Background Omalizumab (OMA) was the first FDA-approved biological drug for severe chronic spontaneous urticaria (CSU), and until today is the only beneficial and truly safe one. The objectives were: To assess the prevalence of CSU patients in whom OMA cannot be stopped over time. We also asked if biomarkers (e.g., anti-TPO antibodies and total IgE) could assist in anticipating this issue.Methods We used our prospective registry of 93 patients, which included CSU disease duration, the onset of OMA treatment, Urticaria Activity Score (UAS7) during follow-up, co-morbidities, serum IgE levels and the presence of anti-TPO antibodies. Finally, we assessed the response to OMA during a period of six years.Results Out of the 93 treated CSU patients, OMA was stopped in ten patients after six months being defined as failures. In another ten patients, OMA was discontinued after 2-4 years of therapy, achieving a remission. Seventy-three patients are still treated between 2 and 6 years, having different degrees of response. Of these, in thirty-eight (52%) patients, we could not stop OMA even after six years due to CSU relapses. The prevalence of lower serum IgE levels and anti-TPO antibody positivity was significantly higher in CSU patients in whom OMA could not be stopped.Conclusion This is the first study where OMA-treated CSU patients were followed up to six years. In half of them, long-term therapy of six years is still required.

Chronic spontaneous urticaria (CSU) is considered an autoimmune disorder in 50% of cases at least, in which T‐ and mast cell mediators are considered to be the primary cause of symptoms. However, H1‐antihistamines, cyclosporine A, and omalizumab fail to achieve complete symptom amelioration in up to 70% of patients. This suggests that other inflammatory pathways are involved and that additional and more effective treatments need to be developed.

ENWEndNote BIBJabRef, Mendeley RISPapers, Reference Manager, RefWorks, Zotero AMA Zuberbier T, Aberer W, Asero R, et al. Wytyczne EAACI/GA2LEN/EDF/WAO dotyczące definicji, klasyfikacji, diagnostyki i leczenia pokrzywki. Alergologia Polska - Polish Journal of Allergology. 2020;7(1):1-28. doi:10.5114/pja.2020.93827. APA Zuberbier, T., Aberer, W., Asero, R., Latiff, A. H., Baker, D., & Ballmer-Weber, B. et al. (2020). Wytyczne EAACI/GA2LEN/EDF/WAO dotyczące definicji, klasyfikacji, diagnostyki i leczenia pokrzywki. Alergologia Polska - Polish Journal of Allergology, 7(1), 1-28. https://doi.org/10.5114/pja.2020.93827 Chicago Zuberbier, T., W. Aberer, R. Asero, A. H Latiff, D. Baker, B. Ballmer-Weber, and J. A Bernstein et al. 2020. "Wytyczne EAACI/GA2LEN/EDF/WAO dotyczące definicji, klasyfikacji, diagnostyki i leczenia pokrzywki". Alergologia Polska - Polish Journal of Allergology 7 (1): 1-28. doi:10.5114/pja.2020.93827. Harvard Zuberbier, T., Aberer, W., Asero, R., Latiff, A., Baker, D., Ballmer-Weber, B., Bernstein, J., Bindslev-Jensen, C., Brzoza, Z., Bedrikow, R., Canonica, G., Church, M., Craig, T., Danilycheva, I., Dressler, C., Ensina, L., Giménez-Arnau, A., Godse, K., Gonçalo, M., Grattan, C., Hebert, J., Hide, M., Kaplan, A., Kapp, A., Katelaris, C., Kocatürk, E., Kulthanan, K., Larenas-Linnemann, D., Leslie, T., Magerl, M., Mathelier-Fusade, P., Meshkova, R., Metz, M., Nast, A., Nettis, E., Oude-Elberink, H., Rosumeck, S., Saini, S., Sánchez-Borges, M., Schmid-Grendelmeier, P., Staubach, P., Sussman, G., Toubi, E., Vena, G., Vestergaard, C., Wedi, B., Werner, R., Zhao, Z., and Maurer, M. (2020). Wytyczne EAACI/GA2LEN/EDF/WAO dotyczące definicji, klasyfikacji, diagnostyki i leczenia pokrzywki. Alergologia Polska - Polish Journal of Allergology, 7(1), pp.1-28. https://doi.org/10.5114/pja.2020.93827 MLA Zuberbier, T. et al. "Wytyczne EAACI/GA2LEN/EDF/WAO dotyczące definicji, klasyfikacji, diagnostyki i leczenia pokrzywki." Alergologia Polska - Polish Journal of Allergology, vol. 7, no. 1, 2020, pp. 1-28. doi:10.5114/pja.2020.93827. Vancouver Zuberbier T, Aberer W, Asero R, Latiff A, Baker D, Ballmer-Weber B et al. Wytyczne EAACI/GA2LEN/EDF/WAO dotyczące definicji, klasyfikacji, diagnostyki i leczenia pokrzywki. Alergologia Polska - Polish Journal of Allergology. 2020;7(1):1-28. doi:10.5114/pja.2020.93827.

