The liver in collagen diseases: pathologic study of 160 cases with particular reference to hepatic arteritis, primary biliary cirrhosis, autoimmune hepatitis and nodular regenerative hyperplasia of the liver

AIMS/BACKGROUND: Among patients with collagen diseases, liver enzyme abnormalities are a relatively common phenomenon. To establish the liver pathology in collagen diseases, detailed pathologic studies were performed on the hepatic diseases in many patients, including various kinds of collagen diseases. METHODS: The livers from 160 patients (120 autopsy and 40 liver biopsy patients) were examined pathologically: 73 with systemic lupus erythematosus (SLE), 32 with rheumatoid arthritis (RA), 18 with polymyositis and dermatomyositis (PM and DM), 15 with systemic sclerosis (SSc), 11 with mixed connective tissue disease (MCTD) and 11 with polyarteritis nodosa (PAN). RESULTS: Liver diseases were divided into three groups: hepatic arteritis, liver diseases associated with collagen diseases (primary biliary cirrhosis, PBC; autoimmune hepatitis, AIH; nodular regenerative hyperplasia of the liver, NRH) and other liver diseases. Hepatic arteritis presenting the features of the PAN type of necrotizing arteritis was found in 27 autopsy patients. The incidence of arteritis in autopsy patients was 100% in PAN and 8.3-25% in other collagen diseases. Primary biliary cirrhosis was observed in 9 patients, 7 of whom (3 with SSc, 2 with RA, 1 with PM and DM, and 1 with MCTD) had antimitochondrial antibodies (AMA)-positive PBC, and 2 SLE patients had AMA-negative PBC. Three patients (2 with SLE and 1 with MCTD) were diagnosed clinicopathologically as having AIH. However, 3 patients (1 with SLE, 1 with MCTD and 1 with PM and DM) with clinical, biochemical and serologic data indicating probable AIH were excluded from the group with AIH association because of the liver histology (no characteristic features of AIH) and clinical course. These results indicated that data without histologic assessments of the liver are not adequate for diagnosing AIH in collagen diseases. Nodular regenerative hyperplasia of the liver was observed in 7 patients (5 with SLE, 1 with SSc and 1 with PAN). CONCLUSION: The present study offers data that are useful for the diagnosis and treatment of patients with collagen diseases and liver abnormalities.     

Anticyclic citrullinated peptide antibodies in patients with mixed connective tissue disease

Abstract

The clinical significance of anticyclic citrullinated peptide (CCP) antibodies in patients with mixed connective tissue disease (MCTD) was assessed. Altogether, 86 sera from MCTD patients, 96 from rheumatoid arthritis (RA) patients, 42 from systemic lupus erythematosus (SLE) patients, 23 from systemic sclerosis (SSc) patients, 21 from poymyositis/dermatomyositis (PM/DM) patients, and 17 from those with Sjögren’s syndrome (SjS) were tested for anti-CCP antibodies using an enzyme-lined immunosorbent assay. Among the 96 RA patients, anti-CCP antibodies were detected in 85%, with the frequency being significantly higher than in MCTD, SLE, SSc, PM/DM, and SjS patients (9%, 14%, 13%, 14%, and 18%, respectively; P < 0.001). Among eight MCTD patients who fulfilled the diagnostic criteria for RA, only 50% had anti-CCP antibodies, and the prevalence was significantly lower than for all RA patients (p < 0.01). All eight patients who fulfilled the criteria for RA had overlap of SLE and SSc, except one patient, whereas the four anti-CCP-positive patients who did not fulfill the criteria for RA had SjS without overlapping features of SLE and SSc; moreover, most of their antibody titers were low. These results suggested that anti-CCP antibodies are associated with RA in MCTD patients, but careful diagnosis of RA is required if patients with low titers of anti-CCP antibodies lack overlapping SLE and SSc.     

