Invasive mycoses in patients with connective tissue disease from Southern China: clinical features and associated factors.

BACKGROUND: A retrospective study was performed to investigate the clinical features and associated factors of invasive mycoses (IM) in patients with connective tissue disease (CTD) from Southern China. METHODS: Demographic and clinical data were recorded. Associated factors were analyzed by logistic regression analysis. RESULTS: A total of 6911 patients with CTD were included. IM was diagnosed in 32 patients (incidence, 0.5%). IM was predominant in patients with ANCA-associated vasculitis (AAV) (incidence, 1.5%, 7/480). Lung was commonly involved (30/32, 93.8%). Aspergillus spp. (81.3%) were the leading strain. The positive rate of fungi detection in sputum culture was 69.0%. Serum galactomannan (GM) test was positive in bronchoalveolar lavage fluid (BALF) from seven (7/10, 70.0%) patients. Ten patients died (31.3%), including three with AAV (42.9%) and seven with SLE (36.8%). Penicillium marneffei was the most fatal (mortality, 100%). Non-survivors had higher prevalence of leukopenia (30.0% vs 4.5%, P = 0.04), lymphopenia (100.0% vs 59.1%, P = 0.02), elevated serum creatinine (70.0% vs 27.3%, P = 0.02), and co-infection (70.0% vs 18.2%, P = 0.004) than survivors. Multivariate logistic regression analysis showed that lymphopenia [odds ratio (OR) = 3.28, 95% confidence interval (CI) 1.29-8.38, P = 0.01] and median-to-high dose of glucocorticoid (GC) [OR = 3.40, 95% CI 1.04-11.13, P = 0.04] were associated with IM in patients with CTD. CONCLUSIONS: IM tended to develop in patients with AAV, resulting in high mortality. Sputum culture and GM test in BALF were effective methods to distinguish IM. Vigilance against lymphopenia, impaired kidney function, and co-infection improved the prognosis of IM.

Pathogenic gene screening in 91 Chinese patients with short stature of unknown etiology with a targeted next-generation sequencing panel.

BACKGROUND: Dwarfism is a common severe growth disorder, but the etiology is unclear in the majority of cases. Recombinant human growth hormone may be a treatment option, but it has limited efficacy. The currently known laboratory assays do not meet the precision requirements for clinical diagnosis. Here, we have constructed a targeted next-generation sequencing (NGS) panel of selected genes that are suspected to be associated with dwarfism for genetic screening. METHODS: Genetic screening of 91 children with short stature of unknown etiology was performed with the help of the NGS panel. All the coding regions and exon-intron boundaries of 166 genes were included in the panel. To clarify the pathogenicity of these mutations, their clinical data were reviewed and analyzed. RESULTS: The assay identified p.A72G, p.I282V, and p.P491S variants of the PTPN11 gene and a p.I437T variant of the SOS1 gene in 4 cases with Noonan syndrome. A frameshift mutation (p.D2407fs) of the ACAN gene was identified in a case of idiopathic short stature with moderately advanced bone age. A p.R904C variant of the COL2A1 gene was found in a patient, who was accordingly diagnosed with Stickler syndrome. Severe short stature without limb deformity was associated with a p.G11A variant of HOXD13. In addition, we evaluated evidence that a p.D401N variant of the COMP gene may cause multiple epiphyseal dysplasia. CONCLUSIONS: Our findings suggest that syndromes, particularly Noonan syndrome, may be overlooked due to atypical clinical features. This gene panel has been verified to be effective for the rapid screening of genetic etiologies associated with short stature and for guiding precision medicine-based clinical management.

Evidence of selection as a cause for racial disparities in fibroproliferative disease.

