摘要
目的通过对我院住院的干燥综合征(SS)患者研究,旨在了解以2002年SS欧美合议分类诊断标准为纳入标准,我院pSS患者合并各系统受累情况与国内外相关文献比较分析异同性,以及pSS和sSS之间的临床特征和相关实验室检查的异同点,分析产生差异的原因,为临床上进一步完善干燥综合征的诊疗避免漏诊误诊提供思路和参考。同时检测41例SS患者唇腺组织中的SSA60、SSB及SS56蛋白的表达,比较SSA60和SSB在血清、唇腺组织中表达,分析SS56蛋白表达阴性组和阳性组的临床表现与实验室检查的异同点,探索SSA60、SSB和SS56蛋白在SS发病及诊断中的意义。
方法(1)收集2003.1.1-2010.12.31我院住院SS病例。记录病例一般情况、临床特征、实验室相关检查及自身抗体等,分组标准为：按2002年SS欧美合议分类诊断标准分为pSS组及sSS组两组。(2)采用链霉菌抗生物素蛋白-过氧化物酶连接免疫组织化学法测定30例pSS患者、11例sSS患者及5例正常唇腺组织中SSA60、SSB蛋白及SS56蛋白的表达(以细胞胞浆、胞核和／或胞膜中出现淡黄到棕黄色细颗粒状物质,着色高于背景底色为阳性)。利用统计学方法得出相关结论。
结果第一部分(1)一般情况：入选的SS患者共有75例,男3例,女72例,男女之比为1：24,年龄最小15岁,最大72岁,平均年龄为51.03±14.12岁。pSS组59例,男女之比为1：18.7,平均年龄50.63±13.84岁；sSS组16例,继发于SLE9例,RA6例,PM1例,均为女性,平均年龄为52.5±15.48岁。其中有一例有家族史,其母亲患有SLE。(2)首发症状：口眼干25例(33.3%),关节痛16例(21.3%),血液系统改变10例(13.3%),发热7例(9.3%),腮腺炎5例(6.7%),皮肤受累5例(6.7%),肾脏受累4例(5.3%),呼吸系统受累2例(2.7%),双眼视力下降1例(1.3%)。(3)59例pSS临床表现及主要实验室检查：59例pSS,口干57例(96.6%),眼干52例(88.1%),鼻干7例(11.9%),发热的14例(23.7%),淋巴结肿大10例(16.9%),猖獗龋齿31例(52.5%),皮肤粘膜受累21例(35.6%),关节痛31例(52.5%),乏力13例(22.0%),腮腺炎13例(22.0%),血液系统受累40例(67.8%),脾脏肿大11例(18.6%),肾脏受累15例(25.4%)；肺部受累32例(54.2%),肝损害12例(20.3%),4例并发下肢静脉血栓形成,1例患者为完全性的内脏转位。角膜染色(±)33／50(84.7%),腮腺扫描47／53(89.8%),唇腺活检有50／54(91.5%),白细胞减少22例(37.3%),贫血18例(30.5%),血小板减少6例(10.2%),血沉(ESR)升高的49例(83.1%),CRP升高16例(27.1%),白蛋白减少的17例(28.8%),球蛋白升高的37例(62.7%),SSA-60(±)(83.1%),SS-52(±)(67.8%),SSB(±)(50.8%),RF(±)24／37(64.9%),抗核抗体均为阳性,核型以斑点型为主,滴度以1：320居多。(4)pSS和sSS临床特征及实验室检查的比较：59例pSS与16例sSS相比口干、眼干、乏力、脾脏肿大、淋巴结肿大、血液系统受累、肝损害、肾脏受累等差异无统计学意义(P>0.05),但pSS组与sSS组出现关节痛(52.5%vs87.5%)和龋齿(52.5%vs18.8%)的阳性率相比差异具有统计学意义(P<0.05)。血常规、ESR增快、球蛋白、抗核抗体、抗SSA抗体、抗SSB抗体、抗核抗体滴度等差异无统计学意义(P>0.05),但sSS组白蛋白降低与pSS组差异比较有显著性意义(P<0.05)。第二部分(1)SSA在SS患者唇腺导管上皮细胞(ductal epithelial cells, DEC)、和腺泡上皮细胞(acinar epithelial cells,AEC)中阳性表达,少许浸润的淋巴细胞亦阳性表达。SSB及SS56不仅阳性表达于SS患者唇腺DEC、AEC,还表达于大量的浸润的淋巴细胞；(2)SSASSB及SS56在pSS和sSS两组患者唇腺组织中的表达无显著差异(P>0.05)；(3)SSA、SSB及SS56在SS患者与正常对照组唇腺中的表达有显著差异(P<0.05)；)；(4)SSA与SSB、SS56阳性表达比较差异有统计学意义(P<0.05),SSB与SS56两者之间表达无差异(P>0.05)。(5) SSA、SSB在血清中和唇腺中的的阳性表达比较差异均有统计学意义(P<0.05); SSA高表达于血清；而SSB高表达于唇腺组织。(6)SS56阳性组与阴性组的临床表现比较差异无统计学意义(P>0.05)；实验室检查中,红细胞、血红蛋白及血沉两组比较差异有统计学意义(P<0.05)。
