Abstract
Background
Sarcoidosis is a chronic, inflammatory, granulomatous, multisystem disease. At the Department of Pneumology of the hospital Gemeinschaftskrankenhaus Havelhöhe, the treatment of sarcoidosis is complemented with a multi-component mixture based on Viscum album L., mistletoe extracts and Ferrum chloratum according to the Havelhöhe Sarcoidosis Protocol (HSP). The aim of this study was to evaluate the course of disease in sarcoidosis patients treated with HSP.
Methods
A retrospective cohort study was conducted by evaluating data on clinical progression, pulmonary function, fatigue, and adverse events in a real-world sarcoidosis cohort using descriptive statistics.
Results
956 patients with sarcoidosis were treated with HSP between 2003 and 2022 and a total of 124 consenting patients (all stages, 35% multi-organ sarcoidosis, mean age 43 years, 69% female) were evaluated for clinical outcomes over a median follow-up of 23 months. The response rate for controlling pulmonary disease in this study cohort was 69%. At baseline, 81 patients (65%) had clinically relevant fatigue, which improved in 48 patients (59%) during HSP therapy. At the last follow-up visit, 103 (83%) did not need glucocorticosteroids or other medications and were receiving only HSP. Pharmacovigilant monitoring demonstrated a safe HSP therapeutic profile, with only 10 (8%) subjects experiencing grade 1 adverse events.
Conclusion
The feasibility and safety of complementary HSP therapy in the treatment of sarcoidosis have been demonstrated. These results should be used for the creation of hypotheses and further investigations.
Introduction
Pulmonary and multiorgan sarcoidosis is a chronic, systemic, inflammatory disease of unknown cause characterized by non-caseating granulomas that may also involve multiple other organs such as the heart, skin, lymphatic and nervous systems.1,2 Treating sarcoidosis aims to improve organ function as well as health-related quality of life (QoL). 3 While oral glucocorticosteroids (OCS) remain the first-line treatment for symptomatic disease, long-term use is associated with substantial toxicity and there is a need for OCS-sparing options. 4 The sarcoidosis community in general and the World Association of Sarcoidosis and Other Granulomatous Diseases (WASOG) in particular have led efforts to improve sarcoidosis diagnosis and care, and evidence-based guidelines for diagnosis and treatment have recently been published. 5 For second-line treatment, immunomodulators such as methotrexate may be used alone or in combination with steroids and biologic therapies, eg targeted tumor necrosis factor (TNF)α inhibitors such as infliximab and adalimumab. 3 A position paper has recently been published 6 by the German Society for Pneumology and Respiratory Medicine (DGP) as a German-language supplement and update to the international guidelines of the European Respiratory Society (ERS) from 2021. In a recent review article, the adverse effects of various sarcoidosis medications are described in detail. 7 However, new treatment strategies for sarcoidosis are needed because patients might develop substantial morbidity from long-term use of high doses of OCS.
In particular, fatigue is a common manifestation of sarcoidosis, often persisting in the absence of radiologically or via laboratory chemistry detectable disease activity. Current therapies for sarcoidosis have limited effect on fatigue. 8 Sarcoid fatigue has similar characteristics to chronic fatigue syndrome and is a major cause of distress. A German study of 1197 sarcoidosis patients revealed that prednisolone administration was associated with increased fatigue levels. However, the observed association between prednisolone and fatigue was relatively weak, and comorbidity emerged as the most significant predictor of fatigue. 9 According to a systematic review, sarcoid fatigue cannot be solved by pharmacological therapies alone and currently no pharmacological treatment is proposed. 10 Some physical activity programs for sarcoidosis patients have been studied, but high-level clinical trials are still limited. 10 Complementary medicine is commonly used by cancer patients. A recent systematic review found that in Iran, for example, about one-third of these practices included the use of medicinal herbs to improve symptom burden. 11 It has been observed in studies with breast cancer patients that herbal preparations, such as mistletoe or a grape juice formulation, have the potential to contribute to a reduction in fatigue symptoms.12,13 The treatment of cancer related fatigue has been studied extensively in oncology patients with mistletoe based formulations containing Viscum album L. extracts being an integral part of an integrative approach to improve overall QoL, including fatigue, in the field of cancer. 14 Preclinical and clinical studies have demonstrated the immunological activity of mistletoe extracts. 15 For example, in a placebo-controlled trial in healthy volunteers, subcutaneous administration of extracts from mistletoe grown on poplar trees resulted in eosinophilia and an increase of cluster of differentiation 4 (CD4) T-lymphocytes. 16 The Department of Pneumology at the hospital Gemeinschaftskrankenhaus Havelhöhe (GKH) has been treating sarcoidosis for several decades and has developed the Havelhöhe Sarcoidosis Protocol (HSP), which includes a multi-component mixture based on mistletoe preparations of Iscucin Salicis and Ferrum Chloratum.17,18 However, detailed clinical data and studies have not yet been published. The objective of this retrospective cohort study is to evaluate the clinical course and safety profile of HSP therapy with mistletoe in a real world sarcoidosis population. It should be evaluated whether this therapy reduces the need for glucocorticoids and whether it improves the symptoms of fatigue.
