Racial and Ethnic Differences in a Biochemical Marker of Rheumatoid Arthritis Disease Activity.

OBJECTIVE: Racial and ethnic disparities in rheumatoid arthritis (RA) disease activity measures have been documented. We compared racial and ethnic differences in disease activity using multiple composite measures, including an objective measure, the multi-biochemical disease activity (MBDA) score. METHODS: Data are derived from the University of California, San Francisco RA Cohort, a longitudinal observational cohort. Participants with at least one MBDA measure and self-reported race and ethnicity were included. Multivariable linear regression evaluated the association between race and ethnicity groups and mean MBDA score, adjusting for potential confounders, including symptom duration and medication use. Sensitivity analyses substituted the Clinical Disease Activity Index (CDAI) and the Disease Activity Score-28 joints with erythrocyte sedimentation rate (DAS28-ESR) for the MBDA in multivariable models. RESULTS: We included 267 participants (86% female, mean age 52.7 ± 13.3 years). The majority were Latinx (n = 137; 51%), followed by Asian (n = 91; 34%). After adjustment, Latinx participants had the highest mean MBDA score (40.6 ± 2.1) compared with White participants at (32.8 ± 6.7). Black participants had the second highest mean MBDA score, followed by Asian participants (36.3 ± 5.3, 36.0 ± 2.7, respectively), although neither were significantly different from White participants. The trends observed for the CDAI and DAS28-ESR were similar to those for the MBDA. CONCLUSION: We found significantly higher disease activity measured by the MBDA and DAS28-ESR in Latinx participants compared with White participants. We also found significantly higher disease activity in Asian participants compared with White participants with the DAS28-ESR. Our findings, although limited by the small number of White participants in the referent group, suggest that RA disease activity measures may be influenced by external factors that have differential impacts by racial and ethnic group.

Identification of Cell-Specific Differential DNA Methylation Associated With Methotrexate Treatment Response in Rheumatoid Arthritis.

OBJECTIVE: We undertook this study to estimate changes in cell-specific DNA methylation (DNAm) associated with methotrexate (MTX) response using whole blood samples collected from rheumatoid arthritis (RA) patients before and after initiation of MTX treatment. METHODS: Patients included in this study were from the Rheumatoid Arthritis Medication Study (n = 66) and the University of California San Francisco Rheumatoid Arthritis study (n = 11). All patients met the American College of Rheumatology RA classification criteria. Blood samples were collected at baseline and following treatment. Disease Activity Scores in 28 joints using the C-reactive protein level were collected at baseline and after 3-6 months of treatment with MTX. Methylation profiles were generated using the Illumina Infinium HumanMethylation450 and MethylationEPIC v1.0 BeadChip arrays using DNA from whole blood. MTX response was defined using the EULAR response criteria (responders showed good/moderate response; nonresponders showed no response). Differentially methylated positions were identified using the Limma software package and Tensor Composition Analysis, which is a method for identifying cell-specific differential DNAm at the CpG level from tissue-level ("bulk") data. Differentially methylated regions were identified using Comb-p software. RESULTS: We found evidence of differential global methylation between treatment response groups. Further, we found patterns of cell-specific differential global methylation associated with MTX response. After correction for multiple testing, 1 differentially methylated position was associated with differential DNAm between responders and nonresponders at baseline in CD4+ T cells, CD8+ T cells, and natural killer cells. Thirty-nine cell-specific differentially methylated regions associated with MTX treatment response were identified. There were no significant findings in analyses of whole blood samples. CONCLUSION: We identified cell-specific changes in DNAm that were associated with MTX treatment response in RA patients. Future studies of DNAm and MTX treatment response should include measurements of DNAm from sorted cells.

Physical Activity Treatment in Adults with Type 2 Diabetes Mellitus per National Treatment Guidelines for Germany: A Telephone-Survey-Based Analysis.

