History of affective disorder and the temporal trajectory of fatigue in rheumatoid arthritis.

This study examines whether the general level and rate of change of fatigue over time is different for those rheumatoid arthritis (RA) patients with and those without a history of affective disorder (AD). Four hundred fifteen RA patients from a national panel had yearly telephone interviews to obtain fatigue and distress reports, and a one-time semistructured assessment of the history of depression and generalized anxiety disorder Growth-curve analysis was used to capture variations in initial fatigue levels and changes in fatigue over 7 years for those with and without a history. RA patients with a history of major AD reported levels of fatigue that were 10% higher than those without a history in the 1st year of the study. Their fatigue reports remained elevated over 7 years. Further analysis showed that the effects of a history of AD on fatigue are fully mediated through current distress, although those with a history had a significantly smaller distress-fatigue slope. Thus, a history of AD leaves RA patients at risk for a 7-year trajectory of fatigue that is consistently higher than that of patients without a history. The elevation in fatigue reports is, at least in part, a function of enduring levels of distress.

Factors associated with low bone mineral density in female patients with systemic lupus erythematosus.

OBJECTIVE: To study risk factors for low bone mineral density (BMD, g/cm) in patients with systemic lupus erythematosus (SLE). METHODS: Ninety-two consecutive patients with SLE followed by rheumatology faculty between 1997 and 1999 completed a questionnaire regarding lifestyle during the clinic visit, a chart review was performed, and data were collected for the time of the first dual energy x-ray absorptiometry (DXA) examination. Univariate and multivariate statistical analyses were used to assess relationships between various risk factors and BMD. RESULTS: Ninety-eight percent of patients had received prednisone, 51% were postmenopausal (9 of whom received hormone replacement therapy), 68% had received hydroxychloroquine, and 15% were osteoporotic. The following factors were found to be significantly related to lower BMD by univariate analysis: Caucasian race, older age at diagnosis, higher age at the time of the first DXA, longer disease duration, higher cumulative corticosteroid dose, higher SLE Damage Index score, and postmenopausal status. In the multivariate analysis only the following factors were significant: Caucasian race, increased number of pregnancies, postmenopausal status, higher SLE Damage Index, and higher cumulative corticosteroid dose. An unexpected finding was that taking hydroxychloroquine was the only factor associated with higher BMD of the hip and spine in the univariate analysis, and it remained predictive of higher BMD of the hip and spine in the multivariate analysis. CONCLUSION: Hydroxychloroquine appears to protect against low BMD in corticosteroid treated patients with SLE.

Measuring disability: application of the Rasch model to activities of daily living (ADL/IADL).

This paper describes a comparative analysis of (ADL) and (IADL) items administered to two samples, 4,430 persons representative of older Americans, and 605 persons representative of patients with rheumatoid arthrisit (RA). Responses are scored separately using both Likert and Rasch measurement models. While Likert scoring seems to provide information similar to Rasch, the descriptive statistics are often contrary if not contradictory, and estimates of reliability from Likert are inflated. The test characteristic curves derived from Rasch are similar despite differences between the levels of disability with the two samples. Correlations of Rasch item calibrations across three samples were .71, .76, and .80. The fit between the items and the samples, indicating the compatibility between the test and subjects, is seen much more clearly with Rasch with more than half of the general population measuring the extremes. Since research on disability depends on measures with known properties, the superiority of Rasch over Likert is evident.

Recombinant human relaxin in the treatment of scleroderma. A randomized, double-blind, placebo-controlled trial.

