Joint tenderness at 3 months follow-up better predicts long-term pain than baseline characteristics in early rheumatoid arthritis patients.

OBJECTIVE: To investigate pain course over time and to identify baseline and 3-month predictors of unacceptable pain with or without low inflammation in early RA. METHODS: A cohort of 275 patients with early RA, recruited in 2012-2016, was investigated and followed for 2 years. Pain was assessed using a visual analogue scale (VAS; 0-100 mm). Unacceptable pain was defined as VAS pain >40, and low inflammation as CRP <10 mg/l. Baseline and 3-month predictors of unacceptable pain were evaluated using logistic regression analysis. RESULTS: After 2 years, 32% of patients reported unacceptable pain. Among those, 81% had low inflammation. Unacceptable pain, and unacceptable pain with low inflammation, at 1 and 2 years was significantly associated with several factors at 3 months, but not at baseline. Three-month predictors of these pain states at 1 and 2 years were higher scores for pain, patient global assessment, and the health assessment questionnaire, and more extensive joint tenderness compared with the number of swollen joints. No significant associations were found for objective inflammatory measures. CONCLUSION: A substantial proportion of patients had unacceptable pain with low inflammation after 2 years. Three months after diagnosis seems to be a good time-point for assessing the risk of long-term pain. The associations between patient reported outcomes and pain, and the lack of association with objective inflammatory measures, supports the uncoupling between pain and inflammation in RA. Having many tender joints, but more limited synovitis, may be predictive of long-term pain despite low inflammation in early RA.

Predictors at diagnosis for start of biologic disease-modifying antirheumatic drugs in patients with early rheumatoid arthritis: a cohort study.

OBJECTIVES: To investigate the relation between patient characteristics at rheumatoid arthritis (RA) diagnosis and subsequent initiation of treatment with biologic disease-modifying antirheumatic drugs (bDMARDs) or targeted synthetic DMARDs (tsDMARDs). DESIGN: A retrospective cohort study. SETTING AND PARTICIPANTS: Consecutive patients (N=330) with early RA (symptom duration <12 months) diagnosed at Skåne University Hospital, Malmö/Lund, Sweden, from 2012 to 2016, were included. Data on demographics, education, comorbidities and treatment were obtained from national registers. OUTCOME: The relation between patient characteristics at diagnosis and time to first bDMARD/tsDMARD initiation was analysed using Cox regression models. As a secondary outcome, the relation between characteristics at diagnosis and b/tsDMARD initiation within 3 years was analysed using logistic regression. RESULTS: A total of 330 patients (mean age 59.2 years; SD 16.4) were included. During follow-up, 41% received a bDMARD (never preceded by a tsDMARD). Higher age at diagnosis was associated with a lower probability of starting bDMARD treatment (multivariable-adjusted HR 0.66 per SD; 95% CI 0.56 to 0.78). Anticitrullinated protein antibody (ACPA) positivity and higher tender joint count at diagnosis were also associated with subsequent bDMARD treatment initiation in multivariable analysis. A higher level of formal education and absence of comorbidities predicted start of a bDMARD in crude, but not in age-adjusted, analyses. CONCLUSIONS: Older patients with RA were less likely to start bDMARDs, whereas ACPA-positive patients, and those with extensive joint involvement at diagnosis, were more likely to receive early bDMARD treatment. The impact of age on the subsequent start of bDMARD therapy was not explained by level of education or comorbidities, suggesting that other aspects of age influence treatment decisions in early RA.

Effectiveness of JAK Inhibitors Compared With Biologic Disease-Modifying Antirheumatic Drugs on Pain Reduction in Rheumatoid Arthritis: Results From a Nationwide Swedish Cohort Study.

