Primary cutaneous small vessel vasculitis: approach to diagnosis and treatment

Authors


Lawrence E. Gibson, md Department of Dermatology Mayo Clinic/Rochester 200 First Street SW Rochester, MN 55905 E-mail: gibson.lawrence@mayo.edu

Definition

Cutaneous leukocytoclastic vasculitis (LCV) most often manifests clinically as dependent palpable purpura. LCV is defined histologically as a predominantly neutrophilic perivascular infiltrate affecting cutaneous postcapillary venules with fibrinoid deposits in and around the vessel wall, endothelial swelling, and extravasation of red blood cells. Cutaneous LCV is commonly associated with a wide spectrum of systemic inflammatory conditions, malignancies, infections, or drug hypersensitivities. Many of these specific conditions are well characterized and have been reviewed in the literature with regard to clinical diagnosis and treatment regimens. It has been documented that, in clinical practice, 30–60% of cutaneous LCV cases appear to be limited to the skin without identifiable systemic or extracutaneous involvement and not attributable to a defined clinical entity.1–4 Termed primary cutaneous small vessel vasculitis (PCSVV), this idiopathic, limited cutaneous manifestation of LCV is therefore the most common clinical presentation of this histologic entity. We prefer the term PCSVV to the Chapel Hill Consensus Conference's “cutaneous leukocytoclastic angiitis” as “leukocytoclasia” is a histologic finding, not a clinical diagnosis, and LCV typically affects postcapillary venules not the arterial system.5 Although excellent reviews of general cutaneous small vessel vasculitides exist,6,7 dedicated articles on the diagnosis and therapeutics of PCSVV are quite rare, leaving the individual clinician without evidence-based guidance for the management of this symptomatic disorder. We present an update, based on both a literature review and our institutional experience, to provide an approach to clinical, serologic, and histologic evaluation and subsequent therapeutics for confirmed PCSVV (Table 1).

Table 1.  Etiologies associated with leukocytoclastic vasculitis
Systemic associated diseases
Drug reactions
 Beta-lactams
 Penicillin
 Sulfa drugs
 Nonsteroidal anti-inflammatory drugs
Infectious
 Viral
  Hepatitis B or C/human immunodeficiency virus
 Bacterial
  Streptococcus
  Staphylococcus
  Chlamydia
  Mycobacterium
 Fungal/yeast
  Candida
 Protozoan
Neoplastic
 Hematologic
  Non-Hodgkin's lymphoma
  Adult T-cell lymphoma
  Multiple myeloma
  Waldenström's macroglobulinemia
 Solid
  Lung
  Colon
  Renal
  Breast
  Prostate
  Head and neck
Inflammatory
 Connective tissue disease
  Systemic lupus erythematosus
  Rheumatoid arthritis
  Sjögren's syndrome
  Behçet's disease
 Vasculitis
  Churg–Strauss syndrome
  Polyarteritis nodosa
  Wegener's granulomatosis
  Microscopic polyangiitis
 Erythema elevatum diutinum
 Nodular vasculitis
 Inflammatory bowel disease
 Bowel bypass syndrome
 Cryoglobulinemia II, III

Based on vessel caliber classification schemes, PCSVV includes all cutaneous-limited LCV without extracutaneous involvement and, therefore, can encompass subsets of defined entities, such as “essential”/non-hepatitis C virus (HCV)-associated mixed cryoglobulinemia (EMC), normocomplementemic urticarial vasculitis (NUV), hypersensitivity vasculitis (HV), and acute hemorrhagic edema of infancy (AHEI). Henoch–Schönlein purpura (HSP), considered as a primary small vessel vasculitis, is absent in this discussion as it has, by clinical definition, variable extracutaneous features of nephropathy, joint, and gastrointestinal manifestations. The clinical manifestations and treatment of HSP have recently been reviewed in the International Journal of Dermatology by Fervenza.8 Because of the pitfalls of the varied clinical expression of HSP manifested over time, significant overlap with PCSVV may occur.9

As PCSVV is a diagnosis of exclusion, much of this article is devoted to subtle changes in clinical, serologic, or histologic manifestations that may be suggestive, but not diagnostic, of systemic disease or specific disease entities. Although considered to be “idiopathic”, PCSVV may simply be the initial clinical presentation of occult, preclinical, evolving systemic disease. With the development of newer and more sensitive laboratory evaluations, such as the relatively recent addition of serologic HCV testing, previously described “idiopathic” or “essential” cases of LCV may be better characterized. Therefore, close long-term patient follow-up with keen observation is a mainstay for the management of patients with PCSVV, as these subtle findings may provide indications of preclinical etiologies or systemic involvement, or may give insight to prognosis and to the need for future evaluation and treatment.

