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Objective: Renal thrombotic microangiopathy (TMA) is an uncommon pathological finding in lupus nephritis (LN), and its clinical significance remains to be defined., Methods: Twenty-four patients with lupus nephritis (LN) and renal TMA were selected from a retrospective review of 677 biopsy-proven LN patients, and compared with 48 LN controls without TMA (1:2 ratio) matched according to demographics and treatments., Results: Renal TMA was noted in 3.5% of kidney biopsies of LN. TMA was associated with a higher prevalence of anti-Ro (45.8% vs 18.8%; p = 0.016), higher Systemic Lupus Erythematosus Disease Activity Index scores (21.4 ± 8.5 vs 10.8 ± 2.3; p < 0.001), lower estimated glomerular filtration rate (eGFR; 16.8 ± 11.7 ml/min vs 77.8 ± 28.6 ml/min; p < 0.001), and a higher percentage of patients who required dialysis (37.5% vs 2.1%; p < 0.001) at the time of kidney biopsy. Activity and chronicity indices [median (range)] were higher in the TMA group [11 (2-19) and 3 (1-8), respectively, compared with 7 (0-15) and 1 (0-3) in controls; p = 0.004 and p < 0.001; respectively]. Patients with TMA showed inferior 5-year renal survival and higher incidence of chronic kidney disease at last followup (70% and 66.6%, respectively, compared with 95% and 29.2% in controls; p = 0.023 and 0.002, respectively). The TMA group also showed lower median eGFR compared with controls [50.1 (IQR 7-132) ml/min vs 85.0 (IQR 12-147) ml/min; p = 0.003]. Five-year patient survival rate was similar between the 2 groups (87% and 98% in TMA and control group, respectively; p = 0.127)., Conclusion: TMA in kidney biopsy was associated with more severe clinical and histological activity, and significantly inferior longterm renal outcome in LN.

Objective: Autoantibodies to the dense fine speckled 70 kDa antigen (DFS70) are reported to be more common in individuals who do not have an antinuclear antibody (ANA)-associated rheumatic disease (AARD) than in patients with AARD. The frequency of anti-DFS70 antibodies has been thoroughly studied in adult but not in pediatric populations. The primary objective of this observational study was to determine the frequency of anti-DFS70 in pediatric AARD and reference cohorts., Methods: Sera from 743 children with AARD and related conditions, and 345 samples from reference cohorts (healthy children and those being investigated for AARD) were studied for anti-DFS70 autoantibodies as measured by a chemiluminescence immunoassay. A de-identified administrative database was used to retrieve demographic, serologic, and clinical data., Results: Anti-DFS70 antibodies were seen in 2.1% of healthy children and in 4.5% of sera from pediatric individuals referred for ANA testing. The frequency of anti-DFS70 was highest in juvenile localized scleroderma (LS; 4/29, 13.8%), juvenile dermatomyositis (JDM; 2/11, 18.2%), childhood systemic lupus erythematosus (cSLE; 19/331, 5.7%), diffuse cutaneous systemic sclerosis (1/22, 4.5%), celiac disease (2/49, 4.1%), and juvenile idiopathic arthritis (JIA; 5/202, 2.5%). Of note, anti-DFS70 antibodies were observed in 3/26 children (11.5%) with uveitis and JIA-associated uveitis., Conclusion: The frequency of anti-DFS70 autoantibodies in healthy pediatric subjects is within the lower range of that reported in adults. Anti-DFS70 antibodies can be found in childhood SSc and cSLE, but has a remarkably high frequency in children with LS, JDM, and uveitis.

Objective: This study evaluates possible correlations between the pattern of antinuclear antibodies (ANA) on indirect immunofluorescence (IIF) testing and nailfold microangiopathy stage (early, active, and late stage) in systemic sclerosis (SSc). Patients with SSc were followed prospectively to monitor progression of microvascular damage., Methods: The ANA pattern on IIF was searched in 42 patients with SSc showing an early pattern of nailfold microangiopathy at baseline, and was followed using nailfold videocapillaroscopy (NVC) for a median time of 91 months., Results: Among patients whose microangiopathy showed a rapid progression from early to late pattern on NVC, the IIF pattern was fine-speckled + nucleolar (Scl-70+) in 44%, centromeric in 33%, nucleolar in 11%, and homogeneous in 11% of patients with SSc. Antitopoisomerase I antibodies were significantly more frequent (57%) in patients with late pattern of microangiopathy on NVC. The median time of progression from early to active disease was significantly lower in patients with both fine-speckled + nucleolar and nucleolar ANA positivity. The severity of microangiopathy was higher in patients with the nucleolar pattern on IIF. Patients already showing a slight reduction of capillary number at baseline were likely to have either the nucleolar or the fine-speckled + nucleolar pattern on IIF. Of note, 37% of patients still showing the early microangiopathy pattern on NVC at the end of the followup were ANA-negative., Conclusion: ANA-negative patients with SSc display a slower progression of nailfold microangiopathy characterized by the early pattern on NVC. Progression to the late NVC pattern (more advanced stage of microvascular damage) seems to be associated with a different autoantibody pattern on IIF (fine-speckled + nucleolar pattern being the most prevalent).

Objective: To describe the longterm effectiveness and safety of cyclosporine (CYC) in patients with anti-Jo1-positive antisynthetase syndrome with corticosteroid-refractory interstitial lung disease (ILD)., Methods: All patients with anti-Jo1 antisynthetase syndrome referred to our division between June 1991 and February 2010 were retrospectively evaluated for ILD. ILD was assessed using pulmonary function tests (PFT) and/or high-resolution computed tomography (HRCT). Kazerooni score was used to evaluate the HRCT extent of ILD. Prednisone was the first-line treatment in all cases (1 mg/kg/day orally, then tapering). Patients with corticosteroid-refractory or relapsing ILD were then included in this retrospective study. All patients started CYC (3 mg/kg/day) without increasing prednisone dosage. Both PFT and chest HRCT were regularly reassessed during followup., Results: Over the period of study we evaluated 18 patients with antisynthetase syndrome; 17 had ILD (13 women; median age at ILD onset 57 yrs); all patients failed prednisone within 12 months of ILD onset and subsequently started CYC. The median followup on CYC was 96 months [interquartile range (IQR) 57-120 mo]. Upon starting CYC, median forced vital capacity (FVC) was 60% (IQR 56%-70%), median DLCO 60% (IQR 50%-62.75%), and median Kazerooni score 16 (IQR 7-18). After 1 year of CYC, FVC (p = 0.0006), DLCO (p = 0.0010), and total Kazerooni score (p = 0.0002) improved and prednisone was tapered (median reduced from 25 mg/day to 2.5 mg/day; p < 0.0001). The results were substantially maintained including at last available followup. CYC side effects were hypertension (5 patients) and creatinine increase (6 patients). CYC was reduced in 3 cases and withdrawn in 4. Three out of 4 patients who interrupted CYC experienced ILD relapse; 2 patients recommenced low-dose CYC with subsequent ILD control. One patient refused re-treatment and subsequently died., Conclusion: CYC is effective and substantially safe in patients with anti-Jo1 antisynthetase syndrome with corticosteroid-refractory ILD. CYC withdrawal may be associated with ILD relapse, and low-dose CYC was effective in ILD control.

