Understanding the Employment Landscape in People With Systemic Sclerosis.

OBJECTIVE: Systemic sclerosis (SSc) can restrict employment participation. Our objectives were to comparatively evaluate health factors, work factors, and workplace accommodations between those who are employed and those who recently gave up employment. METHODS: A cross-sectional study was conducted of employed and recently working, but now unemployed, individuals with SSc. Demographics, employment sectors, health factors, flare frequency, work context, and information about the need, availability, and use of workplace supports were collected. RESULTS: Participants were 140 individuals (108 [77.1%] women, 32 [22.9%] men), of whom 110 (78.6%) were employed and 30 (21.4%) were unemployed. Participants worked in education/health/sciences/arts (n = 51, 36.4%), sales/retail (n = 23, 16.5%), banking/insurance/business/technology (n = 22, 15.7%), government (n = 15, 10.7%), construction/utilities (n = 10, 7.1%), and manufacturing/agriculture/mining/logging (n = 10, 7.1%). Employed participants had a lower mean age (48.4 vs 54.3 yrs), and higher level of education (77.3% with postsecondary education vs 22.7% without). Those who had no flares were more frequently employed (41.7%), compared to those who had 1 to 2 flares (35.2%) and ≥ 3 flares (23.1%). The availability of workplace accommodations differed significantly between the employed and unemployed: flexible hours (74.5% vs 40%, P = 0.0005), more rest periods (73.6% vs 46.7%, P = 0.0001), special equipment (82.7% vs 46.7%, P < 0.0001), and work schedule flexibility (66.4% vs 33.3%, P = 0.003). CONCLUSION: Health factors alone do not differentiate those who are employed and those who gave up employment. This study lays the groundwork for where SSc-specific efforts in workplace policies and practices should be directed, especially workplace support.

Advanced Autoantibody Testing in Systemic Sclerosis.

Systemic sclerosis is a systemic autoimmune rheumatic disease characterized by immune abnormalities, leading to vasculopathy and fibrosis. Autoantibody testing has become an increasingly important part of diagnosis and prognostication. Clinicians have been limited to antinuclear antibody (ANA), antitopoisomerase I (also known as anti-Scl-70) antibody, and anticentromere antibody testing. Many clinicians now have improved access to an expanded profile of autoantibody testing. In this narrative review article, we review the epidemiology, clinical associations, and prognostic value of advanced autoantibody testing in people with systemic sclerosis.

Quality Measures in Systemic Sclerosis.

Quality improvement is an emerging field, that applies principles of improvement science and utilizes measurement methods with the aim of improving patient care. Systemic sclerosis (SSc) is a systemic autoimmune rheumatic disease associated with increased healthcare burden, cost, morbidity, and mortality. Gaps in delivering care to patients with SSc have been consistently observed. In this article, we introduce the discipline of quality improvement and its use of quality measures. We summarize and comparatively evaluate three sets of quality measures that have been proposed to evaluate the quality of care of patients with SSc. Finally, we highlight the areas of unmet needs and indicate future directions for quality improvement and quality measures in SSc.

Epidemiology and Survival of Systemic Sclerosis-Sarcoidosis Overlap Syndrome.

