The effectiveness of metagenomic next-generation sequencing (mNGS) in respiratory pathogen detection and clinical decision-making in critically rheumatic patients remains largely unexplored.
A single-center retrospective study of 58 rheumatic patients who were admitted to ICU due to suspected pneumonia with acute respiratory failure if they underwent both bronchoalveolar lavage fluid specimen mNGS and combined microbiological tests (CMTs) was conducted to compare their diagnostic performance, using clinical composite diagnosis as the gold standard. Treatment modifications based on mNGS results were also reviewed.
Forty-three patients were diagnosed with microbiologically confirmed pneumonia and 15 were considered as a non-infectious disease. mNGS outperformed CMTs in the accurate diagnosis of infectious and non-infectious lung infiltration (98.1% [57/58] vs. 87.9% [51/58], P = 0.031). A total of 94 causative pathogens were defined by the gold standard and 27 patients had polymicrobial pneumonia. The sensitivity of pathogen detection and complete concordance with the gold standard by mNGS exceeded those by CMTs (92.6% [87/94] vs. 76.6% [72/94], P < 0.001 and 72.1% [31/43] vs. 51.2% [22/43], P = 0.004, respectively). Moreover, 22 pathogens were detected only by mNGS and confirmed by orthogonal test. Accordingly, the etiological diagnosis changed in 19 cases, and the empirical treatment improved in 14 cases, including 8 cases of rescue treatment and 11 of antibiotics de-escalation. At the pathogen-type level, both methods were comparable for bacteria, but mNGS was advantageous to identify viruses (accuracy: 100% vs. 81%, P = 0.004). For Pneumocystis jirovecii detection, mNGS improved the sensitivity compared with Gomori\'s methenamine silver stain (91.7% vs. 4.2%, P < 0.001) and was higher than polymerase chain reaction (79.2%), but the difference was not significant (P = 0.289). In terms of Aspergillus, the better sensitivity with a combination of culture and galactomannan test than that with mNGS was found (100% vs. 66.7%, P = 0.033).
mNGS has an excellent accuracy in etiological diagnosis and pathogen detection of suspected pneumonia in critically rheumatic patients, which has potential significance for clinical decision-making. Its superiority to different types of pathogens depends on the comprehensiveness of CMTs.

Anti-rheumatic drugs can increase the predisposition to infection, and patients may be unaware of continuing their treatment during the COVID-19 pandemic.
This study aimed to assess whether patients maintain their treatment for rheumatic conditions during the pandemic period and determine the factors responsible for discontinuation.
Patients were randomly selected from the prospectively collected database of our tertiary referral center. The patients were interviewed by telephone through a standardized closed-ended questionnaire, which is targeting the continuity of the treatment plan and the considerations related to the individual choice. The patients were asked whether they hesitated to visit the hospital for follow-up or intravenous drug administration.
A total of 278 patients completed the questionnaire. While 62 of the patients (22.3%) had reduced or interrupted the treatment, only 11 patients (3.9%) stopped the treatment completely. A significant difference was observed between the duration of illness and the discontinuation of treatment. (p = 0.023) There was a significant difference in disease activity between the group that stopped treatment and continued treatment. (p = 0.001) There was no statistically significant difference in other demographic characteristics. One hundred thirty-five patients (48.6%) made the treatment decision by themselves, and 80% continued the treatment. Reasons for stopping the treatment were anxiety (48.4%), not being able to go to the hospital for intravenous treatment (45.1%), and not being able to find the drug (6.5%).
Since patients with long-term illnesses were found to be significantly more likely to stop their treatment, this group of patients should be monitored.

