RANKL blockade for erosive hand osteoarthritis: a randomized placebo-controlled phase 2a trial.

Erosive hand osteoarthritis (OA) is a prevalent and disabling disease with limited treatment options. Here we present the results of a monocentric, placebo-controlled, double-blind, randomized phase 2a clinical trial with denosumab, a receptor activator of nuclear factor-κB ligand inhibitor, evaluating the effects on structure modification in erosive hand OA. Patients were randomized to 48 weeks treatment with denosumab 60 mg every 3 months (n = 51, 41 females) or placebo (n = 49, 37 females). The primary (radiographic) endpoint was the change in the total Ghent University Scoring System (GUSS) at week 24, where positive changes correspond to remodeling and negative changes to erosive progression. Secondary endpoints were the change in the GUSS at week 48 and the number of new erosive joints at week 48 by the anatomical phase scoring system. Baseline mean GUSS (standard deviation) of target joints was 155.9 (69.3) in the denosumab group and 158.7 (46.8) in the placebo group. The primary endpoint was met with an estimated difference between groups of 8.9 (95% confidence interval (CI) 1.0 to 16.9; P = 0.024) at week 24. This effect was confirmed at week 48 (baseline adjusted GUSS (standard error of the mean) denosumab and placebo were 163.5 (2.9) and 149.2 (3.9), respectively; with an estimated difference between groups of 14.3 (95% CI 4.6 to 24.0; P = 0.003)). At patient level, more new erosive joints were developed in the placebo group compared with denosumab at week 48 (odds ratio 0.24 (95% CI 0.08 to 0.72); P = 0.009). More adverse events occurred in the placebo group (125 events in 44 patients (90%)) compared with the denosumab group (97 events in 41 patients (80%)). These results demonstrate that denosumab has structure modifying effects in erosive hand OA by inducing remodeling and preventing new erosive joints. EU Clinical Trials Register identifier 2015-003223-53 .

Etanercept in patients with inflammatory hand osteoarthritis (EHOA): a multicentre, randomised, double-blind, placebo-controlled trial.

OBJECTIVE: Hand osteoarthritis is a prevalent disease with limited treatment options. Since joint inflammation is often present, we investigated tumour necrosis factor (TNF) as treatment target in patients with proven joint inflammation in a proof-of-concept study. METHODS: This 1-year, double-blind, randomised, multicentre trial (NTR1192) enrolled patients with symptomatic erosive inflammatory hand osteoarthritis. Patients flaring after non-steroidal anti-inflammatory drug washout were randomised to etanercept (24 weeks 50 mg/week, thereafter 25 mg/week) or placebo. The primary outcome was Visual Analogue Scale (VAS) pain at 24 weeks. Secondary outcomes included clinical and imaging outcomes (radiographs scored using Ghent University Scoring System (GUSS, n=54) and MRIs (n=20)). RESULTS: Of 90 patients randomised to etanercept (n=45) or placebo (n=45), respectively, 12 and 10 discontinued prematurely. More patients on placebo discontinued due to inefficacy (6 vs 3), but fewer due to adverse effects (1 vs 6). The mean between-group difference (MD) in VAS pain was not statistically significantly different (-5.7 (95% CI -15.9 to 4.5), p=0.27 at 24 weeks; - 8.5 (95% CI -18.6 to 1.6), p=0.10 at 1 year; favouring etanercept). In prespecified per-protocol analyses of completers with pain and inflammation at baseline (n=61), MD was -11.8 (95% CI -23.0 to -0.5) (p=0.04) at 1 year. Etanercept-treated joints showed more radiographic remodelling (delta GUSS: MD 2.9 (95% CI 0.5 to 5.4), p=0.02) and less MRI bone marrow lesions (MD -0.22 (95% CI -0.35 to -0.09), p = 0.001); this was more pronounced in joints with baseline inflammation. CONCLUSION: Anti-TNF did not relieve pain effectively after 24 weeks in erosive osteoarthritis. Small subgroup analyses showed a signal for effects on subchondral bone in actively inflamed joints, but future studies to confirm this are warranted.

99mTc-labelled S-HYNIC certolizumab pegol in rheumatoid arthritis and spondyloarthritis patients: a biodistribution and dosimetry study.

