Recent studies suggest antinuclear antibodies (ANA) may be related to mortality risk, but evidence is sparse and inconclusive. Thus, we investigated ANA associations with all-cause and cause-specific ...mortality in U.S. adults.
Our sample included 3357 adults (ages ≥20 years) from the 1999-2004 National Health and Nutrition Examination Survey with ANA measurements (1:80 dilution) and mortality data through 2011 (median follow-up: 9.4 years). We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) via weighted Cox regression to assess ANA associations with mortality from all causes, cardiovascular disease (CVD), and cancer. Models adjusted for age, sex, race/ethnicity, education, and obesity. Analyses examined mortality in the full sample and in subgroups based on self-reported histories of CVD and cancer, both overall and stratified by sex and age at enrollment.
Overall, ANA were not strongly associated with death from all causes (HR: 1.13; CI: 0.79, 1.60), from CVD (HR: 1.60; CI: 0.80, 3.20), or from cancer (HR: 1.58; CI: 0.75, 3.33), though all three HR estimates exceeded 1. In the subgroup with a history of cancer, ANA were associated with elevated all-cause mortality in men (HR: 2.28; CI: 1.01, 5.14) and in participants who enrolled at age ≥75 years (HR: 1.99; CI: 1.04, 3.80).
These findings suggest that ANA are not strongly associated with mortality in the general population. Longitudinal studies with repeated assessments are needed to understand the temporal relationship between ANA, aging-associated diseases, and mortality.
IgG isotypes can differentially bind to Fcγ receptors and complement, making the selection of which isotype to pursue for development of a particular therapeutic antibody important in determining the ...safety and efficacy of the drug. IgG2 and IgG4 isotypes have significantly lower binding affinity to Fcγ receptors. Recent evidence suggests that the IgG2 isotype is not completely devoid of effector function, whereas the IgG4 isotype can undergo in vivo Fab arm exchange leading to bispecific antibody and off-target effects. Here an attempt was made to engineer an IgG1-based scaffold lacking effector function but with stability equivalent to that of the parent IgG1. Care was taken to ensure that both stability and lack of effector function was achieved with a minimum number of mutations. Among the Asn297 mutants that result in lack of glycosylation and thus loss of effector function, we demonstrate that the N297G variant has better stability and developability compared with the N297Q or N297A variants. To further improve the stability of N297G, we introduced a novel engineered disulfide bond at a solvent inaccessible location in the CH2 domain. The resulting scaffold has stability greater than or equivalent to that of the parental IgG1 scaffold. Extensive biophysical analyses and pharmacokinetic (PK) studies in mouse, rat, and monkey further confirmed the developability of this unique scaffold, and suggest that it could be used for all Fc containing therapeutics (e.g. antibodies, bispecific antibodies, and Fc fusions) requiring lack of effector function or elimination of binding to Fcγ receptors.
Abstract
Objective
The ACR-EULAR Myositis Response Criteria (MRC) were developed as a composite measure using absolute percentage change in six core set measures (CSMs). We aimed to further validate ...the MRC by assessing the contribution of each CSM, frequency of strength vs extramuscular activity improvement, representation of patient-reported outcome measures (PROM), and frequency of CSM worsening.
Methods
Data from adult dermatomyositis/polymyositis patients in the rituximab (n = 147), etanercept (n = 14), and abatacept (n = 19) trials, and consensus patient profiles (n = 232) were evaluated. The Total Improvement Score (TIS), number of improving vs worsening CSMs, frequency of improvement with and without muscle-related CSMs, and contribution of PROM were evaluated by MRC category. Regression analysis was performed to assess contribution of each CSM to the MRC.
Results
Of 412 adults with dermatomyositis/polymyositis, there were 37%, 24%, 25%, and 14% with no, minimal, moderate, and major MRC improvement, respectively. The number of improving CSMs and absolute percentage change in all CSMs increased by improvement category. In minimal-moderate improvement, only physician-reported disease activity contributed significantly more than expected by MRC. Of patients with at least minimal improvement, 95% had improvement in muscle-related measures and a majority (84%) had improvement in PROM. Patients with minimal improvement had worsening in a median of 1 CSM, and most patients with moderate-major improvement had no worsening CSMs. Physician assessment of change generally agreed with MRC improvement categories.
