Antibodies toward infliximab are associated with low infliximab concentration at treatment initiation and poor infliximab maintenance in rheumatic diseases

Introduction  

A proportion of patients receiving infliximab have antibodies toward infliximab (ATI), which are associated with increased risk of infusion reaction and reduced response to treatment. We studied the association of infliximab concentration at treatment initiation and development of ATI as well as the association of the presence of ATI and maintenance of infliximab.     

Outcome measures in inflammatory rheumatic diseases

Inflammatory rheumatic diseases are generally multifaceted disorders and, therefore, measurement of multiple outcomes is relevant to most of these diseases. Developments in outcome measures in the rheumatic diseases are promoted by the development of successful treatments. Outcome measurement will increasingly deal with measurement of low levels of disease activity and avoidance of disease consequences. It is an advantage for patient management and knowledge transfer if the same outcomes are used in practice and in trials. Continuous measures of change are generally the most powerful and, therefore, are preferred as primary outcomes in trials. For daily clinical practice, outcome measures should reflect the patients' state and have to be easily derivable. The objective of this review is to describe recent developments in outcome measures for inflammatory rheumatic diseases for trials and clinical practice, with an emphasis on rheumatoid arthritis.     

Cardiovascular co-morbidity in patients with rheumatic diseases

During recent years atherosclerosis, the major cause of cardiovascular disease (CVD), has been recognised as a chronic inflammatory condition in which rupture of atherosclerotic lesions appears to play a major role. The risk of CVD is raised in many rheumatic diseases. This risk is high in systemic lupus erythematosus - as much as a 50-times increase among middle-aged women has been reported. Studies on CVD and atherosclerosis in rheumatic disease could thus provide interesting information about CVD and atherosclerosis in addition to being an important clinical problem. A combination of traditional and nontraditional risk factors accounts for the increased risk of CVD and atherosclerosis in rheumatic disease. One interesting possibility is that atherosclerotic lesions in rheumatic disease are more prone to rupture than normal atherosclerotic lesions. It is also likely that increased risk of thrombosis may play an important role, not least in systemic lupus erythematosus. Further, it is not clear whether an increased risk of CVD is a general feature of rheumatic disease, or whether this only occurs among subgroups of patients. It should be emphasised that there is an apparent lack of treatment studies where CVD in rheumatic disease is the end point. Control of disease activity and of traditional risk factors, however, appears to be well founded in relation to CVD in rheumatic disease. Further studies are needed to determine the exact role of lipid-lowering drugs as statins. Hopefully novel therapies can be developed that target the causes of the inflammation in atherosclerotic lesions both in rheumatic patients and in the general population.     

Renal co-morbidity in patients with rheumatic diseases

Renal co-morbidity is common in patients with rheumatic disease based on regular assessment of serum and urine parameters of renal function. When patients present with both arthritis and renal abnormalities the following questions have to be addressed. Is kidney disease a complication of rheumatic disease or its management, or are they both manifestations of a single systemic autoimmune disease? Is rheumatic disease a complication of kidney disease and its management? How do rheumatic disease and kidney disease affect each other even when they are unrelated? The present review provides an overview of how to address these questions in daily practice.     

Renal co-morbidity in patients with rheumatic diseases

Renal co-morbidity is common in patients with rheumatic disease based on regular assessment of serum and urine parameters of renal function. When patients present with both arthritis and renal abnormalities the following questions have to be addressed. Is kidney disease a complication of rheumatic disease or its management, or are they both manifestations of a single systemic autoimmune disease? Is rheumatic disease a complication of kidney disease and its management? How do rheumatic disease and kidney disease affect each other even when they are unrelated? The present review provides an overview of how to address these questions in daily practice.     

