Showing papers in "Arthritis & Rheumatism in 2010"
Medical University of Vienna1, Boston University2, Arthritis Research UK3, Johns Hopkins University4, University of California, San Francisco5, Humboldt University of Berlin6, University of Toronto7, National Jewish Health8, Brigham and Women's Hospital9, Paris Descartes University10, University of Leeds11, Catholic University of the Sacred Heart12, Erasmus University Rotterdam13, University of Colorado Denver14, Leiden University15, University of California, San Diego16, University of Massachusetts Medical School17, University of Michigan18, University of Washington19, McGill University Health Centre20, University of Pittsburgh21, Ministry of Health (New Zealand)22, New York University23, University of Manchester24, University of Amsterdam25, University of Kansas26, Women's College Hospital27
TL;DR: This new classification system redefines the current paradigm of RA by focusing on features at earlier stages of disease that are associated with persistent and/or erosive disease, rather than defining the disease by its late-stage features.
Abstract: Objective The 1987 American College of Rheumatology (ACR; formerly the American Rheumatism Association) classifi cation criteria for rheumatoid arthritis (RA) have been criticised for their lack of sensitivity in early disease. This work was undertaken to develop new classifi cation criteria for RA. Methods A joint working group from the ACR and the European League Against Rheumatism developed, in three phases, a new approach to classifying RA. The work focused on identifying, among patients newly presenting with undifferentiated infl ammatory synovitis, factors that best discriminated between those who were and those who were not at high risk for persistent and/ or erosive disease—this being the appropriate current paradigm underlying the disease construct ‘RA’. Results In the new criteria set, classifi cation as ‘defi nite RA’ is based on the confi rmed presence of synovitis in at least one joint, absence of an alternative diagnosis better explaining the synovitis, and achievement of a total score of 6 or greater (of a possible 10) from the individual scores in four domains: number and site of involved joints (range 0–5), serological abnormality (range 0–3), elevated acute-phase response (range 0–1) and symptom duration (two levels; range 0–1). Conclusion This new classifi cation system redefi nes the current paradigm of RA by focusing on features at earlier stages of disease that are associated with persistent and/or erosive disease, rather than defi ning the disease by its late-stage features. This will refocus attention on the important need for earlier diagnosis and institution of effective disease-suppressing therapy to prevent or minimise the occurrence of the undesirable sequelae that currently comprise the paradigm underlying the disease construct ‘RA’.
7,120 citations
American College of Rheumatology1, Mayo Clinic2, Stanford University3, Johns Hopkins University4, University of Colorado Hospital5, Cleveland Clinic6, University of Calgary7, National Institutes of Health8, University of Kentucky9, University of Illinois at Chicago10, Harvard University11, SUNY Downstate Medical Center12, University of California, San Diego13
TL;DR: Criteria for the classification of giant cell (temporal) arteritis were developed by comparing 214 patients who had this disease with 593 patients with other forms of vasculitis, and 2 other variables were included: scalp tenderness and claudication of the jaw or tongue or on deglutition.
Abstract: Criteria for the classification of giant cell (temporal) arteritis were developed by comparing 214 patients who had this disease with 593 patients with other forms of vasculitis. For the traditional format classification, 5 criteria were selected: age greater than or equal to 50 years at disease onset, new onset of localized headache, temporal artery tenderness or decreased temporal artery pulse, elevated erythrocyte sedimentation rate (Westergren) greater than or equal to 50 mm/hour, and biopsy sample including an artery, showing necrotizing arteritis, characterized by a predominance of mononuclear cell infiltrates or a granulomatous process with multinucleated giant cells. The presence of 3 or more of these 5 criteria was associated with a sensitivity of 93.5% and a specificity of 91.2%. A classification tree was also constructed using 6 criteria. These criteria were the same as for the traditional format, except that elevated erythrocyte sedimentation rate was excluded, and 2 other variables were included: scalp tenderness and claudication of the jaw or tongue or on deglutition. The classification tree was associated with a sensitivity of 95.3% and specificity of 90.7%.
2,204 citations
American College of Rheumatology1, University of Illinois at Chicago2, Mayo Clinic3, Stanford University4, University of Colorado Hospital5, Cleveland Clinic6, University of Calgary7, National Institutes of Health8, University of Kentucky9, Harvard University10, Johns Hopkins University11, University of California, San Diego12
TL;DR: Criteria for the classification of Churg-Strauss syndrome were developed by comparing 20 patients who had this diagnosis with 787 control patients with other forms of vasculitis, and advantages of the traditional format compared with the classification tree format are discussed.
Abstract: Criteria for the classification of Churg-Strauss syndrome (CSS) were developed by comparing 20 patients who had this diagnosis with 787 control patients with other forms of vasculitis. For the traditional format classification, 6 criteria were selected: asthma, eosinophilia greater than 10% on differential white blood cell count, mononeuropathy (including multiplex) or polyneuropathy, non-fixed pulmonary infiltrates on roentgenography, paranasal sinus abnormality, and biopsy containing a blood vessel with extravascular eosinophils. The presence of 4 or more of these 6 criteria yielded a sensitivity of 85% and a specificity of 99.7%. A classification tree was also constructed with 3 selected criteria: asthma, eosinophilia greater than 10% on differential white blood cell count, and history of documented allergy other than asthma or drug sensitivity. If a subject has eosinophilia and a documented history of either asthma or allergy, then that subject is classified as having CSS. For the tree classification, the sensitivity was 95% and the specificity was 99.2%. Advantages of the traditional format compared with the classification tree format, when applied to patients with systemic vasculitis, and their comparison with earlier work on CSS are discussed.
