Having More Tender Than Swollen Joints Is Associated With Worse Patient-Reported Outcomes in Patients With Early RA.

BACKGROUND/OBJECTIVE: In patients with rheumatoid arthritis (RA), high tender-swollen joint differences (TSJDs) have been associated with worse outcomes. A better understanding of the phenotype and impact of high TSJD on patient-reported outcomes (PROs) in early RA may lead to earlier personalized treatment targeting domains that are important to patients today. Our objectives were to evaluate the impact of TSJD on updated PROs in patients with early RA over 1 year and to determine differences in associations by joint size. METHODS: This longitudinal cohort study followed patients with active, early RA enrolled in the Canadian Early Arthritis Cohort between 2016 and 2022, who completed clinical assessments and PROMIS-29 measures over 1 year. Twenty-eight joint counts were performed and TSJDs calculated. Adjusted associations between TSJD and PROMIS-29 scores were estimated using separate linear-mixed models. Separate analyses of large versus small-joint TJSDs were performed. RESULTS: Patients with early RA (n = 547; 70% female; mean [SD] age, 56 [15] years; mean [SD] symptom duration, 5.3 [2.9] months) were evaluated. A 1-point increase in TSJD was significantly associated with worse PROMIS T-scores in all domains: physical function (adjusted regression coefficient, -0.27; 95% confidence interval [CI], -0.39, -0.15), social participation (adjusted regression coefficient, -0.34; 95% CI, -0.50, -0.19), pain interference (adjusted regression coefficient, 0.49; 95% CI, 0.35, 0.64), sleep problems (adjusted regression coefficient, 0.29; 95% CI, 0.16, 0.43), fatigue (adjusted regression coefficient, 0.34; 95% CI, 0.18, 0.50), anxiety (adjusted regression coefficient, 0.23; 95% CI, 0.08, 0.38), and depression (adjusted regression coefficient, 0.20; 95% CI, 0.06, 0.35). Large-joint TSJD was associated with markedly worse PROs compared with small-joint TSJD. CONCLUSIONS: Elevated TSJD is associated with worse PROs particularly pain interference, social participation, and fatigue. Patients with more tender than swollen joints, especially large joints, may benefit from earlier, targeted therapeutic interventions.

A validation study of the Cantonese Chinese version of short form McGill pain questionnaire 2 in Cantonese-speaking patients with chronic pain in Hong Kong.

OBJECTIVE: The study tests the reliability and validity of the Cantonese Chinese version of Short Form McGill Pain Questionnaire 2 (SF-MPQ-2-CC). METHODS: The original Short Form McGill Pain Questionnaire (SF-MPQ-2) was translated into Cantonese Chinese version. Cantonese-speaking chronic pain patients from three pain centers in Hong Kong were recruited and asked to complete SF-MPQ-2-CC, validated Chinese versions of Identification Pain questionnaire (ID Pain), Pain Catastrophizing Scale (PCS), and Short Form Health Survey (SF-36) for evaluation of convergent and divergent validity, 2 weeks apart for evaluation of internal consistency. RESULTS: A total of 333 and 197 participants completed the first and second set of questionnaires, respectively. SF-MPQ-2-CC was shown to have excellent internal consistency, with an overall Cronbach's alpha value of 0.933. The overall correlation coefficient was 0.875 that shows good test-retest reliability. Construct validity was evaluated using confirmatory factor analysis, where a seconder-order factor model demonstrated a good fit with our data (χ2 = 826.51, p < 0.001, CFI = 0.92, TLI = 0.908, RMSEA = 0.097; SRMR = 0.063; error terms adjusted). SF-MPQ-2-CC also showed good convergent validity with Chinese versions of ID Pain (neuropathic pain) and PCS (continuous pain), and divergent validity was shown by a negative correlation with Chinese version of SF-36. CONCLUSIONS: Our study demonstrated that SF-MPQ-2-CC is a valid and reliable pain assessment tool for Cantonese-speaking patients in Hong Kong with a wide range of chronic pain conditions. It also helps to identify the presence of neuropathic pain and negative pain cognition among respondents.

