Advances in Psoriatic Disease Research: Insights From GRAPPA Pilot Research Awardees.

Research progress from the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) pilot award program was presented and discussed at the GRAPPA 2023 annual meeting. Topics included identification of protein biomarkers associated with enthesitis in psoriatic arthritis (PsA), the role of HLA-B27 on gut microbial dysbiosis in PsA, single-cell profiling of synovial fluid vs psoriatic skin lesions in PsA, and the role of mechanotransduction in hyperactivation of transforming growth factor-ß via αVß6 integrin in psoriatic epidermis.

Effects of TNF-α inhibition versus secukinumab on active ultrasound-confirmed enthesitis in psoriatic arthritis.

Introduction: Enthesitis is a hallmark of psoriatic disease, but its clinical assessment is problematic in terms of diagnostic sensitivity and overlap with other comorbid conditions. Ultrasound is a useful tool that can give a more detailed assessment of enthesitis. Research demonstrates that those with persistent ultrasound entheseal disease are at risk of progressive articular damage. With limited data to guide choice between biologic therapy for psoriatic arthritis (PsA) patients, we wanted to assess the response of ultrasound-confirmed enthesitis to different forms of biologic therapies and study its utility in making more informed decisions. Methods: This was an open label observational study including patients aged ⩾18 years, who fulfil the classification criteria for PSA (CASPAR) and were due to commence on their first biologic therapy. The primary outcome was the change in MAdrid Sonographic Enthesitis Index (MASEI) score at 16 weeks of treatment. The MASEI score was also modified to assess the active elementary lesions (ActiveMASEI). Results: In all, 80 PsA patients were enrolled with 75 patients completing the study [secukinumab n = 23 and tumour necrosis factor inhibitor (TNFi) n = 52]. The mean reduction in MASEI score after 16 weeks of treatment was 3.42 with TNFi versus 1.74 with secukinumab (p = 0.097). There was a significant difference in the change in the MASEIActive score for TNFi versus secukinumab (4.37 versus 2.26; p = 0.030) and this difference was more pronounced when only power Doppler signal within 2 mm of the enthesis insertion was included (4.37 versus 2.00; p = 0.007). Clinical outcomes were similar for both classes of biologic apart from a significant reduction in regards to the Dermatology Life Quality Index and Psoriasis Area and Severity Index score with secukinumab versus TNFi. Conclusions: We have for the first time compared the effect of ultrasound-confirmed enthesitis between different forms of biologic therapies for PsA. We have seen an overall improvement in entheseal scores for both classes of medications and demonstrated a larger reduction in active entheseal disease for TNFi versus secukinumab that merits further exploration.

Introduction: An enthesis is the point at which ligament and tendon insert into the bone and enthesitis is the inflammation at these sites causing pain and reduced function.Enthesitis is particularly common in patients with psoriatic arthritis and it has been shown to be important in the development, diagnosis and prognosis of the condition. Clinical examination has limitations and imaging techniques like ultrasound have been proven to give a more detailed assessment of enthesitis potentially revealing clues to the condition itself. In psoriatic arthritis, we do not have a good way of choosing between biologic therapies that can treat inflammation. With a better understanding of enthesitis and its response to various therapies, we may be able to make better decisions. We wanted to examine the extent of enthesitis within a group of psoriatic arthritis patients who were to commence on their first biologic therapy by examining them both with ultrasound and then with clinical examination. Methods: We recruited 80 patients in which their consultant rheumatologist had decided to commence them on therapy. We carried out an ultrasound assessment of six entheseal sites as per an established assessment tool called the MAdrid Sonographic Enthesitis Index (MASEI). We then proceeded to take a history from the patients and examine all aspects of their joint disease just before they began their therapy. We repeated the ultrasound and clinical examination after 16 weeks of treatment without knowing what treatment they were on. Results: In all, 75 patients completed the study and 23 of these were treated with secukinumab, a drug that targets interleukin-17a (IL-17i), an important protein in psoriatic disease and 52 patients were treated with medications that target tumour necrosis factor inhibitor (TNFi), another important inflammatory protein. Overall, we demonstrated a reduction in ultrasound scores for entheseal disease in those treated with both classes of medication. For the TNFi group, there was a larger improvement in scores compared with the IL-17i which was not significant for the primary focus of the study, the overall MASEI score. We have also demonstrated that there may be a larger improvement in TNFi response versus IL-17i when only counting the inflammatory disease component of the MASEI score. In terms of clinical results, the findings were broadly similar except that secukinumab was better at improving skin psoriasis. Conclusion: Our work is the first with ultrasound to compare outcomes for enthesitis between classes of biologic therapy and should form the basis of future studies attempting to confirm these findings to make better decisions for those living with psoriatic arthritis.

