Neoepitopes as biomarkers of cartilage catabolism

Progressive degradation of articular cartilage is a central feature of arthritis and a major determinant of long term joint dysfunction. There are no treatments able to halt the progression of cartilage destruction presently available, and monitoring the benefit of potential therapies is hampered by our inability to measure the "health" of articular cartilage. Serial radiographic assessment of joint space narrowing, the current gold standard, requires measurements over a prolonged time (1-5 years) and is prone to technical difficulties. Other strategies for evaluating cartilage degradation are needed to enable both short and long term monitoring of disease progression and response to therapy. One avenue that holds promise is the use of biomarkers that accurately reflect the degradative state of the articular cartilage. Antibodies that recognise terminal amino acid sequences generated by proteolysis at specific sites in the core protein of both aggrecan and type II collagen (neoepitope antibodies) have become available in recent years. These antibodies have been invaluable for identifying the proteinases responsible for cartilage breakdown both in vitro and in vivo. The presence of neoepitope sequences generated by specific metalloenzyme cleavage of aggrecan and type II collagen correlates well with the progression of cartilage degeneration, both in vitro and in mouse models of arthritis. Preliminary results with quantitative assays of type II collagen neoepitopes suggest that they may be useful markers of joint disease in humans. Long term studies correlating neoepitope concentration with clinical and radiographic disease are now required to validate the utility of neoepitopes as surrogate markers of cartilage degeneration and joint disease.     

Current understanding of rheumatoid arthritis

A full understanding of rheumatoid arthritis depends on the appreciation of clinical, radiological, immunological, genetic, biochemical, and structural mechanisms. Rheumatoid arthritis is characterized by the destruction of tissue structures such as articular cartilage and bone, but may also involve tendonous tissue, artery walls, cardial structures, and sciera of the eye. Structural analysis of tissue obtained by biopsy and operation in rheumatoid arthritis patients reveals a complicated mosaic of different components, which are together responsible for the clinical symptoms and destructive nature of the disease.     

Current Status of Gene Therapy for Rheumatoid Arthritis

Despite the high prevalence of the disease, at present little effective pharmacological treatment of rheumatoid arthritis is available. Novel approaches utilising biological agents have resulted in the development of new antiarthritic and antiinflammatory agents, such as tumour necrosis factor-alpha (TNFalpha)-specific antibodies and interleukin-1 receptor antagonist (IL-1ra). Local gene therapy not only allows the pharmaceutical use of these biologicals, but also allows for continuous drug supply, which is necessary for chronic diseases like rheumatoid arthritis. We discuss the basics of rheumatoid arthritis therapy, candidate genes and possible gene transfer methods. A current clinical gene therapy trial is focusing on the IL-1 system using IL-1ra as a transgene. The transfer system, clinical protocol and preliminary results are described. After treatment of 11 patients we feel that gene therapy will offer potential as a new avenue to treat rheumatoid arthritis.     

Functional biomaterials for cartilage regeneration

The injury and degeneration of articular cartilage and associated arthritis are leading causes of disability worldwide. Cartilage tissue engineering as a treatment modality for cartilage defects has been investigated for over 20 years. Various scaffold materials have been developed for this purpose, but has yet to achieve feasibility and effectiveness for widespread clinical use. Currently, the regeneration of articular cartilage remains a formidable challenge, due to the complex physiology of cartilage tissue and its poor healing capacity. Although intensive research has been focused on the developmental biology and regeneration of cartilage tissue and a diverse plethora of biomaterials have been developed for this purpose, cartilage regeneration is still suboptimal, such as lacking a layered structure, mechanical mismatch with native cartilage and inadequate integration between native tissue and implanted scaffold. The ideal scaffold material should have versatile properties that actively contribute to cartilage regeneration. Functional scaffold materials may overcome the various challenges faced in cartilage tissue engineering by providing essential biological, mechanical, and physical/chemical signaling cues through innovative design. This review thus focuses on the complex structure of native articular cartilage, the critical properties of scaffolds required for cartilage regeneration, present strategies for scaffold design, and future directions for cartilage regeneration with functional scaffold materials.     

