[Influence of underlying disease and immunosuppression on the immunocompetence in inflammatory rheumatic diseases]. / Einfluss von Grunderkrankung und Immunsuppression auf die Immunkompetenz bei entzündlich rheumatischen Erkrankungen.

Patients with inflammatory rheumatic diseases have a higher risk of infections in comparison to the general population. For this patient group, in addition to cardiovascular diseases, infections play an important role with respect to morbidity and mortality. Even if it is difficult to make concrete statements with respect to individual diseases, it can be assumed that there is a lower risk of infections in inflammatory joint diseases in comparison to connective tissue diseases and vasculitides. The increased risk of infections is determined by multiple factors, whereby the underlying factors are classified into three main categories: patient-related factors (age, comorbidities, lifestyle), disease-related factors (immunological dysfunction as part of the disease pathophysiology) and drug-related factors (type and dosage of the immunosuppression and/or immunomodulation). An improved understanding of the complexity of these associations enables the optimization of treatment and disease control taking the individual risk factors into account, with the aim of a significant reduction in the risk of infections.

Evidence for changes in population-level subjective well-being during the COVID-19 pandemic from 30 waves of representative panel data collected in Austria between March 2020 and March 2022.

OBJECTIVES: This study was conducted to describe how population-level subjective well-being (SWB) evolved throughout the pandemic. STUDY DESIGN: Thirty waves of panel data representative of the Austrian population aged ≥14 years were collected between March 2020 and March 2022. Participants were quota sampled from a pre-existing online panel based on key demographics closely mirroring the Austrian resident population. METHODS: We present wave-specific means of SWB throughout 2 years of the COVID-19 pandemic next to the evolution of the pandemic (cases and deaths) and stringency of lockdown measures in Austria as well as estimate their bivariate correlations. RESULTS: The analysed sample consisted of 3,293 participants contributing to a total of 46,168 observations. All components of SWB - negative affect, positive affect and life satisfaction - showed population-level fluctuation between March 2020 and March 2022. The magnitude of these changes was small. Population-level SWB correlated with the incidence rate of COVID-19 deaths (negative affect: r = 0.69, positive affect: r = -0.70, life satisfaction: r = -0.47), the Stringency Index (negative affect = 0.50, positive affect = -0.47, life satisfaction = -0.47) and less so with the incidence of COVID-19 cases (negative affect = 0.43, positive affect = -0.31, life satisfaction = -0.38). CONCLUSIONS: Population-level SWB fluctuated in accordance with rises and falls in COVID-19 cases and deaths as well as with the stringency of lockdown measures. This connection suggests that incidence of COVID-19 cases and deaths, as well as public health measures to contain the pandemic affect population-level SWB and could thereby impact population health and productivity.

Induction of cross-reactive, mucosal anti-SARS-CoV-2 antibody responses in rheumatoid arthritis patients after 3rd dose of COVID-19 vaccination.

Systemic vaccination against SARS-CoV-2 elicited high titers of specific antibodies in the blood and in the oral cavity. Preexisting autoimmune diseases, such as rheumatoid arthritis, and biological treatments, like B cell depletion, are known to exhibit higher risk of severe COVID-19 manifestation and increased frequency of breakthrough infections after vaccination. We hypothesized that such increased risk is associated with an aberrant induction of secreted antibodies in the oral cavity. Here we evaluated the levels of secreted antibodies in the oral cavity against the SARS-CoV-2 Spike protein during the course of vaccination in RA patients with or without B cell depletion. We found that total salivary IgG levels were correlated with number of B cells in the blood. Anti-Spike IgG responses 7 days after second vaccination were induced in the oral cavity of all healthy individuals, while only 6 out 23 RA patients exhibited anti-Spike IgG in their saliva regardless of B cell depleting therapy. Importantly, both salivary and serologic anti-Spike IgG and IgA responses towards WT and omicron Spike variants were efficiently induced by third vaccination in RA patients with or without B cell depletion to the levels that were similar to healthy individuals. Altogether, these data advocate for the necessity of three dose vaccination for RA patients to mount anti-Spike antibody responses at the mucosal surfaces and annotate the reduction of secreted salivary IgG by B cell depletion.

Adolescents' Perspective on Their Sexual Knowledge and the Role of School in Addressing Emotions in Sex Education: An Exploratory Analysis of Two School Types in Austria.

