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Since the late 1990s, tumor necrosis factor alpha (TNF-α) inhibitors (anti-TNFs) have revolutionized the therapy of immune-mediated inflammatory diseases (IMIDs) affecting the gut, joints, skin and eyes. Although the therapeutic armamentarium in IMIDs is being constantly expanded, anti-TNFs remain the cornerstone of their treatment. During the second decade of their application in clinical practice, a large body of additional knowledge has accumulated regarding various aspects of anti-TNF-α therapy, whereas new indications have been added. Recent experimental studies have shown that anti-TNFs exert their beneficial effects not only by restoring aberrant TNF-mediated immune mechanisms, but also by de-activating pathogenic fibroblast-like mesenchymal cells. Real-world data on millions of patients further confirmed the remarkable efficacy of anti-TNFs. It is now clear that anti-TNFs alter the physical course of inflammatory arthritis and inflammatory bowel disease, leading to inhibition of local and systemic bone loss and to a decline in the number of surgeries for disease-related complications, while anti-TNFs improve morbidity and mortality, acting beneficially also on cardiovascular comorbidities. On the other hand, no new safety signals emerged, whereas anti-TNF-α safety in pregnancy and amid the COVID-19 pandemic was confirmed. The use of biosimilars was associated with cost reductions making anti-TNFs more widely available. Moreover, the current implementation of the “treat-to-target” approach and treatment de-escalation strategies of IMIDs were based on anti-TNFs. An intensive search to discover biomarkers to optimize response to anti-TNF-α treatment is currently ongoing. Finally, selective targeting of TNF-α receptors, new forms of anti-TNFs and combinations with other agents, are being tested in clinical trials and will probably expand the spectrum of TNF-α inhibition as a therapeutic strategy for IMIDs. © 2022, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.

Giant cell arteritis (GCA) is a large-vessel vasculitis that affects cranial and extra-cranial arteries. Extra-cranial GCA presents mainly with non-specific symptoms and the differential diagnosis is very broad, while the cranial form has more typical clinical picture and physicians have a lower threshold for diagnosis and treatment. Although temporal artery biopsy (TAB) has an established role, ultrasound (US) is being increasingly used as the first-line imaging modality in suspected GCA. Vasculitides (especially ANCA-associated), hematological disorders (mainly amyloidosis), neoplasms, infections, atherosclerosis and local disorders can affect the temporal arteries or might mimic the symptoms of cranial GCA and produce US and TAB findings that resemble those of temporal vasculitis. Given that prompt diagnosis is essential and proper treatment varies significantly among these diseases, in this review we aimed to collectively present disorders that can masquerade cranial GCA. © 2022 Elsevier B.V.

Psoriatic arthritis (PsA) is a highly heterogenous disease. Apart from arthritis and psoriasis, other manifestations can also occur, including enthesitis, dactylitis, axial-, nail-, eye- and bowel- involvement. Comorbidities are also frequent in the setting of PsA, with cardiovascular disease and mental-health disorders being the most frequent. The Rheumatologist's arsenal has many different treatment options for treating PsA. Despite their effectiveness, there are some differences in terms of efficacy and safety that might affect clinician's decision for one or the other drug. Comparing biologic DMARDs and JAK-inhibitors, one could say that they have similar effectiveness in terms of musculoskeletal manifestations. However, anti-IL-17 and anti-IL-23 drugs seem to be more effective for skin manifestations. In contrast, JAK-inhibitors and etanercept might be less effective for these manifestations. Inflammatory bowel disease and uveitis are non-responsive to etanercept and anti-IL-17 drugs. As regards to comorbidities, data are scarce, but future studies will shed light on possible differential effect of bD MARDs or JAK-inhibitors. Safety is always an important drive for choosing the appropriate treatment. Infections are the most common adverse event of these drugs. Etanercept and anti-IL-17 drugs are safer for patients having latent tuberculosis, while herpes zoster is more common in individuals receiving JAK-inhibitors. Finally, venous thromboembolism risk, should be taken into account when JAK-inhibitors are used. In this review, we comparatively present, as outlined above, the various aspects that could affect the choice of the appropriate bDMARD or JAK-inhibitor for the treatment of a PsA patient. © 2022. All Rights Reserved.

