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Juvenile localized scleroderma (jLS) is a chronic autoimmune and fibrosing disease associated with a high risk for functional impairment. Antifibrotic options are limited, so current treatment strategies are focused on disease activity control. Pediatric rheumatologists are in consensus on the need to treat with systemic immunosuppressants, in particular, methotrexate. However, more than 30% of patients fail initial methotrexate treatment. This review provides an update on current management and reviews reports on potential alternative treatments.An overview of current treatment recommendations and its efficacy are discussed. Recent studies have identified several factors associated with likelihood of treatment response. These include time to initiation of treatment, certain subtypes, and extracutaneous involvement. Findings from recent reports of alternative systemic immunomodulators, including biologic medications, will be summarized.Methotrexate treatment has greatly improved outcome for most jLS patients but a substantial portion have refractory cutaneous and/or extracutaneous disease. Treatment response factors are being identified, which could lead to improved management strategies. Recent studies provide further support on mycophenolate mofetil as an alternative treatment. Data on biologic therapies is encouraging, with data suggesting efficacy for many extracutaneous manifestations but more studies are needed to evaluate these and other options for jLS.

To evaluate disease activity of late onset psoriatic arthritis (LoPsA) patients at presentation, during follow-up, and after 5years of follow-up, compared to young onset PsA patients (YoPsA).The study included patients with PsA followed prospectively within 2years from diagnosis. Patients were divided into two groups: (1) LoPsA - defined as disease onset ≥ 50 years, (2) YoPsA - defined as disease onset 50 years. Descriptive statistics are provided and multivariable logistic regression models were developed to compare these groups.Five hundred and sixty-six patients were included at presentation. Regression analysis showed that the LoPsA group at presentation was characterized by: less males (OR 0.4, p = 0.001), less HLA-C*06 (OR 0.3, p = 0.005), longer psoriasis duration (OR 1.04, p = 0.0005), higher BMI (OR 1.1, p = 0.005) and higher modified Steinbrocker score (mSS) (OR 1.1, p = 0.005). Regression analysis adjusted for gender, BMI, psoriasis duration, HLA and treatments after 5years of follow-up revealed a trend toward higher adjusted mean active joint count (OR 7.98, p = 0.052) and higher mean mSS score (OR 13.39, p = 0.007) in the LoSpA group compared to the YoPsA group. During 5years of follow-up, the YoPsA patients were treated with more NSAIDs (96% vs. 88%, p = 0.04), while there were no significant differences in the DMARDs and biologic drugs.The LoPsA patients at presentation are characterized by female predominance, higher BMI, more damage and less HLA-C*06. After 5years of follow-up the LoPsA patients have worse prognosis manifested by a trend toward higher disease activity burden and significantly more damage.

ObjectivesWe aimed to identify soluble biomarkers that differentiate psoriatic arthritis (PsA) from osteoarthritis (OA).MethodsMarkers of cartilage metabolism (cartilage oligomeric matrix protein [COMP], hyaluronan), metabolic syndrome (adiponectin, adipsin, resistin, hepatocyte growth factor [HGF], insulin, leptin) and inflammation (C-reactive protein [CRP], interleukin-1β [IL-1β], IL-6, IL-8, tumour necrosis factor alpha [TNFα], monocyte chemoattractant protein-1 [MCP-1], nerve growth factor [NGF]) were compared in serum samples from 201 patients with OA, 77 patients with PsA and 76 controls. Levels across the groups were compared using the Kruskal-Wallis test. Pairwise comparisons were made with Wilcoxon rank-sum test. Multivariate logistic regression analyses were performed to identify markers that differentiate PsA from OA. Receiver operating characteristic (ROC) curves were constructed based on multivariate models. The final model was further validated in an independent set of 73 PsA and 75 OA samples using predicted probabilities calculated with coefficients of age, sex and biomarkers.ResultsLevels of the following markers were significantly different across the three groups (pConclusionA panel of four biomarkers may distinguish PsA from OA. These results need further validation in prospective studies.

