Nghiên cứu một số tự kháng thể và mối tương quan với tổn thương da trên bệnh nhân lupus ban đỏ hệ thống tom tat tieng anh le huyen my

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MINISTRY OF MINISTRY OF HEALTH EDUCATION & TRAINING HANOI MEDICAL UNIVERSITY LE HUYEN MY STUDY OF SOME ANTIBODIES AND THE ASSOCIATIONS WITH CUTANEOUS MANIFESTATIONS IN PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS Subject: Dermatology Code: 62720152 SUMMARY OF THESIS OF PHYLOSOPHY DOCTOR IN MEDICINE HA NOI – 2018 Research completed in HANOI MEDICAL UNIVERSITY Scientific supervisor Assoc Prof Ph.D Tran Lan Anh Scientific reviewer 1: Assoc Prof Ph.D Tran Dang Quyet Scientific reviewer 2: Assoc Prof Ph.D Nguyen Duy Hung Scientific reviewer 3: Assoc Prof Ph.D Nguyen Van Doan The thesis will be defended in front of The Council for Philosophy Doctor in Medicine at Hanoi Medical University At………………………….201 - The thesis can be found at: The National Library Central Medical Information Library Hanoi Medical University Library - Library of National hospital of Dermatology and Venereology LIST OF PUBLISHED PAPERS RELATIVE TO THIS DISSERTATION Le Huyen My, Tran Lan Anh, Luu Phuong Lan (2017) Cutaneous manifestations in patients with systemic lupus erythematosus Journal of Military Medicine, 322, 32 – 45 Le Huyen My, Tran Lan Anh (2018) Study of some antibodies in SLE patients with cutaneous lupus erythematosus Journal of Practical Medicine, (1068), 39 - 41 INTRODUCTION Urgency of topics Systemic Lupus Erythematosus (SLE) is one of the most common connective tissue diseases, which has a complicated pathogenesis mechanism SLE is characterized by a global loss of self-tolerance with activation of autoreactive T and B cells leading to production of pathogenic autoantibodies and tissue injury Skin is the second most affected organ (after arthritis), the incidence of skin lesions in SLE is relatively high (over 75% of patients) 25% of patients with skin lesions appear before systemic manifestations from weeks to months Although only four types of skin lesions are included in the American College of Reumatology criteria for SLE diagnosis, in reality the cutaneous manifestations of the SLE patients are varied, which can occur at any stage of the disease Sometimes, the active skin lesions may also reflect systemic organ damages Many types of skin lesions can become irreversible damages, and can also cause psychological effects Therefore the oppurtunities of seeking jobs and patient’s quality of life can be affected The identification of lupus skin lesions helps physicians make early diagnosis, early intervention, and helps to reduce complications and improve the quality of life for patients Autoantibodies play an important role in the pathogenesis of SLE The four main extractable nuclear antigens (ENAs) used for detection of SLE are Ro, La, Smith, U1-RNP Even though the presence of autoantibodies in SLE has been known for years, still nowadays a number of researches are being made to understand the pathogenetic, diagnostic, and prognostic meaning of such autoantibodies Some antibodies associate with the organ’s manifestations, some associate with skin’s manifestations of SLE In Vietnam, there are many studies on clinical, laboratory aspects of SLE But up to now, no author has looked into the associations between anti-Smith, anti U1-RNP, antiRo/SSA, anti-La/SSB antibodies and cutaneous manifestations of SLE patient Therefore, this thesis is run to focuse on two main objectives: To assess cutaneous manifestations of patients with SLE To investigate the associations between anti-Smith, anti U1RNP, anti-Ro/SSA, anti-La/SSB antibodies and cutaneous manifestations of SLE patients New contributions of the thesis - This is the first research in Vietnam that studied on the cutaneous manifestations of SLE patients according to Gilliam and sontheimer classification, the histopathology and immunohistochemical expression of granzyme B in specific skin lesions This study also evaluated the associations between the incidences and concentrations of anti-Smith, anti U1-RNP, anti-Ro/SSA, anti-La/SSB antibodies with cutaneous manifestations of SLE patient, with RCLASI scores and some histologic findings of specific skin lesions The results of the study have shown that these antibodies associated with some cutaneous manifestations, especially anti Ro/SSA antibodies AntiRo/SSA antibodies were significantly