Evidence-based curative health promotion : a systems biology-orientated treatment of seasonal allergic rhinitis with Citrus/Cydonia comp.

The prognosis of higher life expectancies of both men and women in the Netherlands, often related to chronic diseases and high healthcare costs, the changed role of patients into competent patients, and the increasing interest of patients in complementary medicine worldwide provides the scientific rationale to put more emphasis in healthcare on developing valid, effective, cost-effective and safe strategies that support and enable patients to actively contribute to their own health and disease status in order to promote their health in a preventive and/ or curative manner.

Although much effort has been invested worldwide, a lot of scientific and practical work still has to be done to develop the health promotion approach into one that is evidenced-based and professional like the fighting disease approach. This thesis focuses on some of the conceptual, methodological and empirical issues of developing professional preventive and curative health promotion as a contribution to the further innovation of medicine and healthcare.

Chapter 2 analyzed historic and current health concepts and developed and preliminarily validated the new concept of ‘health by self-regulation’ by means of analyzing its internal consistency, its accordance with other scientific concepts (e.g. the concepts of epigenetics, systems biology, and emergence) and its accordance with empirical facts. Finally, it demonstrated two examples of integration of the fighting disease and the health promotion approach and discussed the theoretical and practical implications of this new concept.

In Chapter 3, the fundamental scientific discussion of holism versus reductionism was summarized. This chapter demonstrated that there are several arguments against the current reductionist point of view. This provides a scientific opening for a more holistic or systems biology-oriented concept of health and a more holistic or systems biology-oriented methodological approach.

Chapter 4 described a new system’s biology-oriented methodological approach in developing immunological biomarkers for monitoring treatment effect in seasonal allergic rhinitis (hay fever) research. Using permuted stepwise regression, pattern variables that reflect immune system functioning on the systems level were computed and tested. Computation was based on a dataset (from a randomized controlled trial comparing two routes of administration) of allergen-specifically induced expression levels of cytokines (IL-1β, IL-5, IL-10, IL-12, IL-13, IL-17, IFN-γ and TNF-α) and symptom severity scores from 22 seasonal allergic rhinitis (SAR) patients measured before and after six weeks of treatment with medicinal products containing Citrus and Cydonia. Further computation and biomarker validation with larger datasets, including data from healthy persons and SAR patients, is indicated.

In Chapter 5, the experiences of 39 Dutch general practitioners with anthroposophic SAR treatment were examined. The results of this survey provide the first practice-based evidence of positive treatment results of Citrus/Cydonia comp. for SAR.

Chapter 6 examined, in two in vitro studies, the immunological pathways of the effects of Citrus/Cydonia comp. from a healthy and an allergic donor, respectively. Peripheral blood mononuclear cells (PBMCs) were isolated out of peripheral blood and analyzed in vitro after polyclonal stimulation of T-cells. The differentiation capacity and the influence regarding Th1 (IFN-γ) and Th2 (IL-5) cells were examined. Citrus/Cydonia comp. has a selective effect on the differentiation of Th-cells by producing relatively more IL-10 than IL-12. It also seems to have an effect on the induction of regulatory (IL-10 producing) T-cell subsets. It is in vitro capable of partly neutralizing the changes, characteristic to allergic rhinitis, regarding the maturation, differentiation, and activity of the immune system. Thus, it was concluded that Citrus/Cydonia comp. can potentially restore the disturbed immune state of rhinitis patients, which essentially could be sufficient to make allergic symptoms disappear permanently.

Chapter 7 examined the effects of the combined product, Citrus e fructibus/Cydonia e fructibus (Citrus/Cydonia), and separate products of Citrus and Cydonia on the immuno-pathological pathways involved in seasonal allergic rhinitis (SAR). Peripheral blood mononuclear cells (PBMCs) from five healthy and five grass pollen-allergic donors were isolated and analyzed in vitro after polyclonal and allergen-specific stimulation of T-cells in the presence of the three extracts. The analyses demonstrated acceptable cell survival with no signs of toxicity. Citrus mainly had a selective effect on reducing allergen-specific chronic inflammatory (TNF-a) and Th2 (IL-5) pathway activity; whereas both Cydonia and Citrus/Cydonia mainly affected the induction of the allergen-specific Th1 (IFN-g) pathway. Citrus and Cydonia demonstrated differential working mechanisms in the treatment of SAR, and the combination product did not demonstrate larger effects than the separate preparations. Hence, it was concluded that further effectiveness and efficacy studies comparing the effects of the products on SAR in vivo are required.

