Efficacy and Safety of Donidalorsen for Hereditary Angioedema.

BACKGROUND: Hereditary angioedema is a rare disorder characterized by episodic, potentially life-threatening swelling caused by kallikrein-kinin dysregulation. Long-term prophylaxis can stabilize this system. Donidalorsen, an antisense oligonucleotide, specifically reduces prekallikrein expression. METHODS: In this phase 3, double-blind, randomized trial, we assigned patients with hereditary angioedema to receive donidalorsen (80 mg subcutaneously) or placebo once every 4 or 8 weeks. The primary end point was the time-normalized number of investigator-confirmed hereditary angioedema attacks per 4 weeks (attack rate) from week 1 to week 25. RESULTS: A total of 90 patients received donidalorsen every 4 weeks (45 patients), donidalorsen every 8 weeks (23 patients), or placebo (22 patients). The least-squares mean time-normalized attack rate was 0.44 (95% CI, 0.27 to 0.73) in the 4-week group, 1.02 (95% CI, 0.65 to 1.59) in the 8-week group, and 2.26 (95% CI, 1.66 to 3.09) in the placebo group. The mean attack rate from week 1 to week 25 was 81% lower (95% CI, 65 to 89) in the 4-week group than in the placebo group (P<0.001) and 55% lower (95% CI, 22 to 74) in the 8-week group than in the placebo group (P = 0.004); the median reduction in the attack rate from baseline was 90% in the 4-week group, 83% in the 8-week group, and 16% in the placebo group. The mean attack rate during weeks 5 to 25 was 87% lower (95% CI, 72 to 94) in the 4-week group than in the placebo group (P<0.001) and 60% lower (95% CI, 25 to 79) in the 8-week group than in the placebo group. Donidalorsen administered every 4 weeks resulted in an improvement in the least-squares mean total score for the change at week 25 on the Angioedema Quality-of-Life Questionnaire (scores range from 0 to 100, with a score of 100 indicating the worst possible quality of life) that was 18.6 points (95% CI, 9.5 to 27.7) better than that with placebo (P<0.001). The most common adverse events were erythema at the injection site, headache, and nasopharyngitis; 98% of adverse events were mild or moderate in severity. CONCLUSIONS: Donidalorsen treatment reduced the hereditary angioedema attack rate, a finding that supports potential prophylactic use for hereditary angioedema. (Funded by Ionis Pharmaceuticals; OASIS-HAE ClinicalTrials.gov number, NCT05139810.).

Interdisciplinary Healthcare Team Experience of Carboplatin and Oxaliplatin Desensitizations in a Tertiary Referral University Hospital.

Purpose: Repeated exposure to platinum compounds increases the risk of immunoglobulin E-mediated immediate hypersensitivity reactions (HSR). To date, many different desensitization protocols with varying success rates have been reported. The presented study is aimed at disseminating the real-world experience of an interdisciplinary healthcare team focusing on platin desensitization. Patients and Methods: This is a cross-sectional, retrospective study of 7 female patients with carboplatin- or oxaliplatin-induced HSRs. After a discussion with the oncologist and the patient, desensitization protocols were performed by a team consisting of an allergy and immunology specialist, a clinical pharmacist, and a nurse. Clinical data were extracted from the patients' medical records, and HSRs were reviewed and classified by an allergist according to severity and type. Results: Twenty-five desensitization protocols were carried out for patients with carboplatin- or oxaliplatin-induced HSRs (N=4 and N=3, respectively; age range: 54-66). Two of the patients did not experience any HSR during a total of 8 desensitization cycles. The other patients had grade 1-3 HSRs on 15 cycles, which were successfully managed by oxygen and/or pharmacological interventions and infusions were resumed at a lower rate after stabilization of the patient. Compared to baseline, serum tryptase levels were elevated during HSRs (4.77±0.21 vs 9.50±1.71, P=0.028). Conclusion: All the patients were able to finish the treatment protocol and receive full chemotherapeutic doses. Interdisciplinary teams may facilitate the preparation and administration of platinum-based chemotherapeutics and increase the success rates of desensitization protocols for platin-based chemotherapy, where the concentration and application of drugs differ from standard procedure.

