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Figure 1.
Histological evidence of cutaneous leukocytoclastic vasculitis, with infiltrating neutrophils, nuclear dust, and fibrinoid necrosis of the vessel walls in the superficial dermis (hematoxylin-eosin, original magnification ×100).

Histological evidence of cutaneous leukocytoclastic vasculitis, with infiltrating neutrophils, nuclear dust, and fibrinoid necrosis of the vessel walls in the superficial dermis (hematoxylin-eosin, original magnification ×100).

Figure 2.
Palpable purpura and severe cutaneous necrosis on the legs of a patient with chronic leukocytoclastic vasculitis limited to the skin.

Palpable purpura and severe cutaneous necrosis on the legs of a patient with chronic leukocytoclastic vasculitis limited to the skin.

Figure 3.
Direct immunofluorescence and duration of the cutaneous vasculitic lesion studied by biopsy. Plus sign indicates positive; minus sign, negative. P<.001 for the 4 groups compared.

Direct immunofluorescence and duration of the cutaneous vasculitic lesion studied by biopsy. Plus sign indicates positive; minus sign, negative. P<.001 for the 4 groups compared.

Table 1. 
Immunological Characteristics of 160 Patients With Leukocytoclastic Vasculitis*
Immunological Characteristics of 160 Patients With Leukocytoclastic Vasculitis*
Table 2. 
Causal Agents, Associated Conditions, and Vasculitis Syndromes Identified
Causal Agents, Associated Conditions, and Vasculitis Syndromes Identified
Table 3. 
Crude and Adjusted Relative Risk of Chronic Evolution of the Cutaneous Vasculitis for All Relevant Factors Examined by Multiple Logistic Regression*
Crude and Adjusted Relative Risk of Chronic Evolution of the Cutaneous Vasculitis for All Relevant Factors Examined by Multiple Logistic Regression*
Table 4. 
Crude and Adjusted Relative Risk of Systemic Vasculitis Involvement for All Relevant Factors Examined by Multiple Logistic Regression*
Crude and Adjusted Relative Risk of Systemic Vasculitis Involvement for All Relevant Factors Examined by Multiple Logistic Regression*
1.
Mackel  SEJordon  RE Leukocytoclastic vasculitis: a cutaneous expression of immune complex disease. Arch Dermatol. 1982;118296- 301Article
2.
Jennette  JCCharles  LAFalk  RJLe  Roy ECed The neutrophil and its role in systemic vasculitis. Systemic Vasculitis: The Biological Basis New York, NY Marcel Dekker Inc1992;65- 92
3.
Fauci  ASHaynes  BFKatz  P NIH Conference: the spectrum of vasculitis: clinical, pathologic, immunologic, and therapeutic considerations. Ann Intern Med. 1978;89660- 676Article
4.
Jennette  CJMilling  DMFalk  RJ Vasculitis affecting the skin: a review. Arch Dermatol. 1994;130899- 906Article
5.
Conn  DL Update on systemic necrotizing vasculitis. Mayo Clin Proc. 1989;64535- 543Article
6.
Sais  GVidaller  AJucglà  ACondom  EPeyrí  J Adhesion molecule expression and endothelial cell activation in cutaneous leukocytoclastic vasculitis: an immunohistological and clinical study on 42 cases. Arch Dermatol. 1997;133443- 450Article
7.
Sánchez  NPVan Hale  HMSu  D Clinical and histopathologic spectrum of necrotizing vasculitis: report of findings in 101 cases. Arch Dermatol. 1985;121220- 224Article
8.
af Ekenstam  ECallen  JP Cutaneous leukocytoclastic vasculitis: clinical and laboratory features of 82 patients seen in private practice. Arch Dermatol. 1984;120484- 489Article
9.
Cupps  TRSpringer  RMFauci  AS Chronic, recurrent, small-vessel cutaneous vasculitis: clinical experience in 13 patients. JAMA. 1982;2471994- 1998Article
10.
Gibson  LE Cutaneous vasculitis: approach to diagnosis and systemic associations. Mayo Clin Proc. 1990;65221- 229Article
11.
Somer  TFinegold  S Vasculitides associated with infections, immunization, and antimicrobial drugs. Clin Infect Dis. 1995;201010- 1036Article
12.
Agnello  VChung  RTKaplan  LM A role for hepatitis C virus infection in type II cryoglobulinemia. N Engl J Med. 1992;3271490- 1495Article
13.
Heart-Holmes  MZahradka  SLBaethge  BAWolf  RE Leukocytoclastic vasculitis associated with hepatitis C. Am J Med. 1991;90765- 766Article
14.
Misiani  RBellavita  PFenili  D  et al.  Hepatitis C virus infection in patients with essential mixed cryoglobulinemia. Ann Intern Med. 1992;117573- 577Article
15.
Popp  JWHarrist  TJDienstang  JL  et al.  Cutaneous vasculitis associated with acute and chronic hepatitis. Arch Intern Med. 1981;141623- 629Article
16.
Daoud  MSel-Azhary  RAGibson  LELutz  MEDaoud  S Chronic hepatitis C, cryoglobulinemia and cutaneous necrotizing vasculitis. J Am Acad Dermatol. 1996;34219- 223Article
17.
Karlsberg  PLLee  WMCasey  DLCockerell  CJCruz Jr  PD Cutaneous vasculitis and rheumatoid factor positivity as presenting signs of hepatitis C virus–induced mixed cryoglobulinemia. Arch Dermatol. 1995;1311119- 1123Article
18.
Gherardi  RBelec  LMhiri  C  et al.  The spectrum of vasculitis in human immunodeficiency virus–infected patients: a clinicopathologic evaluation. Arthritis Rheum. 1993;361164- 1174Article
19.
Calabresse  LHEstes  MYen-Lieberman  B  et al.  Systemic vasculitis in association with human immunodeficiency virus infection. Arthritis Rheum. 1989;32569- 576Article
20.
Sanchez Guerrero  JGutierrez Urena  JVidaller  AReyes  EIglesias  AAlarcon-Segovia  D Vasculitis as a paraneoplastic syndrome: report of 11 cases and review of the literature. J Rheumatol. 1990;171458- 1462
21.
