Treatment Of Inflammatory Joint Diseases Research Articles

SP0071 Biologics Therapies - Changing the Podiatry Needs of People with Inflammatory Arthritis?

Over recent years treatment of inflammatory joint disease has seen dramatic changes with the introduction of ‘biological drugs’. Despite benefits of clinical and radiological outcomes for this group, several potentially...

Medical management of ulcerative colitis with a specific focus on 5-aminosalicylates.

Medical management of ulcerative colitis has continued to evolve over more than half of a century. Perhaps, the important advance was the development of sulfasalazine, a drug initially used for the treatment of inflammatory joint disease and only later in the treatment of inflammatory bowel disease. Sulfasalazine was a combination designer drug consisting of sulfapyridine, a sulfa-containing antibacterial agent, and 5-amino-salicylate (5-ASA), an anti-inflammatory agent. Its value appeared to be its ability to target a therapeutic concentration of the 5-ASA component of the medication primarily in the colon, largely avoiding proximal small intestinal absorption. With increasing experience, however, it also became evident that many patients treated with sulfasalazine developed intolerance to the drug and, in some rare instances, serious drug-induced hypersensitivity reactions, largely to the sulfapyridine portion. As a result, a number of alternative forms of delivery of 5-ASA were developed consisting of either a similar sulfasalazine-like prodrug formulation requiring luminal destruction of an azo-bond releasing the 5-ASA or a pH-dependent 5-ASA packaging system that permitted release in the distal intestine, particularly in the colon. As a result, 5-ASA—containing medications continue to provide a valuable management tool for remission induction in mildly to moderately active distal or extensive ulcerative colitis, an additional option for more severely symptomatic disease and value for maintenance therapy with limited potential side effects, even with long-term use.

Histone deacetylase inhibitors: New treatment options for inflammatory joint disease?

Histone deacetylase inhibitors (HDIs) are a new class of compounds that are being developed for the treatment of malignancies such as cutaneous T-cell lymphoma. HDIs inhibit the removal of acetyl groups from histones. The histone acetylation process is dependent on two enzymes, histone acetyl transferase (HAT) and histone deacetylase (HDAC), and regulates the expression of genes, including those encoding cell survival or apoptosis. In addition to regulating cell growth, HDIs exert anti-inflammatory effects by controlling the production of anti-inflammatory cytokines; modulating the function of cells such as T cells, monocytes-macrophages, chondrocytes, and osteoclasts; and modulating angiogenesis. In several animal models of arthritis, HDIs improve the clinical manifestations and prevent damage to the bone and cartilage. In humans, the only relevant data available so far come from studies of HAT and HDAC expression in the synovial membrane of patients with rheumatoid arthritis. HDIs may hold promise for the treatment of inflammatory joint disease.

Discussion: DMARDs and biologic therapies in the management of inflammatory joint diseases

Therapy for inflammatory joint diseases, such as rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis, includes various conventional disease-modifying antirheumatic drugs (DMARDs). These therapeutic agents are termed DMARDs because they have the potential to reduce or prevent joint damage and preserve joint integrity and function. Conventional DMARDs are used as monotherapy or in combination and include methotrexate, leflunomide, azathioprine, ciclosporin, hydroxychloroquine, sulfasalazine, gold and minocycline. Biologic response modifiers, which are based on proteins made by living cells, are newer agents available for the treatment of various inflammatory joint diseases. Biologic therapies now approved for use in inflammatory joint diseases are TNF inhibitors, T-cell modulators and B-cell depleters. They have all been shown to have clinical efficacy and are able to retard structural damage. However, all current immune-modulating therapies also have potential side effects, and the decision to use a particular agent for treatment should be based on a thorough discussion of the benefits and risks with the patient. Newer biologic response modifiers and other immunologic therapies are currently being developed for the treatment of inflammatory joint diseases and are discussed in this review.