Fifteen-minute guide to managing oligoarticular juvenile idiopathic arthritis.

Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease affecting children and young people today. However, it is not a single disease entity, but an umbrella term that gathers together a heterogeneous collection of complex, chronic inflammatory conditions with oligoarticular JIA the most common form in both Europe and North America. Due to its relative rarity in daily practice and potential to mimic other conditions, oligoarticular JIA can present a diagnostic and management challenge to healthcare professionals in both primary care and general paediatrics. The aim of this article is to provide a summary of the key aspects of diagnosis, investigation and management of this condition, with the hopes of building clinicians' confidence when facing a possible case of oligoarticular JIA.

The relationship between the nail and systemic enthesitis in psoriatic arthritis.

OBJECTIVE: Psoriatic nail disease is more common in PsA than in isolated skin psoriasis (PsO). The nail is closely integrated to the DIP joint entheses. US data have shown that those patients with nail disease in PsO are more likely to have systemic enthesitis. We examined whether there was a relationship between nail disease, DIP enthesitis and systemic enthesitis in established PsA. METHODS: Forty-six PsA participants with nail disease underwent US scanning of the nail unit and the DIP entheses along with peripheral entheseal sites according to the Madrid sonographic enthesitis index (MASEI). RESULTS: At the finger level, there was a mild to moderate correlation between nail US changes and both clinical nail disease and DIP enthesis changes (DIP US) [Spearman correlation (r S) = 0.30, P < 0.001 and r S = 0.16, P < 0.001, respectively]. At the patient level, there was a moderate correlation between the nail US score and nail psoriasis severity index score and DIP US (r S = 0.33, P = 0.024 and r S = 0.43, P = 0.003, respectively). At the patient level, there was also a positive correlation between a higher nail US score and the active peripheral enthesitis score (MASEI-active) (r S = 0.35, P = 0.018). When power Doppler was part of nail US score, similar results were demonstrated at both the finger and patient levels. CONCLUSION: This study has demonstrated the utility of nail US imaging and the close relationship, on scanning, between the DIP entheses and the nail unit. In PsA, we have seen a correlation between active US changes at the nail and peripheral enthesitis, which requires further analysis. TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov, NCT03955861.

Integrating imaging and biomarker assessment to better define psoriatic arthritis and predict response to biologic therapy.

The treatment options for PsA have substantially expanded over the last decade. Approximately 40% of patients will not respond to first-line anti-TNF-α therapies. There is limited data to help clinicians select the most appropriate biologic therapy for PsA patients, including guidance for decisions on biologic therapy switching. In this review we will examine the current understanding of predictors of response to treatment. Imaging technology has evolved to allow us to better study psoriatic disease and define disease activity, including synovitis and enthesitis. Enthesitis is implicated in the pathogenesis, diagnosis and prognosis of PsA. It appears to be a common thread among all of the various PsA clinical presentations. Enthesitis mainly manifests as tenderness, which is difficult to distinguish from FM, chronic pain and mechanically associated enthesopathy, and it might be relevant for understanding the apparent 40% failure of existing therapy. Excess adipose tissue makes if more difficult to detect joint swelling clinically, as many PsA patients have very high BMIs. Integrating imaging and clinical assessment with biomarker analysis could help to deliver stratified medicine in PsA and allow better treatment decision making. This could include which patients require ongoing biologic therapy, which class of biologic therapy that should be, and who alternatively requires management of non-inflammatory disease.

Development and characterisation of novel poly (vinyl alcohol)/poly (vinyl pyrrolidone)-based hydrogel-forming microneedle arrays for enhanced and sustained transdermal delivery of methotrexate.