Greer  JMLongley  SEdwards  NLElfenbein  GJPanush  RS Vasculitis associated with malignancy: experience with 13 patients and literature review. Medicine (Baltimore). 1988;67220- 230Article
22.
Sais  GVidaller  AJucglà  AGallardo  FPeyrí  J Colchicine in the treatment of cutaneous leukocytoclastic vasculitis: results of a prospective, randomized controlled trial. Arch Dermatol. 1995;1311399- 1402Article
23.
Conn  DLLe  Roy ECed Overview of therapy and management of systemic vasculitis. Systemic Vasculitis: The Biological Basis New York, NY Marcel Dekker Inc1992;547- 574
24.
Hunder  GHArend  WPBloch  DA  et al.  The American College of Rheumatology 1990 criteria for the classification of vasculitis. Arthritis Rheum. 1990;331065- 1144Article
25.
Lie  JTMembers and Consultants of the American College of Rheumatology Subcommittee on Classification of Vasculitis, Illustrated histopathologic classification criteria for selected vasculitis syndromes. Arthritis Rheum. 1990;331074- 1087Article
26.
Prins  MVeraart  JCJMVermeulen  AHMHulsmans  FHJNeumann  HAM Leukocytoclastic vasculitis induced by prolonged exercise. Br J Dermatol. 1996;134915- 918Article
27.
Zax  RHHodge  SJCallen  JP Cutaneous leukocytoclastic vasculitis: serial histopathologic evaluation demonstrates the dynamic nature of the infiltrate. Arch Dermatol. 1990;12669- 72Article
28.
Gower  RGSams Jr  WMThorne  EG Leukocytoclastic vasculitis: sequential appearance of immunoreactants and cellular changes in serial biopsies. J Invest Dermatol. 1977;69477- 484Article
29.
Michel  BAHunder  GGBloch  DACalabrese  LH Hypersensitivity vasculitis and Henoch-Schönlein purpura: a comparison between the 2 disorders. J Rheumatol. 1992;19721- 728
30.
Schroeter  ALCopeman  PWMJordon  RESams Jr  WMWinkelman  RK Immunofluorescence of cutaneous vasculitis associated with systemic disease. Arch Dermatol. 1971;104254- 259Article
31.
Hené  RJVelthuis  Pvan de Wiel  AKlepper  DDorhout Mees  EJKater  L The relevance of IgA deposits in vessel walls of clinically normal skin: a prospective study. Arch Intern Med. 1986;146745- 749Article
32.
Helander  SDDe Castro  FRGibson  LE Henoch-Schönlein purpura: clinicopathologic correlation of cutaneous vascular IgA deposits and the relationship to leukocytoclastic vasculitis. Acta Derm Venereol. 1995;75125- 129
33.
Van Hale  HMGibson  LESchroeter  AL Henoch-Schönlein vasculitis: direct immunofluorescence study of uninvolved skin. J Am Acad Dermatol. 1986;15665- 670Article
34.
Tsai  CCGiangiacomo  JZuckner  J Dermal IgA deposits in Henoch-Schönlein purpura and Berger's nephritis. Lancet. 1975;1342- 343Article
35.
Saklayen  MGSchroeter  ANafs  MAJalil  K IgA deposition in the skin of patients with alcoholic liver disease. J Cutan Pathol. 1996;2312- 18Article
36.
Hirbec  GBelghiti  DWechsler  JSobel  ALagrue  G Immunofluorescence study of skin biopsy specimens from patients with chronic renal diseases. Kidney Int. 1977;12374Abstract
37.
Swerdlow  MAChowdhury  LNMishra  VKavin  H IgA deposits in skin in alcoholic liver disease. J Am Acad Dermatol. 1983;9232- 236Article
38.
Thompson  AJChan  Y-LWoodroffe  AJ Vascular IgA deposits in clinically normal skin of patients with renal disease. Pathology. 1980;12407- 413Article
39.
Van der Woude  FJLobato  SPermin  H  et al.  Autoantibodies against neutrophils and monocytes: tool for diagnosis and marker of disease activity in Wegener's granulomatosis. Lancet. 1985;1425- 429Article
40.
Jennette  JCFalk  RJ Antineutrophil cytoplasmic antibodies and associated diseases: a review. Am J Kidney Dis. 1990;15517- 529Article
41.
Cohen Tervaert  JWGoldschmeding  RElema  JD  et al.  Association of autoantibodies to myeloperoxidase with different forms of vasculitis. Arthritis Rheum. 1990;331264- 1272Article
42.
Venning  MCArfeen  SBird  AG Antibodies to neutrophil cytoplasmic antigen in systemic vasculitis. Lancet. 1987;2850Article
43.
Falk  RJJennette  JC Anti-neutrophil cytoplasmic autoantibodies with specificity for myeloperoxidase in patients with systemic vasculitis and idiopathic necrotizing and crescentic glomerulonephritis. N Engl J Med. 1988;3181651- 1657Article
44.
Savage  COSWinearls  CGJones  SMarshall  PDLockwood  CM Prospective study of radioimmunoassay for antibodies against neutrophil cytoplasm in diagnosis of systemic vasculitis. Lancet. 1987;11389- 1393Article
45.
Gross  WLSchmitt  WHCsernok  E Antineutrophil cytoplasmic autoantibody-associated diseases: a rheumatologist's perspective. Am J Kidney Dis. 1991;18175- 179Article
46.
Kemmett  DHarrison  DJHunter  JAA Antibodies to neutrophil cytoplasmic antigens: a serologic marker for Sweet's syndrome. J Am Acad Dermatol. 1991;24967- 969Article
47.
Kemmett  DHunter  JAA Sweet's syndrome: a clinicopathologic review of twenty-nine cases. J Am Acad Dermatol. 1990;23503- 507Article
48.
Burrows  NPLockwood  CM Antineutrophil cytoplasmic antibodies and their relevance to the dermatologist. Br J Dermatol. 1995;132173- 181Article
49.
Irvine  ADBruce  INWalsh  MBurrows  DHandley  J Dermatological presentation of disease associated with antineutrophil cytoplasmic antibodies: a report of two contrasting cases and a review of the literature. Br J Dermatol. 1996;134924- 928Article
50.
Dolman  KMGans  ROBVerbaat  TJ  et al.  Vasculitis and antineutrophil cytoplasmic autoantibodies associated with propylthiouracil therapy. Lancet. 1993;342651- 652Article
51.
Kawachi  YNukaga  HHoshino  MIwata  MOtsuka  F ANCA-associated vasculitis and lupus-like syndrome caused by methimazole. Clin Exp Dermatol. 1995;20345- 347Article
Study
March 1998

