Version May 2024
INTRODUCTION — The nomenclature of cutaneous small vessel vasculitis (CSVV) is diverse and often confusing. Names often used interchangeably but not always accurately, have included hypersensitivity angiitis, drug-induced vasculitis, leukocytoclastic vasculitis, cutaneous leukocytoclastic angiitis, serum sickness, serum sickness-like reactions, and allergic vasculitis. (See 'Definitions' below.)
This topic will present an overview of CSVV as a single-organ vasculitis limited to the skin. The evaluation and management of adults with cutaneous lesions of vasculitis are discussed in detail separately (see "Evaluation of adults with cutaneous lesions of vasculitis" and "Management of adults with idiopathic cutaneous small vessel vasculitis"). An overview of the approach to the vasculitides is also presented elsewhere. (See "Overview of and approach to the vasculitides in adults".)
DEFINITIONS
●Cutaneous small vessel vasculitis – Cutaneous small vessel vasculitis (CSVV) is defined as a single-organ, skin-isolated small vessel vasculitis or angiitis, often leukocytoclastic (LCV), without systemic vasculitis or glomerulonephritis [1,2].
It is important to note that the same cutaneous presentation can be seen in many other systemic small vessel vasculitides such as antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (eg, granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis, microscopic polyangiitis), cryoglobulinemic vasculitis, immunoglobulin A vasculitis (IgAV; Henoch-Schönlein purpura [HSP]), as well as other conditions such as infective endocarditis; thus, it should be regarded as a syndrome rather than a specific defined entity. When a patient presents with palpable purpura that reveals LCV on biopsy, the patient must be evaluated for a variety of causes and associated conditions (see "Evaluation of adults with cutaneous lesions of vasculitis" and "Overview of cryoglobulins and cryoglobulinemia"). Further delineation of etiology can only be done by integrating the clinical presentation, and in some cases (such as IgAV [HSP]), the presence or absence of vascular immunoglobulin deposition on skin biopsy. Some patients who are diagnosed initially as having a single organ cutaneous LCV can later develop a systemic form of small vessel vasculitis.
Cutaneous polyarteritis nodosa is a medium vessel vasculitis, as discussed elsewhere. (See "Cutaneous polyarteritis nodosa".)
Other terms that have been used interchangeably with CSVV, but should be considered separately are defined below:
●Leukocytoclastic vasculitis – LCV is a histopathologic term that defines vasculitis of the small vessels in which the inflammatory infiltrate is composed of neutrophils. After degranulation, neutrophils undergo death and break down, a process named leukocytoclasia, releasing nuclear debris, also described as nuclear dust.
●Lymphocytic vasculitis – Lymphocytic vasculitis is not a universally accepted concept. The inflammatory infiltrate targeting the vessel wall (not merely trafficking through) is predominantly lymphocytic; the pathogenesis is presumed to be cell-mediated; it is not the result of a stage of evolution of LCV where neutrophils are replaced with mononuclear cells. It should also be differentiated from conditions associated with perivascular lymphocytic infiltrates without fibrinoid necrosis [3].
●Hypersensitivity vasculitis – Hypersensitivity vasculitis is a term originally used by Pearl Zeek in 1948 to differentiate small vessel necrotizing vasculitis attributed to a hypersensitivity reaction from the classic polyarteritis nodosa [4] (see "Clinical manifestations and diagnosis of polyarteritis nodosa in adults"). Distinguishing features included prominent involvement of the skin, and the observation that the condition frequently appeared to be caused by a presumed "hypersensitivity" to serum or drugs. However, this term has fallen out of favor since the Chapel Hill 1994 consensus on the classification of vasculitides excluded the term because of a lack of specificity of clinical (palpable purpura) and histologic presentation (LCV), as well as the inability to describe the precise immune mechanism that caused the small vessel vasculitis. Patients who previously would have been classified as having hypersensitivity vasculitis are now diagnosed with cutaneous small vessel vasculitis if vasculitis is limited to the skin, or with another type of specific small vessel vasculitis if there is evidence of systemic involvement.
●Serum sickness – Serum sickness and serum sickness-like reaction are terms that are often used inconsistently. Historically, they have been applied to a clinical pathologic syndrome occurring 8 to 12 days after exposure to a therapeutic administration of foreign proteins. Consensus opinion would apply the diagnostic term "serum sickness" to the development of a rash (generally urticarial, morbilliform, or even angioedema), arthralgia, arthritis, and fever occurring 5 to 14 days after foreign protein, protein-based therapeutic biologic, or other drug exposure. Serum sickness and serum sickness-like reactions are discussed in detail elsewhere. (See "Serum sickness and serum sickness-like reactions".)
●Immune complex small vessel vasculitis – Immune complex small vessel vasculitis refers to vasculitis associated with immune complex and/or complement deposition, predominantly affecting small vessels. If limited to the skin, this is identical to cutaneous small vessel vasculitis. However, other systemic manifestations may occur, such as glomerulonephritis. When appropriate, immune complex vasculitis can be characterized as vasculitis associated with probable etiologies such as cryoglobulinemic vasculitis related to hepatitis C, systemic lupus erythematosus (SLE), Sjögren's disease, or rheumatoid arthritis [1]. Other examples of immune complex small vessel vasculitis include antiglomerular basement membrane disease, IgAV (HSP), and hypocomplementemic urticarial vasculitis. (See "Overview of and approach to the vasculitides in adults", section on 'Immune complex small-vessel vasculitis'.)
