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Despite gains at lower levels, women have made limited inroads into leadership roles in international organizations. Using a novel data set of both nominees and selected heads of 129 international organizations, we uncover several empirical patterns. Women’s representation at the highest levels remains far below parity but has been improving steadily since the 1990s. One caveat is that this improvement has only occurred in a subset of institutions, which suggests a concentration of women leaders. Based on the available data, we examine whether the appointment of a woman leader impacts equality in the institution’s overall staffing profile. We find that such changes occur only once there is a history of appointing women. We also look at the nominations process and find that when women are included in the nominee pool, they tend to be selected, although often they are absent. Our analysis contributes much-needed data to the broader literature on leadership in international organizations and introduces a new data set with a range of other potential applications.

Objective To test whether the presence of structural entheseal lesions in psoriasis patients influences the risk for the progression to psoriatic arthritis (PsA). Methods Prospective cohort study on psoriasis patients without clinical evidence of musculoskeletal involvement receiving baseline assessment of structural entheseal lesions and volumetric bone mineral density (vBMD) at entheseal and intra-articular sites by high-resolution peripheral quantitative computed tomography (HR-pQCT). Adjusted relative risks of developing PSA associated with baseline volumetric bone density and the presence of structural entheseal lesions were calculated using multivariable Cox regression models. Results The cohort included 114 psoriasis patients (M/F 72/42) with a mean (SD) follow-up duration of 28.2 (17.7) months, during which 24 patients developed PsA (9.7 /100 patient-years, 95%CI 6.2 to 14.5). Patients with structural entheseal lesions were at higher risk of developing PsA compared to patients without such lesions (21.4/100 patient-years, 95%CI 12.5 to 34.3, HR 5.10, 95%CI 1.53 to 16.99, p=0.008). With respect to vBMD, a 1-standard deviation increase in entheseal, but not intra-articular vBMD was associated with an approximate 30% reduced risk to progress to PsA. Especially, higher cortical vBMD at entheseal segments was associated with a lower risk of developing PsA (HR 0.32 per SD, 95%CI 0.14 to 0.71), and remained robust after multiple imputation of missing data (HR 0.64, 95%CI 0.42 to 0.98). Conclusion Presence of structural entheseal lesions as well as low cortical vBMD at entheseal segments are associated with an increased risk of developing PsA in patients with psoriasis.

The balance between bone forming osteoblasts and bone resorbing osteoclasts can be disturbed in autoimmune diseases resulting in local and systemic bone loss. It was long time believed that autoantibodies only indirectly contribute to bone loss by fueling the overall inflammation. However, in the last decade, more and more evidence emerged that autoantibodies and immune complexes directly activate osteoclasts and pre-osteoclasts by binding to Fcγ receptors (FcγRs) on the (pre)-osteoclast cell surface. This pro-osteoclastogenic effect seems to be dependent on the absence of sialic acid in the IgG Fc glycan, which is a typical feature of many autoantibodies. Clinical studies revealed the importance of autoantibody-mediated bone loss mainly in rheumatoid arthritis, but also in other diseases, such as celiac disease. In summary, the gained knowledge about autoantibody-mediated bone loss helps to better understand bone pathologies of autoimmune diseases. However, studies are still relatively limited and more research is needed to fully understand the impact of autoantibodies on bone and to develop future therapeutic strategies. Das Gleichgewicht zwischen knochenbildenden Osteoblasten und knochenresorbierenden Osteoklasten kann bei Autoimmunerkrankungen gestort sein, wodurch es zu lokalem und systemischem Knochenverlust kommt. Es wurde lange Zeit angenommen, dass Autoantikorper nur indirekt zum Knochenverlust beitragen, indem sie die Entzundung befeuern. In den letzten zehn Jahren gab es jedoch immer mehr Hinweise darauf, dass Autoantikorper und Immunkomplexe Osteoklasten und Praosteoklasten direkt aktivieren, indem sie an Fcγ-Rezeptoren (FcγRs) auf der (Pra-) Osteoklastenoberflache binden. Diese pro-osteoklastogene Wirkung scheint von der Abwesenheit von Sialinsaure im IgG-Fc-Glykan abhangig zu sein, was ein typisches Merkmal vieler Autoantikorper ist. Klinische Studien zeigten die Bedeutung des autoantikorpervermittelten Knochenverlusts hauptsachlich bei rheumatoider Arthritis, aber auch bei anderen Krankheiten wie Zoliakie. Zusammengenommen hilft das gewonnene Wissen uber autoantikorpervermittelten Knochenverlust, die Knochenpathologien von Autoimmunerkrankungen besser zu verstehen. Bisher gibt es jedoch nur relativ wenige Studien und es sind weitere Forschungsarbeiten erforderlich, um die Auswirkungen von Autoantikorpern auf den Knochen vollstandig zu verstehen und zukunftige Therapiestrategien zu entwickeln.