Disproportionate articular pain is a frequent phenomenon in rheumatoid arthritis and responds to treatment with sarilumab.

OBJECTIVES: In some patients with RA, joint pain is more severe than expected based on the amount of joint swelling [referred to as disproportionate articular pain (DP)]. We assessed DP prevalence and the effects of sarilumab, an IL-6 inhibitor, on DP. METHODS: Data from RA patients treated with placebo or 200 mg sarilumab in the phase 3 randomized controlled trials (RCTs) MOBILITY and TARGET, adalimumab 40 mg or sarilumab 200 mg in the phase 3 RCT MONARCH and sarilumab 200 mg in open-label extensions (OLEs) were used. DP was defined as an excess tender 28-joint count (TJC28) over swollen 28-joint count (SJC28) of ≥7 (TJC28 - SJC28 ≥ 7). Treatment response and disease activity were determined for patients with and without DP. RESULTS: Of 1531 sarilumab 200 mg patients from RCTs, 353 (23%) had baseline DP. On average, patients with DP had higher 28-joint DAS using CRP (DAS28-CRP) and pain scores than patients without DP, whereas CRP levels were similar. After 12 and 24 weeks, patients with baseline DP treated with sarilumab were more likely to be DP-free than those treated with placebo or adalimumab. In RCTs, more sarilumab-treated patients achieved low disease activity vs comparators, regardless of baseline DP status. In OLEs, patients were more likely to lose rather than gain DP status. CONCLUSION: About one-quarter of patients with RA experienced DP, which responded well to sarilumab. These data support the concept that other mechanisms (potentially mediated via IL-6) in addition to inflammation may contribute to DP in RA. TRIAL REGISTRATIONS: NCT01061736, NCT02332590, NCT01709578, NCT01146652.

Differences in symptom experience among patients with systemic sclerosis: a cluster analytic approach to identifying subgroups.

OBJECTIVES: Symptoms of people who have SSc are heterogeneous and difficult to address clinically. Because diverse symptoms often co-occur and may share common underlying mechanisms, identifying symptoms that cluster together may better target treatment approaches. We sought to identify and characterize patient subgroups based on symptom experience. METHODS: An exploratory hierarchical agglomerative cluster analysis was conducted to identify subgroups from a large SSc cohort from a single US academic medical centre. Patient-reported symptoms of pain interference, fatigue, sleep disturbance, dyspnoea, depression and anxiety were used for clustering. A multivariate analysis of variance (MANOVA) was used to examine the relative contribution of each variable across subgroups. Analyses of variance were performed to determine participant characteristics based on subgroup assignment. Presence of symptom clusters were tallied within subgroup. RESULTS: Participants (n = 587; 84% female, 41% diffuse cutaneous subtype, 59% early disease) divided into three subgroups via cluster analysis based on symptom severity: (i) no/minimal, (ii) mild, and (iii) moderate. Participants in mild and moderate symptoms subgroups had similar disease severity, but different symptom presentation. In the mild symptoms subgroup, pain, fatigue and sleep disturbance was the main symptom cluster. Participants in the moderate symptoms subgroup were characterized by co-occurring pain, fatigue, sleep disturbance, depression and anxiety. CONCLUSION: Identification of distinct symptom clusters, particularly among SSc patients who experience mild and moderate symptoms, suggests potential differences in treatment approach and in mechanisms underlying symptom experience that require further study.

Predicting Disease Activity in Rheumatoid Arthritis With the Fibromyalgia Survey Questionnaire: Does the Severity of Fibromyalgia Symptoms Matter?

