Use of magnetic resonance imaging and p-31 magnetic resonance spectroscopy to detect and quantify muscle dysfunction in the amyopathic and myopathic variants of dermatomyositis.
код для вставкиСкачатьARTHRITIS & RHEUMATISM Volume 38 Number 1, January 1995, pp 68-77 0 1995, American College of Rheumatology 68 USE OF MAGNETIC RESONANCE IMAGING AND P-3 1 MAGNETIC RESONANCE SPECTROSCOPY TO DETECT AND QUANTIFY MUSCLE DYSFUNCTION IN THE AMYOPATHIC AND MYOPATHIC VARIANTS OF DERMATOMYOSITIS JANE H. PARK, NANCY J. OLSEN, LLOYD KING, JR, TERRI VITAL, ROBERT BUSE, SURESH KARL MARTA HERNANZ-SCHULMAN, and RONALD R. PRICE Objective. To investigate the use of magnetic resonance imaging (MRI) and P-31 magnetic resonance spectroscopy (MRS) in characterizing the metabolic and functional status of muscles in patients with amyopathic dermatomyositis (DM) and to compare the findings with those in patients with classic myopathic DM. Methods. Nine patients with amyopathic DM, 11 patients with myopathic DM, and 11normal individuals were studied. MRI images of thigh muscles were obtained, and T1 and T2 relaxation times were calculated. Biochemical status was quantitated with P-31 MRS, by determining concentrations of phosphate metabolites during rest and exercise. Results. Patients with amyopathic DM showed no muscle inflammation, and MRS data obtained during rest were normal. During exercise at 25% and 50% maximum voluntary contractile force, the MRS data revealed significant differences between amyopathic DM patients and control subjects indicating inefficient metabolism. In contrast, muscles of patients with myopathic DM showed inflammation and metabolic abnormalities even during rest. Conclusion. Metabolic deficiencies in patients with amyopathic DM were unmasked by exercise, sugDr. Olsen’s and Dr. Park’s work was supported in part by a Clinical Research Grant from the Arthritis Foundation and by NIH grant AR-43156. Dr. King’s work was supported by funds from the Bureau of Veterans Affairs. Jane H. Park, PhD, Nancy J. Olsen, MD, Lloyd King, Jr., MD, PhD, T e m Vital, BS, Robert Buse, MD, Suresh Kari, BS, BE, Marta Hernanz-Schulman, MD, Ronald R. Price, PhD: Vanderbilt University School of Medicine, Nashville, Tennessee. Address reprint requests to Nancy J. Olsen, MD, Department of Medicine, T-3219 MCN, Vanderbilt University School of Medicine, Nashville, TN 37232. Submitted for publication February 22, 1994; accepted in revised form July 13, 1994. gesting that the 2 DM syndromes may share muscle abnormalities. MRYMRS may be useful in diagnosis and optimization of treatment. Dermatomyositis (DM) is an autoimmune disease characterized by a typical erythematous, photosensitive rash and severe proximal muscle weakness associated with an inflammatory myopathy (1,2). A subset of DM patients has been described in which typical cutaneous features are present but no muscle weakness or only minor muscle involvement is clinically apparent and serum levels of muscle enzymes are usually normal (3-7). In 1979, Pearson suggested the term amyopathic DM to refer to this group of DM patients, in whom no apparent myopathy developed over at least 2 years of observation (8). Euwer and Sontheimer (6) conducted a systematic review of amyopathic DM starting with the first report by Krain (4), who characterized 6 patients without initial muscle involvement. Recently, Stonecipher et a1 reported on the evaluation and followup of 13 additional patients with typical cutaneous findings but absent or minimal muscle disease (9). In the patient series described by Krain (4), the most commonly reported symptoms were lethargy and fatigue, followed by photosensitivity and then arthralgias. Among the 6 patients described by Euwer and Sontheimer, the most common symptom was photosensitivity, while lethargy and fatigue were present in 50% of the group (6). This finding of lethargy and fatigue in the absence of objective weakness or other supporting diagnostic data suggested the possibility of subtle defects in muscle function which might not be detected by the usual clinical evaluation. In order to examine this possibility, we evaluated the muscles of 9 69 MRUMRS IN AMYOPATHIC DM Table 1. Clinical features of 9 patients with amyopathic dermatomyositis (DM) studied by magnetic resonance imaging (MRI) and P-31 magnetic resonance spectroscopy (MRS), and of comparison groups* Agelsedrace Amyopathic DM Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Patient 7 Patient 8 Patient 9 Myopathic DM Normal subjects 27/F/W 58IFlW 49/F/W 35/F/W 47/F/W 34/F/W 35/F/W 42/F/W 39/F/W 34 f 5/7F, 4M 44 f 5/6F, 5M Duration (years)t Gottron’s papules ADL