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Chronic rheumatological diseases are multifactorial conditions in which both the neuroendocrine hormone pathway, including cortisol, sex hormones and active vitamin D3 (calcitriol), all deriving from cholesterol, and the epigenetic modifications that they cause play an important role. In fact, epigenetics modulates the function of the DNA of immune cells, through three main mechanisms: DNA methylation, modifications to the histones that make up chromatin and production of non-coding RNAs (microRNA - miRNA). In this narrative review, the main data regarding the epigenetic modifications induced by cortisol, 17β-oestradiol, progesterone, testosterone and calcitriol on immune cells were collected, discussing how these can interfere in the predisposition and course of chronic rheumatological diseases (i.e. rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis). An ever-increasing number of miRNAs have been identified, which are produced by neuroendocrine hormones and can influence the inflammatory-fibrotic response at various levels. Concerning the involvements of the neuro-endocrine-immunology within the pathophysiology of rheumatic diseases, the epigenetic effects induced by steroid hormones must be taken into consideration to evaluate their impact on the progression of the single condition and even inside the single patient.

Background and Objectives : Vitamin D is a secosteroid hormone essential for calcium homeostasis and skeletal health, but established evidence highlights its significant roles also in muscle health and in the modulation of immune response. This review aims to explore the impact of impaired vitamin D status on outcomes of muscle function and involvement in inflammatory and autoimmune rheumatic diseases damaging the skeletal muscle efficiency both with direct immune-mediated mechanisms and indirect processes such as sarcopenia. Methods : A comprehensive literature search was conducted on PubMed and Medline using Medical Subject Headings (MeSH) terms: "vitamin D, muscle, rheumatic diseases." Additionally, conference abstracts from The European Alliance of Associations for Rheumatology (EULAR) and the American College of Rheumatology (ACR) (2020-2023) were reviewed, and reference lists of included papers were scanned. The review emphasizes the evidence published in the last five years, while also incorporating significant studies from earlier years, structured by the extent of evidence linking vitamin D to muscle health in the most commonly inflammatory and autoimmune rheumatic diseases encountered in clinical practice. Results : Observational studies indicate a high prevalence of vitamin D serum deficiency (mean serum concentrations < 10 ng/mL) or insufficiency (<30 ng/mL) in patients with idiopathic inflammatory myopathies (IIMs) and polymyalgia rheumatica, as well as other autoimmune connective tissue diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and systemic sclerosis (SSc). Of note, vitamin D insufficiency may be associated with reduced muscle strength (2 studies on RA, 2 in SLE and 1 in SSc), increased pain (1 study on SLE), fatigue (2 studies on SLE), and higher disease activity (3 studies on IIMs and 1 on SLE) although there is much heterogeneity in the quality of evidence and different associations for the different investigated diseases. Therefore, linked to the multilevel biological intervention exerted by vitamin D, several translational and clinical studies suggest that active metabolites of this secosteroid hormone, play a role both in reducing inflammation, but also in enhancing muscle regeneration, intra-cellular metabolism and mitochondrial function, although interventional studies are limited. Conclusions : Altered serum vitamin D status is commonly observed in inflammatory and autoimmune rheumatic diseases and seems to be associated with adverse muscle health outcomes. While maintaining adequate serum vitamin D concentrations may confer muscle-protective effects, further research is needed to confirm these findings and establish optimal supplementation strategies to obtain a safe and efficient serum threshold.

Inflammatory rheumatic diseases are different pathologic conditions associated with a deregulated immune response, codified along a spectrum of disorders, with autoinflammatory and autoimmune diseases as two-end phenotypes of this continuum. Despite pathogenic differences, inflammatory rheumatic diseases are commonly managed with a limited number of immunosuppressive drugs, sometimes with partial evidence or transferring physicians' knowledge in different patients. In addition, several randomized clinical trials, enrolling these patients, did not meet the primary pre-established outcomes and these findings could be linked to the underlying molecular diversities along the spectrum of inflammatory rheumatic disorders. In fact, the resulting patient heterogeneity may be driven by differences in underlying molecular pathology also resulting in variable responses to immunosuppressive drugs. Thus, the identification of different clinical subsets may possibly overcome the major obstacles that limit the development more effective therapeutic strategies for these patients with inflammatory rheumatic diseases. This clinical heterogeneity could require a diverse therapeutic management to improve patient outcomes and increase the frequency of clinical remission. Therefore, the importance of better patient stratification and characterization is increasingly pointed out according to the precision medicine principles, also suggesting a new approach for disease treatment. In fact, based on a better proposed patient profiling, clinicians could more appropriately balance the therapeutic management. On these bases, we synthetized and discussed the available literature about the patient profiling in regard to therapy in the context of inflammatory rheumatic diseases, mainly focusing on randomized clinical trials. We provided an overview of the importance of a better stratification and characterization of the clinical heterogeneity of patients with inflammatory rheumatic diseases identifying this point as crucial in improving the management of these patients., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest for this work., (Copyright © 2024. Published by Elsevier B.V.)

