| 1. |
- Hindy, George, et al.
(author)
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Cardiometabolic Polygenic Risk Scores and Osteoarthritis Outcomes : A Mendelian Randomization Study Using Data From the Malmö Diet and Cancer Study and the UK Biobank
- 2019
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In: Arthritis and Rheumatology. - : Wiley. - 2326-5191 .- 2326-5205. ; 71:6, s. 925-934
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Journal article (peer-reviewed)abstract
- Objective: To investigate the causal role of cardiometabolic risk factors in osteoarthritis (OA) using associated genetic variants. Methods: We studied 27,691 adults from the Malmö Diet and Cancer Study (MDCS) and replicated novel findings among 376,435 adults from the UK Biobank. Trait-specific polygenic risk scores for low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol levels, triglyceride levels, body mass index (BMI), fasting plasma glucose (FPG) levels, and systolic blood pressure (BP) were used to test the associations of genetically predicted elevations in each trait with incident OA diagnosis (n = 3,559), OA joint replacement (n = 2,780), or both (total OA; n = 4,226) in Mendelian randomization (MR) analyses in the MDCS, and with self-reported and/or hospital-diagnosed OA (n = 65,213) in the UK Biobank. Multivariable MR, MR-Egger, and weighted median MR were used to adjust for potential pleiotropic biases. Results: In the MDCS, genetically predicted elevation in LDL cholesterol level was associated with a lower risk of OA diagnosis (odds ratio [OR] 0.83 [95% confidence interval (95% CI) 0.73–0.95] per 1SD increase) and total OA (OR 0.87 [95% CI 0.78–0.98]), which was supported by multivariable MR for OA diagnosis (OR 0.84 [95% CI 0.75–0.95]) and total OA (0.87 [95% CI 0.78–0.97]), and by conventional 2-sample MR for OA diagnosis (OR 0.86 [95% CI 0.75–0.98]). MR-Egger indicated no pleiotropic bias. Genetically predicted elevation in BMI was associated with an increased risk of OA diagnosis (OR 1.65 [95% CI 1.14–2.41]), while MR-Egger indicated pleiotropic bias and a larger association with OA diagnosis (OR 3.25 [1.26–8.39]), OA joint replacement (OR 3.81 [95% CI 1.39–10.4]), and total OA (OR 3.41 [95% CI 1.43–8.15]). No associations were observed between genetically predicted HDL cholesterol level, triglyceride level, FPG level, or systolic BP and OA outcomes. The associations with LDL cholesterol levels were replicated in the UK Biobank (OR 0.95 [95% CI 0.93–0.98]). Conclusion: Our MR study provides evidence of a causal role of lower LDL cholesterol level and higher BMI in OA.
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| 2. |
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| 3. |
- Ali, Abukar, 1988, et al.
(author)
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Antibiotic-killed Staphylococcus aureus induces destructive arthritis in mice.
- 2015
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In: Arthritis & rheumatology (Hoboken, N.J.). - : Wiley. - 2326-5205 .- 2326-5191. ; 67:1, s. 107-116
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Journal article (peer-reviewed)abstract
- Objective: Permanent reduction in joint function is a severe post-infectious complication in patients with Staphylococcus aureus septic arthritis. This reduction in joint function might be caused by persistent joint inflammation after the adequate eradication of bacteria by antibiotics. Methods: We studied whether antibiotic-killed S. aureus induced joint inflammation in mice and elucidated the molecular and cellular mechanism of this type of arthritis. Results: The intraarticular injection of antibiotic-killed S. aureus induced mild to moderate synovitis and bone erosions that lasted for a minimum of 14 days. The frequency and severity of synovitis were significantly reduced in tumor necrosis factor receptor 1 (TNFR1), receptor for Advanced Glycation End Products (RAGE), and toll like receptor 2 (TLR2) knockout mice compared with wild-type animals. The combined depletion of monocytes and neutrophils resulted in a significantly lower frequency of synovitis. Among bacterial factors, insoluble cell debris played a more important role than bacterial DNA or soluble components in inducing joint inflammation. Importantly, anti-TNF therapy abrogated the joint inflammation induced by antibiotic-killed S. aureus. Conclusion: Antibiotic-killed S. aureus induced and maintained the joint inflammation that is mediated through TLR2, TNFR1, and RAGE receptor. The cross-talk between neutrophils and monocytes is responsible for this type of arthritis. Anti-TNF therapy might be used as a novel therapeutic strategy, in combination with antibiotics, to treat staphylococcal septic arthritis. © 2014 American College of Rheumatology.
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| 4. |
- Funck-Brentano, Thomas, et al.