Conclusion
The ACR-EULAR MRC performs consistently across multiple studies, further supporting its use as an efficacy end point in future myositis therapeutic trials.
Abstract
Objective
To compare muscle ultrasound (MUS) parameters in patients with juvenile JDM and healthy controls, and examine their association with JDM disease activity measures and MRI.
Methods
...MUS of the right mid-rectus femoris was performed in 21 patients with JDM meeting probable or definite Bohan and Peter criteria and 28 demographically matched healthy control subjects. MUS parameters were quantitated by digital image processing and correlated with JDM disease activity measures and semi-quantitative thigh MRI short tau inversion recovery (STIR) and T1 scores.
Results
Rectus femoris MUS echogenicity was increased (median 47.8 vs 38.5, P = 0.002) in patients with JDM compared with controls. Rectus femoris MUS echogenicity correlated with Physician Global Activity (PGA), Manual Muscle Testing (MMT), and Childhood Myositis Assessment Scale (CMAS) (rs 0.4–0.54). Some MUS parameters correlated with functional quantitative measures of muscle strength: resting RF area on MUS strongly correlated with knee extension quantitative muscle testing (rs 0.76), and contracted area correlated with proximal MMT, knee extension quantitative muscle testing, and CMAS (rs 0.71–0.80). MUS echogenicity correlated with both STIR and T1 MRI (rs 0.43), and T1 MRI correlated inversely with RF contracted area (rs -0.49) on MUS. There were differences in pre- and post-exercise vascular power and colour Doppler on MUS in patients with JDM vs controls, with the percentage change of post-exercise vascular power Doppler lower in JDM compared with controls (7.1% vs 100.0%).
Conclusions
These data suggest MUS may be a valuable imaging modality to assess JDM disease activity and damage.
Four-and-a-half LIM domains 1 (FHL1) is a muscle-specific protein. Autoantibodies against FHL1 were recently discovered in adults with idiopathic inflammatory myopathies (IIMs) and were found to be ...associated with clinical features and outcomes indicative of increased disease severity. Anti-FHL1 autoantibodies have not been described in children. Here, the prevalence and clinical features associated with anti-FHL1 autoantibodies were examined in a large North American cohort of juvenile patients with IIM.
Sera from 338 juvenile IIM patients and 91 juvenile healthy controls were screened for anti-FHL1 autoantibodies by ELISA. Clinical characteristics and HLA alleles of those with and without anti-FHL1 autoantibodies were compared among those with juvenile IIM.
Anti-FHL1 autoantibodies were present in 10.9% of juvenile IIM patients and 1.1% of controls. The frequency of anti-FHL1 autoantibodies among clinical and serologic subgroups did not differ. A higher percentage of Asian patients had anti-FHL1 autoantibodies (11% vs 0.7%; P = 0.002). Myositis-associated autoantibodies (MAAs) odds ratio (OR) 2.09 (CI 1.03, 4.32), anti-Ro52 autoantibodies specifically OR 4.17 (CI 1.83, 9.37) and V-sign rash OR 2.59 (CI 1.22, 5.40) were associated with anti-FHL1 autoantibodies. There were no differences in other features or markers of disease severity. No HLA associations with anti-FHL1 autoantibodies in Caucasian myositis patients were identified.
Anti-FHL1 autoantibodies are present in ∼11% of juvenile IIM patients and commonly co-occur with MAAs, including anti-Ro52 autoantibodies. In contrast to adult IIM, anti-FHL1 autoantibodies in juvenile myositis are associated with V-sign rash but not with other distinctive clinical features or worse outcomes.
Asthma is a chronic disease of the airways that impairs normal breathing. The etiology of asthma is complex and involves multiple factors, including the environment and genetics, especially the ...distinct genetic architecture associated with ancestry. Compared to early-onset asthma, little is known about genetic predisposition to late-onset asthma. We investigated the race/ethnicity-specific relationship among genetic variants within the major histocompatibility complex (MHC) region and late-onset asthma in a North Carolina-based multiracial cohort of adults.
We stratified all analyses by self-reported race (i.e., White and Black) and adjusted all regression models for age, sex, and ancestry. We conducted association tests within the MHC region and performed fine-mapping analyses conditioned on the race/ethnicity-specific lead variant using whole-genome sequencing (WGS) data. We applied computational methods to infer human leukocyte antigen (HLA) alleles and residues at amino acid positions. We replicated findings in the UK Biobank.