Concerns about malaria parasite resistance to treatment with artemisinin drugs (ARTs) have grown with findings of prolonged parasite clearance t1/2s (>5 h) and their association with mutations in Plasmodium falciparum Kelch-propeller protein K13. Here, we describe a P. falciparum laboratory cross of K13 C580Y mutant with C580 wild-type parasites to investigate ART response phenotypes in vitro and in vivo. After genotyping >400 isolated progeny, we evaluated 20 recombinants in vitro: IC50 measurements of dihydroartemisinin were at similar low nanomolar levels for C580Y- and C580-type progeny (mean ratio, 1.00; 95% CI, 0.62–1.61), whereas, in a ring-stage survival assay, the C580Y-type progeny had 19.6-fold (95% CI, 9.76–39.2) higher average counts. In splenectomized Aotus monkeys treated with three daily doses of i.v. artesunate, t1/2 calculations by three different methods yielded mean differences of 0.01 h (95% CI, −3.66 to 3.67), 0.80 h (95% CI, −0.92 to 2.53), and 2.07 h (95% CI, 0.77–3.36) between C580Y and C580 infections. Incidences of recrudescence were 57% in C580Y (4 of 7) versus 70% in C580 (7 of 10) infections (−13% difference; 95% CI, −58% to 35%). Allelic substitution of C580 in a C580Y-containing progeny clone (76H10) yielded a transformant (76H10C580Rev) that, in an infected monkey, recrudesced regularly 13 times over 500 d. Frequent recrudescences of ART-treated P. falciparum infections occur with or without K13 mutations and emphasize the need for improved partner drugs to effectively eliminate the parasites that persist through the ART component of combination therapy.

Malaria parasites transmitted by mosquito bite are remarkably efficient in establishing human infections. The infection process requires roughly 30 minutes and is highly complex as quiescent sporozoites injected with mosquito saliva must be rapidly activated in the skin, migrate through the body, and infect the liver. This process is poorly understood for Plasmodium vivax due to low infectivity in the in vitro models. To study this skin-to-liver-stage of malaria, we used quantitative bioassays coupled with transcriptomics to evaluate parasite changes linked with mammalian microenvironmental factors. Our in vitro phenotyping and RNA-seq analyses revealed key microenvironmental relationships with distinct biological functions. Most notable, preservation of sporozoite quiescence by exposure to insect-like factors coupled with strategic activation limits untimely activation of invasion-associated genes to dramatically increase hepatocyte invasion rates. We also report the first transcriptomic analysis of the P. vivax sporozoite interaction in salivary glands identifying 118 infection-related differentially-regulated Anopheles dirus genes. These results provide important new insights in malaria parasite biology and identify priority targets for antimalarial therapeutic interventions to block P. vivax infection.

Objectives: The aim of our study was to evaluate the incidence, prevalence, characteristics, disease associations, risk factors and outcome of clinical enthesitis in patients with PsA. Methods: The study included patients with PsA followed prospectively. Enthesitis was defined as the presence of at least one tender enthesis at one of the 18 entheseal sites of the Spondyloarthritis Research Consortium of Canada enthesitis index. Results: Between 2008 and 2014, 281 of 803 patients had enthesitis providing a prevalence of 35%. 192 patients developed enthesitis during the course of follow-up, with an annual incidence of 0.9%. Most of the patients had 1 (48.4%) or 2 (32.2%) tender entheseal sites and the mean (s.d.) number of sites per visit was 2.03 (1.6). The 3 most common sites were at the insertions of the Achilles tendons and plantar fascia on the calcaneus, and the lateral epicondyles (24.2%, 20.8% and 17.2%, respectively). More active disease (higher actively inflamed joint count, tenosynovitis and dactylitis), more pain and less clinical damage were associated with enthesitis. Higher BMI, more actively inflamed joints and younger age were risk factors for developing this condition. Enthesitis resolved in most patients without changing treatment. Conclusion: Clinical enthesitis is common with a period prevalence of 35% of PsA patients. It usually involves only 1 or 2 sites simultaneously. The most common tender sites are at the insertions of the Achilles tendon, plantar fascia and the lateral epicondyles. More active disease and more pain are associated with enthesitis. This article is protected by copyright. All rights reserved.

