Gabriel Herrero-Beaumont

Eular evidence based recommendations for the management of hand osteoarthritis - report of a task force of the Eular Standing Committee for International Clinical Studies Including Therapeutics(ESCISIT)

Objectives: To develop evidence based recommendations for the management of hand osteoarthritis (OA). Methods: The multidisciplinary guideline development group comprised 16 rheumatologists, one physiatrist, one orthopaedic surgeon, two allied health professionals, and one evidence based medicine expert, representing 15 different European countries. Each participant contributed up to 10 propositions describing key clinical points for management of hand OA. Final recommendations were agreed using a Delphi consensus approach. A systematic search of Medline, Embase, CINAHL, Science Citation Index, AMED, Cochrane Library, HTA, and NICE reports was used to identify the best available research evidence to support each proposition. Where possible, the effect size and number needed to treat were calculated for efficacy. Relative risk or odds ratio was estimated for safety, and incremental cost effectiveness ratio was used for cost effectiveness. The strength of recommendation was provided according to research evidence, clinical expertise, and perceived patient preference. Results: Eleven key propositions involving 17 treatment modalities were generated through three Delphi rounds. Treatment topics included general considerations (for example, clinical features, risk factors, comorbidities), non-pharmacological (for example, education plus exercise, local heat, and splint), pharmacological (for example, paracetamol, NSAIDs, NSAIDs plus gastroprotective agents, COX-2 inhibitors, systemic slow acting disease modifying drugs, intra-articular corticosteroids), and surgery. Of 17 treatment modalities, only six were supported by research evidence (education plus exercise, NSAIDs, COX-2 inhibitors, topical NSAIDs, topical capsaicin, and chondroitin sulphate). Others were supported either by evidence extrapolated from studies of OA affecting other joint sites or by expert opinion. Strength of recommendation varied according to level of evidence, benefits and harms/costs of the treatment, and clinical expertise. Conclusion: Eleven key recommendations for treatment of hand OA were developed using a combination of research based evidence and expert consensus. The evidence was evaluated and the strength of recommendation was provided.

Glucosamine inhibits IL-1β-induced NFκB activation in human osteoarthritic chondrocytes

Abstract Objective : Glucosamine sulfate (GS) is a commonly used drug for the treatment of osteoarthritis. The mechanism of the action of this drug does, however, remain to be elucidated. In human osteoarthritic chondrocytes (HOC) stimulated with a proinflammatory cytokine, we studied whether GS could modify the NFκB activity and the expression of COX-2, a NFκB-dependent gene. Methods : Using HOC in culture stimulated with interleukin-1 β (IL-1β), the effects of GS on NFκB activation, nuclear translocation of NFκB/Rel family members, COX-1 and COX-2 expressions and syntheses and prostaglandin E2 (PGE2) concentration were studied. Results : GS significantly inhibited NFκB activity in a dose-dependent manner, as well as the nuclear translocation of p50 and p65 proteins. Furthermore, GS-preincubated IL-1β-stimulated HOC showed an increase in IκBα in the cell cytoplasm in comparison with HOC incubated with IL-1β alone. GS also inhibited the gene expression and the protein synthesis of COX-2 induced by IL-1β, while no effect on COX-1 synthesis was seen. GS also inhibited the release of PGE2 to conditioned media of HOC stimulated with IL-1β. Conclusions : GS inhibits the synthesis of proinflammatory mediators in HOC stimulated with IL-1β through a NFκB-dependent mechanism. Our study further supports the role of GS as a symptom- and structure-modifying drug in the treatment of OA.

Osteoarthritis associated with estrogen deficiency

Osteoarthritis (OA) affects all articular tissues and finally leads to joint failure. Although articular tissues have long been considered unresponsive to estrogens or their deficiency, there is now increasing evidence that estrogens influence the activity of joint tissues through complex molecular pathways that act at multiple levels. Indeed, we are only just beginning to understand the effects of estrogen deficiency on articular tissues during OA development and progression, as well as on the association between OA and osteoporosis. Estrogen replacement therapy and current selective estrogen receptor modulators have mixed effectiveness in preserving and/or restoring joint tissue in OA. Thus, a better understanding of how estrogen acts on joints and other tissues in OA will aid the development of specific and safe estrogen ligands as novel therapeutic agents targeting the OA joint as a whole organ.