To study the effect of levilimab or baricitinib in combination with standard therapy (ST) on the incidence of severe viral pneumonia associated with a new coronavirus infection COVID-19.A multicenter, open-label observational study of the efficacy and safety of levilimab in combination with ST (group 1, n=100), baricitinib in combination with ST (group 2, n=139), or in comparison with ST (group 3, n=200) in outpatients with verified CT-1 pneumonia.According to the results of laboratory tests, patients treated with levilimab in combination with ST had the best dynamics of changes in CRP from reliably the highest level (mg/L) to the lowest in comparison with other groups. In the group of patients with ST, in contrast to the other groups, no dynamics of CRP was observed by day 5 of therapy. In group of hospitalized patients initially receiving levilimab in addition to ST, the rate of transfer to the intensive care unit (2 patients, 9.52%) and length of stay (4 days) was significantly lower compared to the values in patients in both the baricitinib group in combination with ST (7 patients, 15.56%; 5 days [interquartile range 36.5]) and in patients receiving ST alone (7 patients, 15.56%; 5 days [interquartile range 36.5]). Also in hospitalized patients we observed no statistically significant intergroup differences in the incidence of infectious complications and thromboembolic events, which confirms the safety of including levilimab or baricitinib in COVID-19 pathogenetic therapy regimens. Observational results support the hypothesis that the initial inclusion of levilimab or baricitinib in addition to ST is accompanied by a reduced risk of viral pneumonia progression.The addition of levilimab or baricitinib to the therapy regimen for coronavirus infection during the outpatient phase has demonstrated a preemptive anti-inflammatory effect and reduced the probability of lung tissue damage progression.Цель. Изучить влияние препаратов левилимаба или барицитиниба в комбинации со стандартной терапией (СТ) на частоту развития тяжелой вирусной пневмонии, ассоциированной с новой коронавирусной инфекцией COVID-19. Материалы и методы. Многоцентровое открытое наблюдательное исследование эффективности и безопасности левилимаба в сочетании с СТ (1-я группа, n=100), барицитиниба в сочетании с СТ (2-я группа, n=139) или в сравнении с СТ (3-я группа, n=200) на амбулаторном этапе у пациентов с верифицированной пневмонией КТ-1. Результаты. По результатам лабораторных исследований у пациентов, получавших левилимаб в сочетании с СТ, была достигнута наилучшая динамика уровня С-реактивного белка (СРБ) с достоверно наибольшего уровня (мг/л) к наименьшему по сравнению с другими группами. У пациентов, которые получали только СТ, в отличие от остальных групп динамика показателя СРБ к 5-му дню терапии не наблюдалась. Среди госпитализированных пациентов, изначально получавших левилимаб в дополнение к СТ, частота перевода в отделение реанимации и интенсивной терапии (2 пациента, 9,52%) и длительность пребывания в нем (4 дня) были существенно ниже по сравнению со значениями показателей как у пациентов в группе барицитиниба в сочетании с СТ (7 пациентов, 15,56%; 5 дней [межквартильный размах 36,5]), так и у пациентов, получавших только СТ (7 пациентов, 15,56%; 5 дней [межквартильный размах 36,5]). У госпитализированных пациентов также отметили отсутствие статистически значимых межгрупповых различий в частоте развития инфекционных осложнений и тромбоэмболических событий, что подтверждает безопасность включения левилимаба или барицитиниба в схемы патогенетической терапии COVID-19. Заключение. При добавлении препаратов левилимаб или барицитиниб в схему терапии коронавирусной инфекции на амбулаторном этапе продемонстрирован упреждающий противовоспалительный эффект и снижение вероятности прогрессии поражения легочной ткани.