BACKGROUND: Relaxin is a pregnancy-related hormone that has tissue remodeling and antifibrotic effects. Systemic sclerosis (scleroderma) is characterized by fibrosis of the skin, vasculature, and internal organs. OBJECTIVE: To assess the efficacy, safety, and dose-response effect of recombinant human relaxin in patients with scleroderma. DESIGN: Multicenter, parallel-group, randomized, double-blind, placebo-controlled trial. SETTING: Academic referral centers. PATIENTS: 68 patients who had had stable, diffuse scleroderma (moderate to severe) for less than 5 years. INTERVENTION: Recombinant human relaxin, 25 or 100 microg/kg of body weight per day, or placebo administered by continuous subcutaneous infusion over 24 weeks. MEASUREMENTS: Modified Rodnan skin score was the primary efficacy measure. Secondary measurements were pulmonary function, the Health Assessment Questionnaire, and other measures of scleroderma that reflected fibrosis. RESULTS: Patients who received 25 microg/kg of recombinant human relaxin per day had significantly lower skin scores than those who received placebo (mean change, -3.6 at 4 weeks [P = 0.021], -7.5 at 12 weeks [P < 0.001], and -8.7 at 24 weeks [P = 0.040]). Similar trends were noted in other outcome measures, including forced vital capacity, measures of oral aperture and hand extension, functional status, and global assessment. Patients who received 100 microg/kg of relaxin per day did not differ from those who received placebo. Drug-related adverse events included menometrorrhagia, reversible anemia, and complications of the subcutaneous drug administration system (site irritation and local infection). CONCLUSIONS: Twenty-four weeks of recombinant human relaxin, 25 microg/kg per day, is associated with reduced skin thickening, improved mobility, and improved function in patients with moderate to severe diffuse scleroderma.

Measuring disability: application of the Rasch model to activities of daily living (ADL/IADL).

This paper describes a comparative analysis of (ADL) and (IADL) items administered to two samples, 4,430 persons representative of older Americans, and 605 persons representative of patients with rheumatoid arthrisit (RA). Responses are scored separately using both Likert and Rasch measurement models. While Likert scoring seems to provide information similar to Rasch, the descriptive statistics are often contrary if not contradictory, and estimates of reliability from Likert are inflated. The test characteristic curves derived from Rasch are similar despite differences between the levels of disability with the two samples. Correlations of Rasch item calibrations across three samples were .71, .76, and .80. The fit between the items and the samples, indicating the compatibility between the test and subjects, is seen much more clearly with Rasch with more than half of the general population measuring the extremes. Since research on disability depends on measures with known properties, the superiority of Rasch over Likert is evident.

A critical evaluation of enzyme immunoassays for detection of antinuclear autoantibodies of defined specificities. I. Precision, sensitivity, and specificity.

OBJECTIVE: To determine the performance characteristics of enzyme-based immunoassay (EIA) kits for the detection of antinuclear and other autoantibodies of defined specificities. METHODS: Nine manufacturers of EIA kits to detect antibodies of defined specificities participated in a study in which they received coded sera from the Centers for Disease Control and Prevention. These coded sera contained different dilutions of antibody of one specificity mixed with sera containing antibodies of other specificities. The manufacturers were asked to use their standard technology to determine antibody content and send the data to a committee of the International Union of Immunological Societies for analysis. The data were analyzed for sensitivity and specificity in the detection of anti-double-stranded DNA (anti-dsDNA), anti-single-stranded DNA, antihistone, anti-Sm, anti-U1 RNP, anti-SSA/Ro, anti-SSB/La, anti-Scl-70 (DNA topoisomerase I), anticentromere, and anti-Jo-1 antibodies. In addition, replicate samples were included in the coded sera to evaluate the precision of each EIA method. RESULTS: Lack of sensitivity and specificity was most evident in the anti-dsDNA and anti-Sm kits, although 2 kits for anti-dsDNA achieved acceptable sensitivity and specificity. Generally, anti-SSA/Ro, anti-SSB/La, anti-Scl-70, anticentromere, and anti-Jo-1 kits performed well. Many false-positive results were obtained with a multiple myeloma serum containing cryoprecipitates, but multiple myeloma sera without cryoprecipitates presented no problem in the EIA system. Precision, based on evaluation of replicate samples, varied from very good to poor. CONCLUSION: No single manufacturer was clearly superior to others in terms of their products' overall sensitivity, specificity, and precision. Areas that needed improvement were in kits for the detection of antibodies to dsDNA and to Sm antigen. Some EIA kits achieved good sensitivity and specificity. Individual manufacturers were informed of the performance of their respective kits so they could take measures to correct perceived deficiencies and thus improve the reliability of a group of important diagnostic assays used in the evaluation of systemic rheumatic diseases.

