Heather Gladue

Recommendations for Screening and Detection of Connective-Tissue Disease Associated Pulmonary Arterial Hypertension

OBJECTIVE Pulmonary arterial hypertension (PAH) affects up to 15% of patients with connective tissue diseases (CTDs). Previous recommendations developed as part of larger efforts in PAH did not include detailed recommendations for patients with CTD-associated PAH. Therefore, we sought to develop recommendations for screening and early detection of CTD-associated PAH. METHODS We performed a systematic review of the literature on the screening and diagnosis of PAH in CTD. Using the RAND/University of California, Los Angeles consensus methodology, we developed case scenarios followed by 2 stages of voting. First, international experts from a variety of specialties voted anonymously on the appropriateness of each case scenario. The experts then met face-to-face to discuss and resolve discrepant votes to arrive at consensus recommendations. RESULTS The key recommendation stated that all patients with systemic sclerosis (SSc) should be screened for PAH. In addition, patients with mixed connective tissue disease or other CTDs with scleroderma features (scleroderma spectrum disorders) should be screened for PAH. It was recommended that screening pulmonary function tests (PFTs) with single-breath diffusing capacity for carbon monoxide, transthoracic echocardiogram, and measurement of N-terminal pro-brain natriuretic peptide (NT-proBNP) be performed in all patients with SSc and scleroderma spectrum disorders. In patients with SSc and scleroderma spectrum disorders, transthoracic echocardiogram and PFTs should be performed annually. The full screening panel (transthoracic echocardiogram, PFTs, and measurement of NT-proBNP) should be performed as soon as any new signs or symptoms are present. CONCLUSION We provide consensus-based, evidence-driven recommendations for screening and early detection of CTD-associated PAH. It is our hope that these recommendations will lead to earlier detection of CTD-associated PAH and ultimately improve patient outcomes.

Prevalence, correlates and outcomes of gastric antral vascular ectasia in systemic sclerosis: A eustar case-control study

Objective. To estimate the prevalence, determine the subgroups at risk, and the outcomes of patients with systemic sclerosis (SSc) and gastric antral vascular ectasia (GAVE). Methods. We queried the European League Against Rheumatism Scleroderma Trials and Research (EUSTAR) network for the recruitment of patients with SSc-GAVE. Each case was matched for cutaneous subset and disease duration with 2 controls with SSc recruited from the same center, evaluated at the time the index case made the diagnosis of GAVE. SSc characteristics were recorded at the time GAVE occurred and the last observation was collected to define the outcomes. Results. Forty-nine patients with SSc and GAVE were included (24 with diffuse cutaneous SSc) and compared to 93 controls with SSc. The prevalence of GAVE was estimated at about 1% of patients with SSc. By multivariate analysis, patients with SSc-GAVE more frequently exhibited a diminished (< 75%) DLCO value (OR 12.8; 95% CI 1.9–82.8) despite less frequent pulmonary fibrosis (OR 0.2; 95% CI 0.1–0.6). GAVE was also associated with the presence of anti-RNA-polymerase III antibodies (OR 4.6; 95% CI 1.2–21.1). SSc-GAVE was associated with anemia (82%) requiring blood transfusion (45%). Therapeutic endoscopic procedures were performed in 45% of patients with GAVE. After a median followup of 30 months (range 1–113 months), survival was similar in patients with SSc-GAVE compared to controls, but a higher number of scleroderma renal crisis cases occurred (12% vs 2%; p = 0.01). Conclusion. GAVE is rare and associated with a vascular phenotype, including anti-RNA-polymerase III antibodies, and a high risk of renal crisis. Anemia, usually requiring blood transfusions, is a common complication.

Measuring response in the gastrointestinal tract in systemic sclerosis.

Purpose of reviewGastrointestinal tract (GIT) involvement in systemic sclerosis (scleroderma, SSc) is the most common internal complication. This review discusses the outcome measures to capture GIT involvement in clinical care and trials. Recent findingsPatient-reported outcome measures have been validated (UCLA Scleroderma Clinical Trial Consortium GIT 2.0 and NIH PROMIS scales) in SSc-GIT. Multiple objective measures are available to assess mucosal involvement and motility in GIT. However, these need to be validated in SSc for trials. SummaryGIT is a common cause of morbidity and has negative impact on quality of life in SSc. Recommendations are given for trial design and evaluation of GIT involvement in SSc.

