Systemic Sclerosis Portends Increased Risk of Conduction and Rhythm Abnormalities at Diagnosis and During Disease Course: A US Population-Based Cohort.

Objectives: To study the incidence, risk factors and outcomes of conduction and rhythm disorders in a population-based cohort of patients with systemic sclerosis (SSc) vs. non-SSc comparators. Methods: An incident cohort of patients with SSc (1980-2016) from Olmsted County, MN was compared to age- and sex-matched non-SSc subjects (1:2). Electrocardiograms (ECGs), Holter ECGs, and need for cardiac interventions were reviewed to determine the occurrence of any conduction or rhythm abnormalities. Results: 78 incident SSc cases and 156 comparators were identified (mean age 56 y, 91% female). The prevalence of any conduction disorder prior to SSc diagnosis compared to non-SSc subjects was 15% vs. 7% (p=0.06), and any rhythm disorder was 18% vs. 13% (p=0.33). During a median follow-up of 10.5 years in patients with SSc and 13.0 years in non-SSc comparators, conduction disorders developed in 25 patients with SSc with cumulative incidence of 20.5% (95% CI: 12.4-34.1%) vs. 28 non-SSc patients with cumulative incidence of 10.4% (95% CI: 6.2-17.4%) (HR: 2.57; 95% CI: 1.48-4.45), while rhythm disorders developed in 27 patients with SSc with cumulative incidence of 27.3% (95% CI: 17.9-41.6%) vs. 43 non-SSc patients with cumulative incidence of 18.0% (95% CI: 12.3-26.4%) (HR: 1.62; 95% CI: 1.00-2.64). Age, pulmonary hypertension and smoking were identified as risk factors. Conclusion: Patients with SSc have an increased risk of conduction and rhythm disorders both at disease onset and over time, compared to non-SSc patients. These findings warrant increased vigilance and screening for ECG abnormalities in SSc patients with pulmonary hypertension.

Hospitalization Rates Are Highest in the First 5 Years of Systemic Sclerosis: Results From a Population-based Cohort (1980-2016).

OBJECTIVE: Few studies have estimated the healthcare resource usage of patients with systemic sclerosis (SSc). The purpose of this study was to compare hospitalization among incident cases of SSc vs age- and sex-matched comparators. METHODS: A retrospective, population-based cohort of patients with SSc in Olmsted County, Minnesota, from January 1, 1980, to December 31, 2016, was assembled. A 2:1 cohort of age- and sex-matched patients without SSc from the same population was randomly selected for comparison. All hospitalizations in the geographic area from January 1, 1987, to September 30, 2018, were obtained. Rates of hospitalization, lengths of stay, and readmissions were compared between groups. RESULTS: There were 76 incident SSc cases and 155 non-SSc comparators (mean age 56 ± 16 yrs at diagnosis/index, 91% female) included. Rates of hospitalization among cases and comparators were 31.9 and 17.9 per 100 person-years, respectively (rate ratio [RR] 1.78, 95% CI 1.52-2.08). Hospitalization rates were higher in patients with SSc than comparators during the first 5 years after SSc diagnosis (RR 2.16, 95% CI 1.70-2.74). This difference decreased over time and was no longer significant at ≥ 15 years after SSc incidence/index. Lengths of stay (median [IQR] 4 [2-6] vs 3 [2-6], P = 0.52) and readmission rates (25% vs 23%, P = 0.51) were similar between groups. CONCLUSION: Patients with SSc were hospitalized more frequently than comparators, indicating high inpatient care needs in this population. Hospitalization rates were highest during the first 5 years following SSc diagnosis.

Untreated Takayasu arteritis: an unusual case of widespread disease.

A 38-year-old man with no medical history presented with bilateral flank and epigastric abdominal pain. CT abdomen and pelvis demonstrated diffuse nodules and lymphadenopathy, which were biopsied and showed chronic inflammatory changes. He later presented with pleuritic chest pain and was sent for a CT chest angiogram, which revealed perivascular inflammation involving the thoracic aortic arch, supra-aortic branch vessels and descending thoracic aorta. Further work-up showed vasculitic involvement of the coeliac, superior mesenteric and femoral arteries with heavy collateralisation. These findings were most consistent with widespread Takayasu arteritis that had been untreated for nearly 20 years. It was necessary to define the degree of active inflammation and need for immediate therapy, as the patient had a concomitant latent tuberculosis infection that precluded the use of immunosuppressive medications. This report illustrates an unusual case of Takayasu arteritis and highlights the presentation, diagnosis and work-up of suspected cases.

