Early undifferentiated connective tissue disease. I. Early clinical manifestation in a large cohort of patients with undifferentiated connective tissue diseases compared with cohorts of well established connective tissue disease.

We identified a cohort of 410 patients with connective tissue disorders (CTD) of less than or equal to 1 year duration among the participating clinics of the Cooperative Systematic Studies of the Rheumatic Diseases Program. Fifty-seven had rheumatic arthritis (RA), 57 systemic lupus erythematosus, 37 poly/dermatomyositis, 46 scleroderma, and 213 early undifferentiated CTD, including patients with Raynaud's phenomenon, unexplained polyarthritis or at least 3 CTD manifestations such as rashes, myalgias, etc. Baseline clinical data are now being reported. The followup of these patients may prove to be valuable in understanding these diseases. To our knowledge no similar cohort of patients is available for further investigation.     

Clinical significance of antinuclear antibodies in malignant diseases: association with rheumatic and connective tissue paraneoplastic syndromes

Our objective was to determine the prevalence of antinuclear antibodies (ANAs) in patients with malignancies and to investigate if their presence might be related with development of musculoskeletal symptoms or paraneoplastic rheumatic syndromes. Antinuclear antibodies were determined by indirect immunofluorescence on Hep-2 cells in 274 neoplastic patients and in a control group of 140 age-adjusted healthy subjects. Antinuclear antibody specificities (anti-DNA and anti-ENA) were investigated in patients with rheumatological symptoms and positive ANA. Antinuclear antibodies were detected in 76 of 274 (27.7%) patients with malignancies and in nine of 140 (6.4%) healthy subjects. Twenty patients reported paraneoplastic rheumatic symptoms or syndromes. Two of them developed clinical symptoms mimicking rheumatoid arthritis (rheumatoid-like arthropathy), one systemic lupus erythematosus (lupus-like syndrome), one dermatomyositis and four cutaneous vasculitides. Musculoskeletal symptoms and paraneoplastic rheumatic symptoms and syndromes were both more frequently observed in patients with positive ANA. Antinuclear antibody specificities were found in only two cases. We can conclude that there is an increased incidence of antinuclear antibodies in malignant conditions. Musculoskeletal symptoms and rheumatic paraneoplastic symptoms and syndromes seem to be more frequent in patients with cancer-related positive ANAs. The failure to find ANA specificities (anti-ENA, anti-DNA) in patients with malignancies and positive ANAs in our study may simply reflect molecular differences between the autoantigens involved in cancer and those characteristically involved in the systemic autoimmune diseases.     

Vascular reactivity in patients with undifferentiated connective tissue diseases

Assessment of changes in plaque volume is increasingly used as a surrogate-endpoint in clinical trials testing the efficacy of anti-atherosclerotic interventions. Multi-detector computed tomography (MDCT) can detect and quantify non-calcified atherosclerotic plaques, but its ability to monitor changes in plaque volume has not yet been tested.We sought to test the ability of MDCT to detect and quantify serial changes in atheroma burden in comparison with magnetic resonance imaging (MRI).MethodsRabbits (n = 12) with experimentally induced abdominal atherosclerosis were randomized to receive a plaque-regressing agent (recombinant apoA-I_Milano, n = 8) or placebo (n = 4). All animals underwent two 64-slice MDCT angiography and MRI studies (pre- and post-treatment). The primary endpoint was the change in plaque burden (defined as vessel wall volume in the 5 cm distal to the left renal artery) between pre- and post-treatment MDCT in comparison with MRI.ResultsMDCT detected a significant decrease in plaque burden caused by recombinant apoA-I_Milano (464 [423–535] to 405 [363–435] mm³, p = 0.03) that was confirmed by MRI (324 [286–412] to 298 [282–399] mm³, p = 0.03). No significant effect was noted in the placebo group either by MDCT or MRI. There were strong correlations between both modalities for the quantification of plaque burden (r = 0.750, p < 0.001) and change in plaque burden (r = 0.657, p = 0.020). MDCT overestimated plaque burden compared to MRI.On MDCT, the mean interobserver variability for plaque burden was 2.5 ± 0.4%.ConclusionsIn an animal model of atherosclerosis, MDCT accurately documented serial changes in aortic plaque burden, demonstrating good correlation and agreement with MRI-derived measurements and low interobserver variability.     

Five-year follow-up of 165 Italian patients with undifferentiated connective tissue diseases.

