HLA and autoantibodies define scleroderma subtypes and risk in African and European Americans and suggest a role for molecular mimicry.

Systemic sclerosis (SSc) is a clinically heterogeneous autoimmune disease characterized by mutually exclusive autoantibodies directed against distinct nuclear antigens. We examined HLA associations in SSc and its autoantibody subsets in a large, newly recruited African American (AA) cohort and among European Americans (EA). In the AA population, the African ancestry-predominant HLA-DRB1*08:04 and HLA-DRB1*11:02 alleles were associated with overall SSc risk, and the HLA-DRB1*08:04 allele was strongly associated with the severe antifibrillarin (AFA) antibody subset of SSc (odds ratio = 7.4). These African ancestry-predominant alleles may help explain the increased frequency and severity of SSc among the AA population. In the EA population, the HLA-DPB1*13:01 and HLA-DRB1*07:01 alleles were more strongly associated with antitopoisomerase (ATA) and anticentromere antibody-positive subsets of SSc, respectively, than with overall SSc risk, emphasizing the importance of HLA in defining autoantibody subtypes. The association of the HLA-DPB1*13:01 allele with the ATA+ subset of SSc in both AA and EA patients demonstrated a transancestry effect. A direct correlation between SSc prevalence and HLA-DPB1*13:01 allele frequency in multiple populations was observed (r = 0.98, P = 3 × 10-6). Conditional analysis in the autoantibody subsets of SSc revealed several associated amino acid residues, mostly in the peptide-binding groove of the class II HLA molecules. Using HLA α/ß allelic heterodimers, we bioinformatically predicted immunodominant peptides of topoisomerase 1, fibrillarin, and centromere protein A and discovered that they are homologous to viral protein sequences from the Mimiviridae and Phycodnaviridae families. Taken together, these data suggest a possible link between HLA alleles, autoantibodies, and environmental triggers in the pathogenesis of SSc.

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.

Measuring response in the gastrointestinal tract in systemic sclerosis.

PURPOSE OF REVIEW: Gastrointestinal 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 FINDINGS: Patient-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. SUMMARY: GIT 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.

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.

Update of screening and diagnostic modalities for connective tissue disease-associated pulmonary arterial hypertension.

OBJECTIVE: Pulmonary arterial hypertension (PAH) has high morbidity and mortality in connective tissue diseases (CTDs), especially systemic sclerosis (SSc). In this systematic review, we provide an update on screening measures for early detection of PAH in CTD. METHODS: Manuscripts published between July 2012 and October 2017, which incorporated screening measures to identify patients with PAH by right heart catheterization, were identified. Risk of bias was assessed using the QUADAS-2 tool. RESULTS: The systematic review resulted in 1514 unique citations and 22 manuscripts were included for final review; the majority of manuscripts had a lower risk of bias based on the QUADAS-2 tool. There were 16 SSc cohort studies and 6 case-control studies (SSc 4, SLE 2). Four SSc cohort studies evaluated transthoracic echocardiography (TTE) only. Eight SSc cohort studies evaluated composite measures including ASIG, DETECT, and a combination of tricuspid regurgitation velocity (TRV) and PFT variables. DETECT and ASIG had greater sensitivity and negative predictive value (NPV) compared to the 2009 ESC/ERS guidelines in different cohorts. The addition of PFT variables, such as DLCO or FVC/ DLCO ratio, to TRV, resulted in greater sensitivity and NPV compared to TRV alone. CONCLUSION: Current screening for PAH in CTDs is centered on SSc. Data continues to support the use of TTE and provides additional evidence for use of composite measures.

Brief Report: Whole-Exome Sequencing to Identify Rare Variants and Gene Networks That Increase Susceptibility to Scleroderma in African Americans.

OBJECTIVE: Whole-exome sequencing (WES) studies in systemic sclerosis (SSc) patients of European American (EA) ancestry have identified variants in the ATP8B4 gene and enrichment of variants in genes in the extracellular matrix (ECM)-related pathway that increase SSc susceptibility. This study was undertaken to evaluate the association of the ATP8B4 gene and the ECM-related pathway with SSc in a cohort of African American (AA) patients. METHODS: SSc patients of AA ancestry were enrolled from 23 academic centers across the US under the Genome Research in African American Scleroderma Patients consortium. Unrelated AA individuals without serologic evidence of autoimmunity who were enrolled in the Howard University Family Study were used as unaffected controls. Functional variants in genes reported in the 2 WES studies in EA patients with SSc were selected for gene association testing using the optimized sequence kernel association test (SKAT-O) and pathway analysis by Ingenuity Pathway Analysis in 379 patients and 411 controls. RESULTS: Principal components analysis demonstrated that the patients and controls had similar ancestral backgrounds, with roughly equal proportions of mean European admixture. Using SKAT-O, we examined the association of individual genes that were previously reported in EA patients and none remained significant, including ATP8B4 (P = 0.98). However, we confirmed the previously reported association of the ECM-related pathway with enrichment of variants within the COL13A1, COL18A1, COL22A1, COL4A3, COL4A4, COL5A2, PROK1, and SERPINE1 genes (corrected P = 1.95 × 10-4 ). CONCLUSION: In the largest genetic study in AA patients with SSc to date, our findings corroborate the role of functional variants that aggregate in a fibrotic pathway and increase SSc susceptibility.

