Effects of half dose etanercept (25 mg once a week) on clinical remission and radiographic progression in patients with rheumatoid arthritis in clinical remission achieved with standard dose.

OBJECTIVES: This prospective long-term follow-up study evaluated the effects of half-dose etanercept (25 mg weekly) on clinical remission and radiographic progression in a large cohort of patients with rheumatoid arthritis (RA) in clinical remission after etanercept 25 mg bi-weekly. METHODS: 524 biologic-naïve RA patients were treated with etanercept 25 mg bi-weekly after failure of conventional drugs. Patients achieving remission (DAS28 <2.6) for ≥12 months were randomised to receive etanercept 25 mg weekly or 25 mg bi-weekly. Patients were assessed at baseline and every 12 weeks. Remission rates, radiographic progression, incidence of infections and costs of the regimens were compared. RESULTS: After a mean follow-up of 18±11 months, 347 patients (66.2%) achieved DAS28 remission; 323 were randomised to one of two dose regimens: etanercept 25 weekly (group A, 159 patients) and etanercept 25 mg bi-weekly (group B, 164 patients). At the end of follow-up, 81.8% patients of group A maintained remission for a mean of 3.6±1.5 years. Radiographic progression occurred in a small number of patients of group A and the rate of radiographic progression (TSS >0) was not significantly different in the two groups (18.85% vs. 19.0% after the first year and 16.9% vs. 21.6% after the second year, respectively). The incidence ratio of severe infections was 2.3/1.000 patient-years in group A. Etanercept half-dose regimen resulted in a saving of €3.190.545 with a cost saving up to €827.318 per year. CONCLUSIONS: Clinical remission and arrest of radiographic progression persisted in a substantial percentage of patients with RA even after reduction of standard-dose etanercept.

Drug survival of the first course of anti-TNF agents in patients with rheumatoid arthritis and seronegative spondyloarthritis: analysis from the MonitorNet database.

OBJECTIVES: To compare drug survival of different anti-TNF drugs (infliximab, INF, etanercept, ETA, and adalimumab, ADA) in rheumatoid arthritis (RA) and spondyloarthritis (SpA) by analysing data collected from an Italian multicenter observational cohort study. METHODS: All patients with RA or SpA registered in the MonitorNet database who started their first course of anti-TNF therapy were included. Overall drug survival was measured, along with specific reasons of discontinuation (inefficacy or adverse events). A first set of analyses using RA as reference category assessed the relationship between diagnosis and drug survival. A second set of analyses stratified by diagnosis (RA and SpA) used INF as reference drug. Adjustment for confounders was performed. The results are presented as adjusted hazard ratios (adjHR) and 95% confidence intervals (95%CI). RESULTS: 2640 RA patients and 1220 SpA patients with a median follow-up of 17 months (IQR 7.2-33.4) were included in the analyses. Patients with a diagnosis of SpA showed a lower risk of drug discontinuation with an adjHR (95%CI) of 0.81 (0.73, 0.90). In SpA, the subset of patients with ankylosing spondylitis (AS) showed the best survival on treatment. In RA, both ETA and ADA showed a significantly lower probability of withdrawal when compared to INF [adjHR (95%CI) 0.46 (0.38, 0.56) and 0.68 (0.57, 0.81), respectively]. Similar results were found in SpA. CONCLUSIONS: Drug survival for SpA is longer than that in RA mainly due to the AS subgroup. In both RA and SpA, ETA and ADA showed a better retention on treatment when compared to INF.

Pathogenetic and clinical rationale for TNF-blocking therapy in psoriatic arthritis.

