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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.

Objectves: Among immunosuppressants, rituximab is most strongly associated with the risk of hepatitis B virus (HBV) reactivation in chronic HBV individuals. Current guidelines recommending antiviral prophylaxis for these patients on rituximab are predominantly based on studies in oncology. However, limited data existed for the precise risk of HBV flares, effectiveness and optimal duration of antiviral prophylaxis in rituximab-treated rheumatic patients, whose immune status and treatment regimen differ significantly from those of oncology patients. Therefore, we aimed to assess the incidence and clinical outcome of HBV reactivation in HBsAg-positive patients receiving rituximab for various autoimmune diseases who discontinue the antiviral agents., Methods: A retrospective analysis was performed on 95 hepatitis B surface antigen (HBsAg)-positive patients treated with rituximab for autoimmune diseases in a single centre in Taiwan. HBV related hepatitis, defined as alanine aminotransferase (ALT) more than 3 times of baseline level and concurrent HBV reactivation, after anti-viral discontinuation, was the primary endpoint. Factors associated with HBV hepatitis flare and off-antiviral hepatitis flare were also analysed., Results: With nucleos(t)ide analogues (NA) prophylaxis, no hepatitis flares occurred. However, without prophylaxis, 59% had flare (24.5 per 100 person-years) and 8% experienced liver decompensation. Concurrent steroid use was a dose-dependent risk factor for flare. After NA discontinuation, rituximab "retreatment" led to flares in 75% of cases and liver decompensation in 63% of patients. Stopping NAs within one-year post-rituximab, even without further rituximab treatment, resulted in a 38% flare rate., Conclusions: This study offers the direct evidence for the necessity of universal antiviral prophylaxis in rheumatic patients with chronic HBV receiving rituximab. After NA discontinuation, rituximab "retreatment" led to even higher flare rate and worse outcome. Patients who completed rituximab treatment should also keep antiviral agents for at least one more year to prevent hepatitis flare.

Objectives: Rheumatic and musculoskeletal diseases (RMD) may exhibit different immune responses to novel coronavirus (COVID-19) infection compared to healthy individuals. While previous studies have primarily investigated changes in COVID-19-related antibodies post-vaccination for RMD patients, this study sought to explore the dynamics of SARS-CoV-2 IgG antibodies and neutralising antibodies (NAb) in RMD patients after COVID-19 infection., Methods: In this longitudinal study, we monitored the SARS-CoV-2 IgG antibodies and NAb levels in RMD patients and healthy controls (HC) at 60 and 90 days post-COVID-19 infection. Chemiluminescent immunoassay was used to detect the levels of novel coronavirus-specific IgG (anti-S1/S2 IgG) antibodies and NAb., Results: A total of 292 RMD patients and 104 HC were enrolled in the study. At both the 60-day and 90-day post-COVID-19 infection, RMD patients exhibited significantly lower levels of anti-S1/S2 IgG and NAb than those in the HC group (p<0.001). The anti-S1/S2 IgG antibody levels remained relatively stable, while the NAb levels in RMD patients could vary greatly between the 60th and 90th days. A logistic regression analysis revealed that the prior administration of glucocorticoids (GC), immunosuppressants, and b/tsDMARDs stood out as independent risk factors associated with reduced anti-S1/S2 IgG and NAb levels, irrespective of the specific RMD subtypes., Conclusions: GC and anti-rheumatic medications can potentially alter the production of specific antibodies, especially NAb, in RMD patients post-COVID-19 infection. These findings emphasise the importance of continuous monitoring for NAb fluctuations in RMD patients following a COVID-19 infection.

Objectives: To evaluate adherence to medication in patients with systemic autoimmune diseases (SAD), comparing pregnant and non-pregnant women., Methods: 200 patients with SAD were consecutively enrolled, 100 pregnant and 100 non-pregnant women. Each patient completed the 8-item Morisky Medication Adherence Scale (MMAS-8), one copy for hydroxychloroquine (HCQ) and one for other treatments for rheumatic disease, and Hospital Anxiety and Depression Scale (HADS)., Results: No significant differences were found in ongoing therapies between pregnant and non-pregnant women. 148 patients (74.0%) were taking HCQ and 160 (80.0%) other therapies for rheumatic disease. The mean MMAS-8 score was >6 in all groups indicating a good adherence, on average. The rate of patients with good medication adherence was higher in pregnant patients (73.9% vs. 63.3% and 76.5% vs. 64.5%, for HCQ and other therapies, respectively) although this difference was not statistically significant. Eight patients had very poor medical adherence, and all were non-pregnant women. Anxiety (15% of patients) was associated to low medication adherence for drugs other than HCQ (p=0.02), while depression (4% of patients) did not seem to have an impact on adherence., Conclusions: In our cohort we recorded a good adherence to prescribed medication, although adequate adherence was not achieved in about 30% of patients, confirming that non-adherence is an important issue in SAD. It is difficult to define a profile of patients at risk of poor adherence, but it appears important to implement communication and adherence monitoring strategies since strict monitoring also during pregnancy could improve medical adherence.

