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Epigenetics is a key mechanism regulating the expression of genes. There are three main and interrelated mechanisms: DNA methylation, post-translational modification of histone proteins and non-coding RNA. Gene activation is generally associated with lower levels of DNA methylation in promoters and with distinct histone marks such as acetylation of amino acids in histones. Unlike the genetic code, the epigenome is altered by endogenous (e.g. hormonal) and environmental (e.g. diet, exercise) factors and changes with age. Recent evidence implicates epigenetic mechanisms in the pathogenesis of common rheumatic disease, including RA, OA, SLE and scleroderma. Epigenetic drift has been implicated in age-related changes in the immune system that result in the development of a pro-inflammatory status termed inflammageing, potentially increasing the risk of age-related conditions such as polymyalgia rheumatica. Therapeutic targeting of the epigenome has shown promise in animal models of rheumatic diseases. Rapid advances in computational biology and DNA sequencing technology will lead to a more comprehensive understanding of the roles of epigenetics in the pathogenesis of common rheumatic diseases.

With every passing year, research on the pathogenesis of rheumatoid arthritis benefits from discoveries in other scientific fields. Three of the best examples that illustrate the benefit of such interdisciplinary bridges and the effects they have on our understanding of rheumatoid arthritis are presented here.

2013 has witnessed the maturation of imaging science with rheumatology research, in part due to large, public databases. Using imaging in osteoarthritis (OA) as an example, breakthroughs include further elucidation of the relationship between obesity and OA, and identification of the importance of bone and meniscus shape in OA development.

Platelets are intimately involved in hemostasis, inflammation, innate and adaptive immunity, tissue regeneration and other physiological and pathological processes. Their granular structure is programmed to release a wide range of bioactive substances in response to agonists. Upon activation, platelet membranes display thrombotic and inflammatory agents, which may take an active part in the pathophysiology of autoimmune and autoinflammatory disorders. The aim of this review is to analyze current evidence of platelet (dys)function in inflammatory rheumatic diseases and overview platelettargeting mechanisms of antirheumatic drug therapies. A comprehensive search through Medline/PubMed, SciVerse/Scopus and Web of Science was performed for English-language original research papers, using the keywords related to platelets in autoimmune and autoinflammatory rheumatic disorders. Additionally, the Cochrane Collaboration database was searched for the literature on the effects of antirheumatic drugs on platelet function. A variety of platelet markers have been tested in systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis, spondyloarthropathies, vasculitides, and some autoinflammatory disorders. It has been shown that platelets circulate in an activated state in most of these disorders and tend to form complexes with other inflammatory and immune cells. Thrombotic and inflammatory agents, released from platelets, may trigger disease-specific complications (e.g., extraarticular features, fibrosis in systemic sclerosis) and propagate endothelial dysfunction. Whether platelet activation is a primary or secondary feature in rheumatic disorders remains to be elucidated. Some widely used antirheumatic drugs may suppress thrombopoiesis and platelet activity, however the clinical implications of this effect have yet to be examined in specifically designed prospective studies. Large retrospective cohort studies supported the use of low-dose aspirin for suppressing platelet function and preventing cerebrovascular events in giant-cell arteritis. However, emerging data suggest that the release rate of activated platelets applied topically to the inflamed cartilage in arthritis or skin ulcers in scleroderma may suppress the inflammation and facilitate tissue repair. Taken together, current evidence necessitates a balanced approach to platelet-activating and suppressing drug therapies in inflammatory rheumatic diseases.

Progress in the laboratory diagnosis of systemic autoimmune rheumatic diseases (SRAD) is caused by the ever increasing clinical introduction of new highly productive methods for immune analysis using computer-aided systems and multiplex proteomic technologies. The urgent problem in the laboratory diagnosis of SRAD is the standardization of current methods for the detection of autoantibodies (autoAb), including the preparation of international reference materials for the calibration and external quality assessment of immunological assay. New autoAb technologies have a higher analytical validity than the previously used classical techniques immunodiffusion, agglutination, and immunofluorescence; however, their diagnostic sensitivity and specificity for SRAD have been poorly studied. Particular emphasis is laid on the standardization of the methods for examining antinuclear antibodies (ANAb), the major serologic marker of SRAD. According to the EULAR/ACR guidelines, indirect immunofluorescence reaction (IIFR) using human HEp-2 cells as substrate is the gold standard and a primary screening ANAb method. New methods for solid-phase analysis (enzyme immunoassay, multiplex test systems, etc.) cannot substitute the primary screening of ANAb using IIFR-HEp-2 as they identify antibodies to the limited number of antigens, increasing the number of false- negative results. The computer-aided systems for interpreting cell fluorescence tests contribute to the standardization and enhancement of the efficiency of detection of ANAb and other autoAb by IIFR. The use of complex diagnostic indices based on the multiparametric analysis of laboratory biomarkers in the serum makes it possible to most fully and objectively assess complex molecular mechanisms for the pathogenesis of SRAD, thus radically improving the early diagnosis, the estimation of the activity and severity of disease, the prediction of the outcomes of a pathological process and the response to treatment.

Dental screening features of patients having rheumatic diseases are reviewed concerning such factors as examination and oral hygiene sessions frequency, specific rheumatic disease (rheumatoid arthritis, system lupus erythematosus and systemic sclerosis), oral and dental disorders (periodontal disease, dental caries, salivary glands disorders).

