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.

Improving patient pathways for systemic lupus erythematosus: a multistakeholder pathway optimisation study.

OBJECTIVE: Among the most significant challenges in SLE are the excessive diagnosis delay and the lack of coordinated care. The aim of the study was to investigate patient pathways in SLE in order to improve clinical and organisational challenges in the management of those with suspected and confirmed SLE. METHODS: We conducted a cross-sectional study of patients with SLE, healthcare providers and other representative stakeholders. Focus groups were conducted, and based on the collected data the most impactful disruption points in SLE patient pathways were identified. A novel framework to improve individual patient pathways in SLE was developed, discussed and validated during a consensus meeting with representative stakeholders. RESULTS: Six thematic clusters regarding disruption in optimal patient pathways in SLE were identified: appropriate and timely referral strategy for SLE diagnosis; the need for a dedicated consultation during which the diagnosis of SLE would be announced, and following which clarifications and psychological support offered; individualised patient pathways with coordinated care based on organ involvement, disease severity and patient preference; improved therapeutic patient education; prevention of complications such as infections, osteoporosis and cancer; and additional patient support. During the consensus meeting, the broader panel of stakeholders achieved consensus on these attributes and a framework for optimising SLE patient pathways was developed. CONCLUSIONS: We have identified significant disruption points and developed a novel conceptual framework to improve individual patient pathways in SLE. These data may be of valuable interest to patients with SLE, their physicians, health organisations as well as policy makers.

[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.

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.

Multi-OMICS analyses unveil STAT1 as a potential modifier gene in mevalonate kinase deficiency.

OBJECTIVES: The objective of the present study was to explain why two siblings carrying both the same homozygous pathogenic mutation for the autoinflammatory disease hyper IgD syndrome, show opposite phenotypes, that is, the first being asymptomatic, the second presenting all classical characteristics of the disease. METHODS: Where single omics (mainly exome) analysis fails to identify culprit genes/mutations in human complex diseases, multiomics analyses may provide solutions, although this has been seldom used in a clinical setting. Here we combine exome, transcriptome and proteome analyses to decipher at a molecular level, the phenotypic differences between the two siblings. RESULTS: This multiomics approach led to the identification of a single gene-STAT1-which harboured a rare missense variant and showed a significant overexpression of both mRNA and protein in the symptomatic versus the asymptomatic sister. This variant was shown to be of gain of function nature, involved in an increased activation of the Janus kinase/signal transducer and activator of transcription signalling (JAK/STAT) pathway, known to play a critical role in inflammatory diseases and for which specific biotherapies presently exist. Pathway analyses based on information from differentially expressed transcripts and proteins confirmed the central role of STAT1 in the proposed regulatory network leading to an increased inflammatory phenotype in the symptomatic sibling. CONCLUSIONS: This study demonstrates the power of a multiomics approach to uncover potential clinically actionable targets for a personalised therapy. In more general terms, we provide a proteogenomics analysis pipeline that takes advantage of subject-specific genomic and transcriptomic information to improve protein identification and hence advance individualised medicine.

Efficacy of Continuous Interleukin 1 Blockade in Mevalonate Kinase Deficiency: A Multicenter Retrospective Study in 13 Adult Patients and Literature Review.

OBJECTIVE: To report efficacy and tolerance of interleukin 1 blockade in adult patients with mevalonate kinase deficiency (MKD). METHODS: We retrospectively collected data on 13 patients with MKD who had received anakinra (n = 10) and canakinumab (n = 7). RESULTS: Anakinra resulted in complete or partial remission in 3/10 and 5/10 patients, respectively, and no efficacy in 2/10, but a switch to canakinumab led to partial remission. Canakinumab resulted in complete or partial remission in 3/7 and 4/7 patients, respectively. CONCLUSION: These data support frequent partial responses, showing a better response with canakinumab. The genotype and therapeutic outcomes correlation should help in the personalization of treatment.

Observational Study of a French and Belgian Multicenter Cohort of 23 Patients Diagnosed in Adulthood With Mevalonate Kinase Deficiency.

The aim of this study was to describe the clinical and biological features of Mevalonate kinase deficiency (MKD) in patients diagnosed in adulthood. This is a French and Belgian observational retrospective study from 2000 to 2014. To constitute the cohort, we cross-check the genetic and biochemical databases. The clinical, enzymatic, and genetic data were gathered from medical records. Twenty-three patients were analyzed. The mean age at diagnosis was 40 years, with a mean age at onset of symptoms of 3 years. All symptomatic patients had fever. Febrile attacks were mostly associated with arthralgia (90.9%); lymphadenopathy, abdominal pain, and skin lesions (86.4%); pharyngitis (63.6%); cough (59.1%); diarrhea, and hepatosplenomegaly (50.0%). Seven patients had psychiatric symptoms (31.8%). One patient developed recurrent seizures. Three patients experienced renal involvement (13.6%). Two patients had angiomyolipoma (9.1%). All but one tested patients had elevated serum immunoglobulin (Ig) D level. Twenty-one patients had genetic diagnosis; most of them were compound heterozygote (76.2%). p.Val377Ile was the most prevalent mutation. Structural articular damages and systemic AA amyloidosis were the 2 most serious complications. More than 65% of patients displayed decrease in severity and frequency of attacks with increasing age, but only 35% achieved remission. MKD diagnosed in adulthood shared clinical and genetic features with classical pediatric disease. An elevated IgD concentration is a good marker for MKD in adults. Despite a decrease of severity and frequency of attacks with age, only one-third of patients achieved spontaneous remission.

