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Table of Contents
ORIGINAL ARTICLE
Year : 2020  |  Volume : 14  |  Issue : 2  |  Page : 42-47

The relationship between direct immunofluorescence findings and clinical and laboratory parameters in patients with cutaneous small vessel vasculitis


1 Department of Dermatology, School of Medicine, Hacettepe University, Ankara, Turkey
2 Department of Pathology, School of Medicine, Hacettepe University, Ankara, Turkey

Date of Submission04-Feb-2020
Date of Decision08-Apr-2020
Date of Acceptance09-Apr-2020
Date of Web Publication16-Jun-2020

Correspondence Address:
Dr. Duygu Gulseren
Department of Dermatology, School of Medicine, Hacettepe University, Ankara
Turkey
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/TJD.TJD_13_20

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  Abstract 

Objective: Cutaneous small-vessel vasculitis (CSVV) is a disease characterized histologically by leukocytoclastic vasculitis (LCV) and immune-complex deposition in small vessel walls. We aimed to evaluate the type of deposited immune complexes in patients with LCV and to determine the relationship between the immune-complex types and clinical and laboratory parameters. Materials and Methods: Patients who had been diagnosed as LCV histopathologically between 2000 and 2018 were retrospectively evaluated. Patients' medical records and pathology databases were reviewed to determine the demographic characteristics, clinical, laboratory, and histopathological findings. Direct immune fluorescence (DIF) findings to determine the immune-complex subtypes, including immunoglobulin A (IgA), immunoglobulin M (IgM), immunoglobulin G (IgG) or C3 deposition, were evaluated. Results: Sixty-eight patients were included in the study. A total of 36 (53%) patients had deposition in the perivascular or vessel walls, with at least one of IgA, IgM, IgG, or C3. IgA deposition was detected in 29 (42.6%) patients, IgM in 13 patients (19.1%), IgG in four patients (5.9%), and C3 in 31 patients (45.6%). Clinical features of the patients, including triggering factors, extracutaneous involvement, lesion localization, and skin findings, were compared with DIF findings. It was found no statistically significant difference between DIF-positive and DIF-negative groups (P > 0.05, for all). There was also no statistically significant difference in terms of laboratory findings between the groups (P > 0.05, for all). Conclusions: Our study showed that DIF findings did not play a role in determining the clinical findings, and they did not affect laboratory parameters in CSVV.

Keywords: Direct, fluorescent antibody technique, vasculitis


How to cite this article:
Gulseren D, Erbağcı E, Gököz &, Atakan N. The relationship between direct immunofluorescence findings and clinical and laboratory parameters in patients with cutaneous small vessel vasculitis. Turk J Dermatol 2020;14:42-7

How to cite this URL:
Gulseren D, Erbağcı E, Gököz &, Atakan N. The relationship between direct immunofluorescence findings and clinical and laboratory parameters in patients with cutaneous small vessel vasculitis. Turk J Dermatol [serial online] 2020 [cited 2020 Jul 14];14:42-7. Available from: http://www.tjdonline.org/text.asp?2020/14/2/42/286894




  Introduction Top


Cutaneous small-vessel vasculitis (CSVV) is a vasculitic process that involves primarily the dermal postcapillary venules and is characterized histologically by leukocytoclastic vasculitis (LCV). Although CSVV with LCV can be seen in the setting of mixed (small- and medium-sized vessel) vasculitides, the term CSVV is generally reserved for small-vessel vasculitis of the skin without medium-sized vessel involvement, irrespective of the clinical severity of the skin disease or the underlying etiology.[1] CSVV is often idiopathic in nature but maybe secondary to an underlying cause such as drugs, infections, malignancies, and systemic inflammatory diseases have been implicated in the etiology.[2]

Clinically, the typical finding is palpable purpura, which is located on the lower extremities, but also, different types of lesions may be seen in different localizations such as upper extremity and trunk. CSVV mainly affects the skin, but the renal, musculoskeletal, and gastrointestinal system (GIS) may also be involved. Patients with no systemic findings at the time of diagnosis are less likely to develop extracutaneous involvement during the disease.[2]

