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Autoimmune diseases (AIDs) share similar serological, clinical, and radiological findings, but, behind these common features, there are different pathogenic mechanisms, immune cells dysfunctions, and targeted organs. In this context, multiple lines of evidence suggest the application of precision medicine principles to AIDs to reduce the treatment failure. Precision medicine refers to the tailoring of therapeutic strategies to the individual characteristics of each patient, thus it could be a new approach for management of AIDS which considers individual variability in genes, environmental exposure, and lifestyle. Precision medicine would also assist physicians in choosing the right treatment, the best timing of administration, consequently trying to maximize drug efficacy, and, possibly, reducing adverse events. In this work, the growing body of evidence is summarized regarding the predictive factors for drug response in patients with AIDs, applying the precision medicine principles to provide high-quality evidence for therapeutic opportunities in improving the management of these patients., (Copyright © 2020. Published by Elsevier B.V.)

Spondyloarthritis (SpA) are a heterogeneous group of inflammatory chronic diseases characterized by sharing common pathogenic, clinical and radiologic features. The aim of this review is to support clinicians in understanding and managing this complex disease, from pathogenesis to therapeutic targets, through a systematic review of the current literature in accordance with PRISMA guidelines and checklist. HLA-B27 has been found to be associated with axial involvement either in SA and in PsA patients: it might be involved through presentation of an "arthritogenic peptide" to autoreactive CD8+ T cells or might accumulate in misfolded form and induce production pro-inflammatory cytokines by binding to several innate immune receptors. This genetic background in combination with mechanical stress leads to the activation of both innate and acquired immune responses as well as a possible role of autoimmunity in SpA pathogenesis. The release of IL-23 and IL-17 is relevant for their systemic and local effect on bone, inducing the activation of osteoclasts. Thus, the regulatory role of IL-17 on fibroblasts, osteoblasts and chondrocytes has an impact in both synovial inflammation and joint destruction. Innovative therapies targeting IL-12/23 and IL-17 and the use of small targeted synthetic molecules, as JAK-inhibitors, proved to be effective in SpA patients representing an alternative strategy to TNF-inhibitors., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objective: To evaluate prevalence and clinical features of immune-related adverse events (irAEs) to immune checkpoint inhibitors (ICIs) in accordance with the gender of treated cancer patients., Methods: A systematic review of the medical literature was conducted by searching all available clinical data up to December 2019 in several databases using a combination of MESH terms related to immune checkpoint inhibitors, autoimmunity, and gender. Analyzed data were related to all FDA approved ICIs and respective indications in cancer., Results: According to data from the literature, male display a slightly lower frequencies of ICIs-related endocrinopathies compared with females, specifically thyroid dysfunction. On the contrary, ICIs-hypophysitis has been reported at higher rates among males compared with females. ICI-induced Sicca/Sjogren's syndrome showed a more frequent occurrence in men than the idiopathic primary form. No differences in gender distribution seem to arise in hematologic and gastrointestinal-irAEs. Interestingly, the gender distribution of neurologic and vascular ICIs-irAEs appears male-dominant., Conclusions: The present systematic review highlights for the first time that the distribution of patients experiencing irAEs associated with ICIs changes among the genders according to the specific drug used, the frequency of the cancer and of the autoimmune conditions in the general population., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Rheumatoid arthritis (RA) and autoimmune thyroid disease (AITD) can occur in the same patient in the autoimmune polyglandular syndrome 2. The association of the two conditions has been recognized long-time ago and the prevalence of AITD in patients with RA and vice versa is well assessed. Geographical variation of AITD and related autoantibodies in RA patients is partly due to ethnic and environmental differences of the studied populations. The impacts of thyroid disorders on RA outcome and vice versa are still controversy. In both AITD and RA genetic susceptibility and environmental factors play a synergic role in the development of the diseases. In this review we aimed at investigating the association of AITD and thyroid autoantibodies with RA, the common pathogenic pathways, the correlation with RA disease activity, and influence of the treatment., Competing Interests: Declaration of Competing interest The authors declare they have no competing interests., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Introduction: