Observational Study Medicine ® OPEN Assessment of nutritional status by dual X-Ray absorptiometry in women with rheumatoid arthritis A case–control study ∗ Delia Reina, MDa, , Carmen Gómez-Vaquero, MD, PhDa, Cesar Díaz-Torné, MD, PhDb, Joan Miquel Nolla Solé, MD, PhDa, Rheumatology Service. Hospital Moisès Broggi. Abstract Rheumatoid arthritis (RA) has been related to an impairment of the nutritional status. Body mass index (BMI) has been used but questions arise about how to properly evaluate nutritional status in RA patients. Few studies have evaluated it by dual-energy X-ray absorptiometry. In women with RA, to analyze: (1) their nutritional status compared to that of a control population, (2) differences between the prevalence of impairment of nutritional status measured by dual energy X ray absorptiometry (DXA) and by classical methods used in clinical care, (3) determinants of nutritional status, (4) prevalence of sarcopenia. Case–control study including 89 women with RA. The control group was composed by 100 patients affected by non-inflammatory rheumatic disorders. Study variables included age, RA duration, history, activity and disability, and in relation to nutritional status: BMI, serum albumin (ALB), whole body DXA assessment, and skeletal muscle index (SMI). Mean age of patients was 62 ± 8 years, mean duration of RA was 14 ± 9 years, mean disease activity score (DAS28) was 3.7 ± 1.4 and mean Health Assessment Questionnaire was 0.88 ± 0.77. BMI was 27.43 ± 5.16 Kg/m2 in patients and 27.78 ± 3.98 Kg/m2 in controls (P: ns). ALB was within normal range in all patients. By whole body DXA, RA patients presented a statistically significant lower lean mass in all locations and lower fat mass in limbs than controls. Patients had a redistribution of fat mass to trunk. Lean mass directly correlated with fat mass. Neither BMI nor ALB correlated with DXA parameters. BMI, appendicular lean mass and SMI correlated inversely with disease duration. Trunk lean mass correlated inversely, and fat mass directly, with RA disability parameters. RA patients fulfilled criteria of sarcopenia in 44% of cases versus 19% of controls (P <.001). In RA patients, regarding SMI, BMI showed a high specificity to detect sarcopenia (94% of the patients with low BMI had sarcopenia) but low sensitivity (47% of the patients with normal BMI or overweight had sarcopenia). RA patients have an impairment of nutritional status associated to disease duration that looks like sarcopenia and that is not predicted by BMI. Abbreviations: ACPA = anti-citrullinated protein antibodies, ALB = albumin, BMI = body mass index, DXA = dual-energy X-ray absorptiometry, MAC = midarm muscular circumference, RA = rheumatoid arthritis, SMI = skeletal muscle index, TSF = triceps skinfold, WBC = whole body composition. Keywords: arthritis, nutritional, rheumatoid, sarcopenia, status Editor: Daryle Wane. The authors have no conflicts of interest to disclose. 1. Introduction a b IDIBELL-Hospital Universitari de Bellvitge, Hospital de la Santa Creu i Sant Rheumatoid arthritis (RA) is a chronic inflammatory process that Pau, Barcelona, Spain. ∗ involves the joints. It is the most common type of inflammatory Correspondence: Delia Reina, Hospital de Sant Joan Despi Moises Broggi, arthritis in adults, affecting 0.5% [0.3–0.9] of the population in Sant Joan Despí, Bacelona, Spain (e-mail: deliareinasanz@gmail.com). Spain[1] and has been an important cause of disability and Copyright © 2019 the Author(s). Published by Wolters Kluwer Health, Inc. premature mortality. This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial License 4.0 (CCBY-NC), where it is permissible to RA has been related to an impairment of the nutritional status download, share, remix, transform, and buildup the work provided it is properly cited. of multifactorial etiology. The old term “rheumatoid cachexia” The work cannot be used commercially without permission from the journal. originally described by James Paget in the 19th century[2] and Medicine (2019) 98:6(e14361) representative of a severe degree of malnutrition is nowadays Received: 24 August 2018 / Received in final form: 7 January 2019 / Accepted: almost in disuse. The tight control of inflammatory activity in the 10 January 2019 treat to target strategy applied currently in RA patients avoids