Molecular Characterization of Circulating Microbiome Signatures in Rheumatoid Arthritis.

Rheumatoid Arthritis (RA) has been increasingly associated with perturbations to the microbial communities that reside in and on the body (the microbiome), in both human and animal studies. To date, such studies have mainly focused on the microbial communities that inhabit the gut and oral cavity. Mounting evidence suggests that microbial DNA can be detected in the blood circulation using a range of molecular methods. This DNA may represent an untapped pool of biomarkers that have the potential to report on changes to the microbiome of distant sites (e.g., example, the gut and oral cavity). To this end, through amplification and sequencing of the bacterial 16S rRNA variable region four, we evaluated the presence and identity of microbial DNA in blood samples obtained from RA patients (both prior to and 3 months following the instigation of treatment) in comparison to a small number of healthy control subjects and samples obtained from patients with ankylosing spondylitis (AS) and psoriatic arthritis (PA). Bacterial-derived DNA was identified in the majority of our patient samples. Taxonomic classification revealed that the microbiome community in RA was distinct from AS, PA, and the healthy state. Through analysis of paired patient samples obtained prior to and 3 months following treatment (V0 vs. V3), we found the microbiome to be modulated by treatment, and in many cases, this shift reduced the distance between these samples and the healthy control samples, suggesting a partial normalization following treatment in some patients. This effect was especially evident in seronegative arthritis patients. Herein, we provide further evidence for the existence of a blood microbiome in health and identify specific taxa modulated in disease and following treatment. These blood-derived signatures may have significant utility as disease biomarkers and suggest this area warrants further investigation.

The association of pain and stiffness with fatigue in incident polymyalgia rheumatica: baseline results from the polymyalgia rheumatica cohort study.

We aimed to examine the association between pain, stiffness and fatigue in newly diagnosed polymyalgia rheumatica (PMR) patients using baseline data from a prospective cohort study. Fatigue is a known, but often ignored symptom of PMR. Newly diagnosed PMR patients were recruited from general practice and mailed a baseline questionnaire. This included a numerical rating scale for pain and stiffness severity, manikins identifying locations of pain and stiffness and the FACIT-Fatigue questionnaire. A total of 652 PMR patients responded (88.5%). The mean age of responders was 72.6 years (SD 9.0) and the majority were female (62.0%). Manikin data demonstrated that bilateral shoulder and hip pain and stiffness were common. The mean fatigue score (FACIT) was 33.9 (SD 12.4). Adjusted regression analysis demonstrated that a higher number of pain sites (23-44 sites) and higher pain and stiffness severity were associated with greater levels of fatigue. In newly diagnosed PMR patients, fatigue was associated with PMR symptom severity.

The real evidence for polymyalgia rheumatic as a paraneoplastic syndrome.

Not available.

Risk of fragility fracture among patients with late-onset psoriasis: a UK population-based study.

This study aimed to examine fracture risk in patients with late-onset psoriasis. A cohort study was conducted using primary care records from the Clinical Practice Research Datalink. Psoriasis patients had a 10% increased risk of fracture compared to matched controls (hazard ratio (HR) = 1.10; 95% confidence interval (CI) 1.04, 1.16). INTRODUCTION: This study aimed to examine fracture risk in patients with late-onset psoriasis and investigate the effect of methotrexate on fracture risk. METHODS: A cohort study was conducted using primary care records from the UK-based Clinical Practice Research Datalink. Individuals aged 40 years and over, with incident (new onset) diagnoses of psoriasis, were identified from 1990 to 2004 and followed up until 2015. For each exposed individual, up to four age-, gender-, and practice-matched controls were randomly selected. Incidence rates of fragility fracture (hip, vertebral, spine, radius or unspecified site) per 10,000 person-years were calculated and hazard rates were compared to the unexposed using Cox regression models. The risk of fracture was also estimated, within the exposed group for patients receiving/not receiving methotrexate. RESULTS: Twenty-four thousand two hundred nineteen patients with psoriasis and 94,820 controls were identified. The absolute rate of fracture in psoriasis patients was 58 per 10,000 person-years (95% CI 55, 61) and 53 per 10,000 person-years in the matched controls (CI 52, 54). Psoriasis patients had a 10% increased risk of fracture compared to their matched controls (HR = 1.10; 95% CI 1.04, 1.16). Methotrexate use was not associated with increased risk (HR = 0.91; 95% CI 0.72, 1.15). CONCLUSIONS: Identifying additional clinical factors associated with increased fracture risk is important in improving fracture risk stratification. Further work is needed to determine the relationship between age of onset of psoriasis and fracture risk, explore causative explanations, and identify if existing fracture risk stratification tools underestimate fracture risk in patients with psoriasis.