Tofacitinib for the treatment of rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic inflammatory disease that affects approximately 1% of the worldwide population. It primarily targets the synovial membrane of joints, leading to a synovial proliferation, joint cartilage lesion and erosions in the adjacent bone tissue. The disease is usually progressive and if the inflammatory process is not adequately suppressed, joint deformity takes place, leading to a significant functional disability and work incapacity. Over the last decade, biological therapy was established as a major step towards disease control in those patients who experienced failure after treatment with disease-modifying antirheumatic drugs. Despite the growing number of biological agents with different immunological targets, a significant number of patients do not receive appropriate disease control, or have the use of these agents limited because of adverse events. As such, the search for new molecules with a higher efficacy and better safety profile is ongoing. This article focuses on a new drug, tofacitinib, which is a synthetic disease-modifying antirheumatic drug for treatment of RA. Preclinical studies in arthritis and transplantation animal models are reviewed as a background for the possible use of tofacitinib treatment in humans. Four Phase II (one A and three B dose-ranging) trials lasting from 6 to 24 weeks in RA patients showed significant American College of Rheumatology 20 improvements as early as week 2 and sustained at week 24 in two studies. Tofacitinib Phase III studies in RA are included in a clinical program called 'ORAL Trials'. Long-term follow-up from ongoing studies will contribute to a more accurate tofacitinib efficacy and safety profile. Trials in other illness such as psoriasis, psoriatic arthritis, renal transplant rejection prevention, inflammatory bowel diseases and dry eye are underway.     

In vivo morphometry and functional analysis of human articular cartilage with quantitative magnetic resonance imaging – from image to data, from data to theory

Analyses of form-function relationships and disease processes in human articular cartilage necessitate in vivo assessment of cartilage morphology and deformational behavior. MR imaging and advanced digital post-processing techniques have opened novel possibilities for quantitative analysis of cartilage morphology, structure, and function in health and disease. This article reviews work on three-dimensional post-processing of MR image data of articular cartilage, summarizing studies on the accuracy and precision of quantitative analyses in human joints. It presents normative values on cartilage volume, thickness, and joint surface areas in the human knee, and describes the correlation between different joints and joint surfaces as well as their association with gender, body dimensions, and age. The article summarizes ongoing work on functional adaptation of articular cartilage to mechanical loading, analyses of in situ cartilage deformation in intact joints in vivo and in vitro, and the quantitative evaluation of cartilage tissue loss in osteoarthritis. We describe evolving techniques for assessment of the structural/biochemical composition of articular cartilage, and discuss future perspectives of quantitative cartilage imaging in the context of joint mechanics, mechano-adaptation, epidemiology, and osteoarthritis research. Specifically, we show that fat-suppressed gradient echo sequences permit valid analysis of cartilage morphology, both in healthy and severely osteoarthritic joints, as well as highly reproducible measurements (CV%=1 to 3% in the knee, and 2 to 10% in the ankle). Relatively small differences in cartilage morphology exist between both limbs of the same person (～5%), but large differences between individuals (CV% ～20%). Men display only slightly thicker cartilage then women (～10%), but significantly larger joint surface areas (～25%), even when accounting for differences in body weight and height. Weight and height represent relatively poor predictors of cartilage thickness (r² <15%), but muscle cross section areas display more promising correlations (r² >40%). The level of physical exercise (sportive activity) does not account for interindividual differences in cartilage thickness. The thickness appears to decrease slightly in the elderly – in particular in women, even in the absence of osteoarthritic cartilage lesions. Strenuous physical exercises (e.g., knee bends) cause a 6% patellar cartilage deformation in young individuals, but significantly less deformation in elderly men and women (<3%). The time required for full recovery after exercise (fluid flow back into the matrix) is relatively long (～90 min). Static in situ compression of femoropatellar cartilage with 150% body weight produces large deformations after 4 h (～30% volume change), but only very little deformation during the first minutes of loading. Quantitative analyses of magnetization transfer and proton density hold promise for biochemical evaluation of articular cartilage, and are shown to be related to the deformational behavior of the cartilage. Application of these techniques to larger cohorts of patients in epidemiological and clinical studies will establish the role of quantitative cartilage imaging not only in basic research on form-function relationships of articular cartilage, but also in clinical research and management of osteoarthritis.     

