Efficacy of guselkumab, a selective IL-23 inhibitor, in Preventing Arthritis in a Multicentre Psoriasis At-Risk cohort (PAMPA): protocol of a randomised, double-blind, placebo controlled multicentre trial.

INTRODUCTION: Psoriatic arthritis (PsA) is a complex, immune-mediated disease associated with skin psoriasis that, if left untreated, can lead to joint destruction. Up to 30% of patients with psoriasis progress to PsA. In most cases, psoriasis precedes synovio-entheseal inflammation by an average of 5-7 years, providing a unique opportunity for early and potentially preventive intervention in a susceptible and identifiable population. Guselkumab is an effective IL-23p19 inhibitor Food and Drug Administration (FDA-approved for treatment of moderate-to-severe psoriasis and PsA. The Preventing Arthritis in a Multicentre Psoriasis At-Risk cohort (PAMPA) study aims to evaluate the efficacy of guselkumab in preventing PsA and decreasing musculoskeletal power Doppler ultrasound (PDUS) abnormalities in a population of patients with psoriasis who are at-increased risk for PsA progression. METHODS AND ANALYSIS: The PAMPA study is a multicentre, randomised, double-blind, placebo-controlled, interventional, preventive trial comparing PDUS involvement and conversion to PsA in patients with psoriasis at-increased risk for progression treated with guselkumab compared with non-biological standard of care. The study includes a screening period, a double-blind treatment period (24 weeks) and an open-label follow-up period (72 weeks). At baseline, 200 subjects will be randomised (1:1) to receive either guselkumab 100 mg (arm 1) or placebo switching to guselkumab 100 mg starting at week 24 (arm 2). Arm 3 will follow 150 at-risk psoriasis patients who decline biological therapy and randomisation. Changes from baseline in the PDUS score at week 24 and the difference in proportion of patients transitioning to PsA at 96 weeks will be examined as the coprimary endpoints. ETHICS AND DISSEMINATION: Ethics approval for this study was granted by the coordinating centre's (NYU School of Medicine) Institutional Review Board (IRB). Each participating site received approval through their own IRBs. The findings will be shared in peer-reviewed articles and scientific conference presentations. TRIAL REGISTRATION NUMBER: NCT05004727.

Does biologic therapy impact the development of PsA among patients with psoriasis?

OBJECTIVE: To examine the association of biologic therapy use for psoriasis with incident psoriatic arthritis (PsA) diagnosis. METHODS: A retrospective cohort study was conducted in the OptumInsights Electronic Health Record Database between 2006 and 2017 among patients with psoriasis between the ages of 16 and 90 initiating a therapy for psoriasis (oral, biologic or phototherapy). The incidence of PsA was calculated within each therapy group. Multivariable Cox models were used to calculate the HR for biologic versus oral or phototherapy using biologics as a time-varying exposure and next in a propensity score-matched cohort. RESULTS: Among 1 93 709 patients with psoriasis without PsA, 14 569 biologic and 20 321 cumulative oral therapy and phototherapy initiations were identified. Mean age was lower among biologic initiators compared with oral/phototherapy initiators (45.9 vs 49.8). The incidence of PsA regardless of therapy exposure was 9.75 per 1000 person-years compared with 77.26 among biologic users, 61.99 among oral therapy users, 26.11 among phototherapy users and 5.85 among those without a prescription for one of the target therapies. Using a multivariable adjustment approach with time-varying exposure, adjusted HR (95% CI) for biologic users was 4.48 (4.23 to 4.75) compared with oral or phototherapy users. After propensity score matching, the HR (95% CI) was 2.14 (2.00 to 2.28). CONCLUSIONS: In this retrospective cohort study, biologic use was associated with the development of PsA among patients with psoriasis. This may be related to confounding by indication and protopathic bias. Prospective studies are needed to address this important question.

The Relationship Between Focal and Generalized Bone Loss in Rheumatoid Arthritis.