score CPK (IU/ml)$ Prednisone (mg/day)§ ANA titer 4 12 10.5 0.87 2.3 0.37 4.5 2.3 1.37 2.2 f 0.5 Yes Yes Yes No Yes No Yes No Yes Rash (all) No NA 1 1 1 1 1.13 1 1 NA 1.54 f 0.3 - 27 51/80 53/83 NA 4011 19 78/97 NA 27/39 281197# 916 f 490 3012 10 10.0 2.5 1.25 None None 4.0 None 5.0 3.0 13 2 5 None 1 :40 <1:40 1:160 1 :40 1:320 1:40 1:160 1:80 1:40 ?1:160 <1:40 - * Values for the myopathic DM patients and the normal subjects are the mean f SEM (n = 1 1 in each group). ADL Living; CPK = creatine phosphokinase; ANA = antinuclear antibody; NA = data not available. t From appearance of rash to MRUMRS examination. $ At or before/after time of MRUMRS examination. § Dosage at time of MRIiMRS examination. 7 Subsequently followed up for 2 years without demonstrable weakness. # Values for this patient obtained at a laboratory with a normal range of 50-160 IU/ml. patients with amyopathic DM, using noninvasive magnetic resonance imaging (MRI) and P-31 magnetic resonance spectroscopy (MRS) (10-12). These techniques were utilized because of their high sensitivity and previous success in characterizing patients with classic DM (13-15) and in evaluating responses of these patients to treatment regimens (16-19). Our results indicate the presence of underlying metabolic abnormalities in muscles of patients whose DM has been designated as amyopathic, a finding which could have an impact on diagnosis and optimization of treatment in individual patients. Furthermore, the data suggest that the 2 variants of DM are closely related and may share elements of pathophysiology which are variably expressed. PATIENTS AND METHODS Patient groups and normal subjects. The amyopathic DM group included 9 patients and the myopathic group included 11 patients, all of whom were referred by either rheumatologists or dermatologists affiliated with Vanderbilt University Medical School. The patients with amyopathic DM (Table 1) were all white women ranging in age from 27 to 58 years. Clinical features included disease duration of up to 12 years; 8 of the 9 patients had positive antinuclear antibody, generally in low titers. All amyopathic DM patients had a characteristic photosensitive, erythematous rash, and 6 had typical Gottron’s papules. Only 1 of these patients was receiving prednisone at 210 mg daily (mean f SEM for the group 3 f 1 mg), although 4 patients had received higher doses of prednisone in the past. Hydroxychloroquine was being used by 1 patient at the time of study, and 3 patients had received courses of this drug in the past. = Activities of Daily Data on creatine phosphokinase (CPK) values were available for 7 of the 9 amyopathic DM patients, and all values were repeatedly in the normal range with the exception of patient 9, who had normal values on 3 tests and 1 isolated value of 197 IU/ml in a test performed at a laboratory which had a normal CPK range of 50-160 IU/ml. Muscle biopsies were performed in 2 patients (patients 3 and 5 ) , and both showed negative results. Five subjects had electromyographic (EMG) testing, and in 2 (patients 3 and 9), the EMG results were consistent with myositis. One of these EMG tests had been obtained 10 years previously, and during the intervening period, no weakness developed (patient 3). Thus, patient 9 had some findings suggestive of myopathic DM, but she never had significant muscle weakness. Eight of the 9 amyopathic DM patients had significant fatigue, which was quantitated by 3 patients on a 10-cm visual analog scale, with values of 4,7, and 7 cm, respectively. Nevertheless, all 9 individuals were employed or were active homemakers. The 7 patients tested had a mean f SEM activities of daily living (ADL) score of 1.02 2 0.02, indicating good functional status (20). The myopathic DM group consisted of 1 black and 10 white patients with ages ranging from 22 to 75 years. There were 7 women and 4 men. Typical features of a group of myopathic DM patients in our institution have been detailed previously (19). For comparative purposes, features of the myopathic DM group in the present study are summarized in Table 1. All myopathic DM patients experienced both fatigue and weakness, and the 6 patients tested had a mean ADL score of 1.54 f 0.30. Nine myopathic DM patients underwent muscle biopsies, all of which had results that were consistent with the diagnosis of DM. Seven patients had EMGs; in 6, the findings were positive for myopathy, and the results were equivocal in 1. Six subjects were receiving prednisone at 2 1 0 mg per day (mean f SEM for the group 13 f 5 mg/day). Four patients were being treated 70 PARK ET AL Figure 1. T2-weighted images (repetition time/echo