Rheumatoid Meningitis a Rare Extra-Articular Manifestation of Rheumatoid Arthritis: Report of 6 Cases and Literature Review.

OBJECTIVES: Central neurological manifestations of rheumatoid arthritis (RA) like rheumatoid meningitis (RM) are rare, little known and have a high rate of morbi-mortality. METHODS: We described six cases of RM that were directly related to RA activity after exhaustive assessment. RESULTS: They were mainly women, aged of 50 to 69. All were positive for anti-cyclic citrullinated peptide antibodies and half for rheumatoid factors. RA activity, duration, and treatments were heterogeneous including oral steroids, conventional synthetic disease modifying anti-rheumatic drugs (DMARDs) and biologic DMARDs. Symptoms were various, with acute or progressive beginning; main were: generalized or focal seizure (4/6), fever (3/6), headaches (3/6), and frontal syndrome (2/6). Imaging lesions were four leptomeningitis, one pachymeningitis, and one association of both. MRI usually showed hypersignal in various territories in T2-FLAIR (fluid attenuated inversion recovery) mode, and enhancement in T1-weighted mode after gadolinium injection. All patients had lumbar puncture that found sterile cerebrospinal fluid, no neoplasic cell, elevated cell count in 5/6 cases and elevated proteins concentration in 3/6 cases. Cerebral biopsy was possible for three patients, and definitively confirmed the diagnosis of aseptic lepto- or pachymenintis, excluding vasculitis and lymphoma. Different treatments were used like intravenous high dose steroids, immunoglobulins or biologic DMARDs, with variable clinical and imaging outcome: one death, one complete recovery, and four recoveries with sequelae. CONCLUSIONS: Clinical symptoms, imaging, lumbar puncture, and serological studies are often nonspecific, only histologic examination can confirm the diagnosis of RM. Any central neurological manifestation in RA patients, even in quiescent and ancient RA, should warn the physician.

[Rheumatoid arthritis†: cardiovascular and pulmonary manifestations]. / Manifestations cardiovasculaires et pulmonaires de la polyarthrite rhumatoïde.

Rheumatoid arthritis (RA) often affects extra-articular structures. Treatments used for arthritis are often also effective on the extra-articular manifestations, but exceptions are numerous, particularly for cardiovascular and pulmonary problems. Cardiovascular disorders mainly include complications related to atherosclerosis : they are probably the main contributor to the increased mortality observed in RA, must be specifically taken into account and largely determine the choice of treatments used to treat RA. The most problematic pulmonary complications are the different types of interstitial lung disease ; they too must be specifically managed and condition the choice of treatments.

La polyarthrite rhumatoïde (PR) touche souvent des structures extra-articulaires. Les traitements efficaces sur l'arthrite le sont souvent aussi sur les manifestations extra-articulaires, mais les exceptions sont nombreuses notamment pour les problèmes ­cardiovasculaires et pulmonaires. Les atteintes cardiovasculaires comprennent surtout les complications liées à l'athérosclérose : elles représentent probablement le principal contributeur à l'augmentation de la mortalité observée dans la PR, doivent être prises en compte de manière spécifique et conditionnent largement le choix des traitements utilisés pour la PR. Les complications pulmonaires les plus redoutables sont les différents types de pneumopathies interstitielles diffuses (PID); elles aussi doivent être prises en charge spécifiquement et conditionnent le choix des traitements.

[Risk factors and prophylaxis of Pneumocystis jirovecii pneumonia in HIV-negative patients]. / Facteurs de risque et prophylaxie de la pneumonie à Pneumocystis jirovecii chez les patients non VIH.

Pneumocystis jirovecii (formely carinii) pneumonia (PcP) affects immunosuppressed patients. Cotrimoxazole prophylaxis has proven to be effective and its indications in HIV patients are well established. In non-HIV patients, the prognosis is poorer and diagnostic tests are of lower sensitivity. Recommendations for prophylaxis in hematology, oncology and solid organ transplantation are based on expert consensus. In rheumatology, the incidence of PcP is mainly related to the administration of corticosteroids. For some inflammatory diseases, a low CD4 cell count, and the administration of anti-TNFα, rituximab or cyclophosphamide may increase the risk. There are currently no well-defined concise guidelines concerning prophylaxis for immunosuppressed patients with inflammatory bowel diseases.

