Analysis of coagulation factors in angioedema/urticaria: increased values of D-dimer and fibrinogen in isolated angioedema.

INTRODUCTION: Recent research has shown that blood coagulation and the extrinsic coagulation cascade are involved in the pathogenesis of chronic spontaneous urticaria (CSU), but little is known about the coagulation factors in angioedema. METHODS: This study included 58 participants: 29 patients with chronic angioedema (14 with isolated angioedema and 15 with angioedema with wheals) and 29 healthy controls (HCs). We compared the values of coagulation factors in patients with isolated angioedema to those with wheals. Plasma levels of D-dimer, fibrinogen, and factor VII were measured by enzyme-linked immunosorbent assay (ELISA) for all participants. RESULTS: Significantly higher D-dimer (p = 0.016; ε² = 0.381) and fibrinogen (p = 0.044; ε² = 0.331) levels were recorded in patients with angioedema (both groups) than in the HCs, with higher levels for angioedema with wheals. Factor VII and fibrinogen levels did not differ significantly between the groups with angioedema, but coagulation factors were more often elevated in both angioedema groups than in HCs. CONCLUSIONS: One characteristic of angioedema is an elevated blood coagulation potential, which may help produce fibrin and may be important in controlling angioedema attacks.

Ciprofloxacin-Induced Anaphylactic Reaction Followed by Negative Provocation Test in Response to Levofloxacin: A Case Report.

Fluoroquinolones are a commonly prescribed class of antibiotics due to their broad spectrum of antimicrobial activity, favorable pharmacokinetic properties, ability to switch from parenteral to oral administration, and global availability. After beta-lactams, they are the second most common antibiotic class associated with drug allergies. The mechanism of fluoroquinolone-induced hypersensitivity reactions has not yet been fully understood, so the true incidence of hypersensitivity reactions remains unknown. Cross-reactivity between fluoroquinolones has been the subject of conflicting and limited clinical research. Due to their similar chemical structure, some argue for close cross-reactivity within the group. However, recent studies have produced contradictory results. We present the case of a young patient who had an anaphylactic reaction to ciprofloxacin but was tolerant to levofloxacin, as determined via a skin prick test followed by a drug provocation test. Our findings support the notion that there is little cross-reactivity between fluoroquinolones. Consequently, exposure to another fluoroquinolone in a hospital setting may be beneficial, particularly for patients who lack adequate antibiotic alternatives. However, additional research on this subject is required.

Safe and Efficient Use of Tocilizumab in Rheumatoid Arthritis Patient on Maintenance Hemodialysis: A Case Report.

Background: Rheumatoid arthritis (RA) is a chronic systemic autoimmune and inflammatory disease. Conventional synthetic and biologic disease-modifying antirheumatic drugs (DMARDs), Janus kinase inhibitors, and rituximab are used to treat the disease. There are no recommendations or guidelines for the treatment of patients with both inflammatory arthritis and end-stage renal disease (ESRD), despite the safety and efficacy of the mentioned drugs. The anti-interleukin-6 receptor antibody tocilizumab (TCZ) has not been used as a long-term therapy for hemodialysis (HD) patients with RA, except in a few case reports. Case Description: We present the case of a 41-year-old patient with RA and ESRD on maintenance HD due to type 1 diabetes-related complications. Due to high RA disease activity, the patient was not a suitable candidate for a kidney transplant. Because TCZ is used to treat both RA and kidney transplant rejection, therapy with a full dose of TCZ was administered. The patient has achieved sustained clinical remission (for the past four years) with no adverse events reported. Conclusions: Herein, we present the safe and effective use of TCZ in an RA patient on HD who is also a candidate for kidney transplant. Consequently, TCZ could be the treatment of choice for RA patients with ESRD who have not achieved disease control (low activity or remission) with conventional synthetic DMARDs. Clinical studies are required to evaluate the efficacy and safety of biologic DMARDs and Janus kinase inhibitors in patients with both inflammatory arthritis and ESRD.