OBJECTIVE: To determine if the degree of baseline fibromyalgia (FM) symptoms in patients with rheumatoid arthritis (RA), as indicated by the Fibromyalgia Survey Questionnaire (FSQ) score, predicts RA disease activity after initiation or change of a disease-modifying antirheumatic drug (DMARD). METHODS: One hundred ninety-two participants with active RA were followed for 12 weeks after initiation or change of DMARD therapy. Participants completed the FSQ at the initial visit. The Disease Activity Score in 28 joints using C-reactive protein (DAS28-CRP) was measured at baseline and follow-up to assess RA disease activity. We evaluated the association between baseline FSQ score and follow-up DAS28-CRP. As a secondary analysis, we examined the relationship between the 2 components of the FSQ, the Widespread Pain Index (WPI) and Symptom Severity Scale (SSS), with follow-up DAS28-CRP. Multiple linear regression analyses were performed, adjusting for clinical and demographic variables. RESULTS: In multiple linear regression models, FSQ score was independently associated with elevated DAS28-CRP scores 12 weeks after DMARD initiation (B = 0.04, P = 0.01). In secondary analyses, the WPI was significantly associated with increased follow-up DAS28-CRP scores (B = 0.08, P = 0.001), whereas the SSS was not (B = -0.03, P = 0.43). CONCLUSION: Higher levels of FM symptoms weakly predicted worse disease activity after treatment. The primary factor that informed the FSQ's prediction of disease activity was the spatial extent of pain, as measured by the WPI.

Pathologically expanded peripheral T helper cell subset drives B cells in rheumatoid arthritis.

CD4+ T cells are central mediators of autoimmune pathology; however, defining their key effector functions in specific autoimmune diseases remains challenging. Pathogenic CD4+ T cells within affected tissues may be identified by expression of markers of recent activation. Here we use mass cytometry to analyse activated T cells in joint tissue from patients with rheumatoid arthritis, a chronic immune-mediated arthritis that affects up to 1% of the population. This approach revealed a markedly expanded population of PD-1hiCXCR5-CD4+ T cells in synovium of patients with rheumatoid arthritis. However, these cells are not exhausted, despite high PD-1 expression. Rather, using multidimensional cytometry, transcriptomics, and functional assays, we define a population of PD-1hiCXCR5- 'peripheral helper' T (TPH) cells that express factors enabling B-cell help, including IL-21, CXCL13, ICOS, and MAF. Like PD-1hiCXCR5+ T follicular helper cells, TPH cells induce plasma cell differentiation in vitro through IL-21 secretion and SLAMF5 interaction (refs 3, 4). However, global transcriptomics highlight differences between TPH cells and T follicular helper cells, including altered expression of BCL6 and BLIMP1 and unique expression of chemokine receptors that direct migration to inflamed sites, such as CCR2, CX3CR1, and CCR5, in TPH cells. TPH cells appear to be uniquely poised to promote B-cell responses and antibody production within pathologically inflamed non-lymphoid tissues.

Fibromyalgianess and glucocorticoid persistence among patients with rheumatoid arthritis.

OBJECTIVES: Over one-third of patients with RA exhibit evidence of fibromyalgianess, which is associated with higher rates of disability and inadequate responsiveness to RA treatment. Patients with RA often remain on glucocorticoids long-term, despite the known risk of dose-dependent morbidity. We undertook this study to examine the relationship between fibromyalgianess and glucocorticoid persistence among RA patients. METHODS: We followed participants with active RA on oral prednisone for ∼3 months after initiating a new DMARD. Fibromyalgianess was measured using the Fibromyalgia Survey Questionnaire (FSQ), previously shown to correlate with key FM features often superimposed upon RA. Severity of fibromyalgianess was stratified as follows: FSQ <8 low, FSQ 8-10 moderate and FSQ >10 high/very high. The association between baseline fibromyalgianess and glucocorticoid persistence, defined as prednisone use at 3-month follow-up visit after DMARD initiation, was assessed using multiple logistic regression adjusted for baseline demographics, RA duration, serostatus and inflammatory activity assessed using swollen joint count and CRP. RESULTS: Of the 97 participants on prednisone at baseline, 65% were still taking prednisone at follow-up. Fifty-seven percent of participants with low baseline fibromyalgianess had persistent glucocorticoid use, compared with 84% of participants with high or very high fibromyalgianess. After adjustment for non-inflammatory factors and inflammatory activity, participants with high/very high baseline fibromyalgianess were more likely to be taking prednisone at follow-up relative to those with low fibromyalgianess [odds ratio 4.99 (95% CI 1.20, 20.73)]. CONCLUSION: High fibromyalgianess is associated with persistent glucocorticoid use, independent of inflammatory activity.

