Inflammatory Joint Disorders Research Articles

A multicellular signal transduction network of AGE/RAGE signaling

Advanced glycation end products (AGEs) are heterogeneous glycated products of proteins, lipids and nucleotides. The major receptor for AGEs, known as receptor for advanced glycation end products (RAGE or AGER), is a multi-ligand transmembrane receptor of immunoglobulin superfamily. It has an extracellular region, a transmembrane domain and a short cytoplasmic domain. Extracellular region of RAGE consists of one V type (critical for ligand binding) and two C type immunoglobulin domains (Schmidt et al. 1994a, b). Although the short cytoplasmic tail of 43 amino acid residues is found to be important for the signaling events mediated by RAGE, it does not have any known domain or motif (Neeper et al. 1992). The other cell surface receptors for AGEs include dolichyl-diphosphooligosaccharide-protein glycosyltransferase (AGE-R1) (Li et al. 1996), protein kinase C substrate, 80KH phosphoprotein (AGE-R2) (Goh et al. 1996), galectin-3 (AGE-R3) (Vlassara et al. 1995), and class A macrophage scavenger receptors type I and II. RAGE is also considered as a pattern recognition receptor due to its ability to bind different AGEs. RAGE has numerous extracellular ligands in addition to AGEs, which include extracellular high mobility group box-1 (HMGB1), S100 family of calcium binding proteins and amyloid-beta peptide (Fritz 2011). RAGE is expressed in diverse tissues such as lung, heart, kidney, brain, and skeletal muscle and in a variety of cells including endothelial cells, macrophages/monocytes, neutrophils, and lymphocytes (Brett et al. 1993; Ding and Keller 2005; Neeper et al. 1992). RAGE has been implicated in the pathogenesis of diverse diseases such as diabetes, cardiovascular disorders, arthritis, cancers and neurological disorders (Yan et al. 2009). Interactions of AGEs with their receptors alter cell function through the generation of free radicals (Schmidt et al. 1994a, b). In diabetes, interaction of AGEs with RAGE induces oxidative stress and inflammatory reactions thereby resulting in vascular damage and related complications (Yamagishi 2011). RAGE also plays an important role in the progression of atherosclerosis through oxidative stress and proinflammatory responses (Sun et al. 2009). Expression of RAGE in synovial tissue, T cells, B cells and macrophages of arthritic patients implies its significance in inflammatory joint disorders (Drinda et al. 2005). Overexpression of RAGE has also been reported in various types of cancers such as pancreatic, gastric, breast, lung cancers and lymphoma (Logsdon et al. 2007). Knockdown of RAGE expression was shown to inhibit ductal neoplasia in an animal model of pancreatic cancer (DiNorcia et al. 2012). A recent study by Liang et al. reported that the inactivation of RAGE in colorectal cancer cells reduced angiogenesis (Liang et al. 2011). The signaling events mediated by RAGE are complex due to the diversity of its ligands and their diverse effects mediated in different cell types. AGE/RAGE signaling in endothelial cells is reported to modulate oxidative stress, inflammation, apoptosis, autophagy, endothelial-mesenchymal-transition, endothelial permeability and dysfunction (Toma et al. 2009; Xu et al. 2010; Li et al. 2011; Xie et al. 2011; Ma et al. 2010; Del Turco et al. 2011). In smooth muscle cells, AGE/RAGE interaction leads to generation of reactive oxygen species, autophagy, proliferation and calcification (Yoon et al. 2009; Hu et al. 2012; Yuan et al. 2011; Tanikawa et al. 2009). AGE/RAGE signaling is reported to mediate proliferation in lymphocytes (Takahashi et al. 2010). In fibroblasts, it induces migration, inflammation and apoptosis (Liu et al. 2010; Shimoda et al. 2011). A diverse array of molecules and signaling modules were identified to be activated by RAGE depending on the intensity and duration of RAGE ligation. Specific signaling modules such as ERK1/2 (Lander et al. 1997), p38 MAPK (Lander et al. 1997), CDC42/RAC (Bondeva et al. 2011), SAPK/JNK (Hu et al. 2012) and NF-κB (Liu et al. 2010) have been shown to be triggered by AGE/RAGE interaction in different cell types. Currently, there are no resources, which contain RAGE signaling pathway data for visualization and analysis. Therefore, we have gathered signaling pathway reactions induced by AGE/RAGE interaction in diverse cell types and tissues from literature. We have also cataloged genes transcriptionally regulated by AGE/RAGE system in humans along with their transcriptional regulators. We have provided the AGE/RAGE signaling pathway data to scientific community through NetPath (http://www.netpath.org), a resource of signaling pathways developed by us (Kandasamy et al. 2010).

