Thomas Osborn

Quantitative assessment of scleroderma by surface wave technique

Scleroderma is a multisystem disease characterized by cutaneous and visceral fibrosis. Skin disease is both a disabling feature of scleroderma and a predictor of visceral involvement. The established method of skin assessment is the modified Rodnan skin score (MRSS) which uses semi-quantitative manual skin scoring. However, the Rodnan method is subjective. We have developed a technique and system for assessing skin health by producing and analyzing surface waves in the skin to determine the skin viscoelastic properties. Viscoelasticity of human skin is measured on 30 healthy volunteers and 10 scleroderma patients at six anatomic sites. A small force, monitored by a force transducer, is applied to the skin using a ball-tipped device attached to a mechanical shaker. The skin motion is measured by a scanning laser vibrometer. The surface wave speed is measured by the phase gradient method. The viscoelasticity is inversely estimated by the wave speed dispersion. A typical measurement of the surface wave speed is 3.25±0.19 m/s on the forearm of a volunteer at 200 Hz. With the wave speed dispersion from 100 Hz to 400 Hz, the shear elasticity μ(1) and shear viscosity μ(2) are estimated, respectively, 7.86±1.86 kPa and 5.03±0.60 Pa on the forearm. Statistical analyses suggest that there are significant differences of viscoelasticity between scleroderma patients and healthy subjects. Scleroderma can be effectively and quantitatively evaluated based on human skin viscoelasticity.

Systemic lupus erythematosus, radiotherapy, and the risk of acute and chronic toxicity: the Mayo Clinic Experience.

PURPOSE To determine the acute and chronic toxic effects of radiotherapy in patients with systemic lupus erythematosus (SLE). METHODS AND MATERIALS Medical records of 21 consecutive patients with SLE, who had received 34 courses of external beam radiotherapy and one low-dose-rate prostate implant, were retrospectively reviewed. Patients with discoid lupus erythematosus were excluded. RESULTS Median survival was 2.3 years and median follow-up 5.6 years. Eight (42%) of 19 patients evaluable for acute toxicity during radiotherapy experienced acute toxicity of Grade 1 or greater, and 4 (21%) had acute toxicity of Grade 3 or greater. The 5- and 10-year incidence of chronic toxicity of Grade 1 or greater was 45% (95% confidence interval [CI], 22-72%) and 56% (95% CI, 28-81%), respectively. The 5- and 10-year incidence of chronic toxicity of Grade 3 or greater was 28% (95% CI, 18-60%) and 40% (95% CI, 16-72%), respectively. Univariate analysis showed that chronic toxicity of Grade 1 or greater correlated with SLE renal involvement (p < 0.006) and possibly with the presence of five or more American Rheumatism Association criteria (p < 0.053). Chronic toxicity of Grade 3 or greater correlated with an absence of photosensitivity (p < 0.02), absence of arthritis (p < 0.03), and presence of a malar rash (p < 0.04). CONCLUSIONS The risk of acute and chronic toxicity in patients with SLE who received radiotherapy was moderate but was not prohibitive of the use of radiotherapy. Patients with more advanced SLE may be at increased risk for chronic toxicity.

A noninvasive ultrasound elastography technique for measuring surface waves on the lung

The purpose of this work was to demonstrate an ultrasound based surface wave elastography (SWE) technique for generating and detecting surface waves on the lung. The motivation was to develop a noninvasive technique for assessing superficial lung tissue disease including interstitial lung disease (ILD). ILD comprises a number of lung disorders in which the lung tissue is stiffened and damaged due to fibrosis of the lung tissue. Currently, chest radiographs and computed tomography (CT) are the most common clinical methods for evaluating lung disease, but they are associated with radiation and cannot measure lung mechanical properties. The novelty of SWE is to develop a noninvasive and nonionizing technique to measure the elastic properties of superficial lung tissue. We propose to generate waves on the lung surface through wave propagation from a local harmonic vibration excitation on the chest through an intercostal space. The resulting surface wave propagation on the lung is detected using an ultrasound probe through the intercostal space. To demonstrate that surface waves can be generated on the lung, an ex vivo muscle-lung model was developed to evaluate lung surface wave generation and detection. In this model, swine muscle was laid atop a swine lung. A vibration excitation of 0.1s 100Hz wave was generated on the muscle surface and the surface waves on the lung were detected using a linear array ultrasound probe at 5MHz. To test its feasibility for patient use, SWE was used to measure both lungs of an ILD patient through eight intercostal spaces. The mean wave speed was 1.71±0.20m/s (±SD) at the functional residual capacity, while the mean wave speed was 2.36±0.33m/s at the total lung capacity. These studies support the feasibility of SWE for noninvasive measurement of elastic properties of lung and demonstrate potential for assessment of ILD.