结缔组织病相关间质性肺病的诊治策略

结缔组织病(connective tissue disease,CTD)是一组全身性自身免疫性疾病,病变累及多种脏器。由于肺和胸膜均富含胶原、血管等结缔组织,因此 CTD 大多可以损伤肺和胸膜等呼吸系统多个器官,包括：呼吸肌、胸膜、肺血管、气道、肺实质和肺间质,且部分患者呼吸道表现为首发症状。间质性肺病(interstitial lung disease,ILD)在 CTD 中十分常见,发生率在数个 CTD 病种中超过50%。与之相对应,15%~30%初诊为特发型间质性肺炎(idiopathic interstitial pneumonia,IIP)的患者最终被确认符合 CTD-ILD 诊断。ILD 是导致 CTD 患者死亡的重要原因之一。CTD 包括包括系统性红斑狼疮(SLE)、类风湿性关节炎(RA)、原发性干燥综合征(pSS)、多发性肌炎(PM)、皮肌炎(DM)、系统性硬化(SSc)和混合性 CTD (MCTD)等。本文就 CTD-ILD 的诊治策略作一简要综述。     

Anticyclic citrullinated peptide antibodies in patients with mixed connective tissue disease

The clinical significance of anticyclic citrullinated peptide (CCP) antibodies in patients with mixed connective tissue disease (MCTD) was assessed. Altogether, 86 sera from MCTD patients, 96 from rheumatoid arthritis (RA) patients, 42 from systemic lupus erythematosus (SLE) patients, 23 from systemic sclerosis (SSc) patients, 21 from poymyositis/dermatomyositis (PM/DM) patients, and 17 from those with Sjögrens syndrome (SjS) were tested for anti-CCP antibodies using an enzyme-lined immunosorbent assay. Among the 96 RA patients, anti-CCP antibodies were detected in 85%, with the frequency being significantly higher than in MCTD, SLE, SSc, PM/DM, and SjS patients (9%, 14%, 13%, 14%, and 18%, respectively; P < 0.001). Among eight MCTD patients who fulfilled the diagnostic criteria for RA, only 50% had anti-CCP antibodies, and the prevalence was significantly lower than for all RA patients (p < 0.01). All eight patients who fulfilled the criteria for RA had overlap of SLE and SSc, except one patient, whereas the four anti-CCP-positive patients who did not fulfill the criteria for RA had SjS without overlapping features of SLE and SSc; moreover, most of their antibody titers were low. These results suggested that anti-CCP antibodies are associated with RA in MCTD patients, but careful diagnosis of RA is required if patients with low titers of anti-CCP antibodies lack overlapping SLE and SSc.     

Cyclosporin A therapy for interstitial pneumonitis associated with rheumatic disease

To determine the efficacy of cyclosporin A (CysA) for the treatment of steroid-resistant interstitial pneumonitis (IP), we enrolled 25 patients with various rheumatic diseases and steroid-resistant IP in a pilot study [4 patients with rheumatoid arthritis (RA), 2 with systemic lupus erythematosus (SLE), 11 with polymyositis/dermatomyositis (PM/DM), 4 with systemic sclerosis (SSc), 1 with mixed connective tissue disease (MCTD), 3 with Sjögren syndrome (SS)]. Twelve patients (48%) showed a persistent response to CysA therapy, and 7 of them had PM/DM, including so-called amyopathic DM. Patients with a persistent response had moderately elevated lactate dehydroxygenase (LDH) levels, whereas patients who died had much higher LDH levels and hypoxia. Even patients with low blood levels of CysA achieved a persistent response. In responding patients, the symptoms, chest X-ray findings, arterial oxygen tension, and LDH level all improved after less than 4 weeks. In conclusion, CysA seem to be useful for treating patients with steroid-resistant IP, whose duration is short and severity is mild.     