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BACKGROUND/AIMS : Osteoarthritis is an inflammatory & degenerative disorder of joints. The exact pro-oxidant & antioxidant status is not clear in osteoarthritis. Our aims were to estimate levels of the lipid peroxidation (in terms of MDA) & enzymatic antioxidant (in terms of superoxide dismutase) in serum of osteoarthritis patients & compare them with the levels in normal healthy controls. MATERIAL & METHODS: A study was performed at the department of biochemistry at Pd. Dr. D. Y. Patil medical college, Pimpri, Pune-18(M.S.) In 30 patients of osteoarthritis serum levels of enzymatic antioxidant Marker (SOD) & lipid peroxidation status (MDA) were estimated by spectrophotometry. Thirty healthy controls were also included in the study & serum levels of same parameters were also measured. STATISTICAL ANALYSIS: It was performed by using the student unpaired t test. RESULT: A serum level of enzymatic antioxidant marker (SOD) was increased in the patients than in the controls. The serum lipid peroxidation (MDA) level was increased in the patients than in the controls.

Pediatric fibromyalgia

Fibromyalgia (FM) is currently defined as chronic widespread pain (CWP) with allodynia or hyperalgesia to pressure pain. It is classified as one of the large group of soft-tissue pain syndromes. Pain is the cardinal symptom of FM; however, most patients also experience additional symptoms such as debilitating fatigue, disrupted or non-restorative sleep, functional bowel disturbances, and a variety of neuropsychiatric problems, including cognitive dysfunction, anxiety and depressive symptoms. Its pathogenesis is not entirely understood, although it is currently believed to be the result of a central nervous system (CNS) malfunction that increases pain transmission and perception. FMS usually involves females, and in these patients it often makes its first appearance during menopause. But it is often diagnosed both in young as well as elderly individuals. Pediatric FMS is a frustrating condition affecting children and adolescents at a crucial stage of their physical and emotional development. Pediatric FMS is an important differential diagnosis to be considered in the evaluation of children suffering from widespread musculoskeletal pain, and must be differentiated from a spectrum of inflammatory joint disorders such as juvenile idiopathic arthritis (JIA), juvenile ankylosing spondylitis, etc. The management of pediatric FMS is centered on the issues of education, behavioral and cognitive change (with a strong emphasis on physical exercise), and a relatively minor role for pharmacological treatment with medications such as muscle relaxants, analgesics and tricyclic agents.

Rheumatoid Arthritis: Cardiovascular Manifestations, Pathogenesis, and Therapy

Rheumatoid Arthritis (RA) is a chronic progressive inflammatory joint disorder that affects 0.5% - 1% of the general population. This review article discusses cardiovascular manifestations of rheumatoid arthritis, pathogenesis of these manifestations, and therapy. This disease not only affects the joints, but it also involves other organ systems. The majority of these patients suffer significant morbidity and mortality from cardiovascular disease. Cardiovascular manifestations of RA include predilection for accelerated atherosclerosis and endothelial dysfunction resulting in coronary artery disease (CAD), stroke, congestive heart failure, and peripheral arterial disease. Some studies have shown that the risk of developing CAD in RA patients is the same as for patients with diabetes mellitus. These patients should be treated with aggressive medical therapy such as disease modifying antirheumatic drugs, tumor necrosis factor alpha inhibitors, and corticosteroids and with appropriate control of risk factors such as smoking, dyslipidemia, hypertension, and obesity. Other manifestations include pericarditis, myocarditis, and vasculitis.