Sex education for adolescents should include building knowledge on the emotional, social and physical aspects of sexuality. This study aimed to find out how adolescents from two different school types perceived their own knowledge on sexual matters, the importance they placed on sex education in school, and how well they felt that emotional, social and physical issues were raised within the frame of sex education. A cross-sectional 74-item questionnaire survey was conducted among adolescents (n = 198, age 13-16 years) from two secondary schools and one polytechnic school in Austria. From the linear regression analyses, secondary school students felt more knowledgeable on sexual matters than polytechnic students (beta = -0.288, p = .005). Secondary school students had more knowledge on the biology of sexuality but were less informed of the emotional aspects and other topics masturbation [mean score (SD)] [2.42(1.24) vs 3.42(1.44); p < .001], forms of sexual contact [2.81(1.08) vs 3.54(1.22), p = .006] and dealing with love and sexual feelings in relationships [2.68(1.19) vs 3.33(2.60); p = .030] than polytechnic students. While teachers were considered important providers of sex education, a more varied and practical means of learning was desired. Sex education should allow for the interplay between fact and emotion using varied teaching and learning strategies.

[Antinuclear antibodies in the diagnostics of rheumatic diseases]. / Antinukleäre Antikörper in der Diagnostik rheumatischer Erkrankungen.

Testing for antinuclear antibodies (ANA) on human epithelial cell lines (HEp-2) using indirect immunofluorescence (IIF) is central for ruling out or for diagnosing connective tissue diseases and other diseases, such as primary biliary cholangitis and autoimmune hepatitis as well as drug-induced ANA. The comprehensive description of 29 different ANA-IIF patterns by the international consensus of ANA patterns (ICAP) facilitates the harmonization of ANA-IIF diagnostics. Positive ANA tests are frequently observed in healthy individuals and a reason for referral to rheumatologists. In these cases, the detection of anti-DFS70 antibodies can be helpful to exclude systemic autoimmune rheumatic diseases.

[Lupus and thrombophilia : Antiphospholipid syndrome]. / Lupus und Thrombophilie : Antiphospholipidsyndrom.

Even early on thromboembolic events were observed in patients with systemic lupus erythematosus (SLE) until the antiphospholipid syndrome (APS) was described in the 1980s as an independent disorder. The APS is a systemic autoimmune disease often overlapping with SLE in which antiphospholipid autoantibodies, including lupus anticoagulant, can cause a hypercoagulation state, which clinically by definition is manifested as arterial and venous occlusions or pregnancy complications. The pathophysiology has not yet been entirely delineated and the clinical spectrum of associated concomitant manifestations is large. As the mortality is increased with SLE and simultaneous APS, focused diagnostics and risk assessment are indispensable. According to the recently published recommendations of the European League Against Rheumatism the therapeutic strategy comprises individualized secondary prevention of thromboembolic complications by means of anticoagulation (with unaltered importance of vitamin K antagonists) and thrombocyte aggregation inhibition, usually lifelong. Statins and antimalarial drugs are recommended for vascular protection while immunosuppressive treatment has not so far been sufficiently proven for APS but remains the subject of current research.

[Biologicals and small molecules for systemic lupus erythematosus]. / Biologika und "small molecules" beim systemischen Lupus erythematodes.

Targeted treatment is a rheumatologist's dream, which, with the advent of biologicals and more recently small molecules, has become true for rheumatoid arthritis and is about to translate into reality for systemic lupus erythematosus (SLE). Belimumab, the first biological approved for SLE, is now also available in a subcutaneous formulation. It is notable that this drug achieved the primary endpoint in four independent trials and demonstrated substantial reduction of organ damage accrual. The B cell depletion with antibodies against CD20 remains clinically relevant and of interest for future developments and the combination of both approaches (belimumab and anti-CD20) is an exciting idea. Blockade of the type I interferon receptor with anifrolumab was effective in a phase 3 trial and blocking interleukin-12 and interleukin-23 with ustekinumab is currently being tested in a phase 3 clinical trial. The old ideas of blocking tumor necrosis factor (TNF) and interleukin­6 have also not yet been forgotten. More novel approaches comprise Janus kinase (Jak) inhibition with positive phase 2 data for baricitinib and soon inhibition of Bruton's tyrosine kinase (BTK) as well as proteasome inhibitors. The treatment of SLE could therefore soon become much more varied.