Objective: To analyze the characteristics, outcomes, and predictive factors of disease-modifying antirheumatic drug (DMARD) use in 48 patients with antisynthetase syndrome [characterized by myositis, interstitial lung disease (ILD), arthritis, Raynaud's phenomenon (RP), and/or mechanic's hands] and the presence of anti-histidyl-transfer RNA synthetase (anti-Jo1) autoantibodies., Methods: Forty-eight patients (33 women, 15 men) who were anti-Jo1-positive referred to one center between 1998 and 2008 were analyzed retrospectively., Results: The median age of disease onset was 43 years [interquartile range (IQR) 33-53 yrs]. The median followup was 5 years (IQR 2-8 yrs). At diagnosis, 81% of patients presented with myositis, 80% ILD, 77% arthralgia, 48% RP, and 21% mechanic's hands. During the followup, 14 patients (29%) had no need for DMARD, while 34 (71%) required DMARD. Patients with mechanic's hands (p=0.02) and higher creatine phosphokinase at diagnosis (median 6070 IU/l vs 1121 IU/l; p=0.002) were more likely to need DMARD. ILD, noted on computed tomography scan by a nonspecific interstitial pneumonia score, was lower in the group of patients with no DMARD need (4 vs 7; p=0.04). Twenty patients (44%) presented with a pulmonary aggravation (worsening of radiologic score of ILD and/or pulmonary function test results) leading to DMARD use. Nonspecific interstitial pneumonia score (7 vs 5; p=0.05) and total lung volume (57.5% vs 70%; p=0.02) values predicted pulmonary aggravation., Conclusion: Our study outlines the burden of chest involvement for the prognosis of antisynthetase syndrome in terms of patients' requirement for DMARD therapy.

Objective: To determine the diagnostic value of anticitrullinated protein antibodies, second generation (ACPA2), by electrochemiluminescent immunoassay (ECLIA) and anti-Sa by ELISA in a large cohort of Chinese patients with early rheumatoid arthritis (RA)., Methods: One hundred ninety-eight patients with early RA (< 1 yr duration), 112 with other rheumatic diseases, and 60 healthy individuals were studied., Results: The combination of anti-Sa and ACPA2 positivity had the highest specificity (99.42%), but it had a rather low sensitivity (50.0%). The combination of anti-rheumatoid factor (RF) and ACPA2 showed the highest sensitivity (80.30%), with specificity of 95.93%. The mean titer of ACPA2 and RF was significantly higher in the anti-Sa-positive group compared to the negative group (ACPA2, p <0.001; RF, p = 0.007). The 28-joint Disease Activity Scores of the anti-Sa-positive patients were significantly higher than those of the negative group (p = 0.01). The anti-Sa had no significant correlation with age, sex, antinuclear antibody, SSA, SSB, erythrocyte sedimentation rate, C-reactive protein, immunoglobulin A (IgA), IgG, IgM, C3, and C4., Conclusion: Our results come from a newly developed ECLIA for detection of ACPA2 and the anti-Sa-antibody-based ELISA system. The combined application of ACPA2 and anti-Sa tests can improve the laboratory diagnosis of early RA.

Objective: To determine whether there is any seasonal variation in the activity of systemic lupus erythematosus (SLE) overall and by individual organs., Methods: The study group comprised 2102 patients with SLE who were followed in a prospective longitudinal cohort study. In this cohort, 92.3% of the patients were women. The mean ± SD age of the patients was 47.9 ± 13.9 years, 56.3% were white, 37.1% were African American, and 3.1% were Asian. Global disease activity was recorded by the Safety of Estrogens in Lupus Erythematosus National Assessment - Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) and the physician's global assessment. Activity of each organ was also recorded using SLEDAI terms and a visual analog scale (VAS; 0 to 3)., Results: There was significant seasonal variation in photosensitive rash (p < 0.0001), which was more frequent in the spring and summer months (p < 0.0001). There was significantly more arthritis activity in spring and summer, as measured by both SELENA-SLEDAI (p = 0.0057) and the joint VAS (p = 0.0047). A decrease in renal activity was found in the summer months compared to the rest of the year (p = 0.0397). Serositis recorded by VAS had higher activity from August to October (p = 0.0392). Anti-dsDNA levels were significantly higher during October and November (p < 0.0001). There was significant seasonal variation in antiphospholipid antibody levels (p < 0.0001) and lupus anticoagulant (p = 0.0003). We found a significant variation in activity through the year in global disease activity as measured by SELENA-SLEDAI (p = 0.048)., Conclusion: In the Hopkins Lupus Cohort, skin and joint activity is increased during the spring and summer, but other organs have different patterns. These seasonal variations likely reflect environmental factors that influence disease activity, including ultraviolet light and infections.

Objective: To study the clinical course and outcome of fetal sinus bradycardia (SB) due to maternal antibody-induced sinus node dysfunction., Methods: We reviewed the maternal, prenatal, and postnatal findings of fetuses with SB associated with elevated maternal anti-SSA/Ro and anti-SSB/La antibodies., Results: Of the 6 cases diagnosed prenatally, 3 had isolated SB persisting after birth and had a good prognosis. Three fetuses with SB and severe myocardial involvement (congenital complete heart block and/or endocardial fibroelastosis) succumbed in utero in spite of treatment. Postmortem histopathology in 1 fetus showed inflammatory destruction of the sinus and atrioventricular nodes. SB was detected incidentally in a 7-year-old girl. She had intermittent heart block with progressive sinus arrest requiring permanent pacemaker., Conclusion: Fetal SB associated with maternal autoantibodies may persist in childhood, with a good prognosis in the absence of widespread cardiac involvement.

Objective: Anti-U3-RNP, or anti-fibrillarin antibodies (AFA), are detected more frequently among African American (AA) patients with systemic sclerosis (SSc) compared to other ethnic groups and are associated with distinct clinical features. We examined the immunogenetic, clinical, and survival correlates of AFA in a large group of AA patients with SSc., Methods: Overall, 278 AA patients with SSc and 328 unaffected AA controls were enrolled from 3 North American cohorts. Clinical features, autoantibody profile, and HLA class II genotyping were determined. To compare clinical manifestations, relevant clinical features were adjusted for disease duration. Cox proportional hazards regression was used to determine the effect of AFA on survival., Results: Fifty (18.5%) AA patients had AFA. After Bonferroni correction, HLA-DRB1*08:04 was associated with AFA, compared to unaffected AA controls (OR 11.5, p < 0.0001) and AFA-negative SSc patients (OR 5.2, p = 0.0002). AFA-positive AA patients had younger age of disease onset, higher frequency of digital ulcers, diarrhea, pericarditis, higher Medsger perivascular and lower Medsger lung severity indices (p = 0.004, p = 0.014, p = 0.019, p = 0.092, p = 0.006, and p = 0.016, respectively). After adjustment for age at enrollment, AFA-positive patients did not have different survival compared to patients without AFA (p = 0.493)., Conclusion: Our findings demonstrate strong association between AFA and HLA-DRB1*08:04 allele in AA patients with SSc. AA SSc patients with AFA had younger age of onset, higher frequency of digital ulcers, pericarditis and severe lower gastrointestinal involvement, but less severe lung involvement compared to AA patients without AFA. Presence of AFA did not change survival.

