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Background:Inflammatory joint diseases, such as psoriatic arthritis (PsA), are frequently treated by biologics. Assessment of treatment efficacy is based upon change in clinical activity scores and in tender and swollen joint counts. Although the response to these agents may be attributed to their central anti-inflammatory effects, synovial response may be operating in parallel. The potential beneficial role of intra-articular injection of tumor necrosis factor (TNF) blockers compared to glucocorticoids (GCs) in reducing synovitis was shown by means of clinical and instrumental validated measures (1). The inflamed synovial fluid is rich in mononuclear cells, however, the different mode of action of the in vitro response of these cells to drugs may contribute to the understanding of cellular response to therapeutic agents in central as opposed to peripheral compartments.Objectives:To evaluate the effect of biologics used in the management of PsA on synovial fluid mononuclear cells (SFMCs) in vitro, and to compare their modes of action to GCs that are used to locally alleviate synovial inflammation.Methods:SFMCs were obtained from PsA patients (n=11) during therapeutic knee arthrocentesis. The cells were cultured in vitro for 7 days in the presence of biologics (adalimumab, infliximab, secukinumab and ustekinumab, 10ug/ml) and GCs (betamethasone and methylprednisolone, 1 ug/ml and 10ug/ml) or medium as control. Levels of the secreted TNF were measured by ELISA. Changes in %CD14+CD16+ monocytes were analyzed by flow cytometry.Results:Both TNF inhibitors (adalimumab pp=0.0003) and GCs (betamethasone and methylprednisolone at 1ug/ml pp+CD16+ SFMCs derived from PsA patients (n=11) were significantly reduced by TNF inhibitors (p=0.0003) compared to medium, however, other biologics and GCs did not display similar activity (Fig. 1B).Figure 1.Both TNF inhibitors and GCs block TNF secretion but exhibit different activity on inflammatory CD14+CD16+ monocytes derived from SFMCs of PsA patients. SFMCs were co-cultured for 7 days in the presence of adalimumab, infliximab, secukinumab and ustekinumab at 10ug/ml or with betamethasone and methylprednisolone at 1ug/ml and 10ug/ml. Medium alone was used as a control. (A) Culture supernatants were analyzed for TNF levels by ELISA (n=8). (B) Cells were analyzed for %CD14+CD16+ monocytes by flow cytometry (n=11). All p values were calculated by the non-parametric one-way ANOVA Kruskal-Wallis test and Dunn’s multiple comparison test, *ppp=0.0003.Conclusion:Our data demonstrated marked activity mediated by TNF inhibitors in comparison with other biologics tested for their ability to suppress TNF secretion and inflammatory CD14+CD16+ monocytes. In contrast, GCs suppressed TNF secretion but did not significantly change the proportion of inflammatory CD14+CD16+ monocytes. These findings suggest an additional mechanism of action exerted directly by TNF inhibitors on synovial monocytes and which differs from that of GCs. These results warrant further studies of the therapeutic potential of local peripheral activity of TNF inhibitors for clinical application.Reference:[1]Carubbi F, Zugaro L, Cipriani P, Conchiglia A, Gregori L, Danniballe C, et al. Safety and efficacy of intra-articular anti-tumor necrosis factor alpha agents compared to corticosteroids in a treat-to-target strategy in patients with inflammatory arthritis and monoarthritis flare. Int J Immunopathol Pharmacol. 2016;29:252-66.Disclosure of Interests:None declared

Objective To evaluate the prevalence of sacroiliitis, the radiographic hallmark of inflammatory spondyloarthropathy, among patients diagnosed with fibromyalgia syndrome (FMS), using the current Assessment of SpondyloArthritis International Society (ASAS) criteria and magnetic resonance imaging. Methods Patients experiencing FMS (American College of Rheumatology 1990 criteria) were interviewed regarding the presence of spondyloarthritis (SpA) features and underwent HLA–B27 testing, C-reactive protein (CRP) level measurement, and magnetic resonance imaging examinations of the sacroiliac joints. FMS severity was assessed by the Fibromyalgia Impact Questionnaire and the Short Form 36 health survey. SpA severity was assessed by the Bath Ankylosing Spondylitis Disease Activity Index. Results Sacroiliitis was demonstrated among 8 patients (8.1%) and ASAS criteria for diagnosis of axial SpA were met in 10 patients (10.2%). Imaging changes suggestive of inflammatory involvement (e.g., erosions and subchondral sclerosis) were demonstrated in 15 patients (17%) and 22 patients (25%), respectively. The diagnosis of axial SpA was positively correlated with increased CRP level and with physical role limitation at recruitment. Conclusion Imaging changes suggestive of axial SpA were common among patients with a diagnosis of FMS. These findings suggest that FMS may mask an underlying axial SpA, a diagnosis with important therapeutic implications. Physicians involved in the management of FMS should remain vigilant to the possibility of underlying inflammatory disorders and actively search for such comorbidities.

The aim of this study was to evaluate the presence of autoantibodies to cyclic citrullinated synthetic peptides (ACPAs) in the sputum of patients with long-standing rheumatoid arthritis (RA).Nineteen consecutive RA patients and 16 age- and sex-matched control subjects participated in this cross-sectional study. All underwent complete lung function tests and provided induced sputum. Antibodies to citrullinated (CitP) and the corresponding norleucine-containing (NorP) peptides in the sputum of the RA patients and control subjects, as well as in the serum of the RA patients, were determined by enzyme-linked immunosorbent assay.Patients with RA had the following characteristics: mean disease duration of 12 years, Disease Activity Score for 28 joints of 3.44, and Sharp-van der Heijde score of 57.5. Ten of the 19 RA patients showed high titers of ACPAs in their sera. Four of the seropositive (40%), none of the seronegative RA patients, and only 1 of the control subjects showed detectable levels of ACPAs in their sputum. The ratio between the reactivity with CitP and NorP peptides in the sputum was significantly higher in RA sputum than in control sputum (1.33 ± 1.2 vs. 0.64 ± 0.14, P = 0.02). A positive correlation was found between sputum ACPAs and age, serum ACPAs, sputum anti-NorP, serum anti-CitP/NorP reactivity ratio, and the proportion of neutrophils and lymphocytes in the sputum. No significant correlation was found between sputum ACPAs and disease severity, history of smoking, lung function tests, or treatment for RA.Anticitrullinated protein/peptide antibodies can be detected in the sputum of RA patients and are correlated with the presence in the serum.

