Puzzling Rash in an Older Woman

A 73-year-old woman presents with apainless, nonpruritic rash of recent onseton her right lower ankle. She has nofever, chills, nausea, vomiting, malaise,or other systemic complaints. Her medicalhistory includes fibromyalgia, osteoarthritis,stable angina, and anxiety;there is no history of connective tissuedisease.The patient recently completedthe eighth day of a 10-day course oftrimethoprim-sulfamethoxazole (TMPSMX)that another clinician had prescribedfor an upper respiratory tractinfection with associated pharyngitis.No cultures had been performed; nomedical records were available to explainwhy this antibiotic was chosen.The rash arose on the seventh day ofantibiotic therapy.The afebrile patient is in no acutedistress; her systolic blood pressure ismildly elevated. The erythema of the medial aspect of the right shin andankle is composed of small, centrallyconfluent petechiae that become moredistinct and scattered toward the peripheryof the involved area (Figure).Trace pitting edema is noted. The palpable,nonblanching rash feels slightlywarmer than the surrounding skin.The differential diagnosis includescellulitis, an urticarial drugreaction to TMP-SMX, deep venousthrombosis, and leukocytoclastic vasculitis.A traumatic cause is not supportedby the history.The patient declines urinalysisand throat culture. Her white bloodcell count is 72,000/μL; erythrocytesedimentation rate, 12 mm/h; plateletcount, 212,000/μL; and creatininelevel, 1.1 mg/dL. Antistreptolysin-Otiters are negative. Histologic examinationof a 2-mm, tan-white skin punchbiopsy specimen from the periphery ofthe rash reveals mild to moderateperivascular mixed inflammatory cellularinfiltrate around small blood vesselsand capillaries within the upperdermis. These findings are consistentwith hypersensitivity angiitis andconfirm the diagnosis of small-vesselvasculitis.Cellulitis--an early diagnosticconsideration--was unlikely becausethere was no fever and the rash wasnontender and nonblanching. Theeruption of an urticarial drug reactionis typically generalized and maculopapular,not localized and petechial asthis patient's rash. Deep venous thrombosiscan cause erythema; however,calf swelling, tenderness or pain, andsignificant risk factors were absent.In this patient, the vasculitis rana benign course and resolved spontaneously.There were no sequelae.PATHOGENESIS
Cutaneous small-vessel vasculitisis also called leukocytoclastic vasculitis,hypersensitivity angiitis, and hypersensitivityvasculitis. Although thepostcapillary venule is the most commonlyinvolved vessel,¹ arterioles andcapillaries may be affected.The process that leads to vasculitisappears to be initiated by thedeposition of circulating immune complexes on the vascular endothelium.These activate the complementpathways, which results in mast celldegranulation and consequent neutrophilchemotaxis. These neutrophilsrelease lysosomal enzymes andoxygen free radicals that damage thevascular endothelium and cause lysisof the leukocyte nuclei.2 The integrityof the endothelial wall is destroyedand red blood cells are extravasatedinto the perivascular area, producingthe nonblanching, petechial or purpuricrash that is the hallmark of thisdisease.A variety of triggers--includingmedications, microorganisms, andtoxins or other foreign or endogenousproteins--can precipitate thisautoimmune phenomenon.³ Agentsfrom nearly every class of drugs, includingneuroleptics such as haloperidol,reportedly have caused vasculitis.⁴ Most drug reactions that involvethe skin occur within 1 to 2weeks after treatment with the agentis initiated.⁵ The most frequently implicated medications are listed inTable 1. Other documented culpritsare infections, food and medicationdyes, insecticides, petroleum products,and milk proteins.^2,6,7HISTORY
The patient usually presentswith a petechial rash that develops onthe legs or on another dependentarea, such as the sacral region. Thelesions can be asymptomatic, pruritic,or painful and may enlarge and eventuallycoalesce into purpura. Nodules,papules, urticaria, ulcers, or bullaeoccur less often.^1,8,9 A history of fever;malaise; and myalgias or joint pains,which can be migratory, may begiven.Ask the patient about a historyof a similar rash; autoimmune syndromes;or infectious disease, includingHIV seropositivity and hepatitis.Note any temporal relationship betweena new medication and the onsetof the rash.DIAGNOSIS