Objective: To evaluate the frequency of malignancies in Italian patients with systemic sclerosis (SSc) and anti-RNA polymerase III (RNAP III), antitopoisomerase I (topo I), or anticentromere antibodies (ACA); and to characterize the temporal relationship between the 2 diseases, in order to confirm data suggesting a close temporal relationship between the onset of SSc and malignancy in American patients with anti-RNAP III antibodies., Methods: From a cohort of 466 consecutive SSc patients, 360 Italians with isolated positivity for anti-RNAP III (n = 16), anti-topo I (n = 101), or ACA (n = 243) were identified. Malignancy cases were divided according to their relationship with SSc onset into 3 categories: preceding, synchronous with, or metachronous to the onset of SSc (diagnosed more than 6 months before; 6 months before to 12 months after; and more than 12 months after onset of SSc, respectively)., Results: Malignancies were more frequent in the anti-RNAP III group (7/16 patients), than in the anti-topo I (11/101) and ACA groups (21/243) (p < 0.001). This difference was accounted for by the number of patients with cancer synchronous to the onset of SSc (3/16 in the anti-RNAP III group vs 0/101 in the anti-topo I and 1/243 in the ACA group; p < 0.001), whereas neither the number of malignancies preceding nor those metachronous to the onset of SSc was significantly different between the groups., Conclusion: In a cohort of Italian patients with SSc we observed a significant association between malignancies synchronous to SSc onset and positivity for anti-RNAP III antibodies, similar to that described in American patients with SSc.

Objective: Maternal anti-SSA/Ro or anti-SSB/La antibodies are associated with neonatal lupus erythematosus syndrome (NLES), especially congenital heart block (CHB), which may be associated with severe endocardial fibroelastosis (EFE) and dilated cardiomyopathy (DCM). A few reports have described severe EFE without CHB associated with anti-SSA/Ro antibodies, with a poor prognosis. EFE has also been observed in biopsies of DCM that had been considered idiopathic. These points, considered in association with 5 unusual cases of mild EFE, led us to consider the relationship between underrecognized cases of isolated autoantibody-associated EFE and DCM that had been considered idiopathic., Methods: We analyzed 5 cases of EFE diagnosed in utero (n = 4) or after birth (n = 1). In 3 cases, maternal antibody status was discovered because of the EFE diagnosis., Results: Endomyocardial hyperechogenicity predominated in the left atrium (n = 3) and mitral annulus (n = 3). No left-heart dysfunction was observed. Two mothers were treated with betamethasone. One mother chose to have a therapeutic abortion, and EFE was confirmed at autopsy. Electrocardiograms at birth (n = 4) did not show CHB. Other manifestations of NLES were present in all cases. One child had right ventricular hypoplasia and underwent a partial cavopulmonary anastomosis. At last followup (4-7 yrs), the other 3 children had normal heart function, and echocardiography showed a normal heart (n = 2) or mild persistent EFE (n = 1)., Conclusion: Middle-term prognosis of isolated autoantibody-associated EFE may be better than previously reported, although the longterm prognosis remains unknown. We hypothesize that a fetal insult can lead to DCM.

Objective: To determine the diagnostic sensitivity and specificity and the clinical usefulness of parallel anticentromere-A and anticentromere-B antibody (anti-CENP-A and anti-CENP-B) testing in patients with systemic sclerosis (SSc)., Methods: Sera from 280 consecutive patients with SSc and 259 controls were tested for the presence of anti-CENP-A and anti-CENP-B antibodies by a monospecific line immunoblot assay (LIA) with recombinant human centromere proteins A and B as well as by indirect immunofluorescence (IIF). Crossreactivity and possible associations with clinical manifestations were studied., Results: Both antibodies revealed a diagnostic sensitivity of 36.8% and a specificity of > 97% for SSc, with a high concordance rate of 94.3% despite different amino acid sequences of the antigens and absence of crossreactivity. There was a significant correlation of the antibody levels measured by LIA. Both antibodies were associated with similar clinical manifestations and identified patients with limited disease and rather mild skin sclerosis., Conclusion: Detected by LIA, anti-CENP-A and anti-CENP-B antibodies show high concordance in patients with SSc and share significant associations to clinical manifestations, but are not completely identical. Detection of both antibodies in parallel may slightly increase the diagnostic sensitivity for SSc.

Objective: Systemic sclerosis (SSc) is a rare connective tissue disease in childhood. We compared the characteristics of adult patients with juvenile-onset SSc (jSSc) from a single-center cohort to an adult-onset group., Methods: Patients with disease onset before the age of 17 years were included in the jSSc cohort, while subjects with SSc onset after age 17 formed the adult-onset cohort., Results: We identified 52 adult subjects with jSSc and compared them to 954 patients with adult-onset SSc. The mean ± SD age at disease onset of the patients with jSSc was 14 ± 2 years, 39 (75%) of them were women, and 24 (46%) had the diffuse cutaneous subset of SSc (dcSSc). There were no differences between the 2 cohorts in terms of sex and disease subset. Overlaps were significantly more frequent among the jSSc cohort (37%) compared to the adult-onset group (18%; p = 0.002). Autoantibody analysis demonstrated significantly more antitopoisomerase I antibody-positive subjects (33% vs 20%; p = 0.034) and significantly fewer anticentromere antibody-positive subjects (2% vs 25%; p < 0.001) in the jSSc cohort. Compared to the adult-onset group at 10 years from disease onset, survival was significantly higher among the subjects with jSSc (98% vs 75%; p = 0.001), pulmonary arterial hypertension had a significantly lower incidence (2% vs 14%; p = 0.032), and there was no difference in terms of pulmonary fibrosis (22% vs 21%) and cardiac scleroderma (3% vs 2%) between the 2 groups., Conclusion: The high survival rates and lower proportion of dcSSc in the adult jSSc cohort may represent a survival bias.

Objective: Patients with scleroderma (systemic sclerosis; SSc) can be classified into subsets based on autoantibody profile and clinical features. Specificities such as anti-Th/To and anti-fibrillarin (U3RNP) are detectable mainly by immunoprecipitation (IP), which is not widely used in clinical laboratories. We examined the autoantibody profiles and clinical manifestations in a cohort of Italian patients with SSc, focusing on anti-Th/To and anticentromere (ACA) antibodies, associated with limited cutaneous SSc (lcSSc)., Methods: Sera from 216 consecutive patients with SSc were tested for ACA (by indirect immunofluorescence), antitopoisomerase I (topo I; by counterimmunoelectrophoresis), and anti-RNA polymerase III (RNAPIII; by ELISA). Forty-one sera negative for these specificities were tested by IP analysis of proteins ((35)S-methionine labeled K562 cell extract) and RNA (silver staining)., Results: Among 216 SSc patients analyzed, anti-topo I, ACA, and anti-RNAPIII were detected in 38% (81/216), 31% (67/216) and 7% (15/216), respectively. Among 41 sera negative for ACA, anti-topo I, and anti-RNAPIII and which were tested by IP, 14 were nucleolar stain-positive. Eight out of 14 (57%) showed anti-Th/To reactivity, but no anti-U3RNP was found. In comparison with ACA-positive patients, anti-Th/To-positive patients were younger (p = 0.0046) and more commonly were male (p = 0.0006). All 8 anti-Th/To-positive and all but one ACA-positive patients had lcSSc. Interstitial lung disease (ILD) and pericarditis were more frequent in anti-Th/To-positive patients., Conclusion: Anti-Th/To are common in antinucleolar antibody-positive Italian patients with SSc. Anti-Th/To and ACA patients had lcSSc, with excellent prognosis. The anti-Th/To group had frequent pericarditis and ILD, although impairment of pulmonary function appeared mild.