1,954 citations
TL;DR: Criteria for the classification of Takayasu arteritis were developed by comparing 63 patients who had this disease with 744 control patients with other forms of vasculitis, and the presence of 3 or more of these 6 criteria demonstrated a sensitivity of 90.5% and a specificity of 97.0%.
Abstract: Criteria for the classification of Takayasu arteritis were developed by comparing 63 patients who had this disease with 744 control patients with other forms of vasculitis. Six criteria were selected for the traditional format classification: onset at age less than or equal to 40 years, claudication of an extremity, decreased brachial artery pulse, greater than 10 mm Hg difference in systolic blood pressure between arms, a bruit over the subclavian arteries or the aorta, and arteriographic evidence of narrowing or occlusion of the entire aorta, its primary branches, or large arteries in the proximal upper or lower extremities. The presence of 3 or more of these 6 criteria demonstrated a sensitivity of 90.5% and a specificity of 97.8%. A classification tree also was constructed with 5 of these 6 criteria, omitting claudication of an extremity. The classification tree demonstrated a sensitivity of 92.1% and a specificity of 97.0%.
1,888 citations
National Institutes of Health1, American College of Rheumatology2, Stanford University3, Mayo Clinic4, University of Colorado Hospital5, Cleveland Clinic6, University of Kentucky7, University of Illinois at Chicago8, Harvard University9, Johns Hopkins University10, SUNY Downstate Medical Center11, University of California, San Diego12
TL;DR: Criteria for the classification of Wegener's granulomatosis were developed by comparing 85 patients who had this disease with 722 control patients with other forms of vasculitis with a high level of sensitivity and specificity.
Abstract: Criteria for the classification of Wegener's granulomatosis (WG) were developed by comparing 85 patients who had this disease with 722 control patients with other forms of vasculitis. For the traditional format classification, 4 criteria were selected: abnormal urinary sediment (red cell casts or greater than 5 red blood cells per high power field), abnormal findings on chest radiograph (nodules, cavities, or fixed infiltrates), oral ulcers or nasal discharge, and granulomatous inflammation on biopsy. The presence of 2 or more of these 4 criteria was associated with a sensitivity of 88.2% and a specificity of 92.0%. A classification tree was also constructed with 5 criteria being selected. These criteria were the same as for the traditional format, but included hemoptysis. The classification tree was associated with a sensitivity of 87.1% and a specificity of 93.6%. We describe criteria which distinguish patients with WG from patients with other forms of vasculitis with a high level of sensitivity and specificity. This distinction is important because WG requires cyclophosphamide therapy, whereas many other forms of vasculitis can be treated with corticosteroids alone.
1,786 citations
TL;DR: The EXPLORER trial enrolled patients with moderately-to-severely active SLE and used aggressive background treatment and sensitive cutoffs for nonresponse, and no differences were noted between placebo and rituximab in the primary and secondary end points.
Abstract: Objective
B cells are likely to contribute to the pathogenesis of systemic lupus erythematosus (SLE), and rituximab induces depletion of B cells. The Exploratory Phase II/III SLE Evaluation of Rituximab (EXPLORER) trial tested the efficacy and safety of rituximab versus placebo in patients with moderately-to-severely active extrarenal SLE.
1,117 citations
American College of Rheumatology1, University of Kentucky2, Stanford University3, Mayo Clinic4, University of California, San Diego5, University of Colorado Hospital6, Cleveland Clinic7, National Institutes of Health8, University of Illinois at Chicago9, Harvard University10, Johns Hopkins University11, SUNY Downstate Medical Center12
TL;DR: Criteria for the classification of polyarteritis nodosa were developed by comparing 118 patients who had this disease with 689 control Patients who had other forms of vasculitis.
Abstract: Criteria for the classification of polyarteritis nodosa were developed by comparing 118 patients who had this disease with 689 control patients who had other forms of vasculitis. For the traditional format classification, 10 criteria were selected: weight loss greater than or equal to 4 kg, livedo reticularis, testicular pain or tenderness, myalgias, mononeuropathy or polyneuropathy, diastolic blood pressure greater than 90 mm Hg, elevated blood urea nitrogen or serum creatinine levels, presence of hepatitis B reactants in serum, arteriographic abnormality, and presence of granulocyte or mixed leukocyte infiltrate in an arterial wall on biopsy. The presence of 3 or more of these 10 criteria was associated with a sensitivity of 82.2% and specificity of 86.6%. A classification tree was also constructed, with 6 criteria being selected. Three of these, angiographic abnormality, biopsy-proven granulocyte or mixed leukocyte infiltrate in arterial wall, and neuropathy, were criteria used in the traditional format. The other 3 criteria used in the tree format included the patient's sex, weight loss greater than 6.5 kg, and elevated serum aspartate aminotransferase or alanine aminotransferase levels above the range of normal. The classification tree yielded a sensitivity of 87.3% and a specificity of 89.3%.
947 citations
TL;DR: Criteria for identifying Henoch-Schönlein Purpura (HSP) and distinguishing HSP from other forms of systemic arteritis were developed by comparing the manifestations in 85 patients who had HSP with those of 722 control patients with other form of vasculitis.
Abstract: Criteria for identifying Henoch-Schonlein Purpura (HSP) and distinguishing HSP from other forms of systemic arteritis were developed by comparing the manifestations in 85 patients who had HSP with those of 722 control patients with other forms of vasculitis. By the traditional format of choosing different combinations of candidate criteria and comparing the combinations for their ability to separate HSP cases from controls, 4 criteria were identified: age less than or equal to 20 years at disease onset, palpable purpura, acute abdominal pain, and biopsy showing granulocytes in the walls of small arterioles or venules. The presence of any 2 or more of these criteria distinguish HSP from other forms of vasculitis with a sensitivity of 87.1% and a specificity of 87.7%. The criteria selected by a classification tree method were similar: palpable purpura, age less than or equal to 20 years at disease onset, biopsy showing granulocytes around arterioles or venules, and gastrointestinal bleeding. These were able to distinguish HSP from other forms of vasculitis with a sensitivity of 89.4% and a specificity of 88.1%.
