Antinuclear antibody-negative systemic sclerosis.

OBJECTIVE: To examine the demographic and clinical characteristics of systemic sclerosis (SSc) patients without antinuclear antibodies (ANA) compared to ANA-positive patients. METHODS: SSc patients enrolled in the Scleroderma Family Registry and DNA Repository were included. Relevant demographic and clinical data were entered by participating sites or obtained by chart review. ANA and SSc-related antibodies were determined in all investigated patients using commercially available kits at our laboratories. RESULTS: This study included 3249 patients, of whom 208 (6.4%) were ANA negative. The proportion of male patients was higher in the ANA-negative group (OR = 1.65; p = 0.008). ANA-negative patients experienced less vasculopathic manifestations of SSc. The percent predicted diffusing capacity of carbon monoxide (DLCO) was higher in ANA-negative patients (p = 0.03). Pulmonary arterial hypertension (PAH) per right heart catheterization was less common in the ANA-negative group (OR = 0.28; p = 0.03). Furthermore, patients with negative ANA had a lower prevalence of telangiectasias and digital ulcers/pits (OR = 0.59, p = 0.03 and OR = 0.38, p = 0.01, respectively). Although diffuse cutaneous involvement was more common, the modified Rodnan Skin Score (mRSS) was lower in the ANA-negative group (2.4 points lower, p = 0.05). Furthermore, they experienced more malabsorption (p = 0.05). There was no difference in the frequency of pulmonary fibrosis or scleroderma renal crisis. All-cause mortality was not different between the 2 groups (p = 0.28). CONCLUSIONS: In conclusion, the results of this study suggest that SSc patients who are ANA negative constitute a distinct subset of SSc with less vasculopathy (less PAH, digital ulcers, and fewer telangiectasias), a greater proportion of males, and possibly, more frequent lower gastrointestinal involvement.

Physical and occupational therapy referral and use among systemic sclerosis patients with impaired hand function: results from a Canadian national survey.

OBJECTIVES: Contractures and deformities of the hand are major factors in disability and reduced health-related quality of life in systemic sclerosis (SSc). Physical (PT) and occupational therapy (OT) have been emphasised to address impaired hand function, but little is known about the extent they are employed. The objective of this study was to determine the proportion of Canadian SSc patients with hand involvement who are referred to and use PT or OT services and factors associated with referral. METHODS: Participants were respondents to the Canadian Scleroderma Patient Survey of Health Concerns and Research Priorities who rated ≥1 of 5 hand problems (hand stiffness, difficulty making fist, difficulty holding objects, difficulty opening hand, difficulty with faucet) as occurring at least sometimes with moderate or higher impact. Patients indicated if their physicians recommended PT or OT and if they used these services. Multivariate logistic regression assessed independent predictors of PT or OT referral. RESULTS: Of 317 patients with hand involvement, 90 (28%) reported PT or OT referral, but only 39 (12%) reported using these services. PT or OT referral was associated with more hand problems (odds ratio [OR]=1.24, 95% confidence interval [CI] 1.02-1.51, p=0.031) younger age (OR=0.96, 95% CI 0.94-0.99, p=0.004) and not being employed (OR=0.50, 95% CI 0.26-0.97, p=.0041). CONCLUSIONS: Few SSc patients with hand involvement are referred to PT or OT, and even fewer use these services. High-quality randomised controlled trials of PT and OT interventions to improve hand function in SSc are needed.

Anti-centromere antibodies in a large cohort of systemic sclerosis patients: comparison between immunofluorescence, CENP-A and CENP-B ELISA.

INTRODUCTION: Anti-centromere antibodies (ACA) are useful biomarkers in the diagnosis of systemic sclerosis (SSc) where they are found in 20-40% of patients and, albeit with lower prevalence, in patients with other systemic autoimmune rheumatic diseases. Historically, ACA were detected by indirect immunofluorescence (IIF) on HEp-2 cells and confirmed by immunoassays using recombinant CENP-B. During the last few years, to accommodate high throughput diagnostics, a number of laboratories changed from IIF to ELISA assays. The objective of this study was to compare the detection of ACA by IIF to CENP-A and a CENP-B ELISA in a large cohort of SSc patients. METHODS: Sera collected from SSc patients (n=834) were tested for ACA by IIF on HEp-2 cells (ImmunoConcepts, Sacramento, CA) and CENP-A and CENP-B ELISA (both Dr. Fooke Laboratorien GmbH, Neuss, Germany). Furthermore, other autoantibodies were determined by QUANTA-Plex(TM) SLE 8 profile (INOVA, San Diego, CA), QUANTA Lite RNA Pol III (INOVA) and PM1-Alpha ELISA (Dr. Fooke). RESULTS: The prevalence of ACA was 35.0% by IIF, 41.6% by CENP-A and 57.8% by CENP-B ELISA. When the CENP-A and the CENP-B ELISA results were compared to the IIF, the area under the curve value derived from receiver operating characteristic analysis was 0.98 for both assays. ACA and anti-topoisomerase I antibodies co-occurred in 1.2% (ACA by IIF), in 3.5% (by CENP-A ELISA) and in 7.4% (by CENP-B ELISA). Anti-CENP-A antibodies were negatively associated with anti-Scl-70, anti-RNA Pol III, (both p<0.0001), anti-U1-RNP (p=0.008) and anti-PM1-Alpha antibodies (p=0.0337). The degree of association was dependent on the cut-off value used. CONCLUSION: Although we found good agreement between IIF and ELISA for the detection of ACA in SSc, a significant portion of CENP ELISA positive sera did not show the typical ACA staining pattern. Based on these findings, we conclude that an IIF ACA negative result might not rule out the presence of ACA. In addition, new CENP ELISA kits are reliable for the detection of anti-CENP in SSc sera.