The primary process in the pathogenesis of CSVV is the immune complex deposition in small vessel walls. This is associated with the activation of complement cascade and production of C5a, which is a neutrophil polymorph chemoattractant. After polymorph influx, lysosomal enzymes are released, and this leads to blood vessel wall damage, fibrin deposition, and the release of red blood cells (purpura) into the perivenular connective tissue. There are convincing findings about the immune-complex mediated pathogenesis of the disease, one of which is that the immune complexes can usually be detected between the basal membranes of endothelial cells and the pericytes of postcapillary venules.[3]

In the literature, there are conflicting reports about the most common immune complex type in LCV and its relationship with clinical and laboratory parameters. In this study, it was aimed to evaluate the presence of immune complex deposition and its subtype, clinical, and laboratory findings in patients with CSVV and to determine whether immune complex deposition detected by direct immune fluorescence (DIF) examination is a risk factor for the development of extracutaneous involvement.


  Materials and Methods Top


Patients

Patients who were examined with the diagnosis of CSVV between January 1, 2000, and February 28, 2018, in the Department of Dermatology were included in the study. The database of the pathology department using the term “LCV” and “DIF”were retrospectively searched. All cases of LCV with DIF findings were reviewed by a dermatologist. Other types of vasculitis or patients diagnosed only with clinical findings were excluded. Patients' medical records were analyzed by another dermatologist to determine their demographic characteristics, clinical, laboratory, and histopathological findings. The patients' medical data such as the age at the time of diagnosis, gender, triggering factors, extracutaneous involvement, lesion localization, skin findings, laboratory parameters, and DIF findings were noted on the standardized paper forms. For extracutaneous involvement, symptoms related to joint, GIS, and kidney were reviewed from the patient's medical history or clinical follow-up records. Laboratory parameters to determine extracutaneous involvement, triggering factors, or underlying causes were reviewed. Joint involvement was defined as the presence of arthritis or arthralgias in medical history or examination. Abdominal pain, melena, hematochezia, or the presence of occult blood in the stool was described as GIS involvement. Renal involvement was defined as the presence of elevated blood creatinine levels, hematuria, spot or 24-h urinary proteinuria, or renal biopsy findings. Laboratory parameters include white blood cell (WBC), hemoglobin, blood urea nitrogen, creatinine, transaminase levels, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), antistreptolysin-O, Complement 3 (C3) and Complement 4 (C4), rheumatoid factor (RF), antinuclear antibody (ANA), extractable nuclear antibody, perinuclear antineutrophilic cytoplasmic antibody (ANCA), cytoplasmic ANCA, urinalysis, occult blood stool (OBS), and 24-h urine protein values were recorded. Immune complexes examined on DIF included immunoglobulin A (IgA), immunoglobulin M (IgM), immunoglobulin G (IgG), and C3.

This study was approved by the Ethics Committee of the university and is registered under the following number GO 18/336-02.

Statistical analyses

Statistical analyses were performed with the Statistical Package for the Social Sciences, software version 22.0. (SPSS Inc., Chicago, IL, USA). Numerical variables were summarized as mean ± standard deviation or median (minimum–maximum). Categorical variables were given as frequencies and percentages. Categorical variables were compared by Chi-square test or Fisher's exact test. A value of P < 0.05 was considered statistically significant.


  Results Top


The study included 68 CSVV patients (27 males and 41 females) with a mean age of 34.7 ± 21.9 years (range: 2–70 years). The median time from the appearance of the rash to the time of biopsy was 14 days (range: 1–3650 days).

A total of 36 (53%) patients had deposition in the perivascular area and/or on vessel walls, with at least one of IgA, IgM, IgG, or C3. The relationship between the clinical features of the patients and DIF findings were analyzed and presented in [Table 1]. The differences in the triggering factors, extracutaneous involvement, lesion localization, and skin findings between DIF-positive and DIF-negative groups were not statistically significant (P > 0.05, for all). DIF positive group was evaluated in detail according to the deposited immune-complex subtypes and summarized in [Table 2]. IgA deposition was detected in 29 (42.6%) patients, IgM in 13 patients (19.1%), IgG in 4 patients (5.9%), and C3 in 31 patients (45.6%). There was no statistically significant difference between IgA, IgM, IgG, and C3 positive and negative groups in terms of triggering factors, extracutaneous involvement, lesion localization, and skin findings (all, P > 0.05). Laboratory findings of patients were compared, and no significant differences were found between DIF positive and DIF negative groups, as shown in [Table 3]. There was also no statistically significant difference in terms of laboratory findings with respect to the subtypes of the immune complexes, as shown in [Table 4] (all, P > 0.05). Due to inadequate number in the IgG group, it was not evaluated statistically.
Table 1: Clinical characteristics of the leukocytoclastic vasculitis patients in direct immune fluorescence positive and direct immune fluorescence negative groups

