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ID PMID Title PublicationDate abstract
31958280 Methotrexate effect on immunogenicity and long-term maintenance of adalimumab in axial spo 2020 Jan OBJECTIVES: Anti-drug antibodies (ADA) are responsible for decreased adalimumab efficacy in axial spondyloarthritis (SpA). We aimed to evaluate the ability of methotrexate (MTX) to decrease adalimumab immunisation. METHODS: A total of 110 patients eligible to receive adalimumab 40 mg subcutaneously (s.c.) every other week were randomised (1:1 ratio) to receive, 2 weeks before adalimumab (W-2) and weekly, MTX 10 mg s.c. (MTX+) or not (MTX-). ADA detection and adalimumab serum concentration were assessed at weeks 4 (W4), 8 (W8), 12 (W12) and 26 (W26) after starting adalimumab (W0). The primary outcome was the proportion of patients with ADA at W26. Four years after the study completion, we retrospectively analysed adalimumab maintenance in relation with MTX co-treatment duration. RESULTS: We analysed data for 107 patients (MTX+; n=52; MTX-; n=55). ADA were detected at W26 in 39/107 (36.4%) patients: 13/52 (25%) in the MTX+ group and 26/55 (47.3%) in the MTX- group (p=0.03). Adalimumab concentration was significantly higher in the MTX+ than MTX- group at W4, W8, W12 and W26. The two groups did not differ in adverse events or efficacy. In the follow-up study, MTX co-treatment >W26 versus no MTX or ≤W26 was significantly associated with adalimumab long-term maintenance (p=0.04). CONCLUSION: MTX reduces the immunogenicity and ameliorate the pharmacokinetics of adalimumab in axial SpA. A prolonged co-treatment of MTX>W26 seems to increase adalimumab long-term maintenance.
32423970 Storm, typhoon, cyclone or hurricane in patients with COVID-19? Beware of the same storm t 2020 May Some of the articles being published during the severe acute respiratory syndrome-coronavirus (SARS-CoV)-2 pandemic highlight a link between severe forms of coronavirus disease 2019 (COVID-19) and the so-called cytokine storm, also with increased ferritin levels. However, this scenario is more complex than initially thought due to the heterogeneity of hyperinflammation. Some patients with coronavirus 2019 disease (COVID-19) develop a fully blown secondary haemophagocytic lymphohistiocytosis (sHLH), whereas others, despite a consistent release of pro-inflammatory cytokines, do not fulfil sHLH criteria but still show some features resembling the phenotype of the hyperferritinemic syndrome. Despite the final event (the cytokine storm) is shared by various conditions leading to sHLH, the aetiology, either infectious, autoimmune or neoplastic, accounts for the differences in the various phases of this process. Moreover, the evidence of a hyperinflammatory microenvironment provided the rationale to employ immunomodulating agents for therapeutic purposes in severe COVID-19. This viewpoint aims at discussing the pitfalls and issues to be considered with regard to the use of immunomodulating agents in COVID-19, such as timing of treatment based on the viral load and the extent of cytokine/ferritin overexpression. Furthermore, it encompasses recent findings in the paediatric field about a novel multisystem inflammatory disease resembling toxic shock syndrome and atypical Kawasaki disease observed in children with proven SARS-CoV2 infection. Finally, it includes arguments in favour of adding COVID-19 to the spectrum of the recently defined 'hyperferritinemic syndrome', which already includes adult-onset Still's disease, macrophage activation syndrome, septic shock and catastrophic anti-phospholipid syndrome.