associated with malar rash, oral mucosal lesions, photosensitivity, SCLE lesions, epidermal colloid bodies, correlated with the number of LE specific skin lesions, RCLASI activity scores Layout of the thesis The thesis has 133 page, including: Introduction (2 pages), Chapter 1- Overview (39 pages); Chapter - Objects and Methods (19 pages); Chapter - Results (31 pages); Chapter - Discussions (39 pages); Chapter - Conclusions (2 pages) and Recommendations (1 page) The thesis has 30 tables, 16 charts and 14 figures and 191 references (including 06 Vietnamese documents and 185 English documents) Chapter OVERVIEW 1.1 Cutaneous manifestations in patients with SLE A classification system for cutaneous manifestations in LE patients based on specific and non-specific clinical and histopathological features, was proposed by two American dermatologists, James Gilliam and Richard Sontheimer’s in 1979 Cutaneous lesions are classified into LE-specific and LE-nonspecific lesions The LE-specific lesions can be further subdivided into acute, subacute and chronic forms LE-nonspecific skin manifestations include a number of different skin symptoms that are related to the LE process but are not specific for LE disease and can be displayed in other autoimmune diseases More than one kind of LE-specific and LEnonspecific lesions can be seen in an SLE patient 1.2 Histopathological findings in LE-specific lesions ACLE: Biopsies exhibit pauci-inflammatory interface dermatitis, slight to absent epidermal atrophy, basement membrane zone thickening minimal or absent, minimal follicular plugging, prominent papillary dermal edema and reticular dermal mucin accumulation SCLE: Biopsies show dyskeratosis extending into upper spinous layers, prominent epidermal atrophy, follicular plugging, basement membrane zone thickening, mild to moderate mononuclear cell infiltrate confined to the superficial CCLE: Lesions of DLE are typified by lymphocyte rich interface dermatitis, epidermal atrophy, sometimes acanthosis, prominent basement membrane zone thickening, prominent follicular hyperkeratosis, dense superficial and deep perivascular and periadnexal infiltrates, prominent follicular degeneration 1.3 Immunohistochemical of granzyme B in LE-specific lesions Granzyme (Gr) B, synthesized by activated cytotoxic lymphocytes and natural killer (NK) cells, is a serine protease able to prime apoptosis through caspase activation Positive immunohistochemical expressions of granzym B in LE specific lesions suggest a central role for apoptotic keratinocytes in the pathogenesis of LE 1.4 Clinical implications of some ENAs autoantibodies in SLE 1.4.1 1.4.2 1.4.3 Anti-Smith antibodies: anti-Smith antibodies are highly specific for SLE and represent one of the ACR diagnostic criteria for this disease The specificity is around 95-99% but the sensitivity is low and they are only detected in 20 - 24% of SLE patients In some studies anti-Sm were found to associate with some LE cutaneous manifestations (malar rash, oral mucosal lesions, Raynaud phenomenon ) Anti U1-RNP antibodies: Anti-U1-RNP antibodies are detected in 20%–30% of SLE patients but they not show a good specificity for SLE since they are commonly found in mixed connective tissue disease (MCTD) The isotype of the antibody response may show the pathogenic mechanism since IgM anti U1-RNP antibodies where predominantly found in SLE whereas IgG anti-U1-RNP in the absence of IgM anti-U1-RNP antibodies are found in MCTD Anti U1-RNP antibodies have been associated to Raynaud’s phenomenon Anti-Ro/SSA antibodies: These antibodies can be detected in 70100% of patients with Sjögren syndrome, in 30-70% of SLE patients, in 70-80% of neonatal lupus erythematosus patients Anti-Ro/SSA 1.4.4 antibodies might have a pathogenetic role in the initiation of tissue damage especially in SLE photosensitivity lesions Anti-La/SSB antibodies: Anti-La/SSB antibodies are specific for Sjögren syndrome and SLE However, anti-La antibodies are rarely detected without anti-Ro because both proteins associate with a common type of human RNA called hYRNA Anti-La/SSB antibodies are seen in 10 - 25% of patients with SLE Anti La/SSB antibodies have been found to associate with SCLE lesions, photosensitivity Chapter SUBJECTS AND METHODS 2.1 Study subjects Including 80 patients, who were diagnosed with systemic lupus erythematosus according to ACR 1997 criteria, treated at Outpatient and Inpatient