time = 2,0001 88) of the thigh muscles of a healthy subject and of patients with amyopathic or myopathic dermatomyositis (DM). A , Healthy subject. VL = vastus lateralis; VI = vastus intermedius; VM = vastus medialis; RF = rectus femoris; BF = biceps femoris. B, Patient with amyopathic DM. There is a homogeneous, low signal with an intensity equivalent to that of normal muscles. C, Patient with severe myopathic DM. Signal intensity is significantly increased (brightness), with irregular distribution in the RF, VL, and VI (arrows), consistent with inflammation. with methotrexate or azathioprine. Clinical status was assessed by the referring physicians. The control group consisted of 11 healthy, nonobese individuals (6 women and 5 men). Their ages ranged from 27 to 75 years, with a mean k SEM of 44 ? 5 years. Among these control subjects, no significant differences in the MRS data between women and men were observed. Furthermore, comparison of the patient groups with either the normal female group or the combined female and male group gave the same statistical results, but, as expected, the P values were more significant when all 11 control subjects were included as the comparison group. MRI/MRS examinations were performed over the same time periods for the control subjects and study patients. These studies were approved by the Committee for the Protection of Human Subjects of the Vanderbilt Institutional Review Board. Procedure for obtaining T1- and TZweighted images. The thigh of the subject was positioned in an extremity coil with a 20-cm diameter. Images were acquired with T1- and TZweighted spin-echo (SE) sequences in the transverse orientation with a 1.5T Magnetom (Siemens Medical Systems, Iselin, NJ) (Figure 1). The T1-weighted images were obtained using a Carr, Purcell, Meiboom, Gill (CPMG) SE pulse sequence500/22, 5 5 , 88 (repetition time [TR] rnsec/ echo time [TE] m s e c k w i t h a 90" flip angle, 256 x 256 matrix, and a 10-mm section thickness separated by 10-mm gaps. The T1-weighted (500/22) images with high resolution were used for identification of specific muscles, including the vastus lateralis (VL), vastus intermedius (VI), vastus medialis, rectus femoris (RF), and biceps femoris (BF), and for evaluation of fat distribution. TZweighted images were acquired with an S E pulse sequence (2,000/22/55/88). Inflammation was identified in diseased muscles as nonhomogeneous regions of high signal intensity (brightness) on T2-weighted images (2,000/88) (Figure 1C). Regions of inflammation are characterized by high signal intensity on only the TZweighted images, while areas of fat infiltration are most easily observed by brightness on T1-weighted images. Calculation of T1 and T2 relaxation times. For quantitative verification of the visual analyses, T1 and T2 relaxation times were calculated as previously described, using the data acquired with the 2 CPMG pulse sequences (13,19,21). The regions of interest in the VL and BF muscles were selected for evaluation of T1 and T2 values, as reported MRI/MRS IN AMYOPATHIC DM previously (13,19). For an individual subject, the mean T1 or T2 relaxation time was the average of 8 determinations for the VL and 4 determinations for the BF, which generally had a more uniform signal intensity. In regions of inflammation, both T1 and T2 values are elevated above normal due to increased water content. In contrast, where there is superficial fat or fat infiltration, TI values are very low, but T2 values are elevated. Exercise protocol. The initial maximum voluntary contraction (MVC) for each subject’s quadriceps muscles was determined outside of the magnet, as previously described (13,19). Increasingly heavy weights were strapped to the ankle of the seated subject, and the foot was raised by full extension of the lower leg, a motion involving the quadriceps muscles. Thereafter, the subject was positioned in the magnet. Spectra were acquired every minute during the initial 6-minute rest period. A nonmagnetic weight equivalent to 25% of the MVC was then secured on the ankle by Velcro straps, and the subject lifted the weight by extension of the lower leg once every 5 seconds over a 6-minute interval. Next, without an intervening rest period, a 50% MVC weight was placed on the ankle and exercise was continued for another 6-minute period. By intermittent lifting of the weight, partial muscle recovery is possible between lifts. This relatively easy exercise protocol was completed by all normal subjects and all but 1 of the 20 study patients, regardless of the level of fitness or training. P-31 MRS. Subjects were placed in a supine position in the