ETIOPATHOGENESIS — Almost all classes of drugs have been associated with cutaneous small vessel vasculitis (CSVV), but penicillins, cephalosporins, sulfonamides (including most loop and thiazide-type diuretics), phenytoin, and allopurinol have been most often implicated (table 1) [5,6]. Drugs may act as haptens to stimulate an immune response. Certain infections, such as hepatitis due to hepatitis B or C virus, chronic bacteriemias (eg, infective endocarditis, infected shunts), and human immunodeficiency virus (HIV), and other viruses, may also be associated with CSVV [6-8]. CSVV has been reported with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections and vaccinations [9,10].
CSVV is often mediated by immune complex deposition in the small vessels. Evidence for circulating immune complex formation includes the detection of soluble complexes, hypocomplementemia in many patients (but not immunoglobulin A vasculitis [IgAV; Henoch-Schönlein purpura (HSP)]), and the deposition of immune reactants in vessels [11,12].
CLINICAL PRESENTATION — The major clinical findings include palpable purpura (0.3 to 1 cm diameter) and/or petechiae (purpuric lesions less than 3 mm in diameter) that are nonblanching (picture 1). Sometimes these lesions coalesce, ulcerate, or are surrounded by hemorrhagic bullae. Urticarial lesions, which have a histologic pattern consistent with leukocytoclastic vasculitis, can also be observed. When the inciting agent is a drug or infectious agent, most patients develop symptoms and/or findings beginning 7 to 10 days after antigen exposure, which is the time required to produce a sufficient quantity of antibody to produce antigen-antibody complexes [13]. However, the latent period may be as short as two to seven days with a secondary antigen exposure, or may be longer than two weeks with a long-acting drug such as benzathine G penicillin [14].
By definition, in cutaneous small vessel vasculitis (CSVV) there is no visceral organ involvement. However, visceral involvement can occur later in the disease course, revealing a systemic small vessel vasculitic process.
In cases of immune complex-mediated vasculitis when the inciting agent persists, such as in hepatitis C-related cryoglobulinemic vasculitis, lupus erythematosus, or rheumatoid arthritis, chronic vasculitis can be observed, with waxing and waning lesions or persistent lesions of different ages. (See "Extrahepatic manifestations of hepatitis C virus infection".)
DIAGNOSIS — The diagnosis of cutaneous small vessel vasculitis (CSVV) is usually suggested by the clinical findings and by the history of an offending drug or infection [15]. If immunoglobulins such as immunoglobulin G (IgG), IgM and/or complement deposition are found on immunofluorescence, an immune complex mechanism is suggested as a cause. The absence of immune complex deposition may be due to late timing of biopsy relative to onset of skin lesion, or may be associated in some cases (but not always) with a pauciimmune type of vasculitis such as microscopic polyangiitis. If IgA deposition is noted on immunofluorescence microscopy of the skin lesion biopsy, and there is a history of joint or gastrointestinal symptoms, an assessment of urine sediment should take place and be repeated on subsequent visits. Immunoglobulin A vasculitis (IgAV), formerly known as Henoch-Schönlein purpura (HSP) is discussed elsewhere. (See "IgA vasculitis (Henoch-Schönlein purpura): Clinical manifestations and diagnosis", section on 'Diagnosis'.)
History and physical examination — The evaluation of the patient with cutaneous lesions suspicious for vasculitis is directed at addressing these questions:
●Is this vasculitis?
●Are other organs involved?
●What is the cause?
A history of new drugs and associated comorbidities (eg, infections, hepatitis C, or a systemic rheumatic disease) should be ascertained.
A comprehensive history and detailed physical examination should also be performed to determine whether the process is truly skin-limited, and that no organ-threatening systemic disease coexists. While the patient may only complain of the rash, more ominous damage, potentially irreversible and/or life-threatening, can coexist in other organs, such as alveolar hemorrhage, glomerulonephritis, mesenteric ischemia, or mononeuritis multiplex. Particular attention must be paid to potential organs targeted in small vessel vasculitis such as, but not limited to: lungs, kidneys, gastrointestinal tract, and peripheral and central nervous system.
Laboratory tests — The possibility of an underlying systemic disease must always be considered in a patient presenting with lesions suspicious for cutaneous vasculitis (table 2). Suggested laboratory tests are discussed separately (See "Evaluation of adults with cutaneous lesions of vasculitis", section on 'Evaluation for etiology and extracutaneous involvement'.)
