Unravelling the complexity of psoriatic arthritis on a journey towards precision medicine

Psoriatic Arthritis (PsA) is a complex, musculoskeletal disease characterized by a heterogeneous clinical phenotype and variable disease course. With new treatment options emerging, it has become difficult for rheumatologists to know which therapy is best for which patient. Postponing efficacious therapy - even for six months - can result in progression of joint erosions, decreased long-term physical function and reduced risk of medication-free remission. Hence, there is an urgent clinical need to tailor medical treatment to individual patients. This thesis discusses recent advances to unravel the complexity of PsA, on a journey towards precision medicine. The clinical work presented in this thesis provides indirect evidence for the efficacy of conventional synthetic disease modifying anti-rheumatic drugs in PsA. The results of a literature review and experimental laboratory research underline the importance of the adaptive immune system in disease pathogenesis. Two new dysregulated T cell mechanisms are discovered, which could be investigated as therapeutic targets. Furthermore, by clinical research and reviewing literature the need for robust predictors is confirmed, both for the development of PsA in psoriasis patients and for the response to therapy. In recent years, advancing experimental methods, analytical techniques and computational modeling approaches have enabled researchers to study an increasing range of clinical, (epi)genetic, immune, and other biomarkers. Future research is warranted to discover and validate robust prediction models to facilitate personalized treatment and prevention of PsA

Unravelling the complexity of psoriatic arthritis on a journey towards precision medicine

Psoriatic Arthritis (PsA) is a complex, musculoskeletal disease characterized by a heterogeneous clinical phenotype and variable disease course. With new treatment options emerging, it has become difficult for rheumatologists to know which therapy is best for which patient. Postponing efficacious therapy - even for six months - can result in progression of joint erosions, decreased long-term physical function and reduced risk of medication-free remission. Hence, there is an urgent clinical need to tailor medical treatment to individual patients. This thesis discusses recent advances to unravel the complexity of PsA, on a journey towards precision medicine. The clinical work presented in this thesis provides indirect evidence for the efficacy of conventional synthetic disease modifying anti-rheumatic drugs in PsA. The results of a literature review and experimental laboratory research underline the importance of the adaptive immune system in disease pathogenesis. Two new dysregulated T cell mechanisms are discovered, which could be investigated as therapeutic targets. Furthermore, by clinical research and reviewing literature the need for robust predictors is confirmed, both for the development of PsA in psoriasis patients and for the response to therapy. In recent years, advancing experimental methods, analytical techniques and computational modeling approaches have enabled researchers to study an increasing range of clinical, (epi)genetic, immune, and other biomarkers. Future research is warranted to discover and validate robust prediction models to facilitate personalized treatment and prevention of PsA

Emerging molecular biomarkers for predicting therapy response in psoriatic arthritis : A review of literature

Psoriatic arthritis (PsA) is a heterogeneous, chronic inflammatory musculoskeletal disorder that affects ~0.1% of the population. PsA may severely impact quality-of-life and constitutes a significant economic burden on our health care system. While early effective treatment is deemed essential to prevent irreversible joint damage and functional impairment, not all patients respond to the same disease modifying anti-rheumatic drugs (DMARDs). DMARD options for PsA are rapidly evolving, yet only 50-60% of patients show a satisfactory response to their first-line DMARD therapy. Hence, there is an urgent medical need to predict which patients benefit from a particular treatment. To this end, molecular biomarkers capable of predicting therapeutic response are currently being scrutinized in clinical studies, that together should build a framework for clinical guidelines that improve personalized targeted treatment. In this review new developments within the field of biomarker discovery for predicting therapeutic response to DMARDs in PsA are examined

Spectrum van psoriatische aandoeningen

Psoriasis is a common immune-mediated inflammatory condition that primarily affects skin and nails. 6-41% of psoriasis patients develop psoriatic arthritis (PsA). The ways in which PsA can manifest itself include peripheral arthritis, axial spondyloarthritis, dactylitis and enthesitis. This heterogeneous clinical picture makes it sometimes difficult to recognise PsA,potentially resulting in permanent joint damage and functional impairments. Some people see psoriasis and PsA as 2 manifestations of a single disease because the multifactorial origins of psoriasis and PsA are largely overlapping. Psoriatic conditions are associated with a high burden of disease, reduced quality of life and comorbidities, including psychiatric and cardiovascular conditions. In recent years, several immunological pathways, immune cells and cytokines have been identified as important factors in pathophysiology and as new therapeutic targets. For many PsA patients treatment with disease modifying anti-rheumatic drugs leads to significant improvement of symptoms and quality of life