Prognostic Factors in Leukocytoclastic VasculitisA Clinicopathologic Study of 160 Patients

Author Affiliations

From the Departments of Dermatology (Drs Sais, Jucglà, Servitje, and Peyrí), Internal Medicine (Dr Vidaller), and Pathology (Dr Condom), Hospital Prínceps d'Espanya, Ciutat Sanitària i Universitària de Bellvitge, Departament de Medicina, Universitat de Barcelona, Barcelona, Spain.

Arch Dermatol. 1998;134(3):309-315. doi:10.1001/archderm.134.3.309
Abstract

Objective  To analyze risk factors for systemic involvement and long-term course in leukocytoclastic vasculitis.

Design  A clinicopathological study of 160 patients with leukocytoclastic vasculitis followed up for at least 3 years. Univariate and multivariate analysis were conducted by logistic regression methods.

Setting  The Bellvitge Hospital, a referral center in Barcelona, Spain.

Patients  One hundred sixty patients with cutaneous leukocytoclastic vasculitis. Patients in the categories cutaneous/systemic vasculitis and acute/chronic cutaneous vasculitis were selected for comparative analysis.

Main Outcome Measures  Clinical, laboratory, and histopathological findings.

Results  Of 89 females and 71 males, aged 14 to 89 years, systemic involvement was documented in 20% of cases. Perinuclear-staining antineutrophil cytoplasmic autoantibodies were found in 21% of patients and cryoglobulins in 25.4%. Of the patients, 1.9% died of systemic vasculitis. The average duration of cutaneous lesions was 27.9 months. In 67.2%, a cause or associated condition was identified. Of the skin specimens, 59.6% showed vasculitis limited to superficial dermal vessels. Direct immunofluorescence was positive in 84.3% of cases. In the multivariate analysis, paresthesia, fever, and absence of painful lesions were found to be risk factors for systemic involvement. Cryoglobulins, arthralgia, and normal temperature were risk factors for chronic cutaneous disease.

Conclusion  Our results identify prognostic factors in leukocytoclastic vasculitis and may provide some aid in the management of this heterogeneous group of patients.

LEUKOCYTOCLASTIC vasculitis (LV) is a small-vessel inflammatory disease mediated by deposition of immune complexes. In its pathogenesis, neutrophils expressing appropriate adhesion molecules adhere to activated endothelial cells and infiltrate into vessel walls, with consequent release of lytic enzymes.16 Lesions are often limited to the skin, but other organs may be involved. The natural course of the cutaneous lesions is unpredictable.710 The diagnosis of LV includes a heterogeneous group of patients having different vasculitic syndromes, with multiple known causes and associated conditions.3,4,1021 Risk factors to distinguish patients with a poor prognosis from those with a benign course have not been identified, and a rational therapy has not been standardized in this disorder.22,23

We describe the clinical, laboratory, and histopathological features of 160 patients with LV, 32 of whom had systemic vasculitic involvement. The study was undertaken to determine whether these variables would discriminate (1) patients with isolated cutaneous vasculitis from those with systemic involvement and (2) patients with acute cutaneous disease from those with cutaneous vasculitis that persisted for more than 6 months.

PATIENTS AND METHODS
PATIENTS

One hundred sixty consecutive patients with histologically proved cutaneous LV were enrolled after they gave informed consent. All patients were seen at Bellvitge Hospital, Barcelona, Spain, a center treating mostly adults, from November 6, 1989, to May 27, 1994. The onset of the disease was determined historically.

CLINICAL STUDY

A complete history and physical examination were performed, according to a standard questionnaire. Laboratory tests and radiological studies at the onset of the study included the following: erythrocyte sedimentation rate; complete blood cell and platelet counts; prothrombin and partial thromboplastin times; serum chemistry profile; serum protein electrophoresis; serum immunoglobulin determination; chest radiography; electrocardiography; urinary sediment; 24-hour urinary protein determination; complement study; determinations of rheumatoid factor (latex), antinuclear antibodies, anti-DNA, anti-Ro, and anti-La antibodies, cryoglobulins, anticardiolipin, and antineutrophil cytoplasmic autoantibodies (ANCA) (indirect immunofluorescence test); and serological determination for human immunodeficiency virus, hepatitis B virus (HBV), and hepatitis C virus (HCV) (enzyme-linked immunosorbent assay and recombinant immunoblot assay).