Influence of interstitial lung disease on outcome in systemic sclerosis: A population-based historical cohort study

BACKGROUND Interstitial lung disease (ILD) is a frequent complication of systemic sclerosis (SSc) and a major cause of SSc-related deaths. This study aimed to determine the influence of ILD on SSc in a population-based historical cohort study. The hypothesis was that patients with SSc who develop ILD have increased morbidity and mortality when compared with patients with SSc without ILD. METHODS Using the record linkage system of the Rochester Epidemiology Project in Olmsted County, Minnesota, this study identified the incidence of SSc between 1980 and 2010 and point prevalence on December 31, 2010 and determined the progression of organ involvement and its influence on outcome. RESULTS During the 30-year interval, we identified 64 incident cases of SSc: 57 women and seven men, median age 49.1 years (interquartile range [IQR], 39.8-67.6 years). There were 43 prevalent cases. ILD occurred in 19 cases, usually after the diagnosis of SSc (median, 2 years; IQR, 0-10 years), with only three cases occurring 6 to 24 months beforehand. Pulmonary arterial hypertension (PAH) was diagnosed in 14 cases, heart failure in 27 cases, and chronic kidney disease (CKD) in 21 cases. Seventeen patients died during the study period, with a median survival time after diagnosis of 22.9 years. ILD, PAH, and CKD were associated with an increased risk of death. CONCLUSIONS The incidence of ILD associated with SSc was relatively low in this population-based cohort. ILD appeared to be a contributing factor to mortality. Other factors, including age, PAH, and CKD, were also associated with poor outcome.

An ultrasound surface wave elastography technique for noninvasive measurement of surface lung tissue

Ultrasonography is not widely used in clinic for lung assessment because ultrasound cannot image deep lung tissue. In this abstract, we present a novel technique, lung ultrasound surface wave elastography (LUSWE), for measuring the elastic properties of superficial lung tissue. In LUSWE, a small, local, and 0.1 second harmonic vibration is generated on the chest of a subject. The speed of surface wave on the lung is measured by using an ultrasound probe. We are evaluating LUSWE for assessing patients with interstitial lung disease (ILD). LUSWE may be useful for assessing ILD because most ILD patients have typical fibrotic scars in the peripheral and subpleural regions of the lung. In a large clinical study of ILD patients, we measure both lungs through six intercostal spaces for patients and controls. The surface wave speed is measured at 100 Hz, 150 Hz, and 200 Hz. In an example, the surface wave speed is 1.88 ± 0.11 m/s and 3.3 ± 0.37 m/s, respectively, for a healthy subject and an ILD patient at 100 Hz...

Lung Ultrasound Surface Wave Elastography: A Pilot Clinical Study

A lung ultrasound surface wave elastography (LUSWE) technique is developed to measure superficial lung tissue elastic properties. The purpose of this paper was to translate LUSWE into clinical studies for assessing patients with interstitial lung disease (ILD) and present the pilot data from lung measurements on 10 healthy subjects and 10 patients with ILD. ILD includes multiple lung disorders in which the lung tissue is distorted and stiffened by tissue fibrosis. Chest radiography and computed tomography are the most commonly used techniques for assessing lung disease, but they are associated with radiation and cannot directly measure lung elastic properties. LUSWE provides a noninvasive and nonionizing technique to measure the elastic properties of superficial lung tissue. LUSWE was used to measure regions of both lungs through six intercostal spaces for patients and healthy subjects. The data are presented as wave speed at 100, 150, and 200 Hz at the six intercostal spaces. As an example, the surface wave speeds are, respectively, 1.88 ± 0.11 m/s at 100 Hz, 2.74 ± 0.26 m/s at 150 Hz, and 3.62 ± 0.13 m/s at 200 Hz for a healthy subject in the upper right lung; this is in comparison to measurements from an ILD patient of 3.3 ± 0.37 m/s at 100 Hz, 4.38 ± 0.33 m/s at 150 Hz, and 5.24 ± 0.44 m/s at 200 Hz in the same lung space. Significant differences in wave speed between healthy subjects and ILD patients were found. LUSWE is a safe and noninvasive technique which may be useful for assessing ILD.