Sarcoidosis is a systemic granulomatous disease that develops due to the Th1, Th17 and Treg lymphocytes disturbance. There is an assumption, that B cells and follicular T-helper (Tfh) cells may play an important role in this disorder, as well as in several other autoimmune diseases. The aim of this study was to determine CD19+ B cells subset distribution in the peripheral blood and to define disturbance in the circulating Tfh cells subsets in patients with sarcoidosis. The prospective comparative study was performed in 2016–2018, where peripheral blood B cell subsets and circulating Tfh cell subsets were analyzed in 37 patients with primarily diagnosed sarcoidosis and 35 healthy donors using multicolor flow cytometry. In the results of our study we found the altered distribution of peripheral B cell subsets with a predominance of “naïve” (IgD + CD27−) and activated B cell (Bm2 and Bm2′) subsets and a decreased frequency of memory cell (IgD+ CD27+ and IgD− CD27+) in peripheral blood of sarcoidosis patients was demonstrated. Moreover, we found that in sarcoidosis patients there are increased levels of B cell subsets, which were previously shown to display regulatory capacities (CD24+++ CD38+++ and CD5 + CD27−). Next, a significantly higher proportion of CXCR5-expressing CD45RA − CCR7+ Th cells in patients with sarcoidosis in comparison to the healthy controls was revealed, that represents the expansion of this memory Th cell subset in the disease. This is the first study to demonstrate the association between the development of sarcoidosis and imbalance of circulating Tfh cells, especially CCR4− and CXCR3-expressing Tfh subsets. Finally, based on our data we can assume that B cells and Tfh2- and Tfh17-like cells – most effective cell type in supporting B-cell activity, particularly in antibody production – may be involved in the occurrence and development of sarcoidosis and in several other autoimmune conditions. Therefore, we can consider these results as a new evidence of the autoimmune mechanisms in the sarcoidosis development.

Background The immune regulatory properties of semaphorin3A (sema3A) (both innate and adaptive) are well established in many in-vitro studies. When sema3A was incubated with active B cells from SLE patients, it could efficiently reduce the expression of TLR-9 in correlation with a significant reduction of relevant auto-antibodies. The injection of sema3A to a mice model of rheumatoid arthritis was proven to be highly beneficial, both in attenuating clinical symptoms and in decreasing inflammatory mechanisms. Objectives This study was designed in order to assess possible therapeutic benefits following the injection of sema3A to NZB/W mice. Results The injection of sema3A to young mice (at week 12) before disease onset, delayed the appearance of proteinuria. Here, the median time to severe proteinuria was 110 days, 95% CI: 88 to 131. However, in mice in which empty vector was injected, median time to severe proteinuria was 63 days, 95% CI: 0 to 139). Sema3A treatment, reduced significantly renal damage, namely, it prevented the development of immune deposits in the glomeruli. When sema3A was injected at the onset of proteinuria, aiming to treat rather than to prevent disease in these mice, survival was significantly increased and the deterioration of proteinuria was significantly delayed. Conclusion Semaphorin3A is highly beneficial in reducing lupus nephritis in NZB/w mice. It delays the appearance and deterioration of proteinuria, and increases survival rates in these mice. Further studies will establish the idea of applying sema3A in the treatment of lupus nephritis.

