Dermatologic Therapy, Vol. 14, 2001, 95–101Printed in the United States · All rights reserved

Copyright © Blackwell Science 2001

DERMATOLOGIC THERAPY

ISSN 1396-0296

95

Therapy of leukocytoclastic (necrotizing) cutaneous vasculitis

Warren W. Piette

Department of Dermatology, University of Iowa, Iowa City, Iowa

ABSTRACT:

There are multiple therapeutic options for cutaneous necrotizing vasculitis. The choice ofthe proper therapy is made more difficult by a variety of competing classification systems, and by apaucity of adequate clinical trials to assess efficacy of the most commonly used therapies. This articleoutlines an approach to therapy based on the diagnosis, the type of cutaneous involvement, the pres-ence or absence of extracutaneous findings, and the known risks and benefits of currently availabletherapies for vasculitis.

KEYWORDS:

skin, therapy, vasculitis.

The term vasculitis has been used to describe avariety of conditions, including “lymphocytic vas-culitis,” which is a controversial designation, andvarious occlusive vasculopathies which are notvessel-directed inflammatory injury and thereforenot vasculitis. This article addresses therapeuticissues relating to the necrotizing, leukocytoclas-tic, or neutrophil-rich variants of vasculitis whichcan affect the small vessels within the skin, withor without associated systemic findings.

Choosing the most appropriate therapy for apatient with a cutaneous necrotizing vasculitissyndrome skin remains a decision that dependson the particular vasculitic syndrome, the extentof the vasculitis, the patient’s desire for relief ofsymptoms, and the patient’s history of drug reac-tions or allergies. Therapeutic decisions also re-quire choosing between a number of therapieswith frequent clinical use but disappointingly fewor no controlled trials to help in the objective as-sessment of their efficacy and safety. The paucityof data is especially severe for those syndromesmost likely to be treated by dermatologists; thatis, syndromes with mild to severe cutaneous in-

volvement, with or without arthritis, and withminimal or no involvement of other organ sys-tems. Of necessity, then, discussions of therapyfor such patients remain dependent on past ex-perience and published therapeutic recommen-dations usually based on expert opinion.

For all syndromes, an appropriate history andphysical examination is an essential prerequisiteto recognizing the likelihood of extracutaneousdisease, and in identifying possible precipitatingfactors such as prescription medications, self-medications with herbals or other patient-initi-ated agents, infections, neoplasms, and rarelyfoods (1).

Syndromes of cutaneous vasculitis with minimal extracutaneous findings

Most cases of idiopathic small vessel vasculitisare self-limited, resolving in 2–4 weeks. In casesin which the vasculitic injury is skin-limited andmild, reduction of activity, leg elevation, leg com-pression, and the use of acetaminophen or non-steroidal anti-inflammatory drugs (NSAIDs) forlesional tenderness may be all that is indicated(2). Antihistamines may be useful in patients with

Address correspondence and reprint requests to: Warren W.Piette, MD, Department of Dermatology, University of Iowa,Iowa City, IA 52240.

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pruritus, and occasionally helpful in patientswith urticarial vasculitis. Most patients resolvetheir lesions within 2–4 weeks and need no fur-ther therapy or follow-up.

More aggressive therapy may be required inpatients with extensive, tender, or painful cuta-neous lesions; cutaneous lesions persisting or in-creasing in number after 2–3 weeks; or significantarthralgias or arthritis. The usual drugs consid-ered in this setting are colchicine, dapsone, or oc-casionally corticosteroids.

Many patients may benefit from colchicine 0.6mg up to three times a day as tolerated. Data re-lating to the use of colchicine are limited andcontradictory (3,4). Until convincing data areavailable as to efficacy, clinical experience wouldseem to support its use, especially in view of itsattractive risk:benefit ratio. When effective, bene-fit is usually evident within 2 weeks of initiation(5) (personal observation). Gastrointestinal symp-toms are the usual limiting factor in dosing. Its in-cidence of serious side effects when given orally israre, though intravenous colchicine has been im-plicated as a cause of aplastic anemia. Once con-trol has been achieved, control can often be main-tained on a slow taper, and the drug can be stoppedafter 2–3 weeks of clinical resolution. The recur-rence of lesions usually responds to the reinstitu-tion of therapy. Because the toxicity of oral colchi-cine, unlike intravenous colchicine, is largely limitedto bowel symptoms which are easily monitored clin-ically by both patient and physician, and because itsonset of action may be earlier than dapsone, colchi-cine may be more appropriate as an initial ther-apy in more active cutaneous syndromes. Colchi-cine is not appropriate for primary use in patientswith serious systemic disease, but may have ste-roid-sparing benefit.

