Increased risk of depression in patients with rheumatoid arthritis: a seven-year population-based cohort study

OBJECTIVE:

Rheumatoid arthritis (RA) is a costly and crippling autoimmune disease that can lead to the development of depression, contributing to suboptimal clinical outcomes. However, no longitudinal studies have identified an association between rheumatoid arthritis and subsequent depression. This study aimed to investigate the incidence and risk factors of depression among RA patients in Taiwan.

METHODS:

Using Taiwan''s National Health Insurance Research Database, we identified 3,698 newly diagnosed RA patients aged 18 years or older, together with 7,396 subjects without RA matched by sex, age and index date, between 2000 and 2004. The incidence of depression and the risk factors among RA cases were evaluated using Cox proportional-hazard regression.

RESULTS:

The incidence of depression was 1.74-fold greater in the RA cohort than in the non-RA cohort (11.80 versus 6.89 per 1,000 person-years; p<0.01). Multivariate analysis showed that RA subjects who were female, were older, or had comorbidities such as stroke, chronic kidney disease, or cancer had a significantly greater risk of depression compared with those without these conditions.

CONCLUSION:

This population-based cohort study showed a strong relationship between RA and a subsequent risk of depression. The findings could be beneficial to healthcare providers for identifying individuals with a higher predisposition for depression, thereby possibly facilitating the provision of an appropriate rehabilitation intervention after RA onset to support the patient''s adaptation.     

Anti-atherosclerotic effects of etanercept in rheumatoid arthritis patients

Epidemic studies have shown that rheumatoid arthritis (RA) patients have shorter life expectancy than healthy persons, primarily due to cardiovascular events. The aim of our study was to explore inhibitory effects on atherosclerosis of RA patients by TNF-inhibitor etanercept (ETN). We studied six RA patients with moderate or high disease activity as defined by the European League Against Rheumatism (EULAR) disease activity score (DAS28-ESR) in spite of treatment with methotrexate (MTX) 8 mg/week. We measured their pulse wave velocity (PWV) before and after treatment with ETN 25 mg/week for one year. There were no additional medications other than ETN that might influence on atherosclerosis. Their PWV decreased in five of six patients and the average decreased from 1474.8 cm/sec to 1432.5 cm/sec. The average of DAS28-ESR score was significantly decreased from 5.56 to 2.87 and they achieved good response by the EULAR criteria. There were no significant changes in the blood pressure, serum lipid (total cholesterol and triglyceride) and HbA1c ; all values were within normal limits before and after ETN treatment. It is suggested that the improvement of PWV is due to anti-inflammatory effects, leading inhibition of atherosclerosis, of ETN in RA patients.     

A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis

BACKGROUND: Etanercept, which blocks the action of tumor necrosis factor, reduces disease activity in patients with long-standing rheumatoid arthritis. Its efficacy in reducing disease activity and preventing joint damage in patients with active early rheumatoid arthritis is unknown. METHODS: We treated 632 patients with early rheumatoid arthritis with either twice-weekly subcutaneous etanercept (10 or 25 mg) or weekly oral methotrexate (mean, 19 mg per week) for 12 months. Clinical response was defined as the percent improvement in disease activity according to the criteria of the American College of Rheumatology. Bone erosion and joint-space narrowing were measured radiographically and scored with use of the Sharp scale. On this scale, an increase of 1 point represents one new erosion or minimal narrowing. RESULTS: As compared with patients who received methotrexate, patients who received the 25-mg dose of etanercept had a more rapid rate of improvement, with significantly more patients having 20 percent, 50 percent, and 70 percent improvement in disease activity during the first six months (P<0.05). The mean increase in the erosion score during the first 6 months was 0.30 in the group assigned to receive 25 mg of etanercept and 0.68 in the methotrexate group (P= 0.001), and the respective increases during the first 12 months were 0.47 and 1.03 (P=0.002). Among patients who received the 25-mg dose of etanercept, 72 percent had no increase in the erosion score, as compared with 60 percent of patients in the methotrexate group (P=0.007). This group of patients also had fewer adverse events (P=0.02) and fewer infections (P= 0.006) than the group that was treated with methotrexate. CONCLUSIONS: As compared with oral methotrexate, subcutaneous [corrected] etanercept acted more rapidly to decrease symptoms and slow joint damage in patients with early active rheumatoid arthritis.     