La pneumonie à Pneumocystis jirovecii (PcP) atteint les patients immunosupprimés. La prophylaxie par cotrimoxazole est efficace et ses indications chez les patients infectés par le VIH sont bien établies. Chez les patients non VIH, le pronostic est plus sombre et les examens diagnostiques sont de plus faible sensibilité. Les recommandations de prophylaxie en hématologie, en oncologie et lors de transplantation d'organes solides sont basées sur des avis d'experts. En milieu rhumatologique, l'incidence de PcP est principalement liée à l'administration de corticostéroïdes. Certaines maladies inflammatoires, un taux de lymphocytes CD4 bas et l'administration d'anti-TNFα, de rituximab ou de cyclophosphamide augmenteraient le risque. L'immunosuppression pour les maladies inflammatoires de l'intestin ne semble pas justifier une prophylaxie.

A 64-Year-Old Woman with Chest Pain, Limb Weakness, and Endometrial Cancer.

Necrotizing autoimmune myopathy (NAM) is a rare subgroup of idiopathic inflammatory myopathies (IIM). This pathology usually affects proximal limb muscles and in some cases the myocardium. Patients usually display proximal limb weakness. Muscular biopsy is required to confirm the diagnosis. We report the case of a 64-year-old woman with an atypical first presentation of NAM, manifested by chest pain in the context of metastatic endometrial cancer. The diagnosis of NAM was however made when she returned a second time with proximal limb weakness. A treatment with prednisone was then initiated, to which rituximab was rapidly associated, beside a specific chemotherapy.

Low pre-treatment B-cell counts are not a risk factor of infection in patients treated with rituximab for autoimmune diseases: An observational study.

OBJECTIVES: Rituximab (RTX) is increasingly used in patients with refractory rheumatoid arthritis (RA) and other severe autoimmune diseases (AID). In practice, many clinicians are reluctant to prescribe RTX in patients with low B-cell counts because of the presumed risk of infection. The aim of this study was therefore to investigate whether B-cell counts before treatment or retreatment with RTX predict the occurrence of infections. METHODS: Observational, single-centre study of 161 patients treated with RTX for RA and other AID at a tertiary hospital. CD19+ B-cell counts were assessed by flow cytometry and multivariate statistical analysis adjusted for various potential predictors was performed. RESULTS: The rate of severe infection was 5.9/100 patient-years in RA patients and 24.9 in non-RA AID (P<0.001). Low B-cell counts at the time of RTX infusion were not associated with subsequent severe (HR=0.55, P=0.60) or overall infection (HR=0.85, P=0.58). Significant pre-treatment predictors of severe infection were a diagnosis other than RA (HR=4.68, P<0.001), immunoglobulin (Ig) G levels <7g/L (HR=2.36, P=0.01), age (HR=1.03, P=0.01), and diabetes (HR=3.61, P=0.01). CONCLUSIONS: Low B-cell counts before RTX infusion did not predict subsequent infections in this population treated with RTX for RA and other AID, therefore not supporting the practice of pre-treatment assessment of B-cells. Nevertheless, a higher risk of severe infection was confirmed for low pre-treatment IgG levels, older age, diabetes, and AID other than RA.

Methotrexate in chronic-recurrent calcium pyrophosphate deposition disease: no significant effect in a randomized crossover trial.

INTRODUCTION: Calcium pyrophosphate deposition (CPPD) may cause severe arthropathy, major joint destruction and treatment options are limited. The aim of this study was to test the therapeutic efficacy of methotrexate (MTX) in chronic or recurrent CPPD arthropathy. METHODS: Patients with CPPD arthropathy were randomized to receive either weekly subcutaneous injections of 15 mg/week of MTX or placebo (PBO) for three months, in a double-blind, crossover randomized controlled trial. Inclusion criteria comprised definite CPPD disease, recurrent arthritis or persistent polyarthritis, and an insufficient response to NSAIDs, glucocorticoids or colchicine. The primary outcome was an improvement in the disease activity scores based on 44 joints (DAS44). The analysis was performed on an intent-to-treat basis. RESULTS: We randomized 26 patients, and compared 25 treatment periods on MTX with 21 treatment periods on PBO. Baseline characteristics were balanced between the groups. The evolution of the DAS44 was not statistically significantly different between groups (median DAS44 decreased by -0.08 on MTX versus -0.13 on PBO, after three months, P = 0.44). Furthermore, pain levels remained stable in both groups (median change in VAS Pain -1 unit on MTX and 0 on PBO, P = 0.43), and none of the secondary outcomes was significantly different between the two groups. Minor adverse events (AE) did not differ in frequency between the groups, but the only serious AE occurred on MTX (bicytopenia). CONCLUSIONS: The results of this trial with MTX in this older population with chronic or recurrent CPPD arthropathy suggest no strong effect of MTX on disease activity. TRIAL REGISTRATION: EudraCT No: 2007-003479-37. Registered 26 April 2008.

