Predictors of quality of life, functional status, depression and fatigue in early arthritis: comparison between clinically suspect arthralgia, unclassified arthritis and rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is often preceded by symptomatic phases during which classification criteria are not fulfilled. The health burden of these "at-risk" stages is not well described. This study assessed health-related quality of life (HRQoL), function, fatigue and depression in newly presenting patients with clinically suspect arthralgia (CSA), unclassified arthritis (UA) or RA. METHODS: Cross-sectional analysis of baseline Patient-Reported Outcome Measures (PROMs) was conducted in patients from the Birmingham Early Arthritis Cohort. HRQoL, function, depression and fatigue at presentation were assessed using EQ-5D, HAQ-DI, PHQ-9 and FACIT-F. PROMs were compared across CSA, UA and RA and with population averages from the HSE with descriptive statistics. Multivariate linear regression assessed associations between PROMs and clinical and sociodemographic variables. RESULTS: Of 838 patients included in the analysis, 484 had RA, 200 had CSA and 154 had UA. Patients with RA reported worse outcomes for all PROMs than those with CSA or UA. However, "mean EQ-5D utilities were 0.65 (95%CI: 0.61 to 0.69) in CSA, 0.61 (0.56 to 0.66) in UA and 0.47 (0.44 to 0.50) in RA, which was lower than in general and older (≥ 65 years) background populations." In patients with CSA or UA, HRQoL was comparable to chronic conditions such as heart failure, severe COPD or mild angina. Higher BMI and older age (≥ 60 years) predicted worse depression (PHQ-9: -2.47 (-3.85 to -1.09), P < 0.001) and fatigue (FACIT-F: 5.05 (2.37 to 7.73), P < 0.001). Women were more likely to report worse function (HAQ-DI: 0.13 (0.03 to 0.21), P = 0.01) and fatigue (FACIT-F: -3.64 (-5.59 to -1.70), P < 0.001), and residents of more deprived areas experienced decreased function (HAQ-DI: 0.23 (0.10 to 0.36), P = 0.001), greater depression (PHQ-9: 1.89 (0.59 to 3.18), P = 0.004) and fatigue (FACIT-F: -2.60 (-5.11 to 0.09), P = 0.04). After adjustments for confounding factors, diagnostic category was not associated with PROMs, but disease activity and polypharmacy were associated with poorer performance across all PROMs. CONCLUSIONS: Patient-reported outcomes were associated with disease activity and sociodemographic characteristics. Patients presenting with RA reported a higher health burden than those with CSA or UA, however HRQoL in the pre-RA groups was significantly lower than population averages.

N-desethyl isotonitazene detected in polydrug users admitted to hospital in Birmingham, United Kingdom.

INTRODUCTION: Nitazenes are potent synthetic opioids and N-desethyl isotonitazene, a metabolite of isotonitazene, has emerged as a drug in its own right. METHODS: This is an observational case series of patients with suspected or declared substance use who were admitted to hospitals in the Sandwell and West Birmingham National Health Service Trust between July and October 2023. All patients were found on toxicological screening to have been exposed to N-desethyl isotonitazene. RESULTS: Twenty presentations involving 19 patients who tested positive for N-desethyl isotonitazene were included in the study. In 19 presentations, multiple substances were detected on toxicological screening. The number of patients testing positive for other substances were: 19 for cocaine and its main metabolite benzoylecgonine, 13 for morphine, 11 for the heroin-specific metabolite 6-monoacetylmorphine, ten for xylazine, eight for gabapentinoids (pregabalin and/or gabapentin), seven for methadone and/or the metabolite, 2-ethylidene-1, 5-dimethyl-3, 3-diphenylpyrrolidine, six for benzodiazepines and five for the synthetic cannabinoid MDMB-4en-PINACA. Only one patient had no other substances detected apart from N-desethyl isotonitazene. This patient presented with coma, miosis, bradypnoea and hypercapnia and responded to naloxone. In this cohort, the median concentration of N-desethyl isotonitazene was 1.53 µg/L (n = 14; range 0.59-5.48) in whole blood and 27.75 µg/L (n = 16; range 0.51-91.53) in urine. DISCUSSION: The majority of the patients in this cohort presented with features typical of an opioid overdose, which is unsurprising as they were all experienced users of diamorphine. Although these features are also consistent with the known effects of N-desethyl isotonitazene, in only one case is it possible to attribute the patient's features to N-desethyl isotonitazene toxicity alone. CONCLUSIONS: This case series highlights the need for toxicovigilance in the illicit drug market as patterns of substance misuse evolve and novel psychoactive substances continue to emerge.

