Current treatment options with immunoglobulin G for the individualization of care in patients with primary immunodeficiency disease

Primary antibody deficiencies require lifelong replacement therapy with immunoglobulin (Ig)G to reduce the incidence and severity of infections. Both subcutaneous and intravenous routes of administering IgG can be effective and well tolerated. Treatment regimens can be individualized to provide optimal medical and quality‐of‐life outcomes in infants, children, adults and elderly people. Frequency, dose, route of administration, home or infusion‐centre administration, and the use of self‐ or health‐professional‐administered infusion can be tailored to suit individual patient needs and circumstances. Patient education is needed to understand the disease and the importance of continuous therapy. Both the subcutaneous and intravenous routes have advantages and disadvantages, which should be considered in selecting each patient's treatment regimen. The subcutaneous route is attractive to many patients because of a reduced incidence of systemic adverse events, flexibility in scheduling and its comparative ease of administration, at home or in a clinic. Self‐infusion regimens, however, require independence and self‐reliance, good compliance on the part of the patient/parent and the confidence of the physician and the nurse. Intravenous administration in a clinic setting may be more appropriate in patients with reduced manual dexterity, reluctance to self‐administer or a lack of self‐reliance, and intravenous administration at home for those with good venous access who prefer less frequent treatments. Both therapy approaches have been demonstrated to provide protection from infections and improve health‐related quality of life. Data supporting current options in IgG replacement are presented, and considerations in choosing between the two routes of therapy are discussed.     

Immunoglobulins for primary or secondary immunodeficiency or for immunomodulation in neurological autoimmune diseases: insights from the prospective SIGNS registry

Aim

Outside the context of clinical trials, there is a lack of data on the management and long-term outcomes of patients with primary or secondary antibody deficiency (PID and SID), or those with neurological autoimmune diseases (AID) treated with immunoglobulins (IG).

Methods

SIGNS is a large-scale prospective observational cohort study with up to 550 patients in currently 50 sites throughout Germany. It investigates treatment patterns, effectiveness, quality of life and long-term outcomes of IG administered for PID, SID or AID. The study identifier at ClinTrials.Gov is NCT01287689.

Results

Of 306 patients currently included (1 Nov 2011), 108 had PID (49 children), 147 SID and 51 neurological AIDs. First symptoms had occurred 7.9 (PID children), 10.4 (PID adults), 5.5 (SID) and 7.2?years (AID) before entry, and disease duration since diagnosis was 4.8 (PID children), 7.0 (PID adults), 5.3 (SID) and 5.9?years (AID). Newly initiated IG therapy was reported in 45% (PID), 54% (SID) and 56% (AID). 13 different IG preparations were utilized at inclusion. In PID, only 25.0% of children and 24.1% of adults had no infection in the past 12?months; while 3 serious bacterial infections (1 meningitis, 2 pneumonia) were reported in children, and 1 in adults. With respect to AID, 21 patients had chronic inflammatory demyelinating polyneuropathy (CIDP), 7 had multifocal motor neuropathy (MMN), 11 multiple sclerosis (MS), 6 myasthenia gravis, 2 myositis, 4 other (no cases of Guillain Barré Syndrome). Quality of life of patients in all groups was reduced as assessed by ED-5D and SF-36.

Conclusions

A broad spectrum of indications and IG preparations is documented in SIGNS. It is expected that the registry will contribute to optimization of therapy in this diverse patient population.     

Endoluminal gastroplication: what are the predictors of outcome?