Fibroproliferative diseases are common complex traits featuring scarring and overgrowth of connective tissue which vary widely in presentation because they affect many organ systems. Most fibroproliferative diseases are more prevalent in African-derived populations than in European populations, leading to pronounced health disparities. It is hypothesized that the increased prevalence of these diseases in African-derived populations is due to selection for pro-fibrotic alleles that are protective against helminth infections. We constructed a genetic risk score (GRS) of fibroproliferative disease risk-increasing alleles using 147 linkage disequilibrium-pruned variants identified through genome-wide association studies of seven fibroproliferative diseases with large African-European prevalence disparities. A comparison of the fibroproliferative disease GRS between 1000 Genomes Phase 3 populations detected a higher mean GRS in AFR (mean = 148 risk alleles) than EUR (mean = 136 risk alleles; T-test p-value = 1.75x10-123). To test whether differences in GRS burden are systematic and may be due to selection, we employed the quantitative trait loci (QTL) sign test. The QTL sign test result indicates that population differences in risk-increasing allele burdens at these fibroproliferative disease variants are systematic and support a model featuring selective pressure (p-value = 0.011). These observations were replicated in an independent sample and were more statistically significant (T-test p-value = 7.26x10-237, sign test p-value = 0.015). This evidence supports the role of selective pressure acting to increase frequency of fibroproliferative alleles in populations of African relative to European ancestry populations.

The Prevalence of Atherosclerosis in Those with Inflammatory Connective Tissue Disease by Race, Age, and Traditional Risk Factors.

Systemic inflammation promotes cardiovascular disease. Inflammatory connective tissue diseases (CTD) like lupus and rheumatoid arthritis associate with cardiovascular risk, but it is unknown whether particular groups of patients have enhanced propensity for atherosclerotic cardiovascular disease (ASCVD) associated with their CTD. Analysis of aggregate health record data at a large U.S. academic center identified CTD and ASCVD status for 287,467 African American and white adults. ASCVD prevalence in those with CTD was 29.7% for African Americans and 14.7% for white patients with prevalence ratios, compared to those without CTD, of 3.1 and 1.8, respectively. When different types of CTD were analyzed individually (rheumatoid arthritis; lupus; scleroderma; Sjögren Syndrome; dermatomyositis/polymyositis; unspecified/mixed CTD; other inflammatory arthropathy), increased ASCVD rates were found in nearly all subsets, always with higher prevalence ratios in African Americans. The prevalence ratio of ASCVD was particularly high in young African Americans. Furthermore, individuals lacking traditional cardiovascular risk factors had more ASCVD if they had CTD (prevalence ratio 2.9). Multivariate analysis confirmed a positive interaction between CTD and African-American race and a negative interaction between CTD and age. The factors driving the observed disproportionate CTD-associated ASCVD in African Americans, young adults, and those without traditional risk factors warrant further study.

Dermatology in the North American Indian/Alaska Native population.

Dermatology is greatly understudied in the American Indian/Alaska Native (AIAN) population. This topic deserves attention in light of the changing demographics of the United States and the healthcare disparities faced by AIAN, including access to dermatologic care. In this review, we discuss disorders that are more prevalent or otherwise important in the AIAN population, such as cutaneous malignancies, photodermatoses, acanthosis nigricans, connective tissue disorders, cutaneous infections, hypertrophic scar formation, and Heck's disease. We aim to provide an updated review and increase awareness of the dermatologic needs of the AIAN population.

Multisystemic diseases and ethnicity: a focus on lupus erythematosus, systemic sclerosis, sarcoidosis and Behçet disease.

We present an overview of the association between ethnicity and the clinical and epidemiological aspects of four multisystemic diseases: lupus erythematosus, systemic sclerosis, sarcoidosis and Behçet disease. In particular, we highlight observed ethnic differences in cutaneous manifestations of these diseases. This article should help guide clinical management, as well as serve to highlight future areas for research.

Effect of race/ethnicity on risk, presentation and course of connective tissue diseases and primary systemic vasculitides.