Objectives: Anti-COVID-19 vaccines have proved to be effective and well tolerated. Great attention is now being paid to the characterisation of possible adverse events associated to their administration. We report a case series of suspected rheumatic diseases (RDs) following anti-COVID-19 vaccination., Methods: We included patients evaluated at first-aid rheumatologic consultancy and at rheumatologic outpatient and inpatient clinic at Padova University Hospital between May and September 2021 presenting with a RD within 30 days after an anti-COVID-19 vaccine dose. Our selection was in accordance with the World Health Organisation guidelines for adverse event following immunisation (AEFI) surveillance. Patients were regularly re-evaluated by telemedicine or face-to-face visit., Results: We identified 30 cases of RD following vaccination: 24 (80.0%) new onsets and 6 (20.0%) flares. Most of patients (76.6%) received the BNT162b2 vaccine. The mean time to RD onset/flare was 12±9 days. The most common manifestations were inflammatory arthritis (40.0%), rheumatic polymyalgia (33.3%) and adult-onset Still's disease (13.3%). At the last FU visit (9.6±2.2 months), 83.3% of patients showed complete response to first- or second-line therapy, 13.3% a partial response and one patient (3.3%) was still experiencing an active disease., Conclusions: Considering the amount of vaccine doses administered during the evaluation period we overall detected a limited number of cases. We noted a clear prevalence of autoinflammatory conditions and seronegative manifestations. The great majority of patients had mild features and showed a good response to therapy.

Objectives: To study treatment decisions of patients with chronic inflammatory rheumatic diseases (CIRD) at the beginning of the SARS- CoV-2 pandemic in relation to disease characteristics with focus on anxiety., Methods: A total of 970 CIRD patients diagnosed with rheumatoid arthritis (RA), axial spondyloarthritis (axSpA), psoriasis arthritis (PsA) and connective tissue diseases (CTD), selected from our records who had presented to our hospital at least twice during last year, were contacted by telephone to be asked about medication changes, health status and therapy satisfaction. Standardised tools were used to assess disease activity, anxiety and depression, the latter by Hospital Anxiety and Depression Score (HADS) with a score ≥8 denoting definite anxiety and/or depression. The cut-off for RADAI was set at ≥3.2 and for BASDAI ≥4. Compliance with prevention rules and vaccination status were assessed., Results: Complete interviews of 557 patients (57.4%) made between April and July 2020 were available for analysis. The median age was 55 (47-63), disease duration 9.0 (4.5-17.0) years, 61.9% females. A recent change in medication was reported by 197 patients (35.4%), 51.2% of which admitted that this decision was mainly made due to the pandemic with more changes occurring with bDMARDs (21.8%) than cDMARDs (6.6%) and corticosteroids (5.4%). There was no major difference between patients who changed because of the pandemic or self-reported inactive disease versus patients who did not change therapy regarding disease activity, depression and anxiety (41%, 17.2%, 31.3% vs. 47.5%, 22.5%, 35.0% vs. 48.9%, 27.7%, 34.1%). More than 90% of patients reported that they rigorously followed Corona prevention rules. The majority of patients were vaccinated against influenza (55.3%) and pneumococci (61.3%), respectively., Conclusions: Anxiety, depression and disease activity did not play an important role in decisions favouring change of therapy, even though many patients changed medication due to the pandemic. Patients probably protected themselves by strictly adhering to hygiene recommendations. Vaccination rates against influenza and pneumococci were better than previously reported, but still too low.

Objectives: To evaluate the incidence of COVID-19 and its main outcomes in rheumatic disease (RD) patients on hydroxychloroquine (HCQ) compared to household cohabitants (HC)., Methods: This is a 24-week nationwide prospective multi-centre cohort with a control group without RD and not using HCQ. All participants were monitored through scheduled phone interviews performed by health professionals. Details regarding COVID-19 symptoms, and epidemiological, clinical, and demographic data were recorded on a specific web-based platform. COVID-19 was defined according to the Brazilian Ministry of Health criteria and classified as mild, moderate or severe., Results: A total of 9,585 participants, 5,164 (53.9%) RD patients on HCQ and 4,421 (46.1%) HC were enrolled from March 29th, 2020 to September 30th, 2020, according to the eligibility criteria. COVID-19 confirmed cases were higher in RD patients than in cohabitants [728 (14.1%) vs. 427 (9.7%), p<0.001] in a 24-week follow-up. However, there was no significant difference regarding outcomes related to moderate/ severe COVID-19 (7.1% and 7.3%, respectively, p=0.896). After multiple adjustments, risk factors associated with hospitalisation were age over 65 (HR=4.5; 95%CI 1.35-15.04, p=0.014) and cardiopathy (HR=2.57; 95%CI 1.12-5.91, p=0.026). The final survival analysis demonstrated the probability of dying in 180 days after a COVID-19 diagnosis was significantly higher in patients over 65 years (HR=20.8; 95%CI 4.5-96.1) and with 2 or more comorbidities (HR=10.8; 95%CI 1.1-107.9 and HR=24.8; 95%CI 2.5-249.3, p=0.006, respectively)., Conclusions: Although RD patients have had a higher COVID-19 incidence than individuals from the same epidemiological background, the COVID-19 severity was related to traditional risk factors, particularly multiple comorbidities and age, and not to underlying RD and HCQ.