32072351 Characterizing hand and wrist ultrasound pattern in primary Sjögren's syndrome: a case-co 2020 Jun INTRODUCTION/OBJECTIVES: To evaluate the clinical relevance of high-resolution hand and wrist ultrasound (US) findings and their possible associations with anti-citrullinated peptide antibodies in primary Sjögren's syndrome (pSS). METHODS: Ninety-seven consecutive pSS patients (American-European Consensus Group, 2002) without meeting the American College of Rheumatology (ACR) criteria (1987) for rheumatoid arthritis (RA); 20 RA patients (ACR/European League Against Rheumatism (EULAR) criteria, 2010); and 80 healthy individuals with comparable age, gender, and ethnicity were enrolled in a case-control study. Disease activity was assessed by EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI). US was performed by one expert blinded to anti-CCP, anti-MCV, and IgM rheumatoid factor tested by ELISA. RESULTS: Frequencies of grade 3 synovitis (9.3 vs. 0%, p = 0.004), tenosynovitis (36.1 vs. 3.8%, p < 0.001), and erosions (27.8 vs. 7.5%, p = 0.001) on US were higher in pSS patients than in healthy controls. ESSDAI presented a moderate correlation with the synovitis number (p = 0.001) and tenosynovitis (p < 0.001). Most pSS patients with erosions on US (81.5%) had negative anti-CCP. Nevertheless, anti-CCP ≥ 3× cut-off value was associated with the presence of erosions in pSS (p = 0.026). Erosions in pSS were mainly small size contrasting with moderate/large size in RA (p < 0.001), and positive power Doppler synovitis predominated in RA (p < 0.001). CONCLUSIONS: US identified significant frequencies of grade 3 synovitis, tenosynovitis, and erosions in pSS. Synovitis and tenosynovitis numbers were correlated with ESSDAI. Association between erosions on US and anti-CCP (high titers) in pSS possibly identifies a subgroup with severe arthritis. These findings suggest that US is a useful method for assessing joint involvement in pSS.Key Points• US identified significant frequencies of grade 3 synovitis, tenosynovitis, and erosions in pSS patients in comparison with age- and race-healthy individuals.• Numbers of synovitis and tenosynovitis on US were correlated with ESSDAI values.• Most pSS patients with erosions on US were negative for anti-CCP, but anti-CCP ≥ 3× cut-off value was associated with the presence of erosions in this disease.• Erosions in pSS were mainly small size contrasting with moderate/large size in RA, and positive power Doppler synovitis predominated in RA.
33331606 COVID-19 and patients with immune-mediated inflammatory diseases undergoing pharmacologica 2020 Nov BACKGROUND: Patients with immune-mediated inflammatory diseases (IMID) are at increased risk of infection. OBJECTIVE: To assess whether patients undergoing pharmacological treatment for IMID present higher risk of worse outcomes when diagnosed with COVID-19. DESIGN AND SETTING: Rapid systematic review conducted in the medical school of the Federal University of São Paulo (SP), Brazil. METHODS: We searched CENTRAL, MEDLINE, EMBASE, LILACS, SCOPUS, Web of Science, L·OVE, ClinicalTrials.gov and WHO-ICTRP for studies evaluating patients diagnosed with COVID-19 who were undergoing pharmacological treatment for IMID. Two authors selected studies, extracted data and assessed risk of bias and certainty of evidence, following the Cochrane recommendations. RESULTS: We identified 1,498 references, from which one cohort study was included. This compared patients with and without rheumatic diseases (RD) who all had been diagnosed with COVID-19. Those with RD seemed to have higher chances of hospitalization and mortality, but no statistical difference was detected between the groups: hospitalization: odds ratio (OR) 1.17; 95% confidence interval (CI) 0.6 to 2.29; mortality rate: OR 1.53; 95% CI 0.33 to 7.11 (very low certainty of evidence). Patients with RD were three times more likely to require admission to intensive care units (ICUs), with invasive mechanical ventilation (IMV), than those without RD: OR 3.72; 95% CI 1.35 to 10.26 (for both outcomes; very low certainty of evidence). CONCLUSION: Patients undergoing pharmacological treatment for IMID seem to present higher chances of requiring admission to ICUs, with IMV. Additional high-quality studies are needed to analyze the effects of different treatments for IMID.
33220446 Associations between comorbidities and immediate and one-year outcomes following supervise 2021 Jan OBJECTIVE: To investigate if comorbidities are associated with change in health outcomes following an 8-week exercise and education program in knee and hip osteoarthritis (OA). METHODS: We included 24,513 individuals with knee or hip OA from the Good Life with osteoArthritis in Denmark (GLA:D®). GLA:D® consists of two patient education sessions and 12 supervised exercise sessions. Before the program, individuals self-reported having one or more of 11 common comorbidities. Physical function was assessed using the 40-m Fast-Paced Walk Test (FPWT, m/sec) before and immediately after the program. Pain intensity and health-related quality of life was self-reported before, immediately after, and at 12 months post-intervention using a visual analogue scale (VAS, 0-100) and the EQ-5D-5L index (-0.624 to 1.000), respectively. Associations of comorbidity combinations with change in outcomes immediately and at 12 months was estimated using mixed linear regression. RESULTS: Individuals with OA improved on average 0.12 m/s (95%CI 0.12 to 0.13) in 40-m FPWT, -12.7 mm (95%CI -13.2 to -12.2) in VAS, and 0.039 (95%CI 0.036 to 0.041) in EQ-5D-5L from before to immediately after the intervention with minor additional improvements at 12 months. Despite that individuals with comorbidities had worse baseline scores in all outcomes than individuals without comorbidities, they had similar levels of improvement immediately and 12 months after the intervention. CONCLUSION: Comorbidities are not associated with worse nor better health outcomes following an 8-week exercise and education program in individuals with OA, suggesting exercise as a viable treatment option for individuals with OA, irrespective of comorbidities.