(author)
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Causal Factors for Knee, Hip, and Hand Osteoarthritis: A Mendelian Randomization Study in the UK Biobank
- 2019
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In: Arthritis & Rheumatology. - : Wiley. - 2326-5191 .- 2326-5205. ; 71:10, s. 1634-1641
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Journal article (peer-reviewed)abstract
- Objective There is no curative treatment for osteoarthritis (OA), which is the most common form of arthritis. This study was undertaken to identify causal risk factors of knee, hip, and hand OA. Methods Individual-level data from 384,838 unrelated participants in the UK Biobank study were analyzed. Mendelian randomization (MR) analyses were performed to test for causality for body mass index (BMI), bone mineral density (BMD), serum high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglyceride levels, type 2 diabetes, systolic blood pressure (BP), and C-reactive protein (CRP) levels. The primary outcome measure was OA determined using hospital diagnoses (all sites, n = 48,431; knee, n = 19,727; hip, n = 11,875; hand, n = 2,330). Odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated. Results MR analyses demonstrated a robust causal association of genetically determined BMI with all OA (OR per SD increase 1.57 [95% CI 1.44-1.71]), and with knee OA and hip OA, but not with hand OA. Increased genetically determined femoral neck BMD was causally associated with all OA (OR per SD increase 1.14 [95% CI 1.06-1.22]), knee OA, and hip OA. Low systolic BP was causally associated with all OA (OR per SD decrease 1.55 [95% CI 1.29-1.87]), knee OA, and hip OA. There was no evidence of causality for the other tested metabolic factors or CRP level. Conclusion Our findings indicate that BMI exerts a major causal effect on the risk of OA at weight-bearing joints, but not at the hand. Evidence of causality of all OA, knee OA, and hip OA was also observed for high femoral neck BMD and low systolic BP. However, we found no evidence of causality for other metabolic factors or CRP level.
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| 5. |
- Ge, Changrong, et al.
(author)
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Structural Basis of Cross-Reactivity of Anti-Citrullinated Protein Antibodies
- 2019
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In: Arthritis & Rheumatology. - : WILEY. - 2326-5191 .- 2326-5205. ; 71:2, s. 210-221
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Journal article (peer-reviewed)abstract
- Objective Anti-citrullinated protein antibodies (ACPAs) develop many years before the clinical onset of rheumatoid arthritis (RA). This study was undertaken to address the molecular basis of the specificity and cross-reactivity of ACPAs from patients with RA. Methods Antibodies isolated from RA patients were expressed as monoclonal chimeric antibodies with mouse Fc. These antibodies were characterized for glycosylation using mass spectrometry, and their cross-reactivity was assessed using Biacore and Luminex immunoassays. The crystal structures of the antigen-binding fragment (Fab) of the monoclonal ACPA E4 in complex with 3 different citrullinated peptides were determined using x-ray crystallography. The prevalence of autoantibodies reactive against 3 of the citrullinated peptides that also interacted with E4 was investigated by Luminex immunoassay in 2 Swedish cohorts of RA patients. Results Analysis of the crystal structures of a monoclonal ACPA from human RA serum in complex with citrullinated peptides revealed key residues of several complementarity-determining regions that recognized the citrulline as well as the neighboring peptide backbone, but with limited contact with the side chains of the peptides. The same citrullinated peptides were recognized by high titers of serum autoantibodies in 2 large cohorts of RA patients. Conclusion These data show, for the first time, how ACPAs derived from human RA serum recognize citrulline. The specific citrulline recognition and backbone-mediated interactions provide a structural explanation for the promiscuous recognition of citrullinated peptides by RA-specific ACPAs.
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| 6. |
- Hagert, C., et al.
(author)
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Chronic Active Arthritis Driven by Macrophages Without Involvement of T Cells : A Novel Experimental Model of Rheumatoid Arthritis
- 2018
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In: Arthritis & Rheumatology. - Hoboken : Wiley. - 2326-5191 .- 2326-5205 .- 1529-0131. ; 70:8, s. 1343-1353
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Journal article (peer-reviewed)abstract
- OBJECTIVE: To develop a new chronic rheumatoid arthritis model that is driven by the innate immune system. METHODS: Injection of a cocktail of 4 monoclonal antibodies against type II collagen, followed on days 5 and 60 by intraperitoneal injections of mannan (from Saccharomyces cerevisiae), was used to induce development of chronic arthritis in B10.Q mice. The role of the innate immune system as compared to the adaptive immune system in this arthritis model was investigated using genetically modified mouse strains. RESULTS: A new model of chronic relapsing arthritis was characterized in B10.Q mice, in which a persistently active, chronic disease was found. This relapsing disease was driven by macrophages lacking the ability to mount a reactive oxygen species response against pathogens, and was associated with the classical/alternative pathway, but not the lectin pathway, of complement activation. The disease was independent of Fcgamma receptor type III, and also independent of the activity of adaptive immune cells (B and T cells), indicating that the innate immune system, involving complement activation, could be the sole driver of chronicity. CONCLUSION: Chronic active arthritis can be driven innately by macrophages without the involvement of T and B cells in the adaptive immune system.