Use of Electronic Cigarettes in European Populations: A Narrative Review.

The increasing popularity of electronic cigarettes in past decades has aroused public health concern. This study aims to review the literature on the prevalence of e-cigarette use among the general adult and young populations in Europe. We searched Medline and Google Scholar from September 2019, and included "prevalence of e-cigarettes", "electronic cigarettes" or "e-cigarettes", and "electronic nicotine delivery system" or "vaping". The prevalence of current e-cigarette use ranged from 0.2% to 27%, ever-use ranged from 5.5% to 56.6% and daily use ranged from 1% to 2.9%. Current smokers of conventional cigarettes showed the highest prevalence for the use of e-cigarettes, ranging from 20.4% to 83.1%, followed by ex-smokers, with ranges from 7% to 15%. The following socio-demographic factors were associated with a higher chance of using e-cigarettes: male sex and younger age groups; results for economic status were inconclusive. In European countries, there is a higher prevalence of e-cigarette use among males, adolescents and young adults, smokers of conventional cigarettes, and former smokers.

[Janus kinase inhibitors : State of the art in clinical use and future perspectives]. / Januskinase-Inhibitoren : State of the Art im klinischen Einsatz und Zukunftsperspektiven.

BACKGROUND: Cytokines and associated intracellular signal cascades play a major role in the pathogenesis of autoimmune diseases. Janus kinases (JAK) are part of these intracellular signal transduction processes. A relatively new drug group of targeted synthetic disease-modifying antirheumatic drugs (tsDMARD) are JAK inhibitors (JAKi) and are a promising treatment approach for autoimmune diseases. EFFICACY: Hitherto, three JAKis, Tofacitinib, Baricitinib and Upadacitinib, have been approved for treatment of Rheumatoid Arthritis (RA) in the USA, Switzerland and the EU. Filgotinib, another JAKi, also showed promising results in the treatment of RA. Furthermore, tofacitinib received approval for the treatment of ulcerative colitis and psoriatic arthritis. In addition to the JAKis already mentioned, several other JAKis, e.g. filgotinib and peficitinib, are being and were investigated in various studies on indications, such as atopic dermatitis, ankylosing spondylitis and systemic lupus erythematosus. SAFETY: Being immunosuppressants, JAKis show an elevated incidence of severe infections, comparable to biologics. The increased reactivation of varicella zoster virus is especially noteworthy. Under JAKi treatment cytopenia is also more frequent. Lymphopenia under JAKi treatment is of particular clinical relevance because of its association with an increase in the number of severe infections. Furthermore, an elevated risk of thromboembolic events, particularly pulmonary embolism has been noted. The risks concerning metabolic alterations and the occurrence of malignant neoplasms are comparable to those under treatment with biologics.

Weight of salivary gland ultrasonography compared to other items of the 2016 ACR/EULAR classification criteria for Primary Sjögren's syndrome.

OBJECTIVE: Major salivary gland ultrasonography (SGUS) is widely used for the diagnosis of primary Sjögren's syndrome (pSS). Our objective was to assess the contribution of SGUS compared to other items of the 2016 ACR/EULAR pSS classification criteria, based on expert opinion. METHODS: A secure web-based relational database was used by 24 experts from 14 countries to assess 512 realistic vignettes developed from data of patients with suspected pSS. Each vignette provided classification criteria items and information on history, clinical symptoms and SGUS findings. Each expert assessed 64 vignettes, and each vignette was assessed by 3 experts. A diagnosis of pSS was defined according to at least 2 of 3 experts. Validation was performed in the independent French DiapSS cohort of patients with suspected pSS. RESULTS: A criteria-based pSS diagnosis and SGUS findings were independently associated with an expert diagnosis of pSS (P < 0.001). The derived diagnostic weights of individual items in the 2016 ACR/EULAR criteria including SGUS were as follows: anti-SSA, 3; focus score ≥ 1, 3; SGUS score ≥ 2, 1; positive Schirmer's test, 1; dry mouth, 1; and salivary flow rate < 0.1 mL/min, 1. The corrected C statistic area under the curve for the new weighted score was 0.96. Adding SGUS improves the sensitivity from 90.2 % to 95.6% with a quite similar specificity 84.1% versus 82.6%. Results were similar in the DiapSS cohort: adding SGUS improves the sensitivity from 87% to 93%. CONCLUSION: SGUS had similar weight compared to minor items, and its addition improves the performance of the 2016 ACR/EULAR classification criteria.

