Inhibition of plasma kallikrein–kinin system to alleviate renal injury and arthritis symptoms in rats with adjuvant-induced arthritis

Background: Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease. Impairment of kidney functions in RA was observed. However, the mechanism of kidney injury of RA has not been clear. Plasma kallikrein–kinin system (KKS) was involved in inflammatory processes in kidney disease.

Aim: This study aimed to explore the role of plasma KKS in immune reactions and kidney injury of RA.

Results: The paw of AA rats appeared to be swelling and redness, the arthritis index was significantly increased on the 18, 21 and 24 d after injection and secondary inflammation in multi-sites was observed. Kidney dysfunction accompanied with inflammatory cell infiltration, tubular epithelial cell mitochondrial swelling and vacuolar degeneration, renal glomerular foot process fusions and glomerular basement membrane thickening were observed in AA rats. The expressions of neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (Kim-1) in kidney of AA rats were increased. In addition, expressions of BK, PK, B1R and B2R in the renal tissue of AA rats were up-regulated. Pro-inflammatory cytokines IL-2, IFN-γ and TNF-α were increased and anti-inflammatory cytokines IL-4 and IL-10 were low in kidney. Plasma kallikrein (PK) inhibitor PKSI-527 attenuated arthritis signs and renal damage, and inhibited BK, PK, B1R and B2R expressions. The protein expressions of P38, p-P38 and p-JNK and IFN-γ and TNF-α were inhibited by PKSI-527.

Conclusions: These findings demonstrate that plasma KKS activation contributed to the renal injury of AA rats through MAPK signaling pathway. Plasma KKS might be a potential target for RA therapy.     

TCR-CD3ζ gene polymorphisms and expression profile in rheumatoid arthritis

Objectives: Recent evidence has demonstrated that CD3ζ (also called CD247) play a vital role in multiple autoimmune diseases. In this study, we explored the association between CD247 gene single-nucleotide polymorphisms (SNPs) and rheumatoid arthritis (RA) in a Chinese Han population. We also evaluated the CD3ζ expression profile in peripheral blood mononuclear cells (PBMCs) from patients with RA and health controls. Methods: Three CD247 polymorphisms (rs704853, rs1214611 and rs858554) were studied in 612 patients with RA and 848 controls in a Chinese population. Genotyping was performed using the Fluidigm 192.24 Dynamic Array? Integrated Fluidic Circuit (IFC). For gene expression study, CD3ζ mRNA levels of 36 patients with RA and 39 healthy individuals were assessed by real-time polymerase chain reaction (RT-PCR). Data were analyzed by SPSS 11.5 software. Results: A significant association between rs858554 polymorphism and RA was found under all genetic models (all p?rs858554 were significant associated with ACCP⁺ and RF⁺ phenotype as compare to health controls (all p?rs704853, rs1214611 and RA susceptibility and autoantibody profiles (all p?>?0.05). The gene expression assays showed that CD3ζ mRNA levels were downregulated in PBMCs of patients with RA when compared to healthy controls. Conclusions: Our results, the first reported for distinct Chinese populations, support a role of the CD247 gene in the susceptibility to RA. Further studies with more sample size are necessary to clarify the exact role of CD247 gene in the pathogenesis of RA.     

Relationship between serum levels of TGF-β1 and clinical parameters in patients with rheumatoid arthritis and Sjögren's syndrome secondary to rheumatoid arthritis

TGF-β1 is a pleiotropic cytokine, which prevents inappropriate autoimmune responses and balances the requirements of proper immune cell levels during pathologic states that trigger the immune response. We assessed the serum levels of TGF-β1 and determined the relationship between TGF-β1 and clinical parameters in patients with rheumatoid arthritis (RA) and Sjögren's syndrome (SS) secondary to RA (SS + RA). Comparison of the serum levels of TGF-β1 in patients with RA, SS + RA and NHD differed significantly (51.7 ± 12.4 ng/ml (RA); 33.0 ± 3.1 ng/ml (SS + RA) and versus 31.6 ± 2.0 ng/ml (NHD)). We further found correlations between TGF-β1 levels and radiologically defined joint damage determined by the Steinbrocker scoring system, symptoms and signs of SS. We conclude that serum levels of TGF-β1 may reflect ongoing autoimmune inflammation and correlate with joint damage in RA.     

