Rag-1 and Rag-2 genes during B lymphocyte develop-University of Cambridge School of Clinical Medicine ment (Billips et al., 1995). Cambridge CB2 2SPThe CD19-CD21 complex achieves these biological United Kingdom responses by synergistically enhancing signaling through † Departments of Medicine and Microbiology mIg. Coligating CD19 or CD21 to mIg lowers the number University of Alabama, Birmingham of mIg required for inducing increases in intracellular Birmingham Veterans Affairs Medical Center Ca 2ϩ concentration ([Ca 2ϩ ] i ) (Carter et al., 1991; Dempsey Birmingham, Alabama 35294 et al., 1996) and the proliferation of B lymphocytes (Car- ‡ National Institute for Medical Research ter and Fearon, 1992). The costimulatory effect of CD19 The Ridgeway on [Ca 2ϩ ]i is associated with the enhanced generation London NW7 1AA of inositol 1,4,5-trisphosphate [I(1,4,5)P 3 ]; ligating CD19 United Kingdom alone also generates I(1,4,5)P 3 , although the amounts are less. The mechanism for this function of CD19 is not known, but both the synergistic and the direct effects Summary of CD19 on the production of I(1,4,5)P 3 occur without its altering the tyrosine phosphorylation of phospholi-CD19 is a coreceptor that amplifies signaling by mempase C (PLC)-␥ (Carter et al., 1991), suggesting that brane immunoglobulin (mIg) to promote responses of CD19 either enhances the efficiency of PLC␥ or inthe B lymphocyte to T-dependent antigens. Vav is a creases the availability of the substrate, phosphatidylguanine nucleotide exchange factor for the Rho, Rac, inositol 4,5-bisphosphate [PI(4,5)P 2], which may become Cdc42 family of small GTPases. We found that coligatrate limiting for inositol lipid hydrolysis (Stephens et al., ing mIg and CD19 causes a synergistic increase in 1993), or does both. the tyrosine phosphorylation of CD19. PhosphorylatedCD19 also costimulates with mIg the mitogen-actityrosine-391 of CD19 binds Vav to mediate a sustained vated protein (MAP) kinases ERK2 (extracellular signalincrease in intracellular Ca 2؉ concentration. This reregulated protein kinase 2), JNK/SAPK (c-Jun N-terminal sponse correlates with activation by the CD19-Vav kinase/stress-activated protein kinase), and p38 (Li et complex of phosphatidylinositol 4-phosphate 5-kinase al., 1997;Tooze et al., 1997). Although ligating mIg or for the synthesis of phosphatidylinositol 4,5-bisphos-CD19 alone causes modest or no activation of these phate. Interaction of CD19 with Vav also mediates the kinases, their coligation causes robust activation of all synergistic activation of the mitogen-activated protein three, even at low levels of mIg cross-linking. Therefore, kinase JNK. Therefore, CD19 is a membrane adaptor at least two general pathways of signaling by mIg are protein that recruits Vav for the activation of lipid and up-regulated by CD19: phosphatidylinositol metaboprotein kinases.lism, leading to elevated [Ca 2ϩ ] i , and the MAP kinase cascades.Vav and the Rho family of small guanosine triphospha-

Background There has been much variation between epidemiological studies that report the prevalence of ankylosing spondylitis (AS). This study aimed to analyze the diagnostic prevalence rates and treatment patterns of male and female AS patients in the United States adult insured population from 2006 to 2016. Methods Trends in AS prevalence were calculated for the 11-year period covering January 1, 2006 to December 31, 2016. Adult (18+ years old) AS patients were included in this retrospective analysis of medical and pharmacy claims data from the IBM Marketscan Commercial, Medicaid and Medicare-Supplemental Claims database. Prevalence was determined as having ≥1 AS diagnostic codes (ICD-9:720.0; ICD-10:M45.x). Trends in treatment patterns were also analyzed and stratified by gender. Results The AS prevalence increased from 0.04 to 0.09% from 2006 to 2016. The mean age between 2006 and 2016 ranged from 49.52–50.00 years. In 2006, approximately 40% of AS patients were female, while in 2016 over 47% of AS patients were female. Rates of use of TNF inhibitors and oral glucocorticoids increased, while NSAIDs and non-biologic DMARDs (sulfasalazine & methotrexate) rates decreased. Opioid use rates were stable. In 2016, males were more likely to be prescribed biologics, while females were more likely to be prescribed methotrexate, sulfasalazine, NSAIDs, muscle relaxants, anticonvulsants, opioids, and glucocorticoids. Conclusions The prevalence of AS diagnosis codes more than doubled between 2006 and 2016, but the very low prevalence suggests that AS continues to be underdiagnosed and under-addressed in routine clinical practice. Despite the increase in female AS patients, females were less likely to be prescribed biologics compared to male AS patients.