OBJECTIVE: To determine if there is an association between focal and systemic bone loss in patients with RA. METHODS: Bone loss is a hallmark finding in rheumatoid arthritis (RA) and manifests as localized, periarticular and systemic bone loss. RA patients were selected from the Consortium of Rheumatology Researchers of North America (CORRONA) database. Multiple logistic regression models were constructed to assess the association between the presence or absence of erosions and T-scores at the lumbar spine (LS) and total hips and adjusted for age, gender, body mass index (BMI), medications and disease activity indices. RESULTS: Data on erosions and T-scores were available in 3,898 and 5,099 subjects, respectively. Patients with erosions had a significantly lower LS T-scores (-0.9) compared to RA patients without erosions (p=0.0002). Similarly, the mean total hip T-scores were significantly lower in patients with (-1.4) compared to subjects without erosions (-1.0) (p<0.01). The odds of having no erosion increased by 21% for each 1-unit increase in LS T-score and 46% for each 1 unit increase in hip Tscore. Patients with erosions were significantly younger (p<0.01) had a lower BMI (p<0.01) and higher DAS28 scores than those without erosions. More patients with erosions were on anti-TNF therapy, disease modifying drugs and osteoporosis medications than patients without erosions (p<0.01, 0.003 and 0.0003). CONCLUSION: RA patients with bone erosions have significantly lower T-scores at the LS and hips compared with RA patients without erosions. These data suggest a relationship between localized and generalized bone loss in RA.

Hospitalization of patients with systemic lupus erythematosus is a major cause of direct and indirect healthcare costs.

Objectives The objective of this study was to calculate the direct and indirect costs of admission for systemic lupus erythematosus (SLE) patients, identify the population at risk and investigate potential reasons for admission. Methods We conducted a financial analysis of all admissions for SLE to Strong Memorial Hospital between 1 July 2013 and 30 June 2015. Patient and financial records for admissions with a SLE diagnosis for the above period were retrieved. The total cost of admissions was used as a measure of direct costs and the length of stay used to assess indirect costs. Additionally, we analyzed the demographics of the hospitalized population. Results The average, annual cost of confirmed admissions to Strong Memorial Hospital for SLE was US$3.9-6.4 m. The mean annual cost per patient for hospitalization was US$51,808.41. The length of stay for all SLE patients was 1564-2507 days with an average of 8.5 days per admission. The majority of patients admitted were young women from the city of Rochester. Infections were the most common reason for admissions. Conclusion We demonstrated that admissions are a source of high direct and indirect costs to the hospital and a significant financial burden to the patient. Implementing measures to improve the quality of care for SLE patients will help decrease the morbidity and lower the economic costs to hospitals.

Therapeutic considerations in spondyloarthritis patients who fail tumour necrosis factor antagonists.

The tumour necrosis factor (TNF) antagonists have significantly improved quality of life and functional status in patients with spondyloarthritis (SpA). The excitement regarding the remarkable success of these agents is justified but challenges remain. In particular, alternative systemic therapies with proven efficacy for patients who fail TNF antagonists have been developed in rheumatoid arthritis but are not yet available in SpA. In this article, the approach to patients with psoriatic arthritis (PsA) or ankylosing spondylitis (AS) who fail TNF antagonists will be discussed with the goal of providing a path to the clinician, who must manage these patients amidst uncertainty. Three central questions will be addressed. Why does a particular SpA patient not respond to a TNF antagonist? How can the clinician improve the probability of treatment response in patients who fail a TNF antagonist? What specific approaches can be taken to control disease activity in PsA or AS following treatment failure with a TNF antagonist? Data from controlled trials, registries and pilot studies will be combined with expert opinion to address these important questions.

Effect of adalimumab on joint disease: features of patients with psoriatic arthritis detected by magnetic resonance imaging.

BACKGROUND: Bone marrow oedema (BMO), synovitis, effusion and joint erosion on magnetic resonance imaging (MRI) may be used as outcome measures in psoriatic arthritis (PsA). OBJECTIVE: To assess the impact of adalimumab on BMO, synovitis, effusion and erosions in PsA, as measured by MRI. METHODS: Fifteen patients with active PsA (> or =3 tender and > or =3 swollen joints) were enrolled in an open-label pilot study. Each received adalimumab subcutaneously every other week for 24 weeks. MRI was obtained at baseline and 24 weeks. RESULTS: MRI was available for 11 patients, pre and post-therapy. BMO and effusion scores improved markedly after 24 weeks of adalimumab, while no significant change was noted in erosion score. An unanticipated finding, however, was the lack of improvement in the MRI synovitis score. CONCLUSIONS: Improvement in BMO and unchanged erosion scores may explain the "anti-erosive" effects of adalimumab in PsA. Persistence of BMO and synovitis on MRI suggests ongoing disease activity and supports the continuation of long-term anti-TNF therapy.

Adalimumab for long-term treatment of psoriatic arthritis: 2-year data from the Adalimumab Effectiveness in Psoriatic Arthritis Trial (ADEPT).