Influence of autoimmune biomarkers on interstitial lung diseases: A tertiary referral center based case-control study

Background The benefit of routinely measuring autoimmune biomarkers to evaluate patients with interstitial lung disease (ILD) remains debated outside specific contexts such as connective tissue disease (CTD). This study aimed at evaluating the influence of biomarkers on outcome on patients with ILD in a case-control study at a tertiary referral center. We hypothesized that patients with positive autoimmune biomarkers have increased odds of developing ILD even in the absence of CTD. Methods We reviewed the medical records of 3573 patients seen at the ILD clinic in Mayo Clinic Rochester between September 2001 and September 2006. We assessed their clinical course through June 25, 2013. We included patients with patterns of ILD most often associated with CTD (n=1256) while excluding patients with other known causes of ILD. Controls (n=2317) included cases seen at the ILD clinic without evidence of ILD. Results We identified 930 (26%) cases of ILD alone, 124 (3%) CTD alone, 326 (9%) ILD combined with CTD, and 2193 (61%) with no ILD or CTD. Positive antinuclear antibodies (ANA), rheumatoid factor and aldolase were associated with ILD. After adjustment for age, gender, race, smoking history and CTD, ANA remained an independent risk factor for ILD (OR 1.70, 95% CI 1.33–2.17). Among patients with ILD, the presence of CTD but not biomarker alone was associated with a better survival. Conclusion In this study, the presence of positive biomarkers was associated with increased odds of ILD, even in the absence of overt CTD, but was not associated with a better outcome.

Incidence of systemic lupus erythematosus in a population-based cohort using revised 1997 American College of Rheumatology and the 2012 Systemic Lupus International Collaborating Clinics classification criteria

In 2012, the Systemic Lupus International Collaborating Clinics (SLICC) group published a new set of classification criteria for systemic lupus erythematosus (SLE). Studies applying these criteria to real-life scenarios have found either equal or greater sensitivity and equal or lower specificity to the 1997 ACR classification criteria (ACR 97). Nonetheless, there are no studies that have used the SLICC 12 criteria to investigate the incidence of lupus. We used the resource of the Rochester Epidemiology Project to identify incident SLE patients in Olmsted County, Minnesota, from 1993 to 2005, who fulfilled the ACR 97 or SLICC 12 criteria. A total of 58 patients met criteria by SLICC 12 and 44 patients met criteria by ACR 97. The adjusted incidence of 4.9 per 100,000 person-years by SLICC 12 was higher than that by ACR 97 (3.7 per 100,000 person-years, p = 0.04). The median duration from the appearance of first criterion to fulfillment of the criteria was shorter for the SLICC 12 than for ACR 97 (3.9 months vs 8.1 months). The higher incidence by SLICC 12 criteria came primarily from the ability to classify patients with renal-limited disease, the expansion of the immunologic criteria and the expansion of neurologic criteria.

Acute and late toxicities of radiotherapy for patients with discoid lupus erythematosus: a retrospective case-control study.

BackgroundThe purpose of this study was to evaluate acute and late toxicities of radiotherapy for patients with discoid lupus erythematosus (DLE).MethodsA retrospective review was performed of patients with DLE who received radiotherapy at our institution between 1980 and 2005. Patients with other connective tissue disorders were excluded. Control patients were matched 2:1 with the DLE treatment courses based on age, cancer diagnosis, year of treatment, radiotherapy dose, and sex. Acute (within 30 days from the completion of radiotherapy) and late toxicities were evaluated for each treatment course using the Common Terminology Criteria for Adverse Events Version 3.0.ResultsTwelve patients with DLE received a total of 15 radiotherapy courses. The median follow-up time was 2.6 years (range, 0.0-15.2 years). Acute toxicity of any organ was observed in 10 (67%) treatment courses, of which 2 (13%) were Grade 3 or higher. Acute Grade 1 or 2 dermatologic toxicity was observed in 8 courses (53%). Late toxicity of any organ was observed in 7 of 12 (58%) evaluable treatment courses, of which 3 (23%) were grade 3 or higher. Late grade 1 or 2 dermatologic toxicity was observed in 5 (42%) courses. No patient experienced acute or late Grade 3 or higher dermatologic toxicity. The rates of any organ or dermatologic acute and late toxicity were not significantly different between DLE and control treatment courses.ConclusionsOur findings do not suggest an increased risk of toxicity to the skin or other organs in patients with DLE receiving radiotherapy.

Lupus-Associated Functional Polymorphism in PNP Causes Cell Cycle Abnormalities and Interferon Pathway Activation in Human Immune Cells

Systemic lupus erythematosus (SLE) is frequently characterized by activation of the type I interferon (IFN) pathway. We previously observed that a missense single‐nucleotide polymorphism (rs1049564) in the purine nucleoside phosphorylase (PNP) gene was associated with high levels of IFN in SLE. PNP is a key enzyme involved in purine metabolism. In this study, we performed functional follow‐up of this polymorphism in human cells.