Immunosenescence and rheumatoid arthritis: does telomere shortening predict impending disease?

The pathogenesis of RA, a disabling autoimmune disease, is incompletely understood. Early in the development of RA there appears to be loss of immune homeostasis and regulation, and premature immunosenescence. While identification of risk factors and understanding of the phases of RA pathogenesis are advancing, means of accurately predicting an individual's risk of developing RA are currently lacking. Telomere length has been proposed as a potential new biomarker for the development of RA that could enhance prediction of this serious disease. Studies examining telomere length in relation to RA have found that telomere erosion appears to proceed more rapidly in subjects with RA than in healthy controls, and that telomere lengths are shorter in those with the RA-risk HLA-shared epitope genes. These studies have been small, however, with retrospective or cross-sectional designs. The potential role of telomere shortening as an independent biomarker for future RA risk, perhaps strongly genetically determined by HLA-SE genes, after controlling for known risk factors such as smoking, body mass index and immunosuppressant medication use, as well as systemic inflammation, is an unanswered question.     

Treatment of psoriatic arthritis with traditional DMARD’s and novel therapies: approaches and recommendations

Introduction: Recent advances in the therapeutics of psoriatic arthritis (PsA) have provided more options to clinicians managing PsA. The purpose of this review is to update the reader on treatment options for PsA using conventional synthetic disease modifying agents (csDMARDs) and novel therapies including tumour necrosis factor alpha inhibitors, interleukin 12/23 inhibitor (ustekinumab), the interleukin 17 antagonists including secukinumab, brodalumab, ixekizumab, and the phosphodiesterase-4 inhibitor, apremilast.

Areas covered: We reviewed published articles on the treatment of PsA. Our main sources of data included treatment recommendations, registry studies, systematic literature reviews, major randomised controlled trials for more recently approved drugs, and abstracts from the American College of Rheumatology and EULAR meetings.

Expert commentary: An overview of the evidence for the use of various pharmacotherapeutic agents for treatment of this heterogeneous disease was compiled. Treatment options for the various domains of PsA are also discussed.     

Mig, GROα and RANTES messenger RNA expression in lining layer, infiltrates and different leucocyte populations of synovial tissue from patients with rheumatoid arthritis, psoriatic arthritis and osteoarthritis

To investigate lymphocyte and monocyte recruitment-specific chemokine expression in synovial tissues from patients with rheumatoid arthritis (RA), psoriatic arthritis (PA) and osteoarthritis (OA), synovial membranes and cytocentrifuge preparations of 7 RA, 8 PA and 10 OA patients were examined by in situ hybridisation with antisense probes of Mig, GROα and RANTES and by immunohistochemistry. Patients’ local disease activity (swelling and tenderness) in order to was graded and histological evaluation was performed compare these data with their chemokine expression profiles. Mig and RANTES hybridisation signals were detected in the synovial lining layer and in cellular infiltrates, whereas GROα expression was localised exclusively in the lining layer of PA and RA. Cytological analysis revealed Mig and GROα mRNA mainly in monocytic cells expressing KI-M6, while RANTES mRNA was demonstrated predominantly in lymphocytic cells expressing CD3. In OA synovial membranes, significantly fewer hybridisation signals were present than in RA and PA synovial membranes. Patients with PA and RA had mild to severe local disease activity, whereas OA patients showed only mild disease activity. Histologically, PA and RA inflammatory scores ranged from 1 to 5, while OA synovium was consistently graded 1. Therefore, we conclude that the differential expression of Mig, GROα and RANTES in resident and in inflammatory cells has an important role in regulating leucocyte traffic in inflammatory arthropathies. The diverse leucocyte specificity of Mig, GROα and RANTES may thus regulate the recruitment of different leucocyte populations, as detected in PA and RA. Therefore, the pattern of cellular infiltration in human synovitis and the corresponding clinical signs of inflammation basically reflect the localisation and expression intensity of chemokines, which may be an important target for future disease modulation. Received: 19 August 1999 / Accepted: 17 January 2000     

IL-33 enhances macrophage release of IL-1β and promotes pain and inflammation in gouty arthritis

Inflammation Research - To investigate the role of IL-33 in gouty arthritis. 174 Balb/c (wild-type) and 54 ST2?/? mice were used in this study. In vitro experiments were conducted in...     