Tolerancia oral en artritis experimental inducida por antígeno en conejos por administración de hidrolizado de cartílago articular

Rheumatoid arthritis is an autoimmune disease characterized by polyarticular inflammation, swelling and inflammation that affects more than 1% of the world population. The pathobiology of rheumatoid arthritis involves several cell populations as T lymphocytes, B, macrófagosy fibroblasts, and a complex proinflammatory cytokines interactions. Conventional and biologic therapies do not always work or produce only a partial improvement. Immunological tolerance is a mechanism by which the immune system prevents autoreactivity. The aim of this pilot study was to evaluate the efficacy of peptides from an from articular cartilage hydrolysate extracted of tarsus (HCA) for the treatment of rheumatoid arthritis in a model of rheumatoid arthritis (AAE) in rabbits. AAE animals showed inflammation and pain within de first month of the primary immunization that was reversed in the AAE + HCA group. The control group showed a normal unnaffected synovial tissue. The AAE group revealed an inflamatory process whith synovial hyperplasia, filtering in lymphocytes and vascular proliferation. The treated group decreased significantly inflammation, lymphocyte proliferation and angiogenesis. Arthritic rabbits increased the levels in flammatory markers as nitric oxide, interferon gamma (INF-ɣ) and tumor necrosis factor alpha (TNF-α) compared to control and significantly reduced levels of interleukin 4 (IL-4). The treatment showed a significant reduction of nitricoxide, IFN-gamma and TNF-alpha and an increase in IL-4. This work suggests that this therapy may be useful in the clinical aspect and the biochemical and immune parameters. Future studies with larger numbers of animals and other laboratory parameters may provide additional evidence in this regard.     

Tofacitinib for the treatment of rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic inflammatory disease that affects approximately 1% of the worldwide population. It primarily targets the synovial membrane of joints, leading to a synovial proliferation, joint cartilage lesion and erosions in the adjacent bone tissue. The disease is usually progressive and if the inflammatory process is not adequately suppressed, joint deformity takes place, leading to a significant functional disability and work incapacity. Over the last decade, biological therapy was established as a major step towards disease control in those patients who experienced failure after treatment with disease-modifying antirheumatic drugs. Despite the growing number of biological agents with different immunological targets, a significant number of patients do not receive appropriate disease control, or have the use of these agents limited because of adverse events. As such, the search for new molecules with a higher efficacy and better safety profile is ongoing. This article focuses on a new drug, tofacitinib, which is a synthetic disease-modifying antirheumatic drug for treatment of RA. Preclinical studies in arthritis and transplantation animal models are reviewed as a background for the possible use of tofacitinib treatment in humans. Four Phase II (one A and three B dose-ranging) trials lasting from 6 to 24 weeks in RA patients showed significant American College of Rheumatology 20 improvements as early as week 2 and sustained at week 24 in two studies. Tofacitinib Phase III studies in RA are included in a clinical program called ‘ORAL Trials’. Long-term follow-up from ongoing studies will contribute to a more accurate tofacitinib efficacy and safety profile. Trials in other illness such as psoriasis, psoriatic arthritis, renal transplant rejection prevention, inflammatory bowel diseases and dry eye are underway.     

In vivo morphometry and functional analysis of human articular cartilage with quantitative magnetic resonance imaging--from image to data, from data to theory