Methotrexate (MTX) is one of the mainstays of treatment for rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA) and it is mainly administered either orally or by subcutaneous (SC) injection, which are not so satisfactory. While orally administered MTX is associated with variable bioavailability and causes gastrointestinal side effects, including nausea and vomiting, SC injection is painful and produces high peak blood levels of MTX. Transdermal delivery presents an attractive alternative administration route. However, MTX passive permeation through the skin is hindered by the skin barrier and MTX physicochemical properties. To address these issues, hydrogel-forming microneedle arrays (HFMN) and a patch-like reservoir loaded with MTX (MTX-RV) were developed and combined to form a minimally invasive patch to deliver MTX transdermally in a sustained manner. HFMN were prepared from an aqueous blend of poly (vinyl alcohol) (PVA) and poly (vinyl pyrrolidone) (PVP) which was crosslinked chemically with citric acid (CA) at 130˚C. MTX-RV was prepared from hydroxypropyl methylcellulose (HPMC) and glycerol. Both the HFMN and MTX-RV were fully characterised and then combined to form an integrated patch, which was evaluated ex vivo and in preclinical studies. The HFMN demonstrated a satisfactory mechanical strength and insertion capability into excised neonatal porcine skin, as well as moderate swelling properties. The MTX-RV incorporated a high dose of MTX (150.3 ± 5.3 µg/mg) without precipitation. The integrated patch delivered MTX at a steady-state flux of 506.8 ± 136.9 µg.cm2/h in an ex vivo setup. Furthermore, in preclinical studies performed in Sprague Dawley rats, MTX appeared in blood after 1 h from patch application at a concentration of 7.6 ± 2.0 nM. MTX blood level increased gradually to reach its peak, Cmax = 35.1 ± 5.1 nM, at 24 h. Importantly, the HFMN were removed intact from the skin with only mild erythema, despite the cytotoxic nature of MTX. Accordingly, the integrated patch produced in this work represents a promising minimally invasive transdermal drug delivery system that can overcome the skin barrier and deliver MTX in a sustained manner. This may help in minimising or even avoiding the nausea and vomiting, associated with the conventional administration routes.

The prevention and treatment of glucocorticoid-induced osteopaenia in juvenile rheumatic disease: A randomised double-blind controlled trial.

BACKGROUND: Children and young people (CYP) with chronic rheumatic conditions; Juvenile Idiopathic Arthritis, Juvenile Systemic Lupus Erythematosus, Juvenile Dermatomyositis and Juvenile Vasculitis, treated with steroids, have low bone density, increased fracture risk and are likely to have suboptimal peak bone mass. There is currently no evidence base for the management of steroid-induced bone loss in children with rheumatic diseases. METHODS: We undertook a multi-centre double dummy double-blind randomised placebo controlled trial to investigate whether the bisphosphonate risedronate was superior to alfacalcidol or calcium and vitamin D supplementation in the prevention and treatment of steroid-induced osteopaenia in these children. Patients were stratified and randomised in a 1:1 ratio, into: placebo; alfacalcidol; risedronate. The primary outcome was the change in lumbar spine bone mineral density z score (LSaBMDz) measured by dual energy x-ray absorptiometry at one year. Secondary outcome was fracture rate. RESULTS: Two hundred and seventeen patients were recruited to the study. Seventy seven placebo, 71 alfacalcidol, and 69 risedronate. Highly statistically significant differences were observed in the change in LSaBMDz between the placebo and risedronate groups; 0.274, 95% CI (0.061, 0.487) (p < 0.001) and between the risedronate and the alfacalcidol groups; 0.326 95% CI (0.109, 0.543) (p < 0.001). The difference observed between the alfacalcidol and placebo group was not statistically significant.Highly statistically significant differences were seen in the change in Total Body Less Head aBMD-Z Score between the placebo and risedronate groups (p < 0.01) but not between the alfacalcidol and risedronate groups. No significant differences in fracture frequency, adverse or serious adverse reactions were observed between the groups. CONCLUSIONS: Children and adolescents receiving steroids for rheumatic diseases benefit from prophylactic treatment with bisphosphonates to increase LSaBMD. Alfacalcidol is ineffective.

Post-streptococcal uveitis syndrome in a Caucasian population: a case series.