Galectin-3 is a β-galactoside-binding lectin that plays an important role in the modulation of immune responses. It has been shown to aggravate joint inflammation and destruction in experimental arthritis. We investigated the role of galectin-3 in TLR-induced cell activation in human synovial fibroblasts (SF) in order to better understand the mechanism(s) of the proinflammatory function of galectin-3 in arthritis. Galectin-3 expression in SF obtained from rheumatoid arthritis and osteoarthritis patients was inhibited by siRNA mediated gene-knockdown. Galectin-3 was also inhibited with modified citrus pectin (MCP), a polysaccharide galectin-3 ligand. Galectin-3 knockdown inhibited TLR-2, -3 and -4-induced IL-6 secretion, but not TLR-2, -3 and -4-mediated matrix metalloproteinase-3 or CC chemokine ligand-5 secretion. When the SF were stimulated with phorbol 12-myristate 13-acetate, a protein kinase C activator that bypasses the membranal receptors, galectin-3 knockdown no longer influenced IL-6 secretion. MCP reduced IL-6 levels in a dose-dependent manner. Our results indicate that galectin-3 is a positive sensor-regulator of TLR-induced IL-6 secretion in human synovial fibroblasts, thus adding new insights into the mechanisms by which galectin-3 augments synovial inflammation. These findings corroborate the potential role of glycan inhibitors of galectin-3 as a therapeutic approach for the treatment of inflammatory arthritis.

Background Rheumatoid arthritis (RA) patients have many therapeutic options. However, there are limited tools to predict the individual patient9s response to therapy. The Genefron personal diagnostic kit (IFR 300) has been developed based on analysis of large databases to select interferon stimulated gene (ISG) expressions which could predict response to a biologic agent Objectives This study aims to evaluate the ability of the Genefron diagnostic kit to predict the individual RA patient response to TNFα blockers. Methods Two separate analyses were performed, one retrospective and one prospective analysis. The response of 61 RA patients reported in 2 published data sets was analyzed retrospectively utilizing the Genefron kit. In addition, 18 patients with RA were assessed prospectively, before and 3 months after starting treatment with a TNFα blocker. Clinical assessment included swollen and tender joint counts, patient and physician assessments of disease activity. Patients9 blood samples were obtained before administration of the TNFα blocker and were analyzed utilizing the Genefron diagnostic kit which measures expression levels of selected genes by quantitative real time PCR. Results Genefron kit analysis of retrospective data correctly predicted the response to a TNFα blocker in 53 of 61 RA patients (accuracy - 86.8%). In the prospective analysis 6 patients achieved a moderate EULAR response, 6 achieved a good EULAR response and 6 did not respond. According to the EULAR moderate response, the Genefron diagnostic kit predicted the response correctly in 16 of 18 patients (accuracy-89%, sensitivity -100%, specificity - 67%). According to the EULAR good response, the kit predicted the response correctly in 15 of 18 patients (accuracy - 83.3%, sensitivity - 100%, specificity - 75%). Conclusions The Genefron diagnostic kit predicted the response to TNFα blockers in a high percentage of RA patients assessed either retrospectively or prospectively in a real life setting. This personal diagnostic kit has the ability to guide selection of a suitable biological drug for the individual RA patient Disclosure of Interest None declared

To evaluate the prevalence of sacroiliitis, the radiographic hallmark of inflammatory spondyloarthropathy, among patients diagnosed with fibromyalgia syndrome (FMS), using the current Assessment of SpondyloArthritis International Society (ASAS) criteria and magnetic resonance imaging.Patients experiencing FMS (American College of Rheumatology 1990 criteria) were interviewed regarding the presence of spondyloarthritis (SpA) features and underwent HLA-B27 testing, C-reactive protein (CRP) level measurement, and magnetic resonance imaging examinations of the sacroiliac joints. FMS severity was assessed by the Fibromyalgia Impact Questionnaire and the Short Form 36 health survey. SpA severity was assessed by the Bath Ankylosing Spondylitis Disease Activity Index.Sacroiliitis was demonstrated among 8 patients (8.1%) and ASAS criteria for diagnosis of axial SpA were met in 10 patients (10.2%). Imaging changes suggestive of inflammatory involvement (e.g., erosions and subchondral sclerosis) were demonstrated in 15 patients (17%) and 22 patients (25%), respectively. The diagnosis of axial SpA was positively correlated with increased CRP level and with physical role limitation at recruitment.Imaging changes suggestive of axial SpA were common among patients with a diagnosis of FMS. These findings suggest that FMS may mask an underlying axial SpA, a diagnosis with important therapeutic implications. Physicians involved in the management of FMS should remain vigilant to the possibility of underlying inflammatory disorders and actively search for such comorbidities.

Background: Statins (3-Hydroxy-3-methylglutaryl-CoA reductase inhibitors) exert favorable effects on lipopro- tein metabolism, but appeared to possess anti-inflammatory properties among others, as suggested by their ability to in- hibit collagen-induced arthritis in mice. Their activity in fibroblast-like synovial cells (FLS) has not yet been studied. Objectives: To evaluate the effect of varying doses of simvastatin on apoptosis of FLS. Methods: Synovial tissue, obtained during total knee replacement due to osteoarthritis, was cut into small pieces and cul- tured in Petri dishes with test materials, as previously described. FLS were incubated for 48 hours with 1 μmol/ml, 5 μmol/ml, 15 μmol/ml and 50 μmol/ml of simvastatin. Following incubation, apoptosis was analyzed by two-dimensional flow cytometry (FACS) using annexin V/PI staining according to the manufacturer's instructions. Results: Different concentrations of simvastatin induced apoptosis of FLS. The level proportion of apoptotic cells of rest- ing or activated with lipopolysaccharide (LPS; 3 μg/ml) FLS, not treated with simvastatin, was 21%. At 48 hours, the rate of apoptosis of activated fibroblasts, incubated with 1 μmol/ml, 5 μmol/ml, 15 and 50 μmol/ml was 22%, 32%, 48% and 41% respectively. Synovial cell viability evaluated by tetrazolium salt XXT was unaffected by the simvastatin concentra- tion used. Conclusion: Varying concentrations of simvastatin induce apoptosis of activated fibroblast-like synoviocytes, suggesting another possible mechanism of anti-inflammatory effects of statins in inflammatory conditions.