777 citations
TL;DR: The incidence of RA in women appears to have increased during the period of time from 1995 to 2007, although the reasons for this recent increase are unknown, but environmental factors may play a role.
Abstract: Objective
To examine the trends in incidence and prevalence of rheumatoid arthritis (RA) from 1995 to 2007.
637 citations
TL;DR: These findings in SLE patients are consistent with the autoimmune mechanism in sanroque mice and identify Tfh effector molecules as possible therapeutic targets in a recognizable subset of patients with SLE.
Abstract: Objective
In the sanroque mouse model of lupus, pathologic germinal centers (GCs) arise due to increased numbers of follicular helper T (Tfh) cells, resulting in high-affinity anti–double-stranded DNA antibodies that cause end-organ inflammation, such as glomerulonephritis. The purpose of this study was to examine the hypothesis that this pathway could account for a subset of patients with systemic lupus erythematosus (SLE).
Methods
An expansion of Tfh cells is a causal, and therefore consistent, component of the sanroque mouse phenotype. We validated the enumeration of circulating T cells resembling Tfh cells as a biomarker of this expansion in sanroque mice, and we performed a comprehensive comparison of the surface phenotype of circulating and tonsillar Tfh cells in humans. This circulating biomarker was enumerated in SLE patients (n = 46), Sjogren's syndrome patients (n = 17), and healthy controls (n = 48) and was correlated with disease activity and end-organ involvement.
Results
In sanroque mice, circulating Tfh cells increased in proportion to their GC counterparts, making circulating Tfh cells a feasible human biomarker of this novel mechanism of breakdown in GC tolerance. In a subset of SLE patients (14 of 46), but in none of the controls, the levels of circulating Tfh cells (defined as circulating CXCR5+CD4+ cells with high expression of Tfh-associated molecules, such as inducible T cell costimulator or programmed death 1) were increased. This cellular phenotype did not vary with time, disease activity, or treatment, but it did correlate with the diversity and titers of autoantibodies and with the severity of end-organ involvement.
Conclusion
These findings in SLE patients are consistent with the autoimmune mechanism in sanroque mice and identify Tfh effector molecules as possible therapeutic targets in a recognizable subset of patients with SLE.
623 citations
TL;DR: It is shown that P gingivalis rapidly generates citrullinated host peptides by proteolytic cleavage at Arg-X peptide bonds by arginine gingipains, followed bycitrullination of carboxy-terminal arginines by bacterial PAD.
Abstract: Objectives
To investigate protein citrullination by the periodontal pathogen Porphyromonas gingivalis (P. gingivalis) as a potential mechanism for breaking tolerance to citrullinated proteins in rheumatoid arthritis (RA).
Mayo Clinic1, University of Colorado Hospital2, American College of Rheumatology3, Cleveland Clinic4, National Institutes of Health5, Stanford University6, University of Kentucky7, University of Illinois at Chicago8, Harvard University9, Johns Hopkins University10, SUNY Downstate Medical Center11, University of California, San Diego12
American College of Rheumatology1, Stanford University2, Mayo Clinic3, University of Colorado Hospital4, Cleveland Clinic5, National Institutes of Health6, University of Kentucky7, University of Illinois at Chicago8, Harvard University9, Johns Hopkins University10, SUNY Downstate Medical Center11, University of California, San Diego12
TL;DR: The Americal College of Rheumatology Subcommittee on Classification of Vasculitis of the Diagnostic and Therapeutic Criteria Committee developed classification criteria for 7 forms of vasculitis: polyarteritis nodosa, Churg-Strauss syndrome, Wegener's granulomatosis, hypersensitivity vasculopathy, Henoch-Schonlein purpura, giant cell (temporal) arteritis, and Takayasu arteritis.
Abstract: The Americal College of Rheumatology Subcommittee on Classification of Vasculitis of the Diagnostic and Therapeutic Criteria Committee developed classification criteria for 7 forms of vasculitis: polyarteritis nodosa, Churg-Strauss syndrome, Wegener's granulomatosis, hypersensitivity vasculitis, Henoch-Schonlein purpura, giant cell (temporal) arteritis, and Takayasu arteritis. The data collection methods, quality control, and analytic procedures used to derive the classification rules are discussed herein
TL;DR: The devastating impact of ILD on survival provides evidence that development of better strategies for the treatment of I LD could significantly lower the excess mortality among individuals with RA.
Abstract: Objective Interstitial lung disease (ILD) has been recognized as an important comorbidity in rheumatoid arthritis (RA). We undertook the current study to assess incidence, predictors, and mortality of RA-associated ILD. Methods We examined a population-based incidence cohort of patients with RA and a matched cohort of individuals without RA. All subjects were followed up longitudinally. The lifetime risk of ILD was estimated. Cox proportional hazards models were used to compare the incidence of ILD between cohorts, to investigate predictors, and to explore the impact of ILD on survival. Results Patients with RA (n = 582) and subjects without RA (n = 603) were followed up for a mean of 16.4 and 19.3 years, respectively. The lifetime risk of developing ILD was 7.7% for RA patients and 0.9% for non-RA subjects. This difference translated into a hazard ratio (HR) of 8.96 (95% confidence interval [95% CI] 4.02-19.94). The risk of developing ILD was higher in RA patients who were older at the time of disease onset, in male patients, and in individuals with more severe RA. The risk of death for RA patients with ILD was 3 times higher than in RA patients without ILD (HR 2.86 [95% CI 1.98-4.12]). Median survival after ILD diagnosis was only 2.6 years. ILD contributed approximately 13% to the excess mortality of RA patients when compared with the general population. Conclusion Our results emphasize the increased risk of ILD in patients with RA. The devastating impact of ILD on survival provides evidence that development of better strategies for the treatment of ILD could significantly lower the excess mortality among individuals with RA.