Physical activity (PA) is effective in the prevention of type 2 diabetes mellitus (T2DM). According to the German national treatment guidelines for T2DM, PA is recommended at all stages of the treatment process. Adults with T2DM were recruited within the cross-sectional telephone survey 'Disease knowledge and information needs-Diabetes mellitus (2017)'. Self-reported data on socio-demographic characteristics, previous and current T2DM treatment, and PA behavior were collected. Using multivariable logistic regression models, the correlation between PA treatment (referrals and recommendations) and PA was investigated. Overall, 1149 adults diagnosed with T2DM are included in the analysis. Of the participants, 66.7% reported having ever received PA as part of their T2DM treatment with 61% of the participants reporting PA treatment at the time of the initial T2DM diagnosis and 54% at the time of the interview. Women, older participants, and those with a lower educational level were less likely to have ever been treated with PA. Currently being treated with PA as part of the T2DM treatment was associated with higher rates of achieving the World Health Organization's PA recommendations (≥150 min per week) (OR = 1.95, 95% CI: 1.42-2.68), as well as ever being treated with PA (OR = 1.74, 95% CI: 1.20-2.38). The analyses showed that PA treatment plays a role in the treatment process of T2DM, but not all patient subgroups benefit in the same way. Efforts to increase PA treatment as part of T2DM treatment are needed, especially for those who are currently not treated with PA. Further research is needed to better understand the type of PA (e.g., structured or unstructured) undertaken by adults with T2DM to develop tailored PA interventions for adults with T2DM and for those in vulnerable subgroups.

Low cumulative disease activity is associated with higher bone mineral density in a majority Latinx and Asian US rheumatoid arthritis cohort.

OBJECTIVE: Prior studies have found conflicting results when evaluating the association between rheumatoid arthritis (RA) disease activity and bone mineral density (BMD). Whether or not cumulative RA disease activity is associated with BMD remains unanswered. METHODS: Data were from the University of California San Francisco RA Cohort from years 2006-2018. Those with BMD measures and at least two study visits prior to BMD measure were included in the study. The association between low cumulative disease activity, as measured by DAS28ESR, with the primary outcome of femoral neck BMD was assessed using multivariable linear regression. Sensitivity analyses were performed substituting CDAI for the disease activity measure as well as total hip and lumbar spine BMD as outcomes. RESULTS: 161 participants with RA were studied. The cohort was 62.4 ± 10.2 years old and 88% female. Hispanic/Latino (N = 73, 45%) and Asian (N = 59, 37%) were the most common racial/ethnic groups in our cohort. Mean RA duration was 10.5 ± 7.3 years and 83% were ACPA positive. Low disease activity was independently associated with higher femoral neck BMD compared to the moderate/high disease activity group (ß= 0.071 [95%CI: 0.021 to 0.122], p = 0.020). The relationship between low cumulative disease activity was similar when CDAI and other BMD sites were substituted in the multivariable models. CONCLUSION: Low cumulative disease activity as measured by DAS28ESR was associated with higher femoral neck BMD, independent of traditional osteoporosis risk factors (e.g., age, sex, BMI) in a unique RA cohort. Results were similar when evaluating cumulative low CDAI and other BMD sites.

Race, Ethnicity, and Disparities in Rheumatology Educational Materials.

OBJECTIVE: To characterize the representation of dark skin color in clinical images across 4 major rheumatology training resources. METHODS: We gathered images of patients with rheumatic diseases from the American College of Rheumatology Image Library, UpToDate, the New England Journal of Medicine Images in Clinical Medicine and Clinical Cases filtered by "Rheumatology," and the 9th edition of Kelley's Textbook of Rheumatology. Investigators used Fitzpatrick's skin phototypes to independently code images depicting visible skin as "light" (skin types I to IV), "dark" (skin types V to VI), or "indeterminate." The representation of dark skin in clinical images was compared to the representation of Asian, Native American, and Black individuals within the US Census population and within lupus cases nationally. RESULTS: Of the 1,043 patient images included in the study, 13.4% had dark skin, 84.0% light skin, and 2.6% indeterminate skin color. Dark skin was underrepresented significantly in rheumatology educational materials and lupus images when compared with the representation of Asian, Native American, and Black individuals within the US Census population (13.4% versus 20.6%; χ2  = 32.8, P < 0.001) and in published studies of patients with systemic lupus erythematous (22.6% versus 44.2%; χ2  = 20.0, P < 0.001). CONCLUSION: Darker skin tones are significantly underrepresented in major rheumatology clinical image banks. Improving representation of racial and ethnic minorities in rheumatology education materials can better equip trainees to recognize and diagnose cutaneous manifestations of rheumatic diseases in these groups.

Activated Peripheral Blood B Cells in Rheumatoid Arthritis and Their Relationship to Anti-Tumor Necrosis Factor Treatment and Response: A Randomized Clinical Trial of the Effects of Anti-Tumor Necrosis Factor on B Cells.