Spondyloarthrits (SpA) share clinical, genetic and immunological features with Inflammatory Bowel Diseases (IBD), and enteropathic SpA (eSpA) represent the clinical evidence of the association between gut and joint diseases. This cross-sectional study aimed to report data of eSpA patients collected from the first Italian database., Patients and Methods: A specific web-based interface has been created to insert and collect the main clinical, serologic and imaging data from patients with eSpA, as well as disease activity, comorbidities and treatment, in a real-life scenario., Results: Data were collected in 14 Italian centers (7 rheumatology and 7 gastroenterology units). A total of 347 eSpA patients were enrolled in the study. Type 1 peripheral eSpA was the most frequent form. Crohn' Disease (CD) was the most represented IBD. CD activity was similar among eSpA, whereas UC activity was slightly higher in the axial and mixed form than in the peripheral eSpA. The disease was active in less than half of axial eSpA patients and in only 18% of patients with peripheral eSpA. Furthermore, most of the patients had an inactive IBD. Nineteen percent of the total eSpA patients were free of therapy at the time of the enrollment and 61% of the patients were receiving biotechnological agents., Conclusions: The multidisciplinary management of eSpA patients, favored by this ad hoc created web-based platform, allowed to obtain data from the largest eSpA cohort. The information coming of this database might advance knowledge of eSpA and improve their standard of care., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Rheumatoid Arthritis (RA) is a chronic inflammatory disease characterized by a heterogeneous clinical response to the different treatments. Some patients are difficult to treat and do not reach the treatment targets as clinical remission or low disease activity. Known negative prognostic factors, such as the presence of auto-antiantibodies and joint erosion, the presence of a genetic profile, comorbidities and extra-articular manifestations, pregnancy or a pregnancy wish may concur to the treatment failure. In this review we aimed at identify difficult to treat RA patients and define the optimal therapeutic and environmental targets. Genetic markers of severity such as HLA-DRB1, TRAF1, PSORS1C1 and microRNA 146a are differently associated with joint damage; other gene polymorphisms seem to be associated with response to biologic disease modifying anti-rheumatic drugs (bDMARDs). The presence of comorbidities and/or extra-articular manifestations may influence the therapeutic choice; overweight and obese patients are less responsive to TNF inhibitors. In this context the patient profiling can improve the clinical outcome. Targeting different pathways, molecules, and cells involved in the pathogenesis of RA may in part justify the lack response of some patients. An overview of the future therapeutic targets, including bDMARDs (inhibitors of IL-6, GM-CSF, matrix metalloproteinases, chemokines) and targeted synthetic DMARDs (filgotinib, ABT-494, pefacitinib, decernotinib), and environmental targets is addressed. Environmental factors, such as diet and cigarette smoke, may influence susceptibility to autoimmune diseases and interfere with inflammatory pathways. Mediterranean diet, low salt intake, cocoa, curcumin, and physical activity seem to show beneficial effects, however studies of dose finding, safety and efficacy in RA need to be performed., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Psoriatic arthritis (PsA) is a chronic inflammatory arthritis that may be present in near 30% of patients affected by psoriasis (PsO), clinically characterized by inflammation of periarticular (e.g., enthesis) and articular structures. Recently, an autoimmune footprint of PsA pathogenesis has been demonstrated with the presence of autoantigens and related autoantibodies in PsA patients' sera. In this context, histological features of PsA synovitis supports the relevance of an autoimmune pathogenesis of the disease. Since there is no currently validated test for PsA, the analysis of PsA synovial tissue revealed pathognomonic characteristics of PsA that may support the clinician in the clinical practice. PsA synovitis is characterized by a sublining infiltrate with T and B cells, vascular proliferation and a relative thin lining layer of proliferating intimal synoviocytes. PsA synovial histopathology shows that ectopic lymphoid-neogenesis with an increase of IL-23 expression. These new pathogenetics features and the systemic nature of the disease raised the concept of a Systemic Psoriatic Disease (SysPsD), characterized by multiple extra-cutaneous and -articular manifestations, highlightening the great heterogeneity of this condition. SyPsD represents a heterogeneous chronic inflammatory condition with a wide spectrum of phenotypical manifestations. The purpose of this review is to describe the new pathogenetic mechanisms and the different clinical pictures of SysPsD, with the ultimate goal of improving the knowledge of this heterogeneous chronic inflammatory condition., (Copyright © 2019. Published by Elsevier B.V.)