magnet, and the thigh was centered and firmly stabilized with straps. The knee was flexed over an arch, and the surface coil was secured over the quadriceps muscles. The magnetic field was adjusted for maximum proton resolution (-0.1 ppm). Spectra of the resting quadriceps muscles were acquired with a Siemens surface coil (8 cm diameter) at 25.7 MHz with a rectangular pulse of 500 psec duration, a TR of 3 seconds, and a resolution of 1.95 Hz. The surface coil monitors a relatively large volume of muscle, and the spectral data represented a weighted average of normal muscle or diseased muscle with focal, nonhomogeneous inflammation. Spectra were acquired during each minute of the 6-minute periods for rest and for exercise at 25% and 50% MVC (Figure 2). Only the last 4 minutes of each 6-minute exercise period were summed for calculation of phosphocreatine/inorganic phosphate (PCrPi) ratios and P-31 metabolite concentrations, in order to assure that measurements were obtained during periods of steady-state kinetics. Phasing of spectra and baseline corrections were performed as previously described (13,19). Resonance areas of Pi, PCr, and ATP were corrected for saturation effects, and relative concentrations of P-31 metabolites were determined from the corrected resonance areas as detailed in previous reports (13,19,22,23). This quantitative approach has been verified in other studies of control subjects, patients, and athletes (13,19,22,24-26). Quality assurance and validation of results were obtained by evaluation of a Siemens P-31 standard before each MRS examination. The variability in the resonance area of this standard over 1 year was +5%. Two control subjects tested frequently over 10 months had stable metabolite levels at rest, with a variation of +6%. The PCr/Pi ratio was determined since it is a sensi- 71 tive indicator of the muscle’s efficiency in generating and maintaining high-energy phosphate compounds (PCr and ATP). A lower-than-normal PCr/Pi ratio indicates a defect in the production and/or utilization of PCr and ATP. To correlate biochemical and functional abnormalities during exercise, the total oxidative capacity (Vmax)of the muscles was determined according to the equations reported by Chance et a1 (24), i.e., V, = V[(0.53 x PCr/Pi) + 11 where V = work in joules as calculated from the exercise data. V/V,,, represents the fraction of the oxidative capacity utilized during exercise. The energy reserve of the muscles was determined as the phosphorylation potential (PP), where PP = ATP/(Pi x ADP). The ATP and Pi concentrations were determined as described above. Concentrations of cytosolic free ADP are in pmoles and below the level of sensitivity of in vivo P-31 MRS measurements. Therefore, the ADP concentration was calculated from the equilibrium equation for the creatine kinase reaction, as formulated and verified by Chance et a1 (24). Statistical analysis. Statistical comparisons of data for the normal subjects and the 2 patient groups were performed by Student’s 2-tailed I-test. P values less than 0.05 were considered significant. RESULTS T1- and T2-weighted MR images. The T1weighted images of the thigh muscles of all patients with amyopathic DM showed no abnormalities, as noted in previous studies of myopathic DM patients (13,14,19). When the signal intensities of the T2weighted images from a normal subject were compared with those from a patient with amyopathic DM, no abnormalities were detected in the patient’s muscles (Figures 1A and B). In contrast, the T2-weighted image from the patient with myopathic DM showed focal regions of high signal intensity in the quadriceps muscles (RF, VL, and VI), indicative of inflammation (Figure 1C). The posterior muscles in the regions of the hamstrings (BF) and the adductors were generally less affected than the quadriceps muscles, as noted previously (13,14,19). T1 and T2 relaxation time. The qualitative visual analyses of the images were quantified with calculated TI and T2 relaxation times (Table 2). The mean TI and T2 values for the VL and BF muscles in the healthy subjects and the amyopathic DM patients showed no statistically significant differences. SEM values were also relatively small in both of these groups. In the myopathic DM group, the VL muscles showed the highest mean TI value and the largest SEM (1,621 +- 84), significantly different from corresponding values in the control group (P < 0.03) and in the amyopathic DM group (P < 0.01). Inflammation 72 PARK ET AL 0 CONTROL AMYOPATHIC MYOPATHIC REST REST PCr > E ‘600 r( Q c en 400 ATP 200 0 - w I /I \ P; 5’ I 0 I -5 I -10 I I -15 d 5’ I -5 I -10 I -15 I PPm PPm