BACKGROUND/OBJECTIVES: Uveitis is an uncommon manifestation of post-streptococcal syndrome (PSUS). Despite reports, the condition is often not well recognised. The purpose of this study is to report a case series of children with post-streptococcal uveitis. SUBJECTS/METHODS: In this retrospective case series, all cases of PSUS were identified from all new paediatric patients diagnosed with uveitis over a 6-year period. Diagnosis of PSUS was based on the following diagnostic criteria: unilateral or bilateral uveitis with positive anti-streptolysin O titres (ASOT) or anti-deoxyribonuclease (anti-DNase) titres, and negative routine investigations for other causes of uveitis. RESULTS: Eleven Caucasian paediatric patients were diagnosed with PSUS. One had a novel finding of peripheral corneal endotheliopathy, 73% of patients presented in spring or winter months and 88% of eyes had a final VA of better than or equal to 6/12 at a mean follow-up of 22 months. Systemic immunosuppressant treatment was used in 36% of patients. Adalimumab was used in 18% of patient's refractory to other treatment. CONCLUSIONS: We report on the largest consecutive series of Caucasian patients under 16 years of age with PSUS. We have demonstrated a seasonal preponderance with presentation typically in winter or spring. We report a novel finding of corneal endotheliopathy in one of our PSUS patients. We also report on the benefit of adalimumab in the management of severe cases of PSUS; use of biologics in this particular cohort of uveitis patients has not previously been reported. With aggressive treatment our patients achieved good visual outcomes comparable to other published series.

Protective parents and permissive children: what qualitative interviews with parents and children can tell us about the feasibility of juvenile idiopathic arthritis trials.

BACKGROUND: Patient recruitment can be very challenging in paediatric studies, especially in relatively uncommon conditions, such as juvenile idiopathic arthritis (JIA). However, involving children and young people (CYP) in the design of such trials could promise a more rapid trajectory towards making evidence-based treatments available. Studies involving CYP are advocated in the literature but we are not aware of any early stage feasibility studies that have qualitatively accessed the perspectives of parents and CYP with a long term condition to inform design and conduct of a trial. In the context of a feasibility study to inform the design of a proposed randomised controlled trial of corticosteroid induction regimen in JIA, we explored families' perspectives on the proposed trial and on JIA trials generally. METHODS: We analysed interviews with 27 participants (8 CYP aged 8-16 years and 19 parents) from four UK paediatric rheumatology centres. CYP had recently received corticosteroids to treat JIA. Audio-recorded interviews were transcribed and analysed thematically, drawing on the Framework Method. RESULTS: Both parents and CYP were capable of engaging with the logic of the proposed trial but pointed to challenges with its design. Treatment preferences influenced willingness to participate in the proposed trial. The preferences of older children and their parents often differed, with CYP being more willing to participate in the proposed trial than parents. Families' current treatment preferences were largely informed by past positive and negative treatment experiences. Some participants also indicated that their treatment preferences were influenced by those of their clinicians. CONCLUSION: Previous research has typically focused on deficits in patients' understandings of trials. We found that both parents and CYP understood trial concepts and were able to identify potential flaws in the proposed trial. We propose recommendations to optimise the design of a planned corticosteroid induction regimen trial in JIA. Accessing both parents' and CYP's perspectives helps to identify and address recruitment challenges, which will ultimately optimise informed consent and future recruitment.

Pediatric Uveitis in a Well-Defined Population: Improved Outcomes with Immunosuppressive Therapy.

PURPOSE: The aim of this study is to assess the incidence, etiology, visual outcomes, and complication rates of pediatric uveitis patients at a dedicated multidisciplinary uveitis clinic in Northern Ireland. METHODS: Data were collected from charts of all patients attending the clinic at the Belfast Health and Social Care Trust between 2011 and 2015. Demographics, disease characteristics, treatments, visual acuity, and complications were recorded. RESULTS: There were 94 patients with uveitis onset before the age of 16 years. Etiology was mixed with JIAU the leading cause accounting for 48% of patients. Thirty-seven percent of patients had known complications at presentation and 65% by final visit. Systemic treatments were used in 65% of cases. Ninety-two percent of eyes had a final visual acuity ≥ 6/12 at a mean follow-up of 5 years. CONCLUSIONS: The etiology of uveitis in this pediatric population is mixed. With close monitoring, most patients maintain good vision.

Methotrexate polyglutamates as a potential marker of adherence to long-term therapy in children with juvenile idiopathic arthritis and juvenile dermatomyositis: an observational, cross-sectional study.