TL;DR: Findings indicate that resting brain activity within multiple networks is associated with spontaneous clinical pain in patients with FM, and may have broader implications for how subjective experiences such as pain arise from a complex interplay among multiple brain networks.
Abstract: Objective. Fibromyalgia (FM) is considered to be the prototypical central chronic pain syndrome and is associated with widespread pain that fluctuates spontaneously. Multiple studies have demonstrated altered brain activity in these patients. The objective of this study was to investigate the degree of connectivity between multiple brain networks in patients with FM, as well as how activity in these networks correlates with the level of spontaneous pain. Methods. Resting-state functional magnetic resonance imaging (FMRI) data from 18 patients with FM and 18 age-matched healthy control subjects were analyzed using dual-regression independent components analysis, which is a data-driven approach for the identification of independent brain networks. Intrinsic, or resting-state, connectivity was evaluated in multiple brain networks: the default mode network (DMN), the executive attention network (EAN), and the medial visual network (MVN), with the MVN serving as a negative control. Spontaneous pain levels were also analyzed for covariance with intrinsic connectivity. Results. Patients with FM had greater connectivity within the DMN and right EAN (corrected P [Pcorr] < 0.05 versus controls), and greater connectivity between the DMN and the insular cortex, which is a brain region known to process evoked pain. Furthermore, greater intensity of spontaneous pain at the time of the FMRI scan correlated with greater intrinsic connectivity between the insula and both the DMN and right EAN (Pcorr < 0.05). Conclusion. These findings indicate that resting brain activity within multiple networks is associated with spontaneous clinical pain in patients with FM. These findings may also have broader implications for how subjective experiences such as pain arise from a complex interplay among multiple brain networks.
TL;DR: The results suggest that compromised autophagy represents a novel mechanism in the development of OA and may be a protective or homeostatic mechanism in normal cartilage.
Abstract: Objective
Autophagy is a process for turnover of intracellular organelles and molecules that protects cells during stress responses. This study evaluated the potential role of ULK1, an inducer of autophagy, Beclin1, a regulator of autophagy and LC3, which executes autophagy, in the development of osteoarthritis (OA) and in cartilage cell death.
TL;DR: Older age, low functional status, and concomitant prednisolone treatment were negative predictors of a clinical response and remission in patients with rheumatoid arthritis.
Abstract: Objective
To compare tumor necrosis factor α inhibitors directly regarding the rates of treatment response, remission, and the drug survival rate in patients with rheumatoid arthritis (RA), and to identify clinical prognostic factors for response.
Methods
The nationwide DANBIO registry collects data on rheumatology patients receiving routine care. For the present study, we included patients from DANBIO who had RA (n = 2,326) in whom the first biologic treatment was initiated (29% received adalimumab, 22% received etanercept, and 49% received infliximab). Baseline predictors of treatment response were identified. The odds ratios (ORs) for clinical responses and remission and hazard ratios (HRs) for drug withdrawal were calculated, corrected for age, disease duration, the Disease Activity Score in 28 joints (DAS28), seropositivity, concomitant methotrexate and prednisolone, number of previous disease-modifying drugs, center, and functional status (Health Assessment Questionnaire score).
Results
Seventy percent improvement according to the American College of Rheumatology criteria (an ACR70 response) was achieved in 19% of patients after 6 months. Older age, concomitant prednisolone treatment, and low functional status at baseline were negative predictors. The ORs (95% confidence intervals [95% CIs]) for an ACR70 response were 2.05 (95% CI 1.52–2.76) for adalimumab versus infliximab, 1.78 (95% CI 1.28–2.50) for etanercept versus infliximab, and 1.15 (95% CI 0.82–1.60) for adalimumab versus etanercept. Similar predictors and ORs were observed for a good response according to the European League Against Rheumatism criteria, DAS28 remission, and Clinical Disease Activity Index remission. At 48 months, the HRs for drug withdrawal were 1.98 for infliximab versus etanercept (95% 1.63–2.40), 1.35 for infliximab versus adalimumab (95% CI 1.15–1.58), and 1.47 for adalimumab versus etanercept (95% CI 1.20–1.80).
Conclusion
Older age, low functional status, and concomitant prednisolone treatment were negative predictors of a clinical response and remission. Infliximab had the lowest rates of treatment response, disease remission, and drug adherence, adalimumab had the highest rates of treatment response and disease remission, and etanercept had the longest drug survival rates. These findings were consistent after correction for confounders and sensitivity analyses and across outcome measures and followup times.
TL;DR: The expression of miR-29a was strongly down-regulated in SSc fibroblasts and skin sections as compared with the healthy controls and is suggested as a potential therapeutic target by researchers investigating the role of microRNA as posttranscriptional regulators of profibrotic genes in systemic sclerosis.