Association of depression symptoms with receipt of healthcare provider advice on physical activity among US adults.

BACKGROUND: Given the high burden and prevalence of depression, various guidelines underscore the role of healthcare providers in supplying advice on physical activity (PA) as a potential modifying factor influencing the incidence and severity of depressive symptoms in adults. We aimed to investigate the extent to which healthcare providers provide PA advice to adults with depressive symptoms in the US. METHODS: Data on adults aged 20-64 years (n = 4971) in the National Health and Nutrition Examination Study between 2011 and 2016 were analysed. Depressive symptoms were assessed using the Patient Health Questionnaire and response options were categorised as "none or minimal", "mild", "moderate-severe". Receipt of PA advice from a healthcare provider was self-reported. We restricted our study sample to adults free from chronic diseases. RESULTS: Higher odds of receiving advice to exercise were reported among adults with mild (OR = 1.7, 95% CI: 1.3-2.3) and moderate-severe depressive symptoms (OR = 1.7, 95% CI: 1.0-2.8). Furthermore, exercise advice was more commonly reported among adults who were overweight, obese, Hispanic, Asian, being insured with private insurance, with education higher than high school, and had access to a routine place for health care. LIMITATIONS: Social and culutral aspects of overweight/obesity may prohibit generalizations. Cross sectional design does not allow for causal realtionships. CONCLUSIONS: In the US, fewer than one in three adults experiencing symptoms of depression report having received exercise advice from a healthcare provider. Providing such advice may be a sustainable clinical strategy in reducing the incidence and severity of depression symptoms.

Work disability patterns before and after incident acute myocardial infarction and subsequent risk of common mental disorders: A Swedish cohort study.

This study investigated the extent to which work disability patterns including sickness absence and disability pension (SA/DP) before and after acute myocardial infarction (AMI) were associated with subsequent common mental disorders (CMDs) such as depression and anxiety in AMI patients without previous CMD. Total 11,493 patients 26-64 years with incident AMI during 2008-10 were followed up for CMD (measured as antidepressant prescription) through 2013. Four SA/DP trajectory groups during the 3-years pre-AMI and 1-year post-AMI were identified. Hazard ratios (HRs) with 95% confidence intervals for subsequent CMD were estimated in Cox models. Higher pre-AMI SA/DP annual levels (>1-12 months/year) were associated with 40-60% increased CMD rate than the majority (78%) with low increasing levels (increasing up to 1 month/year). Regarding post-AMI findings, constant high (~25-30 days/month) SA/DP levels within the first 3 months was associated with a 76% higher CMD rate, compared to constant low (0 days/month). A gradually decreasing post-AMI SA/DP pattern over a 12-month period suggested protective influences for CMD (HR = 0.80). This is the first study to demonstrate that pre- and post-AMI work disability patterns are associated with subsequent CMD risk in AMI patients. Work disability patterns should be considered as an indicator of AMI prognosis in terms of CMD risk.

Antigenic response to CT-P13 and infliximab originator in inflammatory bowel disease patients shows similar epitope recognition.

AIM: To test the cross-immunogenicity of anti-CT-P13 IBD patients' sera to CT-P13/infliximab originator and the comparative antigenicity evoked by CT-P13/infliximab originator sera. METHODS: Sera of patients with IBD with measurable anti-CT-P13 antibodies were tested for their cross-reactivity to 5 batches of infliximab originator and CT-P13. Anti-drug antibody positive sera from treated patients were used to compare antigenic epitopes. RESULTS: All 42 anti-CT-P13 and 37 anti-infliximab originator IBD sera were cross-reactive with infliximab originator and CT-P13 respectively. Concentration of anti-drug antibodies against infliximab originator or CT-P13 were strongly correlated both for IgG1 and IgG4 (P < 0.001). Anti-CT-P13 sera of patients with IBD (n = 32) exerted similar functional inhibition on CT-P13 or infliximab originator TNF binding capacity and showed reduced binding to CT-P13 in the presence of five different batches of CT-P13 and infliximab originator. Anti-CT-P13 and anti-infliximab originator IBD sera selectively enriched phage-peptides from the VH (CDR1 and CDR3) and VL domains (CDR2 and CDR3) of infliximab. Sera reactivity detected major infliximab epitopes in these regions of infliximab in 60%-79% of patients, and no significant differences were identified between CT-P13 and infliximab originator immunogenic sera. Minor epitopes were localised in framework regions of infliximab with reduced antibody reactivity shown, in 30%-50% of patients. Monoclonal antibodies derived from naïve individuals and ADA-positive IBD patients treated with CT-P13 provided comparable epitope specificity to five different batches of CT-P13 and infliximab originator. CONCLUSIONS: These results strongly support a similar antigenic profile for infliximab originator and CT-P13, and point toward a safe switching between the two drugs in anti-drug antibody negative patients.

