Janne Björkander

Icatibant, a New Bradykinin-Receptor Antagonist, in Hereditary Angioedema

BACKGROUND Hereditary angioedema is characterized by recurrent attacks of angioedema of the skin, larynx, and gastrointestinal tract. Bradykinin is the key mediator of symptoms. Icatibant is a selective bradykinin B2 receptor antagonist. METHODS In two double-blind, randomized, multicenter trials, we evaluated the effect of icatibant in patients with hereditary angioedema presenting with cutaneous or abdominal attacks. In the For Angioedema Subcutaneous Treatment (FAST) 1 trial, patients received either icatibant or placebo; in FAST-2, patients received either icatibant or oral tranexamic acid, at a dose of 3 g daily for 2 days. Icatibant was given once, subcutaneously, at a dose of 30 mg. The primary end point was the median time to clinically significant relief of symptoms. RESULTS A total of 56 and 74 patients underwent randomization in the FAST-1 and FAST-2 trials, respectively. The primary end point was reached in 2.5 hours with icatibant versus 4.6 hours with placebo in the FAST-1 trial (P=0.14) and in 2.0 hours with icatibant versus 12.0 hours with tranexamic acid in the FAST-2 trial (P<0.001). In the FAST-1 study, 3 recipients of icatibant and 13 recipients of placebo needed treatment with rescue medication. The median time to first improvement of symptoms, as assessed by patients and by investigators, was significantly shorter with icatibant in both trials. No icatibant-related serious adverse events were reported. CONCLUSIONS In patients with hereditary angioedema having acute attacks, we found a significant benefit of icatibant as compared with tranexamic acid in one trial and a nonsignificant benefit of icatibant as compared with placebo in the other trial with regard to the primary end point. The early use of rescue medication may have obscured the benefit of icatibant in the placebo trial. (Funded by Jerini; ClinicalTrials.gov numbers, NCT00097695 and NCT00500656.)

IgG subclasses in selective IgA deficiency: importance of IgG2-IgA deficiency.

A SELECTIVE deficiency in IgA appears in about one in 700 persons.1 Many of these persons are healthy,2 but there is an increased frequency of infections, autoimmune disorders, atopy, and malabsorp...

Subcutaneous immunoglobulin replacement in patients with primary antibody deficiencies: safety and costs

Immunoglobulins (IgG) as replacement therapy in primary antibody deficiencies can be given as intramuscular injections, or as intravenous or subcutaneous infusions. Our aims were to obtain information on the frequency of adverse systemic reactions during subcutaneous therapy, the occurrence and intensity of tissue reactions at the infusion sites, and serum IgG changes. Furthermore, we compared costs between the different replacement regimes. Our study included 165 patients (69 women, 96 men, aged 13-76 years) with primary hypogammaglobulinaemia or IgG-subclass deficiencies. Data were compiled from questionnaires filled in by the patients and from their medical records. 33,168 subcutaneous infusions (27,030 in home therapy) had been given. 106 (of which 16 were at home) adverse systemic reactions (100 mild, 6 moderate) were recorded in 28 patients (17%). No severe or anaphylactoid reactions occurred. Despite large immunoglobulin volumes given during 434 patient years (28,480 infusions), no signs have been found that indicate the transmission of hepatitis virus. Transient tissue reactions occurred at the infusion sites but were not troublesome to most patients and we found significant increases in mean serum IgG. The use of subcutaneous instead of intravenous infusions at home would reduce the yearly cost per patient for the health-care sector by US

Impaired Lung Function in Patients with IgA Deficiency and Low Levels of IgG2 or IgG3

10,100 in Sweden alone. We conclude that subcutaneous administration of IgG is a safe and convenient method of providing immunoglobulins. We were able to reach serum IgG concentrations similar to those by the intravenous therapy and we found that the method could also be used successfully in patients with previous severe or anaphylactoid reactions to intramuscular injections.