Objectives: Tumor necrosis factor alpha (TNF- ) therapy has been implicated in the development of autoim- mune diseases. Our aim was to describe three patients with spondyloarthropathies who responded to infliximab, a chi- meric monoclonal antibody specific for TNF- , but developed new symptoms of spondyloarthropathies. In parallel, a re- view of the literature on psoriasis induced by TNF- blockers was undertaken. Results: The first patient had been suffering from ankylosing spondylitis (AS) for more than 12 years. Infliximab induced a remission of AS, but he developed overt Crohn's disease two years after starting treatment. The second patient had AS for more than 20 years. Infliximab had an excellent effect on his AS, but he developed palmo-plantar psoriasis a few months after initiating therapy with the drug. The third patient, whose long-term and severe psoriasis had responded to in- fliximab developed peripheral arthritis. A review of the literature revealed 63 cases of psoriasis induced by TNF- block- ers (33 on Infliximab, 16 on Etanercept and 14 on Adalimumab). The underlying diseases were variable, including all the spectrum of conditions for which TNF- blockers are indicated. Patients developed psoriasis after a mean duration of treatment of 11 months. Interstingly, a substantial proportion of patients continued treatment with TNF  blockers, the psoriasis improving in a majority of cases under topical treatment only. Conclusion: While Infliximab may change the course of spondyloarthropathy, depressing the original symptoms it may uncover other occult aspects of these diseases.

Objective: Monitoring of immune responses is essential in the care of immunosuppressed individuals, including rheumatic patients. Evaluation of cellular immunity is essential for confirming virus-specific effector cell functions, but it is poorly standardized, and suffers from technical limitations and inaccurate results. There is, therefore, a need for reliable techniques for assessing cell-mediated immunity. In this study we compared the cell-mediated immunity response to influenza vaccine between a population of rheumatoid arthritis (RA) patients and healthy subjects by three methods. Methods: Trivalent influenza subunit vaccine was administered to 18 RA patients who were taking disease-modifying antirheumatic drugs and to 18 healthy controls. Peripheral blood mononuclear cells (PBMCs) and sera were obtained immediately before and ~28 days after vaccination. Cell-mediated immunity responses to vaccination were evaluated by (1) flow cytometric analysis of IL-2/IFN-γ production in activated CD4/CD8 T-cells, (2) enzyme-linked immunosorbent assay for the analysis of IFN-γ secretion, and (3) Granzyme B activity assay. Humoral response was evaluated by the hemagglutination inhibition assay. Results: Vaccination induced a significant increase in PBMC IFN-γ secretion and Granzyme B activity in the RA patients. Granzyme B activity also significantly increased in the controls, but there was no change in the levels of secreted IFN-γ. No group differences in the frequencies of IFN-γ/IL-2-producing activated CD4/CD8 T-cells were observed by flow cytometry. The geometric mean of hemagglutination inhibition antibody titers increased significantly for the H1N1/H3N2 influenza strains in both groups. Conclusions: Granzyme B activity assay was the only method to detect a significant cell-mediated immunity response in both groups while significant increase in IFN-γ secretion was demonstrated only in RA patients. Flow cytometric analysis failed to show IL-2 and IFN-γ production in both groups. Currently available methods for measuring cellular responsiveness to influenza vaccination are inconsistent and limited in their ability to reflect acquired cellular immunity.

The CNS manifestations of the antiphospholipid syndrome (APS) can mimic multiple sclerosis both clinically and radiologically.To compare evoked potential studies in APS patients and patients with multiple sclerosis with similar neurological disability.30 APS patients with CNS manifestations and 33 patients with definite multiple sclerosis and similar neurological disability underwent studies of visual evoked potentials (VEP), somatosensory evoked potentials (SSEP) in the upper and lower limbs (UL, LL), and sympathetic skin responses (SSR) in the upper and lower limbs.The neurological manifestations in the APS patients included stroke (n = 17), transient ischaemic attacks (n = 10), and severe headache with multiple white matter lesions on brain MRI (n = 3). Abnormal SSEP (LL), and SSR (UL; LL) were seen in APS patients (37%, 27%, and 30%, respectively) but VEP and UL SSEP were rarely abnormal (10% and 6%, respectively in APS v 58% and 33% in multiple sclerosis; p = 0.0005, p = 0.008). Mean VEP latencies were more prolonged in multiple sclerosis (116 ms v 101 ms, p0.001). Only one APS patient had abnormal findings in all three evoked potential studies, compared with seven patients in the multiple sclerosis group (p = 0.04)Abnormal VEPs are uncommon in APS in contrast to multiple sclerosis. Coexisting abnormalities in all other evoked potentials were similarly rare in APS. In patients with brain MRI findings compatible either with multiple sclerosis or APS, normal evoked potential tests, and especially a normal VEP, may support the diagnosis of APS.

To assess the efficacy and safety of vaccination against influenza virus in patients with rheumatoid arthritis, with special emphasis on the effect of disease modifying antirheumatic drugs (DMARDs), including tumour necrosis factor alpha (TNFalpha) blockers.82 rheumatoid patients and 30 healthy controls were vaccinated with a split-virion inactivated vaccine containing 15 mug haemagglutinin (HA) per dose of each of B/Hong Kong/330/2001 (HK), A/Panama/2007/99 (PAN), and A/New Caledonian/20/99 (NC). Disease activity was assessed by tender and swollen joint count, morning stiffness, evaluation of pain, Health Assessment Questionnaire, ESR, and C reactive protein on the day of vaccination and six weeks later. Haemagglutination inhibiting (HI) antibodies were tested by a standard WHO procedure. Response was defined as a fourfold or more rise in HI antibodies six weeks after vaccination, or seroconversion in patients with a non-protective baseline level of antibodies (1/40). Geometric mean titres (GMT) were calculated to assess the immunity of the whole group.Six weeks after vaccination, a significant increase in GMT for each antigen was observed in both groups, this being higher in the healthy group for HK (p=0.004). The percentage of responders was lower in rheumatoid patients than healthy controls (significant for HK). The percentage of responders was not affected by prednisone or any DMARD, including methotrexate, infliximab, and etanercept. Indices of disease activity remained unchanged.Influenza virus vaccine generated a good humoral response in rheumatoid patients, although lower than in healthy controls. The response was not affected by the use of prednisone or DMARDs.