Clinical Presentation

PCSVV traditionally manifests clinically as either single or recurrent crops of nonthrombogenic palpable purpura, primarily involving dependent areas such as the buttocks, lower legs, ankles, and feet (Fig. 1). At times, the trunk and upper extremities can also be involved. Necrosis, ulceration, bullae, and nodules can also be seen, but are less prevalent in PCSVV.1,4,10 Nodular lesions, in particular, are often more suggestive of systemic involvement or involvement of larger caliber vessels, such as polyarteritis nodosa (PAN), especially in the clinical setting of livedo reticularis (Fig. 2).11 Purpuric lesions are frequently symptomatic, with tenderness, burning, stinging, and/or pruritus. Individual episodic crops traditionally resolve over 3–4 weeks and frequently leave ecchymotic stains or hyperpigmentation. Involvement is also frequently seen in areas of pressure or friction, such as waistbands, belts, shoulder straps, or sock collars. The extent of disease can be aggravated by exercise, sun exposure, extreme temperatures, and prolonged stasis or dependence. The majority of PCSVV cases are singly episodic and self-limited, although it has been reported that approximately 8–10% of patients can go on to develop recurrent or chronic involvement.10,12,13 Despite recurrent, relapsing, or chronic disease, most PCSVV cases carry a good overall prognosis.2,4,14

Figure 1.

Clinical photographs of palpable purpura/leukocytoclastic vasculitis (a) and urticarial vasculitis (b)

Figure 2.

Clinical photograph of livedo reticularis and polyarteritis nodosa

Fever and other constitutional symptoms occur frequently with PCSVV but, by definition, should be limited and without evidence of significant extracutaneous organ involvement. Prolonged or high fever and/or paresthesias in association with LCV have been shown to indicate a higher incidence of systemic involvement.10 Frank neuropathy/mononeuritis multiplex is suggestive of more significant vasculitic involvement, including perineural vessels. Interestingly, one case series has shown that painful discrete cutaneous lesions may have a prognostic significance towards PCSVV without systemic involvement.10 The reason for this finding is unclear. Mild myalgias and/or arthralgias can be seen in PCSVV, but frank arthritis with joint swelling or effusion is more suggestive of systemic disease or connective tissue disease.2,12,15 Significant subcutaneous edema associated with cutaneous vasculitic lesions can, at times, obscure the differentiation between simple arthralgias and joint or tendon swelling suggestive of true arthritis or ensethopathy.4

PCSVV can also include the subset of NUV, as frequently this entity is limited to the skin without identifiable systemic or etiologic causes. In contrast, hypocomplementemic urticarial vasculitis (HUV) is frequently associated with systemic lupus erythematosus (SLE) or SLE-like systemic findings, often with multiorgan involvement. Urticarial vasculitic lesions are clinically distinct, manifesting as more annular urticaria-like, edematous lesions lasting longer than 24 h, followed by ecchymosis, purpuric staining, or postinflammatory hyperpigmentation. Angiedematous involvement can also frequently be seen concomitantly with urticarial vasculitis eruption or between episodes. Urticarial vasculitis lesions have less predilection than traditional LCV for areas of dependence, and can occur on any area on the body. Patients often describe a burning or painful sensation more frequently than with the pruritus of simple urticaria.14 With regard to prognosis, urticarial vasculitis has been associated with a more chronic, relapsing/remitting disease course.2,15

PCSVV may also encompass some cases of EMC that do not have identifiable traditional systemic associations, including viral hepatitis, connective tissue disease, and hematologic malignancies. EMC frequently manifests clinically with systemic findings of arthralgias/arthritis, nephropathy, and neuropathy (mononeuritis multiplex/paresthesias), but may manifest solely in the skin. Mixed cryoglobulinemic vasculitis types II and III [polyclonal immunoglobulin G (IgG) and either monoclonal or polyclonal IgM, respectively] are manifested clinically by palpable purpura of dependent areas, as well as lesional involvement of cooler, acral sites thought to be secondary to temperature-sensitive cryoprecipitates of Ig complexes. A strong association between mixed cryoglobulinemic vasculitis and chronic HCV infection is well established.16,17 Prior to the recent development of HCV serologic/polymerase chain reaction testing, many “essential” cryoglobulinemias were likely to be secondary to occult HCV infection.18 In addition, it has been shown that the clinical manifestations of HCV can remain occult for up to more than 10 years after the initial infection. Therefore, the suspicion of hepatic viral infection in EMC should always remain high.14