Early symptoms of systemic lupus erythematosus (SLE) recalled by 339 SLE patients.

Objective The European League Against Rheumatism and the American College of Rheumatology jointly embarked on a new classification criteria for systemic lupus erythematosus (SLE) project. Its first phase involved generation of a broad set of items potentially useful for classification of SLE. This study was undertaken to add the patient perspective to an expert Delphi approach and an early patient cohort study. Methods A national cross-sectional study was conducted. A self-report questionnaire was published in the "Schmetterling" (Butterfly), the quarterly journal of the German SLE patient association. Individuals with SLE were asked to anonymously complete the questionnaire, which asked for demographic details, organ manifestations, autoantibodies and symptoms. Results A total of 339 completed questionnaires out of 2498 were returned, a response rate of 13.6%; 83.2% reported they were ANA positive and 81.7% reported joint, 66.1% skin and 33.0% renal involvement. For the time before and in the first year after their SLE diagnosis, the majority reported fatigue (89.4%), joint pain (86.7%), photosensitivity (79.4%) and myalgia (76.1%). Of interest, more than half of the patients reported fever as an early symptom (53.7%). Conclusion For a Caucasian European SLE patient population, the overall characteristics suggest meaningful representation. While many symptoms were reported as expected, the high percentage of patients reporting fever and the significant number of patients with unexpected gastrointestinal complaints are of particular interest. These data add to the information on early SLE symptoms informing the development process of new SLE classification criteria.

[Revised version of the statement by the DGRh on biosimilars-update 2017]. / Neufassung der Stellungnahme der DGRh zu Biosimilars ­ Update 2017.

The treatment of rheumatic diseases with bioloics has significantly improved the prognosis of patients. Currently, there are 13 preparations available in Germany for the treatment of patients with inflammatory rheumatic diseases. These original preparations generally have-depending on the individual country-15 years of patent protection. As soon as the patent has expired, approved biosimilars can be brought into use. For the approval of a biosimilar, authorities such as the European Medical Agency or the American Food and Drug Administration require proof of the best possible comparability with respect to efficacy and safety in comparison to the original or reference product. Since 2015, biosimilars of inifliximab, adalimumab, etanercept and rituximab have been granted approval in the European Union, the USA, Japan and in other countries. Further biosimilar products for these reference products are in development for treatment in rheumatology. From a societal and medical point of view, this opens up the possibility to increase the availability of biopharmaceutical products for patients through lower prices. In Germany, this possibility has already occurred-statutory health insurance physicians have introduced quotas for biosimilars, which will ultimately decrease spending and healthcare costs. This can lead to price reductions of the original products, which has already happened in Germany. Biosimilars can be prescribed for new patients or as a change from the original to the generic drug. When switching, a distinction is made between individual switching (interchangeability), which is made in individual consultation between the physician and the patient, and nonmedical switching (substitution) made at the societal or governmental level, which is made in the context of health care cost containment, and then, for example, implemented at the pharmacy level. Preliminary data from Norway and Denmark are available for substitution on the basis of results from large studies or registries in which systematic changes were made. The previous conclusion was that this does not lead to new problems for the patients. The German Society for Rheumatology recognizes the advantages of introducing biosimilars in Germany, but recommends that their use be based primarily on a joint decision by the treating physician and patient.

[Efficacy and safety analysis of off-label treatment with biologics in autoinflammatory diseases : Experiences from a German registry (GRAID2)]. / Wirksamkeits- und Sicherheitsanalyse von Off-label-Biologikatherapien bei Patienten mit autoinflammatorischen Erkrankungen : Erfahrungen aus einem Deutschen Register (GRAID2).