MIN score predicts primary response to infliximab/adalimumab and vedolizumab therapy in patients with inflammatory bowel diseases

Infliximab/adalimumab (IFX/ADA) and vedolizumab (VDZ) are the most widely used biologics in inflammatory bowel diseases. Current models used to predict their efficacies are restricted to either Crohn's disease or ulcerative colitis or to only one type of biologic, which makes them limited in external validation. We therefore designed a comprehensive comparison among these models to identify the most meaningful predictors for patient responses. Several biomarkers and models were compared for their abilities to predict both IFX/ADA and VDZ responses by receiver operating characteristic curves. Least absolute shrinkage and selection operator regression was adopted to determine a simplified gene signature. Verification was performed in biopsy samples by immunohistochemical staining. The GIMATS module (based on counts of IgG plasma cells, inflammatory monocytes, activated T cells, and stromal cells) had the best overall performance for response prediction in both biologics (IFX/ADA, AUC = 0.720–0.853; VDZ, AUC = 0.661–0.728). Based on this module, patients were equally divided into 3 groups: M type (GIMATS-low, metabolism), with a preference for IFX/ADA; I type (GIMATS-high, immune), with a preference for VDZ; and N type (GIMATS-medium, normal), with no preference for either treatment. Furthermore, to improve clinical utility, a simplified 6-gene model, MIN score, was established to determine the baseline expression of G0S2, S100A9, SELE, CHI3L1, MMP1 and CXCL13 and function as a substitute for GIMATS module. Our study suggested that the classification of metabolic or immune type by MIN score was valuable for IBD diagnosis to assist with selection of IFX/ADA and VDZ.     

Total radical-trapping antioxidative capacity of plasma and whole blood chemiluminescence in patients with inflammatory and autoimmune rheumatic diseases

The total radical-trapping antioxidative capacity (TRAC) of plasma was evaluated in samples from patients suffering from various inflammatory and autoimmune rheumatic diseases (n=104) and correlated with the phorbol ester-stimulated chemiluminescence (CL) of neutrophils and monocytes in unseparated blood. Plasma and blood samples from age- and sex-matched healthy volunteers (n=25) and from patients with non-rheumatic internal diseases (n=31) served as controls.

A 2 to 10 fold increase in whole blood chemiluminescence was found in rheumatic patients, which paralleled 50–80% decreased levels of plasma TRAC-values. While significant correlations between CL and TRAC were determined for patients with inflammatory arthritic diseases no correlations were found with patients suffering from connective tissue diseases. Prednisolone treatment of individual patients increased plasma TRAC-values substantially and decreased elevated levels of phagocytic CL generation to that of healthy controls.

The main potential application of the assays described here is for the convenient assessment of disease activity and progression in individual patients with rheumatic diseases.     

Aseptic necrosis of the head of the femur in patients with major rheumatic diseases of inflammatory and dystrophic genesis

A total of 2392 patients treated at the Unit of Rheumatology, Tula Regional Hospital, in 2002 and 2003 were analyzed. Among them, there were 71 patients who were found to have aseptic necrosis of the head of the femur. A statistical analysis of clinical, laboratory, and X-ray data revealed a number of correlations. It was established that the risk factors of aseptic necrosis of the femoral heads were anemia concurrent with the high laboratory values in rheumatoid arthritis and elevated lipid levels and blood coagulative system activation in primary coxarthrosis.     

Gender related differences in quality of life and affective status in patients with inflammatory bowel disease

