Alterazioni metaboliche e nutrizionali in corso di artrite reumatoide e malattie autoimmuni Alessio Molfino, MD, PhD

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1 Alterazioni metaboliche e nutrizionali in corso di artrite reumatoide e malattie autoimmuni Alessio Molfino, MD, PhD Direttore: Prof. Filippo Rossi Fanelli alessio.molfino@uniroma1.it

Rheumatoid arthritis (RA) RA is a chronic inflammatory autoimmune disease resulting in joint inflammation, increased risk of cardiovascular disease and

6%) had RA in 2005 The prevalence among women in 1995 was approximately double that in men (1.06% versus 0.61%).

dollars) per person in the year 1987 ($5,763.32 in U.S. 2000 dollars). People with RA are approximately six times (odds ratio=6.4, 95% CI=5.4, 7.

2 Rheumatoid arthritis (RA) RA is a chronic inflammatory autoimmune disease resulting in joint inflammation, increased risk of cardiovascular disease and osteoporosis, with high circulating levels of cytokines and acute phase proteins. An estimated 1.3 million adults aged 18 and older (0.6%) had RA in 2005 The prevalence among women in 1995 was approximately double that in men (1.06% versus 0.61%). A study conducted at the Mayo Clinic of direct (i.e., medical) costs among people with RA found an average cost of $3, (in U.S. dollars) per person in the year 1987 ($5, in U.S dollars). People with RA are approximately six times (odds ratio=6.4, 95% CI=5.4, 7.7) more likely than people without arthritis to incur medical charges. These charges are not just for musculoskeletal disorders but for care of disorders of most body systems. Source: US Center for Disease Control and Prevention

3 Evans et al. Clin Nutr 2008

4 Cachexia: what does it mean? From the greek language, kako exi : A bad condition The flesh is consumed and becomes water,...the abdomen fills with water, the feet and the legs swell, the shoulders, clavicles, chest and thighs melt away...this illness is fatal Hippocrates from Kos, IV Century BC

5 PubMed Search Cachexia Review articles 847 Original articles

6 Summers GD, et al. Nat Rev Rheumatol, 2010

7 Differing definitions of rheumatoid cachexia Summers GD, et al. Nat Rev Rheumatol, 2010

8 Summers GD, et al. Nat Rev Rheumatol, 2010

9 Prevalence of cachexia in RA Classic cachexia is rare, occurring in 1-13% of RA population (Elkan 2009; Engvall 2008; Morgan 1997; Westhoff 2007) Rheumatoid cachexia occurs in 10-20% of pts with wellcontrolled disease and in 38% of pts with active-disease, but lack of agreed criteria make prevalence assessment uncertain (Elkan 2009; Engvall 2008; Giles 2008) Changes in body composition more frequent in women and in individuals with BMI within the range of normality ( ) (Giles 2008) Mortality rate in RA is higher than in general population and largely attributable to CVD (Symmons 1988; Maradit-Kremers 2005) Summers GD, et al. Nat Rev Rheumatol, 2010

10 Kalantar-Zadek K. Seminars in Dialysis, 2007

11 APPETITE REGULATION Science 2003

12 Prevalence of secondary anorexia in chronic diseases Disease Prevalence Advanced cancer 66% 1 Advanced liver cirrhosis >50% 2 Chronic renal failure (HD) 29% 3 Cancer upon diagnosis 15-25% 4,5 1 Support Care Cancer 8: , Gastroenterology 124: , Nephron Clin Pract Hematol Oncol Clin North Am 5:103-23, Anticancer Drugs 4:115-25, 1993

13 How to diagnose the presence of anorexia? The ESPEN SIG sarcopenia and pre-cachexia document Adapted from AC/S-12 of FAACT questionnaire It si proposed that a score 24 may be sufficient to make a diagnosis of anorexia Muscaritoli M, et al. Clin Nutr 2010

