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- Material and methods
Background: Many clinical trials with omalizumab, Xolair, have been reported but the treatment period has always been short, i.e. <12 months. After withdrawal, the clinical symptoms tend to return. A group of patients who stopped treatment after approx. 6 years allowed studies of the long-term effects of Xolair.
Methods: The patient’s cat or mite allergen sensitivity was quantitated as basophil allergen threshold sensitivity, CD-sens, and immunoglobulin E (IgE) and IgE- and IgG4-antibodies were determined before start and during treatment withdrawal. Asthma severity was evaluated from forced expiratory volume (FEV), peak expiratory flow (PEF) and a questionnaire.
Results: At 6–14 months without Xolair 13 of the 18 cat and mite allergic asthmatics had either improved or remained the same as on treatment. Most of the patients were in a stable clinical condition reporting high quality of life, no increased nightly asthma attacks, no emergency visits as well as little or no increase in medication. The CD-sens to cat showed a peak 4 months after withdrawal but then decreased to levels below those of untreated patients with allergic asthma and at 12 months six of 14 had nonreactive basophils. Cat IgG4 antibody levels were higher than in cat allergics in general.
Conclusion: Most of the patients 12–14 months had, after closing of 6-year Xolair treatment, a surprisingly mild asthma. Interestingly, and probably contributing to the clinical results, a downregulation of basophil, and presumably also mast cell, reactivity, was seen.
During the last years, the humanized monoclonal anti-immunoglobulin E (IgE) antibody omalizumab has been approved in the United States and European Union for the treatment of patients over 12 years of age with moderate to severe IgE-mediated allergic asthma. Omalizumab has been shown to decrease levels of circulating IgE by binding to the constant region (Cε3) of the IgE molecule and thereby blocking the structures responsible for the reaction with FcεRI and FcεRII receptors on mast cells and basophils (1). Several reports show a reduced level of free IgE by as much as 99% within 3 days followed by a 90% decrease in FcεRI expression on basophils after 7 days (2, 3), and by the time of nasal and skin prick tests (SPT) responses were significantly reduced (4). Withdrawal of omalizumab after a few months of treatment results in a return to pretreatment clinical state, FcεRI number and serum IgE levels within months (5).
The positive results on allergic disease are the most promising, and now when omalizumab is available for prescription, there is an urgent need for a simple test to select responders and to monitor treatment efficacy. There are several in vivo and in vitro methods to monitor different immunological and inflammatory factors. Some of them, like the measurement of IgE, sometimes referred to as ‘total IgE’ and allergen-specific IgE antibodies in serum, are well standardized and easy to handle, although the results obtained do not mirror allergy-related inflammatory factors like cell responses and bronchial mucosal hyper-reactivity (6, 7). Other methods such as skin tests are simple and safe but not useful for quantitation of sensitivity as the precision is very low (8). Target organ allergen challenge tests, on the other hand, could be used but are difficult to handle, time-consuming, not very quantitative and potentially dangerous for the patient.
Over the last 10 years, flow cytometric methods allowing detection of activated basophils in blood have been developed and refined. By using a combination of CD63 as a basophil activity marker and CD203c for basophil identification, these methods allow objective analyses of a high number of basophils in a relatively short time (9, 10). Basophil allergen threshold challenge, CD-sens (11), as a measure of patient allergen sensitivity, correlated well with clinical tests for allergen sensitivity-like SPT titration (12), nasal allergen provocation (12) and bronchial allergen provocation (unpublished). Thus, CD-sens is useful for monitoring the efficacy of different treatments, e.g. IgE-specific immunomodulation treatment (ESIT) with omalizumab or allergen-specific immunotherapy (ASIT), with small intra-assay/interassay variations (12).
The aim of this study was to follow basophil allergen sensitivity, CD-sens, serological parameters and the perception of symptoms and need for drugs in patients after withdrawal of omalizumab after a very long time of treatment, i.e. 6 years.
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- Material and methods
A new approach to treatment of allergic disease was introduced during 2003 in the USA and during 2005 in Europe when a humanized, monoclonal antibody to IgE, omalizumab, Xolair®, became available. Injection of Xolair results in a rapid 99% decrease in free serum IgE within 3 days (2), followed by 99% and 90%, respectively, downregulation within 7 days of the high-affinity IgE receptor (FcεRI) on basophils (1, 3) and mast cells (3). As a result, IgE antibody-mediated allergic disease symptoms are diminished (4, 7, 13). Omalizumab is well tolerated and effectively prevents exacerbations in patients with severe, persistent asthma (14–16).
