Drug-free remission: the goal of the future in management of patients with rheumatoid arthritis.

Management of patients with rheumatoid arthritis according to the "treat-to-target" strategy requires achievement of remission or low disease activity when remission cannot be achieved (mostly in patients with advanced disease). The assessment of remission and low disease activity is based on a number of definitions depending on the applied instruments which do not always correspond to one another. The role of biomarkers and imaging techniques (ultrasound and magnetic resonance imaging) in predicting the risk for disease relapse after achieving remission and tapering disease-modifying antirheumatic drugs treatment are presented. The concept of achieving the full control of inflammation including residua synovial inflammation and drug free-remission is discussed.

Prevalence of thyroid diseases and antithyroid antibodies in women with rheumatoid arthritis.

INTRODUCTION: Thyroid abnormal function and and/or autoimmune thyroid disease (ATD) are observed in 6% to 33.8% patients with rheumatoid arthritis (RA). OBJECTIVES: The aim of the study was to determine whether ATD is more prevalent in patients with RA compared to the control group involving age and sex-matched subjects without RA and whether these patients should be screened for thyroid disease. PATIENTS AND METHODS: In 100 patients with RA and 55 patients without RA (control group) hormonal thyroid function and antithyroid antibodies were assessed. RESULTS: ATD was more prevalent (16%) in patients with RA than in the control group (9%). The difference was no statistically significant. The RA patients with concomitant ATD had lower RA activity than non-ATD RA patients. Antithyreoglobulin (anti-TG) and antithyroid peroxidase (anti-TPO) antibodies were present in similar percentage of patients with RA (12% and 15%, respectively) and in the control group (9% and 18%, respectively). The most common thyroid dysfunction observed in both groups was subclinical hypothyroidism. An association between thyroid dysfunction and clinical symptoms suggestive of thyroid disease in RA patients was not demonstrated. In patients with RA low free triiodothyronine concentrations were significantly more common. CONCLUSIONS: A higher prevalence of ATD in female RA patients compared with controls indicates the need for screening not only of thyroid function, but also of the presence of anti-TPO antibodies as the ATD marker in RA patients. Their presence does not correlate with the occurrence of thyroid disorders in RA patients. Monitoring of thyroid function is of particular importance since as already shown the course of thyroid disease in RA patients is often asymptomatic.

Reactive arthritis.

Reactive arthritis (ReA) is a non-purulent joint inflammation that usually follows bacterial gastrointenstinal or urogenital infections. The classic presentation of ReA is characterized by an asymmetric arthritis usually in the lower limbs associated with urethritis, conjunctivitis and occurrence of other articular or extra-articular manifestations. ReA is classified as a type of seronegative spondyloarthopathy. Approximately 65-85% of patients with ReA are HLA-B27 positive. Regardless of the preceding infection, the clinical picture is similar, but management can differ according to the triggering infection. Treatment of Chlamydia-induced ReA should be started with antibiotics because of several mechanisms by which Chlamydia can cause persistent infection. The disease may have an acute or self-limited course, however some patients develop chronic arthritis.

[Elderly onset rheumatoid arthritis]. / Reumatoidalne zapalenie stawów o poczatku w wieku póznym.

Elderly-onset rheumatoid arthritis (EORA), defined as rheumatoid arthritis (RA) with the onset at the age > or =60 differs sligthy at presentation from younger-onset RA (YORA) by a more equal sex distribution, a higher frequency of an acute onset, more frequent involvement of large joints, especially of the shoulder, and higher disease activity. Longitudinal studies have shown greater disease activity, more severe radiographic damage and functional decline in patients with EORA than in those with YORA. These differences were only found in seropositive patients. In seronegative EORA patients a less severe course of the disease and a better outcome have been observed, with the clinical manifestations of polymyalgia rheumatica or remitting seronegative symmetrical synovitis with pitting edema. This article is a review of available data concerning differences between EORA and YORA.

[Polymyalgia rheumatica mimicking neoplastic disease--significant problem in elderly patients]. / Polimialgia reumatyczna a choroba nowotworowa--problem wieku podeszlego.

Polymyalgia rheumatica is a rheumatic disease which mainly affects the elderly, and is seldom diagnosed in patients <50 years of age. The prevalence of polymyalgia rheumatica is approximately 16.8 to 53.7 per 100,000 of the population >50 years of age. Patients may present with spiking fever, malaise, fatigue, weight loss and other features suggesting inflammation, which in each case requires differential diagnosis from malignancies. Neoplastic disease in turn can manifest itself in symptoms resembling those of polymyalgia, which are named "polymyalgia-like syndrome" and are in fact paraneoplastic syndromes presenting as polymyalgia rheumatica. These observations suggest that a careful clinical evaluation and a long term follow-up are necessary for a correct diagnosis of polymyalgia rheumatica.