BACKGROUND: Biologicals directed against tumour necrosis factor (TNF) have proven their efficacy in the treatment of spondyloarthritis and rheumatoid arthritis. We present a radiolabelling method for certolizumab pegol (CZP), a commercially available humanized Fab'-fragment directed against TNF. A biodistribution and dosimetry study was conducted. Tc-S-HYNIC CZP was synthesized. The in vitro TNF neutralizing activity was tested by exposing L929s-cells to various concentrations 99mTc-S-HYNIC CZP and measuring TNF-induced cytotoxicity. For biodistribution and dosimetry, WB images and blood and urine sampling were performed up to 24 h pi. Cumulative activities were estimated using mono-exponential fitting, and organ doses were estimated using OLINDA/EXM. The effective dose was calculated using the International Commission on Radiological Protection 103 recommendations. The uptake of the tracer in the peripheral joints was assessed visually and semiquantitatively. RESULTS: In vitro tests showed blocking of TNF cytotoxicity by the 99mTc-S-HYNIC CZP formulation comparable to the effect obtained with the unlabelled CZP with or without the HYNIC linker. We analysed eight patients with rheumatoid arthritis or spondyloarthritis. The highest mean absorbed organ doses were recorded for kidneys, spleen, and liver: 56 (SD 7), 34 (SD 6), and 33 (SD 7) µGy/MBq. The effective dose was 6.1 (SD 0.9) mSv for a mean injected activity of 690 (SD 35) MBq. The urinary excretion was 15.1% (SD 8.1) of the IA at 22.5 h. Blood analysis yielded a distribution half-life of 1.2 h (SD 1.5) and an elimination half-life of 26.9 h (SD 2.7). Visual analysis of the scans revealed marked tracer accumulation in the clinically affected peripheral joints. In addition, there was a statistically significant higher uptake of the tracer in the swollen joints (median uptake ratio compared to background of 3.3 in rheumatoid arthritis and 2.4 in peripheral spondyloarthritis) compared to clinically negative joints (respectively 1.3 and 1.6). CONCLUSIONS: We present a radiolabelling technique for CZP, a Fab'-fragment directed against TNF and currently used as a therapeutic agent in rheumatology. An effective dose of 6.1 mSv (SD 0.9) was estimated. We confirmed the uptake of this new radiopharmaceutical in clinically affected peripheral joints.

Histologic assessment of acetabular labrum healing.

PURPOSE: The purpose of this study was to histologically examine the human healing response of arthroscopically repaired acetabular labrum tears. METHODS: Biopsy specimens were retrieved from 6 patients during total hip arthroplasty after clinical failure of the index arthroscopic procedure. All patients were diagnosed as having femoroacetabular impingement with a concomitant labral tear. In all cases severe chondral damage was observed during arthroscopy (Beck grades 3 to 4). Despite successful technical repair of the labral tear, chondral damage in these patients was so advanced that the clinical progress after the procedure was unsatisfactory and arthroplasty of the joint was required. Biopsy specimens of the repaired acetabular labra were harvested during the arthroplasty surgery and processed for standard histologic evaluation. RESULTS: Macroscopically and histologically, all repaired labra kept their triangular shape more or less and appeared to have healed. All harvested biopsy specimens displayed a typical fibrocartilaginous appearance with limited vascular supply. Calcifications were present in only 1 biopsy specimen. In 3 cases neovascularization of the labral tissue was noticed in the proximity of the sutures. In the superficial and deep parts of the labral body, small clefts were observed in all cases. CONCLUSIONS: In this study the histologic aspects of arthroscopically repaired human labral tears were addressed. It was shown that human labral tears show healing potential after surgical repair. The surfaces of the labral tissues were intact, and neither remnants of the tear nor the presence of fibrovascular scar tissue was observed. However, some small clefts in the superior and deep parts of the repaired structures were noticed in all cases. LEVEL OF EVIDENCE: Level IV, therapeutic case series.

The use of scaffolds in the treatment of osteochondral lesions in the knee: current concepts and future trends.