Analyses of form-function relationships and disease processes in human articular cartilage necessitate in vivo assessment of cartilage morphology and deformational behavior. MR imaging and advanced digital post-processing techniques have opened novel possibilities for quantitative analysis of cartilage morphology, structure, and function in health and disease. This article reviews work on three-dimensional post-processing of MR image data of articular cartilage, summarizing studies on the accuracy and precision of quantitative analyses in human joints. It presents normative values on cartilage volume, thickness, and joint surface areas in the human knee, and describes the correlation between different joints and joint surfaces as well as their association with gender, body dimensions, and age. The article summarizes ongoing work on functional adaptation of articular cartilage to mechanical loading, analyses of in situ cartilage deformation in intact joints in vivo and in vitro, and the quantitative evaluation of cartilage tissue loss in osteoarthritis. We describe evolving techniques for assessment of the structural/biochemical composition of articular cartilage, and discuss future perspectives of quantitative cartilage imaging in the context of joint mechanics, mechano-adaptation, epidemiology, and osteoarthritis research. Specifically, we show that fat-suppressed gradient echo sequences permit valid analysis of cartilage morphology, both in healthy and severely osteoarthritic joints, as well as highly reproducible measurements (CV%=1 to 3% in the knee, and 2 to 10% in the ankle). Relatively small differences in cartilage morphology exist between both limbs of the same person (approximately 5%), but large differences between individuals (CV% approximately 20%). Men display only slightly thicker cartilage then women (approximately 10%), but significantly larger joint surface areas (approximately 25%), even when accounting for differences in body weight and height. Weight and height represent relatively poor predictors of cartilage thickness (r2 <15%), but muscle cross section areas display more promising correlations (r2 >40%). The level of physical exercise (sportive activity) does not account for interindividual differences in cartilage thickness. The thickness appears to decrease slightly in the elderly--in particular in women, even in the absence of osteoarthritic cartilage lesions. Strenuous physical exercises (e.g., knee bends) cause a 6% patellar cartilage deformation in young individuals, but significantly less deformation in elderly men and women (<3%). The time required for full recovery after exercise (fluid flow back into the matrix) is relatively long (approximately 90 min). Static in situ compression of femoropatellar cartilage with 150% body weight produces large deformations after 4 h (approximately 30% volume change), but only very little deformation during the first minutes of loading. Quantitative analyses of magnetization transfer and proton density hold promise for biochemical evaluation of articular cartilage, and are shown to be related to the deformational behavior of the cartilage. Application of these techniques to larger cohorts of patients in epidemiological and clinical studies will establish the role of quantitative cartilage imaging not only in basic research on form-function relationships of articular cartilage, but also in clinical research and management of osteoarthritis.     

The cast of clasts: catabolism and vascular invasion during bone growth,repair, and disease by osteoclasts,chondroclasts, and septoclasts

Three named cell types degrade and remove skeletal tissues during growth, repair, or disease: osteoclasts, chondroclasts, and septoclasts. A fourth type, unnamed and less understood, removes nonmineralized cartilage during development of secondary ossification centers. “Osteoclasts,” best known and studied, are polykaryons formed by fusion of monocyte precursors under the influence of colony stimulating factor 1 (CSF)-1 (M-CSF) and RANKL. They resorb bone during growth, remodeling, repair, and disease. “Chondroclasts,” originally described as highly similar in cytological detail to osteoclasts, reside on and degrade mineralized cartilage. They may be identical to osteoclasts since to date there are no distinguishing markers for them. Because osteoclasts also consume cartilage cores along with bone during growth, the term “chondroclast” might best be reserved for cells attached only to cartilage. “Septoclasts” are less studied and appreciated. They are mononuclear perivascular cells rich in cathepsin B. They extend a cytoplasmic projection with a ruffled membrane and degrade the last transverse septum of hypertrophic cartilage in the growth plate, permitting capillaries to bud into it. To do this, antiangiogenic signals in cartilage must give way to vascular trophic factors, mainly vascular endothelial growth factor (VEGF). The final cell type excavates cartilage canals for vascular invasion of articular cartilage during development of secondary ossification centers. The “clasts” are considered in the context of fracture repair and diseases such as arthritis and tumor metastasis. Many observations support an essential role for hypertrophic chondrocytes in recruiting septoclasts and osteoclasts/chondroclasts by supplying VEGF and RANKL. The intimate relationship between blood vessels and skeletal turnover and repair is also examined.     