Materials and Methods
Study Design
We conducted a retrospective monocentric cohort study by extracting and analyzing demographic data, information on diagnosis, sarcoidosis histology, as well as fatigue symptoms and adverse events from medical records of patients with all stages of pulmonary and/ or extrapulmonary sarcoidosis. This study conforms to the tenets of the Declaration of Helsinki and has been approved by the Ethics Committee of the Berlin Medical Association (Eth-41/21 on 28 September 2021) and was registered (DRKS00029126 on 08/07/2022). Only patients who had given their written consent to the retrospective analysis of their data were included.
Patients with sarcoidosis are treated on an out-patient basis in the department of Pneumology at the Gemeinschaftskrankenhaus Havelhöhe. Treatment with HSP followed a medical consultation in which patients were informed about the drug's approval and that this was an individual treatment trial. This patient information and consent were included in the outpatient care. Patients with sarcoidosis who were being treated between May 2003 and April 2022 at the Department of Pneumology at the GKH in Berlin, Germany, were invited and informed by letter to participate in this study. The diagnosis of sarcoidosis requires a compatible clinical presentation, histological evidence and the exclusion of other diseases with similar clinical features. Therefore, patients were enrolled if they had a histologically proven diagnosis of sarcoidosis, according to the consensus statement of the European Respiratory Society (ERS)1,19 and if the patient had sufficient and persistent symptoms to warrant therapy. Patients were enrolled in the study if they gave written consent to retrieve information from their medical records, and if they received at least one HSP treatment cycle. Patients without chronic sarcoidosis (acute sarcoidosis (Löfgren's syndrome)) or with pre-existing comorbidities, such as active tumor or autoimmune disease, were excluded and if less than 80% documentation of clinical outcome parameters or less than two chest radiographs were available during the course of their treatment. Demographic data as well as information on diagnosis, co-morbidities and previous treatment regimen were retrieved from their medical records.
Treatment
The standard systemic therapy for sarcoidosis is the treatment with corticosteroids, which are used in cases of relevant organ dysfunction, such as heart failure or renal insufficiency, or sarcoidosis with a progressive course.1,2,5 Sarcoidosis treatment, following the Havelhöhe Sarcoidosis Protocol (HSP) was performed according to current guidelines 20 and was complemented by a cyclic therapy which includes a multi-component mixture based on mistletoe preparations of Iscucin Salicis and Ferrum Chloratum.17,18 Iscucin Salicis from WALA is manufactured from willow tree mistletoe extract according to an official production protocol (GHP) and contains viscum lectins in a multi-component blend. 21 The HSP treatment is described in detail in Appendix A. The drugs used in HSP are a mixture of different compounds and three different medications I, II, and III. An HSP treatment cycle lasts 12 weeks, with medication I (Ferrum sesquichloratum D2/ Graphites D14 / Tatarus Stibiatus D4) given for the entire 12 weeks, medication II (Phosphorus met.präparatum D5) given for the first 4 weeks, and medication III (Iscucin Salicis) given for weeks 5 through 12.
