Management of adults with idiopathic cutaneous small vessel vasculitis

INTRODUCTION — Cutaneous small vessel vasculitis (CSVV) is a disorder characterized by leukocytoclastic vasculitis involving the small blood vessels in the skin. By definition, vasculitis affecting other organ systems must be absent, and direct immunofluorescence should not reveal immunoglobulin A (IgA) predominance. CSVV may develop in association with a wide variety of factors, including drugs, infections, vaccines, systemic disease, or malignancy. An inciting factor is not detected in around one-third to one-half of patients. Such patients are designated here as having idiopathic CSVV.

Idiopathic CSVV often resolves within a few weeks, and thus, the management of most patients involves confirming the lack of an identifiable cause and the alleviation of symptoms. Systemic immunomodulatory therapy to arrest the disease process is usually reserved for the subset of patients who develop complications, such as hemorrhagic bullae, ulceration, or chronic or recurrent disease (algorithm 1).

The management of patients with idiopathic CSVV will be reviewed here. The evaluation of patients with cutaneous lesions of vasculitis and the clinical features and treatment of specific disorders that may present with vasculitis involving small vessels of the skin are discussed separately.

●(See "Evaluation of adults with cutaneous lesions of vasculitis".)

●(See "Overview of cutaneous small vessel vasculitis".)

●(See "Urticarial vasculitis".)

●(See "IgA vasculitis (Henoch-Schönlein purpura): Management".)

●(See "Treatment of rheumatoid vasculitis".)

●(See "Eosinophilic granulomatosis with polyangiitis (Churg-Strauss): Treatment and prognosis".)

●(See "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy".)

●(See "Mixed cryoglobulinemia syndrome: Treatment and prognosis".)

TERMINOLOGY AND DEFINITIONS

Cutaneous small vessel vasculitis — Cutaneous small vessel vasculitis (CSVV) is characterized by the presence of cutaneous lesions in conjunction with histopathologic evidence for a leukocytoclastic vasculitis involving the capillaries, venules, and arterioles in the skin. Although palpable purpura are the most common associated skin manifestations, other lesions such as petechiae, hemorrhagic bullae, ulcers, and urticaria may also develop (picture 1A-D). The skin lesions are often most prevalent on the lower legs and other dependent areas.

Other terms that have been used to refer to "cutaneous small vessel vasculitis" include "cutaneous leukocytoclastic vasculitis," "cutaneous leukocytoclastic angiitis," and "cutaneous necrotizing venulitis," all of which refer to the characteristic histopathologic findings in CSVV. The term "hypersensitivity vasculitis" has also been used to refer to CSVV but is most appropriately applied to CSVV caused by a known drug or infection. (See "Overview of cutaneous small vessel vasculitis", section on 'Definitions'.)

The 2012 Revised International Chapel Hill Consensus Conference Nomenclature classifies CSVV as a single-organ vasculitis, as does the dermatologic addendum to the 2012 Revised International Chapel Hill Consensus Conference [1,2].

Idiopathic cutaneous small vessel vasculitis — Idiopathic CSVV is CSVV that is limited to the skin and lacks an identifiable cause. In addition, direct immunofluorescence should not reveal IgA predominance, a finding supportive of IgA vasculitis. (See "IgA vasculitis (Henoch-Schönlein purpura): Clinical manifestations and diagnosis".)

A wide variety of factors can induce CSVV, including drugs, infections, systemic diseases, vaccines, malignancy, and, rarely, dietary factors [3,4]. In such cases, removal of the underlying cause may result in the resolution of CSVV [5-7]. Idiopathic CSVV, which accounts for 30 to 60 percent of cases, is a diagnosis of exclusion that can only be made when clinical history, review of recent medications, and clinical and laboratory investigations fail to yield both an underlying cause and the presence of systemic vasculitis [3,8]. In addition, systemic involvement should be excluded prior to making this diagnosis, since a more aggressive approach to therapy is usually indicated in patients with internal disease. (See "Evaluation of adults with cutaneous lesions of vasculitis", section on 'Evaluation for etiology and extracutaneous involvement'.)

PROGNOSIS — In most patients with cutaneous small vessel vasculitis (CSVV), the condition is self-limited and spontaneously resolves within two to four weeks [4,8]. In patients with self-limited disease, new lesion formation usually continues to occur during the first one to two weeks of the disease process. Chronic or recurrent disease occurs in approximately 10 percent of patients [3,4,9].