Efficacy of anti-CD20 treatment in patients with rheumatoid arthritis resistant to a combination of methotrexate/anti-TNF therapy

Rheumatoid arthritis (RA) is characterized by chronic joint inflammation and destruction. B cells play important role in modulating immune responses in RA. In the present study we assessed the impact of the B cell targeting as a third line treatment option. Forty-six patients with established erosive RA non-responding to combination treatment with DMARDs and TNF-alpha inhibitors were treated with anti-CD20 antibodies (rituximab). Rituximab was given intravenously once weekly on four occasions. All patients continued with the previous DMARD. Patients were followed by DAS28, levels of circulating B cells, frequency of immunoglobulin-producing cells, immunoglobulins, and rheumatoid factor levels during the period of 12-58 months. Clinical improvement was achieved in 34 of 46 patients (73%) supported by a significant reduction in DAS28 (from 6.04 to 4.64, P < 0.001). Infusion of rituximab resulted in the elimination of circulating B cells in all but one patient. Within 12 months follow-up, B cells returned to circulation in 86% of patients. Fifty-three percent of the patients were successfully retreated with rituximab or re-started with anti-TNF-alpha treatment. Of the 11 non-responders, five were retreated with anti-CD20 within 2 months, four of them with success, four patients received TNF-alpha inhibitors, the remaining two patients received an additional DMARD. Most of the RA patients resistant to TNF-alpha inhibitors may be effectively treated with anti-CD20 antibodies. The treatment is well tolerated and may be used repeatedly in the same patient and potentially increase sensitivity to previously inefficient treatment modalities.     

Role of the complement system in rheumatoid arthritis and psoriatic arthritis: relationship with anti-TNF inhibitors

The complement system is an essential component of innate immunity and also plays an important role in modulating adaptive immunity. It comprises more than 30 plasma and membrane-bound proteins and can be activated through three pathways: the classical, the alternative and the lectin pathways. Its activation contributes to the pathogenesis of several autoimmune and inflammatory conditions. The evidence of complement activation in synovial fluid of Rheumatoid Arthritis (RA) patients is abundant, while few data exist in Psoriatic Arthritis (PsA) patients. Levels of complement proteins are generally depressed in the synovial fluid of patients with RA, reflecting consumption of complement. On the other hand, elevated levels of several complement cleavage products have been observed in synovial fluid. Involvement of complement in the pathogenesis of RA was also confirmed in animal models of arthritis: mice deficient for complement proteins are protected against the development of collagen-induced arthritis and administration of the anti-C5 monoclonal antibody prevents the onset of this arthritis. In the last decade anti-tumor necrosis factor agents have shown to be effective for the treatment of both RA and PsA and some studies suggest that the interaction between TNFα and complement system may contribute to the pathogenesis of these diseases. Reduction of the complement activation could be one of the mechanism by which TNFα-inhibitors exert their effectiveness in inflammatory arthritides. Because of these findings, complement could be an attractive therapeutic target both in RA and in PsA.     

Organ-specific autoantibodies in patients with rheumatoid arthritis treated with adalimumab: A prospective long-term follow-up

Background: Rheumatoid arthritis (RA) is frequently associated with organ or non-organ-specific autoantibodies or overt autoimmune disorders. Aim of our study was to assess the prevalence and concentration of a panel of organ-specific autoantibodies in patients with RA and to evaluate their relationship with clinical manifestations and treatment efficacy.

Methods: Clinical and serological data from 20 patients with active RA (3M/17F), aged from 28 to 80 years and 50 healthy controls were analyzed. All patients fulfilled the 1987 American College of Rheumatology (ACR) classification criteria for RA and were treated with adalimumab and methotrexate. At baseline and after 6 months of therapy we tested anti-thyroid antibodies for thyroperoxidase (TPOAb) and thyroglobulin (TgAb) using an automated immunochemiluminescence assay (Immulite 2000, DPC, Los Angeles, CA), and anti-tissue transglutaminase (anti-tTG) using the ELISA assay (Phadia, Freiburg, Germany). Anti-smooth muscle (SMA), anti-liver kidney microsome (LKM), anti-parietal cells (APCA), anti-mithocondrial (AMA) and anti-liver cytosolic protein type 1 (LC1), anti-adrenal gland (ACA), anti-pancreatic islet (ICA) and anti-steroid-producing cell (stCA) antibodies were analyzed using a commercially available indirect immunofluorescence methods. Statistics were performed by the SPSS statistical software for Windows, using non parametric tests.

