Treatment Of Inflammatory Arthritis Research Articles

The role of human umbilical cord tissue-derived mesenchymal stromal cells (UCX®) in the treatment of inflammatory arthritis

BackgroundECBio has developed proprietary technology to consistently isolate, expand and cryopreserve a well-characterized population of stromal cells from human umbilical cord tissue (UCX® cells). The technology has recently been optimized in order to become compliant with Advanced Medicine Therapeutic Products. In this work we report the immunosuppressive capacity of UCX® cells for treating induced autoimmune inflammatory arthritis.MethodsUCX® cells were isolated using a proprietary method (PCT/IB2008/054067) that yields a well-defined number of cells using a precise proportion between tissue digestion enzyme activity units, tissue mass, digestion solution volume and void volume. The procedure includes three recovery steps to avoid non-conformities related to cell recovery. UCX® surface markers were characterized by flow cytometry and UCX® capacity to expand in vitro and to differentiate into adipocyte, chondrocyte and osteoblast-like cells was evaluated. Mixed Lymphocyte Reaction (MLR) assays were performed to evaluate the effect of UCX® cells on T-cell activation and Treg conversion assays were also performed in vitro. Furthermore, UCX® cells were administered in vivo in both a rat acute carrageenan-induced arthritis model and rat chronic adjuvant induced arthritis model for arthritic inflammation. UCX® anti-inflammatory activity was then monitored over time.ResultsUCX® cells stained positive for CD44, CD73, CD90 and CD105; and negative for CD14, CD19 CD31, CD34, CD45 and HLA-DR; and were capable to differentiate into adipocyte, chondrocyte and osteoblast-like cells. UCX® cells were shown to repress T-cell activation and promote the expansion of Tregs better than bone marrow mesenchymal stem cells (BM-MSCs). Accordingly, xenogeneic UCX® administration in an acute carrageenan-induced arthritis model showed that human UCX® cells can reduce paw edema in vivo more efficiently than BM-MSCs. Finally, in a chronic adjuvant induced arthritis model, animals treated with intra-articular (i.a.) and intra-peritoneal (i.p.) infusions of UCX® cells showed faster remission of local and systemic arthritic manifestations.ConclusionThe results suggest that UCX® cells may be an effective and promising new approach for treating both local and systemic manifestations of inflammatory arthritis.

Biosimilars in rheumatology: a view from Latin America

The treatment of inflammatory arthritis has been revolutionized in the past decade by the introduction of targeted biologic therapies. They are genetically engineered monoclonal or fusion proteins that could interfere with the biological activity of cytokines or inhibit T cell co-stimulation or could deplete B cell [1]. The patent for some of these agents that are currently used will soon expire, and a growing interest of the pharmaceutical industry is now in the development of “biosimilar” or copies of biological medical products. A copy which could claim to be a biosimilar to a reference or innovator, unlike a chemical generic, would not be identical depending on the chemical and biological characteristics of the molecule directly related to the manufacturing process which could not be precisely duplicated. Consequently, biosimilars would require an approach different from both originators and generics. Although biosimilars aim to mimic the innovator product in molecular size and complexity, during the manufacturing process, minor changes in production can have serious implications in terms of safety and efficacy [2]. Regulatory policy for biosimilars is being developed in several countries and in general following guidelines that were set up by the World Health Organization or the European Medical Agency. Besides general guidelines on quality, clinical issues are being defined and are continually being revised. They include indications of differences in the amino acid chain and glycosylation patterns on the biochemical quality side and the kind of clinical trial that would be require from the clinical side trying to measure efficacy and at the same time the possibility of extrapolation of indication. If a non-inferiority trial versus an equivalence trial would be required, it could affect not only the budget to develop the biosimilar but also the time of the launching as it will need many more patients. Also, the need for an extensive follow-up (for how long) to assure to the medical community the safety of the new drug and the possible immunogenicity is being debated. To perform the pharmacodynamic and pharmacokinetic assays previous or at the same time of the clinical trial is still not absolutely clear [3]. One of the main benefits of biosimilars should be a reduced cost when compared with the innovator. However, it is a general understanding that it will not be in the same order of magnitude as is in the cases of generic medicines due to elevated manufacturing costs and the need for extensive clinical and non-clinical studies. A growing interest in this area should be expected in the rheumatology community since the potential reduction in costs will lead to increasing number of patients having access to these drugs [4–7]. In Latin America, the regulation of biosimilars varies considerably between different countries, and in some the so-called biosimilars were approved before adequate clinical testing was performed. Others are in the process of creating their regulations. Some have decided to open the discussion with the academic community like in Colombia that after approving one biosimilar without clear guidelines is now creating and revising their own (Table 1). Argentina has produced two different norms 7075 and 7729 from 2011 where it clearly states the requirement for well-defined non-clinical and clinical data to have the biological products approved and the 7729 where it states the requirement for biosimilars (http://www.anmat.gov.ar/boletin_ anmat/noviembre_2011/Dispo_7729-11.pdf). E. Mysler Organizacion Medica de Investigacion, Buenos Aires, Argentina