Introduction: Semaphorin-4D (CD100), generated by CD4/CD8 T-cells and its receptor on B cells - CD72, play a role in immune regulation. Both have soluble forms - sCD100/sCD72. Methods: 5CD100 and sCD72 levels were determined by ELISA (MyBioSource, USA). Results: 28 chronic HIV patients and 50 matched healthy volunteers participated in our study. Before treatment, CD4 T-cells counts were 267 +/- 216 cells/mcl and viral load (VL) was 586,675 +/- 1897,431 copies/ml. Two years following HAART, CD4 T-cells counts rose to 475 +/- 264 cells/mcl and VL dropped to 2050 +/- 10,539 copies/ml. CD8 T-cells counts were stable. sCD72 levels prior (4.13 +/- 2.03 ng/ml) and following HAART (3.53 +/- 2.01 ng/ml) were similar to control levels (4.51 +/- 2.66 ng/ml). 5CD100 levels before (40.47 +/- 31.4 ng/ml) and following HAART (37.68 +/- 29.44 ng/ml) were significantly lower compared to controls (99.67 +/- 36.72 ng/ml) despite the significant increase in CD4 T-cells counts. Conclusions: The permanent low levels of the immunoregulator sCD100 suggest a role for CD100 in the immune dysfunction and T cells exhaustion of HIV. (C) 2017 Elsevier Inc. All rights reserved.

In this case, we present a patient with unilateral salivary gland enlargement and periorbital edema with erythematous rash. We discuss the differential diagnosis and the relevant therapy. Mediterr J Rheumatol 2017;28(1):57-8 https://doi.org/10.31138/mjr.28.1.57 Article Submitted 21/09/2016; Revised form 28/11/2016; Accepted 13/12/2016 Corresponding author: Alexandros A. Drosos, MD, FACR, PhD Professor of Medicine/Rheumatology Rheumatology Clinic, Department of Internal Medicine Medical School of the University of Ioannina Ioannina 45110, Greece Tel.: +302651007503 Fax: +302651007054 E-mail: adrosos@cc.uoi.gr Dermatomyositis sine myositis – Case presentation Evripidis Kaltsonoudis, Eleftherios Pelechas , Alexandros A. Drosos Rheumatology Clinic, Department of Internal Medicine, Medical School University of Ioannina, Ioannina, Greece MEDITERRANEAN JOURNAL OF RHEUMATOLOGY 28 1 2017 58 2. Although Sjögren’s syndrome could manifest with parotid gland enlargement (unilateral or bilateral) as the first manifestation,3 in this case, the patient did not have xerostomia, xerophthalmia and also had a negative Schirmer’s test and a negative salivary gland biopsy. Finally, the laboratory workup did not show any specific autoantibodies. 3. In order to diagnose SLE, 4 out of 11 criteria should be met.4 In our case, the patient had (subjective) photosensitivity, and a (weakly) positive ANA titer only two of those criteria. Patients with Dermatomyositis are at times difficult to distinguish from patients with subacute cutaneous lupus erythematosus.5 4. Dermatomyositis sine myositis or amyopathic Dermatomyositis is a rare but distinct subtype of Dermatomyositis.6 It is diagnosed in patients with typical cutaneous manifestations (consisting of heliotrope rash, facial erythema and edema, Gottron’s papules and periungual telangiectasia) in whom there is no evidence of muscle weakness and who repeatedly have normal serum muscle enzyme levels. There is a female to male preponderance (3:1) and the onset of the disease usually occurs in early adulthood. Dermatomyositis sine myositis should be aggressively treated even in the absence of muscle involvement since intense and prolonged skin inflammation can result in cutaneous ulceration and calcinosis. Treatment is based on systemic immunosuppressive therapy (high dose corticosteroids, methotrexate, azathioprine, mycophenolate) or immunomodulatory therapy (high dose intravenous immunoglobulins). In the presented case, the patient was treated with high dose of methylprednisolone (32mg) once a day along with calcium and vitamin D supplements. A month later, the patient showed significant improvement of the rash (Figure 1 right). In addition, she did not develop muscle weakness or muscle enzyme abnormalities. In conclusion, DsM, even a rare condition, should be a differential to be borne in mind for clinicians because it needs an aggressive treatment in order to prevent chronic skin changes and systemic complications such as pulmonary involvement. Finally, a close observation of the patient is mandatory, as DsM has been associated with different types of malignancies. CONFLICT OF INTEREST The authors declare no conflict of interest.