Short-Term Contact Kinematic Changes and Longer-Term Biochemical Changes in the Cartilage After ACL Reconstruction: A Pilot Study

Investigation of the development of cartilage degeneration after ACL reconstruction is important for improving current surgical treatment of ACL injuries to prevent long-term knee joint degeneration. This pilot study examined the relationship between the changes in weight-bearing knee contact kinematics 6 months after ACL reconstruction and the biochemical composition changes in the knee cartilage measured using T2 relaxation values 3 years after the surgery in seven patients. The analysis indicated that the change of the knee contact kinematics in short-term after ACL reconstruction is associated with an increase of T2 values of the cartilage in longer follow up times. The data of this study could provide preliminary data to power future studies that use prospective, longitudinal research and large patient populations to establish prognostic biomechanical markers for determination of long-term cartilage degeneration after ACL reconstruction.     

Biochemical markers of bone remodeling: pre-analytical variations and guidelines for their use. SFBC (Société Française de Biologie Clinique) Work Group. Biochemical markers of bone remodeling

Biochemical markers of bone turnover have been developed over the past 20 years that are more specific for bone tissue than conventional ones such as total alkaline phosphatase and urinary hydroxyproline. They have been widely used in clinical research and in clinical trials of new therapies as secondary end points of treatment efficacy. Most of the interest has been devoted to their use in postmenopausal osteoporosis, a condition characterized by subtle modifications of bone metabolism that cannot be detected readily by conventional markers of bone turnover. Although several recent studies have suggested that biochemical markers may be used for the management of the individual patient in routine clinical practice, this has not been clearly defined and is a matter of debate. Because of the crucial importance to clarify this issue, the Société Francaise de Biologie Clinique prompted an expert committee to summarize the available data and to make recommendations. The following paper includes a review on the biochemical and analytical aspects of the markers of bone formation and resorption and on the sources of variability such as sex, age, menstrual cycle, pregnancy and lactation, physical activity, seasonal variation and effects of diseases and treatments. We will also describe the effects of pre-analytical factors on the measurements of the different markers. Finally based on that review, we will make practical recommendations for the use of these markers in order to minimize the variability of the measurements and improve the clinical interpretation of the data.     

PCR-SSO typing in HLA-disease association studies

Associations between a large number of diseases and markers within the major histocompatibility complex (MHC) have been described. In particular, susceptibility to several autoimmune disorders, including type I diabetes mellitus and rheumatoid arthritis, is linked to genes within the MHC and strong population associations are demonstrable between certain HLA class II alleles and these conditions. Genetic mapping of HLA susceptibility loci has traditionally relied on the use of phenotypic markers defined by alloantisera, cellular typing reagents and biochemical analysis of histocompatibility antigens. Polymerase chain reaction sequence-specific oligonucleotide (PCR-SSO) typing combines the ability to define the finest of HLA specificities, by analysis of the corresponding DNA sequences, with the possibility of study large populations of normal and affected individuals. The applications of this technology to characterizing precisely the MHC loci associated with susceptibility to autoimmune diseases such as rheumatoid arthritis, type I diabetes mellitus, coeliac disease and pemphigus vulgaris are reviewed here.     

Enzyme and combination therapy with cyclosporin A in the rat developing adjuvant arthritis

Recent knowledge of the pathophysiology of rheumatoid arthritis and the mechanism of drug effects have enabled the use of new drugs and drug combinations in rheumatoid arthritis therapy. This study investigates the efficacy of both enzyme therapy and combined therapy with cyclosporin in rats with adjuvant arthritis. Rats with adjuvant-induced arthritis were administered either cyclosporin A (2.5 or 5.0 mg/kg/day per os), a mixture of enzymes (Phlogenzym (PHL); 45 mg/kg twice daily intrarectally), or a combination of 2.5 mg cyclosporin A and 90 mg PHL for a period of 40 days from the adjuvant application. Levels of serum albumin, changes in hind paw swelling and bone erosions were measured in rats as variables of inflammation and arthritis-associated destructive changes. Treatment with 5 mg of cyclosporin A, as well as with the combination therapy with cyclosporin A plus PHL, significantly inhibited both the inflammation and destructive arthritis-associated changes. However, 2.5 mg of cyclosporin A and PHL alone inhibited these disease markers, although to a lesser extent and at a later stage of arthritis development. The results show the inhibitory effect of enzyme therapy on rat adjuvant arthritis, as well as the efficacy of a low dose of cyclosporin A given in combination with enzyme therapy, which may be useful in the treatment of rheumatoid arthritis.     