Subchondral bone microstructural damage by increased remodelling aggravates experimental osteoarthritis preceded by osteoporosis

IntroductionOsteoporosis (OP) increases cartilage damage in a combined rabbit model of OP and osteoarthritis (OA). Accordingly, we assessed whether microstructure impairment at subchondral bone aggravates cartilage damage in this experimental model.MethodsOP was induced in 20 female rabbits, by ovariectomy and intramuscular injections of methylprednisolone hemisuccinate for four weeks. Ten healthy animals were used as controls. At week 7, OA was surgically induced in left knees of all rabbits. At 22 weeks, after sacrifice, microstructure parameters were assessed by micro-computed tomography, and osteoprotegerin (OPG), receptor activator of nuclear factor-κB ligand (RANKL), alkaline phosphatase (ALP) and metalloproteinase 9 (MMP9) protein expressions were evaluated by Western Blot at subchondral bone. In addition, cartilage damage was estimated using the histopathological Mankin score. Mann-Whitney and Spearman statistical tests were performed as appropriate, using SPSS software v 11.0. Significant difference was established at P < 0.05.ResultsSubchondral bone area/tissue area, trabecular thickness and polar moment of inertia were diminished in OPOA knees compared with control or OA knees (P < 0.05). A decrease of plate thickness, ALP expression and OPG/RANKL ratio as well as an increased fractal dimension and MMP9 expression occurred at subchondral bone of OA, OP and OPOA knees vs. controls (P < 0.05). In addition, the severity of cartilage damage was increased in OPOA knees vs. controls (P < 0.05). Remarkably, good correlations were observed between structural and remodelling parameters at subchondral bone, and furthermore, between subchondral structural parameters and cartilage Mankin score.ConclusionsMicrostructure impairment at subchondral bone associated with an increased remodelling aggravated cartilage damage in OA rabbits with previous OP. Our results suggest that an increased subchondral bone resorption may account for the exacerbation of cartilage damage when early OA and OP coexist simultaneously in same individuals.

A Sonographic Enthesitic Index of lower limbs is a valuable tool in the assessment of ankylosing spondylitis

Background: Enthesitis is a remarkable feature of ankylosing spondylitis (AS) not specifically approached by the available measuring tools for the disease. Ultrasonography (US) has proved to be an excellent technique for the assessment of tendon pathology. Objective: To test a Sonographic Entheseal Index (SEI) of the lower limbs in a cohort of patients with AS, as a potential measuring tool. Methods: 44 patients with AS and 10 healthy controls were enrolled. Bath Ankylosing Spondylitis Functional Index and Bath Ankylosing Spondylitis Disease Activity Index, pain at entheseal points, severity of symptoms, acute-phase reactants, Schober’s test and stage of sacroiliitis were recorded. Patients underwent US examination of five entheseal regions from both lower limbs by two experts. Hypoechogenicity, increased tendon thickness, peritendinous oedema and bursitis were considered signs of active inflammation. Insertional bone erosions, intratendinous calcifications, decreased thickness and tears were considered signs of chronic injury. Each alteration independently scored one point. Data were analysed with Spearman’s correlation method. Results: A significant interobserver correlation in SEI scores (p<0.001) and a fine discriminative power between controls and patients were observed. Acute entheseal lesions predominated (63% vs 37%), the most frequent alteration being tendon hypoechogenicity (43%). 72% of all lesions were located at the foot. The SEI correlated with reduction of Schober’s test (p<0.02), but not with other activity or severity parameters. Conclusions: A scoring method such as the SEI may be of help in characterising entheseal injury in AS, and for decision making in these patients.

Subchondral bone as a key target for osteoarthritis treatment.

