Examining the biological pathways underlying clinical heterogeneity in Sjogren's syndrome: proteomic and network analysis.

OBJECTIVES: Stratification approaches are vital to address clinical heterogeneity in Sjogren's syndrome (SS). We previously described that the Newcastle Sjogren's Stratification Tool (NSST) identified four distinct clinical subtypes of SS. We performed proteomic and network analysis to analyse the underlying pathobiology and highlight potential therapeutic targets for different SS subtypes. METHOD: We profiled serum proteins using O-link technology of 180 SS subjects. We used 5 O-link proteomics panels which included a total of 454 unique proteins. Network reconstruction was performed using the ARACNE algorithm, with differential expression estimates overlaid on these networks to reveal the key subnetworks of differential expression. Furthermore, data from a phase III trial of tocilizumab in SS were reanalysed by stratifying patients at baseline using NSST. RESULTS: Our analysis highlights differential expression of chemokines, cytokines and the major autoantigen TRIM21 between the SS subtypes. Furthermore, we observe differential expression of several transcription factors associated with energy metabolism and redox balance namely APE1/Ref-1, FOXO1, TIGAR and BACH1. The differentially expressed proteins were inter-related in our network analysis, supporting the concept that distinct molecular networks underlie the clinical subtypes of SS. Stratification of patients at baseline using NSST revealed improvement of fatigue score only in the subtype expressing the highest levels of serum IL-6. CONCLUSIONS: Our data provide clues to the pathways contributing to the glandular and non-glandular manifestations of SS and to potential therapeutic targets for different SS subtypes. In addition, our analysis highlights the need for further exploration of altered metabolism and mitochondrial dysfunction in the context of SS subtypes.

Impact of hyperuricaemia on patients with psoriatic arthritis treated with secukinumab in the FUTURE 2-5 and MAXIMISE studies.

OBJECTIVES: Patients with psoriatic arthritis (PsA) are at a significantly increased risk of hyperuricaemia and development of gout, and those with hyperuricaemia have been found to respond poorly to PsA treatment and have more peripheral and destructive joint damage. We present a comprehensive post hoc analysis using pooled data from the FUTURE 2-5 studies and the MAXIMISE study to further evaluate the impact of hyperuricaemia on clinical presentation/disease severity and response to secukinumab in patients with PsA. METHODS: Patients were stratified into two groups based on baseline serum uric acid (SUA) level (threshold of 360 µmol/L). A sensitivity analysis was also performed based on SUA thresholds of 300 µmol/L and 420 µmol/L. Demographics, clinical, radiological characteristics and comorbidities data were collected. RESULTS: At baseline, patients with hyperuricaemia were mostly male, reported a higher prevalence of hypertension, with more clinical dactylitis, more psoriasis and more severe skin disease compared with patients with normouricaemia. A similar proportion of patients in the normouricaemic and hyperuricaemic cohorts achieved American College of Rheumatology responses, resolution of enthesitis and dactylitis, inhibition of structural damage progression and improvement in health-related quality of life across all secukinumab doses at week 52. CONCLUSION: Patients with PsA and hyperuricaemia have different clinical characteristics from patients with PsA and normouricaemia. Identification of these patients at an early stage may facilitate a personalised treatment approach and improved management of comorbidities. Furthermore, secukinumab provided a rapid and sustained response across all manifestations of PsA up to week 52, irrespective of baseline uricaemia status.

Association Between Bruton's Tyrosine Kinase Gene Overexpression and Risk of Lymphoma in Primary Sjögren's Syndrome.

OBJECTIVE: We undertook this study to analyze whole blood gene expression and to investigate the role of B cell genes in primary Sjögren's syndrome-related non-Hodgkin lymphoma (primary SS-NHL). METHODS: Peripheral whole blood samples were collected from 345 well-phenotyped patients with primary SS enrolled in the prospective Assessment of Systemic Signs and Evolution in Sjögren's Syndrome (ASSESS) cohort. Transcriptomic analysis was performed using human Clariom S Arrays (Affymetrix). In our primary analysis, we considered patients with incident lymphoma (i-primary SS-NHL) as the case group and all patients without lymphoma as the comparison group. In our sensitivity analyses, we considered all patients with primary SS-NHL, including those with a history of lymphoma (h-primary SS-NHL), as the case group and primary SS patients without lymphoma, stratified on their risk factors of lymphoma, as the comparison group. RESULTS: Twenty-one patients with primary SS-NHL (including 8 with i-primary SS-NHL and 13 h-primary SS-NHL) were eligible for transcriptomic analysis; we compared these patients to 324 primary SS controls without lymphoma, including 110 with moderate to severe disease activity and 61 with no risk factor of lymphoma. Functional clustering analyses revealed an enrichment of genes related to innate and adaptive immunity, including B cell-related genes. Bruton's tyrosine kinase (BTK) and a proliferation-inducing ligand (APRIL) genes were overexpressed before the occurrence of lymphoma in patients with incident lymphoma compared with patients without lymphoma. In sensitivity analyses, BTK was consistently up-regulated across all comparisons performed. BTK expression was associated with risk of lymphoma on multivariate analyses, which considered 9 validated predictors of lymphoma in primary SS. CONCLUSION: BTK and APRIL were overexpressed in the peripheral blood of primary SS patients prior to lymphoma. The association between BTK, APRIL, and primary SS-NHL requires confirmation in other prospective cohorts.