Classification, diagnosis, and management of idiopathic inflammatory myopathies.

The detection and characterization of a large array of autoantibodies, including at least 8 different antisynthetase, anti-SRP, -200/100 (HMGCR), -Mi-2, -CADM-140 (MDA5), -SAE, -p155, -MJ (NXP-2), and -PMS1, frequently associated with distinct and well-defined clinicopathological features, allowed for significant improvement in the definition and diagnosis of idiopathic inflammatory myopathies (IIM). Classification remains difficult, with lingering divergence between the different specialties involved in IIM care, but several categories clearly stand out, including dermatomyositis (DM), overlap myositis (OM), polymyositis, necrotizing myositis, and sporadic inclusion body myositis (s-IBM). Biopsy and histological analysis remain crucial, particularly in the absence of autoantibodies, to accurately specify the diagnosis and rule out mimics such as muscular dystrophies and metabolic myopathies. Numerous infectious agents (in particular human immunodeficiency virus and human T cell lymphotrophic virus-1) and drugs (statins, tumor necrosis factor inhibitors, and proton pump inhibitors) can cause mimic IIM that must also be excluded. Pharmacological treatment, in addition to glucocorticoids and immunoglobulins, now includes mycophenolate mofetil and rituximab, which proved helpful in resistant cases, particularly rituximab in DM and OM. Exercise, initially seen as potentially deleterious, recently was shown to be efficacious and safe. IIM can thus be reasonably well controlled in most cases, although aggressive disease remains refractory to treatment, including some cases of necrotizing myopathy. Sporadic IBM still seems resistant to all medications tested to date.

Rheumatoid meningitis occurring during adalimumab and methotrexate treatment.

Rheumatoid arthritis is well known for multiple extra-articular manifestations. Here, we present a case of chronic rheumatoid meningitis occurring during treatment with methotrexate and the tumour necrosis factor (TNF) alpha antibody adalimumab. Nine and seven months, respectively, into the course of these two treatments, a 59-year-old Caucasian lady with mild, early, seropositive rheumatoid arthritis developed headaches and psychomotor retardation followed by seizures. The diagnosis was confirmed by a brain biopsy showing a necrotizing granulomatous meningitis. Withdrawal of both drugs and high dose corticosteroids led to marked improvement. The addition of the anti-CD20 antibody rituximab allowed discontinuation of the corticosteroids. This is the fifth published case describing the occurrence of rheumatoid meningitis during treatment with TNF blockers. TNF blockers and methotrexate thus do not appear to prevent this complication, and may even contribute to its development.

Impact of synthetic and biologic disease-modifying antirheumatic drugs on antibody responses to the AS03-adjuvanted pandemic influenza vaccine: a prospective, open-label, parallel-cohort, single-center study.

OBJECTIVE: To identify the determinants of antibody responses to adjuvanted split influenza A (H1N1) vaccines in patients with inflammatory rheumatic diseases. METHODS: One hundred seventy-three patients (82 with rheumatoid arthritis, 45 with spondylarthritis, and 46 with other inflammatory rheumatic diseases) and 138 control subjects were enrolled in this prospective single-center study. Controls received 1 dose of adjuvanted influenza A/09/H1N1 vaccine, and patients received 2 doses of the vaccine. Antibody responses were measured by hemagglutination inhibition assay before and 3-4 weeks after each dose. Geometric mean titers (GMTs) and rates of seroprotection (GMT≥40) were calculated. A comprehensive medical questionnaire was used to identify the determinants of vaccine responses and adverse events. RESULTS: Baseline influenza A/09/H1N1 antibody levels were low in patients and controls (seroprotection rates 14.8% and 14.2%, respectively). A significant response to dose 1 was observed in both groups. However, the GMT and the seroprotection rate remained significantly lower in patients (GMT 146 versus 340, seroprotection rate 74.6% versus 87%; both P<0.001). The second dose markedly increased antibody titers in patients, with achievement of a similar GMT and seroprotection rate as elicited with a single dose in healthy controls. By multivariate regression analysis, increasing age, use of disease-modifying antirheumatic drugs (DMARDs) (except hydroxychloroquine and sulfasalazine), and recent (within 3 months) B cell depletion treatment were identified as the main determinants of vaccine responses; tumor necrosis factor α antagonist treatment was not identified as a major determinant. Immunization was well tolerated, without any adverse effect on disease activity. CONCLUSION: DMARDs exert distinct influences on influenza vaccine responses in patients with inflammatory rheumatic diseases. Two doses of adjuvanted vaccine were necessary and sufficient to elicit responses in patients similar to those achieved with 1 dose in healthy controls.