Non-Enzymatic Decomposition of Collagen Fibers by a Biglycan Antibody and a Plausible Mechanism for Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a systemic autoimmune inflammatory and destructive joint disorder that affects tens of millions of people worldwide. Normal healthy joints maintain a balance between the synthesis of extracellular matrix (ECM) molecules and the proteolytic degradation of damaged ones. In the case of RA, this balance is shifted toward matrix destruction due to increased production of cleavage enzymes and the presence of (autoimmune) immunoglobulins resulting from an inflammation induced immune response. Herein we demonstrate that a polyclonal antibody against the proteoglycan biglycan (BG) causes tissue destruction that may be analogous to that of RA affected tissues. The effect of the antibody is more potent than harsh chemical and/or enzymatic treatments designed to mimic arthritis-like fibril de-polymerization. In RA cases, the immune response to inflammation causes synovial fibroblasts, monocytes and macrophages to produce cytokines and secrete matrix remodeling enzymes, whereas B cells are stimulated to produce immunoglobulins. The specific antigen that causes the RA immune response has not yet been identified, although possible candidates have been proposed, including collagen types I and II, and proteoglycans (PG's) such as biglycan. We speculate that the initiation of RA associated tissue destruction in vivo may involve a similar non-enzymatic decomposition of collagen fibrils via the immunoglobulins themselves that we observe here ex vivo.

Novel regulation of TNFα-induced-IL-18 bioactivity in rheumatoid arthritis synovial fibroblasts by reducing caspase-1 Via JAK2 inhibition

Background/purposeRheumatoid arthritis (RA) is the most common inflammatory chronic joint disorder. Interleukin-1 (IL-1) family members play a key part in the pathogenesis of RA. Among the IL-1 cytokine family members,...

Effects of Ankaferd hemostat on the synovial fluid of patients with osteoarthritis

Ankaferd Blood Stopper (ABS) is a novel topical hemostatic agent with antiinfective, wound healing, and antineoplastic properties. In this study, we evaluated the macroscopic and biochemical effects of ABS in the joint fluid of patients with osteoarthritis. Materials and methods: Synovial fluid samples were obtained from 10 patients with osteoarthritis (5 women, 5 men; mean age 57.6 ± 11.2 years). From each patient, 4 mL of synovial fluid was drawn and put into 2 different serum separator tubes, and 1 mL of ABS was added to the first sample and 1 mL of 0.9% saline was added to the second sample. Macroscopic evaluation and biochemical analyses for glucose, protein, albumin, and lactate dehydrogenase (LDH) were performed. Results: The addition of ABS into synovial fluid revealed a rapid and apparent reaction resulting in dense coagulation within seconds in all of the samples. No reaction was observed in the saline group. Total protein, albumin, globulin, and LDH levels significantly decreased in the ABS group, while glucose levels remained unchanged. Conclusion: ABS can work in the synovial fluid, causes rapid frozen gel-like solidification, and decreases the protein component of the synovial fluid. This observation, together with hemostatic and wound healing properties of ABS, might provide an important starting point for testing its actions on distinct hemorrhagic, neoplastic, or inflammatory joint disorders.

Potential of18F-FDG-PET as a valuable adjunct to clinical and response assessment in rheumatoid arthritis and seronegative spondyloarthropathies

