[Joint manifestations in connective tissue diseases]. / Manifestations ostéo-articulaires dans les connectivites.

Joint manifestations are common and often constitute the first symptoms or signs of a connective tissue disease, which should be carefully looked for, according to the clinic, in particular with ultrasound and the research of autoantibodies. Articular manifestations are often severe and must be treated accordingly. In lupus, one can distinguish non-deforming non-erosive arthropathy, Jaccoud's arthropathy (deforming non-erosive) and erosive arthropathy (rhupus). Ultrasound has recently shown that destructive forms are in fact more frequent than initially considered. In addition, lupus can be complicated by necrosis or fractures, which are characterized by mechanical pain. In other connective tissue diseases, similar forms of arthropathies and complications are found, with some distinctions.

[Diagnostic imaging for atraumatic shoulder pain]. / Epaule douloureuse atraumatique: diagnostic radiologique.

Shoulder pain is a common cause of consultation in primary care medicine. A detailed history and a carefully carried out physical exam allow to orientate the diagnosis towards an intrinsic or extrinsic cause and to the differential diagnosis. Rotator cuff injury is the most frequent affection. Plain radiography will often be done in first intention since it identifies direct or indirect signs associated with certain pathologies. Ultrasonography is an excellent way of evaluating soft tissue injury and allows a diagnosis in most cases (rotator cuff injury, tendinopathy of the long head of the biceps, bursitis, effusion, calcifications). Other imaging studies may be carried out depending on the pathology suspected.

EULAR recommendations for calcium pyrophosphate deposition. Part II: management.

OBJECTIVES: To develop evidence-based recommendations for management of calcium pyrophosphate deposition (CPPD). METHODS: A multidisciplinary guideline development group of 15 experts, representing 10 European countries, generated key propositions for management of CPPD using a Delphi consensus approach. For each recommendation research evidence was searched systematically. Whenever possible, the effect size and number needed to treat for efficacy and RR or OR for side effects were calculated for individual treatment modalities. Strength of recommendation was assessed by the European League Against Rheumatism visual analogue scale. RESULTS: Nine key recommendations were generated, including topics for general management, treatment of acute attacks, prophylaxis against recurrent acute attacks and management of chronic symptoms. It was recommended that optimal treatment requires both non-pharmacological and pharmacological treatments. For acute CPP crystal arthritis, cool packs, temporary rest and joint aspiration combined with steroid injection are often sufficient. For prophylaxis or chronic inflammatory arthritis with CPPD, oral non-steroidal anti-inflammatory drugs with gastroprotective treatment and/or low-dose colchicine 0.5-1.0 mg daily may be used. Other recommendations included parenteral or oral corticosteroid for acute CPP arthritis in those unresponsive or unsuited to other measures, and low-dose corticosteroid, methotrexate or hydroxychloroquine for chronic inflammatory arthritis with CPPD. Asymptomatic CPPD requires no treatment. Strength of recommendations varies from 79% to 95%. CONCLUSION: Nine key recommendations for management of CPP crystal associated arthritis were developed using both research evidence and expert consensus. Strength of recommendations was provided to assist the application of these recommendations.

European League Against Rheumatism recommendations for calcium pyrophosphate deposition. Part I: terminology and diagnosis.

OBJECTIVES: To agree terminology and to develop recommendations for the diagnosis of calcium pyrophosphate deposition (CPPD). METHODS: The European League Against Rheumatism (EULAR) CPPD Task Force, comprising 15 experts from 10 countries, agreed the terms and recommendations for diagnosis of CPPD using a Delphi consensus approach. Evidence was systematically reviewed and presented in terms of sensitivity, specificity and positive likelihood ratio (LR) to support diagnosis; ORs were used for association. Strength of recommendation (SOR) was assessed by the EULAR visual analogue scale. RESULTS: It was agreed that 'CPPD' should be the umbrella term that includes acute calcium pyrophosphate (CPP) crystal arthritis, osteoarthritis (OA) with CPPD and chronic CPP crystal inflammatory arthritis. Chondrocalcinosis (CC) defines cartilage calcification, most commonly due to CPPD and detected by imaging or histological examination. A total of 11 key recommendations were generated on the topics of clinical features, synovial fluid (SF) examination, imaging, comorbidities and risk factors. Definitive diagnosis of CPPD relies on identification of SF CPP crystals. Rapid onset inflammatory symptoms and signs are suggestive but not definitive for acute CPP crystal arthritis. Radiographic CC is not highly sensitive or specific, whereas ultrasonography appears more useful (LR=24.2, 95% CI 3.51 to 168.01) for peripheral joints. Recognised risk factors for CPPD include ageing, OA and metabolic conditions such as primary hyperparathyroidism, haemochromatosis and hypomagnesaemia; familial forms are rare. SORs varied from 53 to 99 (maximum 100). CONCLUSION: New terms for CPPD were agreed and 11 key recommendations for diagnosis of CPPD were developed using research evidence and expert consensus.

