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Annals of the rheumatic diseases [journal]
- B-cell depletion attenuates serological biomarkers of fibrosis and myofibroblast activation in IgG4-related disease. [JOURNAL ARTICLE]
- Ann Rheum Dis 2014 Aug 20.
Fibrosis is a predominant feature of IgG4-related disease (IgG4-RD). B-cell depletion induces a prompt clinical and immunological response in patients with IgG4-RD, but the effects of this intervention on fibrosis in IgG4-RD are unknown. We used the enhanced liver fibrosis (ELF) score to address the impact of rituximab on fibroblast activation. The ELF score is an algorithm based on serum concentrations of procollagen-III aminoterminal propeptide, tissue inhibitor of matrix metalloproteinase-1 and hyaluronic acid.Ten patients with active, untreated IgG4-RD were enrolled. ELF scores were measured and correlated with the IgG4-RD Responder Index, serum IgG4, circulating plasmablasts and imaging studies. Through immunohistochemical stains for CD3, CD20, IgG4 and α-smooth muscle actin, we assessed the extent of the lymphoplasmacytic infiltration and the degree of fibroblast activation in one patient with tissue biopsies before and after rituximab.The ELF score was increased in patients with IgG4-RD compared with healthy controls (8.3±1.4 vs 6.2±0.9; p=0.002) and correlated with the number of organs involved (R(2)=0.41; p=0.04). Rituximab induced significant reductions in the ELF score, the number of circulating plasmablasts and the IgG4-RD Responder Index (p<0.05 for all three parameters). Rituximab reduced both the lymphoplasmacytic infiltrate and myofibroblast activation. IgG4-RD relapse coincided with recurrent increases in the ELF score, indicating reactivation of collagen deposition.The ELF score may be a clinically useful indicator of active fibrosis and the extent of disease in IgG4-RD. B-cell depletion has the potential to halt continued collagen deposition by attenuating the secretory phenotype of myofibroblasts in IgG4-RD lesions.
- How much does Disease Activity Score in 28 joints ESR and CRP calculations underestimate disease activity compared with the Simplified Disease Activity Index? [JOURNAL ARTICLE]
- Ann Rheum Dis 2014 Aug 20.
Disease Activity Score in 28 joints calculated with C-reactive protein (DAS28-CRP) is used instead of erythrocyte sedimentation rate (DAS28-ESR) to assess rheumatoid arthritis disease activity; however, values for remission and low disease activity (LDA) for DAS28-CRP have not been validated. American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) guidelines suggest remission should be calculated by Simplified Disease Activity Index (SDAI) rather than DAS28-ESR. We examined values of remission and LDA of DAS28-CRP that correspond to the respective cut-off points for DAS28-ESR and SDAI from five clinical trials.DAS28-CRP cut-offs that best correspond to DAS28-ESR remission <2.6 and LDA ≤3.2 were obtained by cumulative distribution plots, receiver operating curves and maximum concordance and averaged for each approach, treatment group and study. Level of agreement between DAS28-CRP and DAS28-ESR remission and LDA cut-offs was compared against each other and versus SDAI remission ≤3.3 and LDA ≤11.Percentage of patients who achieved remission and LDA by DAS28-ESR cut-offs was greater for DAS28-CRP versus DAS28-ESR regardless of patient population or treatment group. Discordance between CRP and ESR cut-offs ranged from 4%-26% and 8%-23% for remission and LDA, respectively, and 19%-40% and 6%-11% for DAS28-CRP versus SDAI, respectively. Estimated (range) remission and LDA thresholds were 2.4 (2.2-2.6) and 2.9 (2.6-3.3), 1.9 (1.6-2.2) and 3.1 (3.1-3.3) and 2.2 (1.1-2.9) and 3.6 (3.4-4.0) for DAS28-CRP versus DAS28-ESR, DAS28-CRP versus SDAI and DAS28-ESR versus SDAI, respectively.DAS28-CRP underestimates disease activity when using cut-off points validated for DAS28-ESR; therefore, DAS28-ESR cut-off values should not be applied to DAS28-CRP. Although DAS28-CRP and DAS28-ESR cut-offs for LDA ≤3.2 correspond to SDAI LDA, neither corresponds well to SDAI remission.
- Comprehensive disease control (CDC): what does achieving CDC mean for patients with rheumatoid arthritis? [JOURNAL ARTICLE]
- Ann Rheum Dis 2014 Aug 19.