The classical definition of psoriatic arthritis (PsA) as an inflammatory arthritis associated with psoriasis reflects only in part the large spectrum of musculoskeletal disorders found in patients with psoriasis. In particular, enthesopathy, dactilytis, osteitis and axial involvement are frequently neglected and probably account for the unsatisfactory response of PsA to traditional drugs, such as NSAIDs, steroids and DMARDs. Furthermore, these drugs showed only a partial ability to influence radiographic progression and psoriasis. The new anti-TNF agents, in particular etanercept but also infliximab and adalimumab, have demonstrated a comprehensive effectiveness on the multiple aspects of the PsA disease, including quality of life and slowing of radiographic progression. Despite this clear efficacy, the actual mechanisms by which TNF-blocking agents are able to obtain all these effects are still incompletely understood. However, the success of this therapy suggested one of the best ways for further research in the field of PsA. In this new fashion, the most stimulating hypotheses involving TNF are those regarding genetic predisposition, angiogenesis and osteoclastogenesis.

Polymyositis-dermatomyositis and infections.

In genetically predisposed individuals, viruses, bacteria, or parasitic infectious agents are suspected to induce autoimmunity and/or to exacerbate the disease once the self-tolerance is broken. Although direct evidence for this association is still lacking, numerous data from animal models as well as from humans support the hypothesis of a direct contribution of pathogens to the induction of several autoimmune diseases. This review focused on the possible role of infectious agents as triggers of autoimmunity in polymyositis (PM) and dermatomyositis (DM). Epidemiological studies, clinical and experimental findings that support the hypothesis of infection-induced PM and DM are summarized and discussed. In addition, immune response abnormalities and immunosuppressive medications may be responsible for the high percentage of infectious complications in PM and DM patients. In this review, the increased risk of developing infections in these patients is also underlined and published data are reported.

Estrogens in pregnancy and systemic lupus erythematosus.

Successful pregnancy depends on an adaptation of the maternal immune system that becomes tolerant to fetal antigens of paternal origin. The altered immune regulation induced by pregnancy occurs predominantly at the maternal-fetal interface, but it has also been observed in the maternal circulation. Th1/Th2 shift is one of the most important immunologic changes during gestation. It is due to the progressive increase of estrogens, which reach peak level in the third trimester of pregnancy. At these high levels, estrogens suppress the Th1-mediated responses and stimulate Th2-mediated immunologic responses. For this reason Th1-mediated diseases, such as rheumatoid arthritis, tend to improve, while Th2-mediated diseases, such as systemic lupus erythematosus (SLE) tend to worsen during pregnancy. However, in some recent studies SLE flare-ups were less frequently observed in the third trimester of gestation in comparison to the second trimester and postpartum period. These data are apparently in contrast to the Th2 immune-response polarization expected during pregnancy due to the progressive increase of estrogens. Some further data suggest that in SLE patients estradiol serum levels are surprisingly lower than expected during the third trimester of pregnancy, probably due to a placental compromise. This occurrence could lead to a lower-than-expected increase of IL-6, accounting for the low humoral immune response and the low disease activity observed in the third trimester of pregnancy in such patients.

Th2 immune deviation induced by pregnancy: the two faces of autoimmune rheumatic diseases.

One of the most important immunological modifications during pregnancy is the Th1/Th2 shift, due to the progressive increase of progesterone and estrogens during pregnancy, which reach their peak-level in the third trimester of gestation. At high levels, estrogens seem mainly to suppress Th1 cytokines and stimulate Th2-mediated immunological responses as well as antibody production. For this reason Th1-mediated diseases, like rheumatoid arthritis (RA), tend to improve and Th2-mediated disease, like systemic lupus erythematosus (SLE), tend to worsen during pregnancy. SLE is the autoimmune rheumatic disease in which pregnancy most frequently occurs because it predominantly affects young females in their childbearing age. Other autoimmune rheumatic diseases, including RA, are less frequently observed during pregnancy due to their low female-to-male ratio and peak onset after the age of 40. This review is focused on the disease course, gestational outcome and management of patients with SLE and RA during pregnancy.

Impact of 24 months of anti-TNF therapy versus methotrexate on body weight in patients with rheumatoid arthritis: a prospective observational study.