Biopsy — Cutaneous lesions suspicious for vasculitis should be biopsied in almost all adult patients. Some experts feel that not all children need to have a biopsy performed. The pattern of cutaneous pathology and immunology is highly sensitive to the timing of the biopsy and the age of the lesion, with the lesions between 24 to 48 hours old preferred for biopsy. The core histological features on biopsy are infiltration with polymorphonuclear neutrophils in and around the vessel walls, with signs of activation, degranulation, and death of neutrophils illustrated by leukocytoclasia (nuclear dust); evidence of tissue damage (extravasated red blood cells, damaged endothelial cells, and occasionally necrosis of skin appendages); and fibrinoid necrosis (picture 1). A biopsy sample should also be sent for direct immunofluorescence (DIF) studies, but this specimen should be taken from the newest lesion that is able to be identified. A detailed discussion of the biopsy of patients with cutaneous vasculitis is presented elsewhere. (See "Evaluation of adults with cutaneous lesions of vasculitis", section on 'Skin biopsy to confirm vasculitis'.)
DIFFERENTIAL DIAGNOSIS — Cutaneous small vessel vasculitis (CSVV) may be impossible to distinguish from other forms of systemic vasculitis, unless other manifestations are present. In addition, palpable purpura and petechial lesions can also be present in other conditions. Examples of conditions that may present with cutaneous lesions of vasculitis include:
●Systemic vasculitides such as microscopic polyarteritis, granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome), immunoglobulin A vasculitis (IgAV; Henoch-Schönlein purpura [HSP]), other systemic immune complex vasculitides, and polyarteritis nodosa (including that due to hepatitis B), may present with predominantly cutaneous involvement, such as palpable purpura (table 2).
●Palpable purpura may, at times, be the presentation of paraneoplastic or malignancy-associated forms of vasculitis frequently due to a lymphoproliferative disease. These patients tend to have chronic purpura, often treatment resistant.
●The same process of red cell extravasation associated with purpuric skin lesions seen in vasculitis can be caused by noninflammatory vascular damage such as in scurvy, Ehlers-Danlos syndrome, cholesterol emboli, actinic and senile purpura, or glucocorticoid-induced purpura; or by coagulation and platelet disorders such as autoimmune thrombocytopenia or thrombotic thrombocytopenic purpura.
A more comprehensive list of differential diagnoses can be found elsewhere. (See "Evaluation of adults with cutaneous lesions of vasculitis", section on 'Types of cutaneous vasculitis'.)
TREATMENT — Once systemic involvement has been excluded and the diagnosis of single-organ cutaneous small vessel vasculitis (CSVV) has been made, the treatment is largely focused on symptom management. For cases in which the cause is thought to be due to a drug, discontinuation of the inciting drug or antigen should lead to resolution within a period of days to a few weeks. The recognition of CSVV due to an ongoing infection is also important since the administration of immunosuppressive medications may be harmful. In such cases, treatment should be aimed at the underlying infection, such as the administration of antibiotics for patients with endocarditis or antivirals for patients with hepatitis C or HIV.
Occasionally, patients develop persistent symptoms that may require systemic immunomodulatory drugs. For cases in which the cutaneous vasculitis is refractory to immunosuppressive therapy, a sustained search for an underlying cause, including malignancy, is indicated [16]. A discussion of the management of adults with cutaneous small vessel vasculitis is presented elsewhere. (See "Management of adults with idiopathic cutaneous small vessel vasculitis", section on 'Management'.)
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".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Beyond the Basics topics (see "Patient education: Vasculitis (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Definitions – Cutaneous small vessel vasculitis (CSVV) is defined as a single-organ, skin-isolated leukocytoclastic vasculitis (LCV) or angiitis without systemic vasculitis or glomerulonephritis. (See 'Definitions' above.)
●Etiopathogenesis – Many medications that can cause cutaneous vasculitis include penicillins, cephalosporins, sulfonamides (including most loop and thiazide-type diuretics), phenytoin, and allopurinol (table 1). Certain infections, such as hepatitis due to hepatitis B or C virus, chronic bacteriemias (eg, infective endocarditis, infected shunts), and HIV, and other viruses, may also be associated with CSVV. (See 'Etiopathogenesis' above.)
●Clinical presentation – The major clinical findings, include palpable purpura (0.3 to 1 cm diameter), and/or petechiae (purpuric lesions less than 3 mm in diameter), that are nonblanching (picture 1). (See 'Clinical presentation' above.)
●Diagnosis – The diagnosis of CSVV is usually suggested by the clinical findings and by the history of an offending drug or infection. A comprehensive history and detailed physical examination must be performed to determine whether the process is truly skin-limited, and that no organ-threatening systemic vasculitis or other disease coexists (table 2). Cutaneous lesions suspicious for vasculitis must be biopsied. (See 'Diagnosis' above.)
●Differential diagnosis – The differential diagnosis for CSVV is broad and includes systemic vasculitides (table 2), paraneoplastic or malignancy-associated vasculitis, and a variety of other causes of noninflammatory vascular damage such as scurvy, Ehlers-Danlos syndrome, cholesterol emboli, actinic and senile purpura, or glucocorticoid-induced purpura; or coagulation and platelet disorders such as autoimmune thrombocytopenia or thrombotic thrombocytopenic purpura. (See 'Differential diagnosis' above.)
●Treatment – Once systemic involvement has been excluded and the diagnosis of single-organ CSVV has been made, the treatment is largely focused on symptom management. (See 'Treatment' above.)
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