Unconventional secretory pathway activation restores hair cell mechanotransduction in an USH3A model.

The pathogenic variant c.144T>G (p.N48K) in the clarin1 gene (CLRN1) results in progressive loss of vision and hearing in Usher syndrome IIIA (USH3A) patients. CLRN1 is predicted to be an essential protein in hair bundles, the mechanosensory structure of hair cells critical for hearing and balance. When expressed in animal models, CLRN1 localizes to the hair bundle, whereas glycosylation-deficient CLRN1N48K aggregates in the endoplasmic reticulum, with only a fraction reaching the bundle. We hypothesized that the small amount of CLRN1N48K that reaches the hair bundle does so via an unconventional secretory pathway and that activation of this pathway could be therapeutic. Using genetic and pharmacological approaches, we find that clarin1 knockout (clrn1KO/KO ) zebrafish that express the CLRN1c.144T>G pathogenic variant display progressive hair cell dysfunction, and that CLRN1N48K is trafficked to the hair bundle via the GRASP55 cargo-dependent unconventional secretory pathway (GCUSP). On expression of GRASP55 mRNA, or on exposure to the drug artemisinin (which activates GCUSP), the localization of CLRN1N48K to the hair bundles was enhanced. Artemisinin treatment also effectively restored hair cell mechanotransduction and attenuated progressive hair cell dysfunction in clrn1KO/KO larvae that express CLRN1c.144T>G , highlighting the potential of artemisinin to prevent sensory loss in CLRN1c.144T>G patients.

Patient adherence with a smartphone app for patient-reported outcomes in rheumatoid arthritis.

OBJECTIVES: Electronic patient-reported outcomes (ePROs) transmitted digitally allow patients to communicate with their clinicians and track the activity of chronic diseases, such as RA. Several ePRO smartphone apps have been developed in rheumatology, yet few data have been reported regarding patient adherence. We developed a PRO app for RA and assessed adherence over 6 months. METHODS: We developed an app to deliver daily assessments to participants (RA App v.1.0). The app was tested as part of a randomized controlled trial examining potential clinical benefits. The current analyses focus on the adherence to the ePRO app for patients randomized to receive the app. We recruited RA patients from an academic rheumatology practice in the USA. Patients randomized to receive the app received daily notifications regarding ePROs. We examined adherence to the PRO questionnaires over the 6-month study and examined factors related to adherence. RESULTS: Seventy-eight patients received the app and have data included in these analyses: 63 (80.7%) were female, mean age was 55.2 years, 71% had attended college or beyond, and the mean Clinical Disease Activity Index at baseline was 9.7 (low disease activity). Median adherence to the daily questions was 79% (interquartile range 48-90%). Significant predictors of increased adherence were age ≥65 (P = 0.03) and low baseline Clinical Disease Activity Index (P = 0.02). CONCLUSION: We developed and tested an ePRO app for RA over a 6-month study. Adherence to the app was strong. There was correlation between older age and better disease control and increased adherence. TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov/, NCT02822521.

Sleep Disturbance Trajectories in Osteoarthritis.