AHEI may also be included under PCSVV. It is characterized clinically by purpuric lesional involvement of the face and extremities, and histologically as LCV. AHEI is frequently seen following bacterial or viral infection, but may occur without identifiable cause. Clinical or serologic evidence of systemic involvement is rare. The disease course is most often self-limited providing an excellent prognosis. AHEI rarely requires treatment. Some consider AHEI to be a variant of HSP, although systemic findings are rare in the former and cutaneous IgA antibody deposition is rarely seen on biopsy, in contrast with HSP.19

Evaluation

PCSVV, as a diagnosis of exclusion, requires a thorough evaluation to eliminate the multitude of etiologies summarized in Table 1. These disorders include connective tissue disorders (Sjögren's syndrome, SLE, rheumatoid arthritis), malignancies (solid tumors, leukemias/lymphomas), infection (streptococcus, bacterial endocarditis, HBV/HCV, human immunodeficiency virus), systemic necrotizing vasculitides (PAN, Wegener's granulomatosis, Churg–Strauss syndrome), and drug hypersensitivities. Prompt evaluation is necessary, as delay in the diagnosis and treatment of many of these etiologies can lead to significant mortality or morbidity. A complete history and physical examination are essential to observe patterns to help discern causative agents or disease characteristics. Careful attention to drug ingestion, inclusive of “homeopathic” medications, is important. A review of possible exposures (i.e. contact, infectious, chemical) and travel history may also elucidate an occult cause.

Laboratory investigation

Laboratory examinations for adults should initially include any pertinent infectious serologies and cultures (i.e. HBV, HCV, human immunodeficiency virus, antistreptolysin-O antibodies, fungal serologies), complete blood count, creatinine,, urine analysis, erythrocyte sedimentation rate (ESR), chest X-ray (CXR), liver function tests (LFTs), cutaneous biopsy for hematoxylin and eosin staining, and direct immunofluorescence (DIF). Stool guaiac testing should be performed to evaluate possible subclinical gastrointestinal involvement. Complement levels (CH50, C3, C4) should be drawn initially in any suspected urticarial vasculitis cases. Additional studies can be added as indicated by the history and physical examination and initial laboratory findings: antineutrophil cytoplasmic antibodies (ANCAs: p-, perinuclear; c-, cytoplasmic), including proteinase-3 (PR-3) and myeloperoxidase (MPO), antinuclear antibodies (ANAs), extractable nuclear antigens (ENAs), complement (CH50, C3, C4), rheumatoid factor (RF), serum protein electrophoresis (SPEP), cryoglobulins, nerve conduction studies, renal biopsy, or bone marrow biopsy (Table 2).

Table 2.  Laboratory evaluations for leukocytoclastic vasculitis
Initial laboratory screening
 Complete blood count with differential
 Erythrocyte sedimentation rate
 Urine analysis with microscopic analysis
 Creatinine
 Chest X-ray
 Infectious serologies/cultures (blood, urine, swabs)
 Liver function tests
 Hepatitis B and C
 Cutaneous biopsy
  Hematoxylin and eosin
  Direct immunofluorescence
 Stool guaiac
Additional evaluations
 Cryoglobulins
 Complement (CH50, C3, C4)
 Rheumatoid factor
 Antinuclear antibody/extractable nuclear antigen
 Anti-ds DNA
 Human immunodeficiency virus
 Serum protein electrophoresis
 Immunofixation
 Antineutrophil cytoplasmic antibodies (proteinase-3/myeloperoxidase)
 Renal biopsy
 Gastrointestinal evaluation/guaiac
 Bone marrow biopsy
 Nerve conduction studies

PCSVV in childhood is fairly rare, as HSP is by far the most likely cause of LCV in children, followed by an association with connective tissue disease.20 As HSP in children is a clinical diagnosis, Blanco et al.20 proposed a more limited initial evaluation in children vs. adults, including only history and physical examination, complete blood count, biochemistry profile, urine analysis, and guaiac test. Cutaneous biopsy in children is frequently not performed, as HSP is often a clinical diagnosis, but is warranted if there is suspicion of connective tissue disease.