结论(1)以2002年SS欧美合议分类诊断标准为纳入标准,本次研究对象中pSS组合并血液系统受累、肝损害及皮肤粘膜受累与国内外文献报道是基本一致的；肺部病变、血栓事件高于以往报道；肾脏受累、甲状腺病变较国内外文献报道的轻(2)pSS组外分泌腺体分泌功能受损,特别是唾液腺,表现比sSS重；sSS组低蛋白血症较pSS组明显。(3) SSA、SSB及SS56在SS患者唇腺组织中均有阳性表达,且SSB、SS56的阳性表达高于SSA60,三者可能参与唇腺局部的炎症损伤过程,参与SS的发病过程。SS56在唇腺中的表达同SSB基本一致,抗SSB抗体被认为是SS的标记性抗体,提示抗SS56抗体可能成为SS等自身免疫性疾病的抗体家族成员之一,且有望成为SS的新的诊断指标；(4)SS56阳性组的红细胞、血红蛋白均低于阴性组,推测SS56阳性的患者血液系统受累较重,而SS56阳性组的血沉增快较阴性组明显,提示SS56可能为疾病活动的指标之一；(5)SSA高表达于血清,而SSB高表达于唇腺组织,提示两种抗体的表达可能有组织特异性。
Objective:To investigate hospitalized patients with Sjogren's syndrome met the 2002 American-European Classification criteria for Sjogren's syndrome.To understand the similarities and differences of the involvement of various systems between Primary Sjogren's Syndrome(pSS) patients in our hospital and pSS of domestic and foreign literature. To analyse the similarities and differences of the clinical features and laboratory tests between pSS and secondary Sjogren's syndrome (sSS) patients. Furthermore, to improve the rate of diagnosis accuracy for Sjogren's syndrome in the future. To detect the expression of, SSA, SSB and SS56 protein in the labial salivary glands of 41 SS patients, compare the expression of SSA and SSB in the serum and labial glands, analyse the similarities and differences of the clinical features and laboratory tests between SS56 negative group and positive group, explore SSA60, SSB and SS56 protein in SS pathogenesis and diagnostic significance.
Method:(1)Hospitalized patients with Sjogren's syndrome in 2003.1.1-2009.2.28 in in-patient department of our hospital were enrolled. Record cases of the general situation, the clinical features, laboratory examination and related autoantibodies. In according to 2002 international diagnostic criteria for Sjogren's syndrome, the patients were divided into pSS group and sSS group. (2) Immunohistochemistry (streptavidin-perosidase, SP) was used to detect the expression of SSA60, SSB and SS56 in the specimens of labial gland of 30 cases of primary SS,11 cases of secondary SS (sSS), and 5 cases of controls. With cell cytoplasm, nuclei and/or cell membrane appeared weak yellow to tan fine granular material, shading above background impression was positive. Record and analyse the clinical manifestations and laboratory tests of 41 cases SS patients.