Effects of clinically relevant concentrations of glucosamine on equine chondrocytes and synoviocytes in vitro

To evaluate the effects of glucosamine on equine articular chondrocytes and synoviocytes at concentrations clinically relevant to serum and synovial fluid concentrations. Articular cartilage and synovium with normal gross appearance from metacarpophalangeal and metatarsophalangeal joints of 8 horses (1 to 10 years of age). In vitro chondrocyte and synoviocyte cell cultures from 8 horses were treated with glucosamine (0.1 to 20 microg/mL) with or without interleukin-1 (IL-1; 10 ng/mL) for 48 hours. Negative control cultures received no glucosamine or IL-1, and positive control cultures received only IL-1. Cultures were assayed for production of proteoglycan (via media containing sulfur 35 (35S)-labeled sodium sulfate and Alcian blue precipitation), prostaglandin E2 (PGE2; via a colorimetric assay), cyclooxygenase-2 (via real-time reverse-transcriptase PCR assay), microsomal PGE2 synthase (mPGEs; via real-time reverse-transcriptase PCR assay), and matrix metalloproteinase (MMP)-13 (via a colorimetric assay). Glucosamine had no impact on proteoglycan production or MMP-13 production under noninflammatory (no IL-1) or inflammatory (with IL-1) conditions. Glucosamine at 0.1 and 0.5 microg/mL significantly decreased IL-1-stimulated production of mPGEs by chondrocytes, compared with that of positive control chondrocytes. Glucosamine at 0.1 and 5 microg/mL significantly decreased IL-1-stimulated production of mPGEs and PGE2, respectively, compared with that of positive control synoviocytes. Glucosamine had limited effects on chondrocyte and synoviocyte metabolism at clinically relevant concentrations, although it did have some anti-inflammatory activity on IL-1-stimulated articular cells. Glucosamine may have use at clinically relevant concentrations in the treatment of inflammatory joint disease.

Involvement of platelet-activating factor and tumour necrosis factor in the pathogenesis of joint inflammation in rabbits.

We have studied the participation of platelet-activating factor (PAF) in antigen-induced arthritis in rabbits, as well as the possible co-operation between PAF and tumour necrosis factor (TNF) in their ability to induce joint inflammation when injected into the knees of healthy rabbits. The administration of two structurally different PAF receptor antagonists, BN52021 and Alprazolam, from 4 h before the intra-articular injection of ovalbumin in preimmunized rabbits, induced an important reduction in the synovial fluid volume, in the amount of cells infiltrating the articular cavity and the synovial membrane, as well as in the prostaglandin E2 (PGE2) concentration. Furthermore, proteoglycans of the articular cartilage, which were found diminished in animals with non-treated arthritis, were well preserved in rabbits treated with PAF antagonists. All the synovial fluids from joints with arthritis had detectable amounts of PAF. The injection of either TNF or PAF into the joints of normal rabbits induced a mild inflammation. When TNF was administered 1 h before PAF, a synergistic response was noted in the synovial fluid volume, in the accumulation of leucocytes, and in the amount of PGE2. The administration of BN50726, a hetrazepine with a potent PAF-receptor antagonist effect, induced a diminution in those parameters. Our results suggest that PAF may be an early and important mediator of joint damage, and that TNF can amplify the inflammatory response induced by PAF. PAF receptor antagonists could play some role in the treatment of inflammatory joint diseases.

Synergistic Collagenase Expression and Cartilage Collagenolysis Are Phosphatidylinositol 3-Kinase/Akt Signaling-dependent

The phosphatidylinositol 3-kinase (PI3K) signaling pathway has emerged as a major regulator of cellular functions and has been implicated in several pathologies involving remodeling of extracellular matrix (ECM). The end stage of inflammatory joint diseases is characterized by excessive ECM catabolism, and in this study we assess the role of PI3K signaling in the induction of collagenolytic matrix metalloproteinases (MMPs) in human chondrocytes. We used the most potent cytokine stimulus reported to promote cartilage ECM catabolism, namely interleukin-1 (IL-1) in combination with oncostatin M (OSM). Both OSM and IL-6 (in the presence of its soluble receptor), but not IL-1 nor leukemia inhibitory factor, induced Akt phosphorylation in human chondrocytes. Inhibition of PI3K signaling using LY294002 blocked IL-1+OSM-mediated Akt phosphorylation, induction of MMP-1 and MMP-13, and cartilage collagenolysis. To further explore the role of downstream substrates within the PI3K pathway, complementary use of small molecule inhibitors and specific small interfering RNAs demonstrated that the PI3K subunit p110alpha and Akt1 were required for MMP-1 mRNA induction. MMP-13 induction was also reduced by loss of function of these molecules and by a lack of p110delta, 3-phosphoinositide-dependent kinase-1 or Akt3. We therefore propose that the activities of specific elements of the PI3K signaling pathway, including Akt, are necessary for the synergistic induction of MMP-1 and MMP-13 and the cartilage breakdown stimulated by IL-1+OSM. Our data provide new insight into the mechanism of synergy between IL-1 and OSM and highlight new therapeutic targets for inflammatory joint diseases that aim to repress the expression of collagenases.