Renal insufficiency was defined as plasma creatinine level of more than 130 µmol/L. Hematuria was defined as 5 or more red blood cells per high-power field in a centrifuged urine sample. Urinary protein excretion greater than 0.3 g/24 hours was considered abnormal. When the results of the physical examination showed a possible mononeuritis, an electromyogram was performed and, if abnormal, a peripheral nerve biopsy was obtained. In patients with severe renal or intestinal disease, a biopsy was performed if extracutaneous involvement had not been histologically documented. Systemic vasculitis was diagnosed when (1) extracutaneous involvement was histologically confirmed, (2) persistent hematuria and abnormal proteinuria were found, with or without increased levels of creatinine and urea, (3) there was electrophysiological evidence of mixed (motor and sensory) neuropathy in a pattern consistent with mononeuritis multiplex, and/or (4) abdominal angiography showed vasculitic changes.

Patients were included in different clinical vasculitis categories according to the criteria for classification of vasculitis.35,10,12,24

Patients were followed up for at least 3 years and reexamined periodically.

HISTOLOGICAL STUDY

In each patient, a skin biopsy specimen (4-mm punch) of a cutaneous lesion was obtained for histopathological examination. The diagnosis of LV was confirmed in all patients by presence of an inflammatory infiltrate predominantly constituted by neutrophils, nuclear fragmentation, extravasation of erythrocytes, and necrosis of dermal vessel walls (Figure 1).35,10,25 Histological diagnosis was classified according to the size of the affected vessels as small-vessel LV in superficial dermis or LV involving small and medium vessels in superficial and deep dermis.

Fifty original slides randomly selected were further studied to evaluate semiquantitatively several histological variables. Intensity of the inflammatory infiltrate was evaluated perivascularly and interstitially in the dermis as follows: 1, weak; 2, moderate; and 3, strong. The constitutive cells in the infiltrate were classified according to the predominating cell type as follows: 1, more than 75% neutrophils and less than 25% mononuclear cells; 2, 50% neutrophils and 50% mononuclear cells; 3, less than 25% neutrophils and more than 75% mononuclear cells; and 4, more than 50% eosinophils. Necrosis was graded as follows: 1, mild; 2, moderate; and 3, severe, according to the intensity of necrosis and percentage of necrotic vessels. Intensity of purpura and leukocytoclasis was evaluated, both at the perivascular and interstitial dermis, as 1, mild; 2, moderate; and 3, severe.

In 102 patients, a second lesional biopsy specimen was obtained, snap-frozen in liquid nitrogen, and processed for direct immunofluorescence examination of IgG, IgA, IgM, and C3 deposition in dermal vessel walls. Duration of the lesions examined by biopsy was recorded and varied from less than 24 hours to 4 days.

STATISTICAL ANALYSIS

All clinical, laboratory, and histopathological data were entered into a computer. Each laboratory variable was dichotomized according to a predetermined cutoff value (normal or abnormal value). Patients in the major categories (cutaneous vasculitis/systemic vasculitis; acute/chronic [>6 months] cutaneous vasculitis) were selected for comparative analysis. The χ2 test was used for comparing qualitative variables initially. To determine whether the significant associated parameters would predict the associated systemic disease or the chronicity of the cutaneous lesions, univariate and multivariate analysis were conducted by logistic regression methods. P values less than .05 were considered significant.

RESULTS
CLINICAL FEATURES

Eighty-nine females (55.6%) and 71 males (44.4%), aged 14 to 89 years (average age, 51 years), were included. In 30.5% of the patients, physical activity aggravated the cutaneous disease. The average duration of the cutaneous vasculitis when patients were first seen was 17.5 months (median, 1.2 months; range, 1 week to 250 months). Palpable purpura was the most prevalent lesion (89.2%), being confluent in 44.6%. In 30.4%, cutaneous necrosis developed (Figure 2). Koebner phenomenon was documented in 22.9% of patients; 20.3% of patients had ulcers; 16.5%, pustules; 10%, nodules; 8.2%, urticaria vasculitis; and 6.3%, livedo reticularis. Distribution of the lesions was as follows: lower extremities, 62.4%; generalized, 28%; arms, 6.4%; and photoexposed skin, 3.2%. Of the patients, 41.4% complained of pruritus, and, in 30%, lesions were painful. Fever was found in 31.6% of patients and toxic syndrome in 24.7%. Arthralgia occurred in 36.7% of patients, paresthesia in 17%, abdominal pain in 9.5%, dyspnea in 7%, and hypertension in 8.7%.

LABORATORY STUDIES

Routine analytical and radiological tests showed an erythrocyte sedimentation rate greater than 20 mm/h in 52.4% of patients; anemia, 37%; leukocytosis, 18%; eosinophilia, 2.5%; thrombocytosis, 10%; urea level greater than 9.7 mmol/L, 16%; creatinine level greater than 130 µmol/L, 13%; elevated transaminase levels, 18%; increased levels of α2-globulins, 26%; hypergammaglobulinemia (>24 g/L), 20%; monoclonal protein, 2.8%; pathologic urine sediment, 21.7%; 24-hour proteinuria of more than 0.3 g, 19%; and 24-hour proteinuria of more than 3.5 g, 3%. Table 1 summarizes the immunological features. In 30 patients an electromyogram was performed, showing mononeuritis multiplex in 17 (56.6%). A biopsy specimen of a peripheral nerve was obtained in 15 patients, showing vasculitis in 9 (60%). A renal biopsy was necessary to confirm systemic involvement in 8 patients and revealed vasculitis in 6 (75%). In 8 patients an intestinal biopsy was obtained, showing vasculitis in 3 (37.5%). Only in 2 patients was an angiographic study undertaken, being positive for vasculitis in 1 patient.