Objectives: To investigate pregnancy outcomes in women with autoimmune rheumatic diseases (ARD) in the Italian prospective cohort study P-RHEUM.it., Methods: Pregnant women with different ARD were enrolled for up to 20 gestational weeks in 29 Rheumatology Centres for 5 years (2018-2023). Maternal and infant information were collected in a web-based database., Results: We analysed 866 pregnancies in 851 patients (systemic lupus erythematosus was the most represented disease, 19.6%). Maternal disease flares were observed in 135 (15.6%) pregnancies. 53 (6.1%) pregnancies were induced by assisted reproduction techniques, 61 (7%) ended in miscarriage and 11 (1.3%) underwent elective termination. Obstetrical complications occurred in 261 (30.1%) pregnancies, including 2.3% pre-eclampsia. Two cases of congenital heart block were observed out of 157 pregnancies (1.3%) with anti-Ro/SSA. Regarding treatments, 244 (28.2%) pregnancies were treated with glucocorticoids, 388 (44.8%) with hydroxychloroquine, 85 (9.8%) with conventional synthetic disease-modifying anti-rheumatic drugs and 122 (14.1%) with biological disease-modifying anti-rheumatic drugs. Live births were 794 (91.7%), mostly at term (84.9%); four perinatal deaths (0.5%) occurred. Among 790 newborns, 31 (3.9%) were small-for-gestational-age and 169 (21.4%) had perinatal complications. Exclusive maternal breast feeding was received by 404 (46.7%) neonates. The Edinburgh Postnatal Depression Scale was compiled by 414 women (52.4%); 89 (21.5%) scored positive for emotional distress., Conclusions: Multiple factors including preconception counselling and treat-to-target with pregnancy-compatible medications may have contributed to mitigate disease-related risk factors, yielding limited disease flares, good pregnancy outcomes and frequency of complications which were similar to the Italian general obstetric population. Disease-specific issues need to be further addressed to plan preventative measures., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: All active scientists stand on the shoulders of giants and many other more anonymous scientists, and this is not different in our field of psycho-neuro-endocrine immunology in rheumatic diseases. Too often, the modern world of publishing forgets about the collective enterprise of scientists. Some journals advise the authors to present only literature from the last decade, and it has become a natural attitude of many scientists to present only the latest publications. In order to work against this general unempirical behavior, neuroimmunomodulation devotes the 30th anniversary issue to the history of medical science in psycho-neuro-endocrine immunology., Summary: Keywords were derived from the psycho-neuro-endocrine immunology research field very well known to the authors (R.H.S. has collected a list of keywords since 1994). We screened PubMed, the Cochran Library of Medicine, Embase, Scopus database, and the ORCID database to find relevant historical literature. The Snowballing procedure helped find related work. According to the historical appearance of discoveries in the field, the order of presentation follows the subsequent scheme: (1) the sensory nervous system, (2) the sympathetic nervous system, (3) the vagus nerve, (4) steroid hormones (glucocorticoids, androgens, progesterone, estrogens, and the vitamin D hormone), (5) afferent pathways involved in fatigue, anxiety, insomnia, and depression (includes pathophysiology), and (6) evolutionary medicine and energy regulation - an umbrella theory., Key Messages: A brief history on psycho-neuro-endocrine immunology cannot address all relevant aspects of the field. The authors are aware of this shortcoming. The reader must see this review as a viewpoint through the biased eyes of the authors. Nevertheless, the text gives an overview of the history in psycho-neuro-endocrine immunology of rheumatic diseases., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Objective: To systematically review the literature concerning temporomandibular disorders (TMDs) in immune-mediated rheumatic diseases (IMRDs) of the adult. The temporomandibular joint (TMJ) outcomes used in clinical studies, the prevalence of TMDs in IMRDs and the risk factors for their development were qualitatively synthetized., Methods: A literature search on PubMed Central, Embase and Cochrane Library databases was performed for studies including TMJ outcomes in IMRDs patients compared with healthy controls, other rheumatic diseases or in the assessed IMRDs patients after follow-up and treatment. Among the IMRDs of the adult, original articles investigating TMJ involvement in inflammatory polyarthritides and/or autoimmune connective tissue diseases were considered. The quality of the studies was scored using the Newcastle-Ottawa scale (NOS)., Results: Of the 3259 screened abstracts, 56 papers were included in the systematic review. Most of the papers (77%) investigated TMDs in rheumatoid arthritis (RA) with a prevalence of signs and symptoms varying from 8% to 70%. The risk factors for TMDs development in RA were female sex, younger age, anti-citrulline peptide autoantibodies (ACPA) positivity, higher disease activity, cervical spine involvement, cardiovascular and neuropsychiatric comorbidities. Ten papers (18%) evaluated TMDs in spondylarthritides (SpA) reporting a prevalence of symptoms and signs in 12%-80% of patients with higher TMDs prevalence in patients with radiographic spine involvement, skin psoriasis and HLADRB1×01 positivity. Among autoimmune connective tissue diseases (CTDs), systemic sclerosis (SSc) displayed the highest evidence of TMDs patient-reported outcomes (PROs) and clinical findings (20-93%), followed by systemic lupus erythematosus (SLE) in 18-85%, primary Sjogren's syndrome (24-54%) and idiopathic inflammatory myopathies (4-26%). In SSc and SLE, TMDs were more frequent in patients with higher disease activity and duration, correlating with the extent of skin fibrosis in SSc and with renal involvement in SLE., Conclusion: TMDs in IMRDs display a significant relevance in the rheumatological clinical practice even if often misdiagnosed. This burden is epidemiologically important in terms of PROs and clinical findings which correlate with disease activity in RA, SpA, SSc and SLE. The early recognition and multidisciplinary management of TMDs is warranted and should be aimed at hindering the TMJ structural damage maximizing the quality of life of patients., Competing Interests: Declaration of Competing Interest All Authors declare no conflict of interest concerning this manuscript., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objectives: To standardly assess and describe nailfold videocapillaroscopy (NVC) assessment in children and adolescents with juvenile rheumatic and musculoskeletal diseases (jRMD) vs healthy controls (HCs)., Material and Methods: In consecutive jRMD children and matched HCs from 13 centres worldwide, 16 NVC images per patient were acquired locally and read centrally per international consensus standard evaluation of the EULAR Study Group on Microcirculation in Rheumatic Diseases. A total of 95 patients with JIA, 22 with JDM, 20 with childhood-onset SLE (cSLE), 13 with juvenile SSc (jSSc), 21 with localized scleroderma (lSc), 18 with MCTD and 20 with primary RP (PRP) were included. NVC differences between juvenile subgroups and HCs were calculated through multivariable regression analysis., Results: A total of 6474 images were assessed from 413 subjects (mean age 12.1 years, 70.9% female). The quantitative NVC characteristics were significantly lower or higher in the following subgroups compared with HCs: for density: lower in jSSc, JDM, MCTD, cSLE and lSc; for dilations: higher in jSSc, MCTD and JDM; for abnormal shapes: higher in JDM and MCTD; for haemorrhages: higher in jSSc, MCTD, JDM and cSLE. The qualitative NVC assessment of JIA, lSc and PRP did not differ from HCs, whereas the cSLE and jSSc, MCTD, JDM and cSLE subgroups showed more non-specific and scleroderma patterns, respectively., Conclusions: This analysis resulted from a pioneering registry of NVC in jRMD. The NVC assessment in jRMD differed significantly from HCs. Future prospective follow-up will further elucidate the role of NVC in jRMD., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Autoimmune rheumatic diseases (ARD) can affect women and men during fertile age, therefore reproductive health is a priority issue in rheumatology. Many topics need to be considered during preconception counselling: fertility, the impact of disease-related factors on pregnancy outcomes, the influence of pregnancy on disease activity, the compatibility of medications with pregnancy and breastfeeding. Risk stratification and individualized treatment approach elaborated by a multidisciplinary team minimize the risk of adverse pregnancy outcomes (APO). Research has been focused on identifying biomarkers that can be predictive of APO. Specifically, preeclampsia and hypertensive disorders of pregnancy tend to develop more frequently in women with ARD. Placental insufficiency can lead to intrauterine growth restriction and small-for-gestational age newborns. Such APO have been shown to be associated with maternal disease activity in different ARD. Therefore, a key message to be addressed to the woman wishing for a pregnancy and to her family is that treatment with compatible drugs is the best way to ensure maternal and fetal wellbeing. An increasing number of medications have entered the management of ARD, but data about their use in pregnancy and lactation are scarce. More information is needed for most biologic drugs and their biosimilars, and for the so-called small molecules, while there is sufficient evidence to recommend the use of TNF inhibitors if needed for keeping maternal disease under control. Other issues related to the reproductive journey have emerged as "unmet needs", such as sexual dysfunction, contraception, medically assisted reproduction techniques, long-term outcome of children, and they will be addressed in this review paper. Collaborative research has been instrumental to reach current knowledge and the future will bring novel insights thanks to pregnancy registries and prospective studies that have been established in several Countries and to their joint efforts in merging data., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Nailfold capillaroscopy is a safe and well-established method for the assessment of structural alterations of the microcirculation. It is a crucial tool in the investigation and monitoring of patients presenting with Raynaud's phenomenon. Detection of the characteristic "scleroderma pattern" on capillaroscopy may indicate an underlying rheumatic disease, particularly systemic sclerosis (SSc). Herein, we highlight the practical aspects of videocapillaroscopy, including image acquisition and analysis, with mention of dermoscopy. Special emphasis is placed on standardized use of terminology to describe capillary characteristics. Systematic evaluation of images in discerning the normal from the abnormal using the validated European Alliance of Associations for Rheumatology (EULAR) Study Group consensus reporting framework is paramount. In addition to the relevance of capillaroscopy in the (very) early diagnosis of SSc, its emerging predictive value (especially capillary loss) for new organ involvement and disease progression is underscored. We further provide capillaroscopic findings in selected other rheumatic diseases., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