OBJECTIVE: To study those conditions with a proven or hypothesised immunologic pathogenesis and denominated under a working definition of undifferentiated connective tissue diseases (UCTD). METHODS: A multicentre prospective study was organised involving 10 tertiary referral centers of internal medicine in Italy, with the aim of describing the natural history of UCTD and the prevalence of its different clinical and immunological manifestations. RESULTS: After a five-year follow-up period, data on 165 patients were available for analysis. UCTDs occur mainly in females in their fourth decade of life. Articular and mucocutaneous features and Raynaud's phenomenon represent the most common findings. Nevertheless, we also detected a relatively high incidence of permanent major organ damage. Regarding the immunologic parameters, we documented some conflicting results in the correlation between serologic abnormalities and clinical features. In 10 patients UCTD evolved to a major disease, generally systemic lupus erythematosus or Sj?gren's syndrome. CONCLUSION: A low rate of evolution to a defined autoimmune disease, the limited use of steroid or immunosuppressive therapy, and a favourable course in the majority of cases are the main characteristics of patients with UCTDs.     

Staining of antinuclear antibodies and antibodies against removable nuclear antigens in connective tissue diseases

Introduction and objectivesConnective tissue diseases are inflammatory, autoimmune diseases and threaten quality of life. To determine the relationship between staining patterns of antinuclear antibodies and antibodies against extractable nuclear antigens in patients with connective tissue disease.Materials and methodsObservational, basic, analytical and transversal study. Study conducted in the Immunology Service of the Arzobispo Loayza National Hospital between January 2017 and June 2017. We analyzed 291 samples of patients with CTD and for the detection of anti-nuclear antibody staining patterns, the immunological kit and observation with microscope of at 40X Immunofluorescence and for the detection of the antibodies against extractable nuclear antigens. The Immunoblot method was employed. Statistical analyses were carried out with the statistical package SPSS version 21 for Windows. We used the Pearson Chi-square test for the categorical variables, a value of p < 0.05 was considered significant.ResultsThere was a significant relationship p < 0.05 of the homogeneous pattern, the mottled pattern with Anti-histones (p = 0.000), Anti-nucleosomes (p = 0.000), Anti-Ro 52 (p = 0.000), Anti-SSA (p = 0.001), Anti-SSB (p = 0.003), Anti-dsDNA (p = 0.000) with the Pearson Chi-square test. There was a significant relationship of p < 0.05 of the centromeric pattern with Anti-Cenp B (p = 0.000) with Fisher⿿s exact statistic.ConclusionsThere was a significant relationship between the anti-nuclear antibody staining patterns and the antibodies to the core extractable antigens in patients with systemic lupus erythematosus, Sjögren⿿s syndrome, Calcinosis, Raynaud⿿s phenomenon, esophageal Dysmotility, sclerodactyly and Telangiectasia (CREST), Scleroderma and Polymyositis.     

Outcome of positive antinuclear antibodies in individuals without connective tissue disease

OBJECTIVE: To determine if individuals with high titer antinuclear antibodies (ANA) but without clinical evidence of connective tissue disease (CTD) subsequently develop CTD or experience a change in ANA positivity. METHODS: We included patients from an initial study database as well as those reviewed in an outpatient rheumatology clinic at the University of Alberta Hospital over the past 8 years. A telephone survey targeting signs and symptoms of CTD was conducted. Serum samples from consenting patients were then assayed for ANA, antibodies to extractable nuclear antigens (ENA), and anti-dsDNA by the Rheumatic Disease Unit at the University of Alberta Hospital. RESULTS: Sixty-two patients completed the telephone survey and 53 completed both the telephone survey and repeat serological blood investigations. Mean length of followup was 5.4 years, with an age range from 19 to 87 years. Forty-eight of 53 patients (91%) remained ANA positive on repeat testing, and 5 patients were also ENA positive. Three patients had been diagnosed with CTD since the previous study. The most common clinical features on telephone survey included joint pain (34 patients) followed by Raynaud's phenomenon (11 patients). CONCLUSION: Patients tended to remain ANA positive on repeat testing. Three out of 53 patients had developed CTD, reflecting the more sensitive but less specific nature of ANA testing. Another common condition associated with ANA positivity was hypothyroidism. Continued longterm followup with larger cohorts is needed.     