Rheumatoid arthritis: what is refractory disease and how to manage it?

Despite the enthusiastic progresses in the field of rheumatoid arthritis pharmacotherapy the presence of prognostic factors associated with an unfavorable outcome and the inappropriate and/or delayed initiation of DMARDs can diminish the likelihood of achieving remission and increase the probability of refractoriness to treatment. During the last decade we have experience exciting developments regarding the approval of new treatment options but few patients are reaching sustained remission and refractory patients continue to be a problem. Thus, it is critical to understand how clinicians can decrease the risk of refractoriness by close monitoring disease activity, using well defined and accepted composite measures, and by early and optimized use of DMARDs, including biologics. The goal of this review paper is to offer an evidence based roadmap to prevent and to deal with refractory RA.     

Autoimmune smoke and fire—coexisting rheumatoid arthritis and chronic obstructive pulmonary disease: a cross-sectional analysis

To assess the association between RA and chronic obstructive pulmonary disease (COPD) in a population-based case-control study. A cross-sectional analysis performed utilizing the database of Clalit Health Services, the largest healthcare provider organization in Israel. Patients over the age of 20 years who were diagnosed with RA (‘cases’) and who were treated with any anti-rheumatic drug were compared with a sample of age- and gender-matched enrollees (‘controls’) without regard for the prevalence of COPD. Data on health-related lifestyles and other comorbidities were collected. χ², t tests, and logistic regression models were used to compare the study groups. The study included 9,039 RA cases and 15,070 controls. The proportion of COPD was significantly higher in patients with RA as compared to the control group (8.6 vs. 4.4 %, p < 0.0001, odds ratio (OR) 2.06, 95 % confidence interval (CI) 1.85–2.29). A multivariate logistic regression model demonstrated that RA was significantly associated with COPD, after controlling for confounders, including age, sex, socioeconomic status, smoking, and obesity (adjusted OR 1.98, 95 % CI 1.77–2.21, p < 0.0001). In this large data-based study, RA was found to be associated with COPD.     

Safety of anti-TNFα agents in the treatment of psoriasis and psoriatic arthritis

Context: The efficacy and favorable safety profile of anti-tumor necrosis factor (TNF) agents in the treatment of psoriasis and psoriatic arthritis (PsA) are supported by several randomized controlled studies and meta-analyses. However, some concerns on the long-term safety of these drugs still exist, as these studies generally included small patient numbers and were performed in selected patient populations.

Objective: This review presents and discusses current evidence on the safety of anti-TNFα agents in patients with psoriasis and PsA, with a focus on European registry studies and case reports of particular importance.

Methods: Key studies on the safety of anti-TNFα agents in the treatment of adult patients with psoriasis or PsA were identified by a MEDLINE search (last updated 10 November 2011) based on several interrelated queries, with a focus on European registries. Other studies and case reports were included if deemed relevant. Studies concerning other conditions, such as rheumatoid arthritis (RA), were included as appropriate when data in psoriatic disease were unavailable or insufficient.

Results: Available data on the safety of anti-TNFα agents such as etanercept in psoriasis and PsA appear reassuring, even if some concerns still exist. Most notably, data suggest a higher incidence of infection and lymphoma amongst patients treated with the anti-TNFα monoclonal antibodies infliximab and adalimumab compared with etanercept.

Conclusion: The overall safety profile of monoclonal antibodies in patients with psoriasis, PsA and RA seems less favorable than that of etanercept, particularly in terms of risk of infection and hepatotoxicity.     

TNF inhibitors in rheumatoid arthritis and spondyloarthritis: Are they the same?