OBJECTIVE: To evaluate the long-term effectiveness and tolerability of adalimumab in the treatment of psoriatic arthritis (PsA). METHODS: Patients with PsA who completed a 24-week, double-blind study of adalimumab versus placebo were eligible to enroll in an open-label extension study and receive adalimumab 40 mg subcutaneously every other week for up to an additional 120 weeks. At the time of this analysis, available efficacy evaluations throughout 2 years of treatment (n = 245) included American College of Rheumatology (ACR) 20%, 50% and 70% improvement scores, measures of joint disease and skin disease, disability and quality of life; modified total Sharp scores (mTSS) were available for 2.75 years of treatment for patients who received adalimumab in the 24-week study. RESULTS: After 24 weeks of double-blind treatment, the mean change in mTSS was -0.2 for the adalimumab group (N = 144) and 1.0 for the placebo group (N = 152; p<0.001), and outcomes for all individual ACR component variables were significantly improved in adalimumab compared with placebo-treated patients. Compared with 24-week responses, inhibition of radiographic progression and improvements in joint disease were maintained in most patients during long-term, open-label adalimumab treatment. Also, improvements in skin disease were maintained, with >20% of patients achieving the strict criterion of psoriasis area and severity index 100. The nature and frequency of adverse events during long-term adalimumab treatment were consistent with the safety profile during short-term treatment. CONCLUSIONS: The clinical and radiographic efficacy of adalimumab demonstrated during short-term treatment was sustained during long-term treatment. Adalimumab has a favourable risk-benefit profile in patients with PsA. TRIAL REGISTRATION NUMBER: NCT00195689.

Treatment recommendations for psoriatic arthritis.

OBJECTIVE: To develop comprehensive recommendations for the treatment of the various clinical manifestations of psoriatic arthritis (PsA) based on evidence obtained from a systematic review of the literature and from consensus opinion. METHODS: Formal literature reviews of treatment for the most significant discrete clinical manifestations of PsA (skin and nails, peripheral arthritis, axial disease, dactylitis and enthesitis) were performed and published by members of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA). Treatment recommendations were drafted for each of the clinical manifestations by rheumatologists, dermatologists and PsA patients based on the literature reviews and consensus opinion. The level of agreement for the individual treatment recommendations among GRAPPA members was assessed with an online questionnaire. RESULTS: Treatment recommendations were developed for peripheral arthritis, axial disease, psoriasis, nail disease, dactylitis and enthesitis in the setting of PsA. In rotal, 19 recommendations were drafted, and over 80% agreement was obtained on 16 of them. In addition, a grid that factors disease severity into each of the different disease manifestations was developed to help the clinician with treatment decisions for the individual patient from an evidenced-based perspective. CONCLUSIONS: Treatment recommendations for the cardinal physical manifestations of PsA were developed based on a literature review and consensus between rheumatologists and dermatologists. In addition, a grid was established to assist in therapeutic reasoning and decision making for individual patients. It is anticipated that periodic updates will take place using this framework as new data become available.

The effect of etanercept on osteoclast precursor frequency and enhancing bone marrow oedema in patients with psoriatic arthritis.

OBJECTIVE: The frequency of osteoclast precursors (OCPF) and the presence of bone marrow oedema (BMO) are potential response biomarkers in psoriatic arthritis (PsA). Previous studies suggest a central role for tumour necrosis factor (TNF) in the formation of osteoclast precursors. To better understand this association, the effect of etanercept on OCPF and BMO was analysed in PsA patients with erosive arthritis. METHODS: A total of 20 PsA patients with active erosive PsA were enrolled. Etanercept was administered twice weekly for 24 weeks. OCPF was measured and clinical assessments were performed at baseline, 2, 12 and 24 weeks. Gadolinium enhanced MR images were obtained at baseline and 24 weeks. RESULTS: Significant improvements in joint score (p<0.001), HAQ scores (p<0.001) and SF-36 parameters were observed after 6 months of therapy with etanercept compared to baseline. The median OCPF decreased from 24.5 to 9 (p = 0.04) and to 7 (p = 0.006) after 3 months and 6 months of treatment, respectively. MR images were available for 13 patients. The BMO volume decreased in 47 and increased in 31 sites at 6 months. No correlation was noted between OCPF, BMO and clinical parameters. CONCLUSION: The rapid decline in OCPF and overall improvement in BMO after anti-TNFalpha therapy provides one mechanism to explain the anti-erosive effects of TNF blockade in PsA. Persistence of BMO after etanercept treatment, despite a marked clinical response, was unexpected, and suggests ongoing subchondral inflammation or altered remodelling in PsA bone.

RANK, RANKL and OPG in inflammatory arthritis and periprosthetic osteolysis.