Chapter 8 studied a small group of 13 patients with a mean history of hay fever with grass pollen allergy of 9 years’ duration, who in previous years used conventional hay fever medication because of the severity of their symptoms during the pollen season. Gencydo injections were administered to 12 patients before the onset of and during the grass pollen season, and in one patient during the grass pollen season only. Nasal and non-nasal hay fever symptom severity, use of rescue medication (antihistamines or corticosteroids), and the subjective experiences of patients were used as outcome measures. It was concluded that there are clear indications that Gencydo treatment is effective in a large subgroup of the research population.

Chapter 9 compared the efficacy and safety of two routes of administration (subcutaneous injections (SI) versus nasal spray (NS)) in a national, randomized, comparative clinical trial with two parallel groups.  A total of 23 patients fulfilled the study requirements. After a one- or two-week wash-out period, twenty-three patients were randomized to a six-week treatment period. The outcomes assessed were immunological and symptom severity changes and safety. Immunologic outcome assessments were blinded to group assignment.It was concluded that both routes of administration are safe and demonstrate immunological and clinical effects, with larger inflammatory and innate immunological effects of the NS route and larger allergen-specific clinical effects in the SI group.

Chapter 10 reported a study that was aiming to update the safety status of anthroposophic and homeopathic solutions for injection through a systematic evaluation of the reported adverse drug reactions (ADRs). ADRs were extracted from the pharmacovigilance databases of eight German anthroposophic and homeopathic manufacturers covering the period of 2000-2009. These eight manufacturers represent, in total, more than 94 percent of the sales of anthroposophic and homeopathic solutions for injection in Germany. Analyzed ADRs included reports in humans only, reports from post-marketing surveillance, literature cases and clinical/safety trials, and spontaneous reports from healthcare professionals and patients. The results suggest an excellent safety profile of solutions for injection as therapeutically applied in anthroposophic medicine and homeopathy, where the overall incidence of ADRs are very rare.

Chapter 11 presented the major findings of this thesis, studying the concept of health, the methodology to monitor (changes in) health states, the effects and safety of Citrus/ Cydonia comp. on seasonal allergic rhinitis as an example of curative health promotion, and the cost-effectiveness of integrative medicine in the Netherlands. The theoretical and practical implications of the results of this thesis were discussed and reflected on the scientific fundament of anthroposophic medicine. Future perspectives were also described for the implementation of new research lines, the further development of professional preventive and curative health promotion as a contribution to the further innovation of medicine and healthcare, and the investment in CAM/IM/AM research.

In the Appendix, a cost-effectiveness study is presented in which the possible contribution of integrative medicine to the reduction of healthcare costs was studied. This study compared the performance of general practitioners who have completed certified additional training in CAM after obtaining their conventional medical degree (GP-CAMs) with general practitioners who have not (GPs). Patients whose GP has completed additional CAM training have 0–30 percent lower healthcare costs and mortality rates, depending on age group and the type of CAM. The lower costs result from fewer hospital stays and fewer prescription drugs. Since the differences are obtained while controlling for confounders, including neighborhood-specific fixed effects at a highly detailed level, the lower costs and longer lives are unlikely to be related to differences in socioeconomic status. Possible explanations include selection (e.g. people with low interest in medical interventions might be more likely to choose CAM) and better practices (e.g. less overtreatment, more focus on preventive and curative health promotion) by GPs with knowledge of complementary medicine. More controlled studies (replication studies, research based on more comprehensive data, cost-effectiveness studies on CAM for specific diagnostic categories) are required. These findings highlight the fact that the health-promoting methods that are considered CAM today could be effective and might have significant cost-saving potential.

With the example of Citrus/Cydonia comp. in SAR treatment, this thesis demonstrates the safety, moderate efficacy and specific immunological working mechanism of this medicine, underscoring that CAM could be effective and might have a significant cost-saving potential, and collectively, the validity of the concept of preventive and curative health promotion.