The real evidence for polymyalgia rheumatica as a paraneoplastic syndrome.

The aim of this study was to systematically consider the evidence for polymyalgia rheumatica (PMR) as a paraneoplastic disease. A systematic review of Medline and Embase was conducted from their inception to February 2017. Risk of bias was assessed using the Newcastle-Ottawa tool. Data were extracted regarding the PMR-cancer association, the types of cancer associated with PMR and the presentation of PMR patients subsequently diagnosed with cancer. Twenty-three full text articles were reviewed from the 1174 unique references identified in the search. Nine articles were included in the final review. There was some evidence of an association between PMR and cancer in the short-term (first 6 to 12 months after diagnosis), but no evidence of an association after this time. Limited evidence suggests that lymphoma, prostate and haematological cancers may be those cancers more commonly diagnosed in those with PMR. There was little evidence to suggest what presenting features may be associated with the development of cancer. There is little evidence of PMR as a true paraneoplastic disease. However, there is reason to be cautious when making the diagnosis of PMR. Clinicians should be aware of this potential association both prior to making a diagnosis and throughout the course of the condition.

Association between characteristics of pain and stiffness and the functional status of patients with incident polymyalgia rheumatica from primary care.

This paper aims to examine the relationship between different characteristics of pain and stiffness and the functional status of patients with newly diagnosed polymyalgia rheumatica (PMR). Baseline analysis of an inception cohort study was conducted. Patients aged ≥18 years, with a new diagnosis of PMR were recruited from 382 English general practices. Participants were mailed a baseline questionnaire, including separate pain and stiffness manikins and numerical rating scales (NRS), a question on their ability to raise their arms above their head and the modified Health Assessment Questionnaire (mHAQ) to examine participants' functional status. Linear regression analysis, reported as regression co-efficients (95% confidence intervals (95% CI)), was used to assess the association of pain and stiffness with function, initially unadjusted and then adjusted for age, gender, deprivation status, smoking status, BMI, anxiety and depression. Six hundred fifty two patients responded to the baseline survey (88.5%). The majority (88.2%) reported no, or mild impairment in their functional status. Adjusted linear regression analysis demonstrated that high (NRS ≥8) pain (0.20 (95% CI 0.10-0.28)) or stiffness (0.18 (0.09-0.26)) ratings, an increasing number of sites of pain (0.18 (0.06-0.29)) or stiffness (0.19 (0.08-0.31)) and shoulder pain (0.18 (0.05-0.31)), stiffness (0.10 (0.01-0.20)) and difficulty raising arms above one's head (0.19 (0.10-0.28)) were all associated with increased functional impairment. The majority of newly diagnosed PMR patients reported no or minimal functional difficulty. However, those who experience severe or widespread pain or stiffness often have significant functional limitation in performing their daily activities and may be a subset worthy of additional focus in primary care.

The extra-articular impacts of rheumatoid arthritis: moving towards holistic care.

Although treat-to-target has revolutionised the outcomes of patients with rheumatoid arthritis (RA) there is emerging evidence that attaining the target of remission is insufficient to normalise patients' quality of life, and ameliorate the extra-articular impacts of RA. RA has a broad range of effects on patient's lives, with four key "extra-articular" impacts being pain, depression and anxiety, fatigue and rheumatoid cachexia. All of these are seen frequently; for example, studies have reported that 1 in 4 patients with RA have high-levels of fatigue. Commonly used drug treatments (including simple analgesics, non-steroidal anti-inflammatory drugs and anti-depressants) have, at most, only modest benefits and often cause adverse events. Psychological strategies and dynamic and aerobic exercise all reduce issues like pain and fatigue, although their effects are also only modest. The aetiologies of these extra-articular impacts are multifactorial, but share overlapping components. Consequently, patients are likely to benefit from management strategies that extend beyond the assessment and treatment of synovitis, and incorporate more broad-based, or "holistic", assessments of the extra-articular impacts of RA and their management, including non-pharmacological approaches. Innovative digital technologies (including tablet and smartphone "apps" that directly interface with hospital systems) are increasingly available that can directly capture patient-reported outcomes during and between clinic visits, and include them within electronic patient records. These are likely to play an important future role in delivering such approaches.

Fatigue as a precursor to polymyalgia rheumatica: an explorative retrospective cohort study.