the http://dx.doi.org/10.1097/MD.0000000000014361 appearance of an evident nutritional impairment. However, the 1 Reina et al. Medicine (2019) 98:6 Medicine nutritional impairment in rheumatic patients is still now a All patients and controls belonged to the same geographical area relevant comorbidity that we have to consider. and came from a similar social status. The recruitment period took Nutritional status is the result of the balance between the 6 months. All patients and controls gave their oral consent to dietary supply and the nutritional requirements necessary to go participate in the study and the local evaluating committee gave the on with physiological activities, to compensate losses and to conformity for it, which means that an official and a written maintain reserves. Nutritional status is a good predictor of approval from the local Institutional Review Board was obtained. health.[3] Many efforts have been made to diagnose malnutri- tion,[4] nevertheless there is no unequivocal definition. It is 3. Study variables generally accepted that it results in a redistribution of fat tissue, muscle mass and the appearance of hipoproteinemia. All the evaluations were made simultaneously. Traditionally, antropometrical measurements, and biochemi- cal parameters have been used to evaluate malnutrition. 3.1. Sociodemographic data and RA evaluation There are several anthropometric methods for the study of the composition and quantification of body fat and muscle mass. The  Sociodemographic data: date at birth most commonly used are body mass index (BMI), midarm Evaluation of: muscular circumference (MAC)[5] and triceps skinfold (TSF)[6]; it is generally accepted that BMI and TSF basically evaluate fat (1) RA history: date at onset, disease duration, rheumatoid factor mass and MAC evaluates skeletal appendicular muscle mass. (RF) and anti-citrullinated protein antibodies (ACPA), Historically, biochemical evaluation for the assessment of the (2) RA activity: tender joint count (TJC), swollen joint count nutritional status had included serum proteins such as albumin (SJC), visual analog scale (VAS), erythrocyte sedimentation (ALB), a protein that reflects the severity and the prognosis of rate (ESR), C-reactive protein (CRP), and disease activity malnutrition.[7] No other biomarker has proved superiority over score (DAS28), and ALB for the evaluation of nutritional status.[8] (3) RA disability: Health Assessment Questionnaire (HAQ). Bioelectrical impedance has also been used for the assessment of the nutritional status.[9] It is based on the application of an electric current of low potential and intensity at different 3.2. Nutritional status assessment frequencies that are transmitted in a different way through lean and adipose tissues. It is useful for determining the fat-free mass.  Anthropometric data: BMI was calculated in both patients and Finally, there is a growing consensus[10] that whole body controls. BMI is the ratio of human body weight to squared composition (WBC) analysis by dual-energy X-ray absorptiome- height expressed in kg/m2. It has been categorized as follows: try (DXA) is the gold standard to evaluate nutritional status. <18.5 kg/m2 is considered underweight; from 18.5 to 25 kg/m2, DXA measures body composition with great reproducibility and normal range; from 25 to 30 kg/m2, overweight or moderately is sensitive to small changes. While different studies have obese; and >30 kg/m2, severely obese. generated curves that can be used as reference for different  Biochemical data: serum ALB was determined only in patients. populations,[11] there is still a lot of work to do in this area to  WBC by DXA assessment was determined in patients and determine universal cutoff points for healthy people. controls. There are very few data in the literature about nutritional  The examinations were made with a densitometer Hologic status measured by DXA in RA patients. In this study, we have QDR 4500 (Hologic Inc, Bedford, MA), recording fat and lean analysed the WBC by DXA in a group of Spanish patients with mass in arms, trunk, and legs. Quality controls are made RA in order to improve the knowledge in this area. weekly with a step phantom to guarantee the proper functioning of the technique. The estimated room occupancy 2. Patients and methods time for a single exam is 8 to 10 minutes. This includes patient placement, image acquisition and generation of the analysis. 