocomplementemic urticarial vasculitis are more likely to show autoantibodies to C1q and vascular endothelial cells.2 The presence of antineutrophilic cytoplasmic antibodies is rare. FrequencyUnited StatesThe exact frequency is not known in the United States or worldwide. InternationalPrevious studies varied in their definitions of the condition. However, when a study in the United Kingdom used consistent criteria restricted to patients diagnosed with vasculitis by biopsy and with urticarial lesions of more than 3 months duration, 2.1% of 1310 patients with urticaria were found to have urticarial vasculitis. Mortality/MorbidityUrticarial vasculitis carries a good prognosis, with most occurrences resolving in months to years. Urticarial vasculitis associated with hypocomplementemia is associated with a greater incidence of coexisting disease (ie, angioedema, connective-tissue disease [primarily SLE], chronic obstructive pulmonary disease). Mortality is rare. SexMale-to-female ratio is 1:2. AgeThe median age of involvement is 43 years with a range of 15-90 years. While this is primarily a disease of middle-aged adults, it can be seen in persons of any age. CLINICALSection 3 of 11
History
PhysicalLesions initially appear as erythematous wheals (see Media File 1). As the lesions progress, purpura may develop. Often, the lesions resolve with postinflammatory pigmentation. Annular or targetoid lesions may be observed. CausesThe etiology of urticarial vasculitis has not been elucidated. Associated conditions are listed in History. DIFFERENTIALSSection 4 of 11
Drug Eruptions
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| Drug Name | Hydroxyzine (Atarax, Vistaril) |
|---|---|
| Description | Antagonizes H1 receptors in periphery. May suppress histamine activity in subcortical region of CNS. Can be used for symptomatic control. The recommended antihistamine for pregnant patients is diphenhydramine. Has been used safely in children. |
| Adult Dose | 0.5 mg/kg PO q6h or 25-100 mg PO qd/qid; not to exceed 50 mg PO q6h |
| Pediatric Dose | 0.5-0.6 mg/kg/dose PO q6h |
| Contraindications | Documented hypersensitivity |
| Interactions | CNS depression may increase with alcohol or other CNS depressants |
| Pregnancy | C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus |
| Precautions | Side effects include drowsiness, headache, dizziness, and nervousness; associated with clinical exacerbations of porphyria (may not be safe for porphyric patients); ECG abnormalities (alterations in T waves) may occur; may cause drowsiness |
| Drug Name | Diphenhydramine (Benadryl, Benylin, Diphen, AllerMax) |
|---|---|
| Description | For symptomatic relief of symptoms caused by release of histamine in hypersensitivity reactions. In pregnancy, use 25-50 mg PO q6h prn. |
| Adult Dose | 25-50 mg PO q6-8h prn; 10-50 mg IV/IM q6-8h prn; not to exceed 400 mg/d |
| Pediatric Dose | 5 mg/kg/d PO/IV/IM divided q6-8h; not to exceed 300 mg/d |
| Contraindications | Documented hypersensitivity, MAOIs |
| Interactions | Potentiates effect of CNS depressants; because of alcohol content, do not administer syrup form to patient taking medications that can cause disulfiramlike reactions |
| Pregnancy | C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus |
| Precautions | May exacerbate angle-closure glaucoma, hyperthyroidism, peptic ulcer, and urinary tract obstruction |
These agents modulate the immune system to reduce inflammation.
| Drug Name | Colchicine |
|---|---|
| Description | Alkaloid extract that inhibits microtubule formation. Often used for treatment of acute gout. Has been reported effective for urticarial vasculitis. Concentrates well in leukocytes and reduces neutrophilic chemotaxis and motility. Histologically, urticarial vasculitis presents with neutrophil involvement; therefore, colchicine possibly is useful. However, drug's effect has not been proven in clinical trials. |
| Adult Dose | 0.6 mg PO bid/tid |
| Pediatric Dose | Children: Not established Adolescents: 0.5 mg/kg PO divided bid/tid |
| Contraindications | Documented hypersensitivity; severe renal, hepatic, GI, or cardiac disorders; blood dyscrasias |
| Interactions | Significantly increases sympathomimetic agent toxicity and effect of CNS depressants; may decrease vitamin B-12 absorption |
| Pregnancy | C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus |
| Precautions | Diarrhea is common; severe hematologic adverse effects can occur; monitor CBC counts and creatinine levels; risk of renal failure, hepatic failure, permanent hair loss, bone marrow suppression, numbness or tingling in hands and feet, disseminated intravascular coagulopathy, and decreased sperm count |
Used for infectious diseases (eg, leprosy); however, sulfones are effective in inflammatory diseases. Mechanism of action may involve inhibiting free radical formation by neutrophils. In most case reports, these medications are effective only in purely cutaneous forms of urticarial vasculitis.
