RHEUMASEARCH

Distinct roles of hepatocyte- and myeloid cell-derived IL-1 receptor antagonist during endotoxemia and sterile inflammation in mice.

J Immunol 2010
 
IL-1R antagonist (IL-1Ra) is a natural inhibitor of the pleiotropic proinflammatory activities of IL-1. Although several reports described the effects of complete IL-1Ra deficiency, no study has examined the consequences of cell type-specific IL-1Ra inactivation during systemic inflammation. Previous in vitro data demonstrated high IL-1Ra production by hepatocytes and myeloid cells after endotoxin stimulation. In addition, hepatocyte IL-1Ra production is regulated as an acute-phase protein in vitro. In this study, we analyzed the production and functional role of hepatocyte- and myeloid cell-derived IL-1Ra during endotoxin-induced septic shock and acute IL-1beta-induced sterile inflammation. Using conditional IL-1Ra knockout mice, we showed that hepatocytes and myeloid cells are the two major cellular sources of circulating IL-1Ra in response to LPS. Interestingly, IL-1Ra production by myeloid cells, but not hepatocytes, is critical for survival during endotoxemia. Furthermore, we provide the first in vivo evidence demonstrating that IL-1Ra is produced as an acute-phase protein by hepatocytes during IL-1beta-induced inflammation and that hepatocyte-derived IL-1Ra functions as an endogenous negative feedback downregulating the proinflammatory effects of IL-1. Taken together, our observations define distinct roles for two major cellular sources of IL-1Ra in response to different types of systemic inflammatory stimuli in vivo.

Adalimumab in acute and severe sciatica. A multicentre, randomised, double-blind, placebo-controlled trial.

Arthritis Rheum 2010
 
OBJECTIVE: Based on several experimental results and on a preliminary study, a trial was undertaken to assess the efficacy of adalimumab, a tumor necrosis factor alpha inhibitor, in patients with radicular pain due to lumbar disc herniation.
 
METHODS: A multicenter, double-blind, randomized controlled trial was conducted between May 2005 and December 2007 in Switzerland. Patients with acute (duration of <12 weeks) and severe (Oswestry Disability Index score of >50) radicular leg pain and imaging-confirmed lumbar disc herniation were randomized to receive as adjuvant therapy either 2 subcutaneous injections of adalimumab (40 mg) at 7-day intervals or matching placebo. The primary outcome was the score for leg pain, based on a visual analog scale (0-100 mm), which was recorded every day for 10 days and at 6 weeks and 6 months.
 
RESULTS: Of the 265 patients screened, 61 were enrolled; 31 patients were assigned to receive adalimumab, and 4 patients in the placebo group were lost to followup. Over time, the course of leg pain was more favorable in the adalimumab group than in the placebo group (P = 0.002). However, the effect size was relatively small, and at the last followup visit the difference was 13.8 (95% confidence interval -11.5, 39.0). Compared with patients in the placebo group, approximately twice as many patients in the adalimumab group fulfilled the criteria for "responders" and for "low residual disease impact" (P < 0.05), and fewer surgical discectomies were performed (6 versus 13 in the placebo group; P = 0.04).
 
CONCLUSION: The addition of a short course of adalimumab to the treatment regimen of patients experiencing acute and severe sciatica resulted in a small decrease in leg pain and in significantly fewer surgical procedures.
 

Anti-Apolipoprotein A-1 IgG Predict Major Cardiovascular Events in Patients with Rheumatoid Arthritis.

Arthritis Rheum 2010
 
OBJECTIVE: To determine whether anti-apolipoprotein (apo) A-1 IgG are associated with major cardiovascular events (MACE) in rheumatoid arthritis (RA) patients.
 
METHODS: We determined anti-apoA-1 IgG levels and the concentrations of cytokines, oxidised low density lipoprotein (oxLDL) and metalloproteinases (MMPs) 1, 2, 3, 9 in the sera of 133 RA patients without cardiovascular disease at baseline, who where all longitudinally followed over a median period of 9 years. MACE was defined as fatal or non-fatal stroke or acute coronary syndrome. The pro-inflammatory effects of anti-apoA-1 IgG were assessed on human macrophages in vitro.
 
RESULTS: During follow-up, overall MACE incidence was 15% (20/133). At baseline, anti-apoA-1 IgG positivity was 17% and was associated with a higher MACE incidence (adjusted Hazard Ratio: 4.2; 95%CI: 1.5-12.1). Patients with subsequent MACE had higher circulating levels of anti-apoA-1 IgG at baseline (Absorbance: 0.58 versus 0.2 Optical Densities at 405 nm, p=0.001). ROC curve analysis showed that anti-apoA-1 IgG was the strongest predictor of all tested biomarkers for subsequent MACE with an area under the curve of 0.73 (p=0.0008). At the predefined and previously validated cut-off levels, the specificity was 50% and the sensitivity 90%. Anti-apoA-1 IgG positivity was associated with higher median circulating levels of IL-8 (p=0.01), oxLDL (p=0.02), MMP-9 (p=0.03), and higher pro-MMP-9 activity as assessed by zymography (p=0.008). On human macrophages, anti-apoA-1 IgG induced a significant dose-dependent increase of IL-8 and MMP-9 levels, and pro-MMP-9 activity.
 