Three different intensity levels of HSP were used. Standard HSP therapy consists of two twelve-week HSP cycles per year with a three-month therapy break between HSP treatment cycles. Patients with a higher symptom burden (high pulmonary symptom burden, joint complaints, fatigue) received an intensified treatment with four HSP cycles per year. Patients with low disease burden receive one HSP cycle per year. Only sarcoidosis patients who were previously informed and consented were treated with HSP.
Clinical Outcome Parameters
Chest radiographs were grouped according to SCADDING. 22 For the exploratory evaluation of spirometry and body plethysmography, forced expiratory volume in one second (FEV1), total lung capacity (TLC), residual volume (RV), and diffusing lung capacity (DLCO) were determined. All of these four parameters were taken into account to determine lung function status, with FEV1 being the primary parameter used. Clinical response rates and changes were determined and outcome parameters over the course of therapy were classified. The course of sarcoidosis was classified by radiologists and pulmonologists. For chest radiography, complete or partial regression, unchanged, alternating or progression could be differentiated. All four lung function parameters, FEV1, TLC, RV and DLCO, were used to assess changes in lung function and to differentiate between complete or partial normalization, consistently within or below the normal range, or progression. Self-reported fatigue was assessed using a Linear Analog Self-Assessment Scale (LAS) ranging from 0 to 10, categorized, and scored at multiple time points.23,24 For fatigue symptoms over the course of the disease, a distinction was made between complete or partial improvement, no change, and change or worsening.
Adverse events (AEs) are retrieved from the documented data of the source data of the pulmonary outpatient clinic. AEs were classified according to the Common Terminology Criteria for AEs, (CTCAE) version 5.0 in terms of preferred terms and severity.
Data Analysis
Demographic and diagnostic variables were collected at the start of HSP therapy (baseline). Continuous variables were described as mean, median with interquartile range (IQR); categorical variables were summarized as frequencies and percentages. No imputation method for missing or lost to follow-up data is used when reporting outcome data. All statistical analyses were performed using the software SAS 9.4 (SAS® Institute, Cary/NC, USA).
Results
Study Subjects
In total, 956 sarcoidosis patients were treated with HSP therapy between 2003 and 2022 at the department of pneumology of the hospital havelhöhe. For a retrospective analysis, all patients were contacted and asked to consent to the intended study analysis. Consent forms were signed by 301 patients and complete data sets were available for analysis for 124 of these patients (Figure 1).
Flow Chart of the Study Population.
For 124 patients, data were retrieved from the patients’ medical records and analyzed. The main characteristics of the patients analyzed for the entire study cohort are presented in Table 1. The mean observed duration of treatment was 4.45 years (standard deviation: 6.54 years), calculated from the first visit to the final visit. A HSP cycle lasts 3 months, a standard HSP therapy consists of two HSP cycles per year and an intensified HSP therapy consists of four HSP cycles per year. We observed good overall compliance and adherence with the HSP protocol. In Table 2 the treatments received within the observation period are listed for the entire study cohort. For the entire study cohort of 124 patients, a total of 552 HSP equivalent treatment years were observed and a total of 662 HSP cycles were administered.
Baseline Characteristics of the Sarcoidosis Population.
IQR: Interquartile Range; n: number; (%): percentage if not indicated otherwise; ND: not determined.
Treatment of the Sarcoidosis Population.
The numbers in rows and columns of treatments applied to patients do not necessarily add to one hundred percent as patients may have received various combinations of medications. n, numbers. P values comparing baseline and last visit are based on Pearson's Chi-squared test with Yates’ continuity correction. Significant p-values are indicated: *: p-value < 0.05.
Between baseline and the last visit, a significant decrease in OCS therapy was observed (see Table 2). At baseline, 61 patients were receiving OCS, with the majority having their OCS dose reduced and 40 patients ultimately discontinuing OCS treatment (p < 0.0001). As a result, at last follow-up visit 103 (83%) of the total cohort did not take OCS or any other anti-sarcoid medication and received HSP cycles only.