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Table 2: Comparison of clinical characteristics according to immune complex subtypes in direct immune fluorescence positive group

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Table 3: Laboratory findings of the leukocytoclastic vasculitis patients in direct immune fluorescence positive and direct immune fluorescence negative groups

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Table 4: Comparison of laboratory findings according to immune complex subtypes in direct immune fluorescence positive group

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  Discussion Top


Multiple factors have been reported in the etiology of CSVV, but approximately 40% of cases are idiopathic.[4] In the literature, 15%–20% of cases have been associated with infections and 10%–15% with drugs. In our study, no underlying cause was found in 41% of cases.[5] The history of the drug was determined by 49% and infection in 41%. Since some patients had taken a newly started drug during the infection, both the drug and infection were defined as triggering factors in the patient. Therefore, the prevalence of drugs and infection in our study might be higher than in the literature. As extracutaneous involvement, 57% of the patients had joint involvement, followed by renal involvement with 52% and GIS involvement with 28%. In the literature, it has been reported that systemic symptoms may develop in 5%–25% of the patients with CSVV, joint involvement in 15%–65% of the patients as being most commonly, genitourinary in 3%–7% and GIS involvement in 3%–5% of the patients.[6] The prevalence of joint involvement in our study was consistent with the literature, but renal and GIS involvements were found to be higher than in the literature. Patients with Henoch-Schönlein purpura (HSP) were also included in our study. It is known that the prevalence of genitourinary involvement in patients with HSP is as high as 40%–50%, and GIS involvement may be seen in 35%–65% of the patients.[7] We think that the high prevalence rates of renal and GIS involvements might be related to the inclusion of patients with HSP in our study. Nearly all of our patients (99%) had lesions on the lower extremities, which are classical localization sites for CSVV.[7] Face, which is an unusual localization site, was also affected in 7% of the patients. Purpura was the most common skin finding with 43% of the patients and this was consistent with usual lesion type in CSVV. In patients with CSVV, mild-to-moderate inflammation may be observed. WBC, ESR, and CRP values may be increased, but there is a greater increase in inflammation markers in case of systemic involvement. In our study, 32% of the patients had an elevation in WBC, 47% in ESR, and 63% in CRP levels, and these results support the systemic inflammatory process in the disease.[7] There is also a known relationship between CSVV and autoimmune connective tissue diseases, and it is considered as the underlying cause in 15%–20% of the patients in the literature.[5] In this study, the laboratory parameters related to autoimmunity showed that 39% of the patients had ANA positivity, 20% had RF positivity, and 4% had ANCA positivity. These autoimmunity markers, which were detected in a large number of our patients, support the necessity to investigate and follow-up patients for autoimmune connective tissue diseases.

Vessel wall injury is related to immune complex deposition in CSVV.[6] In the literature, there are conflicting reports about the most common immune complex type in DIF.[6],[8],[9],[10],[11] In the study of Lath et al.,[10] DIF was positive in 60% of the patients, with the deposition of IgA being the most common, followed by C3. Nandeeshand Tirumalae[12] reported that 39% of patients were positive for DIF and they reported the most common immune complex subtype as C3, IgA, IgG, and IgM, in descending frequency. DIF positivities and the most common immune complex subtypes differ among different studies in the literature. In this study, the most common immune complex was C3 in 47% of patients, followed by IgA in 43%, IgM in 19%, and IgG in 6% of patients. There are many reports which indicate the close relationship between DIF positivity and timing of biopsy.[13],[14],[15],[16] Because of the differences in the biopsy time and the faster dissipation of immunoglobulins compared to the complement, deposited immune -complex types were thought to differ between our study and other studies in the literature. C3 is expected to be deposited in late-stage lesions of vasculitis.[17] DIF findings are usually negative and unreliable in biopsies taken from older lesions of >48 h.[18] Therefore, early lesions should be preferred for biopsy. In this study, the age of the lesion, which was sampled, was not detected. This is one of the limitations which may have affected the DIF results. Another limitation is that it was not considered whether the biopsy site was exposed to the sun or not. It might have an effect on immune-complex depositions.[19] Biopsy site is also an important factor for stasis-related immune complex depositions.[20] IgA deposition can be detected in other dermatological diseases related to stasis,[20] but this limitation was not considered in the study when investigating DIF findings.