Introduction Ixekizumab, a humanized interleukin-17A antibody, has shown efficacy in ankylosing spondylitis (AS), with a greater proportion of ixekizumab-treated patients achieving an ASAS40 (Assessment of Spondyloarthritis International Society 40) endpoint compared to placebo. An ASAS40 response is a high standard that is not routinely used in clinical practice. The goals of this study were (a) to measure improvement in ixekizumab-treated patients in the four ASAS treatment response domains and in other patient-reported outcomes, and (b) to determine how the ASAS response was associated with changes in spinal pain at night, fatigue, sleep, and the Short Form 36-Item Physical Component Summary (SF-36 PCS). Methods The COAST-V and COAST-W trials were randomized, double-blind, controlled trials examining ixekizumab efficacy in patients with AS who were biologic disease-modifying antirheumatic drug (bDMARD)-naïve and tumor necrosis factor inhibitor (TNFi)-experienced, respectively. Data for the ASAS treatment response domains and other outcomes were collected through 16 weeks. Comparisons between treatment groups were made using a mixed-effects model for repeated measures. To determine how the ASAS response was associated with the changes in spinal pain at night, fatigue, sleep, and SF-36 PCS, comparisons were made between patient groups according to their level of treatment response (ASAS40 vs. ASAS20 vs. ASAS20 nonresponse) using analysis of covariance. Results Compared with placebo, patients treated with ixekizumab reported significantly greater improvement in the four ASAS treatment response domains and other outcomes ( p < 0.05). Results were consistent for bDMARD-naïve and TNFi-experienced patients. Compared to ASAS20 nonresponders, patients who achieved ASAS40 reported significantly greater mean changes in spinal pain at night (1.0 vs. 5.1 for bDMARD-naïve; 0.5 vs. 5.4 for TNFi-experienced), fatigue (0.6 vs. 3.8 for bDMARD-naïve; 0.2 vs. 3.9 for TNFi-experienced), sleep quality (1.1 vs. 4.0 for bDMARD-naïve; 0.8 vs. 4.9 for TNFi-experienced), and SF-36 PCS (2.6 vs. 11.6 for bDMARD-naïve; 1.2 vs. 12.6 for TNFi-experienced) ( p < 0.0001). Conclusion Patients with AS who were treated with ixekizumab reported greater improvements in multiple patient-reported outcomes than patients who received placebo. Importantly, achieving ASAS40 was associated with a 2.6-fold to 5.3-fold greater improvement in pain, fatigue, sleep, and quality of life for bDMARD-naïve patients, and a 5.1-fold to 18.5-fold greater improvement for TNFi-experienced patients, compared to ASAS20 nonresponders. Trial Registration ClinicalTrials.gov identifiers: NCT02696785 and NCT02696798. Funding Eli Lilly and Company.

Objectives The aim of this study was to compare the symptoms, treatment patterns, and quality of life (QoL) of ankylosing spondylitis (AS) patients to non-radiographic axial spondyloarthritis (nr-axSpA) patients in the USA. Method A cross-sectional survey was conducted with rheumatologists and their consulting patients in the USA from June through August 2018. Patients who had a rheumatologist confirmed diagnosis of AS and nr-axSpA were eligible to participate. Patient demographics, symptoms, and medication use were reported by the rheumatologist, while work disability and QoL measures were reported by the patient. Patient demographics, symptoms, QoL and treatment patterns of AS and nr-axSpA patients were compared using parametric tests and non-parametric tests when appropriate. Results A total of 515 AS patients and 495 nr-axSpA patients were included in this analysis. A higher proportion of AS patients were male (p < 0.001), older (p = 0.014), and more likely to be prescribed a biologic (p < 0.0001). On average, AS patients experienced slightly more symptoms at diagnosis (p = 0.023); however, nr-axSpA patients were more likely to experience enthesitis (p = 0.048) and synovitis (p = 0.003). Patient reported outcomes such as the ASAS Health Index (p = 0.171), ASQoL (p = 0.296), BASDAI (p = 0.124), and WPAI (p = 0.183) were similar between AS and nr-axSpA patients after adjusting for confounding variables such as medication use. Conclusions AS and nr-axSpA patients share the same clinical features. The burden of the disease, as assessed by QoL measurements, is also similar in AS and nr-axSpA patients; however, despite these similarities, patients with nr-axSpA are less likely to be treated with a biologic. Key Points • Ankylosing spondylitis and non• radiographic axial spondyloarthritis patients share similar clinical features and burden of disease.• Quality of life is similar among ankylosing spondylitis and non• radiographic axial spondyloarthritis after adjusting for current treatment patterns.