This cross-sectional online study was designed by the study group on Capillaroscopy and Microcirculation in Rheumatic Diseases (CAP) of the Italian Society of Rheumatology (SIR) to provide an overview of the management of nailfold capillaroscopy in Italian rheumatology centers. Therefore, SIR distributed the survey to its members in July 2021, and each center's physician with the most expertise in capillaroscopy completed the questionnaire. The survey was completed by 102 centers, with at least one representative from each Italian region. Ninety-three centers perform capillaroscopy, and 52 (56) conduct more than 200 investigations annually. Seventy-eight (84%) of respondents have more than five years of experience with the technique, and 75 centers (80.6%) have received certification from specific national or international training courses. In 85 centers, a videocapillaroscope with 200x magnification is employed (91.4%). The average waiting period for the examination is 2.4 months, and less than 3 months in 64 of the locations (68.8%). The study demonstrates that capillaroscopy is an integral part of both the diagnostic phase of Raynaud's phenomenon and the monitoring of autoimmune connective tissue diseases (CTDs). However, the reporting methods and timing of patient followup are heterogeneous.

Objective: We conducted a systematic review, on behalf of the EULAR Study Group on Microcirculation in Rheumatic Diseases (EULAR SG MC/RD), to investigate the value of nailfold videocapillaroscopy (NVC) in idiopathic inflammatory myopathies (IIM)., Methods: Three electronic databases were systematically searched to find all relevant manuscripts reporting NVC outcomes in IIM patients. Articles were assessed based on study design, population, NVC methodology and description of NVC results. To allow comparison between the articles, all NVC results were interpreted according to standardised capillaroscopic terminology, as previously consented by the EULAR SG MC/RD and the Scleroderma Clinical Trials Consortium (SCTC) Group on Capillaroscopy., Results: Of the 653 identified records; five were retained after critical appraisal on title, abstract and manuscript level. A marked difference in NVC was observed between (juvenile) dermatomyositis [(j)DM] versus polymyositis, healthy controls and systemic sclerosis patients. In addition, reduced capillary density and scleroderma pattern seem to be associated with active disease in (j)DM, while immunosuppressive treatment appears to reduce NVC abnormalities., Conclusion: This is the first systematic review investigating NVC in IIM, interpreting the results according to an international consented standardised manner, as proposed by the EULAR SG MC/RD and SCTC Group on Capillaroscopy. We can conclude that NVC presents a promising asset in the diagnosis of (j)DM. Moreover, NVC could be a biomarker for organ involvement and follow-up. Large multicentre prospective standardised studies are further needed to definitely describe associations with clinical and laboratory parameters in the different IIM subtypes., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: We aimed to investigate the clinical off-label use of mycophenolate mofetil (MMF), including its safety and efficacy in patients with rare and complex rheumatic connective tissue diseases (rCTDs)., Methods: A survey was distributed across experts from ERN-ReCONNET reference centres in order to assess the experience with MMF off-label use. Patient-level data of patients with rCTDs under treatment with MMF was also collected for analysis of safety and efficacy., Results: Twelve experts from eleven centres distributed throughout Europe (7 countries) answered the survey. The experience was concordant in that, despite of its off-label use, experts reported opting frequently for this therapeutic alternative with robust confidence on its efficacy and safety. The analysis of 108 patients with rCTDs under MMF revealed a good safety profile, as well as good clinical outcomes, especially for systemic lupus erythematosus and idiopathic inflammatory myopathies. The presence of interstitial lung disease was, as expected, associated with a worse clinical outcome despite use of MMF., Conclusions: MMF is widely used in reference centres for rCTDs. Its safety profile and efficacy seem to be recognised by experts and demonstrated with patient-level analysis. While selected rCTDs will likely remain an off-label indication for MMF, robust data seem to support this therapy as an appropriate alternative for safely and effectively treating many manifestations of rCTDs.

The concern about the offspring's health is one of the reasons for a reduced family size of women with rheumatic diseases (RD). Increased risk of autoimmune diseases (AD) and neurodevelopmental disorders (ND) has been reported in children born to patients with RD. Within a nationwide survey about reproductive issues of women with RD, we aimed at exploring the long-term outcome of their children. By surveying 398 patients who received their diagnosis of RD during childbearing age (before the age of 45), information about the offspring were obtained from 230 women who declared to have had children. A total of 148 (64.3%) patients were affected by connective tissue diseases (CTD) and 82 (35.7%) by chronic arthritis. Data on 299 children (156 males, 52.1%; mean age at the time of interview 17.1 ± 9.7 years) were collected. Twelve children (4.0%), who were born to patients with CTD in 75% of the cases, were affected by AD (8 cases of celiac disease). Eleven children had a certified diagnosis of ND (3.6%; 6 cases of learning disabilities); 9 of them were born to mothers with CTD (5 after maternal diagnosis). No association was found between ND and prenatal exposure to either maternal autoantibodies or anti-rheumatic drugs. Absolute numbers of offspring affected by AD and ND were low in a multicentre cohort of Italian women with RD. This information can be helpful for the counselling about reproductive issues, as the health outcomes of the offspring might not be an issue which discourage women with RD from having children., (© 2021. The Author(s).)