Advanced imaging techniques may enable early diagnosis and monitoring of therapy in various rheumatic diseases. To prevent irreversible tissue damage, inflammatory rheumatic disease must be diagnosed and treated in pre-clinical stages, requiring highly sensitive detection techniques. Positron emission tomography (PET) provides highly sensitive, quantitative imaging at a molecular level, revealing the important pathophysiological processes underlying inflammation. This review provides an overview of the current utility of 18 F-fluorodeoxyglucose (FDG)-PET/computed tomography (CT) in patients with active rheumatic diseases such as rheumatoid arthritis, spondyloarthritis, polymyalgia rheumatica, adult-onset Still's disease, relapsing polychondritis, immunoglobulin G4-related disease, large-vessel vasculitis, Wegener's granulomatosis, polymyositis, and dermatomyositis. We also discuss the role of FDG-PET/CT in the diagnosis and monitoring of these diseases.

To compare the intra- and interobserver reliability of three-dimensional (3D) volumetric versus conventional two-dimensional (2D) power Doppler ultrasonography (US) in the assessment of peripheral enthesitis in spondylarthritis (SpA). Sixteen patients with SpA according to ASAS criteria were included. Two rheumatologists (one experimented in musculoskeletal US (sonographer 1) and one beginner (sonographer 2)) performed independently a 2D US scoring of the enthesis using the Madrid Sonographic Enthesis Index score followed by a 3D acquisition of the same entheseal sites. The reading of the 3D acquisition was performed a minimum of 1 week apart. Intraobserver reliability was evaluated by a second reading of the same images. The duration of 2D US scanning, 3D US acquisition and reading was recorded. Intraclass correlation coefficients (ICCs) were used for the reliability analysis. Intraobserver reproducibility was good to excellent for 2D US and good for 3D US (ICC (95 %CI) 2D US 0.776 (0.471-0.916) and 0.96 (0.892-0.986) and ICC (95 %CI) 3D US 0.796 (0.498-0.921) and 0.703 (0.325-0.886) for sonographer 1 and 2, respectively). Interobserver reliability was slightly better for 3D US than for 2D US (ICC (95 %CI) 0.776 (0.471-0.916) for 3D US versus 0.641 (0.221-0.859) for 2D US). The mean time (±SD) for 2D US scanning was 23 min (±4) whereas the mean time for 3D US volume acquisition and reading was 16.5 min (±2.6) (p < 0.001). 3D US showed good intra- and interobserver reliability in the assessment of enthesitis in SpA and shortened the needed time for scanning. It can be performed by a nonexperienced examiner without loss of reliability.

A physician estimate of global status (DOCGL) is among the seven core data set measures to assess patients with rheumatoid arthritis (RA) and included in many rheumatic disease indices. In clinical trials designed to reduce in flammation, DOCGL is directed to estimate inflammatory activity. However, patients with inflammatory rheumatic diseases also may be affected by organ damage (e.g., to joints in RA, kidneys in SLE, muscles in polymyositis, and so forth.). Furthermore, fibromyalgia has been reported in 20% to 40% of patients with RA and other inflammatory rheumatic diseases, which may complicate their management. We sought to clarify a global summary of patient status by supplementing DOCGL with three additinal separate (0-10) physician global estimates for inflammation (DOCINF), damage (DOCDAM), and neither inflammation nor damage (DOCNON) (often fibromyalgia, but may be other chronic pain or somatization syndromes). In analyses of new patients with six diagnoses, mean overall DOCGL scores were highest for patients with fibromyalgia, followed by RA, spondyloarthropathy, osteoarthritis, gout, and systemic lupus erythematosus. Among the three subscales, mean DOCINF scores were highest in RA, spondyloar- thropathy, gout, and systemic lupus erythematosus; mean DOCDAM highest in osteoarthritis; and mean DOCNON in fibromyalgia. In patients with RA, mean DOCDAM and DOCNON scores indicated coexistence of clinically impor tant damage or fibromyalgia in some patients. These data indicate face validity of the three physician global estimates on subscales for inflammation, damage, and symptoms due to neither inflammation nor damage. These estimates reflect the expertise of the rheumatologist and may be helpful to interpret rheumatic disease indices.

Introduction: A number of new biological immune modulators have become available as treatments for inflammatory diseases over the past two decades. Most prominent among them are TNF-α inhibitors (TNFi) which have been available in the clinic since the late 1990s. TNFi have demonstrated efficacy in various rheumatologic diseases as well as in inflammatory bowel disease and psoriasis. Golimumab is one of the most recently introduced TNFi., Areas Covered: Although golimumab is generally well tolerated, as is the case with other TNFi and indeed with most of the marketed immunomodulatory drugs, potential adverse events may be associated with its use. Herein, we the potential adverse effects associated with golimumab therapy are reviewed. Adverse effects are divided into target-related and agent-related categories., Expert Opinion: Golimumab has been demonstrated to be generally safe and well tolerated. Its safety profile seems to be very comparable to the other available TNFi. Long-term studies of golimumab and other TNFi will help establish the durability of response to golimumab as well as identify any potential delayed or cumulative adverse effects.