32040727 Chest CT imaging features for prediction of treatment response in cryptogenic and connecti 2020 May OBJECTIVES: To investigate CT imaging features associated with poor clinical outcome after corticosteroid treatment in patients diagnosed with cryptogenic organizing pneumonia (COP) and connective tissue disease-related organizing pneumonia (CTD-OP) and to assess the difference in CT findings and treatment responses between COP and CTD-OP. METHODS: Chest CT images from 166 patients (COP, 131; CTD-OP, 35) with pathologically proven organizing pneumonia were reviewed by two thoracic radiologists. The type, distribution pattern, and extent of parenchymal abnormalities, along with other associated imaging features, were assessed for each patient. Logistic regression analyses were used to identify features associated with poor clinical outcomes such as residual disease (RD) and disease relapse. The differences between COP and CTD-OP were also analyzed. RESULTS: Consolidation involving more than 10% of parenchyma (hazard ratio [HR], 2.27), detectable bronchiectasis (HR, 3.59), and diagnosis of CTD-OP (HR, 4.31) were associated with a higher risk of RD after adjustments for patient age and sex. More than 10% consolidation involvement (HR, 2.54) and diagnosis of CTD-OP (HR, 6.42) were also associated with a higher risk of disease relapse. Compared with COP, CTD-OP demonstrated a greater extent of parenchymal abnormalities, especially consolidation, and was less likely to show a peribronchovascular distribution pattern. CONCLUSION: Bronchiectasis and a greater extent of consolidation were associated with RD, with the latter also being associated with disease relapse. Compared with COP, CTD-OP was associated with worse treatment outcomes and demonstrated a greater extent of parenchymal abnormalities, which were also less likely to show a peribronchovascular pattern. KEY POINTS: • The presence of bronchiectasis and a high parenchymal involvement of consolidation on initial chest CT were associated with a worse response to corticosteroids in patients with organizing pneumonia. • Connective tissue disease-related organizing pneumonia (CTD-OP) was associated with worse treatment outcomes than its idiopathic counterpart cryptogenic organizing pneumonia (COP). • Compared with COP, CTD-OP generally demonstrated a greater extent of parenchymal abnormalities, especially consolidation, and was less likely to show a peribronchovascular distribution pattern.
33047724 [Analysis of clinical features and prognosis in patients with primary Sjögren's syndrome 2020 Oct 18 OBJECTIVE: To analyze the clinical features and prognosis in patients with primary Sjögren's syndrome (pSS) and autoimmune liver diseases (ALD). METHODS: A retrospective analysis of clinical manifestation and prognosis was performed in patients with ALD or without ALD during the three years (February 2014 to December 2017). RESULTS: Totally, 203 patients with pSS were included in this study, 68 patients had ALD (31 patients with autoimmune hepatitis, 37 patients with primary biliary cholangitis), while 135 patients did not have ALD. There were no differences between the two groups regarding age, gender, clinical manifestations, such as dry mouth, dry eyes, pain, fatigue, lymphadenopathy, glandular swelling, cutaneous involvement, lung involvement, and renal involvement, and the incidence rate of other autoimmune diseases, such as autoimmune thyroid disease, rheumatoid arthritis, and vasculitis. There were also no differences in the titer of antinuclear antibody (ANA), the positive rates of anti-Sjögren's syndrome A antibody (SSA), SSA52, and anti-Sjögren's syndrome B antibody (SSB), and at the levels of erythrocyte sedimentation rate and C-reactive protein between the two groups. Most importantly, the pSS patients with ALD had a shorter disease course, a higher positive rate of anti-mitochondrial M2 antibody (AMA-M2) and anti-centromere antibody, a higher level of IgG and IgM, a lower level of complement 3, and a decreased number of blood cells. They also had a higher level of liver related serum index, such as alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, alkaline phosphatase and total bilirubin, direct bilirubin, indirect bilirubin, a higher incidence rate of liver cirrhosis, an increased death incident (the mortality was 13.24% in the pSS patients with ALD, while 2.96% in the controls, P=0.013), and a worse prognosis. Binary Logistic regression analysis revealed that liver cirrhosis, the EULAR Sjögren's syndrome disease activity index (ESSDAI) scores and the level of total bilirubin were the prognostic factors of mortality in the pSS patients with ALD. The survival curve was estimated by the Kaplan-Meier method. It demonstrated that the pSS patients with ALD had a lower survival rate when compared with the controls. CONCLUSION: The patients with both pSS and ALD will suffer from a more severe disease and a higher death incident. We should pay more attention to these patients and provide a better symptomatic treatment for them during clinical practice.