Cardiovascular Risk Factors and Atherosclerotic Cardiovascular Events Among Incident Cases of Systemic Sclerosis: Results From a Population-Based Cohort (1980-2016).

OBJECTIVE: To characterize cardiovascular (CV) risk factors and outcomes among incident cases of systemic sclerosis (SSc) in a population-based cohort. METHODS: Medical records of patients with SSc diagnosed in Olmsted County, Minnesota, between January 1, 1980, and December 31, 2016, were reviewed to identify 78 incident SSc cases. The comparators were 156 sex- and age-matched individuals from the same population. Data for SSc characteristics, traditional CV risk factors, and CV events were collected. Cumulative incidence was adjusted for the competing risk for death. RESULTS: During a median follow-up of 9.8 (SSc) and 9.2 years (non-SSc), 21 patients with SSc and 17 patients without SSc developed CV events, corresponding to 10-year cumulative incidence of 24.4% and 15.2%, respectively. The risk for incident CV disease was increased by 2-fold (hazard ratio, 2.38; 95% CI, 1.28-4.43) in patients with SSc vs comparators, predominately due to coronary artery disease (hazard ratio, 2.35; 95% CI, 1.17-4.71). Mean body mass index and prevalence of diabetes mellitus were lower in SSc vs non-SSc. There was no significant difference in smoking, hypertension, or hyperlipidemia. Observed CV events were increased compared with CV events predicted by the Framingham Risk Score and American College of Cardiology/American Heart Association score with standardized incident ratios of 4.16 (95% CI, 2.16-7.99) and 5.69 (95% CI, 2.71-11.94), respectively. CONCLUSION: Patients with SSc are at >2-fold increased risk for experiencing a CV event compared with persons without SSc. Framingham Risk Score and American College of Cardiology/American Heart Association score dramatically underestimate CV risk in SSc.

Lung US Surface Wave Elastography in Interstitial Lung Disease Staging.

Background Lung US surface wave elastography (SWE) can noninvasively quantify lung surface stiffness or fibrosis by evaluating the rate of surface wave propagation. Purpose To assess the utility of lung US SWE for evaluation of interstitial lung disease. Materials and Methods In this prospective study, lung US SWE was used to assess 91 participants (women, 51; men, 40; mean age ± standard deviation [SD], 62.4 years ± 12.9) with interstitial lung disease and 30 healthy subjects (women, 16; men, 14; mean age, 45.4 years ± 14.6) from February 2016 through May 2017. Severity of interstitial lung disease was graded as none (healthy lung [F0]), mild (F1), moderate (F2), or severe (F3) based on pulmonary function tests, high-resolution CT, and clinical assessments. We propagated surface waves on the lung through gentle mechanical excitation of the external chest wall and measured the lung surface wave speed with a US probe. Lung US SWE performance was assessed, and the optimal cutoff wave speed values for fibrosis grades F0 through F3 were determined with receiver operating characteristic (ROC) curve analysis. Results Lung US SWE had a sensitivity of 92% (95% confidence intervals [CI]: 84%, 96%; P < .001) and a specificity of 89% (95% CI: 81%, 94%; P < .001) for differentiating between healthy subjects (F0) and participants with any grade of interstitial lung disease (F1-F3). It had a sensitivity of 50% and a specificity of 81% for differentiating interstitial lung disease grades F0-F2 from F3. The sensitivity was 88% and the specificity was 97% for differentiating between F0 and F1. The highest area under the ROC curve (AUC) values were obtained at 200 Hz and ranged from 0.83 to 0.94 to distinguish between healthy subjects and study participants with any interstitial lung disease. Conclusion Lung US surface wave elastography may be adjunct to high-resolution CT for noninvasive evaluation of interstitial lung disease. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Verschakelen in this issue.

Mycophenolate mofetil for scleroderma-related interstitial lung disease: A real world experience.