Abstract: Objective To investigate the role of microRNA (miRNA) as posttranscriptional regulators of profibrotic genes in systemic sclerosis (SSc). Methods MicroRNA, which target collagens, were identified by in silico analysis. Expression of miRNA-29 (miR-29) was determined by TaqMan real-time polymerase chain reaction analysis of skin biopsy and fibroblast samples from SSc patients and healthy controls as well as in the mouse model of bleomycin-induced skin fibrosis. Cells were transfected with precursor miRNA (pre-miRNA)/anti-miRNA of miR-29 using Lipofectamine. Collagen gene expression was also studied in luciferase reporter gene assays. For stimulation, recombinant transforming growth factor beta (TGFbeta), platelet-derived growth factor B (PDGF-B), or interleukin-4 (IL-4) was used. The effects of inhibiting PDGF-B and TGFbeta signaling on the levels of miR-29 were studied in vitro and in the bleomycin model. Results We found that miR-29a was strongly down-regulated in SSc fibroblasts and skin sections as compared with the healthy controls. Overexpression in SSc fibroblasts significantly decreased, and accordingly, knockdown in normal fibroblasts increased, the levels of messenger RNA and protein for type I and type III collagen. In the reporter gene assay, cotransfection with pre-miR-29a significantly decreased the relative luciferase activity, which suggests a direct regulation of collagen by miR-29a. TGFbeta, PDGF-B, or IL-4 reduced the levels of miR-29a in normal fibroblasts to those seen in SSc fibroblasts. Similar to human SSc, the expression of miR-29a was reduced in the bleomycin model of skin fibrosis. Inhibition of PDGF-B and TGFbeta pathways by treatment with imatinib restored the levels of miR-29a in vitro and in the bleomycin model in vivo. Conclusion These data add the posttranscriptional regulation of collagens by miR-29a as a novel aspect to the fibrogenesis of SSc and suggest miR-29a as a potential therapeutic target.
TL;DR: Treatment with rituximab led to prompt clinical and serologic improvement in these patients with refractory IgG4-RSD, and is a viable treatment option for this condition, suggesting that ritUXimab achieves its effects in IgG 4- RSD by depleting the pool of B lymphocytes that replenish short-lived IgG3-secreting plasma cells.
Abstract: Objective. Patients with IgG4-related systemic disease (IgG4-RSD) frequently show an incomplete response to treatment with glucocorticoids and traditional disease-modifying antirheumatic drugs (DMARDs). B lymphocyte depletion is a therapeutic strategy known to be effective for pemphigus vulgaris, an autoimmune condition mediated by IgG4 autoantibodies. This study was performed to assess the clinical and serologic responses to B lymphocyte depletion therapy with rituximab in patients with IgG4-RSD. Methods. Four patients with IgG4-RSD were treated with 2 intravenous doses (1 gram each) of rituximab. Clinical improvement was assessed by monitoring the tapering/discontinuation of prednisone and DMARDs, and by measuring the serum concentrations of B lymphocytes, immunoglobulins, and IgG subclasses before and after therapy. Results. Clinical features of IgG4-RSD in these 4 patients included autoimmune pancreatitis, sclerosing cholangitis, lymphoplasmacytic aortitis, salivary gland involvement, orbital pseudotumor, and lacrimal gland enlargement. The 3 patients with elevated serum IgG and IgG4 levels at baseline had a mean IgG concentration of 2,003 mg/dl (normal range 600–1,500 mg/dl) and a mean IgG4 concentration of 2,160 mg/dl (normal range 8–140 mg/dl). Among these patients, the serum IgG4 concentrations declined by a mean of 65% within 2 months of rituximab administration. All 4 patients demonstrated striking clinical improvement within 1 month of the initiation of rituximab therapy, and tapering or discontinuation of their treatment with prednisone and DMARDs was achieved in all 4 patients. A decrease in IgG concentration was observed for the IgG4 subclass only. Conclusion. Treatment with rituximab led to prompt clinical and serologic improvement in these patients with refractory IgG4-RSD, and is a viable treatment option for this condition. The decline in serum IgG4 concentrations was substantially steeper than that of the autoantibody concentrations in immune-mediated conditions in which rituximab is effective, such as in rheumatoid arthritis. In addition, the reduction in IgG-subclass levels appeared to be specific for IgG4. The swift improvement of IgG4-RSD suggests that rituximab achieves its effects in IgG4-RSD by depleting the pool of B lymphocytes that replenish short-lived IgG4-secreting plasma cells.
TL;DR: LY2439821 added to oral DMARDs improved signs and symptoms of RA, with no strong adverse safety signal noted, and supports neutralization of IL-17 as a potential novel goal for the treatment of RA.
Abstract: Objective
We undertook this study to evaluate safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of LY2439821, a humanized anti–interleukin-17 (anti–IL-17) monoclonal antibody, in a first in-human trial in rheumatoid arthritis (RA) patients taking oral disease-modifying antirheumatic drugs (DMARDs).
Methods
This randomized, double-blind, placebo-controlled study consisted of 2 parts. In part A, 20 patients received 1 intravenous (IV) dose of LY2439821 (0.06, 0.2, 0.6, or 2.0 mg/kg, escalating) or placebo followed by 8 weeks of evaluation. End points included safety, tolerability, and pharmacokinetics. In part B, 77 patients received 1 IV dose of LY2439821 (0.2, 0.6, or 2.0 mg/kg) or placebo every 2 weeks for a total of 5 doses, with a total evaluation period of 16 weeks. End points included safety, tolerability, pharmacokinetics/pharmacodynamics, and efficacy (Disease Activity Score in 28 joints [DAS28] and percentages of patients meeting American College of Rheumatology 20%, 50%, or 70% improvement criteria [achieving an ACR20, ACR50, or ACR70 response]). The primary efficacy end point was the DAS28 at week 10.
Results
Baseline characteristics were similar across all groups. Changes in the DAS28 were significantly greater in the 0.2 mg/kg, 2.0 mg/kg, and all-LY2439821–combined groups (−2.3, −2.4, and −2.3, respectively) than in the placebo group (−1.7) at week 10 (P ≤ 0.05), and these differences were significant as early as week 1. Percentages of ACR20, ACR50, and ACR70 responses as well as improvements in the ACR core set of measures were greater in LY2439821-treated patients than in placebo-treated patients at multiple time points. There was no apparent dose-response relationship in treatment-emergent adverse events.