[Myositis: current data on the classification, diagnosis and treatment]. / Myosites: données actuelles sur la classification, le diagnostic et le traitement.

The classification of idiopathic inflammatory myopathies has been refined with the characterization of new antibodies and their clinicopathological associations. The most widely used classification (Troyanov) defines pure polymyositis (PM) and dermatomyositis (DM), myositis overlap (presence of extra-muscular-extra-cutaneous manifestations or auto-antibodies), myositis associated to cancers and sporadic inclusion body myositis IBM). Overlap myositis are generally more severe and chronic than pure forms, and almost always require immunosuppressants. IBM remains difficult to treat, but immunosuppressants or immunoglobulins may be proposed, especially at the beginning of evolution.

[Polymyalgia rheumatica and giant cell arteritis: recent data and current situation]. / Polymyalgia rheumatica et artérite giganto-cellttulaire: données actuellttes.

Polymyalgia rheumatica (PMR) and giant cell arteritis (GCA) are two frequently linked inflammatory diseases of the elderly. The diagnosis of GCA is based on temporal artery biopsy, but results must not delay steroid therapy because of the potential sudden ocular and neurologic ischemic complications. PET-scan and MRI angiography can be helpful in difficult cases. The diagnosis of PMR is essentially clinical, centred on subacute onset of morning aching and stiffness in the shoulder and hip girdles. The treatment of both entities is still based on glucocorticoids (10-20 mg/j of prednisone for PMR, and 40-60 for GCA). Methotrexate, though, now appears a sometimes-useful corticosteroid-sparing agent, both in PMR and GCA. There also appears to be a role for low dose aspirin to decrease ischemic events in GCA.

Synovium as a source of interleukin 6 in vitro. Contribution to local and systemic manifestations of arthritis.

Synovial inflammation is often associated with systemic changes, such as increased levels of acute phase proteins and hypergammaglobulinemia, which cannot be explained by the cytokines described in synovial fluids and synoviocyte secretions. Interleukin 6 (IL-6) has recently been characterized as a mediator of multiple inflammatory responses. This cytokine promotes T and B lymphocyte growth and differentiation, and acute phase protein synthesis. We therefore examined IL-6 production by human synoviocytes and its presence in synovial fluids. In vitro, synoviocytes spontaneously released IL-6, which was increased by IL-1 and tumor necrosis factor-alpha. Synoviocyte-derived IL-6 activity was able to induce hybridoma-plasmacytoma proliferation, and immunoglobulin and acute-phase protein synthesis. The synovial fluids from patients with diverse arthropathies contained IL-6 activity, but higher levels were present in inflammatory arthropathies than in osteoarthritis. These results demonstrate that synoviocytes are a potent source of IL-6, which can contribute to important manifestations of inflammatory arthropathies.

[Advances in the management of gout]. / Approches thérapeutiques de la goutte en 2006.

Gout is the most frequent cause of man's inflammatory arthritis after forty years of age and its prevalence is increasing. Although the physiopathology of this condition is starting to be thoroughly recognized, therapeutic approaches have not fundamentally changed during the last decades. In the absence of renal or digestive contraindications, non steroidal inflammatory drugs are the treatment of choice for acute flares of gout arthritis. If an indication for urate-lowering therapy exists, a xanthine oxydase inhibitor or an uricosurical treatment remains the treatment of choice, depending on the patient's co-morbidity. Purine restrictive diet, weight loss in case of obesity and lower alcohol intake are highly necessary co-measures.

[Calcium pyrophosphate dihydrate crystal induced arthropathy]. / Arthropathies à cristaux de pyrophosphate de calcium.