Involvement of 15‐lipoxygenase in the inflammatory arthritis

15-Lipoxygenase (15-LOX) is involved in many pathological processes. The aim of this study is to examine the role of 15-LOX in the matrix metalloproteinase (MMP) expression and inflammatory arthritis. It was found that treatment of 15-LOX downstream product of 15-(S)-HETE (15-S-hydroxyeicosatetraenoic acid) increased the mRNA and protein levels of MMP-2 in rheumatoid arthritis synovial fibroblast (RASF) derived from rheumatoid arthritis patients. The enhancement effect of 15-(S)-HETE was antagonized by the addition of LY294002 (PI3K inhibitor) and PDTC (NF-κB inhibitor). Treatment of 15-(S)-HETE increased the phosphorylation of AKT, nuclear translocation of p65 and the breakdown of IκBα. TNF-α and IL-1β are the key cytokines involved in arthritis and also increase the activity of MMP-2 in RASF, which was antagonized by pretreatment with 15-LOX inhibitor PD146176 or knockdown of 15-LOX. It was also found that these two cytokines increased the expression of 15-LOX in RASF. Treatment of glucocorticoid but not NSAIDs inhibited 15-(S)-HETE-induced expression of MMP-2. In comparison with wild-type mice, adjuvant-induced arthritis and MMP-2 expression in synovial membrane were markedly inhibited in 15-LOX knockout (KO) mice. These results indicate that 15-LOX plays an important role in the disease progression of arthritis and may be involved in the inflammatory action induced by TNF-α and IL-1β. 15-LOX is thus a good target for developing drugs in the treatment of inflammatory arthritis.

Advances in the treatment of inflammatory arthritis

The inflammatory arthritides are a diverse group of conditions characterised by joint inflammation which can lead to pain, deformity and disability. Of these diseases, rheumatoid arthritis (RA) and spondyloarthritis are two of the most common. While the clinical and demographic features of these diseases differ, the central role of inflammation in their pathogenesis has allowed the development of highly effective treatment strategies with wide applicability. These strategies include the use of biological agents which target the cytokine tumour necrosis factor (TNF), a key mediator of inflammation. With the advent of effective agents, therapy has become more aggressive, reducing disease activity and allowing, at least in RA, remission in many patients. While the array of available effective treatments is extensive, the use of objective measures of disease activity can guide treatment decisions (treat to target) and lead to improved outcomes.

Escorted for Efficacy

Nanoparticles targeting macrophage folate receptors can increase the efficacy of methotrexate therapy for arthritis.

Safety of non-steroidal anti-inflammatory drugs, including aspirin and paracetamol (acetaminophen) in people receiving methotrexate for inflammatory arthritis (rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, other spondyloarthritis)