32460496 Metabolic Disturbances in Urinary and Plasma Samples from Seven Different Systemic Autoimm 2020 Aug 7 Systemic autoimmune diseases (SADs) are characterized by dysfunctioning of the immune system, which causes damage in several tissues and organs. Among these pathologies are systemic lupus erythematosus (SLE), systemic sclerosis or scleroderma, Sjögren's syndrome, rheumatoid arthritis, primary antiphospholipid syndrome (PAPS), mixed connective tissue disease (MCTD), and undifferentiated connective tissue disease (UCTD). Early diagnosis is difficult due to similarity in symptoms, signs, and clinical test results. Hence, our aim was to search for differentiating metabolites of these diseases in plasma and urine samples. We performed metabolomic profiling by liquid chromatography-mass spectrometry (LC-MS) of samples from 228 SADs patients and 55 healthy volunteers. Multivariate PLS models were applied to investigate classification accuracies and identify metabolites differentiating SADs and healthy controls. Furthermore, we specifically investigated UCTD against the other SADs. PLS models were able to classify most SADs vs healthy controls (area under the roc curve (AUC) > 0.7), with the exception of MCTD and PAPS. Differentiating metabolites consisted predominantly of unsaturated fatty acids, acylglycines, acylcarnitines, and amino acids. In accordance with the difficulties in defining UCTD, the UCTD metabolome did not differentiate well from the other SADs. However, most UCTD cases were classified as SLE, suggesting that metabolomics may provide a tool to reassess UCTD diagnosis into other conditions for more well-informed therapeutic strategies.
33125391 Clinicogenomic factors of biotherapy immunogenicity in autoimmune disease: A prospective m 2020 Oct BACKGROUND: Biopharmaceutical products (BPs) are widely used to treat autoimmune diseases, but immunogenicity limits their efficacy for an important proportion of patients. Our knowledge of patient-related factors influencing the occurrence of antidrug antibodies (ADAs) is still limited. METHODS AND FINDINGS: The European consortium ABIRISK (Anti-Biopharmaceutical Immunization: prediction and analysis of clinical relevance to minimize the RISK) conducted a clinical and genomic multicohort prospective study of 560 patients with multiple sclerosis (MS, n = 147), rheumatoid arthritis (RA, n = 229), Crohn's disease (n = 148), or ulcerative colitis (n = 36) treated with 8 different biopharmaceuticals (etanercept, n = 84; infliximab, n = 101; adalimumab, n = 153; interferon [IFN]-beta-1a intramuscularly [IM], n = 38; IFN-beta-1a subcutaneously [SC], n = 68; IFN-beta-1b SC, n = 41; rituximab, n = 31; tocilizumab, n = 44) and followed during the first 12 months of therapy for time to ADA development. From the bioclinical data collected, we explored the relationships between patient-related factors and the occurrence of ADAs. Both baseline and time-dependent factors such as concomitant medications were analyzed using Cox proportional hazard regression models. Mean age and disease duration were 35.1 and 0.85 years, respectively, for MS; 54.2 and 3.17 years for RA; and 36.9 and 3.69 years for inflammatory bowel diseases (IBDs). In a multivariate Cox regression model including each of the clinical and genetic factors mentioned hereafter, among the clinical factors, immunosuppressants (adjusted hazard ratio [aHR] = 0.408 [95% confidence interval (CI) 0.253-0.657], p < 0.001) and antibiotics (aHR = 0.121 [0.0437-0.333], p < 0.0001) were independently negatively associated with time to ADA development, whereas infections during the study (aHR = 2.757 [1.616-4.704], p < 0.001) and tobacco smoking (aHR = 2.150 [1.319-3.503], p < 0.01) were positively associated. 351,824 Single-Nucleotide Polymorphisms (SNPs) and 38 imputed Human Leukocyte Antigen (HLA) alleles were analyzed through a genome-wide association study. We found that the HLA-DQA1*05 allele significantly increased the rate of immunogenicity (aHR = 3.9 [1.923-5.976], p < 0.0001 for the homozygotes). Among the 6 genetic variants selected at a 20% false discovery rate (FDR) threshold, the minor allele of rs10508884, which is situated in an intron of the CXCL12 gene, increased the rate of immunogenicity (aHR = 3.804 [2.139-6.764], p < 1 × 10-5 for patients homozygous for the minor allele) and was chosen for validation through a CXCL12 protein enzyme-linked immunosorbent assay (ELISA) on patient serum at baseline before therapy start. CXCL12 protein levels were higher for patients homozygous for the minor allele carrying higher ADA risk (mean: 2,693 pg/ml) than for the other genotypes (mean: 2,317 pg/ml; p = 0.014), and patients with CXCL12 levels above the median in serum were more prone to develop ADAs (aHR = 2.329 [1.106-4.90], p = 0.026). A limitation of the study is the lack of replication; therefore, other studies are required to confirm our findings. CONCLUSION: In our study, we found that immunosuppressants and antibiotics were associated with decreased risk of ADA development, whereas tobacco smoking and infections during the study were associated with increased risk. We found that the HLA-DQA1*05 allele was associated with an increased rate of immunogenicity. Moreover, our results suggest a relationship between CXCL12 production and ADA development independent of the disease, which is consistent with its known function in affinity maturation of antibodies and plasma cell survival. Our findings may help physicians in the management of patients receiving biotherapies.