Frequency and impact of symptoms experienced by patients with systemic sclerosis: results from a Canadian National Survey.

OBJECTIVE: Knowledge about the range of symptoms experienced by patients with SSc, and their impact on daily functioning is limited. The objective of the present study was to identify symptoms of SSc that patients rated as frequent and that highly impacted their ability to carry out daily activities. METHODS: A total of 464 persons with SSc responded to the Canadian Scleroderma Patient Survey of Health Concerns and Research Priorities, including questions regarding the frequency and impact of 69 SSc symptoms. Descriptive analyses were performed dichotomizing symptom frequencies as never or rarely vs sometimes, most of the time or always and symptom impact on daily activities as no or minimal impact vs moderate to severe impact. RESULTS: The five highest rated symptoms in terms of frequency and moderate to severe impact on daily activities, respectively, were: fatigue (89 and 72%), RP (86 and 67%), hand stiffness (81 and 59%), joint pain (81 and 64%) and difficulty sleeping (76 and 59%). In addition to these symptoms, items related to decreased hand function (difficulty making a fist and difficulty holding objects) and pain (muscle pain and joint tenderness) were frequently endorsed and commonly associated with moderate to severe impact on daily activities. CONCLUSION: This study confirmed the importance for quality of life of core symptoms of SSc, such as pain, fatigue and limitations in hand function. It also identified areas with very little research, such as sleep problems, that appear to play important roles in daily functioning, and that merit more focused study.

Sociodemographic, disease, and symptom correlates of fatigue in systemic sclerosis: evidence from a sample of 659 Canadian Scleroderma Research Group Registry patients.

OBJECTIVE: To assess fatigue levels and demographic, socioeconomic, disease, and psychosocial correlates of fatigue in patients with systemic sclerosis (SSc). METHODS: We conducted a cross-sectional, multicenter study of 659 patients with SSc from the Canadian Scleroderma Research Group Registry. Fatigue was assessed during annual Registry visits with the Short Form 36 (SF-36) health survey vitality subscale. Patients completed measures of depressive symptoms and pain and underwent clinical histories and medical examinations. Kendall's tau was used to assess bivariate association of sociodemographic, medical, and psychosocial variables with fatigue. Multivariable associations of demographic (step 1), socioeconomic (step 2), global disease (step 3), specific disease and lifestyle (step 4), and psychosocial (step 5) factors with fatigue were assessed using hierarchical multiple linear regression. RESULTS: The mean +/- SD score of the patients on the SF-36 vitality subscale was 45.6 +/- 10.8, substantially lower (indicating more fatigue) than the mean +/- SD score for the Canadian general population (65.8 +/- 18.0). In multivariate analysis, higher fatigue was significantly associated with the number of medical comorbidities (standardized beta = -0.11, P = 0.004), breathing problems (standardized beta = -0.23, P < 0.001), the number of gastrointestinal (GI) symptoms (standardized beta = -0.27, P < 0.001), and current smoking (standardized beta = -0.08, P = 0.018). As a group, specific symptom and lifestyle variables predicted the most incremental variance in fatigue (R(2) = 21.6%, P < 0.001), despite being added to the model after demographic, socioeconomic, and global disease duration/severity indicators. Symptoms of depression (beta = -0.42) and pain (beta = -0.21) were also independently associated with fatigue (P < 0.001). CONCLUSION: High levels of fatigue are common in patients with SSc and are independently associated with clinical variables, including number of comorbidities, breathing problems, GI symptoms, and smoking.

Prevalence and clinical correlates of symptoms of depression in patients with systemic sclerosis.