Dapsone, in doses of 100–200 mg/day in adults,may be helpful in treating idiopathic cutaneousvasculitis, including Henoch–Schönlein purpura(6). It often requires several weeks to demonstrateefficacy in some patients. For such patients, othertherapies may be more appropriate in whomrapid relief of symptoms or interruption of dis-ease progression is vital. Dapsone has severalimportant risks, including hemolysis, and rarely,liver dysfunction, methemoglobinemia, agranu-locytosis, and neuropathy (7,8). Hemolysis is anexpected and dose-related complication in all pa-tients, but it is especially severe in patients withglucose-6-phosphate dehydrogenase (G6PD) de-ficiency.

Occasionally patients with minimal to modesthemolysis not ordinarily requiring discontinua-tion of the drug will have a disproportionate pro-duction of methemoglobin. Patients with acral orlip cyanosis, increasing fatigability, decreasing ex-ercise tolerance, or other symptoms which mightbe due to decreased oxygen-carrying capacity ofthe blood should have their methemoglobin levelchecked.

Laboratory monitoring of patients on dapsonetherapy should include complete blood count,liver enzymes, blood urea nitrogen, and creati-nine at the initiation of therapy. Screens for G6PDdeficiency are of some help in predicting thehemolytic response to dapsone. Recommenda-tions for further monitoring vary, but a reason-able approach is checking a CBC at 1 and 3 weeksafter initiation of therapy, monthly for 2–3 months,and a CBC and liver enzyme screen every 3–4months thereafter. Because dapsone, compared tocolchicine, appears to have a greater risk of toxicity,a delayed onset of action, and a greater need forlaboratory monitoring, dapsone might be moreappropriate for use when colchicine has failed.For patients with an incomplete response to ei-ther agent alone, but whose disease is milder andwithout serious extracutaneous disease, the use ofboth agents in combination may achieve control (5).Table 1 presents an overview of therapeutic strate-gies based on presenting signs and symptoms.

Corticosteroids are seldom indicated in skin-limited or skin-predominant vasculitic syndromes.However, even in patients with skin-limited dis-ease, progression of vasculitic lesions to plaques,necrotic vesicles, nodules, or ulcers may warrant atrial of corticosteroids. In addition, many patientsmay achieve symptomatic relief from arthritisonly with corticosteroid use. A short course ofcorticosteroid therapy when lesser therapies havefailed, or would be expected to act too slowly,may be useful in such settings (9). There is nocontrolled trial to support a long-term benefitfrom corticosteroids in isolated small vessel leu-kocytoclastic vasculitis.

In patients in whom the potential short-termbenefits appear to outweigh the well-known risksof corticosteroid therapy, an initial oral singledaily dose of 30–60 mg is usually sufficient to con-trol symptoms and lesion formation. The doseshould be discontinued by tapering at a pace gov-erned by response, usually over a 2- to 3-week pe-riod in an initial steroid responsive episode. Alter-nate therapies should be considered for patients

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who do not respond to this therapy, or in patientswhose disease recurs on tapering.

Even if colchicine or dapsone has failed toquiet vasculitis, it is reasonable to continue oneor both while using corticosteroid therapy in thehope that corticosteroids may be tapered morequickly once the syndrome is controlled.

Chronic or recurrent urticarial lesions are com-mon in both primary care and referral medicine(10). Diagnosis and treatment are usually a chal-lenge for both the patient and the physician. Mostpatients are eventually diagnosed with chronicidiopathic urticaria; only a minority (approxi-mately 10%) of patients with chronic urticariallesions have urticarial vasculitis. Although somecases are benign, urticarial vasculitis by itself cancause significant morbidity, and it is often a man-ifestation of a serious illness. Successful diagno-sis and treatment of urticarial vasculitis requirescareful assessment over time for underlying dis-eases such as systemic lupus erythematosus, hy-pocomplementemic urticarial vasculitis syndrome,Sjögren’s syndrome, and mixed cryoglobuline-mia (10).

