Mixed connective tissue disease in childhood: A nationwide retrospective study in Japan

Sixty-six children with mixed connective tissue disease (MCTD) were analyzed by a nationwide prospective study. The diagnostic significance of Raynaud's phenomenon and positive anti-RNP antibody was confirmed, and additional symtoms including swelling of fingers, facial erythema, and polyarthralgia, and laboratory findings such as positive rheumatoid factor, hypergammaglobulinemia, and increased levels of myogenic enzymes, were variably positive. These clinical and laboratory characteristics of MCTD were critically different from those of systemic lupus erythematosus, indicating that MCTD is an independent entity of disease.     

Mixed connective tissue disease in childhood. Relationship Sj?gren's syndrome

Mixed connective tissue disease (MCTD) seems to be a distinct entity that has some manifestations of systemic lupus erythematosus, scleroderma, polymyositis, and Sj?gren's syndrome and is serologically characterized by the presence of an antibody to ribonucleoprotein. We report the cases of three children with MCTD with high titers of antibody to ribonucleoprotein. Two fulfilled criteria of lupus erythematosus, two had polymyosis; all three had suggestive features of scleroderma, fulfilled criteria for the diagnosis of juvenile rheumatoid arthritis, and had Sj?gren's syndrome. Additional superimposed features of another connective tissue disease should arouse suspicion of MCTD. All three of our patients responded adequately to corticosteroid treatment that makes recognition of this entity by the pediatrician all the more important.     

儿童混合性结缔组织病9例临床分析

目的总结分析儿童混合性结缔组织病(MCTD)的临床及转归特点。方法对2001—2009年间确诊为MCTD的9例患儿的临床表现、实验室检查、诊治及随访情况进行总结分析。结果 9例患儿均有雷诺现象,其次常见的症状包括关节肿痛、手指肿胀、硬指、发热、乏力、贫血、活动后气短等。血液系统受累4例,其中3例轻度贫血,1例血小板减少。1例肾活检提示符合狼疮肾炎IIA型。实验室指标中红细胞沉降率增快8例,IgG升高7例,C4降低3例,CH50升高5例,CK升高4例(该4例患儿均行肌电图检查,3例未见明显肌源性损害,1例为可疑肌源性损害)。自身抗体ANA阳性9例,抗U1-RNP抗体阳性9例,抗SSA抗体低滴度阳性3例。6例行肺功能检查,4例存在弥散功能障碍。6例行肺部高分辨CT检查,2例示肺间质病变。超声心动图检查示肺动脉高压3例,合并右心增大、主动脉增宽2例,轻度肺动脉高压1例,合并少量心包积液1例。3例行食管造影检查,未见明显食管蠕动障碍。多数患儿入院前曾诊断为系统性红斑狼疮、幼年特发性关节炎、雷诺现象、结缔组织病、发热原因待查等,不规律接受激素或免疫抑制剂治疗者4例。9例患儿经确诊后予规范激素和(或)免疫抑制剂治疗,8例病情好转,1例病情控制无明显进展,无死亡病例。结论儿童MCTD为多系统受累,早期以雷诺现象、关节症状、发热多见,在尚未出现肺部症状时可存在肺功能、肺部高分辨CT异常,可伴有肺动脉高压,误诊率较高。早期完善相关免疫指标、超声心动图、肺功能、肺部高分辨CT、食管造影等检查可帮助诊断。规范的激素及免疫抑制剂治疗对病情转归及预后极为重要,需长期对患儿进行随访观察。     

A nationwide surveillance study of rheumatic diseases among Japanese children

To estimate the number of children with rheumatic diseases, a questionnaire was distributed to the pediatrics department of 1290 hospitals in Japan in June 1994. From this survey, 1606 cases with juvenile rheumatoid arthritis (JRA), 906 cases with systemic lupus erythematosus (SLE), 320 cases with dermatomyositis/polymyositis (DM/PM), 28 cases with scleroderma (PSS), 70 cases with Sjögren's syndrome (Sjs), 93 cases with mixed connective tissue disease (MCTD), 25 cases with aortitis syndrome, 20 cases with polyarteritis (PN) and 51 cases with Behçet disease were reported. The crude annual incidence rates per 100 000 among the childhood population were estimated as JRA, 0.83; SLE, 0.47; DM/PM, 0.16; PSS, 0.01; Sjs, 0.04; MCTD, 0.05; aortitis syndrome, 0.01; PN, 0.01; and Behçet disease, 0.03. The present study reveals that there are more children with rheumatic diseases than are estimated from the reported cases in the literature and the number of children who are receiving Assistance Medical Costs Insurance covered by the Japanese government.     