Assess the texture, location,blanching characteristics, and extentof the cutaneous disease; often thedegree of lesion confluence correlateswith the age of the rash. Evaluatethe vital signs and perform acomplete physical examination to determinewhether systemic involvementexists or an infectious source,such as an upper respiratory tractinfection, has triggered the vasculitis.Although systemic disease is rare,several organ systems can be involved(Table 2).Relatively few diagnostic testswere needed in this patient, althougha urinalysis--which the patient declined--would have been prudentto rule out renal involvement. Furthertesting is warranted in patients withsystemic symptoms and those withsignificant risk factors. These testsmay include renal and liver functionstudies; urinalysis; throat culture; chest films; assessments of antinuclearantibody titer, HIV status, rheumatoidfactor titer, and cryoglobulinlevel; hepatitis B and C panels; andserum protein electrophoresis.⁹ Ifnecessary, biopsy of the newer, peripheralarea of the rash can confirmthe diagnosis.Table 3 lists the American Collegeof Rheumatology's criteria fordiagnosing hypersensitivity vasculitis.Satisfying 3 of the 5 criteria is associatedwith a specificity of 83.9% and asensitivity of 71%.10 The first criterionconcerns the patient's age at diseaseonset; this parameter distinguishesa diagnosis of hypersensitivity vasculitisfrom Henoch-Schnlein purpura,the most common vasculitic syndromethat affects children youngerthan 16.¹¹ Some consider this IgA-mediatedvasculitis of the small vesselsto be the pediatric form of chroniccutaneous small-vessel vasculitis,⁹whereas others believe the conditionis a subset of small-vessel vasculitisthat is specifically IgA-mediated.²In one study, researchers identifiedpredictors of systemic involvementand chronicity in leukocytoclasticvasculitis.⁸ Paresthesias and feverwere significant risk factors for systemic involvement. The best predictorsof chronicity were the presenceof cryoglobulins, arthralgias, and anormal temperature. Painful cutaneouslesions were associated withnonrelapsing disease.TREATMENT
The first step is to determine andremove the offending agent. Often,elimination of the inciting factor issufficient therapy; however, in recalcitrantdisease, additional treatmentmay be necessary.It is often difficult to determinethe culprit in a patient who has recently started a new medication foran infection; as in this patient, eitherthe infection or the treatment maybe the possible cause of the vasculitis.If cultures and sensitivity tests areperformed, an appropriate change ofmedication can be made. Here, theinfectious process had resolved andthe antibiotic was discontinued. Thepatient was cautioned to avoid TMPSMXand other sulfonamides as wellas penicillins in the future.Milder forms of the vasculitismay require only symptomatic relief.This patient's mild and localizedvasculitis resolved spontaneously without treatment. In symptomaticpatients, corticosteroid or antibioticcreams can be helpful.2 Edema ofthe legs may respond to the useof compression hosiery. NSAIDs arenot likely to affect the course ofthe disease; however, these agentscan alleviate associated pain andarthralgias.In patients with uncomplicateddisease, lesions may resolve in 1 to 4weeks; residual hyperpigmentation islikely to occur. Close follow-up of allpatients is necessary. Although mostrashes resolve spontaneously, someminor lesions can progress to necroticulcerations and eventual gangrene.If laboratory studies reveal systemicinvolvement or if the patienthas extensive or ulcerative lesions,consult with a dermatologist orrheumatologist before therapy is undertaken.Typically, a short taperingcourse of prednisone, 40 to 60 mg/d,is prescribed. Do not discontinue themedication abruptly, because a "rebound"rash may erupt. Colchicine,0.6 mg/d in 2 or 3 divided doses for7 to 10 days and tapered thereafter,is another option. Other medicationsto consider include:

• Azathioprine, 150 mg/d for severalweeks.
• Dapsone, 75 to 150 mg/d, for skininvolvement only.
• Cyclophosphamide, 2 mg/kg/d, formultiple organ involvement that hasnot been controlled by prednisone.^2,9

References:

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