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| 7. |
- Hellgren, K., et al.
(author)
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Rheumatoid Arthritis and Risk of Malignant Lymphoma - Is the risk still increased?
- 2017
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In: Arthritis & Rheumatology. - : Wiley. - 2326-5191 .- 2326-5205. ; 69:4, s. 700-708
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Journal article (peer-reviewed)abstract
- OBJECTIVE: Patients with rheumatoid arthritis (RA) are at increased risk of malignant lymphomas with a strong correlation with RA disease severity. Given the changes in RA therapy over recent decades, we aimed at assessing whether lymphoma risk remains increased, and if so, to explore risk predictors and lymphoma subtypes.METHODS: We identified 12,656 incident RA patients from the Swedish Rheumatology Register 1997-2012 including information on therapy and inflammatory activity during the first year following diagnosis. Each patient was matched to 10 population comparator subjects. Through linkage to the Swedish Cancer Register, lymphomas including subtypes were identified. We assessed Hazard ratios (HRs) using Cox regression.RESULTS: Overall, the HR of lymphoma was increased, 1.6, 95% confidence interval [CI] 1.2-2.1. Taking RA duration into account, risks did not appear to have declined over successive calendar years of RA diagnosis. Neither use of methotrexate the 1(st) year following RA diagnosis nor ever use of TNF inhibitors (HR=0.9; 95% CI 0.4-1.9) increased lymphoma risk. Use of oral corticosteroids the 1(st) year following RA diagnosis was associated with a reduced risk (HR=0.6; 95% CI 0.5 -0.9). Inflammatory activity during the 1(st) year following RA diagnosis did not predict future lymphoma risk. Chronic lymphocytic lymphoma occurred less, and Hodgkin lymphoma more frequently than expected compared to the general population.CONCLUSION: The average lymphoma risk in recently diagnosed RA is of similar magnitude as that reported from historical cohorts. Standard anti-rheumatic treatment including TNF inhibitors did not predict future lymphoma risk. Distribution of lymphoma subtypes warrants further investigation.
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| 8. |
- Roemer, Frank W., et al.
(author)
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Molecular and Structural Biomarkers of Inflammation at Two Years After Acute Anterior Cruciate Ligament Injury Do Not Predict Structural Knee Osteoarthritis at Five Years
- 2019
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In: Arthritis and Rheumatology. - : Wiley. - 2326-5191 .- 2326-5205. ; 71:2, s. 238-243
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Journal article (peer-reviewed)abstract
- Objective: To determine the role of inflammatory biomarkers at 2 years post–anterior cruciate ligament (ACL) injury to predict radiographic knee osteoarthritis (OA) and magnetic resonance imaging (MRI)–defined knee OA at 5 years postinjury, with a secondary aim of estimating the concordance of inflammatory biomarkers assessed by MRI and synovial fluid (SF) analysis. Methods: We studied 113 patients with acute ACL injury. Knee scans using 1.5T MRIs were read for Hoffa- and effusion-synovitis. Biomarkers of inflammation that we assessed included interleukin-6 (IL-6), IL-8, IL-10, tumor necrosis factor, and interferon-ɣ in serum and SF, and IL-12p70 in serum. We defined the outcome as radiographic knee OA (ROA) or MRI-defined OA (MROA) at 5 years. The area under the receiver operating characteristic curve (AUC), sensitivity, and specificity were evaluated in models that included MRI features only (model 1), inflammation biomarkers only (serum [model 2a] or SF [model 2b]), both MRI features and serum biomarkers (model 3a), or both MRI features and SF (model 3b) biomarkers. Linear regression analysis was used to evaluate the association between MRI features and SF biomarkers. Results: At 5 years postinjury, ROA was present in 26% of the injured knees, and MROA was present in 32%. The AUCs for ROA in each model were 0.44 (95% confidence interval [95% CI] 0.42, 0.47) for model 1, 0.62 (95% CI 0.59, 0.65) for model 2a, 0.53 (95% CI 0.50, 0.56) for model 2b, 0.58 (95% CI 0.55, 0.61) for model 3a, and 0.50 (95% CI 0.46, 0.53) for model 3b. The AUCs for MROA in each model were 0.67 (95% CI 0.64, 0.70) for model 1, 0.49 (95% CI 0.47, 0.52) for model 2a, 0.56 (95% CI 0.52, 0.59) for model 2b, 0.65 (95% CI 0.61, 0.68) for model 3a, and 0.69 (95% CI 0.66, 0.72) for model 3b. The concordance between MRI and SF biomarkers was statistically significant only for effusion-synovitis and IL-8. Conclusion: Neither MRI-detected inflammation nor selected SF/serum inflammation biomarkers at 2 years postinjury predicted ROA or MROA at 5 years postinjury. Concordance between MRI and SF inflammatory biomarkers was weak.