If serologic testing reveals frankly positive results, further appropriately directed evaluation is mandatory. In clinical practice, serologic tests in patients with PCSVV are frequently negative or positive in low titre (i.e. ANA, RF, cryoglobulins), which can lead to difficulty in the interpretation of relevance.2,4,10 A review of case series suggests that certain trends may be helpful in predicting the clinical course and/or severity of involvement. An elevated ESR has been found in more than 50% of patients with limited cutaneous LCV; however, significantly elevated ESR in association with LCV (> 20–60 mm/h) has been suggested to be indicative of a higher incidence of systemic disease.2,3,4,10 Elevated RF, complement level abnormalities, and cryoglobulins have been found to be more suggestive of recurrent or chronic disease.10 The linkage of this triad of serologic abnormalities to chronicity in PCSVV and/or EMC mirrors the serologic findings in HCV-associated mixed cryoglobulinemia.16,17,20 A direct predictive relationship may exist between increasing cryoglobulins and the chance of chronic HCV infection. Many “essential” cryoglobulinemias in the past were probably HCV positive, although unidentified because of a previous lack of confirmatory serologic testing.16,18,20 As mentioned above, suspicion should remain high for HCV infection in PCSVV/EMC with these laboratory findings.

Commonly ordered serologic evaluations in practice include ANAs, ENAs, and ANCAs, including MPO and PR-3 antibodies. In general, ANCAs are strongly suggestive of systemic necrotizing vasculitic disorders, such as c-ANCA/PR-3 positivity in Wegener's granulomatosis. The combination of p-ANCA/MPO is more consistent with systemic vasculitides, especially microscopic polyangiitis (MPA), PAN, and Churg–Strauss syndrome, although p-ANCAs have also been found with PCSVV without evidence of systemic involvement.10,21,22 A comprehensive discussion of the relevance of ANCAs for the dermatologist has been published recently.21

Serum complement has long been implicated as a mediator of induction of vascular inflammation after initial immune complex deposition. Significant consumption/depletion suggests more extensive, severe, or systemic involvement, such as depressed complement in hepatitis-associated EMC.17 As mentioned earlier, abnormal levels of complement in association with urticarial vasculitis are strongly associated with SLE or SLE-like systemic disease, and therefore, when seen, portend a poorer prognosis.15

At least once-yearly clinical and serologic re-evaluation is recommended in all patients with recurrent or chronic disease, especially if prolonged immunosuppressive therapy is employed to exclude an occult or systemic disorder in evolution.

Biopsy/histology

Purpuric lesions alone are not sufficient to diagnose PCSVV. Cutaneous biopsy should always be performed to confirm LCV. It is well known that LCV has distinct dynamic histologic findings that vary in a progressive, time-dependent fashion. The timing and location of biopsy are critical to aid in a correct diagnosis. Ideally, a lesion should be sampled between 18 and 48 h of age, as findings for lesions over 48 h of age often reveal nonspecific inflammatory or healing reactions. Histologically, LCV is defined by a predominantly polymorphonuclear neutrophilic infiltrate, primarily affecting superficial postcapillary venules, with fibrinoid deposits in and around the vessel wall, endothelial swelling, and extravasation of red blood cells. Despite the known pathogenic role of neutrophils in vessel damage, LCV most often consists of a mixed cellular infiltrate of polymorphonuclear cells admixed with mononuclear cells, with mononuclear cells predominating as lesions reach more than 48 h of age.10,23,24 A predominantly dermal interstitial neutrophilic infiltrate has been shown to be more frequent in HUV, whereas LCV associated with eosinophils is more commonly seen in NUV.14,15 A direct predictive relationship of the severity of histologic changes in LCV and clinical severity has been described.25 The depth of vascular involvement can also be of significance. Sanchez and Su suggested that LCV extending into the deeper dermis is seen more often with systemic involvement. Therefore, biopsy to subcutaneous tissue is recommended. If nodose lesions are identified, biopsy selection should be made after the patient has stood for a few minutes, and a deeper biopsy should be performed to ensure the evaluation of deeper medium-sized vessels in order to rule out larger caliber vasculitic disease, such as cutaneous PAN.11 Finally, true lymphocytic vasculitis remains controversial, but may be found with more frequency in connective tissue disease, viral infection, and drug reactions.11,26 Granulomatous inflammation should lead to a strong consideration of a systemic necrotizing vasculitis or illness (Fig. 3).

Figure 3.