Usefulness of antinuclear antibody testing to screen for rheumatic diseases

OBJECTIVE: To assess the usefulness of the indirect immunofluorescence antinuclear antibody test (FANA) using human laryngeal epithelial carcinoma cells as nuclear substrate, to screen for childhood rheumatic diseases. STUDY DESIGN: A review of all FANA tests performed on children at British Columbia's Children's Hospital between 7 March 1991 and 31 July 1995. RESULTS: FANA tests were positive at titres of 1:20 or greater in 41% of all subjects tested, and in 65% of all subjects in whom the diagnosis was obtained. FANA positivity occurred in 67% of those with a rheumatic disease, compared with 64% of those with a non-rheumatic disease (p = 0.4). More girls had high titre FANA positivity than boys independent of whether or not they had a rheumatic disease (p = 0.05). At a screening serum dilution of 1:40 a positive test has a sensitivity of only 0.63, and a positive predictive value of only 0.33 for any rheumatic disease. For systemic lupus erythematosus (SLE), mixed connective tissue disease (MCTD), or overlap syndrome at a screening dilution of 1:40 the test has a very high sensitivity of 0.98, but a very low positive predictive value of only 0.10, the test having slightly better characteristics for boys than girls. CONCLUSION: Although a negative FANA test makes a diagnosis of SLE or MCTD extremely unlikely, a positive test even at moderately high titres of 1:160 or higher is found so frequently in children without a rheumatic disease that a positive result has little or no diagnostic value. It is suggested that a screening serum dilution of 1:160 or 1:320 would increase the usefulness of the test, by decreasing false positive tests, without significantly increasing false negative tests for SLE or MCTD, and would have the potential for considerable cost savings.     

Usefulness of antinuclear antibody testing to screen for rheumatic diseases

OBJECTIVE—To assess the usefulness of the indirect immunofluorescence antinuclear antibody test (FANA) using human laryngeal epithelial carcinoma cells as nuclear substrate, to screen for childhood rheumatic diseases.
STUDY DESIGN—A review of all FANA tests performed on children at British Columbia''s Children''s Hospital between 7 March 1991 and 31 July 1995.
RESULTS—FANA tests were positive at titres of 1:20 or greater in 41% of all subjects tested, and in 65% of all subjects in whom the diagnosis was obtained. FANA positivity occurred in 67% of those with a rheumatic disease, compared with 64% of those with a non-rheumatic disease (p=0.4). More girls had high titre FANA positivity than boys independent of whether or not they had a rheumatic disease (p=0.05). At a screening serum dilution of 1:40 a positive test has a sensitivity of only 0.63, and a positive predictive value of only 0.33 for any rheumatic disease. For systemic lupus erythematosus (SLE), mixed connective tissue disease (MCTD), or overlap syndrome at a screening dilution of 1:40 the test has a very high sensitivity of 0.98, but a very low positive predictive value of only 0.10,the test having slightly better characteristics for boys than girls.
CONCLUSION—Although a negative FANA test makes a diagnosis of SLE or MCTD extremely unlikely, a positive test even at moderately high titres of 1:160 or higher is found so frequently in children without a rheumatic disease that a positive result has little or no diagnostic value. It is suggested that a screening serum dilution of 1:160 or 1:320 would increase the usefulness of the test, by decreasing false positive tests, without significantly increasing false negative tests for SLE or MCTD, and would have the potential for considerable cost savings.