According to the literature, quality of life has been shown to be reduced in females compared with males with Inflammatory Bowel Disease (IBD). Psychosocial factors are also playing an important role in IBD, especially emotional lability. The aims of study was to investigate the sex differences in general and specific health-related quality of life (HRQoL), anxiety and depression in IBD patients. Hundred and twelve outpatients of the Gastroenterology Division, Clinical Hospital Centre Rijeka, were enrolled in our study and divided in two groups: 50 females (31 with ulcerative colitis, UC and 19 with Crohn disease, CD) and 62 males (30 with UC and 32 with CD), age range 19 to 74 (M = 41.46; SD = 13.06). Most patients have been in long clinical remission or with mild disease according to Clinical Disease Activity Index (CDAI) score for CD and Clinical Activity Index (CAI) score for UC. There were significant differences in physical (F = 13.96, p < .0001) and mental (F = 9.44, p < .001) component of the general HRQoL, emotional domain ((F = 9.26, p < .001) and bowel symptoms (F = 7.04, p < .001) of the Inflammatory Bowel Disease Quality of life (IBDQoL), as well as, in anxiety (F = 7.03, p < .001) and depression (F = 12.09, p < .0001) between men and women with IBD. Women have expressed significantly lower level of the general HRQoL and more emotional disturbances connected with their disease as well as more frequent bowel symptoms compared with men. Effect sizes of those differences were large. Results of this study confirm that women with IBD are more prone to the negative impact of the disease on their HRQoL than men. Women with higher level of depression and anxiety experienced more emotional disturbances, bowel and systemic symptoms and lower general HRQoL. These results should deserve more considerations in the clinical treatment of IBD patients.     

Current treatment of hepatitis C-associated rheumatic diseases

The hepatitis C virus (HCV) is both hepatotropic and lymphotropic, responsible for a great number of hepatic and extrahepatic immune-system disorders that comprise the so-called HCV syndrome. HCV-associated rheumatic diseases are characterized by frequent clinico-serological overlap; therefore, correct classification of individual patients is necessary before therapeutic decisions are made. This is particularly difficult to do, however, because of the coexistence of viral infection and complex autoimmune alterations. In this context, mixed cryoglobulinemia syndrome (MCs) represents the prototype of virus-related autoimmune-lymphoproliferative diseases. MCs can be treated at different levels by means of etiological treatment with antivirals (peg-interferon-alpha plus ribavirin) aimed at HCV eradication and/or pathogenetic/symptomatic treatments directed to both immune-system alterations and the vasculitic process (rituximab, cyclophosphamide, steroids, plasmapheresis, and so on). In clinical practice, the therapeutic strategy should be modulated according to severity/activity of the MCs and possibly tailored to each individual patient''s conditions. Cryoglobulinemic skin ulcers may represent a therapeutic challenge, which should be managed by means of both local and systemic treatments. HCV-associated arthritis should be differentiated from the simple comorbidity of HCV infection and classical rheumatoid arthritis. It may be treated with low doses of steroids and/or hydroxychloroquine; the use of biologics (rituximab) may be considered in more severe cases. Primary Sjögren''s syndrome is rarely associated with HCV infection, while sicca syndrome and myalgia are frequently detectable in hepatitis C patients, with or without cryoglobulinemic vasculitis. Other autoimmune rheumatic disorders (poly/dermatomyositis, polyarteritis nodosa, osteosclerosis, fibromyalgia, and so on) have been reported as potentially associated with HCV infection in patient populations from different countries, suggesting the role of genetic and/or environmental co-factors. The therapeutic approach to these disorders should be decided according to each individual patient''s evaluation, including hepatic, virological, and immunological findings.     

A meta-analysis of the risk of venous thromboembolism in inflammatory rheumatic diseases

Introduction

We performed a meta-analysis to investigate the risk of deep vein thrombosis (DVT) and/or pulmonary embolisms (PEs) in patients with inflammatory arthritis, vasculitis and connective tissue diseases (CTDs) (systemic lupus erythematosus (SLE), Sjögren’s syndrome, inflammatory myositis and systemic sclerosis (SSc)).

Methods

PubMed, Embase, the Cochrane databases and MEDLINE were searched to identify full-text English-language publications about adult patients with rheumatologic inflammatory diseases and venous thromboembolisms (VTEs). Data regarding rates of DVTs and PEs were extracted. Using random-effects models, pooled estimates for VTEs in individual and pooled diseases were compared with matched populations where possible. Studies were excluded if VTEs were described in the setting of pregnancy, postoperative outcomes or solely antiphospholipid antibody syndrome.