Immune-escape hepatitis B virus (HBV) mutants play an important role in HBV spread. Recently, the multivalent vaccine Bubo®-Unigep has been developed to protect against both wild-type HBV and the most significant G145R mutant. Here, we compared the effects of recombinant HBsAg antigens, wild-type and mutated at G145R, both included in the new vaccine, on activation of a human high-density culture of peripheral blood mononuclear cells (PBMC) in vitro. The antigens were used either alone or in combination with phytohemagglutinin (PHA). None of the antigens alone affected the expression of CD40, HLA-DR or CD279. Wild-type HBsAg enhanced CD86 and CD69 expression, and induced TNF-α, IL-10, and IFN-γ, regardless of the anti-HBsAg status of donor. In the presence of PHA, wild-type HBsAg had no effect on either of the tested surface markers, but increased IFN-γ and IL-10 and inhibited IL-2. In contrast, the G145R mutant alone did not affect CD86 expression, it induced less CD69, and stimulated IL-2 along with lowering levels of TNF-α, IL-10, and IFN-γ. The G145R mutant also suppressed PHA-induced activation of CD69. The dramatic differences in the immune responses elicited by wild-type HBsAg and the G145R mutant HBsAg suggest distinct adaptive capabilities of the G145R mutant HBV.

Developing countries today have become more active participants in regional trade agreements. This raises questions about how the benefits of integration are distributed, and the extent to which lower‐income countries are able to capture development gains. Historically, such impacts have been difficult to identify with precision. This paper seeks to address this gap by empirically analysing the impact of regional integration on development, particularly the effects on growth and welfare. Using both bilateral and regional integration measures, we show that the ability to capture gains from integration varies across developing country regional groups, with developing Asia benefiting on par with developed countries. The findings in the paper indicate that trade and trade policy play an important role in reducing inequality and poverty in developing countries. It also shows that regionalism can function as a channel to make multilateralism a more adept way of addressing national challenges.

Objectives Psoriatic arthritis (PsA) is associated with bone erosion and inflammation-induced bone loss, which are mediated by osteoclasts (OC) and modulated by inflammatory cytokines. Apremilast (APR) (a selective phosphodiesterase 4 inhibitor) is efficacious in PsA and acts by inhibiting cytokine production. However, there are no direct data informing whether and how APR affects osteoclast formation in humans. Methods Osteoclastogenic cytokine production by activated human peripheral blood mononuclear cells (PBMCs) was measured in the presence and absence of APR. Effects of APR on osteoclast differentiation were tested (i) in co-cultures of activated PBMCs and human CD14+ blood monocytes as well as (ii) in CD14+ blood monocytes stimulated with activated-PBMCs supernatant, TNF or IL-17A. Bone resorption was measured on OsteoAssay plates. Effects of APR on ex vivo osteoclast differentiation were compared in PsA, pre-PsA and psoriasis patients, as well as in healthy controls. Results APR significantly impaired the expression of key osteoclastogenic cytokines in activated PBMCs. Furthermore, APR dose-dependently and significantly inhibited activated PBMC-driven osteoclast differentiation and ex vivo osteoclast differentiation of PBMCs derived from PsA and pre-PsA patients, but not from psoriasis patients or healthy controls. TNF and IL-17A-enhanced osteoclastogenesis and osteolytic activity of CD14+ blood monocytes from PsA patients was also significantly inhibited by APR. Finally, APR inhibited expression of the key osteoclast fusion protein dendritic cell-specific transmembrane protein. Conclusion Phosphodiesterase 4 targeting by APR not only inhibits osteoclastogenic cytokine production, but also directly suppresses inflammation-driven osteoclastogenesis. These data provide initial evidence that APR has the potential to provide a direct bone protective effect in PsA.

