Comparison of Adults With Polyarticular Juvenile Idiopathic Arthritis to Adults With Rheumatoid Arthritis: A Cross-sectional Analysis of Clinical Features and Medication Use.

BACKGROUND/OBJECTIVE: Many individuals with juvenile idiopathic arthritis (JIA) have persistent disease into adulthood. Polyarticular JIA (pJIA) is often mislabeled as rheumatoid arthritis (RA) in adult rheumatology clinics, and treatment for adult pJIA patients is not well defined. We aimed to describe clinical features and medication use in the adult pJIA population in relation to an RA control cohort. METHODS: We performed a cross-sectional study of 45 adults with pJIA and 94 with RA seen from 2013 to 2017. Clinical characteristics including RA classification criteria were compared using χ and McNemar tests. Medication use was analyzed focusing on tumor necrosis factor inhibitor (TNFi) survival, and an accelerated failure-time model was developed for time to methotrexate initiation. RESULTS: Polyarticular JIA patients were less likely to be rheumatoid factor or cyclic citrullinated peptide antibody positive; fewer than half of pJIA subjects met the RA 2010 American College of Rheumatology/European League Against Rheumatism Classification Criteria. Time from diagnosis to methotrexate initiation was associated with longer disease duration in both groups (p < 0.01). Current TNFi use was more prevalent in pJIA patients (49% vs. 18%, p < 0.01), and TNFi use, particularly for etanercept, was sustained longer with a median drug survival of 4.41 years compared with 0.70 years in RA patients (p < 0.01). CONCLUSIONS: Although often considered together in adult rheumatology practice, adults with pJIA are distinct from patients with RA. Medication use markedly differed between the 2 populations with greater prevalence and duration of TNFi use in pJIA patients. Further study is needed to improve outcomes in this unique population.

Peripheral vascular disease in systemic lupus patients.

BACKGROUND: Systemic lupus erythematosus (SLE) is an independent risk factor for cardiovascular disease (CVD). Ankle-brachial index (ABI) is a measure of peripheral vascular disease (PVD), low values of which are associated with CVD. OBJECTIVES: Objectives were to identify the prevalence of PVD in SLE, to identify risk factors associated with PVD in SLE, and to determine whether SLE is an independent risk factor for PVD as assessed by ABI. METHODS: In a cross-sectional analysis of SLE subjects and control subjects, free of known CVD, SLE-related variables and cardiovascular risk factors were measured. Peripheral vascular disease was assessed using ABI. The prevalence of PVD (ABI ≤ 1.0) and comparisons of mean ABI, between SLE and control subjects, were examined. Systemic lupus erythematosus was examined as an independent risk for PVD in the cohort using propensity score matching. Logistic regression was performed to identify independent risk factors for PVD in SLE. RESULTS: Ankle-brachial index was lower in the 134 SLE subjects compared with 77 control subjects: 1.05 versus 1.09 (P = 0.003), and the prevalence of PVD was higher in SLE than in control subjects (33% vs 20%; P = 0.037). Systemic lupus erythematosus was not an independent risk for PVD. In the SLE subjects, the only significant risk factor for PVD was smoking. CONCLUSIONS: Ankle-brachial index, a marker of subclinical CVD, is an inexpensive and easy method in which to assess PVD. There was a 33% prevalence of PVD in SLE, which was independently associated with smoking. As PVD is a coronary artery disease risk equivalent, screening and diagnosis may change lipid management in preventive cardiovascular risk assessment in patients with SLE. The combination of SLE and a smoking history may identify individuals for whom checking an ABI makes particular sense.

Arthroplasty Rates Not Increasing in Young Patients With Rheumatoid Arthritis: A National Database Review, 2005 Versus 2014.