| Drug Name | Dapsone (Avlosulfon) |
|---|---|
| Description | Preferred sulfone. Other sulfones must be metabolized to dapsone for their effect. Mechanism of action is similar to that of sulfonamides in which competitive antagonists of PABA prevent formation of folic acid, inhibiting bacterial growth. Dosing guidelines for dermatologic use have been well described in dermatitis herpetiformis. Most case reports about effect in urticarial vasculitis use dermatitis herpetiformis dosing guidelines. Has been used extensively in chronic bullous disease of childhood. |
| Adult Dose | 50 mg/d PO initial; can be increased by 50 mg/wk to 300 mg/d |
| Pediatric Dose | 1-2 mg/kg/d PO |
| Contraindications | Absolute: Documented hypersensitivity Relative: G-6-PD deficiency (especially in African Americans, persons of Middle Eastern heritage, and Asians); significant cardiopulmonary disease; significant hematologic disease; sulfa allergy (cautious use in patients with sulfa allergy may be attempted; cross-reactivity is relatively rare and mild) |
| Interactions | Trimethoprim, probenecid, folic acid antagonists (eg, pyrimethamine, methotrexate) increase dapsone levels; activated charcoal, PABA, and rifampin decrease dapsone levels; sulfonamides and hydroxychloroquine may increase hemolysis |
| Pregnancy | C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus |
| Precautions | Evaluate liver and renal function; adverse effects usually involve hematologic and neurologic systems; may cause damage to axons of motor nerves and, rarely, sensory nerves; perform weekly WBC counts (first mo); then perform WBC counts monthly (6 mo); then semi-annually; discontinue if significant reduction in platelets, leukocytes, or hematopoiesis is seen; methemoglobin reductase deficiency, G-6-PD deficiency, or hemoglobin M because of high risk for hemolysis and Heinz body formation; patients exposed to other agents or conditions (eg, infection, diabetic ketosis) capable of producing hemolysis; peripheral neuropathy can occur (rare); phototoxicity may occur when exposed to UV light |
Like other medications used to treat urticarial vasculitis, antimalarials are believed to exert their effect by their anti-inflammatory properties. Antimalarials reduce neutrophilic chemotaxis. In addition, they increase pH in lysosomes, which may affect antigen presentation. This class of medications usually is effective only in cutaneous disease.
| Drug Name | Hydroxychloroquine (Plaquenil) |
|---|---|
| Description | Preferred antimalarial agent because of its low toxicity and high effectiveness profile. Usually well tolerated if carefully monitored by prescribing physician. Therapy is required for 4-8 weeks before evaluating effectiveness. |
| Adult Dose | 6.5 mg/kg PO or 400 mg/d PO, whichever is less |
| Pediatric Dose | 3-5 mg/kg/d PO divided bid; not to exceed 400 mg/d |
| Contraindications | Absolute: Documented hypersensitivity; retinopathy from any cause Relative: Pregnancy or breastfeeding; retinal or visual-field changes; severe blood dyscrasias; psoriasis; G-6-PD deficiency (caution advocated, but routine G-6-PD screening not recommended; associated with hemolysis, but not in usual dosage range); significant hepatic dysfunction; myasthenia gravis, significant neurologic disease; long-term therapy in children (listed in Physicians Desk Reference as contraindication for hydroxychloroquine; main concern is overdose/toxicity; chronic toxicity risk, however, thought to be no greater than in adults); neither drug available as a syr; crush tab and mask bitter taste in jam, applesauce, or other soft food |
| Interactions | Combination of antimalarials may increase incidence of retinal toxicity; serum levels increase with cimetidine; magnesium trisilicate may decrease absorption |
| Pregnancy | C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus |
| Precautions | Hepatic disease, G-6-PD deficiency, psoriasis, and porphyria; not recommended for long-term use in children; perform periodic (6 mo) ophthalmologic examinations; test periodically for muscle weakness |
Most commonly used for relief of mild to moderate pain. The basis behind the use of indomethacin is empiric. It was used with some effectiveness on the cutaneous manifestations of the disease in several case reports.