Large macrophage colony-forming cells identical to high proliferative potential colony-forming cells in peripheral blood of patients with collagen vascular diseases: high occurrence among patients with systemic sclerosis and dermatomyositis

OBJECTIVE: To examine peripheral blood (PB) of patients with various collagen vascular diseases (CVD) for the presence of colony-forming cells (CFC) that form large macrophage colonies (> 2.5 mm in diameter, > 10,000 cells). METHODS: Peripheral blood mononuclear cells were obtained from 92 patients with various active CVD and 20 healthy controls, and assayed for in vitro colony formation. There were 14 patients with systemic lupus erythematosus (SLE), 30 with rheumatoid arthritis (RA), 17 with systemic sclerosis (SSc), 20 with polymyositis (PM)/dermatomyositis (DM) (11 PM, 9 DM) and 11 with systemic vasculitis. RESULTS: Large macrophage CFC were detected in PB of 7% of patients with SLE (1/14), 17% with RA (5/30), 47% with SSc (8/17), 30% with PM/DM (6/20) [9% PM (1/11) and 56% DM (5/9)], 0% of those with systemic vasculitis (0/11) and 0% of the healthy subjects (0/20). There was a significant difference between the occurrence of CFC in patients with PM versus patients with DM (p < 0.05). The occurrence of CFC in patients with SSc or DM was significantly higher than that in patients with other CVD including SLE, RA, PM, and systemic vasculitis (p < 0.05). CONCLUSION: Based on the size of the colonies they formed, the CFC corresponded to high proliferative potential colony-forming cells, a subset of primitive hematopoietic cells. Our findings among patients with CVD indicate that these primitive hematopoietic progenitor cells, which are believed to constitute a noncirculating population in healthy individuals, are found most frequently in PB of patients with SSc and DM. It is likely that primitive hematopoietic cells are frequently mobilized into the peripheral circulation during the pathogenesis of SSc and DM.     

Association of systemic and thyroid autoimmune diseases

Objective: There are few large cohort studies available on the association of systemic and thyroid autoimmune diseases. In this study, we wished to determine the association of Hashimotos thyroiditis (HT) and Graves disease (GD) with systemic autoimmune diseases. Methods: One thousand five hundred and seventeen patients with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), systemic sclerosis (SSc), mixed connective tissue disease (MCTD), Sjögrens syndrome (SS) and polymyositis/dermatomyositis (PM/DM) were included in the study. The HT and GD were diagnosed based on thorough clinical evaluation, imaging and fine-needle aspiration cytology (FNAC). The frequency of HT and GD in these diseases was assessed. In addition, 426 patients with HT or GD were assessed and the incidence of SLE, RA, SSc, MCTD, SS and PM/DM among these patients was determined. Prevalence ratios indicating the prevalences of GD or HT among our autoimmune patients in comparison to prevalences of GD or HT in the general population were calculated. Results: Altogether 8.2% of systemic autoimmune patients had either HT or GD. MCTD and SS most frequently overlapped with autoimmune thyroid diseases (24 and 10%, respectively). HT was more common among MCTD, SS and RA patients (21, 7 and 6%, respectively) than GD (2.5, 3 and 1.6%, respectively). The prevalences of HT in SLE, RA, SSc, MCTD, SS and PM/DM were 90–, 160–, 220–, 556–, 176– and 69-fold higher than in the general population, respectively. The prevalences of GD in the same systemic diseases were 68-, 50-, 102-, 76-, 74- and 37-fold higher than in the general population, respectively. Among all thyroid patients, 30% had associated systemic disease. In particular, 51% of HT and only 16% of GD subjects had any of the systemic disorders. MCTD, SS, SLE, RA, SSc and PM/DM were all more common among HT patients (20, 17, 7, 4, 2 and 2%, respectively) than in GD individuals (2, 5, 5, 1, 2 and 1%, respectively). Conclusion: Systemic and thyroid autoimmune diseases often overlap with each other. HT and GD may be most common among MCTD, SSc and SS patients. On the other hand, these systemic diseases are often present in HT subjects. Therefore it is clinically important to screen patients with systemic autoimmune diseases for the co-existence of thyroid disorders.Take home message: Autoimmune thyroid diseases, such as Hashimotos thyroiditis and Graves disease are often associated with systemic autoimmune diseases, most commonly with Sjögrens syndrome and mixed connective tissue disease.     