Systemic Lupus Erythematosus (SLE) is a connective tissue disease that involves multiple organs. Ocular structures and visual pathways can be affected in SLE because of disease-related eye involvement or drug toxicity. All the part of the eye may be interested with an external, anterior involvement, responsible of the dry eye disease, or posterior (retina) and neuro-ophtalmic manifestations. Retinopathy in SLE is suggestive of high disease activity being a marker of poor visual outcome and prognosis for survival. The early diagnosis is thus the key to a better management and successful treatment. Antimalarial drugs are the cornerstone of SLE treatment and recently the American Academy of Ophthalmology updated the recommendations for hydroxychloroquine retinal toxicity screening which includes the standard automated visual fields and the spectral domain optical coherent tomography. More recently new imaging techniques have been investigated to assess retinal function and reveal subclinical eye involvement. In this review we focalize on the evidence of eye manifestations in SLE, the eye drug toxicity related to antimalarial agents and steroids, and the methods employed for the eye screening. Moreover, the future perspectives on new techniques, such as the optical coherence tomography angiography, are dissected giving new insights on evaluation of microvasculature of the retina and choroid in SLE., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Pregnancy requires a special management in women with inflammatory rheumatic diseases (RDs), with the aim of controlling maternal disease activity and avoiding fetal complications. Despite the heterogeneous course of RDs during pregnancy, their impact on pregnancy largely relates to the extent of active inflammation at the time of conception. Therefore, accurate evaluation of disease activity is crucial for the best management of pregnant patients. Nevertheless, there are limitations in using conventional measures of disease activity in pregnancy, as some items included in these instruments can be biased by symptoms or by physiological changes related to pregnancy and the pregnancy itself may influence laboratory parameters used to assess disease activity. This article aims to summarize the current literature about the available instruments to measure disease activity during pregnancy in RDs. Systemic lupus erythematosus is the only disease with instruments that have been modified to account for several adaptations which might interfere with the attribution of signs or symptoms to disease activity during pregnancy. No modified-pregnancy indices exist for women affected by other RDs, but standard indices have been applied to pregnant patients. The current body of knowledge shows that the physiologic changes that occur during pregnancy need to be either adapted from existing instruments or developed to improve the management of pregnant women with RDs. Standardized instruments to assess disease activity during pregnancy would be helpful not only for clinical practice but also for research purposes., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Psoriatic arthritis (PsA) is a chronic inflammatory joint disease, seen in combination with psoriasis. Both genetic and environmental factors are responsible for the development of PsA, however little is known about the different weight of these two distinctive components in the pathogenesis of the disease. Genomic variability in PsA is associated with the disease and/or some peculiar clinical phenotypes. Candidate genes involved are crucial in inflammation, immune system, and epithelial permeability. Moreover, the genesis and regulation of inflammation are influenced by the composition of the human intestinal microbiome that is able to modulate both mucosal and systemic immune system. It is possible that pro-inflammatory responses initiated in gut mucosa could contribute to the induction and progression of autoimmune conditions. Given such premises, the aim of this review is to summarize immune-mediated response and specific bacterial changes in the composition of fecal microbiota in PsA patients and to analyze the relationships between bacterial changes, immune system, and host genetic background., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Rheumatoid arthritis (RA) is a systemic chronic inflammatory disease characterized by extensive synovitis resulting in erosions of articular cartilage and marginal bone with joint destruction. The lack of immunological tolerance in RA represents the first step toward the development of autoimmunity. Susceptible individuals, under the influence of environmental factors, such as tobacco smoke, and silica exposure, develop autoimmune phenomena that result in the presence of autoantibodies. HLA and non-HLA haplotypes play a major role in determining the development of specific autoantibodies differentiating anti-citrullinated antibodies (ACPA)-positive and negative RA patients. Rheumatoid factor (RF) and ACPA