Primer: Toll-like receptor signaling pathways—what do rheumatologists need to know?

Toll-like receptors (TLRs) have caught the attention of rheumatologists searching for additional therapeutic targets for diseases such as rheumatoid arthritis and systemic lupus erythematosus. Signaling from these molecules can induce the expression of cytokines such as tumor necrosis factor and interferon alpha. Strategies that target TLRs and their co-receptors (such as MD2 for TLR4 or CD36 for TLR2) might be a more-selective approach than inhibition of global signals such as nuclear factor kappaB or p38 mitogen-activated protein kinase. TLR signaling requires adaptor proteins, including MyD88, Mal, TRIF and TRAM, which are recruited to specific receptors: Mal is used only by TLR2 and TLR4, TRIF is used by TLR3 and TLR4, and TRAM is recruited by TLR4 alone. Mal and TRAM are subject to complex biochemical regulation. Inhibition of Mal or MyD88 blocks the production of inflammatory mediators in synovial tissue. Another possible intracellular target is Unc93b, a protein involved in signaling from TLR3, TLR7 and TLR9. Inhibition of TLR4, TLR7 and TLR9 has produced intriguing results, which indicate that TLRs and their signaling pathways might indeed have great potential as novel targets for the treatment of inflammatory joint disease.

In vitro resistance of articular chondrocytes to 5‐Aminolevulinic acid based photodynamic therapy

5-Aminolevulinic acid based photodynamic therapy (5-ALA-PDT) has revealed promising results in the treatment of inflammatory joint diseases due to the sensitivity of inflamed synovial tissue. For 5-ALA-PDT to be safe and beneficial for intra-articular applications, resistance of chondrocytes is essential to prevent cartilage damage. As no data yet exist, the aim of the present study was to assess in vitro the response of the chondrocytes to 5-ALA-PDT and to compare with osteoblasts and synovial tissue derived cells. Bovine articular chondrocytes, osteoblasts, and synovial cells were subjected to 5-ALA-PDT in cell culture. The PpIX accumulation and the function of the cells were assessed for up to 12 days. Bovine chondrocytes showed lower PpIX fluorescence upon incubation with 5-ALA (0.0-2.0 mM) for 4 hours as compared to osteoblasts and synovial cells suggesting a low PpIX accumulation. After incubation with 0.5 mM 5-ALA and application of light at a dose of 20 J/cm2, chondrocytes were functionally not affected (collagen type II and aggrecan mRNA, glycosaminoglycan synthesis) whereas a decrease in the proportion of viable cells was observed in osteoblasts and synovial cells (2+/-2% and 14+/-8%, respectively; chondrocytes 91+/-13%). Chondrocytes showed a 58% reduction of 5-ALA uptake using [3H]5-ALA as compared to osteoblasts and a lower mitochondrial content as assessed by the activity of the mitochondrial marker enzyme citrate synthase (9.2+/- 3.6 mU/mg protein) than osteoblasts (32.6+/-10.5 mU/mg) and synovial cells (60.0+/-10.8 mU/mg). The reduced uptake of 5-ALA and/or the low mitochondrial content, an adaptation to their in vivo environment and the site of PpIX synthesis, presumably explains the lower PpIX content in chondrocytes and their resistance against 5-ALA-PDT. 5-ALA-PDT might represent a treatment strategy in inflammatory joint diseases without endangering the cartilage function. However, further in vitro and in vivo experiments are required to confirm this data in the authentic environment of chondrocytes, the articular cartilage.