Figure 2. Comparison of P-31 spectra of the quadriceps muscles of a control subject at rest (A) and of patients with amyopathic and myopathic dermatomyositis (DM) (B). The spectrum for the patient with amyopathic DM shows slightly reduced levels of phosphocreatine (PCr) and ATP. The spectrum for the patient with myopathic DM and severe proximal muscle weakness demonstrates significantly reduced levels of PCr and ATP. Pi = inorganic phosphate. was less severe in the BF and adductor muscles. Only 4 severely ill patients with myopathic DM showed high signal intensity and T1 values >1,500 msec in the biceps. For the T2 values, only the data for the VL muscle were significantly higher in myopathic DM patients compared with either the control group (P< 0.01) or the amyopathic DM group (P < 0.02). For subcutaneous fat, the T1 value was low (330 msec) and the T2 value high (55 msec). Since the T1 and T2 values were both found to be high in the diseased VL muscle (Table 2), the increased signal (brightness) in Figure 1C cannot be attributed to fatty infiltration. PCr/Pi ratios during rest and exercise. The mean PCr/Pi ratios in the amyopathic DM group were not significantly different from the control values either during rest or during exercise at 25% MVC (Figure 3). However, during exercise at 50% MVC, the PCr/Pi ratio was significantly lower for the amyopathic DM group compared with the controls (P< 0.05), indicating metabolic deficiencies which became apparent at the higher work load. In muscles of the myopathic DM patients, the mean PCr/Pi ratios were significantly lower than those in the normal or the arnyopathic DM group during rest (P < 0.01 and P < 0.005, respectively) and during exercise at 25% MVC (P < 0.001 and P < 0.01, respectively). The low PCr/Pi ratios can be explained on the basis of the relative concentrations of P-3 1 metabolites, discussed below. Table 2. T1 and T2 values in the thigh muscles of patients with amyopathic and myopathic dermatomyositis (DM) and in normal controls * T2 (msec) T1 (msec) Group VL BF BF VL ~ Controls 1,384 f 29 (n = 10) Amyopathic DM 1,302 f 42 (n = 9) Myopathic DM 1,621 2 84t (n = 9) * Values 1,316 f 50 38 t 0.4 39 2 1,397 f 50 40 38 f 0.6 42 f 2.0 1,454 2 47 f 0.8 51 f 4.0$ 0.6 are the mean f SEM. P values were calculated by student’s t-test. VL = vastus lateralis muscle; BF = biceps femoris muscle. t P < 0.03 versus control group; P < 0.01 versus amyopathic DM group. $ P < 0.01 versus control group; P < 0.02 versus amyopathic DM PUP. 73 MRUMRS IN AMYOPATHIC DM Normal 0 Amyopathic ae m- B Myopathic 6- '= 0 4 - ** ** 2- 0REST 25% MVC 50% MVC Figure 3. PCdPi ratios in the quadriceps muscles of control subjects and of patients with amyopathic or myopathic DM during rest and exercise (25% and 50% maximum voluntary contraction [MVC]). The PCrlPi ratios were calculated from spectroscopic determinations of the concentrations of PCr and Pi (Table 3) and are shown as the mean and SEM. + = P < 0.05 versus normal subjects; * = P < 0.01 versus normal subjects and P < 0.005 versus patients with amyopathic DM; ** = P < 0.001 versus normal subjects and, for 25% MVC only, versus patients with amyopathic DM. See Figure 2 for other definitions. Concentrations of P-31 metabolites during rest and exercise. The mean PCr/Pi ratios for the amyopathic DM group during rest or during exercise at 25% MVC were not significantly different from normal values, because the mean PCr and Pi concentrations were both somewhat lower in the muscles of patients with amyopathic DM than in controls (Table 3). At higher work loads (50% MVC), the proportionately greater loss of PCr from the amyopathic muscles was reflected in a statistically significant decrease in the PCr/Pi ratio when compared with normal muscles (P< 0.05). In contrast, very low PCr/Pi ratios, largely due to low levels of PCr, were seen in the myopathic muscles at all stages of the protocol (Figure 3 and Table 3). For example, during rest, the mean concentration of PCr in myopathic muscles was approximately 40% lower than the normal value (P < 0.001) and 30% below that of the amyopathic DM group (P< 0.005), whereas the Pi concentration remained equivalent to control values. During exercise at 25% MVC, the PCr decrease was proportionately greater in the myopathic than in the amyopathic muscles, and the P value for the comparison of PCr/Pi ratios between myopathic DM patients and control subjects was decreased accordingly (P < 0.001). In general, the concentrations of ATP (pphosphate peak) followed the same pattern as those for PCr (Table 3). Thus, the average ATP levels in the muscles of patients with amyopathic DM