Objective The purpose of this open pilot study was to assess possible mechanisms of the effects of leflunomide by studying the influence of the drug on the serum levels of MMP-1, MMP-3, IL-10, IL-6 and their possible correlation with clinical disease parameters. Patients and methods Thirty patients with long standing active rheumatoid arthritis were enrolled in this study. All patients failed at least 5 DMARDs in the past and were on stable treatment for at least 3 months before starting the protocol. The patients received a loading dose of 100 mg for 3 days followed by 20 mg/day thereafter and followed up monthly for 6 months. Disease activity was assessed at baseline, 2 weeks, and every month of therapy thereafter using the following variables: tender joint count, swollen joint count, morning stiffness duration, pain, tiredness, physician's and patient's global assessment, using VAS, ESR and CRP. Clinical effects of the treatment regimen were calculated using the American College of Rheumatology (ACR) criteria for clinical response. Adverse events were recorded. Serum levels of MMP-1, MMP-3, IL-10 and IL-6 were measured before and 3 months after starting the protocol. Results Except for tiredness, a statistically significant improvement in all clinical and laboratory parameters of disease activity was reached after 3 months. At this time point the ACR-20 response rate was 46.2%. The levels of MMP-1, MMP-3, IL-6 and IL-10 decreased significantly after 3 months. A statistically significant correlation between serum levels of MMP-1, IL-10 and IL-6 and clinical and laboratory parameters was also shown. After 6 months, 16 out of 30 patients withdrew from the study [adverse events (35.4%), lack of efficacy (9.7%), and low compliance (6.4%)]. Conclusions Leflunomide was clinically efficacious in this group of long standing resistant RA in an open study “real life” design. These results comply with those reported in previous clinical trials. Serum MMP-1, MMP-3, IL-10 and IL-6 levels decreased significantly. Despite high withdrawal rate, no serious adverse effects were recorded.

Background: Leflunomide is now an approved agent for the management of adult rheumatoid arthritis (RA). Its active metabolite A771726 inhibits de novo pyrimidine biosynthesis. Although considered to be an immunosuppressive agent, its mechanism of action remains obscure. Objectives: Evaluation of the leflunomide active metabolite A771726 (LEF) effect on interleukin 1s (IL1s), tumour necrosis factor (TNFα), nitric oxide (NO), and stromelysin (metalloproteinase-3 (MMP-3)) production by activated human synovial tissue in culture. Methods: Synovial tissue was obtained during surgery from patients undergoing total knee replacement owing to RA or osteoarthritis (OA), cut into small pieces, and cultured in Petri dishes with test materials as previously described. IL1s, TNFα, NO, and MMP-3 were measured in the culture media after 48 hours incubation with different doses of LEF by methods previously described. Results: LEF (0.3, 3, and 9 µg/ml) inhibited IL1s production in the presence of lipopolysaccharide (LPS; 3 µg/ml) in a dose dependent manner (p

Prevention of bacterial infection, which is a leading cause of morbidity in patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), is a priority. However, the safety and immunogenicity of the pneumococcal vaccine in such patients remain controversial. We evaluated the currently available pneumococcal vaccine in patients with RA or SLE. Pneumococcal vaccination was not associated with an appreciable deterioration in any clinical or laboratory measure of disease activity in either group. One month after vaccination, patients in both groups had significant increases in geometric mean concentrations of pneumococcal polysaccharide-specific IgG to all 7 serotypes tested, as did control subjects. However, 14 (33.3%) of 42 patients with RA and 5 (20.8%) of 24 patients with SLE responded either to none or to only 1 of the 7 polysaccharides. Pneumococcal vaccination is generally safe and immunogenic in patients with RA or SLE, but a subset of patients may remain unprotected by the currently available vaccine.

We aimed to assess the immunogenicity and safety of vaccination against seasonal influenza in psoriatic arthritis (PsA) and psoriasis (Pso) patients.Patients with PsA or Pso and healthy controls were vaccinated with the Sanofi Pasteur vaccine recommended by the WHO in 2012. Clinical and laboratory assessments were performed on the day of the vaccination and 4-6 weeks later. The immunogenicity of the vaccine was evaluated by haemagglutination inhibition assay.The study included 63 consecutive PsA patients and 4 Pso patients (mean age 50.1, 37 females, 30 males, 55.2% treated with tumour necrosis factor alpha blockers [TNF-α], 31.3% on disease-modifying anti-rheumatic drugs [DMARDs]) and 30 healthy controls. The geometric mean titers increased significantly in all participants for each of the subtypes tested. A substantial and similar proportion of patients in both groups responded to the vaccine. The response rate was not affected by parameters such as age, gender, disease activity or the use of TNF-α blockers or DMARDs. There were no significant changes in the patients' 68 tender and 66 swollen joint counts, dactylitis, PASI, global evaluation of the patient and physician and ESR, while there was a rise in CRP levels.Vaccination against seasonal influenza is safe and induces an appropriate response in patients with PsA, similar to healthy controls.

Objective To evaluate the effects of fluoxetine and amitriptyline on nitric oxide (NO), prostaglandin E2 (PGE2), and hyaluronic acid (HA) production in human synovial cells and synovial tissue cultures. Methods Human synovial cells, synovial tissue, and cartilage were cultured in the presence or absence of cytokines, lipopolysaccharides (LPS), fluoxetine, or amitriptyline. Production of NO, PGE2, and HA was determined in culture media. Sulfated glycosaminoglycan (S-GAG) synthesis was evaluated in cartilage by 35S incorporation. Results Fluoxetine (0.3 μg/ml, 1 μg/ml, and 3 μg/ml) inhibited NO release by 56%, 62%, and 71%, respectively, in the media of synovial cells stimulated by interleukin-1α (IL-1α; 1 ng/ml) plus tumor necrosis factor α (TNFα; 30 ng/ml). Amitriptyline (0.3 μg/ml, 1 μg/ml, and 3 μg/ml) caused a 16%, 27.3%, and 51.4% inhibition of NO release. Fluoxetine and amitriptyline (0.3 μg/ml, 1 μg/ml, and 3 μg/ml) significantly (P < 0.05) inhibited PGE2 release in the media of human synovial cells in the presence of IL-1α plus TNFα, in a dose-dependent manner (up to 88% inhibition). Fluoxetine (0.3 μg/ml, 1 μg/ml, and 3 μg/ml) and amitriptyline (1 μg/ml and 3 μg/ml) significantly (P < 0.05) inhibited PGE2 release in the media of human synovial tissue in the presence of LPS. Fluoxetine and amitriptyline (0.3 μg/ml, 1 μg/ml, and 3 μg/ml) also significantly (P < 0.05) inhibited HA production by human synovial cells in the presence of IL-1β plus TNFα. Fluoxetine and amitriptyline (1 μg/ml) partially reversed IL-1β–induced inhibition of 35S-GAG synthesis by human cartilage cultures (P < 0.05). Neither fluoxetine nor amitriptyline had a toxic effect on cells in the concentrations used. Conclusion Inhibition of NO and PGE2 production by connective tissue cells is a mechanism by which some antidepressant medications may affect pain, articular inflammation, and joint damage.