Objective: Some patients with systemic lupus erythematosus (SLE) are clinically quiescent despite persistent serologic activity. We determined the frequency of serologically active clinically quiescent (SACQ) SLE and its outcomes in prospectively followed patients with SLE., Methods: Patients with SLE followed between July 1970 and April 2008 with visits < or = 18 months apart were identified. SACQ was defined as a > or = 2-year sustained period without clinical activity with persistent serologic activity (increased anti-dsDNA and/or hypocomplementemia), during which antimalarials but neither steroids nor immunosuppressives were permissible. Characteristics of patients with an SACQ period and its features were analyzed. To determine flare predictors, anti-dsDNA and complement levels in SACQ patients who experienced flare were compared to levels in those who did not. Descriptive statistics were used; comparisons were made using t tests and chi-squared tests., Results: Of the patients studied, 56/924 (6.1%) were SACQ. They differed significantly from the non-SACQ SLE population only in the presenting SLE Disease Activity Index 2000 (7.34 vs 10.1 in non-SACQ), and frequency of steroid use (33.9% vs 60.8% in non-SACQ) and immunosuppressive use (3.6% vs 19.4% in non-SACQ) at first visit. Median SACQ period was 158 weeks. Thirty-three (58.9%) patients who were SACQ experienced flare (at median 155 weeks), 6 (10.7%) became clinically and serologically quiescent (236 weeks), and 17 continued to be SACQ (159 weeks). Common flare manifestations were arthritis, mucous membrane involvement, and sterile pyuria. Fluctuations in anti-dsDNA or complement levels did not predict flare., Conclusion: Fifty-nine percent of SACQ patients experienced flare, but after a median of 3 years. Fluctuations in complement and anti-dsDNA levels did not predict flare, thus treatment decisions in these patients must rely upon close clinical observation. Alternative predictive biomarkers warrant study.

Objective: Systemic lupus erythematosus (SLE) is more common among women than men, a ratio of about 10 to 1. We undertook this study to describe familial male SLE within a large familial SLE cohort., Methods: SLE families (2 or more patients) were identified from the Lupus Multiplex Registry and Repository. Genomic DNA and blood samples were obtained using standard methods. Autoantibodies were determined by multiple methods. Medical records were abstracted for SLE clinical data. Fluorescent in situ hybridization (FISH) was performed with X and Y centromere-specific probes, and a probe specific for the Toll-like receptor 7 gene on the X chromosome., Results: Among 523 SLE families, we found 5 families in which all the SLE patients were male. FISH found no yaa gene equivalent in these families. SLE-unaffected primary female relatives from the 5 families with only-male SLE patients had a statistically increased rate of positive antinuclear antibodies compared to SLE-unaffected female relatives in other families. White men with SLE were 5 times more likely to have an offspring with SLE than White women with SLE, but there was no difference in this likelihood among Black men., Conclusion: Because women in the all-male families had positive antinuclear antibodies, and men are more likely to have children with SLE, these data suggest genetic susceptibility factors that act only in men.

Objective: Sjögren's syndrome (SS) has a varied clinical spectrum and has been associated with various chest computed tomography (CT) findings. We sought to delineate the characteristic CT features in various subsets of SS, especially poor prognosis subsets., Methods: Retrospectively identified 80 never-smoker SS patients [56 primary SS (1-SS), 24 secondary SS (2-SS)] who underwent chest CT at our institution during a 3-year period from 2004 through 2007 were included in this study. Chest CT findings were qualitatively and semiquantitatively analyzed with comparison between 1-SS and 2-SS, and correlation with anti-SSB/La seropositivity and the presence of clonally derived lymphoproliferative disorder (cLPD), which are known to be pathognomonic and prognostic clinical features of SS patients., Results: All patients were women with median age of 60 years. Anti-SSB/La antibodies were found in 17 primary SS patients and 4 2-SS patients. Eleven patients with cLPD were identified and all of them had 1-SS. The most frequent CT finding in both types of patients was interlobular septal thickening. Secondary SS was associated with a significantly greater frequency and extent of honeycombing versus 1-SS. Univariate and multivariate analysis showed a significant association between honeycombing and 2-SS. In patients with 1-SS and in the SS group as a whole, we observed independent and significant associations between cysts and anti-SSB/La seropositivity or cLPD., Conclusion: Cysts are significantly associated with anti-SSB/La seropositivity and cLPD. The presence of lung cysts revealed by chest CT might be a prognostic clinical feature, a clue, or a predictor of cLPD in patients with SS.

Objective: Inflammation and autoimmunity are associated with increased cardiovascular (CV) risk in patients with rheumatoid arthritis. This association may also be present in those without rheumatic diseases. Our purpose was to determine whether rheumatoid factor (RF), antinuclear antibody (ANA), and cyclic citrullinated peptide antibody (CCP) positivity are associated with increased risk of CV events and overall mortality in those with and without rheumatic diseases., Methods: We performed a population-based cohort study of all subjects who had a RF and/or ANA test performed between January 1, 1990, and January 1, 2000, and/or CCP test performed between September 1, 2003, and January 1, 2005, with followup until April 1, 2007. Outcomes were ascertained using diagnostic indices from complete medical records, including CV events [myocardial infarction (MI), heart failure (HF), and peripheral vascular disease (PVD)] and mortality. Cox models were used to analyze the data., Results: There were 6783 subjects with RF, 7852 with ANA, and 299 with CCP testing. Of these, 10.4%, 23.9%, and 14.7% were positive for RF, ANA, and CCP, respectively. Adjusting for age, sex, calendar year, comorbidity, and rheumatic disease, RF and ANA positivity were significant predictors of CV events [hazard ratio (HR) 1.24 and 1.26] and death (HR 1.43 and 1.18). Adjusting for age, CCP positivity was associated with CV events, but this association was not statistically significant (HR 3.1; 95% CI 0.8, 12.3)., Conclusion: RF and ANA positivity are significant predictors of CV events and mortality in both those with and those without rheumatic diseases. These results support the role of immune dysregulation in the etiology of CV disease.

Objective: To compare live birth rates in women with recurrent pregnancy loss (RPL) and either autoantibodies or a coagulation abnormality, treated with low molecular weight heparin plus aspirin (LMWH/ASA) or ASA alone, and to place our results in context with other randomized clinical trials (RCT) with similar cohorts., Methods: The HepASA Trial was an RCT including patients with a history of RPL and at least 1 of the following: antiphospholipid antibody (aPL), an inherited thrombophilia, or antinuclear antibody. Treatment groups were stratified by aPL status and history of early versus late pregnancy losses. Patients received either LMWH/ASA or ASA alone. The primary outcome was live birth; secondary outcomes included adverse events and bone loss at the spine and femoral neck. Literature over the past 20 years was reviewed to identify comparable RCT., Results: Over 4 years, 859 women with RPL were screened: 88 (10.2%) fulfilled inclusion criteria, became pregnant and were randomized to receive either LMWH/ASA or ASA alone. aPL were present in 42 (47.7%) patients in each group. The trial was stopped after 4 years when an interim analysis showed no difference in live birth rates in the 2 groups, and a lower rate of pregnancy loss in the ASA only group than expected. In the LMWH/ASA group, 35/45 (77.8%) had a live birth versus 34/43 (79.1%) in the ASA only group (p = 0.71). Neither number of prior losses nor aPL status was correlated with pregnancy outcome. There were no cases of pregnancy related thrombosis in either group. Mean change in BMD did not differ by treatment group at either the lumbar spine (p = 0.57) or femoral neck (p = 0.15). RCT since 2000 for aPL positive women with RPL and similar inclusion criteria report a mean live birth rate of 75% with either LMWH or ASA., Conclusion: LMWH/ASA did not confer incremental benefit compared to ASA alone for this population. Regardless of treatment regimen, number of prior losses, or aPL positivity, almost 80% of women in our RPL cohort had a successful pregnancy outcome. These findings contribute to a growing body of literature that contests the emerging standard of care comprising LMWH/ASA for this population.