Systemic inflammatory diseases are inflammatory syndromes that are associated with increased cardiovascular morbidity and mortality. The link between inflammatory and cardiovascular diseases can be attributed to coexistence of classical risk factors and of inflammatory mechanisms activated in systemic inflammatory diseases and involving the immune system. Yet, clinical implications of these findings are not entirely clear and deeper knowledge and awareness of cardiac involvement in inflammatory diseases are necessary. The aims of this review are to summarize cardiac involvement in systemic inflammatory diseases and to identify areas where evidence is currently lacking that deserve further investigation in the future., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Aim: To provide the clinical, laboratory, radiological, morphological, and immunomorphological signs that permit the differential diagnosis to be made in patients with involvement of the nasal cavity and accessory sinuses (NCAS)., Subjects and Methods: In the period 2009 to 2013, the Laboratory for Intensive Therapy for Rheumatic Diseases, V.A. Nasonova Research Institute of Rheumatology, Russian Academy of Medical Sciences, associated the disease onset with NCAS involvement in 39 (7.6%) of 512 examinees. NCAS involvement was present at disease onset in 100% of the patients with natural killer (NK) cell lymphoma (NK/T lymphoma), in 84.5% of those with Wegener granulomatosis (WG), in 29.5% of those with IgG4-related disease (IgG4-RD), and in 17.5% of those with sarcoidosis. Such an onset could be extremely rarely observed in histiocytosis., Results: Despite the similar clinical manifestations, NCAS involvements in NK/T lymphoma of nasal type and WG at disease onset show clear differences in the laboratory and systemic manifestations of these diseases. The patients with lymphoma have no characteristic laboratory abnormalities at disease onset, except the 100% presence of Epstein-Barr virus (EBV) DNA in blood and, only as a tumor grows, fever appears and there are elevated C-reactive protein and lactate dehydrogenase levels and pronounced destructive changes in the facial bones with mandatory hard palate destruction; at the same time the signs of systemic involvement are virtually absent. The patients with WG at disease onset have fever, high erythrocyte sedimentation rate, elevated C-reactive level, significant anemia, leukocytosis and 90% are found to have anti-neutrophil cytoplasmic antibodies with the rapid development of systemic manifestations: involvements of the lung, kidney, and peripheral nervous system. Destructive changes in the facial bones are minimal and hard palate destructions are absent. The patients with IgG4-RD, sarcoidosis, and juvenile xanthogranuloma have similar clinical and laboratory manifestations in the absence of hemorrhagic nasal discharge, nasal septal perforation, and facial bone destruction, with the practically involvement of the salivary/lacrimal glands and orbital regions. A third of the patients are observed to have different allergic manifestations, moderate eosinophilia, and signs of autoimmune disorders (the presence of rheumatoid and antinuclear factors, hypergammaglobulinemia). Elevated serum IgG4 levels are characteristic of IgG4-RD., Conclusion: Blood anti-neutrophil cytoplasmic antibodies, EBV DNA, and IgG4 levels should be determined in all patients with NCAS involvement. Mini-invasive incision biopsies of the nasal mucosa, orbital regions, and major salivary glands should be done, by morphologically verifying the diagnosis of sarcoidosis, histiocytosis, and WG and by making an immunomorphological examination to diagnose NK/T lymphoma and IgG4-RD.

Yoga is a popular activity which may be well suited to some individuals with specific rheumatic disorders. Regular yoga practice can increase muscle strength and endurance, proprioception, and balance, with emphasis on movement through a full range of motion to increase flexibility and mobility. Additional beneficial elements of yoga include breathing, relaxation, body awareness, and meditation, which can reduce stress and anxiety and promote a sense of calmness, general well-being, and improved quality of life. Yoga also encourages a meditative focus, increased body awareness and mindfulness; some evidence suggests yoga may help reduce inflammatory mediators including C-reactive protein and interleukin-6. Yoga is best learned under the supervision of qualified teachers who are well informed about the potential musculoskeletal needs of each individual. Here, we briefly review the literature on yoga for healthy, musculoskeletal, and rheumatic disease populations and offer recommendations for discussing ways to begin yoga with patients.

The fibromyalgia syndrome (FMS) is characterized by chronic and widespread musculoskeletal pain and soreness accompanied by sleep disorders, chronic fatigue and affective disorders. FMS is often associated with other forms of immuno-rheumatic diseases. Although FMS pathophysiology is still not fully understood, a number of neuroendocrine, neurotransmission and neurosensitive disorders might generate a mechanism for the elicitation of pain by "central sensitization," which is common to many other painful conditions. The present case describes the success of a therapeutic scheme, which associates two different pharmacological classes, anticonvulsants and new-generation antidepressants, when FMS complicates a rare pathology called Cogan's syndrome. The association of two drugs might noticeably affect the molecular mechanisms of difficult pain, thus solving painful conditions of multifactorial origin., (© 2013 The Authors Pain Practice © 2012 World Institute of Pain.)

The notion of 'autoinflammatory' disease was introduced at the end of the 1990s, and, since then, this concept has rapidly evolved. As a result, multiple definitions of autoinflammatory disease, and classifications of conditions encompassed by these definitions, have been proposed; this succession highlights advances that have been made in understanding of the innate immune system, and especially the roles of IL-1β and the inflammasome in autoinflammtory conditions. However, the definitions and classifications that have been suggested to date face a number of structure and content issues. We therefore propose another, more clinically-oriented, definition: autoinflammatory diseases are diseases with clinical signs of inflammation, associated with elevated levels of acute-phase reactants, which are attributable to dysfunction of the innate immune system, genetically-determined or triggered by an endogenous factor. From this foundation, we propose a clinically-based classification of autoinflammatory diseases, and go on to discuss how immunological diseases as a whole, including autoimmune diseases, can be appropriately located within a continuum only if the classification process is multidimensional. For this purpose, we appeal to the philosophical concepts of family resemblance and signature.