Morphological and functional analysis of the microcirculation are objective outcome measures that are recommended for use in the presence of clinical signs of altered peripheral blood flow (such as Raynaud phenomenon), which can occur in systemic sclerosis (SSc) and other autoimmune rheumatic diseases. Several advanced non-invasive tools are available for monitoring the microcirculation, including nailfold videocapillaroscopy, which is the best-studied and most commonly used method for distinguishing and quantifying microvascular morphological alterations in SSc. Nailfold videocapillaroscopy can also be used alongside laser Doppler techniques to assist in the early diagnosis and follow-up of patients with dermatomyositis or mixed connective tissue disease. Power Doppler ultrasonography, which has been used for many years to evaluate the vascularity of synovial tissue in rheumatoid arthritis, is another promising tool for the analysis of skin and nailbed capillary perfusion in other autoimmune rheumatic diseases. Other emerging methods include raster-scanning optoacoustic mesoscopy, which offers non-invasive high-resolution 3D visualization of capillaries and has been tested in psoriatic arthritis and SSc. The principle functions and operative characteristics of several non-invasive tools for analysing microvascular changes are outlined in this Review, and the clinical roles of validated or tested imaging methods are discussed for autoimmune rheumatic diseases., (© 2021. Springer Nature Limited.)

Background: Uveitis is one of the most frequent ophthalmologic manifestations in rheumatology. Uveal inflammation can underlie a systemic inflammatory rheumatic disease (SIRD) in approximately 30% of cases with a significant burden on the quality of life since it represents a cause of blindness in up to 20% of cases in Western countries., Methods: In this review, we provide a comprehensive overview of the pathophysiology of uveitis associated with SIRDs. According to our literature survey on the epidemiology of uveitis among SIRDs, spondyloarthritides, Behçet's disease and sarcoidosis get the major impact., Results: In Behçet's uveitis, the key players are highly polarized Th1 and Th17 lymphocytes, natural killer T cells and γδ T cells. All contribute to a great destructive inflammatory environment with the most serious visual damage resulting from the involvement of the posterior segment of the eye. In contrast, spondyloarthritides-related uveitis derives from a complex interaction between genetic background and extra-ocular inflammatory mediators originating from enthesitis, arthritis, psoriatic lesions and microbiome pro-inflammatory alterations. In such conditions, the immune infiltration of CD4+ T cells, Th17 and natural killer cells along with pro-inflammatory cytokines, TNF-α among all, leads to intraocular inflammation. Lastly, granuloma formation represents the primary hallmark lesion in sarcoid uveitis. This suggests a profound link between the innate system that mainly recruits activated macrophages and adaptive system involving by Th1, Th17 and Th17.1 cells., Conclusions: Awareness among rheumatologists of a potential severe ocular involvement generates new insights into targeted therapeutic approaches and personalized treatments for each patient., (© 2021 The Authors. European Journal of Clinical Investigation published by John Wiley & Sons Ltd on behalf of Stichting European Society for Clinical Investigation Journal Foundation.)

Pathological eye involvement represents a quite common finding in a broad spectrum of autoimmune rheumatic diseases (ARDs). Ocular signs, often occur as early manifestations in ARDs, ranging from symptoms related to the mild dry eye disease to sight-threatening pathologies, linked to the immune response against retinal and choroidal vessels. Retinovascular damage driven by markedly inflammatory reactivity need a prompt diagnosis and treatment. Immune-complexes formation, complement activation and antibody-mediated endothelial damage seem to play a key role, particularly, in microvascular damage and ocular symptoms, occurring in systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and Sjögren's syndrome (SS). Conversely, early alterations of retinal and choroidal vessels in the asymptomatic patient, often detectable coincidentally, might be indicators of widespread vascular injury in other connective tissue diseases. Particularly, endothelin-induced hypoperfusion and pathological peri-choroidal extracellular matrix deposition, might be responsible for the micro-architectural alterations and loss of capillaries detected in systemic sclerosis (SSc). Instead, interferon alpha-mediated microvascular rarefaction, combined with endothelial lesions caused by specific autoantibodies and immune-complexes, appear to play a significant role in retinal vasculopathy associated to inflammatory idiopathic myopathies (IIM). The immuno-pathophysiological mechanisms of ocular microcirculatory damage associated with the major ARDs will be discussed under the light of the most recent achievements., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Autoimmune rheumatic diseases (ARDs) are chronic conditions with a striking female predominance, frequently affecting women of childbearing age. Sex hormones and gender dimorphism of immune response are major determinants in the multifactorial pathogenesis of ARDs, with significant implications throughout reproductive life. Particularly, pregnancy represents a challenging condition in the context of autoimmunity, baring profound hormonal and immunologic changes, which are responsible for the bi-directional interaction between ARDs outcome and pregnancy course. In the latest years epigenetics has proven to be an important player in ARDs pathogenesis, finely modulating major immune functions and variably tuning the significant gender effects in autoimmunity. Additionally, epigenetics is a recognised influencer of the physiological dynamic modifications occurring during pregnancy. Still, there is currently little evidence on the pregnancy-related epigenetic modulation of immune response in ARDs patients. This review aims to overview the current knowledge of the role of epigenetics in the context of autoimmunity, as well as during physiologic and pathologic pregnancy, discussing under-regarded aspects in the interplay between ARDs and pregnancy pathology. The outline of a new ongoing European project will be presented., (Copyright © 2020. Published by Elsevier B.V.)

In autoimmune rheumatic diseases, oestrogens can stimulate certain immune responses (including effects on B cells and innate immunity), but can also have dose-related anti-inflammatory effects on T cells, macrophages and other immune cells. By contrast, androgens and progesterone have predominantly immunosuppressive and anti-inflammatory effects. Hormone replacement therapies and oral contraception (and also pregnancy) enhance or decrease the severity of autoimmune rheumatic diseases at a genetic or epigenetic level. Serum androgen concentrations are often low in men and in women with autoimmune rheumatic diseases, suggesting that androgen-like compounds might be a promising therapeutic approach. However, androgen-to-oestrogen conversion (known as intracrinology) is enhanced in inflamed tissues, such as those present in patients with autoimmune rheumatic diseases. In addition, it is becoming evident that the gut microbiota differs between the sexes (known as the microgenderome) and leads to sex-dependent genetic and epigenetic changes in gastrointestinal inflammation, systemic immunity and, potentially, susceptibility to autoimmune or inflammatory rheumatic diseases. Future clinical research needs to focus on the therapeutic use of androgens and progestins or their downstream signalling cascades and on new oestrogenic compounds such as tissue-selective oestrogen complex to modulate altered immune responses.

Objectives: Nailfold videocapillaroscopy (NVC) is the current gold standard for detection and quantification of capillary abnormalities in Raynaud's phenomenon (RP). The objective of this study is to evaluate the role of dermatoscopy as a further screening tool in RP., Methods: Nailfold capillaries of RP patients were examined by a hand-held non-contact polarised dermatoscope connected to the digital camera (D1) and connected to an iPad (D2). Both dermatoscopic images were marked with an arrowhead. NVC examination was evaluated at the arrowhead. Single blinded reader performed all examinations. NVC was graded as per standard of European League against Rheumatism (EULAR) study group on microcirculation in rheumatic diseases. Consensus evaluation of dermatoscopy characteristics/grade was determined and each dermatoscopic image was given a final impression of 'normal', 'non-specific' or 'scleroderma' pattern. The final interpretation by both techniques was compared after completion of the blinded reading., Results: Classification of 100 consecutive dermatoscopic images resulted in 37 (wide view) 'non-interpretable', 2 'normal', 48 'non-specific' and 13 'scleroderma' pattern with D1; 23 'non-interpretable', 4 'normal', 52 'non-specific' and 21 'scleroderma' pattern by the experts with D2; 0 non-interpretable, 4 normal, 13 non-specific and 83 'scleroderma' pattern with NVC., Conclusions: Overall, 50% of dermatoscopic images were classified as non-specific and 30% were classified as non-interpretable in RP patients. However, all images classified by dermatoscopy as "normal" or as overt "scleroderma" pattern were confirmed by concomitant NVC analysis. These findings demonstrate tenuous promise for dermatoscopy as a tool for the initial screening of nailfold capillaries in RP. Further regular work up with NVC is needed to further clarify non-interpretable and non-specific findings possibly related to non-scleroderma patterns.