Subclinical pulmonary involvement assessed by bronchoalveolar lavage in patients with early undifferentiated connective tissue disease

OBJECTIVE: To assess the presence of neutrophil and lymphocyte fibrosing alveolitis by bronchoalveolar lavage in patients with early undifferentiated connective tissue disease (EUCTD) and systemic sclerosis (SSc). METHOD: Bronchoalveolar lavage (BAL) was performed in 13 patients with EUCTD who exhibited signs of lung involvement by non-invasive methods including lung function tests and high resolution computed tomography. The mean age of cases was 48.1 +/- 6.6, and the mean disease duration was 1.8 +/- 0.8 years. Differential cell counts of BAL were evaluated. Eleven patients with systemic sclerosis and 5 healthy control subjects were also investigated. RESULTS: Eleven of the 13 EUCTD and 10 of the 11 SSc patients showed an elevated total cell number (above the median cell/ml of control + 2 SD) in the BAL fluid. In patients with EUCTD, the lymphocyte count was elevated in 6, and the polymorphonuclear neutrophil count in 2 patients. One of the patients with EUCTD had simultaneously elevated lymphocyte and neutrophil granulocyte counts. In the SSc group, 6 patients had an elevated lymphocyte and 6 an increased neutrophil count. Three of these cases had both increased neutrophil and elevated lymphocyte counts, simultaneously. CONCLUSION: Subclinical, predominantly lymphocyte alveolitis can be present in patients with EUCTD. Patients with SSc tend to exhibit neutrophil alveolitis.     

Open-label study of clarithromycin in patients with undifferentiated connective tissue disease

OBJECTIVE: The macrolide family of antibiotics (erythromycin, clarithromycin, and others), have both antimicrobial and immunomodulatory effects. This study explored the effect of clarithromycin on the clinical course of patients with undifferentiated connective tissue disease (UCTD) in a 12-week open-label study. METHODS: The diagnosis of UCTD was based on symptoms/signs of connective tissue disease, and the presence of 1 or more positive autoimmune disease tests, but with insufficient criteria to make a definitive diagnosis. Screening and monthly follow-up visits over 12 weeks included the following: history and physical examination; concurrent medications; the 68/66 tender/swollen joint count; visual analog scores 0 to 100 mm for patient and physician global assessment of disease activity, and patient pain; antinuclear antibody panel, rheumatoid factor, erythrocyte sedimentation rate, C-reactive protein, and blood chemistry. RESULTS: Seven patients with rheumatic disease were treated with clarithromycin; 6 of 7 had symptomatic relief. Two subjects treated empirically before the decision to perform an open-label study responded favorably. Four of 5 patients who completed the prospective open-label study had mean maximal improvements from baseline of 78, 75, and 79% in patient pain, patient global, and investigator global assessments, respectively. Pain relief occurred as early as 1 week. Drug withdrawal with rechallenge in 2 patients resulted in flare followed by recapture of symptomatic relief. CONCLUSIONS: Clarithromycin, a macrolide antibiotic, led to clinical improvement in patients with UCTD. Efficacy and safety data support further investigation of macrolide antibiotic use as a primary or adjunctive treatment in various connective tissue diseases.     

Unclassified or undifferentiated connective tissue disease.

This chapter deals primarily with the evidence available regarding the use of the term unclassified or undifferentiated connective tissue disorders (CTDs) to refer to patients with manifestations suggestive, but not diagnostic, of either defined CTDs, a well-defined overlap syndrome (manifestations and criteria for two or more CTDs), or mixed CTD (MCTD). Possible outcomes for these patients include remaining undifferentiated, differentiating into a defined CTD or going into remission. MCTD and atypical CTD (term used by the parties involved in the 'Silicone breast implant' controversy) are only briefly discussed.     

Association of immunoglobulin Km and Gm allotypes with specific antinuclear antibodies and disease susceptibility among connective tissue disease patients.

The distribution of the immunoglobulin Km(1) and Gm phenotypes was examined in patients with connective tissue diseases, including systemic lupus erythematosus, mixed connective tissue disease, and scleroderma, whose sera were characterized for antibodies against nuclear antigens and polypeptides of U small nuclear ribonucleoproteins. We found a strong association between Km(1) phenotype and susceptibility to systemic lupus erythematosus (P less than 0.00001, relative risk = 17). We also found a positive association between the Km(1) phenotype and the presence of anti-double-stranded DNA antibodies. The presence of certain immunoglobulin genes or gene families may have a role in susceptibility to the development of autoantibodies and/or of connective tissue disease.     

Breast implants in patients with differentiated and undifferentiated connective tissue disease

Objective. To assess the frequency of breast implantation and the relationship of the implants to the onset of symptoms in patients with differentiated and undifferentiated connective tissue disease (CTD). Methods. We evaluated an inception cohort of patients with differentiated and undifferentiated CTD and symptoms of < 12 months duration when enrolled in 1983–1987. The risk of having breast implants in those patients with early symptoms of CTD was determined in comparison with that in a non-concurrent control group. Results. Only 3 of 323 women in the cohort had historical, physical, or chest radiographic evidence of breast implantation. In 1 of the 3 patients, the symptoms of CTD began before the breast implantation. The odds ratio was calculated at 1.15, with a 95% confidence interval ranging from 0.23 to 3.41. Conclusion. This study showed an absence of significant risk for prior breast implantation surgery in patients with well-defined or undifferentiated CTD.     