OBJECTIVE: To evaluate the safety and efficacy of therapy with biologics in patients with autoinflammatory diseases (AIF) or macrophage activating syndrome (MAS) in a real-life setting in Germany. METHODS: The German Register of Autoimmune Diseases 2 (GRAID2) is a retrospective, non-interventional, multicenter registry collecting data from all patients with inflammatory rheumatic diseases refractory to conventional therapy and treated with initial off-label biologics between August 2006 and December 2013. Patients with MAS could be included without prior treatment with a biologic agent. RESULTS: Data from 26 patients with AIF and 5 with MAS were collected. Of the AIF patients 13 (50%) were diagnosed with adult onset Still's disease (AOSD), 6 (23%) with familial Mediterranean fever (FMF), 4 (15.4%) with tumor necrosis factor-associated periodic syndrome (TRAPS), 1 (3.8%) patient with cryopyrin-associated periodic syndrome (CAPS) and 2 (8%) with undifferentiated fever syndromes. The 5 MAS patients suffered from rheumatoid arthritis (RA) with chronic myeloid leukemia, systemic lupus erythematosus and in 2 cases AOSD. In 1 patient a chronic neurological disease was documented without further differentiaton. All patients with TRAPS were primarily treated with etanercept and all CAPS patients with canakinumab. The AOSD and FMF patients were treated with anakinra as the first line off-label biologic in 6 out of 13 and 5 out of 6 cases, respectively. The MAS patients responded very well or well to therapy in 40% and 60% had a moderate response. There were no non-responders. Within the group of AIF patients the physicians documented a very effective or effective treatment in 38.5%, a moderate response in 30.8% and no response in 30.7%. The tolerance was very good in 5 out of 5 of the MAS and in 92% of the AIF patients. CONCLUSION: The data of this retrospective register provide indications for an effective and safe treatment with off-label biologic medication in patients with AIF and MAS in daily practice.

[Safety and efficacy of off-label use of biologic therapies in patients with inflammatory rheumatic diseases refractory to standard of care therapy : Data from a nationwide German registry (GRAID2)]. / Sicherheit und Wirksamkeitshinweise zum Off-label-Einsatz von Biologikatherapien nach Versagen konventioneller Therapien bei Patienten mit entzündlich rheumatischen Erkrankungen : Ergebnisse eines nationalen Registers (GRAID2).

BACKGROUND: The German Registry of Autoimmune Diseases 2 (GRAID2) is a retrospective, non-interventional, multicenter registry study collecting data from patients with inflammatory, mainly rheumatic diseases refractory to standard of care therapy and treated with an off-label biologic therapy. The retrospective documentation comprised case history, diagnosis, course of disease (including safety and global efficacy). The objective was to evaluate the global clinical outcome and safety of off-label biologic therapy in clinical practice. RESULTS: Data from 311 patients with an overall observation period of 338.5 patient-years were collected. The mean patients age was 47.8 years with 56.9% females. The most frequently documented diagnoses comprised rejection prophylaxis/therapy after renal transplantation (NTX, 18.3%), ANCA-vasculitides (17.4%), systemic lupus erythematosus (SLE, 10.3%), autoinflammatory fever syndromes (8.4%), autoimmune myositis (7.4%) and pemphigus (5.8%). Documented biologic therapies included rituximab (RTX, 70.1%), tocilizumab (TCZ, 9.3%), infliximab (IFX, 7.1%), anakinra (ANK, 5.5%), adalimumab (ADA, 3.5%), etanercept (ETA, 2.3%) and certolizumab (CTZ, 0.6%). After initiation of off-label biologic treatment, tolerability was assessed by the physicians as "very good"/"good" in 95.5%. Altogether, 275 adverse events were documented and of these, 104 were classified as serious adverse events and occurred in 62 patients. In 19 of these patients severe infections (30.6%) were documented, resulting in a rate of 5.6 severe infections per 100 patient years. A total of six deaths were documented, while five of these cases were rated as not related to the biologics treatment. Notably, the use of RTX in patients with small vessel vasculitides and of TCZ in patients with large vessel vasculitides prior to their approval support their relevance in clinical management of patients with severe diseases. CONCLUSION: The results of this registry together with data of GRAID1 provide evidence that use of off-label biologic therapies in patients with inflammatory rheumatic diseases refractory to conventional treatment did not result in any new safety signal already known for these compounds or subsequently shown by clinical trials in certain entities.