OBJECTIVE: We evaluated the epidemiology, manifestations, serology, comorbidities, and survival among patients with systemic sclerosis (SSc) with and without sarcoidosis. METHODS: We conducted a retrospective cohort study comparing patients with SSc with and without sarcoidosis. All patients fulfilled the American College of Rheumatology/European Alliance of Associations for Rheumatology classification criteria for SSc. Sarcoidosis was based on physician diagnosis and/or confirmatory biopsy. The primary outcome was time from diagnosis to all-cause mortality. Survival was evaluated using Kaplan-Meier curves. RESULTS: We included 1977 patients (1971 with SSc, 6 with SSc-sarcoidosis) with a SSc-sarcoidosis prevalence of 0.30%. Sarcoidosis frequently preceded SSc (66.66%). The most frequent sarcoidosis manifestations were pulmonary (66.66%), lymphadenopathy (66.66%), arthritis (50%), cutaneous (33.33%), and hepatic (16.66%). Patients with SSc and SSc-sarcoidosis had female to male sex ratios of 4.5:1 vs 5:1 and median ages of SSc onset of 48.3 vs 43.8 years, respectively. Interstitial lung disease (35% vs 66.66%) and pulmonary hypertension (24.91% vs 50%) tended to occur more frequently whereas abnormal nailfold capillaries (34.7% vs 16.66%) and digital ulcers (33.33% vs 16.66%) tended to occur less frequently among patients with SSc-sarcoidosis, but the differences were not significant. There was an increased frequency of stroke among the patients with SSc-sarcoidosis (relative risk 8.59, 95% CI 1.02-72.00). The median survival times were 23.4 years for SSc-sarcoidosis and 18.6 years for SSc, with no differences in survival curves (log-rank test, P = 0.55). CONCLUSION: Sarcoidosis in SSc is rare but appears to occur more frequently than in the general population. It is associated with pulmonary, lymph node, cutaneous, joint, and hepatic involvement. Stroke occurs more frequently in patients with SSc-sarcoidosis but with no differences in survival.

Interferon and interferon-induced cytokines as markers of impending clinical progression in ANA+ individuals without a systemic autoimmune rheumatic disease diagnosis.

BACKGROUND: Elevated levels of interferons (IFNs) are a characteristic feature of systemic autoimmune rheumatic diseases (SARDs) and may be useful in predicting impending symptomatic progression in anti-nuclear antibody-positive (ANA+) individuals lacking a SARD diagnosis. Typically, these are measured by their effect on gene expression in the blood, which has limited their utility in clinical settings. Here, we assessed whether the measurement of serum IFN-α or selected IFN-induced cytokines accurately mirrors IFN-induced gene expression in ANA+ individuals and investigated their utility as biomarkers of clinical progression. METHODS: A total of 280 subjects were studied, including 50 ANA- healthy controls, 160 ANA+ individuals without a SARD diagnosis (96 asymptomatic, 64 with undifferentiated connective tissue disease), and 70 SARD patients. IFN-induced gene expression was measured by nanoString and cytokine levels by ELISA or Simoa. ANA+ individuals lacking a SARD diagnosis who had the new onset of SARD criteria over the subsequent 2 years were defined as progressors. RESULTS: Measurement of IFN-α levels by high-sensitivity ELISA or Simoa correlated much better with IFN-induced gene expression than measurement of CXCL-10 or Galectin-9 levels. Despite this, high CXCL-10 and Galectin-9 levels were better predictors of subsequent progression in ANA+ individuals than measures of IFN-α or IFN-induced gene expression with the optimal combination of predictive cytokines (CXCL-10 and IFN-α as measured by ELISA), resulting in a specificity and positive predictive value of 100%. CONCLUSION: Easily performed ELISA assays for CXCL-10 and IFN-α can be used to predict ANA+ individuals at high risk of imminent symptomatic progression.

Environmental Risks for Systemic Sclerosis.

There is an increasing body of literature suggesting a relationship between environmental factors and the development of systemic sclerosis (SSc). These include occupational exposures, chemical materials, medications, alterations in the microbiome, and dysbiosis. Environmental exposures may impact epigenetic regulation thereby triggering an aberrant immune response resulting in the clinical and serologic phenotype that we diagnose as SSc. Screening and studying putative triggers will not only improve our understanding of the pathogenesis of SSc but also inform the institution for protective measures.

Altered Balance of Pro-Inflammatory Immune Cells to T Regulatory Cells Differentiates Symptomatic From Asymptomatic Individuals With Anti-Nuclear Antibodies.