OBJECTIVE: To assess the prevalence and predictors of symptoms of depression in a large sample of patients with systemic sclerosis (SSc). METHODS: We conducted a cross-sectional, multicenter study of 376 patients with SSc from the Canadian Scleroderma Research Group Registry. Patients were assessed with the Center for Epidemiologic Studies Depression Scale (CES-D) and through extensive clinical histories and medical examinations. Hierarchical multiple linear regression was used to assess the relationship of sociodemographic and clinical variables with symptoms of depression. RESULTS: The percentages of patients who scored > or =16 and > or =23 on the CES-D were 35.1% and 18.1%, respectively. Patients with less education; patients who were not married; patients with higher physician-rated overall disease severity; and patients with more tender joints, more gastrointestinal symptoms, and more difficulty breathing had significantly higher total CES-D scores. As a group, specific symptom indicators (tender joints, gastrointestinal symptoms, breathing) predicted the most incremental variance in depressive symptoms (DeltaR(2) = 14.2%, P < 0.001) despite being added to the model after demographic, socioeconomic, and global disease duration/severity indicators. CONCLUSION: High levels of depressive symptoms are common in patients with SSc and are related to overall SSc disease severity, as well as specific medical symptoms. Screening for depression among patients with SSc is recommended, although more research is needed to determine the best method for doing this. Successfully treating dyspnea, gastrointestinal symptoms, and joint pain may improve mood, although this has not yet been demonstrated.

Reliability and validity of the center for epidemiologic studies depression scale in patients with systemic sclerosis.

OBJECTIVE: Reported rates of depressive symptoms in patients with systemic sclerosis (SSc) are high. No depression assessment tools, however, have been validated for patients with SSc. Our objective was to assess the internal consistency reliability, convergent validity, and structural/construct validity of the Center for Epidemiologic Studies Depression Scale (CES-D) in patients with SSc. METHODS: We conducted a cross-sectional, multicenter study of 470 SSc patients. Internal consistency reliability was assessed with Cronbach's alpha and structural/construct validity with confirmatory factor analysis. RESULTS: Internal consistency reliability was good for the overall CES-D scale (alpha = 0.88) and for its 4 factors (alpha = 0.67-0.88). Correlations of the CES-D total score were -0.73 with mental health, -0.36 with physical health, 0.41 with disability, and 0.44 with pain. The 4-factor model originally found in the general population and validated for patients with rheumatoid arthritis (depressed affect, somatic/vegetative, [lack of] positive affect, and interpersonal factors) fit the data well, as did a second-order version of the same model with an overarching depression factor that loaded onto each of the 4 first-order factors. The 4-factor model fit the SSc data better than alternative models. CONCLUSION: Internal consistency reliability and convergent validity were good, the 4-factor structure reported in the general population was replicated, and a second-order model with an overarching depression factor fit well. These findings indicate that the CES-D is a valid and reliable measure of depressive symptoms for patients with SSc.

High rates of depressive symptoms among patients with systemic sclerosis are not explained by differential reporting of somatic symptoms.

OBJECTIVE: Between 36% and 65% of patients with systemic sclerosis (SSc) report symptoms of depression above cutoff thresholds on self-report questionnaires. The objective of this study was to assess whether these high rates result from differential reporting of somatic symptoms related to the high physical burden of SSc. METHODS: Symptom profiles reported on the Center for Epidemiologic Studies Depression Scale (CES-D) were compared between a multicenter sample of 403 patients with SSc and a sample of respondents to an Internet depression survey, matched on total CES-D score, age, race/ethnicity, and sex. An exact nonparametric generalized Mantel-Haenszel procedure was used to identify differential item functioning between groups. RESULTS: Patients with SSc reported significantly higher frequencies (moderate to large effect size; P < 0.01) on 4 CES-D somatic symptom items: bothered, appetite, effort, and sleep. Internet respondents had higher item scores on 2 items that assessed interpersonal difficulties (unfriendly, large effect size; P < 0.01; disliked, large effect size; P < 0.01) and on 2 items that assessed lack of positive effect (happy, moderate effect size; P = 0.01; enjoy, large effect size; P < 0.01). Adjustment of standard CES-D cutoff criteria for potential bias due to somatic symptom reporting resulted in a reduction of only 3.6% in the number of SSc patients with significant symptoms of depression. CONCLUSION: High rates of depressive symptoms in SSc are not due to bias related to the report of somatic symptoms. The pattern of differential item functioning between the SSc and Internet groups, however, suggests some qualitative differences in depressive symptom presentation.

Depression in patients with systemic sclerosis: a systematic review of the evidence.

