Personalized therapy in rheumatoid arthritis (PETRA): a protocol for a randomized controlled trial to test the effect of a psychological intervention in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic autoimmune disease that primarily affects cartilage and bone. Psychological stress can both trigger disease exacerbation and result from disease activity. As standard pharmacological interventions alone have limited success in treating RA, a more comprehensive biopsychosocial approach to treatment has been recommended. In this prospective randomized controlled trial (RCT), a psychotherapeutically guided, group-based intervention program will be conducted with RA patients over a period of 9 months. This program combines a dynamic-interactional model with disorder-specific coping-oriented perspectives to improve patients' social, emotional, and problem-solving competencies as well as stress system functional status. The enrolment of 440 patients, randomly allocated to either an intervention (n = 220) or control group (n = 220), is planned. To evaluate the intervention effect, various indicators of RA disease activity, stress system activity, and psychological condition will be assessed through sets of standardized questionnaires and biochemical analyses of blood and saliva samples. Moreover, healthcare-related costs for each patient will be obtained using routine health insurance data. Outcome variables will be measured in all patients at regular intervals prior to intervention (baseline), during the 9-month intervention (five time points), and during a 9-month follow-up phase (three time points), allowing the comprehensive analysis of within- and between-subject effects, i.e. trajectories of the target variables in the intervention and control groups. In addition, to investigate the intervention effects on real-life stress system functioning in RA, 10 integrative single-case studies (n = 5 from the intervention group, n = 5 from the control group) will be conducted. In each study, once before and after the 9-month intervention, urine samples will be collected, and patients will fill out questionnaires for approximately 1 month at 12-h intervals. Moreover, weekly in-depth interviews will be conducted with patients to determine their previous week's emotionally positive and negative incidents. Using time series analysis, it is then possible to investigate whether and how stress system function in these RA patients has improved from the applied intervention. By using both an investigational macro- and microperspective, this project aims to evaluate a psychological intervention in the routine care of individuals with RA.Trial registration German Clinical Trials Register DRKS00028144. Registered on 1 March 2022.

Emotional states predict cellular immune system activity under conditions of life as it is lived: A multivariate time-series analysis approach.

The relationship between emotional states and immune system activity is characterized by bidirectional influences; however, limited information is available regarding the temporal dynamics of these effects. The goal of this investigation was to examine how these psychoimmunological interdependencies unfold over time under conditions of "life as it is lived". For this purpose, three healthy women collected their entire urine over a period of approximately two months at 12-h intervals (8 am-8 pm, 8 pm-8 am), resulting in a total of 112 to 126 consecutive measurements per subject. In addition, among other regular psychological assessments, the subjects completed the EWL-60-S, an emotional state questionnaire, each morning and evening. To assess the extent of T-helper type 1 immune activation, the neopterin per creatinine concentration was measured in the urine samples using high-pressure liquid chromatography. The dynamic relationships between the time series of the six emotional states (performance-related activity, general inactivity, extraversion/introversion, general feeling of comfort, emotional irritation, anxiety/depressiveness) and urinary neopterin levels were estimated in vector-autoregressive models and evaluated using Granger-causality tests, impulse-response functions and forecast error variance decompositions. The findings showed that emotional states explained up to 20% of the variance of urinary neopterin per creatinine levels, whereby most of the effects occurred within a period of approximately three days. Across all subjects, increases in anxiety/depressiveness and extraversion led to increases in neopterin levels, while a general feeling of comfort led to decreases in neopterin. These results emphasize the importance of the interdependencies between emotional states and immune system activity and showcase the potential that intensive longitudinal study designs offer for psychoneuroimmunology.

On the Role of Psychoneuroimmunology in Oral Medicine.