OBJECTIVE: B cells can become activated in germinal center (GC) reactions in secondary lymphoid tissue and in ectopic GCs in rheumatoid arthritis (RA) synovium that may be tumor necrosis factor (TNF) and lymphotoxin (LT) dependent. This study was undertaken to characterize the peripheral B cell compartment longitudinally during anti-TNF therapy in RA. METHODS: Participants were randomized in a 2:1 ratio to receive standard dosing regimens of etanercept (n = 43) or adalimumab (n = 20) for 24 weeks. Eligible participants met the American College of Rheumatology 1987 criteria for RA, had clinically active disease (Disease Activity Score in 28 joints >4.4), and were receiving stable doses of methotrexate. The primary mechanistic end point was the change in switched memory B cell fraction from baseline to week 12 in each treatment group. RESULTS: B cell subsets remained surprisingly stable over the course of the study regardless of treatment group, with no significant change in memory B cells. Blockade of TNF and LT with etanercept compared to blockade of TNF alone with adalimumab did not translate into significant differences in clinical response. The frequencies of multiple activated B cell populations, including CD21- double-negative memory and activated naive B cells, were higher in RA nonresponders at all time points, and CD95+ activated B cell frequencies were increased in patients receiving anti-TNF treatment in the nonresponder group. In contrast, frequencies of transitional B cells-a putative regulatory subset-were lower in the nonresponders. CONCLUSION: Overall, our results support the notion that peripheral blood B cell subsets are remarkably stable in RA and not differentially impacted by dual blockade of TNF and LT with etanercept or single blockade of TNF with adalimumab. Activated B cells do associate with a less robust response.

Effect of Immunosuppression on the Immunogenicity of mRNA Vaccines to SARS-CoV-2 : A Prospective Cohort Study.

BACKGROUND: Patients with chronic inflammatory disease (CID) treated with immunosuppressive medications have increased risk for severe COVID-19. Although mRNA-based SARS-CoV-2 vaccination provides protection in immunocompetent persons, immunogenicity in immunosuppressed patients with CID is unclear. OBJECTIVE: To determine the immunogenicity of mRNA-based SARS-CoV-2 vaccines in patients with CID. DESIGN: Prospective observational cohort study. SETTING: Two U.S. CID referral centers. PARTICIPANTS: Volunteer sample of adults with confirmed CID eligible for early COVID-19 vaccination, including hospital employees of any age and patients older than 65 years. Immunocompetent participants were recruited separately from hospital employees. All participants received 2 doses of mRNA vaccine against SARS-CoV-2 between 10 December 2020 and 20 March 2021. Participants were assessed within 2 weeks before vaccination and 20 days after final vaccination. MEASUREMENTS: Anti-SARS-CoV-2 spike (S) IgG+ binding in all participants, and neutralizing antibody titers and circulating S-specific plasmablasts in a subset to assess humoral response after vaccination. RESULTS: Most of the 133 participants with CID (88.7%) and all 53 immunocompetent participants developed antibodies in response to mRNA-based SARS-CoV-2 vaccination, although some with CID developed numerically lower titers of anti-S IgG. Anti-S IgG antibody titers after vaccination were lower in participants with CID receiving glucocorticoids (n = 17) than in those not receiving them; the geometric mean of anti-S IgG antibodies was 357 (95% CI, 96 to 1324) for participants receiving prednisone versus 2190 (CI, 1598 to 3002) for those not receiving it. Anti-S IgG antibody titers were also lower in those receiving B-cell depletion therapy (BCDT) (n = 10). Measures of immunogenicity differed numerically between those who were and those who were not receiving antimetabolites (n = 48), tumor necrosis factor inhibitors (n = 39), and Janus kinase inhibitors (n = 11); however, 95% CIs were wide and overlapped. Neutralization titers seemed generally consistent with anti-S IgG results. Results were not adjusted for differences in baseline clinical factors, including other immunosuppressant therapies. LIMITATIONS: Small sample that lacked demographic diversity, and residual confounding. CONCLUSION: Compared with nonusers, patients with CID treated with glucocorticoids and BCDT seem to have lower SARS-CoV-2 vaccine-induced antibody responses. These preliminary findings require confirmation in a larger study. PRIMARY FUNDING SOURCE: The Leona M. and Harry B. Helmsley Charitable Trust, Marcus Program in Precision Medicine Innovation, National Center for Advancing Translational Sciences, and National Institute of Arthritis and Musculoskeletal and Skin Diseases.