were somewhat lower than normal, but the differences were not statistically significant. In contrast, the relative ATP levels in the muscles of patients with myopathic DM during rest were well below the normal or amyopathic DM values (by 35% and 25%, respectively) (P< 0.001 and P < 0.005, respectively). During exercise (25% MVC), ATP was lost from the myopathic muscles but not from the amyopathic muscles, and the difference between the 2 patient groups reached a greater level of statistical significance (P < 0.001). V,,,, V/V,,,, and phosphorylation potential. The metabolic data were correlated with functional capacity by calculation of the V,, and VIV,,, values (Table 4). The work (V) performed by the amyopathic DM and myopathic DM patients at 25% MVC was not significantly different. However, the calculated V values for both patient groups were substantially lower than that for the controls (P < 0.005 and P < 0.001, respectively). The total oxidative capacity (V,,,) was the parameter that most clearly differentiated the 3 PARK ET AL 74 Table 3. Levels of P-31 metabolites in muscles of patients with amyopathic and myopathic dermatomyositis (DM) and normal controls, during rest and exercise* 25% MVC Rest 50% MVC Group Pi Controls (n = 11) Amyopathic DM 3.120.2 24.521.1 5.420.3 6.020.4 21.1t1.1 5.420.3 7.9r0.5 19.2r1.2 5.3t0.3 2.5 f 0.2$ 22.1 t 1.4 4.7 t 0.2 5.9 2 0.6 18.2 f 1.0 4.7 2 0.3 8.5 f 0.6 15.6 4.6 f 0.2 2.6 15.4 t 1.41 3.5 t 0.35 5.4 2 0.5 11.6 f 1.17 3.1 I 0 . 3 7 7.0 10.6 f 1.11 3.4 f 0.31 (n PCr ATPt Pi PCr ATPt Pi PCr f 1.0 ATPt = 9) Myopathic DM (n = 11) f 0.2 * Values are the mean f SEM mmoles/kg (wet weight). MVC = maximum voluntary contraction; Pi phosphocreatine. t Calculated as the pphosphate peak, which contained no adenine nucleotide impurities. $ P < 0.05 versus control group. 1 P < 0.001 versus control group; P < 0.005 versus amyopathic DM group. 7 P < 0.001 versus control group and versus amyopathic DM group. groups of subjects. The oxidative capacity of the amyopathic DM and myopathic DM patients was, respectively, 30% and 55% below that of the normal subjects (P < 0.002 and P < 0.001, respectively). These decreased V,, values in the case of the amyopathic DM group were due to the low V values, while for myopathic patients a combination of low V values and low PCr/Pi ratios contributed to the reduced V,,. data points for all subjects are Individual V and V, values at the higher shown in Figure 4. The V, exercise level (50% MVC) also statistically differentiated the 3 groups of subjects. Thus, the MRS procedures were able to detect subtle abnormalities in the muscles of patients with amyopathic DM, particularly during exertion. The calculation of V/V,,,, which represents the fraction of the oxidative capacity utilized during exercise, gave values of 35%, 38%, and 47% for the controls, amyopathic DM patients, and myopathic DM f 0.5 = inorganic phosphate; PCr patients, respectively. There was no significant difference between the control and the amyopathic DM groups, but a significant difference was noted between each of these groups and the myopathic DM group (P < 0.01 for each). The V/V,,, ratio in the amyopathic DM group was normal because both the V and the V, values were significantly lower in these patients than in controls. Another useful measure is the phosphorylation potential, which is defined as the free energy available for phosphorylation. The mean -+ SEM phosphorylation potential of muscles of patients in the amyopathic DM group (28.7 iz 5.0) was almost twice as high as that of muscles of patients in the myopathic DM group (16.8 ? 2.4; P < 0.05). The V, and PP values indicate that the oxidative capacity of the amyopathic DM group was significantly greater than that of the myopathic DM group, providing further quantitative substantiation of differences in muscle function. _ _ _ Table 4. Total oxidative capacity (Vmax) and Dhosohorvlation Dotential (PP) in patients with amyopathic and myopathic dermatomyositis (DM) and normal controls, during exercise at 25% maximum voluntary contraction* ~ ~~ Group V Controls (n = 11) Amyopathic DM (n = 9) Myopathic DM 81.4 f 3.5 235.2 f 12.9 0.35 60.4 4.8$ 163.5 t 14.01 0.38 2 0.03 51.1 f 7.011 107.1 2 13.0# 0.47 (n & Vmax VNmax ? ? 0.01 0.02# = 11) * Values are the mean 2 SEM. t Expressed as mmoles~'. $ P < 0.005 versus control group. 5 P < 0.002 versus control group. = ll P < 0.001 versus control group. # P < 0.001 versus control group; P < 0.01 versus amyopathic DM group. ** P < 0.002 versus control group; P < 0.05 versus amyopathic DM group. PPt 53.9 2 11.1 28.7 f 5.0 16.8 f 2.4** 75 MRUMRS IN AMYOPATHIC DM B A 1 300 0 lZO 100 -2 80 .