To evaluate the role of fluorine-18-labeled fluorodeoxyglucose positron emission tomography ((18)F-FDG PET) in various rheumatic diseases and its potential in the early assessment of treatment response in a limited number of patients. This study involved 28 newly diagnosed patients, of these 17 had rheumatoid arthritis (RA) and 11 had seronegative spondyloarthropathy (SSA). In the SSA group, 7 patients had ankylosing spondylitis, 3 had psoriatic arthritis, and one had non-specific SSA. Patients with RA were selected as per the American College of Rheumatology criteria. One hour after FDG injection, a whole body PET scan was performed from the skull vertex to below the knee joints using a GE Advance dedicated PET scanner. Separate scans were acquired for both upper and lower limbs. Post-treatment scans were performed in 9 patients in the RA group (at 6-9 wk from baseline) and in 1 patient with psoriatic arthropathy. The pattern of FDG uptake was analysed visually and quantified as maximum standardized uptake value (SUVmax) in a standard region of interest. Metabolic response on the scan was assessed qualitatively and quantitatively and was correlated with clinical assessment. The qualitative FDG uptake was in agreement with the clinically involved joints, erythrocyte sedimentation rate, C-reactive protein values and the clinical assessment by the rheumatologist. All 17 patients in the RA group showed the highest FDG avidity in painful/swollen/tender joints. The uptake pattern was homogeneous, intense and poly-articular in distribution. Hypermetabolism in the regional nodes (axillary nodes in the case of upper limb joint involvement and inguinal nodes in lower limb joints) was a constant feature in patients with RA. Multiple other extra-articular lesions were also observed including thyroid glands (in associated thyroiditis) and in the subcutaneous nodules. Treatment response was better appreciated using SUVmax values than visual interpretation, when compared with clinical evaluation. Four patients showed a favourable response, while 3 had stable disease and 2 showed disease progression. The resolution of regional nodal uptake (axillary or inguinal nodes based on site of joint involvement) in RA following disease modifying anti-rheumatoid drugs was noteworthy, which could be regarded as an additional parameter for identifying responding patients. In the SSA group, uptake in the affected joint was heterogeneous, low grade and non-symmetrical. In particular, there was intense tendon and muscular uptake corresponding to symptomatic joints. The patients with psoriatic arthritis showed intense FDG uptake in the joints and soft tissue. (18)F-FDG PET accurately delineates the ongoing inflammatory activity in various rheumatic diseases (both at articular and extra-articular sites) and relates well to clinical symptoms. Different metabolic patterns on FDG-PET scanning in RA and SSA can have important implications for their diagnosis and management in the future with the support of larger studies. FDG-PET molecular imaging is also a sensitive tool in the early assessment of treatment response, especially when using quantitative information. With these benefits, FDG-PET could play a pivotal clinical role in the management of inflammatory joint disorders in the future.

Interleukin-4 Promotes Antinociception While β-endorphin Influence Over Nociceptive Interleukin-8 Is Disrupted in TMJ Patients

We have earlier reported that patients with chronic closed lock in the temporomandibular joint (TMJ) have increased plasma β-endorphin (βE) levels and decreased pressure pain thresholds (PPT) and increased pain scoring on a numeric rating scale (NRS) as a consequence of chronic nociceptive activity. After discectomy surgery the plasma βE and the NRS scoring of pain are decreased. The auriculotemporal nerve is at risk for irritation or entrapment between the articular fossa and the condyle which could explain TMJ pain. Inflammatory mediators, such as the cytokines, will be released. IL-8 is expressed in elevated levels in both serum and synovial fluid in chronic inflammatory joint disorders. βE may suppress IL-8 in mononuclear cells and in neutrophils. Interleukin 4 (IL-4) inhibits the hyperalgesic response to pro- inflammatory IL-8. The aims of this study were to investigate if the pain thresholds correlate with plasma cytokines in TMJ patients compared to healthy controls and to explore a balance between βE and cytokines in plasma. The PPTs were measured over the index finger and masseter muscle with an algometer in 6 patients with TMJ disc disturbances (DD) and 6 age- and sex-matched healthy controls. The electrical pain thresholds were measured over the index finger with a specific device, the PainMatcher. Venous blood samples were collected to analyze for βE and for a multiplex of 23 cytokines. Differences between the patients and the control group were tested with Mann-Whitney U test, 2-paired. The Spearman rank-correlation tests were used to investigate correlations between pain, βE, EPTs and PPTs. The patients had lower PPTs over the finger (P = .002) and over the masseter muscle (P = .002) compared to healthy controls. The EPTs over the finger were lower (P = .015) in the patient group compared to healthy controls. The plasma levels of IL- 4 and the PPTs over the finger correlated significantly in the healthy group (rs=0.828, n=6, P = .04) and in the patient group (rs=0.811, n=6, P = .049). Further, the plasma levels of IL-4 and the PPTs over the masseter muscle correlated in the healthy group (rs=0.942, P = .004) and in the patient group (rs=0.811, P = .049). The plasma levels of IL-8 and βE correlated in the healthy group (rs=0.811, P = .049) but not in the patient group (rs=−0.352, P = .493). On the contrary, there was a tendency towards a correlation between the plasma IL-8 and lower pain pressure thresholds over the masseter muscle (rs=−0.072, P = .08) in the patient group. Patients with TMJ DD have decreased PPTs and EPTs compared to healthy sex- and age-matched controls. In both groups a significant correlation was seen between IL-4 and PPTs over the finger and masseter muscle and this is referred to an antinociceptive effect of IL-4. In the healthy group the pro-inflammatory IL-8 correlated to the plasma βE levels. In the patients this correlation was absent, on the contrary, in TMJ DD IL-8 tended to be correlated to pain over masseter muscle. These findings indicate that βE is an important mediator in the balance between the nervous- and immune system.