Secretory antibodies in IgA-deficient and immunosuppressed individuals

Abstract We examined the relation between serum levels of IgG subclasses and lung function, as determined by spirometry, lung volumes, the single-breath nitrogen test, and static recoil pressures, in 29 patients with IgA deficiency and repeated upper or lower respiratory tract infections. Four of the patients had decreased levels of IgG2, and two had decreased levels of IgG3. Two or more lung-function values were abnormal in each of these six patients and also in three others with normal levels of IgG subclasses. Low levels of IgG2 and IgG3 were significantly related to abnormal lung function (P<0.01). The 20 patients with normal lung function all had IgG-subclass levels above the lower range. There may be a causal relation between low levels of IgG subclasses and deterioration in lung function, suggesting that patients with combined IgA and IgG-subclass deficiencies may benefit from immunoglobulin prophylaxis. (N Engl J Med 1985; 313: 720–4.)

Basophil Interleukin 4 and Interleukin 13 Production Is Suppressed during the Early Phase of Rush Immunotherapy

Total levels of IgM and secretory IgM as well as specific antibodies to poliovirus type I antigen,Escherichia coli O antigens, and β-lactoglobulin were measured in unstimulated and stimulated saliva as well as nasal secretion using an enzyme-linked immunosorbent assay (ELISA). The levels of these antibodies in IgA-deficient adults with and without frequent respiratory infections and children under immunosuppressive therapy for malignant disease were compared to those in normal adults and infants 1–7 months of age. The IgA-deficient adults had significantly higher IgM levels (P<0.002) than the normal adults as well as higher levels of IgM antibodies to poliovirus type I (P<0.05) andE. coli O antigen (P<0.002). There was a less pronounced IgM anti-β-lactoglobulin compensation. Secretory component (SC)-carrying antibodies against all three antigens were lower than in normal adults. The infants studied had levels of IgM in secretions close to those of the normal adults and significantly lower than those of the IgA-deficient adults (P<0.001) but with a higher proportion of SC-carrying IgM. The increase in total IgM and specific bacterial and viral IgM antibodies in saliva above that of the normal adults was significant(P<0.001–0.005) for those IgA-deficient individuals without, but not for those with, frequent infections. There was, however, no significant difference between the levels in the two groups of IgA-deficient adults. The total levels of SIgA and specific antibodies toE. coli O antigens and poliovirus type I antigen in saliva from children treated with multiple cytotoxic drugs for malignant disease did not differ from normal levels, irrespective of the duration of treatment. The lower IgM levels in saliva of IgA-deficient individuals with many infections was seen in spite of their frequent infections, suggesting a primary defect in an important compensatory defense mechanism.

The heterogeneity of IgA deficiency

Background: Studies using rush immunotherapy (RIT) have shown that rapid protection can be achieved using protocols allowing a fast increment of allergen dose. We examined the early effects of RIT on basophil numbers and expression of CD203c, production of interleukin (IL)-4 and IL-13 and histamine release by basophils in the peripheral blood of patients treated with immunotherapy and controls. Methods: Twelve patients treated with RIT and 4 untreated controls were included in the study. Any adverse events were evaluated during the incremental phase of RIT. Mononuclear cells were isolated before the start of RIT and 3 days, 1 week, 4 weeks and 3 months after the beginning of the treatment. Histamine release upon allergen stimulation, expression of CD203c and allergen-induced production of IL-4 and IL-13 by basophils were examined. Results: Significant decreases in blood basophil count (p = 0.02) were observed early in the treatment, returning to baseline values 1 week after the start of RIT. Similarly, histamine release decreased at day 3 (p = 0.02), but returned to pretreatment levels after 1 week. Also, the percentage of IL-4+ and IL-13+ basophils and levels of CD203c expression were markedly reduced early in the treatment. IL-4 and IL-13 production correlated with histamine release and CD203c expression. Histamine release and production of IL-4 and IL-13 by basophils before the treatment correlated with the severity of adverse events during the incremental phase of RIT. Conclusion: We report the decrease in blood basophil numbers, their lower activation status and the reduced production of IL-4 and IL-13 early in the course of RIT. This early suppression of basophil activation could be one mechanism behind the protective effect of RIT.