OBJECTIVE: To compare the effectiveness of JAK inhibitors (JAKis) and biologic disease-modifying antirheumatic drugs (bDMARDs) on pain in patients with rheumatoid arthritis. METHODS: In this retrospective study, we investigated patients with a diagnosis of rheumatoid arthritis, starting treatment with a JAKi (n = 1,827), a tumor necrosis factor inhibitor (TNFi; n = 6,422), an interleukin-6 inhibitor (n = 887), abatacept (n = 1,102), or rituximab (n = 1,149) in 2017 to 2019, using data from several linked Swedish national registers. Differences in change in pain, assessed with a visual analogue scale (0-100 mm), from baseline to 3 months, as well as proportions of patients remaining on initial treatment with low pain (visual analogue scale pain <20) at 12 months, were compared between treatments. Comparisons of treatment responses between JAKis and bDMARDs were evaluated using multivariable linear regression, adjusted for patient characteristics, comorbidities, current comedication, and previous treatment. RESULTS: JAKi treatment was associated with a greater decrease in pain at 3 months compared with TNFi treatment (adjusted mean additional decrease 4.0 mm; 95% confidence interval 1.6-6.3), with similar trends in comparisons with non-TNFi bDMARDs. More patients achieved low pain at 12 months on JAKis compared with TNFis, in particular among those previously treated with at least two bDMARDs (adjusted change contrast 5.3 percentage points; 95% confidence interval 1.0-9.6). CONCLUSION: JAKis had a slightly better effect on pain outcomes at 3 and 12 months compared with TNFis, with significantly greater differences in patients previously treated with at least two bDMARDs. The effect of JAKis on pain reduction was at least similar to that of non-TNFi bDMARDs.

Targeted isolation of Methanobrevibacter strains from fecal samples expands the cultivated human archaeome.

Archaea are vital components of the human microbiome, yet their study within the gastrointestinal tract (GIT) is limited by the scarcity of cultured representatives. Our study presents a method for the targeted enrichment and isolation of methanogenic archaea from human fecal samples. The procedure combines methane breath testing, in silico metabolic modeling, media optimization, FACS, dilution series, and genomic sequencing through Nanopore technology. Additional analyzes include the co-cultured bacteriome, comparative genomics of archaeal genomes, functional comparisons, and structure-based protein function prediction of unknown differential traits. Successful establishment of stable archaeal cultures from 14 out of 16 fecal samples yielded nine previously uncultivated strains, eight of which are absent from a recent archaeome genome catalog. Comparative genomic and functional assessments of Methanobrevibacter smithii and Candidatus Methanobrevibacter intestini strains from individual donors revealed features potentially associated with gastrointestinal diseases. Our work broadens available archaeal representatives for GIT studies, and offers insights into Candidatus Methanobrevibacter intestini genomes' adaptability in critical microbiome contexts.

Radiographic damage in early rheumatoid arthritis is associated with increased disability but not with pain-a 5-year follow-up study.

OBJECTIVES: To evaluate how radiographic damage, overall and measured as joint space narrowing score (JSNS) and erosion score (ES), as well as other clinical and laboratory measures, relate to disability and pain in early rheumatoid arthritis (RA). METHODS: An inception cohort of 233 patients with early RA, recruited in 1995-2005, was followed for 5 years. Disability was assessed with the Health Assessment Questionnaire (HAQ), and pain with a visual analogue scale (VAS; 0-100 mm). Radiographs of hands and feet were evaluated using the Sharp-van der Heijde score (SHS), including JSNS and ES. The relation for radiographic scores and other clinical parameters with pain and HAQ were evaluated cross-sectionally by multivariate linear regression analysis and over time using generalized estimating equations. RESULTS: ES was significantly associated with HAQ cross-sectionally at inclusion, after 2 and after 5 years, and over time. Associations for HAQ with SHS and JSNS were weaker and less consistent compared with those for ES. There was no association between radiographic scores and pain at any visit. Both HAQ and pain were associated with parameters of disease activity. The strongest cross-sectional associations were found for the number of tender joints (adjusted p<0.001 at all visits). CONCLUSION: Joint damage was associated with disability already in early RA. Erosions of hands and feet appear to have a greater influence on disability compared with joint space narrowing early in the disease. Pain was associated with other factors than joint destruction in early RA, in particular joint tenderness-suggesting an impact of pain sensitization.

Male Sex Predicts a Favorable Outcome in Early ACPA-Negative Rheumatoid Arthritis: Data From an Observational Study.