Background and Aims: Joint hypermobility when associated with symptoms in the absence of systemic rheumatologic disease is termed as benign joint hypermobility syndrome (BJHS). BJHS is often an under-recognised and a poorly managed entity. Indian studies on BJHS are very few and none have been carried out in any of the service rheumatology centres. Hence this retrospective study was carried out at a tertiary medical institute of the Indian Army to assess the varied clinical profile of BJHS., Methods: All patients consecutively diagnosed as BJHS at the rheumatology clinic of the Army Hospital (Research and Referral) Delhi from May 2010 to May 2011 were included in the study. Their age, sex, presenting features, clinical profile, laboratory and radiological parameters were studied., Results: The mean age of these patients was 30 ± 5.71 years with a median duration of symptoms of 42 (06-120) months. There were 45 males and 39 females (male : female = 1.15 : 1.00). The median Beighton's score in these patients was 6/9 (range 4-9). Most of our patients were military personnel (43/84), and all had knee joint pain with evidence of degenerative changes in 19 and synovitis in two patients. Eleven patients including nine military personnel had evidence of soft tissue rheumatism with associated fibromyalgia in four and anxiety disorder in one. Out of 18 patients with a Beighton's score of ≥ 7, nine had incidental findings of lateral head tilt on frontal observation. There was evidence of carpal tunnel syndrome in a patient with wrist synovitis and one patient had associated skin laxity without features of Ehlers-Danlos syndrome., Conclusion: BJHS is often under-recognized in clinical practice and is usually missed because of a lack of awareness. A high index of clinical suspicion to diagnose this entity is essential due to its associated morbidities, especially among those exposed to strenuous physical activities., (© 2013 The Authors International Journal of Rheumatic Diseases © 2013 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd.)

More than one-third of patients with IBD are affected by extraintestinal manifestations or extraintestinal complications beyond the intestinal manifestation of the disease. The most common manifestations include arthropathies, mucocutaneous and ophthalmological manifestations, as well as conditions affecting the hepatobiliary system, both in Crohn's disease and ulcerative colitis. However, less frequent manifestations, such as pulmonary or neurological manifestations, should also be considered in patients with IBD. Several extraintestinal manifestations follow the course of the underlying intestinal activity, whereas others are independent from the intestinal inflammation. Extraintestinal complications such as iron-deficiency anaemia and osteoporosis are consequences of the intestinal disease or of disease-specific treatment. As extraintestinal manifestations and complications strongly influence quality of life, and to avoid severe complications, adequate treatment is mandatory in affected patients. We provide a comprehensive overview of different extraintestinal manifestations and complications, including their management, in patients with IBD.

Objective: Chronic pain from rheumatic and musculoskeletal conditions is associated with cortical changes and altered tactile acuity. Tactile acuity is considered a clinical signature of primary somatosensory representation. The two-point discrimination (TPD) threshold is increasingly used both clinically and in research. Remarkably, the reliability and precision of the measure at commonly used sites has not been determined. This study aimed to determine the utility, intra- and inter-rater reliability, bias and variability of TPD threshold assessment at the neck, back, hand and foot using mechanical callipers., Methods: Intra- and inter-rater reliability of TPD was assessed at the back, neck, hand and foot of 28 healthy young adults by 28 clinicians. Each clinician received training in the assessment of TPD using mechanical callipers and following a standardized protocol. Intraclass correlation coefficients (ICCs) and Bland-Altman plots were used to assess reliability, bias and variability., Results: Intra-rater assessments in all four regions and inter-rater assessments at the neck and foot were reliable (ICC range 0.79-0.86), but large variability was seen in all assessments. Inter-rater assessment of the back (ICC = 0.66) and hand (ICC = 0.62) was deemed unreliable. Negligible systematic bias suggested learning did not affect reliability., Conclusion: Individual clinicians are able to reliably assess TPD threshold at the neck, back, hand and foot using mechanical callipers. Measures obtained by different clinicians were only reliable for the neck and foot. Large variability was observed in all assessments, which suggests clinicians should be cautious when interpreting changes in tactile acuity in individual patients.

Objectives: To describe the construction and psychometric properties of the Belgian Rheumatoid Arthritis Disability Assessment (BRADA) questionnaire, a self-report tool to evaluate chronic activity limitations in patients with rheumatoid arthritis (RA). The BRADA was developed to assess the eligibility of patients with RA for financial and social support measures., Methods: The BRADA questionnaire evaluates functioning in 6 functional domains (mobility, nutrition, self care, household tasks, awareness of danger and communication) over the past week and the past 3 months. To assess the psychometric properties of the BRADA, patients with moderate to severe RA filled out the BRADA, HAQ-DI and SF-36 questionnaires twice, with a four-week interval. At each visit, the total number of swollen and tender joints, and global disease activity were recorded. DAS 28 was measured at the first visit. Internal consistency of items per domain was evaluated with Cronbach's alpha method. Intraclass correlation coefficient (ICC) analysis was used to assess test-retest reliability. BRADA scores were compared to HAQ, SF-36 scores and disease activity parameters with Spearman's Rho correlation coefficients to assess construct validity., Results: Experts considered the content and face validity of BRADA to be adequate. Internal consistency was satisfactory for all functional domains (alpha >0.75), as was the test-retest reliability (ICC 0.78). BRADA scores showed excellent correlation with other validated questionnaires in RA (HAQ-DI, SF-36) and with measures of disease activity (VAS, DAS28)(p<0.001)., Conclusions: Its psychometric properties indicate that the BRADA questionnaire is a suitable instrument to evaluate disease-specific activity limitations in patients with RA.

Vitamin D is a dietary vitamin that can also be synthesized in adequate amounts from cholesterol in most mammals exposed to sunlight. Vitamin D has classical roles in calcium and phosphate metabolism, and thus the skeleton; however, this molecule also has nonclassical effects that might influence the function of the immune, cardiovascular and endocrine systems. Vitamin D deficiency, due to insufficient sunlight exposure, dietary uptake and/or abnormalities in its metabolism, has been associated with rheumatic diseases, and both the classical and nonclassical effects of vitamin D might be of relevance to patients with rheumatic disease. However, conclusive data from intervention trials demonstrating the relationship between vitamin D levels and pathogenetic processes separate from classical effects of this molecule are lacking. Furthermore, the majority of studies linking vitamin D to health outcomes, harmful or beneficial, are observational in nature, linking clinical events to vitamin D exposure or serum levels of vitamin D metabolites. Evidence from high quality, prospective, double-blind, placebo-controlled, randomized trials should be obtained before vitamin D supplementation is recommended in the treatment of the many rheumatic conditions in which deficiency of this compound has been implicated. Herein, we review the evidence for vitamin D supplementation in the management of patients with rheumatic diseases.