The treatment of urticarial vasculitis, espe-cially when skin-limited, is less clear, with reportsof beneficial treatment with NSAIDs, colchicine,hydroxychloroquine, dapsone, methotrexate, in-

tramuscular gold therapy, azathioprine, and cy-clophosphamide (11–14). Colchicine, dapsone, andantimalarials may be the most frequently tried ther-apies in skin-predominant urticarial vasculitis.

While antimalarial drugs have been used inother syndromes of small vessel cutaneous vas-culitis, their effectiveness is not known (15). Dap-sone remains the treatment of choice in eryth-ema elevatum diutinum (EED) patients (11).

Henoch–Schönlein purpura/idiopathic IgA vasculitis

The use of either of Henoch–Schönlein purpura(HSP) or IgA vasculitis leads to some ambiguity ofmeaning. HSP is a clinical syndrome of skin, ab-dominal, renal, and other findings thought by someto be primarily limited to children. However, evi-dence suggests that childhood HSP is associatedwith IgA immune complexes, and idiopathic IgAvasculitis in both children and adults shares somecommon features. If IgA vasculitis is defined as anidiopathic vasculitis (thereby excluding IgA pre-dominant vasculitis seen in some patients with lu-pus, rheumatoid arthritis, and essential mixed cryo-globulinemia), then the finding of a small vessel

Table 1.

Treatment of cutaneous leukocytoclastic (necrotizing) vasculitis

Skin lesions only, minimal or no symptoms.

Minimize strenuous activity, leg compression, elevation.

Skin lesions painful, vesicular, extensive, or arthralgias, mild arthritis.

Colchicine 0.6 mg up to three times a day as tolerated (allow 1–2 weeks to judge response), or Dapsone 50–200 mg/day (allow 3–4 weeks to judge response).

If no response to first agent, try the second.If partial response to first agent, consider adding the second drug in

combination.Skin lesions necrotic/ulcerative,

moderate to severe arthralgias or arthritis, abnormal urinarysediment but normal creatinine.

Consider prednisone at dose of 30–60 mg/day each morning, and begin or continue colchicine or dapsone. Taper prednisone over a period of3–6 weeks, as therapeutic response allows.

If unable to completely taper steroids and maintain remission with dapsone or colchicine, consider use of other steroid-sparing agents, such as methotrexate, azathioprine, occasionally antimalarials.

Cutaneous vasculitis in association with more extensive systemic involvement or ANCA.

See text.

Special situations: Erythema elevatum diutinum: dapsone still treatment of choice.Urticarial vasculitis: rarely antihistamines and occasionally

antimalarials may be helpful in some cases. Hypocomplementemia may be sign of important systemic involvement.

Essential mixed cryoglobulinemia: always consider possibility of underlying hepatitis C

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leukocytoclastic vasculitis with predominant IgAimmune complex deposition may have certainprognostic and therapeutic implications (16).

Patients with idiopathic IgA vasculitis/HSPmay have milder syndromes of primarily cutane-ous vasculitis appropriately followed by derma-tologists and treated as described in the previoussection. However, some patients may developcomplications best treated in collaboration withprimary care or other specialist physicians.

IgA vasculitis/HSP tends to be recurrent inboth children and adults (16–18). It is importantto follow these patients closely because of the riskof recurrence and because of renal complica-tions. While acute glomerulonephritis is frequentin HSP, this is usually insignificant with respect tolong-term prognosis. However, primarily in chil-dren, there is risk of a rapidly progressive cres-centic glomerulonephritis, and this is what usu-ally leads to childhood renal failure due to HSP.Recent evidence suggests that pulse predniso-lone in conjunction with azathioprine or cyclo-phosphamide may be beneficial in patients withthis severe nephritis (18–21). In adult patients,the more likely risk for important renal diseaseresults from IgA mesangial glomerulonephritis(16). This renal complication has a smolderingcourse, with a long latency between onset of sub-clinical disease and the ultimate development ofrenal insufficiency or failure. Just as with diabeticnephropathy, careful monitoring for hyperten-sion and the use of angiotensin-converting en-zyme (ACE) inhibitors when indicated may slowthe silent progression of this disease and reducethe incidence of late-onset renal failure.