BACKGROUND AND OBJECTIVE: Interstitial lung disease (ILD) remains the number one cause of mortality in scleroderma (SSc). Our goal was to determine the effectiveness of mycophenolate mofetil (MMF) in treating SSc-ILD in a retrospective study. METHODS: A retrospective, computer-assisted search was performed to identify patients with SSc-ILD treated with MMF from 1997 through 2014. We used a novel software tool, Computer-Aided Lung Informatics for Pathology Evaluation and Rating (CALIPER), to quantify parenchymal lung abnormalities on high-resolution computed tomography. Lung function was evaluated at baseline, 6, 12, and 24 months of MMF therapy. RESULTS: We identified 46 patients (28 females) with SSc-ILD (mean age at diagnosis 55 y) treated with MMF for at least 1 year (majority on 2 gm/day). Twenty-one patients (45.7%) stopped using MMF during the follow up period after the first 12 months, and they took MMF for a median of 2.12 years (range, 0.91-8.93 years). Only 4 discontinued MMF because of disease progression. Compared to baseline, the mean percentage change in forced vital capacity (95% CI) at 6, 12, and 24 months, respectively, was 1.01% (-2.38%-4.39%) (n = 26), 2.06% (-1.09%-5.22%) (n = 31), and -0.07% (-3.31%-3.17%) (n = 30), and the mean percentage change in ILD as measured by CALIPER (95% CI) was -5.40% (-18.62%-7.83%) (n = 18), -1.51% (-14.69%-11.68%) (n = 17), and -8.35% (-20.71%-4.02%) (n = 22).The mean right ventricular systolic pressure (RVSP) remained stable over the study period. CONCLUSIONS: MMF is well tolerated and slows the rate of decline in lung function in SSc-ILD patients, even at doses lower at 3 g/day.

Indocyanine green angiographic evidence of choroiditis in scleroderma.

PURPOSE: The purpose of this case report was to demonstrate evidence of indocyanine green angiography leakage consistent with choroiditis in a patient with scleroderma. METHODS: In this case report, the patient underwent a variety of tests and examinations, including systemic evaluation, full ocular examination, skin biopsy, indocyanine green, and fluorescein angiography testing. A 52-year-old man had blurred vision centrally in both eyes. Vision was 20/25 and 20/20. Posterior examination showed cotton-wool spots in both eyes. The patient met European League against Rheumatism (EULAR) criteria for scleroderma. RESULTS: Fluorescein angiography confirmed the presence of leakage from the retinal vessels. More importantly, indocyanine green angiography revealed choroidal vessel leakage in both eyes. This provided evidence of choroiditis before vessel obliteration. Previous studies have shown evidence of choriocapillaris obliteration. Choroidal vessel leakage, however, has not been reported in patients with scleroderma. CONCLUSION: The results of this case demonstrate the usefulness of indocyanine green angiography in detecting the presence of choroiditis in scleroderma.

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.

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.

A unique case of relapsing polychondritis presenting with acute pericarditis.

Relapsing polychondritis (RP) is an inflammatory disease of the cartilaginous tissue primarily affecting the cartilaginous structures of the ear, nose, joints, and the respiratory system. Cardiovascular complications of RP are associated with high morbidity and mortality and occur most commonly as valvular disease. Pericarditis is a less common complication, occurring in 4% of patients with RP and has not previously been described at presentation. We describe a case of relapsing polychondritis with acute pericarditis at presentation.

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

BACKGROUND: The purpose of this study was to evaluate acute and late toxicities of radiotherapy for patients with discoid lupus erythematosus (DLE). METHODS: A 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. RESULTS: Twelve 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. CONCLUSIONS: Our findings do not suggest an increased risk of toxicity to the skin or other organs in patients with DLE receiving radiotherapy.

Extreme hypercomplementemia in the setting of mixed cryoglobulinemia.

Elevated levels of complement components, C3 and C4, are often seen in inflammatory diseases. They are generally not thought to be responsible for organ injury but simply reflect stimulation of the immune system. Extremely high elevations of these components are rarely seen. Such values are usually reported in patients with hematopoietic malignancies. We report here a case of C3 elevation to 9.22 g/L (5 times the upper limit of normal) and C4 elevation to 2.48 g/L (6 times the upper limit of normal). To our knowledge, no prior elevations of this magnitude have been reported previously from our institution or in the published medical literature (+/- MEDLINE search, using keywords hypercomplementemia, C3, C4, and lymphoplasmacytic lymphoma). In this case, there appeared to be no adverse end-organ damage from the excessive complement components or their activation.