2.1. Study design The patient is placed supine, centerd at the table with arms stretched to the sides of the body, hands looking at the legs An observational case–control study was carried out. without touching them and the thumbs upwards.  Skeletal muscle index (SMI) was calculated in patients and 2.2. Subjects recruitment controls to measure sarcopenia. SMI is established by the The study included women diagnosed with RA (along with 1987 formula: appendicular skeletal muscle mass/height2. According ACR criteria),[12] and most of them fulfilled also ACR 2010 to Jannsen et al,[14] sarcopenia is defined as a relative SMI criteria.[13] Patients were recruited consecutively as they were 5.75 Kg/m2 in women and <8.50 Kg/m2 in men. routinely visited from the outpatient clinics in the rheumatology service of a university tertiary hospital in which around 900 RA are regularly evaluated. At inclusion, none of the patients had been 4. Statistical analysis recently hospitalized by a flare of the disease. Selected patients were To calculate the sample number, we considered the incidence of not affected by any potentially consuming disease as neoplasms, undernutrition in our general population and the calculated risk cardiac or respiratory insufficiency or chronic liver or kidney of undernutrition in RA patients (from the study of Helliwell diseases, and also other debilitating disorders such as VIH, eating et al).[15] Accepting an alfa risk of 0.05 and a beta risk of 0, the disorders, or psychiatric disorders were excluded. Controls were sample needed was 80 patients per arm. recruited, age-matched to patients, consecutively, from the All the results were recorded in an Access 2003 database. The outpatient clinics during the same period of time. They were statistical software package used was Windows SPSS 15.0. women with mild soft tissue rheumatism as tendonitis or The results are presented as absolute numbers (percentage) or osteoarthritis; the exclusion criteria were the same as in patients. as mean ± standard deviation. Differences between groups were 2 Reina et al. Medicine (2019) 98:6 www.md-journal.com Table 1 regarding RF and ACPA and had a moderate activity of the Clinical characteristics of RA patients (n: 89). disease. The results of nutritional assessment are detailed in Table 2. Disease duration (years) 13.7 ± 9.5 (1–42) BMI was 27.43 ± 5.16 Kg/m2 in the patients and 27.78 ± 3.98 Kg/ RF positive 65 (73%) m2 in controls (P: ns). Eight percent of the patients versus 18% of ACPA positive 66 (75%) controls were underweighted (P <.05). TJC 4.2 ± 6.3 (0–28) All RA patients had normal levels of serum ALB. Whole body SJC 1.2 ± 2.2 (0–10) DXA results showed a decrease of lean mass in all locations and a VAS general health patient 48.4 ± 25.9 (0–100) ESR, mm/h 24.24 ± 15.65 (3–103) decrease of fat mass in limbs in RA patients. Fat mass CRP, mg/L 8.25 ± 10.96 (0.2–83) redistributed to trunk (P <.01) in RA patients although absolute DAS28 3.7 ± 1.39 (1.5–6.7) trunk fat mass was not different between patients and controls. <2.6 (remission) 21 (24%) Forty-four percent of the patients with RA and 19% of the 2.6-3.2 (low activity disease) 11 (12%) controls had sarcopenia (P <.001). >3.2 (moderate activity disease) 37 (41%) BMI was very specific to detect sarcopenia in patients with RA >5.1 (high activity disease) 20 (23%) (94% of patients with low BMI had sarcopenia), but not very HAQ 0.88 ± 0.74 (0–2.75) sensitive (47% of patients with normal BMI or overweight had ACPA = anti-citrullinated peptide antibodies, CRP = C-reactive protein, DAS28 = disease activity sarcopenia). score, ESR = erithrocyte sedimentation rate, HAQ = health assessment questionnaire, RA = There were more patients than controls with sarcopenia rheumatoid arthritis, RF = rheumatoid factor, SJC = swollen joint count, TJC = tender joint count, evaluated by SMI, and the overweight subgroup assessed by BMI VAS = visual analogue scale. was significantly higher in patients than in controls. This group could correspond to patients with sarcopenic obesity. calculated by JI squared or analysis of variance. Spearman In Table 3, we present the correlations between nutritional and correlations were calculated where indicated. Statistical signifi- RA variables. Appendicular lean mass and SMI correlated cance was established at P < .05. inversely with disease duration. Trunk lean mass correlated inversely, and fat mass directly, with RA disability parameters. 