B regulatory cells (Bregs) belong to a subgroup of activated B cells tasked with maintaining self-tolerance and preventing autoimmunity. While sharing similar regulatory mechanisms such as IL-10 dependency, they also defer in exhibiting their suppressive effects by expressing Fas-Ligand, TGF-beta and PDL-1. In this study we show, for the first time, the expansion of CD25highFoxP3high Bregs in systemic lupus erythematosus (SLE) patients compared to healthy individuals (18.5 ± 3.052% vs 11.0 ± 1.654%, p < 0.001, respectively). This expansion was also shown to correlate with SLE disease activity (r = 0.75). In addition, CD25highFoxP3high Bregs were also IL-10high expressing, and further expanded when stimulated with semaphorin3A. In sum we show that CD25highFoxP3high are an additional subtype of Bregs, involved in regulating SLE disease activity. Being IL-10 expressing, we may assume that they are one of the sources of increased serum IL-10 in SLE patients. Further studies are required in order to assess the relation between high serum IL-10 and CD25highFoxp3high Breg cells.

Introduction Though of dual function, CD72 is appreciated for being a regulatory receptor on B cells. B cell receptor (BCR) -mediated signals are enhanced when CD72 expression is deficient on B cells in both animal models and autoimmune diseases such as systemic lupus erythematosus (SLE). The significance of soluble CD72 (sCD72) has not been elucidated. Methods We evaluated and compared the presence of sCD72 in the serum of patients with SLE and healthy individuals in order to ascertain whether sCD72 serum level is increased in SLE patients, using specific ELISA. Possible correlation was assessed between increased sCD72, SLE disease activity (SLEDAI), renal involvement and SLE related autoantibodies. Results The serum level of sCD72 in 159 SLE patients was found to be significantly increased compared to that of 80 healthy individuals (20 ± 1.2 ng/ml vs 8.2 ± 0.4 ng/ml; p < 0.001). Soluble CD72 levels were significantly higher in patients positive for double –stranded DNA (dsDNA) antibodies than that in patients without (23±1.5ng\ml vs 14.1±1.4ng\ml; p=0.003), also for anti-cardiolipin Ab (aCL) (28.5±3.1ng\ml vs 15.2±1.8ng\ml; p < 0.005); the levels were also significantly higher in patients with lupus nephritis than that in patients without (31.8 ± 2.3 ng/ml vs 13.9 ± 0.9 ng/ml; p < 0.001). Finally, sCD72 correlated positively with SLE disease activity (r = 0.703; p < 0.001). Conclusion Soluble CD72 is significantly increased in SLE patients. It is a possible marker for renal involvement, aCL and anti-dsDNA antibodies positivity in SLE and in positive correlation with SLE disease activity.