Long after the first reports on human autologous chondrocyte implantation (ACI) by Brittberg in 1994, the development of a so-called optimal technology for osteochondral tissue regeneration is still one of the most challenging issues in knee surgery. Although the short- and intermediate-term results of ACI appear to be favorable, resources are being directed toward scaffold research to improve the technology. Scaffolds used for osteochondral repair may be either cell or noncell-based before its implantation in the knee. The characteristics that make scaffolds optimal for clinical use are that they be biocompatible, biodegradable, permeable, reproducible, mechanically stable, noncytotoxic, and capable of serving as a temporary support for the cells while allowing for eventual replacement by matrix components synthesized by the implanted cells. There is a growing interest in noncell and last-minute cell seeding technologies since they allow for a one-step surgery eliminating the morbidity and necessity of a previous chondral biopsy. Although clinical and histological results from many, already clinically available scaffolds seem to be promising, improvements throughout these technologies and the developments of new ones are still necessary to obtain a more efficient biological response as well as to improve the implant's stability. Moreover, as the understanding of interactions between articular cartilage and subchondral bone continues to evolve, increased attention should be directed at treatment options for the entire osteochondral unit, rather than focusing on the articular surface only.

A pilot study of the use of an osteochondral scaffold plug for cartilage repair in the knee and how to deal with early clinical failures.

PURPOSE: To present our short-term experience with an osteochondral scaffold plug (TruFit plug; Smith & Nephew, Andover, MA) for cartilage repair in the knee and, more importantly, to discuss our approach to treat early clinical failures. METHODS: Twenty patients were consecutively treated for their cartilage lesions with the plug technique. These patients were prospectively clinically evaluated at 6 and 12 months of follow-up. Magnetic resonance imaging (MRI) was used for morphologic analysis of the cartilage repair. Biopsy samples were taken from 3 cases during revision surgery, allowing histologic assessment of the repair tissue. RESULTS: The short-term clinical and MRI outcome of this pilot study are modest. No signs of deterioration of the repair tissue were observed. Of the 15 patients followed up during 1 year, 3 (20.0%) showed persistent clinical symptoms or even more clinical symptoms after insertion of the plug. These patients were considered as failures and therefore eligible for revision surgery. During revision surgery, the repair tissue was carefully removed. The remaining osteochondral defect was filled with autologous bone grafts. Immediate and persistent relief of symptoms was observed in all 3 patients. Histologic assessment of biopsy specimens taken during revision surgery showed fibrous vascularized repair tissue with the presence of foreign-body giant cells. CONCLUSIONS: The overall short-term clinical and MRI outcome of the osteochondral scaffold plug for cartilage repair in the knee is modest. In this pilot study a modest clinical improvement became apparent at 12 months of follow-up. MRI data showed no deterioration of the repair tissue. Of the 15 patients, 3 (20%) had persistent clinical symptoms after surgery. These patients were successfully treated with removal of the osteochondral plug remnants and the application of autologous bone grafts. LEVEL OF EVIDENCE: Level IV, therapeutic case series.

Tumour necrosis factor blockade for the treatment of erosive osteoarthritis of the interphalangeal finger joints: a double blind, randomised trial on structure modification.

BACKGROUND: Adalimumab blocks the action of tumor necrosis factor-α and reduces disease progression in rheumatoid arthritis and psoriatic arthritis. The effects of adalimumab in controlling progression of structural damage in erosive hand osteoarthritis (HOA) were assessed. METHODS: Sixty patients with erosive HOA on radiology received 40 mg adalimumab or placebo subcutaneously every two weeks during a 12-month randomized double-blind trial. Response was defined as the reduction in progression of structural damage according to the categorical anatomic phase scoring system. Furthermore, subchondral bone, bone plate erosion, and joint-space narrowing were scored according to the continuous Ghent University Score System (GUSSTM). RESULTS: The disease appeared to be active since 40.0% and 26,7% of patients out of the placebo and adalimumab group, respectively, showed at least one new interphalangeal (IP) joint that became erosive during the 12 months follow-up. These differences were not significant and the overall results showed no effect of adalimumab. Risk factors for progression were then identified and the presence of palpable soft tissue swelling at baseline was recognized as the strongest predictor for erosive progression. In this subpopulation at risk, statistically significant less erosive evolution on the radiological image (3.7%) was seen in the adalimumab treated group compared to the placebo group (14.5%) (P = 0.009). GUSSTM scoring confirmed a less rapid rate of mean increase in the erosion scores during the first 6 months of treatment in patients in adalimumab-treated patients. CONCLUSION: Palpable soft tissue swelling in IP joints in patients with erosive HOA is a strong predictor for erosive progression. In these joints adalimumab significantly halted the progression of joint damage compared to placebo.

