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.

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.

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.

Midterm results of the treatment of cartilage defects in the knee using alginate beads containing human mature allogenic chondrocytes.

BACKGROUND: The treatment of chondral lesions is still an important challenge for the orthopaedic surgeon. Attempts have been made to restore cartilage lesions by filling the defects with a temporary biocompatible matrix. PURPOSE: The authors present their midterm experience with the implantation of alginate beads containing human mature allogenic chondrocytes for the treatment of cartilage lesions 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 cartilage lesions in the knee. Twenty-one patients were clinically prospectively evaluated with use of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and a visual analog scale (VAS). The mean follow-up time was 6.3 years (range, 5-8 years). Magnetic resonance imaging (MRI) data were analyzed based on the MOCART (Magnetic Resonance Observation of Cartilage Repair Tissue) system, allowing morphologic assessment of the repair tissue. Magnetic resonance images were taken at 1 year of follow-up and at a mean follow-up of 6.1 years (range, 5-7 years). RESULTS: During the follow-up period, the WOMAC and VAS scores improved significantly. No signs of clinical deterioration or adverse reactions to the alginate beads/allogenic chondrocyte implantation were observed. Four failures occurred during the follow-up period in this study (19.05%). The MOCART scores were moderate and remained stable in time. CONCLUSION: This investigation provided useful information on the efficacy of the implantation of alginate beads containing human mature allogenic chondrocytes for the treatment of cartilage lesions in the knee. The midterm clinical outcome of the presented technique was satisfactory. However, these results were not confirmed by the MRI findings.

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.

Predictors of functional impairment and pain in erosive osteoarthritis of the interphalangeal joints: comparison with controlled inflammatory arthritis.

OBJECTIVE: To compare levels of pain and functional limitation in patients with erosive osteoarthritis (OA) of the interphalangeal finger joints with those in patients with nonerosive OA and patients with controlled inflammatory arthritis affecting the hands, and to explore predictors of functional impairment in erosive OA. METHODS: A cross-sectional study including 270 patients with OA of the hands who were referred to rheumatology clinics was performed. A group of patients with inflammatory arthritis (rheumatoid arthritis or psoriatic arthritis) with a low Disease Activity Score in 28 joints (<3.2; n = 79) was examined. Levels of functional impairment (measured by the Functional Index for Hand OA [FIHOA] and Australian/Canadian OA Hand Index [AUSCAN]) and pain were compared between the groups. Predictors of functional impairment in erosive OA were evaluated by generalized linear models. RESULTS: Of 270 patients with hand OA, 167 (61.9%) were classified as having erosive OA. Despite a higher percentage of patients taking analgesics (almost 60%), patients with erosive OA had worse functional outcome and pain scores than patients with controlled inflammatory arthritis or nonerosive OA. Pain scores remained significantly higher in patients with erosive OA after correction for potential confounders. FIHOA and AUSCAN function scores showed a trend toward more disability in patients with erosive OA. Female sex and the number of radiographic affected joints (consisting of joints in the erosive and remodeled radiographic phases) were the strongest predictors of functional impairment in erosive OA. Whether the carpometacarpal joints were affected did not influence functional status in patients with erosive OA. CONCLUSION: Our findings indicate that patients with erosive OA have more functional impairment and significantly more pain compared to patients with controlled inflammatory arthritis affecting the hands. This highlights the significant clinical burden of erosive OA and warrants the search for new treatment strategies.

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.

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.

Optimized alkylated cyclodextrin polysulphates with reduced risks on thromboembolic accidents improve osteoarthritic chondrocyte metabolism.