To evaluate the impact of anti-TNF-α therapy on the body weight of rheumatoid arthritis (RA) patients following 24 months of treatment. Data were collected on all RA patients included in the Veneto Region's Registry of Biological Therapy from January 2007 to July 2012. Inclusion criteria were: start of monotherapy with adalimumab, etanercept, or methotrexate, no previous use of biologic therapy, and at least 24 months of treatment. At baseline, 12, and 24 months, each patient completed a questionnaire about physical activity, smoking, alcohol, and food habits. One hundred and thirty-one RA patients in monotherapy with etanercept (n = 47), adalimumab (n = 44), and methotrexate (n = 40) were enrolled for this study. After 24 months of therapy, there was an increase of weight only in patients treated with anti-TNF-α. Patients on etanercept and adalimumab therapy showed a risk to gain weight six times greater compared to those on methotrexate therapy. The results of present study show that the use of anti-TNF-α in RA patients can be associated to a significant increase of body weight. This increase is not shown in patients under treatment with methotrexate. A more careful evaluation of weight changes needs to be considered in RA patients under anti-TNF-α treatment.

Clinical manifestations and outcome of polyarthralgia associated with chronic lymphocytic thyroiditis.

OBJECTIVES: Arthralgia is among the most frequent musculoskeletal symptoms occurring in patients with chronic lymphocytic thyroiditis (CLT), often causing pain and physical impairment over extended periods of time. Our study aims to characterize arthralgia and, in particular, polyarthralgia (PA) associated with CLT and to evaluate the influence of thyroid replacement therapy. METHODS: Of 130 patients affected with CLT attending the Division of Rheumatology for rheumatic complaints, the authors sequentially selected 20 patients with PA without any known rheumatic diseases. Of these 20 patients, 8 were euthyroid, 2 hyperthyroid, and 10 hypothyroid. The last group had never undergone therapy for thyroid disease; then, they were treated with thyroxine and followed up for 24 months. Clinical assessment included the number of joints affected by pain (NAJ), the visual analogic scale of pain (VAS), the duration of PA (number of days), and the intake of acetaminophen. RESULTS: At baseline, the only correlations in the 20 patients with PA were between NAJ and antithyroid microsomal antibodies (r =.782; P <.001), thyroid stimulation hormone (r =.651; P =.001), and erythrocyte sedimentation rate (r =.511; P = 0.021), respectively. During follow-up, although symptoms improved in the 10 hypothyroid patients treated with thyroxine, a statistical significance was reached only after 12 months. CONCLUSIONS: Patients with CLT may be affected with PA severely, even in absence of hypothyroidism. Replacement therapy with thyroxine in hypothyroid patients with CLT induced a progressive but gradual improvement of symptoms.

Fibromyalgia in Italian patients with primary Sjögren's syndrome.

OBJECTIVE: To assess the prevalence of fibromyalgia in primary Sjögren's syndrome and to evaluate the clinical differences between patients affected with both primary fibromyalgia and primary Sjögren's syndrome and those affected only with primary fibromyalgia. METHODS: Clinical features of fibromyalgia were evaluated in 100 consecutive outpatients with primary Sjögren's syndrome and, as controls, in 90 patients with non-insulin-dependent diabetes mellitus, in 75 patients with primary fibromyalgia and in 30 healthy subjects. RESULTS: Fibromyalgia was recorded in 22% of patients with primary Sjögren's syndrome, in 12.2% with diabetes and in 3.3% of healthy controls. In the primary Sjögren's syndrome group the prevalence was significantly higher than in healthy controls (P < 0.01), but not significantly different than in diabetes. Moreover, primary Sjögren's syndrome with fibromyalgia and primary fibromyalgia patients did not differ with respect to the number of tender points, while the mean pain threshold was lower in the latter (P = 0.05). Purpura, hypergammaglobulinemia, rheumatoid factor, and a focus score > or = 1 on lip biopsy were significantly more frequent in primary Sjögren's syndrome patients without than with fibromyalgia. CONCLUSIONS: As recently reported by other authors, our study confirms the moderate increase of fibromyalgia prevalence in primary Sjögren's syndrome. Typical fibromyalgic findings are quite similar to those of primary fibromyalgia, but surprisingly, primary Sjögren's syndrome patients with fibromyalgia show a less severe global involvement than those with primary Sjögren's syndrome alone.