     

Significance of a positive antinuclear antibody test in a pediatric population

Clinical and laboratory findings in 138 children seen during a ten-year period with a positive antinuclear antibody (ANA) test were reviewed. Two thirds (91 of 138) of the patients had specific autoimmune or rheumatic diseases, including systemic lupus erythematosus (n = 37), juvenile rheumatoid arthritis (n = 33), Sj?gren's syndrome (n = 9), mixed connective tissue disease (n = 7), dermatomyositis (n = 3), and discoid lupus (n = 2). Another 27 patients had symptoms of autoimmune disease but did not fit criteria for specific disorders. Nine patients with IgA deficiency had a positive ANA test but did not have symptomatic autoimmune disease. Ten children had a positive ANA test in association with infections, mainly viral, and one had leukemia. Because most children with a positive ANA test had readily diagnosable autoimmune disorders, pediatric patients with a positive ANA on repeated testing should undergo clinical and laboratory studies for autoimmune or rheumatic disease.     

Venous thrombosis associated with lupus anticoagulant and anticardiolipin antibodies

We describe deep vein thrombosis associated with lupus anticoagulant and anticardiolipin antibodies in three children aged 10 to 14 years. One of them also had arterial thromboses. None of the patients had systemic lupus erythematosus when the thrombosis first occurred, but one fulfilled the criteria for systemic lupus erythematosus 3 years later. At presentation all had symptoms suggestive of pulmonary embolism and evidence of an autoimmune disease: Addison's disease in one, anti-DNA or antinuclear antibodies in all three, and a positive Coombs' test in two. Two of the three gave a false-positive test for syphilis. In the patient with systemic lupus erythematosus recurrent thrombocytopenia and severe haemolytic anaemia necessitated splenectomy. A child should be tested for lupus anticoagulant or anticardiolipin antibody if venous or arterial occlusion occurs without a known predisposing cause, or if there is pulmonary embolism or symptoms or laboratory findings suggestive of a connective tissue disease.     

Venous Thrombosis Associated with Lupus Anticoagulant and Anticardiolipin Antibodies

ABSTRACT. We describe deep vein thrombosis associated with lupus anticoagulant and anticardiolipin antibodies in three children aged 10 to 14 years. One of them also had arterial thromboses. None of the patients had systemic lupus erythematosus when the thrombosis first occurred, but one fulfilled the criteria for systemic lupus erythematosus 3 years later. At presentation all had symptoms suggestive of pulmonary embolism and evidence of an autoimmune disease: Addison's disease in one, anti-DNA or antinuclear antibodies in all three, and a positive Coombs' test in two. Two of the three gave a false-positive test for syphilis. In the patient with systemic lupus erythematosus recurrent thrombocytopenia and severe haemolytic anaemia necessitated splenectomy. A child should be tested for lupus anticoagulant or anticardiolipin antibody if venous or arterial occlusion occurs without a known predisposing cause, or if there is pulmonary embolism or symptoms or laboratory findings suggestive of a connective tissue disease.     

Antinuclear antibodies using HEp-2 cells in normal children and in children with common infections

Antinuclear antibody (ANA) immunofluorescence tests, using HEp-2 cells, were performed on 100 children without a history of connective tissue disease. Eighteen (18%) were positive at titres greater than or equal to 1:40, nine (9%) being greater than 1:160. Interlaboratory variability was demonstrated with some specimens. No association with possible intercurrent infection was found to account for positive results. Of 44 children with proven infections five (11%) were positive. Antinuclear antibody may be found in some normal children when using the sensitive HEp-2 cell substrate, and in the absence of clinical features should not necessarily suggest the presence of a connective tissue disease.     

Kollagenosen

Connective tissue diseases are chronic autoimmune disorders that include systemic lupus erythematosus, systemic sclerosis, dermatomyositis and polymyositis, mixed connective tissue disease, and Sjogren’s syndrome. The incidence of connective tissue diseases is much lower in childhood; however, the clinical picture in children morphologically shows greater variability than in adults. Nonspecific clinical signs include fatigue, fever, and weight loss, and often precede any systemic organ involvement. This review summarizes recent information on clinical manifestations, diagnostic procedures, and treatment strategies for different connective tissue diseases, with a focus on specific problems in childhood.     