Objective: To describe the rate and type of adverse effects (AEs) and the frequency of disease flares after COVID-19 vaccination and to assess the reasons for vaccination hesitancy (non-vaccination) in SRD patients. Methods: Telephone interviews were conducted of SRD patients consecutively enrolled (15/06/2021–1/7/2021). Participants were asked about the type of AEs and disease flare after vaccination. Reasons for vaccination hesitancy were recorded. Univariate and mutivariable analyses examined associations of demographic, clinical and other features, with occurrence of AEs, disease flare and non-vaccination. For the latter, association with negative vaccination behaviour (not influenza vaccinated for the last 2 years) and nocebo-prone behaviour (denoting AEs attributed to negative expectations [Q-No questionnaire]) was also tested. Results: 561 out of 580 contacted patients were included in the study. 441/561 (78.6%) patients were vaccinated [90% (Pfizer, Moderna), 10% (Astra-Zeneca)]. AEs were reported by 148/441 (33.6%), with rates being comparable between the three vaccines. AEs were more common in females and those with chronic obstructive pulmonary disease [OR, 95% CI; females: 2.23 (1.30–3.83); COPD: 3.31 (1.24–8.83)]. Disease flare was reported in 9/441 (2%) patients. For those unvaccinated, fear that the vaccine would be harmful (53.3%), could cause disease flare (24.2%) and/or could cause thrombosis (21.7%) were the main reasons to do so. Multivariable analysis identified as independent variables for non-vaccination: nocebo-prone behaviour (OR; 95% CI, 3.88; 1.76–8.55), negative vaccination behaviour (6.56; 3.21–13.42) and previous COVID-19 infection (2.83; 1.13–7.05). Higher educational status was protective (0.49; 0.26–0.92). Conclusion: No new safety signals for COVID-19 vaccination were observed. Vaccination campaign should target SRD patients with nocebo-prone and negative influenza vaccination behaviour. © 2021, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.

Objectives: Predicting serious infections (SI) in patients with rheumatoid arthritis (RA) is crucial for the implementation of appropriate preventive measures. Here we aimed to identify risk factors for SI and to validate the RA Observation of Biologic Therapy (RABBIT) risk score in real-life settings. Methods: A multi-centre, prospective, RA cohort study in Greece. Demographics, disease characteristics, treatments and comorbidities were documented at first evaluation and one year later. The incidence of SI was recorded and compared with the expected SI rate using the RABBIT risk score. Results: A total of 1557 RA patients were included. During follow-up, 38 SI were recorded [incidence rate ratio (IRR): 2.3/100 patient-years]. Patients who developed SI had longer disease duration, higher HAQ at first evaluation and were more likely to have a history of previous SI, chronic lung disease, cardiovascular disease and chronic kidney disease. By multivariate analysis, longer disease duration (IRR: 1.05; 95% CI: 1.005, 1.1), history of previous SI (IRR: 4.15; 95% CI: 1.7, 10.1), diabetes (IRR: 2.55; 95% CI: 1.06, 6.14), chronic lung disease (IRR: 3.14; 95% CI: 1.35, 7.27) and daily prednisolone dose ≥10 mg (IRR: 4.77; 95% CI: 1.47, 15.5) were independent risk factors for SI. Using the RABBIT risk score in 1359 patients, the expected SI incidence rate was 1.71/100 patient-years, not different from the observed (1.91/100 patient-years; P = 0.97). Conclusion: In this large real-life, prospective study of RA patients, the incidence of SI was 2.3/100 patient-years. Longer disease duration, history of previous SI, comorbidities and high glucocorticoid dose were independently associated with SI. The RABBIT score accurately predicted SI in our cohort. © 2020 The Author(s). Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved.