Anti-apolipoprotein A-1 IgG predicts major cardiovascular events in patients with rheumatoid arthritis.

OBJECTIVE: To determine whether anti-apolipoprotein A-1 (anti-Apo A-1) IgG are associated with major cardiovascular events in patients with rheumatoid arthritis (RA). METHODS: We determined anti-Apo A-1 IgG levels and the concentrations of cytokines, oxidized low-density lipoprotein (LDL), and matrix metalloproteinase 1 (MMP-1) MMP-2, MMP-3, and MMP-9 in sera from 133 patients with RA who did not have cardiovascular disease at baseline, all of whom were longitudinally followed up over a median period of 9 years. A major cardiovascular event was defined as a fatal or nonfatal stroke or acute coronary syndrome. The proinflammatory effects of anti-Apo A-1 IgG were assessed on human macrophages in vitro. RESULTS: During followup, the overall incidence of major cardiovascular events was 15% (20 of 133 patients). At baseline, anti-Apo A-1 IgG positivity was 17% and was associated with a higher incidence of major cardiovascular events (adjusted hazard ratio 4.2, 95% confidence interval 1.5-12.1). Patients who experienced a subsequent major cardiovascular event had higher circulating levels of anti-Apo A-1 IgG at baseline compared with those who did not have a major cardiovascular event. Receiver operating curve analysis showed that anti-Apo A-1 IgG was the strongest of all tested biomarkers for the prediction of a subsequent major cardiovascular event, with an area under the curve value of 0.73 (P = 0.0008). At the predefined and previously validated cutoff levels, the specificity and sensitivity of anti-Apo A-1 IgG to predict major cardiovascular events were 50% and 90%, respectively. Anti-Apo A-1 IgG positivity was associated with higher median circulating levels of interleukin-8 (IL-8), oxidized LDL, and MMP-9 and higher proMMP-9 activity as assessed by zymography. On human macrophages, anti-Apo A-1 IgG induced a significant dose-dependent increase in IL-8 and MMP-9 levels and proMMP-9 activity. CONCLUSION: Anti-Apo A-1 IgG is an independent predictor of major cardiovascular events in RA, possibly by affecting vulnerability to atherosclerotic plaque.

[Chondrocalcinosis and calcium pyrophosphate (CPP) crystal deposition disease in 2010]. / Chondrocalcinose et arthropathies a dépôts de cristaux de pyrophosphate de calcium: actualité 2010.

Chondrocalcinosis may be asymptomatic or take three classical forms (acute recurrent inflammatory, chronic inflammatory, with osteoarthritis). Apart form that, CPP crystal arthropathies can mimic several rheumatic diseases, including polymyalgia, septic arthritis and spondylodiscitis. Several conditions can predispose to chondrocalcinosis, including hemochromatosis, hyperparathyroidism, familial hypocalciuric hypercalcemia, hypomagnesemia and treatment with tacrolimus or diuretics. The diagnostic sensitivity of ultrasound seems better than radiography and CT is useful in spinal forms but whenever possible, the identification of crystals in synovial fluid remains essential. NSAIDs and/or glucocorticoids are frequently sufficient to control symptoms but methotrexate, at anti-inflammatory doses (10-20 mg/wk) appears useful in refractory forms.

Influence of cytokine inhibitors on concentration and activity of MMP-1 and MMP-3 in disc herniation.