Objective Primary generalized osteoarthritis (OA), the most prevalent joint disease, is usually symmetric. Sporadic case reports mention decreased OA manifestations in limbs in which there are neurologic deficits, but no systematic research has been published. The aim of the present study was to examine these observations in a planned and controlled survey in a group of patients with OA. Methods Seventy-five geriatric patients with a history of stroke and hemiparalysis were studied clinically and radiographically (hand radiographs; graded according to a modified Altman method) for the presence and the degree of OA in the hands. Detailed clinical and radiologic scores were calculated for each hand. Demographic, occupational, and neurologic data were collected. Patients with other joint or neurologic conditions were excluded. A group of 55 elderly patients without stroke were similarly studied (controls). Scores in the paralyzed hand were compared with those in the nonparalyzed hand in the stroke patients and subgroups (by Student's paired t-test and Wilcoxon test). Scores in the dominant hands were compared with those in the nondominant hands in stroke patients and control subjects (by Student's paired t-test and Mann-Whitney test). Correlation between the degree of neurologic damage and OA asymmetry (Pearson's correlation coefficient) was also sought. Results Paralyzed hands showed significantly fewer OA changes than nonparalyzed hands, both clinically and radiologically. This trend, accentuated in patients with more severe paralysis, disappeared in those with mild residual paresis. Asymmetry of OA was more pronounced in patients with flaccid, compared with spastic, paralysis. The degree of paralysis and loss of muscle strength correlated with the degree of OA asymmetry. Women had significantly higher OA scores than men. In the control group, dominant hands had higher OA scores, but this finding was concealed among hemiparalyzed patients. Lifetime gross occupational load and present grip strength did not correlate with the degree of OA. Conclusion In elderly patients, hemiparalysis reduces ipsilateral hand expression of OA, while OA is accentuated (or increased) in the dominant hand of patients without paralysis. This first systematic study confirms the findings of previous case reports and lends support to the role of biomechanical factors in the development of OA.

Monogenic periodic fever syndromes are characterized by recurrent episodes of fever, accompanied by localized inflammatory manifestations. Among them, familial Mediterranean fever (FMF) is the most studied and is by far the most prevalent periodic fever syndrome in Israel. We present a diagnostic workup of a patient suffering from a periodic fever syndrome, initially thought to be FMF and characterized by attacks of fever, severe abdominal pain, a migratory erythematous rash and conjunctivitis. The development of periorbital edema presenting as diplopia led to consideration of tumor necrosis factor receptor-1-associated periodic syndrome (TRAPS). Genetic tests confirmed the diagnosis. This case should alert us that even in Israel, a patient with periodic fever not fully consistent with the typical features of FMF, should be evaluated for other periodic fever syndromes.

We describe herein a patient with rheumatoid arthritis who developed proteinuria due to AA amyloidosis, in whom the inflammatory disease was rapidly and completely suppressed by treatment with infliximab. This response was accompanied by resolution of the proteinuria and stabilization of the amyloid deposits as seen on serial (123)I-labeled serum amyloid P scintigraphy.

Hepatitis B infection and vaccination against it have been implicated in the potential triggering or flare of some autoimmune diseases, including rheumatoid arthritis (RA). However, the safety of hepatitis B vaccination in patients with pre-existing RA is not known.To assess the safety and antibody response of immunisation with a recombinant DNA hepatitis B vaccine in patients with RA.The study comprised 44 patients with RA, of whom 22 received three doses (the second and third dose being given after one and six months) of a recombinant DNA hepatitis B vaccine (study group) and 22 did not receive the vaccine (control group). Both groups had comparable proportions of women and similar mean age (51 years). Clinical assessment before and two and seven months after the first immunisation included evaluation of daytime pain with a 10 cm visual analogue scale, duration of morning stiffness, and number of tender and swollen joints. Erythrocyte sedimentation rate (ESR) and C reactive protein (CRP) were measured at each visit. Antibodies to hepatitis B surface antigen (HBsAg) were determined by a commercial enzyme linked immunosorbent assay (ELISA) test kit.Hepatitis B vaccination was not associated with an appreciable deterioration in any clinical or laboratory measure of disease. The measures of disease activity of the patients and controls during the study period did not differ significantly: p=0.76 for daytime pain, p=0.1 for morning stiffness, p=0.24 and p=0.3 for tender and swollen joints respectively, p=0.08 for CRP, and p=0.12 for ESR. Fifteen of the 22 patients responded to vaccination, with an antibody level against HBsAg of 10 IU/l after seven months. Lack of response was associated with older age and higher scores of daytime pain.Hepatitis B vaccination is safe in RA and produces antibodies in 68% of the patients.

Objective To assess the efficacy and safety of vaccination against pandemic H1N1 virus in patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), psoriatic arthritis (PsA), and ankylosing spondylitis (AS) compared with healthy controls. Methods The study population comprised 41 RA patients, 21 SLE patients, 17 PsA patients, 15 AS patients, and 25 healthy controls. All were vaccinated using the Novartis MF59-adjuvanted H1N1v monovalent influenza vaccine. The immunogenicity of the vaccine was assessed on day 1 and again 4 weeks later by hemagglutination inhibition assay. Geometric mean titers and seroconversion rates were calculated for each group. The safety of the vaccine was evaluated using the 28-joint Disease Activity Score (DAS28) for RA and PsA, the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), and the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). Results The proportion of baseline protective levels of antibodies against H1N1 was similar in all but the AS group, in which it was lower. The geometric mean titers increased significantly in all 5 groups. A substantial proportion of patients and controls responded to the vaccine. The healthy controls demonstrated a better response than each of the other groups: 84% versus 56% for RA, 67% for SLE, 59% for PsA, and 53% for AS. Multivariate logistic regression analysis identified RA and PsA as parameters of significantly lower response. The DAS28, BASDAI, and SLEDAI remained unchanged after vaccination. Conclusion Vaccination against pandemic H1N1 using an adjuvanted H1N1v monovalent influenza is safe and induced an appropriate response in patients with RA, SLE, PsA, and AS.

To assess the efficacy and safety of the influenza virus vaccine in systemic sclerosis (SSc) patients compared to healthy controls.Twenty-six SSc patients and 16 healthy controls were vaccinated with a trivalent influenza subunit vaccine (H1N1 A/Brisbane/59/2007(TGA 2008/81B) (H1N1), H3N2 A/Uruguay/716/2007 (A/Brisbane/10/2007-like, NIBSC8/124) (H3N2) and B B/Brisbane/60/2008 (TGA 2009/82/B) (B)). The subjects were evaluated on the day of vaccination and 6 weeks later. Disease activity was assessed by the Rodnan score, number of ulcers, number of tender and swollen joints, the presence of dyspnea, cough, dyspepsia and dysphagia, and patient (PDAI) and physician (PHDAI) disease activity evaluation by the visual activity score (VAS), erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) level. The humoral response was evaluated by haemagglutination inhibition (HI).At baseline, 62%, 15% and 88% of the SSc patients had protective levels against H1N1, H3N2 and B, respectively, versus 56%, 62% and 87% for controls. Six weeks later, the proportion of responders to H1N1 was significantly higher in the SSc patients (73%) compared to controls (37.5%) (p=0.0225). The proportion of responders to H3N2 and B was similar in both groups, and both had a significant increase in geometric mean titers for each antigen. A lower response to H1N1 was associated with interstitial lung disease, while patients on combination calcium channel blockers and iloprost therapy showed significantly better response to H1N1 and B antigens. Most underlying disease activity parameters remained unchanged.The influenza virus vaccine was safe and generated a satisfactory humoral response in SSc patients.