Psychoneuroimmunology (PNI) is an area of interdisciplinary research exploring the complex interactions within the immuno-neuro-endocrine system in response to psychosocial influences. Such influences can trigger neurological changes, leading to immunological effects related to the emergence and course of various diseases. This concise clinical review explores the role of PNI in oral medicine in three exemplary models of oral disease: periodontitis, herpes labialis, and oral lichen planus. Previous literature has shown that psychosocial stress is related to exacerbations in these three oral diseases and to poorer overall oral health. The presumed biological mechanisms affect the activity of stress axes, i.e. the hypothalamus-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS), and subsequent immune system dysregulation. Although these PNI mechanisms remain poorly understood, several stress reduction interventions in clinical oral medicine have already yielded promising results. In future work, the elucidation of pathways within PNI networks will require carefully designed studies with sensitive methodology, e.g. the integrative single-case design. A biopsychosocial approach has the potential to move disease models in oral medicine from simple connections rooted in empirical dualism and reductionism to the establishment of network-based models. Further research on these complex connections should lead to novel clinical approaches and preventive strategies in oral medicine.

About-Weekly Pattern in the Dynamic Complexity of a Healthy Subject's Cellular Immune Activity: A Biopsychosocial Analysis.

In a previous integrative single-case study, we collected biological, psychological and social time-series data on a 25-year-old healthy woman over the course of 126 12-h intervals (63 days) and used urinary neopterin as an indicator of cellular immune activity [Schubert et al. 2012 (1)]. The present re-evaluation introduced Dynamic Complexity (DC) as an additional non-linear and non-stationary measure to further investigate the subject's biopsychosocial dynamics during the study. The new time series dealing with urinary neopterin complexity revealed a cyclic, circaseptan (about-weekly) repeating pattern (6.59 days). The only weekly reoccurring events over the course of the study that were associated with this immunological pattern were the in-depth interviews with the subject (mean distance between interviews: 6.5 days). Superposed epoch analysis (SEA) revealed a U-shaped relation between neopterin complexity and interviews, with a decrease in neopterin complexity before and during interviews and an increase after interviews. Furthermore, the complexity scores for irritation, anxiousness/depressiveness and mental activity were positively correlated with neopterin complexity. The results suggest that the interviews, which had been found to be related to the subject's need for educational and/or social accomplishment, were marked by stress (decrease in psycho-immunological flexibility and adaptability), which was then relieved after the interviews (increase in psycho-immunological flexibility and adaptability). It appears that the subject's cellular immune activity, as indicated by neopterin complexity, functionally mirrored the emotional meaning she ascribed to the in-depth interviews. This re-evaluation is in line with the view that biopsychosocial research requires multimodal analysis of single cases based on qualitative (e.g., in-depth interviews) and quantitative (e.g., time series analysis) data under conditions of "life as it is lived".

Case Report: Dynamic Interdependencies Between Complementary and Alternative Medicine (CAM) Practice, Urinary Interleukin-6 Levels, and Fatigue in a Breast Cancer Survivor.

Background: This study investigated the influence of complementary and alternative medicine (CAM) techniques (i.e., Jin Shin Jyutsu, music, physiotherapy, Tai Chi, and energy healing) on urinary interleukin-6 (IL-6) levels and fatigue in a 49-year-old breast cancer survivor suffering from cancer-related fatigue and depression. Data were sampled under conditions of "life as it is lived." Methods: For 28 days, a female breast cancer survivor collected her full urine output in 12-h intervals from about 8 a.m. to 8 p.m. and from about 8 p.m. to 8 a.m. These urine samples were used to determine urinary IL-6 levels through ELISA and creatinine concentrations via HPLC. In 12-h intervals (every morning and evening), the patient completed the DIARI, which included fatigue measurement and notes on incidents and activities such as CAM practice. In addition, the patient was interviewed weekly to identify meaningful everyday incidents. In this context, CAM practice was also discussed. Time series analysis consisted of ARIMA modeling and cross-correlational analyses (p < 0.05). Results: When each CAM technique was considered separately in time series analysis, CAM was consistently associated with increases in urinary IL-6 release and decreases in fatigue. Furthermore, when all CAM techniques experienced as positive were included in one time series, a biphasic urinary IL-6 response pattern was found in which CAM practice was first preceded by decreases in IL-6 by 12-0 h and then followed by increases in IL-6 after 108-120 h. Finally, cross-correlations between IL-6 and fatigue showed that increases in IL-6 were followed by decreases in fatigue intensity after 48-60 h and, conversely, that decreases in fatigue intensity were followed by decreases in IL-6 after 24-36 h and 48-60 h. Conclusion: IL-6 increases and fatigue decreases highlight potential health-promoting effects of CAM practice. Moreover, a cyclic IL-6 pattern in response to all CAM activities experienced as positive underscores that CAM was meaningful to the patient. Additionally, a negative feedback circuit between IL-6 and fatigue intensity was detected. Taken together, this study confirms the necessity of integrating subjective meaning and dynamic complexity into biopsychosocial research in order to understand human functioning under real-life conditions.

