Low frequency of anti‐D alloimmunization following D+ platelet transfusion: the Anti‐D Alloimmunization after D‐incompatible Platelet Transfusions (ADAPT) study

The reported frequency of D alloimmunization in D? recipients after transfusion of D+ platelets varies. This study was designed to determine the frequency of D alloimmunization, previously reported to be an average of 5 ± 2%. A primary anti‐D immune response was defined as the detection of anti‐D ≥ 28 d following the first D+ platelet transfusion. Data were collected on 485 D? recipients of D+ platelets in 11 centres between 2010 and 2012. Their median age was 60 (range 2–100) years. Diagnoses included: haematological (203/485, 42%), oncological (64/485, 13%) and other diseases (218/485, 45%). Only 7/485 (1·44%; 95% CI 0·58–2·97%) recipients had a primary anti‐D response after a median serological follow‐up of 77 d (range: 28–2111). There were no statistically significant differences between the primary anti‐D formers and the other patients, in terms of gender, age, receipt of immunosuppressive therapy, proportion of patients with haematological/oncological diseases, transfusion of whole blood‐derived or apheresis platelets or both, and total number of transfused platelet products. This is the largest study with the longest follow‐up of D alloimmunization following D+ platelet transfusion. The low frequency of D alloimmunization should be considered when deciding whether to administer Rh Immune Globulin to D? males and D? females without childbearing potential after transfusion of D+ platelets.     

Conformational anti‐cytochrome P4502E1 (CYP2E1) auto‐antibodies contribute to necro‐inflammatory injury in chronic hepatitis C

Summary. Circulating auto‐antibodies against cytochrome P4502E1 (CYP2E1) have been observed in a significant fraction of patients with chronic hepatitis C (CHC). This study investigated the clinical significance of these auto‐antibodies in relation to their antigen specificity. The presence of anti‐CYP2E1 IgG was investigated in 137 consecutive patients with biopsy‐proven CHC. Anti‐CYP2E1 IgG above control threshold levels was detected in 52 (38%) subjects. By combined immunoprecipitation and western blotting, we observed that among anti‐CYP2E1 IgG‐positive sera, 23 (44%) were unreactive towards denaturated CYP2E1, indicating a prevalent recognition of conformational CYP2E1 antigens. Conformational anti‐CYP2E1 auto‐antibodies were unrelated to circulating gamma‐globulins, alcohol intake or infection by specific HCV genotypes. The presence of anti‐CYP2E1 auto‐antibodies was associated with an 11‐fold (OR 10.9 95%CI 1.4–86.6 P = 0.008) increased prevalence of necro‐inflammatory grading ≥4 (Ishack’s criteria) and 4‐fold (OR 4.0; 95%CI 1.3‐11‐7: P = 0.014) increased prevalence of fibrosis staging ≥2, respectively. Multivariate analysis confirmed conformational anti‐CYP2E1 IgG (P = 0.005) and age (P = 0.033) as independent predictors of necro‐inflammatory grading ≥4. The development of anti‐CYP2E1 auto‐antibodies targeting conformational CYP2E1 epitopes is associated with more severe liver damage in CHC.     

Regular use of non‐steroidal anti‐inflammatory drugs increases the risk of adult‐onset asthma: a population‐based follow‐up study

Background: Little is known about the relation between regular use of non‐steroidal anti‐inflammatory drugs (NSAIDs) and the risk of asthma at the population level. The aim of this study was to examine a possible association between intake of NSAIDs and risk of adult‐onset asthma. Methods: Using data from two multidisciplinary postal questionnaire surveys concerning health and lifestyle, we prospectively studied 19 349 adult twins enrolled in the nationwide Danish Twin Registry. Results: We found a higher prevalence of new‐onset asthma in subjects who used NSAIDs (other than aspirin) regularly compared with non‐users (7.7% vs 4.3%), OR = 1.87 (1.25–2.81), P = 0.002. The result remained significant after adjusting for sex, age, smoking, BMI, hay fever, eczema and intake of medications other than NSAIDs, OR = 1.90 (1.26–2.85), P = 0.002. Conclusions: Regular use of NSAIDs other than aspirin may be a risk factor for adult‐onset asthma. This observation must be accommodated in explanations of the relationship between use of analgesics and risk of asthma. Please cite this paper as: Thomsen SF, Kyvik KO, Skadhauge LR, Steffensen I and Backer V. Regular use of non‐steroidal anti‐inflammatory drugs increases the risk of adult‐onset asthma: a population‐based follow‐up study. The Clinical Respiratory Journal 2009; 3: 82–84.     