Results:The first part (1) General condition:A total of 75 patients with Sjogren's syndrome patients were enrolled,3males and 72 females, and male to female ratio was 1:24. The youngest is 15 years old, while the oldest is 72 years, with an average age of 51.03±14.12 years. pSS group of 59 patients, which the male to female ratio was 1:18.7 and the average age was 50.63±13.84 years. sSS group included 16 female cases, which secondary to SLE 9 cases、RA 6 cases、PM 1 case, the average age was 52.5±15.48 years. One case had a family history, whose mother has been suffering from SLE. (2) Initial symptoms:25 cases(33.3%) with dry mouth and dry eryes,16 cases(21.3%) with arthralgia,10 patients (13.3%) with blood system involvement,7 patients(9.3%) with fever,5 cases(6.7%) with skin involvement,5 cases(6.7%) with parotitis,4 case(5.3%) with renal involvement,2 cases(2.7%) with respiratory system involvementin,1 case(1.3%) with binocular vision decrease. (3) 59 pSS cases clinical manifestations and main laboratory tests:The clinical manifestations of pSS group were various. Among the 59 patients, there were 57 patients with dry mouth (96.6%),52 cases(88.1%) with dry eyes,7 cases (11.9%) with dry nose,14 cases (23.7%) with fever,10 patients (16.9%) with swollen lymph nodes,31 cases (52.5%) with rampant dental caries,21(35.6%) cases with mucocutaneous involvement; 31 cases (52.5%) with arthralgia,13 cases (22.0%) with fatigue,13cases (22.0%) with parotitis,40 cases (67.8%) with blood system involvement; 11 cases (18.6%) with spleen enlargement; 15 cases (25.4%) with renal involvement; 32 cases (54.2%) with Lung involvement,12 patients (20.3%) with liver damage and 4 cases with venous thrombosis, one patient had complete transposition of internal organs. The main laboratory tests were listed as follow:Corneal staining (+) 33/50 (84.7%), parotid scanning 47/53 (89.8%), labial gland biopsy 50/54 (91.5%), 22 cases of leukopenia (37.3%), anemia in 18 cases (30.5%), thrombocytopenia in 6 patients (10.2%), elevated erythrocyte sedimentation rate (ESR) in 49 cases (83.1%), increasing CRP in 16 patients (27.1%), decreasing albumin in 17 patients (28.8%), increasing globulin in 37 cases (62.7%), SSA60 (+) (83.1%), SS52 (+) (67.8%), SSB (+) (50.8%), RF (+) 24/37 (64.9%). Antinuclear antibodies were positive, the main type of which was spot and titer was 1:320 majority. (4)pSS and sSS clinical features and laboratory Comparison:While 59 cases of pSS were compared with 16 cases sSS, the difference of dry mouth, dry eyes, fatigue, enlarged spleen, swollen lymph nodes, blood system involvement, liver damage, kidney involvement, etc between the two groups had no statistical significance (P> 0.05). However, the difference of the positive rate of joint pain (52.5% vs87.5%) and dental caries (52.5% vsl8.8%) between the two groups had statistical significance (P<0.05). The difference of blood count, ESR faster, globulin, antinuclear antibodies, anti-SSA antibodies, anti-SSB antibodies, antinuclear antibody titers, etc had had no statistical significance (P> 0.05), but sSS group differences in albumin decreasing compared with pSS group was more significant (P<0.05). The second part (1) SSA in SS patients lip gland ductal epithelial cells (DEC) and acinar cells epithelial cells (AEC) positively expressed, a little infiltration of lymphocytes also positively expressed; SSB and SS56 not only positive expression in SS patients AEC, DEC, lip glands in mass also expressed the infiltration of lymphocytes. (2) SSA, SSB and SS56 in pSS and sSS two groups of the patient's labial salivary glands expressed no significant difference (P> 0.05). (3) SSA, SSB and SS56 in the SS patients and normal control group of the patient's labial salivary glands expressed no significant difference (P> 0.05). (4) SSA comparing to SSB and SS56 expressed comparative differences with a statistical significance (P<0.05), there was no statistical significance between SSB and SS56 (P> 0.05). (5) SSA, SSB positive expression in serum and the labial glands were statistically significant comparative difference (P＜0.05). SSA highly expressed in serum, and SSB highly expressed in labial gland. (6) The clinical features of SS56 positive and negative groups were no significant difference (P> 0.05).Of the laboratory tests, the red blood cells, hemoglobin and erythrocyte sedimentation rate difference was statistically significant (P<0.05).
Conclusions:(1)According with 2002 American-European Classification criteria for Sjogren's syndrome, pSS with blood system involvement, liver damage, mucocutaneous involvement coincide between pSS patients in our hospital and pSS of domestic and foreign literature; Lungs involvement, thromboembolic are more than literature, while kidney, thyroid involvement are lower than the literature;(2) Exocrine gland secretory dysfunction of pSS group is more serious than sSS group, especially the salivary gland; (3) SSA, SSB and SS56 in the labial glands of SS patients in both positive expression, and the SSB, SS56 more positive expression than SSA60, these three proteins might be involved in the local inflammatory salivary gland injury and pathogenesis of SS. SS56 expression in the labial glands was consistent with the SSB, anti-SSB antibodies was considered SS mark antibody, suggesting that anti-SS56 antibodies might become one member of the family in SS and other autoimmune diseases, and was expected to become a new diagnostic indicator. (4) The red blood cells and hemoglobin in SS56 positive group were less than the negative group, suggesting that blood system involvement might be heavier in patients with SS56-positive, while ESR elevated significantly in SS56 positive group than negative group, indicating that SS56 might be an indicator of disease activity. (5) SSA highly expressed in serum, while the SSB highly expressed in labial salivary glands, suggesting that expression of two antibodies might have organization specificity.
引文
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