Quantification of sarcopenia in patients with rheumatoid arthritis by measuring the cross-sectional area of the thigh muscles with magnetic resonance imaging

Design and study population

The study enrolled consecutive female RA patients. RA diagnosis was formulated in accordance to the 2010 criteria of the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) [18]. RA patients have been included at the Rheumatology Clinic, Università Politecnica delle Marche, “Carlo Urbani” Hospital, Jesi (Ancona), between June 2021 and August 2022.

Patients were included regardless of disease activity status and without contraindications to MRI. Patients with co-existing neurological, muscular, cardiovascular, pulmonary, renal, oncological diseases, chronic infections, or who were taking medication that could influence the study variables, were excluded.

Demographic data, anthropometric variables, comorbidities and laboratory investigations

Age, level of education, disease duration (defined as time since diagnosis), body mass index (BMI), and current treatment [glucocorticoids, conventional synthetic disease modifying anti-rheumatic drugs (csDMARDs) and/or biologic DMARDs (bDMARDs)], were variables included in the study. Comorbidities burden was estimated with the modified Rheumatic Disease Comorbidity Index (mRDCI) [19].

For each patients were registered the erythrocyte sedimentation rate (ESR) in mm/h, the C-reactive protein (CRP) in mg/dl, the presence of IgM-rheumatoid factor (RF) and of anti–citrullinated protein antibodies (ACPA).

Composite disease activity indices

Disease activity was assessed using the Simplified Disease Activity Index (SDAI). SDAI is based on a linear sum of five variables: counts for swollen and tender joints on 28 joints (SJC and TJC, respectively), patient and physician assessments of disease activity (PhGA and PaGA, respectively) on 0–10 numerical rating scales (NRS), and CRP (in mg/dl). SDAI ranges from 0 to 86. The cut-off values distinguishing remission (REM), low disease activity (LDA), and moderate disease activity (MDA) are 3.3, 11 and 26, respectively [20].

Radiographic scoring

Radiographs of hands, wrists and feet were used to estimate the radiographic damage and scored according to the Simple Erosion Narrowing Score (SENS) [21] by two readers (FS and MC) with experience with this method. SENS accurately reflects radiographic development assessing the same joints included in Sharp-van der Heijde score for the presence of erosion (if present, scored 1 for each joint) and joint space narrowing (if present, scored 1 for each joint). The SENS ranges from 0 to 86 [22].

Diagnosis of sarcopenia

Sarcopenia was diagnosed according to the EWGSOP2 operational definition [2]. EWGSOP2 definition applies low muscle strength as the primary variable for sarcopenia diagnosis which is “probable” when low muscle strength is documented. The diagnosis is established by the presence of low muscle quantity or low muscle quality. If low muscle strength, low muscle quantity/quality, and low physical performance are coexisting, sarcopenia is defined severe. For the purposes of this study, the diagnosis of sarcopenia was confirmed by US detection of low muscle quality, arbitrarily defined by the presence of grades 2 and 3 of increased echogenicity of the rectus femoris and vastus intermedius muscles on a semiquantitative scale [10], as described in detail below.

EWGSOP2 recommends the SARC-F as screening tool. SARC-F is a self-reported 5-item questionnaire that estimate the sarcopenia risk according to the patient’s perception of limitations in different daily life domains (strength, walking ability, rising from a chair, stair climbing and falls) [23]. SARC-F has been used as a screening measure in the diagnostic flow-chart but has not played a role in confirming the diagnosis of sarcopenia.

Handgrip strength assessment

The handgrip strength (HGs) was measured using a cylindrical-shaped grip device with five force sensors connected to a microprocessor [24]. HGs was measured twice in the dominant hand, considering the mean of the two results for the analyses, and expressed in kilograms. HGs was estimated with patients sitting in a standardised position, with the elbows flexed at a 90-degree angle and the forearm in a neutral position [25]. The cut-off used for low HGs was < 16 kg, as indicated by EWGSOP2 for women [2].

Physical performance

Physical performance is a multidimensional concept involving functions of the whole body and related to locomotion. It refers to the integrated action of muscles, central and peripheral nerve functions such as balance, and can be measured with the Short Physical Performance Battery (SPPB). SPPB includes three evaluations: 1) repeated chair stands; 2) balance tests (side-by-side, semi tandem and tandem balance tests); 3) an eight-foot walk test. Each assessment is graded on a four-point scale, with the results of the three tests added together to provide a total score ranging from 0 (worst result) to 12 (best result) [26]. According to EWGSOP2, in this study low performance was identified for SPPB ≤ 8 [2].