Histologic example of leukocytoclastic vasculitis (hematoxylin and eosin ×20)

Immunofluorescence

In clinical practice, it appears that many physicians forego cutaneous biopsy for DIF evaluation because of difficulty in identifying a lesion of the ideal age and in the interpretation of the result. Immune complexes are seen very early in a given lesion, but can be absent as soon as 48 h after appearance. DIF biopsy is best taken 8–24 h after appearance. Ideally, separate biopsies for hematoxylin and eosin and DIF should be performed, although logistics often dictate sampling of one lesion at one given time point. Frequently, especially in patients with widespread, recurrent crops of palpable purpura, knowledge of the age of lesions can be extremely difficult.

One prominent confounder of the interpretation of DIF staining is that areas of dependency, specifically the lower legs, demonstrate nonspecific fluorescence in uninvolved, normal skin, probably secondary to hydrostatic extravasation of circulating antibody complexes. We recommend biopsy for DIF of a noninfarcted lesion taken from the highest, most proximal, location possible27 (Fig 4).

Figure 4.

Direct immunofluorescence: (a) predominant, strong immunoglobulin A (IgA) staining of papillary vessels in Henoch–Schönlein purpura, this direct immunofluorescence is ×20; (b) IgM staining of hypocomplementemic urticarial vasculitis with granular staining of the basement membrane zone, suggestive of systemic lupus erythematosus this direct immunofluorescence is ×40

When evaluating LCV by DIF, the most common immunoreactants seen are IgM, C3, and fibrin.1,23,26 Prominent IgM can suggest RF-associated diseases, such as cryoglobulinemias or monoclonal lymphoproliferation.11 Strong deposition of C3 in either blood vessels or the basement membrane zone is more suggestive of HUV and less common in NUV.14 Predominant vascular IgA antibody deposition is thought to be quite sensitive for HSP in the appropriate clinical setting, whereas IgA seen mixed with other Ig (IgM, IgG) staining is nonspecific and can be frequently seen in non-HSP PCSVV and with streptococcal infection-associated LCV.1,10,23,27 A continuous granular band of C3 or IgG at the basement membrane zone, known as the lupus band, is found frequently in association with HUV, correlating with the higher incidence of SLE or SLE-like systemic disease.11 Unlike the depth of vasculitic involvement on hematoxylin and eosin staining, the depth of blood vessel Ig deposition does not correlate with the severity or prognosis of cutaneous vasculitis10,23 (Table 3).

Table 3.  High-yield clinical and laboratory findings for significant systemic disease-associated leukocytoclastic vasculitis
FindingAssociation
  1. c-ANCA, cytoplasmic-antineutrophil cytoplasmic antibody; BMZ, basement membrane zone; CSS, Churg–Strauss syndrome; ESR, erythrocyte sedimentation rate; HCV, hepatitis C virus; HSP, Henoch–Schönlein purpura; Ig, immunoglobulin; MPA, microscopic polyangiitis; PAN, polyarteritis nodosa; PR-3, proteinase-3; SLE, systemic lupus erythematosus; WG, Wegener's granulomatosis.

Clinical
High feverInfection, severe systemic inflammation
ParesthesiasSuggestive of deeper, perineural vasculature
Abdominal painVasculitic involvement of gastrointestinal vasculature (HSP)
Frank arthritisInfection, severe systemic inflammation
Laboratory evaluation
Abnormal creatinine and/or urine analysisSensitive for systemic disease (WG, MPA, SLE, HSP, CSS)
ESR > 40 mm/hInfection, hematologic malignancies, severe systemic inflammation
Elevated rheumatoid factor, cryoglobulins, and low complementTriad very suggestive of viral hepatitis/HCV
Abnormal complete blood countHematologic malignancies, infection, severe inflammation
Depressed complementSuggests SLE or SLE-like disease if associated with clinical urticarial vasculitis
Chest X-ray abnormalitiesInfection, WG, CSS, MPA, malignancy
c-ANCA/PR-3Strongly suggestive of Wegener's granulomatosis
Histological
Hematoxylin and eosin
 Vasculitis of deeper/larger vasculatureSuggestive of more severe, systemic disease (PAN)
Direct immunofluorescence
 Lupus band (granular IgG, IgM ± C3 at the BMZ)SLE or SLE-like disease associated with urticarial vasculitis
 Predominantly IgA vasculature depositionHighly suggestive of HSP