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.

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, Raynaud's 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 ±â€Š13.7 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 Raynaud's phenomenon (RP) in a randomized controlled clinical trial (RCT) and to evaluate the difficulties of conducting a RP RCT. METHODS: A pilot single center RCT of acupressure vs. 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, Raynaud's attack symptoms, Raynaud's 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: 23 patients were randomized and 7 discontinued prematurely. 78% 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 vs. 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 vs. 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 vs. 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. CONCLUSION: This pilot study does not support efficacy of acupressure for RP.

An Unusual Mimicker of Systemic Lupus Erythematosus: A Case Report.

We present a case of a 47 year-old African American female with 15 pack-years of tobacco use and heavy alcohol use who presented with arthritis and was found to have a positive antinuclear antibodies (ANA), anti double stranded DNA antibodies (anti-dsDNA), and anti-Sjogren's syndrome-related antigen A and antigen B (anti-SSA and anti-SSB). She was subsequently found to have a lung adenocarcinoma associated with hypertrophic pulmonary osteoarthropathy (HPO). This demonstrates a case of positive antinuclear antibodies and arthritis in a patient with lung adenocarcinoma, which can be falsely diagnosed as systemic lupus erythematosus.

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.

Treatment of acute gout: a systematic review.

OBJECTIVE: Acute gout is traditionally treated with NSAIDs, corticosteroids, and colchicine; however, subjects have multiple comorbidities that limit the use of some conventional therapies. We systematically reviewed the published data on the pharmacologic and non-pharmacologic agents used for the treatment of acute gouty arthritis. METHODS: A systematic search was performed using PubMed and Cochrane database through May 2013. We included only randomized controlled trials (RCTs) that included NSAIDs, corticosteroids, colchicine, adrenocorticotropic hormone (ACTH), interleukin-1 (IL-1) inhibitors, topical ice, or herbal supplements. RESULTS: Thirty articles were selected for systematic review. The results show that NSAIDs and COX-2 inhibitors are effective agents for the treatment of acute gout attacks. Systemic corticosteroids have similar efficacy to therapeutic doses of NSAIDs, with studies supporting oral and intramuscular use. ACTH is suggested to be efficacious in acute gout. Oral colchicine demonstrated to be effective, with low-dose colchicine demonstrating a comparable tolerability profile as placebo and a significantly lower side effect profile to high-dose colchicine. The IL-1ß inhibitory antibody, canakinumab, was effective for the treatment of acute attacks in subjects refractory to and in those with contraindications to NSAIDs and/or colchicine. However, rilonacept was demonstrated to be not as effective, and there are no RCTs for the use of anakinra. CONCLUSION: NSAIDs, COX-2 selective inhibitors, corticosteroids, colchicine, ACTH, and canakinumab have evidence to suggest efficacy in treatment of acute gout.

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.

Evaluation of test characteristics for outcome measures used in Raynaud's phenomenon clinical trials.

OBJECTIVE: Randomized controlled trials (RCTs) in Raynaud's 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. METHODS: We analyzed core set measures from 249 patients in the placebo-treated groups from 3 RCTs. Core set measures analyzed included the Raynaud's Condition Score (RCS); patient and physician assessment of RP; pain, numbness, and tingling during an RP attack; average number of attacks/day; and duration of attacks. Intraclass correlation coefficients (ICCs) were calculated during the run-in period to the RCTs. RESULTS: ICCs of ≥0.70 were observed for the RCS, attack symptoms, and average attacks/day. A high placebo response rate was observed for all individual core measures except the duration of attacks. For the RCS, the placebo response ranged from 56% with ≥10% improvement to 19.5% with ≥60% improvement. In contrast, placebo response rates of 10-20% were observed when several core set measures were combined to develop a composite score. CONCLUSION: Outcome measures used in RCTs of RP are associated with marked variability. A combination of outcome measures is associated with low placebo responses. Future studies are needed to assess if a composite score will be able to differentiate placebo from an effective agent.

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.