Methotrexate is routinely used in the treatment of inflammatory arthritis. There have been concerns regarding the safety of using concurrent non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin, or paracetamol (acetaminophen), or both, in these people. To systematically appraise and summarise the scientific evidence on the safety of using NSAIDs, including aspirin, or paracetamol, or both, with methotrexate in inflammatory arthritis; and to identify gaps in the current evidence, assess the implications of those gaps and to make recommendations for future research to address these deficiencies. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, second quarter 2010); MEDLINE (from 1950); EMBASE (from 1980); the Cochrane Database of Systematic Reviews (CDSR) and the Database of Abstracts of Reviews of Effects (DARE). We also handsearched the conference proceedings for the American College of Rheumatology (ACR) and European League against Rheumatism (EULAR) (2008 to 2009) and checked the websites of regulatory agencies for reported adverse events, labels and warnings. Randomised controlled trials and non-randomised studies comparing the safety of methotrexate alone to methotrexate with concurrent NSAIDs, including aspirin, or paracetamol, or both, in people with inflammatory arthritis. Two authors independently assessed the search results, extracted data and assessed the risk of bias of the included studies. Seventeen publications out of 8681 identified studies were included in the review, all of which included people with rheumatoid arthritis using various NSAIDs, including aspirin. There were no identified studies for other forms of inflammatory arthritis.For NSAIDs, 13 studies were included that used concurrent NSAIDs, of which nine studies examined unspecified NSAIDs. The mean number of participants was 150.4 (range 19 to 315), mean duration 2182.9 (range 183 to 5490) days, although the study duration was not always clearly defined, and the studies were mainly of low to moderate quality. Two of these studies reported no evidence for increased risk of methotrexate-induced pulmonary disease; one study assessed the effect of concurrent NSAIDs on renal function and found no adverse effect; one study identified no adverse effect on liver function; three studies demonstrated no increase in methotrexate withdrawal; and one study showed no increase in all adverse events, including major toxic reactions. However, transient thrombocytopenia was demonstrated in one study, specifically when NSAIDs were taken on the same week day as methotrexate. This study was a retrospective review that involved small numbers only and was of moderate quality; these finding have not been replicated since.Four studies looked at specific NSAIDs (etodolac, piroxicam, celecoxib and etoricoxib), with a mean number of participants of 25.8 (range 14 to 50) and mean study duration of 16.8 (range 14 to 23) days. These studies were mainly of moderate quality. The studies were primarily pharmacokinetic studies but also reported adverse events as secondary outcomes. There were no clinically significant adverse effects with concomitant piroxicam or etodolac; and only mild adverse events with celecoxib or etoricoxib, such as nausea and vomiting, and headaches.For aspirin, seven studies provided data on adverse events with the use of aspirin and methotrexate. These studies included a mean number of participants of 100 (range 11 to 232), had a mean duration of 1325 (range 8 to 2928) days and were mainly of low to moderate quality. Two of the studies reported no evidence for increased risk of methotrexate-induced pulmonary disease and two studies showed no increase in all adverse events including major toxic reactions; however, none of these studies specified the dose of aspirin that was used. One study demonstrated that concurrent aspirin adversely affected liver function at a mean dose of 6.84 tablets of aspirin per day, which is a possible daily dose of 2.1 g presuming that 300 mg aspirin tablets were given. A further study described a partially reversible decline in renal function with 2 g daily of aspirin. One study reported no increase in adverse events with 975 g aspirin daily, however the study duration was only one week.For paracetamol, no studies were identified for inclusion. In the management of rheumatoid arthritis, the concurrent use of NSAIDs with methotrexate appears to be safe provided appropriate monitoring is performed. The use of anti-inflammatory doses of aspirin should be avoided.

Mesenchymal stem cells and JIA

Background Mesenchymal stem cells (MSC) are adult stem cells present in bone marrow (BM), fat and in many other tissues. MSC have strong immunosuppressive qualities in vitro. The immunosuppression seems to work both by paracrine action and cell-cell contact. MSC inhibit NKcells, B-cells, dendritic cells, Th1-cells and activate regulatory T-cells. The presence of floating single MSC in human synovial fluid (SF) is a normal phenomenon and the number of MSC in SF is much lower in RA than in osteoarthritis (OA). SF in RA might be impaired in recruiting MSC to the joint and the proliferation potential of MSC in RA patients could be suppressed by the synovitis or be exhausted as suggested by the decreased telomere length. Administration of additional MSC might therefore have great potential in the treatment of inflammatory arthritis as we and others have shown in different experimental arthritis models.