33213505 Deep sequencing reveals a DAP1 regulatory haplotype that potentiates autoimmunity in syste 2020 Nov 19 BACKGROUND: Systemic lupus erythematosus (SLE) is a clinically heterogeneous autoimmune disease characterized by the development of anti-nuclear antibodies. Susceptibility to SLE is multifactorial, with a combination of genetic and environmental risk factors contributing to disease development. Like other polygenic diseases, a significant proportion of estimated SLE heritability is not accounted for by common disease alleles analyzed by SNP array-based GWASs. Death-associated protein 1 (DAP1) was implicated as a candidate gene in a previous familial linkage study of SLE and rheumatoid arthritis, but the association has not been explored further. RESULTS: We perform deep sequencing across the DAP1 genomic segment in 2032 SLE patients, and healthy controls, and discover a low-frequency functional haplotype strongly associated with SLE risk in multiple ethnicities. We find multiple cis-eQTLs embedded in a risk haplotype that progressively downregulates DAP1 transcription in immune cells. Decreased DAP1 transcription results in reduced DAP1 protein in peripheral blood mononuclear cells, monocytes, and lymphoblastoid cell lines, leading to enhanced autophagic flux in immune cells expressing the DAP1 risk haplotype. Patients with DAP1 risk allele exhibit significantly higher autoantibody titers and altered expression of the immune system, autophagy, and apoptosis pathway transcripts, indicating that the DAP1 risk allele mediates enhanced autophagy, leading to the survival of autoreactive lymphocytes and increased autoantibody. CONCLUSIONS: We demonstrate how targeted sequencing captures low-frequency functional risk alleles that are missed by SNP array-based studies. SLE patients with the DAP1 genotype have distinct autoantibody and transcription profiles, supporting the dissection of SLE heterogeneity by genetic analysis.
32424614 Angiostrongyliasis infection masquerading as granulomatosis with polyangiitis: a case-base 2020 Jul Pulmonary angiitis is a small vessel vasculitis commonly reported in granulomatosis with polyangiitis (GPA) but is rarely attributed to angiostrongyliasis. We report a case of a patient with well-controlled rheumatoid arthritis, who was treated for GPA based on lung biopsy results with glucocorticoids (GC). Upon re-review of the initial pathology, along with peripheral eosinophilia and history of recent travel, the patient was eventually diagnosed with angiostrongylus-like nematode infection. GCs were subsequently discontinued and instead, the patient was treated with anthelmintics with complete resolution of symptoms. Commonly associated with eosinophilic meningitis or abdominal angiostrongyliasis in humans, clinical pulmonary manifestations of this parasite species are rare. With parasitic infiltration of the pulmonary vessels mimicking clinical GPA, diagnosis and treatment can be difficult in these patients. We discuss the third-reported case and first-reported survivor of Angiostrongylus-induced pulmonary angiitis followed by a focused review of the literature.