Immunoglobulin prophylaxis in 350 adults with IgG subclass deficiency and recurrent respiratory tract infections: A long-term follow-up

IgA deficiency (IgAd) was initially described not only in two healthy individuals (1) but also in patients with various diseases (2, 3). Some had an increased frequency of infections, while others had autoimmune diseases, atopy, malabsorption, turnouts, or various less common problems. The autoimmune diseases, as well as tumours, atopy, and malabsorption, may well be causally related to the IgAd but the involved mechanisms are unknown. The increased frequency of infections seen in many patients may be related more directly to the antibody deficiency. The lack of serum IgA is accompanied by a deficiency of secretory IgA, which is a major component in the defense of mucosal membranes (4). Actually more than half of the bodys total content of all antibodies consists of IgA. Against this background it is surprising that not many more individuals with selective IgAd have an increased tendency to infections. This article discusses the concept that IgAd is a heterogeneous group of conditions ranging from well-compensated healthy individuals to those with an uncompensated deficiency who can have relatively severe infectious problems. The latter group should receive more clinical attention than is usually given today.

1040 Prophylactic infusions with an unmodified intravenous immunoglobulin product causing few side-effects in patients with antibody deficiency syndromes

350 adult patients in Sweden were included in a retrospective study covering more than 2000 patient-y, to evaluate the efficacy of immunoglobulin (Ig) prophylaxis. All patients had selective or combined IgG subclass deficiency, without IgA deficiency, and suffered from recurrent respiratory tract infections (RTIs). The patients had been given Ig prophylaxis for 0.5–21 y (mean 5.5 y). In total, 164/350 of the patients had a concomitant lung disease. Because of the heterogeneity of this retrospective material we evaluated only those patients with 4 or more antibiotic-demanding (i.e. presumably bacterial) episodes of RTI per y treated with an Ig dose of about 100 mg/kg/week (132/350). The frequency of antibiotic treated RTIs prior to and during latest y/s of Ig prophylaxis was compared. No difference in response could be found between patients with and without chronic lung diseases. In 92/132 a ≥50% reduction of the rate of episodes of antibiotic-demanding RTIs was recorded (p < 0.001). The overall reduction of the RTI frequency was for IgG1 57%, IgG2 59%, IgG3 63% and for the combinations 61% (all p<0.001).

Quantifying the burden of disease and perceived health state in patients with hereditary angioedema in Sweden