Indirect comparison of etanercept, infliximab, and adalimumab for psoriatic arthritis: mixed treatment comparison using placebo as common comparator

Psoriatic arthritis (PsA) is a chronic inflammatory joint disorder that is commonly associated with skin psoriatic lesions and can lead to severe disability. Current pharmacologic therapy for PsA includes TNFα-blocking agents for patients who are intolerant of or have an inadequate response to conventional disease-modifying antirheumatic drugs. Currently, there are no published randomized controlled trials providing a head-to-head comparison of the effectiveness of the three TNFα-blocking agents used most often to treat patients with PsA (adalimumab, etanercept, and infliximab). In this study, we have performed the first indirect comparison among these biologic agents, in this setting, using a mixed treatment comparison analysis of the data from pivotal trials regarding efficacy profiles of adalimumab, etanercept, and infliximab evaluated as American College of Rheumatology (ACR) 20 response. Our results suggest that etanercept is expected to provide the greatest ACR20 response among the anti-TNFα agents compared with placebo in the treatment of patients with PsA unresponsive to conventional treatments. This analysis may be relevant for clinical decision-making, hence improving the management of PsA patients.

MO‐D‐220‐04: Imaging of Arthritis with Both Light and Ultrasound

Purpose: To explore the potential of photoacoustic tomography (PAT), as an emerging optical imaging technology, for early diagnosis of inflammatory joint disorders and accurate monitoring of disease progression and response to therapy. Methods: Pulsed laser light in the near‐infrared (NIR) region was directed toward a joint with resultant ultrasonic signals recorded and used to reconstruct images that present the optical properties in subsurface joint tissues. The feasibility of this bench‐top joint imaging system in delineating soft articular tissue structures in a noninvasive manner was validated first on rat models and then on human peripheral joints harvested from fresh cadavers. Based on the study on a commonly used adjuvant induced arthritis rat model, the capability of PAT to differentiate arthritic joints from the normal was also examined. Results: With sufficient imaging depth in the NIR region, PAT can realize tomographic imaging of a human or a small‐animal joint as a whole organ noninvasively. Based on the optical contrast, various intra‐ and extra‐articular tissues, including skin, fat, muscle, blood vessels, periosteum and bone, were presented successfully in images with satisfactory spatial resolution that was primarily limited by the bandwidth of detected photoacoustic signals rather than by optical diffusion as occurs in traditional optical imaging. In comparison with the images from the normal joints, significant differences were found in the images from the inflammatory joints, including enlarged periosteum diameter and enhanced intra‐articular optical absorption. Conclusions: By presenting additional optical contrast and tissue functional information such as blood volume and blood oxygen saturation, PAI is a natural and promising complement to conventional ultrasound technologies for musculoskeletal imaging. PAT, with its intrinsic advantages, may provide a unique opportunity to enable early diagnosis of inflammatory joint disorders, e.g. rheumatoid arthritis, and to monitor therapeutic outcomes with improved sensitivity and accuracy.