Autoantibodies represent a hallmark of rheumatoid arthritis (RA), with the rheumatoid factor (RF) and antibodies against citrullinated proteins (ACPA) being the most acknowledged ones. RA patients who are positive for RF and/or ACPA (“seropositive”) in general display a different etiology and disease course compared to so-called “seronegative” patients. Still, the seronegative patient population is very heterogeneous and not well characterized. Due to the identification of new autoantibodies and advancements in the diagnosis of rheumatic diseases in the last years, the group of seronegative patients is constantly shrinking. Aside from antibodies towards various post-translational modifications, recent studies describe autoantibodies targeting some native proteins, further broadening the spectrum of recognized antigens. Next to the detection of new autoantibody groups, much research has been done to answer the question if and how autoantibodies contribute to the pathogenesis of RA. Since autoantibodies can be detected years prior to RA onset, it is a matter of debate whether their presence alone is sufficient to trigger the disease. Nevertheless, there is gathering evidence of direct autoantibody effector functions, such as stimulation of osteoclastogenesis and synovial fibroblast migration in in vitro experiments. In addition, autoantibody positive patients display a worse clinical course and stronger radiographic progression. In this review, we discuss current findings regarding different autoantibody types, the underlying disease-driving mechanisms, the role of Fab and Fc glycosylation and clinical implications.

Digital technologies have features that may attenuate the core benefits of industrial hubs. The assumption that geography via co-location facilitates technology spillover provides the basis for the policy design of industrial hubs. Yet, this goes against digital trends in global value chains which enable longer and more dispersed value chains by reducing the need for high levels of trust between entities. We explore the impact of one specific type of digital technology—blockchain—that fundamentally shifts the importance of geography for trade. We illustrate some of the problems with hubs using an extended discussion of multilateral trading rules. Finally, we close with a look at the sustainability angle and whether using a distributed architecture can promote the sustainability production with which hubs struggle.

Background C-reactive protein (CRP) is often normal in patients with psoriatic disease. Herein, we aimed to define markers of systemic inflammation in patients with monomorphic and polymorphic psoriatic skin, entheseal, and joint disease. Methods Three-step approach: (i) selection of serum markers elevated in psoriatic arthritis compared healthy controls from a panel of 10 different markers reflecting the pathophysiology of psoriatic disease; (ii) testing of these selected markers as well as C-reactive protein (CRP) in a larger cohort of 210 individuals- 105 healthy controls and 105 patients with psoriatic disease with either monomorphic skin (S), entheseal (E) or joint (A) involvement or polymorphic disease with various combinations of skin, entheseal and joint disease (SE, SA, EA, SEA); (iii) testing whether tumor necrosis factor (TNF) and interleukin (IL)-17 inhibitor therapy normalizes these markers. Results CRP was not elevated or was rarely elevated in the subgroups (S 0%, E 0%, A 20%, SE 7%, SA 33%, EA 27%, SEA 33%) despite active psoriatic disease. In sharp contrast, beta-defensin 2 and lipocalin-2 levels were elevated in the majority of patients with monomorphic skin (93% and 73%) and entheseal (both 53%), but not joint disease (27% and 20%). Conversely, elevations of calprotectin and IL-8 were found in the majority of patients with monomorphic joint disease (both 73%). IL-22 was elevated in all three monomorphic disease manifestations (S 60%, E 46%; A 60%). Furthermore, the vast majority of patients with polymorphic psoriatic disease (SE, SA, EA, SEA) showed widespread marker elevation. IL-17- and TNF inhibitor treatment significantly lowered all 5 markers of inflammation in PsA patients. Conclusions Systemic inflammation is detectable in the majority of patients with psoriatic disease, even if CRP is normal. The respective marker pattern depends on the manifestation of psoriatic disease with respect to skin, entheseal, and joint involvement.

Monomeric serum immunoglobulin A (IgA) can contribute to the development of various autoimmune diseases, but the regulation of serum IgA effector functions is not well defined. Here, we show that the two IgA subclasses (IgA1 and IgA2) differ in their effect on immune cells due to distinct binding and signaling properties. Whereas IgA2 acts pro-inflammatory on neutrophils and macrophages, IgA1 does not have pronounced effects. Moreover, IgA1 and IgA2 have different glycosylation profiles, with IgA1 possessing more sialic acid than IgA2. Removal of sialic acid increases the pro-inflammatory capacity of IgA1, making it comparable to IgA2. Of note, disease-specific autoantibodies in patients with rheumatoid arthritis display a shift toward the pro-inflammatory IgA2 subclass, which is associated with higher disease activity. Taken together, these data demonstrate that IgA effector functions depend on subclass and glycosylation, and that disturbances in subclass balance are associated with autoimmune disease., Immunoglobulin A (IgA) has two subclasses, IgA1 and IgA2, but differential effects on inflammation are unclear. Here the authors show that IgA2, when compared with IgA1, has stronger pro-inflammatory functions associated with changed glycosylation and higher disease scores in patients with rheumatoid arthritis.