Objective: To study serum levels of serum amyloid P component (SAP) and SAP-DNA complexes in a population-based cohort of patients with systemic lupus erythematosus (SLE)., Methods: The study population comprised 82 unselected patients of predominantly Scandinavian ancestry with SLE according to current classification criteria. Serum samples were collected at baseline and serially for up to 2 years. SAP component and SAP-DNA complexes were measured by ELISA. Associations between SAP-DNA and clinical manifestations or serological findings were analyzed. Ninety healthy, age-matched blood donors served as controls., Results: SLE patients had normal serum concentrations of SAP, whereas SAP-DNA complexes were decreased. Two-thirds of the SLE patients tested persistently SAP-DNA complex-negative. There was no relationship between the occurrence of SAP-DNA complexes and clinical manifestations. SAP-DNA-negative patients tended to have lower leukocyte counts and complement C3 levels, and higher erythrocyte sedimentation rates and C3d levels versus SAP-DNA-positive patients. There was an inverse association between the occurrence of anti-double-stranded DNA (anti-dsDNA) antibodies and SAP-DNA complexes. Co-occurrence of SAP-DNA complexes and anti-dsDNA antibodies was demonstrated in only one SLE patient, implying that 81/82 patients were discordant for the presence of anti-dsDNA antibodies and SAP-DNA complexes., Conclusion: The decreased level of SAP-DNA complexes in SLE patients and the inverse relationship between these complexes and anti-dsDNA antibody supports the concept that SAP component is implicated in the clearance of cell nuclear debris.

Objective: To clarify the clinical features of patients with systemic sclerosis (SSc) who developed severe gastrointestinal tract (GIT) involvement in the early stage of the disease., Methods: Three hundred two consecutive Japanese patients with SSc were investigated: Group 1 comprised 14 patients with severe GIT involvement (malabsorption syndrome and/or pseudo-obstruction) within 2 years of onset of SSc; group 2 consisted of all patients without severe GIT involvement (n = 288); and group 3 consisted of 117 patients without severe GIT involvement within 2 years of onset of SSc. Autoantibodies were evaluated using double immunodiffusion, ELISA, and immunoprecipitation., Results: We found significant differences in clinical features among the 3 groups. Diffuse cutaneous type, erosive esophagitis, and myositis were more common in group 1 than in group 2 (p = 0.007, 0.003, and 0.003, respectively) or group 3 (p = 0.04, 0.002, and 0.01, respectively), whereas interstitial lung disease (ILD) was more frequent in group 2 (p = 0.005) and group 3 (p = 0.02) versus group 1. Antinuclear antibodies showed a nucleolar pattern significantly more frequently in group 1. Myositis-related autoantibodies, including anti-U1RNP, anti-U3RNP, anti-Ku, and anti-signal recognition particle antibodies, were observed in 57% of group 1., Conclusion: Our findings strongly suggest the existence of a subgroup of SSc patients with severe GIT involvement in the early stage. Among the Japanese individuals, these patients never developed severe ILD, even though they were classified as having diffuse cutaneous SSc.

Objective: To evaluate the prevalence and clinico-serological correlations of anti-enolase, anti-C1q, and anti-dsDNA antibodies in patients with systemic lupus erythematosus (SLE)., Methods: Sixty-eight sera randomly obtained from SLE patients were examined. Anti-alpha-enolase antibodies were detected by immunoblot on recombinant protein; anti-C1q and anti-dsDNA antibodies were detected using an ELISA., Results: Anti-alpha-enolase, anti-C1q, and anti-dsDNA antibodies were positive in 21%, 62%, and 63% of patients, respectively. A correlation was found between anti-dsDNA and anti-C1q antibodies, while anti-enolase antibodies did not correlate with the other 2 specificities. Anti-alpha-enolase antibodies were not correlated with any of the clinical and serological variables examined. Anti-C1q antibodies were correlated with ECLAM score, leukopenia, complement levels, and active renal involvement. Anti-dsDNA antibodies correlated with arthritis, leukopenia, complement levels, and the presence of renal involvement, independent of activity. In patients with active renal disease anti-dsDNA antibodies were correlated with a poor renal outcome, occurring after a mean period of 24 months., Conclusion: These data suggest the association of anti-C1q antibodies with disease flares and active renal disease in SLE. The observed association of anti-dsDNA antibodies and renal disease was expected. Further analysis is required to fully assess the clinical significance of anti-a-enolase antibodies.

Objective: To investigate the effect of longterm infliximab therapy on serum levels of fluorescent antinuclear and anti-double and single-stranded DNA antibodies (FANA, anti-dsDNA, anti-ssDNA) in patients with rheumatoid arthritis (RA), and their possible association with clinical evolution., Methods: Sera from 58 RA patients, treated for one to 3 years with infliximab, were retrospectively analyzed. Matched control groups were RA patients treated with corticosteroids or methotrexate. FANA were tested using HEp-2 cells, and anti-dsDNA and anti-ssDNA IgG by ELISA. After 28 months of infliximab therapy, clinical status was evaluated in 43/58 patients with uninterrupted therapy and associations with autoantibody levels were investigated. Data were documented for patients who discontinued infliximab., Results: Over the 3 year period, significant increases in FANA and anti-ssDNA IgG levels were observed in infliximab treated patients (p < 0.001 and p < 0.01, respectively). In 43 patients with an uninterrupted infliximab regimen, association was found between high FANA (>or= 1/1280) and lower age (p = 0.048) and patient's assessment of infliximab's efficacy (p = 0.014). Three patients developed anti-dsDNA IgG, preceded by high anti-ssDNA IgG levels, and one of them developed a lupus-like syndrome. Neither the initial presence of high FANA levels nor their increase >or= 1/1280 was significantly associated with discontinuation of infliximab. In contrast, at baseline (p = 0.0012) and at the time of infliximab discontinuation (p = 0.0078), anti-ssDNA IgG (>or= 500 arbitrary units) were more frequent in 7 patients who stopped infliximab due to skin or systemic anaphylactoid reactions., Conclusion: Monitoring of serum FANA, anti-dsDNA, and anti-ssDNA IgG antibodies provided predictors of lupus-like symptoms and/or anaphylactoid reactions in patients with RA.

Objective: To describe the patterns and time course of arthritis in patients with antinuclear antibody (ANA)-positive juvenile idiopathic arthritis (JIA)., Methods: We identified patients followed during a 16-year period who had JIA by ILAR criteria, were ANA-positive (i.e., had >or= 2 positive ANA test results at titer >or= 1:160), and had a disease duration >or= 2 years. Demographic and clinical features, including ILAR category and cumulative number and type of joints affected over time, were recorded., Results: A total of 195 patients were studied. The ILAR category was oligoarthritis in 159 patients and rheumatoid factor-negative polyarthritis in 36 patients. The cumulative rate of polyarticular extension in patients with oligoarticular onset was 26%, 38%, 45%, 49%, and 51% at 1, 2, 3, 4, and 5 years, respectively. At disease onset, most patients had monoarthritis and 95% had

B cells lacking RP105 molecule, a member of the Toll-like receptor family, were increased in the peripheral blood of 2 patients with antinuclear antibody (ANA) negative systemic lupus erythematosus (SLE). The increased proportion of RP105-lacking B cells was associated with disease activity in patients with ANA-negative SLE. When there are no significant serological markers for SLE, analysis of expression of RP105 may be helpful in evaluation of activity in ANA-negative SLE. We describe a new approach, using phenotyping of B cells, to evaluate activity of ANA-negative SLE.