[Infliximab combined with methotrexate in the treatment of rheumatoid arthritis]. / Infliximab in associazione con methotrexate nel trattamento dell'artrite reumatoide.

Infliximab is a chimeric anti-tumor necrosis factor alpha (anti-TNF-alpha) monoclonal IgG1 antibody successfully used for the treatment of active rheumatoid arthritis (RA) not completely controlled with methotrexate or other disease modifying anti-rheumatic drugs. We evaluated both clinical efficacy and safety of infliximab in 63 patients with persistently active RA (Disease activity score > or = 3.7). All the patients received infliximab (3 mg/Kg) at week 0, 2, 6 and then every 5 weeks in combination with methotrexate (7.5-10 mg/week) in an open label study. At week 14th, ACR 20% response criteria have been fulfilled by 43 (91.4%) out of 47 patients, 31 (72%) of them achieving also an ACR 50% and 9 (21%) an ACR 70% response. At the time of this report 33 patients touched 22 weeks of treatment: ACR 20% response was achieved in 95%, while ACR 50% and ACR 70% were respectively found in 78% and 39% of the cases. Only 1 case of bronchopulmonary mycosis and 2 of mild urticaria were observed. The initiation of infliximab therapy in patients with active RA resulted in a rapid and sustained improvement of articular manifestations and quality of life. Even though, major adverse events were rare, clinicians should be aware of this possibility.

Elderly onset of primary Sjögren's syndrome: clinical manifestations, serological features and oral/ocular diagnostic tests. Comparison with adult and young onset of the disease in a cohort of 336 Italian patients.

OBJECTIVES: To study and compare the clinical and serological features of patients with elderly versus adult and younger onset of primary Sjögren's syndrome (pSS). METHODS: We analyzed retrospectively 336 consecutive pSS patients followed at our unit. They were subdivided into three groups according to the age at disease onset: elderly (>65 years), adult (>40 and ≤65 years), and young (≤40 years). Clinical and immunological features of the disease, labial salivary glands biopsy, ocular and oral tests were collected at time of diagnosis and then compared among the three groups. RESULTS: In 21 (6%) patients, disease onset occurred after the age of 65 years. At the time of diagnosis, 15 (71.4%) of these patients reported symptoms of dry mouth and 16 (76.1%) of dry eye. The most common extraglandular manifestation were arthralgias in 14 (66.7%), Raynaud's phenomenon in five (23.8%) and purpura in three (14.2%) cases. Ocular diagnostic tests (Schirmer's I and Rose-Bengal staining) were positive respectively in 17 (80%) and nine (44.4%) patients. In eight (38%) cases, unstimulated whole salivary flow showed normal values, while 12 patients (57.1%) showed positivity for salivary sialography. A focus score greater or equal to 1 per 4mm(2) was demonstrated in 11 (53.3%) of the 21 cases. CONCLUSION: Elderly onset of pSS was associated with similar incidence of the diagnostic tests positivity (parotid sialography, ocular tests, minor salivary gland biopsy) in comparison with adult and younger onset. Moreover, no statistical differences were found among the three groups concerning sex, disease duration, as well as ocular and oral symptoms.

Methods used to assess remission and low disease activity in rheumatoid arthritis.

The aim of the treatment in rheumatoid arthritis (RA) is to prevent articular damage and functional loss by decreasing the activity of the disease. The overall goal is the full suppression of the activity of the disease, also called clinical remission. The most reliable indices to assess RA activity were defined by the American College of Rheumatology (ACR), the European League Against Rheumatism (EULAR) and the International League Against Rheumatism (ILAR) and are habitually used for the evaluation of remission. The Food and Drug Administration (FDA) established three increasingly restrictive categories of disease remission: complete clinical response, major clinical response, and remission. Then, OMERACT (Outcome Measures in Rheumatoid Arthritis Clinical Trials) advanced the concept of low disease activity state (LDAS) or minimal disease activity (MDA). Thus, those reported by FDA are the only criteria for remission which consider radiographic arrest of the disease. This review aims to describe the criteria for RA remission and to discuss their advantages and limitations.