Anti-endothelial cell antibodies in systemic sclerosis: significant association with vascular involvement and alveolo-capillary impairment.

OBJECTIVE: To assess the frequency of antiendothelial cell autoantibodies (AECAs) in a group of patients with systemic sclerosis (SSc) and possible associations with clinical and serologic features of the disease. METHODS: Sera from 50 patients with SSc (38 with the limited and 12 with the diffuse form) were screened for AECA (ELISA). The reference limits were were 56.6% for the IgM isotype and 3.3.5% for the IgG isotype. AECA results were analyzed in relation to lung involvement (chest x-ray, high resolution computed tomography (HRCT), ventilation scintiscan with radioaereosol (DTPA), pulmonary pressure (echodoppler technique): heart involvement (EKG, 24 hr ambulatory EKG, echocardiography), cutaneous involvement (skin score), capillaroscopic characteristics and digital ulcers. AECA were also correlated with the erythrocyte sedimentation rate (ESR), anticentromere (ACA) and antitopoisomerase I (ATA) autoantibodies, and angiotensin converting enzyme plasma levels (ACE). RESULTS: The AECA IgG prevalence was 40% (22/50) for the SSc group as a whole, without significant differences between subsets. A significant negative correlation was shown between the AECA and ACE plasma levels in both subsets. In the diffuse form, a significant positive correlation was found between AECA and ESR and significant associations were found between AECA and the parameters reflecting alveolo-capillary involvement (DLco, DTPA), the pulmonary artery pressures, digital ulcers and capillaroscopic abnormalities. No statistically significant correlations were found between AECA and heart involvement, the skin score or pulmonary interstitial fibrosis. CONCLUSIONS: These data suggest that in SSc the anti-endothelial cell antibodies are directly linked to vascular injury and could reflect endothelial damage. Further studies are needed to verify whether AECA might identify a subgroup of patients at higher risk for the development of vascular crises and whether they might therefore be considered a predictor of outcome in SSc patients.

Oral iloprost treatment in patients with Raynaud's phenomenon secondary to systemic sclerosis: a multicenter, placebo-controlled, double-blind study.

OBJECTIVE: To evaluate the efficacy and tolerability of an oral preparation of iloprost, a prostacyclin analog, in patients with Raynaud's phenomenon (RP) secondary to systemic sclerosis (scleroderma). METHODS: A multicenter, randomized, parallel-group, placebo-controlled double-blind study was performed at university and community-based medical centers. Patients were randomly assigned to receive either 50 microg of iloprost orally twice daily or an identical gelatin-coated capsule containing placebo for 6 weeks. Outcome measures included average total daily duration of RP attacks, average number of RP attacks, and RP condition scored via a standardized daily diary. RESULTS: Three hundred eight patients with scleroderma (272 women, 36 men, mean age 49 years [range 18-80]) were enrolled. One hundred fifty seven were assigned to receive iloprost and 151 to receive placebo. One hundred forty-three patients in the iloprost group (91.1%) and 144 in the placebo group (95.4%) completed the 6-week treatment phase. Fifteen of these treated patients (8 iloprost, 7 placebo) failed to complete all of the followup visits. The mean reduction in the average duration of attacks from baseline to week 5-6 was 24.32 minutes in the iloprost group and 34.34 minutes in the placebo group (P = 0.569). Likewise, the mean reduction from baseline to week 5-6 in the daily frequency of attacks was 1.02 in the iloprost group and 0.83 in the placebo group (P = 0.459). The Raynaud's condition score, a patient-completed assessment of the severity of RP attacks, was reduced by 1.32 in the iloprost group and 1.00 in the placebo group (P = 0.323). The lack of significant difference between treatment groups did not change when a variety of factors, including use of other vasodilators, duration of disease, classification of scleroderma (limited versus diffuse), or number of baseline digital ulcers were taken into account. Premature withdrawal from the study due to adverse events occurred in 10 patients (6.4%) in the iloprost group and 3 (2.0%) in the placebo group (P = 0.058). CONCLUSION: Oral iloprost at a dosage of 50 microg twice daily is no better than placebo for management of RP secondary to scleroderma, either during 6 weeks of treatment or during 6 weeks of posttreatment followup.

