New trends in rehabilitation: patient profiling as pain biomarkers. Marta Imamura MD PhD University of São Paulo Medical School

Transcription

1 New trends in rehabilitation: patient profiling as pain biomarkers Marta Imamura MD PhD University of São Paulo Medical School

2 Our Mission To develop studies that can objectively evaluate and improve the impact of new technologies in clinical functioning and to understand the mechanisms involved in clinical improvement

3 Disability DISABILITY An umbrella term for impairments, activity limitations, and participation restrictions denoting the negative aspects of the interaction between an individual (with a health condition) and that individual s contextual factors (environmental and personal factors). WHO, The World Bank. The World Report on Disability. 2011

4 Global Situation Global Situation Around 150 million adults experience significant difficulties functioning Disability prevalence is increasing Disproportionately affects vulnerable populations: women, older people and poor households

5 WHO global disability action plan : Better health for all people with disability VISION A world where people with disabilities and their families enjoy the highest attainable standard of health

6 Health Conditions related to Disability National Survey in Australia (2004) Arthritis Back problems Hearing disorders Hypertension Heart disease Stroke Asthma Vision disorders Noise-induced hearing loss Speech problems Diabetes Depression Dementia (74) Disability and its relationship to health conditions and other factors. Canberra, Australian Institute of Health and Welfare, 2004 (

7 Health Conditions related to Disability Adults 15 years and older: Arthritis Back problems Hearing disorders Heart disease Soft tissue disorders (bursitis and fibromyalgia) Affective disorders Asthma Vision disorders Diabetes National Survey in Canada (2006) Custom tabulation of PALS 2006 data. Ottawa, Statistics Canada, Children aged 0 14 years: Learning disabilities (autism and attention deficit) Asthma Hearing problems Cerebral palsy Vision disorders Congenital abnormalities

8 Health Conditions related to Disability National Survey in US (2010) 1. Rheumatism - leading cause among elderly people (30% of adults aged 65 years or older) 2. Heart problems (23%) 3. Hypertension 4. Back or neck problems 5. Diabetes 6. Vision disorders 7. Lung and breathing problems 8. Fractures 9. Stroke 10.Hearing problems Lafortune G, Balestat G. Trends in severe disability among elderly people: assessing the evidence in 12 OECD countries and the future implications [OECD Health Working Papers No. 26]. Paris, Organisation for Economic Co-operation and Development, 2007 (

9 Anatomical, Cellular and Molecular Changes Imbalance of biosynthesis and degradation in cartilage and synovial fluid Softening and loss of articular cartilage Decrease in concentration and avarage molecular weight of hyaluronic acid in synovial fluid BRANDT KD (1994) In: Harrison s principles of internal medicine 13th ed. New York, NY: Mc Graw-Hill, 1994: DALAZS EA, DENLINGER JL (1993) J Rheumatol 20 (Suppl 39: 3-9)

10 Effect Sizes PAIN FUNCTION Self management/education 0.06 to 0.29 Education 0.06 to 0.29 Strengthening Land-based exercises Weight management Modalities (TENS) Modalities (US) 0.49 Acupuncture McAlindon et al OARSI guidelines for the non-surgical management of knee osteoarthritis Osteoarthritis Cartilage 2014;22:

11 Effect Sizes PAIN FUNCTION Acetaminophen 0.18 Oral NSAIDs 0.37 Opioid analgesics Diacerein Glucosamine sulphate 0.17 to 0.47 Condroitin sulphate 0.13 to 0.75 Avocado soybean unsponifiables 0.39 Intra-articular hyaluronans McAlindon et al OARSI guidelines for the non-surgical management of knee osteoarthritis Osteoarthritis Cartilage 2014;22:

12 Annual Number of Procedures (in 000s) Projected Number of Primary Total Hip and Knee Arthroplasties, USA Primary total hip arthroplasty Source: Kurtz S, Lau E, Mowat F, al: The future burden of hip and knee revisions: U.S. projections from 2005 to Paper presented at: 73 rd Annual Meeting of the American Academy of Orthopaedic Surgeons: Chicago, IL; Used with permission of the primary author Primary total knee arthroplasty

13 Economic Burden Dramatic increase in number of total knee replacements 31.2 per 100,000 person-years during the period to in More than 670,000 total knee replacements in the US alone Corresponding aggregate charges of $36.1 billion Skou et al. NEJM, 2015;373:

14 Percent (95% CI) OA Pain and disability Mild Moderate Severe Work time missed (n=258) Work productivity and impairment Impairment while Working (n=286)* Overfall working impairment (n=252)* Overfall activity impairment (n=675)* Mean annual cost of lost productivity per patient (95% CI) $ $ $8.000 $0 * * * $6.096 $ $ Mild Moderate Severe Self reported OA severity Sadosky et al. 2010

15 Knee Osteoarthritis

16 Imaging Kellgren-Lawrence IV. Altman et al. (1986). Arthritis Rheum 29:

17 Neuroplasticity Imamura et al Arthritis Rheum 2008;59:

18 Mendell, Sahenk NEJM 2003;348(13):

19 Generalized Sensitization Time Arendt-Nielsen et al. 2010

20 VAS VISUAL ANALOGUE SCALE Patellar Tendon (kg/cm 2 ) Subcutaneous S 2 (kg/cm 2 ) Adductor longus (kg/cm 2 ) R 2 =0.614 Imamura M et al. Arthritis Rheum 2008;59(10): p<0.001

21 WOMAC - Pain WOMAC - PAIN Patellar Tendon (kg/cm 2 ) Subcutaneous S 2 (kg/cm 2 ) Adductor longus (kg/cm 2 ) R 2 =0.608 Imamura M et al. Arthritis Rheum 2008;59(10): p<0.001