Objective.We aimed to determine the prevalence and quality of sleep in patients with psoriatic arthritis (PsA) and those with psoriasis without PsA (PsC) followed in the same center, to identify factors associated with sleep disturbance, and to compare findings to those of healthy controls (HC).Methods.The study included 113 PsA [ClASsification for Psoriatic ARthritis (CASPAR) criteria] and 62 PsC (PsA excluded by a rheumatologist) patients and 52 HC. Clinical variables were collected using a standard protocol. The sleep quality was evaluated using the Pittsburgh Sleep Quality Index (PSQI). Other patient-reported outcomes collected included the Health Assessment Questionnaire (HAQ), Dermatology Life Quality Index, EQ-5D, Medical Outcomes Study Short Form-36 survey, patient’s global assessment, and the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-fatigue) scale. Statistical analyses included descriptive statistics, Wilcoxon rank-sum test, and linear regression.Results.The prevalence of poor sleep quality was 84%, 69%, and 50% in PsA, PsC, and HC, respectively. Total PSQI score was higher in both patients with PsA and patients with PsC compared with HC (p < 0.01) and higher in patients with PsA compared to patients with PsC (p < 0.0001). EQ-5D anxiety component, EQ-5D final, and FACIT-fatigue were independently associated with worse PSQI in patients with PsC and those with PsA (p < 0.05). Actively inflamed (tender or swollen) joints are independently associated with worse PSQI in patients with PsA (p < 0.01).Conclusion.Patients with psoriatic disease have poor sleep quality. Poor sleep is associated with fatigue, anxiety, and lower EQ-5D. In patients with PsA, poor sleep is associated with active joint inflammation.

Background Adjuvant chemotherapy (ACT) improved survival in the NCIC Clinical Trials Group JBR.10 trial of resected stage IB/II non–small-cell lung cancer. A prognostic 15-gene expression signature was developed, which may also predict for benefit from ACT. An exploratory economic analysis was conducted to assess the potential cost-effectiveness of using the 15-gene signature in guiding ACT decisions. Methods A decision analytic model was populated by study patients with quantitative reverse transcription polymerase chain reaction tumor profiling, current costs, and quality-adjusted survival. Analysis was performed over the 6-year follow-up from the perspective of the Canadian public health care system in 2015 Canadian dollars (discounted 5%/year). Incremental cost-effectiveness and cost-utility ratios were determined for ACT versus observation using clinical stage, gene signature, or a combined approach to select treatment. Results The mean survival gain of ACT versus observation was higher using the gene signature (1.86 years) compared with clinical stage (1.28 years). Although more costly, ACT guided by the gene signature remained cost-effective at $10,421/life-year gained (95% confidence interval [CI], $466-$19,568 Canadian), comparable to stage-directed selection ($7081/life-year gained; 95% CI, −$2370 to $14,721; P = .52). Incremental cost-utility ratios were $13,452/quality-adjusted life-year (95% CI, $373-$31,949) and $9194/quality-adjusted life-year (95% CI, −$4104 to $23,952), respectively ( P = .53). Comparing the standard and test-and-treat approaches, use of the gene signature did not significantly alter survival compared with the standard strategy, but it reduced the ACT rate by 25%. Conclusion If validated, the use of the 15-gene expression signature to select patients for ACT may increase the survival gain of treatment in patients with high-risk stage IB/II non–small-cell lung cancer, while avoiding toxicities in low-risk patients.

OBJECTIVE The Psoriatic Arthritis Disease Activity Score (PASDAS) is a composite measure of psoriatic arthritis (PsA) disease activity. The length of its patient-reported components raises concern about questionnaire burden. The PASDAS includes the Medical Outcomes Study Short Form 36 (SF-36) health survey. We undertook this study to investigate the agreement between the PASDAS and a modified PASDAS (mPASDAS), which substituted the SF-36 with the shortened SF-12. METHODS A total of 100 patients who fulfilled the criteria of the Classification of Psoriatic Arthritis Study Group for PsA were consecutively recruited. All of the PASDAS-required variables were collected. The 12 item responses for SF-12 were extracted from the SF-36 questionnaire. The PASDAS and the mPASDAS were calculated using the SF-36 and SF-12 scores, respectively. A Bland-Altman plot of the mean differences in PASDAS and mPASDAS scores was generated to evaluate agreement. Construct validity was assessed by examining correlations of the PASDAS and the mPASDAS with the Health Assessment Questionnaire, the Functional Assessment of Chronic Illness Therapy-Fatigue subscale, the EuroQol 5-domain instrument (health-related quality of life), and pain scores (range 0-10, visual analog scale). The kappa statistic was used to measure agreement between disease activity states as determined by the PASDAS and mPASDAS. RESULTS The mean ± SD PASDAS and mPASDAS was 3.29 ± 1.39 and 3.24 ± 1.27, respectively. The correlation between the 2 scores was 0.998 (P < 0.0001), and the mean difference was -0.05 (95% confidence interval [95% CI] -0.07, -0.03). Construct validity was found, with nearly identical correlations of the PASDAS and mPASDAS with each of the external health measures. The misclassification rate with the mPASDAS was only 6%. The weighted κ = 0.90 (95% CI 0.82, 0.97). CONCLUSION The mPASDAS may replace the PASDAS in disease activity assessment given the excellent agreement, validity, and low misclassification rate.