-c a 1 Q c i - .-2 200 - E E 1 -ga 60 - -a \ 0 : -J0 7 0 2 : 100 - 0 E > 2o 1 0 0 Control Amyopathic Myopathic Control Amyopathic 1 Myopathic Figure 4. Individual values for work load (V) (A) and total oxidative capacity (VmaX)(B) in control subjects, amyopathic dermatomyositis (DM) patients, and myopathic DM patients studied during exercise at 25% maximum voluntary contraction. Although there is some overlap among the groups, there is a clear downward trend in these values as the severity of muscle involvement increases. Statistical analyses of these data are shown in Table 4. DISCUSSION The criteria for classification of patients with amyopathic DM have been the subject of debate for 2 decades (1,6,9). One reason for this may be that patients with minimal or no clinical evidence of muscle disease present problems with regard to diagnostic procedures such as biopsy or EMG. If the serum levels of muscle enzymes such as CPK are not elevated, the risk and discomfort of invasive procedures may not seem warranted in clinical practice (6). The question then arises as to whether the diagnosis of amyopathic DM can be accurately made in the absence of muscle biopsy and EMG (1,2). Precise evaluation in these cases assumes importance as it may affect the decision as to whether to initiate aggressive immunosuppressive therapy. Another difficulty is that a patient’s condition may change from an amyopathic to a myopathic state very slowly over time, or there may be a flare of the myopathic state that was not detected by clinical or laboratory investigations. As a partial solution to these ongoing dilemmas, we have used noninvasive MRI/MRS procedures to acquire unique data on the morphologic/metabolic status of muscles of patients with presumed amyopathic DM (10-12). In earlier investigations, we and others have shown that MRI is a very sensitive method for localization and characterization of the nonhomogeneous inflammation of myopathic DM (13-15). In the present study, none of our patients with amyopathic DM showed visible inflammation on T2-weighted images of the thigh muscles. In a recent longitudinal study of 11 patients with myopathic DM, inflammation was initially observed by MRI in most patients, but during treatment, the extent and severity of inflammation decreased at varying rates, which were not necessarily concordant with rates of change in CPK levels or the more prolonged metabolic abnormalities detected by P-31 MRS (19). In cases of discordant longitudinal MRI/MRS data, our experience suggests that MRS provides the more useful information for evaluation of disease status (1619). These findings may explain why some DM patients become slowly but progressively weaker based on physical testing but show little or no evidence of inflammation or muscle damage. Although the PCr/Pi ratio is not diagnostic for specific muscle diseases, it serves as an important measure of defective bioenergetics in given muscle disorders (26-28). This ratio is particularly useful for analysis of data acquired during exercise and recovery, when muscles are more dependent on oxidative rather than glycolytic pathways for energy production. In the present group of patients with amyopathic DM, the PCr/Pi ratio was normal during rest and during exercise at low levels (25% MVC) (Figure 3). However, at 50% MVC, the PCr/Pi ratio in the amyopathic DM patients was significantly below normal, indicating deficient bioenergetic status. The inability to generate and/or utilize PCr and ATP at the higher work 76 loads is consistent with subjective fatigue and lethargy noted in earlier reports (4,6) and reported by 8 of our 9 amyopathic subjects. In contrast, the patients with myopathic DM showed serious abnormalities even during rest, as demonstrated by the low PCr/Pi ratios resulting from low PCr levels. For the patients with amyopathic DM, whose energy metabolism was statistically superior to that of the myopathic DM group, the relatively high PCr levels were the major factor in determining the high values for the ratio. The Pi level remained more constant, with essentially equivalent values in all 3 groups of subjects. Underlying mechanisms responsible for the observed biochemical abnormalities are not defined by the present studies. However, it is of interest to note that muscle biopsy samples from DM patients have been shown to have significantly reduced capillary density, even in the absence of inflammation (29). Reduced capillary density may lead to decreased tissue oxygenation, which might in turn contribute to metabolic abnormalities such as decreased ATP synthesis in the Krebs cycle