Use of a new silica clotting time for diagnosing lupus anticoagulant in patients who meet the clinical criteria for antiphospholipid syndrome.

The silica clotting time (SCT) is a phospholipid-dependent coagulation assay used for the laboratory diagnosis of lupus anticoagulant (LA) antibodies. The sensitivity and specificity of a new commercial SCT for identifying LA in patients who meet the clinical criteria for antiphospholipid syndrome (APS), and its association with thrombotic events were evaluated here. Forty-five patients who met the clinical criteria for APS according to the Sapporo International Consensus Statement were examined. Sixty-nine patients who did not meet the clinical criteria for APS, and 20 blood donors were used as controls. Plasma samples from the patients and controls were tested for LA using a new commercial SCT with low and high synthetic phospholipid concentrations. The results were compared with those obtained by diluted Russell's viper venom time (dRVVT) and activated partial thromboplastin time (APTT). SCT's sensitivity for identifying LA in patients who met the clinical criteria of APS was higher compared to APTT and dRVVT (53.3% vs. 31.1% and 31.1%), and the specificities of these assays were 96.6%, 100%, and 98.9%, respectively. When dRVVT was combined with SCT, and dRVVT was combined with APTT their sensitivities were 57.7% and 48.8%, and their specificities were 96.6% and 98.9%, respectively. A stepwise logistic regression analysis indicated that the combination of dRVVT with SCT was associated with total thrombotic events (odds ratio (OR)=11.5, 95% confidence interval (CI)=1.25-106.3, P=0.031) as well as with venous thrombosis (OR=4.09, 95% CI=1.16-14.43, P=0.028). According to our results, SCT is the most sensitive assay for identifying LA in patients who meet the clinical criteria for APS. Moreover, the highest sensitivity was reached with a combination of SCT and dRVVT. The method's association with total thrombotic events and venous thrombosis was in fact significant.

Long-term prognosis and causes of death in systemic lupus erythematosus.

PURPOSE: We studied survival rate, prognostic factors, and causes of death in patients with systemic lupus erythematosus (SLE), particularly focusing on the influence of disease severity. PATIENTS AND METHODS: A cohort of 207 consecutive Italian patients with SLE were prospectively studied. All prominent clinical and serologic parameters were evaluated and considered as prognostic risk factors. Causes of death were defined on the basis of clinical data and, when available, postmortem examination. Survival was calculated from the time of diagnosis by Kaplan-Meier method. RESULTS: A total of 17 of 207 patients died; causes of death were active disease manifestations in 35.3% of cases and complication of the disease or its treatment in 64.7% of cases. The survival rates at 5, 10, and 15 years after the diagnosis were 96%, 93% and 76%, respectively. By multivariate analysis of the risk factors, a predictive model consisting of male gender, positive lupus anticoagulant, and "severe" SLE was identified. The survival curve of the patients with severe disease was similar to that of patients with mild disease until 10 to 15 years from the diagnosis. Thereafter the two curves tended to diverge, showing a clear survival decline in patients with severe disease. CONCLUSIONS: Our study confirms the increase of short- and medium-term survival in patients with SLE, but long-term prognosis remains poor in patients with severe SLE manifestations.

Influence of coping skills on health-related quality of life in patients with systemic lupus erythematosus.