5. Results 6. Discussion Eighty-nine patients and 100 controls were included in the study. Mean age of the patients was 62 ± 8 years without differences In this study, we have analyzed by DXA the nutritional status of a with controls (64 ± 9 years). The clinical characteristics of the group of Spanish women with RA representative of the RA patients are shown in Table 1. Most patients were seropositive population in a tertiary hospital, evaluating 2 body compart- Table 2 Assessment of nutritional status in RA patients and controls. RA patients (n: 89) Controls (n: 100) P Weight, Kg 65.51 ± 10.98 66.36 ± 14.76 ns Height, cm 155.41 ± 6.35 156.9 ± 9.81 ns BMI, Kg/cm2 27.78 ± 3.98 27.42 ± 5.16 ns <18.5, underweight 8% 18% <.05 18.5–25, normal 15% 20% 25–30, overweight 54% 33% >30, severely obese 23% 29% ALB, g/dL 40.44 ± 4 (28–48) — — Fat left arm 2117 ± 899 2416 ± 966 <.01 Fat right arm 2434 ± 1187 2561 ± 1083 ns Fat arms 4552 ± 2036 5146 ± 1982 <.05 Fat trunk 12016 ± 3793 11567 ± 4309 ns Fat left leg 3962 ± 1303 4351 ± 1102 <.05 Fat right leg 4021 ± 1321 4453 ± 1173 <.05 Fat legs 7992 ± 2601 8865 ± 2183 <.05 Fat extremities 12561 ± 4231 13999 ± 3777 <.05 Fat total 25616 ± 7308 26424 ± 7467 ns Lean left arm 1641 ± 360 1988 ± 400 <.001 Lean right arm 1911 ± 455 2222 ± 487 <.001 Lean arms 3552 ± 761 4219 ± 791 <.001 Lean trunk 18966 ± 2505 20557 ± 3677 <.01 Lean left leg 5277 ± 897 5987 ± 1076 <.001 Lean right leg 5455 ± 855 6081 ± 1076 <.001 Lean legs 10733 ± 1690 11913 ± 1700 <.001 Lean extremities 14286 ± 2301 16126 ± 2327 <.001 Lean total 37153 ± 4723 40943 ± 6419 <.001 SMI, Kg/m2 5.93 ± 0.93 6.55 ± 0.9 <.001 ALB = albumin, BMI = body mass index, RA = rheumatoid arthritis, SMI = skeletal muscle index. 3 Reina et al. Medicine (2019) 98:6 Medicine Table 3 Correlations between nutritional and RA variables in RA patients. Lean extremities Lean trunk Fat extremities Fat trunk BMI ALB SMI Age ns ns ns r: 0.20 ns ns Ns P <.05 Disease duration r: -0.27 ns ns ns ns ns r: -0.27 P <.05 P <.05 TJC ns ns ns ns ns r: -0.37 Ns P <.05 SJC r: 0.22 r: 0.26 ns ns ns ns Ns P <.05 P <.05 HAQ ns r: -0.28 r: 0.31 r: 0.28 r: 0.44 ns r: 0.31 P <.01 P <.01 P <.01 P <.05 P <.05 CRP ns ns ns ns ns ns Ns ESR ns ns ns ns ns r: -0.37 Ns P <.05 VAS ns ns ns ns ns ns ns DAS28 ns ns ns ns ns ns ns ALB = serum albumin, BMI = body mass index, CRP = C-reactive protein, DAS28 = disease activity score, ESR = erythrocyte sedimentation rate, HAQ = health assessment questionnaire, SJC = swollen joint count, SMI = skeletal muscle index, TJC = tender joint count, VAS = visual analogue scale. ments: fat and lean mass. RA patients had a decrease of lean mass was only seen in the patients with worse functionality and BMI, it in all locations and fat mass in limbs with a redistribution of fat does not seem useful in patients without clear clinical malnutri- mass to trunk. The assessment of BMI or ALB was not useful to tion. detect these alterations. Studies in the literature on nutritional status in RA are RA is a chronic disease characterized by a high inflammatory heterogeneous. The majority of them only measure either burden. Inflammation, secondary to an excess of production of anthropometric or biochemical parameters, and very few assess inflammatory cytokines as tumor necrosis factor-alpha, inter- whole body DXA. Furthermore, lately, they are centered more in leukins 1 and 6 and others, accelerates protein catabolism. While obesity as an additional cardiovascular risk factor for RA patients the recent and widespread use of more effective therapies and a or as a contributor, through the production of proinflammatory tight control of inflammation in RA have nearly extinguished adipokines, to disease severity than in undernutrition. rheumatoid cachexia, some degree of impairment of nutritional Elkan et al evaluated body composition and nutritional status status is still present in RA patients and more studies are needed using DXA and bioelectrical impedance in 80 patients with RA to address the problem.