Objectives: Rituximab (RTX) use in the treatment of RA can be complicated by decrease in IgG, IgM or IgA levels (hypogammaglobulinemia-HGG). The aim of this study was to define the frequency of HGG in RA patients treated with RTX and to identify associations between its occurrence and patients' characteristics, disease outcomes and serious infections rate. Methods: RA patients treated with RTX in two rheumatology centers from January 2007 to January 2020 were retrospectively examined. Demographical, clinical and laboratory parameters were recorded at baseline and at last visit. Results: Eighty-three patients (84.3% females) with a mean age of 63.2 years were enrolled. They had baseline DAS28(CRP) of 5.2 (1.1) and received a median (range) of 8 (2-20) RTX cycles. A total of 43.4%, 24.1% and 31.3% developed 'any HGG', 'low IgG' and 'low IgM', respectively. Lower baseline IgG and IgM levels were predictors of 'low IgG' and 'low IgM' occurrence, respectively. Patients who developed 'low IgM' exhibited lower DAS28(CRP) and increased rates of remission and low disease activity compared with those with normal IgM levels. Patients who maintained normal IgG were receiving methotrexate more frequently. No differences were observed in serious infections rate among subgroups. Conclusion: HGG occurred in 43% of RTX-treated patients. Patients who developed low IgG or low IgM had lower baseline levels than those who did not. Concomitant DMARD and corticosteroid therapy was not associated with HGG. Low IgM, but not low IgG, development was associated with better disease outcomes. HGG was not associated with an increased incidence of serious infections. © 2020 The Author(s). Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved.

IgG4-related disease (IgG4-RD) can affect almost every tissue/organ. Vascular involvement in the setting of IgG4-RD is increasingly being recognized with most of the cases pertaining patients with aortitis and/or periaortitis with or without aneurysm formation. However, it is now evident that other vessels like iliac arteries, coronary arteries, carotids, and others can also be affected being often underdiagnosed. Vascular involvement is expressed as vessel wall thickening, while aneurysm formation is also occasionally seen. Although histopathological findings are the cornerstone in the diagnosis of IgG4-RD, imaging modalities like magnetic resonance imaging (MRI) and positron emission tomography (PET) are similarly important when vascular involvement occurs, helping in the mapping of the disease and in identifying other, more accessible to biopsy, affected organs. Inflammation markers like erythrocyte sedimentation rate and C-reactive protein have also been described in IgG4-RD patients with vascular involvement. Herein, we present a case of a middle-aged man with long-term high inflammation markers who eventually diagnosed with IgG4-RD after an ascending aorta aneurysm operation, while a subsequent comprehensive magnetic resonance angiography revealed also involvement of the abdominal aorta and the left subclavian and left common carotid. Moreover, we sought to review the current literature about medium- and large-vessel involvement, beyond the aorta, in patients with IgG4-RD. © 2020, International League of Associations for Rheumatology (ILAR).

To assess non-compliance and potential changes in seasonal flu vaccination coverage before and during the Covid-19 pandemic in patients with autoimmune rheumatic diseases (ARDs). Consecutive patients with ARDs followed-up in 2 tertiary hospitals were telephone-interviewed (December 12–30, 2020) regarding seasonal flu vaccination during the 2019/20 and 2020/21 time periods. Self-reported disease flares that occurred after flu vaccination, as well as reasons for non-vaccination were recorded.One thousand fifteen patients were included. The rate of flu vaccination increased from 76% before to 83% during the COVID-19 pandemic (p = 0.0001). The rate of self-reported disease flares was < 1% among vaccinated patients. Reasons for not vaccination in both periods, respectively, included: ‘was not recommended by their rheumatologists’ (35.0vs.12.2%, p < 0.0001), ‘did not feel that they would have any benefit’ (36.9 vs. 32.6%), felt unsafe to do so (27.5 vs. 30.2%), or other reasons (18.9 vs. 23.8%). By multivariate analysis, age [OR = 1.03 (95% CI 1.02–1.04)] vs. [1.04 (95% CI 1.02–1.05)] and treatment with biologics [OR = 1.66 (95% CI 1.22–2.24) vs. [1.68 (95% CI 1.19–2.38)] were independent factors associated with vaccination in both periods. These findings, although are temporally encouraging, emphasize the need for continuous campaigns aiming at increasing patients’ and physicians’ awareness about the benefits of vaccination. © 2021, The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature.