Evaluation of Test Characteristics for Outcome Measures Used in Raynaud's Phenomenon Clinical Trials

Randomized controlled trials (RCTs) in Raynauds phenomenon (RP) have shown conflicting efficacy data. Also, there is no consensus on the outcome measures that should be used. Our objectives were to assess the reliability of individual core set measures used in 3 RCTs, evaluate the placebo response for individual core set measures, and determine if a composite of individual core set measures will decrease the placebo response, which may improve our ability to see treatment effects in future trials.

Combination of echocardiographic and pulmonary function test measures improves sensitivity for diagnosis of systemic sclerosis-associated pulmonary arterial hypertension: analysis of 2 cohorts.

Objective. To evaluate routinely collected non-invasive tests from 2 systemic sclerosis (SSc) cohorts to determine their predictive value alone and in combination versus right heart catheterization (RHC)-confirmed pulmonary arterial hypertension (PAH). Methods. We evaluated 2 cohorts of patients who were at risk or with incident PAH: (1) The Pulmonary Hypertension Assessment and Recognition Outcomes in Scleroderma (PHAROS) cohort and (2) an inception SSc cohort at Cochin Hospital, Paris, France. Estimated right ventricular systolic pressure (eRVSP) as determined by transthoracic echocardiogram (TTE) and pulmonary function test (PFT) measures was evaluated, and the predictive values determined. We then evaluated patients with PAH missed on TTE cutoffs that were subsequently identified by a PFT measure. Results. In the PHAROS cohort (n = 206), 59 (29%) had RHC-defined PAH. An eRVSP threshold of 35–50 mm Hg failed to diagnose PAH in 7% to 31% of patients, 50% to 70% of which (n = 2–13) were captured by PFT measures. In the Cochin cohort (n = 141), 10 (7%) patients had RHC confirmed PAH. An eRVSP threshold of 35–50 mm Hg missed 0% to 70% (n = 0–7) of patients, of which 0% to 68% (n = 0–6) were met by PFT measures. The combination of TTE and PFT improved the negative predictive value for diagnosing PAH. Conclusion. In 2 large SSc cohorts, screening with TTE and PFT captured a majority of patients with PAH. TTE and PFT complement each other for the diagnosis of PAH.

Screening and diagnostic modalities for connective tissue disease-associated pulmonary arterial hypertension: A systematic review

OBJECTIVE Pulmonary arterial hypertension (PAH) is a frequent complication in connective tissue diseases (CTD), especially in systemic sclerosis (SSc), and is associated with a high degree of morbidity and mortality. We undertook a systematic review for the screening tests for CTD-PAH. METHODS A systematic literature search of PAH in CTD was performed in available databases through June 2012. Our evaluation of diagnostic tests was focused on patients with PAH confirmed by right heart catheterization (RHC). RESULTS The search resulted in 2805 titles and 838 abstracts. Our final inclusion encompassed 22 articles-six of which were case-control studies and 16 were cohort studies. Twelve studies assessed the tricuspid regurgitation velocity (VTR) or equivalent right ventricular systolic pressure (RVSP) using transthoracic echocardiogram (TTE) as a threshold for RHC in patients suspected as having PAH. The screening threshold for RHC was VTR from >2.73 to >3.16 m/s without symptoms or 2.5-3.0m/s with symptoms and resulted in 20-67% of patients having RHC-proven PAH. Three studies looked at pulmonary function tests and found that a low lung diffusing capacity for carbon monoxide (DLCO) (45-70% of predicted) is associated with a 5.6-7.4% development of PAH, and a decline in DLCO% is associated with an increase in the specificity (for DLCO ≤ 60%, spec = 45%; and for DLCO ≤ 50%, spec = 90%) for PAH. Five studies assessed N-terminal prohormone of brain natriuretic peptide (NT-ProBNP), where a cutoff >239 pg/ml had a sensitivity of 90-100%. CONCLUSIONS Our systematic review revealed that most evidence exists for TTE, pulmonary function tests, and NT-ProBNP for screening and diagnosis of SSc-PAH; however, more robust studies are needed.

Voriconazole-induced periostitis causing arthralgias mimicking a flare of granulomatosis with polyangiitis.

We describe a case of voriconazole-induced periostitis that occurred in a 68-year-old woman with granulomatosis with polyangiitis. Our patient presented with months of severe hip pain limiting her daily activities, which was initially felt to be a flare of her granulomatosis with polyangiitis. However, upon further review, she had an elevated alkaline phosphatase and periostitis on her hip radiograph; voriconazole was held, and within 2 days she had marked improvement in her pain. Although this clinical syndrome is well documented in transplant patients, it is a rare complication in patients with autoimmune disorders. However, it is important because it may cause severe arthralgias that can mimic a flare of rheumatic diseases.