Results: At baseline 6 out of 20 (30%) patients were positive for TPOAb and 8 (40%) for TgAb. After 6 months of treatment 5 (25%) patients had TPOAb and 8 (40%) TgAb. At baseline and after 6 months of treatment only 1 (5%) patient tested positive for IgA anti-tTG (celiac disease was confirmed by intestinal biopsy), and no patients had IgG anti-tTG. However, in RA patients IgG anti-tTG levels significantly increased during treatment (p = 0.017) and were higher than in healthy individuals both at baseline (p = 0.028) and after 6 months of treatment (p = 0.001). Only 1 (5%) patient was positive for APCA and no patient was positive for the other anti-organ-specific antibodies either at baseline or after 6 months of treatment.

Conclusion: The prevalence of organ-specific antibodies does not seem to change during anti-TNF treatment in RA patients. However, a slight and probably irrelevant increase of IgG anti-tTG antibody levels was observed.     

Pneumocystis pneumonia developed in two patients with rheumatoid arthritis during treatment of adalimumab

While tumor necrosis factor (TNF) inhibitors have dramatically improved the clinical outcomes of rheumatoid arthritis (RA) in recent years, infectious complications are a serious concern. Adalimumab (ADA) is a newly-developed human monoclonal antibody against TNF-alpha. Here we report 2 cases of pneumocystis pneumonia (PCP) which developed in RA patients during ADA therapy. One patient is a 66-year-old woman who had a history of RA for 6 months. The patient was given ADA at 40 mg biweekly for her active arthritis which had been refractory to 6 mg/week of methotrexate (MTX), and 5 mg/day of prednisolone (PSL). One hundred and six days later, she was admitted to our hospital because of fever, cough, and dyspnea. Another patient is a 62-year-old man who had a history of RA for 3 years. Since his arthritis was so active even under the treatment with MTX (8 mg/week) and PSL (15 mg/day), the patient started to be given ADA at 40 mg biweekly. After 28 days, the patient was admitted to the hospital because of dyspnea. Chest roentgenogram and computed tomography revealed interstitial pneumonia in both patients. Beta-D-glucan levels were so high in their serum suggesting the diagnosis of PCP, which was confirmed by the detection of Pneumocystis jirovecii DNA in the sputa by polymerase chain reaction. The patients were immediately treated with sulfamethoxazole/trimethoprim and high-dose prednisolone, which successfully improved pneumonia, and they were discharged from the hospital on the 8(th) and 16(th) day, respectively. PCR and β-D-glucan were useful for the early diagnosis of PCP and lead to the timely induction of adequate treatment and the rescue of these patients.     

Long-term safety of abatacept in patients with rheumatoid arthritis

Abatacept is a selective T cell co-stimulation modulator that was first approved by the Italian Medicines Agency and reimbursed by the Italian National Health Service when used to treat active rheumatoid arthritis “not sufficiently responsive to other disease-modifying anti-rheumatic drugs (DMARDs) including at least one TNF inhibitor”, and is now also approved as a first line biological agent.     

Treatment with etanercept for patients with juvenile rheumatoid arthritis in Taiwan--a preliminary report.

Tumor necrosis factor (TNF) is a major inflammatory cytokine involved in the pathogenesis of juvenile rheumatoid arthritis (JRA). Etanercept, approved in the United States and in Europe for use in patients with rheumatoid arthritis (RA) and JRA, is an effective inhibitor of TNF that has been shown to provide rapid and sustained improvement in both diseases. Here we report the preliminary results of etanercept use in 3 cases of JRA with poor response to traditional therapy including non-steroidal anti-inflammatory drugs and disease-modifying antirheumatic drugs. Two of the patients had polyarticular JRA and 1 had systemic JRA. Etanercept was administered at a dosage of 0.4 mg/kg (maximum 25 mg) subcutaneously twice a week. Clinical as well as inflammatory parameter improvement was noted after use of etanercept in all cases. The preliminary results of etanercept use in these 3 cases showed significant clinical benefit without obvious adverse effects.     

T-cell expression of CD91 - a marker of unresponsiveness to anti-TNF therapy in rheumatoid arthritis

The aim of this study was to investigate the expression of thrombospondin-1 (TSP-1) and its receptors, lipoprotein receptor-related protein/cluster of differentiation (CD)91, calreticulin (CRT), and CD47, on T cells and monocytes from patients with rheumatoid arthritis (RA) treated with anti-tumor necrosis factor (TNF) therapy. The surface expression of CD91 and associated components on CD3- and CD14-positive cells was examined using flow cytometry in 12 patients with established RA before and after beginning therapy and compared with that of 9 healthy controls and 12 patients with early RA treated with conventional therapies. CD3-positive cells from anti-TNF non-responders showed significantly greater expression of CD91 expression than those from responders (p<0.05) after 6 weeks and when all measurements were pooled (p<0.001). CD91 expression on CD3-positive cells from non-responders to other therapies was at the same level as in healthy controls. In contrast, CD14-positive cells showed no differences in CD91 expression between patients and controls or between responders and non-responders to anti-TNF therapy. The expression of TSP-1, CRT, and CD47 showed no differences between responders and non-responders. The results suggest T-lymphocyte expression of CD91 to be a biomarker that signifies unresponsiveness to anti-TNF therapy in patients with RA and may be used to identify potential responders and non-responders.     