Objectives: To assess the prevalence of anti-SARS-CoV-2 antibodies in autoimmune inflammatory rheumatic disease (AIIRD) patients, and to define clinical factors associated with seropositivity., Methods: A cross sectional study was conducted at a tertiary rheumatology department in Israel. Consecutive patients completed a questionnaire and were tested for SARS-CoV-2 anti-nucleoprotein IgG (N-IgG). If this was positive, an anti-S1/S2 spike IgG (S-IgG) test was done. If both were positive, the patient was considered seropositive. Seropositive patients were retested after 3 months., Results: The study included 572 AIIRD patients. Thirty patients were found seropositive, for a seroprevalence of 5.24%. The seropositive rate was significantly lower for patients treated with immunosuppressive medications (3.55%, p≤0.01), and specifically for patients treated with biologic disease-modifying anti-rheumatic drugs (bDMARDs) (2.7%, p≤0.05). These associations remained significant in the multivariate regressions adjusting for age, sex and exposure to a known COVID-19 patient. A second serology test 3 months later was collected in 21 of the 30 seropositive patients. In a mean±standard deviation (SD) of 166.63±40.76 days between PCR and second serology, 85% were still positive for N-IgG, and 100% were still positive for S-IgG, with a higher mean±SD titre compared to the first S-IgG (166.77±108.77 vs. 132.44±91.18, respectively, p≤0.05)., Conclusions: Humoral response to SARS-CoV-2 in AIIRD patients may be affected be immunosuppressive treatment, especially bDMARDs. In patients with AIIRD, titres of SARS-CoV-2 IgG antibodies, especially N-IgG antibodies, fade with time, while S-IgG antibodies persist.

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.

Objectives: To elucidate the characteristics of patients with rheumatic diseases with cytomegalovirus (CMV) reactivation., Methods: In our study, we consecutively reviewed patients with rheumatic diseases who received remission induction therapy in our institution from January 2012 to March 2016 and enrolled the patients who were evaluated about CMV infection. CMV reactivation was characterised by the detection of polymorphonuclear leukocytes with CMV pp65. The characteristics and clinical courses of the patients with CMV reactivation were compared to those without CMV., Results: We observed CMV reactivation in 71 (39.7%, CMV-positive group) out of 179 patients. Age (odds ratio [OR] 1.023, 95% confidence interval [CI] 1.002-1.044, p=0.03), lymphocyte counts (OR 0.999, 95% CI 0.999-1.000, p=0.03), and initial prednisolone dose (OR 18.596, 95% CI 2.399-144.157, p<0.01) were considered as independent relevant risk factors for CMV reactivation. Patients in the CMV-positive group showed significantly higher incidences of all infections (48%) and severe infections (31%) than those in the CMV-negative group (48% vs .31%, p=0.037; 31% vs. 6%, p<0.001, respectively). Higher mortality was observed in the CMV-positive group than in the CMV-negative group (14.1% vs. 1.9%). The lymphocyte counts were more relevant to CMV infection and mortality than were the serum IgG levels., Conclusions: Our study revealed that CMV reactivation occurred in one third of all patients with rheumatic diseases who were undergoing intensive remission induction therapy, and it was found to be relevant to other severe infections and infection-related deaths.

Objectives: The purpose of this systematic review was to identify existing guidelines for antimalarial prescribing and monitoring, specifically for hydroxychloroquine, and how these guidelines compare and have evolved over time., Methods: A literature search was conducted using Embase and Medline to identify guidelines published from 1946-2018. MeSH terms were used and alternative spelling and related words were entered as keywords to broaden results., Results: 243 results were reviewed to obtain 11 recommendations. Ophthalmology sources included the American Academy of Ophthalmology, Royal College of Ophthalmologists and Canadian editorials. The American College of Rheumatology and Canadian Rheumatology Association consensus statements summarised rheumatology recommendations. Recently, American and British guidelines changed from suggesting hydroxychloroquine doses ≤6.5 mg/kg/day to ≤5 mg/kg/day. American guidelines recommended baseline visual field (VF) testing and annual screening after five years. Visual field (VF) testing evolved from the Amsler grid to current recommendations of 10-2 automated VF and spectral-domain optical coherence tomography (SD-OCT). The 2012 Canadian recommendations suggested initial VF testing every two years, with SD-OCT after 10 years. Older British guidelines advocated for baseline and annual assessment with Amsler grids during rheumatology clinic visits. The 2018 British guidelines supported baseline and annual screening after five years with 10-2 VF, SD-OCT and fundus autofluorescence., Conclusions: The newest recommendations are heterogeneous suggesting lower hydroxychloroquine dosing. Retinal toxicity is irreversible and the risk increases over time. Annual screening after five years with automated VF and SD-OCT may be warranted to detect early changes and discontinue therapy if necessary.