Inflammasomes are key inducers of inflammation in response to exogenous and endogenous stimuli, because they regulate the processing and secretion of the proinflammatory cytokines IL-1β and IL-18. Thus, inflammasomes have a crucial role in host defence against infection, but they can also be involved in inflammatory diseases. Indeed, the NLRP3 (NOD-, LRR- and pyrin domain-containing 3) inflammasome has been shown to play a part in several inflammatory rheumatic disorders, although the mechanisms involved are better elucidated in some of these diseases than in others. In particular, the pathogenesis of cryopyrin-associated periodic syndromes and microcrystal-induced arthritides is thought to be dependent on activation of the NLRP3 inflammasome, and IL-1 inhibition has shown efficacy as a therapeutic strategy in both groups of conditions. In this Review, we describe the current understanding of the mechanisms that trigger the inflammasome, and consider the relevance of the inflammasome to a variety of rheumatic diseases. In addition, we discuss the current therapies targeting this molecular complex, as well as future therapeutic prospects.

Macrophage activation syndrome (MAS) is a potentially fatal complication of rheumatic diseases. The condition is considered part of secondary hemophagocytic lymphohistiocytoses (HLH). There are similarities in genetic background, pathogenesis, and clinical and laboratory features with primary HLH (p-HLH). We describe findings in mouse models of secondary HLH, comparing them with models of p-HLH and the cellular and molecular mechanisms involved, and relate them to recent findings in patients with secondary HLH. A multilayer model is presented in which background inflammation, infections, and genetics all contribute in different proportions and in several ways. Once the "threshold" has been reached, inflammatory cytokines are the final effectors, independent of the interplay between different upstream pathogenic factors.

Background: Knowledge about the clinical features, outcomes and predictors of short-term mortality in critically ill patients with systemic rheumatic disease (SRD) requires further characterization., Methods: Single center retrospective observational cohort study of 149 critically ill patients with SRD followed in a French medical intensive care unit over a 20-year period. Multivariate logistic regression was used to identify predictors of day-30 mortality., Results: Most patients (63%) had systemic lupus erythematosus, rheumatoid arthritis, or systemic sclerosis. The critical illness usually developed late after the diagnosis of SRD (median time to ICU admission 82 months, IQR [9-175] in the 127 patients with a previous diagnosis of SRD). Two-thirds of patients were taking immunosuppressive drugs to treat their SRD. Reasons for ICU admission were infection (47%), SRD exacerbation (48%), and iatrogenic complications (11%); the most common organ failure was acute renal failure. Thirty-day mortality was 16%. Predictors of 30-day mortality were the LODS score on day 1 (OR 1.3 (1.06-1.48)), bacterial pneumonia (OR 3.8 (1.03-14.25)), need for vasoactive drugs (OR 7.1 (1.83-27.68)), SRD exacerbation (OR 4.3 (1.15-16.53)), and dermatomyositis (OR 9.2 (1.05-80.78)) as the underlying disease. Year of ICU admission was not significantly associated with 30-day survival., Conclusion: Patients with SRD are mostly admitted in the ICU with infection or SRD exacerbation, and can be treated with immunosuppressive therapy and life-sustaining interventions with acceptable 30-day mortality. Death is associated with both the severity of the acute medical condition and the characteristics of the underlying SRD., (Copyright © 2012 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

Aim: This study examines possible predictors of physical and social functioning in adolescents with rheumatological conditions. Condition-related variables and psychosocial variables were studied, and their relative contribution as predictors was examined., Methods: The study population was one hundred and twelve adolescents (11-18 years) attending secondary and tertiary paediatric rheumatology outpatient clinics in south-west England. These adolescents completed validated self-report accounts of disease history, pain and functioning (condition-related variables) and the Bath Adolescent Pain Questionnaire (psychosocial variables). Correlation and regression analyses were used to establish influences on physical and social functioning, examining condition-related variables and psychosocial variables as separate blocks., Results: Physical functioning was independently associated with age at onset, intensity of pain, presence of depression and pain-specific anxiety. Social functioning was only associated with general anxiety. The presence of an inflammatory diagnosis had no bearing on optimal functioning in this study., Conclusion: Condition-related variables (age at onset, pain intensity) and psychosocial variables (depression, pain-specific anxiety) were equally important for physical functioning, whereas psychosocial variables (general anxiety) were more influential for social functioning. Understanding the impact of disease and associated variables in the adolescent rheumatology population should optimize targeted multidisciplinary rehabilitation for the young person and their family., (©2012 The Author(s)/Acta Paediatrica ©2012 Foundation Acta Paediatrica.)

In 2012, several new concepts emerged that widen our view of the regulation of bone mass in health and disease. Three key studies outline these discoveries, which affect our understanding of the skeletal system, particularly its physiological function and the changes it undergoes during inflammatory disease.

A number of microRNAs have been implicated in the pathogenesis of various rheumatic diseases, and evidence in support of the therapeutic potential of microRNA-based strategies for these conditions is growing, as demonstrated by several new findings published in 2012.