Relationship Between Inflammation and Metabolism in Patients With Newly Presenting Rheumatoid Arthritis.

Background: Systemic inflammation in rheumatoid arthritis (RA) is associated with metabolic changes. We used nuclear magnetic resonance (NMR) spectroscopy-based metabolomics to assess the relationship between an objective measure of systemic inflammation [C-reactive protein (CRP)] and both the serum and urinary metabolome in patients with newly presenting RA. Methods: Serum (n=126) and urine (n=83) samples were collected at initial presentation from disease modifying anti-rheumatic drug naïve RA patients for metabolomic profile assessment using 1-dimensional 1H-NMR spectroscopy. Metabolomics data were analysed using partial least square regression (PLS-R) and orthogonal projections to latent structure discriminant analysis (OPLS-DA) with cross validation. Results: Using PLS-R analysis, a relationship between the level of inflammation, as assessed by CRP, and the serum (p=0.001) and urinary (p<0.001) metabolome was detectable. Likewise, following categorisation of CRP into tertiles, patients in the lowest CRP tertile and the highest CRP tertile were statistically discriminated using OPLS-DA analysis of both serum (p=0.033) and urinary (p<0.001) metabolome. The most highly weighted metabolites for these models included glucose, amino acids, lactate, and citrate. These findings suggest increased glycolysis, perturbation in the citrate cycle, oxidative stress, protein catabolism and increased urea cycle activity are key characteristics of newly presenting RA patients with elevated CRP. Conclusions: This study consolidates our understanding of a previously identified relationship between serum metabolite profile and inflammation and provides novel evidence that there is a relationship between urinary metabolite profile and inflammation as measured by CRP. Identification of these metabolic perturbations provides insights into the pathogenesis of RA and may help in the identification of therapeutic targets.

Vitamin D and early rheumatoid arthritis.

BACKGROUND: Previous studies have linked rheumatoid arthritis (RA) risk and disease activity with vitamin D-deficiency (low serum 25-hydroxyvitamin D (25OHD)), but a causal role for vitamin D in RA is still unclear, with conflicting results from many previous studies, partly due to heterogeneity in study design and patient populations. In this study we aimed to (1) analyse serum 25OHD in early inflammatory arthritis, (2) compare 25OHD with disease activity and fatigue in early RA and (3) determine whether low 25OHD is associated with progression to RA. METHODS: An analysis of 790 patients recruited to the Birmingham Early Inflammatory Arthritis Cohort and followed longitudinally to determine clinical outcomes. The following were recorded at baseline: demographic data, duration of symptoms, duration of early morning stiffness (EMS), tender and swollen joint counts, Visual Analogue Scale (VAS) pain/fatigue/EMS, PHQ-9, HAQ and FACIT-Fatigue scores, DAS28-ESR, DAS28-CRP, CRP, ESR, anti-CCP antibody status, rheumatoid factor status, and serum 25OHD (ng/ml). Diagnosis was recorded at 0 and 12 months onwards as either RA, Undifferentiated Inflammatory Arthritis (UIA; synovitis not meeting other classification/diagnostic criteria), Clinically Suspect Arthralgia (CSA; arthralgia of an inflammatory type without synovitis), or Other. RESULTS: Baseline demographic data were similar between all groups, with median symptom duration of 16.8-34.0 days. Baseline 25OHD was not significantly different between groups [median, interquartile range (IQR): RA 46.7, 30.0-73.3; UIA 51.4, 30.0-72.3; CSA 47.7, 30.3-73.0; Other 39.9, 28.6-62.2]. In RA (n = 335), there were no significant differences between 25OHD and measures of disease activity or fatigue. No association between 25OHD and progression from UIA or CSA to RA was observed. CONCLUSIONS: There was no clear association between serum 25OHD and baseline diagnosis, RA disease activity, or progression from UIA or CSA to RA. Future studies of other vitamin D metabolites may better define the complex role of vitamin D in RA.

Symptoms in individuals at risk of rheumatoid arthritis.