In summary, systemic involvement (other than articular) was documented in 20% of the patients. Table 2 shows the prevalence of the vasculitic syndromes diagnosed as well as the causes and associated diseases identified.

EVOLUTION OF THE LV

All patients were followed up for at least 3 years (average, 56 months). According to the evolution of the cutaneous vasculitis, the disease was classified as acute (resolved in <6 months) in 46.9% of the patients; chronic (resolved in ≥6 months or not resolved at the end of the study) in 43.8%; unavailable for follow-up in 3%; death from systemic vasculitis in 1.9%; and death not related to vasculitis in 4.4%. At the end of the study, 28.8% of patients showed chronic active cutaneous vasculitis. The duration of the cutaneous vasculitis ranged from 1 week to 318 months, with an average (±SD) duration of 27.9±49.1 months (median, 3.7 months).

HISTOLOGICAL STUDY

In 59.6% of the specimens, the vasculitis affected dermal vessels of small diameter; in 40.4% of the medium-sized vessels, the deeper dermis were also involved. In most cases, the infiltrate was distributed around the vessels. In 76% of cases, neutrophils accounted for more than 75% of the total infiltrating cells. In 2.5% (specimens from vasculitic lesions of more than 48 hours' duration), most infiltrating cells were mononuclear cells. In 3 cases of cutaneous LV in the context of Churg-Strauss vasculitis, the inflammatory infiltrate was mainly constituted by eosinophils. Vascular necrosis was mild in 42% of the patients, moderate in 32%, and marked in 26%. Although leukocytoclasis and extravasation of erythrocytes tended to be more intense around dermal vessels, in almost 50% of patients some diffuse distribution was observed.

Direct immunofluorescence study in 42.2% of the patients showed IgG deposition in the dermal vessels; in 64.7%, IgA; in 49%, IgM; and in 80.4%, C3. In 15.8% of patients, direct immunofluorescence was negative. Figure 3 shows the inverse relationship between deposition of immunoreactants and duration of the lesion (P<.01).

STATISTICAL ANALYSIS

Table 3 shows crude (cRR) and adjusted (aRR) relative risks of long-term evolution of the cutaneous vasculitis for all the factors found to have a significant association in the bivariate analysis, together with the 95% confidence intervals. The following factors were demonstrated to significantly influence the univariate analysis: arthralgia, exacerbation of the disease with physical activity, paresthesia, increased rheumatoid factor, cryoglobulins, and positive serological determinations for HCV. Protective factors found were sex (male), fever, upper respiratory tract infection before developing LV, increased levels of α2-globulins, and normal levels of total hemolytic complement and C4.

These factors were controlled for by means of multiple logistic regression analysis, and aRRs were calculated for each factor in a collective model. Cryoglobulins were the most relevant independent risk factor of developing chronic cutaneous LV (aRR, 32.08); detection of HCV and increased levels of rheumatoid factor lost their significance. Arthralgia was the second factor to be considered (aRR, 8.85). Fever continued to be a protective factor by multivariable methods (aRR, 0.03). The aRRs for sex and physical activity did not reach significance.

Table 4 shows the RR and 95% confidence interval of systemic vasculitic involvement for all of the factors with a significant initial association. The univariate evaluation found the following predictors of systemic vasculitic disease: elevated erythrocyte sedimentation rate, leukocytosis, thrombocytosis, increased rheumatoid factor, abdominal pain, paresthesia, positivity of HBV core antibody, fever, and toxic syndrome. Presence of painful skin lesions was a protective factor in this analysis.

When all of these factors were entered in the multivariate analysis, paresthesia was the most relevant independent risk factor for developing systemic vasculitis (aRR, 36.95). Fever also maintained its significance (aRR, 8.88). All of the laboratory variables, presence of abdominal pain, and toxic syndrome lost their influence. Presence of painful cutaneous lesions continued to be a protective factor when tested by multivariate methods (aRR, 0.05).

COMMENT

Our results reflect the diversity of manifestations of LV. Systemic involvement was documented in 20% of patients. A causal agent or an associated condition was identified in 67.2% of the patients. A careful reading of previous reports shows similar percentages.710 The prevalence of HCV in the Spanish population is 0.8%, and this can explain the high incidence of LV associated with HCV in our series (21.4%). In almost 47% of our patients, cutaneous LV resolved in less than 6 months, and a subgroup of patients (8%) presented with successive crops of cutaneous lesions for more than 10 years. (Exercise aggravated the cutaneous vasculitis in 30.4% of our patients.26) Less than 2% of patients died of systemic vasculitis.

As previously stated, the infiltrate was mainly constituted by neutrophils, and the proportion of mononuclear cells significantly correlated with duration of the lesion studied by biopsy (P<.001).1,2,4,27 Predominance of infiltrating eosinophils was associated with Churg-Strauss disease in our series. We did not find a significant association between the histological variables studied and prognosis.