departments – National Hospital of Dermatology and Venereology from December 2014 to December 2017 Patient inclusion criteria: SLE patients with cutaneous manifestations who accepted to participate in the study, were selected regardless of age, gender, occupation, education level and place of residence Patient exclusion criteria: Patients with other connective tissue diseases, patients with insufficient laboratory test results, patients refused to participate in the study 2.2 Methods 2.2.1 Methods of study: prospective, cross-sectional descriptive research 2.2.2 Sample selection: Samples were selected by convenient sampling The objects were selected in chronological order, irrespective of age, sex, level of activity and damage 2.2.3 Sample size Sample size calculated according to the formula: n = Z (21−α ) p (1 − p ) ∆2 n is the minimum sample size; α is a statistically significant level corresponding to a 95% confidence interval, α = 0.05; Z(1- α /2) is the Z score corresponding to the desired statistical significance level, where α = 0.05, Z(1- α /2) = 1.96; p is the positive rate of anti SSB antibody in SLE patients (we chose p = 0,08 according to Wang (1986)); ∆ is the absolute precision desired, we chose ∆= 0,06 From there, we calculated n = 78 Our study had a sample size of 80 patients 2.2.4 Steps to conduct After being diagnosed for SLE and coding list, patients underwent the following research steps: - Interviewed for personal and family history - Analysed LE specific, LE nonspecific lesions according to the classification made by Gilliam and Sontheimer, assessed revised cutaneous lupus erythematosus disease area and severity Index (RCLASI) for LE specific lesions - Performed biopsy of LE specific lesions, stainned for HE, PAS, Alcian Blue pH 2,5 - Performed immunohistochemical staining for granzyme B - Performed ELISA to detect anti-Smith, anti-SSA, anti-SSB, anti U1RNP antibodies 2.2.5 Places and methods of laboratory tests 2.2.5.1 The basic subclinical tests were performed at the corresponding departments of National hospital of Dermatology and Venereology 2.2.5.2 Histopathology and immunohistochemical tests were performed at department of Hematology, Biochemistry, Immunology and Histopathology of National hospital of Dermatology and Venereology - HE stanning: Hematoxylin Harris reagent was produced by Diapath, Italia, eosin was produced by Thermo Scientific, England - PAS stanning: reagent was produced by Thermo Scientific, England - Alcian blue pH 2,5 stanning: reagent was produced by Cell Marque, USA - Immunohistochemical staining for granzyme B: monoclonal antigranzyme B antibody was produced by Cell Marque kháng thể đơn dòng sản xuất Cell Marque, USA; other reagents were produced by Dako Cytomation, Denmark 2.2.5.3 Antibodies detections These tests were performed at department of Hematology, Biochemistry, Immunology and Histopathology of National hospital of Dermatology and Venereology Anti U1-RNP, anti-Smith, anti-SSA, anti-SSB antibodies were detected by ELISA ELX system (Biotek, USA) ELISA kits were produced by Orgentec, Germany 2.2.6 Evaluation criteria used in the study - Diagnosis of SLE: based on the ACR 1997 criteria - Evaluate the skin manifestations of SLE: based on the Gilliam and Sonthemer’s classification - Evaluate the activity and damage score taking into account various clinical features of the different subtypes of CLE based on Revised Cutaneous Lupus Erythematosus Disease Area and Severity Index (RCLASI) 2.2.7 Data processing: The data were processed by SPSS 20.0 statistical software 2.2.8 Ethics Research: The research was conducted in prestigious medical centers with the consent of the leaders of the units This is a descriptive study, no intervention, based on the willingness of the participate The data were collected for research and patient care purposes only and not for other purposes 10 CHAPTER RESULTS 3.1 General characteristics of the studied subjects Table 3.1 Age and sex characteristics Age group n % 0-9 2,1 10 - 19 14 17,5 20 - 29 16 20,0 30 - 39 23 28,8 40 - 49 16 20,0 50 – 59 8,8 ≥ 60 3,8 Total 80 100 Mean age 33,4 ± 13,3 (year) Male/female ratio 1/6 The mean age of patients was 33,4 ± 13,3 (range – 68 year) The most affected age group was group of 30-39 year (28,8%) Group of 60 years and over accounted for 3,8% There was a predominance of female gender with a male/female ratio of 1/6 3.2 Characteristics of cutaneous