In the clinical trials, the patients were usually treated for a few months up to 1 year. When Xolair was withdrawn, the serum IgE levels and number of IgE receptors on the basophils returned to pretreatment values (5). Not surprisingly, also the clinical symptoms of asthma and allergic rhinitis usually return forcing the patient to start again with regular drugs, to increase the dosage of conventional drugs like antihistamines or local steroids and to seek medical help.
No study has reported the long-term effect of Xolair. In 1998, from Sweden, 22 patients were enrolled in the international omalizumab trial of severe allergic asthma, CIGE 0250011 followed by three extensions. The patients had perennial, allergic asthma that needed continuous treatment with rather high doses of local steroids. However, they were pleased with the effects of omalizumab and urged to be allowed to continue with the drug. This was accepted and they continued without any significant intervention until the summer of 2005, when Xolair became available by prescription in Sweden. It was then decided that before a decision was taken on prescribing the drug, the ongoing treatment should be closed and Xolair withdrawn.
This decision presented a unique opportunity to monitor clinical and immunological parameters during the withdrawal phase. Of the 22 patients, 18 accepted to participate in the withdrawal study. Cat and mite allergies were parts of the recruitment criteria and of the participants, 15 were cat and three were mite IgE sensitized. Basophil allergen threshold sensitivity, CD-sens (12), to both cat and mite were analysed but only cat CD-sens was used for further comparisons. The reason is that CD-sens of different allergens cannot generally be compared because of inadequate allergen extract standardization and, in addition, the number of mite allergic patients was too low. During the first 6 months after the last Xolair dosage, an expected increase in cat allergen sensitivity was seen. CD-sens peaked at 4 months, and was followed by a slow decrease but at 6 months, the mean value was still significantly higher than it was during treatment. However, CD-sens continued to decrease and at 12–14 months, seven patients had a CD-sens lower than that on treatment and six of them had nonreactive basophils. The median CD-sens of all 15 cat IgE-sensitized patients was significantly lower at 12–14 months than that of cat allergic patients, in general.
The plasma ABA decreased slightly during the follow up as did serum levels of IgG4 antibodies to cat allergen. At 12–14 months, the median levels of ABA and IgG4 antibodies were lower than those of cat allergics. Thus, even if IgG4 antibodies could play a part in the decrease of sensitivity, as had been seen during ASIT (17), they may not be the most important factor in these patients. This is further supported by the finding that the serum levels of IgG4 antibodies to cat did not change much from pretreatment in 1998 to the last withdrawal sample despite a more generous attitude to cat contacts. It is possible that the cat IgE antibodies in the omalizumab–IgE immune complexes can also play a part in ABA.
The clinical evaluation was based on a physical examination consisting of spirometry with particular emphasis on FEV1 and PEF values. Thus, FEV1 was measured at each visit during the withdrawal and no decrease over time was seen in any but one patient.
At the final visit a year after the end of ESIT, the patients were asked to fill in a simplified symptom questionnaire with some of the questions used in the primary study during 1999. Of the 18 cat or mite allergic patients, 12 reported that their asthma had improved or not changed during the 12–14 months they had been without Xolair compared with when they were taking the drug. A CD-sens below the low quartile of the controls was found in eight of the 15 cat allergic patients. Seven of those eight reported less or the same asthma symptoms and seven less or unchanged nightly attacks and were taking less or the same medication. Of the eight patients reporting of asthma symptoms today compared with before treatment, i.e. 7 years ago, six were of the opinion that their symptoms now were less pronounced. Interestingly, three of the five patients reporting deterioration of their asthma had 1 year after the last injection improved in FEV1 and had nonresponsive basophils. Thus, other factors such as no longer being taken care of at the allergy clinic visits every 2–4 weeks, might influence the patient’s experience of their symptoms and well-being.
Before the trial in 1998, 18 of 22 patients had detectable serum levels of IgE antibodies to cat. Interestingly, the concentration of IgE antibodies expressed in percentage of IgE was the same both before treatment and during treatment indicating that the IgE antibodies in the IgE–omalizumab complexes are accessible and that serum IgE antibody levels measured during Xolair treatment could be a clinically relevant expression of allergen exposure.
In conclusion, in this open long-term study, treatment of allergic asthma with Xolair allowed a significant proportion of patients, more than half of them, to stabilize their asthma with unchanged lung function, even 1 year after Xolair therapy was stopped. The mechanism seems to be mostly a downregulation of the basophil, and presumably mast cell reactivity perhaps combined with allergen-specific IgG4 antibodies. These most interesting findings need to be further studied. Allergy is mainly a disease of young people and the long-term effect of Xolair should be monitored in that group where an even better promotion of the natural disappearance of an IgE-mediated allergy can be expected.