are the serological markers for RA, and during the preclinical immunological phase, autoantibody titers increase with a progressive spread of ACPA antigens repertoire. The presence of ACPA represents an independent risk factor for developing RA in patients with undifferentiated arthritis or arthralgia. Moreover, anti-CarP antibodies have been identified in patients with RA as well as in individuals before the onset of clinical symptoms of RA. Several autoantibodies mainly targeting post-translational modified proteins have been investigated as possible biomarkers to improve the early diagnosis, prognosis and response to therapy in RA patients. Psoriatic arthritis (PsA) is distinguished from RA by infrequent positivity for RF and ACPA, together with other distinctive clinical features. Actually, specific autoantibodies have not been described. Recently, anti-CarP antibodies have been reported in sera from PsA patients with active disease. Further investigations on autoantibodies showing high specificity and sensibility as well as relevant correlation with disease severity, progression, and response to therapy are awaited in inflammatory arthritides., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Spondyloarthritis (SpA) and inflammatory bowel disease (IBD) are chronic autoinflammatory diseases that partially share the genetic predisposition and the unchecked inflammatory response linking the gut to the joints. The coexistence of both conditions in patients and the increased cross-risk ratios between SpA and IBD strongly suggest a shared pathophysiology. The prevalence of Enteropathic-related Spondyloarthritis (ESpA) in IBD patients shows a wide variation and may be underestimated. It is well accepted that the management of joint pain requires rheumatological expertise in conjunction with gastroenterologist assessment. In this view, we aimed at assessing, in a prospective study performed in a combined Gastro-Intestinal and Rheumatologic "GI-Rhe" clinic: (1) the prevalence of ESpA and other rheumatologic diseases in IBD patients with joint pain; (2) the features of the ESpA population; and (3) the diagnostic delay and the potential impact of the combined assessment. From November 2012 to December 2014, IBD patients with joint pain referring to a dedicated rheumatologist by the IBD-dedicated gastroenterologist were enrolled. Clinical and biochemical evaluations, joint involvement and disease activity assessment, diagnostic delay, and treatment were recorded. IBD patients (n=269) with joint pain were jointly assessed in the "GI-Rhe" Unit. A diagnosis of ESpA was made in 50.5% of IBD patients with joint pain. ESpA patients showed a peripheral involvement in 53% of cases, axial in 20.6% and peripheral and axial in 26.4% of cases. ESpA patients had a higher prevalence of other autoimmune extra-intestinal manifestations and received more anti-TNF treatment compared with IBD patients. A mean diagnostic delay of 5.2 years was revealed in ESpA patients. Patients with joint disease onset in the 2002-2012 decade had reduced diagnostic delay compared with those with onset in the 1980-1990 and 1991-2001 decades. Diagnostic delay was further reduced for patients with joint onset in the last two years in conjunction with the establishment of the GI-Rhe clinic. Multidisciplinary approach improved management of rheumatic disorders in IBD patients allowing a more comprehensive care., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Evidence from the literature suggests that autoimmune processes may drive features of psoriatic arthritis (PsA). Such hypothesis is supported by the evidence that class I major histocompatibility complex (MHC) genes are associated with susceptibility to develop PsA and auto-reactive cells, such as CD8 T cells, T helper (h) 17 and plasma cells, have been demonstrated in PsA. However, no autoantigens have ever been demonstrated in PsA. The presence of a new autoantibody system, anti-carbamylated protein (anti-CarP) antibodies, has been identified in rheumatoid arthritis (RA) patients. These autoantibodies have been associated with a worse disease progression independent of anti-citrulline antibodies (ACPA). In PsA, anti-CarP antibodies have not been evaluated yet. We aimed at analyzing, for the first time, the anti-CarP antibodies in sera of patients with active PsA who were negative for ACPA in order to explore both their presence and their relationship with disease activity. A total of 70 individuals, 30 patients with diagnosis of PsA (according to CASPAR criteria) and 40 healthy controls (HC) were enrolled. We found significantly increased levels of anti-CarP antibodies in PsA patients compared with HC (P<0.0001). Our findings indicate that anti-CarP antibodies are detectable with high specificity and sensibility in PsA patients suggesting an autoimmune background of PsA. Anti-CarP antibodies can be useful in improving the diagnosis of PsA and are correlated with disease activity., (Copyright © 2015. Published by Elsevier B.V.)