Diagnostic performance of amyloid A protein quantification in fat tissue of patients with clinical AA amyloidosis.

OBJECTIVE: Amyloid A protein quantification in fat tissue is a new immunochemical method for detecting AA amyloidosis, a rare but serious disease. The objective was to assess diagnostic performance in clinical AA amyloidosis. METHODS: Abdominal subcutaneous fat tissue of patients with AA amyloidosis was studied at the start of an international clinical trial with eprodisate (NC-503; 1,3-propanedisulfonate; Kiacta), an antiamyloid compound. All patients had renal findings, i.e. proteinuria (> or =1 g/day) or reduced creatinine clearance (20 - 60 ml/min). Controls were patients with other types of amyloidosis and arthritic patients without amyloidosis. Amyloid A protein was quantified by ELISA using monoclonal antihuman serum amyloid A antibodies. Congo red stained slides were scored by light microscopy in a semiquantitative way (0 to 4+). RESULTS: Ample fat tissue (>50 mg) was available for analysis in 154 of 183 patients with AA amyloidosis and in 354 controls. The sensitivity of amyloid A protein quantification for detection of AA amyloidosis (>11.6 ng/mg fat tissue) was 84% (95% CI: 77 - 89%) and specificity 99% (95% CI: 98 - 100%). Amyloid A protein quantification and semiquantitative Congo red scoring were concordant. Men had lower amyloid A protein values than women (p < 0.0001) and patients with familial Mediterranean fever had lower values than patients with arthritis (p < 0.001) or other inflammatory diseases (p < 0.01). CONCLUSIONS: Amyloid A protein quantification in fat tissue is a sensitive and specific method for detection of clinical AA amyloidosis. Advantages are independence from staining quality and observer experience, direct confirmation of amyloid AA type, and potential for quantitative monitoring of tissue amyloid over time.

[The prevalence and clinical significance of antiphospholipid antibodies in rheumatoid arthritis]. / Wystepowanie przeciwcial antyfosfolipidowych i ich znaczenie kliniczne u chorych na reumatoidalne zapalenie stawów.

Published data were reviewed to evaluate the occurrence of antiphospholipid antibodies (aPL) in rheumatoid arthritis (RA) patients and to investigate their clinical relevance in this population. The mean prevalence of aPL in RA patients was calculated at 28%. Few studies have found a relationship between aPL and thrombosis, particularly in combination with other risk factors. Conflicting results have been reported on the association of anticardiolipin antibodies (aCL) positivity and neurologic symptoms, Reynaoud's phenomenon, radiologic erosions, extra-articular RA manifestations, rheumatoid factor, and atherosclerosis. Some studies, however, suggest that there is a correlation present between those antibodies and C-reactive protein levels, rheumatoid factor (RF) and antinuclear antibodies. Tumor necrosis factor blocking agents may cause an induction of aCL, but it seems like they do not cause any clinical features related to the antiphospholipid syndrome.

The efficacy and safety of rituximab in patients with active rheumatoid arthritis despite methotrexate treatment: results of a phase IIB randomized, double-blind, placebo-controlled, dose-ranging trial.

OBJECTIVE: To examine the efficacy and safety of different rituximab doses plus methotrexate (MTX), with or without glucocorticoids, in patients with active rheumatoid arthritis (RA) resistant to disease-modifying antirheumatic drugs (DMARDs), including biologic agents. METHODS: A total of 465 patients were randomized into 9 treatment groups: 3 rituximab groups (placebo [n = 149], 500 mg [n = 124], or 1,000 mg [n = 192] on days 1 and 15) each also taking either placebo glucocorticoids, intravenous methylprednisolone premedication, or intravenous methylprednisolone premedication plus oral prednisone for 2 weeks. All patients received MTX (10-25 mg/week); no other DMARDs were permitted. RESULTS: Significantly more patients who received 2 500-mg or 2 1,000-mg infusions of rituximab met the American College of Rheumatology 20% improvement criteria (achieved an ACR20 response) at week 24 (55% and 54%, respectively) compared with placebo (28%; P < 0.0001). ACR50 responses were achieved by 33%, 34%, and 13% of patients, respectively (P < 0.001), and ACR70 responses were achieved by 13%, 20%, and 5% of patients (P < 0.05). Changes in the Disease Activity Score in 28 joints (-1.79, -2.05, -0.67; P < 0.0001) and moderate to good responses on the European League Against Rheumatism criteria (P < 0.0001) reflected the ACR criteria responses. Glucocorticoids did not contribute significantly to the primary efficacy end point, ACR20 response at 24 weeks. Intravenous glucocorticoid premedication reduced the frequency and intensity of first infusion-associated events; oral glucocorticoids conferred no additional safety benefit. Rituximab was well tolerated; the type and severity of infections was similar to those for placebo. CONCLUSION: Both rituximab doses were effective and well tolerated when added to MTX therapy in patients with active RA. The primary end point (ACR20 response) was independent of glucocorticoids, although intravenous glucocorticoid premedication improved tolerability during the first rituximab infusion.