Clinical and laboratory features of overlap syndromes of idiopathic inflammatory myopathies associated with systemic lupus erythematosus,systemic sclerosis,or rheumatoid arthritis

Because overlap syndromes (OSs) are rarely described, we analyzed retrospectively their frequencies and correlations in Brazilian series of 31 patients with dermatomyositis (DM)/polymyositis (PM) associated with systemic lupus erythematosus (SLE), systemic sclerosis (SSc), or rheumatoid arthritis (RA) attended at a referral single center. Myositis-specific autoantibodies (MSAs: anti-Jo-1, anti-PL-7, anti-PL-12, anti-EJ, anti-OJ, anti-SRP, anti-Mi-2) and myositis-associated autoantibodies (MAAs: anti-PM-Scl75, anti-PM-Scl100, anti-Ku) as well as specific autoantibodies related to SLE, SSc, and RA were investigated. The mean age of the OS patients (9 DM and 22 PM) was 44.6?±?15.4 years, with a predominance of women (83.9 %) and white ethnicity (58.1 %). PM was the most frequent inflammatory myopathy, and the clinical presentation of DM/PM was significantly different among the OS groups. Overlap was found with SSc (48.4 %), SLE (29.0 %), and RA (22.6 %). The clinical manifestations of DM/PM were identified simultaneously with SSc and RA in the majority of cases, in contrast to identification in the SLE group (p?<?0.05). All patients were positive for antinuclear antibodies, and the prevalence of MSA and MAA was 38.8 % in all OS groups, mutually exclusive, and more frequent in the SSc group. Comparing the clinical and laboratory features, there was a higher frequency of vascular (skin ulcers, Raynaud’s phenomenon) and pulmonary (interstitial lung disease) involvement in the SSc group (p?<?0.05). Moreover, there were no differences among the groups in relation to disease relapse and deaths. Concluding, this is the first study to show the different characteristics of a series of patients with connective tissue disease (CTD)-OS in the heterogeneous Brazilian population.     

Decreased CD161+CD8+ T cells in the peripheral blood of patients suffering from rheumatic diseases

OBJECTIVES: Although it has been reported that the numbers of both CD4(-)CD8(-) and CD4(+) natural killer T (NKT) cells are selectively decreased in the peripheral blood of patients with rheumatic diseases, there have been no reports concerning a novel subpopulation of CD8(+) NKT cells. To examine whether CD161(+)CD8(+) T cells, which are closely related to CD8(+) NKT cells, are also decreased in patients with rheumatic diseases, we have investigated the expression of CD161, together with that of CD28, CD25 and CD62L, on T cells in the peripheral blood of these patients. METHODS: The rheumatic diseases evaluated in this study were systemic lupus erythematosus (SLE) (n= 54), mixed connective-tissue disease (MCTD) (n= 15), systemic sclerosis (SSc) (n= 14), polymyositis/dermatomyositis (PM/DM) (n= 13) and rheumatoid arthritis (RA) (n= 24). Healthy donors were examined as controls (n= 18). The expression of CD161, CD28, CD25 and CD62L on T cells was analysed by flow cytometry. RESULTS: Both the frequency of CD161 expression on CD8(+) cells and the absolute number of CD161(+)CD8(+) cells were significantly decreased in patients with SLE, MCTD, SSc and PM/DM. Only the absolute number of CD161(+)CD8(+) T cells was significantly decreased in RA. CD161 expression on CD28(-)CD8(+) T cells was significantly decreased in SLE, MCTD and SSc. The absolute number of CD161(+)CD8(+)CD62L(-) T cells was significantly decreased in SLE, MCTD and SSc. CONCLUSIONS: Both the frequency and the absolute number of CD161(+)CD8(+) T cells were decreased in the peripheral blood of patients suffering from SLE, MCTD, SSc and PM/DM. This result suggests that there is also an abnormality of NKT cells in the CD8(+) population.     