BACKGROUND: For 20 years, authors have predicted an expansion in total knee arthroplasty (TKA) and total hip arthroplasty (THA) utilization. Over this same period, the introduction of biological disease-modifying antirheumatic drugs has dramatically altered the treatment of rheumatoid arthritis (RA) with hopes of preventing articular damage and obviating the need for prosthetic replacement. The goal of our investigation was to evaluate TKA and THA utilization in young patients with RA (<65 years) in 2005 vs 2014 compared to patients with osteoarthritis (OA). METHODS: Using relevant International Classification of Disease Ninth Revision (ICD-9) and Current Procedural Terminology codes, the Truven MarketScan Database (over 46 million enrollees) was queried to determine THA and TKA incidence rates for RA and OA patients aged <65 years during the final decade of ICD-9 use. Patients with potentially confounding ICD-9 codes were excluded to limit coding variation. Statistical analysis consisted of student t-tests, Pearson's chi-square tests, and Breslow-Day tests. RESULTS: For patients with OA, TKAs increased substantially from 0.07% in 2005 to 0.1% in 2014 (+42.9% change, P < .001). Similarly for patients with OA, THAs increased from 0.04% to 0.06% over the same time period (+66.0% change, P < .001). For young patients with RA, the rate of TKA remained relatively stable-1.06% in 2005 to 1.04% in 2014 (-1.7% change, P = .65)-as did THA-0.44% to 0.48% (+9.0% change, P = .14). CONCLUSIONS: Dramatic increases in THA and TKA rates for OA patients aged <65 years were indeed observed from 2005 to 2014. This trend, however, was not seen in the RA population where TKA and THA rates remained unchanged.

Determining Rheumatology Patient Interest in a Group Strength Training Program - Results of an Exercise Survey.

BACKGROUND: Exercise has proven benefits in rheumatologic disease including reducing inflammation and improving symptoms. A Group Strength Training (GST) program design has improved adherence to exercise in primary care patients but the effect is unknown in rheumatology patients. We examined the interest of rheumatology patients with different diagnoses and the effect of comorbidities in pursuing an organized GST program. METHODS: We conducted a cross-sectional survey of patients from a rheumatology practice in central Pennsylvania in February and April 2017. This survey assessed self-reported interest of patients in a GST program in addition to demographics, comorbidities, and quality of life measures. Primary care data from a previous survey were used for comparative analysis for the primary outcome: interest in a GST program. RESULTS: Fifty percent of rheumatology patients were interested in a GST program and there was no difference of interest compared to primary care patients (X2 = 2.04, p = 0.15). There was no difference in interest in a GST program for rheumatology patients with poor health compared to patients with good health (OR = 0.9, p = 0.8). Female patients were more interested in a group strength training program than male patients (OR = 3.7, p = 0.001). Patients with a BMI of 25-30 (OR = 2.2, p = 0.04) or > 30 (OR = 1.7, p = 0.12) were more interested compared to those with a normal BMI. There was no difference in interest in group strength training regardless of rheumatology diagnosis or comorbidities. CONCLUSION: Our data suggest that rheumatology patients are interested in a GST program regardless of disease, medical comorbidities, perceived mental or physical health, or education level. Further study is needed to determine the effects of GST on rheumatologic diseases.

1,25-Dihydroxyvitamin D3 Ameliorates Collagen-Induced Arthritis via Suppression of Th17 Cells Through miR-124 Mediated Inhibition of IL-6 Signaling.

Objectives: To explore the molecular mechanisms in which vitamin D (VD) regulates T cells, especially Th17 cells in collagen-induced arthritis (CIA). Methods: DBA1/J mice induced for CIA were intraperitoneally treated with VD. CIA clinical symptoms and inflammatory responses including Th1/Th17/Tregs percentages were determined and compared. Mouse naïve CD4+ T cells transduced with miR-124 inhibitor or not were polarized to Th17 cells with or without VD. Subsequently, cellular differentiation and IL-6 signaling moleculars were analyzed. Results: VD treatment significantly delayed CIA onset, decreased incidence and clinical scores of arthritis, downregulated serum IgG levels and ameliorated bone erosion. VD downregulated IL-17A production in CD4+ T cells while increased CD4+Foxp3+Nrp-1+ cells both in draining lymph nodes and synovial fluid in arthritic mice. VD inhibited Th17 cells differentiation in vivo and in vitro and potentially functioning directly on T cells to restrain Th17 cells through limiting IL-6R expression and its downstream signaling including STAT3 phosphorylation, while these effects were blocked when naïve CD4+ T cells were transduced with miR-124 inhibitor. Conclusions: VD treatment ameliorates CIA via suppression of Th17 cells and enhancement of Tregs. miR-124-mediated inhibition of IL-6 signaling, provides a novel explanation for VD's role on T cells in CIA mice or RA patients and suggests that VD may have treatment implications in rheumatoid arthritis.