Syndromes of cutaneous vasculitis unresponsive to colchicine, dapsone, or short-course corticosteroid therapy

When patients fail colchicine or dapsone therapy,or recur whenever corticosteroids (alone or incombination with colchicine or dapsone) are ta-pered, alternate therapy is indicated. In additionto these three agents, cutaneous small vessel vas-culitis has been treated with a wide variety oftherapeutic agents, including NSAIDs, potassiumiodide, fibrinolytic agents, aminocaproic acid, cy-clophosphamide, azathioprine, methotrexate, cy-closporine, and monoclonal antibodies (22,23). De-

ciding when it is appropriate to use these agents isdifficult, especially with a paucity of clinical trialdata. The four agents usually considered in thissetting include azathioprine, methotrexate, cy-closporine, and cyclophosphamide, and their usehas been reviewed recently (24).

Azathioprine may be effective treatment forsmall vessel vasculitis (25,26). When colchicine ordapsone therapy has failed or is not tolerated,and severe chronic cutaneous vasculitis is beingcontrolled primarily with corticosteroids, azathi-oprine can be considered as adjunctive therapyearly in the course, just as steroid-sparing agentsare used in many rheumatic syndromes. When ef-fective, azathioprine may eventually allow the dis-continuation of corticosteroids in patients withchronic small vessel leukocytoclastic vasculitis.

The effective dose for cutaneous vasculitis isprobably between 50 and 150 mg/day (1–2 mg/kg/day) (24). It is a relatively safe drug when usedappropriately, although careful monitoring is im-portant. Screening for CBC with differential, re-nal, and hepatic function at 1 week, and then ev-ery week or every other week for the first 6 weeksseems reasonable. Follow-up thereafter may bemonthly. Once a stable dose is achieved, moni-toring of hematologic, hepatic, and renal screensare warranted at least every 3–4 months. Since al-lopurinol inhibits the xanthine oxidase-relatedmetabolism of azathioprine, the two should becombined only when absolutely necessary. Thedosage of azathioprine should be reduced by atleast two-thirds when used in conjunction withallopurinol (24). Myelosuppression and hepato-toxicity are some of the more common compli-cations of azathioprine therapy. The risk of myelo-suppression with azathioprine (and the chemicallyrelated drug mercaptopurine) can be substantiallyhigher in patients with intermediate or low thiopu-rine methyltransferase (TPMT) serum activity (27).Long-term use is associated with an increased riskof malignancies, especially skin cancers and lym-phomas. Pancreatitis can occur, and some patientsdevelop gastric intolerance.

An important, uncommon syndrome of azathi-oprine hypersensitivity can be fatal if not recog-nized and the drug discontinued (28,29). This syn-drome most commonly presents with fever andgastrointestinal symptoms, but with continueduse or rechallenge may result in multisystem fail-ure. It is not known whether TPMT activity pre-dicts a risk of the hypersensitivity syndrome. Inone patient who developed angioedema second-

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ary to azathioprine, a desensitization procedureappeared to be successful (30).

Methotrexate may be helpful in treating smallvessel leukocytoclastic vasculitis (31). Low-doseonce a week oral methotrexate, in a dose of up to25 mg/week, may be helpful as a single agent, orin reducing the amount of prednisone used tocontrol a vasculitic syndrome (32). Since its pri-mary route of excretion is renal, renal disease ormedications which impair renal excretion of meth-otrexate, such as aspirin or NSAIDs, can greatly in-crease the potential for life-threatening cytopeniasor cutaneous necrosis (33–35). Methotrexate hasrarely been implicated in induction or exacerba-tion of cutaneous vasculitic syndromes (36,37).

Cyclosporin A is an immunomodulating drugwith important side effects, including hyperten-sion, nephrotoxicity, and an increased risk of skincancer and lymphoma (24). Used alone or in com-bination with prednisolone, prednisone, or low-dose methotrexate, it has been useful in somecases of persistent idiopathic cutaneous vasculi-tis, polyarteritis nodosa, and vasculitis associatedwith connective tissue diseases and rheumatoidarthritis (23).

Cyclophosphamide is an important agent inthe treatment of certain cutaneous-systemic vas-culitides, but its use is associated with significanttoxicity and long-term risk of complications (seebelow). For this reason, cyclophosphamide andother alkylating agents are seldom indicated forskin-limited or minor cutaneous-systemic vascu-litic syndromes.

Cutaneous-systemic vasculitic syndromes with major systemic involvement or risk

Many vasculitic syndromes combine cutaneousand systemic involvement. In most instances, asidefrom the patient with minor arthritis, such patientsshould be followed in collaboration with a primarycare physician skilled in treating systemic vasculitis.