Background: Illness perceptions have been found to change over time and following health care. Hence, addressing illness perceptions alongside existing health care interventions may be important for the sustainment of health gains following rehabilitation. The aim of this study was to measure the illness perceptions of patients receiving inpatient rheumatology rehabilitation and assess the association with aspects of health and outcomes at baseline, discharge and 12 months., Methods: Patients with a rehabilitation stay of one week or more at three institutions in Norway in 2009 were invited to participate in the study. At baseline, discharge and 12 months, patients completed The Rheumatic Disease Illness Perception Questionnaire (RD-IPQ) which includes aspects of illness perceptions important to patients with rheumatic diseases. Stepwise regression analysis was used to assess associations between RD-IPQ scores and different aspects of health at baseline and follow-up after controlling for other aspects of health and sociodemographic variables., Results: For the 134 patients included in the study, baseline RD-IPQ scores had a mean of 58.2 (SD 14.9) on a 0-100 scale, where 100 is the worst possible. Scores showed improvement after the rehabilitation stay which were maintained at 12 months. RD-IPQ scores were positively associated with health and outcomes. At baseline RD-IPQ scores were statistically significant in explaining variation in pain, physical function and SF-36 mental health scores. Baseline RD-IPQ scores were significant in explaining fatigue, pain, SF-36 role limitations and social function scores following rehabilitation and at 12 months., Conclusion: Illness perceptions as measured by the RD-IPQ were associated with health and outcomes as measured by rheumatology-specific and generic instruments. The consideration of illness perceptions as a component of rehabilitation may be important in achieving desired outcomes.

Palindromic rheumatism is characterized by episodes of arthritis or para-arthritis leaving no residual or radiographic changes. Several diseases should be ruled out in the differential diagnosis. Evolution to rheumatoid arthritis is common, especially in patient with positive rheumatoid factor and anticitrullinated peptides. In seronegative patients, palindromic rheumatism could be part of the spectrum of autoinflammatory diseases because of a high frequency of MEFV mutations. Treatment remains discussed. The use of antimalarials could delay the development of rheumatoid arthritis or another connective tissue disease., (Copyright © 2012. Published by Elsevier SAS.)

It is not inflammation but functional and/or anatomical loss of integrity of target organs that is the major determinant of morbidity in many immune-mediated inflammatory diseases (IMIDs). This structural and often irreversible tissue damage is generally considered to be a direct or indirect consequence of inflammation (through failed repair mechanisms). However, recent clinical observations in rheumatic diseases, demonstrate clearly that the postulated causal relationship between inflammation and structural damage does certainly not hold true in all IMIDs. On the contrary, potent anti-inflammatory treatments suggest an uncoupling of inflammation and damage in diseases such as ankylosing spondylitis. The author proposes a third and intriguing alternative hypothesis: inflammation and stromal remodelling are causally linked but it is the latter that drives the former. If this hypothesis is correct, we should focus our therapeutic efforts on pathways of tissue remodelling rather than on inflammation in IMIDs such as ankylosing spondylitis, but potentially also scleroderma or asthma.

Aim: To assess the risk of severe adverse events (AEs) within 6 months after treatment with biological agents in patients with rheumatic diseases (RD)., Subjects and Methods: The 6-month open-label trial included 107 patients with rheumatoid arthritis, antineutrophil cytoplasmic antibody-associated vasculitides, systemic lupus erythematosus, and other RDs who received genetically engineered biological agents (GEBAs), primarily rituximab (n = 66) and infliximab (n = 31)., Results: The majority of patients were noted to have improvements, including complete and partial remission in 62 (57.9%) and 42 (39.3%), respectively. There were mild or moderate AEs in 22 (20.6%) of the 107 patients, severe AEs in 6 (5.6%): grade IV neutropenia in 2 patients (after the use of rituximab), severe infusion reactions in 2 (after the administration of infliximab and rituximab), and systemic infections in 2 (fatal nocardial sepsis after rituximab treatment and unspecified sepsis after infliximab treatment)., Conclusion: The rate of serious AEs, mainly infusion AEs and infections during treatment with infliximab, rituximab, and other GEBAs proved to be relatively low in patients with different RDs. At the same time, the use of biological agents could lower RD activity in the presence of severe visceral injuries refractory to conventional immunosuppressive therapy.

Activation of the immune system has been increasingly recognised to be associated with procoagulatory status in patients with inflammatory rheumatic disease. Changes in endothelial cell and platelet activation, blood flow, expression and activity of different coagulation factors, and impaired fibrinolysis serve as pathophysiological basis for enhanced risk of venous thromboembolism in inflammatory rheumatic diseases, such as rheumatoid arthritis (RA), connective tissue diseases and vasculitides. Recent studies identifying mechanisms for a functional role of coagulation factors beyond haemostasis have provided examples of interesting links between the coagulation system and innate immune activation. Furthermore, citrullinated fibrinogen is an important and early autoantigen in patients with RA carrying the HLA-DRβ1 shared epitope allele, which demonstrates an adaptive immune response to a coagulation factor in an inflammatory rheumatic disease. Additional studies have provided strong evidence that a multitude of different components of the haemostatic system (such as thrombin, fibrinogen, coagulation factor XIII and factors of the fibrinolytic system) are relevant mediators of inflammatory processes as well as of inflammatory control. Understanding the interactions between coagulation and the immune system in inflammatory rheumatic diseases will not only improve our knowledge of disease mechanisms, but could also permit the development of innovative therapeutic interventions.