Treatment

After the exclusion of systemic disorders, the treatment of PCSVV is, for the most part, based on experience. Evidence-based recommendations are limited to case reports/series of both idiopathic and systemically associated cutaneous LCV.28 Treatment is clinically driven and based on the severity of symptoms and the extent of cutaneous involvement. The primary aim of therapy is to comfort the patient and prevent extensive cutaneous infarction. PCSVV carries an excellent prognosis and often is a single, episodic, self-limited disease, so initial therapy can be conservative. Bed rest, warming, and elevation of the lower extremities, nonsteroidal anti-inflammatory drugs (NSAIDs), analgesics, and antihistamines are used to treat symptomatic complaints such as pruritus and/or burning. None of these measures has been shown to significantly modify the disease course or prevent recurrences.3 Should the eruption be significantly symptomatic, recurrent, or progress to a nodular, ulcerative, or vesicobullous form, more aggressive systemic medications may be required. If more aggressive, prolonged, immunosuppressant modalities are employed, periodic (e.g. every 6–12 months) re-evaluation is highly recommended, as treatment may mask symptomatology or serologic abnormalities that would otherwise herald an underlying occult systemic disorder in evolution.

Diet has long been implicated as inciting clinical cutaneous manifestations, such as LCV. Two case series have shown moderate success in the treatment of cutaneous LCV with empiric elimination diets. Bland, low-antigenic diets were shown to prevent recurrences of palpable purpura, as well as to decrease serum levels of either immune complexes or cryoglobulins.29,30 In both incidences, there was clinical and serologic relapse on return to a normal diet. In conclusion, if ingestion-linked LCV or specific food allergen is suspected, allergy testing is first recommended; this can be followed by elimination or bland diet as long as adequate nutrition is maintained.

Colchicine, in doses of 0.6–1.8 mg/day, has been shown to induce prompt resolution of LCV and NUV within 1–2 weeks in multiple case reports.31–33 In contrast, the only prospective, randomized trial using colchicine in LCV showed no significant improvement, although the patients enrolled had LCV that was previously refractory to other traditional therapies and/or HCV infection. If patients can tolerate the gastrointestinal side-effects, colchicine appears to be a frequently effective, inexpensive medication used either as monotherapy or in combination.

Dapsone is primarily an anti-inflammatory medication with a predominantly antineutrophilic effect that is frequently used in various vasculitic diseases and neutrophilic dermatoses, such as Sweet's syndrome (SS), erythema elevatum diutinum (EED), pyoderma gangrenosum (PG), dermatitis herpetiformis (DH), and HSP.34 A few cases have shown complete resolution in cutaneous LCV and refractory HUV with doses of 100–200 mg daily.35–37 Although directly reported cases are few in the literature, dapsone is considered a frequent treatment modality in many vasculitis reviews.6,7,11 In patients with normal glucose-6-phosphate dehydrogenase (G6PD) function, the medication is frequently well tolerated, even with long-term administration, with minimal side-effects if administered and monitored correctly. The coadministration of pentoxifylline or colchicine with dapsone has been shown in a few case reports to be more efficacious than either drug as monotherapy.38–40

Prednisone is probably the most widely used treatment for PCSVV. Although no randomized, prospective studies exist, efficacy has frequently been reported in case reports and reviews.3,4,6,11,13 Initial doses of 0.5–1 mg/kg daily, with prolonged taper to prevent rebound, can be very effective to treat acute or single episodic PCSVV. Prednisone monotherapy, because of significant serious side-effects with long-term use, is not recommended for the treatment of recurrent or chronic PCSVV, as disease activity can persist for more than 10 years.10,12,13 In the setting of patients with four or more episodes per year, long-term use of other nonsteroidal agents is recommended to reduce prednisone dosing or as alternative monotherapies.

The efficacy of hydroxychloroquine in PCSVV in the literature appears to be limited to urticarial vasculitis, predominantly HUV, in doses of 200–400 mg daily.41 This limited efficacy may be explained by the fact that limited connective tissue disease is often responsive to hydroxychloroquine, perhaps mirroring the strong association of HUV with SLE or SLE-like systemic disease. Although controversial, G6PD evaluation is suggested prior to the initiation of therapy. Despite efficacy in HUV, there is no support in the literature for the use of hydroxychloroquine in PCSVV.3