Ultrasound assessment of thigh muscle

All the US examinations were carried out using a MyLab ClassC (Esaote SpA) provided with a broadband linear probe (frequency range 4–13 MHz). The US examinations were performed on the dominant lower limb. A rheumatologist trained in musculoskeletal US (MDC, with 10 years of experience in musculoskeletal US) carried out the US examinations on the patients adopting a protocol described previously [11]. US was conducted with patients lying supine and with the lower limbs extended, relaxed and avoiding muscle contraction and extrotation of the hips. The focus of US assessment was at the midpoint between the upper pole of the patella and the anterior superior iliac spine (ASIS). The US was conducted with transverse scans, with an adequate amount of gel to avoid compression of the underlying tissues. Specifically, with the US beam perpendicular to the long axis of the femur, the probe was moved slightly (laterally or medially to the previously identified skin landmark) to optimally visualize the belly of the rectus femoris muscle, acquiring images with the rectus femoris muscle in the center of the screen and the vastus intermedius muscle below it. On the US images obtained, rheumatologists (FS and MDC) were asked to consensually score muscle echogenicity of rectus femoris and vastus intermedius muscles according to a visual semi-quantitative scale, recently developed, grading muscle echogenicity from 0 to 3: 0 = normal (normal hypoechoic muscle), 1 = mild (increased echogenicity regarding less than one-third of muscle tissue), 2 = moderate (increased echogenicity in more than one-third but less than two-thirds of muscle tissue), and 3 = severe (increased echogenicity in more than two-thirds of muscle tissue) (Fig. 1) [10].

Fig. 1figure 1

Illustrative reference images for semi-quantitative ultrasound evaluation of the rectus femoris and vastus intermedius muscles

MRI examination and images analysis

MRI of the thighs was performed using a 1.5 T scanner with a 16-channel “dStream torso coil” coil (Achieva Philips Medical Systems, Best, the Netherlands) (Supplementary Table 1). Examinations were performed in supine position. All the MRI examinations were assessed independently by two musculoskeletal radiologists (MC and ACP, with an expertise of 5 and 20 years in interpreting MRI images, respectively) blinded to clinical, US and laboratory data. To establish intra-rater reliability, the two radiologists performed the images analysis two week later.

Images analysis was carried out using Horos™, an open-source medical image viewer to segment the quadriceps muscle CSA (expressed in cm2). Horos™ is available under the GNU Lesser General Public License, Version 3 (LGPL-3.0). Muscles have been segmented with the “closed polygon” function that allows automatic measurement of CSA. With one click on the image, points can be placed and used to create the polygon. After placing the third point, a line is drawn connecting the last placed point to the first. This tool is useful for delineating and finding the area (and volume) of structures. In segmetation, the four components of the quadriceps muscle (rectus femoris, vastus lateralis, vastus intermedius, and vastus medialis), the four components of the hamstrings muscles (biceps femoris short head, biceps femoris long head, semitendinosus and semimembranosus), and the adductors (adductor longus, brevis, magnus and pectineus, the sartorius and gracilis) have been included. Since identification of the individual components of the adductor muscles is not straightforward in the region chosen for segmentation, they were all considered together with the exception of the gracilis muscle, which is well recognizable (Fig. 2) [27]. Adipose tissue, femoral bone, blood vessels and nerves were excluded as far as possible from the segmented muscle regions. The muscle CSAs selected for analyses were located in the thigh, 25 cm above the knee joint (CSA-25) [28]. MRI-CSA-25 estimation was performed on a single scan, also to simplify image acquisition and processing [27, 29].

Fig. 2figure 2

Illustrative magnetic resonance image of a segmented muscle region of the thigh at a 25 cm above the knee joint (MRI-CSA-25) of a 50-year-old female patient, acquired as axial T1-weighted gradient-echo. Group muscles are color-coded: rectus femoris (RF), vastus lateralis (VL), vastus intermedius (VI), and vastus medialis (VM), the four muscles composing the hamstrings muscles (HAMST) [biceps femoris short head (BFB), biceps femoris long head (BFL), semitendinosus (ST) and semimembranosus (SM], and adductors (ADDUC) [adductor longus, brevis, magnus, pectineus, sartorius and gracilis (GR)]. Because the delineations between adductors muscles were not so obvious at proximal part, all adductors’ muscles were segmented together, except for the gracilis which was easily recognizable. Note the exclusion of non-muscular elements (blood vessels, nerves) in the manual segmentation

Statistical analysis

The analyses were carried out with MedCalc Statistical Software, version 19.0 (Ostend, Belgium). Categorical variables were reported in terms of descriptive statistics using numbers and percentages, while continuous variables were reported using mean, standard deviation (SD) and median. Percentage differences between groups were analyzed using Chi-square test or Fisher's exact test. The intra-class correlation coefficient (ICC) was used to evaluate the intra-observer reliability for the repeated MRI-CSA-25 measurements, interpreting an ICC > 0.80 as indicative of “almost perfect” agreement [30]. The association between the MRI-CSA-25 and the other variables (US score, SPPB, SARC-F, HGs, age, mRDCI, and SDAI) was investigated with the Pearson correlation analysis, interpreting the strength of correlations: low = 0.26–0.49, moderate = 0.50–0.69, high = 0.70–0.89, and very high = 0.90–1.00. The accuracy of MRI-CSA-25 in detecting sarcopenia was compared to EWGSOP2 using the receiver operating characteristic (ROC) curve analysis, using the Youden index as optimal cut-off point.

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