A review of a strategic roadmapping exercise to advance clinical translation of photoacoustic imaging: From current barriers to future adoption.

Photoacoustic imaging (PAI), also referred to as optoacoustic imaging, has shown promise in early-stage clinical trials in a range of applications from inflammatory diseases to cancer. While the first PAI systems have recently received regulatory approvals, successful adoption of PAI technology into healthcare systems for clinical decision making must still overcome a range of barriers, from education and training to data acquisition and interpretation. The International Photoacoustic Standardisation Consortium (IPASC) undertook an community exercise in 2022 to identify and understand these barriers, then develop a roadmap of strategic plans to address them. Here, we outline the nature and scope of the barriers that were identified, along with short-, medium- and long-term community efforts required to overcome them, both within and beyond the IPASC group.

Quantitative magnetic resonance imaging (qMRI) in axial spondyloarthritis.

Imaging, and particularly MRI, plays a crucial role in the assessment of inflammation in rheumatic disease, and forms a core component of the diagnostic pathway in axial spondyloarthritis. However, conventional imaging techniques are limited by image contrast being non-specific to inflammation and a reliance on subjective, qualitative reader interpretation. Quantitative MRI methods offer scope to address these limitations and improve our ability to accurately and precisely detect and characterise inflammation, potentially facilitating a more personalised approach to management. Here, we review quantitative MRI methods and emerging quantitative imaging biomarkers for imaging inflammation in axial spondyloarthritis. We discuss the potential benefits as well as the practical considerations that must be addressed in the movement toward clinical translation of quantitative imaging biomarkers.

Multi-Omic Biomarkers for Patient Stratification in Sjogren's Syndrome-A Review of the Literature.

Sjögren's syndrome (SS) is a heterogeneous autoimmune rheumatic disease (ARD) characterised by dryness due to the chronic lymphocytic infiltration of the exocrine glands. Patients can also present other extra glandular manifestations, such as arthritis, anaemia and fatigue or various types of organ involvement. Due to its heterogenicity, along with the lack of effective treatments, the diagnosis and management of this disease is challenging. The objective of this review is to summarize recent multi-omic publications aiming to identify biomarkers in tears, saliva and peripheral blood from SS patients that could be relevant for their better stratification aiming at improved treatment selection and hopefully better outcomes. We highlight the relevance of pro-inflammatory cytokines and interferon (IFN) as biomarkers identified in higher concentrations in serum, saliva and tears. Transcriptomic studies confirmed the upregulation of IFN and interleukin signalling in patients with SS, whereas immunophenotyping studies have shown dysregulation in the immune cell population frequencies, specifically CD4+and C8+T activated cells, and their correlations with clinical parameters, such as disease activity scores. Lastly, we discussed emerging findings derived from different omic technologies which can provide integrated knowledge about SS pathogenesis and facilitate personalised medicine approaches leading to better patient outcomes in the future.

Optimisation of methods for bacterial skin microbiome investigation: primer selection and comparison of the 454 versus MiSeq platform.

BACKGROUND: The composition of the skin microbiome is predicted to play a role in the development of conditions such as atopic eczema and psoriasis. 16S rRNA gene sequencing allows the investigation of bacterial microbiota. A significant challenge in this field is development of cost effective high throughput methodologies for the robust interrogation of the skin microbiota, where biomass is low. Here we describe validation of methodologies for 16S rRNA (ribosomal ribonucleic acid) gene sequencing from the skin microbiome, using the Illumina MiSeq platform, the selection of primer to amplify regions for sequencing and we compare results with the current standard protocols.. METHODS: DNA was obtained from two low density mock communities of 11 diverse bacterial strains (with and without human DNA supplementation) and from swabs taken from the skin of healthy volunteers. This was amplified using primer pairs covering hypervariable regions of the 16S rRNA gene: primers 63F and 519R (V1-V3); and 347F and 803R (V3-V4). The resultant libraries were indexed for the MiSeq and Roche454 and sequenced. Both data sets were denoised, cleaned of chimeras and analysed using QIIME. RESULTS: There was no significant difference in the diversity indices at the phylum and the genus level observed between the platforms. The capture of diversity using the low density mock community samples demonstrated that the primer pair spanning the V3-V4 hypervariable region had better capture when compared to the primer pair for the V1-V3 region and was robust to spiking with human DNA. The pilot data generated using the V3-V4 region from the skin of healthy volunteers was consistent with these results, even at the genus level (Staphylococcus, Propionibacterium, Corynebacterium, Paracoccus, Micrococcus, Enhydrobacter and Deinococcus identified at similar abundances on both platforms). CONCLUSIONS: The results suggest that the bacterial community diversity captured using the V3-V4 16S rRNA hypervariable region from sequencing using the MiSeq platform is comparable to the Roche454 GS Junior platform. These findings provide evidence that the optimised method can be used in human clinical samples of low bacterial biomass such as the investigation of the skin microbiota.