Immunogenicity of Mycobacterium tuberculosis RD1 region gene products in infected cattle

Rheumatoid arthritis (RA) is a chronic inflammatory disease primarily affecting cartilaginous joints but also extra-articular tissues such as the nose and upper respiratory tract. We have investigated extra-articular cartilage involvement in two commonly used animal models for RA, collagen-induced and pristane-induced arthritis, by immunizing rats with different susceptibility to disease (LEW.1 A, LEW.1F and DA rats). We found that nasal and tracheolaryngeal cartilage is affected in LEW.1 A and DA rats to varying degrees in collagen-induced arthritis but not in any strain in the pristane-induced model. Antibodies to matrilin-1, a cartilage-specific protein expressed mainly in tracheolaryngeal and nasal cartilage but not in joints, were positively associated with the presence of inflammation in nasal cartilage. In contrast, no antibody response to matrilin-1 could be detected in pristane-induced arthritis. In addition, nasal vaccination with collagen type II prior to immunization in DA rats significantly decreased the antibody response to matrilin-1 at day 56, but not at earlier time points, indicating a late protective effect on extra-articular cartilage. We conclude that pristane-induced arthritis is a joint-specific model whereas collagen-induced arthritis affect joints as well as extra-articular cartilage. Furthermore, collagen immunization induces an antibody response to matrilin-1.     

Correlating high‐resolution magic angle spinning NMR spectroscopy and gene analysis in osteoarthritic cartilage

Osteoarthritis (OA) is a common multifactorial and heterogeneous degenerative joint disease, and biochemical changes in cartilage matrix occur during the early stages of OA before morphological changes occur. Thus, it is desired to measure regional biochemical changes in the joint. High‐resolution magic angle spinning (HRMAS) NMR spectroscopy is a powerful method of observing cartilaginous biochemical changes ex vivo, including the concentrations of alanine and N‐acetyl, which are markers of collagen and total proteoglycan content, respectively. Previous studies have observed significant changes in chondrocyte metabolism of OA cartilage via the altered gene expression profiles of ACAN, COL2A1 and MMP13, which encode aggrecan, type II collagen and matrix metalloproteinase 13 (a protein crucial in the degradation of type II collagen), respectively. Employing HRMAS, this study aimed to elucidate potential relationships between N‐acetyl and/or alanine and ACAN, COL2A1 and/or MMP13 expression profiles in OA cartilage. Thirty samples from the condyles of five subjects undergoing total knee arthroplasty to treat OA were collected. HRMAS spectra were obtained at 11.7 T for each sample. RNA was subsequently extracted to determine gene expression profiles. A significant negative correlation between N‐acetyl metabolite and ACAN gene expression levels was observed; this provides further evidence of N‐acetyl as a biomarker of cartilage degeneration. The alanine doublet was distinguished in the spectra of 15 of the 30 specimens of this study. Alanine can only be detected with HRMAS NMR spectroscopy when the collagen framework has been degraded such that alanine is sufficiently mobile to form a distinguished peak in the spectrum. Thus, HRMAS NMR spectroscopy may provide unique localized measurements of collagenous degeneration in OA cartilage. The identification of imaging markers that could provide a link between OA pathology and chondrocyte metabolism will facilitate the development of more sensitive diagnostic techniques and will improve methods of monitoring treatment for patients suffering from OA. Copyright © 2015 John Wiley & Sons, Ltd.     

Understanding inflammation in juvenile idiopathic arthritis: How immune biomarkers guide clinical strategies in the systemic onset subtype

The translation of basic insight in immunological mechanisms underlying inflammation into clinical practice of inflammatory diseases is still challenging. Here we describe how—through continuous dialogue between bench and bedside—immunological knowledge translates into tangible clinical use in a complex inflammatory disease, juvenile idiopathic arthritis (JIA). Systemic JIA (sJIA) is an autoinflammatory disease, leading to the very successful use of IL‐1 antagonists. Further immunological studies identified new immune markers for diagnosis, prediction of complications, response to and successful withdrawal of therapy. Myeloid related protein (MRP)8, MRP14, S100A12, and Interleukin‐18 are already used daily in clinic as markers for active sJIA. For non‐sJIA subtypes, HLA‐B27, antinuclear‐antibodies, rheumatoid factor, erythrocyte sedimentation rate, and C‐reactive protein are still used for classification, prognosis or active disease. MRP8, MRP14, and S100A12 are now under study for clinical practice. We believe that with biomarkers, algorithms can soon be designed for the individual risk of disease, complications, damage, prediction of response to, and successful withdrawal of therapy. In that way, less time will be lost and less pain will be suffered by the patients. In this review, we describe the current status of immunological biomarkers used in diagnosis and treatment of JIA.     