Objective: The reproductive choices of women affected by rheumatic diseases (RD) can be influenced by several factors, including the quality of physician-patient communication. We conducted a survey on reproductive issues aiming at exploring the unmet needs of women with RD during childbearing age., Methods: We administered 65 multiple-choice and 12 open-answer questions about pregnancy counselling, contraception, use of drugs during pregnancy and other women reproductive issues to 477 consecutive women with RD aged 18-55 years followed-up in 24 rheumatology centres in Italy. Analysis was restricted to 398 patients who received their diagnosis of RD before the age of 45. According to the RD diagnosis, patients were subdivided into 2 groups: connective tissue diseases (n = 249) and chronic arthritis (n = 149)., Results: At the time of interview, women in both groups had a mean age of 40 years. Nearly one third of patients in each group declared not to have received any counselling about either pregnancy desire nor contraception. A smaller family size than desired was reported by nearly 37% of patients, because of concerns related to maternal disease in one fourth of the cases. A "Disease Knowledge Index" (DKI) was created to investigate the degree of patients' information about the implications of their RD on reproductive issues. Having received counselling was associated with higher DKI values and with a positive impact on family planning., Conclusion: Italian women of childbearing age affected by RD reported several unmet needs in their knowledge about reproductive issues. Strategies are needed to implement and facilitate physician-patient communication., (Copyright © 2018. Published by Elsevier Masson SAS.)

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.)

Progress in rheumatology has been remarkable in the past 70 years, favourably affecting quality of life for people with rheumatic and musculoskeletal diseases. Therapeutics have advanced considerably in this period, from early developments such as the introduction of glucocorticoid therapy to the general use of methotrexate and other disease-modifying agents, followed by the advent of biologic DMARDs and, most recently, small-molecule signalling inhibitors. Novel strategies for the use of such agents have also transformed outcomes, as have multidisciplinary nonpharmacological approaches to the management of rheumatic musculoskeletal disease including surgery, physical therapy and occupational therapy. Breakthroughs in our understanding of disease pathogenesis, diagnostics and the use of 'big data' continue to drive the field forward. Critically, the patient is now at the centre of management strategies as well as the future research agenda.

Biological drugs and their originated biosimilars are large, highly complex molecules derived from living cells or organisms. Traditional medicines, by contrast, are usually simple molecules of low molecular weight, synthesised by chemical means. The distinct complexities and methods of manufacture create an important difference between biosimilars and conventional generic drugs: while chemical generics can be fully characterised as identical to the originator product, biosimilars cannot. In addition, biological therapies are inherently variable, creating unavoidable differences between even subsequent batches of the same product. An expiring patent does not necessarily mean that the manufacturing process of the originator product becomes available to the biosimilar developers (for instance, the relevant cell line clone and growth medium). Therefore, it cannot be guaranteed that biosimilar products are identical to their reference product on a molecular level. This difference has important implications for the regulation and licensing of biosimilars. While conventional generic drugs require only a limited comparison and demonstration of identical chemical structure to the reference product, biosimilars require far more rigorous testing. In general, there must be a thorough comparison of structural and functional characteristics between biosimilar and originator drug. Stepwise nonclinical in vitro and in vivo approaches are recommended to evaluate the similarity of both drugs and any identified micro-heterogeneities must then be assessed for their impact on safety and clinical performance. Subsequently, clinical pharmacokinetic (PK) studies need to be performed in order to demonstrate a similar PK profile, prior to conducting clinical efficacy trials.

There is convincing evidence for the known and unambiguously accepted beneficial effects of glucocorticoids at low dosages. However, the implementation of existing recommendations and guidelines on the management of glucocorticoid therapy in rheumatic diseases is lagging behind. As a first step to improve implementation, we aimed at defining conditions under which long-term glucocorticoid therapy may have an acceptably low level of harm. A multidisciplinary European League Against Rheumatism task force group of experts including patients with rheumatic diseases was assembled. After a systematic literature search, breakout groups critically reviewed the evidence on the four most worrisome adverse effects of glucocorticoid therapy (osteoporosis, hyperglycaemia/diabetes mellitus, cardiovascular diseases and infections) and presented their results to the other group members following a structured questionnaire for final discussion and consensus finding. Robust evidence on the risk of harm of long-term glucocorticoid therapy was often lacking since relevant study results were often either missing, contradictory or carried a high risk of bias. The group agreed that the risk of harm is low for the majority of patients at long-term dosages of ≤5 mg prednisone equivalent per day, whereas at dosages of >10 mg/day the risk of harm is elevated. At dosages between >5 and ≤10 mg/day, patient-specific characteristics (protective and risk factors) determine the risk of harm. The level of harm of glucocorticoids depends on both dose and patient-specific parameters. General and glucocorticoid-associated risk factors and protective factors such as a healthy lifestyle should be taken into account when evaluating the actual and future risk., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