Postinflammatory hyperpigmentation and red-brown hemosiderin deposits in the skin that are secondary to the breakdown of extravasated erythrocytes commonly remain after an episode of CSVV. These lesions tend to resolve slowly over time; several months or more may be required for resolution.

MANAGEMENT — The clinical presentation of idiopathic cutaneous small vessel vasculitis (CSVV) influences the approach to treatment (algorithm 1). The management of patients with acute, uncomplicated disease differs from those with complicated, chronic, or recurrent idiopathic CSVV.

Acute and uncomplicated idiopathic cutaneous small vessel vasculitis — Acute and uncomplicated CSVV may be considered CSVV with:

●Duration of less than four weeks

●Palpable purpura or petechiae without blisters, skin necrosis, or ulceration

●No history of prior occurrence

Due to the high likelihood for spontaneous resolution, treatment to suppress the vasculitic process is not necessary in patients who present with acute and uncomplicated idiopathic CSVV (algorithm 1). However, some of these patients experience bothersome pruritus, pain, or local edema and may benefit from interventions that improve these symptoms.

Clinical experience suggests that the following measures can be beneficial [3]:

●Rest, leg elevation, and compression stockings – Disease may be exacerbated by exercise or prolonged maintenance of affected areas in dependent positions [3]. Leg elevation and use of compression stockings may decrease immune complex deposition in the lower extremities, thereby decreasing the progression of vasculitic skin lesions.

●Nonsteroidal anti-inflammatory drugs (NSAIDs) – NSAIDs may be useful for pain management. (See "NSAIDs: Therapeutic use and variability of response in adults", section on 'General principles'.)

●Oral antihistamines – Antihistamines may help to suppress pruritus. (See "Pruritus: Therapies for generalized pruritus", section on 'Role of antihistamines'.)

Complicated, chronic, or recurrent idiopathic cutaneous small vessel vasculitis — Complicated or chronic CSVV may be considered CSVV with:

●Associated hemorrhagic blisters, skin necrosis, or ulceration

●Active disease that persists for more than four weeks

●A history of prior occurrence

Whom to treat — Treatment aimed at arresting the disease process is indicated in patients with idiopathic CSVV complicated by the presence of hemorrhagic blisters, cutaneous necrosis, or ulceration, as these manifestations may lead to secondary infections, chronic wounds, and scarring (algorithm 1).

Patients with chronic idiopathic CSVV (active disease that persists for more than four weeks) or recurring disease are also candidates for therapeutic intervention. However, when chronic or recurrent disease is asymptomatic and patients are not bothered by the appearance of skin lesions, deferring treatment is a reasonable alternative.

Patients with chronic idiopathic CSVV who do not proceed with treatment should be re-evaluated every three to six months to ensure disease stability. The evaluation should consist of a directed review of systems, physical examination, and urinalysis to detect signs of worsening cutaneous involvement or new systemic involvement. Additional testing should be performed only if symptoms are present. (See "Evaluation of adults with cutaneous lesions of vasculitis", section on 'Review of systems'.)

Initial therapy — Systemic immunomodulatory drugs are the mainstays of treatment for patients with complicated or chronic idiopathic CSVV (algorithm 1). Our approach to these patients involves the initial use of a short course of prednisone in an attempt to abruptly suppress the disease process, followed by the use of colchicine and/or dapsone in patients who continue to have active disease. If the response to this regimen is inadequate, we consider the use of immunosuppressive agents. (See 'Relapse or persistent disease' below and 'Refractory disease' below.)

Much of the data used to guide the approach to the treatment of idiopathic CSVV are derived from case reports and small case series of patients with cutaneous leukocytoclastic vasculitis associated with a predisposing factor, with or without concomitant extracutaneous disease. The paucity of data on the efficacy of treatments precludes definitive conclusions on the efficacy of any specific therapy.

Systemic glucocorticoids — Systemic glucocorticoids are the most commonly utilized agents for the management of acute single episodes of CSVV [3]. In our experience, the vast majority of patients with idiopathic CSVV improve during therapy:

●Administration – We typically initiate treatment with prednisone at a dose of 0.5 mg/kg per day of ideal body weight until new lesion formation ceases (usually one to two weeks). The initial prednisone dose typically falls between 20 and 40 mg per day. This is followed by a taper to treatment cessation over the course of three to six weeks. Improvement is often detectable within one week after starting therapy. Patients who do not respond to prednisone should be transitioned to a glucocorticosteroid-sparing agent, such as colchicine or dapsone. (See 'Relapse or persistent disease' below.)