manifestations of SLE patients 3.2.1 Clinical characteristics Table 3.2: Distribution of patients by LE-specific cutaneous lesions LE-specific n % cutaneous lesions ACLE Malar rash 49 61,3 Generalized ACLE 12 15,0 SCLE Papulosquamous SCLE 11,3 Annular SCLE 5,0 CCLE Localised DLE 11,3 Generalised DLE 7,5 Lupus panniculitis 1,3 The commonest skin symptoms was malar rash (61,3%) Percentage of patients with papulosquamous SCLE (11,3%) was higher than those with annular SCLE (5,0%) 11,3% of patients had localised ACLE while 7,5% of patients had generalised ACLE, 2,5% of patients had lupus panniculitis 13 infiltration dermis Reticular dermis Periappendag eal Loss of epithelial structures of adnexa 30 39 62, 81, 10 11 76, 84, 7,7 15 14 93, 87, 25, 0,05 0,91 0,002 Hyperkeratosis, epidermal atrophy, basement membrane thickening, basal vacuolation were more common in SCLE compared with CCLE (p < 0,05) Percentage of epidermal colloid bodies was highest in SCLE (53,8%) Percentage of dermal edema was highest in ACLE 60,4% (p 0,05) Table 3.8: Associations between Granzyme B expression and histopathological features Granzym B expression Histopathological Negative Positive p features (%) (%) (n = 11) (n = 66) Hyperkeratosis 36,4 57,6 0,33 Epidermal atrophy 63,6 42,4 0,33 Basement membrane 0,75 54,5 60,6 thickening Basal vacuolation Epidermal colloid bodies Dermal colloid bodies Telangiectasias in upper dermis Follicular plugging Loss of epithelial structures of adnexa 100 18,2 77,3 24,2 15,2 90,9 93,9 72,7 92,5 7,6 0,11 1,0 0,34 0,55 0,04 1,0 15 Lymphocytic infiltration peri-appendageal 54,5 87,9 Adnexal basal membrane vacuolation 63,6 62,1 18,5 33,3 93,8 100,0 86,2 86,7 Neutrophils beneath epidermis Lymphocytic infiltration in upper dermis Lymphocytic infiltration in reticular dermis 0,02 1,0 0,29 1,0 1,0 The percentage of follicular plugging and lymphocytic infiltration peri-appendageal were significantly higher in cases showing granzyme B positive expression compared with those showing granzyme B negative (p < 0,05) 3.2.2 Associations between antibodies and clinical, histopathological manifestations of cutaneous LE lesions Table 3.9: Prevalence and concentration of autoantibodies Prevalance Mean Antibodies concentratio n % n Anti Smith 26 32,5 24,6 ± 43,6 Anti U1-RNP 15 18,8 16,8 ± 40,3 Anti SSA 52 65,0 76,7 ± 68,7 Anti SSB 22 27,5 25,5 ± 53,8 The prevalence of anti-SSA antibodies was 65%, anti-SSB antibodies was 27,5%, anti-Smith antibodies was 32,5%, anti U1-RNP antibodies was 18,8% The mean concentration of anti-SSA antibodies was 76,7 ± 68,7, anti-SSB antibodies was 25,5 ± 53,8, anti-Smith antibodies was 24,6 ± 43,6, anti U1-RNP antibodies was 16,8 ± 40,3 Table 3.10: Prevalence of antibodies between groups treated and nontreated with immunosuppressant drugs 16 Antibodies Anti Smith Anti U1-RNP Anti SSA Anti SSB Non-treated group (n=62) n % 20 32,3 12 19,4 37 59,7 14 22,6 Treated group (n=18) n % 33,3 16,7 15 83,3 44,4 p 1,0 1,0 0,06 0,08 No significant difference for the prevalence of anti-Smith, anti U1RNP, anti-SSA, anti-SSB antibodies were observed between SLE patient groups treated and non-treated with immunosuppressant drugs in month recently (p > 0,05) Table 3.11: Associations of antibodies with clinical manifestations of LE lesions Symptoms CCLE SLCE Malar rash Photosensitivit y Raynaud phenomenon Palmar erythema Periungual telangiectasia Periungual hemorrhage U1-RNP Smith OR p OR 0,2 0,7 3,0 1,0 5,5 0,6 0,9 7,1 0,2 0,2 2,0 2,8 0,6 1,2 0,3 1,2 1,6 1,0 0,1 1,0 0,0 0,4 1,0 0,0 Ro/SSA p OR p 0,06 0,3 0,08 0,33 8,1 0,03 0,04 3,2 4,9 1,6 0,8 6,4 3,5 0,39 0,71 0,18 0,74 0,68 0,01 0,00 0,71 0,79 0,86 0,41 La/SSB OR p 0,3 4,0 2,0 2,0 1,6 1,0 1,6 0,4 0,2 0,0 0,1 0,3 0,6 1,0 0,4 0,6 17 Oral ulcer Non-scarring alopecia Scarring alopecia 2,1 1,6 0,8 0,2 0,4 0,5 3,1 1,7 0,6 0,02 0,29 0,17 3,1 0,6 0,3 0,04 2,8 0,38 0,7 0,34 0,7 0,0 0,4 0,3 Anti-U1RNP antibodies were significantly associated with Raynaud phenomenon (OR = 5,55, p = 0,04), periungual hemorrhage (OR = 7,15, p = 0,02) Anti-Smith antibodies were significantly associated with malar rash (OR = 2,87, p = 0,046), oral mucosal lesions (OR = 3,15, p = 0,02) Anti-Ro/SSA antibodies were significantly associated with malar rash (OR = 3,29, p = 0,01), oral mucosal lesions (OR = 3,12, p = 0,04), photosensitivity (OR = 4,96, p = 0,004), SCLE lesions (OR = 8,1, p = 0,03) Anti-La/SSB antibodies were significantly associated with oral