A European League Against Rheumatism (EULAR) task force was established to define points to consider on use of antirheumatic drugs before pregnancy, and during pregnancy and lactation. Based on a systematic literature review and pregnancy exposure data from several registries, statements on the compatibility of antirheumatic drugs during pregnancy and lactation were developed. The level of agreement among experts in regard to statements and propositions of use in clinical practice was established by Delphi voting. The task force defined 4 overarching principles and 11 points to consider for use of antirheumatic drugs during pregnancy and lactation. Compatibility with pregnancy and lactation was found for antimalarials, sulfasalazine, azathioprine, ciclosporin, tacrolimus, colchicine, intravenous immunoglobulin and glucocorticoids. Methotrexate, mycophenolate mofetil and cyclophosphamide require discontinuation before conception due to proven teratogenicity. Insufficient documentation in regard to fetal safety implies the discontinuation of leflunomide, tofacitinib as well as abatacept, rituximab, belimumab, tocilizumab, ustekinumab and anakinra before a planned pregnancy. Among biologics tumour necrosis factor inhibitors are best studied and appear reasonably safe with first and second trimester use. Restrictions in use apply for the few proven teratogenic drugs and the large proportion of medications for which insufficient safety data for the fetus/child are available. Effective drug treatment of active inflammatory rheumatic disease is possible with reasonable safety for the fetus/child during pregnancy and lactation. The dissemination of the data to health professionals and patients as well as their implementation into clinical practice may help to improve the management of pregnant and lactating patients with rheumatic disease., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Objective: To propose simple capillaroscopic definitions for interpretation of capillaroscopic morphologies and to assess inter-rater reliability., Methods: The simple definitions proposed were: normal--hairpin, tortuous or crossing; abnormal--not hairpin, not tortuous and not crossing; not evaluable--whenever rater undecided between normal and abnormal. Based upon an aimed kappa of 0.80 and default prevalences of normal (0.4), abnormal (0.4) and not evaluable (0.2) capillaries, 90 single capillaries were presented to three groups of raters: experienced independent raters, n = 5; attendees of the sixth EULAR capillaroscopy course, n = 34; novices after a 1-h course, n = 11. Inter-rater agreement was assessed by calculation of proportion of agreement and by kappa coefficients., Results: Mean kappa based on 90 capillaries was 0.47 (95% CI: 0.39, 0.54) for expert raters, 0.40 (95% CI: 0.36, 0.44) for attendees and 0.46 (95% CI: 0.41, 0.52) for novices, with overall agreements of 67% (95% CI: 63, 71), 63% (95% CI: 60, 65) and 67% (95% CI: 63, 70), respectively. Comparing only normal vs the combined groups of abnormal and not evaluable capillaries did increase the kappa: 0.51 (95% CI: 0.37 ,: 0.65), 0.53 (95% CI: 0.49, 0.58) and 0.55 (95% CI: 0.49, 0.62). On the condition that the capillaries were classifiable, the mean kappa was 0.62 (95% CI: 0.50, 0.74) for expert raters (n = 65), 0.76 (95% CI: 0.69, 0.83) for attendees (n = 20) and 0.81 (95% CI: 0.74, 0.89) for novices (n = 44)., Conclusion: This multicentre, international study showed moderate reliability of simple capillaroscopic definitions for describing morphology of capillaries by rheumatologists with varying levels of expertise. Novices were capable of distinguishing normal from abnormal capillaries by means of a 1-h training session. In future studies, the class not evaluable may be obsolete., (© The Author 2016. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Purpose: This consensus review article considers the question of whether glucocorticoid (GC) therapy is still relevant in the treatment of rheumatic diseases, with a particular focus on rheumatoid arthritis (RA), and whether its side effects can be adequately managed. Recent basic and clinical research on the molecular, cellular and clinical effects of GCs have considerably advanced our knowledge in this field. An overview of the subject seems appropriate., Methods: This review is the result of a multidisciplinary expert working group, organised by European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis. The recent literature was surveyed and the salient evidence synthetized., Results: The pathophysiological basis of RA (and other inflammatory rheumatic diseases) now strongly implicates the adaptive immune system in addition to innate mechanisms. The molecular effect of GCs and differential GC sensitivity is better understood, although exploiting this knowledge is still in its infancy. The newer treatment strategies of early and aggressive control of RA have gr eatly improved clinical outcomes, but improvements are still possible. Newer targeted anti-inflammatory drugs have made an important impact, yet they too are associated with numerous side effects., Discussion: Short durations of moderate doses of GCs are generally well tolerated and have a positive benefit/risk ratio. Patients should be assessed for fracture risk and bone preserving agents and be prescribed calcium and vitamin D supplementation., Conclusions: Within a strategy of a disease modifying approach to inflammatory disease, combination therapy including a GC is effective approach.

Objective: Bone loss is typical in chronic inflammatory diseases such as rheumatoid arthritis, psoriasis, ankylosing spondylitis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel diseases, pemphigus vulgaris, and others. It is also typical in transplantation-related inflammation and during the process of aging. While we recognized that bone loss is tightly linked to immune system activation or inflamm-aging in the form of acute, chronic active, or chronic smoldering inflammation, bone loss is typically discussed to be an "accident of inflammation.", Methods: Extensive literature search in PubMed central., Results: Using elements of evolutionary medicine, energy regulation, and neuroendocrine regulation of homeostasis and immune function, we work out that bone waste is an adaptive, evolutionarily positively selected program that is absolutely necessary during acute inflammation. However, when acute inflammation enters a chronic state due to the inability to terminate inflammation (e.g., in autoimmunity or in continuous immunity against microbes), the acute program of bone loss is a misguided adaptive program., Conclusions: The article highlights the complexity of interwoven pathways of osteopenia., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Throughout the last decade, increasing awareness has been raised on issues related to reproduction in rheumatic diseases including basic research to clarify the important role of estrogens in the etiology and pathophysiology of immune/inflammatory diseases. Sub- or infertility is a heterogeneous condition that can be related to immunological mechanisms, to pregnancy loss, to disease burden, to therapy, and to choices in regard to family size. Progress in reproductive medicine has made it possible for more patients with rheumatic disease to have children. Active disease in women with rheumatoid arthritis (RA) affects their children's birth weight and may have long-term effects on their future health status. Pregnancy complications as preeclampsia and intrauterine growth restriction are still increased in patients with systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS), however, biomarkers can monitor adverse events, and several new therapies may improve outcomes. Pregnancies in women with APS remain a challenge, and better therapies for the obstetric APS are needed. New prospective studies indicate improved outcomes for pregnancies in women with rare diseases like systemic sclerosis and vasculitis. TNF inhibitors hold promise for maintaining remission in rheumatological patients and may be continued at least in the first half of pregnancy. Pre-conceptional counseling and interdisciplinary management of pregnancies are essential for ensuring optimal pregnancy outcomes., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Rheumatic and musculoskeletal diseases (RMDs) represent a multitude of degenerative, inflammatory and auto-immune conditions affecting millions of people worldwide. Persons with these diseases may potentially experience severe chronic pain, joint damage, increasing disability and even death. With an increasingly ageing population, the prevalence and burden of RMDs are predicted to increase, placing greater demands on the global practice of rheumatology and related healthcare budgets. Effective treatment of RMDs currently faces a number of challenges in both the developed and developing world, and individual countries may face more specific local challenges. However, limited understanding of the burden of RMDs amongst public health professionals and policy-makers means that these diseases are often not considered a public health priority. The objective of this review is to increase awareness of the RMDs and to identify opportunities to address RMD challenges on both a local and global scale. On 26 September 2014, rheumatology experts from five different continents met at the World Forum on Rheumatic and Musculoskeletal Diseases (WFRMD) to discuss and identify some key challenges for the RMDs community today. The outcomes are presented in this review, focusing on access to rheumatology services, diagnostics and therapies, rheumatology education and training and on clinical trials, as well as investigator-initiated and epidemiological research. The long-term vision of the WFRMD is to increase perception of the RMDs as a major burden to society and to explore potential opportunities to improve global and local RMD care.