Melatonin in Dermatologic Allergic Diseases and Other Skin Conditions: Current Trends and Reports.

Melatonin is the main hormone that regulates the sleep cycle, and it is mostly produced by the pineal gland from the amino acid tryptophan. It has cytoprotective, immunomodulatory, and anti-apoptotic effects. Melatonin is also one of the most powerful natural antioxidants, directly acting on free radicals and the intracellular antioxidant enzyme system. Furthermore, it participates in antitumor activity, hypopigmentation processes in hyperpigmentary disorders, anti-inflammatory, and immunomodulating activity in inflammatory dermatoses, maintaining the integrity of the epidermal barrier and thermoregulation of the body. Due predominantly to its positive influence on sleep, melatonin can be used in the treatment of sleep disturbances for those with chronic allergic diseases accompanied by intensive itching (such as atopic dermatitis and chronic spontaneous urticaria). According to the literature data, there are also many proven uses for melatonin in photoprotection and skin aging (due to melatonin's antioxidant effects and role in preventing damage due to DNA repair mechanisms), hyperpigmentary disorders (e.g., melasma) and scalp diseases (such as androgenic alopecia and telogen effluvium).

Divergent Trends in the Prevalence of Children's Asthma, Rhinitis and Atopic Dermatitis and Environmental Influences in the Urban Setting of Zagreb, Croatia.

BACKGROUND: Previous studies have reported that the allergy epidemic in developed countries has reached its plateau, while a rise is expected in developing ones. Our aim was to compare the prevalence of allergic diseases among schoolchildren from the city of Zagreb, Croatia after sixteen years. METHODS: Symptoms of asthma, allergic rhinitis (AR) and atopic dermatitis (AD) and risk factors were assessed using the International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire. An allergic profile was determined by a skin prick test. RESULTS: The prevalence of current, ever-in-a-lifetime and diagnosed AR of 35.7%, 42.5% and 14.9% and AD of 18.1%, 37.1% and 31.1% demonstrated a significant increase. The asthma prevalence has remained unchanged. The allergen sensitivity rate has remained similar, but pollens have become dominant. Mould and dog exposure are risks for asthma (OR 14.505, OR 2.033). Exposure to cat allergens is protective in AR (OR 0.277). Parental history of allergies is a risk factor in all conditions. CONCLUSION: Over sixteen years, the prevalence of AR and AD, but not of asthma, have increased. The proportion of atopy has remained high. The AR/AD symptom rise is probably a consequence of increased pollen sensitisation united with high particulate matter concentrations. The stable asthma trend could be a result of decreasing exposures to indoor allergens.

Incidence of immediate allergic reactions to mRNA COVID-19 vaccines in adults with drug allergies and other allergic disorders.

Concerns have been raised about allergic reactions to messenger ribonucleic acid (mRNA) coronavirus disease 2019 (COVID-19) vaccines. A history of allergic reactions, including anaphylaxis to drugs, has been frequently reported in individuals with anaphylaxis to mRNA vaccines. To estimate the rate of immediate allergic reactions in patients with a history of drug allergy or other allergic disorders. We included adult patients who had received at least 1 dose of an mRNA COVID-19 vaccine at the Special Hospital for Pulmonary Diseases between March 1, 2021, and October 1, 2021, and who reported a history of drug allergy or other allergic diseases (asthma, allergic rhinitis, atopic dermatitis, food or insect venom allergy, mastocytosis, idiopathic anaphylaxis, acute or chronic urticaria, and/or angioedema). Immediate allergic reactions, including anaphylaxis, occurring within 4 hours of vaccination were recorded. Six immediate allergic reactions were noted in the cohort of 1679 patients (0.36%). One patient experienced anaphylaxis (0.06%), which resolved after epinephrine administration, and the other reactions were mild and easily treatable. Most patients with a history of allergies can safely receive an mRNA COVID-19 vaccine, providing adequate observation periods and preparedness to recognize and treat anaphylaxis.