The lead signals, rs9265901 on the 5' end of HLA-B, rs55888430 on HLA-DOB, and rs117953947 on HCG17, were significantly associated with late-onset asthma in all, White, and Black participants, respectively (OR = 1.73, 95%CI: 1.31 to 2.14,
= 3.62 × 10
; OR = 3.05, 95%CI: 1.86 to 4.98,
= 8.85 × 10
; OR = 19.5, 95%CI: 4.37 to 87.2,
= 9.97 × 10
, respectively). For the HLA analysis, HLA-B*40:02 and HLA-DRB1*04:05, HLA-B*40:02, HLA-C*04:01, and HLA-DRB1*04:05, and HLA-DRB1*03:01 and HLA-DQB1 were significantly associated with late-onset asthma in all, White, and Black participants.
Multiple genetic variants within the MHC region were significantly associated with late-onset asthma, and the associations were significantly different by race/ethnicity group.
Objective
Dermatomyositis (DM) has been associated with geospatial differences in ultraviolet (UV) radiation, but the role of individual determinants of UV exposure prior to diagnosis is unknown. The ...objective was to examine the role of those individual determinants.
Methods
We analyzed questionnaire data from 1,350 adults in a US national myositis registry (638 with DM, 422 with polymyositis PM, and 290 with inclusion body myositis IBM diagnosed at ages 18–65 years), examining the likelihood of DM compared with PM and IBM diagnosis, in relation to self‐reported sunburn history and job‐ and hobby‐related sun exposures in the year prior to diagnosis. We estimated odds ratios (ORs) and 95% confidence intervals (95% CIs) using logistic regression adjusted for age, skin tone, and sex, to determine the association of individual UV exposures with DM diagnosis. We also evaluated the proportion of DM by maximum daily ambient UV exposure, based on UVB erythemal irradiances for participant residence in the year prior to diagnosis.
Results
DM was associated with sunburn in the year before diagnosis (2 or more sunburns OR 1.77 95% CI 1.28–2.43 versus PM/IBM; 1 sunburn OR 1.44 95% CI 1.06–1.95) and with having elevated job‐ or hobby‐related sun exposure (high exposure OR 1.64 95% CI 1.08–2.49 or moderate exposure OR 1.35 95% CI 1.02–1.78 versus low or no exposure). Ambient UV intensity was associated with DM in females (β = 3.97, P = 0.046), but not overall.
Conclusion
Our findings suggest that high or moderate personal exposure to intense sunlight is associated with developing DM compared with other types of myositis. Prospective research on UV exposure as a modifiable risk factor for DM is warranted.
Little is known about arsenic and diabetes in youth. We examined the association of arsenic with type 1 and type 2 diabetes in the SEARCH for Diabetes in Youth Case-Control (SEARCH-CC) study. Because ...one-carbon metabolism can influence arsenic metabolism, we also evaluated the potential interaction of folate and vitamin B12 with arsenic metabolism on the odds of diabetes.
Six hundred eighty-eight participants <22 years of age (429 with type 1 diabetes, 85 with type 2 diabetes, and 174 control participants) were evaluated. Arsenic species (inorganic arsenic iAs, monomethylated arsenic MMA, dimethylated arsenic DMA), and one-carbon metabolism biomarkers (folate and vitamin B12) were measured in plasma. We used the sum of iAs, MMA, and DMA (∑As) and the individual species as biomarkers of arsenic concentrations and the relative proportions of the species over their sum (iAs%, MMA%, DMA%) as biomarkers of arsenic metabolism.
Median ∑As, iAs%, MMA%, and DMA% were 83.1 ng/L, 63.4%, 10.3%, and 25.2%, respectively. ∑As was not associated with either type of diabetes. The fully adjusted odds ratios (95% CI), rescaled to compare a difference in levels corresponding to the interquartile range of iAs%, MMA%, and DMA%, were 0.68 (0.50-0.91), 1.33 (1.02-1.74), and 1.28 (1.01-1.63), respectively, for type 1 diabetes and 0.82 (0.48-1.39), 1.09 (0.65-1.82), and 1.17 (0.77-1.77), respectively, for type 2 diabetes. In interaction analysis, the odds ratio of type 1 diabetes by MMA% was 1.80 (1.25-2.58) and 0.98 (0.70-1.38) for participants with plasma folate levels above and below the median (P for interaction = 0.02), respectively.
