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Hong Phuoc Duong,1,&ast; Bertrand Léger,1 Stefan Markus Scholz-Odermatt,2 Cyrille Burrus,1,3 Philippe Vuistiner,1 Michel Konzelmann,1,3 François Luthi1,3,4,&ast; 1Department of Medical Research, Clinique romande de réadaptation, Sion, 1951, Switzerland; 2Department of Statistics, Sammelstelle für die Statistik der Unfallversicherung (SSUV), c/o Swiss Accident Insurance Fund (Suva), Lucerne, 6002 Switzerland; 3Department of Musculoskeletal Rehabilitation, Clinique Romande de Réadaptation, Sion, 1951, Switzerland; 4Department of Rheumatology and Rehabilitation, Hôpital Orthopédique, University and University Hospital of Lausanne, Lausanne, 1011, Switzerland&ast;These authors contributed equally to this workCorrespondence: Bertrand Léger, Tel +41 27 603 2075, Email Bertrand.Leger@crr-suva.chPurpose: To assess and compare the healthcare costs, time to fitness for work (TFW) between chronic complex regional pain syndrome (CRPS) and non-CRPS; and identify factors associated with these outcomes in a comparative longitudinal study.Patients and Methods: 148 patients with chronic CRPS of the hand and 273 patients with chronic hand impairments but without CRPS (non-CRPS) were admitted at a Swiss rehabilitation clinic between 2007 and 2016. Healthcare costs and TFW were retrieved from insurance data over 5 years after the accident. Socio-demographic factors, biopsychosocial complexity measured by means of the INTERMED questionnaire, pain intensity and DASH disability scores were collected during rehabilitation. Generalized estimation equations and Cox proportional-hazards models were used to identify factors associated with outcomes.Results: Healthcare costs were increased by 20% for the CRPS versus non-CRPS group (coefficient = 1.20, 95% CI = 1.08– 1.35, p< 0.001). The median TFW was longer for CRPS than non-CRPS patients (816 vs 672 days, p = 0.02). After adjusting for covariates, TFW did not differ between the two groups (hazard ratio = 0.94, 95% CI = 0.73– 1.21, p=0.61). For CRPS patients, higher healthcare costs were associated with severe or moderate initial injury, high INTERMED or DASH disability scores. Longer TFW were associated with severe initial injury, low educational level, no work contract, and high INTERMED or DASH disability scores.Conclusion: Overall, the healthcare costs were higher for CRPS than non-CRPS patients, but the TFW was comparable. We demonstrated also the significant associations of disability and biopsychosocial factors with the healthcare costs and TFW in CRPS patients.Keywords: complex regional pain syndrome, healthcare costs, biopsychosocial complexity, work incapacity, fitness for work, CRPS

Joane Le Carré,1,2 François Luthi,2– 4 Cyrille Burrus,2,3 Michel Konzelmann,2,5 Philippe Vuistiner,1,2 Bertrand Léger,1,2 Charles Benaïm1,4 1Department of Medical Research, Clinique Romande de Réadaptation, Sion, Switzerland; 2Institute for Research in Rehabilitation, Clinique Romande de Réadaptation, Sion, Switzerland; 3Department of Musculoskeletal Rehabilitation, Clinique Romande de Réadaptation, Sion, Switzerland; 4Department of Physical Medicine and Rehabilitation, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland; 5Assessment and Consultation Department, Clinique Romande de Réadaptation, Sion, SwitzerlandCorrespondence: Joane Le Carré, Ave Grand-Champsec 90, Sion, 1950, Switzerland, Tel +41 27 603 20 73, Email joane.lecarre@crr-suva.chPurpose: Chronic pain is a complex phenomenon. Understanding its multiple dimensions requires the use of a combination of several patient-reported outcome measures (PROMs). However, completing multiple PROMs is time-consuming and can be a burden for patients. The objective of our study was to simultaneously reduce the French versions of the Pain Catastrophizing Scale (PCS) and Tampa Scale for Kinesiophobia (TSK) questionnaires to enable their use in an ambulatory and clinical settings.Patients and Methods: We conducted a clinical study between May 2014 and August 2020 in our rehabilitation center. 1428 chronic musculoskeletal pain patients (CMSP) were included. The originality of our approach is that the reduction method included qualitative as well as quantitative analyses. The study was divided into two parts: 1) reduction of the questionnaires (n=1363) based on internal consistency (item-to-total correlation), principal component analysis (item loadings), Rasch analysis (infit/outfit), floor and ceiling effect (quantitative analyses) and expert judgment of items (qualitative analysis), and 2) validation of the reduced questionnaires (n=65), including test–retest reliability (intraclass correlation coefficient [ICC]), homogeneity (Cronbach α), criterion validity (Pearson correlation [r] with the long-version score), determination of the pathological cutoff and Minimal Clinically Important Difference (MCID). The two full-length questionnaires include 30 items in total.Results: The reduction resulted in a 5-item PCS (score 0– 20) and 6-item TSK (score 0– 24). Psychometric properties of the reduced questionnaires were all acceptable as compared with other version (α=0.89 and 0.71, ICC=0.75 and 0.60, r=0.86 and 0.70, MCID=2 and 2 for PCS and TSK, respectively) while keeping the structure and coherence of the long versions.Conclusion: The two reduced versions of the PCS and TSK can be used in CMSP patient. As their administration only requires a few minutes, they can be implemented in outpatient consultation as well as in clinical settings.Keywords: chronic musculoskeletal pain, CMSP, patient-reported outcomes measures, PROMs, Pain Catastrophizing Scale, PCS, Tampa Scale for Kinesiophobia, TSK