Reactive nitrogen intermediates,antinuclear antibodies and copper-thionein in serum of patients with rheumatic diseases

Summary Sera from 354 patients with various inflammatory and autoimmune rheumatic diseases were screened for the presence of reactive nitrogen intermediates, antinuclear antibodies and the antioxidase copper-thionein (Cu-thionein), and compared to sera from healthy donors and patients with non-rheumatic diseases including AIDS, various internal as well as neurological diseases and carcinoma of different organs. When compared to healthy individuals, the levels of nitric oxides in sera from patients with autoimmune rheumatic diseases were elevated by 240–600% (P<0.01). The status of reactive nitrogen intermediates (NO_x, RNI) in sera from donors with inflammatory rheumatic diseases was increased by 170–540%, but was also significantly enhanced in sera of patients with non-rheumatic diseases, indicating a general inflammatory mechanism that is predominately triggered by inducible nitric oxide (NO) syntheses of phagocytes. All rheumatic sera were dramatically depleted of the antioxidase Cu-thionein (P<0.001), a powerful consumer of hydroxyl radicals and singlet oxygen and an efficient superoxide dismutase. The NO_x levels were positively correlated with the serum titers of antinuclear antibodies (r=0.77) and negatively correlated with Cu-thionein levels (r=0.94), reflecting a high steady-state concentration of free radicals generated during inflammatory and autoimmune rheumatic diseases.     

结缔组织病肺间质病变的临床特点及治疗效果分析

目的探讨不同结缔组织病肺间质病变（CTD-ILD）的临床特点和治疗效果。方法分析82例CTD-ILD患者的临床特征及胸部高分辨CT（HRCT）特点并观察治疗后HRCT的变化。结果（1）SSc—ILD的发生率最高，为70．0％。其次为pSS—ILD、PM／DM-ILD、RA—ILD、SLE—ILD，系统性红斑狼疮继发的ILD（SLE—ILD）发病年龄（26．2±7．8）较其他CTD-ILD早（P〈0．05）。RA—ILD、SSc—ILD病程较长，pSS—ILD、SLE一[LD和PM—ILl）病程较短。RA．ILD出现活动后气促少见（P〈0．05）。pSS—ILD出现呼吸道症状（40％）和体征（50％）最多见。85．7％SSc-ILD出现雷诺现象，支持雷诺现象与ILD相关。（2）SLE—ILD以磨玻璃影多见，丽蜂窝状改变较少；pSS-ILD以蜂窝状改变和纵隔淋巴结肿大相对较多。（3）大部分患者治疗后肺部间质病变吸收好转（56．7％），其中88．2％SLE—ILD吸收好转，28．4％患者肺部病变处于静止，14．9％患者间质病变较前进展。结论CTD—ILD患者一旦确诊，应尽早用激素联合免疫抑制剂治疗。     

Diagnostic and prognostic significance of different antinuclear antibodies in more than 1000 consecutive Albanian patients with rheumatic diseases.

In an unselected population of 1390 consecutive Albanian patients with rheumatic diseases (RD) and other miscellaneous non-rheumatic diseases (MNRD), for whom antinuclear antibody (ANA) testing was requested, we calculated the diagnostic sensitivity, specificity and positive predictive value (PPV) of ANA positive results, ANA titres over 1:100, anti-native DNA (nDNA), anti-Sm, anti-U1 RNP, anti-SSA (Ro) anti-SSB (La) and anti-non-identified extractable nuclear antigen (NIENA) antibodies. The PPVs of these ANA types were found to be appreciable only for systemic lupus erythematosus (SLE); only the positive predictive value of ANA for SLE (26.4%) was lower than that for RA (34.3%). The anti-snRNP (Sm/U1RNP) positive SLE patients were more likely to have over 4 of the ARA criteria for SLE, ANA titres over 1:100, and anti-nDNA antibodies, in contrast with the anti-snRNP negative subgroup. On the other hand, the anti-ENA positive and anti-nDNA positive SLE patients generally showed higher frequencies of renal disease, over 4 of the criteria for SLE and ANA titres over 1:100, compared to anti-ENA positive and anti-nDNA negative patients. Our data suggest that the association of anti-snRNP antibodies with a more severe form of SLE is not to be attributed to these antibodies themselves, but rather to their close association with the concomitant presence of anti-nDNA antibodies.     

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.