BACKGROUND/OBJECTIVE: Sleep disturbance is common among adults with osteoarthritis (OA), but little is known about patterns over time. In this cohort study, we identified restless sleep trajectories and associated factors in adults with or at high risk for knee OA. METHODS: Longitudinal (2004-2014) restless sleep (≥3 nights/week) annual reports over 8 years from 4359 Osteoarthritis Initiative participants were analyzed. Group-based trajectory modeling identified heterogeneous temporal patterns. Logistic regression identified baseline health and behavioral predictors of trajectory membership. RESULTS: Four restless sleep trajectory groups were identified: good (69.7%, persistently low restless sleep probabilities), worsening (9.1%), improving (11.7%), and poor (9.5%, persistently high). Among 2 groups initially having low restless sleep prevalence, the worsening trajectory group had an increased likelihood of baseline cardiovascular disease (odds ratio [OR], 1.53; 95% confidence interval [CI], 1.01-2.33), pulmonary disease (OR, 1.48; 95% CI, 1.07-2.05), lower physical activity (OR, 1.29; 95% CI, 1.03-1.61), knee pain (OR, 1.04; 95% CI, 1.00-1.07), depressive symptoms (OR, 1.03; 95% CI, 1.01-1.06), and a decreased likelihood of better mental health (OR, 0.97; 95% CI, 0.95-0.98) at baseline. Among 2 groups initially having high restless sleep prevalence, the poor group had an increased likelihood of baseline depressive symptoms (OR, 1.03; 95% CI, 1.00-1.05). CONCLUSIONS: Four trajectories of restless sleep over 8 years were identified using data collected from over 4000 older adults aged 45 to 79 years with or at higher risk for knee OA. The presence of depressive symptoms, less physical activity, knee pain, poor mental health, cardiovascular disease, or pulmonary disease was each associated with unfavorable trajectories.

In-vivo imaging of neuroinflammation in veterans with Gulf War illness.

Gulf War Illness (GWI) is a chronic disorder affecting approximately 30% of the veterans who served in the 1991 Gulf War. It is characterised by a constellation of symptoms including musculoskeletal pain, cognitive problems and fatigue. The cause of GWI is not definitively known but exposure to neurotoxicants, the prophylactic use of pyridostigmine bromide (PB) pills, and/or stressors during deployment have all been suspected to play some pathogenic role. Recent animal models of GWI have suggested that neuroinflammatory mechanisms may be implicated, including a dysregulated activation of microglia and astrocytes. However, neuroinflammation has not previously been directly observed in veterans with GWI. To measure GWI-related neuroinflammation in GW veterans, we conducted a Positron Emission Tomography (PET) study using [11C]PBR28, which binds to the 18 kDa translocator protein (TSPO), a protein upregulated in activated microglia/macrophages and astrocytes. Veterans with GWI (n = 15) and healthy controls (HC, n = 33, including a subgroup of healthy GW veterans, HCVET, n = 8), were examined using integrated [11C]PBR28 PET/MRI. Standardized uptake values normalized by occipital cortex signal (SUVR) were compared across groups and against clinical variables and circulating inflammatory cytokines (TNF-α, IL-6 and IL-1ß). SUVR were validated against volume of distribution ratio (n = 13). Whether compared to the whole HC group, or only the HCVET subgroup, veterans with GWI demonstrated widespread cortical elevations in [11C]PBR28 PET signal, in areas including precuneus, prefrontal, primary motor and somatosensory cortices. There were no significant group differences in the plasma levels of the inflammatory cytokines evaluated. There were also no significant correlations between [11C]PBR28 PET signal and clinical variables or circulating inflammatory cytokines. Our study provides the first direct evidence of brain upregulation of the neuroinflammatory marker TSPO in veterans with GWI and supports the exploration of neuroinflammation as a therapeutic target for this disorder.

Novel Methylated DNA Markers Discriminate Advanced Neoplasia in Pancreatic Cysts: Marker Discovery, Tissue Validation, and Cyst Fluid Testing.