Successful treatment of post-pericardiotomy syndrome via C1 inhibitor replacement therapy in a hereditary angioedema patient with Marfan syndrome.

BACKGROUND: Hereditary angioedema with C1 inhibitor deficiency (HAE-C1INH) is caused by dysfunctional C1-INH protein due to mutations in the SERPING1 gene encoding C1-INH. Marfan syndrome is a genetic connective tissue disease that affects the cardiovascular and ocular systems along with the skeletal system. In this case, we present the successful treatment of post-pericardiotomy syndrome unresponsive to classical therapy, which has not been described in the literature. The syndrome developed in a patient with hereditary angioedema (HAE) who underwent open heart surgery due to cardiac involvement in Marfan syndrome. CASE: A nine-year-old male HAE-C1INH patient underwent open heart surgery secondary to cardiac involvement caused by Marfan syndrome. To prevent HAE attacks, 1000 units of C1 inhibitor concentrate therapy were given 2 hours before and 24 hours after the operation. Post-pericardiotomy syndrome was diagnosed on the postoperative second day and ibuprofen 15 mg/kg/day (3 weeks) was started. Since there was no response to classical treatment on the 21st postoperative day, C1 inhibitor concentrate treatment was planned as 1000 units/ dose for 2 days a week considering a prolonged hereditary angioedema attack. In the second week of treatment, complete recovery was achieved for pericardial effusion with a total of 4 doses. CONCLUSIONS: We emphasize that in patients with hereditary angioedema undergoing this treatment, care should be taken in terms of complications that may be associated with the disease even if short-term prophylaxis is given before operations and that longer-term use of C1 inhibitor concentrate has a place in treatment.

Age-related changes in the immunomodulatory effects of human dental pulp derived mesenchymal stem cells on the CD4+ T cell subsets.

Mesenchymal stem cells (MSCs) are powerful immunomodulatory cells. The effects of the aging on these abilities of MSCs have not been adequately clarified. In this study, alterations in immunomodulatory abilities of MSCs caused by aging were investigated. For this, dental pulp (DP) MSCs and peripheral blood mononuclear cells (PBMCs) of elderly and young donors were co-cultured age-matched and cross. We detected that the effects of DP-MSCs on Th1 and Th2 cells and their specific cytokines IFN-γ and IL-4 are not affected by aging. However, we observed that young and elderly DP-MSCs have different effects on Th17 and Treg cells. Th17 frequencies of young and elderly PBMCs were significantly increased only by young DP-MSCs, in contrast, Treg frequencies were significantly increased by elderly DP-MSCs. IL-6, IL-17a and HGF levels of both young and elderly PBMCs showed a significant increase only by young DP-MSCs, but TGF-ß levels were significantly increased only by elderly DP-MSCs. The oral cavity is home to a rich microflora. The interactions of dental tissues with this microflora can lead them to acquire different epigenetic modifications. Aging can affect the microflora composition of the oral cavity and change this process in different directions. According to our findings, DP-MSCs are effective cells in the regulation of CD4+ T cells, and their effects on Th1 and Th2 cells were not affected by aging. However, pleiotropic molecules IL-6 and HGF expressions, which are important in dental and bone tissue regeneration, decreased significantly in elderly DP-MSCs. This situation may have indirectly made a difference in the modulation effects of young and elderly DP-MSCs on the Th17 and Treg cells.

Novel homozygous variants in the SERPING1 gene in two Turkish families with hereditary angioedema of recessive inheritance.