To assess the effect of rituximab on the efficacy and safety of influenza virus vaccine in patients with rheumatoid arthritis (RA).The study group comprised patients with RA treated with conventional disease-modifying drugs with or without rituximab. Split-virion inactivated vaccine containing 15 microg haemagglutinin/dose of B/Shanghai/361/02 (SHAN), A/New Caledonian/20/99 (NC) (H1N1) and A/California/7/04 (CAL) (H3N2) was used. Disease activity was assessed by the number of tender and swollen joints, duration of morning stiffness and evaluation of pain on the day of vaccination and 4 weeks later. CD19-positive cell levels were assessed in rituximab-treated patients. Haemagglutination inhibition (HI) antibodies were tested and response was defined as a greater than fourfold rise 4 weeks after vaccination or seroconversion in patients with a non-protective baseline level of antibodies (1/40). Geometric mean titres (GMT) were calculated in all subjects.The participants were divided into three groups: RA (n = 29, aged 64 (12) years), rituximab-treated RA (n = 14, aged 53 (15) years) and healthy controls (n = 21, aged 58 (15) years). All baseline protective levels of HI antibodies and GMT were similar. Four weeks after vaccination, there was a significant increase in GMT for NC and CAL antigens in all subjects, but not for the SHAN antigen in the rituximab group. In rituximab-treated patients, the percentage of responders was low for all three antigens tested, achieving statistical significance for the CAL antigen. Measures of disease activity remained unchanged.Influenza virus vaccine generated a humoral response in all study patients with RA and controls. Although the response was significantly lower among rituximab-treated patients, treatment with rituximab does not preclude administration of vaccination against influenza.

The synovial fluid (SF) cells of rheumatoid arthritis (RA) patients express a specific CD44 variant designated CD44vRA. Using a cellular model of this autoimmune disease, we show in this study that the mammalian lectin, galectin-8 (gal-8), is a novel high-affinity ligand of CD44vRA. By affinity chromatography, flow cytometry, and surface plasmon resonance, we demonstrate that gal-8 interacts with a high affinity (Kd, 6 × 10−9 M) with CD44vRA. We further demonstrate that SF cells from RA patients express and secrete gal-8, to a concentration of 25–65 nM, well within the concentration of gal-8 required to induce apoptosis of SF cells. We further show that not all gal-8 remains freely soluble in the SF and at least part forms triple complexes with CD44 and fibrinogen that can be detected, after fibrinogen immunoprecipitation, with Abs against fibrinogen, gal-8 and CD44. These triple complexes may therefore increase the inflammatory reaction by sequestering the soluble gal-8, thereby reducing its ability to induce apoptosis in the inflammatory cells. Our findings not only shed light on the receptor-ligand relationships between CD44 and gal-8, but also underline the biological significance of these interactions, which may affect the extent of the autoimmune inflammatory response in the SF of RA patients.

Case history A 48 year old man with 17 year history of primary Sjogren syndrome (pSS) presented with a sudden swelling of the left lower limb without pain, fever or any other symptom. The diagnosis of pSS was based on xerophthalmia, xerostomia, and swelling of the parotid glands in the presence of positive antinuclear antibodies (ANA), rheumatoid factor (RF), anti-Ro ( 85 IU ELISA, normal range

Aspirin is commonly used by elderly patients. In previous studies we found transient changes in renal function induced by low doses of aspirin.To investigate the mechanisms of these effects.The study group included 106 long-term care stable geriatric inpatients. Diet and drugs were kept stable. The study lasted 5 weeks; during the first 2 weeks 100 mg aspirin was administered once a day. Clinical and laboratory follow-up was performed at baseline and weekly for the next 3 weeks. The glomerular filtration rate was estimated by creatinine clearance measured in 24 hour urine and serum creatinine, and by the Cockcroft-Gault formula (C-G) equation. Uric acid clearance was determined from serum concentrations and 24 hour excretion of uric acid. Patients with serum creatinine1.5 mg/dl were not included.After 2 weeks on low dose aspirin, measured creatinine and uric acid clearances decreased significantly compared with the initial values in 70% and 62% of the patients, respectively, with mean decreases of 19% and 17%, respectively (P0.001). Blood urea nitrogen increased by 17% while serum creatinine and uric acid concentrations increased by 4% (P0.05 for all). The C-G values decreased by 3% (P0.05). After withdrawal of aspirin all parameters improved. However, 67% of the patients remained with some impairment in their measured Ccr, compared to baseline. Patients who reacted adversely to low dose aspirin had significantly better pre-study renal function (Ccr), lower hemoglobin and lower levels of serum albumin.Short-term low dose aspirin affected renal tubular creatinine and uric acid transport in the elderly, which may result in a prolonged or permanent deterioration of the renal function. It is suggested that renal functions be monitored even with the use of low dose aspirin in elderly patients.

Objective To assess the levels of anti–cyclic citrullinated peptide (anti-CCP) and IgA rheumatoid factor (IgA-RF) in synovial fluids of patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), and osteoarthritis (OA). Methods Knee effusions of 29 patients with RA (23 women, 6 men; mean ± SD age 60 ± 15 years), 20 with PsA (6 women, 14 men; mean age 51 ± 12 years), and 19 with OA (9 women, 10 men; mean age 73 ± 11.8 years) were aspirated, tested for white blood cell (WBC) counts, centrifuged, and stored at −20°. Sera of 22, 11, and 12 of these patients with RA, PsA, and OA, respectively, were similarly stored. IgG anti-CCP and IgA-RF were detected by enzyme-linked immunosorbent assay. Erythrocyte sedimentation rate and C-reactive protein levels were used as measures of disease activity. Results Mean levels of synovial fluid anti-CCP and IgA-RF were significantly increased in RA joint effusions compared with PsA and OA (anti-CCP: 150 ± 134, 34 ± 29, and 24 ± 26 units, respectively [P < 0.003]; IgA-RF: 76 ± 77, 15.7 ± 10, and 18 ± 20 units, respectively). No significant difference was noted between OA and PsA. A significant correlation was found between synovial fluid anti-CCP and serum anti-CCP and IgA-RF. In patients with RA, a significant correlation was found between synovial fluid WBC counts and IgA-RF (P = 0.03) and serum IgA-RF (P = 0.008), but not between synovial fluid and serum anti-CCP levels. In RA patients, C-reactive protein correlated with serum IgA-RF. Conclusion Anti-CCP and IgA-RF were significantly increased in synovial fluid of RA in comparison with PsA and OA patients.