Histamine induces interleukin-6 expression in the human synovial sarcoma cell line (SW982) through the H1 receptor

The effect of histamine on inositol phosphate generation and interleukin-6 (IL-6) release from the synovial sarcoma cell line SW982 was investigated. SW982 cells express functional H1 and H2 receptors. The H1 receptor antagonist [3H]-mepyramine binds to membranes from SW982 cells with high affinity and the binding was potently blocked by H1 antagonists. Histamine potently stimulated phosphoinositide (PI) hydrolysis and Ca2+ mobilization with EC50 of 4.0 +/- 0.8 microM and 1.3 +/- 0.6 microM respectively and these activities were blocked by the H1 selective antagonist mepyramine. Histamine (EC50 = 1.8 +/- 1.1 microM) stimulated the release of IL-6 that was attenuated by selective H1 antagonists. The PKC inhibitor, GF1090203X, blocked the histamine stimulated IL-6 release. The H2 selective antagonist, cimetidine, had no significant effect on histamine-induced PI turnover, Ca2+ mobilization and IL-6 release. We conclude that histamine stimulates IL-6 release from SW982 cells by binding to the H1 receptor and this is coupled to the PI/PKC signal transduction pathway. Development of an H1 antagonist that inhibits the release of IL-6 from synoviocytes may be beneficial for the treatment of inflammatory joint disease.

Musculoskeletal disorders: an introduction

Abstract Musculoskeletal disorders remain the most common cause of physical disability in an ageing population. The importance of increased cardiovascular disease in this group is being recognized. The dramatic therapeutic impact of the cytokine specific inhibitors in the treatment of inflammatory joint disease has been balanced by the controversy over the potential cardiovascular toxicity of the newer selective Cox-2 inhibitors. Ultrasound is rapidly emerging as a valuable diagnostic tool and circulating anti-cyclical citrullinated peptide (anti-CCP) antibodies seem a promising early diagnostic and prognostic test in rheumatoid arthritis.

Experience of Tizol gel administration for local therapy of rheumatoid arthritis

Objective. To assess efficacy, tolerability and safety of 1% Tizol gel in monotherapy and in combination with diclofenac (0,5%) and hydrocortisone (0,05%) in rheumatoid arthritis (RA). Material and methods. 88 RA pts with exudation in damaged joints were included in the study. They were randomized into 3 groups. Group I (30 pts) received local therapy with 1% Tizol gel. Group U (30 pts) - a complex drug contained 1% Tizol, diclofenac 0,5% and hydrocortisone 0,05%. Group 111 served as control and was treated locally with 1% diclofenac gel (Hiperion S.A., Rumania). Preparations were administered as thin layer on the whole surface of the inflamed joint trice a day for 14 days. Efficacy was assessed after the course of treatment. Pain intensity (VAS), joint circumference and functional impairment degree (WOMAC index) were used as outcome measures. Laboratory examination included complete blood count, hepatic enzymes level and urinanalysis. Results. Local therapy provided decrease of pain and joint circumference, increase mobility and allowed to diminish NSAID dose. Good effect was achieved in group I and II (53% and 60% respectively). Local effect of the drug in group 1 lasted in average 2,5 hours according to pts' opinion. Tolerability of the local therapy was good in ail pts. Systemic adverse events were absent. Conclusion. 1% Tizol gel and its combination with diclofenac (0,5%) and hydrocortisone (0,005%) are effective for local therapy of RA, decrease pain and inflammation in damaged joints. They can be used for treatment of inflammatory joint diseases particularly in pts with concomitant gastrointestinal diseases, hypertension absence of possibility of oral administration of NSAIDs and/or necessity of decrease of their dose.

Adalimumab – a new TNF-α antibody for treatment of inflammatory joint disease

Tumour necrosis factor alpha (TNF-α) is a pro-inflammatory cytokine with various roles in inflammatory processes. Several TNF blockers are currently approved for use in rheumatoid arthritis (RA) as well as in other inflammatory arthropathies. The latest of these compounds is the human monoclonal antibody, adalimumab, which was obtained using phage display technology and successfully produced in a mammalian expression system. Clinical application of this compound led to significant improvement in patients suffering from RA, both as monotherapy and in combination with various disease modifying antirheumatic drugs (DMARDs), including methotrexate (MTX). Moreover, radiographic progression is significantly inhibited and quality of life improved. This article summarises the available information.