Systemic Autoimmune Rheumatic Diseases (SARDs) are characterized by the production of anti-nuclear antibodies (ANAs). ANAs are also seen in healthy individuals and can be detected years before disease onset in SARD. Both the immunological changes that promote development of clinical symptoms in SARD and those that prevent autoimmunity in asymptomatic ANA+ individuals (ANA+ NS) remain largely unexplored. To address this question, we used flow cytometry to examine peripheral blood immune populations in ANA+ individuals, with and without SARD, including 20 individuals who subsequently demonstrated symptom progression. Several immune populations were expanded in ANA+ individuals with and without SARD, as compared with ANA- healthy controls, particularly follicular and peripheral T helper, and antibody-producing B cell subsets. In ANA+ NS individuals, there were significant increases in T regulatory subsets and TGF-ß1 that normalized in SARD patients, whereas in SARD patients there were increases in Th2 and Th17 helper cell levels as compared with ANA+ NS individuals, resulting in a shift in the balance between inflammatory and regulatory T cell subsets. Patients with SARD also had increases in the proportion of pro-inflammatory innate immune cell populations, such as CD14+ myeloid dendritic cells, and intermediate and non-classical monocytes, as compared to ANA+ NS individuals. When comparing ANA+ individuals without SARD who progressed clinically over the subsequent 2 years with those who did not, we found that progressors had significantly increased T and B cell activation, as well as increased levels of LAG3+ T regulatory cells and TGF-ß1. Collectively, our findings suggest that active immunoregulation prevents clinical autoimmunity in ANA+ NS and that this becomes impaired in patients who progress to SARD, resulting in an imbalance favoring inflammation.

Serological abnormalities that predict progression to systemic autoimmune rheumatic diseases in antinuclear antibody-positive individuals.

OBJECTIVE: We investigated the autoantibody (autoAb) profiles in ANA+ individuals lacking systemic autoimmune rheumatic disease (SARD) and early SARD patients to determine the key differences between these groups and identify factors that are associated with an increased risk of symptomatic progression within the next 2 years in ANA+ individuals. METHODS: Using custom antigen (Ag) microarrays, 144 IgM and IgG autoAbs were surveyed in 84 asymptomatic and 123 symptomatic (48 UCTD and 75 SARD patients) ANA+ individuals. AutoAbs were compared in ANA+ individuals lacking a SARD diagnosis with ≥2 years follow-up (n = 52), including all those who demonstrated progression (n = 14) during this period, with changes over time assessed in a representative subset. RESULTS: We show that ANA+ individuals have autoAb to many self-Ags that are not being captured by current screening techniques and very high levels of these autoAbs are predominantly restricted to early SARD patients, with SLE patients displaying reactivity to many more autoAgs than the other groups. In general, the symptoms that developed in progressors mirrored those seen in SARD patients with similar patterns of autoAbs. Only anti-Ro52 Abs were found to predict progression (positive predictive value 46%, negative predictive value 89%). Surprisingly, over 2 years of follow-up the levels of autoAbs remained remarkably stable regardless of whether individuals progressed or not. CONCLUSION: Our findings strongly argue that development of assays with an expanded set of auto-Ags and enhanced dynamic range would improve the diagnostic and prognostic ability of autoAb testing.

Botulinum toxin in the management of primary and secondary Raynaud's phenomenon.

Raynaud's phenomenon (RP) is common in rheumatic diseases. In the setting of systemic sclerosis (SSc), it can be complicated by digital ischemia that includes ulceration and gangrene. Systemic adverse effects may preclude the use of oral or topical vasodilators for the treatment of RP and its complications. In this article, we review effectiveness/efficacy of botulinum toxin injection in primary and secondary RP. We discuss botulinum toxin formulations, dosage, sites of administration, and adverse effects. The evidence for botulinum toxin in the treatment of primary and SSc-associated RP is promising. Consistency across patient populations, treatment options (botulinum serotype, dose, and injection site), and outcome measures will be essential for further research.

Ethnic Variations in Systemic Sclerosis Disease Manifestations, Internal Organ Involvement, and Mortality.