Achilles Tendinopathy After Treatment with Ophthalmic Moxifloxacin

To the Editor: Systemic fluoroquinolones have been known to cause tendinopathy. Since 2008, the US Food and Drug Administration has required a “black-box” warning on all systemic fluoroquinolones because of the risk of tendinopathy and tendon rupture1. Fluoroquinolone-associated tendinopathy symptoms have been documented from as early as 2 hours after the initial exposure to as late as 6 months after discontinuation of therapy2. However, in contrast to systemic fluoroquinolones, no reported cases of tendinopathy have been associated with the use of ophthalmic fluoroquinolones. Further, there is no black-box label for this formulation. We describe a case of tendinopathy following topical ophthalmic fluoroquinolone treatment. A 56-year-old man with a history of hypothyroidism and cataracts underwent cataract surgery and was administered daily moxifloxacin ophthalmic drops. On day 14 of … Address correspondence to Dr. Gladue; E-mail: hgladue{at}med.umich.edu

Clinical and serological features of systemic sclerosis in a multicenter African American cohort: Analysis of the genome research in African American scleroderma patients clinical database

Abstract Racial differences exist in the severity of systemic sclerosis (SSc). To enhance our knowledge about SSc in African Americans, we established a comprehensive clinical database from the largest multicenter cohort of African American SSc patients assembled to date (the Genome Research in African American Scleroderma Patients (GRASP) cohort). African American SSc patients were enrolled retrospectively and prospectively over a 30-year period (1987–2016), from 18 academic centers throughout the United States. The cross-sectional prevalence of sociodemographic, clinical, and serological features was evaluated. Factors associated with clinically significant manifestations of SSc were assessed using multivariate logistic regression analyses. The study population included a total of 1009 African American SSc patients, comprised of 84% women. In total, 945 (94%) patients met the 2013 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria for SSc, with the remaining 64 (6%) meeting the 1980 ACR or CREST (calcinosis, Raynauds phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia) criteria. While 43% were actively employed, 33% required disability support. The majority (57%) had the more severe diffuse subtype and a young age at symptom onset (39.1 ± 13.7 years), in marked contrast to that reported in cohorts of predominantly European ancestry. Also, 1 in 10 patients had a severe Medsger cardiac score of 4. Pulmonary fibrosis evident on computed tomography (CT) chest was present in 43% of patients and was significantly associated with anti-topoisomerase I positivity. 38% of patients with CT evidence of pulmonary fibrosis had a severe restrictive ventilator defect, forced vital capacity (FVC) ⩽50% predicted. A significant association was noted between longer disease duration and higher odds of pulmonary hypertension, telangiectasia, and calcinosis. The prevalence of potentially fatal scleroderma renal crisis was 7%, 3.5 times higher than the 2% prevalence reported in the European League Against Rheumatism Scleroderma Trials and Research (EUSTAR) cohort. Our study emphasizes the unique and severe disease burden of SSc in African Americans compared to those of European ancestry.

A randomized controlled trial of acupressure for the treatment of Raynaud’s phenomenon: the difficulty of conducting a trial in Raynaud’s phenomenon

Objective To examine the effect of acupressure on Raynauds phenomenon (RP) in a randomized controlled clinical trial (RCT) and to evaluate the difficulties of conducting an RP RCT. Methods A pilot single-center RCT of acupressure versus targeted patient education was conducted for the treatment of RP. Patients with either primary (n = 15) or secondary (n = 8) RP were randomized in an 8-week study. The primary endpoints included a decrease in the frequency and duration of RP. Secondary endpoints included several serum biomarkers including endothelial dysfunction, Raynauds attack symptoms, Raynauds Condition Score, and patient and physician global assessments of RP. Primary data analysis was conducted using the last observation carried forward and t-tests or a Wilcoxon rank test was used to compare the two groups. Results Twenty-three patients were randomized and seven discontinued prematurely. Seventy-eight percent of patients were female, 96% were Caucasian, and the mean age was 49.8 (SD = 16) years. No statistically significant differences were detected between the acupressure versus education groups in primary and secondary outcomes (p>0.05). Frequency of attacks decreased by 6.7 attacks (SD = 8.8) in the acupressure group versus 7.2 (SD = 12.8) in the education group (p = 0.96), and the duration of attacks decreased by 11.4 (SD = 19.9) minutes in the acupressure group versus an increase of 0.8 minutes (SD = 11.2) in the education group (p = 0.14). There were no adverse events noted in the RCT. Conclusions This pilot study does not support efficacy of acupressure for RP. Trial registration ClinicalTrials.gov Identifier: NCT01784354. https://clinicaltrials.gov/ct2/show/NCT01784354?term=acupressure&rank=15