●Efficacy – No randomized trials have evaluated the efficacy of systemic glucocorticoid therapy in CSVV, and the use of these agents is primarily based upon reports of efficacy from small series of patients with various forms of cutaneous leukocytoclastic vasculitis [3,10-12].

Relapse or persistent disease — For patients in whom disease recurs upon tapering or discontinuation of an initial course of prednisone or who do not respond adequately to prednisone, continuation of long-term prednisone is not recommended due to the risk for drug-related side effects [13-17]. Rather, such patients should be transitioned to glucocorticoid-sparing medications, such as colchicine or dapsone (algorithm 1). If significant morbidity is likely to result from a disease flare, we continue prednisone at the lowest effective dose until the onset of action of the glucocorticoid-sparing agent. (See "Major adverse effects of systemic glucocorticoids".)

Colchicine or dapsone are inhibitors of neutrophil function. Although the data to support the efficacy of these therapies are limited, a trial of these agents is reasonable prior to the use of more aggressive immunosuppressive therapies [9]. (See 'Refractory disease' below.)

In our experience, both colchicine and dapsone therapy are useful for decreasing the reliance on prednisone in the majority of treated patients. We usually attempt treatment with colchicine first, due to the broader range of adverse effects associated with dapsone therapy.

Colchicine

●Precautions – Caution is indicated for colchicine therapy in patients with renal or hepatic impairment or who are taking a P-glycoprotein (P-gp) inhibitor (table 1) or strong cytochrome P450 3A4 (CYP3A4) inhibitor (table 2) due to increased risk for toxicity. Colchicine is contraindicated in patients who have renal or hepatic impairment who are also taking a P-gp inhibitor or strong CYP3A4 inhibitor. (See "Colchicine: Drug information".)

●Administration – Colchicine for CSVV is usually given as a 0.6 mg dose twice daily. Initial signs of response are typically observed within one to two weeks. Patients who respond typically continue treatment for a few months. (See 'Duration of therapy' below.)

If no response is noted after one week, increasing the dose to 0.6 mg three times per day may be attempted. However, drug-related, gastrointestinal adverse effects, such as diarrhea, nausea, vomiting, and abdominal pain, often limit dose escalation.

●Efficacy – Data conflict on the efficacy of colchicine in CSVV. An unblinded, randomized trial in which 41 patients with histopathologically confirmed cutaneous leukocytoclastic vasculitis (either idiopathic or associated with a predisposing factor) were treated for at least one month with either colchicine alone (0.5 mg twice daily) or topical emollients found no significant difference in efficacy between the two treatments [18]. The study included 16 patients who had been treated with other agents with variable responses, suggesting that an unspecified proportion of patients may have had refractory disease.

In contrast to the randomized trial, case series and case reports have suggested that colchicine therapy can be beneficial [8,11,19-22]. In one series, seven out of nine patients with chronic, biopsy-proven leukocytoclastic vasculitis who demonstrated improvement during treatment with colchicine had disease flares upon discontinuation of the drug and recurrent improvement with drug reinitiation [20].

Dapsone

●Precautions – Clinicians who prescribe dapsone must remain cognizant of the drug's potential adverse effects. Hemolytic anemia is a common consequence of treatment that occurs in all patients with varying severity, and close monitoring of hematologic status, especially early in the course of therapy, is essential. In particular, dapsone therapy should be avoided in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency due to a high risk for severe hemolytic anemia. Other potential adverse effects of dapsone include idiosyncratic agranulocytosis, a hypersensitivity syndrome, hepatitis, and peripheral motor neuropathy. (See "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency", section on 'Avoidance of unsafe drugs and chemicals'.)

●Administration – If baseline laboratory studies, including a complete blood count, comprehensive metabolic panel to assess liver and renal function, and a G6PD assay are within normal limits, we typically begin treatment with 100 mg of dapsone per day. Signs of improvement are often noted as early as one week after the initiation of therapy [23]. Patients who respond typically continue treatment for a few months. (See 'Duration of therapy' below.)