Range of antinuclear antibodies in "healthy" individuals.

OBJECTIVE: To determine the range of antinuclear antibodies (ANA) in "healthy" individuals compared with that in patients with systemic lupus erythematosus (SLE), systemic sclerosis (SSc; scleroderma), Sjögren's syndrome (SS), rheumatoid arthritis (RA), or soft tissue rheumatism (STR). METHODS: Fifteen international laboratories experienced in performing tests for ANA by indirect immunofluorescence participated in analyzing coded sera from healthy individuals and from patients in the 5 different disease groups described above. Except for the stipulation that HEp-2 cells should be used as substrate, each laboratory used its own in-house methodology so that the data might be expected to reflect the output of a cross-section of worldwide ANA reference laboratories. The sera were analyzed at 4 dilutions: 1:40, 1:80, 1:160, and 1:320. RESULTS: In healthy individuals, the frequency of ANA did not differ significantly across the 4 age subgroups spanning 20-60 years of age. This putatively normal population was ANA positive in 31.7% of individuals at 1:40 serum dilution, 13.3% at 1:80, 5.0% at 1:160, and 3.3% at 1:320. In comparison with the findings among the disease groups, a low cutoff point at 1:40 serum dilution (high sensitivity, low specificity) could have diagnostic value, since it would classify virtually all patients with SLE, SSc, or SS as ANA positive. Conversely, a high positive cutoff at 1:160 serum dilution (high specificity, low sensitivity) would be useful to confirm the presence of disease in only a portion of cases, but would be likely to exclude 95% of normal individuals. CONCLUSION: It is recommended that laboratories performing immunofluorescent ANA tests should report results at both the 1:40 and 1:160 dilutions, and should supply information on the percentage of normal individuals who are positive at these dilutions. A low-titer ANA is not necessarily insignificant and might depend on at least 4 specific factors. ANA assays can be a useful discriminant in recognizing certain disease conditions, but can create misunderstanding when the limitations are not fully appreciated.

Analysis of IgG subclasses of human antitopoisomerase I autoantibodies suggests chronic B cell stimulation.

Antitopoisomerase I autoantibodies are highly specific of scleroderma and are mainly IgG. The present study was designed to evaluate the prevalence of each IgG antitopoisomerase I subclass. An ELISA for the detection of IgG antitopoisomerase I subclasses was standardized and used to study the antibodies from 49 antitopoisomerase I-positive patients identified from a total of 541 patients. Correlations and multivariate analysis were performed to determine the frequency of associations between the IgG antitopoisomerase I subclasses. All IgG antitopoisomerase I subclasses were found. Twelve patients (24.5%) had all four IgG antitopoisomerase I subclasses, 13 (26.5%) had three, 16 (32.7%) had two, and 7 (14.3%) had only one antitopoisomerase I subclass. The presence of all four IgG antitopoisomerase I subclasses suggests that this specific B-cell is the target of multiple activation pathways which indicate that there is a complex T-cell-cytokine-driven process. Together with the absence of other autoantibodies in these sera, our results support the concept of a multiple but highly selected and chronic B-cell activation in scleroderma patients with antitopoisomerase I.

A cross-reactive idiotype in scleroderma.

Autoantibodies to centromere proteins (anti-CENPs) and to topoisomerase-I are highly specific for scleroderma. Unlike most autoantibodies in other diseases, these autoantibodies are mutually exclusive. We have analysed the idiotypes (Ids) expressed by anti-CENP-B, antitopoisomerase-I, and IgGs from 20 scleroderma patients. Rabbit anti-Ids were prepared to antitopoisomerase-I from two scleroderma patients, and to anti-CENP-B from four patients. These six anti-Ids were used to study the purified autoantibodies from 20 scleroderma patients: four antitopoisomerase-I, 10 anti-CENP-B, and six purified IgG from scleroderma patients who were negative for both autoantibodies. In addition, we studied sera from 40 normal autoantibody-negative controls, and sera and purified immunoglobulins from 17 systemic lupus erythematosus (SLE) patients containing high titres of anti-double-stranded DNA, and/or autoantibodies to extractable nuclear antigens (ENA). Using direct binding, and competitive inhibition ELISAs and immunoblots, we identified an Id present in the heavy chains of all the affinity-purified antitopoisomerase-I, and anti-CENP-B. Interestingly, this Id was also present in the immunoglobulins of the scleroderma patients who had neither of the two autoantibodies. By contrast, cross-reactive Id-EM was not found in the sera or immunoglobulins from 17 SLE patients, or in the sera from 40 normal subjects. Several samples from two patients showed that this cross-reactive Id-EM was stable over time. The scleroderma disease-specific autoantibodies may be identified through a common structural feature at the variable region of the heavy chain: cross-reactive Id-EM.