The respiratory function in children with collagen disease]

Respiratory function tests were performed on 60 children with collagen disease. Twenty-seven cases (45%) showed abnormalities in the respiratory function. These abnormalities were restrictive in 14 cases (52%), obstructive in 6 cases (22%), and mixed type in 7 cases (26%). Eight out of 14 SLE patients (57%) showed abnormalities of various types. Abnormalities were seen in 9 out of 25 JRA patients (36%) including 6 cases (67%) with restrictive type changes. Four out of 6 MCTD (67%) and 3 out of 9 DM (33%) patient showed functional abnormalities. Most of patients with these two types of collagen disease showed restrictive changes. Investigations performed by a research group of the Ministry of Health and Welfare showed the incidence of restrictive type changes (% VC less than 80) in adult patients of collagen disease to be in the following descending order: PM/DM greater than PSS greater than MCTD greater than SLE. Though small in number, our investigation revealed that a considerable proportion of MCTD and SLE patients showed restrictive changes in respiratory function. In evaluating the clinical course of the disease, it was thus considered to be important to follow up the progress of respiratory functions in children with collagen disease.     

Efficacy of combination treatment with cyclosporin A and corticosteroids for acute interstitial pneumonitis associated with dermatomyositis

Abstract

Interstitial pneumonitis (IP) associated with polymyositis and dermatomyositis (PM/DM) is a serious complication that affects prognosis. We therefore undertook a retrospective multicenter study to examine the efficacy of a combination treatment with cyclosporin A (CsA) and corticosteroids. Fifty-three IP patients with PM/DM (9 PM, 44 DM) were analyzed. Thirty-two patients treated with CsA plus corticosteroids (9 PM, 23 DM) were included in the study. Four parameters, i.e., subjective symptoms, ausculatory sound, chest radiographs, and respiratory index, were serially evaluated. A general evaluation was performed 4 weeks after the start of the combination treatment. All patients with PM and chronic IP with DM, and 52% of those with acute IP with DM were graded as better than “partially effective” in the general evaluation. In contrast, all patients graded as “progressive” in the general evaluation had acute IP with DM. It is of note that in acute IP with DM, the survival rate of the group primarily treated with CsA and corticosteroids from the early stage of their disease was significantly higher than that of the group initially treated with corticosteroids alone (P = 0.049). In conclusion, a combination treatment of CsA and corticosteroids from the early stage of disease may be advantageous for patients with IP with PM/DM, especially acute IP with DM.     

Performance of the Revised Classification Criteria for Systemic Autoimmune Rheumatic Diseases and Their Overlap Syndromes

Objective We evaluated the performance of the revised classification criteria for assessing different systemic autoimmune rheumatic diseases and their overlap syndromes. Methods A total of 652 patients with or highly suspected of having systemic lupus erythematosus (SLE), systemic sclerosis (SSc), polymyositis (PM)/dermatomyositis (DM) or rheumatoid arthritis (RA)were included in this study. The 1997 revised American College of Rheumatology (ACR) and the 2019 European League Against Rheumatism (EULAR)/ACR criteria for SLE, the 1980 ACR and the 2013 ACR/EULAR criteria for SSc, the criteria by Bohan and Peter and the 2017 EULAR/ACR criteria for PM/DM, and the 1987 revised ACR and 2011 ACR/EULAR criteria for RA were used for disease classification. Results The old and new criteria and a clinical diagnosis were used to respectively classify 103, 106 and 105 SLE patients; 35, 47 and 58 SSc patients; 18, 23 and 33 PM/DM patients; and 297, 389 and 468 RA patients. Sensitivity increased from 82.9% to 92.4% in SLE, from 56.9% to 79.3% in SSc, from 54.5% to 66.7% in PM/DM, and from 62.6% to 80.8% in RA. SLE-SSc was the predominant type of clinical overlap syndrome, while SLE-RA was the most classifiable. Conclusion The revised classification criteria for all the diseases showed an improved sensitivity, and SLE-overlap syndrome was predominant, regardless of the criteria sets.     

Estimation of the symptoms for GERD by GerdQ in the patients with rheumatic diseases

Objective: Gastroesophageal reflux disease (GERD) is one of the most common comorbidity in many diseases, but the frequency in rheumatic disease has not been well understood.