OBJECTIVES: Pancreatic cystic lesions (PCLs) may be precancerous. Those likely to harbor high-grade dysplasia (HGD) or pancreatic cancer (PC) are targets for surgical resection. Current algorithms to predict advanced neoplasia (HGD/PC) in PCLs lack diagnostic accuracy. In pancreatic tissue and cyst fluid (CF) from PCLs, we sought to identify and validate novel methylated DNA markers (MDMs) that discriminate HGD/PC from low-grade dysplasia (LGD) or no dysplasia (ND). METHODS: From an unbiased whole-methylome discovery approach using predefined selection criteria followed by multistep validation on case (HGD or PC) and control (ND or LGD) tissues, we identified discriminant MDMs. Top candidate MDMs were then assayed by quantitative methylation-specific polymerase chain reaction on archival CF from surgically resected PCLs. RESULTS: Of 25 discriminant MDMs identified in tissue, 13 were selected for validation in 134 CF samples (21 cases [8 HGD, 13 PC], 113 controls [45 ND, 68 LGD]). A tree-based algorithm using 2 CF-MDMs (TBX15, BMP3) achieved sensitivity and specificity above 90%. Discrimination was significantly better by this CF-MDM panel than by mutant KRAS or carcinoembryonic antigen, with areas under the receiver operating characteristic curve of 0.93 (95% confidence interval: 0.86-0.99), 0.71 (0.57-0.85), and 0.72 (0.60-0.84), respectively. Cutoffs for the MDM panel applied to an independent CF validation set (31 cases, 56 controls) yielded similarly high discrimination, areas under the receiver operating characteristic curve = 0.86 (95% confidence interval: 0.77-0.94, P = 0.2). DISCUSSION: Novel MDMs discovered and validated in tissue accurately identify PCLs harboring HGD/PC. A panel of 2 MDMs assayed in CF yielded results with potential to enhance current risk prediction algorithms. Prospective studies are indicated to optimize and further evaluate CF-MDMs for clinical use.

Utilizing a PTPN22 gene signature to predict response to targeted therapies in rheumatoid arthritis.

Despite the development of several targeted therapies for rheumatoid arthritis (RA), there is still no reliable drug-specific predictor to assist rheumatologists in selecting the most effective targeted therapy for each patient. Recently, a gene signature caused by impaired induction of PTPN22 in anti-CD3 stimulated peripheral blood mononuclear cells (PBMC) was observed in healthy at-risk individuals. However, the downstream target genes of PTPN22 and the molecular mechanisms regulating its expression are still poorly understood. Here we report that the PTPN22 gene signature is also present in PBMC from patients with active RA and can be reversed after effective treatment. The expression of PTPN22 correlates with that of more than 1000 genes in Th cells of anti-CD3 stimulated PBMC of healthy donors and is inhibited by TNFα or CD28 signals, but not IL-6, through distinct mechanisms. In addition, the impaired induction of PTPN22 in PBMC of patients with active RA can be normalized in vitro by several targeted therapies. More importantly, the in vitro normalization of PTPN22 expression correlates with clinical response to the targeted therapies in a longitudinal RA cohort. Thus, in vitro normalization of PTPN22 expression by targeted therapies can potentially be used to predict clinical response.

Brain glial activation in fibromyalgia - A multi-site positron emission tomography investigation.

Fibromyalgia (FM) is a poorly understood chronic condition characterized by widespread musculoskeletal pain, fatigue, and cognitive difficulties. While mounting evidence suggests a role for neuroinflammation, no study has directly provided evidence of brain glial activation in FM. In this study, we conducted a Positron Emission Tomography (PET) study using [11C]PBR28, which binds to the translocator protein (TSPO), a protein upregulated in activated microglia and astrocytes. To enhance statistical power and generalizability, we combined datasets collected independently at two separate institutions (Massachusetts General Hospital [MGH] and Karolinska Institutet [KI]). In an attempt to disentangle the contributions of different glial cell types to FM, a smaller sample was scanned at KI with [11C]-L-deprenyl-D2 PET, thought to primarily reflect astrocytic (but not microglial) signal. Thirty-one FM patients and 27 healthy controls (HC) were examined using [11C]PBR28 PET. 11 FM patients and 11 HC were scanned using [11C]-L-deprenyl-D2 PET. Standardized uptake values normalized by occipital cortex signal (SUVR) and distribution volume (VT) were computed from the [11C]PBR28 data. [11C]-L-deprenyl-D2 was quantified using λ k3. PET imaging metrics were compared across groups, and when differing across groups, against clinical variables. Compared to HC, FM patients demonstrated widespread cortical elevations, and no decreases, in [11C]PBR28 VT and SUVR, most pronounced in the medial and lateral walls of the frontal and parietal lobes. No regions showed significant group differences in [11C]-L-deprenyl-D2 signal, including those demonstrating elevated [11C]PBR28 signal in patients (p's ≥ 0.53, uncorrected). The elevations in [11C]PBR28 VT and SUVR were correlated both spatially (i.e., were observed in overlapping regions) and, in several areas, also in terms of magnitude. In exploratory, uncorrected analyses, higher subjective ratings of fatigue in FM patients were associated with higher [11C]PBR28 SUVR in the anterior and posterior middle cingulate cortices (p's < 0.03). SUVR was not significantly associated with any other clinical variable. Our work provides the first in vivo evidence supporting a role for glial activation in FM pathophysiology. Given that the elevations in [11C]PBR28 signal were not also accompanied by increased [11C]-L-deprenyl-D2 signal, our data suggests that microglia, but not astrocytes, may be driving the TSPO elevation in these regions. Although [11C]-L-deprenyl-D2 signal was not found to be increased in FM patients, larger studies are needed to further assess the role of possible astrocytic contributions in FM. Overall, our data support glial modulation as a potential therapeutic strategy for FM.