Reactive oxygen species downregulate the expression of pro-inflammatory genes by human chondrocytes.

To determine the regulatory effects of reactive oxygen species (ROS) on the expression by human osteoarthritic chondrocytes of interleukin (IL)-1beta, -6 and -8, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) gene in response to interleukin (IL)-1beta or lipopolysaccharide (LPS). Human chondrocytes in monolayer culture were incubated for 3 h with ROS generating molecules such as S-nitroso-N-acetyl-D,L-penicillamine (SNAP, 100 microM), 3-morpholinosydnonimine (SIN-1, 100 microM), with chemically synthesised peroxynitrite (ONOO-, 10 microM) or hydrogen peroxide (H2O2, 100 microM). After treatment by ROS, chondrocytes were washed and then cultured for the next 24 h with or without lipopolysaccharide LPS (10 microg/ml) or IL-1beta (1.10(-11) M). IL-1beta, IL-6, IL-8, iNOS and COX-2 gene expression was analysed by real time and quantitative RT PCR. IL-6, IL-8 and prostaglandin (PG) E2 productions were assayed by specific immunoassays. Nitrite was measured in the culture supernatants by the Griess procedure. LPS and IL-1beta stimulated IL-1beta, IL-6, IL-8, iNOS and COX-2 gene expression. SNAP significantly downregulated LPS induced overall gene expressions, whereas SIN-1 had no effect. ONOO- inhibited iNOS and COX-2 gene expression but not that of the cytokine genes. When chondrocytes were incubated with IL-1beta, SIN-1 and ONOO dramatically decreased all gene expressions while SNAP was inefficient. H2O2 treatment inhibited both LPS and IL-1beta induced gene expressions. These data provide an evidence that ROS may have anti-inflammatory properties by depressing inflammatory gene expression. Further, we demonstrate that ROS effects are dependent on the nature of radical species and the signalling pathway that is activated. These findings should be taken into consideration for the management of antioxidant therapy in treatment of inflammatory joint diseases.

Adalimumab ? a new TNF-alpha antibody for treatment of inflammatory joint disease

Adalimumab ? a new TNF-alpha antibody for treatment of inflammatory joint disease

Synergistic interactions of proinflammatory cytokines with oncostatin M: implications for joint destruction

Oncostatin M (OSM) is an IL-6 family cytokine that we have previously shown to synergise with IL-1 to induce cartilage proteoglycan and collagen degradation in a cartilage explant culture system, and these observations now extend to IL-6 [1,2]. A significant finding of these studies was the synergistic induction of the collagenase, matrix metalloproteinase (MMP)-1, which occurs via interplay between the JAK/STAT, AP-1 and MAPK pathways [3]. These studies have important implications for inflammatory joint disease since OSM (and, indeed, IL-6) have been proposed to be protective in rheumatoid arthritis. Recently, we also demonstrated that OSM can exacerbate the effects of another important proinflammatory mediator, tumour necrosis factor (TNF)-α [4]. In order to assess the effects of these cytokine combinations in vivo, we have assessed the effects of intra-articular gene transfer of OSM in combination with either IL-1 or TNF-α on murine knee joints using recombinant adenovirus. Engineered adenoviruses were administered for only 7 days, after which time joints were fixed, decalcified and sectioned. Histological analyses indicated marked synovial hyperplasia and inflammatory cell infiltration for IL-1-treated, TNF-α-treated and OSM-treated joints, but not in controls (joints treated with an 'empty' adenovirus). The inflammation was more pronounced for both the OSM + IL-1 and OSM + TNF-α combinations with evidence of cartilage and bone destruction. Significant loss of both proteoglycan and collagen was also seen for these combinations, and immunohistochemistry revealed an increased expression of MMPs with decreased tissue inhibitors of metalloproteinases in both articular cartilage and synovium. The effects of these combinations were significantly greater than those seen with any of the cytokines alone. Taken together, these data confirm that, in vivo, OSM can significantly exacerbate the effects of both IL-1 and TNF-α, resulting in inflammation and tissue destruction characteristic of that seen in rheumatoid arthritis. This study provides further evidence to implicate the upregulation of MMPs as a key factor in joint pathology, and further supports the concept of combinatorial therapeutic approaches for the treatment of inflammatory joint diseases.