Background: Neuroendocrine immunology in musculoskeletal diseases is an emerging scientific field. It deals with the aspects of efferent neuronal and neurohormonal bearing on the peripheral immune and musculoskeletal systems. This review aims to add new information that appeared since 2001., Search Strategy: The following PubMed search sentence was used to find a total of 15,462 references between 2001 and March 2013: "(rheum* OR SLE OR vasculitis) AND (nerve OR hormone OR neurotransmitter OR neuropeptide OR steroid)." In a continuous process, year by year, this search strategy yielded relevant papers that were screened and collected in a database, which build the platform of this review., Results: The main findings are the anti-inflammatory role of androgens, the loss of androgens (androgen drain), the bimodal role of estrogens (support B cells and inhibit macrophages and T cells), increased conversion of androgens to estrogens in inflammation (androgen drain), disturbances of the gonadal axis, inadequate amount of HPA axis hormones relative to inflammation (disproportion principle), biologics partly improve neuroendocrine axes, anti-corticotropin-releasing hormone therapies improve inflammation (antalarmin), bimodal role of the sympathetic nervous system (proinflammatory early, anti-inflammatory late-most probably due to catecholamine-producing local cells), anti-inflammatory role of alpha melanocyte-stimulating hormone, vasoactive intestinal peptide, and the Vagus nerve via α7 nicotinergic receptors. Circadian rhythms of hypothalamic origin are responsible for circadian rhythms of symptoms (neuroimmune link revealed). Important new pain-sensitizing immunological pathways were found in the last decade., Conclusions: The last decade brought much new information that gave birth to the first therapies of chronic inflammatory diseases on the basis of neuroendocrine immune targets. In addition, a new theory linked evolutionary medicine, neuroendocrine regulation of distribution of energy-rich fuels, and volume regulation that can explain many disease sequelae in patients with chronic inflammatory diseases., (Copyright © 2013 Elsevier Inc. All rights reserved.)

To develop recommendations for the management of medium to high-dose (ie, >7.5 mg but ≤100 mg prednisone equivalent daily) systemic glucocorticoid (GC) therapy in rheumatic diseases. A multidisciplinary EULAR task force was formed, including rheumatic patients. After discussing the results of a general initial search on risks of GC therapy, each participant contributed 10 propositions on key clinical topics concerning the safe use of medium to high-dose GCs. The final recommendations were selected via a Delphi consensus approach. A systematic literature search of PubMed, EMBASE and Cochrane Library was used to identify evidence concerning each of the propositions. The strength of recommendation was given according to research evidence, clinical expertise and patient preference. The 10 propositions regarded patient education and informing general practitioners, preventive measures for osteoporosis, optimal GC starting dosages, risk-benefit ratio of GC treatment, GC sparing therapy, screening for comorbidity, and monitoring for adverse effects. In general, evidence supporting the recommendations proved to be surprisingly weak. One of the recommendations was rejected, because of conflicting literature data. Nine final recommendations for the management of medium to high-dose systemic GC therapy in rheumatic diseases were selected and evaluated with their strengths of recommendations. Robust evidence was often lacking; a research agenda was created.

The investigation of the hypothalamicpituitary-adrenal (HPA) axis in chronic inflammation has demonstrated: 1) an anti-inflammatory influence of the HPA axis; 2) low serum levels of adrenal androgen; 3) equivocal results with respect to levels of adrenocorticotropic hormone and cortisol; 4) inadequately low secretion of adrenal hormones in relation to inflammation (the disproportion principle); 5) modulating role of TNF and IL-6 on the HPA axis; 6) disturbed cooperativity of HPA axis and sympathetic nervous system (uncoupling); 7) observable glucocorticoid resistance; 8) the circadian rhythmicity explains morning symptoms; 9) new medications based on malfunction of the HPA axis (e.g. adapted to the circadian rhythm of hormones and cytokines); and 10) the newly described role of the HPA axis in the context of misguided energy regulation in chronic inflammatory diseases. This review discusses items 1-6 and 10, while the other items are presented elsewhere in this Supplement. Evidence is presented that the basis for many alterations is in an adaptive program positively selected for short-lived inflammatory responses (energy appeal reaction), which becomes a disease-inherent pathogenetic factor, if it continues too long, that can drive systemic disease sequelae of chronic inflammatory diseases such as the metabolic syndrome.

Despite evidence for the important role of oestrogens in the aetiology and pathophysiology of chronic immune/inflammatory diseases, the previous view of an unequivocal beneficial effect of oestrogens on RA compared with a detrimental effect on SLE has to be reconsidered. Likewise, the long-held belief that RA remits in the majority of pregnant patients has been challenged, and shows that only half of the patients experience significant improvement when objective disease activity measurements are applied. Pregnancies in patients with SLE are mostly successful when well planned and monitored interdisciplinarily, whereas a small proportion of women with APS still have adverse pregnancy outcomes in spite of the standard treatment. New prospective studies indicate better outcomes for pregnancies in women with rare diseases such as SSc and vasculitis. Fertility problems are not uncommon in patients with rheumatic disease and need to be considered in both genders. Necessary therapy, shortly before or during the pregnancy, demands taking into account the health of both mother and fetus. Long-term effects of drugs on offspring exposed in utero or during lactation is a new area under study as well as late effects of maternal rheumatic disease on children.

Epidemiological evidence indicates a significant association between vitamin D deficiency and an increased incidence of autoimmune diseases. The presence of vitamin D receptors (VDRs) in the cells of the immune system and the fact that several of these cells produce the vitamin D hormone suggested that vitamin D could have immunoregulatory properties, and now potent immunomodulatory activities on dendritic cells, Th1 and Th17 cells, as well as B cells have been confirmed. Serum levels of vitamin D have been found to be significantly lower in patients with systemic lupus erythematosus, undifferentiated connective tissue disease, and type-1 diabetes mellitus than in the healthy population. In addition, it was also found that lower levels of vitamin D were associated with higher disease activity in rheumatoid arthritis. Promising clinical results together with evidence for the regulation of multiple immunomodulatory mechanisms by VDR agonists represent a sound basis for further exploration of their potential in the treatment of rheumatic autoimmune disorders., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Objective: To develop recommendations on monitoring for adverse events (AEs) of low-dose glucocorticoid (GC) therapy (≤7.5 mg prednisone or equivalent daily) in clinical trials and daily practice., Methods: Literature was searched for articles containing information on incidence and monitoring of GC-related AEs using PubMed, EMBASE and Cochrane databases. Second, the authors searched for broad accepted guidelines on the monitoring of certain AEs (eg, WHO guidelines on screening for diabetes). Available data were summarised and discussed among experts (rheumatologists and patients) of the EULAR Task Force to decide which potential AEs should be monitored, how and at which interval., Results: Data on monitoring proved to be scarce; most articles were focused on therapeutic effects of GCs, not on occurrence and monitoring of AEs. Most recommendations had to be based on consensus. Those for clinical trials aimed at getting insights into incidence, prevalence and clinical relevance of AEs to create a comprehensive and valid AE-profile of GC therapy. The set of AEs to monitor is therefore more extensive, and often consists of assessments at baseline and at end of trials. Recommendations for daily practice are meant to protect patients from real dangers, which can be prevented or treated. Standard care monitoring needs NOT be extended for patients on low-dose GC therapy, except for osteoporosis (follow national guidelines), and baseline assessments of ankle edema, fasting blood glucose and risk factors for glaucoma., Conclusion: Given the incompleteness of literature data, consensus-based recommendations on monitoring for GC-related AEs were created, separately for daily practice and clinical trials.