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| 9. |
- Steen, Johanna, et al.
(author)
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Recognition of Amino Acid Motifs, Rather Than Specific Proteins, by Human Plasma Cell-Derived Monoclonal Antibodies to Posttranslationally Modified Proteins in Rheumatoid Arthritis
- 2019
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In: Arthritis & Rheumatology. - : WILEY. - 2326-5191 .- 2326-5205. ; 71:2, s. 196-209
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Journal article (peer-reviewed)abstract
- Objective: Antibodies against posttranslationally modified proteins are a hallmark of rheumatoid arthritis (RA), but the emergence and pathogenicity of these autoantibodies are still incompletely understood. The aim of this study was to analyze the antigen specificities and mutation patterns of monoclonal antibodies (mAb) derived from RA synovial plasma cells and address the question of antigen cross-reactivity.Methods: IgG-secreting cells were isolated from RA synovial fluid, and the variable regions of the immunoglobulins were sequenced (n = 182) and expressed in full-length mAb (n = 93) and also as germline-reverted versions. The patterns of reactivity with 53,019 citrullinated peptides and 49,211 carbamylated peptides and the potential of the mAb to promote osteoclastogenesis were investigated.Results: Four unrelated anti-citrullinated protein autoantibodies (ACPAs), of which one was clonally expanded, were identified and found to be highly somatically mutated in the synovial fluid of a patient with RA. The ACPAs recognized >3,000 unique peptides modified by either citrullination or carbamylation. This highly multireactive autoantibody feature was replicated for Ig sequences derived from B cells from the peripheral blood of other RA patients. The plasma cell-derived mAb were found to target distinct amino acid motifs and partially overlapping protein targets. They also conveyed different effector functions as revealed in an osteoclast activation assay.Conclusion: These findings suggest that the high level of cross-reactivity among RA autoreactive B cells is the result of different antigen encounters, possibly at different sites and at different time points. This is consistent with the notion that RA is initiated in one context, such as in the mucosal organs, and thereafter targets other sites, such as the joints.
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| 10. |
- Steen Pettersen, Pernille, et al.
(author)
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Peripheral and Central Sensitization of Pain in Individuals With Hand Osteoarthritis and Associations With Self-Reported Pain Severity
- 2019
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In: Arthritis and Rheumatology. - : Wiley. - 2326-5191 .- 2326-5205. ; 71:7, s. 1070-1077
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Journal article (peer-reviewed)abstract
- Objective: Pain sensitization, an important osteoarthritis (OA) pain mechanism, has not been substantially investigated in patients with hand OA. It is unknown how peripheral and central sensitization are related to self-reported hand pain. Methods: Individuals with verified hand OA in the Nor-Hand study underwent quantitative sensory testing of pressure pain thresholds (PPTs) locally (painful and nonpainful finger joints) and remotely (wrist, trapezius, and tibialis anterior muscles), and testing of temporal summation (TS), a manifestation of central sensitization. We examined cross-sectional associations of PPT tertiles and TS with hand pain using the Numerical Rating Scale (NRS) (range 0–10) and the Australian/Canadian Osteoarthritis Hand Index (AUSCAN) pain subscale (range 0–20). Linear regression models were adjusted for demographics, psychosocial factors, and radiographic severity. Results: This study included 282 participants (88% female) with a median age of 61 years (interquartile range [IQR] 57–66). Participants with the lowest PPTs in their finger joints and in most remote locations reported higher NRS pain values, compared to patients with the highest PPTs, with adjusted β values ranging from 0.6 (95% confidence interval [95% CI] 0.0, 1.2) to 0.9 (95% CI 0.3, 1.5). The 118 participants (42%) with TS reported higher mean ± SD NRS pain values compared to those without TS (4.1 ± 2.4 versus 3.1 ± 1.7; adjusted β = 0.6 [95% CI 0.2, 1.1]). Neither PPTs nor the presence of TS were associated with AUSCAN pain. Conclusion: Central sensitization was common in patients with hand OA. Lower local and widespread PPTs and the presence of TS were associated with higher hand pain intensity, even after adjustment for demographics, psychosocial factors, and radiographic severity. Sensitization may therefore represent a possible treatment target.
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