The pharmacokinetics of 124I-rituximab in patients with rheumatoid arthritis

Rheumatoid arthritis is a destructive inflammatory joint disorder. Pre- and mature B-cells, characterized by CD20 antigen expression, play an important role in the inflammatory process. Rituximab, a chimeric monoclonal antibody against the CD20 antig

Low-level laser irradiation treatment reduces CCL2 expression in rat rheumatoid synovia via a chemokine signaling pathway

Rheumatoid arthritis (RA) is an inflammatory joint disorder whose progression leads to the destruction of cartilage and bone. Although low-level laser irradiation (LLLI) is currently being evaluated for the treatment of RA, the molecular mechanisms underlying its effectiveness remain unclear. To investigate possible LLLI-mediated antiinflammatory effects, we utilized a collagen-induced arthritis (CIA) rat model and analyzed gene expression profiles in the synovial membranes of the knee joint. Total RNA was isolated from the synovial membrane tissue of the joints of untreated CIA rats or CIA rats treated with LLLI (830 nm Ga-Al-As diode), and gene expression profiles were analyzed by DNA microarray (41,000 rat genes), coupled with Ingenuity pathways analysis (IPA). DNA microarray analysis showed that CCL2 gene expression was increased in CIA tissue, and that LLLI treatment significantly decreased CIA-induced CCL2 mRNA levels. IPA revealed that chemokine signal pathways were involved in the activation of CCL2 production. These microarray data were further validated using real-time PCR and reverse transcription PCR. Immunohistochemistry confirmed that CCL2 production was decreased in CIA rats treated with LLLI. These findings suggest that decreased CCL2 expression may be one of the mechanisms involved in LLLI-mediated RA inflammation reduction.

REDUCTION OF CXCR4 EXPRESSION IN RHEUMATOID ARTHRITIS RAT JOINTS BY LOW LEVEL DIODE LASER IRRADIATION

Rheumatoid arthritis (RA) is an inflammatory joint disorder, whose progression leads to the destruction of cartilage and bone. Chemokines and their receptors are potential therapeutic targets in RA. Among these, it has been suggested that CXC chemokine 4 (CXCR4) and its ligand CXC ligand 12 (CXCL12) are involved in RA pathogenesis. Low-level laser irradiation (LLLI) is currently being evaluated for the treatment of RA; however, the molecular mechanisms underlying its effectiveness remain unclear. To understand the anti-inflammatory effect of LLLI, we used the collagen-induced arthritis (CIA) rat as RA model and analyzed the gene expression profile in synovial membrane in the hindpaw joints of control, CIA and CIA + LLLI. Expression of CXCR4 and CXCL12 genes were also studied. Total RNA was isolated from the synovial membrane tissue of CIA rat joints or CIA joints treated with LLLI (830 nm Ga-Al-As diode), and gene expression profiles were analyzed by DNA microarray (41,000 rat genes). The mRNA levels were confirmed by reverse transcription polymerase chain reaction (RT-PCR) and real-time PCR. Immunohistochemical examination to examine CXCR4 protein expression was also carried out. DNA microarray analysis showed that CXCR4 gene expression was increased in CIA tissue and LLLI treatment significantly decreased CIA-induced CXCR4 mRNA levels. In contrast, CXCL12 did not show any significant changes. The microarray data of CXCR4 mRNA levels were further validated using RT-PCR and real-time PCR. Increased CXCR4 mRNA levels by CIA and its reduction following LLLI was successfully confirmed. CXCR4 production was increased in CIA joints and its production was decreased by LLLI. Decreased CXCR4 expression may be one of the mechanisms in LLLI-mediated reduction of RA inflammation.