Conclusion
LY2439821 added to oral DMARDs improved signs and symptoms of RA, with no strong adverse safety signal noted. This first evaluation of LY2439821 supports neutralization of IL-17 as a potential novel goal for the treatment of RA.
TL;DR: Although neutropenia may limit the maximum dosage of tocilizumab in patients with SLE, the observed clinical and serologic responses are promising and warrant further studies to establish the optimal dosing regimen and efficacy.
Abstract: Objective
To assess the safety of interleukin-6 receptor inhibition and to collect preliminary data on clinical and immunologic efficacy of tocilizumab in patients with systemic lupus erythematosus (SLE).
TL;DR: Rituximab treatment is an effective and safe treatment strategy for patients with primary Sjögren's syndrome and significant improvements were found in comparison with baseline values.
Abstract: Objective. To study the efficacy and safety of B cell depletion with rituximab, a chimeric murine/human anti-CD20 monoclonal antibody, in patients with primary Sjogren's syndrome (SS) in a double-blind, randomized, placebo-controlled trial. Methods. Patients with active primary SS, as determined by the revised American-European Consensus Group criteria, and a rate of stimulated whole saliva secretion of >= 0.15 ml/minute were treated with either rituximab (1,000 mg) or placebo infusions on days 1 and 15. Patients were assigned randomly to a treatment group in a ratio of 2: 1 (rituximab: placebo). Followup was conducted at 5, 12, 24, 36, and 48 weeks. The primary end point was the stimulated whole saliva flow rate, while secondary end points included functional, laboratory, and subjective variables. Results. Thirty patients with primary SS (29 female) were randomly allocated to a treatment group. The mean +/- SD age of the patients receiving rituximab was 43 +/- 11 years and the disease duration was 63 +/- 50 months, while patients in the placebo group were age 43 +/- 17 years and had a disease duration of 67 +/- 63 months. In the rituximab group, significant improvements, in terms of the mean change from baseline compared with that in the placebo group, were found for the primary end point of the stimulated whole saliva flow rate (P = 0.038 versus placebo) and also for various laboratory parameters (B cell and rheumatoid factor [RF] levels), subjective parameters (Multidimensional Fatigue Inventory [MFI] scores and visual analog scale [VAS] scores for sicca symptoms), and extraglandular manifestations. Moreover, in comparison with baseline values, rituximab treatment significantly improved the stimulated whole saliva flow rate (P = 0.004) and several other variables (e.g., B cell and RF levels, unstimulated whole saliva flow rate, lacrimal gland function on the lissamine green test, MFI scores, Short Form 36 health survey scores, and VAS scores for sicca symptoms). One patient in the rituximab group developed mild serum sickness-like disease. Conclusion. These results indicate that rituximab is an effective and safe treatment strategy for patients with primary SS.
TL;DR: It is indicated that the rate of mortality from polyarteritis nodosa remains high, especially for the elderly, and relapses do occur, particularly in patients with non-HBV-related PAN with cutaneous manifestations.
Abstract: Objective Previous studies of polyarteritis nodosa (PAN) included patients with microscopic polyangiitis, because these entities were not distinguished prior to the Chapel Hill Consensus Conference (CHCC). This study was undertaken to describe the main characteristics of and long-term outcomes in patients with well-characterized PAN diagnoses. Methods We conducted a systematic retrospective study of 348 patients who were diagnosed as having PAN between March 1963 and October 2005, were registered in the French Vasculitis Study Group database, and satisfied the American College of Rheumatology and CHCC criteria. Patient characteristics and outcomes were analyzed and compared according to hepatitis B virus (HBV) status. Results At diagnosis, the mean +/- SD age was 51.2 +/- 17.3 years. The most frequent findings were general symptoms (93.1%), neurologic manifestations (79%), skin involvement (49.7%), abdominal pain (35.6%), and hypertension (34.8%); 66.2% had renal artery microaneurysms; 70.1% had histologically proven PAN. Patients with HBV-related PAN (n = 123) had more frequent peripheral neuropathy, abdominal pain, cardiomyopathy, orchitis, and hypertension compared with patients with non-HBV-related PAN (n = 225). During a mean +/- SD followup of 68.3 +/- 63.5 months, 76 patients (21.8%) relapsed (63 with non-HBV-related PAN [28%] versus 13 with HBV-related PAN [10.6%]; P 65 years, hypertension, and gastrointestinal manifestations requiring surgery or at least consultation with a surgeon as independent predictors of death, whereas patients with cutaneous manifestations or non-HBV-related PAN had a higher risk of relapse. Conclusion Our findings indicate that the rate of mortality from PAN remains high, especially for the elderly, and relapses do occur, particularly in patients with non-HBV-related PAN with cutaneous manifestations.
TL;DR: Findings indicate that UC MSCT results in amelioration of disease activity, serologic changes, and stabilization of proinflammatory cytokines in patients with severe and treatment-refractory SLE.