Objective: Studies suggest that anti-52 kDa Ro antibodies are more sensitive and specific than anti-60 kDa Ro antibodies for neonatal lupus. However, these studies mainly used immunoblot or ELISA using recombinant protein, which have poor sensitivity for anti-60 kDa Ro antibodies. In addition, the control patients were not disease matched. We reassessed the sensitivity and specificity of anti-52 kDa Ro, anti-60 kDa Ro, and anti-La, addressing these limitations., Methods and Results: To assess sensitivity, 125 mothers of children with neonatal lupus (NLM) were recruited. All maternal sera were assessed using a commercial line immunoassay that uses natural 60 kDa Ro protein (Inno-Lia ANA Update, Innogenetics NV, Gent, Belgium). By this method, 96% of the sera had antibodies to 60 kDa Ro, 86% to 52 kDa Ro, and 78% to 48 kDa La. Immunoblot of 65 NLM showed significantly fewer positive results for anti-60 kDa Ro (p < 0.001) and anti-52 kDa Ro (p < 0.05). Sensitivity of the 3 antibodies was assessed in the symptomatic mothers of children with congenital heart block (CHB) (78 women) and disease matched controls with unaffected children (65 women) using Inno-Lia ANA Update. The sensitivity of each antibody was compared by multiple logistic regression to adjust for maternal disease. There was no significant difference between the groups for 60 kDa Ro or for anti-52 kDa Ro antibody. However, there was a significant difference for the anti-La antibody (p = 0.001), with an odds ratio of 3.59. This translates to an increase in risk from a published 2% for CHB in an anti-Ro-positive mother to 3.1% if the woman is also anti-La antibody-positive, and to a decrease in risk to 0.9% if anti-La-negative., Conclusion: Contrary to previous reports, 52 kDa Ro as detected by Inno-Lia ANA Update is not more specific for or frequent in CHB than 60 kDa Ro. However, the presence of anti-La antibodies significantly increases the risk for CHB.

Objective: To determine which centromere proteins are recognized in Sjögren's syndrome (SS) and whether antibodies recognizing centromere proteins (CENP) B and CENP C identify a specific serologic subset., Methods: Sera from 47 patients with SS, 12 xerostomic controls without SS, and 12 healthy controls were studied. All 47 patients met San Diego criteria for SS. Of these, 45 patients had primary SS and 2 had secondary SS with CREST. Sera were analyzed by immunoprecipitation of [35S] methionine-labeled Ro 52, La, and CENP B and C generated by coupled in vitro transcription/translation. Human salivary gland cells were also lysed and immunoprecipitated to determine antibody status against Ro 60. Serological and clinical profiles of patients recognizing CENP were defined. Proportions of sera recognizing CENP B, CENP C, Ro, or La across the 3 groups were compared using Fisher's exact test., Results: Twenty-eight of 45 primary SS patients (62%) recognized Ro 52, and 24 patients (53%) recognized La. Ten of these 45 (22%) sera recognized CENP B or C. Furthermore, 7 of these 10 recognized exclusively CENP C; these 7 (100%) all tested positive for antibodies to both Ro 52 and La. This was in contrast to the group of SS patients that did not recognize CENP C alone, in whom anti-Ro 52 antibodies were found in 21 of 38 (55%; p = 0.034), and antibodies to La in 17 (45%; p = 0.01). Five of 7 CENP C positive sera were also positive for Ro 60. One of 3 patients with antibodies to CENP B also had antibodies to Ro 52, while none of these 3 had antibodies to La. Only patients with antibodies to CENP B showed a centromere pattern on immunofluorescence staining., Conclusion: Antibodies to both CENP B and CENP C occur in SS. In a subset representing 15% of SS patients studied, these anticentromere antibodies recognize exclusively CENP C, and were uniformly associated with antibodies to Ro 52 and La.

Objective: To determine if anti-endothelial cell antibodies (AECA) and plasma markers of endothelial cell function are related to disease severity in systemic lupus erythematosus (SLE)., Methods: We measured AECA by human umbilical vein endothelial cell binding, endothelial markers von Willebrand factor, soluble thrombomodulin, and soluble E-selectin by ELISA, and disease severity by SLEDAI and SLICC/ACR in 35 patients with SLE., Results: Despite high levels of IgG AECA (p = 0.001) and von Willebrand factor (p = 0.0007) compared to 21 healthy controls, we found a positive correlation only between IgG AECA and the SLEDAI index (r = 0.393, p = 0.021)., Conclusion: IgG AECA seem to be related to disease activity in SLE, possibly in a pathogenic role. Conversely, plasma markers of endothelial cell damage seem to be an epiphenomenon and may simply be related to excess inflammation.

Objective: To investigate the clinical significance of anti-TS1-RNA antibodies in patients with mixed connective tissue disease (MCTD)., Methods: Anti-TS1-RNA antibodies were detected by immunoprecipitation using 32P-UTP labeled TS1-RNA as the antigen source. In total, 104 patients with MCTD, 30 with Sjögren's syndrome, 30 with systemic lupus erythematosus (SLE), 25 with systemic sclerosis, 23 with polymyositis or dermatomyositis, and 10 with rheumatoid arthritis were examined. Specificity of anti-TS1-RNA antibodies was analyzed by immunoprecipitation using HeLa cell extracts., Results: The frequency of anti-TS1-RNA antibodies was 31.7% in patients with MCTD, significantly higher than in SLE (p < 0.05). In anti-TS1-RNA positive patients, the incidence of hypertension and proteinuria and the frequency of anti-Sm and anti-dsDNA antibodies associated with SLE were higher than those of anti-TS1-RNA negative patients. Clinical features of SS such as sicca complex, the serum level of IgA, and anti-SSA antibodies were also elevated. The frequency of anti-TS1-RNA antibodies was significantly higher in SLE patients with anti-U1-RNP antibodies (p < 0.01); however, anti-TS1-RNA positive sera did not precipitate the specific RNA including U1 RNA in immunoprecipitation using HeLa cell extracts. In longitudinal studies, the level of anti-TS1-RNA antibodies changed in parallel with disease activity., Conclusion: We found that the level of anti-TS1-RNA antibodies was possibly correlated with the disease activity of lupus-like clinical features in patients with MCTD.

Objective: Autoantibodies observed in patients with rheumatoid arthritis (RA) during clinical trials of immunomodulating agents may cause concern about possible induction of autoimmunity by the therapeutic intervention. We determined the frequency and variability of selected autoantibodies in patients with early rheumatoid factor (RF) positive RA during a prospective observational study., Method: The study cohort consisted of 276 patients with active RA and with RF > or = 40 IU, who were enrolled between January 1, 1993, and April 1, 2000, before starting disease modifying antirheumatic drug (DMARD) therapy (average duration of symptoms, 7 mo). During an average of 3.5 years followup, a panel of autoantibodies was determined at entry, 6 months, 12 months, and yearly thereafter, in addition to routine clinical, radiographic, and laboratory assessments. After enrollment, patients were treated with DMARD at the discretion of their rheumatologists., Results: At entry before any DMARD therapy, antinuclear antibody (ANA; by HEp-2) values were negative in 31%, borderline (8 IU/ml) in 26%, and > 8 (mean 65.5 IU/ml) in 41%. Tender and swollen joint counts, Disease Activity Score, and RF values were significantly higher in those with ANA > 8. During followup 726 paired serial specimens were available; 12.5% changed from negative to positive ANA and 12.3% from positive to negative. Additional autoantibodies were present in specimens of 20% of the subjects; 8% had 2 and 1.4% had 3 other autoantibodies. Anti-dsDNA was detected in 13 (5.5%) patients; 4 changed from negative to positive and one from positive to negative. SSA IgG and SSB IgG autoantibodies were both present in one of these patients. Ribosomal P protein autoantibodies were noted in 2 other patients, but Sm (Smith) and uRNP/snRNP IgG autoantibodies were not present in any patient. No patient had a diagnosis of systemic lupus erythematosus. Antithyroid peroxidase (20 patients), parietal cell (15), smooth muscle (14), reticulin (9), mitochondrial (5), striational (2), SSB (2) and SCL-70 (1) autoantibodies were detected in some specimens. Seven patients were diagnosed with hypothyroidism, one with chronic thyroiditis, one with hepatitis C, and 9 with malignancies., Conclusion: In patients with early RF positive RA the frequent occurrence of autoantibodies before and during treatment with standard DMARD may make it difficult to attribute their presence to new therapies.