PURPOSE OF REVIEW: Understanding the effects of race/ethnicity on the risk and expression of systemic rheumatic diseases has potential clinical implications and provides insight into their etiopathogeneses. This review summarizes knowledge of the effects of race/ethnicity on the following nine conditions: antineutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV), Behçet's disease, dermatomyositis/polymyositis, Henoch-Schönlein purpura, Kawasaki disease, large-vessel vasculitis (LVV), primary Sjögren's syndrome (pSS), systemic lupus erythematosus (SLE) and systemic sclerosis (SSc). RECENT FINDINGS: Distinct racial/ethnic patterns have emerged for most of the conditions considered here. Areas of progress include the finding that the two AAVs, granulomatosis with polyangiitis (Wegener's) (GPA) and microscopic polyangiitis, exhibit distinct racial/ethnic susceptibilities in disease risk. In addition, nonwhites, with known high risk of SLE and SSc, may also be at a high risk for pSS and have more severe disease. Evidence is accumulating that nonwhites are rarely affected by the LVV giant-cell arteritis. Race/ethnicity-specific genetic risk factors were recently detected for GPA. SUMMARY: Epidemiologic data have allowed discerning the racial/ethnic profiles for many of the considered systemic rheumatic conditions. Future challenges will be to unravel the genetic, environmental and/or socio-econonomic determinants of the observed racial/ethnic disparities. More research is needed to clarify the impact of race/ethnicity on the AAV Churg-Strauss syndrome, dermatomyositis/polymyositis and Takayasu arteritis.

Antinuclear antibody positive autoimmune disorders in North India: an appraisal.

The autoimmune disorders (AID) have since long been considered to be commoner in Western world as compared to Asian countries. This, however, may not be true as in developing countries, there are incomplete epidemiological data and lack of advanced diagnostic facilities leading to under diagnosis in many cases. In this study, we performed an 11-year retrospective analysis of medical records of all clinically suspected and immunofluorescence antinuclear antibody test (IF-ANA)-positive cases. The IF-ANA-positive cases in the year 2006-2007 were further analyzed to find out the morbidity contribution by IF-ANA-positive AID. A total of 36,310 serum samples were screened for antinuclear antibody (ANA) between the years 1996 and 2006. The mean positivity was 12.3%. A constant and statistically significant increase in AID was noticed over the last 11 years. In the year 2006-2007, out of 3,435 suspected AID cases, 18.9% were ANA positive. Of these, 86.0% were adult patients with age ranging from 2» to 88 years. A female preponderance was also noted with a female-to-male ratio of 3:1. Among the ANA-positive connective tissue disorders (CTD), systemic lupus erythematosus was the most common clinical diagnosis (4.6/10,000 cases) followed by scleroderma (1.2/10,000) and overlap syndrome (0.7/10,000). Rheumatic, renal and hematopoietic systems were commonly involved. The overall frequency of CTD was 21%. The report is the first and largest hospital-based study from India, highlighting the rising incidence and clinical profile of ANA-positive AID.

Evaluation of anti-ribosomal P protein immunoassay in Japanese patients with connective tissue diseases: comparison with an indirect immunofluorescence assay.

OBJECTIVES: To investigate the prevalence of anti-ribosomal P protein (anti-P) antibodies in Japanese patients with connective tissue diseases (CTDs) using enzyme-linked immunosorbent assays (ELISAs) and western blotting (WB) and to evaluate the indirect immunofluorescence (IIF) staining patterns of anti-P-positive sera. METHODS: Anti-P antibodies were measured by two different commercially available ELISA kits and WB in 239 outpatients, 99 with systemic sclerosis (SSc), 73 with systemic lupus erythematosus (SLE), 45 with dermatomyositis (DM), and 22 with Sjögren's syndrome (SjS). Sera positive for anti-P antibodies by WB were analysed by IIF. RESULTS: The frequency of positive WB findings in SLE (18/73, 25%) was higher than in other diseases. ELISA kits A and B for anti-P antibodies showed 21% and 43% sensitivity, and 93% and 88% specificity, respectively, for diagnosing SLE, based on the manufacturer's cut-off values. Receiver operating characteristic (ROC) curve analysis, based on positive WB findings, determined a new cut-off threshold but revealed that both ELISA kits still had good diagnostic characteristics. In IIF assays on anti-P antibody positive sera, typical anti-P antibody cytoplasmic staining patterns (n=8) were seen less frequently than other staining patterns (n=17). CONCLUSIONS: Routine screening for anti-P antibodies by IIF has low sensitivity. ELISAs using cut-off values established by individual facilities are suitable for detecting anti-P antibodies and provide a tool with good diagnostic characteristics, on a parity with WB.