[16,17] (they were about 60 years old and had a mean disease duration of In our study, we have found that RA disability is inversely 6 years) and concluded that rheumatoid cachexia and central correlated to lean mass and directly to fat trunk; also, that RA obesity were common by DXA and bioelectrical impedance and time of evolution correlates inversely with lean mass in limbs and that BMI was unable to detect them. Cachexia, defined as fat-free SMI. More long and aggressive disease provokes a loss of muscle mass index below the 25th percentile and fat mass index above mass. In our cohort, we did not find correlation between the 50th percentile of a reference population, was not related to inflammatory activity and nutritional parameters, but this is not diet fat intake, but associated with high levels of LDL cholesterol contradictory because, in cross-sectional studies, parameters of and a high frequency of hypertension.[22] inflammation represent a punctual moment and nutritional Popescu et al found that 107 RA women (they were about 56 status, the burden of years of disease. years old and had a mean disease duration of 10 years) had a Rheumatoid cachexia or its current equivalent to a much lesser higher prevalence of normal weight obesity than controls. degree, loss of lean body mass, is under-recognized in clinical Disease duration and severity were associated with higher whole practice. Usually, it runs in parallel with an increased body fat body and regional adiposity.[23] mass, resulting in a normal BMI.[18] This also involves an under- In a recent review[24] in search of an association between diagnosis of obesity when using the traditional values of BMI in obesity and RA activity, in 6 of 11 studies there was a significant well controlled RA patients, compared to DXA parameters.[19] direct correlation between clinical activity and BMI. The studies Stravroupulos-Kalinoglu et al pointed out that BMI could be an did not provide enough data to assess the relationship between inexact tool to categorize the nutritional status in RA and that the body composition and clinical activity. In the only study in which standard cut-offs point should be modified.[20] In the same sense, DXA was used, the analysis was centered in obesity and we have found that they don’t always detect sarcopenia: BMI was associated cardiovascular risk.[25] very specific but not very sensitive to detect sarcopenia in patients Ngeuleu et al evaluated the prevalence of sarcopenia (defined with RA. as a SMI <5.5 Kg/m2 in women) in 123 patients with RA and the We found that controls and patients had globally a similar influence of sarcopenia on disease activity. Sarcopenia was BMI, but comparing the subgroups there were remarkable prevalent and related to age, bone erosion, normal or overweight differences in this nutritional parameter in the underweight and BMI, and high cardiometabolic risk according to waist the overweight groups: controls had more underweight than RA circumference but not with disease activity.[26] patients (8% in RA, 18% in controls) and RA patients had more Rheumatologist may need to assess nutritional status among overweight than controls (54% in RA, 33% in controls). other comorbidities in RA patients because chronic inflammation In a previous study of our group, hypoalbuminemia was increases the metabolic index and nutritional requirements. present and closely related to RA activity parameters,[21] but this When malnutrition is clinically evident is very difficult to correct 4 Reina et al. Medicine (2019) 98:6 www.md-journal.com it, that is why is so important to have new methods to establish an [8] Fogelholm M, van Marken Lichtenbelt W. Comparison of body composition methods: a literature analysis. Eur J ClinNutr early diagnose, obviously the sooner we can make the diagnosis, 1997;51:495–503. the better we can apply therapeutic strategies. Nevertheless, [9] Elkan AC, Engvall IL, Tengstrand B, et al. Malnutrition in women with nowadays, is not common to see a high chronic inflammatory rheumatoid arthritis is not revealed by clinical anthropometrical state that provokes an evident malnutrition in RA patients. measurements or nutritional evaluation tools. Eur J Clin Nutr Hence, the identification of mild impairment of nutritional status 2008;62:1239–47. [10] Franzoni E, Ciccarese F, Di Pietro E, et al. 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