Regulation of p38 MAP kinase in CD4+ lymphocytes by infliximab therapy in patients with rheumatoid arthritis

Tumor necrosis factor alpha (TNFalpha) plays a key role in the pathogenesis of rheumatoid arthritis (RA) and most patients treated with anti-TNFalpha agents show significant improvement in both signs and symptoms. While TNFalpha inhibitors rapidly reduce joint inflammation, the mechanisms by which these agents exert their long-term effects remain unclear. The p38 MAP kinase pathway is one of the signaling pathways triggered by TNFalpha and pharmacological inhibitors of this kinase are being developed for use in RA. Since p38 MAP kinase is involved in interferon gamma (IFNgamma) production by CD4+ T helper 1 (Th1) cells and a Th1 immune response has been associated with RA, we investigated whether anti-TNFalpha therapy could affect the activation of this signaling pathway in the CD4+ T cells of RA patients. We show that in five patients, treatment with infliximab caused a marked reduction of activated p38 MAP kinase levels in CD4+ T cells, without affecting the total levels of p38 MAPK. In contrast to T cells, infliximab therapy did not affect the levels of active p38 MAP kinase in macrophages from the same patients. The selective effect of anti-TNFalpha therapy on the p38 MAP kinase signaling pathway of CD4+ T cells in patients with RA suggests that prolonged benefit with these agents may be mediated by their effect on CD4+ T cells.     

Patients with pemphigus are at an increased risk of developing rheumatoid arthritis: a large-scale cohort study

Immunologic Research - Data regarding the association between pemphigus and rheumatoid arthritis (RA) is inconclusive and yet to be firmly established. In the current study, we aimed to evaluate...     

Comparison of rheumatoid factors of rheumatoid arthritis patients,of individuals with mycobacterial infections and of normal controls: evidence for maturation in the absence of an autoimmune response

We analyzed the rheumatoid factors (RF) produced by Epstein-Barr virus-transformed monoclonal B cells established from four patients with rheumatoid arthritis (RA), three individuals with a history of Mycobacterium tuberculosis (TB) and four normal controls (NI). Fifty-eight RF were analyzed for specific activity (international units-RF/μg) for the Fc part of IgG and their interaction with tetanus toxoid (TT) and DNA (polyspecificity). Furthermore, we sequenced the V-D-J heavy chain region of 16 (9TB-/7RA-) RF. Significant differences were observed between the NI-RF and the TB- and RA-RF. While the RF repertoire of normal individuals comprised of low-avidity RF of which the majority (15/17) were polyspecific, more than half of the TB- and RA-RF were monoreactive. Furthermore, the monospecific TB- and RA-RF were of significantly higher avidity than the NI-RF (RA > TB ≫ NI). With respect to poly-specificity, the RF in the three groups were comparable: the interaction with DNA, TT as well as with Fc was inhibited either by an increase of the ionic strength to 0.3–0.5 M NaCl or by addition of the polyanion dextran sulfate, indicating that the antibodies interacted with similar anionic epitopes shared by the three antigens. Analysis of the V-D-J heavy chain regions showed significant differences between the respective RF. The salt-sensitive binding was highly correlated with the presence of arginine in the complementarity-determining region 3 (CDR3). Furthermore, whereas the polyspecific RF consisted predominantly of germ-line encoded antibodies, the genes of the monospecific RA/TB-RF were somatically mutated (RA > TB). It is therefore likely that maturation of RF can be initiated by chronic infections and that monospecific, somatically mutated RF are not a unique characteristic of autoimmune diseases.     