For more recurrent, chronic, symptomatic PCSVV, steroid-sparing agents, such as azathioprine, mycophenolate mofetil, and cyclosporine, have been utilized. Azathioprine has been shown to be effective in preventing clinical recurrence, either as monotherapy or with low-dose continued prednisone.3,4,6,11,42 If employing azathioprine, it is extremely important to tailor medication dosing according to individual patient thiopurine methyltransferase (TPMT) levels to ensure appropriate therapeutic levels and to avoid toxicity.43,44 A comprehensive review of azathioprine has recently been published in the International Journal of Dermatology.44 Mycophenolate mofetil has been effective and well tolerated in systemic necrotizing vasculitis (Wegener's granulomatosis and MPA), as well as HUV, but no direct literature exists to support its use with PCSVV.45 Although probably similar in action to azathioprine, the significant expense of mycophenolate mofetil will probably continue to limit the expanded use of this drug. The use of cyclosporine in doses of 2.5–5 mg/kg/day is seen more frequently in the European literature, with good efficacy, although its use is limited to the treatment of acute disease, secondary to potentially significant serious side-effects with continued use.46,47 Methotrexate has been used in connective tissue-associated LCV and has been suggested to be helpful for cutaneous LCV;48 however, there have been multiple cases reports of methotrexate-induced LCV, making this a less attractive choice of therapy.

Ig administration has been effective in isolated severe cases with persistent ulcerations, suspected comorbid infection, or common variable immune deficiency, when added to traditional therapies.49,50 A recent practical review of the use of Ig therapy has been published in the International Journal of Dermatology.51 Plasma exchange has been shown to be effective in combination with or without prednisone in cases refractory to traditional therapies alone, but is very expensive, logistically cumbersome, and frequently requires continued use up to several times weekly52 (Table 4).

Table 4.  Review of options, cost, and considerations for treatment of primary cutaneous small vessel vasculitis (PCSVV)
TreatmentOpinionDoseConsiderationsPrice*
  • bid, twice daily; G6PD, glucose-6-phosphate dehydrogenase; GI, gastrointestinal; HUV, hypocomplementemic urticarial vasculitis; IVIG, intravenous immunoglobulin; LCV, leukocytoclastic vasculitis; NA, not applicable; TPMT, thiopurine methyltransferase.

  • *

    Based on a 70-kg patient per month.

Elimination dietMay be helpful in food allergen-suspected casesNAEnsure proper nutritionNA
ColchicineCan be efficacious as monotherapy or in combination with other modalities0.6 mg 1–3 times daily as toleratedFrequent GI complaints, monitor for hematologic abnormalities Extra caution in elderlyInexpensive, ∼$12/month (bid dosing)
DapsoneFrequently used, good evidence for efficacy in PCSVV100–200 mg/ kg/dayNeed prior G6PD testing Laboratory monitoring required for liver and hematologic changesInexpensive ∼$20 per month (200 mg/day)
PrednisoneExcellent for single episodic disease Frequently used0.5–1.0 mg/ kg/dayNeed slow taper (4–6 weeks) to prevent rebound. For long-term, use: GI prophylaxis, evaluations of blood pressure and glucose Inexpensive ∼$21 per month (1.0 mg/kg/day)
HydroxychloroquineUseful for HUV, no evidence in PCSVV200–400 mg/ kg/dayNeed G6PD and eye examination at baseline With eye examination every 6–12 months Inexpensive ∼$36 per month (200 mg bid)
AzathioprineGood efficacy/evidence for prednisone- sparing agent in PCSVVDependent on TPMT levelsNeed to check TPMT levels Need frequent laboratory monitoring Infection riskModerate expense ∼$60 per month (high TPMT, 1.5 mg/kg)
Mycophenolate mofetilHelpful in systemic vasculitides No reported cases in PCSVVUp to 2 g total dailyLaboratory monitoring for hematologic and liver abnormalities Infection riskVery expensive ∼$500 per month (1.5 g/day)
CyclosporineGood efficacy for acute disease with short-term use2.5–5 mg/ kg/dayMonitor for blood pressure, renal function, neurologic changes. Multiple drug–drug interactionsVery expensive ∼$300 per month (3 mg/kg/day)
MethotrexateNot indicated Few reports with LCV Many cases of inducing LCV   
IVIGCan be of benefit in LCV associated with immunodeficiency, persistent ulcers or chronic infection200–1000 mg/kg single dose given daily for 3–4 days or single doses every 3–4 weeksCardiovascular risk, anaphylaxisVery expensive ∼$50 per gram
PlasmapheresisHelpful in refractory casesAs neededCardiovascular riskVery expensive ∼$875–950 per treatment

Conclusion

PCSVV is one of the most common presentations of LCV in the skin. Fortunately, the great majority of patients with PCSVV have limited disease in terms of both duration and clinical involvement, and have a very good prognosis. Thorough and thoughtful initial evaluation frequently results in successful and appropriate care for these patients. As PCSVV is a diagnosis of exclusion, and may simply be representative of early preclinical or occult systemic disease in development, healthy suspicion is always warranted. Long-term, observant follow-up is therefore absolutely critical for the management of these patients. This is exceedingly important for patients with recurrent or chronic disease treated with immunosuppressant modalities, as therapy may mask clinical or serologic findings that otherwise would be harbingers of evolving systemic disease.