mucosal lesions (OR = 2,87, p = 0,04), SCLE lesions (OR = 4,04, p = 0,04) 18 Table 3.12: Association of antibodies with histopathological features of LE lesions Histopathological features Hyperkeratosis Epidermal atrophy Basement membrane thickening U1-RNP OR p Smith OR p Ro/SSA OR 0,57 0,33 0,46 0,112 1,35 0,77 0,666 0,53 0,19 0,59 p La/SSB OR p 0,53 0,73 0,52 0,26 0,61 0,34 0,58 0,35 0,64 0,35 0,82 0,67 1,42 0,49 Basal vacuolation Epidermal colloid bodies 1,01 1,0 0,62 0,39 1,02 0,98 0,62 0,54 1,21 0,75 1,29 0,64 3,70 0,04 1,79 0,29 Dermal colloid bodies Telangiectasias in upper dermis Dermal edema Dermal melanosis Follicular plugging Loss of epithelial structures of adnexa Lymphocytic infiltration peri-appendageal 0,35 0,45 0,65 0,74 0,72 0,74 1,39 0,73 0,32 0,23 0,71 0,66 1,26 1,0 1,56 1,55 0,58 0,41 0,45 0,39 0,36 0,93 0,54 0,56 0,88 0,23 0,42 0,69 0,32 0,49 0,44 0,02 0,39 1,55 0,39 0,57 0,31 1,37 1,0 1,09 1,0 0,50 1,0 0,33 0,34 0,64 1,0 1,00 1,0 0,54 0,28 0,56 0,35 1,17 1,0 Adnexal basal 0,37 0,08 1,10 membrane vacuolation 0,85 1,20 0,70 1,25 0,68 Neutrophils beneath epidermis Lymphocytic infiltration in upper dermis Lymphocytic infiltration in reticular dermis GrB positive expression 1,0 2,21 0,29 0,83 0,76 1,38 0,59 0,77 0,77 1,24 1,0 1,47 1,0 1,58 2,92 1,15 1,05 1,0 0,82 0,74 1,07 1,0 0,39 0,16 2,22 0,68 0,49 0,31 0,37 0,31 4,35 0,27 1,0 Epidermal colloid bodies was more common in SSA antibodies positive group compared with negative group (30,8% vs 10,7%, p = 19 0,04) Dermal melanosis was less common in SSA positive group compared with negative group (26,9% vs 53,6%, p = 0,02) There was no significant difference for histopathological features and granzym B expression between groups with anti-Smith, anti U1RNP, anti La/SSB antibodies and those without these antibodies (p > 0,05) Chart 3.3: Correlation between antibodies and total number of LEspecific lesions There was a positive correlation between the concentration of antiSmith antibodies and total number of LE-specific lesions (r = 0,237, p = 20 0,034) The concentration of anti-SSA antibodies also correlated with total number of LE-specific lesions (r = 0,298, p = 0,007) We didn’t observed any correlation between the other antibodies and total number of LE-specific lesions Chart 3.4: Correlation between antibodies and RCLASI activity scores There was a positive correlation between the concentration of antiSSA antibodies and RCLASI activity scores (r = 0,363, p = 0,001) No correlation between the other antibodies and RCLASI activity scores was found Chapter 4: DISCUSSION 21 4.1 General characteristics of the studied subjects In the present study 80 cases of SLE were encountered The mean age of patients was 33,4 ± 13,3 (range – 68 year) The most affected age group was group of 30-39 year (28,8%) There was a predominance of female gender with a male/female ratio of 1/6 These results are consistent with previous reports SLE are more likely to occur in women of reproductive age, the period that endogenous sex hormones are most active Abnormal oestrogen metabolism has been demonstrated in the pathogenesis of SLE 4.2 Characteristics of cutaneous manifestations of SLE patients 4.2.1 Clinical characteristics The commonest skin symptom was malar rash (61,3%) Percentage of patients with papulosquamous SCLE (11,3%) was higher than those with annular SCLE (5,0%) 11,3% of patients had localised ACLE while 7,5% of patients had generalised ACLE, 2,5% of patients had lupus panniculitis Our findings are in agreement with the results of some researches in SLE patients ACLE was the commonest LE lesion, SCLE and CCLE accounted for around 20% Lupus panniculitis was a rare symptom of SLE Among the LE-nonspecific lesions, photosensitivity was the symptom with highest percentage (78,8%), following by non-scarring alopecia (65%), vasculitic lesions (41,3%), oral ulcers (32,5%), bullous lesions (3,8%) We observed some kinds of vasculitic lesions including palmar erythema (26,3%), periungual telangiectasia (13,8%), Raynaud phenomenon (10%), periungual hemorrhage (8,8%), livedo reticularis 1,3%, atrophie blanche (1,3%) Our results are in agreement with the results of Rabbani (2003), Hau (2006), Mohammad (2010) LE cutaneous lesions in patients with SLE are varied The identification of lupus skin lesions helps physicians make early diagnosis, early intervention, and helps to reduce complications and improve the quality of life for