INTRODUCTION: Spontaneous resorption of disc herniation (DH) after sciatica is well documented. The matrix metalloproteinases (MMP)-1 and MMP-3 are enzymes potentially involved in this process. Glucocorticoid injections are commonly used for treatment, and other anti-inflammatory molecules like tumor necrosis factor (TNF) inhibitors are under clinical investigation. However, little is known about the effect of these molecules on DH resorption. METHODS: DH tissue was harvested from patients undergoing surgery for sciatica. Samples were thoroughly washed. Diced explants were cultured ex-vivo in 1) 0.5 ml Dulbecco's modified Eagle's medium (DMEM) 10% fetal calf serum (FCS), (controls), 2) recombinant interleukin 1 receptor antagonist (IL-1Ra), (100 ng/ml), 3) dexamethasone (10E-5 M), or 4) TNF inhibitor monoclonal antibody (10 microg/ml). Supernatants were harvested at 48 hours and frozen. Immunocapture activity assays determined total MMP activity, active MMP levels and pro-MMP levels. RESULTS: Fourteen DH tissue samples were analysed. Levels of all forms of MMP-3 were higher than the respective levels of MMP-1(P < 0.01). In particular, the median (interquartile range [IQR]) total MMP-3 level was 0.97 (0.47 - 2.19) ng/mg of tissue compared to 0.024 (0.01 - 0.07) ng/mg of total MMP-1 level (P < 0.01). Incubation with IL-1Ra, dexamethasone, or TNF inhibitors significantly decreased levels of all forms of MMP-3 (P < 0.05). Dexamethasone significantly decreased the ratio of active MMP-3 to total MMP-3 activity. A significant inhibitory effect of dexamethasone was observed only on active MMP-1, while IL-1 and TNF inhibitor had no significant effect on any form. CONCLUSIONS: MMP-3 appears to play a greater role than MMP-1 in DH resorption. Dexamethasone, IL-1-Ra and TNF inhibitor decreased active MMP-3, indicating that the clinical use of these drugs may affect the resorption of DH under certain conditions.

Magnetically retainable microparticles for drug delivery to the joint: efficacy studies in an antigen-induced arthritis model in mice.

INTRODUCTION: Conventional corticosteroid suspensions for the intra-articular treatment of arthritis suffer from limitations such as crystal formation or rapid clearance from the joint. The purpose of this study was to investigate an innovative alternative consisting of corticosteroid encapsulation into magnetically retainable microparticles. METHODS: Microparticles (1 or 10 microm) containing both superparamagnetic iron oxide nanoparticles (SPIONs) and dexamethasone 21-acetate (DXM) were prepared. In a preliminary study, we compared the persistence of microparticles of both sizes in the joint. A second study evaluated the influence of a subcutaneously implanted magnet near the knee on the retention of magnetic microparticles in the joint by in vivo imaging. Finally, the efficacy of 10-microm microparticles was investigated using a model of antigen-induced arthritis (AIA) in mice. Phosphate-buffered saline, DXM suspension, SPION suspension, blank microparticles and microparticles containing only SPIONs were used as controls. Arthritis severity was assessed using 99mTc accumulation and histological scoring. RESULTS: Due to their capacity of encapsulating more corticosteroid and their increased joint retention, the 10-microm microparticles were more suitable vectors than the 1-microm microparticles for corticosteroid delivery to the joint. The presence of a magnet resulted in higher magnetic retention in the joint, as demonstrated by a higher fluorescence signal. The therapeutic efficacy in AIA of 10-microm microparticles containing DXM and SPIONs was similar to that of the DXM suspension, proving that the bioactive agent is released. Moreover, the anti-inflammatory effect of DXM-containing microparticles was more important than that of blank microparticles or microparticles containing only SPIONs. The presence of a magnet did not induce a greater inflammatory reaction. CONCLUSIONS: This study confirms the effectiveness of an innovative approach of using magnetically retainable microparticles as intra-articular drug delivery systems. A major advantage comes from a versatile polymer matrix, which allows the encapsulation of many classes of therapeutic agents (for example, p38 mitogen-activated protein kinase inhibitors), which may reduce systemic side effects.

Anakinra is a possible alternative in the treatment and prevention of acute attacks of pseudogout in end-stage renal failure.

We describe the case of a 71-year-old man with recurrent pseudogout attacks affecting multiple joints. He had end-stage renal failure that contra-indicated the use of non-steroidal anti-inflammatory drugs and was resistant to therapy with glucocorticoids. Based on the recent findings that interleukin (IL)-1beta is involved in crystal-induced inflammation, the patient received anakinra, a specific IL-1 inhibitor, in order to treat an acute attack of pseudogout. In addition, anakinra was administered as preventive therapy 3days per week after each hemodialysis session. Under this treatment, he did not present any severe episode of arthritis after a follow-up of 8 months. This observation suggests that anakinra is efficacious and safe for the prevention of crystal-induced arthritis in patients with severe renal failure.

Clinical experience with mycophenolate mofetil in systemic autoimmune conditions refractory to common immunosuppressive therapies.