CONCLUSION: Anti-apoA-1 IgG is an independent predictor of MACE in RA, possibly by affecting atherosclerotic plaque vulnerability.
 

Diagnostic Value of Anti-Cyclic Citrullinated Peptides and Association with HLA-DRB1 Shared Epitope Alleles in African Rheumatoid Arthritis Patients.

Arthritis Res Ther 2010
 
INTRODUCTION: The purpose of this study was to examine the diagnostic performance of autoantibodies against citrullinated peptides/proteins (ACPA) and to determine the prevalence of HLA-DRB1 shared epitope alleles (SE) in African patients with rheumatoid arthritis (RA).
 
METHODS: Serum levels of anti-cyclic citrullinated peptides antibodies (anti-CCP2, anti-CCP3), IgM and IgA rheumatoid factors (RF) were measured by enzyme-linked immunosorbent assay in the serum of 56 consecutive RA patients regularly followed in the Rheumatology Unit of the School of Medicine, University of Yaoundé, Yaoundé, Cameroon. Genotyping of HLA-DRB1 alleles was performed by polymerase chain reaction and hybridization with sequence-specific oligonucleotide probes on microbeads arrays. Fifty-one patients with other inflammatory rheumatic diseases and 50 healthy individuals were included as controls.
 
RESULTS: An anti-CCP2 assay showed the best diagnosis sensitivity (82%) and specificity (98%) with high positive predictive (PPV) (96%) and negative predictive values (NPV) (91%). Thirty percent of RA patients were carrying at least one copy of the HLA-DRB1 shared epitope (SE) compared to 10% and 14% of patients with other inflammatory rheumatic diseases and healthy individuals, respectively. The presence of the SE was associated with the production of ACPA.
 
CONCLUSIONS: Anti-CCP2 antibodies are useful markers of RA in African patients. In this cohort, the prevalence of the SE is higher in RA patients than in controls but lower than that reported in patient cohorts of European ancestry. The discrepancy between the high prevalence of ACPA-positive patients and the relatively low number of SE-positive cases suggest that, in addition to SE, other genetic factors control the development of ACPA in African RA patients.
 

Progression of radiographic joint damage in alcohol drinkers versus non drinkers: should patients with RA cease drinking?

Arthritis Rheum 2010
 
OBJECTIVE: Alcohol consumption reduces the risk of development of rheumatoid arthritis (RA) and significantly attenuates the development of erosive arthritis in animal models. It remains unknown whether alcohol consumption influences joint damage progression in RA. This study was undertaken to compare the rates of radiographic damage progression in alcohol drinkers and nondrinkers in a large prospective cohort of patients with RA.
 
METHODS: All patients in the population-based Swiss Clinical Quality Management in RA registry database with at least 2 sequential radiographs were included. Joint erosions were assessed in 38 joints in the hands and feet using a validated scoring method. The rate of progression of erosions was analyzed using multivariate regression models for longitudinal data and was adjusted for potential confounders.
 
RESULTS: The study included 2,908 patients with RA with a mean of 4 sequential radiographs and 3.9 years of followup. A trend toward reduced radiographic progression existed in drinkers compared with nondrinkers, with a mean rate of erosive progression of 0.99% (95% confidence interval [95% CI] 0.89-1.09) and 1.13% (95% CI 1.01-1.26) at 1 year, respectively. Alcohol consumption displayed a J-shaped dose-response effect, with a more favorable evolution in occasional consumers (P = 0.01) and daily consumers (P = 0.001) as compared with nondrinkers, while heavy drinkers demonstrated worse radiographic evolution (P = 0.0001). We found significant effect modification by sex, with male drinkers displaying significantly less erosive progression compared with male nondrinkers (mean 0.86% [95% CI 0.70-1.03] versus 1.35% [95% CI 1.02-1.67]; P = 0.007).
 
CONCLUSION: Our findings indicate a trend toward reduced radiographic progression in alcohol drinkers compared with nondrinkers, specifically in occasional and daily alcohol consumers. In particular, male patients with RA who consume alcohol demonstrate less radiographic progression than do male nondrinkers.
 

Influence of anti-infliximab antibodies and residual infliximab concentrations on the occurrence of acquired drug resistance to infliximab in rheumatoid arthritis patients.

Bone Joint Spine 2010
 
BACKGROUND: Infliximab (IFX) can be immunogenic for humans and lead to the formation of antibodies against IFX (anti-IFX Ab), which could induce acquired IFX resistance.
 