Objectives: Epidemiologic studies evaluating associations between specific arthritis medications and perinatal outcomes are limited. We evaluated the association between conventional synthetic DMARD (csDMARD) use among women with rheumatic disease (RD) and neonatal outcomes., Methods: We linked population-based data in British Columbia, Canada from 01/01/2002 to 12/31/2012 on all inpatient/outpatient visits and medications with a perinatal registry. For small-for-gestational-age (SGA) births, we assessed csDMARD exposure 90 days preconception or during pregnancy until date of delivery. For congenital anomalies, we determined csDMARD exposure 90 days preconception or during the first trimester. We used multivariable logistic regression models fitted with generalised estimating equations and calculated post-hoc power., Results: There were 185 pregnancies in 175 women (31.3±5.4 years) and 6,064 pregnancies in 4,387 women (31.1±5.4 years) in the csDMARD exposed and unexposed groups, respectively. Hydroxychloroquine, azathioprine, sulfasalazine, and methotrexate exposure before or during pregnancy were not associated with SGA births. The most sufficiently powered analyses were those for hydroxychloroquine, where exposure during pregnancy resulted in an adjusted odds ratio (aOR) of 1.12 (95% confidence interval [CI], 0.65-1.94) for SGA births. Although post-hoc power calculations indicate less power to detect associations between csDMARDs and congenital anomalies, results indicate methotrexate exposure during the first trimester is associated with elevated odds for congenital anomalies (aOR 6.58, 95% CI 1.15-37.75)., Conclusions: Findings are consistent with current guidelines regarding specific csDMARD use during the perinatal period for women with RD. It is important to report well-designed epidemiologic studies to facilitate future RD/csDMARD-specific meta-analyses.

Objectives: To provide evidence-based recommendations for vaccination against influenza virus and S. pneumoniae in patients with autoimmune rheumatic diseases (ARDs)., Methods: A Consensus Committee including physicians with expertise in rheumatic and infectious diseases was established by two Italian scientific societies, Società Italiana di Reumatologia (SIR) and Società Italiana di Malattie Infettive e Tropicali (SIMIT). The experts were invited to develop evidence-based recommendations concerning vaccinations in ARDs patients, based on their clinical status before and after undergoing immunosuppressive treatments. Key clinical questions were formulated for the systematic literature reviews, based on the clinical pathway. A search was made in Medline (via PubMed) according to the original MeSH strategy from October 2009 and a keyword strategy from January 2016 up to December 2017, updating existing EULAR recommendations. Specific recommendations were separately voted and scored from 0 (no agreement with) to 100 (maximal agreement) and supporting evidence graded. The mean and standard deviation of the scores were calculated to determine the level of agreement among the experts' panel for each recommendation. Total cumulative agreement ≥70 defined consensus for each statement., Results: Nine recommendations, based on 6 key clinical questions addressed by the expert committee, were proposed. The aim of this work is to integrate the 2011 EULAR recommendations on vaccination against influenza and S. pneumoniae in ARDs patients. An implementation plan was proposed to improve the vaccination status of these patients and their safety during immunosuppressive treatments., Conclusions: Influenza and pneumococcus vaccinations are effective and safe in patients with ARDs. More efforts should be made to translate the accumulated evidence into practice.

Objectives: Reports to-date indicate similarity between infliximab biosimilar (IB) and infliximab bio-original (IO) in clinical efficacy and safety. This study examines the survival of IB and IO using routinely collected data over a 2-year period., Methods: Routinely collected clinical data inputted directly in an electronic database at a large rheumatology centre were analysed. Adult patients taking IO or IB for any rheumatological diagnosis were included. Kaplan-Meier survival analyses were used to examine IB and IO survival, with a sub-group analysis among those starting infliximab from 2008 onwards., Results: Out of 395 patients analysed, 53% (n=209) were female; the majority had rheumatoid arthritis (31%) followed by spondyloarthritis (28%). Ninety-nine patients had IB as the first infliximab drug. Patients who started on IB vs. IO as their first infliximab product, had better survival over the first 2 years (log rank=0.001). Discontinuation due to inefficacy was much commoner in IO versus IB users (18 vs. 5%). In patients switching from IO to IB, drug survival was better versus those receiving IB as the first infliximab drug (log rank=0.073)., Conclusions: IB was well-tolerated and comparable to IO, with no additional safety signals identified. The results suggest superior survival of IB over IO over the first 2 years.

Objectives: Management of rheumatic diseases (RD) is often problematic in pregnant patients, hence the need for guideline implementation. This survey-based study aimed to assess beliefs among obstetricians and rheumatologists about managing RD in pregnant Lebanese patients., Methods: Questionnaires were completed by a representative sample of rheumatologists and obstetricians practicing throughout Lebanon. Collected data included physicians' information, opinion on pregnancy in RD patients, compatible drugs with fertility, pregnancy and breastfeeding, references used in their clinical management, referral to specialists, and knowledge about guidelines. Qualitative variables were analysed using Chi-square or Fisher's exact tests, and quantitative variables using Wilcoxon or Student t-tests. Results were matched against a scoring system based on the EULAR/BSR guidelines. p-value <0.05 indicated statistical significance., Results: Analysis showed high response rates of physicians, especially among rheumatologists. Overall, physicians practice was in concordance with international guidelines and only few misconceptions were reported. Systemic lupus erythematosus (SLE) was associated with risk on fertility, foetal malformation and eclampsia while anti-phospholipid (APL) syndrome was associated with miscarriage and vasculitis with eclampsia. Spondyloarthritis was considered 'safe' in pregnancy. Most physicians think that cyclophosphamide, leflunomide, methotrexate, mycophenolate mofetil and azathioprine compromise fertility, pregnancy, and breastfeeding., Conclusions: Our data showed relatively good concordance of the physicians' beliefs with the current literature and recommendations. However, we identified misconceptions about anti-rheumatic drugs safety in pregnancy and discrepancy between rheumatologists and obstetricians practices; hence the need for promoting collaboration between both specialties and disseminating knowledge to physicians and patients in the Middle East region.