31823505 Serum levels of interleukin-34 and clinical correlation in patients with primary Sjögren' 2020 Mar OBJECTIVES: To measure the levels of serum interleukin (IL)-34 in patients with primary Sjögren's syndrome (pSS) and evaluate the cytokine's clinical association with the disease. METHODS: Serum samples were obtained from 66 pSS patients and 32 healthy controls (HCs) and measured by enzyme-linked immunosorbent assay for IL-34 levels. The clinical parameters, including autoantibodies, immunoglobulins (Igs), complements (Cs), inflammatory indicators, involvement of the blood system, lung and arthritis, were collected simultaneously. Two-sample t test was applied for comparison between 2 groups, and Pearson's correlation coefficient was used to assess the associations between IL-34 levels and laboratory parameters. RESULTS: Serum IL-34 levels were significantly elevated in pSS patients compared with HCs. Patients with anti-Ro/SSA antibody positivity showed higher serum IL-34 levels than those who were negative, as did the anti-La/SSB antibody-positive patients. Serum IL-34 levels were positively associated with the levels of rheumatoid factor, IgG and gamma-globulin, but not associated with IgA, IgM, C3, C4, erythrocyte sedimentation rate or C-reactive protein. For the pSS subgroups with and without leucopenia, thrombocytopenia, anemia or interstitial lung disease (ILD), there was no significant difference in serum IL-34 levels. Interestingly, the pSS patients with arthritis had higher levels of IL-34 compared with the no-arthritis patients. CONCLUSIONS: IL-34 may be involved in B cell activation and production of antibodies in pSS.
31650726 Laboratory Monitoring of Biological Therapies in Rheumatology: The Role of Immunogenicity. 2020 Mar Biological drugs, such as proteins and immunogens, are increasingly used to treat various diseases, including tumors and autoimmune diseases, and biological molecules have almost completely replaced synthetic drugs in rheumatology. Although biological treatments such as anti-tumor necrosis factor (TNF) drugs seem to be quite safe, they cause some undesirable effects, such as the onset of infections due to weakening of the immune system. Given the biological nature of these drugs, they might be recognized as extraneous; this would induce an immune reaction that neutralizes their effectiveness or lead to more serious consequences. Laboratories play a pivotal role in appropriate therapeutic management. The aim of this review was to underline the production of anti-drug antibodies during treatment with biological drugs and highlight the role of laboratories in ensuring appropriate use of these drugs.
32513809 Prevalence of progressive multifocal leukoencephalopathy (PML) in adults and children with 2020 Jun OBJECTIVE: To define the risk of progressive multifocal leukoencephalopathy (PML) in SLE. METHODS: This is a retrospective observational study to evaluate PML cases in patients with SLE admitted to two large academic hospitals. Using electronic medical record (EMR) data, International Classification of Diseases (ICD) codes identified PML cases among patients with SLE, rheumatoid arthritis (RA) (controls), had renal transplant and with HIV. Medication exposure was reviewed. RESULTS: A total of 5409 Columbia University Medical Center (CUMC) patients and 2046 Northwell Health patients were identified using one ICD code for SLE. Of 7455 patients, three had an ICD code for PML. On EMR review, however, PML was substantiated in only one fatal SLE case with significant immunosuppressant use and severe lymphopenia (<0.5 cells x 10(9)/L); one patient was evaluated for PML but cerebrospinal fluid (CSF) was negative for JC virus and improved with treatment of central nervous system (CNS) lupus. EMR data were very limited for the third patient and diagnosis could not be confirmed. None of the 13 342 patients with RA ICD codes had PML. Of the 5409 patients with an SLE ICD code at CUMC, 212 also had a renal transplant ICD code, and 83 had concomitant HIV/AIDS. Based on inpatient pharmacy records of 5409 hospitalised patients at CUMC, 59.2% were treated with steroids, and 16.09% with immunosuppressants (7.76% mycophenolate, 3.42% cyclophosphamide, 2.88% azathioprine and 2.03% rituximab). No patients with paediatric SLE (pSLE) (n=538) had PML. The combined prevalence of PML in hospitalised patients with SLE at the two hospitals was 13-27/100 000 patients. CONCLUSION: Among 7455 adult patients with SLE ICD codes, there were two PML cases, with only one confirmed case associated with severe lymphopenia and immunosuppressants, corresponding to a prevalence of 13-27 per 100 000 patients. No PML cases in pSLE were found. A high index of suspicion in patients with SLE and CNS manifestations is required for the prompt diagnosis of PML.