OBJECTIVES: Polymyalgia rheumatica (PMR) is the commonest inflammatory disorder of older adults. Although not part of the recently published classification criteria, patients with PMR frequently complain of fatigue. We compared consultation for fatigue and sleep problems between individuals with and without PMR. METHOD: Consulters receiving a Read-coded diagnosis of PMR at nine general practices between 2000 and 2009 were matched by age, gender, general practice, and year of consultation to four patients without PMR. Fatigue and sleep problems were defined using Read codes. Cox regression was used to determine the association between PMR diagnosis and consultation for a fatigue/sleep problem. RESULTS: In total, 549 PMR patients were identified. Their mean (SD) age was 73.9 (8.6) years and 71% of the participants were female. Prior to the index date, 33 PMR patients and 80 matched non-PMR patients consulted with fatigue (0.43 vs. 0.25 consultations per 10 000 person-years, p = 0.006). PMR was associated with significantly more multiple fatigue consultations in the 12 months before PMR diagnosis [hazard ratio (HR) 1.95, 95% confidence interval (CI) 1.23-3.08]; no significant difference was seen in rates of consultations for sleep problems between patients with and without PMR. CONCLUSIONS: PMR patients were significantly more likely to have had multiple fatigue consultations before being diagnosed with PMR. Given the overproduction of inflammatory cytokines seen in PMR, this fatigue may represent a prodromal phase prior to consulting with more classical musculoskeletal symptoms. This suggests that clinicians should consider PMR as a potential diagnosis in older patients consulting with fatigue.

Increased cardiovascular mortality associated with gout: a systematic review and meta-analysis.

BACKGROUND: Hyperuricaemia, the biochemical precursor to gout, has been shown to be an independent risk factor for mortality from cardiovascular disease (CVD), although studies examining the clinical phenomenon of gout and risk of CVD mortality report conflicting results. This study aimed to produce a pooled estimate of risk of mortality from cardiovascular disease in patients with gout. DESIGN: Systematic review and meta-analysis. METHODS: Electronic bibliographic databases were searched from inception to November 2012, with results reviewed by two independent reviewers. Studies were included if they reported data on CVD mortality in adults with gout who were free of CVD at time of entry into the study. Pooled hazard ratios (HRs) for this association were calculated both unadjusted and adjusted for traditional vascular risk factors. RESULTS: Six papers, including 223,448 patients, were eligible for inclusion (all (CVD) mortality n = 4, coronary heart disease (CHD) mortality n = 3, and myocardial infarction mortality n = 3). Gout was associated with an excess risk of CVD mortality (unadjusted HR 1.51 (95% confidence interval, CI, 1.17-1.84)) and CHD mortality (unadjusted HR 1.59, 95% CI 1.25-1.94)). After adjusting for traditional vascular risk factors, the pooled HR for both CVD mortality (HR 1.29, 95% CI 1.14-1.44) and CHD mortality (HR 1.42, 95% CI 1.22-1.63) remained statistically significant, but none of the studies reported a significant association with myocardial infarction. CONCLUSIONS: Gout increases the risk of mortality from CVD and CHD, but not myocardial infarction, independently of vascular risk factors.

Genetic polymorphisms in key methotrexate pathway genes are associated with response to treatment in rheumatoid arthritis patients.

We investigated the effect of single-nucleotide polymorphisms (SNPs) spanning 10 methotrexate (MTX) pathway genes, namely AMPD1, ATIC, DHFR, FPGS, GGH, ITPA, MTHFD1, SHMT1, SLC19A1 (RFC) and TYMS on the outcome of MTX treatment in a UK rheumatoid arthritis (RA) patient cohort. Tagging SNPs were selected and genotyping was performed in 309 patients with predefined outcomes to MTX treatment. Of the 129 SNPs tested, 11 associations were detected with efficacy (P-trend 0.05) including four SNPs in the ATIC gene (rs12995526, rs3821353, rs7563206 and rs16853834), six SNPs in the SLC19A1 gene region (rs11702425, rs2838956, rs7499, rs2274808, rs9977268 and rs7279445) and a single SNP within the GGH gene (rs12681874). Five SNPs were significantly associated with adverse events; three in the DHFR gene (rs12517451, rs10072026, and rs1643657) and two of borderline significance in the FPGS gene. The results suggest that genetic variations in several key MTX pathway genes may influence response to MTX in the RA patients. Further studies will be required to validate these findings and if confirmed these results could contribute towards a better understanding of and ability to predict MTX response in RA.

MTHFR gene polymorphisms and outcome of methotrexate treatment in patients with rheumatoid arthritis: analysis of key polymorphisms and meta-analysis of C677T and A1298C polymorphisms.