Association Between Genetic Variation in FOXO3 and Reductions in Inflammation and Disease Activity in Inflammatory Polyarthritis.

OBJECTIVE: Genetic variation in FOXO3 (tagged by rs12212067) has been associated with a milder course of rheumatoid arthritis (RA) and shown to limit monocyte-driven inflammation through a transforming growth factor ß1-dependent pathway. This genetic association, however, has not been consistently observed in other RA cohorts. We sought to clarify the contribution of FOXO3 to prognosis in RA by combining detailed analysis of nonradiographic disease severity measures with an in vivo model of arthritis. METHODS: Collagen-induced arthritis, the most commonly used mouse model of RA, was used to assess how Foxo3 contributes to arthritis severity. Using clinical, serologic, and biochemical methods, the arthritis that developed in mice carrying a loss-of-function mutation in Foxo3 was compared with that which occurred in littermate controls. The association of rs12212067 with nonradiographic measures of RA severity, including the C-reactive protein level, the swollen joint count, the tender joint count, the Disease Activity Score in 28 joints, and the Health Assessment Questionnaire score, were modeled longitudinally in a large prospective cohort of patients with early RA. RESULTS: Loss of Foxo3 function resulted in more severe arthritis in vivo (both clinically and histologically) and was associated with higher titers of anticollagen antibodies and interleukin-6 in the blood. Similarly, rs12212067 (a single-nucleotide polymorphism that increases FOXO3 transcription) was associated with reduced inflammation, both biochemically and clinically, and with lower RA activity scores. CONCLUSION: Consistent with its known role in restraining inflammatory responses, FOXO3 limits the severity of in vivo arthritis and, through genetic variation that increases its transcription, is associated with reduced inflammation and disease activity in RA patients, effects that result in less radiographic damage.

The skin microbiome in psoriatic arthritis: methodology development and pilot data.

BACKGROUND: Skin microbiota are likely to be important in the development of conditions such as psoriatic arthritis. Profiling the bacterial community in the psosriatic plaques will contribute to our understanding of the role of the skin microbiome in these conditions. The aim of this work was to determine the optimum study design for work on the skin microbiome with use of the MiSeq platform. The objectives were to compare data generated from two platforms for two primer pairs in a low density mock bacterial community. METHODS: DNA was obtained from two low density mock communities of 11 diverse bacterial strains (with and without human DNA supplementation) and from swabs taken from the skin of four healthy volunteers. The DNA was amplified with primer pairs covering hypervariable regions of the 16S rRNA gene: primers 63F and 519R (V1-V3), and 347F and 803R (V3-V4). The resultant libraries were indexed for the MiSeq and Roche454 platforms and sequenced. Both datasets were de-noised, cleaned of chimeras, and analysed by use of QIIME software (version 1.8.0). FINDINGS: No significant difference in the diversity indices at the phylum and the genus level between the platforms was seen. Comparison of the diversity indices for the mock community data for the two primer pairs demonstrated that the V3-V4 hypervariable region had significantly better capture of bacterial diversity than did the V1-V3 region. Amplification with the same primer pairs showed strong concordance within each platform (98·9-99·8%), with negligible effect of spiked human DNA contamination. Comparison at the family level classification between samples processed on the MiSeq and Roche454 platforms using the V3-V4 hypervariable region also showed a high level of concordance (87%), although less so for the V1-V3 primers (10%). The pilot data from healthy volunteers were similar. INTERPRETATION: Results obtained from the V3-V4 16S rRNA hypervariable region, sequencing on the MiSeq and Roche454 platforms, were concordant between replicates, and between each other. These findings suggest that the MiSeq platform, and these primers, is a comparable method for determining skin microbiota to the widely used Roche454 methodology. FUNDING: NIHR Manchester Musculoskeletal Biomedical Research Unit.

The bacterial skin microbiome in psoriatic arthritis, an unexplored link in pathogenesis: challenges and opportunities offered by recent technological advances.

The resident microbial community, harboured by humans in sites such as the skin and gastrointestinal tract, is enormous, representing a candidate environmental factor affecting susceptibility to complex diseases, where both genetic and environmental risk factors are important. The potential of microorganisms to influence the human immune system is considerable, given their ubiquity. The impact of the host-gene-microbe interaction on the maintenance of health and the development of disease has not yet been assessed robustly in chronic inflammatory conditions. PsA represents a model inflammatory disease to explore the role of the microbiome because skin involvement and overlap with IBD implicates both the skin and gastrointestinal tract as sources of microbial triggers for PsA. In parallel with genetic studies, characterization of the host microbiota may benefit our understanding of the microbial contribution to disease pathogenesis-knowledge that may eventually inform the development of novel therapeutics.

Comparison of the psychometric properties of health-related quality of life measures used in adults with systemic lupus erythematosus: a review of the literature.