Hereditary angioedema as a result of deficiency of the C1 inhibitor (HAE-C1INH; MIM# 106100) is a rare autosomal disorder and affected individuals are generally heterozygous for dominant negative variants in the SERPING1 gene. Homozygosity for SERPING1 pathogenic variants was long considered to be embryonically lethal; however, five nonrelated families with a recessive HAE pattern have been described in the last decade. In this report, we functionally characterized two newly reported nonrelated, consanguineous families with a recessive presentation of HAE attributed to SERPING1 variants in the reactive center loop (family D; S438F) and gate (family A; I379T) regions. S438F heterozygotes (family D) showed variable levels of intact 105-kDa and cleaved/inactive 96-kDa isoforms of C1INH, whereas their homozygous relative presented only the 96-kDa band. Functional studies showed that S438F reduced C1INH interaction with target proteases in heterozygous (C1s, 32-38% of controls and FXIIa, 28-35% of controls) and homozygous (C1s, 18-24% of controls and FXIIa, 4-8% of controls) carriers, which is consistent with the more severe presentation of HAE in the family and decreased C1q levels in homozygous patients. By contrast, plasma C1INH from I379T heterozygotes (family A) showed normal C1INH/C1s binding (84-94% of controls) and no significant reduction in C1INH/FXIIa complexes (50-70% of controls). However, the homozygote failed to inhibit both C1s (25-42% of controls) and FXIIa (14-18% of controls). This profile is concordant with the less severe presentation of HAE in the family and the conserved C4 and C1q levels in heterozygous and homozygous patients.

Deletions in SERPING1 Lead to Lower C1 Inhibitor Function: Lower C1 Inhibitor Function Can Predict Disease Severity.

BACKGROUND: How genotype affects phenotype in hereditary angioedema with C1 inhibitor deficiency (C1-INH-HAE) has not been totally clarified. In this study, we investigated the relationship between different types of mutations and various phenotypic characteristics. METHODS: Clinical data from 81 patients from 47 families were recorded. Complement proteins were analyzed from 61 untreated patients. The coding exons and the exon-intron boundaries of the SERPING1 gene were sequenced, and deletion/duplication analysis with multiple ligation dependent probe amplification was performed. The relationship of complement protein with the mutation type was analyzed by using generalized estimating equations. RESULTS: Thirty-five different mutations (15 novel and 2/15 homozygous) were identified. There was no causative mutation in 6 patients (7.4%). Patients with deletion and large deletion had the lowest (5.05%, 0-18.7; 5.8%, 0-16.5%, respectively), and the none mutation group had the highest C1 inhibitor function (23.3%, 11-78%, p < 0.001). C1 inhibitor function levels decreased as the age of the disease progressed (r = -0.352, p = 0.005). Lower C1 inhibitor function levels caused severer disease (r = -0.404, p = 0.001) and more frequent annual attacks (r = -0.289, p = 0.024). In the off-attack period, C1q levels were lower than normal in 9.8% of the patients. CONCLUSION: Deletion mutations may represent the most unfavorable effect on C1 inhibitor function. The earlier disease onset age could be a sign for lower C1 inhibitor function levels in adult life. C1q levels could also be low in C1-INH-HAE patients, as in acquired angioedema. Lower C1 inhibitor function can predict disease severity and may have negative impacts on the course of C1-INH-HAE.

Misleading Allergens in the Diagnosis of Latex Allergy: Profilin and Cross-Reactive Carbohydrate Determinants.

BACKGROUND: It has been suggested that latex-specific IgE analysis may lead to false-positive results, especially in patients with pollen allergy. In the present study, the reasons underlying clinically irrelevant latex-specific IgE positivity were investigated. METHODS: Thirty patients with latex allergy (group 1), 89 patients sensitised to aeroallergens (group 2a), and 98 healthy individuals without allergy (group 2b) were enrolled. Participants from all 3 groups were subjected to skin prick tests with aeroallergens including latex, latex-specific IgE analysis (ImmunoCAP), and nasal provocation test with latex. All cases demonstrating positive latex-specific IgE also underwent specific IgE tests (ImmunoCAP) with latex profilin, birch pollen profilin, peach lipid transfer protein, and pineapple bromelain as cross-reactive carbohydrate determinants. RESULTS: Comparison of the atopic and healthy control groups showed that the rate of positive latex-specific IgE was significantly higher in group 2a. Latex profilin-, birch pollen profilin-, and bromelain-specific IgE were remarkably higher in group 2a. CONCLUSION: False positivity to latex-specific IgE in ImmunoCAP analysis may be observed in approximately 19% of patients with pollen allergy. Profilins and bromelain are the main contributors to clinically irrelevant positive latex-specific IgE.