Association of two key variants mapping to the MTHFR gene (C677T (rs1801133) and A1298C (rs1801131)) with response to methotrexate (MTX) remains controversial. We investigated these and other markers spanning the gene as predictors of MTX efficacy and adverse events in a UK rheumatoid arthritis (RA) patient cohort and performed a meta-analysis of the two key variants using all published data. The tagging single nucleotide polymorphisms (SNPs) were genotyped in 309 patients with well-defined outcomes to MTX treatment and 17 studies were included in the meta-analysis. No association of the SNPs tested was detected with MTX efficacy or toxicity in our UK cohort. After combining our data with previous studies by meta-analysis, the random effects pooled odds ratios (OR) for both C677T and A1298C showed no association with efficacy or toxicity for either of the SNPs (efficacy: OR=1.05 (95% confidence interval (CI) 0.83-1.32) and OR=0.81 (95% CI 0.53-1.24), respectively; toxicity: OR=1.38 (95% CI 0.90-2.12) and OR=1.19 (95% CI 0.80-1.78), respectively). The available evidence suggests that the MTHFR C677T and A1298C gene polymorphisms are not reliable predictors of response to MTX treatment in RA patients.

Fibromyalgia in patients with rheumatoid arthritis: driven by depression or joint damage?

OBJECTIVES: Studies have shown an increased incidence of fibromyalgia (FMS) in RA patients. The aims of this study were to explore the effect of mood and disease damage on the prevalence of FMS. METHODS: RA patients underwent a standardised clinical assessment, including disease activity (DAS-28), disease damage (mechanical joint score, MJS), fibromyalgia tender point assessment and the Hospital Anxiety and Depression Scale (HADS) and Health Assessment Questionnaire (HAQ). Patients were classified with FMS using two criteria a) tender-swollen joint count was ≥7 or b) tender point score of ≥11/18. RESULTS: 44/285 (15%) patients were classified as having FMS using the joint count difference of ≥7, compared to 18/285 (6%) using the tender point score of >11. Using the joint count difference to classify patients as having FMS, those with FMS had higher HAQ scores than those without FMS (2.12 vs. 1.5, p<0.0001). Although the DAS-28 was higher in this group (5.4 vs. 3.82, p<0.0001), the MJS was similar (8 vs. 7, p=0.19), suggesting similar levels of joint damage. Those classified as having FMS were more likely to have HAD-D scores of >11 (25% vs. 6%, p=0.0001). CONCLUSIONS: Coexistent FMS was common in our cohort, although using the tender point count to define FMS classified fewer patients with FMS. Within this group those with FMS had higher levels of depression but similar scores for joint damage indicating that in this cohort FMS and poorer physical functioning is mediated by low mood rather than joint damage.

Can clinical factors at presentation be used to predict outcome of treatment with methotrexate in patients with early inflammatory polyarthritis?

PURPOSE: Methotrexate (MTX) is the first choice conventional disease-modifying antirheumatic drug (DMARD) for rheumatoid arthritis. It is not universally effective, however; although to date it is not possible to predict with any accuracy which patients will respond to treatment. The aim of this analysis was to examine whether clinical and genetic variables could be used to predict response to MTX. METHODS: Patients recruited to the Norfolk Arthritis Register (NOAR), a primary care based inception cohort of patients with inflammatory polyarthritis, were eligible for this analysis if they were commenced on MTX as their first DMARD within 3 months of their baseline visit and had at least 2 years of follow-up data. Outcome on MTX was defined as: (1) stopped for adverse events; (2) stopped for inefficacy or second DMARD added; (3) stopped for other reasons; or (4) remained on MTX monotherapy. Multiple logistic regression was used to establish which variables (including demographics, disease activity and Health Assessment Questionnaire score) predicted stopping monotherapy for inefficacy or adverse event (with those remaining on treatment taken as the referent category). The area under the Receiver Operating Characteristic curves (AUC ROC), were used to determine how accurate the model was at predicting outcome. RESULTS: 309 patients were included in this analysis. At 1 year (2 years), 34 (46) patients had stopped for adverse events and 25 (49) had either stopped monotherapy for inefficacy or had a second DMARD added. 231 (188) patients remained on MTX monotherapy. The strongest predictor of inefficacy at both time points was shared epitope positivity: odds ratios (OR) 5.8 (95% confidence intervals (CI) 1.3 to 25.6) at 1 year, OR 3.0 (95% CI 1.3 to 7.3) at 2 years. High Health Assessment Questionnaire score (OR 1.84 95% CI 1.12 to 3.01) and female gender (OR 2.2, 95% CI 0.92 to 5.28) were associated with adverse events on MTX at 1 year. However, even the most optimal combinations of the factors analysed were only weakly predictive of treatment outcome: AUC ROC for adverse events 0.68 (95% CI 0.58 to 0.78) and for inefficacy AUC ROC 0.71 (95% CI 0.6 to 0.81). CONCLUSIONS: Within this cohort, routine clinical and laboratory factors were poor at predicting outcome of treatment with MTX. Given the major therapeutic advantage to be derived from accurate prediction of treatment outcome, further studies will need to investigate novel biological and other markers.