Differential roles of TNFα-TNFR1 and TNFα-TNFR2 in the differentiation and function of CD4+Foxp3+ induced Treg cells in vitro and in vivo periphery in autoimmune diseases.

Tumor Necrosis Factor (TNF) α is a multifunctional cytokine with pro-inflammatory and anti-inflammatory characteristics. Increasing evidence suggests that thymus-derived, natural regulatory T cells (nTreg) express a remarkably high level of TNF Receptor 2 (TNFR2) and TNFα modulates the number or function of nTreg via TNFR2 in autoimmune diseases. Nonetheless, Treg cells consist of at least nTreg and iTreg that are induced in the periphery or in vitro and two subsets may have different biological characteristics. However, the role of TNF-TNFR signaling in development and function of these iTreg cells is less clear. In this study, we systemically studied the effect of TNFα and its receptor signals on iTreg differentiation, proliferation, and function in vitro and in vivo. We further investigated the expression and requirement of TNFR1 or TNFR2 expression on iTreg by utilizing TNFR1-/- and TNFR2-/- mice. We found that exogenous TNFα facilitated iTreg differentiation and function in vitro. TNFR2 deficiency hampered iTreg differentiation, proliferation, and function, while TNFR1 deficiency decreased the differentiation of inflammatory T cells such as Th1 and Th17 cells but maintained the regulatory capabilities of iTreg both in vitro and in vivo. Using colitis model, we also revealed TNFR2 but not TNFR1 deficiency compromised the iTreg functionality. Interestingly, inflammation affects TNFR expression on nTreg but not iTreg subset. Our results demonstrate that exogenous TNFα may enhance the differentiation and function of iTreg via TNFR2 signaling. The expression of TNFR2 on Treg might be downregulated in some autoimmune diseases, accompanied by an increased level of TNFR1. Thus, TNFR2 agonists or TNFR1-specific antagonists hold a potential promise for clinical application in treating patients with autoimmune diseases.

Sonic Hedgehog Signaling Pathway Mediates Proliferation and Migration of Fibroblast-Like Synoviocytes in Rheumatoid Arthritis via MAPK/ERK Signaling Pathway.

Fibroblast-like synoviocytes (FLSs) are the major effector cells that lead to rheumatoid arthritis (RA) synovitis and joint destruction. Our previous studies showed that Sonic Hedgehog (SHH) signaling pathway is involved in aberrant activation of RA-FLSs and inhibition of SHH pathway decreases proliferation and migration of RA-FLSs. The objective of this study was to investigate if the SHH pathway mediates proliferation and migration of RA-FLSs via the mitogen-activated protein kinases/extracellular signal-regulated kinases (MAPK/ERK) signaling pathway. SHH signaling was studied by using SHH agonist (Purmorphamine) and antagonist (Cyclopamine) targeting the Smoothened (SMO) in FLSs. U0126-EtOH was used to inhibit the MAPK/ERK signaling pathway. The phosphorylation of ERK 1/2 (p-ERKl/2) was examined by western blot. Cell viability was detected using cell proliferation and cytotoxicity kit-8 (CCK8), and cell cycle distribution and proliferating cells were evaluated by the flow cytometry. Cell migration was examined by Transwell assay. Results showed that, compared with the control group, Purmorphamine increased the levels of p-ERK1/2 in concentration-and time-dependent manners (P < 0.01). Co-treated with Purmorphamine and U0126-EtOH or Cyclopamine both decreased the levels of p-ERK1/2 (P < 0.05). RA-FLSs treated with Purmorphamine resulted in alteration of cell cycle distribution, increasing of proliferating cells, cell viability, and migration cells compared to controls (P < 0.01). However, the above phenomenon can be abolished by U0126-EtOH (P < 0.05). The findings suggest that SHH signaling pathway mediates proliferation and migration of RA-FLSs via MAPK/ERK pathway and may contribute to progression of RA. Targeting SHH signaling may have a therapeutic potential in patients with RA.

Apremilast Ameliorates Experimental Arthritis via Suppression of Th1 and Th17 Cells and Enhancement of CD4+Foxp3+ Regulatory T Cells Differentiation.