Corticosteroid therapy is more routinely givenas treatment for patients with the higher risk vas-culitic syndromes. Prednisone is the usual agent,given at 1 mg/kg/day orally, occasionally in di-vided doses every 6 hours in fulminant cases. Thedecision to taper to an alternate day regimen orto discontinue corticosteroid therapy is based onclinical response.

In many instances, corticosteroid therapy isinsufficient. This is especially true in patients withWegener’s granulomatosis, where the addition ofcyclophosphamide therapy has been a major ad-vance in improving prognosis and has becomethe treatment of choice as either daily oral or cy-clic intravenous pulse therapy. The usual oral reg-imen is 1–2 mg/kg/day of oral cyclophosphamide.The dosage is adjusted to maintain the total leu-kocyte count above 3000/mm

3

and the neutrophilcount above 1000–1500/mm

3

, assessed weekly (38).Patients should be treated for 1 year after achiev-ing remission, and then the cyclophosphamideshould be stopped and the patient followed care-fully for evidence of relapse. Cyclophosphamidetherapy is not without significant risk. Complica-tions include hemorrhagic cystitis, bone marrowsuppression, opportunistic infections, gonadal dys-function and possible sterility, and rarely, blad-der carcinoma, leukemia, or lymphoma.

Therapy of the anti-neutrophil cytoplasmic anti-body-associated vasculitides as well as other po-tentially life-threatening vasculitides continues toevolve. While cyclophosphamide remains a main-stay of therapy for many of these patients, theconsiderable acute and chronic toxicity of thismedication continues to drive trials of alternativeregimens. In cases resistant to conventional ther-apy, high-dose intravenous immunoglobulin, anti-thymocyte globulin, humanized monoclonal an-tibodies to CD4 or CDw52, or therapy directedagainst tumor necrosis factor may be helpful(39,40). Azathioprine may be as effective as cyclo-phosphamide for maintenance of remission, andrelapses may be prevented by elimination of

Staph-ylococcus

(39). Methotrexate has been used inconjunction with prednisone to treat Wegener’sgranulomatosis in patients without immediatelylife-threatening disease (41–43). Mycophenolatemofetil and leflunomide appear as alternativesfor maintenance therapy in pilot studies of theANCA vasculitides (44). Treatment for micro-scopic polyangiitis is often initially identical tothat for Wegener’s granulomatosis, though it isless clear that cyclophosphamide and corticoste-roid therapy is more beneficial than corticosteroidtherapy alone (45). Churg–Strauss vasculitis, an-other ANCA-associated vasculitis, is usually treatedwith corticosteroid alone, but interferon (IFN)-

�

may be effective in resistant cases (44). Intrave-nous immunoglobulin may be helpful occasion-ally in both Wegener’s granulomatosis and Churg–Straus vasculitis (46).

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100

Virus-associated vasculitides

Therapy of some vasculitides have been signifi-cantly affected by the recognition that viral infec-tions may be an underlying trigger for these syn-dromes in some patients. The most common ofthese is the association of hepatitis B virus (HBV)with classic polyarteritis nodosa (PAN), and hep-atitis C virus (HCV) with most cases of “essential”mixed cryoglobulinemia. In such cases, therapy isaltered compared to the same syndrome withoutunderlying viral association, though more suc-cessfully in some settings than in others. For ex-ample, antiviral agents are more successful in treat-ing HBV infection than HCV (47). HBV-related PANis more responsive to a combination of initial corti-costeroids to rapidly control the most severe life-threatening manifestations of PAN common dur-ing the first weeks of disease. This therapy may befollowed by abrupt cessation of corticosteroids toenhance immunologic clearance of HBV-infectedhepatocytes and to favor Hbe-Ag to anti-HBeAbseroconversion, followed by plasma exchanges tocontrol the course of PAN (47). Therapy of HCV-associated mixed cryoglobulinemia has been lesssuccessful, but clearly IFN-

�

or ribavarin can beused successfully in treating HCV essential mixedcryoglobulinemia (44,47).

Conclusion

The treatment of cutaneous vasculitis is currentlybased on approaches drawn primarily from ex-pert advice and anecdotal reports. The dangers ofrelying on such sources are well known and havebeen highlighted recently (2,48). However, untilappropriate trials can be conceived, funded, andcompleted, this remains the best available evi-dence for deciding therapy. For those interestedin the appropriate treatment of these patients,the challenge is clear.

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