Objectives: Pneumocystis jiroveci pneumonia (PJP) is an opportunistic infection with high mortality among patients with underlying rheumatologic conditions. Given the paucity of prospective data to guide treatment, clinical guidelines to initiate PJP prophylaxis are based on expert opinion and identify patients on ≥20 mg daily prednisone for ≥4 weeks duration for treatment. Herein we describe the PJP experience in rheumatic disease over a 20-year period at a single academic medical centre to investigate this 20 mg threshold and risk associated with lymphocyte counts, co-existing lung disease and immunosuppressive medications., Methods: We conducted a retrospective review of all admitted patients who received a PJP or PCP ICD-9 code (136.3) from January 1996 through October 2015., Results: Twenty-one cases of confirmed PJP (by immunofluorescence or polymerase chain reaction) were reviewed, averaging to one case/year. The most common underlying rheumatologic conditions were inflammatory myopathy, lupus, and granulomatosis with polyangiitis. None of these 21 patients was receiving PJP prophylaxis upon admission. Eighteen (86%) were receiving ≥20 mg prednisone daily at the time of PJP diagnosis. Of the 3 treated with <20 mg prednisone, all received concomitant immunosuppressive medications, 2 with cyclophosphamide. Overall, there was a 43% (9/21) mortality rate. Immunosuppressant medication use, interstitial lung disease, or lymphocyte count did not impact mortality risk., Conclusions: PJP portends high mortality yet is a largely preventable complication of rheumatic disease treatment. Consideration to initiate prophylaxis should be made for patients exceeding the daily 20 mg prednisone threshold, and those receiving cyclophosphamide.

Objectives: To directly assess the prevalence of inflammatory rheumatic disease under treatment with biologic disease modifying anti-rheumatic drugs (b-DMARDs) and compare treatment patterns between rheumatoid arthritis (RA) and spondyloarthropathy (SpA), including psoriatic arthritis., Methods: The obligatory country-wide prescription electronic database covering 10.223.000 Greek citizens (95.1% of the population, 99.5% Caucasian), all of whom with fully reinbursed access to b-DMARDs, was used to retrospectively capture all patients under b-DMARDs for RA/SpA between June 2014-May 2015. Age, gender and medications for RA/SpA and co-morbid classical cardiovascular risk factors (hypertension, dyslipidaemia, diabetes) were retrieved and analysed., Results: A total of 9.824 RA (61.2±14.0 years, 79% women) and 9.279 SpA patients (51.4±13.1 years, 41% women) using pharmacy-dispensed prescriptions for b-DMARDs were identified (overall prevalence 0.19%). Tumour necrosis factor inhibitors were used in 73% and 99% of RA and SpA patients, respectively. B-DMARD monotherapy (RA: 18.71%, SpA: 52.11%), b-DMARD switching during 12 months (RA: 7.73%, SpA: 6.26%), and use of methotrexate (RA: 50.25%, SpA: 27.35%) and corticosteroids (RA: 55.8%, SpA: 23.63%) differed between the two patient subgroups. In both subgroups, women received more often than men methotrexate, leflunomide, hydroxychloroquine and corticosteroids, and less often b-DMARD monotherapy. After adjustments for age, gender and concomitant drugs, the probability for anti-hypertensive and lipid-lowering drug prescription was higher in SpA than RA [OR=1.41 (95%CI: 1.29-1.54) and 1.24 (1.14-1.36), respectively, p<0.001], whereas for anti-diabetics it was similar., Conclusions: In the first country-wide study that examines the characteristics of rheumatic disease patients under b-DMARD we show that their exact prevalence is 0.19%, with RA patients being older by 10 years, only slightly more numerous, and less likely to receive treatment for hypertension and dyslipidaemia than their demographically matched SpA counterparts. Longitudinal studies should assess the implications of these novel findings on the differential financial burden of rheumatic diseases, as well as on cardiovascular morbidity and mortality of these patients.