SummaryThirty-two patients with common variable immunodeficiency (CVID) and two patients with IgA and IgG subclass deficiency received a total of 1,040 intravenous (i.v.) infusions during 60 patient years with 7,575 g of a new immunoglobulin (Ig) preparation. The content of prekallikrein activators and the anti-complementary activity in the tested Ig preparation was low and, in comparison to seven other commercial i.v. Igs, so was the proportion of IgG polymers and fragments. The IgA content was always ≤0.02 g/l, often <0.004 g/l, and it was possible to continuously give the Ig prophylactically to four patients with anti-IgA antibodies, i.e. three with CVID and one with combined IgA-IgG2 deficiency. Adverse reactions were only noted in 4.7% of the 1,040 infusions and in 12 out of the 34 patients. None of the reactions were of the anaphylactic type, but two patients had moderate reactions and one had anuria, probably not caused by the Ig. A simultaneous infection seemed to increase the risk of phlogistic reactions, as five out of six patients who reacted with temperature rise and chills had a simultaneous upper respiratory tract infection. A substudy of various dosage schedules was performed with 11 patients receiving 203 infusions over 10.8 patient years. On 25 mg/kg/week of Ig given i.v. every five weeks, a mean increase in the preinfusion serum IgG level of 0.3 g/l was observed, as compared to earlier i.m. prophylaxis with the same dose. Only 1/4 of the patients on 25 mg/kg/week every five or three weeks reached a preinfusion IgG level ≥3 g/l. On 50 mg/kg/week every two weeks, 4/4 CVID patients had preinfusion levels above 3 g/l with a mean preinfusion increase of 1.5 g/l over the start level. Finally, 100 mg/kg/week every three weeks gave 5/5 patients a preinfusion serum IgG level of >4 g/l with a mean rise of 3.6 g/l, as compared with the levels before the study. An association between decreasing preinfusion IgG serum levels and the presence of infection was noted on 13/17 occasions, while increasing IgG was seen in healthy periods on 14/14 observations.Zusammenfassung32 Patienten mit gewöhnlichem variablen Immunglobulinmangel (CVID) und zwei Patienten mit fehlenden IgA- und IgG-Subklassen erhielten zusammen 1040 intravenöse (i.v.) Infusionen innerhalb von 60 Patientenjahren mit 7575 g einer neuen Immunglobulinpräparation (Ig). Der Gehalt an Prä-Kallikrein-Aktivatoren und die anti-komplementäre Aktivität in der getesteten Ig-Präparation war gering, verglichen mit sieben anderen kommerziell erhältlichen i.v. Immunglobulinen. Dasselbe gilt für den Anteil an IgG-Polymeren und -Fragmenten. Der IgA-Gehalt betrug immer ≤0,02 g/l, oft ≤0,004 g/l. Das Ig konnte vier Patienten mit IgA-Antikörpern, d. h. drei mit CVID und einem mit kombiniertem IgA-IgG-Mangel kontinuierlich verabreicht werden. Nur bei 4,7% der 1040 Infusionen und bei 12 der 34 Patienten wurden Nebenwirkungen beobachtet. Keine der Nebenwirkungen war vom anaphylaktischen Typ, aber zwei Patienten hatten mittelschwere Nebenwirkungen und einer eine Anurie, die wahrscheinlich nicht durch das Ig verursacht war. Das Risiko für phlogistische Reaktionen schien durch gleichzeitige Infektionen erhöht zu werden. Dies wurde bei fünf von sechs Patienten beobachtet, die bei Infektion der oberen Atemwege auf die Infusion mit Temperaturanstieg und Schüttelfrost reagierten. Bei 11 Patienten, die über 10,8 Patientenjahre 203 Infusionen erhielten, wurde eine Sonderstudie zu verschiedenen Dosierungen durchgeführt. Bei Infusion von 25 mg/kg/Woche i.v. alle fünf Wochen wurde ein mittlerer Anstieg der Serumspiegel vor Infusion gemessen, der um 0,3 g/l höher war als bei früherer i.m. Prophylaxe mit derselben Dosis. Nur bei 1/4 Patienten, die alle fünf oder drei Wochen 25 mg/kg/Woche erhielten, wurde ein IgG-Spiegel vor Infusion von ≥3 g/l erreicht. Bei Gabe von 50 mg/kg/Woche alle zwei Wochen hatten 4/4 CVID-Patienten vor Infusion Spiegel über 3 g/l, dabei stiegen die Spiegel vor Infusion um 1,5 g/l höher an als vor Therapiebeginn. Bei 100 mg/kg/Woche alle drei Wochen wiesen 5/5 Patienten ein Serum IgG von >4 g/l auf; der mittlere Anstieg gegenüber den Werten vor Studienbeginn betrug 3,6 g/l. Bei 13/17 Fällen wurde eine Assoziation von abnehmenden IgG-Serumspiegeln vor Infusion mit einer Infektion beobachtet; in gesunden Phasen waren bei 14/14 Beobachtungen Anstiege der IgG-Spiegel zu