Alcohol consumption is a consistent protective factor for the development of autoimmune diseases such as rheumatoid arthritis (RA). The underlying mechanism for this tolerance-inducing effect of alcohol, however, is unknown. Here we show that alcohol and its metabolite acetate alter the functional state of T follicular helper (TFH) cells in vitro and in vivo, thereby exerting immune regulatory and tolerance-inducing properties. Alcohol-exposed mice have reduced Bcl6 and PD-1 expression as well as IL-21 production by TFH cells, preventing proper spatial organization of TFH cells to form TFH:B cell conjugates in germinal centers. This effect is associated with impaired autoantibody formation, and mitigates experimental autoimmune arthritis. By contrast, T cell independent immune responses and passive models of arthritis are not affected by alcohol exposure. These data clarify the immune regulatory and tolerance-inducing effect of alcohol consumption., Moderate consumption of alcohol is associated with protection from some autoimmune diseases. Here the authors show that ethanol and its metabolite acetate can protect mice from collagen-induced arthritis and provide evidence that the mechanism of this effect might be via inhibition of the effector function of T follicular helper cells.

Objectives A substantial proportion of RA patients flare upon withdrawal of DMARDs, and thus the definition of prognostic markers is crucial. ACPA positivity has been identified as a risk factor for flare. However, only the role of IgG ACPA is established in this context, while the role of IgA ACPA is poorly defined. We thus aimed to investigate the role of IgA ACPA in flaring of RA. Methods Serum levels of IgA1 and IgA2 ACPA at baseline and after 12 months were measured in 108 patients from the randomized controlled RETRO study. RA patients in stable remission for at least 6 months at study recruitment were assigned to either one of the DMARD tapering arms or to continuation of DMARDs. Results In patients remaining in remission but not in the ones who flared, IgA2 ACPA levels and proportion of IgA2 in ACPA (IgA2% ACPA) significantly declined (median of 17.5%; P Conclusion In this study, IgA ACPA was identified as a risk factor for flare in combination with IgG ACPA. IgA2 ACPA levels were associated with flare severity and declined in patients in stable remission.

OBJECTIVE: B cell depletion is an established therapeutic principle in a wide range of autoimmune diseases. However, B cells are also critical for inducing protective immunity after infection and vaccination. We undertook this study to assess humoral and cellular immune responses after infection with or vaccination against SARS-CoV-2 in patients with B cell depletion and controls who are B cell-competent. METHODS: Antibody responses (tested using enzyme-linked immunosorbent assay) and T cell responses (tested using interferon-I³ enzyme-linked immunospot assay) against the SARS-CoV-2 spike S1 and nucleocapsid proteins were assessed in a limited number of previously infected (n = 6) and vaccinated (n = 8) autoimmune disease patients with B cell depletion, as well as previously infected (n = 30) and vaccinated (n = 30) healthy controls. RESULTS: As expected, B cell and T cell responses to the nucleocapsid protein were observed only after infection, while respective responses to SARS-CoV-2 spike S1 were found after both infection and vaccination. A SARS-CoV-2 antibody response was observed in all vaccinated controls (30 of 30 [100%]) but in none of the vaccinated patients with B cell depletion (0 of 8). In contrast, after SARS-CoV-2 infection, both the patients with B cell depletion (spike S1, 5 of 6 [83%]; nucleocapsid, 3 of 6 [50%]) and healthy controls (spike S1, 28 of 30 [93%]; nucleocapsid, 28 of 30 [93%]) developed antibodies. T cell responses against the spike S1 and nucleocapsid proteins were found in both infected and vaccinated patients with B cell depletion and in the controls. CONCLUSION: These data show that B cell depletion completely blocks humoral but not T cell SARS-CoV-2 vaccination response. Furthermore, limited humoral immune responses are found after SARS-CoV-2 infection in patients with B cell depletion.