22 WOMAC Physical Activity WOMAC Physical Activity Subcutaneous S Subcutaneous L 2 (kg/cm 2 2 (kg/cm 2 ) ) Peroneus longus (kg/cm 2 ) R 2 =0.611 Imamura M et al. Arthritis Rheum 2008;59(10): p<0.001

23 Patient profiling as pain biomarkers Active search for somatosensory abnormalities

24 Patient profiling as pain biomarkers

25 Hypoderm Deep Extract Deep Fascia Muscle Alcian Blu 1.25 X Hypoderm Deep Extract Deep Fascia Muscle Ematossilin 1.25 X Courtesy Antonio Stecco Univerity of Padova

26 Courtesy Antonio Stecco Univerity of Padova

27 pg/ml 400 Substance P Gr.1 Gr.2 Gr p< :00 2:24 4:48 7:12 9:36 12:00 14:24 16:48 Time Shah JP et al. (2005) J Appl Physiol 99(5):

28 pg/ml 400 CGRP Gr.1 Gr.2 Gr p< :00 2:24 4:48 7:12 9:36 12:00 14:24 16:48 Time Shah JP et al. (2005) J Appl Physiol 99(5):

29 pg/mil TNF-α Group 1 Group 2 Group p< :00 2:24 4:48 7:12 9:36 12:00 14:24 16:48 Time Shah JP et al. (2005) J Appl Physiol 99(5):

30 ph units ph Gr.1 Gr.2 Gr.3 p< :00 2:24 4:48 7:12 9:36 12:00 14:24 16:48 Time Shah JP et al. (2005) J Appl Physiol 99(5):

31 Serum Cytokines Profile Serum levels of pro-inflammatory cytokines: IL-6, IL-8, and TNF-α Serum levels of anti-inflammatory cytokines: IL-10 Correlation with pain intensity, functional capacity status and pressure pain threshold (PPT) values Comparison with healthy controls Imamura M et al International Journal of Inflammation: 1-8

32 Serum Cytokines Profile Serum levels of pro-inflammatory cytokines: IL-6, IL-8, IL-12 and, IL-1β and TNF-α Serum levels of anti-inflammatory cytokines: IL-10 People with knee osteoarthritis and fibromyalgia with the same duration and intensity of pain demonstrate similar concentrations of serum cytokines Aging may play a role in cytokine profile Imamura M et al Clinical Interventions in Aging:

33 Biochemical Profile Age differences in cytokine expression under conditions of health using experimental pain models Cruz-Almeida et al. Exp Gerontol 2015;72:150-6 Evaluation of the anti-inflammatory effects of two plateletrich gel supernatants in an in vitro system of cartilage inflammation Ríos et al. Cytokine 2015;76: Mucosal-associated invariant T cell: a potential marker to distinguish fibromyalgia syndrome from arthritis Sugimoto et al. PLoS One 2015;10(4):e Inhibition of IL-1β-induced inflammatory response in human osteoarthritic chondrocytes Piao et al. Eur J Pharmacol 2015;756:38-42 Increased plasma pro-inflammatory cytokine: comorbidities (myocardial infarctation and depression) Wilkowska et al. Psychiatr Pol. 2015;49(3):455-64

34 Biomarkers Association between pressure pain thresholds and serologic markers in people with different degrees of knee osteoarthritis: High sensitivity C-reactive protein (hscrp) Matrix Metalloproteinase (MMP) mediated breakdown of CRP (CRPM) MMP-mediated degradation of type I collagen (C1M) Arendt-Nielsen et al. Arthritis Rheum 2014;66:

35 Brain Activity Neural Networks Somatosensory processing Affective emotion processing Executive processing Thalamus Cortical Areas Limbic System

36 Functional Brain Imaging and Joint Pain Gwilym et al. Arthritis Rheum 2009;61(9):

37 Reduction of cortical gray matter volume Related to pain intensity and duration Pre frontal and dorsolateral circuitry and descending inhibitory systems Hippocampus Perihippocampus Cingulate Changes in Brain Anatomy Kuchinad A, et al. J Neurosci 2007;27: Apkharian AV, et al. J Neurosci 2004;24: Geha PY et al. Neuron 2008;60: Kuchinadey. J Neurosci 2007;404: Davis KD et al. Neurology 2008;70:153-4

38 Structural Brain Changes Voxel-based morphometry (VBM) analysis of magnetic resonance brain images Chronic pain is associated with altered brain morphology Changes in brain gray matter, particularly in regions involved in pain perception, pain modulation, and stress Comparison with healthy controls Imamura et al In Press

39 Efficacy of radial extracorporeal shock wave therapy (reswt) for disabling pain due to severe primary knee osteoarthritis: a prospective, randomized, placebo controlled, double blind study with subjective and objective endpoints Imamura M et al. Submitted for publication

40 Patient profiling as pain biomarkers PAIN A platform of mechanistic pain biomarkers: Structure-related serologic biomarkers Local microenvironment

41 Patient profiling as pain biomarkers

42 Patient profiling as pain biomarkers Peripheral Changes Interventions that target peripheral structures

43 Patient profiling as pain biomarkers Dysfunction of the dorsal horn of the spinal cord, with increased neuronal activity Treatment should include spinal desensitization

44 Patient profiling as pain biomarkers Disfunction of brain and neuronal hyperactivity Treatment should target cortical structures

45 Genetic Profile Courtesy Prof Walter R. Frontera

46 Genetic Profile Same genome, but different phenotypes Courtesy Prof Walter R. Frontera

47 Genetic Profile Genetics and the response to exercise therapy Courtesy Prof Walter R. Frontera

48 Thank you for your kind attention