Methods: We investigated the prevalence of GERD by GerdQ in 530 rheumatic patients [systematic lupus erythematosus (SLE; n?=?120), rheumatoid arthritis (RA; n?=?117), polymyalgia rheumatica (PMR; n?=?40), dermatomyositis and polymyositis (PM/DM; n?=?38), systemic scleroderma (SSc; n?=?37), mixed connective tissue disease (MCTD; n?=?18), Behçet disease (BD; n?=?17), adult onset still disease (AOSD; n?=?14), and other rheumatic diseases (n?=?129)].

Results: The mean GerdQ scores of patients was 6.2?±?1.8, respectively, and no significant differences were observed between all patients. However, the GERD prevalence in SSc and BD was increased compared to that in SLE, RA, PMR, PM/DM, MCTD, and AOSD. In no medication of proton pump inhibitors (PPIs), a significant increase in the risk of GERD symptoms was 2.5 times compared with that in the medication of PPIs in all patients by multivariable regression analysis. On the other hand, there were no increased risks of GERD symptoms with corticosteroids.

Conclusion: In rheumatic diseases, GerdQ would be the useful tool of diagnosis GERD, regardless whether the patients complain or not about gastrointestinal (GI) symptoms.     

Efficacy of combination treatment with cyclosporin A and corticosteroids for acute interstitial pneumonitis associated with dermatomyositis

Interstitial pneumonitis (IP) associated with polymyositis and dermatomyositis (PM/DM) is a serious complication that affects prognosis. We therefore undertook a retrospective multicenter study to examine the efficacy of a combination treatment with cyclosporin A (CsA) and corticosteroids. Fifty-three IP patients with PM/DM (9 PM, 44 DM) were analyzed. Thirty-two patients treated with CsA plus corticosteroids (9 PM, 23 DM) were included in the study. Four parameters, i.e., subjective symptoms, ausculatory sound, chest radiographs, and respiratory index, were serially evaluated. A general evaluation was performed 4 weeks after the start of the combination treatment. All patients with PM and chronic IP with DM, and 52% of those with acute IP with DM were graded as better than partially effective in the general evaluation. In contrast, all patients graded as progressive in the general evaluation had acute IP with DM. It is of note that in acute IP with DM, the survival rate of the group primarily treated with CsA and corticosteroids from the early stage of their disease was significantly higher than that of the group initially treated with corticosteroids alone (P = 0.049). In conclusion, a combination treatment of CsA and corticosteroids from the early stage of disease may be advantageous for patients with IP with PM/DM, especially acute IP with DM.     

CD13/aminopeptidase N in collagen vascular diseases

To determine the significance of CD13/aminopeptidase N in collagen vascular diseases (CVD), we examined its activity and expression in sera and disease sites of patients with CVD. Significantly higher aminopeptidase activity was detected in bronchoalveolar lavage fluid from patients with interstitial lung diseases due to rheumatoid arthritis (RA), polymyositis/dermatomyositis (PM/DM), systemic sclerosis (SSc), and Sjögren's syndrome than from control subjects. Increased aminopeptidase activity and increased expression of CD13/aminopeptidase N protein were found in alveolar macrophages from CVD patients with interstitial lung diseases. Significantly higher aminopeptidase activity was detected in pleural effusions from patients with systemic lupus erythematosus (SLE) than in transudate effusions. The mean aminopeptidase activity in synovial fluids from RA patients was significantly higher than from patients with osteoarthritis. The mean value of serum aminopeptidase activity was significantly higher in patients with SLE, RA, SSc, and PM/DM than in normal subjects. This study suggests that the activity of CD13/aminopeptidase N, locally produced in the disease site, is a useful marker for CVD and that CD13/aminopeptidase N may have an important role in the pathogenesis of CVD.     