Low iAs% versus high MMA% and DMA% was associated with a higher odds of type 1 diabetes, with a potential interaction by folate levels. These data support further research on the role of arsenic metabolism in type 1 diabetes, including the interplay with one-carbon metabolism biomarkers.
Objective
Autoantibodies recognizing specificity protein 4 (Sp4) were recently discovered in adults with idiopathic inflammatory myopathies (IIM). Anti‐Sp4 autoantibodies co‐occurred in patients with ...anti–transcription intermediary factor 1 (anti‐TIF1) autoantibody‐positive dermatomyositis (DM) and were associated with a reduced risk of cancer. In the present study, the prevalence and clinical features associated with anti‐Sp4 autoantibodies in juvenile‐onset IIM were investigated.
Methods
Serum samples from 336 patients with juvenile myositis in a cross‐sectional cohort and 91 healthy controls were screened for anti‐Sp4 autoantibodies using enzyme‐linked immunosorbent assay. Clinical characteristics, outcomes, and HLA alleles of those with and those without anti‐Sp4 autoantibodies were compared.
Results
Anti‐Sp4 autoantibodies were present in 23 patients (7%) with juvenile myositis and were not present in any of the controls. Anti‐Sp4 autoantibodies were found among each clinical myositis subgroup. The frequency of TIF1 autoantibody positivity was significantly higher among those with anti‐Sp4 autoantibodies (21 91% versus 92 30%, P < 0.001). In the anti‐TIF1 autoantibody–positive subgroup, Raynaud's phenomenon (8 38% versus 2 2%, P < 0.001) was more common and peak aspartate aminotransferase was significantly lower in those with anti‐Sp4 autoantibodies. None of the patients with anti‐Sp4 autoantibodies required a wheelchair. Among White patients, DQA1*04 and DRB1*08 were associated with anti‐Sp4 autoantibodies.
Conclusion
Anti‐Sp4 autoantibodies were found in patients with juvenile‐onset IIM, predominantly those with coexisting anti‐TIF1 autoantibodies. Patients with anti‐Sp4 autoantibodies represent a phenotypic subset of anti‐TIF1 autoantibody–positive myositis characterized by frequent Raynaud's phenomenon and less pronounced muscle involvement, similar to adults with these autoantibodies. Novel immunogenetic risk factors for White patients with IIM were identified among juveniles with anti‐Sp4 autoantibodies.
Juvenile idiopathic inflammatory myopathies (JIIM) are rare, chronic autoimmune muscle diseases of childhood, with the potential for significant morbidity. Data on long-term outcomes is limited. In ...this study we investigate correlations between clinical and demographic features with long-term outcomes in a referral population of adult patients with JIIM.
Forty-nine adults with JIIM were assessed at two referral centers between 1994 and 2016. Features of active disease and damage at a cross-sectional assessment were obtained. Regression modeling was used to examine factors associated with long-term outcomes, defined by the presence of calcinosis or a higher adjusted Myositis Damage Index (MDI) score. A multivariable model of MDI was constructed using factors that were statistically significant in bivariate models.
At a median of 11.5 IQR 4.5–18.9 years following diagnosis, median American College of Rheumatology (ACR) functional class was 2 1.5–3.0, Health Assessment Questionnaire (HAQ) score was 0.4 out of 3.0 0.0–1.0, and manual muscle testing (MMT) score was 229 out of 260 212.6–256.8. Median MDI score was 6.0 3.5–8.9, with the most commonly damaged organ systems being cutaneous and musculoskeletal. Factors associated with an elevated MDI score were the presence of erythroderma and other cutaneous manifestations, disease duration, and ACR functional class. Calcinosis was present in 55% of patients. The strongest predictors of calcinosis were disease duration, periungual capillary changes, and younger age at diagnosis.
In a tertiary referral population, long-term functional outcomes of JIIM are generally favorable, with HAQ scores indicative of mild disability. Although most patients had mild disease activity and virtually all had significant disease damage, severe or systemic damage was rare. Certain clinical features are associated with long-term damage and calcinosis.
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