Direct immunofluorescence test showed vascular deposition of immunoreactants in 84.3% of the vasculitic biopsy specimens studied. Similar positive results were reported previously.1,7,2830 Destruction and removal of immunoglobulins deposited in the affected dermal vessels takes place in less than 48 hours, and direct immunofluorescence studies of vasculitic lesions older than 48 hours are frequently negative.29 The positivity of the immunofluorescence test was inversely correlated with the duration of the lesion studied by biopsy (P<.001). C3 deposition persisted longer than immunoglobulins did. Unlike previous authors,7,10,29 we found that IgA was the immunoglobulin most frequently detected. However, in only 8 patients (2 with Henoch-Schönlein purpura with mesangial IgA deposition, 1 with alcoholic liver disease, 1 with Crohn disease, 1 with sore throat and amoxicillin intake, 1 with Churg-Strauss disease, and 2 with chronic HBV infection), IgA was not associated with IgM or IgG deposition. The finding of IgA deposition in dermal vessels is not restricted to Henoch-Schönlein disease, and its diagnostic value is still a matter of controversy.3134 It may also be seen in various vasculitic and nonvasculitic disorders, including chronic glomerular diseases and alcoholic liver disease.3538

Our results suggest that in the context of LV, the finding of IgA fluorescence with additional immunoreactants (IgG, IgM) within the vessel walls has a low specificity for differentiating Henoch-Schönlein disease. However, it can be argued that vascular, isolated IgA (or C3) staining may be characteristic of Henoch-Schönlein disease.1,29,3234

As previously reported, we did not find a significant correlation between direct immunofluorescence results and long-term evolution of the cutaneous vasculitis or systemic involvement.1,7

In this study, 21% of patients had positive ANCA. Perinuclear-staining ANCA was the pattern detected in all these cases. Systemic involvement was documented in 40% of the ANCA-positive cases (microscopic polyarteritis, classic polyarteritis nodosa, Churg-Strauss disease, and mixed cryoglobulinemia), but in 60% the disorder remained limited to the skin (idiopathic LV, cryoglobulinemia related to HCV and HBV infection, and paraneoplastic vasculitis). The usefulness of ANCA when diagnosing necrotizing systemic vasculitis is well known.3945 However, when considering a patient with cutaneous LV, the presence of perinuclear-staining ANCA does not appear to be a specific enough marker of systemic involvement. None of our patients had cytoplasmic-staining ANCA, a highly specific test for Wegener granulomatosis, but perinuclear-staining ANCA was positive in 15% of patients with LV limited to the skin—in opposition to suggestions made in previous reports4649 —with or without associated connective-tissue disorders, such as systemic lupus erythematosus or scleroderma.50,51

We tested all the variables assessed in this study to identify prognostic factors in LV. The univariate analysis demonstrated a significant association between systemic vasculitic involvement and elevated erythrocyte sedimentation rate (cRR, 4.15), leukocytosis (cRR, 4.33), and thrombocytosis (cRR, 6.9). All these laboratory abnormalities are nonspecific markers of systemic inflammation. When entered in the multiple regression analysis, only erythrocyte sedimentation rate maintained a similar influence in predicting systemic involvement (aRR, 4.21), although the 95% confidence interval was 22.31 to 0.79. Analysis of other laboratory variables showed elevated levels of rheumatoid factor (cRR, 3.07) and positive HBV core antibodies (cRR, 3.41) to have a significant influence in predicting extracutaneous involvement. Both factors lost their mild univariate predictive power when entered in the multivariate model. Concerning the clinical variables, fever (cRR, 3.23), evidence of toxic syndrome (cRR, 3.07), and abdominal pain (cRR, 9.48) were also influential factors when examined individually, but when tested by multivariable techniques only fever reached statistical significance (aRR, 8.88). As expected, paresthesia was the main prognostic factor identified (aRR, 36.95), and in our study 56.3% of patients who complained of paresthesia had positive findings in the electromyogram and/or in the biopsy specimen of a peripheral nerve. The type of cutaneous lesion had no prognostic influence in our series, but patients with pain were more likely to have disease limited to the skin (aRR, 0.05; 95% confidence interval, 0.01-0.45).

It can be argued that pain is related to a more necrotic cutaneous disease, reflecting a greater deposition of circulating immune complexes in the dermis and decreased extracutaneous involvement. Age and sex were not useful predictors of systemic involvement. As af Ekenstam and Callen8 suggested in a clinical observation, duration of cutaneous disease did not significantly increase the risk of systemic involvement. These considerations may provide some help in the management of persistent cutaneous vasculitis.

The results of our study indicate that a subgroup of patients having mixed cryoglobulinemia with arthralgia, increased rheumatoid factor level, and decreased total hemolytic complement and C4 activity has an elevated risk of having cutaneous vasculitis for several months. Most of these patients showed positive serological determinations for HCV in our series. Some authors have proved the association between chronic HCV infection and mixed cryoglobulinemia. It is likely that such persistent infection elicits and maintains the immunomediated vasculitic disorder.15,16 In this sense, detection of cryoglobulins was found to be the most powerful and independent risk factor of chronicity in our statitistical analysis. Contrarily, fever may select a subgroup of patients with acute disease. The existence of fever resulting from a curable infection that causes the LV may partially explain this association. Although most autoimmune or immune-mediated diseases show a preponderance of women, the influence of sex in vasculitic syndromes has not been established. Our results allow us to suggest a possible influence of sex in the chronicity of cutaneous vasculitis.

In summary, LV is seen in a heterogeneous group of patients with variable prognosis and a low mortality rate (<2%). The findings on histological examination are time dependent. The multivariate analysis of clinical and histological data found paresthesia and fever to be risk factors for systemic involvement. Painful cutaneous lesions had a protective influence. Interestingly, perinuclear-staining ANCA was not predictive of systemic vasculitis. Cryoglobulins, arthralgia, and normal temperature were the most relevant risk factors for chronic cutaneous disease in this analysis.