INTRODUCTION: Methotrexate (MTX) is a cornerstone of treatment in a wide variety of inflammatory conditions, including juvenile idiopathic arthritis (JIA) and juvenile dermatomyositis (JDM). However, owing to its narrow therapeutic index and the considerable interpatient variability in clinical response, monitoring of adherence to MTX is important. The present study demonstrates the feasibility of using methotrexate polyglutamates (MTXPGs) as a biomarker to measure adherence to MTX treatment in children with JIA and JDM. METHODS: Data were collected prospectively from a cohort of 48 children (median age 11.5 years) who received oral or subcutaneous (SC) MTX therapy for JIA or JDM. Dried blood spot samples were obtained from children by finger pick at the clinic or via self- or parent-led sampling at home, and they were analysed to determine the variability in MTXPG concentrations and assess adherence to MTX therapy. RESULTS: Wide fluctuations in MTXPG total concentrations (>2.0-fold variations) were found in 17 patients receiving stable weekly doses of MTX, which is indicative of nonadherence or partial adherence to MTX therapy. Age (P = 0.026) and route of administration (P = 0.005) were the most important predictors of nonadherence to MTX treatment. In addition, the study showed that MTX dose and route of administration were significantly associated with variations in the distribution of MTXPG subtypes. Higher doses and SC administration of MTX produced higher levels of total MTXPGs and selective accumulation of longer-chain MTXPGs (P < 0.001 and P < 0.0001, respectively). CONCLUSIONS: Nonadherence to MTX therapy is a significant problem in children with JIA and JDM. The present study suggests that patients with inadequate adherence and/or intolerance to oral MTX may benefit from SC administration of the drug. The clinical utility of MTXPG levels to monitor and optimise adherence to MTX in children has been demonstrated. TRIAL REGISTRATION: ISRCTN Registry identifier: ISRCTN93945409 . Registered 2 December 2011.

Antiviral antibody profiling by high-density protein arrays.

Viral infections elicit antiviral antibodies and have been associated with various chronic diseases. Detection of these antibodies can facilitate diagnosis, treatment of infection, and understanding of the mechanisms of virus-associated diseases. In this work, we assayed antiviral antibodies using a novel high-density nucleic acid programmable protein array (HD-NAPPA) platform. Individual viral proteins were expressed in situ directly from plasmids encoding proteins in an array of microscopic reaction chambers. Quality of protein display and serum response was assured by comparing intra- and inter-array correlation within or between printing batches with average correlation coefficients of 0.91 and 0.96, respectively. HD-NAPPA showed higher signal-to-background ratio compared with standard NAPPA on planar glass slides and ELISA. Antibody responses to 761 antigens from 25 different viruses were profiled among patients with juvenile idiopathic arthritis and type 1 diabetes. Common and unique antibody reactivity patterns were detected between patients and healthy controls. We believe HD-viral-NAPPA will enable the study of host-pathogen interactions at unprecedented dimensions and elucidate the role of pathogen infections in disease development.

A study of erosive phenotypes in lupus arthritis using magnetic resonance imaging and anti-citrullinated protein antibody, anti-RA33 and RF autoantibody status.

OBJECTIVES: The aims of this study were to investigate the extent of MRI-determined joint disease (erosion and synovitis) in SLE and to link this to autoantibody profiles known to be relevant to SLE, including ACPA, RF and anti-RA33 antibodies. METHODS: Contrast-enhanced MRI of the hand and wrist was performed in 34 symptomatic SLE patients and in 15 RA patients with similar disease duration. Images were scored by two observers using the OMERACT rheumatoid arthritis MRI scoring (RAMRIS) system. Findings were correlated with clinical examination and autoantibody status. RESULTS: Erosions were present at the wrist in 93% of SLE patients and at the MCP joints in 61% of SLE patients. Despite the high prevalence of MRI-determined erosion, only 8.8% of SLE patients were ACPA positive, although these patients had a higher burden of erosive disease. There was no positive correlation with anti-RA33 titres and erosion scores in the SLE patients, but there was a negative correlation with anti-RA33 titres and total bone oedema scores in the SLE patients. Ninety-three per cent of SLE patients had at least grade 1 synovitis at one or more MCP joints, and wrist joint synovitis was present in all the SLE patients. CONCLUSION: An MRI-determined joint erosive phenotype is common in SLE, even in ACPA-negative cases. The conventional radiographic observation that anti-RA33 is not positively associated with erosion in patients with RA was also found to be the case in SLE patients.