Therapeutic efficacy of humanized recombinant anti–interleukin‐6 receptor antibody in children with systemic‐onset juvenile idiopathic arthritis

Objective

To investigate the safety and efficacy of a recombinant human anti–interleukin‐6 (anti–IL‐6) receptor monoclonal antibody (MRA) that indirectly inhibits the effects of IL‐6 in children with systemic‐onset juvenile idiopathic arthritis (JIA) refractory to high‐dose, long‐term corticosteroids.

Methods

An individual escalating‐dose trial was conducted in 11 children with active systemic‐onset JIA who met the inclusion criteria. All were first administered an intravenous dose of 2 mg/kg MRA. Each child without active inflammation was given a second identical dose 2 weeks later and a third identical dose 2 weeks after the second dose. Children with disease flares according to laboratory marker values received a 4‐mg/kg dose. Those without disease flares at this dose received a second 4‐mg/kg dose 2 weeks later and a third 4‐mg/kg dose 2 weeks after the second dose, while those with active inflammation received an additional 3 doses of 8 mg/kg MRA. Efficacy was evaluated every 2 weeks according to responses on the JIA core set of improvement criteria and the results of laboratory tests.

Results

MRA abruptly reduced disease activity in 10 of the 11 children, as assessed by the occurrence of febrile episodes, active arthritis, scores on the Childhood Health Assessment Questionnaire, and levels of acute‐phase reactants. However, levels of inflammatory reactants fluctuated until the proper MRA dose for each child was reached. Two weeks after the third fixed dose of MRA, 90.9% of all patients had a 30% improvement response, 90.9% had a 50% improvement response, and 63.6% had a 70% improvement response.

Conclusion

MRA treatment of children with active systemic disease results in clinical improvement and in normalized levels of acute‐phase reactants. MRA was safe and well tolerated and provided greater clinical benefit than conventional corticosteroids, considering the ill effects of IL‐6 and adverse events.

     

Serum concentrations of DKK‐1 decrease in patients with multiple myeloma responding to anti‐myeloma treatment

Lytic bone destruction is a hallmark of multiple myeloma (MM) and is because of an uncoupling of bone remodeling. Secretion of Dickkopf (DKK)‐1 by myeloma cells is a major factor which causes inhibition of osteoblast precursors. In this study, the effect of different treatment regimens for MM on serum DKK‐1 was evaluated and correlated with the response to treatment in 101 myeloma patients receiving bortezomib, thalidomide, lenalidomide, adriamycin and dexamethasone (AD) or high‐dose chemotherapy (HDCT) followed by autologous stem cell transplantation (ASCT). At baseline, myeloma patients had increased serum DKK‐1 as compared with patients with MGUS (mean 3786 pg/mL vs. 1993 pg/mL). There was no difference between previously untreated MM patients and patients at relapse. A significant decrease of DKK‐1 after therapy was seen in the following groups: Bortezomib (4059 pg/mL vs. 1862 pg/mL, P = 0.016), lenalidomide (11837 pg/mL vs. 4374 pg/mL, P = 0.039), AD (1668 pg/mL vs. 1241 pg/mL, P = 0.016), and AD + HDCT + ASCT (2446 pg/mL vs. 1082 pg/mL, P = 0.001). Thalidomide led to a non‐significant decrease in DKK‐1 (1705 pg/mL vs. 1269 pg/mL, P = 0.081). Within all groups, a significant decrease of DKK‐1 was only seen in responders (i.e. patients achieving complete remission or partial remission), but not in non‐responders. We show for the first time that serum DKK‐1 levels decrease in myeloma patients responding to treatment, irrespective of the regimen chosen. These data suggest that myeloma cells are the main source of circulating DKK‐1 protein and provide a framework for clinical trials on anti‐DKK‐1 treatment in MM.     

Treatment of allergic bronchopulmonary aspergillosis (ABPA) in CF with anti‐IgE antibody (omalizumab)

Allergic bronchopulmonary aspergillosis (ABPA) results from IgE induced pulmonary response to aspergillus species. Recognition and management of ABPA is challenging in cystic fibrosis (CF) patients because changes in symptoms, lung function and chest radiograph are similar to that seen in CF related pulmonary infection. Standard therapy for ABPA includes systemic steroids and adjunctive use of antifungal agents. Little has been published regarding the use of monoclonal anti‐IgE antibody in those with ABPA. We report a CF patient with her third exacerbation of ABPA who was treated with monoclonal anti‐IgE (omalizumab) antibody; she had unfavorable side effects with prednisone therapy. This therapy resulted in improvement of pulmonary symptoms and lung function not achieved with antibiotics or prednisone alone. Pediatr. Pulmonol. 2008; 43:1249–1251. © 2008 Wiley‐Liss, Inc.     