beobachten.Thirty-two patients with common variable immunodeficiency (CVID) and two patients with IgA and IgG subclass deficiency received a total of 1,040 intravenous (i.v.) infusions during 60 patient years with 7,575 g of a new immunoglobulin (Ig) preparation. The content of prekallikrein activators and the anti-complementary activity in the tested Ig preparation was low and, in comparison to seven other commercial i.v. Igs, so was the proportion of IgG polymers and fragments. The IgA content was always ≤0.02 g/l, often <0.004 g/l, and it was possible to continuously give the Ig prophylactically to four patients with anti-IgA antibodies, i.e. three with CVID and one with combined IgA-IgG2 deficiency. Adverse reactions were only noted in 4.7% of the 1,040 infusions and in 12 out of the 34 patients. None of the reactions were of the anaphylactic type, but two patients had moderate reactions and one had anuria, probably not caused by the Ig. A simultaneous infection seemed to increase the risk of phlogistic reactions, as five out of six patients who reacted with temperature rise and chills had a simultaneous upper respiratory tract infection. A substudy of various dosage schedules was performed with 11 patients receiving 203 infusions over 10.8 patient years. On 25 mg/kg/week of Ig given i.v. every five weeks, a mean increase in the preinfusion serum IgG level of 0.3 g/l was observed, as compared to earlier i.m. prophylaxis with the same dose. Only 1/4 of the patients on 25 mg/kg/week every five or three weeks reached a preinfusion IgG level ≥3 g/l. On 50 mg/kg/week every two weeks, 4/4 CVID patients had preinfusion levels above 3 g/l with a mean preinfusion increase of 1.5 g/l over the start level. Finally, 100 mg/kg/week every three weeks gave 5/5 patients a preinfusion serum IgG level of >4 g/l with a mean rise of 3.6 g/l, as compared with the levels before the study. An association between decreasing preinfusion IgG serum levels and the presence of infection was noted on 13/17 occasions, while increasing IgG was seen in healthy periods on 14/14 observations. 32 Patienten mit gewöhnlichem variablen Immunglobulinmangel (CVID) und zwei Patienten mit fehlenden IgA- und IgG-Subklassen erhielten zusammen 1040 intravenöse (i.v.) Infusionen innerhalb von 60 Patientenjahren mit 7575 g einer neuen Immunglobulinpräparation (Ig). Der Gehalt an Prä-Kallikrein-Aktivatoren und die anti-komplementäre Aktivität in der getesteten Ig-Präparation war gering, verglichen mit sieben anderen kommerziell erhältlichen i.v. Immunglobulinen. Dasselbe gilt für den Anteil an IgG-Polymeren und -Fragmenten. Der IgA-Gehalt betrug immer ≤0,02 g/l, oft ≤0,004 g/l. Das Ig konnte vier Patienten mit IgA-Antikörpern, d. h. drei mit CVID und einem mit kombiniertem IgA-IgG-Mangel kontinuierlich verabreicht werden. Nur bei 4,7% der 1040 Infusionen und bei 12 der 34 Patienten wurden Nebenwirkungen beobachtet. Keine der Nebenwirkungen war vom anaphylaktischen Typ, aber zwei Patienten hatten mittelschwere Nebenwirkungen und einer eine Anurie, die wahrscheinlich nicht durch das Ig verursacht war. Das Risiko für phlogistische Reaktionen schien durch gleichzeitige Infektionen erhöht zu werden. Dies wurde bei fünf von sechs Patienten beobachtet, die bei Infektion der oberen Atemwege auf die Infusion mit Temperaturanstieg und Schüttelfrost reagierten. Bei 11 Patienten, die über 10,8 Patientenjahre 203 Infusionen erhielten, wurde eine Sonderstudie zu verschiedenen Dosierungen durchgeführt. Bei Infusion von 25 mg/kg/Woche i.v. alle fünf Wochen wurde ein mittlerer Anstieg der Serumspiegel vor Infusion gemessen, der um 0,3 g/l höher war als bei früherer i.m. Prophylaxe mit derselben Dosis. Nur bei 1/4 Patienten, die alle fünf oder drei Wochen 25 mg/kg/Woche erhielten, wurde ein IgG-Spiegel vor Infusion von ≥3 g/l erreicht. Bei Gabe von 50 mg/kg/Woche alle zwei Wochen hatten 4/4 CVID-Patienten vor Infusion Spiegel über 3 g/l, dabei stiegen die Spiegel vor Infusion um 1,5 g/l höher an als vor Therapiebeginn. Bei 100 mg/kg/Woche alle drei Wochen wiesen 5/5 Patienten ein Serum IgG von >4 g/l auf; der mittlere Anstieg gegenüber den Werten vor Studienbeginn betrug 3,6 g/l. Bei 13/17 Fällen wurde eine Assoziation von abnehmenden IgG-Serumspiegeln vor Infusion mit einer Infektion beobachtet; in gesunden Phasen waren bei 14/14 Beobachtungen Anstiege der IgG-Spiegel zu beobachten.