Failure of anti-TNF treatment in patients with rheumatoid arthritis: The pros and cons of the early use of alternative biological agents

The five TNF inhibitors currently approved for the treatment of RA are characterised by differences in their molecular structures, half-lives, administration routes, dosing intervals, immunogenicity, and use in women who wish to become pregnant. TNF inhibitors still represent the first biologic after conventional synthetic DMARD (csDMARD) in the majority of patients according to registry data. This was possibly because they were historically the first biological agents available (biological DMARDS with a different mechanism of action or targeted synthetic DMARDs did not become available until 2006s), and so switching from one to another was frequent in the case of an inadequate response and/or side effects. TNF inhibitors are also efficacious for other inflammatory joint and spine diseases, and have been approved for inflammatory bowel disease, uveitis and psoriasis. In addition, national registries have provided long-term safety data and demonstrated their beneficial effect on cardiovascular morbidity and mortality. However, approximately 30–40% of patients discontinue anti-TNF treatment because of primary failure, secondary loss of response, or intolerance. The options for managing anti-TNF treatment failures include switching to an alternative anti-TNF (cycling) or to another class of targeted drug with a different mechanism of action (swapping).The aim of this review is to evaluate the pros and cons of whether it is more appropriate to choose a second anti-TNF biological agents after the failure of the first or swap treatment early.     

Immune effects of therapy with Adalimumab in patients with rheumatoid arthritis

The aim of this study was to assess the effect of Adalimumab on different immune parameters in patients with RA. Adalimumab was administered (40 mg every other week for 26 weeks) to eight patients with RA that were refractory to conventional drug therapy. Peripheral blood samples were obtained at days 0, 15 and 180 of Adalimumab therapy, and the following immune parameters were assessed: Number, phenotype, and function of regulatory T lymphocytes. The induction of apoptosis of immune cells and the in vitro and in vivo reactivity towards M. tuberculosis were also analysed. All patients responded to Adalimumab (ACR response 50-70), and a modest but significant increase in the number and function of regulatory T cells was observed at day 15 of anti-TNF-alpha therapy. In addition, an increased percent of apoptotic cells was detected in the peripheral blood at day 15 of Adalimumab therapy. Unexpectedly, most of these effects were not further observed at day 180. However, two patients showed a persistent and marked reduction in the reactivity to M. tuberculosis. Although we have found that Adalimumab affects the number and function of regulatory T lymphocytes, and the apoptosis of immune cells, these effects are transient and its possible causal relationship with the therapeutic activity of this biological agent remains to be determined. Nevertheless, the down-regulatory effect of Adalimumab on the reactivity to M. tuberculosis could be related to an enhanced risk of tuberculosis reactivation.     

The immunological consequences of gold therapy: a prospective study in patients with rheumatoid arthritis.

Gold sodium thiomalate (GST) is known to modify the disease process in patients with active rheumatoid arthritis (RA). To help understand the mechanism of action of GST, several immunological parameters were prospectively evaluated in 10 patients with active RA following the introduction of gold therapy. Before therapy, absolute numbers of peripheral blood T suppressor/cytotoxic lymphocytes were significantly depressed (P less than 0.01) and a raised T helper/T suppressor cell ratio was found. After 1 g of GST, an absolute reduction in total lymphocyte numbers including HLA/DR positive mononuclear cells, was evident (P less than 0.01). This lymphopenic effect was not selective for a single population since the proportions of T cells, T cell subsets and B cells remained unchanged. Lymphocyte function was also examined. Raised in vitro production of IgG (P less than 0.01) and IgA (P less than 0.05) was found before therapy. After GST, in vitro immunoglobulin synthesis was reduced and this was significant with respect to the IgM (P less than 0.001) and IgA (P less than 0.01) isotypes. Similarly, a parallel reduction in serum immunoglobulin levels developed. GST therapy was also associated with a reduced proliferative response to phytohaemagglutinin, concanavalin A and pokeweed mitogen in the initial phase of gold administration. The significant finding in this study suggest that the in vivo immunosuppressive effect of GST is explained not only by impaired mononuclear cell function but also by a significant reduction in T and B lymphocyte numbers.     

Comparison of intramuscular and oral meloxicam in rheumatoid arthritis patients

Inflammation Research - Objective: This double-blind, double-dummy, two-way comparative trial evaluated the overall efficacy and tolerability of intramuscular (im) vs oral meloxicam.¶Subjects:...     

Listeria-associated arthritis in a patient undergoing etanercept therapy: case report and review of the literature

Listeriosis can be a cause of infectious arthritis. Here, we present a case of articular listeriosis in a patient with rheumatoid arthritis receiving treatment with etanercept, a tumor necrosis factor antagonist. We review the literature of articular listeriosis and discuss the role of tumor necrosis factor blockade in precipitating listeriosis.