OBJECTIVE: A review of the literature was undertaken to evaluate the development and psychometric properties of health-related quality of life (HRQoL) measures used in adults with SLE. This information will help clinicians make an informed choice about the measures most appropriate for research and clinical practice. METHODS: Using the key words lupus and quality of life, full original papers in English were identified from six databases: OVID MEDLINE, EMBASE, Allied and Complementary Medicine, Psychinfo, Web of Science and Health and Psychosocial Instruments. Only studies describing the validation of HRQoL measures in adult SLE patients were retrieved. RESULTS: Thirteen papers were relevant; five evaluated generic instruments [QOLS-S (n = 1), EQ-5D/SF-6D (n = 1), SF-36 (n = 3)] and eight evaluated disease-specific measures [L-QOL (n = 1), LupusQoL (UK) (n = 1), LupusQoL (US) (n = 1), SSC (n = 2), SLEQOL (n = 3)]. For the generic measures, there is moderate evidence of good content validity and internal consistency, whereas there is strong evidence for both these psychometric properties in disease-specific measures. There is limited to moderate evidence to support the construct validity and test-retest reliability for the disease-specific measures. Responsiveness and floor/ceiling effects have not been adequately investigated in any of the measures. CONCLUSIONS: Direct comparison of the psychometric properties was difficult because of the different methodologies employed in the development and evaluation of the different HRQoL measures. However, there is supportive evidence that multidimensional disease-specific measures are the most suitable in terms of content and internal reliability for use in studies of adult patients with SLE.

The LupusQoL and associations with demographics and clinical measurements in patients with systemic lupus erythematosus.

OBJECTIVE: Having developed and validated a disease-specific health-related quality of life (HRQOL) measure for patients with systemic lupus erythematosus (SLE), the LupusQoL, we determined its relationship to demographic and clinical measurements in a group of patients with SLE. METHODS: A group of 322 outpatients completed the LupusQoL. Demographic (age, sex, marital status, ethnicity) and clinical variables (disease duration, disease activity, damage) were recorded. Associations between the 8 LupusQoL domains and age, disease duration, disease activity, and damage were explored using Spearman's correlation coefficients. Differences in LupusQoL scores were examined for sex and marital status using the Mann-Whitney U test. Ethnic groups were compared using ANOVA. RESULTS: All domains of LupusQoL were impaired, with fatigue (56.3) being the worst affected and body image (80.0) the least. The correlations between the LupusQoL domain scores and age (r = -0.01 to -0.22) and disease duration (r = 0 to 0.16) were absent or weak. Similarly, there were no significant differences in the LupusQoL scores regarding sex, marital status, or the 3 main ethnic groups (Black-Caribbean, Asian, White). Although there were statistically significant correlations between the scores of the LupusQoL domains and some scores of the British Isles Lupus Assessment Group index (r = -0.22 to 0.09) and the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (r = -0.29 to 0.21), these were weak. CONCLUSION: HRQOL was impaired in this cohort of outpatients with SLE as assessed by the validated lupus-specific LupusQoL. There were no clinically important associations between the 8 domains of the LupusQoL and clinical or demographic variables in this group of patients. Thus, the LupusQoL is a relatively independent outcome measure in patients with SLE.

Genetic susceptibility factors for psoriatic arthritis.

PURPOSE OF REVIEW: Psoriatic arthritis (PsA) has a large genetic component to its heritability, yet investigation into the genetic basis of the disease has lagged behind other rheumatic diseases mainly because of the difficulty in defining classification criteria that would accurately differentiate it from other forms of inflammatory arthritis. However, using a variety of approaches, some confirmed associations have now been identified with PsA susceptibility, making a review of these recent developments timely. RECENT FINDINGS: Family studies continue to suggest a large genetic contribution to PsA. Using a candidate gene approach, genes robustly confirmed to be associated with psoriasis vulgaris (PsV) have also been found to be associated with PsA (HLA-Cw*0602, IL23R, IL12B). There is less overlap reported with rheumatoid arthritis (RA) than PsV susceptibility loci but one report suggests that the AFF3 locus may be associated with both RA and PsA. SUMMARY: Large, well powered genome-wide association studies are currently underway and should provide further insights into the cause of this common arthritic disease over the next few months. The bulk of evidence so far suggests that the genetic factors underlying PsV are also associated with PsA suggesting that future studies of PsV could include patients with PsA.

Wegener's granulomatosis in pregnancy: a case report and review of the medical literature.

A Caucasian woman in the third trimester of her sixth pregnancy was diagnosed with Wegener's granulomatosis (WG) following investigation for recurrent ear infections and a persistent dry cough. Chest radiograph showed granulomatous lesions and the c-ANCA (antineutrophil cytoplasmic antibody) was strongly positive. She required pulsed methylprednisolone and cyclophosphamide followed by oral prednisolone and azathioprine to control the disease process during and after pregnancy. Neither the disease nor aggressive treatment adversely affected the pregnancy and she delivered a healthy baby girl by elective induction at 37 weeks. A review of the literature on Wegener's granulomatosis in pregnancy is presented.