Dynamic Effects of CAM Techniques on Inflammation and Emotional States: An Integrative Single-Case Study on a Breast Cancer Survivor.

BACKGROUND: This study on a breast cancer survivor investigated how episodic practice of various complementary and alternative medicine (CAM) techniques affected the dynamics of emotional states and urinary neopterin-an inflammation marker. METHODS: The 49-year-old female patient (diagnosis: ductal breast carcinoma 5 years before study start, suffering from chronic fatigue and depression) collected her entire urine in 12-hour intervals (from about 8 a.m. to 8 p.m. and from about 8 p.m. to 8 a.m.) for 28 days. The resulting 55 consecutive urine samples were analyzed for neopterin and creatinine levels using HPLC. Also in 12-hour intervals, the patient filled out questionnaires on emotional states and everyday routine, including CAM practice. Weekly, she was interviewed to identify emotionally meaningful everyday incidents, including use of CAM techniques. Time series analysis consisted of ARIMA modeling and cross-correlational analyses. RESULTS: Qualitative evaluation revealed that, with the exception of Tai Chi, all CAM techniques, that is, Jin Shin Jyutsu, music, physiotherapy and energy healing, were experienced as positive. Cross-correlational analyses showed that practice of such CAM techniques was followed first by significant (P < .05) increases in positive mood and mental activity on the same day (lag 0) and then by decreases in positive mood after a total of 72 to 84 hours (+lag 6) and in mental activity after a total of 84 to 96 hours (+lag 7). Negative mood, by contrast, first decreased on the day of CAM practice (lag 0) and then increased after a total of 84 to 96 hours (+lag 7) following CAM. Moreover, urinary neopterin levels first increased on the day of CAM practice (lag 0) and then decreased after a total of 36 to 48 hours (+lag 3). Similar biphasic effects were also detected for irritation in response to CAM, although only partly significant. CONCLUSION: Cyclic psychophysiological response patterns following CAM practice were attributable to biopsychosocial feedback mechanisms involving personally meaningful experiences. As lower neopterin levels following CAM point to a health-promoting effect, the patient of this study may have actively contributed to her healing process through episodic CAM practice.

[Psychoneuroimmunology of the life span: impact of childhood stress on immune dysregulation and inflammatory disease in later life]. / Psychoneuroimmunologie des Lebenslaufs: Einfluss von Stress in der Kindheit auf Immunfunktionsstörung und entzündliche Erkrankung im weiteren Leben.

Studies have shown clearly that childhood mistreatment, abuse and neglect are associated with severe inflammatory disease in adulthood (e. g. cancer, heart disease, autoimmune disorder) and shortened life span. This review deals with the psychoneuroimmunological pathways of this connection. It shows that chronic stressors interfere very early in life with those protective mechanisms of the biological stress system that normally down-regulate potentially harmful inflammation. In the long term, serious inflammatory diseases, such as allergic asthma, can result. In this review, the pathogenetic connections between allergic asthma and early stress and stress system dysfunction are discussed. As our understanding of the dysfunctional psychophysiological mechanisms of inflammatory disease increases, psychodiagnostic and psychotherapeutic intervention in the treatment of physical disease will become more specific.

Stress system dynamics during "life as it is lived": an integrative single-case study on a healthy woman.