Concerns about malaria parasite resistance to treatment with artemisinin drugs (ARTs) have grown with findings of prolonged parasite clearance t(1/2)s (>5 h) and their association with mutations in Plasmodium falciparum Kelch-propeller protein K13. Here, we describe a P. falciparum laboratory cross of K13 C580Y mutant with C580 wild-type parasites to investigate ART response phenotypes in vitro and in vivo. After genotyping >400 isolated progeny, we evaluated 20 recombinants in vitro: IC(50) measurements of dihydroartemisinin were at similar low nanomolar levels for C580Y- and C580-type progeny (mean ratio, 1.00; 95% CI, 0.62–1.61), whereas, in a ring-stage survival assay, the C580Y-type progeny had 19.6-fold (95% CI, 9.76–39.2) higher average counts. In splenectomized Aotus monkeys treated with three daily doses of i.v. artesunate, t(1/2) calculations by three different methods yielded mean differences of 0.01 h (95% CI, −3.66 to 3.67), 0.80 h (95% CI, −0.92 to 2.53), and 2.07 h (95% CI, 0.77–3.36) between C580Y and C580 infections. Incidences of recrudescence were 57% in C580Y (4 of 7) versus 70% in C580 (7 of 10) infections (−13% difference; 95% CI, −58% to 35%). Allelic substitution of C580 in a C580Y-containing progeny clone (76H10) yielded a transformant (76H10(C580Rev)) that, in an infected monkey, recrudesced regularly 13 times over 500 d. Frequent recrudescences of ART-treated P. falciparum infections occur with or without K13 mutations and emphasize the need for improved partner drugs to effectively eliminate the parasites that persist through the ART component of combination therapy.

INTRODUCTION Malaria remains a devastating global parasitic disease, with the majority of malaria deaths caused by the highly virulent Plasmodium falciparum . The extreme AT-bias of the P. falciparum genome has hampered genetic studies through targeted approaches such as homologous recombination or CRISPR-Cas9, and only a few hundred P. falciparum mutants have been experimentally generated in the past decades. In this study, we have used high-throughput piggyBac transposon insertional mutagenesis and quantitative insertion site sequencing (QIseq) to reach saturation-level mutagenesis of this parasite. RATIONALE Our study exploits the AT-richness of the P. falciparum genome, which provides numerous piggyBac transposon insertion targets within both gene coding and noncoding flanking sequences, to generate more than 38,000 P. falciparum mutants. At this level of mutagenesis, we could distinguish essential genes as nonmutable and dispensable genes as mutable. Subsequently, we identified 2680 genes essential for in vitro asexual blood-stage growth. RESULTS We calculated mutagenesis index scores (MISs) and mutagenesis fitness scores (MFSs) in order to functionally define the relative fitness cost of disruption for 5399 genes. A competitive growth phenotype screen confirmed that MIS and MFS were predictive of the fitness cost for in vitro asexual growth. Genes predicted to be essential included genes implicated in drug resistance—such as the “ K13 ” Kelch propeller, mdr , and dhfr-ts —as well as targets considered to be high value for drugs development, such as pkg and cdpk5 . The screen revealed essential genes that are specific to human Plasmodium parasites but absent from rodent-infective species, such as lipid metabolic genes that may be crucial to transmission commitment in human infections. MIS and MFS profiling provides a clear ranking of the relative essentiality of gene ontology (GO) functions in P. falciparum . GO pathways associated with translation, RNA metabolism, and cell cycle control are more essential, whereas genes associated with protein phosphorylation, virulence factors, and transcription are more likely to be dispensable. Last, we confirm that the proteasome-degradation pathway is a high-value druggable target on the basis of its high ratio of essential to dispensable genes, and by functionally confirming its link to the mode of action of artemisinin, the current front-line antimalarial. CONCLUSION Saturation-scale mutagenesis allows prioritization of intervention targets in the genome of the most important cause of malaria. The identification of more than 2680 essential genes, including ~1000 Plasmodium -conserved essential genes, will be valuable for antimalarial therapeutic research.