In our study, no statistically significant difference was found between DIF-positive and DIF-negative groups in terms of triggering factors, extracutaneous involvements, lesion localizations, and skin findings. There was also no statistically significant difference in the same parameters between immune-complex subtype groups. Takatu et al.[11] reported the association between IgM deposition and connective tissue disease or inflammatory comorbidities in LCV. In our study, laboratory parameters, including ANA, RF, ANCA, C3, and C4 levels, which are well-known autoimmunity markers, were not statistically different between DIF-positive and DIF-negative groups. Takatu et al.[11] found a statistically significant difference with respect to ANA, SSA (anti-Ro)/ SSB (anti-La) antibodies, C3/C4 levels, and IgM deposition and also with respect to ANCA and IgG deposition. Alalwani et al.[21] showed the correlation between DIF positivity and autoimmune markers, as well. Our study and contradictory data in the literature show that further studies are needed to elucidate the relationship between DIF findings and autoimmunity. In this study, no any association was found between extracutaneous involvement and DIF results, as in the study of Sais et al.[8] Unlike our results, Barnadas et al.[22] showed IgA deposition in patients with renal involvement and also, Alalwani et al.[21] detected IgA deposition in renal and GIS involvements. Takatu et al.[11] reported an association between C3 deposition and renal involvement, and between IgM deposition and autoimmune diseases. In our study, laboratory parameters, including blood creatinine levels, hematuria, spot or 24-h urinary proteinuria and OBS, showing renal or GIS involvement, were also not correlated with DIF findings.

The skin findings of this study were found to vary from petechiae, purpura, macule, and patch to more severe lesions, including papules, plaques, ecchymoses, bullae, and necrosis. No association between DIF findings and skin findings indicates that immune complex deposition does not affect the severity of skin lesions, and DIF findings cannot be predicted by lesion type.

It has been reported that the lesions located above the waist might be related to IgA deposition and organ involvement.[23] In this study, variable descriptions for skin findings and localizations were used. Because of the retrospective nature of the study, the objectivity of these variables might be limited. In addition to this limitation, there is a disequilibrium between the numbers of groups, which may lead to question the negative results of the study.

IgA deposition on DIF examination is an important diagnostic criterion for only HSP,[24] not for other vasculitis. This laboratory test should be requested to differentiate HSP from other small vessel vasculitis. Therefore, performing DIF examination only with IgA, not with other antibodies, fibrinogen, or complement, maybe enough for the diagnosis of HSP.


  Conclusion Top


Based on the reports in the literature and our results, we think that DIF results did not play a role in determining the clinical findings and laboratory parameters in patients with CSVV. Therefore, the necessity of DIF examination, which is an expensive method, should be clarified with the prospective, large patient series.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Alalwani M, Billings SD, Gota CE. Clinical significance of immunoglobulin deposition in leukocytoclastic vasculitis: A 5-year retrospective study of 88 patients at Cleveland clinic. Am J Dermatopathol 2014;36:723-9.  Back to cited text no. 21
    
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Barnadas MA, Pérez E, Gich I, Llobet JM, Ballarín J, Calero F, et al. Diagnostic, prognostic and pathogenic value of the direct immunofluorescence test in cutaneous leukocytoclastic vasculitis. Int J Dermatol 2004;43:19-26.  Back to cited text no. 22
    
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  [Table 1], [Table 2], [Table 3], [Table 4]



 

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