14 Food Intake and exercise in RA Most RA patients have normal energy and protein intake (Helliwell 1984; Roubenoff 1992, 1994, 2002; Summers 2008) This observation implies that anorexia is not frequent in RA patients Physical activity is markedly reduced in RA patients (Akner 2001; Metsios 2009; Metsios 2008; Munneke 2004) Reduced of energy expended on physiscal activity combined with normal energy intake results in positive energy balance and tendency to fat accumulation (Akner 2001) ( and LBM depletion )

Body composition in RA (1979-2007 studies)

15 Body composition in RA ( studies) Modified from Summers GD, et al. Rheumatology, 2008

16 Chronic disease, inflammation, disuse Muscle loss Decreased motility THE VICIOUS CYCLE MUSCLE LOSS- DECREASED MOTILITY- MUSCLE LOSS Decreased motility Further muscle loss Muscle loss Muscaritoli M, et al. 3rd Cachexia Conference, Rome 2005

17 Muscle loss in rheumatoid arthritis: is it cachexia or sarcopenia?

18 What is sarcopenia? Age-associated loss of skeletal muscle mass and muscle strength Less-than-expected muscle mass in an individual of a specified age, gender and race Baumgartner RN, Waters DL, 2006 Roubenoff R, J Gerontol Med Sci 2003; 58:

19 A Sarcopenia Consensus

Sarcopenia: European consensus on definition & diagnosis European Working Group on Sarcopenia in Older People (EWGSOP) European Geriatric Medicine Society European Society for Clinical Nutrition &

20 Sarcopenia: European consensus on definition & diagnosis European Working Group on Sarcopenia in Older People (EWGSOP) European Geriatric Medicine Society European Society for Clinical Nutrition & Metabolism International Association of Gerontology & Geriatrics European Region International Association of Nutrition & Aging Rationale: Need to recognize sarcopenia as a geriatric syndrome Lack of broadly accepted clinical definition, consensus diagnostic criteria or ICD-9 codes or treatment guideline

22 Consequences of sarcopenia Risk for functional impairment and disability - two times greater in older sarcopenic men - three times greater in older sarcopenic women Janssen I et al, J Am Geriatr Soc 2002; 50: Reduced skeletal muscle strength predicts all-cause mortality Metter EJ et al, J Gerontol Series A 2002; 57: B Estimated direct health-care costs in the US: $ 18.5 billion ($ 10.8 billion in men, $ 7.7 billion in women) Janssen I et al, J Am Geriatr Soc 2004; 52: 80-85

23 Is it possible to distinguish sarcopenia from malnutrition and cachexia? Not always Muscaritoli M et al. Clin Nutr 2010

24 Factors contributing to muscle depletion in physiological and pathological conditions Insufficient substrate availability Reduced activity or inactivity Inflammation Imbalance between anabolism and catabolism Neuronal damage Hypoxia Acidosis Drugs (e.g. corticosteroids) Muscaritoli M, et al. Clinical Nutrition, 2010

25 Sarcopenia as the common feature of different conditions ESPEN SIGs Cachexia-Anorexia & Nutrition in Geriatrics. Muscaritoli M, et al. Clin Nutr, 2010

26 The muscle in cachectic RA patients Matschke V, et al. The Journal of Rheumatology, 2010

27 Lemmey AB, et al. Arthritis & Rheumatism, 2009

28 Lemmey AB, et al. Arthritis & Rheumatism, 2009

29 Elkan AC, et al. Arthritis Research & Therapy, 2009

30 Elkan AC, et al. Arthritis Research & Therapy, 2009

31 Criteria used to diagnose rheumatoid cachexia Cachectic 18% F; 21%M 18% F; 26%M Summers GD, et al. Nat Rev Rheumatol, 2010 Elkan AC, et al. Arthritis Research & Therapy, 2009

32 Proposed therapeutic approaches to sarcopenic conditions Drugs Nutrition Exercise Improved muscle mass and function

Take-home messages Diagnostic criteria for Rheumatoid Cachexia (RC) are not yet entirely defined RC has peculiarities with respect to other forms of cachexia, such as the lack of anorexia In RA two