Background: Endoluminal gastroplication (EndoCinch) has emerged as an endoscopic anti-reflux therapy, but predictive factors for symptom relief have not been established. The aim of this study was to evaluate the major determinants to predict outcome in patients treated with EndoCinch. Methods: A total of 53 consecutive patients, treated with EndoCinch at a single center were included in this prospective study. Inclusion criteria were symptoms of chronic heartburn, dependency on proton-pump inhibitors, documented pathological esophageal acid exposure, and a hiatal hernia smaller than 3?cm in length. All patients underwent endoscopy, 24-h pH monitoring, esophageal manometry, barium esophagram, and a detailed questionnaire regarding their symptoms before treatment. Patients were stratified into a responder and a non-responder group using a questionnaire at 3-month follow-up. A multivariate analysis was performed. Results: The success rate was 64% (34/53 patients). Three variables were significantly predictive for successful endoscopic anti-reflux treatment at the multivariate level: presence of typical symptoms (P?=?0.01), complete symptom relief with acid suppressive therapy (P?=?0.01), and normal lower esophageal sphincter pressure (P?=?0.04). Not predictive of outcome were age, body mass index, esophagitis, other manometric findings, hiatal hernia size, or pathological level of pH &;lt;4/24?h. Barium esophagram did not add any additional predictive information. Conclusions: Since no single factor can predict outcome after EndoCinch, a careful patient selection is mandatory to maximize the success rate. The ideal candidate for EndoCinch is a gastroesophageal (GERD) patient with a normal lower esophageal sphincter pressure, whose typical symptoms completely resolved with acid suppressive therapy.     

Entry age into day care and later development of allergic disorders--results from the city of Leipzig cohort of the LISA study

The situation in early childhood is supposed to be a risk factor for later development of allergic diseases. The birth cohort from the LISA (Lifestyle-Immune System-Allergy) study gave us the opportunity to investigate the relationship between early childhood situation and the development of allergic diseases. This paper describes our findings regarding to the relationship between entry age into day care and obstructive bronchitis as well as allergic rhinitis and atopic eczema. Study was designed as a longitudinal birth cohort study. Children were examined by a physician at birth, 1/2 year, 1 year, 1 1/2 year, 2 years, 3 years and 4 years. Further information was collected using a structured questionnaire which was answered by the parents. Outcomes under investigation were atopic eczema, allergic rhinitis, wheezing (with and without cold), obstructive bronchitis and asthma (after 2nd year of life). Logistic regression analysis adjusted for infectious diseases of the mother during pregnancy, vaccination of the mother during pregnancy, antibiotics, prenatal smoking of the mother or other persons in the apartment and vaccination state showed an significant promoting effect of entry age into day care against obstructive bronchitis over the first three years of life (OR 1/2 year: 8.55; 95%CI: 2.93...24.97; OR 1st year: 4.96; 95% CI: 1.73...14.24; OR 2nd year: 3.06 95% CI: 1...9.37). A further significant effect was found for crowding against asthma in the fourth year of life (OR 25.7; 95%CI: 1.65...400.17). No significant effects were found between the other periods under investigation (1st year until 4th year of life). On the base of our findings we recommend an entry age into day care of more than six months to prevent effects shown.     

Btk is a positive regulator in the TREM-1/DAP12 signaling pathway

The triggering receptor expressed on myeloid cells 1 (TREM-1) has been implicated in the production of proinflammatory cytokines and chemokines during bacterial infection and sepsis. For downstream signal transduction, TREM-1 is coupled to the ITAM-containing adaptor DAP12. Here, we demonstrate that Bruton tyrosine kinase (Btk), a member of the Tec kinases, becomes phosphorylated upon TREM-1 triggering. In U937-derived cell lines, in which expression of Btk was diminished by shRNA-mediated knockdown, phosphorylation of Erk1/2 and PLCγ1 and Ca2? mobilization were reduced after TREM-1 stimulation. Importantly, TREM-1-induced production of the pro-inflammatory cytokines, TNF-α and IL-8, and up-regulation of activation/differentiation cell surface markers were impaired in Btk knockdown cells. Similar results were obtained upon TREM-1 stimulation of BMDCs of Btk(-/-) mice. The analysis of cells containing Btk mutants revealed that intact membrane localization and a functional kinase domain were required for TREM-1-mediated signaling. Finally, after TREM-1 engagement, TNF-α production by PBMCs was reduced in the majority of patients suffering from X-linked agammaglobulinemia (XLA), a rare hereditary disease caused by mutations in the BTK gene. In conclusion, our data identify Btk as a positive regulator in the ITAM-mediated TREM-1/DAP12 pathway and suggest its implication in inflammatory processes.     