Results of the Health Assessment Questionnaire for Japanese patients with systemic sclerosis--measuring functional impairment in systemic sclerosis versus other connective tissue diseases.

OBJECTIVE: To evaluate the physical functional impairment in patients with systemic sclerosis (SSc) using the Health Assessment Questionnaire (HAQ) and to estimate the correlation of HAQ scores with the severity of SSc. METHODS: One hundred and twenty-four outpatients with connective tissue disease, including 50 patients with SSc, were evaluated using the HAQ. Twelve patients were classified as having diffuse cutaneous SSc (dSSc) and 38 limited cutaneous SSc (lSSc). The severity classification and the guidelines for treatment (2004) were applied to Japanese SSc patients in order to evaluate the relationship between HAQ scores and disease activity in patients with multiple organ involvement. RESULTS: In dSSc the HAQ category scores for eating, walking, grip, activity and the HAQ-disability index (HAQ-DI) showed the greatest deficits in all disease groups. The severity of disease activity correlated significantly with the scores for walking, reach, and the HAQ-DI. The severity of joint, heart, and pulmonary hypertension were correlated independently with the HAQ-DI score by multiple linear regression analysis. CONCLUSION: Patients with dSSc suffer greater functional impairment than patients with other connective tissue diseases, and improvements in hand use and walking represent very important targets for both drug development and rehabilitation. As improvement in organ involvement (joints, heart as well as pulmonary hypertension) can lead to reduced functional impairment, they constitute an important target for therapy in SSc.

Brief report: illness intrusiveness and adjustment among Native American and Caucasian parents of children with juvenile rheumatic diseases.

OBJECTIVE: To investigate cognitive appraisal-adjustment relationships in Native American (NA) and Caucasian parents of children diagnosed with juvenile rheumatic diseases. METHODS: NA (n = 16) and Caucasian (n = 24) parents completed measures of disease status, illness intrusiveness, and adjustment; the rheumatologist provided estimates of disease severity. RESULTS: Hierarchical regression analysis revealed a moderating effect for racial group membership on the illness intrusiveness-parent adjustment relationship. Specifically, parent-perceived illness intrusiveness was more closely related to poorer adjustment among NA parents relative to Caucasian parents. Post hoc tests indicated that illness intrusiveness was significantly associated with poorer adjustment in NA parents, but was unrelated to parent adjustment in the Caucasian sample. CONCLUSIONS: Results highlight the importance of examining racial group differences in cognitive appraisal-adjustment outcome relationships. Results are discussed with respect to the need for incorporating cultural issues into pediatric chronic illness research and treatment.

Pulmonary arterial hypertension among Filipino patients with connective tissue diseases.

We describe the clinical features, therapies, and clinical course of pulmonary arterial hypertension (PAH) in a group of Filipinos with connective tissue diseases (CTDs). We retrospectively reviewed the records of patients diagnosed with PAH by a two-dimensional echocardiogram as a tricuspid regurgitant jet of more than 25 mmHg. All patients had underlying CTDs, defined by the American College of Rheumatology criteria, and were seen at the rheumatology clinics of the University of Santo Tomas Hospital and the St. Luke's Medical Center, Philippines. Of the 33 patients (32 women) included in the analysis, there were 14 patients with systemic lupus erythematosus (SLE), 12 with scleroderma, 5 with mixed connective tissue disease (MCTD), 1 with primary antiphospholipid syndrome (APS), and 1 with dermatomyositis. The average age at PAH diagnosis was 38 +/- 14 years (mean +/- SD), and the mean duration of illness from CTD to PAH diagnosis was 53 +/- 52 months. Twelve patients had died at the time of this report, with a median duration of 15 months (range 1-57 months) from PAH diagnosis to mortality: six of these had scleroderma, five with SLE, and one with APS. The following therapies were used in this group of patients: low molecular weight heparin, warfarin, calcium-channel blockers, aspirin, cyclophosphamide, bosentan, iloprost, and sildenafil. We have described the clinical profile of PAH in a group of Filipino patients with CTDs, most commonly SLE. Various forms of pharmacologic therapies were used among these patients. Mortality remains high, particularly among those with underlying scleroderma. Early recognition and treatment are crucial in order to provide a better outcome for these patients.