Standard monitoring recommendations include a complete blood count once weekly during the first month of therapy and periodic monitoring of liver function tests. Obtaining complete blood counts and liver function tests every other week during the first month of therapy has seemed sufficient in the author's practice. Provided the drug dose remains stable, the frequency of these studies can then be reduced to once monthly for three to four months, followed by once every three to four months.

For patients who fail to exhibit signs of improvement after two weeks at 100 mg of dapsone per day, we increase the daily dose to 150 mg. If the response to 150 mg per day of dapsone is unsatisfactory, we proceed to immunosuppressive therapy. An alternative that we typically reserve for select patients with relatively mild, uncomplicated CSVV is a trial of combination therapy with dapsone and pentoxifylline prior to proceeding to immunosuppressive therapy. (See 'Refractory disease' below.)

●Efficacy – Data in support of dapsone use are limited to case reports in patients with various forms of cutaneous leukocytoclastic vasculitis [23-31]. As with colchicine, there are reports in which disease improved during treatment and recurred upon the discontinuation of dapsone therapy [23,24].

The addition of pentoxifylline (400 mg three times daily) to dapsone (100 mg per day) was associated with improvement of dapsone-resistant cutaneous leukocytoclastic vasculitis related to rheumatoid arthritis and urticarial vasculitis within two weeks in two patients [32]. However, additional studies are necessary to confirm the efficacy of the dapsone-pentoxifylline combination.

Refractory disease — When disease persists despite treatment with prednisone, colchicine, and dapsone, we initiate systemic immunosuppressive therapy (algorithm 1). Because no high-quality studies have evaluated the efficacy of these agents for cutaneous vasculitis, patient-specific concerns for drug adverse effects and contraindications heavily influence treatment selection.

The immunosuppressive agents we most frequently prescribe for idiopathic CSVV are mycophenolate mofetil, azathioprine, and methotrexate:

●Mycophenolate mofetil – Data on the efficacy of mycophenolate mofetil in CSVV are limited. Treatment with mycophenolate mofetil (1 to 1.5 g twice daily) led to the resolution of idiopathic CSVV within two months in a patient who improved only partially on colchicine and dapsone therapy [33]. Mycophenolate mofetil has also been associated with beneficial effects in a few patients with cutaneous leukocytoclastic vasculitis related to IgA vasculitis (Henoch-Schönlein purpura) or urticarial vasculitis [34,35]. (See "Mycophenolate: Overview of use and adverse effects in the treatment of rheumatic diseases".)

●Azathioprine – Azathioprine may be administered in doses of 0.5 to 2.5 mg/kg per day, with appropriate dosing dependent upon the patient's thiopurine methyltransferase (TPMT) enzyme activity [36]. Responses to therapy are typically evident within two months. (See "Pharmacology and side effects of azathioprine when used in rheumatic diseases" and "Thiopurines: Pretreatment testing and approach to therapeutic drug monitoring for adults with inflammatory bowel disease".)

Although a randomized trial in 19 patients with cutaneous leukocytoclastic vasculitis and rheumatoid arthritis failed to find significant benefit of treatment with azathioprine plus prednisone when this regimen was compared with the continuation of arthritis regimens containing NSAIDs, hydroxychloroquine, aurothioglucose, penicillamine, or sulfasalazine [37], small case series have documented improvement in cutaneous leukocytoclastic vasculitis during azathioprine therapy [11,38,39].

●Methotrexate – Methotrexate (10 to 20 mg per week) has been reported to be effective in individual patients with cutaneous vasculitis related to autoimmune disorders, with responses often detected within four to eight weeks [40-43]. However, treatment with methotrexate has also been associated with the induction of cutaneous vasculitis [44-46]. (See "Major side effects of low-dose methotrexate".)

Cyclosporine may also be beneficial in some patients with cutaneous vasculitis. In a small, open-label study of patients with severe or refractory cutaneous vasculitis, a regimen containing cyclosporine (5 mg/kg per day) or cyclosporine followed by prednisone therapy was linked to good responses in 5 out of 12 patients (follow-up period of 4 to 12 months) [47]. However, the development of renal toxicity may limit the duration of treatment with cyclosporine. (See "Pharmacology of cyclosporine and tacrolimus" and "Cyclosporine and tacrolimus nephrotoxicity".)

Cyclophosphamide, an aggressive immunosuppressive agent used in the management of systemic vasculitis, is not typically prescribed for CSVV due to the possibility for serious, drug-related adverse effects, including infertility. (See "General toxicity of cyclophosphamide in rheumatic diseases".)