This study assessed the impact of simultaneous achievement of clinical, functional and structural efficacy, herein referred to as comprehensive disease control (CDC), on short-term and long-term work-related outcomes, health-related quality of life (HRQoL), pain and fatigue.Data were pooled from three randomised trials of adalimumab plus methotrexate for treatment of early-stage or late-stage rheumatoid arthritis (RA). CDC was defined as 28-joint Disease Activity Score using C reactive protein <2.6, Health Assessment Questionnaire <0.5 and change from baseline in modified Total Sharp Score ≤0.5. Changes in scores at weeks 26 and 52 for work-related outcomes, Short Form 36 (SF-36) physical (PCS) and mental component scores (MCS), a Visual Analogue Scale measuring pain (VAS-Pain) and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) were compared between patient groups defined by achievement of CDC at week 26 using linear regression with adjustment for baseline scores.Patients with RA who achieved CDC at week 26 (n=200) had significantly greater improvements in VAS-Pain (46.9 vs 26.9; p<0.0001), FACIT-F (13.3 vs 7.5; p<0.0001), SF-36 PCS (19.7 vs 8.9; p<0.0001) and SF-36 MCS (8.1 vs 5.0; p=0.0004) than those who did not (n=1267). Results were consistent at week 52 and among methotrexate-naive patients with early RA, methotrexate-experienced patients with late-stage RA and patients with inadequate response to methotrexate.Patients with RA who achieved CDC at week 26 had improved short-term and long-term HRQoL, pain, fatigue and work-related outcomes compared with patients who do not. These results demonstrate that the joint achievement of all CDC components provides meaningful benefits to patients.DE019: NCT00195702, PREMIER: NCT00195702, OPTIMA: NCT00195702.
- NLRP3 and ASC suppress lupus-like autoimmunity by driving the immunosuppressive effects of TGF-β receptor signalling. [JOURNAL ARTICLE]
- Ann Rheum Dis 2014 Aug 18.
The NLRP3/ASC inflammasome drives host defence and autoinflammatory disorders by activating caspase-1 to trigger the secretion of mature interleukin (IL)-1β/IL-18, but its potential role in autoimmunity is speculative.We generated and phenotyped Nlrp3-deficient, Asc-deficient, Il-1r-deficient and Il-18-deficient C57BL/6-lpr/lpr mice, the latter being a mild model of spontaneous lupus-like autoimmunity.While lack of IL-1R or IL-18 did not affect the C57BL/6-lpr/lpr phenotype, lack of NLRP3 or ASC triggered massive lymphoproliferation, lung T cell infiltrates and severe proliferative lupus nephritis within 6 months, which were all absent in age-matched C57BL/6-lpr/lpr controls. Lack of NLRP3 or ASC increased dendritic cell and macrophage activation, the expression of numerous proinflammatory mediators, lymphocyte necrosis and the expansion of most T cell and B cell subsets. In contrast, plasma cells and autoantibody production were hardly affected. This unexpected immunosuppressive effect of NLRP3 and ASC may relate to their known role in SMAD2/3 phosphorylation during tumour growth factor (TGF)-β receptor signalling, for example, Nlrp3-deficiency and Asc-deficiency significantly suppressed the expression of numerous TGF-β target genes in C57BL/6-lpr/lpr mice and partially recapitulated the known autoimmune phenotype of Tgf-β1-deficient mice.These data identify a novel non-canonical immunoregulatory function of NLRP3 and ASC in autoimmunity.
- A homeostatic function of CXCR2 signalling in articular cartilage. [JOURNAL ARTICLE]
- Ann Rheum Dis 2014 Aug 18.
ELR+ CXC chemokines are heparin-binding cytokines signalling through the CXCR1 and CXCR2 receptors. ELR+ CXC chemokines have been associated with inflammatory arthritis due to their capacity to attract inflammatory cells. Here, we describe an unsuspected physiological function of these molecules in articular cartilage homeostasis.Chemokine receptors and ligands were detected by immunohistochemistry, western blotting and RT-PCR. Osteoarthritis was induced in wild-type and CXCR2(-/-) mice by destabilisation of the medial meniscus (DMM). CXCR1/2 signalling was inhibited in vitro using blocking antibodies or siRNA. Chondrocyte phenotype was analysed using Alcian blue staining, RT-PCR and western blotting. AKT phosphorylation and SOX9 expression were upregulated using constitutively active AKT or SOX9 plasmids. Apoptosis was detected by terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) assay.CXCL6 was expressed in healthy cartilage and was retained through binding to heparan sulfate proteoglycans. CXCR2(-/-) mice developed more severe osteoarthritis than wild types following DMM, with increased chondrocyte apoptosis. Disruption of CXCR1/2 in human and CXCR2 signalling in mouse chondrocytes led to a decrease in extracellular matrix production, reduced expression of chondrocyte differentiation markers and increased chondrocyte apoptosis. CXCR2-dependent chondrocyte homeostasis was mediated by AKT signalling since forced expression of constitutively active AKT rescued the expression of phenotypic markers and the apoptosis induced by CXCR2 blockade.Our study demonstrates an important physiological role for CXCR1/2 signalling in maintaining cartilage homeostasis and suggests that the loss of ELR+ CXC chemokines during cartilage breakdown in osteoarthritis contributes to the characteristic loss of chondrocyte phenotypic stability.