ObjectiveWe aimed to determine the agreement between rheumatologist-judged inflammatory back pain (IBP) and criteria defining IBP in patients with psoriatic arthritis (PsA) and predictive value of IBP in identifying axial involvement in PsA.MethodsUsing prospectively collected data, we investigated the agreement between rheumatologist judgement of IBP and IBP criteria (Calin, Rudwaleit and Assessment of Spondyloarthritis International Society) using the kappa coefficient. We also determined the sensitivity, specificity and likelihood ratios of the presence of back pain, rheumatologist-judged IBP and the three IBP criteria for detecting axial PsA (AxPsA). Finally, we compared the clinical and genetic markers in patients with PsA with axial radiological changes with and without back pain.Results171 patients (52% male, mean age 46.6 years) were identified. Ninety-six (56.13%) patients reported chronic back pain. Sixty-five (38.01%) had IBP. 54 (32%) patients had evidence of radiological change in the spine. The agreement between rheumatologist judgement of IBP and IBP criteria was highest for the Calin criteria (0.70). Positive likelihood ratio for the presence of radiological axial involvement was highest for Rudwaleit criteria (2.17). No differences between patients with AxPsA with or without back pain were found, except for higher Bath Ankylosing Spondylitis Disease Activity Index and lower prevalence of human leucocyte antigen-B*38 in those with back pain.ConclusionRheumatologist-judged IBP or the criteria for IBP developed for ankylosing spondylitis may not perform well when ascertaining axial involvement in PsA.

Malaria remains one of the most devastating parasitic diseases worldwide, with 90% of the malaria deaths in Africa in 2013 attributable to Plasmodium falciparum. The clinical symptoms of malaria include cycles of fever, corresponding to parasite rupture from red blood cells every 48 h. Parasite pathways involved in the parasite’s ability to survive the host fever response, and indeed, the functions of ~40% of P. falciparum genes as a whole, are still largely unknown. Here, we evaluated the potential of scalable forward-genetic screening methods to identify genes involved in the host fever response. We performed a phenotypic screen for genes linked to the parasite response to febrile temperatures by utilizing a selection of single-disruption P. falciparum mutants generated via random piggyBac transposon mutagenesis in a previous study. We identified several mutants presenting significant phenotypes in febrile response screens compared to the wild type, indicating possible roles for the disrupted genes in this process. We present these initial studies as proof that forward genetics can be used to gain insight into critical factors associated with parasite biology. IMPORTANCE Though the P. falciparum genome sequence has been available for many years, ~40% of its genes do not have informative annotations, as they show no detectable homology to those of studied organisms. More still have not been evaluated via genetic methods. Scalable forward-genetic approaches that allow interrogation of gene function without any pre-existing knowledge are needed to hasten understanding of parasite biology, which will expedite the identification of drug targets and the development of future interventions in the face of spreading resistance to existing frontline drugs. In this work, we describe a new approach to pursue forward-genetic phenotypic screens for P. falciparum to identify factors associated with virulence. Future large-scale phenotypic screens developed to probe other such interesting phenomena, when considered in parallel, will prove a powerful tool for functional annotation of the P. falciparum genome, where so much remains undiscovered.