OBJECTIVE: Patients with rheumatic disease taking long-term disease-modifying anti-rheumatic drugs (DMARDs) are expected to have a higher risk of infection due to the alterations in cellular immunity associated with these medications. However, the potential risks associated with these drugs remain unclear. This study aimed to estimate the risk of COVID-19 infection in patients with rheumatic disease taking disease-modifying anti-rheumatic drugs.
METHODS: Patients with autoimmune rheumatic disease taking DMARDs with or without long-term (> 6 months) HCQ treatment prior to the COVID-19 outbreak were selected consecutively. The diagnosis of COVID-19 was made based on the history of symptoms suggestive of the disease and/or serum IgG positivity. During statistical analysis, the risk of COVID-19 infection was calculated in rheumatic patients taking DMARDs versus controls, as well as in patients taking HCQ versus those who are not. The ORs and 95% CIs were also calculated. The participants in the control group were selected from individuals without RD.
RESULTS: A total of 800 patients with RD and 449 controls were analyzed. COVID-19 infection was detected in 16.8% of rheumatic patients versus 17.6% of controls (OR 0.95; 95% CI 0.7-1.28). The proportions of COVID-19 infection in HCQ users versus non-users were 15.3% and 18.1%, respectively (OR 0.87; 95% CI 0.61-1.26). These results remained unchanged after adjusting for all covariates using logistic regression analysis.
CONCLUSIONS: These findings indicate that rheumatic patients taking DMARDs are not at a higher risk of COVID-19 infection, and that HCQ therapy has no influence on the risk of COVID-19 infection. Key points • The risk of COVID-19 infection is not higher in patients with RD on DMARD therapy. • The prevalence of COVID-19 infection in HCQ users has not significant difference relative to non-users. • Significant percent of RD patients taking DMARDs had asymptomatic infection. • There was a positive association between leflunamide therapy and the risk of COVID-19 infection.

Chronic hepatitis B virus (HBV) infection may be reactivated by immunosuppressive drugs in patients with autoimmune inflammatory rheumatic diseases. This study evaluates HBV serum markers\' prevalence in rheumatic outpatients belonging to Spondyloarthritis, Chronic Arthritis and Connective Tissue Disease diagnostic groups in Italy. The study enrolled 302 subjects, sex ratio (M/F) 0.6, mean age ± standard deviation 57 ± 15 years, 167 (55%) of whom were candidates for immunosuppressive therapy. The Spondyloarthritis group included 146 subjects, Chronic Arthritis 75 and Connective Tissue Disease 83 (two patients had two rheumatic diseases; thus, the sum is 304 instead of 302). Ten subjects (3%) reported previous anti-HBV vaccination and tested positive for anti-HBs alone with a titer still protective (>10 IU/mL). Among the remaining 292 subjects, the prevalence of positivity for HBsAg, isolated anti-HBc, anti-HBc/anti-HBs, and any HBV marker was 2%, 4%, 18%, and 24%, respectively. A total of 26/302 (9%) patients with γ-globulin levels ≤0.7 g/dL were more frequently (p = 0.03455) prescribed immunosuppressive therapy, suggesting a more severe rheumatic disease. A not negligible percentage of rheumatic patients in Italy are at potential risk of HBV reactivation related to immunosuppressive therapy. Before starting treatment, subjects should be tested for HBV markers. Those resulting positive should receive treatment or prophylaxis with Nucleos (t) ides analogue (NUCs) at high barrier of resistance, or pre-emptive therapy, according to the pattern of positive markers. HB vaccination is recommended for those who were never exposed to the virus.

Objectives: To describe our experience with a coronavirus disease 2019 (COVID-19) outbreak within a large rheumatology department early in the pandemic. Methods: Symptomatic and asymptomatic healthcare workers (HCWs) had a naso-oropharyngeal swab for detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and were followed clinically. Reverse transcription polymerase-chain reaction (RT-PCR) was repeated to document cure, and serological response was assessed. Patients with risk contacts within the department in the 14 days preceding the outbreak were screened for COVID-19 symptoms. Results: 14/34 HCWs (41%; 40 ± 14 years, 71% female) tested positive for SARS-CoV-2, and 11/34 (32%) developed symptoms but were RT-PCR-negative. Half of RT-PCR-positive HCWs did not report fever, cough, or dyspnea before testing, which were absent in 3/14 cases (21%). Mild disease prevailed (79%), but 3 HCWs had moderate disease requiring further assessment, which excluded severe complications. Nevertheless, symptom duration (28 ± 18 days), viral shedding (31 ± 10 days post-symptom onset, range 15-51), and work absence (29 ± 28 days) were prolonged. 13/14 (93%) of RT-PCR-positive and none of the RT-PCR-negative HCWs had a positive humoral response Higher IgG indexes were observed in individuals over 50 years of age (14.5 ± 7.7 vs. 5.0 ± 4.4, p = 0.012). Of 617 rheumatic patients, 8 (1.3%) developed COVID-19 symptoms (1/8 hospitalization, 8/8 complete recovery), following a consultation/procedure with an asymptomatic (7/8) or mildly symptomatic (1/8) HCW. Conclusions: A COVID-19 outbreak can occur among HCWs and rheumatic patients, swiftly spreading over the presymptomatic stage. Mild disease without typical symptoms should be recognized and may evolve with delayed viral shedding, prolonged recovery, and adequate immune response in most individuals.