Multicohort Analysis Identifies Monocyte Gene Signatures to Accurately Monitor Subset-Specific Changes in Human Diseases.

Monocytes are crucial regulators of inflammation, and are characterized by three distinct subsets in humans, of which classical and non-classical are the most abundant. Different subsets carry out different functions and have been previously associated with multiple inflammatory conditions. Dissecting the contribution of different monocyte subsets to disease is currently limited by samples and cohorts, often resulting in underpowered studies and poor reproducibility. Publicly available transcriptome profiles provide an alternative source of data characterized by high statistical power and real-world heterogeneity. However, most transcriptome datasets profile bulk blood or tissue samples, requiring the use of in silico approaches to quantify changes in cell levels. Here, we integrated 853 publicly available microarray expression profiles of sorted human monocyte subsets from 45 independent studies to identify robust and parsimonious gene expression signatures, consisting of 10 genes specific to each subset. These signatures maintain their accuracy regardless of disease state in an independent cohort profiled by RNA-sequencing and are specific to their respective subset when compared to other immune cells from both myeloid and lymphoid lineages profiled across 6160 transcriptome profiles. Consequently, we show that these signatures can be used to quantify changes in monocyte subsets levels in expression profiles from patients in clinical trials. Finally, we show that proteins encoded by our signature genes can be used in cytometry-based assays to specifically sort monocyte subsets. Our results demonstrate the robustness, versatility, and utility of our computational approach and provide a framework for the discovery of new cellular markers.

Glucocorticoids and B Cell Depleting Agents Substantially Impair Immunogenicity of mRNA Vaccines to SARS-CoV-2.

BACKGROUND: Individuals with chronic inflammatory diseases (CID) are frequently treated with immunosuppressive medications that can increase their risk of severe COVID-19. While novel mRNA-based SARS-CoV-2 vaccination platforms provide robust protection in immunocompetent individuals, the immunogenicity in CID patients on immunosuppression is not well established. Therefore, determining the effectiveness of SARS-CoV-2 vaccines in the setting of immunosuppression is essential to risk-stratify CID patients with impaired protection and provide clinical guidance regarding medication management. METHODS: We conducted a prospective assessment of mRNA-based vaccine immunogenicity in 133 adults with CIDs and 53 immunocompetent controls. Blood from participants over 18 years of age was collected before initial immunization and 1-2 weeks after the second immunization. Serum anti-SARS-CoV-2 spike (S) IgG + binding, neutralizing antibody titers, and circulating S-specific plasmablasts were quantified to assess the magnitude and quality of the humoral response following vaccination. RESULTS: Compared to immunocompetent controls, a three-fold reduction in anti-S IgG titers (P=0.009) and SARS-CoV-2 neutralization (p<0.0001) were observed in CID patients. B cell depletion and glucocorticoids exerted the strongest effect with a 36- and 10-fold reduction in humoral responses, respectively (p<0.0001). Janus kinase inhibitors and antimetabolites, including methotrexate, also blunted antibody titers in multivariate regression analysis (P<0.0001, P=0.0023, respectively). Other targeted therapies, such as TNF inhibitors, IL-12/23 inhibitors, and integrin inhibitors, had only modest impacts on antibody formation and neutralization. CONCLUSIONS: CID patients treated with immunosuppressive therapies exhibit impaired SARS-CoV-2 vaccine-induced immunity, with glucocorticoids and B cell depletion therapy more severely impeding optimal responses.

Reweighting to address nonparticipation and missing data bias in a longitudinal electronic health record study.

PURPOSE: We examined whether weighting techniques could account for longitudinal differences in disease activity by race/ethnicity between research participants and nonparticipants with rheumatoid arthritis (RA). METHODS: We included 377 patients with RA from a public hospital in San Francisco, CA. We estimated the probability of not enrolling in a research study by constructing weights using inverse probability weighting. Disease activity over time by race/ethnicity was analyzed across the entire patient population and among research participants only using multivariable mixed-effects models. RESULTS: There were no differences in RA disease activity scores between research participants and nonparticipants at baseline; however, longitudinal differences in disease activity between research participants and nonparticipants were found by race/ethnicity. Weighting research participants in accordance with sociodemographic and clinical characteristics of the nonparticipant population did not result in any meaningful changes in disease activity by race/ethnicity over time. CONCLUSIONS: In our study of patients with RA, inverse probability weighting using select sociodemographic and clinical variables was not sufficient to account for longitudinal disease activity differences by race/ethnicity between research participants and nonparticipants.