Duration of therapy — The duration of colchicine, dapsone, and immunosuppressive treatment in patients with chronic or complicated CSVV varies. We typically attempt to discontinue therapy once existing lesions have healed and no new lesions have developed for two to three months. If lesions recur, treatment is reinitiated. The optimal regimen for discontinuing therapy in idiopathic CSVV is unknown; we typically decrease the dose of medication over the course of a few weeks and monitor for disease flares prior to complete drug cessation.

Other therapies — Hydroxychloroquine is a well-tolerated drug that has been reported to be effective in the treatment of urticarial vasculitis. The efficacy of hydroxychloroquine in other forms of idiopathic CSVV is unknown. (See "Urticarial vasculitis", section on 'Treatment'.)

Additional agents reported to be useful in individual patients with cutaneous leukocytoclastic vasculitis include minocycline [48], rituximab [49], chlorambucil [50], and intravenous immune globulin [51]. Topical corticosteroids are commonly used for the management of inflammatory skin diseases, but these agents have not been formally evaluated in the treatment of CSVV. In our experience, treatment with topical corticosteroids has not been beneficial.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Vasculitis".)

SUMMARY AND RECOMMENDATIONS

●Overview – Cutaneous small vessel vasculitis (CSVV) is a vasculitic disorder characterized by involvement limited to the skin and histopathologic evidence for a leukocytoclastic vasculitis involving the capillaries, venules, and arterioles in the skin. Palpable purpura are the most common clinical manifestations.

Idiopathic CSVV is CSVV for which an underlying cause cannot be identified. Idiopathic CSVV is a diagnosis of exclusion that accounts for 30 to 60 percent of cases of CSVV. (See 'Terminology and definitions' above.)

●Acute and uncomplicated idiopathic cutaneous small vessel vasculitis – Acute and uncomplicated idiopathic CSVV may be considered an initial episode of idiopathic CSVV that has persisted for less than four weeks and lacks blistering, skin necrosis, and ulceration.

In most patients, idiopathic CSVV resolves spontaneously within a few weeks, negating the need for treatment to stop the disease process. For patients with acute, uncomplicated idiopathic CSVV, we suggest supportive care rather than systemic immunomodulatory treatment (algorithm 1) (Grade 2C). Supportive care focuses on the alleviation of symptoms and includes rest, leg elevation, compression stockings, and treatment for pain and pruritus. (See 'Acute and uncomplicated idiopathic cutaneous small vessel vasculitis' above and 'Prognosis' above.)

●Complicated, chronic, or recurrent idiopathic cutaneous small vessel vasculitis – Systemic immunomodulatory therapy to arrest disease activity is indicated for idiopathic CSVV complicated by blisters, skin necrosis, or ulcers (algorithm 1). Systemic immunomodulatory therapy is also appropriate for chronic (lasting more than four weeks) or recurrent idiopathic CSVV. Deferring treatment is a reasonable alternative for patients with asymptomatic chronic or recurrent CSVV who are not bothered by the skin lesions (see 'Complicated, chronic, or recurrent idiopathic cutaneous small vessel vasculitis' above and 'Whom to treat' above):

•Initial therapy – For patients with complicated, chronic, or recurrent idiopathic CSVV, we suggest prednisone as the initial systemic therapy rather than other immunomodulatory therapies (algorithm 1) (Grade 2C). Prednisone (0.5 mg/kg per day of ideal body weight) is given until new lesion formation ceases (usually one to two weeks) and is subsequently tapered over three to six weeks. (See 'Initial therapy' above.)

•Relapse or persistent disease – The potential serious adverse effects of systemic glucocorticoid therapy limit the long-term use of this therapy. For patients who relapse upon tapering or discontinuation of prednisone or fail to respond adequately to prednisone, we suggest treatment with colchicine or dapsone rather than other immunomodulatory therapies (algorithm 1) (Grade 2C). We typically attempt treatment with colchicine first, due to the broader range of adverse effects associated with dapsone therapy. (See 'Colchicine' above and 'Dapsone' above.)

•Refractory disease – Patients with CSVV refractory to prednisone, colchicine, and dapsone may benefit from immunosuppressive therapies, such as azathioprine, mycophenolate mofetil, or methotrexate. (See 'Refractory disease' above.)