BACKGROUND: This study is to explore the prevalence of different stages of bone loss and the potential risk factors in rheumatic patients.
METHODS: A cross-sectional study recruits 1398 rheumatic patients and 302 healthy subjects. Demographic data, blood, and bone mineral density (BMD) tests are collected. Risk factors for bone loss in rheumatic patients are analyzed by logistic regression.
RESULTS: (1) Rheumatic patients are consisted of 40.0% rheumatoid arthritis (RA), 14.7% systemic lupus erythematosus (SLE), 14.2% osteoarthritis (OA), 9.2% ankylosing spondylosis (AS), 7.9% gout, 7.0% primary Sjogren syndrome (pSS), 3.8% systemic sclerosis (SSc), and 3.2% mixed connective tissue disease (MCTD). (2) In male patients aged under 50 and premenopausal female patients, the bone mineral density score of AS (53.9%, P < 0.001) and SLE (39.6%, P = 0.034) patients is lower than the healthy controls (18.2%). (3) Osteopenia and osteoporosis are more prevailing in male patients aged or older than 50 and postmenopausal female patients with RA (P < 0.001), OA (P = 0.02) and SLE (P = 0.011) than healthy counterparts. (4) Those with SLE, RA and AS gain the highest odd ratio of \'score below the expected range for age\', osteopenia and osteoporosis, respectively. (5) Age, female, low BMI and hypovitaminosis D are found negatively associated with bone loss. Dyslipidemia and hyperuricemia could be protective factors.
CONCLUSIONS: Young patients with AS and SLE have a significant higher occurrence of bone loss, and older patients with RA, OA and SLE had higher prevalence than healthy counterparts. SLE, RA, SSc and AS were founded significant higher risks to develop into bone loss after adjustment. Age, BMI and gender were commonly-associated with bone loss in all age-stratified rheumatic patients. These findings were not markedly different from those of previous studies.

The relationship between inflammation and formation of reactive oxygen species (ROS) is still not completely understood and excessive inflammatory reaction is attributed to increased yet also to reduced ROS formation. To compare ROS formation in severe and low inflammation, neutrophil oxidative burst was analyzed in rheumatic patients before and during therapy with TNFα- or interleukin-6 receptor-neutralizing antibodies. Intracellular and extracellular ROS productions were evaluated on the basis of luminol- and isoluminol-enhanced chemiluminescence in isolated peripheral neutrophils. Disease activity score DAS28 and platelet to lymphocyte ratio were used as markers of arthritis activity and the intensity of systemic inflammation. Biological therapy effectively reduced the intensity of inflammation. Of the twenty-six patients studied eighteen achieved remission or low disease activity. Highly active arthritis persisted only in one patient, though prior to the therapy it was evident in all subjects tested. In patients receiving biological therapy, intracellular chemiluminescence was significantly higher than in patients before this therapy; ROS produced by neutrophils extracellularly were not affected. The increased ROS formation associated with reduced inflammation supports the need to revise the view of the role of ROS in inflammation - from toxic agents promoting inflammation towards a more complex view of ROS as regulators of immune pathways with inflammation-limiting capacity. From this perspective, the interference with neutrophil-derived oxidants may represent a new mechanism involved in the anti-inflammatory activity of biological therapy.