Treatment of chronic hepatitis C in polytransfused thalassaemic patients: a meta‐analysis

Summary. Hepatitis C virus (HCV) infection is a major cause of liver‐related morbidity and mortality among thalassaemic patients. In order to analyse the effect of the current anti‐HCV treatment in this subset of HCV‐infected patients, we conducted a systematic review with meta‐analysis of the available literature. The outcome was sustained viral response. Both comparative [odds ratio (OR)] and non‐comparative indeces (success rate) were used to run the meta‐analytical procedure. Data encompassing 429 thalassaemic HCV‐infected patients treated with conventional or pegylated interferon monotherapy or combination therapy with ribavirin were collected from 13 articles (10 prospective cohort studies, 1 randomized‐controlled trial and 2 controlled trials). Pooled sustained viralogical response (SVR) was 44.7% (34.6–54.9). Pooled ORs of SVR for Genotype 1 vs non‐Genotype 1 infected thalassaemic patients were 0.46 (95% CI: 0.22–0.95) in IFN monotherapy and 1.7 (95% CI: 0.46–6.04) in ribavirin combination therapy. Our meta‐analysis shows that thalassaemic patients with Genotype 1 infection significantly benefit from the addition of ribavirin to their therapeutic regimen. It seems that using ribavirin in thalassaemic patients increases transfusion need by a median of 30–40%, but does not increase major adverse events or treatment withdrawal. Current literature is lacking sufficient evidence about the use of PEG‐IFN as monotherapy or in combination with ribavirin in thalassaemic patients.     

Growth hormone deficiency (GHD) in adult thalassaemic patients

BACKGROUND AND OBJECTIVE: Short stature and growth hormone deficiency (GHD) are frequent occurrences in thalassaemic children, while data on the prevalence of GHD in adult patients are lacking. Therefore, we elected to study the growth hormone and insulin-like growth factor-I (GH-IGF-I) axis in a large group of adult thalassaemic subjects. DESIGN: Cross-sectional study on the prevalence of GHD in 94 adult thalassaemic patients (69 with thalassaemia major and 25 with thalassaemia intermedia, 39 men and 55 women, aged 31.5 +/- 6.8 years, on sex steroid replacement when necessary). METHODS: All patients underwent GHRH (1 microg/kg as an i.v. bolus) plus arginine (0.5 g/kg as a 30 min i.v. infusion) testing. Severe GHD was defined by GH peaks lower than 9 microg/l, whereas partial GHD was defined by GH peaks ranging from 9-16.5 microg/l. Blood samples for IGF-I, ferritin and pseudocholinesterase measurements were collected. Urinary free cortisol (UFC) levels were also assayed. RESULTS: Severe GHD was demonstrated in 21 of the 94 patients (22.3%), while 18 additional patients (19.1%) displayed partial GHD. GH peaks were positively correlated with IGF-I standard deviation score (SDS) (r = 0.22, P < 0.05), although 1 of the 21 patients with severe GHD showed normal IGF-I SDS values, and 44 of the 55 patients with normal GH reserve displayed low IGF-I SDS. A strong positive correlation (r = 0.48, P < 0.0001) between IGF-I SDS and pseudocholinesterase was identified. No correlations were found between ferritin and UFC levels on the one hand and GH peaks and IGF-I SDS on the other. CONCLUSION: Findings from this study demonstrate that GHD, either partial or severe, is not a rare occurrence in adult thalassaemic patients. GHD is associated with a higher prevalence of low serum IGF-I levels, recorded also in patients with normal GH secretion. The lack of correlation between ferritin and both GH peaks and IGF-I SDS suggests that mechanisms additional to iron overload, whose relevance cannot however be definitely ruled out, play a role in the pathophysiology of somatotrophin-somatomedin deficiency in this clinical condition. The positive correlation between IGF-I SDS on the one hand and GH peaks and pseudocholinesterase values on the other hand indicates that reduced liver protidosynthetic activity, in addition to somatotrophin secretory status, is a major determinant of the impaired IGF-I production in thalassaemia. Therefore biosynthetic GH replacement therapy in GH-deficient thalassaemic adults is worth considering.