| Drug Name | Indomethacin (Indocin) |
|---|---|
| Description | Only NSAID reported effective in urticarial vasculitis. Rapidly absorbed; metabolism occurs in liver by demethylation, deacetylation, and glucuronide conjugation; inhibits prostaglandin synthesis. |
| Adult Dose | 100-150 mg/d PO in divided doses |
| Pediatric Dose | 1-2 mg/kg/d PO in 2-4 divided doses; not to exceed 150-200 mg/d |
| Contraindications | Documented hypersensitivity; avoid in GI bleeding or renal insufficiency |
| Interactions | Coadministration with aspirin increases risk of serious NSAID-related adverse effects; may decrease effects of beta-blockers, hydralazine, and captopril; may decrease diuretic effects of furosemide and thiazides; coadministration with anticoagulants may prolong PT (monitor bleeding); may increase risk of methotrexate toxicity, which can manifest as stomatitis, bone marrow suppression, or nephrotoxicity; coadministration may increase phenytoin levels; probenecid may increase toxicity of NSAIDs |
| Pregnancy | C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus |
| Precautions | Category D in third trimester of pregnancy; acute renal insufficiency, hyperkalemia, hyponatremia, interstitial nephritis, and renal papillary necrosis may occur; increases risk of acute renal failure in patients with preexisting renal disease or compromised renal perfusion; reversible leukopenia may occur (discontinue in persistent leukopenia, granulocytopenia, or thrombocytopenia) |
Azathioprine may be used as a steroid-sparing agent once other therapeutic options have been exhausted. Measurement of thiopurine methyltransferase can help ensure safe and optimal treatment with azathioprine.
| Drug Name | Azathioprine (Imuran) |
|---|---|
| Description | Purine precursor that affects formation of adenine and guanine. Results in impaired DNA synthesis in immunocompetent cells such as lymphocytes, which are dividing rapidly during inflammatory process. Has slow onset of action; rarely used as monotherapy. |
| Adult Dose | 1 mg/kg/d qd/bid (empiric) or based on TPMT level (see Precautions); increase dose by 0.5 mg/kg/d after 6-8 wk if necessary; increase q4wk; 2 mg/kg/d maximum dose for most dermatologic purposes |
| Pediatric Dose | Not established. |
| Contraindications | Absolute: Allergy to azathioprine, pregnancy or attempting pregnancy, clinically significant active infection Relative: Concurrent use of allopurinol, prior treatment with alkylating agents (cyclophosphamide, chlorambucil, melphalan, others) because of high risk of neoplasia; pediatric patients (safety and efficacy in pediatric population not established) |
| Interactions | Toxicity increases with allopurinol; concurrent use with ACE inhibitors may induce severe leukopenia; may increase levels of methotrexate metabolites; may decrease effects of anticoagulants, neuromuscular blockers, and cyclosporine |
| Pregnancy | D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus |
| Precautions | TPMT testing is not entirely reliable but it involves testing activity of TPMT activity in RBCs, which correlates with systemic TPMT activity; functional enzyme test has been shown to have variability between test sites and the kits may contain varying amounts of enzyme inhibitor; starting at low doses, monitoring for pancytopenia, then increasing dose is an alternative; if clinical response is not good, patient may be homozygote for high activity and may need an increased dose; Wolverton Comprehensive Dermatologic Drug Therapy; other references recommend checking before treatment in all patients TPMT <5 U: No treatment with azathioprine TPMT 5-13.7 U: Dose not to exceed 0.5 mg/kg TPMT 13.7-19 U: Dose not to exceed 1.5 mg/kg TPMT >19 U: Dose not to exceed 2.5 mg/kg |
Often the treatment of choice. However, given their long-term adverse effect profiles, they are used only for significant cutaneous disease or systemic involvement. For long-term treatment, combination of prednisone and another medication may be required.
| Drug Name | Prednisone (Deltasone) |
|---|---|
| Description | Although is most effective, adverse effect profiles preclude it from use as a first-line agent. Consider only after failure of antihistamines, indomethacin, colchicine, dapsone, or hydroxychloroquine. Effect on urticarial vasculitis likely is mediated by its anti-inflammatory effect. This class of medications decreases capillary permeability and inhibits the mitotic rate of lymphocytes. |
| Adult Dose | 0.5-1.5 mg/kg/d PO initial; taper as disease responds; if chronic use required, qod administration is safer |
| Pediatric Dose | 0.5-2 mg/kg/d PO in divided dose bid to qid |
| Contraindications | Documented hypersensitivity; viral infection, peptic ulcer disease, hepatic dysfunction, connective-tissue infections, and fungal or tubercular skin infections; GI disease |
| Interactions | Coadministration with estrogens may decrease prednisone clearance; when used with digoxin, digitalis toxicity secondary to hypokalemia may increase; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics |
| Pregnancy | B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals |
| Precautions | Abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur with glucocorticoid use |
| Media file 1: Raised erythematous wheals with postinflammatory hyperpigmentations suggest urticarial vasculitis. | |
 | View Full Size Image | Media type: Photo |
| Media file 2: A low-power histologic image of urticarial vasculitis shows leukocytoclastic vasculitis with damage to the vessel wall and a neutrophilic infiltrate. | |
 | View Full Size Image | Media type: Photo |
| Media file 3: A high-power view of the histology of urticarial vasculitis shows extensive fibrin deposition in the vessel walls. Surrounding the vessels is a mixed infiltrate predominately composed of neutrophils with leukocytoclasis. | |
 | View Full Size Image | Media type: Photo |
Article Last Updated: Mar 16, 2007