[Follow-up studies of rheumatoid arthritis patients with the presence of antiphospholipid antibodies]. / Odlegle obserwacje chorych na reumatoidalne zapalenie stawów z obecnymi przeciwcialami antyfosfolipidowymi.

UNLABELLED: The aim of the study was 2 years follow-up observation of clinical course in RA patients with the presence of anticardiolipin antibodies (aCL). METHODS: Among 395 patients with RA hospitalized in the Clinic of Rheumatology from January 2003 to December 2004 (2 years), in 39 patients with suspicion of antiphopspholipid syndrome the aCL antibodies were determined. In 7 cases we confirm the presence of aCL antibodies. Patients positive for antiphospholipid antibodies were invited to the Clinic on the beginning of 2006 (after 2 years from previous hospitalization) to analyze clinical course of disease and to perform laboratory examination. RESULTS: In the group of patients with RA positive for antiphospholipid antibodies, 3 had active RA with vascular changes. Aggressive therapy with disease modifying antirheumatic drugs (DMARDs) and corticosteroids caused conversion of anticardiolipin antibodies. Analogically antibiotic therapy in 2 patients with concomitant infections (urinary tract, respiratory system) caused conversion of aCL antibodies. 1 patient developed blastic coat cell lymphoma. 1 patient died because of cardiovascular complications. CONCLUSION: Presence of anticardiolipin antibodies can be the indicator of serious prognosis, it can predict vasculitis, persistent infections, cardiovascular complications or neoplasmatic disease. We suggest that antiphospholipid antibodies should be measure in patient with aggressive course of rheumatoid arthritis.

[The role of Salmonella and Yersinia in the pathogenesis of spondyloarthropathies and rheumatoid arthritis. I. Detection of bacteria, bacterial DNA, lipopolysaccharide and ECA antigen in synovial fluid or blood]. / Udzial paleczek z rodzaju Salmonella i Yersinia w patogenezie zapalenia stawów ze szczególnym uwzglednieniem spondyloartropatii i reumatoidalnego zapalenia stawów. I. Wystepowanie paleczek z rodzaju Salmonella i Yersinia, fragmentów ich genów, lipopolisacharydów oraz antygenu ECA w plynie stawowym badz we krwi osób z zapaleniem stawów.

To investigate the role of Salmonella and Yersinia in the pathogenesis of spondyloarthropathies and rheumatoid arthritis synovial specimens from 92 patients were analysed for the presence of bacterial DNA with the use of polymerase chain reaction and for the presence of lipopolysaccharide and enterobacterial common antigen (ECA) with the use of Dot-ELISA. In addition, peripheral blood samples were available for PCR analysis from 68 patients. Salmonella and Yersinia chromosomal DNA was not found in any of the synovial specimens and blood samples from the patients. All of the synovial fluids were also culture-negative. Salmonella LPS antigens were observed in 8 (8.6%), Yersinia in 20 (21.7%) and ECA antigens in 32 (34.9%) synovial specimens. Our findings revealed the presence of bacterial degradation products, but not bacteria from the genus Salmonella and Yersinia or their DNA in the synovial fluid or blood of patients with spondyloarthropathies and rheumatoid arthritis.

[Role of Salmonella and Yersinia in the pathogenesis of spondyloarthropathies and rheumatoid arthritis. II. Antibodies to Salmonella and Yersinia in sera and synovial fluids]. / Udzial paleczek z rodzaju Salmonella i Yersinia w patogenezie zapalenia stawów ze szczególnym uwzglednieniem spondyloartropatii i reumatoidalnego zapalenia stawów. II. Wystepowanie przeciwcial dla paleczek Salmonella i Yersinia w surowicy i plynie stawowym osób z zapaleniem stawów.