Infantile systemic hyalinosis: a fatal disorder commonly diagnosed among Arabs.

We retrospectively reviewed 19 patients (11 male, 8 female) with infantile systemic hyalinosis (ISH) seen at a tertiary care hospital. Fifteen patients (83.3%) presented in the neonatal period. The referral diagnosis was inaccurate in 14 patients (73.7%). Thirteen patients were products of first-degree cousin marriages (68%) and 5 families had more than one affected child. All patients had painful joint contractures and typical mucocutaneous changes (hyper-pigmented sclerodermatous skin over the knuckles and malleoli, gingival hyperplasia, subcutaneous and perianal fleshy nodules). Growth failure was noted in all of them and 39% had profuse diarrhea, 72% had low serum albumin. Radiological findings included osteopenia, periosteal reaction and osteolytic lesions. Tissue biopsy was consistent with the diagnosis in the 8 patients who had the biopsies. Despite aggressive management with physiotherapy and different medications (including NSAIDs, penicillamine and methotrexate), the disorder was progressive and none of them showed improvement. 16 patients died with a mean age of 11 months and only 3 are alive with a mean age of 20 months. This report represents the largest series of ISH. Our data suggests that ISH is a commonly diagnosed disorder in Saudi Arabia and among Arabs.

Pelvic organ prolapse and connective tissue abnormalities in Korean women.

OBJECTIVE: To evaluate the relationship between pelvic organ prolapse in Korean women and joint hypermobility, which suggests a metabolic collagen fiber abnormality. STUDY DESIGN: Between March 1998 and March 2000, we investigated 55 patients with prolapse. The prevalence of joint hypermobility, by measuring finger extension angle, and the proportion of patients with joint hypermobility were measured in patients with pelvic organ prolapse and benign gynecologic patients (control group). RESULTS: In middle-aged women (40-59 years), the average finger extension angles were higher in the POP group than in the control group (50.04 +/- 9.70 degrees vs. 39.50 +/- 12.19 degrees, respectively; P < .05), but in older women there was no significant difference between the two groups (42.84 +/- 13.05 degrees vs. 43.00 +/- 13.34 degrees, respectively; P > .05). CONCLUSION: The prevalence of joint hypermobility was higher in the POP group and with advanced POP stage (III, IV) than in the control group and early POP stage (I, II). Our results suggest that intrinsic connective tissue abnormality is related to the development of pelvic organ prolapse. Further study involving more patients with pelvic organ prolapse is warranted, and molecular studies to determine the genetic basis of pelvic organ prolapse are also required to further elucidate this abnormality.

Cancers of skin, bone, connective tissues, brain, eye, thyroid and other specified and unspecified sites in Inuit.

Low rates of skin cancer, both melanoma and non-melanoma, were observed in Inuit after 20 years of observation. Tumours of the brain and central nervous system, of the thyroid, bone and connective tissues and other specified sites occurred with rates similar to those in comparison populations in Denmark, Connecticut and Canada. These findings support that neither UV and ionizing radiation from nuclear fall-out, nor pollution of herbicides and pesticides in the Arctic area have yet had any noticeable impact on cancer risk. However, unspecified and secondary neoplasms constitute 7-8% of the total Circumpolar cancer incidence and the pattern of rare cancers must be interpreted with caution. Increased diagnostic efforts with a higher precision in the future are warranted.