CPPD deposition disease is a common and potentially severe arthropathy. Hyperparathyroidism, hemochromatosis and hypomagnesaemia can favour chondrocalcinosis and must be looked for in early disease (< or =60 years). Chondrocalcinosis can cause severe attacks of inflammatory arthritis (pseudogout) as well as various forms of chronic arthropathies including pseudo RA, pseudo OA and pseudo neuropathic joint disease. Diagnosis is based on synovial fluid analysis, (positively birefringent CPPD crystals) and X-rays (punctuated and linear radio densities in cartilage). NSAIDs and i.a. or systemic glucocorticoids are the most useful treatments. Colchicine can be effective in recurring pseudogout, and magnesium for attacks' prevention. Methotrexate proved effective in a small uncontrolled series, and can be used when other treatments fail.

[Treatment of rheumatoid arthritis in 2005: prompt, agressive and customized]. / Traitement de la polyarthrite rhumatoïde en 2005: prompt, énergique et ajusté.

Treatment of rheumatoid arthritis in 2005: prompt, aggressive and customized Rheumatoid arthritis can be extremely serious (joint destruction, functional loss, decrease in life expectancy). Fortunately, our therapeutic means have recently progressed enormously (better appreciation of efficacy and ways to use DMARDs combinations and new molecules such as leflunomide and anti-TNFs, understanding of the importance of early adequate and intensive treatments when necessary). Huge progresses have also been performed with regards to evaluation and follow-up strategies (disease activity score--DAS, health assessment questionnaire--HAQ), which allows us to adapt the treatment much better. The goal now can and must be quick and total remission of the disease in all patients thus avoiding as much as possible irreversible joint damages with accompanying morbidities.

Effects of IL-6 and its soluble receptor on proteoglycan synthesis and NO release by human articular chondrocytes: comparison with IL-1. Modulation by dexamethasone.

Contradictory results have been reported on the effects and role of IL-6 on proteoglycan (PG) synthesis. Having shown recently that in vitro IL-6 depends on the presence of soluble IL-6 receptor alpha (sIL-6Ralpha) to fully exert its effects on chondrocytes, we conducted the present study to analyse the effects of IL-6 on PG synthesis by human articular chondrocytes in the presence of sIL-6Ralpha. PG synthesis was quantified by specific ELISA using a monoclonal antibody (MAB) raised against the keratan sulphate region of PG as a capture antibody, and a MAB to the acid binding region as a detector. It proved specific for PG from primary (differentiated) chondrocytes. In the absence of sIL-6Ralpha, IL-6 had a slight inhibitory effect on PG synthesis by articular chondrocytes. sIL-6Ralpha alone also had slight but consistent inhibitory effects. When adding sIL-6Ralpha at concentrations of 50 ng/ml corresponding to levels found in synovial fluid, the effects of IL-6 increased consistently. However, even at optimal concentrations (30-100 ng/ml of IL-6sR per 100 ng/ml of IL-6), maximal inhibition (48%) did not equal the degree of inhibition achieved by IL-1 at 1 ng/ml (66%). Similar effects, although slightly weaker, were observed on osteoarthritic cells. Dexamethasone, over a wide range of concentrations, markedly enhanced proteoglycan synthesis and completely reversed the downregulatory effects of IL-1 and IL-6 + sIL-6Ralpha. The effects of IL-1 were partially inhibited by an anti-IL-6 antibody. Finally, unlike IL-1, IL-6 + sIL-6Ralpha only weakly stimulated nitric oxide (NO) synthesis. In conclusion, sIL-6Ralpha potentiates the inhibitory effect of IL-6 on PG synthesis by articular chondrocytes, but the overall effect of IL-6 + IL-6sR is moderate compared to the effects of IL-1.

Primary ciliary dyskinesia: a genome-wide linkage analysis reveals extensive locus heterogeneity.

Primary ciliary dyskinesia (PCD), or immotile cilia syndrome (ICS), is an autosomal recessive disorder affecting ciliary movement with an incidence of 1 in 20000-30000. Dysmotility to complete immotility of cilia results in a multisystem disease of variable severity with recurrent respiratory tract infections leading to bronchiectasis and male subfertility. Ultrastructural defects are present in ciliated mucosa and spermatozoa. Situs inversus (SI) is found in about half of the patients (Kartagener syndrome). We have collected samples from 61 European and North American families with PCD. A genome-wide linkage search was performed in 31 multiplex families (169 individuals including 70 affecteds) using 188 evenly spaced (19cM average interval) polymorphic markers. Both parametric (recessive model) and non-parametric (identity by descent allele sharing) linkage analyses were used. No major locus for the majority of the families was identified, although the sample was powerful enough to detect linkage if 40% of the families were linked to one locus. These results strongly suggest extensive locus heterogeneity. Potential genomic regions harbouring PCD loci were localised on chromosomes 3p, 4q, 5p, 7p, 8q, 10p, 11q, 13q, 15q, 16p, 17q and 19q. Linkage analysis using PCD families with a dynein arm deficiency provided 'suggestive' evidence for linkage to chromosomal regions 8q, 16pter, while analyses using only PCD families with situs inversus resulted in 'suggestive' scores for chromosomes 8q, and 19q.