32785008 The Essential Role of Peptidylarginine Deiminases 2 for Cytokines Secretion, Apoptosis, an 2020 Aug 10 OBJECTIVE: The study aims to investigate the functional roles of peptidylarginine deiminase 2 (PADI2) in macrophages. METHODS: The clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein-9 nuclease (Cas9) system was used to knockout PADI2 in U937 cells. U937 cells were introduced to differentiate macrophages and were stimulated with lipopolysaccharides (LPS). The protein expression of PADI2, PADI4, and citrullinated proteins were analyzed by Western blotting. The mRNA and protein levels of interleukin 1 beta (IL-1β), IL-6, and tumor necrosis factor-alpha (TNF-α) were analyzed using RT-PCR and ELISA, respectively. Cell apoptosis was analyzed using flow cytometry. Cell adhesion assay was performed using a commercially available fibrinogen-coated plate. RESULTS: PADI2 knockout could markedly suppress the PADI2 protein expression, but not the PADI4 protein expression. PADI2 knockout decreased the protein levels of citrullinated nuclear factor κB (NF-κB) p65, but not those of citrullinated histone 3, resulting in the decreased mRNA expression levels of IL-1β and TNF-α in the U937 cells and IL-1β and IL-6 in the differentiated macrophages and the macrophages stimulated with LPS. The cytokines levels of IL-1β, IL-6, and TNF-α were all dramatically decreased in the PADI2 knockout group compared with in the controls. PADI2 knockout prevented macrophages apoptosis via the decreased caspase-3, caspase-2, and caspase-9 activation. PADI2 knockout also impaired macrophages adhesion capacity through the decreased protein levels of focal adhesion kinase (FAK), phospho-FAK, paxillin, phospho-paxillin, and p21-activated kinase 1. CONCLUSION: This study showed that PADI2 could promote IL-1β, IL-6, and TNF-α production in macrophages, promote macrophage apoptosis through caspase-3, caspase-2, and caspase-9 activation and enhance cell adhesion via FAK, paxillin, and PAK1. Therefore, targeting PADI2 could be used as a novel strategy for controlling inflammation caused by macrophages.
32645478 Hydroxychloroquine safety: A meta-analysis of randomized controlled trials. 2020 Jul BACKGROUND: Hydroxychloroquine (HCQ) is currently being examined for COVID-19. No previous meta-analysis has evaluated its side effects versus placebo. We conducted this meta-analysis to compare the safety of HCQ versus placebo. METHODS: Two authors independently searched PubMed and EMBASE databases for randomized controlled trials (RCTs) of adults comparing the adverse events (AEs) of HCQ versus placebo for any indication. Peto odds ratios (Peto ORs) and 95% confidence intervals (CIs) were calculated based on random-effects models. The heterogeneity (I(2)) was assessed using Cochran's Q test. RESULTS: Nine RCTs (eight were double-blind) with a total of 916 patients were included. HCQ caused significantly more skin pigmentation than placebo (Peto OR, 4.64; 95% CI, 1.13 to 19.00; P-value = 0.033; I(2) = 0%). The increase in other AEs did not reach statistical significance: rash (Peto OR, 1.11; 95% CI, 0.3 to 3.77; P-value = 0.03; I(2) = 0%); gastrointestinal AEs (Peto OR, 1.43; 95% CI, 0.55 to 3.72; P-value = 0.46; I(2) = 15.17%); headache (Peto OR, 1.94; 95% CI, 0.65 to 5.78; P-value = 0.23; I(2) = 9.99%); dizziness (Peto OR, 1.32; 95% CI, 0.49 to 3.52; P-value = 0.58; I(2) = 0%); fatigue (Peto OR, 2.13; 95% CI, 0.76 to 5.98; P-value = 0.15; I(2) = 0%); and visual AEs (Peto OR, 1.61; 95% CI, 0.76 to 3.41; P-value = 0.22; I(2) = 0%). Cardiac toxicity was not reported. CONCLUSIONS: This meta-analysis of RCTs found a significantly higher risk of skin pigmentation in HCQ users versus placebo. More data are needed to evaluate HCQ in the context of COVID-19 treatment.
33505813 Risk of Major Adverse Cardiovascular Events in Patients With Rheumatoid Arthritis. 2020 Dec 23 Introduction Rheumatoid arthritis is a chronic, inflammatory, and multisystem disease, which, along with the joints, can involve the cardiovascular system. The treatment of rheumatoid arthritis or rheumatoid arthritis itself can lead to atherosclerosis, which is considered one of the major causes by which it can affect the cardiovascular system. In this study, we will assess the risk of cardiovascular events in patients with rheumatoid arthritis as compared to the general population. Method This case-control study was conducted from January 2018 to November 2018. Two-hundred twenty-two (222) patients with diagnosed rheumatoid arthritis were included as cases in the study. Two-hundred eleven (211) patients were included in the study as the control group (patients without rheumatoid arthritis). All the data were recorded in a self-structured questionnaire. Result Participants with rheumatoid arthritis also showed an increased risk of myocardial infarction (MI) by an odds ratio of 2.50 (95% CI; 0.77-8.14). There was also an increased risk of cardiovascular death in participants with rheumatoid arthritis by an odds ratio of 1.99 (0.58-6.71). Conclusion The study suggests that rheumatoid arthritis along with joint inflammation can also affect the cardiovascular system. Hence, a multidisciplinary team of rheumatologists and cardiologists should manage patients suffering from rheumatoid arthritis, which will improve morbidity and mortality in such patients.