OBJECTIVE: To describe a novel iatrogenic immunological reaction produced by minocycline. CASE REPORTS: The clinical course and laboratory results of three women who presented with similar rheumatological manifestations after a prolonged exposure to minocycline are described. All three presented a unique reaction manifested by fever, arthritis/arthralgia and livedo reticularis during treatment with minocycline for acne vulgaris. The clinical syndrome was associated with high titre of serum perinuclear anticytoplasmatic antibodies (p-ANCA) and antimyeloperoxidase antibody (anti-MPO). Symptoms resolved after stopping the drug and recurred promptly after rechallenge in all three patients. CONCLUSIONS: Minocycline, which is widely used in the treatment of acne, often without adequate supervision, may induce arthritis and livedo vasculitis associated with anti-MPO.

Synovial fluid cells from joints of rheumatoid arthritis (RA) patients express a novel variant of CD44 (designated CD44vRA), encoding an extra trinucleotide (CAG) transcribed from intronic sequences flanking a variant exon. The CD44vRA mutant was detected in 23 out of 30 RA patients. CD44-negative Namalwa cells transfected with CD44vRA cDNA or with CD44v3-v10 (CD44vRA wild type) cDNA bound FGF-2 to an equal extent via their associated heparan sulfate chains. However, Namalwa cells, immobilizing FGF-2 via their cell surface CD44vRA, bound substantially more soluble FGF receptor-1 (FGFR-1) than did Namalwa cells immobilizing the same amount of FGF-2 via their cell surface CD44v3-v10. The former cells stimulated the proliferation of BaF-32 cells, bearing FGFR-1, more efficiently than did the latter cells. Finally, isolated primary synovial fluid cells from RA patients expressing CD44vRA bound more soluble FGFR-1 to their cell surface–associated FGF-2 than did corresponding synovial cells expressing CD44v3-v10 or synovial cells from osteoarthritis patients. The binding of soluble FGFR-1 to RA synovial cells could be specifically reduced by their preincubation with Ab’s against the v3 exon product of CD44. Hence, FGF-2 attached to the heparan sulfate moiety expressed by the novel CD44 variant of RA synovium cells exhibits an augmented ability to stimulate FGFR-1–mediated activities. A similar mechanism may foster the destructive inflammatory cascade not only in RA, but also in other autoimmune diseases.

A 37 year old man presented at another centre with a three week history of high grade fever, chills, and cervical lymphadenopathy. Routine laboratory tests as well as a purified protein derivative (PPD) test were within the normal ranges. Computed tomography of the chest and abdomen showed massive lymphadenopathy in the mediastinum and retroperitoneum. A cervical lymph node biopsy disclosed non-caseating granuloma negative for Mycobacterium tuberculosis by acid fast staining and culture. Sarcoidosis was diagnosed and the patient was treated with corticosteroids at a maximum dose of 60 mg/day for two months with complete resolution of the fever and lymphadenopathy. Four months later, the patient developed right carpal tunnel syndrome, which was attributed to a lesion occupying space in the right radius; the tumour was removed and histology demonstrated non-caseating granuloma, interpreted as osseous sarcoidosis. A short course of corticosteroids was renewed and tapered off. He remained asymptomatic during the following six months when he developed oligoarthritis affecting the right ankle and wrist. Synovectomy of his right wrist showed non-caseating granuloma. Culture of the synovium was negative for Mycobacterium tuberculosis . Despite treatment with systemic and intra-articular steroids and addition of a three month course of weekly methotrexate, chronic and disabling monarthritis of the right ankle …

The incidence of lower urinary tract infection in 120 women with rheumatoid arthritis and secondary Sjögren's syndrome was evaluated retrospectively. Thirty one patients (26%) had secondary Sjögren's syndrome. Recurrent urinary tract infection was significantly more common in these patients (11/31) than in patients without Sjögren's syndrome (4/89). Habitual leucocyturia was also more common in patients with secondary Sjögren's syndrome (18/31) than in patients with rheumatoid arthritis without Sjögren's syndrome (8/89). Of seven patients with vaginal sicca symptoms, six had recurrent urinary tract infection. Urinary 24 hour mucopolysaccharide excretion in 20 patients with Sjögren's syndrome was similar to the excretion in 10 patients without Sjögren's syndrome. These results show that recurrent urinary tract infection is significantly more common in women with rheumatoid arthritis and secondary Sjögren's syndrome. A local deficit in protective urinary mucosal secretion or other immune mechanisms may be responsible for this susceptibility.

Objective Aspirin is known to have a bimodal effect on the renal handling of uric acid (UA). High dosages (>3 gm/day) are uricosuric, while low dosages (1–2 gm/day) cause UA retention. Although very-low-dose (mini-dose) aspirin is used increasingly as a platelet aggregation inhibitor, no studies have been published on whether aspirin's renal effects occur at dosages of

OBJECTIVE To report on four patients with autoimmune disorders who developed acute myocardial infarction (MI) during or soon after treatment with high dose intravenous immunoglobulins (IVIG) and to determine the clinical profile of patients prone to this complication. METHODS The clinical history of the four patients is reported with details concerning age, sex, indication for IVIG treatment, risk factors, timing of the MI and outcome. The relevant medical literature has been reviewed. RESULTS The patients, three men and one woman, aged 42–67, received IVIG treatment for different autoimmune disorders. All had a history of atherosclerosis or previous risk factors such as hypertension, stroke, hyperlipidaemia and obesity. Two of the patients suffered a MI after the first infusion of IVIG while the others—after the 5th and 15th pulses. MI occurred during the infusion in two patients and after a few days in the others. All the patients recovered from the acute event. These observations are in concert with sporadic cases of IVIG related thrombosis reported in the medical literature. CONCLUSION In patients with vascular risk factors such as old age, hypertension, history of stroke or coronary artery disease, the possibility of IVIG related vascular complications should be considered and IVIG prescribed with a cautious reweighted risk/benefit consideration.