during exercise and recovery. It should be noted that in previous studies of patients with myopathic DM, resolution of inflammation on MRI was not always concordant with normalization of MRS values, suggesting that metabolic changes are, at least in part, independent of inflammatory processes (19). We have previously demonstrated that patients with myopathic DM have significantly lower levels of PCr than normal subjects, and that during the course of treatment, increases in PCr levels correlate with improved clinical status (16-19). The relative changes in PCr levels were greater than those of ATP; therefore, PCr was the better quantitative indicator of changes in disease status. In the amyopathic DM patients in the present study, PCr levels were lower than, but not statistically different from, normal values (Table 3). When the 2 DM groups were compared, the amyopathic DM patients were found to have significantly greater levels of PCr than the myopathic DM patients. Moreover, PCr levels were maintained more effectively during exercise in the amyopathic DM patients than in the myopathic DM patients, consistent with the former group’s greater capacity for daily activities and employment. ATP concentrations in the amyopathic DM patients were slightly lower than, but not statistically different from, control values, and were significantly higher than values in the weaker patients with myopathic DM. Subtle defects in amyopathic muscles were best detected by correlations between functional capacity PARK ET AL during exercise and biochemical parameters, calculated as the total oxidative capacity (V,,,) shown in Table 4. The data clearly demonstrated the superior oxidative capacity (endurance) of the controls as compared with the amyopathic DM patients. Thus, the symptoms of fatigue and lack of endurance noted by patients with amyopathic DM were substantiated by calculations. In turn, the superior capacity the V, for sustained energy generation by amyopathic DM patients as compared with the myopathic DM group was also documented with the calculations of V,, values and phosphorylation potential. The severe weakness and fatigue of the myopathic DM patients correlated with the very low V,,, and PP values (Table 4). In practical terms, these data indicate that patients with amyopathic DM may perform efficiently at low work loads, but due to lack of oxidative capacity and endurance, they would not be able to sustain the activity as long as normal individuals. Thus, during the MRS protocol with exercise of short duration, muscle metabolism (PCr/Pi ratios) of these patients may appear normal at low work loads. In contrast, myopathic DM patients are not able to efficiently generate energy for muscle contraction at any time during the exercise protocol, or in some cases, even during rest. Thus, on a quantitative basis, the patients with myopathic DM have more severe metabolic abnormalities and dysfunction than do those with the amyopathic variant. During the course of this study, patient 5 (Table 1) showed a sudden flare in disease activity. The precipitous onset of myopathy in this patient required hospitalization and substantial changes in her treatment regimen, as previously reported (12,19). After the development of myopathy, the MRI examination revealed inflammation of the thigh muscles, and MRS data showed the expected serious decline in her metabolic status. Her response to immunosuppressive therapy was monitored by MR procedures to determine when the medication should be tapered (12,19). It was important to accurately evaluate these metabolic changes in order to determine as soon as possible what therapeutic interventions might be indicated to avoid further functional deterioration. In conclusion, this investigation shows the unique capability of MRVMRS examinations to detect subtle defects in patients with amyopathic DM. These metabolic defects may be responsible for clinical findings such as fatigue and may provide objective data on this otherwise purely subjective symptom. The nonin- MRUMRS IN AMYOPATHIC DM vasive MR tests can be readily repeated for longitudinal evaluations and are very useful in making the decision to start, modify, or stop immunosuppressive therapy, thereby minimizing complications and maximizing therapeutic efficacy (12,19). ACKNOWLEDGMENTS These studies would not have been possible without the support of our refemng physicians, Drs. John S. Johnson, Joseph Huston, Porter Meadors, and s. Bob0 Tanner. We would also like to thank the many people who assisted with the performance of these studies, including Drs. 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