Psychometric Characteristics of the Croatian Version of the Zarit Burden Interview Questionnaire Among Informal Caregivers of Long-Term Mechanically Ventilated Patients.

BACKGROUND: The aim is to evaluate the reliability and validity of the Croatian version of the Zarit Caregiver Burden Interview (ZBI) among the population of informal caregivers of long-term mechanically ventilated patients. SUBJECTS AND METHODS: After a preliminary analysis, 25 participants were selected by using strictly defined criteria and they were asked to complete the Croatian version of the ZBI. The test - retest method was used for reliability assessment while an exploratory strategy of factor analysis was used to identify real-life existent subscales. RESULTS: After reliability and validity assessment, 3 items were removed from the original ZBI so that the Croatian version of the ZBI consists of 19 items. Internal consistency, observed through Cronbach's alpha for extracted subscales and for the whole questionnaire, were identified as high ranged from 0.875 to 0.922. Furthermore, exploratory factor analysis using Guttman-Kaiser criterion identified the 6 subscales for the ZBI. CONCLUSIONS: Due to the fact that approximately 30 % of targeted population was included in the study, the Croatian version of the ZBI can be accepted as a reliable and valid tool for measuring burden among informal caregivers of long-term mechanically ventilated patients. Family caregiver's burden level assessment can be crucial to enhance outcomes associated with future caregiving.

Chronic inducible urticaria: classification and prominent features of physical and non-physical types.

Chronic inducible urticaria (CIndU) is a common inflammatory skin condition characterized by the recurrence of itchy wheals and/or angioedema that lasts more than 6 weeks and is induced by specific physical or environmental stimuli (cold, heat, exercise, pressure, sunlight, vibration, water, etc.). According to the current international classification, it includes physical urticarias (dermographism, delayed-pressure urticaria, exercise-induced urticaria, cold urticaria, heat urticaria, solar urticaria, and vibratory urticaria) and non-physical urticarias caused by exposure to specific stimuli (cholinergic urticaria, contact urticaria, and aquagenic urticaria). In terms of frequency, more common types of CIndU are dermographism, cholinergic urticaria, and delayed-pressure urticaria. In clinical practice, it is often difficult to define the exact type of CIndU; management thus begins with accurate identification of a possible trigger and its avoidance. The definite diagnosis for CIndU requires obtaining a detailed medical history of a patient with comprehensive information about predisposing factors, physical examination, and provocation testing (challenge tests). It is always necessary to recognize the prophylactic options for all the types and to have access to different therapies (primarily second-generation H1 antihistamines, but also H2 antihistamines, hydroxyzine, doxepin, oral glucocorticoids, omalizumab/anti-IgE therapy, phototherapy, physical desensitization, immunomodulatory agents, etc.) individualized for each patient.

FasL (rs763110) gene polymorphism is not associated with susceptibility to rheumatoid arthritis in Croatian population.

AIM: To investigate the association of FasL gene polymorphism (rs763110) with rheumatoid arthritis occurrence, disease activity, and tumor necrosis factor-α (TNF-α) plasma concentration in Croatian patients, and to conduct an updated meta-analysis. METHODS: This cross-sectional study enrolled 81 patients with rheumatoid arthritis and 94 control patients. After the assessment of the Disease Activity Score (DAS)-28, blood was taken for analysis. DNA was isolated from the whole blood to determine FasL polymorphism (rs763110) by polymerase chain reaction. Protein levels of TNF-α were determined with ELISA. After a detailed literature search, we conducted an updated meta-analysis using the Review Manager 5 software. RESULTS: Rheumatoid arthritis patients had significantly higher TNF-α concentration in plasma (1.65 [1.2-2.42] pg/mL) than controls (0.99 [0.77-1.35] pg/mL, P<0.001). The FasL rs763110 polymorphism was not associated with rheumatoid arthritis occurrence in either codominant, dominant, recessive, overdominant, or log additive model. Furthermore, the rs763110 genotype was not associated with DAS 28 score or TNF-α concentration. After we added our results to an updated meta-analysis, the significant association previously reported for Western Eurasians was abolished. CONCLUSION: Our data suggest that the association between FasL rs763110 polymorphism and RA susceptibility in Western Eurasians observed in previous studies might be overestimated and should be limited to the population of Southwestern Asia until further investigations are performed.