patients The mean RCLASI activity scores were highest in SCLE group, the mean RCLASI damage scores were highest in CCLE group The RCLASI activity was scored on the basis of erythema, scaling/ hyperkeratosis, edema/infiltration, subcutaneous nodule/plaque, mucous membrane lesions, nonscarring alopecia and ‘lupus hair’ Erythema was scored from to points, while scaling ⁄hyperkeratosis, edema/infiltration, subcutaneous nodules/plaques can be scored from 22 to points at each anatomical region Compared with ACLE and CCLE, patients with SCLE in this research had more lesions, the erythemas are darker, the lesions had more scales, so the mean RCLASI activity scores were highest in SCLE group CCLE group included patients with DLE, lupus paniculitis, which had dyspigmentation and scarring/atrophy The total number of damage lesions in this group was also higher than the others, so the mean RCLASI damage scores were highest in this group 4.2.2 Histopathology features In the present study, biopsies of ACLE exhibit papillary dermal edema, mild mononuclear cell infiltrate confined to the superficial dermis and subtle basal layer vacuolopathic degeneration of keratinocytes Histopathology features of SCLE are characterized of hyperkeratosis, epidermal atrophy, basement membrane zone thickening, pigmentary incontinence, prominent basal vacuolation and epidermal colloid bodies Lesions of DLE are typified by hyperkeratosis, basement membrane thickening, epidermal atrophy, dermal colloid bodies Heavy superficial and deep perivascular and periappendageal lymphocytic infiltrates were observed Loss of epithelial structures of adnexa was more common compared with ACLE and SCLE All the cutaneous LE lesions in this research had mucin deposition with different degrees We use Alcian blue preparations for stanning of mucin These deposits manifest globules and strings of blue color between and adherent to the collagen bundles This is a most useful morphologic finding which favors a diagnosis of LE over other causes of a cell poor interface dermatitis such as morbilliform drug reactions and viral exanthemata or other lichenoid dermatitis with epidermal atrophy Both proportion of positive granzym B expression and mean percentage of positive cells were higher in DLE and SCLE compared with ACLE SCLE and CCLE were the lesions that we found the number of colloid bodies, proportion and degree of basal vacuolation, infiltration of lymphocyte in upper dermis higher than in ACLE This may indicates the apoptosis and cytotoxicity of the infiltrate in these lesions and may explain why granzym B expression was higher Granzyme B is considered a specific marker that shows the extent of the direct local cytotoxic damage However, the difference was not significant, one of the reasons may due to our small size of samples 23 The current study demonstrates that the percentage of follicular plugging and lymphocytic infiltration periappendageal was significantly higher in cases showing positive granzyme B expression compared with those negative Abdou (2013) found the association between positive granzyme B expression and follicular plugging Wenzel (2007) observed a strong expression of the cytotoxic granzyme B specifically in lesional lymphocytes of adnexal basal membrance He concluded that granzyme B expression associated with lymphocytic infiltration of epidermis, periappendageal and tissue damages 4.2.3 Associations between antibodies and clinical, histopathological manifestations of cutaneous LE lesions The prevalence of anti-SSA antibodies was 65%, anti-SSB antibodies was 27,5%, anti-Smith antibodies was 32,5%, anti U1-RNP antibodies was 18,8% Our results are in agreement with some researches although the prevalence of anti-Ro/SSA antibodies were higher Differences in geography, race, study population account for this No significant difference for the prevalence of anti-Smith, anti U1RNP, anti-SSA, anti-SSB antibodies were observed between SLE patient groups treated and non-treated with immunosuppressant drugs in month recently 80 patients of this study admitted to the hospital the first time At the time of examination, 62 patients had not been using any immunosuppressant drug and 18 patients had been treated with immunosuppressant drugs (corticosteroid) by other hospitals in month recently Faria (2005) conducted a retrospective study on one hundred and thirty patients, who fulfilled American College of