OBJECTIVE: To identify coping strategies used by patients with systemic lupus erythematosus (SLE), and to assess the influence of main clinical and coping variables on health-related quality of life (HRQOL). METHODS: We administered the Coping Orientation to Problems Experienced and the Short Form 36 questionnaire to a group of 144 patients with SLE and a group of 129 healthy controls. At the time of the psychological assessment, all patients underwent a complete clinical and laboratory evaluation. RESULTS: SLE patients had higher scores in acceptance (P < 0.001) and turning to religion (P = 0.05) and lower scores in planning (P = 0.001), suppression of competing activities (P = 0.010), restraint coping (P = 0.031), focusing on and venting of emotion (P = 0.009), and strategies focused on problem (P = 0.012) compared with controls. By means of linear regression analysis, HRQOL in SLE patients seemed to be influenced positively by restraint coping and positive reinterpretation and growth, and negatively by focusing on and venting of emotion, behavioral disengagement, and mental disengagement. When clinical variables were added to the multivariate analysis for coping strategies, more significant regression models that included joint pain were obtained. CONCLUSION: In facing stressful situations, patients with SLE tend to use coping skills that are generally adopted for events perceived as nonmodifiable. Strategies that show a passive attitude and joint pain seem to impair these patients' HRQOL.

A randomized pilot trial comparing cyclosporine and azathioprine for maintenance therapy in diffuse lupus nephritis over four years.

There is not agreement about the best maintenance treatment for patients with diffuse lupus nephritis. This multicenter, randomized trial compared the safety and efficacy of cyclosporine and azathioprine. Seventy-five patients with diffuse proliferative lupus were given three intravenous methylprednisolone pulses followed by prednisone and oral cyclophosphamide for a median of 90 d. Subsequently, patients were randomly assigned either to cyclosporine or to azathioprine for 2 yr (core study). Treatment continued for up to 4 yr (follow-up study). The primary outcome measure was the incidence of disease flares. Secondary end points were proteinuria per day, creatinine clearance, and adverse effects. Seven flares occurred in the cyclosporine group, and eight occurred in the azathioprine group. At the end of the core study, mean proteinuria decreased from 2.8 +/- 3.57 to 0.4 +/- 0.85 g/d (P < 0.0001) in the cyclosporine group and from 2.2 +/- 1.94 to 0.5 +/- 0.78 g/d (P < 0.0002) in the azathioprine group. After 4 yr, mean proteinuria was 0.2 +/- 0.24 and 0.3 +/- 0.33 g/d, respectively. At the core study end and at the follow-up completion, creatinine clearance and BP levels did not change significantly from baseline in either group. Five of 36 patients who were receiving cyclosporine and four of the 33 who were receiving azathioprine stopped the treatment because of adverse effects. For patients with diffuse proliferative lupus nephritis, azathioprine or cyclosporine combined with corticosteroids demonstrated equal efficacy in the prevention of flares.

Epithelial CXCR3-B regulates chemokines bioavailability in normal, but not in Sjogren's syndrome, salivary glands.

Expression of CXCR3-targeting chemokines have been demonstrated in several diseases, suggesting a critical role for CXCR3 in recruiting activated T cells to sites of immune-mediated inflammation. Sjögren's syndrome (SS) is an autoimmune disease characterized by a mononuclear cell infiltrate of activated T cells around the duct in the salivary gland. Analysis of minor salivary gland biopsy specimens from 20 healthy subjects and 18 patients with primary SS demonstrated that CXCR3, in particular, the B form of this receptor, is constitutively expressed by human salivary gland epithelial cells. Salivary gland epithelial cell cultures demonstrated that CXCR3 participate in removing relevant amount of agonists from the supernatant of exposed cells without mediating calcium flux or chemotaxis while retaining the ability to undergo internalization. Although in normal salivary gland epithelial cells, CXCR3 behaves as a chemokine-scavenging receptor, its role in SS cells is functionally impaired. The impairment of this scavenging function might favor chemotaxis, leading to heightened immigration of CXCR3-positive T lymphocytes. These findings suggest that epithelial CXCR3 may be involved in postsecretion regulation of chemokine bioavailability. They also support a critical role for CXCR3 in the pathogenesis of SS and identify its agonists as potential therapeutic targets.