Reference sera for antinuclear antibodies. II. Further definition of antibody specificities in international antinuclear antibody reference sera by immunofluorescence and western blotting.

OBJECTIVE: To define the fine specificity of the 10 reference sera used for determination of antinuclear antibodies (ANA) and ANA subsets which are available from the Arthritis Foundation (AF) and from the Centers for Disease Control and Prevention (CDC). METHODS: AF/CDC sera were assessed by experienced laboratory staff, using indirect immunofluorescence and Western blotting. RESULTS: The original assignment of fluorescence patterns to 4 reference sera was confirmed, and the fluorescence intensities were determined using reference fluorescent beads. On Western blots, sera AF/CDC2 (anti-SS-B/La) and AF/CDC7 (anti-SS-A/Ro) did not detect Ro antigens, sera AF/CDC9 and AF/CDC10 appeared to be monospecific anti-Scl-70 and anti-Jo-1 sera, respectively, serum AF/CDC4 (anti-U1 small nuclear RNP) recognized the 70-kd band, and serum AF/CDC5 recognized the Sm antigen with its multiple bands. Semiquantitative analyses revealed that AF/CDC5, AF/CDC2, and AF/CDC10 were strongly reactive sera, whereas AF/CDC4 and AF/CDC9 were much weaker and should be used at lower dilutions on Western blots. CONCLUSION: The AF/CDC ANA reference sera, originally described as reference reagents for indirect immunofluorescence and double immunodiffusion techniques, are also useful for Western blotting. The data presented herein further support the use of these sera for reference purposes.

Chiasmal herniation as a complication of bromocriptine therapy.

INTRODUCTION: Medical treatment of macroprolactinomas with dopamine agonists decreases tumor mass and improves visual defects. We report an unusual complication of a macroprolactinoma responding to bromocriptine: a visual field defect caused by downward herniation of the optic chiasm. MATERIALS AND METHODS: A 64-year-old woman was found to have a 4.5 cm macroprolactinoma with superior displacement of the optic chiasm, bitemporal hemianopia, and serum prolactin concentration (P) of 17,060 micrograms/L. Bromocriptine was initiated at 2.5 mg/day and increased to 7.5 mg/day over 2 months. RESULTS: After 2 months, visual fields improved significantly and tumor height decreased to 3 cm with resolution of the optic chiasm displacement. P decreased to 1,180 micrograms/L. After 5 months of therapy, visual fields were normal, and P was 8 micrograms/L. After 8 months of therapy, new bilateral visual defects were observed. Magnetic resonance imaging (MRI) revealed further decrease of the tumor height to 1.5 cm, and inferior and leftward traction of the optic chiasm as the probable mechanism for the new visual field deficit. P was < 1 microgram/L. Bromocriptine was decreased to 5 mg/day to allow reduced traction on the optic chiasm and its blood supply. Over the next 4 months, visual field abnormalities resolved. CONCLUSIONS: We report the development of a visual field abnormally that is explained by chiasmal herniation caused by a shrinking macroprolactinoma. This complication resolved with a decrease in the bromocriptine dose. We suggest that patients undergoing bromocriptine therapy for macroprolactinomas be followed for this potential complication.

Localization of histidyl-tRNA synthetase (Jo-1) in human laryngeal epithelial carcinoma cell line (HEp-2 cells).