Evaluation of Outcome Parameters
For the entire study cohort, chest radiographic images and clinical outcome parameters were analyzed and improvements or deteriorations during treatment course were assessed. Findings are summarized in Table 3.
Clinical Outcomes of the Entire Sarcoidosis Cohort.
n, number, ND, not determined.
For the entire cohort pulmonary function improved or normalized in 69% (Table 3). At baseline, 81 patients in the entire sarcoidosis cohort reported increased fatigue (Table 1), which improved completely in 14 patients and partially in 34 patients (Table 3). Of the 81 patients who suffered from fatigue at baseline, 48 patients (59%) experienced an improvement in fatigue symptoms during HSP therapy. In ten patients (8%), adverse events with a possible relationship to HSP treatment were documented during the course of treatment (Table 4). All adverse events on record were mild, CTCAE grade 1 (Table 4).
Categorization of Adverse Events in the Sarcoidosis Cohort.
The ten affected patients are coded (a-i). The terms and grades are classified in accordance with the CTCAE version 5.0. Patients b, c, d, f, h, i, and j were treated with prednisone. At the last follow-up visit, with the exception of patient i, all of the other nine patients were treated with HSP alone.
Discussion
This current analysis of real-world data shows that complementary HSP therapy may be a promising approach for the treatment of sarcoidosis. The disease control response rate was 69% and in particular, improvements of fatigue symptoms were observed. Further research is needed to confirm the effectiveness and safety of this approach.
There is limited evidence available on the treatment options for chronic sarcoidosis. Evidence of progressive disease or increased risk of future mortality or permanent disability 6 as justification for primary immunosuppressive therapy is available, but has not yet been validated by prospective studies. Much of the data supporting the use of glucocorticoids is indirect and comes from association studies. 7 In addition, there is no uniform recommendation for glucocorticoid therapy, and patients often suffer from clinical symptoms such as fatigue for which there is no proven therapy. Approximately half of all chronic sarcoidosis patients require systemic therapy to treat severe organ involvement and OCS are the first-line treatment for sarcoidosis, but side effects of long-term use of OCS limit their use and new effective recommendations are needed. 20 The present systematic analysis of multidrug therapy with HSP was conducted to provide a basis for a prospective, randomized clinical trial. Here, we evaluated a large sarcoidosis cohort with baseline characteristics similar to those described for other sarcoidosis populations 25 over a long treatment period. The period of time covered here in total is more than 500 equivalent years of treatment. Over the course of treatment with HSP, most patients were able to reduce or discontinue their OCS therapy, with 83% being treated with HSP alone at their last visit. Sarcoid fatigue is a severe and common symptom of sarcoidosis, reported by up to 80% of patients.4,8 During HSP therapy, a considerable improvement in fatigue was observed in this study. In addition, only one subject explicitly reported fatigue symptoms during HSP treatment (subject i in Table 4).
Managing fatigue in sarcoidosis remains challenging, and comorbidity has emerged as the most important predictor of fatigue. 9 A recent systematic meta-analysis showed that pulmonary rehabilitation can improve exercise capacity and dyspnea perception in patients with sarcoidosis. 26 In the field of oncology, there is growing evidence that mistletoe compounds may mediate and exert anti-inflammatory and immunologic effects. 15 Phytochemicals, including components of mistletoe preparations are capable of selectively reducing cyclooxygenase-2 (COX-2) levels. 27 A study in colorectal cancer patients hypothesized that these mistletoe-mediated COX-2 effects may have an impact on cancer-related fatigue. 28 It is possible that these immunomodulatory properties may account for the reduction in fatigue observed in sarcoidosis patients treated with HSP.