We present a case of a 63-year old man with microscopic polyangiitis (MPA) in which the initial clinical presentation resembled the cranial form of giant cell arteritis (GCA) (headache, jaw claudication, low grade fever and raised inflammation markers). Ultrasound of both superficial common temporal arteries revealed signs indicative of vessel wall inflammation. Based on clinical picture and compatible imaging findings, treatment with corticosteroids for GCA was started. After initial improvement and steroid tapering, lung infltrations, mononeuritis of the right peroneal nerve and cutaneous necrosis appeared and p-antineutrophil cytoplasmic antibodies (ANCA) turned out to be positive. Three intravenous cy-clophosphamide pulses for MPA led in disease remission and maintenance treatment with azathioprine followed. Two years later, the patient has no symptoms and laboratory parameters are normal. This case highlights that MPA can affect temporal arteries and can masquerade as cranial GCA. ©Evangelatos G, Fragoulis GE, Iliopoulos A. This work is licensed under a Creative Commons Attribution 4.0 International License.

Background: Data regarding the real-life predictors of low disease activity (LDA) in rheumatoid arthritis (RA) patients are limited. Our aim was to evaluate the rate and predictors of LDA and treatment patterns in RA. Methods: This was a multicenter, prospective, RA cohort study where patients were evaluated in two different time points approximately 12 months apart. Statistical analysis was performed in order to identify predictors of LDA while patterns of disease-modifying anti-rheumatic drug [DMARDs; conventional synthetic (csDMARD) or biologic (bDMARD)] and glucocorticoid (GC) use were also recorded. Results: The total number of patients included was 1317 (79% females, mean age: 62.9 years, mean disease duration: 10.3 years). After 1 year, 57% had achieved LDA (DAS28ESR3.2), 21% initiated (among csDMARDs users) and 22% switched (among bDMARDs users) their bDMARDs. Conclusion: In a real-life RA cohort, during 1 year of follow-up, 43% of patients do not reach treatment targets while only ~20% of those with active RA started or switched their bDMARDs. Male sex, younger age, lower HAQ, body mass index and co-morbidity index were independent factors associated with LDA while use of GCs or ⩾2 bDMARDs were negative predictors. © The Author(s), 2020.