Palindromic rheumatism: part of or apart from the spectrum of rheumatoid arthritis.

Palindromic rheumatism (PR), originally described in 1944, is characterized by recurrent episodes of mostly oligoarticular arthritis with peri- and para-articular tissue inflammation, leaving no residual clinical and radiographic changes. It appears that palindromic syndrome is a heterogeneous entity, encompassing other inflammatory conditions at early stages of their evolution, and whose relationship with rheumatoid arthritis (RA) is evident but still unclear. Evolution of up to 50% of these cases into otherwise typical RA, commonly accompanied by the conversion to rheumatoid factor seropositivity, the frequent occurrence of nodules, the reported response to RA treatment, and the observation of familial aggregation of the two conditions suggest that PR is part of the spectrum, or a stage in the evolution of RA. However, justification for the distinct existence of PR comes from reports that identify well-defined and recognizable clinical manifestations such as descriptions of the acute attacks, the frequent peri-articular manifestations, the absence of bone and cartilage destruction even after extended periods of time, and the generally good long-term prognosis. Immunogenetic studies with HLA-DR phenotyping and the absence of female preponderance tend to add additional support for the separate identity of PR.

[Mechanisms of microcrystalline inflammation]. / Les mécanismes de l'inflammation microcristalline.

The inflammatory mechanisms which take place in microcrystalline arthropathies can be divided into several stages, each of them being characterized by the activation of a set of mediators. The process begins with activation by crystals of resident cells in the synovial fluid which release various pro-inflammatory factors including several cytokines. Among these, interleukin 1 (IL-1) and tumor-necrosis factor alpha (TNF-alpha) have multiple effects and play a predominant role in the starting of inflammation. With the contribution of humoral factors, also activated by the crystals, IL-1 and TNF-alpha activate notably the endothelial cells to allow leucocyte extravasation. The attraction and massive activation of polymorphonuclear neutrophils (PMNs) which then occurs and characterizes acute microcrystalline arthropathies mainly depend on IL-8, another cytokine secreted by synoviocytes. At the same time, an acute phase systemic reaction principally induced by IL-6 develops. When inflammation is prolonged mechanisms of tissue destruction begin to act, notably by releasing proteases induced by IL-1 and TNF-alpha. These mechanisms are counterbalanced by release of antiproteases, notably those induced by the transforming growth factor beta (TGF-beta) and by IL-6. Finally, these inflammatory processes may limit themselves or even stop spontaneously, due to a series of control mechanisms including cytokines with anti-inflammatory effects, ACTH release and physico-chemical changes in crystals.

Elevated levels of tumor necrosis factor-alpha in periradicular fat tissue in patients with radiculopathy from herniated disc.

STUDY DESIGN: Case-control study. OBJECTIVE: To determine whether inflammatory cytokines [tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6 and IL-8] are elevated in tissues intimately surrounding involved nerve roots of patients suffering from radiculopathy form herniated disc (HD). SUMMARY OF BACKGROUND DATA: Proinflammatory cytokines are postulated to play an important role in radiculopathy from HD. Although TNF-alpha has been found in human HD, it is not known whether TNF-alpha concentrations are increased in symptomatic patients. Epidural fat (EF) is another tissue in close contact with nerve roots. Histologic modifications of EF have been reported in patients with sciatica but concentrations of inflammatory cytokines have never been studied. METHODS: Twenty-three lumbar HD along with adjacent EF (EFHD) were harvested from patients with radicular syndrome. As controls, 14 intervertebral discs (IVDs) and 10 samples of EF (EFC) were obtained from patients without radicular syndrome undergoing spine surgery. Tissue explants were incubated ex vivo for 48 hours and the concentrations of cytokines were measured by elisa in the supernatants. Results were standardized according to tissue weight. RESULTS: All 4 cytokines were found at higher concentrations in EFHD compared with HD (P < 0.001). TNF-alpha was the only cytokine found in significantly higher levels in EFHD compared with EFC [median, interquartile range 6.6, (1.6-16.3) pg/mL per milligram of tissue vs. 2.3 (1.3-5.0), P < 0.05] and to subcutaneous fat [0.35 (0-2.28), P < 0.001]. No significant increase of either cytokines was found in HD compared with IVD. CONCLUSION: Higher concentrations of TNF-alpha were found in EF from patients with radiculopathy from HD compared with patients suffering from other type of back pain. These results support the role of TNF-alpha in the pathogenesis of radiculopathy from HD.