An increasing interest in treating individuals at risk of rheumatoid arthritis (RA) to prevent the development of this chronic condition has focussed attention on the identification of risk factors of this disease. Most patients who develop RA progress through a preceding symptomatic phase that may take the form of arthralgia, palindromic rheumatism or unclassified arthritis before a disease currently classifiable as RA is established. An understanding of symptoms that identify individuals as being at risk of RA is a critical issue. Constellations of relevant symptoms could (1) form the basis of public health campaigns to encourage rapid consultation, (2) inform primary health care providers regarding which patients to perform additional tests in or whom to refer to a rheumatologist and (3) be included in algorithms to predict RA development. In this review, we present qualitative and quantitative data summarising current understanding of the symptoms experienced by individuals at risk of RA.

New pathogenic insights into rheumatoid arthritis.

PURPOSE OF REVIEW: Rheumatoid arthritis (RA) is a heterogeneous chronic immune-mediated inflammatory disease, associated with significant morbidity and reduced life expectancy. Here, we review recent discoveries; particularly those which have attempted to integrate genome-wide association studies (GWAS) with biological pathways and cell types known to play a role in disease pathology in order to expand our current understanding of the pathogenesis of RA. As the role of stromal cells in the pathogenesis of RA has been reviewed in detail in Current Opinions in Rheumatology, this area will not be covered in this review. RECENT FINDINGS: Although our understandings of the pathogenic processes that drive disease in RA remain incomplete, remarkable advances over the past year can be highlighted. GWAS have raised awareness of important new risk loci with genes that either are the targets of approved therapies for RA, or involve pathways for drugs that could be repurposed from other disease indications such as cancer. Furthermore, promising strides have been made in predicting the likelihood of developing RA in those at risk using human leukocyte antigen (HLA), smoking, and autoantibody status prediction models. These findings give a fresh insight into RA pathogenesis and help identify new, or repurpose known therapeutic targets from other disease areas. SUMMARY: The findings discussed in this review underscore the progress made to date and the need for future studies, investigating disease mechanisms in RA, with particular interest in at-risk RA gene loci, their function in immune and stromal cells within the synovium, and how they interact with environmental factors to initiate and perpetuate disease.

Metabolomics to identify biomarkers and as a predictive tool in inflammatory diseases.

There is an overwhelming need for a simple, reliable tool that aids clinicians in diagnosing, assessing disease activity and treating rheumatic conditions. Identification of biomarkers in partially understood inflammatory disorders has long been sought after as the Holy Grail of Rheumatology. Given the complex nature of inflammatory conditions, it has been difficult to earmark the potential biomarkers. Metabolomics, however, is promising in providing new insights into inflammatory conditions and also identifying such biomarkers. Metabolomic studies have generally revealed increased energy requirements for by-products of a hypoxic environment, leading to a characteristic metabolic fingerprint. Here, we discuss the significance of such studies and their potential as a biomarker.

Systematic review of randomized controlled trials on interventions for melasma: an abridged Cochrane review.

BACKGROUND: Multiple treatments exist for melasma; they are often substandard and associated with side effects. OBJECTIVES: We sought to assess the effectiveness of interventions used in the management of all types of melasma. METHODS: We undertook a systematic review using the methodology of the Cochrane Collaboration. RESULTS: We included 20 studies with a total of 2125 participants covering 23 different treatments. A meta-analysis was not possible because of the heterogeneity of treatments. Triple-combination cream (hydroquinone, tretinoin, and fluocinolone acetonide) was more effective at lightening melasma than hydroquinone alone (relative risk 1.58, 95% confidence interval 1.26-1.97) or any of the agents in a dual-combination cream. Azelaic acid (20%) was significantly more effective than 2% hydroquinone (relative risk 1.25, 95% confidence interval 1.06-1.48) at lightening melasma. In 2 studies where tretinoin was compared with placebo, objective measures demonstrated significant reductions in the severity. However, only in 1 study did participants rate a significant improvement (relative risk 13, 95% confidence interval 1.88-89.74). LIMITATIONS: There was poor methodology, a lack of standardized outcome assessments, and short duration of studies. CONCLUSIONS: The current limited evidence supports the efficacy of multiple interventions. Randomized controlled trials on well-defined participants with long-term outcomes are needed.