Background: We explore the spectrum of comorbidities in psoriatic arthritis (PsA) patients in comparison with other high comorbidity-burden diseases like rheumatoid arthritis (RA) and diabetes mellitus (DM). Methods: Two hundred and fifteen PsA patients, cross-sectionally collected from two tertiary hospitals, were compared with 215 RA and 215 DM patients (age/sex-matched, similar disease duration). Cardiovascular risk factors [hypertension, current smoking, hyperlipidaemia, obesity (body mass index (BMI) ⩾30)], coronary artery disease (CAD), stroke, major adverse cardiac events (MACEs; combined CAD and stroke), depression, osteoporosis and malignancies were recorded. Odds ratios (ORs) for stroke, CAD and MACE were adjusted for age, sex, hypertension, smoking, hyperlipidaemia, BMI, glucocorticoids use and those for depression were adjusted for age, sex, disease duration, skin involvement and smoking. Within the PsA group, associations between comorbidities and demographic/clinical features were assessed. Results: Depression [OR (95% confidence interval (CI)): 3.02 (1.57–5.81)], obesity [OR (95% CI): 2.83, (1.65–4.86)] and hyperlipidaemia [OR (95% CI): 1.96 (1.32–2.90)] were more prevalent in PsA compared with RA, while no differences were observed for CAD, stroke, MACE and malignancies. Depression [OR (95% CI): 4.85 (2.37–9.93)] and osteoporosis [OR (95% CI): 6.22 (1.33–29.2)] were more common in PsA than in DM. Hypertension, but not the other cardiovascular risk factors, was more frequent in DM [OR (95% CI) 0.49 (0.33–0.74)]. However, prevalence of stroke, CAD and MACE did not differ between PsA and DM. Within PsA group, depression was associated with age [OR (95% CI): 1.03 (0.99–1.06)], female sex [OR (95% CI): 3.47 (1.51–7.99)] and smoking [OR (95% CI): 2.78 (1.31–5.88)] while MACEs were associated with age [OR (95% CI): 1.08 (1.00–1.17)], male sex [OR (95% CI) for females: 0.26 (0.06–1.23) and hypertension [OR (95% CI): 6.07 (1.12–33.0)]. No differences were recorded in comorbidities between the different PsA phenotypes. Conclusion: Depression was more prevalent in PsA compared with RA and DM, while cardiovascular comorbidity was comparable to both groups, supporting the need for their assessment and management. © The Author(s), 2020.

Background: The COVID-19 pandemic is associated with emotional distress and significant disruptions in health-care services. These are key players in the development of nocebo phenomena. We aimed to investigate nocebo-prone behaviour in patients with autoimmune rheumatic diseases (ARD) amid the COVID-19 pandemic-associated lockdown. Methods: Consecutive patients were telephone-interviewed during the COVID-19 pandemic in Greece. Clinical and socioeconomic characteristics (eg, level of education) were recorded. For nocebo behaviour, a four-item validated questionnaire (Q-No, cut-off score>15), was used. Results were compared with pre-COVID-19 Q-No scores collected from patients followed-up in our department. Results: Nocebo behaviour was detected in 51/500 (10.2%) individuals. In patients with nocebo behaviour, use of anti-hypertensives was less common (17.6% vs 31.8%, p=0.04), but a higher level of education was more common (58.8% vs 35.9%, p=0.002), compared with patients with Q-No score ≤15; the latter retained statistical significance in multivariate regression analysis (p=0.009, OR [95%CI]: 2.29, [1.23-4.25]). Total Q-No scores were higher in the COVID-19-period compared to the pre-COVID-19 era [median (range); 12 (4-20) vs 11 (4-20), p=0.02]. Among 78 patients with available Q-No questionnaires in the pre-COVID-19 era, 11 (14.1%) displayed nocebo behaviour, which increased to 16 (20.5%) amid the COVID-19 pandemic. Interim development of nocebo behaviour was also associated with higher educational level (p=0.049, OR: 3.65, 95%CI: 1.005-13.268). Conclusion: A considerable proportion of ARD patients manifested nocebo-prone behaviour during the COVID-19 pandemic which was more common among those with high educational level. © 2020. Mediterranean Journal of Rheumatology.All Rights Reserved

The above article originally referred to 'Sex disparities in clinical characteristics and prognosis of immunoglobulin G4- related disease: a prospective study of 403 patients' by Wang et al., instead of 'Clinical phenotypes of IgG4-related disease reflect different prognostic outcomes' by Lanzillotta et al. This has now been corrected online. The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. © 2020 Oxford University Press. All rights reserved.