Objectives: To assess body composition of patients with inflammatory rheumatic disease and the effect of TNF inhibitors on it., Methods: This was systematic review with meta-analysis of studies consulted on PubMed, Cochrane Library and EMBASE and assessing body composition in patients with rheumatoid arthritis or spondyloarthritis. We compared i) patients with healthy controls and ii) body components before and after TNF inhibitors., Results: Among the 703 articles reviewed, 19 met the inclusion criteria. In patients with rheumatoid arthritis, a significant increase in fat mass (+1.85 kg, p=0.02), adiposity (+3.53%, p<0.00001) and android mass (+1.7 kg, p<0.00001) and a significant decrease in lean mass (-3.03 kg, p=0.01), were observed. In patients with spondyloarthritis, a significant but modest increase in fat mass (+0.69 kg, p=0.03) and a significant decrease in lean mass (-3.74 kg, p=0.03) were observed. Nine studies assessed impact of TNF inhibitors on body composition, with an increase of fat mass in the short and long term in all studies. Data on lean mass were controversial. Two studies found an increase in visceral or android mass under TNF inhibitors., Conclusions: Patients with inflammatory rheumatic disease have a significant decrease in lean mass and increase in fat mass. The use of TNF inhibitors is associated with a further increase in fat mass including android fat, which could potentially have cardiovascular consequences.

The Corrona US national registry collects data concerning patient status from both the rheumatologist and patient at routine clinical encounters. Corrona has functioning disease registries in rheumatoid arthritis, psoriatic arthritis, spondyloarthropathies, psoriasis and inflammatory bowel disease. Corrona merges data concerning long-term effectiveness and safety, as well as comparative and cost effectiveness of agents to treat these autoimmune diseases.

The Rheumatology Informatics System for Effectiveness (RISE) Registry was developed by the American College of Rheumatology (ACR) to serve US rheumatologists for the significant challenges of a rapidly changing healthcare environment. More than 400 rheumatologists have sent data from more than 3 million encounters of more than 650,000 patients as of August 11, 2016, through their electronic medical records (EMRs), with no additional work or interference with workflow on the part of the rheumatologists. RISE includes patients with all diagnoses seen by participating rheumatologists, at no cost to the rheumatologist.

The National Data Bank for Rheumatic Diseases (NDB) is a longitudinal observational patient-driven database, founded as a non-profit research organization in 1998 by Dr. Frederick Wolfe. Patients are sent a primary questionnaire twice a year. More than 50,000 patients with more than 100 various rheumatic diseases under the care of more than 1,500 rheumatologists have completed at least one 6-month questionnaire. Many important publications concerning rheumatoid arthritis, osteoarthritis, systemic lupus erythematosus, fibromyalgia, and pharmaco-epidemiology have resulted from NDB research.

Patient monitoring has been emphasised in rheumatology for decades. However, many obstacles must be overcome before successful monitoring is part of routine care. We describe one model: GoTreatIT.

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.

Anakinra is a biologic response modifier that competitively antagonises the biologic effects of interleukin-1, the ancestor pleiotropic proinflammatory cytokine produced by numerous cell types, found in excess in the serum, synovial fluid and any involved tissues of patients with many inflammatory diseases. The magnitude of the risk of different infections, including Mycobacterium tuberculosis (Mtb) infection, associated with the large use of anakinra in many rheumatologic, metabolic or autoinflammatory disorders is still unknown. In addition, it is unclear whether this effect is modified by the concomitant use of antirheumatic drugs and corticosteroids. The rates of development of Mtb disease in patients treated with anakinra due to rheumatoid arthritis, systemic autoinflammatory diseases, Schnitzler's syndrome, Behçet's disease, adult-onset Still disease, systemic juvenile idiopathic arthritis, gout and diabetes mellitus have been usually very low. However, clinicians must carefully weigh the benefits of biological drugs against their risks, particularly in patients prone to infections. Additional data are needed to understand whether this risk of Mtb infection and reactivation are representative of a class effect related to biologics or whether anakinra bears specifically an intrinsic lower risk in comparison with other biologic drugs.

Objectives: Despite the high incidence of rheumatic diseases during the reproductive years, little is known about the impact of disease-modifying anti-rheumatic drug (DMARD) use during pregnancy. Our objective was to systematically review and appraise evidence in women with rheumatic disease on the use of traditional and biologic DMARDs during pregnancy and the risk of congenital malformation outcomes., Methods: We conducted a systematic search of MEDLINE, EMBASE, and INTERNATIONAL PHARMACEUTICAL ABSTRACTS databases. Inclusion criteria were: 1) study sample including women with rheumatic disease; 2) use of traditional and/or biologic DMARDs during pregnancy; and 3) congenital malformation outcome(s) reported. We extracted information on study design, data source, number of exposed pregnancies, type of DMARD, number of live births, and number of congenital malformations., Results: Altogether, we included 79 studies; the majority were based on designs that did not involve a comparison group, including 26 case reports, 17 case series, 20 cross-sectional studies, and 4 surveys. Studies that had a comparator group included 1 case control, 10 cohort studies, and 1 controlled trial. Hydroxychloroquine and azathioprine represent the most studied traditional DMARD exposures and, among biologics, most of the reports were on infliximab and etanercept., Conclusions: This is the first systematic review on the use of both traditional and biologic DMARDs during pregnancy among women with rheumatic diseases and congenital malformation outcomes, with a focus on study design and quality. Findings confirm the limited number of studies, as well as the need to improve study designs.