33318731 Radiographically Occult Manifestation of Rheumatoid Arthritis in a Patient With Prolonged 2020 Jun OBJECTIVE: The purpose of this case report is to present a case of rampant rheumatoid synovitis and arthritis of a patient with a long duration of symptoms and no radiographic abnormalities of rheumatoid arthritis at the initial diagnosis. CLINICAL FEATURES: A 49-year-old Hispanic woman presented to a chiropractic teaching clinic with an 8-month history of bilateral, symmetrical hand pain and stiffness noted specifically in her second and third metacarpophalangeal joints. The patient has reported no other health changes and no history of rheumatoid arthritis in the family. INTERVENTION AND OUTCOME: Based on this patient's complaint, initial bilateral 3-view radiographic examination of the hands using computed radiography was performed. Despite prolonged history of inflammatory joint pain and rheumatoid arthritis confirmed by abnormally high levels of rheumatoid factor, C-reactive protein, and anti-cyclic citrulline peptide antibodies, the patient had no radiographic evidence of rheumatoid arthritis during the initial and repeat radiographic studies. CONCLUSION: Some patients with rheumatoid arthritis may present with rampant clinical and laboratory abnormalities despite an apparent lack of radiographically detectable rheumatoid arthritis. This case demonstrates that astute clinicians should primarily rely on the results of clinical and laboratory abnormalities of rheumatoid arthritis and not be deterred or mislead by an apparent lack of radiographic changes at diagnosis. If the diagnosis of rheumatoid arthritis requires diagnostic imaging confirmation, then magnetic resonance imaging or diagnostic ultrasound of the hands should be used, especially if the initial radiographic assessment remains unrewarding.
33224668 A Case of Rheumatoid Arthritis-Associated Interstitial Lung Disease - An Unfortunate Compl 2020 Oct 21 Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is a rare extraarticular manifestation of the systemic autoimmune disease rheumatoid arthritis. RA-ILD is one of the leading causes of morbidity and mortality in patients with rheumatoid arthritis. It is more commonly seen in patients with risk factors, which include male sex, severe rheumatoid arthritis, and smoking. The presentation depends on the extent of the underlying pathology. Patients can remain asymptomatic for extended periods of time and progressively develop symptoms such as shortness of breath on exertion and a nonproductive cough. The diagnosis is made using a combination of clinical presentation, pulmonary function testing, and imaging. It is difficult for a practitioner to distinguish the presentation of interstitial lung disease from other causes and RA-ILD. However, it is extremely important to differentiate them due to the differences in management. The treatment usually involves a multidisciplinary team guided approach towards treating the underlying rheumatoid arthritis. Asymptomatic patients are managed by observation, while symptomatic patients are managed with glucocorticoids and immunosuppressants. Accurate and early treatment can lead to an improvement in a patient's symptoms and significantly improve their quality of life. We present an interesting case of a female with a long-standing history of rheumatoid arthritis not on any treatment presenting to the ED with exertional shortness of breath, dry cough, and abdominal distension.
32648334 Characterization of the Effect of Upadacitinib on the Pharmacokinetics of Bupropion, a Sen 2021 Mar This phase 1 study characterized the effect of multiple doses of upadacitinib, an oral Janus kinase 1 selective inhibitor, on the pharmacokinetics of the cytochrome P450 (CYP) 2B6 substrate bupropion. Healthy subjects (n = 22) received a single oral dose of bupropion 150 mg alone (study period 1) and on day 12 of a 16-day regimen of upadacitinib 30 mg once daily (study period 2). Serial blood samples for measurement of bupropion and hydroxybupropion plasma concentrations were collected in each study period. The central values (90% confidence intervals) for the ratios of change were 0.87 (0.79-0.96) for bupropion maximum plasma concentration (C(max) ), 0.92 (0.87-0.98) for bupropion area under the plasma-concentration time curve from time 0 to infinity (AUC(inf) ), 0.78 (0.72-0.85) for hydroxybupropion C(max) , and 0.72 (0.67-0.78) for hydroxybupropion AUC(inf) when administered with, relative to when administered without, upadacitinib. After multiple-dose administration of upadacitinib 30 mg once daily, upadacitinib mean ± SD AUC(0-24) was 641 ± 177 ng·h/mL, and C(max) was 83.3 ± 30.7 ng/mL. These results confirm that upadacitinib has no relevant effect on pharmacokinetics of substrates metabolized by CYP2B6.