OBJECTIVE: A multiethnic systemic sclerosis (SSc) cohort study to evaluate ethnic variations in disease manifestations, internal organ involvement, and survival. METHODS: Adults who fulfilled the American College of Rheumatology/European League Against Rheumatism classification criteria for SSc between 1970 and 2017 were included. Self-reported ethnicity was categorized as European-descent white, Afro-Caribbean, Hispanic, Arab, East Asian, South Asian, First Nations, or Persian. The primary outcome was the time from diagnosis to death from all causes. Survival probabilities and median survival times were determined using Kaplan-Meier survival curves. RESULTS: There were 1005 subjects evaluated, the majority of whom were European-descent white (n = 745, 74%), Afro-Caribbean (n = 58, 6%), South Asian (n = 70, 7%), and East Asian (n = 80, 8%). Compared to European-descent white subjects, East Asians less frequently had calcinosis (29% vs 9%, p = 0.002) and esophageal dysmotility (88% vs 69%, p = 0.002); Afro-Caribbeans more frequently had interstitial lung disease (31% vs 53%, p = 0.007); and First Nations subjects more frequently had diffuse cutaneous disease (35% vs 56%, p = 0.02) and diabetes (5% vs 33%, p = 0.03). We found no difference in the short-term survival across ethnicities. Hispanic subjects have better longterm survival (81.3%, 95% CI 63-100) compared to European-descent white subjects (55%, 95% CI 51-60). East Asians appear to have the longest median survival time (43.3 yrs) and Arabs the shortest median survival time (15 yrs). There was no significant difference in median survival times between Afro-Caribbean and European-descent white subjects (22.2 vs 22.6 yrs). CONCLUSION: Ethnic variations in some SSc disease manifestations are observed. However, this does not result in significant differences in short-term survival but may affect longterm survival.

Epidemiology and Survival of Systemic Sclerosis-Systemic Lupus Erythematosus Overlap Syndrome.

OBJECTIVE: Systemic sclerosis (SSc) may overlap with systemic lupus erythematous (SLE). Little is known about the epidemiology, clinical characteristics, and survival of SSc-SLE overlap. We evaluated the prevalence of SSc-SLE overlap and differences in SSc characteristics, and compared survival with SSc without SLE. METHODS: A cohort study was conducted including subjects who fulfilled the American College of Rheumatology (ACR)/European League Against Rheumatism classification criteria for SSc and/or the ACR criteria for SLE. The primary outcome was time from diagnosis to all-cause mortality. Survival was evaluated using Kaplan-Meier and Cox proportional hazard models. RESULTS: We identified 1252 subjects (SSc: n = 1166, SSc-SLE: n = 86) with an SSc-SLE prevalence of 6.8%. Those with SSc-SLE were younger at diagnosis (37.9 yrs vs 47.9 yrs, p < 0.001), more frequently East Asian (5.5% vs 20%) or South Asian (5.1% vs 12%), had lupus anticoagulant (6% vs 0.3%, p < 0.001), anticardiolipin antibody (6% vs 0.9%, p < 0.001), and pulmonary arterial hypertension (PAH; 52% vs 31%, p < 0.001). Those with SSc-SLE less frequently had calcinosis (13% vs 27%, p = 0.007), telangiectasia (49% vs 75%, p < 0.001), and diffuse subtype (12% vs 35%, p < 0.001). There were no significant differences in the occurrence of renal crisis (7% vs 7%), interstitial lung disease (ILD; 41% vs 34%), and digital ulcers (38% vs 32%). Those with SSc-SLE had better median survival time (26.1 vs 22.4 yrs), but this was not statistically significant (log-rank p = 0.06). Female sex and diffuse subtype attenuated survival differences between groups (HR 1.07, 95% CI 0.67-1.67). CONCLUSION: Patients with SSc-SLE are younger at diagnosis, more frequently have PAH, and less frequently have cutaneous manifestations of SSc. They should be monitored for ILD, renal crisis, and digital ulcers.

Venous Thromboembolism in Systemic Sclerosis: Prevalence, Risk Factors, and Effect on Survival.