Impairment and impact of pain in female patients with Ehlers-Danlos syndrome: a comparative study with fibromyalgia and rheumatoid arthritis.

OBJECTIVE: The purpose of this study was to investigate functional impairment and the impact of pain in patients with Ehlers-Danlos syndrome, hypermobility type (EDS-HT), and to compare the burden of disease with that in women with fibromyalgia (FM) and rheumatoid arthritis (RA). METHODS: A total of 206 female patients were compared (72 with EDS-HT, 69 with FM, and 65 with RA). Functional impairment was assessed with the Sickness Impact Profile (SIP), and the psychosocial impact of chronic pain was quantified with the Multidimensional Pain Inventory (MPI). Data on symptoms were collected. RESULTS: SIP results showed clinically relevant health-related dysfunction in all groups. Significantly poorer physical, psychosocial, and overall function was found in the EDS-HT group compared with the RA group. In comparison with the FM group, the EDS-HT group reported similar physical and overall function, but better psychosocial function. T scores from the MPI revealed significantly higher levels of pain severity and life interference due to pain, and a lower level of perceived life control, in the EDS-HT group compared to the RA group. In contrast, the EDS-HT group showed significantly lower levels of pain severity, life interference, and affective distress in comparison with the FM group. Social support for help in coping with pain was similar between the 3 groups. CONCLUSION: EDS-HT is associated with a consistent burden of disease, similar to that of FM and worse than that of RA, as well as a broad impact of chronic pain on daily life, which needs to be addressed in the health care system.

The effect of Lidocaine on the viability of cultivated mature human cartilage cells: an in vitro study.

PURPOSE: More and more orthopedic procedures are performed in an outpatient setting. A commonly used strategy in pain management is the intra-articular injection of local anesthetics. Recent attention has been drawn to their possible toxic effect on chondrocytes. Local anesthetics, and in particular Lidocaine, are also used for diagnostic joint infiltrations. A controlled laboratory study was performed to investigate the possible toxic effect of Lidocaine on human articular chondrocytes. METHODS: Mature human articular chondrocytes were harvested from the knees of human tissue donors or patients undergoing total knee replacement. The cells were exposed to Lidocaine 1 and 2% with and without epinephrine and to a saline 0.9% control group, with variable exposure times in different experiments. The activity and viability of the cells were assessed by lactate dehydrogenase activity, interleukin-6 production and a live/dead cell count. RESULTS: After a 1-h exposure, devastating results were seen for Lidocaine 1, 2 and 2% with epinephrine showing cell death rates of 91, 99 and 97%, respectively, compared with 26% in the saline control group (P-values of 0.004, 0.010, 0.006, respectively). Exposing the chondrocytes to a 50/50 mixture of culture medium and local anesthetics substantially decreased cytotoxicity but still showed high toxicity when compared with the saline group (90% dead cells for Lidocaine 2%, P = 0.047). Lidocaine also showed a time-dependent cytotoxicity with gradually more dead cells after exposure for 15, 30 or 60 min. CONCLUSION: In vitro, local anesthetics containing Lidocaine are significantly more toxic to mature human articular chondrocytes than a saline 0.9% control group. The effect of Lidocaine on the viability of human chondrocytes in vivo needs further investigation. However, based on our in vitro results, cautious use of intra-articular Lidocaine in clinical practice is recommended.

The use of adalimumab for cricoarytenoid arthritis in ankylosing spondylitis--an effective therapy.

This report describes cartilaginous regeneration in a cricoarytenoid joint affected by spondyloarthropathy using tumor necrosis factor-alpha (TNF-α) blockade, monitored by magnetic resonance (MR) and computed tomography (CT) imaging. This case is interesting for several reasons. It is only the eighth case of destructive ankylosing spondylitis-related cricoarytenoid arthritis published in the English language literature. It describes, for the first time, full recovery of vocal cord mobility following TNF-α blockade. It is also the first case to be published with MR imaging demonstrating regeneration of the cricoarytenoid cartilage following treatment. This case represents a landmark in the treatment of patients presenting with destructive arthritis involving the cricoarytenoid joint.