Objectives: Studying the characteristics of resilience may help to explain how, in the face of a chronic disease, people are able to cope in productive and effective ways. The Wagnild and Young Resilience Scale (RS) is an appropriate instrument to study resilience and has already been translated from the original English version into several languages. The aim of this study was to validate the Italian version of the RS, a 25-item scale ranging from 25 to 175 where higher scores indicate stronger resilience., Methods: The Minimal Translation Criteria were followed to translate the scale which was then filled out by 1090 students to assess the reliability, stability, internal consistency and concurrent validity., Results: Time stability was assessed in a sample of 117 students (M age=20.18 yr, SD 1.25) by test-retest correlation (r=0.78). RS reliability was evaluated in a second sample of 973 students (M age=16.95 yr, SD 1.50) with RS mean of 126.6 (SD 17.4). Concurrent validity was assessed by correlation with General Health Questionnaire (r=-0.51), Ego-Resilience Scale (r=0.63) and Beck Depression Inventory (r=-0.45). Internal consistency was evaluated by Cronbach alpha (α=0.84). Principal component analysis was performed on 24 out of the 25 items and resulted in six components., Conclusions: Our data indicated that the 24-item Italian version of the RS scale can be considered a useful instrument to measure resilience and can be used by healthcare staff to help patients cope effectively with stressful situations such as rheumatic and other chronic diseases.

Objective: To explore perspectives among patients and rheumatologists on glucocorticoid (GC) therapy and European League Against Rheumatism (EULAR) recommendations on the management of systemic GC therapy in order to enhance implementation of the recommendations., Methods: Rheumatologists (from eight countries) and patients (from five countries) acquainted with GCs participated in separate meetings, during which positive and negative aspects of GC therapy were discussed and possible adverse events (AEs) were ranked for importance; in addition participants were asked to evaluate the published EULAR recommendations. The reports from these meetings and themes related to implementation of the recommendations were discussed during an international forum of the experts who had formulated the recommendations and patient participants., Results: In all, 140 patients (78% women; mean age 53 years; 61% patients with rheumatoid arthritis) and 110 rheumatologists (mean work experience 15 years) participated in the meetings. Osteoporosis, diabetes and cardiovascular diseases were ranked among the five most worrisome AEs by patients and rheumatologists. In both groups, there was agreement with most of the recommendations; the recommendations on GC information cards and GC use during pregnancy scored lowest. Ideas to improve implementation of the recommendations and a research agenda were generated., Conclusion: The patient and rheumatologist views on GCs corresponded to a large extent, reflected by concerns in both groups about osteoporosis, diabetes and cardiovascular diseases. Specific problems with the EULAR recommendations were identified and addressed to improve their implementation. This exercise shows that patient and rheumatologist perspectives should be included early in the process of formulating recommendations.

Purpose of Review: Steroid hormones are deeply involved in the pathophysiology of immune-mediated rheumatic diseases and used for their treatment. Purpose of the review is to update on recent roles and mechanisms of action of important steroid hormones such as glucocorticoids, estrogens, and D hormone (vitamin D) in order to optimize their therapeutical use., Recent Findings: Endogenous glucocorticoids are characterized by a circadian rhythm of production that must be respected in case of exogenous low-dose long-term glucocorticoid replacement therapy of rheumatic diseases. Estrogens are enhancers of the humoral immune response and increase cell proliferation. Therefore, estrogens represent a risk factor for the development of autoimmunity and their therapeutical use must be avoided in patients with active immune-mediated diseases. Vitamin D, as synthesized in the skin from cholesterol, is a real steroid hormone (D hormone). The immunosuppressive activities of D hormone are reduced in chronic rheumatic diseases, as low plasma levels of the hormone are evident and justify its therapeutical use., Summary: The optimization of the therapeutical use of steroid hormones such as glucocorticoids, estrogens or D hormone is now possible following recent basic and clinical research achievements.

Immunological, epidemiological, and clinical evidence suggest that female sex hormones play an important role in the etiology and pathophysiology of chronic immune/inflammatory diseases. Several significant factors generate confusion and opposite conclusions in evaluating the role of estrogens in these diseases, including relatively superficial translational studies from animals to the human condition, the different effects of estrogens on their different receptors or on different target cells, the different estrogen concentrations employed, and opposite effects (especially on cell proliferation) exerted by different peripheral estrogen metabolites. A preponderance of 16alpha-hydroxylated estrogens, as observed in rheumatoid arthritis synovial fluids, is an unfavorable sign in synovial inflammation. Since 17beta-estradiol administered during hormone replacement therapy will rapidly increase estrone sulfate after conversion in adipose tissue by aromatases, hormone replacement therapy can have proinflammatory effects by providing estrone sulfate to the inflamed synovial tissue. In addition, it appears that the use of combined oral contraceptives is associated with an increased risk of at least systemic lupus erythematosus. In conclusion, estrogens are generally considered as enhancers of cell proliferation and humoral immune response.

Objective: We have developed a self-taught course by which rheumatologists in training can learn how to conduct capillaroscopy examinations using a computerized videomicroscopy system. We assessed the effectiveness of this course by following the learning curve of one specialist trainee with no experience in capillaroscopy., Methods: The student's training consisted of 10 practical sessions held on three consecutive days. The perceived difficulty in completing each session was graded from 0 (least difficult) to 10 (most difficult). All the images obtained were stored and the time spent by both the trainee and the tutor during the sessions was recorded. Each image was blindly judged by both the novice and the tutor for quality, assigning a score from 0 (lowest quality) to 10 (highest quality). The minimum acceptable score for standard clinical practice was considered to be >5., Results: The student spent a total of approximately 5 non-consecutive hours engaged in 'direct' capillaroscopy and recorded a total of 172 images. The mean time required to produce each image varied from approximately 1.0 to 2.0 minutes. The perceived difficulty in completing a session decreased from the first to the last session. A quality score > 5 was assigned by the novice and tutor, respectively, to 16/49 images for the first group of sessions, 26/45 for the second group of sessions, and 56/78 for the third group of sessions. The overall agreement between the novice and tutor was good (K=0.617, SE=0.021)., Conclusions: The monitoring of one rheumatologist in training indicates that novices can quickly learn, through an intensive self-teaching programme under the supervision of an expert, how to use computerized videomicroscopy to conduct capillaroscopy studies.