Results

Most of the 5,206 studies were excluded because they did not state the rate or incidence of VTEs. In total, 25 studies remained for analysis. Ten studies that included rheumatoid arthritis comprised an aggregate of 5,273,942 patients and 891,530,181 controls with a cumulative VTE incidence of 2.18% (95% confidence interval (CI): 1.82% to 2.54%) and an odds ratio of 2.23 (95% CI: 2.02 to 2.47) compared to age- and sex-matched populations. Ten studies comprised an aggregate of 54,697 SLE patients with a cumulative VTE incidence of 7.29% (95% CI: 5.82% to 8.75%). Four Sjögren’s syndrome studies comprising an aggregate of 25,100 patients demonstrated a cumulative VTE incidence of 2.18% (95% CI: 0.79% to 3.57%). Four studies of inflammatory myositis comprising an aggregate of 8,245 patients yielded a cumulative VTE incidence of 4.03% (95% CI: 2.38% to 5.67%). The SSc- and antineutrophil cytoplasmic antibody vasculitis–related cumulative VTE rates (four studies each) were 3.13% and 7.97%, respectively.

Conclusions

The inflammatory rheumatologic diseases studied were all associated with high rates of VTEs—more than three times higher than in the general population.

Electronic supplementary material

The online version of this article (doi:10.1186/s13075-014-0435-y) contains supplementary material, which is available to authorized users.     

Angiogenesis and chemokines in rheumatoid arthritis and other systemic inflammatory rheumatic diseases

Angiogenesis, the formation of new vessels, is important in the pathogenesis of rheumatoid arthritis (RA) and other inflammatory diseases. Chemotactic cytokines termed chemokines mediate the ingress of leukocytes, including neutrophils and monocytes into the inflamed synovium. In this review, authors discuss the role of the most important angiogenic factors and angiogenesis inhibitors, as well as relevant chemokines and chemokine receptors involved in chronic inflammatory rheumatic diseases. RA was chosen as a prototype to discuss these issues, as the majority of studies on the role of angiogenesis and chemokines in inflammatory diseases were carried out in arthritis. However, other systemic inflammatory (autoimmune) diseases including systemic lupus erythematosus (SLE), systemic sclerosis (SSc), Sjögren's syndrome (SS), mixed connective tissue disease (MCTD), polymyositis/dermatomyositis (PM/DM) and systemic vasculites are also discussed in this context. As a number of chemokines may also play a role in neovascularizaton, this issue is also described here. Apart from discussing the pathogenic role of angiogenesis and chemokines, authors also review the regulation of angiogenesis and chemokine production by other inflammatory meditors, as well as the important relevance of neovascularization and chemokines for antirheumatic intervention.     

Predictors of infusion reactions during infliximab treatment in patients with arthritis

In the present study we evaluated the impact of baseline antinuclear antibody (ANA) status and use of methotrexate on development of infliximab-related infusion reactions in patients with rheumatoid arthritis (RA) or spondylarthropathies (SpAs), including psoriatic arthritis. All patients with RA (n = 213) or SpA (n = 76) treated with infliximab during the period 1999–2005 at the Department of Rheumatology in Lund, Sweden were included. ANAs were present in 28% and 25% of RA and SpA patients, respectively. Because of differences in baseline characteristics, we used a binary logistic regression model to calculate odds ratios (ORs), adjusting for age, sex and prednisolone dosage. Altogether 21% of patients with RA and 13% of patients with SpA developed infusion reactions (P = 0.126). The OR for development of infusion reactions in RA patients with baseline ANA positivity alone was 2.1. Infliximab without methotrexate and infliximab as monotherapy were associated with ORs of 3.1 and 3.6, respectively. Combining infliximab without methotrexate and ANA positivity yielded an OR for infusion reaction of 4.6. Lower age at disease onset and longer disease duration were associated with infusion reactions (P = 0.012 and P = 0.036, respectively), but age, sex, C-reactive protein, erythrocyte sedimentation rate, Health Assessment Questionnaire and Disease Activity Score-28 at baseline were not. No predictors of infusions reactions were identified in SpA patients. RA patients treated with infliximab without methotrexate, and who are positive at baseline for ANAs are at increased risk for developing infliximab-related infusion reactions.     