Necrotizing Fasciitis in Paroxysmal Nocturnal Hemoglobinuria.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, progressive, and life-threatening hematopoietic stem cell disorder characterized by complement-mediated intravascular hemolysis and a prothrombotic state. Patients with PNH might have slightly increased risk of infections due to complement-associated defects subsequent to CD59 deficiency. Here, we report a rare case of a 65-year-old male patient with necrotic ulcers on both legs, where the recognition of pancytopenia and microthrombi led to the diagnosis of PNH based on FLAER (FLuorescent AERolysin) flow cytometric analysis. He was subsequently started on eculizumab therapy, with starting and maintenance doses set as per drug labelling. Progression of the patient's leg ulcers during follow-up, with fulminant tissue destruction, purulent discharge, and necrotic patches, led to a later diagnosis of necrotizing fasciitis due to Pseudomonas aeruginosa and Klebsiella pneumonia infection. Courses of broad-spectrum antibiotics, surgical debridement, and superficial skin grafting were applied with successful effect during ongoing eculizumab therapy. This case highlights the point that it is important to maintain treatment of underlying disorders such as PNH in the presence of life-threatening infections like NF.

PNH is a debilitating, fatal but treatable disease: same disease, different clinical presentations.

Paroxysmal nocturnal hemoglobinuria (PNH) is a disease characterized by chronic persistent hemolysis, multi-organ damage and eventually multiple organ failure. PNH develops as a result of increased sensitivity to complement due to an acquired deficiency of certain glycosylphosphatidylinositol (GPI)-linked proteins. The clinical presentation of PNH varies greatly from one patient to another. We present three cases of PNH with different clinical presentations to illustrate the debilitating nature of the disease, possible fatal outcomes, and the need to timely diagnosis and targeted therapy. These cases also underline the need for increased awareness of PNH among relevant healthcare specialties. PNH should be considered as a differential diagnosis in patients with unexplained abdominal pain, dyspnea, renal failure, thrombosis and non-immune hemolytic anemia.

CD31 expression on peripheral blood stem cells predicts both early neutrophil and platelet engraftments.

No detailed information currently exists about the immune phenotypic profiles of peripheral blood stem cells (PBSCs) obtained by different mobilization regimens. The effects of these profiles on the outcome of transplantation are largely unknown. In this prospective study, the surface immune phenotypic features (CD11a, CD18, CD31, CD38, CD44, CD62e, CD62L, CD90, CD117, CD135 and CD184 expression) of sorted PBSCs that had been mobilized by growth factor with (group I and group II) or without (group III) disease-specific chemotherapies were investigated. The immune phenotypic features on mobilized PBSCs in groups I, II and III were not significantly different. The CD31 (platelet endothelial cell adhesion molecule-1) positivity ratio on PBSCs inversely correlated with both the duration of neutrophil (r=-0.32, p=0.03) and platelet (r=-0.36, p=0.02) engraftment. No relationship was found between the engraftment (neutrophil and platelet) durations and CD184 (chemokine receptor CXC motif receptor 4 [CXCR4]) expression on PBSCs. We demonstrated that the surface immune phenotypic profiles on PBSCs obtained by several mobilization regimens were not different. To our knowledge, this is the first study to demonstrate that CD31 expression on human PBSCs may positively affect both neutrophil and platelet engraftment. Contrary to our expectations, CD184 (CXCR4) expression on PBSCs has no effect on neutrophil or platelet engraftment. Considered together, our results suggest that additional surface antigens (such as CD31) may be more effective in the homing process.

Risk factors for a poor hematopoietic stem cell mobilization.

Poor mobilization is an important problem in autologous stem cell transplantation. We retrospectively reviewed the data of 165 mobilized patients to identify possible risk factors for a poor stem cell mobilization. 27 patients (16.4%) were categorized as poorly mobilized. The poor mobilization ratio differed according to diagnosis (lymphoma: 25.4%, acute leukemia: 15.4%, amyloidosis: 14.3%, and multiple myeloma: 9.6%). Being diagnosed as lymphoma (odds ratio [OR]=6.02, p=0.001), advanced age (OR=1.05, p=0.007) and increased weight (OR=1.03, p=0.03) were found as possible risk factors. Being diagnosed as lymphoma was shown to be the most important risk factor for a poor mobilization. Leukapheresis staff should be aware of the increased risk of a poor mobilization in lymphoma patients and remobilization methods should be considered from the beginning.