The advent of anti-tumour necrosis factor (TNF) drugs for rheumatoid arthritis (RA) or spondyloarthritis (SpA) has revolutionised the approach to patients with active disease who do not respond to conventional therapy. Although there are differences in their structure, morphology, pharmacokinetic properties and activity, all anti-TNF drugs ultimately neutralise the TNFα pathway of inflammation. However, despite their similar clinical efficacy, there are disagreements concerning drug survival and safety, with systematic reviews and meta-analyses confirming one result or the other. The fact that 20–30% of patients fail to respond to TNFα inhibitors indicates the possibility of primary resistance or the development of an immune response to the drugs themselves, which may act as antigens. The overall benefit of switching to another anti-TNF drug or a biological agent with a different mechanism of action, may be a valuable option in individual patients. There are few data concerning the use of anti-TNF drugs in patients with SpA but it seems that there are fewer adverse advents and higher drug survival in comparison with patients with RA.     

Therapeutic role of a vaccine targeting RANKL and TNF-α on collagen-induced arthritis

Targeting tumor necrosis factor-α (TNF-α) and activator of NF-κB ligand (RANKL) has been proved highly successful in rheumatoid arthritis (RA) models and patients. This raises a possibility whether a single agent simultaneously targeting TNF-α and RANKL provides a potential therapeutic opportunity. This study aimed to design a dual functional vaccine and evaluate its therapeutic effects in RA mice model. Standard molecular biological techniques were used to generate human RANKL-TNF-like core fusion protein (RTFP-2) vaccine. High titers of antibodies against human TNF-α and RANKL were elicited and the RTFP-2 antiserum decreased TNF-α mediated apoptosis of L929 cells to 41% compared with 90% in positive controls. In addition, the antiserum completely abrogated osteoclastogenesis in?vitro. Immunization with RTFP-2 also reduced the mortality of TNF-α induced cachexia from 56% to 28%. The RANKL-mediated hypercalcemic effects were significantly attenuated in RTFP-2 vaccinated mice. Furthermore, RTFP-2 vaccine significantly mitigated the incidence and severity of CIA via inhibition of inflammation and bone resorption. Our results showed the RTFP-2 vaccine of dual targets ameliorated the symptoms of CIA mice, suggesting the potential possibility to treat inflammatory bone diseases such as RA.     

Progress in understanding and utilizing TNF-α inhibition for the treatment of psoriatic arthritis

The improved recognition of pathogenetic molecular mechanisms has led to the use of drugs targeting cytokines in different inflammatory arthropathies as well psoriatic arthritis (PsA). In particular, the progress in knowledge on tumor necrosis factor (TNF)-α in the pathogenesis of PsA has changed the therapeutic approach by use of direct and receptor cytokine antagonists. Currently, infliximab (IFX), adalimumab, etanercept, golimumab and certolizumab pegol represent the five anti-TNF-α available for the treatment of PsA. This review describes evidence on treatment aimed at neutralizing TNF-α in PsA patients, from the first study in 2000 until today, mainly derived from randomized clinical trials. In comparison with traditional therapies, anti-TNF-α agents have shown to have more efficacy both in treating clinical aspects, including enthesitis, dactylitis, joint pain and swelling, axial involvement, nail and skin lesions, and in reducing radiographic progression. Moreover, anti-TNF-α agents have been demonstrated to be reasonably safe in PsA, as confirmed by data derived by different registries.     

Inflammation and dementia: Using rheumatoid arthritis as a model to develop treatments?

Dementia is a major international public health problem which looks set to grow as the ageing population increases. Despite large amounts of investment there has been relatively little progress in developing new therapies to combat this. There is a growing body of evidence that both local and systemic inflammation are important in dementia; with cerebral inflammation occurring secondarily to beta-amyloid plaques, raised levels of serum inflammatory molecules and cytokines being present in Alzheimer's disease patients and systemic inflammation being associated with cerebral microvasculature disease in vascular dementia. Observational studies had suggested that non-steroidal anti-inflammatory drugs may reduce the risk of dementia, but subsequent interventional studies have been disappointing. More recently some observational studies have suggested a protective effect from conventional synthetic disease modifying anti-rheumatic drugs (csDMARDS) and tumour necrosis factor inhibiting (TNFi) biological therapies. Treatments for inflammatory rheumatic diseases have previously been repurposed and used successfully in other diseases, such as TNFi for inflammatory bowel disease. There are also studies looking at the use of csDMARDs such as methotrexate to improve outcomes after cardiovascular events. Ongoing interventional trials are currently looking at whether therapies designed to treat inflammatory and autoimmune diseases have the potential to be used to treat dementia.