Osteoarthritis (OA), the most common form of arthritis, is a debilitating and progressive disease that has become a major cause of disability and impaired quality of life in the elderly. OA is considered an organ disease that affects the whole joint, where the subchondral bone (SB) plays a crucial role. Regardless of whether SB alterations precede cartilage damage or appear during the evolution of the disease, SB is currently recognised as a key target in OA treatment. In fact, bone abnormalities, especially increased bone turnover, have been detected in the early evolution of some forms of OA. Systemic osteoporosis (OP) and OA share a paradoxical relationship in which both high and low bone mass conditions may result in induction and/or OA progression. Recent findings suggest that some drugs may be useful in treating both processes simultaneously, at least in a subgroup of patients with OA and OP. This review focuses on the role of SB in OA pathogenesis, describing relevant underlying mechanisms involved in the process and examining the potential activity as disease-modifying anti-osteoarthritic drugs (DMOADs) of certain SB-targeting agents currently under study.

A 40-month multicentre, randomised placebo-controlled study to assess the efficacy and carry-over effect of repeated intra-articular injections of hyaluronic acid in knee osteoarthritis: the AMELIA project

Objective AMELIA (OsteoArthritis Modifying Effects of Long-term Intra-articular Adant) was designed to compare against placebo the efficacy and safety of repeated injections of hyaluronic acid (HA) and its effect on disease progression over 40 months. Methods A multicentre, randomised, patient and evaluator-blinded, controlled study in 306 patients fulfilling American College of Rheumatology criteria for knee osteoarthritis, radiological grades II–III (Kellgren–Lawrence) and joint space width ≥2 mm. Patients received four cycles of five intra-articular HA or placebo injections with a follow-up of 6 months after the first and second cycles, and 1 year after the third and fourth cycles. Osteoarthritis Research Society International (OARSI) 2004 responder criteria were used to assess efficacy. The consumption of rescue medication was a secondary outcome. Adverse events were recorded for safety purposes. Results At the 40-month visit significantly more patients responded to HA compared with placebo (OARSI 2004, p=0.004). The number of responders to HA increased through the study, whereas those to placebo did not change. Significant differences were also found in favour of HA for each individual component of the OARSI 2004. No safety problems were recorded. Conclusions The results of AMELIA offer pioneer evidence that repeated cycles of intra-articular injections of HA not only improve knee osteoarthritis symptoms during the in-between cycle period but also exert a marked carry-over effect for at least 1 year after the last cycle. In this respect, it is not possible to establish if this carry-over effect reflects true osteoarthritis remission or just a modification of the diseases natural course. ClinicalTrials.gov number, NCT00669032

Characterization of a new experimental model of osteoporosis in rabbits

To characterize an experimental model of osteoporosis in rabbits induced either by ovariectomy (OVX), glucocorticoids, or by a combination of both. Thirty-five rabbits were randomly allocated into five groups: bilateral OVX, daily methylprednisolone hemisuccinate (MPH) injections at a 1.5 mg/kg/day dose for 4 consecutive weeks (MPH group), or variable dose of MPH between 0.5 and 2 mg/kg/day in combination with OVX (OVX + MPH at low, medium, and high dose). Twenty-two animals were killed 6 weeks after OVX, and 13 were killed 16 weeks later. Dual-energy X-ray absorptiometry was obtained at baseline and 6 and 16 weeks after OVX. High-resolution magnetic resonance imaging (MRI) was carried out at 0 and 6 weeks after OVX. Glucose, total cholesterol, triglyceride, and oestradiol blood levels before and 16 weeks after OVX were determined. Bone mineral density (BMD) decreased significantly at lumbar spine in MPH and OVX + MPH medium-dose groups, and at global knee and subchondral bone of the knee in MPH, OVX + MPH low- and medium-dosage groups (P < 0.05). BMD variations in OVX rabbits were not significant in any of the three anatomical locations analyzed. BMD variation 16 weeks after OVX was significant at lumbar spine and global knee in the OVX + MPH medium-dose group and only at global knee in the OVX + MPH low-dose group (P < 0.05). MRI did not show bone or cartilage changes. Osteoporosis can be induced experimentally in rabbits through isolated MPH or by a combination of OVX and medium dose corticosteroid for 4 weeks. OVX alone was not sufficient to induce osteoporosis.