Objective: To define a novel RNA epitope recognized by serum from a patient with Sjögren's syndrome (SS) from a randomized RNA epitope library and investigate the epitope reactivity of the anti-RNA antibodies in patients with various connective tissue diseases., Methods: Serum from a patient with SS was used to select ligands from a library of RNA oligomers with a central region of 25 degenerate nucleotides. Bound RNA was recovered by reverse transcription, PCR amplification, and subcloning. The relationship between the antibodies to the selected RNA and disease specificity was studied using immunoprecipitation., Results: From the random RNA library, several unique RNA sequences were obtained. Sera from 32 of 61 patients with SS (52.5%) precipitated with one of the selected RNA (TS1-RNA), whereas sera from 8 of 41 patients with systemic lupus erythematosus (19.5%) and 3 of 25 patients with rheumatoid arthritis (12.0%) precipitated. Although the frequency of reactivity to the TS1-RNA was higher in anti-SSA/Ro positive sera, the presence of either native or recombinant SSA/Ro antigen showed no detectable competition, and no apparent sequence homology was found between the TS1-RNA and hY RNA., Conclusion: These data suggest that anti-TS1-RNA is a novel antibody against sequence-specific RNA in many patients with SS.

Objective: To analyze the performance of different commercial enzyme immunoassay (EIA) kits for measuring antibody levels of antinuclear antibodies (ANA) specific for double stranded (ds) DNA, SSB/La, Sm, and Scl-70., Methods: Twenty companies that were known major purveyors of EIA kits for detection of ANA were approached to determine their interest and willingness to participate in this study. The manufacturers were advised that they would be sent coded sera containing mixtures of the Arthritis Foundation/Centers for Disease Control reference reagents, and that they were to use their own test kits to analyze the antibody specificities of these sera and to report the data, in optical density (OD) units, or their equivalent. The analysts were blinded to the concentration of the antibodies and the specificities., Results: Initially, 11 manufacturers out of 20 agreed to participate, but 2 subsequently withdrew. The commercial EIA kits have the potential of being able to quantitate specific autoantibody content to ds-DNA, SSB/La, Sm, and Scl-70. However, certain deficiencies in these kits were also detected, the most obvious being lack of uniformly good performance, with kits of certain manufacturers showing exceptional accuracy in 3 out of 4 of their antibody-specific kits and poor accuracy for a 4th kit., Conclusion: It is important for clinicians to appreciate that there is marked inter-manufacturer variation in the performance of EIA kits used as an aid in the diagnosis of systemic rheumatic diseases. Manufacturers need to exercise constant surveillance of kit performance and to provide assurance that such is being done. Improved EIA kits would lend themselves to reliable quantitation of antibody levels in human sera and help to determine whether serial measurement of antibody levels might be useful in monitoring disease activity.

We describe the first case in which de novo production of multiple IgG antinuclear antibodies (ANA) occurred in a female neonate of an ANA negative mother. The infant presented at 4 weeks of age with hemorrhagic panencephalitis, diffuse intraparenchymal hemorrhages, and straight sinus thrombosis. She had been vaccinated against hepatitis B at birth. No other cause was found and maternal prenatal care was unremarkable. The infant's screening ANA test by ELISA was positive at 6 weeks with specificity for ssDNA, Sm, and nRNP/Sm. At 8 weeks antibodies to dsDNA and centromere were detected as well. By 8 months, she still had slightly elevated anti-dsDNA, Sm, and nRNP/Sm antibodies. The ANA test by immunofluorescence was abnormal at 8 weeks through 13 weeks with centromere and then homogeneous pattern. Based on similarities with other reported cases, we speculate that hepatitis B vaccination may have been involved in the development of antinuclear antibodies.

Pregnancies in women with autoantibodies against Ro/SSA and/or La/SSB may be associated with permanent and treatment resistant fetal atrioventricular (AV) block. We describe a patient with primary S ogren's syndrome and anti-Ro (60 kDa and 52 kDa) and anti-La autoantibodies, in whom fetal bradycardia with second-degree AV block was detected at 19 + 0 weeks of gestation. Maternal treatment with dexamethasone (4 mg/day po) was started 2 days later. The baby's heart rate improved gradually, returning to normal after about 6 weeks of treatment. Our case illustrates the importance of close monitoring of the fetal heart rate in risk-pregnancies from about week 16 of gestation and initiation of dexamethasone treatment without delay when a block is detected.

Objective: The presence of antinuclear autoantibodies in systemic lupus erythematosus (SLE) is influenced by genetic factors. The presence of autoantibodies in healthy family members of patients has been reported. Our hypothesis was that autoantibodies are directed against the same antigens in first-degree family members of patients with SLE as in their patient relative., Methods: Plasma was harvested from 50 patients with SLE, 154 unaffected first-degree family members, and 330 healthy controls. Presence of autoantibodies against 14 specific nuclear antigens was tested by the ELISA based line immunoassay INNO-LIA method., Results: Seventy-four percent of patients, 32% of first-degree family members, and 1.5% of healthy controls had antibodies against any nuclear antigen. Most frequent autoantibodies in the patients were anti-histone and anti-SSA, whereas in the family members these were anti-RNP-C and anti-Topo-I/Scl. Presence and specificity of autoantibodies in family members were independent of the presence or absence of that autoantibody in their patient relative (chi-square p > 0.1 for all 14 antigens)., Conclusion: Autoantibodies in family members and their patient relatives are not directed against the same nuclear antigens. Thus a familial aspecific dysfunction of the B lymphocyte is the most likely explanation for autoantibody production in SLE.

Objective: To investigate the association between complete congenital heart block (CCHB) in the fetus and adult disease., Methods: We prospectively studied 111 consecutive patients with systemic lupus erythematosus (SLE) or a positive extractable nuclear antigen (Ro, La, or RNP) attending a connective tissue disease (CTD) clinic and 19 patients who had had children with CCHB. Electrocardiographs were recorded on all patients and subsequently analyzed blindly., Results: There was a significantly shorter PR interval in the mothers of children with CCHB compared to patients attending the CTD clinic (p < 0.02). There was no significant difference in PR interval between Ro positive and Ro negative patients in the CTD clinic. There were no significant differences in QRS or QTc duration between mothers with CCHB children and Ro positive or Ro negative patients attending the CTD clinic. The shorter PR interval in the mothers with CCHB children may be explained by their significantly younger age compared to patients in the CTD clinic (p < 0.02, 95% CI) and the lower incidence of CTD., Conclusion: We were unable to confirm the association between anti-Ro antibodies and cardiac conduction defects in adults. This supports theories that CCHB is due to vulnerability peculiar to the fetal heart during a particular stage of development between 16 and 30 weeks of gestation.