Hereditary angioedema (HAE) is an autosomal dominant disease resulting from the deficiency of C1 inhibitor (C1-INH), a glycosylated serine protease inhibitor that plays a regulatory role in the complement system (CS), the contact system and the intrinsic coagulation cascade. HAE disease severity is highly variable and may be influenced by genetic polymorphisms as well as by other factors, such as gender hormone-mediated effects. In HAE, the potential inadequate clearance of immune-complexes (IC) in the presence of reduced levels of CS components and in turn an excess of IC in the tissues results in inflammatory damage and release of autoantigens that may trigger an autoimmune response. Occasional reports link HAE with autoimmune conditions and only few studies have been conducted on large patient populations with controversial results. Although several immunoregulatory disorders have been documented, the prevalence of defined autoimmune diseases in patients with HAE remains debated. The occurrence of autoimmune conditions in HAE patients may worsen the disease severity enhancing the complexity of the comprehensive care., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Psoriatic Arthritis (PsA) is a chronic inflammatory arthropathy associated with psoriasis. Psoriasis (PsO) is a chronic, inflammatory skin disease, characterized by hyperproliferation and aberrant differentiation of keratinocytes. PsA and PsO can be considered as a unique disease and are immune-mediated diseases and both innate and adaptive immunity play a role in their pathogenesis. Initially, PsO and PsA were thought to be Th1-mediated diseases, however, in the last years, several studies have shown the role of interleukin 17 (IL-17) and Th17 cells in the pathogenesis of PsA and PsO. Th17 cells have been detected in dermal infiltrates of psoriatic lesions as well as in synovial fluid. Interleukin (IL)-23, produced by antigen presenting cells (APC), especially by dendritic cells (DC), is the key regulator cytokine for Th17 and IL-17 production. In this review we discuss the role of IL-17 and IL-23 in the pathogenesis of PsO and PsA and their role as therapeutic targets for PsO and PsA treatment., (© 2013 Elsevier B.V. All rights reserved.)

In this review we report the recent progresses, available in the literature, concerning the biology and the potential therapeutic role of both mesenchymal stem cells (MSCs) and hematopoietic stem cells in autoimmune diseases. Mesenchymal stem cells (MSCs) are responsible for the normal turnover and maintenance of adult mesenchymal tissues and their pleiotropic nature allows them to sense and respond to an event in the local environment, be it injury or inflammation. Recently, MSCs have been shown to have immune-modulatory properties and immunosuppressive capacities, acting on different immune cells both in vitro and in vivo, in addition to an immunologically privileged phenotype. Moreover, several works suggest that MSCs are defective in autoimmune diseases. These aspects are now considered the most intriguing aspect of their biology, introducing the possibility that these cells might be used as effective therapy in autoimmune diseases. Autoimmune diseases represent a failure of normal immune regulatory processes as they are characterized by activation and expansion of immune cell subsets in response to non-pathogenic stimuli. As autoimmune diseases can be transferred, or alternatively, cured, by stem cell transplantation, a defect in the hemopoietic stem cell as a cause of autoimmune diseases may be postulated. The rationale for autologous hematopoietic stem cell transplantation (HSCT) in autoimmune diseases is the ablation of an aberrant or self-reactive immune system by chemotherapy and regeneration of a new and hopefully self-tolerant immune system from hematopoietic stem cells. In the past 15years, more than 1500 patients worldwide have received HSCT, mostly autologous, as treatment for a severe autoimmune disease and the majority were affected by multiple sclerosis, systemic sclerosis, systemic lupus erythematosus, rheumatoid arthritis, juvenile idiopathic arthritis and idiopathic cytopenic purpura., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Psoriatic arthritis (PsA) is a chronic inflammatory arthropathy associated with psoriasis. Pathogenesis is incompletely understood and pathophysiological role of synovium is just beginning to be elucidated. PsA could be considered an enthesal disease and this hypothesis is the link between mechanical stress (entheses) and immunologically active tissue (synovium). Histologically, PsA is characterized by lining layer hyperplasia, diffuse infiltrate of B, T, macrophages and dendritic cells associated with neutrophils' proliferation and angiogenesis. T cells are present, and oligoclonal T-cell expansions have been demonstrated in both skin and synovium. Histological findings are associated with monocyte-derived cytokines expression, as Myeloid-related protein (S100A8/A9). They play an important role in intracellular functions and cytoskeleton-membrane interactions. S100A8/A9 has a role in the propagation and perpetuation of the inflammatory process in patients with psoriasis and PsA, because of an activated monocyte/macrophage system that involve, distal to the skin, the "enthesal-complex." Complement system can be considered part of the acute phase response as demonstrated by higher plasma levels of C3 and C4 complement components in PsA patients compared with healthy subjects. These abnormal levels are then reverted by anti-TNF drugs. Evidences of efficacy of anti-TNF are expressed by reduction of vascularity and immune cells in synovial tissue. Therefore, innate response generates high concentrations of inflammatory cytokines which promote effector functions of a variety of tissue cells and sustain the characteristic chronicity of synovitis. The challenge will be the development of molecules affecting the balance between innate and adaptive immunity without affecting beneficial functions of the perfect concert of immunological process., (Crown Copyright © 2012. Published by Elsevier B.V. All rights reserved.)