The recent availability of biosimilars as a result of the expiry of the patents of first-generation biotechnological drugs may theoretically reduce the direct costs of such treatments, making their use accessible to a larger number of patients. However, the currently available clinical data refer to a relatively small number of patients, and do not provide sufficient information concerning long-term efficacy and safety or the frequency of rare adverse events. Given the importance of the introduction of biosimilar drugs and the limitations of our current knowledge of their efficacy and safety profiles, we believe it is mandatory to draw up a position paper for Italian Rheumatologists. Moreover, in order to guarantee their safety, it is mandatory to indicate behavioural rules for the involved specialists and competent authorities, and perform ad hoc clinical trials and appropriate drug surveillance.

With current advances in medical treatment, reproductive issues have become more important for women with chronic immune-mediated diseases. Most, if not all, patients report that their disease affects their personal relationships, their decision to have children, and the size of their family. These decisions are multi-factorial, influenced mainly by concerns over the effect of pregnancy on the rheumatic disease, the impact of disease activity during pregnancy on foetal health, the patient's ability to care for the child, and the possible harmful effects medication could have on the child, both pre- and post-natally during breastfeeding. Apart from that, women's health issues tend to be overlooked in favour of the management of the underlying rheumatic disease. To this end, we convened an expert panel to review the published literature on women's health and reproductive issues and provide evidence- and eminence-based points to consider for the treating physicians. We conclude that there is a need for a change in mind-set from one which 'cautions against pregnancy' to one which 'embraces pregnancy' through the practice of individualised, pre- and post-conceptual, multi-disciplinary care.

Registers facilitate the collection and communication of safety concerns. There are as many different register structures as registers, making the merging of rare data and comparison between registers difficult. BIOBADASER, the Safety Register of the Spanish Society of Rheumatology has served as template for other registers within the specialty, BIOBADAMERICA, and outside rheumatology, BIOBADADERM. Here we present the limitations and strengths of such template registers.

A vast amount of important information on the various rheumatic diseases that the rheumatologist treats is available in the medical records derived from the patient consultation. Until recently, it has been difficult to assemble and interpret this data. Moreover, the 'everyday' rheumatologist seeing the 'everyday' patient often does not contribute data to better understanding of 'everyday' clinical issues. We discuss an approach to this problem by describing a blending of a customised electronic medical record with a consortium of like-minded clinicians. We feel that this approach demonstrates the powerful potential for targeted point of care data collection in rheumatology research and patient management.

Objectives: Given that the clinical features of several IgG4-related diseases (IgG4-RD) can mimic those of autoimmune disorders, the aim of this study was to find possible distinguishing characteristics that would help us identify such cases from the pool of patients in a rheumatology clinic., Methods: From our clinic's medical records, we identified patients who fulfilled the recently published diagnostic criteria for IgG4-RD. We recorded their presenting features, co-morbid conditions, laboratory, radiologic and histologic findings as well as their treatment and outcome., Results: We identified 11 cases of IgG4-RD: 4 cases of IgG4-related autoimmune pancreatitis (AIP), 5 cases of IgG4-related retroperitoneal fibrosis (RPF)/ periaortitis, 2 cases of IgG4-related sialadenitis and one of IgG4-related interstitial nephritis. 5 out of the 11 patients had been diagnosed with an autoimmune disease, namely rheumatoid arthritis (RA), Sjogren's syndrome (SS) and antiphospholipid syndrome (APS). 3 out of 11 patients were subsequently diagnosed with neoplastic disorders. All patients with IgG4-related AIP had raised CRP levels at presentation. Presenting features of RPF/periaortitis patients were constitutional symptoms, abnormal renal function, hypertension and back pain. Patients with IgG4-related sialadenitis had clinical features mimicking SS. The majority of patients had a favourable response to steroids., Conclusions: We present common IgG4-RD presentations in the setting of a rheumatology clinic. Increased awareness may avoid delay in diagnosis.

New therapeutic options are constantly emerging for the treatment of rheumatic diseases. To evaluate the safety and efficacy of newly introduced anti-rheumatic treatment alternatives, registers are an important source of information. The Swedish Rheumatology Quality Register (SRQ) collects clinical data on patients with rheumatoid arthritis, as well as other rheumatic diseases, and may be enriched with data on comorbid conditions, prescription drug dispensings, and mortality from national data sources in Sweden. In this setting, many different outcomes can be investigated over a long period of time in a diverse population of patients recruited in daily clinical practice.