Long term NSAID treatment inhibits COX-2 synthesis in the knee synovial membrane of patients with osteoarthritis: differential proinflammatory cytokine profile between celecoxib and aceclofenac

Objective: To compare the effect of celecoxib with that of a classic non-steroidal anti-inflammatory drug (NSAID) on synovial inflammation and on the synovial expression of proinflammatory genes in patients with knee osteoarthritis (OA). Methods: 30 patients with severe knee OA scheduled for total knee replacement surgery were included in a 3 month clinical trial. They were randomised to two groups: patients treated with celecoxib (CBX) (200 mg/24 h) and patients treated with aceclofenac (ACF) (100 mg/12 h). Those patients with OA who did not want to be treated with NSAIDs served as a control group. During knee surgery, synovial fluid (SF) and synovial membrane (SM) were collected. A SM specimen was fixed and embedded in paraffin and another part was frozen for molecular biology studies. Results: At the end of study both CBX and ACF treated patients showed a significant improvement in pain and knee function compared with controls. Both drugs significantly reduced prostaglandin E2 (PGE2) SF concentration and down regulated COX-2 mRNA and protein expression at the SM. However, synovial macrophage infiltration (CD68 antigen staining) and expression of proinflammatory mediators, such as interleukin 1β and tumour necrosis factor α, were decreased only by CBX treatment. Conclusion: Both drugs improved joint pain and function, inhibited SF PGE2 concentration, and induced a decrease in synovial COX-2 expression and synthesis not related to the tissue inflammatory status. These data suggest that PGE2 blocking agents may decrease PGE2 production not only by direct COX-2 inhibition but also by down regulating COX-2 expression and synthesis. However, CBX and ACF appear to have different anti-inflammatory profiles in controlling OA synovial macrophage infiltration and proinflammatory expression.

Improving subchondral bone integrity reduces progression of cartilage damage in experimental osteoarthritis preceded by osteoporosis

PURPOSE Impairment of subchondral bone density and quality aggravates cartilage damage in osteoarthritis (OA). Accordingly, we assessed whether improving microstructure and quality at subchondral bone by the bone-forming agent parathyroid hormone (PTH) [1-34] prevent cartilage damage progression in a rabbit model of OA preceded by osteoporosis (OP). METHODS OP was induced in 20 female rabbits. At week 7, these rabbits underwent knee surgery to induce OA and, at week 12, they started either saline vehicle (n=10) or PTH (n=10) for 10 weeks. Ten healthy animals were used as controls. At week 22, microstructure was assessed by micro-computed tomography and bone remodelling by protein expression of alkaline phosphatase (ALP), metalloproteinase-9 (MMP9), osteoprotegerin (OPG) and receptor activator of nuclear factor-κB ligand (RANKL) at subchondral bone. Cartilage damage was evaluated using Mankin score. RESULTS PTH reversed the decrease of bone area/tissue area, trabecular thickness, plate thickness, polar moment of inertia, ALP expression and OPG/RANKL ratio, as well as counteracted the increase of fractal dimension and MMP9 expression at subchondral bone of osteoarthritis preceded by osteoporosis (OPOA) rabbits compared to vehicle administration (P<0.05). Likewise, PTH decreased cartilage damage severity in OPOA rabbits. Good correlations were observed between subchondral bone structure or remodelling parameters, and cartilage Mankin score. CONCLUSIONS Improvement of microstructural and remodelling parameters at subchondral bone by PTH [1-34] contributed to prevent cartilage damage progression in rabbits with early OPOA. These findings support the role of subchondral bone in OA. Further studies are warranted to establish the place of bone-forming agents as potential treatment in OA.