[Which taxonomy for inflammatory diseases in rheumatology? The concept of Psout]. / Quelle taxonomie des maladies inflammatoires en rhumatologie ? - Le concept de psoutte.

Clinical practice needs the identification of the patient disease. The physician has to rationalize symptoms allowing the recognition of a realistic entity and its classification in a reference nosology. Unlike other practices, the biomedical model uses scientific census methodology, from a tabular perspective to the definition of diseases. Due to its simplification process, it therefore neglects transitional or complex cases. In Rheumatology, this reasoning is challenged by the lack of objectivity and specificity of the items supporting the clinician when he builds the diagnosis, but also by the physiopathological complexity. Sometimes, diseases may be confused or superposed, possibly leading to the description of novel entities. The authors describe herein the difficulties encountered in practical clinical medicine. They show, from a concrete and real personal situation, how it can possibly lead to the justification of a new entity.

TITLE: Quelle taxonomie des maladies inflammatoires en rhumatologie ? - Le concept de psoutte. ABSTRACT: La pratique clinique de la médecine nécessite la reconnaissance de la maladie dont souffre le patient par le médecin. Pour cela, celui-ci rationnalise les signes permettant d'isoler une entité réaliste et de la classer dans la nosologie de référence. Contrairement à d'autres pratiques, le modèle biomédical utilise la méthodologie scientifique du recensement, dans une logique de classification pour définir les maladies. Du fait de son processus de simplification, ce modèle néglige les cas de transition ou les cas complexes. En rhumatologie, ce raisonnement classifiant est mis à l'épreuve par le manque d'objectivité et de spécificité des éléments sur lesquels s'appuie le clinicien pour construire le diagnostic, mais aussi par la complexité des mécanismes physiopathologiques des maladies rhumatismales. Ces maladies peuvent en effet se confondre ou s'intriquer, pour aboutir alors à la description de nouvelles entités non envisagées dans les classifications. Nous présentons dans cette revue les difficultés rencontrées au cours de l'exercice de la médecine dans ces contextes, et comment, à partir d'un cas concret, vécu, celles-ci peuvent donner naissance à la proposition d'un nouveau taxon1.

Seasonal effect on fatigue, pain and dryness in primary Sjögren's syndrome.

BACKGROUND: To assess the presence of a seasonal effect on fatigue, pain and dryness in primary Sjögren's syndrome (pSS). METHODS: Data (date; visual analogue scales (VAS) for pain, fatigue and dryness) were extracted from three randomised placebo-controlled trials (RCTs) evaluating infliximab (TRIPSS; n = 103 patients), hydroxychloroquine (JOQUER; n = 120 patients) and rituximab (TEARS; n = 120 patients) and from the 5-year follow-up of the ASSESS prospective cohort (n = 395 patients). Data were analysed at each visit for each patient, according to the day, the month of the year and the season. Linear mixed models were used to take into account the repeated structure of the data and to analyse a potential cyclic effect. RESULTS: A total of 744, 584, 848 and 682 pain, fatigue and dryness VASs were collected on 632 subjects in spring, summer, fall and winter, respectively. No significant difference was observed in pain, fatigue and dryness, according to the month of the year or the season (all p values > 0.05). CONCLUSION: In pSS, seasonality does not affect patient-reported outcomes (PROs) on fatigue, pain and dryness.

At the crossroads of gout and psoriatic arthritis: "psout".

Psoriatic arthritis and gout are frequently encountered conditions sharing a number of common risk factors, which render their independent study difficult. Epidemiological studies have demonstrated a strong link between these diseases, suggesting the presence of underlying, intertwined pathophysiological mechanisms that currently remain unknown. Indeed, sodium urate crystals could play a pathogenic role in psoriasis and psoriatic arthritis. In daily practice, the distinction between psoriatic arthritis associated with hyperuricemia and a gouty arthropathy with psoriasis is complex. Several common pathogenic features suggest a more intricate relationship than their mere coexistence in the same patient. Thus, the concurrence of these two diseases should be seen as a novel overlap syndrome, at the boundary between inflammatory and metabolic rheumatism. The present update aims to clarify the determinants of the link and to define this new nosological entity. Its recognition could have therapeutic implications that appear essential for treatment optimization in a personalized setting.Key Points• What is already known about this subject? Psoriatic arthritis (PsA) and gout have strong interconnections, including comorbidities and pathophysiology. One must note that confounding clinical symptoms and radiological signs of PsA and gout are similar and difficult to differentiate in patients whose radiological lesions become too advanced to be differentiated or with less clearly defined phenotypes.• What does this study add? The pathogenic role of chronic hyperuricemia in the development and maintenance of PsA is based on epidemiological, clinical, and fundamental arguments and hence does not appear fortuitous. These two pathological processes can influence each other.• How might this impact on clinical practice? This new line of thinking regarding the convergence of gout and PsA, involving the role of urate crystals, could prompt a potential new approach to treatment (urate-lowering therapy) among patients with active/refractory PsA.