Folate‐targeted nanoparticles show efficacy in the treatment of inflammatory arthritis

To investigate the uptake of a poly(amidoamine) dendrimer (generation 5 [G5]) nanoparticle covalently conjugated to polyvalent folic acid (FA) as the targeting ligand into macrophages, and to investigate the activity of an FA- and methotrexate (MTX)-conjugated dendrimer (G5-FA-MTX) as a therapeutic for the inflammatory disease of arthritis. In vitro studies were performed in macrophage cell lines and in isolated mouse macrophages to check the cellular uptake of fluorescence-tagged G5-FA nanoparticles, using flow cytometry and confocal microscopy. In vivo studies were conducted in a rat model of collagen-induced arthritis to evaluate the therapeutic potential of G5-FA-MTX. Folate-targeted dendrimer bound and internalized in a receptor-specific manner into both folate receptor β-expressing macrophage cell lines and primary mouse macrophages. The conjugate G5-FA-MTX acted as a potent antiinflammatory agent and reduced arthritis-induced parameters of inflammation such as ankle swelling, paw volume, cartilage damage, bone resorption, and body weight decrease. The use of folate-targeted nanoparticles to specifically target MTX into macrophages may provide an effective clinical approach for antiinflammatory therapy in rheumatoid arthritis.

Rheumatoid arthritis: bringing care closer to home

The move to offer more treatment in primary care started before the current round of NHS reforms and is generally well supported With the advent of GP and clinician led commissioning, and the move to shift the care of people with long term conditions out of the hospital setting, the focus on care in the community has never been stronger. Recent publications from organizations such as the King’s Fund (2011) argue for greater integration between primary and secondary care, improved medication management and self management. However, for some conditions the move has been slower and developing good community care requires funding and the parallel de-commissioning of hospital based services, something that patients themselves at times resist. Rheumatoid Arthritis is one example of this. It is a complex disease which is primarily currently treated in secondary care by a consultant led, specialist multi-disciplinary team, which also includes the GP and other primary care professionals as well as, of course, the patient themselves. Major government funding and training has enabled conditions such as asthma, diabetes and cardiovascular assessment and prevention strategies to be successfully delivered in primary care in recent years. Alongside this has been significant improvement in patient education and self management particularly in diabetes. No such funding or training has been allocated to the treatment of inflammatory arthritis (IA) and the majority of GPs lack the experience and skills necessary to safely diagnose or follow up patients with Inflammatory Arthritis. Treatment of IA has changed in a revolutionary way since the introduction of biological therapies over 10 years ago and such drugs can only be prescribed by a consultant rheumatologist, with the result that GPs are often unaware of the advances in treatment regimens for people with Rheumatoid Arthritis. The need for rapid referral for anyone with suspected inflammatory arthritis to a consultant rheumatologist to obtain a diagnosis at the earliest opportunity in order to maximize long term outcomes is paramount but delays persist. Whilst the issue of GP education was flagged in 2009 in the National Audit Office Report into Rheumatoid Arthritis services, it will take time for the Royal Colleges to address changes in the training of health professionals. However, there are aspects of the care of people with RA which are well placed to sit within primary care, such as cardiovascular risk assessment and advice. CV disease is increased in people with RA and similar to the risk in people with Type II Diabetes. The benefit of effective patient education and self management is also something which is well understood by GPs. The National Rheumatoid Arthritis Society has developed a self management programme for Rheumatoid Arthritis that is delivered by allied health professionals in rheumatology and people living with Rheumatoid Arthritis. Results of the pilot are encouraging and indicate positive changes in health-related behavior and an increase in the skills needed to manage the condition which in turn may help reduce the risk of developing cardio vascular disease especially where there are lifestyle issues present. Disease specific programmes such as the RA Self Management Programme could be commissioned and prescribed by GPs and community nurses who are providing support to people living with RA. This will benefit patients and potentially help improve medication adherence and increase health-related behaviours, which may offset some of the risk factors of cardiovascular disease. It may also help patients living with rheumatoid arthritis who are used being managed through secondary care begin to think about making more use of support that is closer to home. BJCN

Advances in rheumatology: new targeted therapeutics

Treatment of inflammatory arthritides - including rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis - has seen much progress in recent years, partially due to increased understanding of the pathogenesis of these diseases at the cellular and molecular levels. These conditions share some common mechanisms. Biologic therapies have provided a clear advance in the treatment of rheumatological conditions. Currently available TNF-targeting biologic agents that are licensed for at east one of the above-named diseases are etanercept, infliximab, adalimumab, golimumab, and certolizumab. Biologic agents with a different mechanism of action have also been approved in rheumatoid arthritis (rituximab, abatacept, and tocilizumab). Although these biologic agents are highly effective, there is a need for improved management strategies. There is also a need for education of family physicians and other healthcare professionals in the identification of early symptoms of inflammatory arthritides and the importance of early referral to rheumatologists for diagnosis and treatment. Also, researchers are developing molecules - for example, the Janus kinase inhibitor CP-690550 (tofacitinib) and the spleen tyrosine kinase inhibitor R788 (fostamatinib) - to target other aspects of the inflammatory cascade. Initial trial results with new agents are promising, and, in time, head-to-head trials will establish the best treatment options for patients. The key challenge is identifying how best to integrate these new, advanced therapies into daily practice.