Author(s): Fotis, Lampros; Shaikh, Nur; Baszis, Kevin; French, Anthony; Tarr, Phillip; Grevich, Sriharsha; Lee, Peggy; Ringold, Sarah; Leroux, Brian; Leahey, Hannah; Yuasa, Megan; Foster, Jessica; Sokolove, Jeremy; Lahey, Lauren; Robinson, William; Newsom, Joshua; Stevens, Anne; Karasawa, Rie; Tamaki, Mayumi; Tanaka, Megumi; Sato, Toshiko; Yudoh, Kazuo; Jarvis, James N; Moncrieffe, Halima; Bennett, Mark F; Tsoras, Monica; Luyrink, Lorie; Xu, Huan; Prahalad, Sampath; Morris, Paula; Dare, Jason; Nigrovic, Peter A; Rosenkranz, Margalit; Becker, Mara; O’Neil, Kathleen M; Griffin, Thomas; Lovell, Daniel J; Grom, Alexei A; Medvedovic, Mario; Thompson, Susan D; Zhu, Lisha; Jiang, Kaiyu; Wong, Laiping; Buck, Michael J; Chen, Yanmin; Moncrieffe, Halima; Brungs, Laura; Liu, Tao; Wang, Ting; Jarvis, James N; Alsaeid, Khaled; Alfailakawi, Jasim; Alenezi, Hamid; Alsaeed, Hazim; Beukelman, Tim; Natter, Marc; Ilowite, Norm; Mieszkalski, Kelly; Burrell, Grendel; Best, Brian; Bristow, Helen; Carr, Shannon; Dennos, Anne; Kaufmann, Rachel; Kimura, Yukiko; Schanberg, Laura; Blier, Peter R; Boneparth, Alexis; Wenderfer, Scott E; Moorthy, L Nandini; Radhakrishna, Suhas M; Sagcal-Gironella, Anna Carmela P; von Scheven, Emily; Gedik, Kader Cetin; Siddique, Salma; Aguiar, Cassyanne L; Erkan, Doruk; Cohen, Ezra; Lee, Yvonne; Dossett, Michelle; Mehta, Darshan; Davis, Roger; Gilbert, Mileka; Goilav, Beatrice; Meidan, Esra

Objectives To evaluate disease activity in the joints and skin during pregnancy and the first-year postpartum in patients with psoriatic arthritis (PsA). Methods Women with PsA who were pregnant between 1990 and 2015 with at least 1 clinic visit during pregnancy were identified from the Toronto PsA database. The course of joint and skin disease activity was defined by the following 5 states: improvement, worsening, stable low, stable high, or a mixed. As controls, 67 nonpregnant PsA women were identified and evaluated over a similar timeframe. Results Altogether, 29 PsA women with 42 pregnancies were identified. Of the 42 pregnancies, 40 (95%) resulted in normal live birth. Arthritis improved or was stable low activity in 24 (58.5%) of pregnancies. During the postpartum period, 21 (52.5%) had either improvement or stable low PsA activity, whereas 16 (40%) had either worsening or stable high disease activity. The skin activity during pregnancy either improved or stayed in a stable low state in 30 (88.2%), and in the postpartum period there was worsening in 15 (42.9%). A logistic regression analysis revealed a favourable skin disease course during the pregnancy period in the pregnant group compared to the control group (OR = 6.8, p = 0.004), but not in joint disease. Conclusions The outcome of pregnancy among patients with PsA is excellent. Arthritis activity trends toward a favourable course while the skin disease shows a favorable course during pregnancy. When compared to controls, pregnancy period has significant beneficial influence only on the skin but not on the joints in PsA.

Objective.To investigate the rate, type, characteristics, and predictors of infection in a cohort of patients with psoriatic arthritis (PsA) and a cohort of patients with psoriasis without arthritis (PsC).Methods.A cohort of patients with PsA and a cohort of patients with PsC were followed according to a standard protocol and information on the occurrence of infections was recorded. The rate of infection was estimated by fitting an exponential model. A Weibull regression model was fitted to estimate the relative risk of first infection associated with a number of covariates. Risk factors for recurrent infections were investigated using generalized estimating equations.Results.There were 498 and 74 infections reported among 695 and 509 patients with PsA and PsC, respectively, with an incidence rate of 19.6 per 100 person-years in the PsA cohort compared with 12.2 in the PsC cohort. The HR of the time to the first infection in PsA versus PsC was 1.6 (p = 0.002), and higher in patients treated with biologics versus nonbiologics at 1.56 (95% CI 1.22–2.00) in PsA and 1.50 (95% CI 0.64–3.54) in the PsC cohorts. Female sex and treatment with biologics were associated with infection in the PsA cohort, whereas a lower Psoriasis Area and Severity Index score and a higher Functional Comorbidity Index were associated with infection in the PsC cohort. Ultraviolet treatment was protective against infection in both cohorts. No difference in rates of hospitalization was found (p = 0.66). There were no infection-related deaths in either cohort.Conclusion.The incidence rate of infection was higher in the PsA than the PsC cohort and higher among patients treated with biologics. The data confirm the association between infection and biologic treatment in psoriatic disease.