Raynaud syndrome in childhood

Twenty-seven patients with Raynaud syndrome (mean age at onset 11.7 years) were studied to determine the prevalence of primary Raynaud syndrome and to assess the predictive role of antinuclear antibody, nail-fold capillary microscopy, and photoelectric plethysmography in this population. Fourteen patients (52%) had a connective tissue disease, four (15%) had a probable connective tissue disease, and nine (33%) had primary Raynaud syndrome. In all patients with either a connective tissue disease or a probable connective tissue disease, there was a positive reaction to antinuclear antibody, in contrast to patients with primary Raynaud syndrome, in whom antinuclear antibody was not detected. Nail-fold capillary microscopy scores differed significantly between patients with either a connective tissue disease or a probable connective tissue disease and those with primary Raynaud syndrome for both enlarged loop score (p less than 0.025 and less than 0.05, respectively) and avascular score (p less than 0.005 and less than 0.01, respectively). Photoelectric plethysmography scores were reduced in all groups but did not differ significantly between groups. Our findings suggest that in children with Raynaud syndrome, the primary type is more common than was originally suspected, and that both antinuclear antibody and nail-fold capillary microscopy, but not photoelectric plethysmography, can distinguish patients with primary Raynaud syndrome from those with either a connective tissue disease or a probable connective tissue disease.     

Mixed connective tissue disease in childhood: A clinical and serologic survey

Mixed connective tissue disease is a syndrome with overlapping clinical features of SLE, scleroderma, and polymyositis. Only one other child with MCTD has been described in detail. In this study 14 children with MCTD are described. Each had overlapping clinical findings that evolved over an extended period of observation, and all 14 had high serum titers of speckled ANA and antibodies to RNP. A serologic survey of 127 children with various rheumatic diseases confirmed the specificity of high titer of speckled ANA and antibodies to RNP for MCTD in children. Significant cardiac and renal involvement, and thrombocytopenia, may be more common in affected children than in adults with MCTD, may lead to longer therapy with higher doses of a corticosteroid, and may contribute to a more serious prognosis than in adults.     

Immunological Studies of the Placenta in Maternal Connective Tissue Disease

Maternal connective tissue disease is an important cause of second-trimester fetal loss. In order to assess the pathological changes in the placenta in maternal connective tissue disease, we reviewed the clinical histories and performed histologic and immunofluorescence studies on nine placentas: five from mothers with systemic lupus erythematosus (SLE), two from mothers with mixed connective tissue disease (MCTD), one from a mother with rheumatoid arthritis (RA), and one from a mother without prior known connective tissue disease. Excessive intervillous fibrin deposition and infarction were noted in all cases. Immunofluorescent and immunoperoxidase studies showed deposits of fibrinogen, IgG, IgM, IgA, and complement 3 (C3) localized to the trophoblast basement membrane (TBM). Electron microscopy documented thickening of the trophoblast basal lamina in three SLE placentas examined. The use of immunofluorescence may be enhanced further if antitrophoblast antibodies can be linked to placental compromise. Received June 11, 1997; accepted May 7, 1998.     

Connective Tissue Disease Presenting With Signs and Symptoms of Pulmonary Hypertension in Children

Our case series describes three children who were initially diagnosed as having severe pulmonary arterial hypertension (PAH) and subsequently found to be positive for specific autoantibodies suggestive of an underlying autoimmune process. The signs and symptoms of PAH are subtle and may be part of the initial presentation of childhood connective tissue disease (CTD). Evaluation for connective tissue disease in the newly diagnosed pulmonary hypertension (PH) patient is important because early diagnosis of PH as well as CTD is crucial in the successful management of these complex patients. Ongoing monitoring for CTD in patients with severe PAH is warranted.     

Autoimmune thyroiditis in antinuclear antibody positive children without rheumatologic disease

Background  

Children are commonly referred to a pediatric rheumatology center for the laboratory finding of an Anti-nuclear antibody (ANA) of undetermined significance. Previous studies regarding adult rheumatology patients have supported an association between ANA and anti-thyroid antibodies, with the prevalence of thyroid antibodies being significantly higher in patients referred to a rheumatology center for an ANA without evidence of connective tissue disease compared to the general population. The purpose of the present study was to determine the frequency of thyroid antibodies in children referred to a pediatric rheumatology center for a positive ANA without evidence of a connective tissue disease.     