Apremilast is a novel phosphodiesterase 4 (PDE4) inhibitor suppressing immune and inflammatory responses. We assessed the anti-inflammatory effects of Apremilast in type II collagen (CII)-induced arthritis (CIA) mouse model. To determine whether Apremilast can ameliorate arthritis onset in this model, Apremilast was given orally at day 14 after CII immunization. Bone erosion was measured by histological and micro-computed tomographic analysis. Anti-mouse CII antibody levels were measured by enzyme-linked immunosorbent assay, and Th17, Th1 cells, and CD4+Foxp3+ regulatory T (Treg) cells were assessed by flow cytometry in the lymph nodes. Human cartilage and rheumatoid arthritis (RA) synovial fibroblasts (RASFs) implantation in the severe combined immunodeficiency mouse model of RA were used to study the role of Apremilast in the suppression of RASF-mediated cartilage destruction in vivo. Compared with untreated and vehicle control groups, we found that Apremilast therapy delayed arthritis onset and reduced arthritis scores in the CIA model. Total serum IgG, IgG1, IgG2a, and IgG2b were all decreased in the Apremilast treatment groups. Moreover, Apremilast markedly prevented the development of bone erosions in CIA mice by CT analysis. Furthermore, in the Apremilast treated group, the frequency of Th17 cells and Th1 cells was significantly decreased while Treg cells' frequency was significantly increased. The high dose of Apremilast (25 mg/kg) was superior to low dose (5 mg/kg) in treating CIA. Apremilast treatment reduced the migratory ability of RASFs and their destructive effect on cartilage. Compared with the model group, Apremilast treatment significantly reduced the RASFs invasion cartilage scores in both primary implant and contralateral implant models. Our data suggest that Apremilast is effective in treating autoimmune arthritis and preventing the bone erosion in the CIA model, implicating its therapeutic potential in patients with RA.

Room for more IL-6 blockade? Sarilumab for the treatment of rheumatoid arthritis.

INTRODUCTION: Rheumatoid arthritis (RA) treatment has been revolutionized by the development of highly efficacious biotherapeutics. However, a significant subset of RA patients has persistently active disease and ongoing erosive joint damage despite the available therapies. Sarilumab targets interleukin-6, one of the main cytokines mediating inflammation in RA. Positive results with sarilumab in RA clinical trials support the licensing application currently under review with the US Food and Drug Administration. AREAS COVERED: The rationale for IL-6 targeting in RA, the pharmacologic properties of sarilumab, and the clinical trial results are reviewed focusing on the pending application for the RA indication. Comparisons with other IL-6 targeting biologics as well as additional potential therapeutic directions are discussed. EXPERT OPINION: Sarilumab is a highly active therapeutic in patients with RA. While pharmacologic data demonstrate that sarilumab has a higher affinity than tocilizumab for the target receptor, available clinical results suggest that efficacy and adverse event profiles are similar to this other IL-6 blocker, which is currently approved for the treatment of RA. Whether there are other distinct differences or advantages of sarilumab that will support the approval and successful marketing of this drug, over existing therapies, remains to be determined.

The use and abuse of diagnostic/classification criteria.

In rheumatic diseases, classification criteria have been developed to identify well-defined homogenous cohorts for clinical research. Although they are commonly used in clinical practice, their use may not be appropriate for routine diagnostic clinical care. Classification criteria are being revised with improved methodology and further understanding of disease pathophysiology, but they still may not encompass all unique clinical situations to be applied for diagnosis of heterogenous, rare, evolving rheumatic diseases. Diagnostic criteria development is challenging primarily due to difficulty for universal application given significant differences in the prevalence of rheumatic diseases based on geographical area and clinic settings. Despite these shortcomings, the clinician can still use classification criteria for understanding the disease as well as a guide for diagnosis with a few caveats. We present the limits of current classification criteria, their use and abuse in clinical practice, and how they should be used with caution when applied in clinics.

Significant activity of single agent vinorelbine against small-cell cancer of the bladder as second line chemotherapy: a case series and review of the literature.