Golimumab — a new tool in the armoury against inflammatory arthritis

The development of biological drugs blocking tumour necrosis factor-alpha (TNF-α) has had a dramatic impact on the treatment of inflammatory arthritis in recent years. Golimumab is a fully human monoclonal antibody which inhibits TNF-α. It is licensed for the treatment of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. In this review we evaluate the results of phase III studies using golimumab and explore the place of golimumab in the treatment of these diseases.

Anticytokine therapy in systemic lupus erythematosus

Systemic lupus erythematosus is a prototype of heterogeneous autoimmune disease. There have been few newly approved therapeutic agents in lupus treatment for many reasons. Several animal studies and human data have shown that many potential cytokines are related to the pathogenesis and disease activity of systemic lupus erythematosus. Cytokines are produced by many immune cell types and have variable functions in the immune system. Following the success of biological agents in the treatment of inflammatory arthritis, inflammatory bowel disease, and psoriasis, biological targeting to specific cytokines or receptor molecules is now promising in the treatment of systemic lupus erythematosus. In addition to B-cell deleting modalities, clinical trials targeting potential cytokines associated with disease pathogenesis are underway at various clinical stages. Among potential cytokines, targeting agents against B-cell activating factor and interferon-alpha are in the most advanced stage, and belimumab (anti-B-cell activating factor antibody) could be the first biological agent approved in the treatment of systemic lupus erythematosus. Anti-tumor necrosis factor was tried with some success, but with a potential risk of infection in a small number of patients. In this review, we discuss the rationale for anticytokine therapies and review agents currently in clinical trials, and those that could be developed in the near future for systemic lupus erythematosus. We present the results mostly from published trials and data from http://clinicaltrials.gov/ct2/

Keratan sulfate suppresses cartilage damage and ameliorates inflammation in an experimental mice arthritis model

Proteoglycans bearing keratan sulfate (KS), such as aggrecan, are components of the human cartilage extracellular matrix (ECM). However, the role of KS in influencing cartilage degradation associated with arthritis remains to be completely understood. KS side chains of the length found in human cartilage are not found in murine skeletal tissues. Using a murine model of inflammatory polyarthritis and cartilage explants exposed to interleukin-1α (IL-1α), we examined whether administering KS could influence intraarticular inflammation and cartilage degradation. Acute arthritis was induced by intravenous administration of an anti-type II collagen antibody cocktail, followed by an intraperitoneal injection of lipopolysaccharide. This treatment was followed by an intraperitoneal KS administration in half of the total mice to evaluate the therapeutic potential of KS for ameliorating arthritis. To investigate the therapeutic potential ex vivo, we examined cartilage fragility by measuring IL-1α-induced aggrecan release from cartilage explants treated with or without KS. Intraperitoneal KS administration ameliorated arthritis in DBA/1J mice. The aggrecan release induced by IL-1α was less in cartilage explants containing media with KS than in those without KS. Our data indicate that exogenous KS ameliorated arthritis in vivo and suppressed cartilage degradation ex vivo. KS may have important therapeutic potential in the treatment of inflammatory arthritis. The mechanism responsible for this requires further investigation, but KS may become a novel therapeutic agent for treating inflammatory diseases such as rheumatoid arthritis.

Stem cells in the treatment of inflammatory arthritis

Autologous haematopoietic stem cell transplantation in patients with rheumatoid arthritis (RA) resulted in a positive short-term outcome clinically with low treatment-related toxicity. However, early conditioning regimens were of low immunoablative intensity and most patients relapsed. Mechanistic studies suggest that residual lesional effector cells may have been responsible for the relapses. The introduction of biopharmaceuticals has, for the moment, reduced the need for further experimental studies. Juvenile idiopathic arthritis patients, mostly of the systemic subgroup, have shown nearly 33% durable drug-free remission, but with significant toxicity, including fatal macrophage-activation syndrome early in the programme. Later modifications to the protocol have reduced this toxicity. Mesenchymal stem cells (MSCs), derived from several sources including bone marrow and adipose tissue, are being tested as tissue-regenerative and immunomodulating agents in many autoimmune diseases and animal models of inflammatory arthritis have been positive. MSCs and other stromal cells derived from actively inflamed synovium and peripheral blood of RA patients do not always demonstrate a full range of differentiation potential compared with healthy MSCs, although their immunomodulalatory capacity is unimpaired.