Objectives: To explore the ability of six outcome measures to capture clinically important changes in patients with rheumatic diseases undergoing hand surgery and to study predictors of changes in activity performance in different patient and surgery strata., Methods: A total of 172 patients (median age 59 years, disease duration 18 years) were stratified into subgroups: diagnosis, age, general function, type of surgery. Performance of daily activities and satisfaction were assessed by the Canadian Occupational Performance Measure (COPM). Clinically important improvement was defined as a two-step improvement in COPM. Hand function was assessed by reference to grip strength (Grippit), pinch strength (pinch gauge), hand pain (visual analogue scale) and grip ability (Grip Ability Test). Responsiveness was calculated as effect size (ES) at 6-month follow-up compared with baseline., Results: Clinically important improvement was reached by 25-69% depending on outcome measure and type of surgery. Improvement was smaller in patients with multiple simultaneous procedures. Regardless of diagnosis, age, general function and type of surgery, patients improved significantly in all measures, with the largest changes in COPM(performance) and COPM(satisfaction) (ES 0.7-1.9). The ES of pain ranged from 0.2 to 0.7, Grippit from 0.1 to 0.5 and pinch gauge from 0.4 to 0.8. Hand pain was the only significant predictor of clinically important improvement of COPM(performance): odds ratio 0.71, 95% CI 0.51, 0.98 (P = 0.041)., Conclusion: COPM was the most sensitive instrument to capture clinically important improvement, and hand pain was a significant predictor of improvement, irrespective of diagnosis, age, general functional level and type of surgery.

No guidelines for the application of qualitative and quantitative analysis of the capillaroscopic examination in the rheumatologic practice exist. The aims of the study were to compare qualitative and quantitative analysis of key capillaroscopic parameters in patients with common rheumatic diseases and to assess the reproducibility of the qualitative evaluation of the capillaroscopic parameters, performed by two different investigators. Two hundred capillaroscopic images from 93 patients with different rheumatic diseases were analysed quantitatively and qualitatively by two different investigators. The distribution of the images according to the diagnosis and the microvascular abnormalities was as follows-group 1: 73 images from systemic sclerosis patients ("scleroderma" type pattern), group 2: 10 images from dermatomyositis ("scleroderma-like" pattern), group 3: 25 images from undifferentiated connective tissue disease and different forms of overlap (24 "scleroderma-like"), group 4: 26 images from systemic lupus erythematosus patients, group 5: 46 images from rheumatoid arthritis and group 6: 20 images from primary Raynaud's phenomenon patients. All the images were mixed and blindly presented to both investigators. For comparison of the quantitative and qualitative method, investigator 1 assessed presence of dilated, giant capillaries and avascular areas quantitatively by the available software programme and his estimates were compared with the results of investigator 2, who assessed the parameters qualitatively. In addition, the capillaroscopic images were evaluated qualitatively by the investigator 1 and 2 for presence of dilated, giant capillaries, avascular areas and haemorrhages. The comparison of the quantitative and qualitative assessment of the two investigators demonstrated statistically significant difference between the two methods for the detection of dilated and giant capillaries (P < 0.05) but no significant difference regarding the detection of avascular areas (P > 0.05). As we further analysed the results for the capillaroscopic images, demonstrating a "scleroderma" and a "scleroderma-like" pattern (170/200), analogous results were found for the evaluated parameters. Among the 20 capillaroscopic images from patients with primary RP, the estimates for the absence of giant capillaries and avascular areas were equal in 100% (P > 0.05). Comparing the qualitative assessment of the two investigators, a statistically significant difference between estimates of the two investigators was found for the presence of dilated capillaries (P < 0.05), while for giant capillaries, avascular areas and haemorrhages the difference was not statistically significant (P > 0.05). The results of the study have shown that qualitative assessment of capillaroscopic parameters in patients with rheumatic diseases is an adequate method for the everyday rheumatologic practice, especially in cases with primary RP for exclusion presence of microangiopathy. No significant difference between qualitative and quantitative methods of assessment was found for the detection of avascular areas. However, the quantitative analysis is more precise especially for the detection of capillary dilation. A good reproducibility of the qualitative evaluation, performed by two different investigators was also found.

Fatigue is a common symptom in a large number of medical and psychological disorders, including many rheumatologic illnesses. A frequent question for health care providers is related to whether reported fatigue is "in the mind" or "in the body"-that is, central or peripheral. If fatigue occurs at rest without any exertion, this suggests psychological or central origins. If patients relate their fatigue mostly to physical activities, including exercise, their symptoms can be considered peripheral. However, most syndromes of fatigue seem to depend on both peripheral and central mechanisms. Sometimes, muscle biopsy with histochemistry may be necessary for the appropriate tissue diagnosis, whereas serological tests generally provide little reliable information about the origin of muscle fatigue. Muscle function and peripheral fatigue can be quantified by contractile force and action potential measurements, whereas validated questionnaires are frequently used for assessment of mental fatigue. Fatigue is a hallmark of many rheumatologic conditions, including fibromyalgia, myalgic encephalitis/chronic fatigue syndrome, rheumatoid arthritis, systemic lupus, Sjogren's syndrome, and ankylosing spondylitis. Whereas many studies have focused on disease activity as a correlate to these patients' fatigue, it has become apparent that other factors, including negative affect and pain, are some of the most powerful predictors for fatigue. Conversely, sleep problems, including insomnia, seem to be less important for fatigue. There are several effective treatment strategies available for fatigued patients with rheumatologic disorders, including pharmacological and nonpharmacological therapies.