Small-cell carcinoma of the urinary bladder is an extremely uncommon form of urologic malignancy, accounting for less that 1% of new cases of bladder cancer. It is an aggressive malignancy which, like its pulmonary counterpart, tends to spread with distant metastases. This malignancy is generally chemotherapy and radiotherapy sensitive. Metastatic disease is typically treated with regimens active against small-cell carcinoma of the lung, such as cisplatin and etoposide. There are no data regarding second-line treatment of this cancer. We report our experience in 3 patients using the second generation vinca alkaloid, vinorelbine, in refractory metastatic small-cell carcinoma of the bladder. These 3 patients had extensive prior therapy but all 3 responded to weekly vinorelbine, with a complete response (CR) in 1, near CR in the second, and partial response in the third. Of note, the patient who sustained a CR has remained without disease and with excellent quality of life for nearly 4 years since starting vinorelbine. Indeed, the therapy was very well tolerated in all 3 patients with grade 2 cytopenia being the only toxicity. We conclude that vinorelbine is well tolerated and has activity in this case series in the second-line treatment of metastatic small-cell carcinoma of the bladder.

Comparison of the Fc fragment from a human IgG1 and its CH2, pFc', and tFc' subfragments. A study using reductive methylation and 13C NMR.

The Fc fragment of a human monoclonal IgG1 was compared with subfragments containing (a) the intact CH2 domain (CH2 fragment) or (b) the intact CH3 domain (pFc' and tFc' fragments). All fragments were reductively 13C-methylated and their resulting dimethyllysyl resonances characterized in 0.1 M KC1 as a function of pH by 13C NMR spectroscopy. Seven resonances were characterized for the 18 lysine residues of the Fc fragment, eight for the 12 lysines of the CH2 fragment, and five each for the 18 lysine residues of the Fc fragment, eight for the 12 lysines of the CH2 fragment, and five each for the 9 lysines of the pFc' and the 6 lysines of the tFc' fragments, respectively. The multiplicity of resonances indicates that the lysine residues in each fragment exist in a variety of microenvironments and that the fragments are all highly structured. The correspondence between 6 of the 12 or 13 perturbed lysine residues in the Fc fragment and the smaller subfragments indicates that the conformation of the CH2 and CH3 domains is largely unchanged in the smaller fragments. However, in addition to three lysines at the CH2-CH3 domain interface, whose environments were known to be disrupted in the smaller fragments, three or four lysine residues have somewhat different properties in the Fc fragment and in the subfragments, indicating that some local perturbations are induced in the domain structure in the subfragments.(ABSTRACT TRUNCATED AT 250 WORDS)

Reductive alkylation with oxidized nucleotides. Use in affinity labeling or affinity chromatography.

A study has been made of the products of a reaction of oxidized ribonucleotides with a primary amine. As a model reaction, periodate-oxidized adenosine was combined with glycine in the presence of NaCNBH3. The purified major product of this reaction, adenine 9,2'-(4'-carboxymethyl-6'-hydroxymethylmorpholine), was characterized by 13C and 1H NMR spectroscopy, ultraviolet spectroscopy, and thin layer chromatography. When used to generate affinity columns, oxidized adenosine or oxidized ATP formed stable products with immobilized diaminohexane when treated with NaCNBH3. Failure to treat with NaCNBH3 yielded an unstable affinity matrix. These results are used in the interpretation of differing results when oxidized nucleotides have been used as affinity labels for different proteins.

Presence of human immunodeficiency virus-1-specific CD4 and CD8 cellular immune responses in children with full or partial virus suppression.

The present study assessed antiviral T cell immune responses in 48 human immunodeficiency virus (HIV)-infected children with a stable or decreasing CD4(+) T cell counts and different levels of viral control, in the presence or absence of antiretroviral therapy. Children with full (<40 copies/mL) or partial (<50,000 copies/mL) virus suppression and with a history of stable CD4(+) T cell counts had significantly increased levels of anti-HIV CD4(+) T cell lymphoproliferative responses, lower levels of CD38(+), and higher CD8(+)/CD28(+) T cell percentage, compared with those in treated children with a lack of virus suppression (>50,000 copies/mL). Levels of anti-HIV CD8(+) T cell activity, although higher in treated children with a lack of virus suppression, were not significantly different between the groups. Although levels of anti-HIV CD4(+) and CD8(+) T cell responses were not associated, these levels of responses were associated with the percentage of specific T cell subsets. Overall, a history of stable CD4(+) T cell counts, as a result of therapy that imparted full or partial virus suppression, was associated with increased levels of anti-HIV CD4(+) T helper responses and decreased T cell activation.