Type I IFNs induce gene expression through Stat1 and Stat2, which can in turn associate either to form Stat1 homodimers or the transcription factor ISGF-3. Stat1 homodimers also transduce signals for IFN-γ. To explore the unique properties of Stat2 and ISGF-3 in type I IFN signaling, its gene was targeted for deletion. Stat2 null mice exhibit a number of defects in immune response. This includes an increased susceptibility to viral infection and the loss of a type I IFN autocrine/paracrine loop, which in turn regulates several aspects of immune response. Intriguingly, Stat2-deficient fibroblasts exhibit a more significant defect in their response to type I IFNs than macrophages, highlighting tissue-specific differences in the response to this family of ligands.

Brain factor-1 (BF-1) is a winged-helix (WH) transcription factor with a restricted pattern of expression in the neural tube. In the embryo, BF-1 is localized to the progenitor cells of the most rostral neural tube, the telencephalic neuroepithelium. Expression of BF-1 persists in the adult brain in the structures derived from the telencephalon, including the cerebral cortex, the hippocampus, the olfactory bulbs and the basal ganglia. Targeted disruption of the BF-1 gene in mice results in hypoplasia of the cerebral hemispheres. Proliferation of the telencephalic neuroepithelium is decreased and neuronal differentiation occurs prematurely. The forebrain of the BF-1 (-/-) mutant also displays dorsal-ventral patterning defects. Development of the ventral (basal) region of the telencephalon is more severely affected than the dorsal region. These anomalies are associated with the ectopic expression of BMP4 in the dorsal telencephalic neuroepithelium and the loss of shh in the ventral telencephalon. These results raise the possibility that BF-1 may modulate both progenitor cell proliferation and regional patterning by regulating the expression or activity of inductive signals which act on the telencephalic neuroepithelium.

Background It is often difficult to differentiate psoriatic arthritis (PsA) from osteoarthritis (OA) in clinical practice. Objectives To aid clinical diagnosis, we aimed to identify soluble biomarkers that differentiate PsA from OA. Methods Serum samples from 201 patients with OA (mean age 65 years, 43.3% males, no history of inflammatory disease), 77 patients with PsA satisfying CASPAR criteria (mean age 45 years, 54.5% males) and 76 healthy controls (mean age 37 years, 50% males) were obtained from the respective biobanks of the Arthritis Program, University Health Network, and the University of Toronto PsA Program. Samples were obtained at the time of joint replacement surgery (OA) or at the time of clinical assessment (PsA, healthy controls), and stored at -80°C until laboratory assays were conducted. Soluble markers of cartilage metabolism (COMP, hyaluronan), metabolic syndrome (adiponectin, adipsin, resistin, HGF, insulin, leptin) and inflammation/immune response (CRP, IL-1b, -6, -8, TNF-α, MCP-1, NGF) were assayed in the samples using Luminex multiplex assay. Marker levels in serum were compared across the 3 groups using the Kruskal-Wallis test. Pair-wise comparisons were made with Wilcoxon rank sum test. To identify markers that differentiate PsA from OA, multivariate logistic regression analyses with backward elimination, adjusted for age and sex, were constructed using markers determined to be significant at a p≤0.1 from univariate analyses. Discriminative ability was assessed by way of receiver operating characteristic (ROC) curves based on findings from multivariate models. The final model was further validated in an independent set of 73 PsA and 75 OA samples using predicted probabilities estimated using coefficients from the model developed on the training set. Results Univariate analyses revealed the following markers significantly differed across groups (p Conclusions A panel of 4 biomarkers (COMP, resistin, MCP-1, NGF) may distinguish PsA from OA. Clinical utility of these markers will need to be determined in prospective studies. Disclosure of Interest None declared