OBJECTIVE: To assess the prevalence, course, and predictors of depression in patients with systemic sclerosis (SSc). METHODS: We conducted a comprehensive search in November 2006 of MEDLINE, PsycINFO, and CINAHL databases to identify original research studies published in any language that used a structured interview or validated questionnaire to assess major depressive disorder or clinically significant symptoms of depression in patients with SSc. The search was augmented by hand searching 26 selected journals through December 2006 and references from identified articles and reviews. Studies were excluded if only an abstract was provided or if depression was not measured by a validated method. RESULTS: No studies used a structured clinical interview to assess the prevalence of major depressive disorder. The prevalence of clinically significant depressive symptoms was 51-65% based on 2 studies that used a Beck Depression Inventory (BDI) score >or=10 and 46-56% based on 2 studies that used a BDI score >or=11. These rates and those reported in 4 other studies that used different assessment tools (36-43%) were consistently high compared with other medical patient groups assessed with the same instruments and cutoffs. Methodologic issues limited the ability to draw strong conclusions from studies of predictors. CONCLUSION: Symptoms of depression are common among patients with SSc. The high rates reported across studies suggest that routine screening is recommended. There is a need for studies that examine depression at different time points from the diagnosis of SSc and that systematically investigate factors associated with high levels of depressive symptoms.

Correlates of illness worry in chronic fatigue syndrome.

BACKGROUND: Anxiety about illness leading to restriction of activity and physical deconditioning has been hypothesized to contribute to the chronicity of fatigue. Pathological symptom attributions, personality traits, and depression have all been hypothesized to contribute to illness worry. METHODS: We compared 45 chronic fatigue syndrome (CFS) and 40 multiple sclerosis (MS) outpatients using a battery of psychometric instruments comprising the 12-item Illness Worry scale, the Symptom Interpretation Questionnaire (SIQ), the NEO Five-Factor Inventory (NEO-FFI), and a modified version of the SCL-90R Depression scale. RESULTS: There was no difference between the two diagnostic groups on neuroticism, depressive symptoms, as well as the three scales of the SIQ. On the illness worry index, the CFS group had significantly higher scores than the MS group. This difference was due to items tapping vulnerability to illness and the perception that others are not taking their illness seriously. Somatic attributional style, neuroticism, depressive symptoms, and age were all significant predictors of illness worry in both CFS and MS patients. CONCLUSIONS: Somatic attributions, neuroticism, and depression all contribute to illness worry in chronic illness. However, these factors do not account for the higher levels of illness worry in CFS as opposed to MS, which may be due to other specific cognitive and social interactional processes.

Predictors of somatic symptoms in depressive disorder.

We explored the relative contribution of potential psychological predictors of somatic symptoms in outpatients with major depressive disorder, including; 1) severity of depression; 2) general anxiety; 3) hypochondriacal worry; 4) somatosensory amplification; and, 5) alexithymia by sampling 100 consecutive outpatients with DSM-IV diagnoses of major depressive disorder attending the psychiatry clinics of general hospitals in Turkey. The subjects were rated by clinicians on depressive symptomatology (Hamilton Depression Rating Scale), and anxiety (Hamilton Anxiety Scale), and completed self-report measures of Hypochondriacal worry (7-item version of the Whiteley Index), the Somatosensory Amplification Scale, and the Toronto Alexithymia Scale. Multivariate models tested the independent contribution of each of the scales to the level of somatic symptoms as measured by a modified version of the SCL-90 somatization scale. At the bivariate level, somatic symptoms were associated with female gender and lower educational level, as well as the Hamilton Depression and Anxiety scales, the Whitely Index, and the Somatosensory Amplification and Alexithymia scales. In multiple regression models incorporating all variables, female gender and higher scores on the anxiety, somatosensory amplification and alexithymia scales all made independent contributions to the level of somatic symptoms and accounted for 54% of the variance. Therefore, somatic symptoms in depression are related to concomitant anxiety, tendency to amplify somatic distress, and difficulty identifying and communicating emotional distress. However, these factors do not account for the tendency for women to report more somatic symptoms.

Psychological correlates of functional status in chronic fatigue syndrome.

BACKGROUND: The present study was designed to test a cognitive model of impairment in chronic fatigue syndrome (CFS) in which disability is a function of severity of fatigue and depressive symptoms, generalized somatic symptom attributions and generalized illness worry. METHODS: We compared 45 CFS and 40 multiple sclerosis (MS) outpatients on measures of functional ability, fatigue severity, depressive symptoms, somatic symptom attribution and illness worry. RESULTS: The results confirmed previous findings of lower levels of functional status and greater fatigue among CFS patients compared to a group of patients with MS. Fatigue severity was found to be a significant predictor of physical functioning but not of psychosocial functioning in both groups. In CFS, when level of fatigue was controlled, making more somatic attributions was associated with worse physical functioning, and both illness worry and depressive symptoms were associated with worse psychosocial functioning. CONCLUSIONS: Our findings support the role of depression and illness cognitions in disability in CFS sufferers. Different cognitive factors account for physical and psychosocial disability in CFS and MS. The SF-36 may be sensitive to symptom attributions, suggesting caution in its interpretation when used with patients with ill-defined medical conditions.