儿童风湿病相关巨噬细胞活化综合征单中心临床研究

目的 总结儿童风湿病相关巨噬细胞活化综合征(MAS)临床和实验室特征、治疗及转归.方法 回顾性分析2008年1月至2019年11月重庆医科大学附属儿童医院75例MAS患儿的临床和实验室特征、治疗及转归.结果 MAS的基础疾病包括全身型幼年特发性关节炎(SJIA) 32例、系统性红斑狼疮(SLE) 22例、川崎病(KD)...     

Soluble intercellular adhesion molecule-1 in paediatric connective tissue diseases

The intercellular adhesion molecule-1 (ICAM-1) is a cytokine-induced glycoprotein involved in the recruitment of cells into tissues undergoing inflammatory responses. The aim of this study was to compare the levels of soluble ICAM-1 (s-ICAM-1) in children with juvenile chronic arthritis (JCA) and systemic lupus erythematosus (SLE) and to evaluate the usefulness of this molecule as marker of disease activity. Levels of s-ICAM-1 were measured in sera using a monoclonal antibody sandwich enzyme-linked immunoassay. Serum levels (mean ± SD) of s-ICAM-1 in 37 children with JCA, 18 patients suffering from SLE and 25 healthy controls were 609 ± 184, 513 ± 139 and 210 ± 95 ng/ml, respectively. A significant difference could be demonstrated between the levels of s-ICAM-1 in sera from each disease, as a group, and those of healthy controls. Higher levels of s-ICAM-1 were recorded in JCA patients with systemic features and patients who had polyarthritis than in children who were pauciarticular. A positive correlation was observed between s-ICAM-1 levels and disease activity score in SLE patients. Moreover, s-ICAM-1 levels closely followed clinical conditions in five children with SLE during follow-up. The data show that s-ICAM-1 levels are increased in children suffering from connective tissue diseases and reflect disease status or activity, suggesting the usefulness of this molecule in the follow-up of these diseases.     

Rapid progression to pulmonary arterial hypertension crisis associated with mixed connective tissue disease in an 11-year-old girl

Mixed connective tissue disease (MCTD) is rare in pediatric rheumatic diseases. Pulmonary arterial hypertension (PAH) associated with MCTD usually progresses gradually and is difficult to note at the asymptomatic phase. We report a 11-year-old girl with MCTD complicated with rapidly progressive PAH. Although PAH was not detected by echocardiogram or chest CT scan at the initial examination, it became clear in 1 year and suddenly came to cardiac arrest during an invasive procedure. She was successfully treated with extracorporeal assist and both vasodilative and immunosuppressive medication. A combination of echocardiogram and plasma BNP levels could be a useful marker for the follow-up of such cases. PAH could develop early in the course of pediatric MCTD and needs attention to unexpected acute exacerbation, especially under emotional stress.     

Esophageal motor abnormalities in children and adolescents with scleroderma and mixed connective tissue disease

To determine the frequency and nature of esophageal motor abnormalities in children and adolescents with scleroderma syndromes and mixed connective tissue disease, esophageal manometry was performed on seven patients with progressive systemic sclerosis, four patients with mixed connective tissue disease, and two patients with linear scleroderma. A total of 73% of patients with progressive systemic sclerosis and mixed connective tissue disease had symptoms of esophageal dysfunction. A significant association between the presence of Raynaud phenomenon and esophageal symptoms was noted. Esophageal motor abnormalities were detected in 73% of patients with progressive systemic sclerosis and mixed connective tissue disease; these abnormalities were characterized by decreased lower esophageal sphincter pressure and abnormal peristalsis in the distal two thirds of the esophageal body. They resemble those described among adults with progressive systemic sclerosis and mixed connective tissue disease but were not related to disease duration or to the presence of Raynaud phenomenon. Patients with linear scleroderma did not have esophageal symptoms and demonstrated only nonspecific motor abnormalities that did not worsen during several years of follow-up.