OBJECTIVE: To test whether the presence of anti-IFX Ab and residual circulating IFX levels are associated with acquired IFX resistance in RA.
 
METHODS: A multivariate logistic regression was used to analyze the relationship between anti-IFX Ab, residual IFX concentrations, and acquired IFX resistance in a nested cohort within the Swiss RA registry (SCQM-RA).
 
RESULTS: Sixty-four RA patients on longstanding IFX therapy were included; 24 with an acquired therapeutic resistance to IFX and 40 with continuous good response to IFX. The two groups had similar disease characteristics, but patients with acquired IFX resistance required significantly higher dosage of IFX (5.4 mg/kg versus 4.3 mg/kg, p=0.02) and shorter infusion intervals (7.1 versus 8.7 weeks, p=0.01) than long-term good responders. The presence of residual IFX tended to be associated with a decreased risk of acquired therapeutic resistance (OR 0.4 [95% CI: 0.1-1.5]), while the presence of anti-IFX Ab tended to be associated with an increased risk of acquired therapeutic resistance (OR: 1.8 [95% CI: 0.4 - 9.0]). The presence of either high anti-IFX Ab levels or low residual IFX concentrations was strongly associated with acquired therapeutic resistance to IFX (OR 5.9, 95% CI 1.3 - 26.6). However, just 42% of patients with acquired IFX resistance had either low IFX or high anti-IFX Ab levels.
 
CONCLUSION: These results suggest that the assessment of anti-IFX Ab and residual IFX levels is of limited value for individual patients in routine clinical care.
 

Myeloid-Cell Specific Interleukin-1 Receptor Antagonist Deficiency Enhances Th1 and Th17 Responses and the Severity of Arthritis.

Arthritis Rheum 2010
 
OBJECTIVE: The balance between interleukin-1 (IL-1) and its specific inhibitor, the IL-1 receptor antagonist (IL-1Ra), plays a major role in the development of arthritis. The purpose of this study was to investigate the role of IL-1Ra produced specifically by myeloid cells in the control of collagen-induced arthritis (CIA) by using myeloid cell-specific IL-1Ra-deficient mice (IL-1Ra(DeltaM)).
 
METHODS: IL-1Ra(DeltaM) mice were generated by using the loxP/Cre recombinase system. CIA was induced in IL-1Ra(DeltaM) mice and littermate control mice by a single immunization with bovine type II collagen (CII) in Freund's complete adjuvant. Arthritis severity was assessed by clinical and histologic scoring. Draining lymph node (DLN) cell responses were examined ex vivo, and ankle extracts were used in the quantification of cytokines and chemokines.
 
RESULTS: Clinical and histopathologic evaluations revealed an early disease onset and a severe form of CIA in IL-1Ra(DeltaM) mice. This was characterized by increased production of interferon-gamma (IFNgamma) and IL-17 by CII-stimulated DLN cells. We also observed that the CII-specific CD4+ T cell response shifted in vivo, from a dominant Th1 response early in the course of the arthritis to the presence of both Th1 and Th17 cytokines later in the disease course. Interestingly, IL-1Ra levels were higher in the arthritic joints of IL-1Ra(DeltaM) mice as compared with the controls, indicating that nonmyeloid cells strongly contribute to the local production of IL-1Ra. However, this enhanced IL-1Ra production was not sufficient to limit joint inflammation and tissue damage.
 
CONCLUSION: Our results suggest that myeloid cell-derived IL-1Ra plays a critical role in the control of the development and the severity of CIA by modulating Th1 and Th17 responses in lymphoid organs.
 

IL-1 pathways in inflammation and human diseases.

Nat Rev Rheumatology 2010
 
Interleukin (IL)-1 was first cloned in the 1980s, and rapidly emerged as a key player in the regulation of inflammatory processes. The term IL-1 refers to two cytokines, IL-1alpha and IL-1beta, which are encoded by two separate genes. The effects of IL-1 are tightly controlled by several naturally occurring inhibitors, such as IL-1 receptor antagonist (IL-1Ra), IL-1 receptor type II (IL-1RII), and other soluble receptors. Numerous IL-1 inhibitors have been developed and tested primarily in rheumatoid arthritis, with only modest effects. By contrast, the use of IL-1 antagonists has been uniformly associated with beneficial effects in patients with hereditary autoinflammatory conditions associated with excessive IL-1 signaling, such as cryopyrinopathies and IL-1Ra deficiency. Successful treatment with IL-1 blockers has also been reported in other hereditary autoinflammatory diseases, as well as in nonhereditary inflammatory diseases, such as Schnizler syndrome, systemic-onset juvenile idiopathic arthritis and adult Still disease. The role of microcrystals in the regulation of IL-1beta processing and release has provided the rationale for the use of IL-1 inhibitors in crystal-induced arthritis. Finally, preliminary results indicating that IL-1 targeting is efficacious in type 2 diabetes and smoldering myeloma have further broadened the spectrum of IL-1-driven diseases.