The present study was designed to determine the subcellular localization of histidyl-tRNA synthetase (Jo-1) in human laryngeal epithelial carcinoma cell line (HEp-2 cells). Indirect immunofluorescence using commercial HEp-2 cells with human serum and human-affinity-purified anti-Jo-1 antibodies was performed using confocal microscopy. Anti-histidyl-tRNA-synthetase-positive sera showed distinct nuclear and cytoplasmic granular staining in HEp-2 cells. Affinity purified anti-Jo-1 produced an identical pattern to the whole serum, whereas the serum fraction that did not bind to the affinity column was negative by immunofluorescence on HEp-2 cells. Two commercial human anti-Jo-1-positive control sera and seven anti-Jo-1-positive sera from patients with myositis reproduced the nuclear and cytoplasmic granular pattern. We conclude that Jo-1 is present in cytoplasm and in intact nuclei from HEp-2 cells. The presence of tRNA synthetases in intact nuclei suggests that they have an unsuspected function in the nucleus.

Racial aspects of comorbidity in systemic lupus erythematosus.

OBJECTIVE: To investigate racial differences in the expression of systemic lupus erythematosus (SLE) by comparing comorbidity at death among individuals with SLE. METHODS: Proportional mortality rates were estimated for common contributing causes of death among white and black females in the United States, 1989-1991, whose death certificates listed SLE as an underlying or contributing cause. Logistic regression analysis was used to assess the effects of SLE and race on variation in proportional mortality using rates from non-SLE deaths as a comparison baseline. RESULTS: Common contributing causes of death listed with SLE included conditions that are known sequelae of the disease. Proportional mortality rates for these conditions varied with race and age. However, among black deaths that listed SLE, the rates of renal disease surpassed those of all other conditions regardless of age. When rates of renal disease among black SLE deaths or among white SLE deaths in any age group were compared to those among white non-SLE deaths, proportional mortality ratios were significantly greater than 1. This also held when rates of renal disease among black non-SLE deaths were compared to rates among white non-SLE deaths. However, across all ages, the proportional mortality ratios for renal disease in black SLE deaths significantly exceeded corresponding ratios for white SLE deaths and for black non-SLE deaths. CONCLUSION: Black females who die with SLE appear to experience a combination of the excess renal disease reported for persons with SLE and for all blacks. This combination may be a source of the elevated SLE mortality rates observed among US blacks.

Antimalarial drugs in pregnancy--the North American experience.

The use of the 4-aminoquinoline antimalarials in pregnancy is controversial. The current practice of discontinuing these medications because of pregnancy makes little sense as the half-life of these medications is so long. Patients with SLE have increased fetal wastage and one of the factors known to contribute to this fetal wastage is disease activity. It is also known that discontinuing the 4-aminoquinoline antimalarial drugs can precipitate flares of disease in lupus patients. Mothers and their potential offspring are therefore at risk for flares of disease and pregnancy failure if these medications are discontinued because of pregnancy. This review addresses the North American experience of the use of antimalarial drugs in pregnant lupus patients. Unlike most centers in North America, we continue our patients on these medications throughout pregnancy and to date have documented 16 lupus patients who have taken these drugs throughout pregnancy. Our most recent study documents nine pregnancies in eight women. All of these pregnancies resulted in live births (five pre-term deliveries and four full-term deliveries). There were no congenital abnormalities in these infants and follow-up to date has revealed no evidence of ocular or oral deficits in any of these children. One patient experienced a flare of disease when her antimalarial therapy was temporarily discontinued.

Sensitivity and specificity of anti-Jo-1 antibodies in autoimmune diseases with myositis.

OBJECTIVE: To determine the sensitivity and specificity of anti-Jo-1 in systemic sclerosis (SSc) patients with and without myositis. METHODS: Immunoblots on HeLa nuclei were used to screen sera from 554 consecutive connective tissue disease patients. Those who had 45-55-kd bands, all patients with polymyositis/dermatomyositis (PM/DM), and a random selection of SSc, Raynaud's disease, systemic lupus erythematosus, and rheumatoid arthritis patients were also studied by anti-Jo-1 enzyme-linked immunosorbent assay and by immunoblots on rabbit pooled aminoacyl-transfer RNA synthetase. RESULTS: Anti-Jo-1 was present only in 8 of the 40 PM/DM patients. CONCLUSION: Anti-Jo-1 is specific for PM/DM.