- Disease-modifying effects of TD-198946 on progressed osteoarthritis in a mouse model. [LETTER]
- Ann Rheum Dis 2014 Aug 18.
- FHL2 regulates the resolution of tissue damage in chronic inflammatory arthritis. [JOURNAL ARTICLE]
- Ann Rheum Dis 2014 Aug 14.
We analysed the role of the adaptor molecule four-and-a-half Lin11, Isl-1 & Mec-3 (LIM) domain protein 2 (FHL2) in the activation of fibroblast-like synoviocytes in human rheumatoid arthritis (RA) and tumour necrosis factor α (TNFα)-dependent animal models of the disease.Synovial tissues of patients with RA and osteoarthritis (OA) as well as hind paw sections from arthritic human TNFα transgenic (hTNFtg) mice and synovial fibroblasts from these were analysed. The effects of cytokines on the expression of FHL2 and disease-relevant matrixmetalloproteases (MMPs) were determined. Analyses of human tissue specimens from patients treated with anti-TNFα as well as anti-TNFα treatment of hTNFtg mice were performed to substantiate the TNFα effects on FHL2 levels. FHL2(-/-) mice and hTNFtg mice (with constitutive or inducible transgene expression) were crossbred to generate TNFα overexpressing FHL2-deficient animals. Signalling pathways were analysed in cells from these mice and in human cells after knock down of FHL2 by western blot.FHL2 levels were higher in RA than in OA and in hTNFtg than in wild-type mice. Surprisingly, while transforming growth factor (TGF)β-induced FHL2 expression, TNFα suppressed FHL2. In vivo, anti-TNFα treatment led to higher FHL2 levels both in RA patients and hTNFtg mice. The loss of FHL2 increased joint destruction in hTNFtg mice, which was accompanied by elevated MMP-13. In vitro, TNFα-mediated MMP-13 was significantly higher in FHL2(-/-) cells and after knock down of FHL2, which was caused by prolonged p38 MAPK activation.These data suggest that FHL2 serves as a protective factor and that, rather than promoting the pathology, the upregulation of FHL2 in RA occurs in frame of a regenerative attempt.
- Insights into the poor prognosis of allopurinol-induced severe cutaneous adverse reactions: the impact of renal insufficiency, high plasma levels of oxypurinol and granulysin. [JOURNAL ARTICLE]
- Ann Rheum Dis 2014 Aug 12.
Allopurinol, an antihyperuricaemic agent, is one of the common causes of life-threatening severe cutaneous adverse reactions (SCAR), including drug rash with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS) and toxic epidermal necrosis (TEN). The prognostic factors for allopurinol-related SCAR remain unclear. This study aimed to investigate the relationship of dosing, renal function, plasma levels of oxypurinol and granulysin (a cytotoxic protein of SJS/TEN), the disease severity and mortality in allopurinol-SCAR.We prospectively enrolled 48 patients with allopurinol-SCAR (26 SJS/TEN and 22 DRESS) and 138 allopurinol-tolerant controls from 2007 to 2012. The human leucocyte antigen (HLA)-B*58:01 status, plasma concentrations of oxypurinol and granulysin were determined.In this cohort, HLA-B*58:01 was strongly associated with allopurinol-SCAR (p<0.001, OR (95% CI) 109 (25 to 481)); however, the initial/maintenance dosages showed no relationship with the disease. Poor renal function was significantly associated with the delayed clearance of plasma oxypurinol, and increased the risk of allopurinol-SCAR (p<0.001, OR (95% CI) 8.0 (3.9 to 17)). Sustained high levels of oxypurinol after allopurinol withdrawal correlated with the poor prognosis of allopurinol-SCAR. In particular, the increased plasma levels of oxypurinol and granulysin linked to the high mortality of allopurinol-SJS/TEN (p<0.01), and strongly associated with prolonged cutaneous reactions in allopurinol-DRESS (p<0.05).Impaired renal function and increased plasma levels of oxypurinol and granulysin correlated with the poor prognosis of allopurinol-SCAR. Allopurinol prescription is suggested to be avoided in subjects with renal insufficiency and HLA-B*58:01 carriers. An early intervention to increase the clearance of plasma oxypurinol may improve the prognosis of allopurinol-SCAR.