Osteoarthritis of the distal interphalangeal joint.

Osteoarthritis occurs with the highest prevalence in the distal interphalangeal joint of the hand and has been divided into an erosive and a nonerosive form. The pathogenesis of the early stages of osteoarthritis is poorly understood, but considerable emphasis has been placed on the role of cartilage and subchondral bone as well as soft tissue structures such as collateral ligaments and tendons. Radiographic evaluation represents the most standardized method to quantify disease progression, with different systems having been developed for defining and grading radiographic features. This current concepts article examines the recent knowledge base regarding the etiology, pathogenesis, and evaluation of osteoarthritis of the distal interphalangeal joint.

Proximal interphalangeal joint arthritis.

Proximal interphalangeal joint function is critical for proper finger and hand function and arthritis of this joint can lead to considerable hand impairment. Proximal interphalangeal joint arthritides are broadly categorized into nonerosive and erosive osteoarthritis (OA), posttraumatic arthritis, and inflammatory arthritis. The nonerosive type is considered idiopathic or primary OA, whereas the erosive form exhibits an inflammatory component. Idiopathic or primary OA occurs as a consequence of abnormal mechanical stress that leads to damage of cartilage and subchondral bone, with subsequent cytokine and growth factor activation. Individual genetics then mediate the cellular responses. Although erosive OA is described as a separate entity, this remains controversial, with many suggesting that it is merely a more aggressive form of nonerosive, primary OA. Inflammatory OA occurs when connective tissues are diseased, allowing for normal use to incite arthritic damage. Treatment modalities for proximal interphalangeal joint arthritis are currently limited.

Invariant natural killer T cells are natural regulators of murine spondylarthritis.

OBJECTIVE: To investigate the role of invariant natural killer T (iNKT) cells in TNF(DeltaARE/+) mice, an animal model of spondylarthritis (SpA) with both gut and joint inflammation. METHODS: The frequency and activation of iNKT cells were analyzed on mononuclear cells from the lymph nodes and livers of mice, using flow cytometry with alpha-galactosylceramide/CD1d tetramers and quantitative polymerase chain reaction for the invariant V(alpha)14-J(alpha)18 rearrangement. Bone marrow-derived dendritic cells (DCs) were obtained by expansion of primary cells with granulocyte-macrophage colony-stimulating factor followed by coculture with iNKT cell hybridomas, and interleukin-2 release into the cocultures was then measured by enzyme-linked immunosorbent assay (ELISA). Cytokine levels were determined by ELISA or cytometric bead array analyses of freshly isolated DCs and iNKT cells in mixed cocultures. TNF(DeltaARE/+) mice were backcrossed onto J(alpha)18(-/-) and CD1d(-/-) mice, and disease onset was evaluated by clinical scoring, positron emission tomography, and histology. CD1d levels were analyzed on mononuclear cells in paired blood and synovial fluid samples from patients with SpA compared with healthy control subjects. RESULTS: In the absence of iNKT cells, symptoms of gut and joint inflammation in TNF(DeltaARE/+)mice were aggravated. Invariant NKT cells were activated during the course of the disease. This was linked to an enrichment of inflammatory DCs, characterized by high levels of CD1d, particularly at draining sites of inflammation. A similar increase in CD1d levels was observed on DCs from patients with SpA. Inflammatory DCs from TNF(DeltaARE/+) mice stimulated iNKT cells to produce immunomodulatory cytokines, in the absence of exogenous stimulation. Prolonged, continuous exposure, but not short-term exposure, to tumor necrosis factor (TNF) was found to be responsible for the enhanced DC-NKT cell crosstalk. CONCLUSION: This mode of iNKT cell activation represents a natural counterregulatory mechanism for the dampening of TNF-driven inflammation.

Systemic levels of IL-23 are strongly associated with disease activity in rheumatoid arthritis but not spondyloarthritis.