Evaluation of the disease modifying activity of Colchicum luteum Baker in experimental arthritis

Colchicum luteum (CL) has been traditionally used in the Unani system of medicine as a chief ingredient of many polyherbal formulations for the treatment of joint pain and rheumatoid arthritis (RA). To evaluate the antiarthritic activity of CL hydroalcoholic extract (CLHE) in formaldehyde and complete Freund's adjuvant (CFA) induced arthritis. Arthritis was induced by administration of either formaldehyde (2% v/v) or CFA into the subplantar surface of the hind paw of the animal. Joint swelling was measured on days 8, 9 and 10 in formaldehyde induced arthritis and days 3, 7, 14 and 21 in CFA induced arthritis. In order to evaluate the effect of CLHE on disease progression, serum TNF-α level and synovial expression of proinflammatory mediators (TNF-R1, IL-6 and IL-1β) was determined in CFA induced arthritis. CLHE produced a significant and dose dependent inhibition of joint swelling during the entire duration of the study in both, formaldehyde and CFA induced arthritis. Serum TNF-α level was also reduced significantly in a dose dependent manner in all the CLHE treated groups. The expression of proinflammatory mediators (TNF-R1, IL-6 and IL-1β) was also found to be less in the CLHE treated group as compared to control. We believe that the antiarthritic activity of CLHE was due to its modulatory effect on the expression of proinflammatory cytokine in the synovium. Our results contribute towards validation of the traditional use of CL in the treatment of RA and other inflammatory joint disorders.

Challenges in Economic Evaluation of Psoriatic Arthritis

Psoriatic arthritis (PsA) is a heterogeneous chronic inflammatory disorder of the peripheral joints, peripheral entheses, synovial sheaths of tendons, and spine associated with psoriasis. PsA is characterized by different clinical phenotypes and its course is variable1. Patients can also have gut2 and eye involvement3. In addition, patients with PsA or psoriasis have increased frequency of insulin resistance, obesity, type 2 diabetes, metabolic syndrome, hypertension, hyperlipidemia, and cardiovascular disease compared with the general population4. Recently, a new designation has been proposed with the aim to cover all these clinical situations: psoriatic disease5. In the past, PsA was considered a rare and mild disease. The prevalence of psoriasis in the general population is currently estimated to be around 2%–3%, with one-third of patients developing associated musculoskeletal manifestations. In the last 20 years, evidence has been gathered demonstrating that PsA is destructive and deforming in 40%–60% of patients, with joint damage emerging in the first years of the disease course6. It is believed that around 20% of patients with PsA develop a serious destructive disease. Patients with PsA suffer from functional impairment, decreased quality of life (QOL), and psychosocial disability, and have a significant increase in mortality versus the general population7,8. Therapies for PsA have been inadequate until recently. Nonsteroidal antiinflammatory drugs are useful in improving symptoms but have no effect on the progression of radiographic joint damage. Local corticosteroid injections may be of great aid in patients with persistent mono- or oligoarthritis but use of systemic glucocorticoid treatment is not supported by evidence. Traditional disease-modifying antirheumatic drugs (DMARD), which are the second-line treatment, are employed in PsA to control symptoms, but there is no evidence that they slow the progression of structural joint damage. The introduction of …

Protective effect of eotaxin-2 inhibition in adjuvant-induced arthritis

Eotaxin-2 is a potent chemoattractant for eosinophils, basophils and T helper type 2 (Th2) lymphocytes. The eotaxin-2/CCL24 receptor CCR3 is expressed in human brain, skin, endothelium and macrophages. The aim of the current study was to evaluate the protective effect of a monoclonal anti-eotaxin-2 antibody on the development of adjuvant-induced arthritis in rats (AIA). Adjuvant arthritis was induced in Lewis rats by intradermal injection of incomplete Freund's adjuvant +Mycobacterium tuberculosis. Rats were treated by intraperitoneal (i.p.) injection with three monoclonal antibodies against eotaxin-2 (G7, G8, D8) three times per week. Controls were treated with total mouse immunoglobulin G (IgG), methotrexate (MTX) or phosphate-buffered saline (PBS). Arthritis severity was evaluated by measuring ankle swelling, arthritic score, whole animal mobility and body weight. Sample joints were obtained for pathological evaluation and postmortem X-ray of ankle joints was performed to document erosions. Significant inhibition of arthritis was observed in rats treated with anti-eotaxin-2 antibodies compared to those treated with immunoglobulin or PBS. Inhibition was manifest in ankle diameter, arthritic score and mobility score. The antibody marked D8 showed the greatest efficacy. The effect was observed both in animals treated before the appearance of arthritis and in those where treatment was begun after development of joint inflammation. Combined treatment with D8 and MTX caused additional protection. Significant reduction of inflammation in D8-treated animals was also demonstrated in pathological and X-ray examinations. Inhibition of eotaxin-2 by monoclonal antibodies has a significant protective effect in adjuvant arthritis. These results may introduce a novel therapeutic target in rheumatoid arthritis and additional inflammatory joint disorders.