Introduction Though of dual function, CD72 is appreciated for being a regulatory receptor on B cells. B cell receptor (BCR) -mediated signals are enhanced when CD72 expression is deficient on B cells in both animal models and autoimmune diseases such as systemic lupus erythematosus (SLE). The significance of soluble CD72 (sCD72) has not been elucidated. Methods We evaluated and compared the presence of sCD72 in the serum of patients with SLE and healthy individuals in order to ascertain whether sCD72 serum level is increased in SLE patients, using specific ELISA. Possible correlation was assessed between increased sCD72, SLE disease activity (SLEDAI), renal involvement and SLE related autoantibodies. Results The serum level of sCD72 in 159 SLE patients was found to be significantly increased compared to that of 80 healthy individuals (20 ± 1.2 ng/ml vs 8.2 ± 0.4 ng/ml; p Conclusion Soluble CD72 is significantly increased in SLE patients. It is a possible marker for renal involvement, aCL and anti-dsDNA antibodies positivity in SLE and in positive correlation with SLE disease activity.

B regulatory cells (Bregs) belong to a subgroup of activated B cells tasked with maintaining self-tolerance and preventing autoimmunity. While sharing similar regulatory mechanisms such as IL-10 dependency, they also defer in exhibiting their suppressive effects by expressing Fas-Ligand, TGF-beta and PDL-1. In this study we show, for the first time, the expansion of CD25 high FoxP3 high Bregs in systemic lupus erythematosus (SLE) patients compared to healthy individuals (18.5 ± 3.052% vs 11.0 ± 1.654%, p high FoxP3 high Bregs were also IL-10 high expressing, and further expanded when stimulated with semaphorin3A. In sum we show that CD25 high FoxP3 high are an additional subtype of Bregs, involved in regulating SLE disease activity. Being IL-10 expressing, we may assume that they are one of the sources of increased serum IL-10 in SLE patients. Further studies are required in order to assess the relation between high serum IL-10 and CD25 high Foxp3 high Breg cells.

KeY WOrds: for editorial see page 493 c hronic urticaria (CU) is a common disabling disorder, occurring in 0.5–1% of the population, with an average duration of 3–5 years in adults [1]. In a previous study conducted in Israel, CU persisted for more than 1 year in over 70% of patients. After 36 months of follow-up 43% of patients were still suffering from CU, and after 5 years – when the study ended – 14% of patients were still suffering [2]. The impact of CU on patients’ quality of life (QoL) is often underestimated. O’Donnell et al. [3] showed that health status scores of patients with CU are comparable to those of patients with coronary artery disease. Understanding the effects of CU on the QoL of affected patients is critical for both optimal management and clinical research. Therefore, QoL should be included as an outcome measure in clinical trials that assess the overall effectiveness of treatment. In the past, the QoL of CU patients was assessed by generic questionnaires applicable to all health conditions, and by a specialty-specific questionnaire developed for skin diseases. In this respect, Baiardini et al. [4] developed a specific questionnaire for evaluating QoL in CU patients. This questionnaire, called the Chronic Urticaria Quality of Life Questionnaire (CU-Q2oL), has been validated, including the physical, emotional, social and practical aspects that characterize this disease. In different countries, such as Germany, Spain and Turkey, CU-Q2oL was translated to the local language and was found to meet the standards for validity, internal consistency, reliability and responsiveness [5-8]. The aim of the present study was to validate and adapt the CU-Q2oL to the Hebrew language in order to make it suitable for use in Israel. Patients and methOds Patients over 18 years old with chronic spontaneous urticaria who visited the allergy outpatient clinic of Bnai Zion Medical

This supplement reports proceedings of the second international Global Urticaria Forum, which was held in Berlin, Germany in November 2015. Omalizumab is approved for the treatment of chronic spontaneous urticaria ( CSU ) in adult and adolescent (12 years and above) patients with inadequate response to/who remain symptomatic despite H 1 ‐antihistamine treatment, and has demonstrated good efficacy and safety in the clinical trial setting. Real‐life clinical experience with omalizumab can be explored to address important practical questions relating to its use in CSU patients. Some experts have proposed that a consensus algorithm, covering various aspects to consider when using omalizumab in real‐life clinical practice for the management of CSU , could answer many of these questions.