Chemokine signals are crucial for enhanced homing and differentiation of circulating osteoclast progenitor cells.

BACKGROUND: The peripheral blood (PB) monocyte pool contains osteoclast progenitors (OCPs), which contribute to osteoresorption in inflammatory arthritides and are influenced by the cytokine and chemokine milieu. We aimed to define the importance of chemokine signals for migration and activation of OCPs in rheumatoid arthritis (RA) and psoriatic arthritis (PsA). METHODS: PB and, when applicable, synovial fluid (SF) samples were collected from 129 patients with RA, 53 patients with PsA, and 110 control patients in parallel to clinical parameters of disease activity, autoantibody levels, and applied therapy. Receptors for osteoclastogenic factors (CD115 and receptor activator of nuclear factor-κB [RANK]) and selected chemokines (CC chemokine receptor 1 [CCR1], CCR2, CCR4, CXC chemokine receptor 3 [CXCR3], CXCR4) were determined in an OCP-rich subpopulation (CD3-CD19-CD56-CD11b+CD14+) by flow cytometry. In parallel, levels of CC chemokine ligand 2 (CCL2), CCL3, CCL4, CCL5, CXC chemokine ligand 9 (CXCL9), CXCL10, and CXCL12 were measured using cytometric bead array or enzyme-linked immunosorbent assay. Sorted OCPs were stimulated in culture by macrophage colony-stimulating factor and receptor activator of nuclear factor-κB ligand, and they were differentiated into mature osteoclasts that resorb bone. Selected chemokines (CCL2, CCL5, CXCL10, and CXCL12) were tested for their osteoclastogenic and chemotactic effects on circulatory OCPs in vitro. RESULTS: The OCP population was moderately enlarged among PB cells in RA and correlated with levels of tumor necrosis factor-α (TNF-α), rheumatoid factor, CCL2, and CCL5. Compared with PB, the RANK+ subpopulation was expanded in SF and correlated with the number of tender joints. Patients with PsA could be distinguished by increased RANK expression rather than total OCP population. OCPs from patients with arthritis had higher expression of CCR1, CCR2, CCR4, CXCR3, and CXCR4. In parallel, patients with RA had increased levels of CCL2, CCL3, CCL4, CCL5, CXCL9, and CXCL10, with significant elevation in SF vs PB for CXCL10. The subset expressing CXCR4 positively correlated with TNF-α, bone resorption marker, and rheumatoid factor, and it was reduced in patients treated with disease-modifying antirheumatic drugs. The CCR4+ subset showed a significant negative trend during anti-TNF treatment. CCL2, CCL5, and CXCL10 had similar osteoclastogenic effects, with CCL5 showing the greatest chemotactic action on OCPs. CONCLUSIONS: In our study, we identified distinct effects of selected chemokines on stimulation of OCP mobilization, tissue homing, and maturation. Novel insights into migratory behaviors and functional properties of circulatory OCPs in response to chemotactic signals could open ways to new therapeutic targets in RA.

JAK INHIBITOR CLINICAL RESPONSE IN POLYARTHRITIS: CASE REPORT.