Objective: To determine the safety and immunogenicity of an idiotypic anti-dsDNA vaccine in patients with nonactive systemic lupus erythematosus (SLE) and stable lupus nephritis., Methods: Patients with SLE with a history of nephritis were randomized for vaccination with the murine anti-dsDNA monoclonal antibody (Mab) 3E10 in a dose ranging, double blind, placebo controlled study (phase I)., Results: Of the 9 patients injected with Mab 3E10, 5 showed a human anti-mouse antibody (HAMA) response, in large part antiidiotypic, which developed within the first 3 months in 3 strong HAMA responders, and more than one year after immunization in an initially weak HAMA responder. All but one nonresponder were receiving low dose prednisone. No adverse events, in particular no evidence of lupus flares, and no untoward laboratory findings were reported over a followup of 2 years., Conclusion: In patients with stable lupus nephritis, immunization with Mab 3E10 appears safe and can generate a significant antiidiotypic response. Idiotypic vaccination may be an approach to specific immunotherapy of autoimmune lupus nephritis.

Objective: Antiperinuclear factor (APF) is an autoantibody detected in >50% of patients with rheumatoid arthritis (RA); it shows a specificity of roughly 90%. We investigated the possible role of APF as a prognostic marker in RA., Methods: A series of 103 patients with RA who fulfilled the 1987 American College of Rheumatology criteria (88 women and 15 men; mean age 55.5 yrs, mean disease duration 9 yrs) were prospectively followed. Sixteen variables were assessed in each patient at inclusion and over a 3 year period. APF was determined by indirect immunofluorescence assay using human buccal mucosal cells as substrate. APF assays were done at entry and at the end of followup without knowledge of the clinical status of the patients. Mann-Whitney U, chi-squared tests, variance analysis, and kappa index were used for statistical analysis., Results: Eighty of 103 patients completed followup. APF was detected in 40 of 80. At inclusion, APF correlated with the visual analog scale (VAS) of pain (p = 0.02). However, patients who showed APF positivity at entry had a less favorable course than APF negative individuals, as shown by a worse VAS of well being (p = 0.01), Ritchie index (p = 0.01), number of painful joints (p = 0.03), grip strength (p = 0.01), C-reactive protein (p = 0.04), and Health Assessment Questionnaire score (p = 0.03) at the end of the study. In addition, APF positive patients showed a worse radiological course (p = 0.03)., Conclusion: Our results suggest APF is a possible marker of poor prognosis in RA.

Objective: To determine the clinical significance of elevated serum levels of VH4-34 encoded antibodies (VH4-34 Ab) with respect to the diagnosis and clinical characteristics of systemic lupus erythematosus (SLE)., Methods: Ninety-five patients with SLE and 344 controls were studied. The controls included 34 healthy individuals, 282 patients with nonautoimmune diseases, and 28 patients with autoimmune diseases other than SLE. VH4-34 Ab levels were measured by inhibition ELISA using anti-idiotope monoclonal antibody (9G4). SLE disease activity, severity, and damage were assessed by visual analog scales, Systemic Lupus Activity Measure, Lupus Severity of Disease Index, and Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index., Results: Fifty-two of 95 patients with SLE had elevated levels of VH4-34 Ab compared to 18 of 344 controls (5%), giving a sensitivity of 55% and a specificity of 95% for elevated VH4-34 Ab as a serologic test for SLE. The positive predictive value of elevated VH4-34 under these conditions was 74-85%. In this study, anti-dsDNA was not VH4-34 encoded. Significant correlations between VH4-34 and disease activity and severity indices were observed (r = 0.29-0.50). The relative risk for severe disease in SLE patients with VH4-34 antibody level in the highest tertile compared to the lowest tertile was 5.25. Twenty-five of 29 patients with lupus nephritis and 6 of 6 patients with central nervous system (CNS) lupus had elevated VH4-34 Ab., Conclusion: With a specificity of 94-95%, the VH4-34 antibody assay may prove valuable as a confirmatory diagnostic test for SLE. In patients with known SLE, serum VH4-34 Ab levels correlate with overall disease severity and activity, but not damage, and with nephritis and CNS lupus.

Objective: To determine the prevalence and clinical correlation of anti-calpastatin antibodies in patients with systemic sclerosis (SSc)., Methods: Serum samples from patients with limited cutaneous SSc (lSSc; n=36), diffuse cutaneous SSc (dSSc; n=27), and healthy control subjects (n=29) were examined by an ELISA using human recombinant calpastatin as antigens., Results: IgG anti-calpastatin antibodies were positive in 15 (24%) of 63 patients with SSc, which was similar to the frequency of IgM anti-calpastatin antibody positivity (14/63, 22%). The presence of anticentromere antibodies was associated with the presence of IgG and/or IgM anti-calpastatin antibodies. The patients with SSc positive for IgG anti-calpastatin antibodies had significantly higher erythrocyte sedimentation rates (ESR) compared with those negative for IgG anti-calpastatin antibodies. Furthermore, the levels of IgG anti-calpastatin antibodies correlated positively with the levels of ESR. The patients with dSSc positive for IgM anti-calpastatin antibodies had significantly higher frequency of inflammatory joint and muscle involvement compared with those negative for IgM anti-calpastatin antibodies. Four (80%) of 5 patients with dSSc with both joint and muscle involvement produced IgM anti-calpastatin antibodies., Conclusion: The presence of anti-calpastatin antibodies may be a clue to mechanisms of the inflammatory change occurring in SSc. Furthermore, the presence of anti-calpastatin antibodies could be a novel and useful serologic tool for recognizing patients with dSSc with inflammatory joint and muscle involvement.

Objective: To find the incidence and prevalence of juvenile chronic arthritis (JCA) in the urban area of San José, Costa Rica., Methods: During the year preceding our 2 year prospective, population based study, we conducted an educational program on JCA. The physicians caring for children < 16 years of age from all centers in the study area followed the program. They were asked to refer all cases of possible JCA according to EULAR criteria. The children were all evaluated at the National Children's Hospital., Results: Of 189 children referred, 48 fulfilled EULAR criteria for JCA. The 2 year incidence rate for JCA was 13.7 per 100,000 children < 16 years old. This corresponds to an annual incidence per 100,000 children of 6.8 (95% CI 4.1-9.6). The incidence rate for pauciarticular onset JCA was 3.9 per 100,000. At the prevalence date, 122 cases of JCA were recorded, corresponding to a prevalence of 34.9 per 100,000 children < 16 years. When patients in remission were excluded, the prevalence was 31.4 per 100,000 (95% CI 25.5-37.2). The pauciarticular onset form was the most common, 71% of all prevalence cases. The highest incidence and prevalence were noted for pauciarticular girls with late onset JCA. No incidence peak was found in preschool age. The girl-to-boy ratio was 1.5/1. Antinuclear antibodies (ANA) were positive in only 7 cases (6.3%). IgM rheumatoid factor was found in 13 children (10.6%). Chronic iritis was observed in 4 cases, all of them ANA negative and older than 7 years of age at onset of arthritis., Conclusion: The incidence and prevalence observed were lower than those reported in other population based studies, but within the confidence intervals of their data. The incidence rate for pauciarticular JCA was significantly lower than that reported in other comparable studies. ANA positive pauciarticular preschool girls and associated uveitis were rarely encountered.