Objectives: Nowadays, several potent immunosuppressive drugs are available for patients with rheumatologic disorders. In general, these treatments are acceptably well tolerated. Nevertheless, in patients with rheumatic diseases, who are taking immunosuppressive drugs, an increased risk of bacterial, viral and fungal, as well as parasitic infections, exists., Methods: We have reviewed literature, on PubMed library, on the topic 'parasitic infections in rheumatic disease patients treated with immunosuppressive drugs, including biological therapies'. We used no language or time restrictions. Search was concluded on January 15th 2014. We grouped all parasitic events among rheumatologic, therapeutically immuosuppressed, patients to estimate the magnitude of this risk. Then we gave our viewpoint in the perspective to screen and follow-up for active and latent chronic parasitoses, developing an hypothetical flow-chart., Results: From data published in the literature the real burden of parasitoses, among patients with rheumatic diseases treated with immunosuppressive treatments, can not be estimated. Nevertheless, a positive trend on publication number exists, probably due to more than one reason: i) the increasing number of patients treated, especially with more than one immunosuppressive treatment, including new biological agents; ii) the increasing number of individuals who move from the north to the south of the world (endemic areas for parasitic infections) and vice versa, due to globalisation, and iii) the fact that more attention is paid for notification/publication of cases., Conclusions: Considering parasitic infections as emerging and potentially serious in their evolution, additional strategies for the prevention, careful screening and follow-up, with a high level of suspicion, identification, and pre-emptive therapy are necessary in candidate patients for biological agents.

Glucocorticoids are widely used to suppress inflammation - especially in the acute phase - in several inflammatory and autoimmune rheumatologic diseases. Despite their efficacy, their long-term use or at high doses is associated with numerous well-characterised side effects. Hyperglycaemia or frank diabetes is one of the most common, as its prevalence is estimated between 10-20%. Its pathophysiology is mainly due to increased insulin resistance. In this review, we provide a practical guide on how to monitor patients who are started on glucocorticoids, and how to detect and manage steroid-induced hyperglycaemia or diabetes.

Over the last decades ultrasound-guided procedures have become increasingly diffused in rheumatology, mainly thanks to the technical advances achieved in the ultrasound (US) field, combined with the greater availability, good portability and reduced cost of US devices, compared to other imaging techniques already used in rheumatology units. The direct visualisation of the tissue under analysis and the real-time imaging performance enabled by US-guidance account for an improved accuracy and directness in needle placement in a number of rheumatology interventions such as tendon and intra-articular injections. Compared with blind procedures, US-guided injections are more accurate and safe and they result in better clinical outcome in terms of joints improvement in function and decreased risk of damages caused by needle misplacement. The accuracy in needle placement of US-guided injections has proven to be important not only in common intra-articular injections, but especially in case of complex anatomical areas like the hip, facet and atlanto-occipital joints, where blinded injections are deemed poorly accurate and thus highly risky. Moreover US guidance can be successfully employed in more complex procedures such as synovial biopsy, portal establishment or arthroscopy, where US can also be combined with other imaging techniques. Overall the employment of US-guided procedures is considered to be safe and well-tolerated, and increases the accuracy and therapeutic effectiveness of the interventions performed. This may pave the way for a more widespread employment of US-guidance in rheumatology units, and new studies could further explore the therapeutic advantages of these procedures.

Despite the significant advantages in clinical practice associated with TNF-inhibitors, a loss of response over time is sometimes observed, in some cases possibly due to immunogenicity, i.e. the development of antibodies direct against the drug. This review evaluates the immunogenicity of different anti-TNF agents, and discusses its effects on efficacy and safety. Available evidence indicates that all anti-TNF drugs may induce an immune response. However, the variation in the occurrence of anti-drug antibodies, as well as the variation in the impact of antibodies on the efficacy and safety, can be explained by drug conformation itself, use of concomitant immunosuppressants and differences in dosing regimen and route of administration. The association between the development of anti-drug antibodies and low drug serum concentrations is clinically relevant since it is likely related to low response. Strict monitoring of neutralising antibodies might be useful for tailoring therapeutic strategy. There is no evidence of cross-reactivity among different drugs: immunogenicity (the development of specific anti-drug antibodies to one TNF inhibitor) does not seem to affect the effectiveness of another anti-TNF agents; therefore, switching to another drug of the same class might be effective in patients who have developed anti-drug antibodies to a TNF inhibitor.

Objectives: Booster vaccination against 2009 H1N1 influenza virus was recommended for rheumatologic patients under immunosuppressive therapy during the 2009/2010 H1N1 pandemic. In this study we assessed whether B cell depletion with rituximab influences of the antiviral immune response in 2009 H1N1 influenza virus-vaccinated patients., Methods: Influenza virus-specific immune responses were analysed after the first and a booster vaccination with pandemrixTM in sixteen consecutive rituximab-treated patients with different rheumatic autoimmune disorders. Antibody titers were determined by a haemagglutination-inhibition assay and virus-specific T cell responses were evaluated by a flow cytometry-based intracellular cytokine-secretion assay. Patients showing clinical symptoms of influenza infection were excluded from this study., Results: Two out of seven patients with low (<10%) and four out of nine with normal (>10%) B cells developed significant antibody responses after the first vaccination. Booster vaccination led to an antibody response in one additional patient. After the first vaccination, virus-specific CD4+ and CD8+ T cell responses were significantly lower in patients with low B cells than in those with normal B cells. Of importance, the booster vaccination stimulated the antiviral T cell response only in patients with low B cells., Conclusions: In the absence of a significant effect of booster vaccinations against 2009 H1N1 influenza virus on the humoral immune response in B cell-depleted patients with autoimmune rheumatic diseases, enhanced antiviral T cell responses in patients with low B cells indicate that T cells, maybe, compensate for the impaired humoral immunity in these patients.