Successful pregnancy is considered a Th1-Th2 cooperation phenomenon (Th, T-helper), with a predominantly Th2-type lymphocytes response, together with the emerging role of interleukin (IL)-12, IL-15 and IL-18 and of other unidentified soluble factors dependent on natural killer (NK) cells. In the pathogenesis of recurrent spontaneous abortion (RSA), immunological factors have been involved such as decidual cells, complement system, cytokines and genes of the hystocompatibility complex that can determine the success or the failure of a pregnancy. A deeper insight into apparently unexplained RSA shows increasing evidences supporting both alloimmune and autoimmune mechanisms, with autoantibodies playing a major role. The best-characterised pathogenic autoantibodies are anti-phospholipid antibodies, and also other autoantibodies, such as anti-Ro/SSA and anti-La/SSB, have been found to be associated with an increased rate of abortion, poor pregnancy outcome and several other obstetric manifestations. This intriguing mixture has been unveiled only in the last few years with the discovery of novel pathogenic mechanisms that can be targeted in the prevention and treatment of obstetrical complications occurring in the course of an autoimmune disease., (© 2012 Elsevier Ltd. All rights reserved.)

Natural killer (NK) cells are large, granular lymphocytes devoted to the defense against microbial agents and cancer cells, traditionally recognized as an important arm of the innate immunity, even if more recent data underpin a role also in the responses of acquired immunity. Several studies have led to ascertain that NK cells are involved in the pathogenesis of many immune-mediated diseases, where they may exert both protective and pathogenic roles. In particular, the CD56(bright) NK cell subset, showing immunoregulatory properties, has been found to accumulate in tissue sites of inflammation, such as the skin lesions in psoriatic patients and the synovial membrane in rheumatoid arthritis (RA) patients. In this latter disease, while data on the number of NK cells are still controversial among the different studies, more consensuses exist on the impaired activity of these cells. In another group of inflammatory arthritides, the spondyloarthropathies (SpA), the presence of peculiar allotypes of the killer cell immunoglobulin-like receptors (KIR) superfamily, coding for molecules expressed on NK cells, seems to modulate the susceptibility to this group of diseases, especially ankylosing spondylitis and psoriatic arthritis. Interestingly, in vitro studies showed that NK cells of patients with inflammatory arthropathies might produce pro-inflammatory Th1 cytokines; furthermore, they are involved in bone damage, interact and activate different cell types such as monocytes, dendritic cells and resident fibroblast-like synoviocites cells, thus creating and/or maintaining the inflammatory response. Certainly, these features encourage more research on the role of NK cells in the pathogenesis of inflammatory arthropathies, which could be essential to define potential new therapeutic strategies., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Anti-TNFα blockers have rapidly become a standard treatment for rheumatoid (RA) and psoriatic arthritis (PsA) because of their acceptable safety profile and efficacy. Clinical and radiological remission may now be a realistic outcome and constitutes the best achievable state. However, clinical practice guidelines and consensus statements on the criteria of introduction, duration and cessation of treatment are under constant revision. Evidence supports that the early use of biologic DMARDs would produce rapid and sustained suppression of inflammatory disease and preserve function and joint erosions. Proof of this concept, anti-TNFα agents would be effective in maintaining response after cessation of treatment. Conversely, when therapy with anti-TNFα is withdrawn, the disease rapidly returns. Remission may be defined as minimal or no clinically detectable disease activity in the presence of continuing drug treatment and a rapid control of disease activity may prevent irreversible damage and disability. The use of US-PD and MRI in the early detection of disease recurrence could become necessary to prevent the relapse and direct the clinician's choice concerning a re-treatment regimen. The use of biological treatment can be for a limited period, at a time when it has the greatest opportunity to make the difference., (Copyright © 2011 Elsevier B.V. All rights reserved.)