Comparison between 3 diagnostic criteria for mixed connective tissue disease. Study of 593 patients

We tested patients with a well defined connective tissue disease (CTD) against 3 different sets of criteria for mixed connective tissue disease (MCTD). Included were 200 patients with systemic lupus erythematosus (SLE), 80 with MCTD, 100 with rheumatoid arthritis (RA), 80 with scleroderma, 53 with dermato/polymyositis (DM/PM) and 80 with primary Sj?gren's syndrome (SS). The 3 sets of criteria fared similarly in capturing nearly all MCTD patients. They also were similar in ruling out most of the other CTD except for 11 patients with SLE, 36 with scleroderma, 13 with DM/PM and 3 with SS who fulfilled the category of possible MCTD included in the set of criteria proposed by Sharp. Because the set of criteria we proposed includes only 5 clinical manifestations (edema of the hands, synovitis, myositis, Raynaud's phenomenon, and acrosclerosis) whereas the other 2 sets include 15 and 13, respectively, it would seem that the 5 included in our criteria are core manifestations of MCTD. Of the 80 patients with MCTD 32 had all 5, 38 had 4, and 10 had 3 of these manifestations. The sensitivity of 3 or more of these clinical criteria for MCTD was 100%, whereas the specificity which, with the clinical criteria was 91.8%, rose to 99.6% with the presence of anti-RNP antibody. However, because testing of our criteria was made internally, they should be further tested, along with the other 2 sets of criteria by unrelated groups of clinical investigators, perhaps in a multicenter study.     

Clinical profiles of patients with antibodies to nuclear ribonucleoprotein

Summary Currently there are no widely accepted criteria for the diagnosis of MCTD. In this work we attempted to define the clinical profile of a group of 68 patients with anti nRNP antibodies, detected by immunoprecipitation in 0.6% agarose. The diagnosis of each collagen vascular disease was established in every patient, who met with the strict diagnostic criteria either at clinical presentation or during the follow-up period. Twenty-eight patients had SLE, 9 had classical erosive RA, three had PSS and one had PM. The only distinctive features in the group of SLE with anti nRNP was an increased incidence of anti Sm antibodies (p<0.05). In the RA group there was a trend towards a high frequency of Raynaud's phenomenon and swollen hands. At clinical presentation twenty-seven patients did not fulfil enough criteria to be diagnosed of any of the well-defined collagen vascular disease. They presented an undifferentiated syndrome, characterized clinically by Raynaud's phenomenon (100%), swollen hands (88.9%) and joint symptoms (88.9%), with scarce tendency of developing severe systemic manifestations. The main laboratory abnormalities in this group were hipergammaglobulinemia, mildly increased ESR, abnormal levels of CIC, negative anti nDNA and anti Sm antibodies, and the virtual absence of hipocomplementemia. During a clinical course of 96±72.5 months only one patient evolved into another collagen disease (SLE). The clinical course in the remaining cases, was stable improving with low doses of prednisone and/or NSAID. We suggest considering this undifferentiated syndrome as a distinct entity, for which the already classical term of MCTD could be reserved.     

Clinical features of liver dysfunction in collagen diseases

Aim: Liver dysfunction is not rare in patients with collagen disease. We sought to elucidate the clinical features of liver dysfunction in the presence of collagen disease. Methods: We analyzed the frequency and causes of liver dysfunction in 607 patients (rheumatoid arthritis [RA], n = 220; systemic lupus erythematosus [SLE], n = 164; systemic sclerosis [SSc], n = 47; Sjögren's syndrome [SjS], n = 44; Behçet's disease, n = 43; polymyositis/dermatomyositis [PM/DM], n = 27; vasculitis syndrome, n = 25; mixed connective tissue disease [MCTD], n = 21; and adult‐onset Still's disease [AOSD], n = 16). Results: Liver dysfunction was observed in 238 (39.2%) of 607 patients showing collagen disease. Patients with AOSD (81.3%), PM/DM (51.9%) and vasculitis syndrome (48.0%) frequently displayed liver dysfunction. Liver dysfunction in collagen diseases results from many causes; drug‐induced liver injury (26.1%), fatty liver (7.6%), viral hepatitis (1.3%), autoimmune hepatitis (4.2%), primary biliary cirrhosis (15.9%) and the collagen disease itself (15.5%). Conversely, primary biliary cirrhosis was a leading cause in SSc (76.1%) and SjS (70.0%). Liver dysfunction in collagen disease tended to be mild. In addition, alanine aminotransferase levels correlated positively with ferritin levels in AOSD (R = 0.708, P < 0.05). Moreover, alkaline phosphatase levels correlated positively with C reactive protein levels in vasculitis syndrome (R = 0.833, P < 0.05). Conclusion: Liver dysfunction in the presence of collagen disease has various causes, and dysfunction associated with collagen disease reflects the activity of the collagen disease itself.     