Merging Orthovoltage X-Ray Minibeams spare the proximal tissues while producing a solid beam at the target.

Conventional radiation therapy of brain tumors often produces cognitive deficits, particularly in children. We investigated the potential efficacy of merging Orthovoltage X-ray Minibeams (OXM). It segments the beam into an array of parallel, thin (~0.3 mm), planar beams, called minibeams, which are known from synchrotron x-ray experiments to spare tissues. Furthermore, the slight divergence of the OXM array make the individual minibeams gradually broaden, thus merging with their neighbors at a given tissue depth to produce a solid beam. In this way the proximal tissues, including the cerebral cortex, can be spared. Here we present experimental results with radiochromic films to characterize the method's dosimetry. Furthermore, we present our Monte Carlo simulation results for physical absorbed dose, and a first-order biologic model to predict tissue tolerance. In particular, a 220-kVp orthovoltage beam provides a 5-fold sharper lateral penumbra than a 6-MV x-ray beam. The method can be implemented in arc-scan, which may include volumetric-modulated arc therapy (VMAT). Finally, OXM's low beam energy makes it ideal for tumor-dose enhancement with contrast agents such as iodine or gold nanoparticles, and its low cost, portability, and small room-shielding requirements make it ideal for use in the low-and-middle-income countries.

Structural Changes over a Short Period Are Associated with Functional Assessments in Rheumatoid Arthritis.

OBJECTIVE: To investigate the correlation between changes in radiological quantitative assessment with changes in clinical and functional assessment from baseline to 3 months in patients with rheumatoid arthritis (RA). METHODS: Twenty-eight patients with RA [methotrexate (MTX) and anti-tumor necrosis factor-α (TNF-α) group with high disease activity (n = 18); and MTX group with low disease activity (n = 10)] underwent assessments at baseline and 3 months: clinical [28-joint count Disease Activity Score (DAS28)], functional [Health Assessment Questionnaire (HAQ) and Michigan Hand Outcome Questionnaire (MHQ)], and imaging-based [3 Tesla magnetic resonance imaging (MRI) and high-resolution peripheral quantitative computed tomography (HR-pQCT)]. MR images were evaluated semiquantitatively [RA MRI scoring (RAMRIS)] and quantitatively for the volume of synovitis and bone marrow edema (BME) lesions. Erosion volumes were measured using HR-pQCT. RESULTS: After 3 months, the anti-TNF-α group demonstrated an improvement in disease activity through DAS28, HAQ, and MHQ. MRI showed significant decreases in synovitis and BME volume for the anti-TNF-α group, and significant increases in the MTX group. HR-pQCT showed significant decreases in bone erosion volume for the anti-TNF-α group, and significant increases in the MTX group. No significance was observed using RAMRIS. Changes in synovitis, BME, and erosion volumes, but not RAMRIS, were significantly correlated with changes in DAS28, HAQ, and MHQ. CONCLUSION: Quantitative measures were more sensitive than semiquantitative grading when evaluating structural and inflammatory changes with treatment, and were associated with patient clinical and functional outcomes. Multimodality imaging with 3T MRI and HR-pQCT may provide promising biomarkers that help determine disease progression and therapy response.

Vasculitis and peripheral neuropathy.

PURPOSE OF REVIEW: Vasculitis of medium-sized and small vessels commonly affects peripheral nerves and can occur in context of a systemic vasculitis with multiorgan involvement or a nonsystemic vasculitis limited to the peripheral nervous system. This review summarizes the clinical and pathological features of systemic and nonsystemic vasculitis of the peripheral nervous system. RECENT FINDINGS: Vasculitis of peripheral nerves is a diffuse process that affects the vasa nervorum along the entire length of affected nerves but appears to cause injury primarily in a zone in the proximal-middle of the nerve that is particularly susceptible to ischemic injury. Nerve biopsy can help establish the diagnosis of a systemic vasculitis, particularly when other organ involvement is not clinically apparent, and is required for diagnosis of nonsystemic vasculitic neuropathy. Observational studies suggest that nonsystemic vasculitic neuropathy responds to immunosuppressive therapy but conclusive data are lacking. SUMMARY: The current review summarizes the clinical and pathological features of both systemic and nonsystemic vasculitis of the peripheral nervous system so that clinicians can better recognize, make a more timely diagnosis, and thus treat this condition more effectively in their patients.