33 Take-home messages Diagnostic criteria for Rheumatoid Cachexia (RC) are not yet entirely defined RC has peculiarities with respect to other forms of cachexia, such as the lack of anorexia In RA two forms of cachexia can be recognized: a classic form and one phenotypically similar to sarcopenic obesity (normal/elevated BMI; increased fat mass; reduced lean body mass) CV risk is increased in RA, particularly in subjects with increased fat mass Although inflammation is the main driver of the cachectic syndrome both TNF-alfa inhibitors and methotrexate are unable to correct cachexia Physical exercise seems to be an effective strategy to revore muscle mass and function in the so-called RC 38

35 Cachexia Several definitions

36 What is Cachexia? The Washington definition Cachexia (also referred to as wasting disease), is a complex metabolic syndrome associated with underlying illness and characterized by loss of muscle with or without loss of fat mass. The prominent clinical feature of cachexia is weight loss in adults (corrected for fluid retention) or growth failure in children (excluding endocrine disorders). Anorexia, inflammation, insulin resistance and increased muscle protein breakdown are frequently associated with wasting disease. Wasting disease is distinct from starvation, age-related loss of muscle mass, primary depression, malabsorption and hyperthyroidism and is associated with increased morbidity. Evans et al. Clin Nutr 2008

37 Evans et al. Clin Nutr 2008

38 Clin Nutr 2010

39 How to define cachexia? The Istanbul definition The ESPEN SIG Sarcopenia and precachexia document Cachexia is a multifactorial syndrome characterized by weight loss due to underlying disease(s) such as CANCER, COPD, CKD, CHF, CLF). It is clinically relevant since it increases patients' morbidity and mortality. Contributory factors to the onset of cachexia are anorexia and metabolic alterations (i.e., increased inflammatory status, increased muscle proteolysis, impaired carbohydrate, protein and lipid metabolism. Considering the wide range of clinical manifestations of cachexia, the staging of this syndrome is warranted. Clin Nutr 2010

40 Why is staging of cachexia necessary? The ESPEN SIG sarcopenia and pre-cachexia document Muscaritoli M et alclin Nutr 2010

41 How to define pre-cachexia? The ESPEN SIG sarcopenia and pre-cachexia document Pre-cachexia is defined based on the presence of all the following criteria: a. Underlying chronic disease b. Unintentional weight loss 5% of usual body weight during the last 6 months c. Chronic or recurrent systemic inflammatory response d. Anorexia or anorexia-related symptoms Inflammation is indicated by elevated serum levels of inflammatory markers like C-reactive protein. Early metabolic alterations (i.e. impaired glucose tolerance, anemia related to inflammation or hypoalbuminemia) may also be present in pre-cachexia Pre-cachexia definition will allow for large multicenter epidemiological and intervention studies aimed at preventing or delaying changes in body composition and nutritional complications linked to chronic diseases. Muscaritoli M et al. Clin Nutr 2010

42 One cachexia, different diseases, different cachexias?

43 Chronic diseases associated with nutritional impairment, wasting and and cachexia Cancer Heart Failure (CHF) Renal Failure (CKD) Chronic Respiratory Failure (COPD) Liver Failure (CLF) Chronic Inflammation (e.g. rheumatoid arthritis)..

44 Definition of Cancer Cachexia- Fearon 2008 Fearon KHC. EJC, 2008

45 Classification of Cancer Cachexia- Fearon 2008 Fearon KHC. EJC, 2008

Clinical Nutrition in the 21st Century Malnutrition, sarcopenia and cachexia

Clinical Nutrition in the 21st Century Malnutrition, sarcopenia and cachexia Stéphane M. Schneider, MD, PhD, FEBGH Professor of Nutrition and ESPEN ECPC Chair In proto-indo-european, Latin and Greek Under