Elucidation of the receptor activator of nuclear factor kappa B (RANK), its ligand (RANKL) and osteoprotegerin (OPG) as the final effectors of bone resorption has transformed our understanding of metabolic bone diseases and revealed novel therapeutic targets. Activation of the RANK-RANKL signaling pathway is directly responsible for dramatic focal erosions that are observed in inflammatory arthritis and aseptic loosening of orthopaedic implants. While these conditions share many features common to all metabolic bone disorders (e.g., osteoclastic resorption), they exhibit several unique properties, which are highlighted in this review. Most important is the relative inability of bisphosphonate therapy to inhibit osteolysis in joint inflammation and periprosthetic joint loosening and the unexpected effectiveness of anti-cytokine therapy in both rheumatoid and psoriatic arthritis. Herein, we provide a review of the role of RANK, RANKL and OPG in erosive arthritis and periprosthetic osteolysis and discuss the potential of anti-RANKL therapy for these conditions.

Recent advances in the treatment of the seronegative spondyloarthropathies.

The observation that anti-tumor necrosis factor (anti-TNF) therapies dramatically reduce joint pain and inflammation and retard radiographic progression in rheumatoid arthritis (RA) has created a considerable amount of enthusiasm among rheumatologists and has set new treatment standards for patients with inflammatory joint disease. A central question that has emerged is whether these agents are effective in treating the seronegative spondyloarthropathies (SpA). A related question is whether second-line agents such as methotrexate (MTX) can improve axial inflammation and functional measures if administered early in disease. The SpA are a cluster of inflammatory arthridites encompassing ankylosing spondylitis (AS), psoriatic arthritis (PsA), Reiter's syndrome/reactive arthritis (ReA), and the arthritis associated with inflammatory bowel disease. These disorders share similar clinical and immunogenetic features including axial arthritis and enthesopathy, a general predilection for males and patients positive for the MHC class I alleles, the absence of rheumatoid factor, and association with infections of the intestinal and genitourinary tracts. Reclassification of SpA based on axial or peripheral involvement may be more relevant from a pathophysiologic and therapeutic perspective than the current stratification, given the strong association between axial disease and the HLAB27 allele and the relative resistance of axial disease to conventional anti-inflammatory therapy.

Quantitative electroencephalography. A new approach to the diagnosis of cerebral dysfunction in systemic lupus erythematosus.

OBJECTIVE: Neuropsychiatric manifestations are common in patients with systemic lupus erythematosus (SLE), but accurate diagnosis is often difficult. We conducted a prospective study to determine the utility of neurometric quantitative electroencephalography (QEEG) as an indicator of cerebral dysfunction in SLE patients. METHODS: Fifty-two SLE patients were divided into 4 groups based on the results of neuropsychiatric evaluations. These included patients with objective evidence of neuropsychiatric SLE (NPSLE), patients with neuropsychiatric symptoms, patients with no evidence of NPSLE, and patients with a prior history of NPSLE: All QEEG findings were compared with data in an age-regressed normative database and with findings in an independent sample of normal subjects. RESULTS: QEEG sensitivity was 87%, and specificity was 75%. QEEG results were abnormal in 74% of the SLE patients with neuropsychiatric symptoms and in 28% of the patients with no evidence of active NPSLE: QEEG profiles varied as a function of the severity and type of neuropsychiatric manifestation present. Within this patient population, QEEG was more sensitive than magnetic resonance imaging, computed tomography scanning, or conventional EEG. CONCLUSION: Neurometric QEEG may be a sensitive indicator of cerebral dysfunction in patients with NPSLE and can differentiate patients with diverse neuropsychiatric manifestations. When combined with a careful clinical history and evaluation, QEEG provides information that may be useful for the early detection of NPSLE and for serial evaluation of disease activity and treatment efficacy.

Potential mechanisms for coordinate gene activation in the rheumatoid synoviocyte: implications and hypotheses.

Evidence is reviewed to support the concept that synovial cells in rheumatoid arthritis have undergone distinctive alterations at the cellular and subcellular level that result in their taking on some of the characteristics that are also manifest by transformed cells. These phenotypic modulations could be indirectly driven by cytokines in a paracrine or autocrine fashion. Specific regional patterns of cell phenotype modulation were used to argue against a simple widely diffusing direct inductive effect to cytokines and in favor of microenvironmental determinants. It is hypothesized that these extracellular factors induce novel activation in a coordinate manner by acting through master regulatory genes operating in cells with specific microenvironmental interactions. Two of these regulatory genes, fos and jun, are discussed in detail because of their induction by growth factors and their central role in the transactivation of genes which have been implicated in rheumatoid synovitis. A model for gene activation in the rheumatoid synovium is proposed based on the premise that fos and jun are an important link in the intracellular transduction pathways used by cytokines to induce cellular phenotypic changes.