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Article Information

Accepted for publication August 5, 1997.

Dr Sais is the recipient of predoctoral grant FI/94-9203 from the Division of Research Resources, Generalitat de Catalunya, Barcelona, Spain.

We thank Francesc Moreso, MD, and Ramon Canet, MD, for their suggestions and statistical assistance.

Corresponding author: Gemma Sais, MD, Taquígraf Garriga, 100, 4-2, 08029 Barcelona, Spain.

References
1.
Mackel  SEJordon  RE Leukocytoclastic vasculitis: a cutaneous expression of immune complex disease. Arch Dermatol. 1982;118296- 301Article
2.
Jennette  JCCharles  LAFalk  RJLe  Roy ECed The neutrophil and its role in systemic vasculitis. Systemic Vasculitis: The Biological Basis New York, NY Marcel Dekker Inc1992;65- 92
3.
Fauci  ASHaynes  BFKatz  P NIH Conference: the spectrum of vasculitis: clinical, pathologic, immunologic, and therapeutic considerations. Ann Intern Med. 1978;89660- 676Article
4.
Jennette  CJMilling  DMFalk  RJ Vasculitis affecting the skin: a review. Arch Dermatol. 1994;130899- 906Article
5.
Conn  DL Update on systemic necrotizing vasculitis. Mayo Clin Proc. 1989;64535- 543Article
6.
Sais  GVidaller  AJucglà  ACondom  EPeyrí  J Adhesion molecule expression and endothelial cell activation in cutaneous leukocytoclastic vasculitis: an immunohistological and clinical study on 42 cases. Arch Dermatol. 1997;133443- 450Article
7.
Sánchez  NPVan Hale  HMSu  D Clinical and histopathologic spectrum of necrotizing vasculitis: report of findings in 101 cases. Arch Dermatol. 1985;121220- 224Article
8.
af Ekenstam  ECallen  JP Cutaneous leukocytoclastic vasculitis: clinical and laboratory features of 82 patients seen in private practice. Arch Dermatol. 1984;120484- 489Article
9.
Cupps  TRSpringer  RMFauci  AS Chronic, recurrent, small-vessel cutaneous vasculitis: clinical experience in 13 patients. JAMA. 1982;2471994- 1998Article
10.
Gibson  LE Cutaneous vasculitis: approach to diagnosis and systemic associations. Mayo Clin Proc. 1990;65221- 229Article
11.
Somer  TFinegold  S Vasculitides associated with infections, immunization, and antimicrobial drugs. Clin Infect Dis. 1995;201010- 1036Article
12.
Agnello  VChung  RTKaplan  LM A role for hepatitis C virus infection in type II cryoglobulinemia. N Engl J Med. 1992;3271490- 1495Article
13.
Heart-Holmes  MZahradka  SLBaethge  BAWolf  RE Leukocytoclastic vasculitis associated with hepatitis C. Am J Med. 1991;90765- 766Article
14.
Misiani  RBellavita  PFenili  D  et al.  Hepatitis C virus infection in patients with essential mixed cryoglobulinemia. Ann Intern Med. 1992;117573- 577Article
15.
Popp  JWHarrist  TJDienstang  JL  et al.  Cutaneous vasculitis associated with acute and chronic hepatitis. Arch Intern Med. 1981;141623- 629Article
16.
Daoud  MSel-Azhary  RAGibson  LELutz  MEDaoud  S Chronic hepatitis C, cryoglobulinemia and cutaneous necrotizing vasculitis. J Am Acad Dermatol. 1996;34219- 223Article
17.
Karlsberg  PLLee  WMCasey  DLCockerell  CJCruz Jr  PD Cutaneous vasculitis and rheumatoid factor positivity as presenting signs of hepatitis C virus–induced mixed cryoglobulinemia. Arch Dermatol. 1995;1311119- 1123Article
18.
Gherardi  RBelec  LMhiri  C  et al.  The spectrum of vasculitis in human immunodeficiency virus–infected patients: a clinicopathologic evaluation. Arthritis Rheum. 1993;361164- 1174Article
19.
Calabresse  LHEstes  MYen-Lieberman  B  et al.  Systemic vasculitis in association with human immunodeficiency virus infection. Arthritis Rheum. 1989;32569- 576Article
20.
Sanchez Guerrero  JGutierrez Urena  JVidaller  AReyes  EIglesias  AAlarcon-Segovia  D Vasculitis as a paraneoplastic syndrome: report of 11 cases and review of the literature. J Rheumatol. 1990;171458- 1462
21.
Greer  JMLongley  SEdwards  NLElfenbein  GJPanush  RS Vasculitis associated with malignancy: experience with 13 patients and literature review. Medicine (Baltimore). 1988;67220- 230Article
22.
Sais  GVidaller  AJucglà  AGallardo  FPeyrí  J Colchicine in the treatment of cutaneous leukocytoclastic vasculitis: results of a prospective, randomized controlled trial. Arch Dermatol. 1995;1311399- 1402Article
23.
Conn  DLLe  Roy ECed Overview of therapy and management of systemic vasculitis. Systemic Vasculitis: The Biological Basis New York, NY Marcel Dekker Inc1992;547- 574
24.
Hunder  GHArend  WPBloch  DA  et al.  The American College of Rheumatology 1990 criteria for the classification of vasculitis. Arthritis Rheum. 1990;331065- 1144Article
25.
Lie  JTMembers and Consultants of the American College of Rheumatology Subcommittee on Classification of Vasculitis, Illustrated histopathologic classification criteria for selected vasculitis syndromes. Arthritis Rheum. 1990;331074- 1087Article