Central diabetes insipidus in a patient with malaria tropica

Up to 21% of severe cases of malaria tropica are associated with polyuria and are life-threatening. We describe a 39-yr-old man with malaria tropica who developed disseminated intravascular coagulation, polyuria, and a pituitary lesion. Empiric treatment with vasopressin improved the polyuria. This is the first case of malaria tropica in which central diabetes insipidus has been documented.     

Rapid Subcutaneous IgG Replacement Therapy is Effective and Safe in Children and Adults with Primary Immunodeficiencies—A Prospective, Multi-National Study

Sixty patients (16 children, 44 adults) participated in the study aiming at evaluating: (i) IgG levels when switching patients from intravenous IgG (IVIG) infusions in hospital to subcutaneous (SCIG) self-infusions at home using the same cumulative monthly dose, (ii) protections against infections, and (iii) safety of a new, ready-to-use 16% IgG preparation. All children and 33 adults had received IVIG therapy for >6 months at enrolment. Ten adults who had been on SCIG therapy for many years served as controls. Mean serum IgG trough levels increased in the pre-IVIG children from 7.8 to 9.2 g/L (non-inferiority: p < 0.001) and in the adults from 8.6 to 8.9 g/L (non-inferiority: p < 0.001). Totally 114 respiratory tract infections occurred, 90% of them mild. One serious bacterial infection (pneumonia) was reported for one adult. The annualized rate of serious infections was 0.04 episodes/patient. In total 2297 infusions were given and 28 (1%) systemic adverse reactions occurred, none of them severe. Local tissue reactions declined over time, this being particularly distinct after 8 to 10 weeks. In conclusion, the SCIG administration route was safe. High IgG levels were easily maintained resulting in a very good protection against infections.     

32-jähriger Patient mit Durchfall und akutem Nierenversagen

A 32-year-old male patient presented in the emergency department of our hospital with acute vomiting and diarrhoea. He reported occasional non-severe diarrhoea over several years in the past. Furthermore, at the time of presentation the patient had had anuria for several days. A prerenal and postrenal origin of the renal failure was excluded. A renal biopsy was performed and histopathological examination displayed findings consistent with a haemolytic-uraemic syndrome but no signs of glomerulonephritis. MRI examination of the small bowel revealed inflammatory alterations typical for Crohn's disease, even without histological verification. We describe haemolytic-waemic syndrome as manifestation of Crohn's disease for the first time.     

Evaluation of correlation between dose and clinical outcomes in subcutaneous immunoglobulin replacement therapy

The importance of serum immunoglobulin (Ig)G concentration in IgG replacement therapy for primary immunodeficiency diseases is established in certain settings. Generally, IgG is infused via the intravenous (IVIG) or subcutaneous (SCIG) route. For IVIG infusion, published data demonstrate that higher IgG doses and trough levels provide patients with improved protection from infection. The same conclusions are not yet accepted for SCIG; data from two recent Phase III studies and a recent post-hoc analysis, however, suggest the same correlation between higher SCIG dose and serum IgG concentration and decreased incidence of infection seen with IVIG. Other measures of clinical efficacy have not been considered similarly. Thus, combined analyses of these and other published SCIG studies were performed; a full comparison of the 13 studies was, however, limited by non-standardized definitions and reporting. Despite these limitations, our analyses indicate that certain clinical outcomes improve at higher SCIG doses and associated higher serum IgG concentrations, and suggest that there might be opportunity to improve patient outcomes via SCIG dose adjustment.