Evaluation of the impact of oral glucocorticosteroids on the QoL of outpatients with sarcoidosis revealed a need for effective glucocorticoid-sparing alternatives with methotrexate and azathioprine most widely used in the second-line treatment.29,30 In addition, leflunomide, which was developed as a less toxic alternative, has been reported as a highly effective treatment option for sarcoidosis, although rare but severe toxic effects (pneumonitis, teratogenic) have been described 20 and therapeutic drug trials and novel sarcoidosis treatment approaches have been reviewed recently. 31
Scientific evidence of the safety of low-dose naturopathic preparations is not yet available, and only a few toxicological animal studies can be found. For example, for salt preparations containing sodium tartrate, tartaric acid, sodium hydroxide, and iron trichloride, toxicological studies in rats indicated that the no-observed-adverse-effect level (NOAEL) was 500 mg/kg body weight per day, 32 which corresponds to a multiple of the concentrations contained in the preparations used in HSP.
Pharmacovigilance has been carried out for mistletoe preparations administered in a large number of oncological studies. As the indication for mistletoe in patients with allergic, atopic or especially autoimmune diseases is limited, 33 there is less safety data available for patients with pre-existing autoimmune diseases. In an observational study of 106 oncology patients with pre-existing autoimmune diseases, including individual cases of sarcoidosis who received mistletoe therapy, no higher rates of adverse events were observed. 34 In a systematic review of 18 clinical oncology trials of mistletoe preparations, the incidence of local reactions was 15.9%, 35 and similarly, data analysis of medical records of 1923 cancer patients treated with subcutaneous mistletoe extracts revealed a safe profile, with mild to moderate local reactions occurring in 21.2% of patients. 36 The concentrations of Iscucin Salicis used to treat sarcoidosis are low compared to those used in oncological preparations. Pharmacologic monitoring of the HSP study cohort over a mean follow-up of 53 months revealed no moderate or severe adverse events potentially related to HSP therapy, and only 8% of patients experienced mild (grade 1) adverse events.
A decision tree for the treatment of symptomatic sarcoidosis has been proposed that includes OCS, anti-metabolites, targeting TNFα inhibition, and consideration of other drugs 20 and in line with this, a treatment algorithm has been proposed, derived from the recommendations of a Delphi consensus. 3 On the basis of this, the following treatment regimen is proposed with complementary HSP therapy from the time of the diagnosis of sarcoidosis (Figure 2). This proposal can form the basis for future prospective studies in comparison with a control arm.
Decision Tree for the Treatment of Sarcoidosis. Adopted from Baughman & Grutters, 2015, 20 adding HSP therapy. HSP: Havelhöhe Sarcoidosis Protocol, OCS: oral glucocorticosteroids such as prednisone or prednisolone; Y: Yes; N: No.
Limitations of this analysis include the monocentric, uncontrolled, non-randomized observational nature of the study design, prone to various biases including selection bias. Furthermore, as routinely occurring and well-known side effects of treatments are often neglected, the frequency of adverse events of HSP therapy may be underestimated. A further weakness of this study is the spontaneous remission, which is possible in sarcoidosis and which cannot be distinguished from a successful course of therapy. The fact that only those who were willing to return for follow-up could be assessed is another potential source of bias. Due to the long study period, a large proportion of the treated patients could no longer be contacted and therefore could not be included in the study. Therefore, no conclusions can be drawn about results for subjects who were unable, unwilling, or deceased. Nevertheless, it is noteworthy that consistent results can be presented here for 124 patients from a cohort of 956 sarcoidosis patients documented over 20 years. A large number of patients experienced improved clinical outcomes when treated with HSP and no moderate or severe adverse events were observed in the study cohort, suggesting that HSP therapy could be a safe and effective option for sarcoidosis patients. This retrospective analysis was carefully performed with an ethically approved and registered study protocol and can now be used as a basis for prospective study projects. The strength of this study lies in its pragmatic design, the integration of real-world daily care data under outpatient conditions, a large number of patients studied, and a very long observation period. In terms of external validity, patient characteristics and outcomes are comparable to published data. 3 Therefore, our data may be of clinical importance.
Conclusions
Despite numerous and commendable efforts, treating chronic sarcoidosis remains poorly understood. Clinical experience with HSP, a multidrug combination in a specialized outpatient clinic, showed favorable results over very long observation periods and no severe adverse events in patients who did not need or wanted immunosuppressive therapy. The findings of this study indicate that HSP therapy may represent a viable and safe approach for the management of sarcoidosis and may have potential for improved clinical outcomes.