Smoking Is Associated with Higher Disease Activity in Rheumatoid Arthritis: A Longitudinal Study Controlling for Time-varying Covariates.

OBJECTIVE: Prior studies around the relationship between smoking and rheumatoid arthritis (RA) disease activity have reported inconsistent findings, which may be ascribed to heterogeneous study designs or biases in statistical analyses. We examined the association between smoking and RA outcomes using statistical methods that account for time-varying confounding and loss to followup. METHODS: We included 282 individuals with an RA diagnosis using electronic health record data collected at a public hospital between 2013 and 2017. Current smoking status and disease activity were assessed at each visit; covariates included sex, race/ethnicity, age, obesity, and medication use. We used longitudinal targeted maximum likelihood estimation to estimate the causal effect of smoking on disease activity measures at 27 months, and compared results to conventional longitudinal methods. RESULTS: Smoking was associated with an increase of 0.64 units in the patient global score compared to nonsmoking (p = 0.01), and with 2.58 more swollen joints (p < 0.001). While smoking was associated with a higher clinical disease activity score (2.11), the difference was not statistically significant (p = 0.22). We found no association between smoking and physician global score, or C-reactive protein levels, and an inverse association between smoking and tender joint count (p = 0.05). Analyses using conventional methods showed a null relationship for all outcomes. CONCLUSION: Smoking is associated with higher levels of disease activity in RA. Causal methods may be useful for investigations of additional exposures on longitudinal outcome measures in rheumatologic disease.

Hypomethylation of CYP2E1 and DUSP22 Promoters Associated With Disease Activity and Erosive Disease Among Rheumatoid Arthritis Patients.

OBJECTIVE: Epigenetic modifications have previously been associated with rheumatoid arthritis (RA). In this study, we aimed to determine whether differential DNA methylation in peripheral blood cell subpopulations is associated with any of 4 clinical outcomes among RA patients. METHODS: Peripheral blood samples were obtained from 63 patients in the University of California, San Francisco RA cohort (all satisfied the American College of Rheumatology classification criteria; 57 were seropositive for rheumatoid factor and/or anti-cyclic citrullinated protein). Fluorescence-activated cell sorting was used to separate the cells into 4 immune cell subpopulations (CD14+ monocytes, CD19+ B cells, CD4+ naive T cells, and CD4+ memory T cells) per individual, and 229 epigenome-wide DNA methylation profiles were generated using Illumina HumanMethylation450 BeadChips. Differentially methylated positions and regions associated with the Clinical Disease Activity Index score, erosive disease, RA Articular Damage score, Sharp score, medication at time of blood draw, smoking status, and disease duration were identified using robust regression models and empirical Bayes variance estimators. RESULTS: Differential methylation of CpG sites associated with clinical outcomes was observed in all 4 cell types. Hypomethylated regions in the CYP2E1 and DUSP22 gene promoters were associated with active and erosive disease, respectively. Pathway analyses suggested that the biologic mechanisms underlying each clinical outcome are cell type-specific. Evidence of independent effects on DNA methylation from smoking, medication use, and disease duration were also identified. CONCLUSION: Methylation signatures specific to RA clinical outcomes may have utility as biomarkers or predictors of exposure, disease progression, and disease severity.

Assessment of 3-month changes in bone microstructure under anti-TNFα therapy in patients with rheumatoid arthritis using high-resolution peripheral quantitative computed tomography (HR-pQCT).