Rheumatology classification criteria for SLE with at least yearly anti-ENA and dsDNA tests between 1987-2002 Antibodies to Ro/SSA were present in 47%, U1-RNP in 36%, Sm in 23%, and La/SSB in 7% of patients Among patients ever positive for a given autoantibody, the frequency of the "always present" pattern was 52% for anti-Ro/SSA, 38% for U1RNP, 17% for Sm, 11% for La/SSB Among patients with a positive test at diagnosis the frequency of those remaining positive between the 2nd and 4th year of follow up decreased to 39-78%, depending upon autoantibody specificity; between the 5th and 10th years this rate was 20-75% In a research of McCarty (1982), anti-Smith antibodies showed little variation in whole treatment periods, although some patients were 24 treated with cytotoxic drugs targeting B cells Unlike anti-ds DNA antibodies which fluctuate in the course of the disease depending on treatment therapies, the presences of anti ENA antibodies (anti smith, U1-RNP, Ro/SSA, La/SSB) are persistent although patients are still treated with immunosuppressive drugs However, there is a need for longitudinal follow-up studies in Vietnamese SLE patients to verify these findings Anti-U1RNP antibodies were significantly associated with Raynaud phenomenon (OR = 5,55, p = 0,04), periungual hemorrhage (OR = 7,15, p = 0,02) Anti-Smith antibodies were significantly associated with malar rash (OR = 2,87, p = 0,046), oral mucosal lesions (OR = 3,15, p = 0,02) Anti-Ro/SSA antibodies were significantly associated with malar rash (OR = 3,29, p = 0,01), oral mucosal lesions (OR = 3,12, p = 0,04), photosensitivity (OR = 4,96, p = 0,004), SCLE lesions (OR = 8,1, p = 0,03) Anti-La/SSB antibodies were significantly associated with oral mucosal lesions (OR = 2,87, p = 0,04), SCLE lesions (OR = 4,04, p = 0,04) Beside the associations of anti-Ro/SSA antibodies with epidermal colloid bodies, there was no associations between other antibodies and histopathological features and granzyme B expression Anti-Ro/SSA is the only one which had a correlation between the concentration and RCLASI activity scores Our results are in agreement with some researches Patsinakidis (2016) found that anti-Smith antibodies were present in 30,6 % of patients with ACLE (including malar rash and generalized ACLE), higher than other groups (p < 0.0001) The presence of anti-U1-RNP antibodies was a positive predictor for CLE (P = 0.0376) in SLE patients The prevalence of anti U1-RNP were higher in ACLE group compared with other LE-specific groups (37,1%, p< 0,0001), while the prevalence of anti-SSA and anti-SSB antibodies were higher in SCLE group than other LE-specific groups (79.2%, p = 0.0007 and 36.1%, p < 0.0001) Vera-Recabarren (2010) studied on 112 patients with SCLE and 158 patients with CCLE, 90 patients with SCLE (8%) had anti U1RNP antibodies Patients with anti U1-RNP antibodies also had a higher frequency of oral ulcers and Raynaud phenomenon than patients without these antibodies Pathogenic roles of antibodies in SLE as well as in CLE have not yet been elucidated Anti-RNP antibodies are directed to at least proteins of 70 kDa (U1), 33 kDa (protein A), and 22 kDa (protein C), 25 respectively, which bind to U1-RNA to form U1-RNP For the U1 protein, the apoptosis-related modified form has been associated with SLE patients presenting skin involvement, while the oxidized form has been associated with patients with Raynaud’s phenomenon, scleroderma like vasculitic lesions Anti-Ro/SSA antibodies were most associated with skin lesions Anti-La were rarely detected without anti-Ro Some hypotheses have been put forward indicating that the pathogenic role of anti-Ro antibodies might have a relationship with UV effects UV irradiation induces de novo synthesis of the Ro antigens in both the cytoplasm and the nucleus in keratinocytes Besides, UV irradiation increases the expression of the antigens on the cell surface, enhancing the possibility of direct injury of keratinocytes by anti-Ro antibodies UV exposure leads to an expression of Ro antigen on the blebs of apoptotic epidermal keratinocyte, and leads to an immune response with anti-Ro antibodies The research of Ioannides (2000) supported for this hypothese of the pathogenic roles of anti-Ro/SSA antibodies His findings indicated that photosensitivity and the presence and titer of circulating anti-Ro/SSA and anti-La/SSB antibodies were both directly correlated with the expression