Background The Psoriatic Arthritis Disease Activity Score (PASDAS) is a newly developed composite disease activity measure that summarizes psoriatic arthritis (PsA) disease activity with a score ranging from 0–10. PASDAS captures articular and extra-articular manifestations of the disease and the impact of the disease on the patient via the following variables: swollen and tender joints, dactylitis, Leeds enthesitis index, C-reactive protein, Health Assessment Questionnaire, physician and patient global disease activity, and the physical component summary score (PCS) of the medical outcomes survey Short Form 36 (SF-36). A limitation of PASDAS is that the score depends on the patient completing the SF-36, which requires a significant amount of time to complete. A shorter 12-question subset of SF-36, the SF-12, with the same range of values, agrees well with the SF-36 in many patient populations. Objectives The objective was to measure the agreement between PASDAS calculated using the standard scoring formula and mPASDAS calculated by replacing the SF-36-PCS with SF-12-PCS. Methods 100 PsA patients attending the University of Toronto PsA clinic for follow-up visits were consecutively recruited in June and July 2015. All variables required to calculate PASDAS were collected and PASDAS was calculated for each patient. The 12 item responses for SF-12 were extracted from the SF-36 questionnaires. A mPASDAS score was subsequently calculated based on the PASDAS scoring formula where SF-36 –PCS is replaced by SF-12 - PCS. A Bland-Altman plot of the differences in scores calculated via PASDAS and mPASDAS measured agreement between the two sets of scores. The rate of missclassification when categorizing the patient9s disease activity state as high, moderate or low using the mPASDAS instead of PASDAS was also examined. Results The analysis [N=100, 53% male, mean (SD) age 57.3 (11.9) years, mean (SD) disease duration 16.9 (11.7) years] revealed that the mean (SD) PASDAS was 3.29 (1.39) and the mean (SD) mPASDAS was 3.24 (1.27). The Bland-Altman plot showed a mean difference (95%CI) between mPASDAS and PASDAS of -0.05 (-0.07, -0.03). The lower limit and upper limits of the difference was (-0.24 [95%CI -0.21, -0.28]) and 0.14 [0.10, 0.17]), respectively. Five (5%) patients were misclassified (4 to the lower disease activity category) when mPASDAS was used instead of PASDAS. Conclusions mPASDAS and PASDAS shows strong agreement without clinically significant systematic bias in mPASDAS scores. In clinical settings, the mPASDAS may replace PASDAS in disease activity assessment given the strong agreement and low misscalssification rate along with significantly reduced questionnaire burden. Disclosure of Interest None declared

To determine the long-term safety and efficacy of rilonacept, an anti-interleukin-1 fusion protein, in patients with active systemic juvenile idiopathic arthritis (JIA).In patients with systemic JIA, ages 4-20 years, the efficacy of rilonacept was evaluated using 30%, 50%, and 70% levels of improvement according to the adapted American College of Rheumatology (ACR) Pediatric 30, 50, and 70 response criteria, respectively. Efficacy and safety were evaluated during 23 months of open-label treatment (3 phases) after a 4-week, double-blind, placebo-controlled phase. Following double-blind treatment with 2.2 mg/kg or 4.4 mg/kg of rilonacept, patients were eligible to receive open-label treatment at their prior dose, with adjustments. Reductions in the median daily dose of oral prednisone and improvements in laboratory parameters of disease activity (i.e., decreased levels of D-dimer and myeloid-related proteins [MRPs]) were also evaluated.Twenty-four patients entered the double-blind study and 23 entered the open-label period. Patients were predominantly white and female, and had a median age of 14.0 years at baseline. No significant differences in efficacy were observed between the rilonacept- and placebo-treated patients during the double-blind phase, but fever and rash completely resolved by month 3 in all patients during the open-label treatment period and did not recur. Adapted ACR Pediatric 30, 50, and 70 response rates at 3 months from the start of the study were 78.3%, 60.9%, and 34.8%, respectively; these responses were generally maintained over the study duration. Levels of D-dimer and MRP-8/MRP-14 dramatically improved during the study, and in 22 of 23 patients, the prednisone dose was decreased or prednisone therapy was discontinued. No serious treatment-related adverse events were observed.Sustained improvements in clinical and laboratory measures of the articular and systemic manifestations of systemic JIA were achieved in50% of rilonacept-treated patients over 2 years. Treatment with rilonacept had a substantial steroid-sparing effect and was generally well-tolerated.

Ultrasound has shown a great potential for serving as an outcome measure for localized scleroderma. High spatial resolution of ultrasound will aid to evaluate Echogenicity, Vascularity index and tissue thickness of localized scleroderma. Echogenicity is higher when the ultrasound waves reflected are lesser in value from any particular body organ. Vascularity index can be defined as the differences in the color pixels of blood vessels in localized scleroderma image and control image.