There is an unmet need for corticosteroid-sparing and corticosteroid-replacing treatments for sarcoidosis itself and its related fatigue syndrome. Currently, the available data for treating sarcoidosis-associated fatigue is limited. 10 Here, an integrative medical approach including HSP therapy is proposed (Figure 2) as a new additive treatment strategy for sarcoidosis to control the disease including symptoms of fatigue. These results are mainly used for hypothesis generation. As this was a retrospective systematic analysis, the results are only as meaningful as the careful documentation of daily clinical practice, but can serve as a reference point for future prospective analyses. In forthcoming surveys, sarcoidosis treatment and symptom burden should be systematically monitored and recorded. In particular, fatigue should be assessed more thoroughly using appropriate patient-reported outcome measures. The present results may be valuable in that they contribute to the ongoing discourse surrounding the efficacy of internationally recommended therapies, which, despite their widespread use, remain a topic of debate as to whether they offer more benefit than harm. However, there is a definite need for the confirmation of these findings in a prospective study in comparison with a control group.
Supplemental Material
sj-docx-1-chp-10.1177_2515690X251345931 - Supplemental material for New Therapy for Chronic Sarcoidosis with Viscum Album L. and Ferrum Chloratum Preparations: Results of a Retrospective Survey
Supplemental material, sj-docx-1-chp-10.1177_2515690X251345931 for New Therapy for Chronic Sarcoidosis with Viscum Album L. and Ferrum Chloratum Preparations: Results of a Retrospective Survey by Christian Grah, Irina Gatov, Shiao Li Oei, Marcus Reif, Hannah Wüstefeld and Annika Marzok in Journal of Evidence-Based Integrative Medicine
Supplemental Material
sj-doc-2-chp-10.1177_2515690X251345931 - Supplemental material for New Therapy for Chronic Sarcoidosis with Viscum Album L. and Ferrum Chloratum Preparations: Results of a Retrospective Survey
Supplemental material, sj-doc-2-chp-10.1177_2515690X251345931 for New Therapy for Chronic Sarcoidosis with Viscum Album L. and Ferrum Chloratum Preparations: Results of a Retrospective Survey by Christian Grah, Irina Gatov, Shiao Li Oei, Marcus Reif, Hannah Wüstefeld and Annika Marzok in Journal of Evidence-Based Integrative Medicine
Footnotes
Acknowledgements
We are grateful to Prof. Dr David Martin for his support in the discussions. We would also like to thank Claudia Leichnitz and all the other members of the medical staff at the Gemeinschaftskrankenhaus Havelhöhe for their support in this work.
Author Contributions
Conceptualization, CG, MR, HW and AM; Data curation and formal analysis, IG, MR and AM; Funding acquisition, CG; Investigation, CG, IG, SLO, MR, HW and AM; Methodology, CG, IG, SLO, MR, HW and AM; Project administration, CG; Resources, CG; Validation, CG, IG, SLO, MR and AM; Visualization, CG and SLO; Writing – original draft, SLO; Writing – review & editing, CG, IG, SLO, MR, HW and AM. All authors have read and agreed to the submitted version of the manuscript.
Declaration of Conflicting Interests
CG reports grant support from AstraZeneca, Takeda, Novartis, Chiesi, Iscador, outside the submitted work. MR is an employee of the company Iscador AG. HW reports grant support from AstraZeneca and Berlin-Chemie outside the submitted work. No other relevant employment or consulting relationships exist. There are no patents, products under development or marketed products to disclose. There are no other relationships/conditions/circumstances that present a potential conflict of interest.
Funding
This study was supported via the institutional budget of the Research Institute Havelhöhe and partially funded by unrestricted research grants from WALA Heilmittel GmbH, Germany. The investigators were contractually independent of the funders. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Supplemental Material
Supplemental material for this article is available online.
Trial Registration
The study received ethics approval by the Ethics Committee of the Berlin Medical Association (Eth-41/21 on 28 September 2021) and was registered (DRKS00029126 on 08/07/2022)
References
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