OBJECTIVES: Th17 cells are an effector T-cell population that plays a role in chronic inflammatory conditions and is dependent on IL-23 for their survival and expansion. More recently, a genetic association was discovered between polymorphisms in the gene coding for the IL-23 receptor and spondyloarthritis. This study aimed to evaluate the role of Th17-associated cytokines in spondyloarthritis pathogenesis by measuring their levels in the joints and circulation as well as correlating them with disease activity parameters. METHODS: Paired synovial fluid (SF), serum and synovial biopsies were obtained from 30 non-PsA (psoriatic arthritis) spondyloarthritis, 22 PsA and 22 rheumatoid arthritis (RA) patients. IL-17, IL-23 and CCL20 were measured by ELISA in the SF and serum of patients and correlated with systemic and local parameters of disease activity. RESULTS: Concentrations of CCL20, a major Th17-attracting chemokine, tended to be higher in the joints of RA than in spondyloarthritis patients. Interestingly, levels of CCL20 were markedly higher in SF as opposed to serum. In addition, there was a remarkable association between the expression of the Th17 cytokine system and the presence of intimal lining layer hyperplasia in RA. Also in the serum, there was a tendency for higher IL-23 levels in RA, which correlated strongly with disease activity parameters. CONCLUSIONS: Th17-related cytokines are expressed in joints of spondyloarthritis as well as RA patients. IL-23 levels, however, correlate with disease activity parameters in RA only. These results point towards a differential regulation of the Th17 cytokine system in spondyloarthritis compared with RA.

Treatment of cartilage defects in the knee using alginate beads containing human mature allogenic chondrocytes.

BACKGROUND: The repair of osteochondral lesions is imperfect and transient; chondral lesions do not heal in mature cartilage. Attempts have been made to restore cartilage lesions by filling the defects with a temporary artificial biocompatible matrix. PURPOSE: To determine whether the implantation of alginate beads containing human mature allogenic chondrocytes is feasible and safe for the treatment of symptomatic cartilage defects in the knee. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: A biodegradable, alginate-based, biocompatible scaffold containing human mature allogenic chondrocytes was used for the treatment of chondral and osteochondral lesions in the knee. Twenty-one patients were clinically and prospectively evaluated with use of the Western Ontario and McMaster Universities Osteoarthritis Index and a visual analog scale for pain preoperatively and at 3, 6, 9, 12, 18, and 24 months of follow-up. Of the 21 patients, 13 consented to having a biopsy sample taken for investigative purposes from the area of implantation at 12 months of follow-up, allowing histologic assessment of the repair tissue. RESULTS: A statistically significant clinical improvement became apparent after 6 months, and patients improved during the 24 months of follow-up. Adverse reactions to the alginate/fibrin matrix seeded with the allogenic cartilage cells were not observed. Histologic analysis of the biopsy specimens rated the repair tissue as hyaline-like in 15.3% of the samples, as mixed tissue in 46.2%, as fibrocartilage in 30.8%, and as fibrous in 7.7%. CONCLUSION: The results of this short-term pilot study show that the alginate-based scaffold containing human mature allogenic chondrocytes is feasible and safe for the treatment of symptomatic cartilage defects of the knee. The described technique provides clinical and histologic outcomes that are equal but not superior to those of other cartilage repair techniques.

Differential expression of alphaB-crystallin and evidence of its role as a mediator of matrix gene expression in osteoarthritis.

OBJECTIVE: Alpha B-crystallin belongs to the family of small heat-shock proteins (HSPs). The role of this protein family in chondrocytes is not well understood. The present study was undertaken to investigate expression levels of alphaB-crystallin in chondrocytes isolated from healthy subjects and patients with osteoarthritis (OA), and to explore the functional role of this potentially interesting protein in chondrocyte metabolism. METHODS: Western blot and real-time reverse transcriptase-polymerase chain reaction (RT-PCR) analyses were performed to determine expression levels of alphaB-crystallin in healthy and OA chondrocytes cultured in alginate beads. RNA interference-mediated gene knockdown was used to explore the role of this small HSP in chondrocyte biology, by transfecting low concentrations of small interfering RNA (siRNA) in cultured chondrocytes. RESULTS: We initially identified alphaB-crystallin as a small HSP that was differentially expressed between healthy and OA-affected chondrocytes. The decreased abundance of this protein in OA chondrocytes was confirmed by Western blotting. Moreover, real-time RT-PCR confirmed the differential expression between chondrocytes isolated from visibly intact and visibly damaged zones of OA cartilage. The proinflammatory cytokines interleukin-1beta and tumor necrosis factor alpha both down-regulated alphaB-crystallin expression. Transfection of low concentrations of siRNA in cultured chondrocytes resulted in efficient knockdown of alphaB-crystallin gene expression. This was accompanied by altered expression of the chondrocyte-specific bone morphogenetic protein 2, aggrecan, and type II collagen genes. CONCLUSION: The present findings identify the small HSP alphaB-crystallin as a novel mediator of chondrocyte matrix gene expression that may contribute to altered chondrocyte metabolism during the development of OA.