BACKGROUND: Although one study showed minimal progression of erosions in patients with rheumatoid arthritis (RA) one year after TNFα inhibition therapy, no studies have investigated very early bone changes after initiation of anti-TNFα treatment. We investigated the effects of 3-month anti-TNFα treatment on bone erosion progression and bone microarchitecture in RA patients using high-resolution peripheral quantitative computed tomography (HR-pQCT). METHODS: Patients with RA (n = 27) (17 in the anti-TNFα and 10 in the MTX-only group) underwent assessment of disease activity score in 28 joints (DAS-28), radiographs, 3-T magnetic resonance imaging (MRI) and HR-pQCT of metacarpophalangeal and wrist joints at baseline and 3 months. HR-pQCT-derived erosion volume, joint volume/width and bone microarchitecture were computed and joint destruction was assessed using Sharp and RAMRIS scorings on radiographs and MRI, respectively. RESULTS: Overall, 73 erosions were identified by HR-pQCT at baseline. Over 3 months, the anti-TNFα group had decreased mean erosion volume; increased erosion volume was observed in one clinical non-responder. The MTX-only group in contrast, trended toward increasing erosion volume despite low disease activity. In the anti-TNFα group, joint-space width and volume of MCP joints decreased significantly and was positively correlated with erosion volume changes (R 2 = 0.311, p = 0.013; R 2 = 0.527, p = 0.003, respectively). In addition, erosion volume changes were significantly negatively correlated with changes in trabecular bone mineral density (R 2 = 0.353, p = 0.020) in this group. We observed significant correlation between percentage change in erosion volume and change in DAS-28 erythrocyte sedimentation rate and C-reactive protein CRP scores (R 2 = 0.558, p < 0.001; R 2 = 0.745, p < 0.001, respectively) in all patients. CONCLUSIONS: Using HR-pQCT, our data suggest that anti-TNFα treatment prevents erosion progression and deterioration of bone microarchitecture within the first 3 months of treatment, one patient not responding to treatment, had significant progression of bone erosions within this short time period. Patients with low disease activity scores (<3.2) can have continuous HR-pQCT-detectable progression of erosive disease with MTX treatment only. HR-pQCT can be a sensitive, powerful tool to quantify bone changes and monitor RA treatment short term (such as 3 months).

Central Nervous System Manifestations of Antiphospholipid Syndrome.

Neurologic manifestations are common in patients with antiphospholipid antibodies and include stroke, seizures, dementia, cognitive dysfunction, chorea, migraine, psychosis, and demyelinating disease. Many of these disorders mimic their idiopathic counterparts, yet treatment for antiphospholipid antibody-associated disease can be quite different compared with treatment of CNS disease not associated with these antibodies. For patients with antiphospholipid antibody-associated neurologic disease, anticoagulation or immunosuppressive therapy or both may significantly improve their symptoms. Thus, one should have a high index of suspicion for antiphospholipid syndrome in the appropriate clinical context.

Central Nervous System Disease in Antineutrophil Cytoplasmic Antibodies-Associated Vasculitis.

Central nervous system (CNS) disease is an uncommon but significant complication of granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) and affects 3 primary areas of the CNS: the pituitary, the pachymeninges, and the CNS vasculature. Pituitary disease in uncommon, but hormonal deficiencies can be long lasting even in the face of excellent disease response. Chronic hypertrophic pachymeninigitis occurs in anti-proteinase 3-positive patients with systemic GPA and in anti-myeloperoxidase-positive patients with a milder and more limited form of the disease. Cerebral and spinal vasculitis due to GPA and MPA presents with focal and general neurologic abnormalities.

A role for muscarinic receptors in neutrophil extracellular trap formation and levamisole-induced autoimmunity.

Levamisole, an anthelmintic drug with cholinergic properties, has been implicated in cases of drug-induced vasculitis when added to cocaine for profit purposes. Neutrophil extracellular trap (NET) formation is a cell death mechanism characterized by extrusion of chromatin decorated with granule proteins. Aberrant NET formation and degradation have been implicated in idiopathic autoimmune diseases that share features with levamisole-induced autoimmunity as well as in drug-induced autoimmunity. This study's objective was to determine how levamisole modulates neutrophil biology and its putative effects on the vasculature. Murine and human neutrophils exposed to levamisole demonstrated enhanced NET formation through engagement of muscarinic subtype 3 receptor. Levamisole-induced NETosis required activation of Akt and the RAF/MEK/ERK pathway, ROS induction through the nicotinamide adenine dinucleotide phosphate oxidase, and peptidylarginine deiminase activation. Sera from two cohorts of patients actively using levamisole-adulterated cocaine displayed autoantibodies against NET components. Cutaneous biopsy material obtained from individuals exposed to levamisole suggests that neutrophils produce NETs in areas of vasculitic inflammation and thrombosis. NETs generated by levamisole were toxic to endothelial cells and impaired endothelium-dependent vasorelaxation. Stimulation of muscarinic receptors on neutrophils by cholinergic agonists may contribute to the pathophysiology observed in drug-induced autoimmunity through the induction of inflammatory responses and neutrophil-induced vascular damage.