A novel dried blood spot-LCMS method for the quantification of methotrexate polyglutamates as a potential marker for methotrexate use in children.

OBJECTIVE: Development and validation of a selective and sensitive LCMS method for the determination of methotrexate polyglutamates in dried blood spots (DBS). METHODS: DBS samples [spiked or patient samples] were prepared by applying blood to Guthrie cards which was then dried at room temperature. The method utilised 6-mm disks punched from the DBS samples (equivalent to approximately 12 µl of whole blood). The simple treatment procedure was based on protein precipitation using perchloric acid followed by solid phase extraction using MAX cartridges. The extracted sample was chromatographed using a reversed phase system involving an Atlantis T3-C18 column (3 µm, 2.1 × 150 mm) preceded by Atlantis guard column of matching chemistry. Analytes were subjected to LCMS analysis using positive electrospray ionization. KEY RESULTS: The method was linear over the range 5-400 nmol/L. The limits of detection and quantification were 1.6 and 5 nmol/L for individual polyglutamates and 1.5 and 4.5 nmol/L for total polyglutamates, respectively. The method has been applied successfully to the determination of DBS finger-prick samples from 47 paediatric patients and results confirmed with concentrations measured in matched RBC samples using conventional HPLC-UV technique. CONCLUSIONS AND CLINICAL RELEVANCE: The methodology has a potential for application in a range of clinical studies (e.g. pharmacokinetic evaluations or medication adherence assessment) since it is minimally invasive and easy to perform, potentially allowing parents to take blood samples at home. The feasibility of using DBS sampling can be of major value for future clinical trials or clinical care in paediatric rheumatology.

Synovial membrane protein expression differs between juvenile idiopathic arthritis subtypes in early disease.

INTRODUCTION: Juvenile idiopathic arthritis (JIA) is the most common rheumatological disease of childhood with a prevalence of around 1 in 1,000. Without appropriate treatment it can have devastating consequences including permanent disability from joint destruction and growth deformities. Disease aetiology remains unknown. Investigation of disease pathology at the level of the synovial membrane is required if we want to begin to understand the disease at the molecular and biochemical level. The synovial membrane proteome from early disease-stage, treatment naive JIA patients was compared between polyarticular and oligoarticular subgroups. METHODS: Protein was extracted from 15 newly diagnosed, treatment naive JIA synovial membrane biopsies and separated by two dimensional fluorescent difference in-gel electrophoresis. Proteins displaying a two-fold or greater change in expression levels between the two subgroups were identified by matrix assisted laser desorption ionization-time of flight mass spectrometry with expression further verified by Western blotting and immunohistochemistry. RESULTS: Analysis of variance analysis (P ≤ 0.05) revealed 25 protein spots with a two-fold or greater difference in expression levels between polyarticular and oligoarticular patients. Hierarchical cluster analysis with Pearson ranked correlation revealed two distinctive clusters of proteins. Some of the proteins that were differentially expressed included: integrin alpha 2b (P = 0.04); fibrinogen D fragment (P = 0.005); collagen type VI (P = 0.03); fibrinogen gamma chain (P = 0.05) and peroxiredoxin 2 (P = 0.02). The identified proteins are involved in a number of different processes including platelet activation and the coagulation system. CONCLUSIONS: The data indicate distinct synovial membrane proteome profiles between JIA subgroups at an early stage in the disease process. The identified proteins also provide insight into differentially perturbed pathways which could influence pathological events at the joint level.

Effects of an enhanced discharge planning intervention for hospitalized older adults: a randomized trial.

PURPOSE OF THE STUDY: To identify needs encountered by older adult patients after hospital discharge and assess the impact of a telephone transitional care intervention on stress, health care utilization, readmissions, and mortality. DESIGN AND METHODS: Older adult inpatients who met criteria for risk of post-discharge complications were randomized at discharge through the electronic medical record. Intervention group participants received the telephone-based Enhanced Discharge Planning Program intervention that included biopsychosocial assessment and an individualized plan following program protocols to address identified transitional care needs. All patients received a follow-up call at 30 days post discharge to assess psychosocial needs, patient and caregiver stress, and physician follow-up. RESULTS: 83.3% of intervention group participants experienced significant barriers to care. For 73.3% of this group, problems did not emerge until after discharge. Intervention patients were more likely than usual care patients to have scheduled and completed physician visits by 30 days post discharge. There were no differences between groups on patient or caregiver stress or hospital readmission. IMPLICATIONS: At-risk older adults may benefit from transitional care programs to ensure delivery of care as ordered and address unmet needs. Although patients who received the intervention were more likely to communicate and follow up with their physicians, the absence of impact on readmission suggests that more intensive efforts may be indicated to affect this outcome.