BACKGROUND:GA²LEN, the Global Allergy and Asthma European Network, has recently launched a program for the development, interaction, and accreditation of centers of reference and excellence in special areas of allergy embedded in its overall quality management of allergy centers of excellence. The first area chosen is urticaria. Urticaria is a common and debilitating condition and can be a challenge for both patients and treating physicians, especially when chronic. Centers of reference and excellence in urticaria (UCAREs) can help to improve the management of hard-to-treat conditions such as urticaria.AIMS:Here, we describe the aims, the requirements and deliverables, the application process, and the audit and accreditation protocol for GA²LEN UCAREs.RESULTS:The main aims of GA²LEN UCAREs are to provide excellence in urticaria management, to increase the knowledge of urticaria by research and education, and to promote the awareness of urticaria by advocacy activities. To become a certified GA²LEN UCARE, urticaria centers have to apply and fulfill 32 requirements, defined by specific deliverables that are assessed during an audit visit.DISCUSSION AND CONCLUSION:The GA²LEN UCARE program will result in a strong network of urticaria specialists, promote urticaria research, and harmonize and improve urticaria management globally.

This supplement reports proceedings of the second international Global Urticaria Forum, which was held in Berlin, Germany in November 2015. Despite the clear international guideline, there remain a number of controversies and challenges in the management of patients with chronic urticaria (CU). As a result of major advancements in urticaria over the past 4 years, the current EAACI/GA(2) LEN/EDF/WAO urticaria guideline treatment algorithm requires updating. Case studies from patients with chronic spontaneous urticaria (CSU) [also called chronic idiopathic urticaria (CIU)], chronic inducible urticaria (CIndU) or diseases and syndromes related to CU are useful in describing and exploring challenges in disease management. Case studies of specific CSU patient populations such as children with CU or patients with angio-edema but no hives also require consideration as potentially challenging groups with unmet needs. The current EAACI/GA(2) LEN/EDF/WAO urticaria guideline provides a general framework for the management of patients with CU but, as these cases highlight, a personalized approach based on the expert knowledge of the physician may be required.

Niniejsze wytyczne są wynikiem systematycznego przeglądu piśmiennictwa dokonanego w oparciu o metodologię GRADE (Grading Recommendations Assessment, Development and Evaluation) oraz dyskusji przeprowadzonych w trakcie konferencji dotyczącej pokrzywki, która odbyła się 28 i 29 listopada 2012 roku w Berlinie. Konferencja ta była wspólną inicjatywą kilku organizacji (Dermatology Section of the European Academy of Allergy and Clinical Immunology [EAACI], EU-funded network of excellence, Global Allergy and Asthma European Network [GA2LEN], European Dermatology Forum [EDF], World Allergy Organization [WAO]) i wzięli w niej udział delegaci z 21 towarzystw zarówno krajowych, jak i międzynarodowych. Pokrzywka jest często rozpoznawaną jednostką chorobową rozwijającą się przy dominującym udziale komórek tucznych, która klinicznie objawia się występowaniem bąbli pokrzywkowych, obrzęku naczynioruchowego lub współistnieniem obu typów objawów skórnych. Ryzyko wystąpienia klinicznych objawów pokrzywki ostrej w ciągu życia w populacji ogólnej szacuje się na około 20%. Przewlekła pokrzywka spontaniczna oraz inne odmiany pokrzywki przewlekłej nie tylko obniżają jakość życia pacjenta, ale wpływają także na poziom funkcjonowania w pracy czy szkole i z tego powodu należy je zaliczyć do grupy ciężkich chorób alergicznych. Niniejsze wytyczne zawierają definicję oraz klasyfikację pokrzywek, uwzględniając postęp, który się ostatnio dokonał w zakresie identyfikacji przyczyn, czynników wyzwalających oraz patomechanizmów zaangażowanych w rozwój objawów klinicznych choroby. Dodatkowo przedstawiają oparte na wiarygodnych dowodach naukowo-badawczych zasady postępowania diagnostycznego i terapeutycznego w różnych podtypach pokrzywek. Niniejsze wytyczne zostały uznane zaakceptowane przez Europejską Unię Lekarzy Specjalistów (European Union of Medical Specialists; UEMS).