OBJECTIVES: To compare the ability of different cyclodextrin polysulphate (CDPS) derivatives to affect human articular cartilage cell metabolism in vitro. METHODS: OA chondrocytes were cultured in alginate and exposed to 5 µg/ml of 2,3,6-tri-O-methyl-ß-cyclodextrin (ME-CD), 2,3-di-O-methyl-6-sulphate-ß-cyclodextrin (ME-CD-6-S), 2,6-di-O-methyl-3-sulphate-ß-cyclodextrin (ME-CD-3-S), (2-carboxyethyl)-ß-CDPS (CE-CDPS), (2-hydroxypropyl)-ß-CDPS (HP-CDPS), 6-monoamino-6-monodeoxy-ß-CDPS (MA-CDPS) or ß-CDPS for 5 days. Effects on IL-1-driven chondrocyte extracellular matrix (ECM) metabolism were assayed by analysis of the accumulation of aggrecan in the interterritorial matrix, IL-6 secretion and qPCR. MA-CDPS, HP-CDPS, CE-CDPS and CDPS were analysed for their in vitro effect on coagulation and their ability to activate platelets in an in vitro assay to detect possible cross-reactivity with heparin-induced thrombocytopenia (HIT) antibodies. RESULTS: The monosulphated cyclodextrins ME-CD-6-S and -3-S failed to affect aggrecan synthesis and IL-6 secretion by the OA chondrocytes. Polysulphated cyclodextrins MA-CDPS, HP-CDPS, CE-CDPS and CDPS at 5 µg/ml concentrations, on the other hand, significantly induced aggrecan production and repressed IL-6 release by the chondrocytes in culture. aPTT and PT for all derivatives were lengthened for polysaccharide concentrations >50 µg/ml. Five micrograms per millilitre of ß-CDPS concentrations that significantly modulated ECM ground substance production in vitro did not affect aPTT or PT. Furthermore, CE-CDPS, in contrast to MA-CDPS, HP-CDPS and CDPS, did not significantly activate platelets, suggesting a minimal potential to induce HIT thromboembolic accidents in vivo. CONCLUSIONS: CE-CDPS is a new, structurally adjusted, sulphated ß-cyclodextrin derivative with preserved chondroprotective capacity and a promising safety profile.

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.

Reliability and construct validity of ultrasonography of soft tissue and destructive changes in erosive osteoarthritis of the interphalangeal finger joints: a comparison with MRI.

OBJECTIVES: To study the reliability and construct validity of ultrasound in interphalangeal finger joints affected by erosive osteoarthritis (EOA) and non-EOA with MRI as the reference method. METHODS: 252 joints were examined by ultrasound, conventional radiography and clinical examination. Ultrasound was performed using a high-frequency linear transducer (12 × 18 MHz). On the same day, magnetic resonance images of 112 joints were obtained on a 3.0 T magnetic resonance unit. The ultrasound and MRI images were re-read independently by other readers unaware of the diagnosis, clinical and other imaging findings. Interobserver reliability was calculated by the percentage of exact agreement obtained and κ statistics. With MRI as the reference method, the sensitivity and specificity of ultrasound in detecting structural (bone erosions and osteophytes) and soft tissue (effusion and grey-scale synovitis) changes in EOA were calculated. RESULTS: Ultrasound and MRI were found to be more sensitive in detecting erosions than conventional radiography in EOA. A high agreement between ultrasound and MRI in the assessment of bone erosions (77.7%), osteophytes (75.9%) and synovitis (86.5%) was present. A high percentage of inflammatory changes was found in EOA, and in smaller amount in non-EOA, both confirmed by MRI. Good interobserver reliability of ultrasound was obtained for all variables (all median κ > 0.8). CONCLUSION: Grey-scale ultrasound proved to be a reliable and valid imaging technique to assess erosions and soft tissue changes, compared with MRI as a reference method in EOA.

Differential mucosal expression of Th17-related genes between the inflamed colon and ileum of patients with inflammatory bowel disease.