Abstract: Objective Umbilical cord (UC)-derived mesenchymal stem cells (MSCs) have shown marked therapeutic effects in a number of diseases in animal studies, based on their potential for self-renewal and differentiation. No data are available on the effectiveness of UC MSC transplantation (MSCT) in human autoimmune disease. This study was undertaken to assess the efficacy and safety of allogeneic UC MSCT in patients with severe and treatment-refractory systemic lupus erythematosus (SLE). Methods We conducted a single-arm trial that involved 16 SLE patients whose disease was refractory to standard treatment or who had life-threatening visceral involvement. All of the patients gave consent and underwent UC MSCT. Clinical changes were evaluated before and after transplantation using the SLE Disease Activity Index (SLEDAI), measurement of serum antinuclear antibody (ANA), anti-double-stranded DNA (anti-dsDNA) antibody, serum complement C3 and C4, and albumin levels, and assessment of and renal function. Evaluation of potential mechanisms of MSCT effects focused on the percentage of peripheral blood Treg cells and serum levels of cytokines. Results From April 2007 to July 2009, a total of 16 patients with active SLE were enrolled and underwent UC MSCT. The median followup time after MSCT was 8.25 months (range 3-28 months). Significant improvements in the SLEDAI score, levels of serum ANA, anti-dsDNA antibody, serum albumin, and complement C3, and renal function were observed. Clinical remission was accompanied by an increase in peripheral Treg cells and a re-established balance between Th1- and Th2-related cytokines. Significant reduction in disease activity was achieved in all patients, and there has been no recurrence to date and no treatment-related deaths. Conclusion Our findings indicate that UC MSCT results in amelioration of disease activity, serologic changes, and stabilization of proinflammatory cytokines. These data provide a foundation for conducting a randomized controlled trial of this new therapy for severe and treatment-refractory SLE.
TL;DR: Individuals in whom RA later developed had significantly increased levels of several cytokines, cytokine-related factors, and chemokines representing the adaptive immune system; after disease onset, the involvement and activation of the immune system was more general and widespread.
Abstract: OBJECTIVE: To identify whether cytokines, cytokine-related factors, and chemokines are up-regulated prior to the development of rheumatoid arthritis (RA).
METHODS: A nested case-control study was p ...
TL;DR: An anti-200/100-kd specificity defines a subgroup of patients with necrotizing myopathy who previously were considered to be autoantibody negative and should be treated with immunosuppressive therapy.
Abstract: Objective
Myofiber necrosis without prominent inflammation is a nonspecific finding in patients with dystrophies and toxic or immune-mediated myopathies. However, the etiology of a necrotizing myopathy is often obscure, and the question of which patients would benefit from immunosuppression remains unanswered. The aim of this study was to identify novel autoantibodies in patients with necrotizing myopathy.
Methods
Muscle biopsy specimens and serum samples were available for 225 patients with myopathy. Antibody specificities were determined by performing immunoprecipitations from 35S-methionine–labeled HeLa cell lysates. Selected biopsy specimens were stained for membrane attack complex, class I major histocompatibility complex (MHC), and endothelial cell marker CD31.
Results
Muscle biopsy specimens from 38 of 225 patients showed predominantly myofiber necrosis. Twelve of these patients had a known autoantibody association with or other etiology for their myopathy. Sixteen of the remaining 26 sera immunoprecipitated 200-kd and 100-kd proteins; this specificity was observed in only 1 of 187 patients without necrotizing myopathy. Patients with the anti-200/100 autoantibody specificity had proximal weakness (100%), high creatine kinase levels (mean maximum 10,333 IU/liter), and an irritable myopathy on electromyography (88%). Sixty-three percent of these patients had been exposed to statins prior to the onset of weakness. All patients responded to immunosuppressive therapy, and many experienced a relapse of weakness when the medication was tapered. Immunohistochemical studies showed membrane attack complex on small blood vessels in 6 of 8 patients and on the surface of non-necrotic myofibers in 4 of 8 patients. Five of 8 patients had abnormal capillary morphology, and 4 of 8 patients expressed class I MHC on the surface of non-necrotic myofibers.
Conclusion
An anti–200/100-kd specificity defines a subgroup of patients with necrotizing myopathy who previously were considered to be autoantibody negative. We propose that these patients have an immune-mediated myopathy that is frequently associated with prior statin use and should be treated with immunosuppressive therapy.
TL;DR: Recording responses to the T cell-dependent protein antigen tetanus toxoid as well as DTH responses were preserved in rituximab-treated RA patients 24 weeks after treatment, suggesting that polysaccharide and primary immunizations should be administered prior to ritUXimab infusions to maximize responses.
Abstract: Objective
To examine immunization responses in patients with rheumatoid arthritis (RA) treated with rituximab and to investigate the effects of rituximab-induced CD20+ B cell depletion on immune responses to tetanus toxoid (T cell–dependent antigen), pneumococcal polysaccharide (T cell–independent antigen), and keyhole limpet hemocyanin (KLH) (neoantigen) and on delayed-type hypersensitivity (DTH).
Methods
In a controlled trial, we enrolled 103 patients with active RA receiving a stable dose of methotrexate (MTX). Tetanus toxoid, pneumococcal polysaccharide, and KLH vaccines as well as a Candida albicans skin test were administered to 1 group of patients receiving rituximab plus MTX (called rituximab-treated patients) for 36 weeks and to 1 group of patients receiving MTX alone for 12 weeks. The primary end point was the proportion of patients with a ≥4-fold rise in antitetanus IgG levels. Antitetanus, antipneumococcal, and anti-KLH serum IgG levels were measured prior to and 4 weeks following vaccine administration. The DTH response to C albicans was measured 2–3 days following placement.
Results
Responses to tetanus toxoid vaccine (≥4-fold rise) were similar in both groups (39.1% of rituximab-treated patients and 42.3% of patients treated with MTX alone). The ability to maintain a positive DTH response to the C albicans skin test was comparable in both groups (77.4% of rituximab-treated patients and 70% of patients treated with MTX alone), showing no effect of rituximab treatment. Rituximab-treated patients had decreased responses to pneumococcal polysaccharide vaccine (57% of patients had a 2-fold rise in titer in response to ≥1 serotype, compared with 82% of patients treated with MTX alone) and to KLH vaccine (47% of patients had detectable anti-KLH IgG, compared with 93% of patients treated with MTX alone).