Rheumatic pain and, in particular, rheumatoid arthritis, osteoarthritis and fibromyalgia, are common and debilitating chronic pain syndromes. Recently, human functional neuroimaging, for example EEG, fMRI, and PET has begun to reveal some of the crucial central nervous system mechanisms underlying these diseases. The purpose of this review is to summarise current knowledge on the brain mechanisms of rheumatic pain revealed by functional neuroimaging techniques. The evidence suggests that two mechanisms may be largely responsible for the clinical pain associated with these rheumatic diseases: abnormalities in the medial pain system and/or central nervous system sensitisation and inhibition. If we can understand how functioning of the central nociceptive system becomes altered, even in the absence of peripheral nociceptive input, by using functional neuroimaging techniques, in the future we may be able to develop improved, more effective treatments for patients with chronic rheumatic pain.

Advanced imaging techniques are promising tools to assist in the early diagnosis and monitoring of therapy in various rheumatic diseases. As there is now increasing emphasis on diagnosing inflammatory rheumatic disease in the pre-clinical stages, so that treatment may be instituted early and ideally prevent irreversible tissue damage, highly sensitive techniques are needed to detect subclinical inflammation. Moreover, there is an increasing need to develop individualised treatment protocols at reasonable cost and with optimal therapeutic effect. Tools are required that can image the therapeutic target and sensitively trace changes in disease activity. Nuclear imaging techniques have the potential to fulfil these clinical needs. Positron emission tomography is emerging as an important modality as it provides highly sensitive, quantitative imaging at a molecular level, to reveal the important pathophysiological processes underlying inflammation. This chapter provides an overview of currently available nuclear imaging techniques, including recent technical developments, and discusses their role in the diagnosis and monitoring of rheumatic disease., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Objectives: To outline rationale and potential strategies for rheumatology experts to be able to develop disease-specific Core Sets under the framework of the International Classification of Functioning, Disability and Health (ICF). ICF is a universal framework introduced by the World Health Organization (WHO) to describe and quantify the impact and burden on functioning of health conditions associated with impairment/disability., Methods: A combined effort of the EULAR Scleroderma Clinical Trial and Research and the ICF Research Branch was initiated to develop an ICF language for scleroderma. From our Medline literature review, using the abbreviation and spelled out version of ICF, we assembled approaches and methodological reasoning for steps of core set development., Results: The ICF can be used for patient care and policy-making, as well as the provision of resources, services and funding. The ICF is used on institutional, regional, national and global levels. Several diseases now have ICF Core Sets. Patients with complex rheumatologic diseases will benefit from a disease-specific ICF Core Set and should be included in all stages of development. ICF Core Set development for rheumatic diseases can be conducted from a number of feasible strategies., Conclusion: This overview should help to clarify useful processes leading to development of an ICF Core Set, and also provide a platform for expert groups considering such an endeavour.

We have previously confirmed a paradoxical mineralizing enthesopathy as a hallmark of X-linked hypophosphatemia. X-linked hypophosphatemia is the most common of the phosphate-wasting disorders mediated by elevated fibroblast growth factor 23 (FGF23) and occurs as a consequence of inactivating mutations of the PHEX gene product. Despite childhood management of the disease, these complications of tendon and ligament insertion sites account for a great deal of the disease's morbidity into adulthood. It is unclear whether the enthesopathy occurs in other forms of renal phosphate-wasting disorders attributable to high FGF23 levels. Here we describe two patients with autosomal recessive hypophosphatemic rickets due to the Met1Val mutation in dentin matrix acidic phosphoprotein 1 (DMP1). In addition to the biochemical and skeletal features of long-standing rickets with elevated FGF23 levels, these individuals exhibited severe, debilitating, generalized mineralized enthesopathy. These data suggest that enthesophytes are a feature common to FGF23-mediated phosphate-wasting disorders. To address this possibility, we examined a murine model of FGF23 overexpression using a transgene encoding the secreted form of human FGF23 (R176Q) cDNA (FGF23-TG mice). We report that FGF23-TG mice display a similar mineralizing enthesopathy of the Achilles and plantar facial insertions. In addition, we examined the impact of standard therapy for phosphate-wasting disorders on enthesophyte progression. We report that fibrochondrocyte hyperplasia persisted in Hyp mice treated with oral phosphate and calcitriol. In addition, treatment had the untoward effect of further exacerbating the mineralization of fibrochondrocytes that define the bone spur of the Achilles insertion. These studies support the need for newer interventions targeted at limiting the actions of FGF23 and minimizing both the toxicities and potential morbidities associated with standard therapy.

Rheumatic pathologies in children include inflammatory articular diseases, or arthritis, and non-inflammatory articular diseases: metabolic, bone diseases, etc. In particular, non-infectious inflammatory rheumatisms which include mainly juvenile idiopathic arthritis and collagen diseases, require specialised treatment.

Elucidating the molecular pathways active in pathologic tissues has important implications for defining disease subsets, selecting therapy, and monitoring disease activity. The development of therapeutics directed at IFN-α or IFN-γ makes the discovery of probes that report precisely on the activity of different IFN pathways a high priority. We show that, although type I and II IFNs induce the expression of a largely overlapping group of molecules, precise probes of IFN-γ activity can be defined. Used in combination, these probes show prominent IFN-γ effects in Sjögren syndrome (SS) tissues. In contrast, dermatomyositis muscle shows a dominant type I IFN pattern. Interestingly, heterogeneity of IFN signatures exists in patients with SS, with some patients demonstrating a predominant type I pattern. The biochemical patterns largely distinguish the target tissues in patients with SS from those with dermatomyositis and provide a relative weighting of the effects of distinct IFN pathways in specific biopsies. In SS, type I and II IFN effects are localized to the same epithelial cells, surrounded by inflammatory cells expressing IFN-γ-induced proteins, suggesting reinforcing interactions. Precise probes of the different IFN pathways active in tissues of complex rheumatic diseases will be critical to classify disease, elucidate pathogenesis, and select therapy.