IgA, IgG and IgM antibodies against Yersinia Yop proteins, Yersinia LPS and Salmonella LPS from different serogroups were determined by enzyme-linked immunosorbent assay (ELISA) in a 885 serum samples and 92 synovial fluids. The control group consisted of 200 healthy blood donors. Compared with control subjects, patients with arthritis showed significantly increased titres of antibodies against Yersinia Yop, Yersinia LPS and Salmonella LPS appropriately in 21.7%, 44.0% and 56.0% serum samples. The prevalence of positive antibody levels was highest in Yersinia serogroup O3 and Salmonella serogroup B and D antibodies. The IgA titres were found to be much higher in adults than in children and youngsters but IgM titres consequently decreased with age. Investigation of synovial fluids obtained from patients with arthritis showed that Yersinia and Salmonella antibodies in synovial fluid mirror those in serum by concentration, by specificity and by distribution in classes.

Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis.

BACKGROUND: An open-label study indicated that selective depletion of B cells with the use of rituximab led to sustained clinical improvements for patients with rheumatoid arthritis. To confirm these observations, we conducted a randomized, double-blind, controlled study. METHODS: We randomly assigned 161 patients who had active rheumatoid arthritis despite treatment with methotrexate to receive one of four treatments: oral methotrexate (> or =10 mg per week) (control); rituximab (1000 mg on days 1 and 15); rituximab plus cyclophosphamide (750 mg on days 3 and 17); or rituximab plus methotrexate. Responses defined according to the criteria of the American College of Rheumatology (ACR) and the European League against Rheumatism (EULAR) were assessed at week 24 (primary analyses) and week 48 (exploratory analyses). RESULTS: At week 24, the proportion of patients with 50 percent improvement in disease symptoms according to the ACR criteria, the primary end point, was significantly greater with the rituximab-methotrexate combination (43 percent, P=0.005) and the rituximab-cyclophosphamide combination (41 percent, P=0.005) than with methotrexate alone (13 percent). In all groups treated with rituximab, a significantly higher proportion of patients had a 20 percent improvement in disease symptoms according to the ACR criteria (65 to 76 percent vs. 38 percent, P< or =0.025) or had EULAR responses (83 to 85 percent vs. 50 percent, P< or =0.004). All ACR responses were maintained at week 48 in the rituximab-methotrexate group. The majority of adverse events occurred with the first rituximab infusion: at 24 weeks, serious infections occurred in one patient (2.5 percent) in the control group and in four patients (3.3 percent) in the rituximab groups. Peripheral-blood immunoglobulin concentrations remained within normal ranges. CONCLUSIONS: In patients with active rheumatoid arthritis despite methotrexate treatment, a single course of two infusions of rituximab, alone or in combination with either cyclophosphamide or continued methotrexate, provided significant improvement in disease symptoms at both weeks 24 and 48.

High levels of osteoprotegerin and soluble receptor activator of nuclear factor kappa B ligand in serum of rheumatoid arthritis patients and their normalization after anti-tumor necrosis factor alpha treatment.

OBJECTIVE: To test the hypotheses that 1) proinflammatory cytokines affect osteoprotegerin (OPG) and soluble receptor activator of nuclear factor kappa B ligand (sRANKL) production and therefore the OPG and sRANKL levels differ in rheumatoid arthritis (RA) patients in comparison with healthy individuals; and 2) anti-tumor necrosis factor alpha (anti-TNF alpha) therapy influences OPG and sRANKL levels. METHODS: Sera were obtained from healthy individuals or RA patients receiving the combination of infliximab and methotrexate. Peripheral blood mononuclear cells (PBMCs) and synovial fluid mononuclear cells (SFMCs) were isolated from RA patients. Fibroblast-like synoviocytes (FLS) were isolated from synovial tissue obtained at total knee replacement in RA patients. Supernatants from cells stimulated with cytokines were collected after culture in vitro. Concentrations of OPG and sRANKL were determined by enzyme-linked immunosorbent assays. RESULTS: A strong positive correlation between OPG concentration and age was observed in healthy individuals but not in RA patients. The OPG and sRANKL levels were higher in RA patients than in healthy controls. Cultured FLS spontaneously secreted much higher amounts of OPG than PBMCs or SFMCs. Proinflammatory cytokines enhanced OPG production. Anti-TNF alpha treatment resulted in the normalization of serum OPG and sRANKL levels in RA patients without influencing the OPG:sRANKL ratio. CONCLUSION: Although higher serum levels of OPG and sRANKL are present in RA patients than in healthy individuals, the ratio of OPG:sRANKL is similar. There is an age-dependent increase of OPG but not sRANKL levels in healthy subjects. Anti-TNF alpha treatment results in the normalization of elevated levels of OPG and sRANKL in RA patients.