Effect of Low-Level Laser Irradiation on CXCL13 Gene Expression in Rheumatoid Arthritis Rat Joints

Rheumatoid arthritis (RA) is an inflammatory joint disorder, the progression of which leads to the destruction of cartilage and bone. Low-level laser irradiation (LLLI) is currently being evaluated for the treatment of RA, but the molecular mechanism underlying the effectiveness of LLLI in RA is unclear. B-cell-attracting chemokine-1 (CXCL13) is classified as a lymphoid chemokine and is a potent B-cell chemoattractant, leading to the local production of the autoantibody. The objective of this study was to determine whether LLLI decreased CXCL13 gene expression in joints of collagen-induced RA (CIA) rats. CIA caused swelling of rat joints, and LLLI significantly decreased the swelling. Total RNA was isolated from synovial membrane tissue of CIA rat joints with or without treatment from an 830 nm Ga-Al-As diode LLLI, and gene expression profiles were analyzed by DNA microarray (rat 41,000 genes). DNA microarray analysis showed that CXCL13 gene expression was increased in CIA tissue, and that LLLI significantly decreased the CIA-induced CXCL13 mRNA level. The reduction in CXCL13 gene expression was confirmed by reverse transcription polymerase chain reaction (RT-PCR) and real-time PCR. The findings suggest that decreased CXCL13 gene expression may be one of mechanisms involved in the reduction of inflammation in RA by LLLI.

Rationale of using different biological therapies in rheumatoid arthritis

Due to ongoing developments of novel agents in the field of biological pharmacotherapy, there are now more arrows available in clinicians' quivers for the treatment of rheumatic conditions. As a consequence, however, clear treatment strategies have to be defined in order to guarantee a qualitatively high and individually stage-adapted, state-of-the-art regimen for affected patients. This review summarizes recent evidence regarding the rationale of using different biological therapies to treat rheumatoid arthritis, the most common inflammatory joint disorder after activated osteoarthritis, and draws an actual picture of a possible standardized therapeutic algorithm without claiming exclusive appropriateness.

Calcifying Tendonitis of the Shoulder Joint

Calcifying tendonitis is a degenerative inflammatory joint disorder. Pain relief can be successfully achieved with low-dose radiotherapy. It is actually unknown which types of calcifying tendonitis respond to radiotherapy and which do not. The authors tried to get predictive objectives for the response to radiotherapy on the basis of different morphological patterns of calcifications evaluated by X-ray and ultrasound. Between August 1999 and September 2002, a total of 102 patients with 115 painful shoulder joints underwent low-dose radiotherapy. At the beginning of radiotherapy, every shoulder joint was examined with a radiograph in two planes. In addition, sonography was performed before and during therapy. This examination was repeated 6 and 18 months after irradiation. Radiotherapy consisted of two series with a total dose of 6.0 Gy. 29 joints with calcifying tendonitis could be further divided using the sonographic and radiographic classification according to Farin and Gärtner, respectively. Pain relief was achieved in 94/115 joints (82%) at a follow-up of 18 months (median). A different response to radiotherapy was found using the sonographic classification of Farin: calcifying tendonitis type III (n = 18) responded well in contrast to a significantly worse result in type I (n = 11). The radiologic classification did not provide a predictive value. Sonographic classification of calcifying tendonitis is predictive for the outcome after radiotherapy. Especially patients with Farin type III calcification will benefit from low-dose radiotherapy.