OBJECTIVES: Standard therapies against inflammatory rheumatic diseases consist of immunosuppressive drugs with high toxicities and many side effects. Except in the treatment of systemic lupus erythematosus with renal involvement, controlled studies with mycophenolate mofetil (MMF) are lacking in other autoimmune and inflammatory systemic diseases. Here we describe our clinical experience with MMF in several unusual indications. METHODS: We collected data including serological findings, adverse events and response to treatment in eleven patients with autoimmune diseases including systemic lupus erythematosus (SLE), mixed connective tissue disease (MCTD), polymyositis (PM), diffuse systemic sclerosis that were treated in our rheumatology unit. RESULTS: Our results show remission in ten patients with minimal side effects and reduced prednisone dosage. The median dose of MMF was 2 g per day. Adverse events were limited, with one case of leucopenia, one tachycardia and one colitis. One patient definitively stopped the treatment because of side effects. CONCLUSIONS: MMF seems to be a very powerful and attractive alternative medication in the treatment of immune-mediated inflammatory diseases. The good tolerance and safety profile makes it an excellent therapeutic option permitting a global reduction of corticosteroids doses.

Treating difficult crystal pyrophosphate dihydrate deposition disease.

Calcium pyrophosphate dihydrate deposition disease is a common and potentially severe metabolic arthropathy. Early disease (in patients

Methotrexate as an alternative therapy for chronic calcium pyrophosphate deposition disease: an exploratory analysis.

OBJECTIVE: To evaluate the effectiveness of methotrexate (MTX), which works not only as an immunosuppressant, but also as a potent antiinflammatory agent, as an alternative therapeutic option for patients with severe calcium pyrophosphate deposition disease (CPDD) who fail to respond to standard therapy with nonsteroidal antiinflammatory drugs and/or glucocorticoids. METHODS: We analyzed, in 2 university hospitals in Switzerland, consecutive patients with CPDD that was resistant to classic treatment and were subsequently treated with MTX. Before and after initiation of MTX therapy, we quantified the frequency of pseudogout attacks, pain intensity, the number of swollen and tender joints, and inflammatory biomarkers. Clinical and biologic side effects of MTX and patients satisfaction with MTX treatment were also evaluated. RESULTS: The study included 5 patients treated with low dosages of MTX (5-20 mg/week). The mean followup time with MTX was 50.4 months (range 6-81 months). All patients reported an excellent clinical response, with marked improvement within a mean period of 7.4 weeks. A significant decrease in pain intensity (P < 0.0001), swollen and tender joint counts (P < 0.0001), and frequency of attacks was observed. The biomarkers of inflammation decreased markedly when systematically analyzed (3 patients). No significant side effects were reported. CONCLUSION: This study suggests that MTX could be a valuable therapeutic option for severe CPDD that is refractory to conventional therapy.

The new IL-1 family member IL-1F8 stimulates production of inflammatory mediators by synovial fibroblasts and articular chondrocytes.

Six novel members of the IL-1 family of cytokines were recently identified, primarily through the use of DNA database searches for IL-1 homologues, and were named IL-1F5 to IL-1F10. In the present study, we investigated the effect of IL-1F8 on primary human joint cells, and examined the expression of the new IL-1 family members in human and mouse joints. Human synovial fibroblasts (hSFs) and human articular chondrocytes (hACs) expressed the IL-1F8 receptor (IL-1Rrp2) and produced pro-inflammatory mediators in response to recombinant IL-1F8. IL-1F8 mRNA expression was increased in hSFs upon stimulation with proinflammatory cytokines, whereas in hACs IL-1F8 mRNA expression was constitutive. However, IL-1F8 protein was undetectable in hSF and hAC culture supernatants. Furthermore, although IL-1beta protein levels were increased in inflamed human and mouse joint tissue, IL-1F8 protein levels were not. IL-1F8 levels in synovial fluids were similar to or lower than those in matched serum samples, suggesting that the joint itself is not a major source of IL-1F8. Serum levels of IL-1F8 were similar in healthy donors, and patients with rheumatoid arthritis, osteoarthritis and septic shock, and did not correlate with inflammatory status. Interestingly however, we observed high IL-1F8 levels in several serum samples in all groups. In conclusion, IL-1F8 exerts proinflammatory effects in primary human joint cells. Joint and serum IL-1F8 protein levels did not correlate with inflammation, but they were high in some human serum samples tested, including samples from patients with rheumatoid arthritis. It remains to be determined whether circulating IL-1F8 can contribute to joint inflammation in rheumatoid arthritis.