The complement system is an essential component of innate immunity and also plays an important role in modulating adaptive immunity. It comprises more than 30 plasma and membrane-bound proteins and can be activated through three pathways: the classical, the alternative and the lectin pathways. Its activation contributes to the pathogenesis of several autoimmune and inflammatory conditions. The evidence of complement activation in synovial fluid of Rheumatoid Arthritis (RA) patients is abundant, while few data exist in Psoriatic Arthritis (PsA) patients. Levels of complement proteins are generally depressed in the synovial fluid of patients with RA, reflecting consumption of complement. On the other hand, elevated levels of several complement cleavage products have been observed in synovial fluid. Involvement of complement in the pathogenesis of RA was also confirmed in animal models of arthritis: mice deficient for complement proteins are protected against the development of collagen-induced arthritis and administration of the anti-C5 monoclonal antibody prevents the onset of this arthritis. In the last decade anti-tumor necrosis factor agents have shown to be effective for the treatment of both RA and PsA and some studies suggest that the interaction between TNFα and complement system may contribute to the pathogenesis of these diseases. Reduction of the complement activation could be one of the mechanism by which TNFα-inhibitors exert their effectiveness in inflammatory arthritides. Because of these findings, complement could be an attractive therapeutic target both in RA and in PsA., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Angiogenesis is the formation of new blood vessels from existing vessels. During RA new blood vessels can maintain the chronic inflammatory state by transporting inflammatory cells to the site of inflammation and supplying nutrients and oxygen to the proliferating inflamed tissue. The increased endothelial surface area also creates an enormous capacity for the production of cytokines, adhesion molecules, and other inflammatory stimuli, simultaneously the propagation of new vessels in the synovial membrane allows the invasion of this tissue supporting the active infiltration of synovial membrane into cartilage and resulting in erosions and destruction of the cartilage. This angiogenic phenotype is promoted by several pro-angiogenic molecules, the most potent of which is vascular endothelial growth factor (VEGF). Although angiogenesis is recognized as a key event in the formation and maintenance the infiltration of synovial membrane during RA, it is unclear whether angiogenesis should be considered a specific feature of the disease or a common inflammation driven process. However the emergence of biological therapies, such as anti TNF blockade, has suggested that there are features of the inflammatory response that are not general but contextual to the specificity of the tissue where inflammation occurs, and point out the relevant role of tissue-resident stromal cells in determining the site at which inflammation occurs and the specific features of chronic inflammation such as that occurs in RA., (Copyright © 2011. Published by Elsevier B.V.)

Increasing attention in the physiopathology of inflammatory/immunomediated diseases has been focused on the role of reactive oxygen species (ROS), oxygen-based molecules possessing high chemical reactivity and produced by activated neutrophils during the inflammatory response. During chronic inflammation, when sustained production of ROS occurs, antioxidant defences can weaken, resulting in a situation termed oxidative stress. Moreover, antioxidant defence systems have been demonstrated to be constitutively lacking in patients affected with chronic degenerative diseases, especially inflammatory/immunomediated. Glutathione, a tripeptide, is the principal component of the antioxidant defence system in the living cells. Glutathione has been demonstrated to have diverse effects on the immune system, either stimulating or inhibiting the immunological response in order to control inflammation. The study of interactions between glutathione and the immune system has attracted many investigators. Altered glutathione concentrations may play an important role in many autoimmune pathological conditions prevalently elicited, detrimed and maintained by inflammatory/immune response mediated by oxidative stress reactions. The role of glutathione in autoimmunity will be reviewed herein.

Natural killer (NK) cells are part of the innate-immune system and respond rapidly to a variety of insults via cytokine secretion and cytolytic activity. Their main function is first line of innate immunity across viral, bacterial and parasitic infections. NK-cells are not solely killers but can also act as regulators of adaptive immunity. It is evident from literature that NK-cells are deeply involved in autoimmunity, but the question is how and why they act as a two edged weapon. Number of circulating NK-cells can be frequently altered depending on the disease taken into consideration. Cytokine milieu, the microenvironment in which they mature and other stimuli acting on different cell surface receptors may differently trigger NK-cells response and influence their role in autoimmune diseases. Functional differences between NK-cells at different anatomical sites, the adaptability of NK-cells effector responses and genetic factors may also explain differences in such responses. Thus, NK-cell alterations may be associated with increased autoimmunity and the modulation in the number of circulating NK-cells seems to be a primary event rather than an active inflammation/drug administration consequence during inflammatory/autoimmune processes, playing a fundamental role in the pathogenesis of a number of autoimmune diseases.