SAR optimization studies on modified salicylamides as a potential treatment for acute myeloid leukemia through inhibition of the CREB pathway.

Disruption of cyclic adenosine monophosphate response element binding protein (CREB) provides a potential new strategy to address acute leukemia, a disease associated with poor prognosis, and for which conventional treatment options often carry a significant risk of morbidity and mortality. We describe the structure-activity relationships (SAR) for a series of XX-650-23 derived from naphthol AS-E phosphate that disrupts binding and activation of CREB by the CREB-binding protein (CBP). Through the development of this series, we identified several salicylamides that are potent inhibitors of acute leukemia cell viability through inhibition of CREB-CBP interaction. Among them, a biphenyl salicylamide, compound 71, was identified as a potent inhibitor of CREB-CBP interaction with improved physicochemical properties relative to previously described derivatives of naphthol AS-E phosphate.

Mobile Apps for Individuals With Rheumatoid Arthritis: A Systematic Review.

BACKGROUND: Mobile health applications (apps) have the potential to help individuals with chronic illnesses learn about, monitor, and manage their condition, but these apps are largely unexamined, with the state and direction of development unclear. OBJECTIVE: We performed a systematic review of publicly available apps, directed toward individuals with rheumatoid arthritis (RA); described their current features; and determined areas of unmet need. METHODS: We searched the iTunes and Google Play App Stores for the term "arthritis" and reviewed the descriptions of these apps for specific mentions of RA. Applications that met inclusion criteria were downloaded and reviewed. Using a set of quality measures identified from literature review, we assessed each app for 4 features: basic characteristics, content source, functionality, and security. Frequencies for each feature were recorded, and percentages were calculated. RESULTS: Twenty apps intended for use by RA patients were identified in December 2016. Fifty percent of apps (n = 10) offered only symptom tracking. Five (20%) provided only information about RA, and 5 (20%) engaged patients by providing both symptom tracking and educational information. Fewer than 50% of apps provided means to contact health care providers or link to an online community, and only 6 (30%) offered security protection for the user. CONCLUSIONS: Most current RA apps do not provide a comprehensive experience for individuals with RA. Areas for optimization include the implementation of smartphone accessibility features and secure methods of protecting individual health information.

Pain and Catastrophizing in Patients With Rheumatoid Arthritis: An Observational Cohort Study.

BACKGROUND: The aims of this study were to define changes in catastrophizing that occur with initiation of a new disease-modifying antirheumatic drug (DMARD) and to examine the relationship between changes in Clinical Disease Activity Index (CDAI) and changes in catastrophizing. METHODS: Participants in an ongoing multisite, observational study completed the Pain Catastrophizing Scale (PCS) before and 12 weeks after DMARD initiation. We used multivariable linear regression models to examine the association between changes in CDAI as the exposure and change in pain catastrophizing as the outcome. We also assessed the relationship between changes in each component of CDAI and change in PCS, using multivariable linear regression models. RESULTS: Among the 165 rheumatoid arthritis patients with data on CDAI at both time points, CDAI decreased from 22 to 11.5 on a 76-point scale (p < 0.0001) after 12 weeks. Pain intensity decreased from a median of 5 to 3 on a 10-point numeric rating scale (p < 0.0001), and catastrophizing decreased, from 16.0 to 12.0 on the 52-point PCS (p = 0.0005). Among the 163 with complete data for the regression analysis, changes in CDAI were positively correlated with changes in catastrophizing (standardized ß = 0.19, p = 0.01). Of the components of the CDAI, change in assessor global score was most strongly associated with changes in catastrophizing (standardized ß = 0.24, p = 0.003). CONCLUSIONS: Pain catastrophizing decreases, in conjunction with disease activity, after initiation of a new DMARD. These findings provide support for catastrophizing as a dynamic construct that can be altered with treatment directed at decreasing inflammatory disease activity and pain.