Identification of autoantibodies to the I protein of the heterogeneous nuclear ribonucleoprotein complex in patients with systemic sclerosis

Objective. To assess the presence of autoantibodies to the I protein (polypyrimidine-tract binding protein) of the heterogeneous nuclear RNPs (hnRNP) in different connective tissue diseases. Antibodies to other hnRNP proteins (A1, A2, and B) have been previously found in patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and mixed connective tissue disease (MCTD). Methods. Sera from 101 patients with various connective tissue diseases and 25 normal controls were investigated by enzyme-linked immunosorbent assay and immunoblotting, for their reactivity to highly purified recombinant hnRNP I. Moreover, reactivity to cellular hnRNP I protein was investigated by immunoblotting using a partially purified preparation of hnRNP proteins (including A1, A2, B, and I), and by indirect immunofluorescence. For the analysis of the fluorescence pattern, affinity-purified antibodies to hnRNP I, obtained from a selected patient, were tested on HEp-2 cells. Results. By immunoblotting, antibodies reacting to recombinant hnRNP I were found in 22 of 40 patients with systemic sclerosis (SSc), 3 of 32 with RA, 0 of 23 with SLE, and 0 of 6 with MCTD. Antibodies to recombinant hnRNP I were more frequently found in patients with pre-SSc or limited SSc (15 of 24) than in those with intermediate or diffuse SSc (7 of 16). In indirect immunofluorescence studies, affinity-purified anti—hnRNP I autoantibodies gave a diffuse nucleoplasmic staining. Using an hnRNP preparation from nuclear extracts, anti—hnRNP I reactivity was detectable in SSc sera, while it was not detectable in RA, SLE, and MCTD sera reacting with hnRNP A/B proteins. Conclusion. Human autoimmune sera show distinct patterns of anti-hnRNP reactivity, i.e., anti-A/B in SLE and RA sera, and anti-I in SSc sera. This suggests that A/B proteins and the I protein may be involved in different dynamic hnRNP complexes that elicit different autoimmune responses. From a clinical perspective, anti—hnRNP I antibodies are frequently associated with pre-SSc features, suggesting an early appearance of these antibodies during the course of the disease.     

Antibodies to type IV collagen in rheumatic diseases

Rheumatic disease sera were examined by a sensitive and specific enzyme linked immunosorbent assay (ELISA) for antibodies to native and to denatured type IV collagen from basement membranes of bovine anterior lens capsules or human placenta. The frequency of antitype IV collagen antibodies depended on the antigen and the disease studied. No controls had human type IV collagen antibodies and only 5.6% had antibody to bovine type IV collagen. Antibody to one or more of our 4 antigens was seen in 20% of children with juvenile rheumatoid arthritis (JRA), 35% of patients with mixed connective tissue disease (MCTD), 40% of those with juvenile dermatomyositis (DM), 52% of adults with rheumatoid arthritis (RA), 56% of patients with scleroderma and 60% of patients with systemic lupus erythematosus (SLE). Antibodies to native human type IV collagen were rare (0-10%) except in SLE (45%). Antibodies to denatured human type IV collagen were commoner in RA, scleroderma and SLE. Antibodies to native bovine type IV collagen occurred in 8-20% of patient sera, and to denatured antigen in 25-26% of scleroderma, MCTD and DM patients. Antibovine type IV collagen activity measured by ELISA could be absorbed from positive sera by preincubation of the sera with bovine type IV collagen but not bovine type I collagen or native human placental type IV collagen, indicating that the antibodies were specific for bovine type IV collagen.