Clinical observations programme in SpA: disease parameters, treatment options and practical management issues.

Spondyloarthritides (SpAs) are a cluster of chronic inflammatory rheumatic diseases that typically involve inflammation of axial and peripheral joint or tendon and ligament insertions, distinct radiographic changes and diverse extra-articular features. Conventional treatments relieve the signs and symptoms but do not prevent disease progression. TNFalpha inhibitors provide clinicians with the potential to treat the underlying pathology and to alter disease progression. By targeting the underlying inflammatory mechanisms, TNFalpha blockade can treat any extra-articular manifestations of SpA.

A single early activation of invariant NK T cells confers long-term protection against collagen-induced arthritis in a ligand-specific manner.

The glycosphingolipid alpha-galactosylceramide (alpha-GalCer) has been shown to be a potent activator of invariant NKT (iNKT) cells, rapidly inducing large amounts of both Th1 and Th2 cytokines upon injection in mice. The C-glycoside analog of alpha-GalCer (alpha-C-GalCer), by contrast, results in an enhanced Th1-type response upon activation of iNKT cells. We administered a single dose of these Ags to DBA/1 mice during the early induction phase of collagen-induced arthritis and demonstrated therapeutic efficacy of alpha-GalCer when administered early rather than late during the disease. Surprisingly, the Th1-polarizing analog alpha-C-GalCer also conferred protection. Furthermore, a biphasic role of IFN-gamma in the effect of iNKT cell stimulation was observed. Whereas in vivo neutralization of IFN-gamma release induced by either alpha-GalCer or alpha-C-GalCer early during the course of disease resulted in partial improvement of clinical arthritis symptoms, blockade of IFN-gamma release later on resulted in a more rapid onset of arthritis. Although no phenotypic changes in conventional T cells, macrophages, or APCs could be detected, important functional differences in T cell cytokine production in serum were observed upon polyclonal T cell activation, 2 wk after onset of arthritis. Whereas alpha-GalCer-treated mice produced significantly higher amounts of IL-10 upon systemic anti-CD3 stimulation compared with PBS controls, T cells from alpha-C-GalCer-treated mice, by contrast, produced substantially lower levels of cytokines, suggesting the involvement of different protective mechanisms. In conclusion, these findings suggest long-term, ligand-specific, time-dependent, and partially IFN-gamma-dependent immunomodulatory effects of iNKT cells in collagen-induced arthritis.

Osteochondral repair in synovial joints.

PURPOSE OF REVIEW: One of the major challenges in rheumatology remains the induction of osteochondral repair in synovial joints. Remarkable progress has been made in controlling the inflammatory pathways of chronic synovitis and tissue damage in rheumatoid arthritis and spondyloarthropathy. Here, we provide an overview of the current knowledge on the mechanisms involved in osteochondral repair in degenerative joint diseases, as well as in immune mediated inflammatory arthritides, with special emphasis on tumor necrosis factor alpha and IL-1. RECENT FINDINGS: Homeostasis of articular cartilage and subchondral bone are essential for maintaining the integrity of osteochondral structures within synovial joints. This is achieved by the regulation of a delicate balance between anabolic and catabolic signals. In articular cartilage one cell type, the chondrocyte, is responsible for regulation of homeostasis. In bone, however, two distinct cell types, osteoblasts and osteoclasts, are responsible for anabolic and catabolic pathways, respectively. In inflammatory joint disorders, this tight regulation is profoundly dysregulated, with tumor necrosis factor alpha acting as an important catalyst of a disturbed homeostasis, together with IL-1. Targeting these cytokines may restore the intrinsic repair capacity of osteochondral structures. SUMMARY: To restore catabolic cytokine balances appears to be a suitable strategy to promote osteochondral repair.