of accessible and immunoreactive SSA/Ro and La/SSB antigens in the skin specimens of patients with LE CONCLUSSION Of the total 80 patients who fulfilled the American Rheumatology Association revised criteria for SLE, 85% were females and 15% were male patients with male to female ratio of 1:6 Mean age at presentation was 33,4 ± 13,3 years We would like to draw some conclusions: Characteristics of cutaneous manifestations of SLE patients 1.1 Clinical characteristics LE specific skin lesions noted were: malar rash 61,3%, generalised ACLE 15%, papulosquamous SCLE 11,3%, annular SCLE 5%, localised discoid 11,3%, generalised discoid 7,5%, lupus profundus 2,5% LE non specific skin lesions noted were: photosensitivity 78,8%, non-scarring alopecia 65%, oral ulcers 32,5%, bullous lesions 3,8%, palmar erythema 26,3%, periungual telangiectasia 13,8%, Raynaud phenomenon 10%, periungual hemorrhage 8,8%, livedo reticularis, 26 atrophie blanche 1,3% The RCLASI activity scores were highest in patients with SCLE (19,1 ± 8,4), the RCLASI damage scores were highest in patients with CCLE (3,6 ± 4,2) 1.2 Histopathological features Hyperkeratosis, epidermal atrophy, thickening of the basal membrane, vacuolization of the basal layer were more common in SCLE and CCLE Epidermal colloid bodies were statistically significant in SCLE (53,8%) Dermal edema was statistically significant in ACLE (60,4%), follicular damage was statistically significant in CCLE (25%) Dermal mucin accumulation was present in all LE specific lesions 81,2% of ACLE cases, 92,3% of SCLE cases, 93,8% of CCLE cases were positive for granzyme B The percentage of periadnexal lymphocytic infiltrate was significantly higher in cases showing granzyme B positive compared with those showing granzyme B negative Associations between antibodies and clinical, histopathological manifestations of cutaneous LE lesions The prevalence of anti-Smith, anti- U1-RNP, anti-Ro/SSA, antiLa/SSB antibody in SLE patients were 32,5%, 18,8%, 65% and 27,5%, respectively Anti-U1RNP antibodies were significantly associated with Raynaud phenomenon, periungual hemorrhage Anti-Smith antibodies were significantly associated with malar rash, oral ulcers, correlated with the number of LE specific skin lesions Anti-Ro/SSA antibodies were significantly associated with malar rash, oral ulcers, photosensitivity, SCLE lesions, epidermal colloid bodies, correlated with the number of LE specific skin lesions, RCLASI activity scores Anti-La/SSB antibodies were significantly associated with oral ulcers, SCLE lesions RECOMMENDATIONS When examining patients, attention should be paid to identify LE specific and non-specific skin lesions, which may be useful in the early diagnosis of cutaneous lupus erythematosus as well as systemic lupus 27 erythematosus, and may help patients be early treated to reduce complications and improve the prognosis All the cutaneous LE lesions had mucin deposition with different degrees, so in clinical practice, when suspected lupus erythematosus lesions, histopathological examination should be performed simultaneously with HE and Alcian Blue stanning The results of this study have shown that these ENA antibodies associated with some cutaneous manifestations, especially anti Ro/SSA antibodies In the future, longitudinal follow-up studies should be done to verify these associations ... cutaneous lesions LE- specific n % cutaneous lesions ACLE Malar rash 49 61,3 Generalized ACLE 12 15,0 SCLE Papulosquamous SCLE 11,3 Annular SCLE 5,0 CCLE Localised DLE 11,3 Generalised DLE 7,5 Lupus. .. some researches in SLE patients ACLE was the commonest LE lesion, SCLE and CCLE accounted for around 20% Lupus panniculitis was a rare symptom of SLE Among the LE- nonspecific lesions, photosensitivity... DISSERTATION Le Huyen My, Tran Lan Anh, Luu Phuong Lan (2017) Cutaneous manifestations in patients with systemic lupus erythematosus Journal of Military Medicine, 322, 32 – 45 Le Huyen My, Tran
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Xem thêm: Nghiên cứu một số tự kháng thể và mối tương quan với tổn thương da trên bệnh nhân lupus ban đỏ hệ thống tom tat tieng anh le huyen my , Nghiên cứu một số tự kháng thể và mối tương quan với tổn thương da trên bệnh nhân lupus ban đỏ hệ thống tom tat tieng anh le huyen my , Table 3.12: Association of antibodies with histopathological features of LE lesions

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