CELEBREX IN TREATMENT OF VERTEBRAL PAIN SYNDROME IN SYSTEMICV LUPUS ERYTHEMATOSUS

Objective. То study of tizol efficacy for local therapy of rheumatoid arthritis (RA). Materials and methods. 90 pts with active RA (2-3 stage of activity) age 41-54 (m=18, f—72). The method оГ double blind controlled comparison of 10 - days therapy with pure tizol, tizol with diclophenac (1%) and placebo (vaseline) was used. In order to evaluate skin permeability of tizol mass-spectrometry of synovial liquid was used. Results. Positive dynamic of joint syndrome under tizol and tizol with diclophenac therapy were showed. There were reduction of arthalgia, decreasing of morning stiffness, increasing of grip strenght. Erythrocyte sedimentation rate didn’t change. Adding of diclophenac to tizol amplified it's analgetic properties. Mass spectrum analysis showed that concentration of titanium in synovial fluid came approximately 10 times higher after 10 days of tizol therapy. Conclusion. The efficacy of local tizol and it’s compounds in inflammatory joint syndrome was showed. Diclophenac intensified analgetic effect of tizol. Efficacy and convenience of treatment, absens of side-effects, low price allow to recommend tizol - gel compounds for local treatment of inflammatory joint diseases.

Small-molecule inhibitors of NF-kappaB for the treatment of inflammatory joint disease.

Recent advances in our understanding of the role of cytokine networks in inflammatory processes have led to the development of novel biological agents for the treatment of chronic inflammatory diseases. At the present time, significant efforts are focused on characterizing the complex signal transduction cascades that are activated by these cytokines and, in turn, regulate their expression. The transcription factor NF-kappaB is a pivotal regulator of the inducible expression of key proinflammatory mediators, and activated NF-kappaB has been observed in several debilitating inflammatory disorders, including rheumatoid arthritis and osteoarthritis. In light of its central role in inflammation, the identification of inhibitors of NF-kappaB should provide novel therapeutics for the treatment of chronic joint disease.

Soluble complement receptor one (sCR1) inhibits the development and progression of rat collagen-induced arthritis.

We set out to determine whether inhibition of complement using sCR1 could influence the development and progression of collagen arthritis in the Lewis rat. Collagen arthritis was successfully established in the Lewis rat, using a novel immunization schedule. In separate experiments, cobra venom factor (CVF) and sCR1 were used to achieve systemic complement inhibition. Their respective effects on disease onset and on the progression of established disease compared with saline-treated control animals was explored. Arthritis was assessed by measurement of clinical score, paw diameter and paw volume. Complement inhibition using either CVF or sCR1, prior to the onset of clinical signs of inflammation, delayed the development of disease. CVF was ineffective in the treatment of established disease, whereas sCR1 delayed the progression of disease in affected joints and prevented the recruitment of further joints while the animals were complement-depleted. In the control saline-treated groups the disease continued to progress relentlessly. We conclude that complement activation is important in the initiation and maintenance of inflammation in collagen arthritis. The potent disease-modulating effect of sCR1 provides persuasive evidence that specific complement inhibiting agents may be an effective approach to the treatment of inflammatory joint diseases

INOS in arthritis – inducible or innocent?

Nitric oxide (NO) overproduction has been linked with the chronic and progressive inflammation and tissue destruction observed in experimental arthritis. Accordingly, modulation of NO activity or biosynthesis has long been considered a therapeutic target for the treatment of inflammatory joint diseases. Endogenous production of NO is governed by the enzyme nitric oxide synthase (NOS), inhibition of which attenuates inflammation and subsequent tissue damage in animal models of arthritis. The inducible isoform of this enzyme, iNOS, is expressed by leukocytes implicated in the pathogenesis of joint inflammation and, furthermore, has been detected in human rheumatoid synovium. This association implies that selective iNOS inhibition could provide benefit in arthritis without affecting the constitutive isoforms of the enzyme, nNOS (neuronal) and eNOS (endothelial), hence avoiding unwanted effects on systems such as the vasculature.