Homozygosity for the V377I mutation in mevalonate kinase causes distinct clinical phenotypes in two sibs with hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS).

OBJECTIVE: Mevalonate kinase (MVK) deficiency is a rare autosomal recessive auto-inflammatory disorder characterised by recurring episodes of fever associated with multiple non-specific inflammatory symptoms and caused by mutations in the MVK gene. The phenotypic spectrum is wide and depends mostly on the nature of the mutations. Hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS) is a relatively mild presentation and predominantly associated with a c.1129G>A (p.V377I) mutation in the MVK gene. We report cases of two sisters homozygous for this mutation but exhibiting distinct (symptomatic vs asymptomatic) phenotypes. METHODS: Patient history was obtained; physical and clinical examination and laboratory tests were performed; lipopolysaccharide (LPS) response of peripheral blood mononuclear cells was quantified. RESULTS: Low MVK enzymatic activity is not necessarily associated with inflammatory symptoms. Increased inflammatory cytokine secretion in response to LPS is associated with symptomatic MVK deficiency. CONCLUSIONS: Individuals who are homozygous for the common p.V377I mutation in the MVK gene may not display the characteristic inflammatory episodes diagnostic of MKD and thus may be lost for correct and timely diagnosis.

In antisynthetase syndrome, ACPA are associated with severe and erosive arthritis: an overlapping rheumatoid arthritis and antisynthetase syndrome.

Anticitrullinated peptide/protein antibodies (ACPA), which are highly specific for rheumatoid arthritis (RA), may be found in some patients with other systemic autoimmune diseases. The clinical significance of ACPA in patients with antisynthetase syndrome (ASS), a systemic disease characterized by the association of myositis, interstitial lung disease, polyarthralgia, and/or polyarthritis, has not yet been evaluated with regard to phenotype, prognosis, and response to treatment. ACPA-positive ASS patients were first identified among a French multicenter registry of patients with ASS. Additionally, all French rheumatology and internal medicine practitioners registered on the Club Rhumatismes et Inflammation web site were asked to report their observations of ASS patients with ACPA. The 17 collected patients were retrospectively studied using a standardized questionnaire and compared with 34 unselected ACPA-negative ASS patients in a case-control study. All ACPA-positive ASS patients suffered from arthritis versus 41% in the control group (P < 0.0001). The number of swollen joints was significantly higher (7.0 ±â€Š5.0 vs 2.9 ±â€Š3.9, P < 0.005), with a distribution resembling that of RA. Radiographic damages were also more frequent in ACPA-positive ASS patients (87% vs 11%, P < 0.0001). Aside from a significantly higher transfer factor for carbon monoxide in ACPA-ASS patients, lung, muscle, and skin involvements had similar incidences, patterns, and severity in both groups. Although Nonbiologic treatments were similarly used in both groups, ACPA-positive patients received biologics more frequently (59% vs 12%, P < 0.0008), mostly due to refractory arthritis (n = 9). Eight patients received anti-Cluster of differentiation 20 (CD20) monoclonal antibodies (mAbs) with good efficacy and tolerance, whereas 2 of the 5 patients treated with antitumor necrosis factor drugs had worsened myositis and/or interstitial lung disease. After a >7-year mean follow-up, extra-articular outcomes and survival were not different. ACPA-positive ASS patients showed an overlapping RA-ASS syndrome, were at high risk of refractory erosive arthritis, and might experience ASS flare when treated with antitumor necrosis factor drugs. In contrast, other biologics such as anti-CD20 mAb were effective in this context, without worsening systemic involvements.

Outcome of hepatitis E virus infection in patients with inflammatory arthritides treated with immunosuppressants: a French retrospective multicenter study.

The clinical presentation and outcome of hepatitis E virus (HEV) infection in inflammatory rheumatic diseases are unknown. We aimed to investigate the severity of acute HEV infection and the risk of chronic viral replication in patients with inflammatory arthritides treated with immunosuppressive drugs. All rheumatology and internal medicine practitioners belonging to the Club Rhumatismes et Inflammation in France were sent newsletters asking for reports of HEV infection and inflammatory arthritides. Baseline characteristics of patients and the course of HEV infection were retrospectively assessed by use of a standardized questionnaire. From January 2010 to August 2013, we obtained reports of 23 cases of HEV infection in patients with rheumatoid arthritis (n = 11), axial spondyloarthritis (n = 5), psoriatic arthritis (n = 4), other types of arthritides (n = 3). Patients received methotrexate (n = 16), antitumor necrosis factor α agents (n = 10), rituximab (n = 4), abatacept (n = 2), tocilizumab (n = 2), and corticosteroids (n = 10, median dose 6 mg/d, range 2-20). All had acute hepatitis: median aspartate and alanine aminotransferase levels were 679 and 1300 U/L, respectively. Eleven patients were asymptomatic, 4 had jaundice. The HEV infection diagnosis relied on positive PCR results for HEV RNA (n = 14 patients) or anti-HEV IgM positivity (n = 9). Median follow-up was 29 months (range 3-55). Treatment included discontinuation of immunosuppressants for 20 patients and ribavirin treatment for 5. Liver enzyme levels normalized and immunosuppressant therapy could be reinitiated in all patients. No chronic infection was observed. Acute HEV infection should be considered in patients with inflammatory rheumatism and elevated liver enzyme values. The outcome of HEV infection seems favorable, with no evolution to chronic hepatitis or fulminant liver failure.