Vitamin D binding protein isoforms as candidate predictors of disease extension in childhood arthritis.

INTRODUCTION: Juvenile idiopathic arthritis (JIA) comprises a poorly understood group of chronic autoimmune diseases with variable clinical outcomes. We investigated whether the synovial fluid (SF) proteome could distinguish a subset of patients in whom disease extends to affect a large number of joints. METHODS: SF samples from 57 patients were obtained around time of initial diagnosis of JIA, labeled with Cy dyes and separated by two-dimensional electrophoresis. Multivariate analyses were used to isolate a panel of proteins which distinguish patient subgroups. Proteins were identified using MALDI-TOF mass spectrometry with expression verified by immunochemical methods. Protein glycosylation status was confirmed by hydrophilic interaction liquid chromatography. RESULTS: A truncated isoform of vitamin D binding protein (VDBP) is present at significantly reduced levels in the SF of oligoarticular patients at risk of disease extension, relative to other subgroups (p<0.05). Furthermore, sialylated forms of immunopurified synovial VDBP were significantly reduced in extended oligoarticular patients (p<0.005). CONCLUSION: Reduced conversion of VDBP to a macrophage activation factor may be used to stratify patients to determine risk of disease extension in JIA patients.

Circulating and synovial antibody profiling of juvenile arthritis patients by nucleic acid programmable protein arrays.

INTRODUCTION: Juvenile idiopathic arthritis (JIA) is a heterogeneous disease characterized by chronic joint inflammation of unknown cause in children. JIA is an autoimmune disease and small numbers of autoantibodies have been reported in JIA patients. The identification of antibody markers could improve the existing clinical management of patients. METHODS: A pilot study was performed on the application of a high-throughput platform, the nucleic acid programmable protein array (NAPPA), to assess the levels of antibodies present in the systemic circulation and synovial joint of a small cohort of juvenile arthritis patients. Plasma and synovial fluid from 10 JIA patients was screened for antibodies against 768 proteins on NAPPAs. RESULTS: Quantitative reproducibility of NAPPAs was demonstrated with > 0.95 intra-array and inter-array correlations. A strong correlation was also observed for the levels of antibodies between plasma and synovial fluid across the study cohort (r = 0.96). Differences in the levels of 18 antibodies were revealed between sample types across all patients. Patients were segregated into two clinical subtypes with distinct antibody signatures by unsupervised hierarchical cluster analysis. CONCLUSION: The NAPPAs provide a high-throughput quantitatively reproducible platform to screen for disease-specific autoantibodies at the proteome level on a microscope slide. The strong correlation between the circulating antibody levels and those of the inflamed joint represents a novel finding and provides confidence to use plasma for discovery of autoantibodies in JIA, thus circumventing the challenges associated with joint aspiration. We expect that autoantibody profiling of JIA patients on NAPPAs could yield antibody markers that can act as criteria to stratify patients, predict outcomes and understand disease etiology at the molecular level.

Biomarkers in rheumatology, now and in the future.

This review examines the biomarker development process by using rheumatic disorders as the disease model for discussion. We evaluate the current role of biomarkers in the practice of rheumatology and discuss their likely role in the future. We define the essential components of the biomarker development pipeline and discuss the issue of fitness for purpose, i.e. what the biomarker(s) might offer in a clinical setting. As a component of this review we also highlight several emerging technologies that are beginning to provide practical solutions to support biomarker validation. In the process, we highlight some scenarios where additional biomarkers would add considerable value to clinical practice, and we review appropriate methods for each. We also emphasize some important but infrequently discussed considerations, including the need for protein variant verification. Ultimately, the adroit application of the methods of proteomics will transform the practice rheumatology and allow personalized clinical practice to become a reality.