Spectrum van psoriatische aandoeningen

Psoriasis is a common immune-mediated inflammatory condition that primarily affects skin and nails. 6-41% of psoriasis patients develop psoriatic arthritis (PsA). The ways in which PsA can manifest itself include peripheral arthritis, axial spondyloarthritis, dactylitis and enthesitis. This heterogeneous clinical picture makes it sometimes difficult to recognise PsA,potentially resulting in permanent joint damage and functional impairments. Some people see psoriasis and PsA as 2 manifestations of a single disease because the multifactorial origins of psoriasis and PsA are largely overlapping. Psoriatic conditions are associated with a high burden of disease, reduced quality of life and comorbidities, including psychiatric and cardiovascular conditions. In recent years, several immunological pathways, immune cells and cytokines have been identified as important factors in pathophysiology and as new therapeutic targets. For many PsA patients treatment with disease modifying anti-rheumatic drugs leads to significant improvement of symptoms and quality of life

Multi‐omics integration reveals a core network involved in host defence and hyperkeratinization in psoriasis

Abstract Objectives The precise pathogenesis of psoriasis remains incompletely explored. We aimed to better understand the underlying mechanisms of psoriasis, using a systems biology approach based on transcriptomics and microbiome profiling. Methods We collected the skin tissue biopsies and swabs in both lesional and non‐lesional skin of 13 patients with psoriasis, 15 patients with psoriatic arthritis and healthy skin from 12 patients with ankylosing spondylitis. To study the similarities and differences in the molecular profiles between these three conditions, and the associations between the host defence and microbiota composition, we performed high‐throughput RNA‐sequencing to quantify the gene expression profile in tissues. The metagenomic composition of 16S on local skin sites was quantified by clustering amplicon sequences and counted into operational taxonomic units. We further analysed associations between the transcriptome and microbiome profiling. Results We found that lesional and non‐lesional samples were remarkably different in terms of their transcriptome profiles. The functional annotation of differentially expressed genes showed a major enrichment in neutrophil activation. By using co‐expression gene networks, we identified a gene module that was associated with local psoriasis severity at the site of biopsy. From this module, we found a ‘core’ set of genes that was functionally involved in neutrophil activation, epidermal cell differentiation and response to bacteria. Skin microbiome analysis revealed that the abundances of Enhydrobacter, Micrococcus and Leptotrichia were significantly correlated with the genes in core network. Conclusions We identified a core gene network that associated with local disease severity and microbiome composition, involved in the inflammation and hyperkeratinization in psoriatic skin

Respiratory syncytial virus prevention and asthma in healthy preterm infants : a randomised controlled trial

BACKGROUND: Respiratory syncytial virus (RSV) infection is associated with subsequent wheeze and asthma. We previously reported on the causal relationship between prevention of RSV infection during infancy and reduced frequency of subsequent wheeze using a double-blind, randomised, placebo-controlled trial (MAKI). We continued follow-up and analysed the effect of RSV prevention during infancy on asthma and lung function at age 6 years. METHODS: We studied 429 infants born at 32-35 weeks of gestation between 2008-10 who had randomly received either palivizumab for RSV immunoprophylaxis or placebo during the RSV season of their first year of life. After the first year of follow-up, single, assessor-blind follow-up of children continued until they were aged 6 years. Primary outcomes were parent-reported current asthma and forced expiratory volume in 0·5 s (FEV0·5). The trial is registered in the ISRCTN registry, number ISRCTN73641710. FINDINGS: 395 (92%) of 429 participants completed this 6-year follow-up study. Parent-reported current asthma was reported in 28 (14·1%) of 199 children in the RSV prevention group and 47 (24·0%) of 196 children in the placebo group (absolute risk reduction [ARR] 9·9%, 95% CI 2·2 to 17·6). The difference in current asthma, which was a composite endpoint, was due to a difference in infrequent wheeze (one to three episodes in the past year; 12 [6·0%] of 199 vs 26 [13·4%] of 194, ARR 7·4%, 95% CI 1·5 to 13·2). FEV0·5percentage predicted values were similar between the RSV prevention group (89·1% [SD 10·6]) and placebo group (90·1% [11·1]), with a mean difference of 1·0 (95% CI -1·3 to 3·3). The proportion of children with current physician-diagnosed asthma was similar between the RSV prevention group (19 [10·3%] of 185) and placebo group (18 [9·9%] of 182), with an ARR of -0·4 (95% CI -6·5 to 5·8). INTERPRETATION: In otherwise healthy preterm infants, this single-blind, randomised, placebo-controlled trial showed that RSV prevention did not have a major effect on current asthma or lung function at age 6 years. Future research will inform on the effect of RSV prevention on asthma at school age in the general population. FUNDING: AbbVie