Hong Phuoc Duong,1 Michel Konzelmann,1,2 Philippe Vuistiner,1 Cyrille Burrus,1,2 Bertrand Léger,1 Friedrich Stiefel,3 François Luthi1,2,4 1Department of Medical Research, Clinique Romande de Réadaptation, Sion, Switzerland; 2Department of Musculoskeletal Rehabilitation, Clinique Romande de Réadaptation, Sion, Switzerland; 3Psychiatric Liaison Service, Lausanne University and Lausanne University Hospital, Lausanne, Switzerland; 4Department of Rheumatology and Rehabilitation, Hôpital Orthopédique, University and University Hospital of Lausanne, Lausanne, SwitzerlandCorrespondence: Bertrand Léger Tel +41 27 603 2075Fax +41 27 603 2072Email Bertrand.Leger@crr-suva.chPurpose: To compare the prevalence of psychiatric comorbidity between patients with complex regional pain syndrome (CRPS) of the hand and non-CRPS patients and to assess the association between biopsychosocial (BPS) complexity profiles and psychiatric comorbidity in a comparative study.Patients and Methods: We included a total of 103 patients with CRPS of the hand and 290 patients with chronic hand impairments but without CRPS. Psychiatric comorbidities were diagnosed by a psychiatrist, and BPS complexity was measured by means of the INTERMED. The odds ratios (OR) of having psychiatric comorbidities according to BPS complexity were calculated with multiple logistic regression (adjusted for age, sex, and pain).Results: Prevalence of psychiatric comorbidity was 29% in CRPS patients, which was not significantly higher than in non-CRPS patients (21%, relative risk=1.38, 95% CI: 0.95 to 2.01 p=0.10). The median total scores of the INTERMED were the same in both groups (23 points). INTERMED total scores (0– 60 points) were related to an increased risk of having psychiatric comorbidity in CRPS patients (OR=1.46; 95% CI: 1.23– 1.73) and in non-CRPS patients (OR=1.21; 95% CI: 1.13– 1.30). The four INTERMED subscales (biological, psychological, social, and health care) were correlated with a higher risk of having psychiatric comorbidity in both groups. The differences in the OR of having psychiatric comorbidity in relation to INTERMED total and subscale scores were not statistically different between the two groups.Conclusion: The total scores, as well as all four dimensions of BPS complexity measured by the INTERMED, were associated with psychiatric comorbidity, with comparable magnitudes of association between the CRPS and non-CRPS groups. The INTERMED was useful in screening for psychological vulnerability in the two groups.Keywords: complex regional pain syndrome, psychiatric comorbidity, biopsychosocial complexity, INTERMED

Ariane Paoloni-Giacobino,1,* François Luthi,2– 4,* Ludwig Stenz,1 Joane Le Carré,2,5 Philippe Vuistiner,2,5 Bertrand Léger2,5 1Medicine Faculty, Department of Genetic Medicine and Development, Geneva University, Geneva, Switzerland; 2Institute for Research in Rehabilitation, Clinique romande de réadaptation, Sion, Switzerland; 3Department of Musculoskeletal Rehabilitation, Clinique romande de réadaptation, Sion, Switzerland; 4Department of Physical Medicine and Rehabilitation, Orthopaedic Hospital, Lausanne University Hospital, Lausanne, Switzerland; 5Department of Medical Research, Clinique romande de réadaptation, Sion, Switzerland*These authors contributed equally to this workCorrespondence: Bertrand Léger Email bertrand.leger@crr-suva.chPurpose: The INTERMED instrument, which was developed to measure patient’s biopsychosocial (BPS) complexity, represents a powerful diagnostic and therapeutic tool. Epigenetic changes are the interface between signals from the environment and genetic modifications, affecting gene expression, in particular, by DNA methylation of CpG dinucleotides in promotor regions of the corresponding genes. The brain-derived neurotrophic factor (BDNF) gene plays a crucial role in the central sensitization (CS) of pain. In this study, we hypothesized that chronic pain modifies the methylation levels of the BDNF gene in a manner that is interconnected with the BPS status.Patients and Methods: Fifty-eight chronic musculoskeletal pain patients (CMSP) were enrolled in the study. DNA was extracted from blood samples, the methylation levels of 13 CpG sites in the BDNF promoter were measured by pyrosequencing, and association studies with various patient parameters and the INTERMED scores were performed.Results: Interestingly, a negative correlation (− 0.40) was found between the total INTERMED scores and the average CpG methylation values of the BDNF gene, but no correlation was observed with the severity of pain, degree of anxiety, depression, or kinesiophobia and catastrophism. Moreover, the association was independent of age, sex and level of comorbidities.Conclusion: This result shows that CMSP, in association with its biopsychosocial context, epigenetically decreases the degree of methylation of the BDNF promoter and should therefore increase the level of BDNF transcription. It also suggests a role of the INTERMED tool to detect a relationship between the BPS complexity and the epigenetic control of a target gene. The possible upregulation of BDNF expression might be, at least in part, the signal for chronic pain-induced central sensitization (CS). This could partly explain why patients with a higher level of complexity feel more pain than those with lower complexity.Keywords: chronic pain, biopsychosocial complexity, BPS, INTERMED, brain-derived neurotrophic factor, BDNF, DNA methylation