OBJECTIVE: Whether systemic sclerosis (SSc) confers increased risk of venous thromboembolism (VTE) is uncertain. We evaluated the prevalence, risk factors, and effect of VTE on SSc survival. METHODS: A cohort study was conducted of subjects with SSc who fulfilled the American College of Rheumatology/European League Against Rheumatism classification criteria between 1970 and 2017. Deep vein thrombosis was defined as thrombus on extremity ultrasound. Pulmonary embolism was defined as thrombus on thorax computed tomography angiogram. Risk factors for VTE and time to all-cause mortality were evaluated. RESULTS: Of the 1181 subjects, 40 (3.4%) experienced VTE events. The cumulative incidence of VTE was 2.7 (95% CI 1.9-3.7) per 1000 patient-years. Pulmonary arterial hypertension (PAH; OR 3.77, 95% CI 1.83-8.17), peripheral arterial disease (OR 5.31, 95% CI 1.99-12.92), Scl-70 (OR 2.45, 95% CI 1.07-5.30), and anticardiolipin antibodies (OR 5.70, 95% CI 1.16-21.17) were predictors of VTE. There were 440 deaths. There was no difference in survival between those with and without VTE (HR 1.16, 95% CI 0.70-1.91). Interstitial lung disease (HR 1.54, 95% CI 1.27-1.88) and PAH (HR 1.35, 95% CI 1.10-1.65) were predictors of mortality. CONCLUSION: The risk of VTE in SSc is comparable to the general population. The presence of PAH, peripheral arterial disease, Scl-70, and anticardiolipin antibodies are risk factors for VTE. VTE does not independently predict SSc survival.

ANCA-associated vasculitis in systemic sclerosis report of 3 cases.

The aim of the study was to describe the occurrence of anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) in systemic sclerosis (SSc) patients. SSc patients who developed biopsy-proven AAV were identified. Their clinical manifestations, autoantibodies, presentation with vasculitis, treatment and outcome were described and compared with previously reported patients with these two conditions. Of 985 patients, 3 were identified. All patients had interstitial lung disease, and all presented with acute renal failure, proteinuria and hematuria, and were P-ANCA- and anti-Scl-70-positive. One required hemodialysis. Two were hypertensive; additionally, one patient had sinusitis, and another had monoarthritis and a macular rash. All were treated with high-dose corticosteroids and responded to therapy and attained remission at 6 months. At 1 year, one patient died of pneumonia. ANCA-associated vasculitis is a rare but serious finding in SSc patients. Positive anti-Scl-70 antibody is found commonly in these patients. Different treatment modalities are effective. Serious infections can complicate therapy and lead to death.

Reaching those most in need: a scoping review of interventions to improve health care quality for disadvantaged populations with osteoarthritis.

OBJECTIVE: To conduct a systematic review to identify and describe the scope and nature of the research evidence on the effectiveness of interventions to improve health care quality or reduce disparities in the care of disadvantaged populations with osteoarthritis (OA) as an example of a common chronic disease. METHODS: We searched electronic databases from 1950 through February 2010 and grey literature for relevant articles using any study design. Studies with interventions designed explicitly to improve health care quality or reduce disparities in the care of disadvantaged adult populations with OA and including an evaluation were eligible. We used the PROGRESS-Plus framework to identify disadvantaged population subgroups. RESULTS: Of 4,701 citations identified, 10 met the inclusion criteria. Eight were community based and 6 targeted race/ethnicity/culture. All 10 studies evaluated interventions aimed at people with OA; 2 studies also targeted the health care system. No studies targeted health care providers. Nine of 10 studies evaluated arthritis self-management interventions; all showed some benefit. Only 1 study compared the difference in effect between the PROGRESS-Plus disadvantaged population and the relevant comparator group. CONCLUSION: There are few studies evaluating the effectiveness of interventions to improve health care quality in disadvantaged populations with OA. Further research is needed to evaluate interventions aimed at health care providers and the health care system, as well as other patient-level interventions. Gap intervention research is also needed to evaluate whether interventions are effective in reducing documented health care inequities.