Little is known about the dynamic characteristics of stress system activity during "life as it is lived". Using as representative a study design as possible, this investigation sought to gain insights into this area. A healthy 25-year-old woman collected her entire urine over a period of 63 days in 12-h intervals (126 measurements) to determine cortisol and neopterin (immune activation marker) levels. In addition, she filled out questionnaires on emotional state and daily routine in 12-h intervals, and was interviewed weekly to identify emotionally negative and positive everyday incidents. Adjusted cross-correlational analyses revealed that stressful incidents were associated with cyclic response patterns in both urinary cortisol and urinary neopterin concentrations. Urinary cortisol levels first decreased 12-24 h after stressful incidents occurred (lag 1: -.178; p = 0.048) and then increased a total of 72-84 h later (lag 6: +.224; p = 0.013). Urinary neopterin levels first increased 0-12 h before the occurrence of stressful incidents (-lag 1: +.185; p = 0.040) and then decreased a total of 48-60 h following such stressors (lag 4: -.181; p = 0.044). Decreases in urinary neopterin levels were also found 24-36 and 48-60 h after increases in pensiveness (lag 2: -.215; p = 0.017) and depressiveness (lag 4: -.221; p = 0.014), respectively. Findings on emotionally positive incidents sharply contrasted with those dealing with negative experiences. Positive incidents were followed first by urinary cortisol concentration increases within 12 h (lag 0: +.290; p = 0.001) and then by decreases after a total of 60-72 h (lag 5: -.186; p = 0.039). Urinary neopterin levels first decreased 12-24 h before positive incidents occurred (-lag 2: -.233; p = 0.010) and then increased a total of 12-24 h following these incidents (lag 1: +.222; p = 0.014). As with previous investigations on patients with systemic lupus erythematosus (SLE), this study showed that stress system response can be considerably longer and more complex and differentiated than findings from conventional group studies have suggested. Further integrative single-case studies will need to be conducted in order to draw firm conclusions about stress system dynamics under real-life conditions.

Symbolic diseases and "mindbody" co-emergence. A challenge for psychoneuroimmunology.

Physical diseases that appear to be symbolic somatic representations of patients' personal meanings or individual 'stories' continue to be reported in the medical literature. The identification of a symbolic disease requires a clinical focus upon a patient's highly individual and nuanced meanings largely rendered invisible by the usual methodologies of clinical and research medicine, which has no coherent model for understanding symbolic disease. Therefore, a model is proposed of co-emergence of physicality and subjectivity, body and mind, disease and meaning, disease and symbol, which does provide a coherent basis for understanding symbolic disease. The 'mindbody' co-emergence model avoids mind and body dualism, assumes unbroken continuity between internal body processes and external interpersonal meanings and influences, and asserts that disease-related 'internal' bodily changes and collateral external interpersonal and environmental fluxes are mutually contingent and crucial to the development of the disease. The co-emergence model is discussed specifically in relation to psychoneuroimmunology, but it has exciting clinical and research implications for the whole of medicine.

[Psychoneuroimmunology: an update]. / Psychoneuroimmunologie: Ein Update.

Psychoneuroimmunology (PNI) is closely associated with the bidirectional pathways between mind/brain and the immune system. PNI research represents a rapidly growing area within psychosomatic research. Recent studies in PNI are based mainly on the immunological concepts of Th1/Th2 dichotomy and inflammation. This review covers human PNI studies dealing with stress-associated changes in cytokine (Th1, Th2) levels in immune-related processes such as wound healing, atopic diseases as well as autoimmune and other inflammatory diseases. It is shown that PNI studies measuring immune activity near the site of the disease (e. g. woundhealing) and dealing with objective stressors show more consistent findings (stress-associated Th1/Th2 shift, stress-associated proinflammatory activation) than those dealing with chronic and complex diseases (e. g., autoimmune disease). This warrants the expansion of the methodological repertoire in future PNI research toward designs allowing for the investigation of complex psychosomatic phenomena.