The heterogeneity of rheumatoid arthritis (RA) presentation and molecular signature of RA subclasses in patients with early changes of small peripheral joints still remains a challenging problem. In clinical setting, classification of the disease subtypes is not possible and treatment adjustment is based on the continuous Disease Activity Score for disease severity recognition. A new approach in the treatment appears with the novel non biologic targeted synthetic disease-modifying antirheumatic drugs from the group of Janus kinase 1 and 3 (JAKI and JAK3), blocking interleukin (IL)-2, IL-4, IL-7, IL-9, IL-15 and IL-21. We report a case of a 48-year-old patient who had suffered from polyarthritis from his age 40. Initial laboratory tests showed low inflammatory parameters and magnetic resonance imaging of both hands indicated an early stage of RA. Methylprednisolone and methotrexate therapy was initiated. The patient underwent additional tests, but there was not sufficient evidence for a precise diagnosis. According to the European League Against Rheumatism/American College of Rheumatology score-based algorithm, the patient was classified as seronegative RA based on joint involvement, duration of the disease, and synovitis not better explained by another disease. A partial clinical effect of the administered therapy (steroids as monotherapy and in combination, methotrexate and leflunomide) was noticed with the use of systemic steroids, but dramatic improvement was only achieved with a JAK inhibitor targeted therapy. Although the use of anti TNF-α blocker is a proposed procedure and the drug has not yet been registered in Europe, we took the opportunity to apply this new medication option. The patient, a construction worker, was treated for 20 months, which led to complete remission of the disease, without the need of basic or corticosteroid therapy. Full functional capacity necessary in his demanding job was also achieved. This result raised a question of timely introduction of immunomodulators in the polyarthritis treatment steps.

DRESS syndrome with mild manifestations as a diagnostic and therapeutic problem: case report.

The group of severe cutaneous drug reactions with systemic symptoms includes several syndromes: toxic epidermal necrolysis, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, and drug reaction with eosinophilia and systemic symptoms (DRESS). These reactions occur several days to six weeks after introducing the incriminating drug. The skin and internal organs (liver, kidneys, lungs, etc.) are usually involved. A great possibility of lethal outcome is a critical characteristic of these syndromes. A patient with pyelonephritis diagnosed during emergency room workup is described. Ciprofloxacin was prescribed and the patient was discharged. After ten days, the patient came back with worsening condition, general inflammatory response, skin changes, liver and kidney damage, and eosinophilia. DRESS syndrome was diagnosed based on clinical and other findings. The diagnosis and treatment of severe drug reactions with cutaneous and systemic symptoms pose a medical challenge.

Influence of UV radiation on immunological system and occurrence of autoimmune diseases.

During the last three decades scientists worldwide have investigated how ultraviolet radiation (UVR) influences the immune system. The vast majority of the researchers was primarily focused on the local immunomodulatory role of UVR. But today evidence is increasing in favor of plural immune activation and systemic reaction of the organism. Most of the attention is directed toward the regulatory T lymphocytes which are responsible for the local and systemic immunosuppressive response under the impact of sunlight. The role of regulatory T cells in autoimmune diseases is well studied on patients with systemic lupus erythematosus (SLE). Epidemiological research shows a proportional interdependence of latitude and prevalence of autoimmune diseases such as multiple sclerosis (MS), insulin-dependent diabetes mellitus (IDDM) and rheumatoid arthritis (RA). There is evidence that UVR has direct influence on the level of antibodies against the SNF2-superfamily helicase (Mi-2), distinctive for dermatomyositis (DM). On this basis a hypothesis is established that UVR is a risk factor for DM. A Croatian epidemiologic study o f systemic sclerosis (SSc) gave results consistent with the hypothesis that there is a higher prevalence of SSc in the Mediterranean regions of Croatia. Such discoveries encouraged further studies that found that not only regulatory T cells are responsible for a systemic immunosuppressive response, but that there is a complex interactive network of immune cells and mediators such as cytokines, neuropeptides, and chromophores like urocanic acid involved. Present findings require continued research on the importance of UVR on autoimmune disease prevalence and immunopathophysiology. Finally, it is necessary to distinguish whether UVR is a protective factor for some autoimmune diseases or a risk factor for their induction.