The difference in lactate dehydrogenase activity between pre- and post-mobilization periods is a good indicator of successful stem cell mobilization.

Predicting poor stem cell mobilization may prevent the costs and complications associated with remobilization. We retrospectively reviewed the relationship between serum lactate dehydrogenase (sLDH) activity and peripheral blood CD34 (PBCD34) cell counts in 46 granulocyte colony stimulating factor (G-CSF) induced mobilization cycles with or without chemotherapy. A significant correlation between post-mobilization (pre-apheresis) sLDH activity and PBCD34 count was found (r(s)=0.43, p=0.007). A strong correlation was shown between the pre- and post-mobilization sLDH activity difference and PBCD34 count (r(s)=0.55, p=0.001). With respect to sLDH activity differences; (a) all patients with a difference of >300 U/L, (b) 71% of patients with a difference of 100-300 U/L, and (c) 44% of patients with a difference of <100 U/L were considered to have good mobilizations. The sLDH activity difference between pre- and post-mobilization is a good indicator of successful mobilization. According to our results, the success of mobilization can be predicted based on sLDH activity differences; (i) good mobilization if the difference is >300 U/L, (ii) intermediate risk if the difference is 100-300U/L, and (iii) high risk if the difference is <100 U/L.

Phagocytic and oxidative burst activity of neutrophils in patients with spinal cord injury.

OBJECTIVE: To evaluate phagocytic activity and neutrophil oxidative burst functions in patients with spinal cord injury (SCI) because alterations in neutrophil metabolic activity can be one of the causes of immune mechanism damage contributing to repeated bacterial infections. DESIGN: A controlled and cross-sectional study. SETTING: Departments of physical medicine and rehabilitation and immunology. PARTICIPANTS: Patients with SCI (N=34) and 28 healthy controls. INTERVENTIONS: Phagocytosis and oxidative burst in whole-blood neutrophils were assessed by flow cytometry. The percentage of phagocytizing cells after in vitro incubation with Escherichia coli, phagocytic activity (mean intensity of fluorescence [MIF]) and the percentage of neutrophiloxidative burst, and the MIF value of the production of reactive oxygen intermediates (ROIs) were analyzed. In addition, clinical assessment including the level of injury, American Spinal Injury Association scores, and functional status were carried out. MAIN OUTCOME MEASURES: Not applicable. RESULTS: Although the percentage of E. coli phagocytizing neutrophils was not different between groups, the MIF value of absorbed E. coli was significantly lower in patients with SCI than in controls (P<.05). The MIF value of ROI production by neutrophils with both stimulator of phorbol 12-myristate 13-acetate and E. coli was significantly higher in patients with SCI (P<.05). CONCLUSIONS: In patients with SCI, decreased phagocytic activity of neutrophils may be a result of a regulatory mechanism to minimize the deleterious effects of increased neutrophil burst activity.

Desensitization effect of preseasonal seven-injection allergoid immunotherapy with olive pollen on basophil activation: the efficacy of olive pollen-specific preseasonal allergoid immunotherapy on basophils.

BACKGROUND: It has previously been demonstrated that subcutaneous immunotherapy with allergoids positively affects clinical and immunological parameters even after 7 preseasonal injections. However, its effect on basophil activation remains unclear. We investigated the effect of preseasonal allergoid immunotherapy on basophils and concomitantly assessed its clinical and immunological efficacy in olive pollen-monosensitized patients. METHODS: This study enrolled 437 consecutive patients with respiratory allergy and positive skin prick tests (SPTs); 212 (48.5%) patients were sensitized to olive pollen, and 33 (7.5%) patients were sensitized to olive pollen only. Of these patients, 23 received preseasonal immunotherapy with an olive pollen allergoid. The olive pollen-specific basophil activation, the titrated nasal provocation test, the nasal symptom score, and olive pollen-specific IgE, IgG1 and IgG4 levels were evaluated before immunotherapy and 8 months after the end of immunotherapy in the follow-up visit. RESULTS: In comparison to baseline evaluation, 7 preseasonal injections of an allergoid resulted in a significant decrease in the percentage of basophils expressing CD63 (29 vs. 7%, respectively, p < 0.0001) and a significant increase in the titrated nasal provocative dose (1/10 vs. 1/1, respectively, p < 0.01). SPT induration diameters caused by an olive pollen extract decreased (12 mm at baseline vs. 5.5 mm at follow-up, p < 0.005), as did nasal symptom score (7 at baseline vs. 3 at follow-up, p < 0.01). Olive pollen-specific IgE (17.5 vs. 50 kU/l, p < 0.012), IgG1 (0.16 vs. 2.9 µg/ml, p < 0.0001) and IgG4 (0.07 vs. 1.92 µg/ml, p < 0.0001) levels significantly increased. CONCLUSIONS: Immunotherapy with 7 preseasonal injections of an olive pollen allergoid decreases olive pollen-specific basophil activation over 8 months, an effect observed in vitro and in vivo.