Conclusion
Recall responses to the T cell–dependent protein antigen tetanus toxoid as well as DTH responses were preserved in rituximab-treated RA patients 24 weeks after treatment. Responses to neoantigen (KLH) and T cell–independent responses to pneumococcal vaccine were decreased, but many patients were able to mount responses. These data suggest that polysaccharide and primary immunizations should be administered prior to rituximab infusions to maximize responses.
TL;DR: The intrinsically elevated expression of RORC, accompanied by biased Th17 cell development, and the resistance of Th17 cells to a natural cytokine antagonist in patients with RA and patients with PsA were suggestive of the underlying molecular mechanisms of uncontrolled Th17 activity in these patients.
Abstract: Objective
To delineate the role of Th17 cells in the pathogenesis of autoimmune arthritides.
Methods
Th17 cells were analyzed in well-defined homogeneous cohorts of patients with the prototypical autoimmune arthritides rheumatoid arthritis (RA) and psoriatic arthritis (PsA), grouped according to patients who had very early active RA (n = 36; mean disease duration 2.8 months, Disease Activity Score in 28 joints 5.0) and those who had very early active PsA (n = 20; mean disease duration 2.3 months), none of whom had received treatment with glucocorticoids or disease-modifying antirheumatic drugs, as well as patients with established RA (n = 21; mean disease duration 68 months) who were considered either responders or nonresponders to therapy. Groups of healthy individuals and patients with osteoarthritis (a noninflammatory arthritis) were used as control cohorts. Expression of T lineage–specific transcription factors (RORC, T-bet, GATA-3, and FoxP3) and the response of CD4 T cells to Th17 cell–inducing conditions were analyzed in vitro.
Results
The frequencies of Th17 cells and levels of interleukin-17 strongly correlated with systemic disease activity at both the onset and the progression of RA or PsA. The values were reduced to control levels in patients with treatment-controlled disease activity. Th17 cells were enriched in the joints, and increased frequencies of synovial Th17 cells expressed CCR4 and CCR6, indicative of selective migration of Th17 cells to the joints. The intrinsically elevated expression of RORC, accompanied by biased Th17 cell development, and the resistance of Th17 cells to a natural cytokine antagonist in patients with RA and patients with PsA were suggestive of the underlying molecular mechanisms of uncontrolled Th17 activity in these patients.
Conclusion
Th17 cells play an important role in inflammation in human autoimmune arthritides, both at the onset and in established disease.
TL;DR: Low-dose colchicine yielded both maximum plasma concentration and early gout flare efficacy comparable with that of high-dose Colchicines, with a safety profile indistinguishable from that of placebo.
Abstract: Objective Despite widespread use of colchicine, the evidence basis for oral colchicine therapy and dosing in acute gout remains limited. The aim of this trial was to compare low-dose colchicine (abbreviated at 1 hour) and high-dose colchicine (prolonged over 6 hours) with placebo in gout flare, using regimens producing comparable maximum plasma concentrations in healthy volunteers. Methods This multicenter, randomized, double-blind, placebo-controlled, parallel-group study compared self-administered low-dose colchicine (1.8 mg total over 1 hour) and high-dose colchicine (4.8 mg total over 6 hours) with placebo. The primary end point was > or = 50% pain reduction at 24 hours without rescue medication. Results There were 184 patients in the intent-to-treat analysis. Responders included 28 of 74 patients (37.8%) in the low-dose group, 17 of 52 patients (32.7%) in the high-dose group, and 9 of 58 patients (15.5%) in the placebo group (P = 0.005 and P = 0.034, respectively, versus placebo). Rescue medication was taken within the first 24 hours by 23 patients (31.1%) in the low-dose group (P = 0.027 versus placebo), 18 patients (34.6%) in the high-dose group (P = 0.103 versus placebo), and 29 patients (50.0%) in the placebo group. The low-dose group had an adverse event (AE) profile similar to that of the placebo group, with an odds ratio (OR) of 1.5 (95% confidence interval [95% CI] 0.7-3.2). High-dose colchicine was associated with significantly more diarrhea, vomiting, and other AEs compared with low-dose colchicine or placebo. With high-dose colchicine, 40 patients (76.9%) had diarrhea (OR 21.3 [95% CI 7.9-56.9]), 10 (19.2%) had severe diarrhea, and 9 (17.3%) had vomiting. With low-dose colchicine, 23.0% of the patients had diarrhea (OR 1.9 [95% CI 0.8-4.8]), none had severe diarrhea, and none had vomiting. Conclusion Low-dose colchicine yielded both maximum plasma concentration and early gout flare efficacy comparable with that of high-dose colchicine, with a safety profile indistinguishable from that of placebo.
TL;DR: The histopathologic criteria for the diagnosis of 7 selected vasculitis syndromes are described: polyarteritis nodosa, Churg-Strauss syndrome, Wegener's granulomatosis, hypersensitivity Vasculitis, Henoch-Schönlein purpura, giant cell (temporal) arteritis, and Takayasu arteritis.
Abstract: We describe the histopathologic criteria for the diagnosis of 7 selected vasculitis syndromes: polyarteritis nodosa, Churg-Strauss syndrome, Wegener's granulomatosis, hypersensitivity vasculitis, Henoch-Schonlein purpura, giant cell (temporal) arteritis, and Takayasu arteritis. The criteria apply to the stereotypical cases in each category; they were formulated after a review of submitted biopsy material from 278 of the 1,000 patients entered into the American College of Rheumatology Vasculitis Study Registry, and from prior experience with the pathologic diagnosis of vasculitis in 1,079 nonregistry patients.