The olive fruit fly pheromone avidin-biotin ELISA immunoassay, based on the use of polyclonal G antibodies derived from rabbits (reported previously) and a newer assay, based on the use of polyclonal Y antibodies isolated from the eggs of laying hens (reported in this paper), were applied successfully for the analysis of natural pheromone in virgin adult female olive fruit flies. According to the results obtained, the pheromone content in the glands of adult female olive fruit flies increases from the third to the ninth day of their age. During the calling period, the female olive fruit flies seem to emit ∼1.1 μg pheromone/insect/day at least. The immunoassay, based on the Y antibodies, is slightly more sensitive (detection limit 40 ng/mL) than the assay based on polyclonal anti-pheromone rabbit antiserum (detection limit 80 ng/mL). As revealed by thorough cross-reactivity studies, including 14 structurally similar to the olive fruit fly pheromone molecules, the newer immunoassay is less selective than the previous one and seems to cross react with few molecules bearing the spiroketal moiety. © 2007 Elsevier B.V. All rights reserved.

An enzyme-linked immunosorbent assay (ELISA) for the olive fruit fly pheromone, Bactrocera oleae Gmelin, was developed. The assay uses polyclonal antibodies, raised in rabbits, against (±)-β-[3-(1,7-dioxaspiro[5.5] undecane)]propionic acid, 2 (hapten I), conjugated to the KLH (keyhole limpet hemocyanin) by the carbodiimide method. A second hapten, (±)-δ-[3- (1,7-dioxaspiro[5.5]undecane)]-butylamine, 3 (hapten II), after conjugation to a biotin moiety, was used for indirect immobilization onto ELISA microwells precoated with the glycoprotein avidin. The developed ELISA method measures the synthetic olive fruit fly pheromone in concentrations ranging between 0.08 and 10 μg/mL and shows great promise for practical applications for pheromone detection in environmental and biological samples. The results obtained strongly indicate that this technique, to our knowledge the first insect pheromone enzyme-linked immunosorbent assay so far reported, is a fast, sensitive, inexpensive, and highly convenient method for the analysis of a volatile and low molecular weight compound such as 1,7-dioxaspiro[5.5]undecane, 1.

Objectives - To analyse biotin concentrations in human cerebrospinal fluid (CSF) and serum from controls without evidence of nutritional or neurological disorders and patients with common neurological disorders. Patients and methods - Cerebrospinal fluid was obtained from patients by lumbar puncture, serum was prepared from freshly drawn whole blood and biotinidase in samples was inhibited before being analysed for biotin by radioligand assay. Results - Assay characteristics were within an acceptable range (intra-and interassay coefficient of variations were 8.8 and 12.0 respectively, recovery: 91-114% and sensitive, lowest standard concentration 15 ng/l). Significantly lower values for biotin were found in patients with multiple sclerosis (both CSF and serum) in comparison to the controls. Significantly reduced values for cerebrospinal fluid biotin were found in epileptics compared to controls, whereas, in serum the difference was approaching significance. No significant differences were observed in other groups of patients. Conclusion - There is a significant reduction in cerebrospinal fluid biotin in epileptics and patients with multiple sclerosis compared to controls. In epileptics this may be related to competition between biotin and anticonvulsants bearing carbamide ring for absorption. Reduction of biotin levels in patients with multiple sclerosis could be attributed to intestinal malabsorption caused by the underlying disease or a biotin-binding immunoglobulin which may be involved in multiple sclerosis pathogenesis.

A large-scale method for the isolation of thymosin beta 4 (up to 120 mg) and thymosin beta 9 (up to 40 mg) from bovine lung (up to 2 kg) was developed. The isolation protocol included tissue homogenization in 0.4 M HClO4, centrifugation, solid-phase extraction through LiChroprep RP-18 material, chromatofocusing on polybuffer exchanger PBE 94-modified Sepharose and dialysis against water. The isolated products were characterized by analytical isoelectric focusing, reversed-phase HPLC, electrospray ionization mass spectrometry and amino acid analysis. The method developed is rapid and convenient, requires no expensive equipment and can be used for the isolation of thymosin beta 4 and homologous peptides from various animal tissues. J Chromatogr B Biomed Appl