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.

Primary Raynaud phenomenon and small-fiber neuropathy: is there a connection? A pilot neurophysiologic study.

The pathophysiologic factors of primary Raynaud phenomenon (RP) are unknown. Preliminary evidence from skin biopsy suggests small-fiber neuropathy (SFN) in primary RP. We aimed to quantitatively assess SFN in participants with primary RP. Consecutive patients with an a priori diagnosis of primary RP presenting to our outpatient rheumatology clinic over a 6-month period were invited to participate. Cases of secondary RP were excluded. All participants were required to have normal results on nailfold capillary microscopy. Assessment for SFN was accomplished with autonomic reflex screening, which includes quantitative sudomotor axonal reflex test (QSART), and cardiovagal and adrenergic function testing, thermoregulatory sweat test (TST), and quantitative sensory test (QST) for vibratory, cooling, and heat-pain sensory thresholds. Nine female participants with a median age of 38 years (range 21-46 years) and a median symptom duration of 9 years (range 5 months-31 years) were assessed. Three participants had abnormal results on QSART, indicating peripheral sudomotor autonomic dysfunction. Two participants had evidence of large-fiber involvement with heat-pain thresholds on QST. Heart rate and blood pressure responses to deep breathing, Valsalva maneuver, and 70° tilt were normal for all participants. Also, all participants had normal TST results. In total, three of the nine participants had evidence of SFN. The presence of SFN raises the possibility that a subset of patients with primary RP have an underlying, subclinical small-fiber dysfunction. These data open new avenues of research and therapeutics for this common condition.

Renal involvement in primary Sjögren's syndrome: a clinicopathologic study.

BACKGROUND & OBJECTIVES: Renal pathology and clinical outcomes in patients with primary Sjögren's syndrome (pSS) who underwent kidney biopsy (KB) because of renal impairment are reported. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Twenty-four of 7276 patients with pSS underwent KB over 40 years. Patient cases were reviewed by a renal pathologist, nephrologist, and rheumatologist. Presentation, laboratory findings, renal pathology, initial treatment, and therapeutic response were noted. RESULTS: Seventeen patients (17 of 24; 71%) had acute or chronic tubulointerstitial nephritis (TIN) as the primary lesion, with chronic TIN (11 of 17; 65%) the most common presentation. Two had cryoglobulinemic GN. Two had focal segmental glomerulosclerosis. Twenty patients (83%) were initially treated with corticosteroids. In addition, three received rituximab during follow-up. Sixteen were followed after biopsy for more than 12 mo (median 76 mo; range 17 to 192), and 14 of 16 maintained or improved renal function through follow-up. Of the seven patients presenting in stage IV chronic kidney disease, none progressed to stage V with treatment. CONCLUSIONS: This case series supports chronic TIN as the predominant KB finding in patients with renal involvement from pSS and illustrates diverse glomerular lesions. KB should be considered in the clinical evaluation of kidney dysfunction in pSS. Treatment with glucocorticoids or other immunosuppressive agents appears to slow progression of renal disease. Screening for renal involvement in pSS should include urinalysis, serum creatinine, and KB where indicated. KB with characteristic findings (TIN) should be considered as an additional supportive criterion to the classification criteria for pSS because it may affect management and renal outcome.

Acrocyanosis from phenazopyridine-induced sulfhemoglobinemia mistaken for Raynaud phenomenon.

Rheumatologists are often asked to evaluate patients with Raynaud phenomenon. Occasionally, an alternate explanation is revealed such as acrocyanosis. Methemoglobinemia and sulfhemoglobinemia are rare causes of cyanosis that can be medication-induced. Both are known complications of therapy with phenazopyridine. We report an unusual case of a 45-year-old woman in whom sulfhemoglobinemia from chronic therapy with phenazopyridine was misdiagnosed as due to Raynaud phenomenon and limited scleroderma. This case illustrates the importance of taking into account medication-related adverse events when evaluating patients with Raynaud-like phenomenon.

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.