Erythema nodosum (EN) is a hypersensitivity reaction associated with many diseases. We describe a family in which 4 sisters had acute or recurrent EN. HLA typing showed a common haplotype in the affected members of the family. A review of familial EN and HLA distribution in EN is presented.

Two 19 year old patients with juvenile chronic arthritis developed liver toxicity during treatment with sulphasalazine. A significant increase in the levels of liver enzymes in serum samples was noticed in relation to the initiation of treatment in one patient and to the increase in dose in the second. The enzymes returned to normal levels 14 days after the drug had been stopped. A rechallenge in one of the patients caused re-exacerbation. This is the first report of liver toxicity induced by sulphasalazine in juvenile chronic arthritis. As spontaneous liver involvement in juvenile chronic arthritis is not rare, the possibility of drug induced hepatitis should be recognised in these patients.

A hereditary chondrocalcinosis is described for the first time in an Ashkenazi Jewish kindred. Of 34 family members in five generations, seven had medical history suggesting the disease. Five of 25 members of generations III-V had direct evidence for their disease. Characteristically, symptoms started at a fairly early age (third decade) while radiological evidence of chondrocalcinosis was delayed to the fourth decade. Joints commonly affected were knees, wrists, and elbows. The course was chronic with acute, exercise induced exacerbations.

In 15 patients with rheumatoid arthritis who were in clinical remission the weekly regimen of methotrexate treatment was changed to fortnightly without a change in dose. A total of 13 patients completed a 12 month trial. No change in clinical or laboratory parameters occurred. There was no change in the use of analgesics or non-steroidal anti-inflammatory drugs and the patients remained in remission. Two patients had to be withdrawn after two and four months respectively because of a flare in disease activity. It is suggested that in most patients with rheumatoid arthritis who are treated with methotrexate and whose disease activity is stable a fortnightly regimen can be permitted without affecting drug efficacy.

A 47 year old man presented with seven years of severe psoriatic polyarticular arthritis of progressive, symmetrical, and additive course, affecting the shoulders, elbows, wrists, metacarpophalangeal joints, proximal interphalangeal joints, distal interphalangeal joints, hips, knees, and feet. Also, his skin and nails were completely affected with severe erythroderma. The patient was treated with methotrexate, chrysotherapy, antimalarial drugs, salazopyrine, azathioprine, cyclosporin, minocycline, and intra-articular and systemic corticosteroids. All these treatments consecutively and in …

Previous work has shown that leucocyte adhesiveness/aggregation (LAA), as measured by the leukergy test, correlates well with disease severity in rheumatic patients. As LAA is probably a manifestation of the acute phase reaction various components of the acute phase reaction were measured in order to identify the best marker of disease activity. In addition to LAA, the following variables were measured in 79 patients with various rheumatic diseases and in 10 controls: white blood cell and platelet counts, erythrocyte sedimentation rate, haptoglobin, fibrinogen, C reactive protein, albumin, globulin, caeruloplasmin, alpha 1, alpha 2, beta, and gamma globulin, and haemoglobin concentrations. Patients were graded according to the state of their disease as mild, moderate, or severe. The extent of leucocyte adhesiveness/aggregation in peripheral blood proved to be the best laboratory variable for the grading of disease activity. Correct grading was obtained in 63% of the patients by means of the LAA, compared with 48% with C reactive protein, 41% with caeruloplasmin, 40% with haptoglobin, and 32% with haemoglobin. It is suggested that LAA of the peripheral blood during inflammation may be used as a reliable marker of disease severity.

The association between aggregates of leucocytes in blood drawn from patients with various inflammatory conditions and the serum concentration of C-reactive protein (CRP) was examined: serum concentration of CRP might contribute to the development of cellular aggregations. A total of 213 patients with various inflammatory or necrotic conditions were examined (including 31 women with normal pregnancy and 59 controls). A significant correlation between the degree of leucocyte aggregation and CRP concentration was noted in patients with bacterial infections and in a group of patients with various inflammatory conditions. In contrast, there was no correlation between the extent of leucocyte aggregation and CRP concentrations in patients with viral infections, malignancies, or pregnancy. The presence or absence of aggregated leucocytes can help in differentiating between the respective bacterial or viral infections. The serum concentrations of CRP were increased in both types of infection, although when a quantitative CRP assay was used, considerably higher concentrations were detected in bacterial diseases.

In a prospective open study 44 Israeli patients with rheumatoid arthritis were treated with weekly low dose methotrexate (MTX) for up to 36 months. Nine patients withdrew from the study: six because of side effects and three due to inefficacy. One patient died of septicaemia following septic arthritis. Significant improvement, graded by Ritchie articular index, grip strength, physician's global assessment, erythrocyte sedimentation rate (ESR), and platelet counts, was noticed in response to treatment. Seronegative patients had a better clinical response. Transient gastrointestinal symptoms were common and correlated with increases of serum aspartate transaminase (AST). HLA-DR1 and DR7 were significantly associated with increased serum AST concentrations.

Three women with classic rheumatoid arthritis, who were receiving weekly doses of methotrexate (MTX), developed accelerated subcutaneous nodulosis, despite good response to the drug. In 2 of the patients, the onset of nodulosis occurred within 3 months and 5 months, respectively, after starting MTX; in the third patient, it was observed only after 4 years of MTX therapy. In all 3 patients, the onset was unusually abrupt, with extensive distribution and remarkable nodule size. Additional manifestations of cutaneous vasculitis in 2 of the patients and Raynaud's phenomenon in the third appeared concomitantly with the nodulosis. Physicians prescribing MTX therapy for patients with rheumatoid arthritis should be aware of these potential complications.

Objective: Evaluation of the effect of a ginger extract (Zintona EC) on patients suffering from gonarthritis.Material and methods: Twenty-nine patients (6 men and 23 women) with symptomatic gonarthritis (ACR criteria), in the age range 42–85 years, were included after randomization in a double blind, placebo controlled, crossover study of 6 months' duration. The treatment group was given a ginger extract (250mg of Zingiberis Rhizoma per capsule, qid), while the placebo group received the same number of identical looking capsules per day. The crossover occurred after 3 months of therapy. Results were evaluated by a 100mm visual analog scale (VAS) of pain on movement and of handicap.Results: Eight patients dropped out because of inefficacy, three from group 1 (ginger extract first) and five from group 2 (placebo first). One patient from group 1 and one from group 2 dropped out because of heartburn (while they were on ginger extract). Twenty patients completed the study period of 24 weeks and 19 that of 48 weeks follow-up. By the end of 24 weeks there was a highly statistically significant difference between the VAS of pain and handicap of the two groups (P