Cannabinoids and Bone: Friend or Foe?

The endocannabinoid system is recognized to play an important role in regulating a variety of physiological processes, including appetite control and energy balance, pain perception, and immune responses. The endocannabinoid system has also recently been implicated in the regulation of bone metabolism. Endogenously produced cannabinoids are hydrophobic molecules derived from hydrolysis of membrane phospholipids. These substances, along with plant-derived and synthetic cannabinoids, interact with the type 1 (CB(1)) and 2 (CB(2)) cannabinoid receptors and the GPR55 receptor to regulate cellular function through a variety of signaling pathways. Endocannabinoids are produced in bone, but the mechanisms that regulate their production are unclear. Skeletal phenotyping of mice with targeted inactivation of cannabinoid receptors and pharmacological studies have shown that cannabinoids play a key role in the regulation of bone metabolism. Mice with CB(1) deficiency have high peak bone mass as a result of an osteoclast defect but develop age-related osteoporosis as a result of impaired bone formation and accumulation of bone marrow fat. Mice with CB(2) deficiency have relatively normal peak bone mass but develop age-related osteoporosis as a result of increased bone turnover with uncoupling of bone resorption from bone formation. Mice with GPR55 deficiency have increased bone mass as a result of a defect in the resorptive activity of osteoclasts, but bone formation is unaffected. Cannabinoids are also produced within synovial tissues, and preclinical studies have shown that cannabinoid receptor ligands are effective in the treatment of inflammatory arthritis. These data indicate that cannabinoid receptors and the enzymes responsible for ligand synthesis and breakdown play important roles in bone remodeling and in the pathogenesis of joint disease.

Classification of rheumatologic opinion on early inflammatory arthritis: Harmonization of a heterogeneous standard

Interrater variability limits rheumatologic opinion as a reference standard for early inflammatory arthritis (IA) classification. The study objectives were to determine whether rheumatologic opinion is associated with potential early IA classification methods despite high interrater variability, and to compare the relative strengths of those associations. Eighteen rheumatologists independently classified 30 initial rheumatology presentation summaries as early IA or not and recommended a pharmacotherapy. Case fulfillment of the following classification methods was independently determined: early referral to rheumatology recommendation for rheumatoid arthritis (ERRR), common early IA cohort inclusion criteria (CEAC), and prevalent IA classification criteria (American College of Rheumatology [ACR]/European Spondylarthropathy Study Group [ESSG]). Associations between rheumatologic opinion, disease-modifying antirheumatic drug (DMARD) recommendation, and each classification method were determined. Participating rheumatologists published on early IA and represented 3 continents. The median case was age 43 (interquartile range [IQR] 30-53) years, had 40 (IQR 24-104) weeks of symptoms, 60 (IQR 18-120) minutes of morning stiffness, a swollen joint count of 6 (IQR 1-13), and an erythrocyte sedimentation rate of 25 (IQR 10-51) mm/hour. The mean ± SD multiple-rater kappa for rheumatologic opinion on early IA was 0.16 ± 0.02. The common odds ratios for associations between rheumatologic opinion and ERRR, CEAC, and ACR/ESSG were 10.3 (95% confidence interval [95% CI] 4.6-23.2), 4.4 (95% CI 2.5-7.7), and 0.7 (95% CI 0.4-1.1), respectively. Odds ratios for associations between DMARD recommendation and ERRR, rheumatologic opinion, CEAC, and ACR/ESSG were 18.7 (95% CI 8.1-43.2), 10.6 (95% CI 6.0-18.8), 2.8 (95% CI 1.7-4.6), and 0.5 (95% CI 0.3-0.7), respectively. Classification methods can be used to harmonize rheumatologic opinion of early IA despite high interrater variability. The ERRR is very strongly associated with both rheumatologic opinions of early IA and DMARD treatment recommendations.