[Diagnosis and treatment of calcium pyrophosphate crystal-induced arthropathy]. / Diagnose und Therapie der Kalziumpyrophosphatkristall-induzierten Arthropathie.

Calcium pyrophosphate dihydrate deposition (CPPDD) disease is the term used to describe a group of common and potentially severe metabolic arthropathies. In these, CPPD crystals form and are deposited in the cartilage matrix (chondrocalcinosis) and induce inflammatory and/or destructive mechanisms. Most cases are idiopathic, but hyperparathyroidism, hemochromatosis, hypomagnesemia and hypophosphatemia can promote or cause chondrocalcinosis. Early disease (with onset before the age of 60 years) thus requires that the patient be examined for these metabolic conditions, particularly hemochromatosis. The prevalence of CPPDD disease in the general population increases with age, being 10-15% in the age group 65-75 years and more than 40% in the over-80s. Although frequently asymptomatic, chondrocalcinosis can involve severe acute attacks of inflammatory arthritis (pseudogout) and also various types of chronic arthropathy including pseudorheumatoid arthritis, pseudo-osteoarthritis, and pseudoneuropathic joint disease. CPPD crystals can also be deposited in the bursae, ligaments, and tendons and generate inflammation and/or ruptures. The diagnosis is based on synovial fluid analysis (positively birefringent CPPD crystals visualized by compensated polarized light microscopy) and X-rays (punctate and linear radiodense areas in fibrocartilage and hyaline cartilage). Treatment is primarily symptomatic, since there is no known drug that can prevent progression of the joint destruction). Nonsteroid anti-inflammatory drugs (NSAIDs) and intra-articular or systemic glucocorticoids (amounts must be only small if use is prolonged) are the most useful treatments. Colchicine can be effective in recurring pseudogout, and magnesium can be used prophylactically. In a small uncontrolled series methotrexate was effective and aroused interest; it can be used when other treatments fail.

Evidence for differential acquired drug resistance to anti-tumour necrosis factor agents in rheumatoid arthritis.

BACKGROUND: Acquired drug resistance or gradual drug failure has been described with most disease modifying antirheumatic drugs (DMARDs) and is also starting to be recognised with anti-tumour necrosis factor (anti-TNF) agents. OBJECTIVE: To study acquired drug resistance to anti-TNF agents in rheumatoid arthritis (RA). METHODS: Swiss health authorities requested continuous monitoring of patients receiving biological agents. Intensification of co-therapy with traditional DMARDs, gradual dose escalation, and drug discontinuation rates in all patients receiving infliximab, etanercept, or adalimumab, adjusting for potential confounders, were analysed. Intensification of DMARD co-therapy and time to discontinuation of the three anti-TNF agents were analysed using a proportional hazards models. Dose escalation and evolution of RA disease activity (DAS28) were analysed using a longitudinal regression model. RESULTS: 1198 patients contributing 1450 patient-years of anti-TNF treatment met the inclusion criteria. The rate of intensification of traditional DMARD co-therapy over time was significantly higher with infliximab (hazards ratio = 1.73 (99% confidence interval (CI) 1.19 to 2.51)) than with the two other agents. Infliximab also showed significant dose escalation over time, with an average dose increase of +12% (99% CI 8% to 16%) after 1 year, and +18% (99% CI 11% to 25%) after 2 years. No significant differences in discontinuation rates were seen between the three anti-TNF agents (ANOVA, p = 0.67). Evolution of disease activity over time indicated a lower therapeutic response to infliximab (DAS28, p<0.001) compared with etanercept, after 6 months' treatment. CONCLUSIONS: In this population, infliximab was associated with a higher risk of requiring intensification of DMARD co-therapy than the other anti-TNF agents and a significant dose escalation over time. Analysis of RA disease activity indicated a reduced therapeutic response to infliximab after the first 6 months of treatment, suggestive of acquired drug resistance.