OBJECTIVE: The aim of the present study was to investigate whether the relationship between sex and clinical outcomes in early rheumatoid arthritis (RA) varies by autoantibody status. METHODS: Two inception cohorts of consecutive patients with early RA (ie, symptom duration ≤ 12 months) in the southern region of Sweden were investigated. Patients were stratified by anticitrullinated peptide antibody (ACPA) status. The primary outcome was remission (Disease Activity Score in 28 joints [DAS28] < 2.6) at 12 months. Secondary outcomes were remission at 6 months and European Alliance of Associations for Rheumatology good response at 6 and 12 months compared to baseline. In logistic regression models, which were adjusted for age, DAS28 values, and Health Assessment Questionnaire values at baseline, the relationship between sex and clinical outcomes, stratified by ACPA status, was investigated. RESULTS: In total, 426 patients with early RA were included: 160 patients were ACPA negative and 266 patients were ACPA positive. At 12 months, 27.1% (38/140) of females and 24.1% (13/54) of males with ACPA-positive RA achieved DAS28 remission. In ACPA-negative RA, 16.0% (13/81) of females and 48.6% (18/37) of males achieved DAS28 remission at 12 months. Males had higher odds of reaching remission at 12 months in the ACPA-negative patient group (pooled adjusted odds ratio [OR] 4.79, 95% CI 1.97-11.6), but not in the ACPA-positive group (pooled adjusted OR 1.06, 95% CI 0.49-2.30). CONCLUSION: Male sex was associated with better clinical outcomes in ACPA-negative early RA, but not in ACPA-positive early RA. The poor outcomes in females with early seronegative RA suggest that this represents a difficult-to-treat patient group.

Predictors of unacceptable pain with and without low inflammation over 5 years in early rheumatoid arthritis-an inception cohort study.

OBJECTIVES: Pain is a major symptom in patients with rheumatoid arthritis (RA). In early RA, pain is usually due to synovitis, but can also persist despite effective anti-inflammatory treatment. The objective of this study was to investigate the pain course over time and predictors of unacceptable pain and unacceptable pain with low inflammation, in patients with early RA. METHODS: An inception cohort of 232 patients with early RA, recruited in 1995-2005, was followed in a structured programme for 5 years. Pain was assessed using a visual analogue scale (VAS; 0-100). Unacceptable pain was defined as VAS pain > 40 based on the patient acceptable symptom state (PASS) and low inflammation as CRP < 10 mg/l. Baseline predictors of unacceptable pain were evaluated using logistic regression analysis. RESULTS: Pain improved significantly during the first 6 months, but then remained basically unchanged. Thirty-four per cent of the patients had unacceptable pain 5 years after inclusion. Baseline predictors of unacceptable pain after 5 years were lower swollen joint counts [odds ratio (OR) 0.71 per standard deviation (95% confidence interval (CI) 0.51-0.99)] and higher VAS for pain and global assessment of disease activity. Unacceptable pain with low inflammation after 5 years was negatively associated with anti-CCP antibodies [OR 0.50 (95% CI 0.22-0.98)]. CONCLUSION: Over one third of the patients had unacceptable pain 5 years after inclusion. Lower swollen joint count was associated with unacceptable pain at 5 years. The results may be explained by the positive effects of treatment on pain related to inflammation. Non-inflammatory long-lasting pain appears to be a greater problem in anti-CCP-negative patients.

Correction: Genetic diversity, genetic structure and diet of ancient and contemporary red deer (Cervus elaphus L.) from north-eastern France.

[This corrects the article DOI: 10.1371/journal.pone.0189278.].

Genetic diversity, genetic structure and diet of ancient and contemporary red deer (Cervus elaphus L.) from north-eastern France.

In north-eastern France, red deer (Cervus elaphus L.) populations were rebuilt from a few hundred individuals, which have subsisted in remote valleys of the Vosges mountains, and to a lesser extent from individuals escaped from private enclosures; at present times, this species occupies large areas, mainly in the Vosges Mountains. In this study, we examined the population dynamics of red deer in the Vosges Mountains using ancient and contemporary mitochondrial DNA (mtDNA) from 140 samples (23 ancient + 117 modern) spanning the last 7'000 years. In addition, we reconstructed the feeding habits and the habitat of red deer since the beginning of agriculture applying isotopic analyses in order to establish a basis for current environmental management strategies. We show that past and present red deer in the Vosges Mountains belong to mtDNA haplogroup A, suggesting that they originated from the Iberian refugium after the last glacial maximum (LGM). Palaeogenetic analysis of ancient bone material revealed the presence of two distinct haplotypes with different temporal distributions. Individuals belonging to the two haplotype groups apparently occupied two different habitats over at least 7'000 years. AM6 correlates with an ecological type that feeds in densely forested mountain landscapes, while AM235 correlates with feeding in lowland landscapes, composed of a mixture of meadows and riverine, herb-rich woodlands. Our results suggest that red deer of north-eastern France was able to adapt, over the long term, to these different habitat types, possibly due to efficient ethological barriers. Modern haplotype patterns support the historical record that red deer has been exposed to strong anthropogenic influences as a major game species.