Decreased levels of serum platelet-activating factor acetylhydrolase in patients with rheumatic diseases

PAF is a potent inflammatory compound known to stimulate the release of various cytokines involved in rheumatic diseases. Elevated blood PAF levels are reported in these patients. We report that serum PAF acetylhydrolase activity (AHA) levels are decreased in patients with rheumatoid arthritis or osteoarthritis as compared to healthy controls. Serum and synovial fluid AHA levels were correlated in these patients. The present study suggests the potential role of AHA in controling systemic and/or local PAF levels in patients with rheumatic diseases.     

The role of stress in rheumatic diseases

Rheumatology patients frequently note the occurrence of stressful or traumatic life events prior to the onset of their illness and/or a relationship between stress and disease flares. For our patients, identifying causal events could represent an effort to give meaning to a chronic and often disabling disease, while noting a link between stress and flares may proffer a sense of control. Whatever purpose the report of stress as an etiological or maintaining factor may serve, the science exploring a causal relationship between stress and autoimmune disease onset and course is expanding. Moreover, stress can also induce symptoms such as pain via nonimmunological mechanisms.     

Contents of antibodies to Bordetella pertussis antigens in patients with rheumatic diseases

Study of presence of antibodies against pertussis in 72 rheumatic patients (with uvenile rheumatoid arthritis, systemic lupus erythematosus, etc.) aged 1-18 year old without history of pertussis was performed. Mean age of the patients was 10.6 +/- 0.48 year old, duration of illness--51.2 +/- 4.42 months. Immunosupressive therapy at the time of the study was conducted in 68 (94.4%) children. Using ELISA method, IgG to pertussis toxin (PT) and to antigens of acellular pertussis vaccine (aPV) were detected in 98.6% and 100% of children. High titers of antibodies were detected more frequently in 7-18 year old age group, which can indicate recent pertussis disease or infection. Vaccination history was studied in 131 children with rheumatic diseases. Incidence of pertussis in 43 unvaccinated children was 116.3 per 1000, and in 16 children with incomplete vaccination--62.5 per 1000. Out of 75 patients, who received vaccination series and revaccination, clinically distinct pertussis was not diagnosed.     

Experimental stress in inflammatory rheumatic diseases: a review of psychophysiological stress responses

Introduction  

Stressful events are thought to contribute to the aetiology, maintenance and exacerbation of rheumatic diseases. Given the growing interest in acute stress responses and disease, this review investigates the impact of real-life experimental psychosocial, cognitive, exercise and sensory stressors on autonomic, neuroendocrine and immune function in patients with inflammatory rheumatic diseases.     

不同护理模式对维持性血液透析患者透析依从性与生活质量的影响

目的探讨不同护理模式对维持性血液透析患者透析治疗依从性与生活质量的影响。方法将行维持性血液透析的患者80例,根据护理模式的不同分为对照组与研究组各40例,对照组采用常规护理模式,研究组采用协同护理模式,两组均干预4个月,并对两组患者干预前后进行透析依从性量表、简明健康调查表(SF-36)、护理满意度进行问卷调查,分析干预前后两组患者透析依从性、生活质量变化及对护理满意度情况。结果与干预前比较,干预后研究组患者在透析依从性评分、SF-36评分及护理满意度方面均明显升高,差异有统计学意义(均P0.01);而且与对照组比较差异亦有显著统计学意义(均P0.01)。结论协同护理模式可显著提高维持性血液透析患者的血透治疗依从性及生活质量,提高了护理满意度,值得临床推广应用。