Polymorphisms within the adenosine receptor 2a gene are associated with adverse events in RA patients treated with MTX.

OBJECTIVE: To examine the role of adenosine receptor 2a gene (ADORA2a) polymorphisms on outcome of MTX treatment in RA. METHODS: Subjects included 309 RA patients with a defined response to MTX. Patients were included if they were (i) good responders (n = 147) (ESR <20 for >6/12 on stable dose of MTX) (ii) inefficacy failures (n = 101) (physician statement and failure to reduce ESR/CRP by 20%) or (iii) adverse event (AE) failures (n = 61) (verified by medical record review). AEs were sub-divided into gastrointestinal (GI) (n = 24), abnormal LFTs (n = 20) or other (n = 17). 8 single nucleotide polymorphisms (SNPs) within ADORA2a were genotyped using the Sequenom MALDI-TOF platform. RESULTS: Five SNPs within ADORA2a were associated with stopping MTX for AEs (OR 2.1-3.07, P < 0.05 for all). Analysis by AE type showed that the association was specific for GI toxicity. No association was observed between ADORA2a and inefficacy outcomes. CONCLUSION: Genetic variation within ADORA2a is significantly associated with AEs on MTX, specifically GI AEs. Knowledge of the ADORA2a genotype may help to improve identification of patients at high risk of GI toxicity with MTX.

Lupus anticoagulant and antibodies to beta 2-glycoprotein I, annexin V, and cardiolipin as a cause of recurrent spontaneous abortion.

The prevalence of lupus anticoagulant (LAC), anticardiolipin (ACA), anti-beta(2) glycoprotein I (beta(2)GPI), and antiannexin V antibodies were determined in 200 recurrent spontaneous abortion (RSA) patients and 200 age-matched control women. ACA IgG was associated with early, while antiannexin V IgG and LAC were associated with late, and ACA IgG, antiannexin V IgG, and LAC were associated with combined early + late RSA, thereby recommending inclusion of their screening in RSA workout.

The pharmacogenetics of methotrexate.

Methotrexate (MTX) is a cornerstone of therapy for rheumatoid arthritis. However, it is not universally effective and up to one-third of patients fail to respond to treatment, either because of inefficacy or adverse events, although at present it is not possible to predict therapy response accurately. Pharmacogenetics is the study of variability in drug response due to heredity. MTX has a complex intracellular metabolism and acts via a number of key enzymes. This review critically appraises the studies of MTX pharmacogenetics and highlights the need for further work in this area.

Comparing the long-term clinical outcome of treatment with methotrexate or sulfasalazine prescribed as the first disease-modifying antirheumatic drug in patients with inflammatory polyarthritis.

OBJECTIVE: To compare the clinical and functional outcome at 2 and 5 years in patients with inflammatory polyarthritis treated with either methotrexate (MTX) or sulfasalazine (SSZ) as the first disease-modifying antirheumatic drug (DMARD). METHODS: Patients recruited to a primary-care-based inception cohort of patients with inflammatory polyarthritis were eligible for this analysis if they were started on either SSZ (n = 331) or MTX (n = 108) as their first DMARD within 3 months. Outcomes assessed included the Disease Activity Score (DAS)28, Health Assessment Questionnaire, radiological erosions (Larsen Score) and cumulative mortality with the proportions still on the original treatment. To overcome potential bias in allocation to these two treatments, a propensity score was calculated based on baseline disease status variables. RESULTS: are expressed as the mean difference between MTX and SSZ, both unadjusted and adjusted for propensity score. RESULTS: The baseline differences between the two groups disappeared after adjusting for propensity score. At 2 and 5 years there were few differences in the clinical outcomes, either unadjusted or after adjustment for propensity. By contrast, at 5 years the proportion that was erosive was lower in the MTX group: odds ratio 0.3 (95% confidence interval 0.1 to 0.8), with a 31% lower Larsen Score after adjustment. At both time points, those treated with MTX were at least twice as likely to remain on that drug as those treated with SSZ. CONCLUSION: Long-term clinical outcome is similar in patients prescribed MTX and SSZ, although it would seem that MTX has greater potential to suppress erosions, which supports it being the first DMARD of choice.