The Turkish Hereditary Angioedema Pilot Study (TURHAPS): the first Turkish series of hereditary angioedema.

BACKGROUND: No published data presently exist concerning hereditary angioedema (HAE) in Turkey. The aim of the study was to initiate a preliminary multicentric evaluation about HAE and to determine the genetic properties of Turkish patients. METHODS: Based on records drawn from four medical centers we identified a total of 70 subjects, belonging to 60 unrelated families, fulfilling clinical and laboratory criteria for diagnosis of HAE with C1 inhibitor deficiency. Ten type I patients, and their first-degree relatives, underwent genetic analysis for HAE. RESULTS: The majority of patients were female (60%), the mean age was 37.7 ± 14.1 years. The mean age at the time of first angioedema symptom was 12.5 ± 9.2 years. Mean time lag between first symptom and diagnosis was 26 ± 14.4 years. All but 3 subjects had HAE type I. Family history of angioedema was present in 75.7% of the cases. Cutaneous swelling was reported by 87.1% of the patients, facial edema by 65%, abdominal symptoms by 74.3% and approximately one half (55.7%) had experienced one or more laryngeal attack. Genetic analysis of 10 families demonstrated that 5 carried a mutation that had never been previously described. CONCLUSION: We found that the clinical features of Turkish HAE patients were consistent with previously described patterns of this rare disease. The most noteworthy feature identified in the study was a significantly long duration between the first symptom appearance and final diagnosis. Our detection of different mutations in 10 patients confirms the allelic heterogeneity of the disease.

Cigarette smoking in primary Sjögren's syndrome: positive association only with ANA positivity.

Smoking is well known to contribute to the pathogenesis and severity of some systemic autoimmune rheumatic diseases and especially to the production of certain autoantibodies. Primary Sjögren's syndrome (pSS) is an autoimmune disease, affecting primarily the exocrine glands. It may also cause extraglandular involvement in some cases. In this study, we aimed to determine the frequency of smoking habits in our cohort of pSS patients and to investigate whether the frequencies of autoantibody positivity and extraglandular involvement were significantly different between patients with and without smoking. In this cross-sectional study, 207 patients with pSS (F/M 203/4), fulfilling the United States-European Consensus Criteria, and 602 healthy controls (F/M 534/68) were included. Patients and controls were classified into five groups: never smokers, current smokers, former smokers; ever smokers, and passive smokers. The χ(2) and Kruskal-Wallis tests were used for statistical analysis; a p value of less than 0.05 was accepted as statistically significant. While the frequency of current smokers was significantly lower in the pSS group compared with the healthy controls (11.6 vs 22.3%), the frequencies of former smokers (30.4 vs 11.8%), ever smokers (42.0 vs 34.1%), and passive smokers (47.3 vs 37.5%) were significantly higher in the pSS group compared with the healthy controls. In pSS patients, only antinuclear antibody (ANA) positivity was significantly associated with smoking habits, while there was no significant association with other autoantibodies or with the presence of extraglandular involvement. We found that in pSS patients smoking was significantly associated only with ANA positivity. Unlike the deleterious effects of smoking upon disease severity and anti-cyclic citrullinated protein (CCP) antibody production in rheumatoid arthritis, we could not find any association of smoking with extraglandular involvement and/or anti-Ro/anti-La antibody positivity in pSS. These results are indeed in line with the limited number of previous studies reported in the literature. Further studies with higher numbers of pSS patients are required to confirm the seemingly negative association of smoking with pSS.