BACKGROUND: Immunological and genetic findings implicate Th17 effector cytokines in the pathogenesis of inflammatory bowel disease (IBD). Expression of Th17 pathway-associated genes is mainly studied in colonic disease. The present study assessed the mRNA expression levels of Th17 effector cytokines (IL17A, IL17F, IL21, IL22 and IL26) and genes involved in differentiation (IL6, IL1B, TGFB1, IL23A and STAT3) and recruitment of Th17 cells (CCR6 and CCL20) by quantitative real-time PCR analysis of colonic and ileal biopsies from 22 healthy control subjects, 26 patients with Crohn's disease (CD) and 12 patients with ulcerative colitis (UC). Inflammation was quantified by measuring expression of the inflammatory mediators IL8 and TNF. RESULTS: Evaluation of mRNA expression levels in colonic and ileal control samples revealed that TNF, TGFB1, STAT3 and CCR6 were expressed at higher levels in the ileum than in the colon. Expression of all the Th17 pathway-associated genes was increased in inflamed colonic samples. The increased expression of these genes was predominantly observed in samples from UC patients and was associated with more intense inflammation. Although increased expression of IL17A, IL17F, IL21 and IL26 was detected in inflamed ileal samples, expression of the indispensable Th17 cell differentiation factors TGFB1 and IL23A, the signaling molecule STAT3 and the Th17 recruitment factors CCR6 and CCL20 were unchanged. CONCLUSIONS: Our findings suggest that immune regulation is different in colonic and ileal disease, which might have important consequences for therapeutic intervention.

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.

Structural and inflammatory sonographic findings in erosive and non-erosive osteoarthritis of the interphalangeal finger joints.

OBJECTIVE: The objectives were: (1) to determine if ultrasound (US) can detect more erosions in erosive osteoarthritis (EOA) of the interphalangeal (IP) joints than conventional radiography (CR); and (2) to explore the frequency of structural and inflammatory findings in EOA and non-EOA. METHODS: Structural changes and the anatomical phase were scored on CR in IP joints of 31 patients with EOA and 7 patients with non-EOA. Structural and inflammatory changes were scored by US. The frequency of sonographic findings was compared between the anatomical phases and between EOA and non-EOA by generalised estimation equation (GEE) modelling. RESULTS: US detected 68 of 72 (94.4%) erosions seen on CR. US detected 45 additional erosive joints in EOA. The frequency of joint effusion and power Doppler signal was similar in EOA compared to non-EOA (p = 0.91 and p = 0.68, respectively). Statistically significantly more synovitis was present in full erosive phase compared to non-erosive phases in EOA (p=0.04). No differences in inflammatory findings were found between non-erosive phases in EOA and non-EOA. CONCLUSION: US is capable of detecting erosions in radiographic non-erosive phases. The highest frequency of synovitis is present in erosive joints but inflammatory findings are common in all anatomical phases of EOA and non-EOA.

A multiparameter approach to monitor disease activity in collagen-induced arthritis.

INTRODUCTION: Disease severity in collagen-induced arthritis (CIA) is commonly assessed by clinical scoring of paw swelling and histological examination of joints. Although this is an accurate approach, it is also labour-intensive and the application of less invasive and less time-consuming methods is of great interest. However, it is still unclear which of these methods represents the most discriminating measure of disease activity. METHODS: We undertook a comparative analysis in which different measurements of inflammation and tissue damage in CIA were studied on an individual mouse level. We compared the current gold standard methods - clinical scoring and histological examination - with alternative methods based on scoring of X-ray or micro-computed tomography (CT) images and investigated the significance of systemically expressed proteins, involved in CIA pathogenesis, that have potential as biomarkers. RESULTS: Linear regression analysis revealed a marked association of serum matrix metalloproteinase (MMP)-3 levels with all features of CIA including inflammation, cartilage destruction and bone erosions. This association was improved by combined detection of MMP-3 and anti-collagen IgG2a antibody concentrations. In addition, combined analysis of both X-ray and micro-CT images was found to be predictive for cartilage and bone damage. Most remarkably, validation analysis using an independent data set proved that variations in disease severity, induced by different therapies, could be accurately represented by predicted values based on the proposed parameters. CONCLUSIONS: Our analyses revealed that clinical scoring, combined with serum MMP-3, anti-collagen IgG2a measurement and scoring of X-ray and micro-CT images, yields a comprehensive insight into the different aspects of disease activity in CIA.