How to interpret viral markers in the management of chronic hepatitis B infection

BackgroundHepatitis B virus (HBV) infection is a global public health issue with several unsolved clinical challenges. As multiple new drugs are under development, HBV markers are gaining importance for both diagnostic and prognostic purposes.ObjectivesThis review summarizes the most important data on the usefulness of HBV markers in the natural history of this infection, and in predicting clinical and treatment outcomes.SourcesSelected peer-reviewed publications on HBV markers published between January 2009 and July 2021.ContentIn addition to the classical markers (e.g. HBV-DNA), newer ones, such as quantitative HBsAg, HBcrAg, HBV-RNA and quantitative anti-HBc, have proven useful for predicting events within the natural history of HBV infection, the development of complications (e.g. hepatocellular carcinoma) and the response to antiviral therapy. Most data regarding the response to treatment have been related to nucleos(t)ide analogues, whereas evidence on new therapeutic agents, such as capsid assembly modulators or small interference RNAs, is promising, but still scarce.ImplicationsKnowledge on the use of viral markers is a key factor for optimizing the clinical appraisal of HBV infection. The new markers have an enhanced ability to predict clinical outcomes. Further studies should expand the current evidence on the use of markers in relation to antiviral agents currently under evaluation. Wide availability of these markers in regions with a high incidence of HBV infection is of paramount importance.     

Whole body low dose irradiation improves the course of beginning polyarthritis in human TNF-transgenic mice

Rheumatoid arthritis (RA) displays a chronic inflammatory joint disease, accompanied by symmetric polyarthritis (PA) which evokes synovial inflammation, cartilage damage, and bone erosion. Patients with RA are routinely treated by immunosuppressive drugs. The therapy of inflammatory diseases and degenerative disorders with Low-dose radiotherapy (LD-RT) (single doses from 0.3 to 1.0 Gy) represents a low cost therapy with low toxicity, and is able to substitute at least in part treatment with drugs. The efficiency of LD-RT has already been proven in several animal models of inducible arthritis. In the present study we used a human TNF transgenic mouse model to examine the effects of LD-RT on PA. We observed a significant temporal improvement of the clinical progression of disease when mice were irradiated at the beginning of the disease. These data emphasize the role of LD-RT in clinical settings to treat patients with chronic and degenerative disorders and diseases.     

Cell sources for the regeneration of articular cartilage: the past,the horizon and the future

Avascular, aneural articular cartilage has a low capacity for self‐repair and as a consequence is highly susceptible to degradative diseases such as osteoarthritis. Thus the development of cell‐based therapies that repair focal defects in otherwise healthy articular cartilage is an important research target, aiming both to delay the onset of degradative diseases and to decrease the need for joint replacement surgery. This review will discuss the cell sources which are currently being investigated for the generation of chondrogenic cells. Autologous chondrocyte implantation using chondrocytes expanded ex vivo was the first chondrogenic cellular therapy to be used clinically. However, limitations in expansion potential have led to the investigation of adult mesenchymal stem cells as an alternative cell source and these therapies are beginning to enter clinical trials. The chondrogenic potential of human embryonic stem cells will also be discussed as a developmentally relevant cell source, which has the potential to generate chondrocytes with phenotype closer to that of articular cartilage. The clinical application of these chondrogenic cells is much further away as protocols and tissue engineering strategies require additional optimization. The efficacy of these cell types in the regeneration of articular cartilage tissue that is capable of withstanding biomechanical loading will be evaluated according to the developing regulatory framework to determine the most appropriate cellular therapy for adoption across an expanding patient population.