Questions

  • 1In the setting of primary cutaneous small vessel vasculitis, elevated rheumatoid factor, cryoglobulins, and abnormal complement levels may suggest which of the following?:
    • a tendency for chronic and recurrent disease;

    • b hypocomplementemic urticarial vasculitis;

    • c occult hepatitis C infection;

    • d a and c;

    • e all of the above.

  • 2Diagnostic direct immunofluorescence testing for specific immune complexes associated with leukocytoclastic vasculitis would probably be nonspecific or negative after:
    • a 8 h;

    • b 24 h;

    • c 48 h;

    • d 72 h.

  • 3The depth of vasculitic involvement on direct immunofluorescence evaluation has a direct predictive relationship to the extent or severity of clinical disease:
    • a true;

    • b false.

  • 4Which clinical or serologic finding is not suggestive of systemic disease involvement or a poor prognosis?:
    • a high fever;

    • b arthritis;

    • c painful individual lesions;

    • d paresthesias;

    • e depressed complement levels.

  • 5A biopsy for direct immunofluorescence has been obtained from a palpable purpuric lesion showing leukocytoclastic vasculitis on routine microscopy. Immunostaining on direct immunofluorescence reveals strong fluorescence of blood vessels with immunoglobulin A (IgA), IgM, and C3. This staining pattern suggests:
    • a Henoch–Schönlein purpura;

    • b background immunofluorescence due to leg dependence;

    • c primary cutaneous small vessel vasculitis;

    • d mixed cryoglobulinemia;

    • e all of the above are possible. Specific types of LCV require clinicopathologic correlation.

  • 6Which effective treatments for primary cutaneous small vessel vasculitis require specific evaluation of G6PD prior to initiation?:
    • a dapsone;

    • b prednisone;

    • c hydroxychloroquine;

    • d azathioprine;

    • e a and c.

  • 7A biopsy of a palpable purpuric lesion stained with hematoxylin and eosin reveals a predominantly mononuclear perivascular infiltrate. What does this suggest about the lesion?:
    • a it is an early lesion;

    • b it is an intermediate lesion;

    • c it is a late lesion;

  • d it is suggestive of hypocomplementemic vasculitis;

    • e it suggests severe systemic involvement.

  • 8An adult with palpable purpuric lesions and IgA blood vessel fluorescence by direct immunofluorescence by definition has Henoch–Schönlein pupura:
    • a true;

    • b false.

  • 9Positive antineutrophil cytoplasmic antibodies (ANCAs) are highly suggestive of systemic necrotizing vasculitis, although p-ANCAs can be found in which of the following?:
    • a microscopic polyangiitis;

    • b some patients with positive antinuclear antibodies;

    • c Churg–Strauss granulomatosis;

    • d infectious diseases;

    • e all of the above.

  • 10Which clinical lesion does not have a distinct predilection for cutaneous areas of dependence?:
    • a palpable purpura;

    • b nodular lesion;

    • c urticarial vasculitic lesion;

    • d bullous lesion;

    • e ulcerations.

  • 11Thiopurine methyltransferase is a critical enzyme in the metabolic pathway of which of the following drugs, and must be checked prior to the initiation of therapy?:
    • a colchicine;

    • b dapsone;

    • c azathioprine;

    • d mycophenolate mofetil;

    • e cyclosporine.

  • 12The recommended evaluation of a child presenting with leukocytoclastic vasculitis includes cutaneous biopsy with direct immunofluorescence if there is suspicion for connective tissue disease, but not with routine evaluation:
    • a true;

    • b false.

Answers

1, d; 2, c; 3, b; 4, c; 5, e; 6, e; 7, c; 8, b; 9, e; 10, c; 11, c; 12, a.

Acknowledgment

The Mayo Clinic and Mayo Foundation, Rochester, MN provided funding for this work.

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