Acute Appendicitis: A Meta-Analysis of the Diagnostic Accuracy of US, CT, and MRI as Second-Line Imaging Tests after an Initial US.

Purpose To evaluate the sensitivity, specificity, and diagnostic odds ratios of US, CT, and MRI as second-line imaging modalities after initial US for assessing acute appendicitis in children and adults. Materials and Methods A literature search was conducted in Medline and Embase to identify articles that used surgery or histopathologic examination alone or in combination with clinical follow-up or chart review to evaluate the diagnostic accuracy of second-line imaging modalities. The quality of articles was assessed by using the Quality Assessment of Diagnostic Accuracy Studies-2 and the Standards for Reporting of Diagnostic Accuracy tools. Results For studies of children, the number of studies and patients were as follows: US, six studies and 548 patients; CT, nine studies and 1498 patients; MRI, five studies and 287 patients. For studies of adults, the number of studies and patients were as follows: US, three studies and 169 patients; CT, 11 studies and 1027 patients; MRI, six studies and 427 patients. Pooled sensitivities and specificities of second-line US for diagnosis of appendicitis in children were 91.3% (95% confidence interval [CI]: 83.8%, 95.5%) and 95.2% (95% CI: 91.8%, 97.3%), respectively; and in adults, the pooled sensitivities and specificities were 83.1% (95% CI: 70.3%, 91.1%) and 90.9% (95% CI: 59.3%, 98.6%), respectively. Regarding second-line CT in children, the pooled sensitivities and specificities were 96.2% (95% CI: 93.2%, 97.8%) and 94.6% (95% CI: 92.8%, 95.9%); and in adults, the pooled sensitivities and specificities were 89.9% (95% CI: 85.4%, 93.2%) and 93.6% (95% CI: 91.2%, 95.3%), respectively. Regarding second-line MRI in children, pooled sensitivities and specificities were 97.4% (95% CI: 85.8%, 100%) and 97.1% (95% CI: 92.1%, 99.0%); and in adults, the pooled sensitivities and specificities were 89.9% (95% CI: 84.8%, 93.5%) and 93.6% (95% CI: 90.9%, 95.5%), respectively. Conclusion Second-line US, CT, and MRI have comparable and high accuracy in helping to diagnose appendicitis in children and adults, including pregnant women. All three modalities may be valid as second-line imaging in a clinical imaging pathway for diagnosis and management of appendicitis.

Mechanisms for Joint Pain in Rheumatoid Arthritis (RA): from Cytokines to Central Sensitization.

PURPOSE OF REVIEW: Pain in rheumatoid arthritis (RA) may be due to different etiologies, ranging from peripheral inflammation to dysregulation of central nervous system (CNS) processing. This review evaluates relevant literature published on RA pain mechanisms in recent years. RECENT FINDINGS: Despite successes of disease-modifying antirheumatic drugs (DMARDs), pain persists for many RA patients. Studies involving patient-reported outcomes, quantitative sensory testing, and neuroimaging indicate that, in addition to joint inflammation, abnormalities in CNS pain processing may contribute to pain. Some DMARDs (e.g., janus kinus inhibitors) may work via multiple pathways to decrease pain. Adjunctive treatments (e.g., antidepressants, antiepileptics) may also be useful in managing pain in RA patients with well-controlled disease. Both peripheral and central mechanisms play key roles in the expression of pain in RA. To effectively manage pain, physicians need accurate assessment tools to identify the pathways involved in each patient so that treatments may be appropriately targeted.