Chondroitin sulfate improves synovitis in rabbits with chronic antigen-induced arthritis

Our aim was to explore the effect of chondroitin sulfate (CS), a natural glycosaminoglycan with attributed anti-inflammatory properties, on synovitis in a rabbit model of chronic arthritis with intense systemic inflammation bolstered by endothelial lesion and atherosclerotic diet. Chronic arthritis was induced by intraarticular injections of ovalbumin in immunized rabbits. Systemic inflammation was boosted in these rabbits by receiving a hyperlipidemic diet after producing an endothelial lesion in the femoral arteries. A group of these rabbits were treated with CS (100mg/kg/day). At sacrifice, synovial membranes were isolated, and cyclooxygenase-2 (COX-2) and chemokine (C-C motif) ligand 2 (CCL2) mRNA, as well as protein expression were assayed by quantitative real-time polymerase chain reaction (RT-PCR) and western blot studies. Histological synovial examination was also carried out employing the histopathological synovitis score (Krenn scale). CS diminished both gene expression and protein synthesis of COX-2 and CCL2, and the histopathological score of the synovial membrane, when compared to untreated rabbits. In fact, CS partially prevented the intimal layer proliferation and the inflammatory cell infiltration in the synovial membrane, which was observed in non-treated animals. CS reduced the inflammatory response of the synovial membrane, as well as decreased the synovial histopathological lesions in our animal model. Further studies are warranted to demonstrate whether CS might be beneficial in the treatment of inflammatory arthritis.

The AMBITION trial: tocilizumab monotherapy for rheumatoid arthritis

Recent years have seen many exciting developments in the treatment of inflammatory arthritis. Tocilizumab (TCZ) is a compound that inhibits the IL-6 receptor. Following initial studies in Japan, it has been extensively studied in five multicenter clinical trials. This report concentrates on the Actemra Versus Methotrexate Double-blind Investigative Trial in Monotherapy (AMBITION), which compared TCZ monotherapy (8 mg/kg every 4 weeks) with methotrexate monotherapy over 24 weeks. TCZ was shown to be the first biologic agent that is superior to methotrexate across a whole range of clinical outcomes measures with a rapid onset of effect. Significant liver toxicity was less common in the TCZ group. However, increases in lipids and decreases in neutrophils and skin infections were more common in the TCZ arm. Long-term efficacy and safety follow-up is ongoing. This trial supports the use of TCZ as monotherapy and suggests it should be regarded as a first-line biologic therapy.

Distinct Roles of Sphingosine Kinase 1 and 2 in Murine Collagen-Induced Arthritis

Sphingosine kinase (SphK) phosphorylates sphingosine into sphingosine-1-phosphate (S1P). S1P plays a critical role in angiogenesis, inflammation, and various pathologic conditions. To date, two mammalian isoenzymes, SphK1 and SphK2, have been identified. Although both SphK1 and SphK2 share overall homology and produce the common product, S1P, it has been proposed they display different unique and separate functions. In this study, we examined the role of SphK1 and SphK2 in a murine collagen-induced arthritis model by down-regulating each isoenzyme via specific small interfering RNA (siRNA). Prophylactic i.p. administration of SphK1 siRNA significantly reduced the incidence, disease severity, and articular inflammation compared with control siRNA recipients. Treatment of SphK1 siRNA also down-regulated serum levels of S1P, IL-6, TNF-alpha, IFN-gamma, and IgG2a anti-collagen Ab. Ex vivo analysis demonstrated significant suppression of collagen-specific proinflammatory/Th1 cytokine (IL-6, TNF-alpha, IFN-gamma) release in SphK siRNA-treated mice. Interestingly, mice received with SphK2 siRNA develop more aggressive disease; higher serum levels of IL-6, TNF-alpha, and IFN-gamma; and proinflammatory cytokine production to collagen in vitro when compared with control siRNA recipients. Together, these results demonstrate the distinct immunomodulatory roles of SphK1 and SphK2 in the development of inflammatory arthritis by regulating the release of proinflammatory cytokines and T cell responses. These findings raise the possibility that drugs which specifically target SphK1 activity may play a beneficial role in the treatment of inflammatory arthritis.

MEK/ERK pathway inhibitors as a treatment for inflammatory arthritis might result in the development of lupus: Comment on the article by Thiel et al

MEK/ERK pathway inhibitors as a treatment for inflammatory arthritis might result in the development of lupus: Comment on the article by Thiel et al