BACKGROUND: Varicella zoster virus (VZV)-specific cellular immunity is essential for viral control, and the incidence of VZV reactivation is increased in patients with rheumatic diseases. Because knowledge of the influence of antirheumatic drugs on specific cellular immunity is limited, we analyzed VZV-specific T cells in patients with rheumatoid arthritis (RA) and seronegative spondylarthritis (SpA), and we assessed how their levels and functionality were impacted by disease-modifying antirheumatic drugs (DMARDs). A polyclonal stimulation was carried out to analyze effects on general effector T cells.
METHODS: CD4 T cells in 98 blood samples of patients with RA (n = 78) or SpA (n = 20) were quantified by flow cytometry after stimulation with VZV antigen and the polyclonal stimulus Staphylococcus aureus enterotoxin B (SEB), and they were characterized for expression of cytokines (interferon-γ, tumor necrosis factor [TNF]-α, interleukin [IL]-2) and markers for activation (CD69), differentiation (CD127), or functional anergy programmed death 1 molecule [PD-1], cytotoxic T-lymphocyte antigen 4 [CTLA-4]. Results of patients with RA were stratified into subgroups receiving different antirheumatic drugs and compared with samples of 39 healthy control subjects. Moreover, direct effects of biological DMARDs on cytokine expression and proliferation of specific T cells were analyzed in vitro.
RESULTS: Unlike patients with SpA, patients with RA showed significantly lower percentages of VZV-specific CD4 T cells (median 0.03%, IQR 0.05%) than control subjects (median 0.09%, IQR 0.16%; p < 0.001). Likewise, SEB-reactive CD4 T-cell levels were lower in patients (median 2.35%, IQR 2.85%) than in control subjects (median 3.96%, IQR 4.38%; p < 0.05); however, expression of cytokines and cell surface markers of VZV-specific T cells did not differ in patients and control subjects, whereas SEB-reactive effector T cells of patients showed signs of functional impairment. Among antirheumatic drugs, biological DMARDs had the most pronounced impact on cellular immunity. Specifically, VZV-specific CD4 T-cell levels were significantly reduced in patients receiving TNF-α antagonists or IL-6 receptor-blocking therapy (p < 0.05 and p < 0.01, respectively), whereas SEB-reactive T-cell levels were reduced in patients receiving B-cell-depleting or IL-6 receptor-blocking drugs (both p < 0.05).
CONCLUSIONS: Despite absence of clinical symptoms, patients with RA showed signs of impaired cellular immunity that affected both VZV-specific and general effector T cells. Strongest effects on cellular immunity were observed in patients treated with biological DMARDs. These findings may contribute to the increased susceptibility of patients with RA to VZV reactivation.

Infectious complications, resulting from reduced activity of immune cells, are the most severe and common adverse effects of biological therapy. This study analyzed the effect of biological therapy on blood phagocytes, focusing on the formation of reactive oxygen species (ROS), an important factor in the defence against invading pathogens. Intra- and extracellular ROS production were recorded separately, on the basis of luminol and isoluminol chemiluminescence in patients treated with antibodies against tumor necrosis factor-α or against interleukin-6 receptor. In comparison to healthy donors or to rheumatic patients treated with classical immunosuppressive drugs, biological therapy increased ROS formation in both compartments. This indicates that the anti-microbial activity of blood phagocytes was not reduced by TNFα- or IL-6-neutralizing therapy, at least in terms of ROS. The method presented does not require blood fractionation, which could modify activity of phagocytes and cause loss of some subpopulations of these cells. The technique is simple, requires microliter volumes of blood and is thus well applicable to clinical studies.

To estimate the risk of reactivation of hepatitis B virus (HBV) and evaluate the effectiveness of antiviral prophylaxis (AVP) in patients with different status of HBV infection undergoing antirheumatic therapies. We searched Cochrane Library, Medline, and EMBASE for randomized controlled trials (RCTs), quasi-RCTs, non-RCTs, cohort studies, or case series studies examining reactivation of HBV in patients undergoing antirheumatic therapy with or without AVP. We estimated the HBV reactivation rate (HRR) and its 95% confidence interval (CI) among different patient groups (indirect comparison). We also calculated rate ratio (RR), rate difference (RD) with their 95% CIs, and the number needed to treat (NNT) of AVP (direct comparison). Fifty-three case series studies with 2162 patients were included. The RD of AVP was - 0.13 (95% CI - 0.21 to - 0.05) for all patients, - 0.16 (95% CI - 0.26 to - 0.06) for rheumatic patients with chronic HBV infection, but not statistically significant for patients with other status of HBV infection. Lamivudine (RD - 0.10, 95% CI - 0.25 to 0.05) was less effective than other prophylactic antiviral drugs (RD - 0.31, 95% CI - 0.52 to - 0.11). The HHR varied from 55 to 5% by HBV status and treatment. There is limited evidence that AVP was effective for preventing reactivation of HBV in patients undergoing antirheumatic therapy. The effectiveness varies by patient HBV status and antiviral regimens. Rheumatic HBV carriers may be more beneficial from AVP, and lamivudine may be inferior to other AVP regimens. Findings in this study warrant further investigation in rigorous RCTs.