26.
Prins  MVeraart  JCJMVermeulen  AHMHulsmans  FHJNeumann  HAM Leukocytoclastic vasculitis induced by prolonged exercise. Br J Dermatol. 1996;134915- 918Article
27.
Zax  RHHodge  SJCallen  JP Cutaneous leukocytoclastic vasculitis: serial histopathologic evaluation demonstrates the dynamic nature of the infiltrate. Arch Dermatol. 1990;12669- 72Article
28.
Gower  RGSams Jr  WMThorne  EG Leukocytoclastic vasculitis: sequential appearance of immunoreactants and cellular changes in serial biopsies. J Invest Dermatol. 1977;69477- 484Article
29.
Michel  BAHunder  GGBloch  DACalabrese  LH Hypersensitivity vasculitis and Henoch-Schönlein purpura: a comparison between the 2 disorders. J Rheumatol. 1992;19721- 728
30.
Schroeter  ALCopeman  PWMJordon  RESams Jr  WMWinkelman  RK Immunofluorescence of cutaneous vasculitis associated with systemic disease. Arch Dermatol. 1971;104254- 259Article
31.
Hené  RJVelthuis  Pvan de Wiel  AKlepper  DDorhout Mees  EJKater  L The relevance of IgA deposits in vessel walls of clinically normal skin: a prospective study. Arch Intern Med. 1986;146745- 749Article
32.
Helander  SDDe Castro  FRGibson  LE Henoch-Schönlein purpura: clinicopathologic correlation of cutaneous vascular IgA deposits and the relationship to leukocytoclastic vasculitis. Acta Derm Venereol. 1995;75125- 129
33.
Van Hale  HMGibson  LESchroeter  AL Henoch-Schönlein vasculitis: direct immunofluorescence study of uninvolved skin. J Am Acad Dermatol. 1986;15665- 670Article
34.
Tsai  CCGiangiacomo  JZuckner  J Dermal IgA deposits in Henoch-Schönlein purpura and Berger's nephritis. Lancet. 1975;1342- 343Article
35.
Saklayen  MGSchroeter  ANafs  MAJalil  K IgA deposition in the skin of patients with alcoholic liver disease. J Cutan Pathol. 1996;2312- 18Article
36.
Hirbec  GBelghiti  DWechsler  JSobel  ALagrue  G Immunofluorescence study of skin biopsy specimens from patients with chronic renal diseases. Kidney Int. 1977;12374Abstract
37.
Swerdlow  MAChowdhury  LNMishra  VKavin  H IgA deposits in skin in alcoholic liver disease. J Am Acad Dermatol. 1983;9232- 236Article
38.
Thompson  AJChan  Y-LWoodroffe  AJ Vascular IgA deposits in clinically normal skin of patients with renal disease. Pathology. 1980;12407- 413Article
39.
Van der Woude  FJLobato  SPermin  H  et al.  Autoantibodies against neutrophils and monocytes: tool for diagnosis and marker of disease activity in Wegener's granulomatosis. Lancet. 1985;1425- 429Article
40.
Jennette  JCFalk  RJ Antineutrophil cytoplasmic antibodies and associated diseases: a review. Am J Kidney Dis. 1990;15517- 529Article
41.
Cohen Tervaert  JWGoldschmeding  RElema  JD  et al.  Association of autoantibodies to myeloperoxidase with different forms of vasculitis. Arthritis Rheum. 1990;331264- 1272Article
42.
Venning  MCArfeen  SBird  AG Antibodies to neutrophil cytoplasmic antigen in systemic vasculitis. Lancet. 1987;2850Article
43.
Falk  RJJennette  JC Anti-neutrophil cytoplasmic autoantibodies with specificity for myeloperoxidase in patients with systemic vasculitis and idiopathic necrotizing and crescentic glomerulonephritis. N Engl J Med. 1988;3181651- 1657Article
44.
Savage  COSWinearls  CGJones  SMarshall  PDLockwood  CM Prospective study of radioimmunoassay for antibodies against neutrophil cytoplasm in diagnosis of systemic vasculitis. Lancet. 1987;11389- 1393Article
45.
Gross  WLSchmitt  WHCsernok  E Antineutrophil cytoplasmic autoantibody-associated diseases: a rheumatologist's perspective. Am J Kidney Dis. 1991;18175- 179Article
46.
Kemmett  DHarrison  DJHunter  JAA Antibodies to neutrophil cytoplasmic antigens: a serologic marker for Sweet's syndrome. J Am Acad Dermatol. 1991;24967- 969Article
47.
Kemmett  DHunter  JAA Sweet's syndrome: a clinicopathologic review of twenty-nine cases. J Am Acad Dermatol. 1990;23503- 507Article
48.
Burrows  NPLockwood  CM Antineutrophil cytoplasmic antibodies and their relevance to the dermatologist. Br J Dermatol. 1995;132173- 181Article
49.
Irvine  ADBruce  INWalsh  MBurrows  DHandley  J Dermatological presentation of disease associated with antineutrophil cytoplasmic antibodies: a report of two contrasting cases and a review of the literature. Br J Dermatol. 1996;134924- 928Article
50.
Dolman  KMGans  ROBVerbaat  TJ  et al.  Vasculitis and antineutrophil cytoplasmic autoantibodies associated with propylthiouracil therapy. Lancet. 1993;342651- 652Article
51.
Kawachi  YNukaga  HHoshino  MIwata  MOtsuka  F ANCA-associated vasculitis and lupus-like syndrome caused by methimazole. Clin Exp Dermatol. 1995;20345- 347Article
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