Skeletal Muscle Involvement in Progressive Systemic Sclerosis (Scleroderma) By THOMAS A. MEDSGER, JR., GERALD P. RODNAN, JOHN M o o s s ~ AND JOHN W. VESTER 53 patients with typical PSS were examined for evidence of muscle weakness, abnormal serum enzymes, disturbances in urinary creatine and creatinine, and histopathologic alterations in skeletal muscle tissue. The majority was found to have clinical and biochemical features C of primary myopathy. Microscopic involvement of muscle fibers or interstitium was present in 14 of 36 cases; the most consistent abnormality was interstitial fibrosis. This muscle involvement is considered an important feature in the course of PSS. involvement of skeletal muscle in progressive systemic sclerosis (PSS) was described in 1876 by Westphal, who noted severe shoulder girdle atrophy in a woman with scleroderma and suggested that a primary myopathy was responsible.’ In 1895, Lewin and Heller reviewed reports of 26 cases of muscle atrophy in this disease.2 These authors, together with Dinkler3 and MCry,4 observed an increase in connective tissue as the dominant microscopic change, although some muscle fiber degeneration was also present. Frequent case reports since that time have confirmed these findings, although it is likely that many of the patients would be classified today as dermatomyositis with skin changes suggestive of PSS.5-12 Brock presented 3 cases illustrating the diagnostic dilemma created when PSS mimics dermatomyositis, and showed that myopathy in the former was not necessarily associated with involvement of directly overlying skin.13 More recently, Tuffanelli and Winklemann have used the term “sclerodermatomyositis” in describing 36 patients in whom muscle disease so dominated the clinical picture that distinguishing between scleroderma and dermatomyositis was imp0ssib1e.l~ Striated muscle abnormalities have also been found in other diseases which clinically overlap PSS. Adams and co-workers described “interstitial nodular polymyositis” in scleroderma; they believe this finding cannot be differentiated microscopically from that seen in rheumatoid arthritis (RA) and systemic lupus erythematosus ( SLE).15 Desmarais et al. called attention to the frequency of histological abnormalities in muscle tissue of patients with From the Departments of Medicine and Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 1521 3. This stu& was supported by a Graduate Training Grant in Arthritis and Rheumatism (2A-5031) USPHS Grant 5-M01-FR-00056, and a grant from the Western Pennsylvania Chapter, Arthritis Foundation. THOMAS A. MEDSGER,JR., M.D.: Trainee in Rheumatic Diseases, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania. GERALDP. RODNAN, M.D.: Professor of Medicine, University of Pittsburgh. JOHN M o o s s ~ , M.D.: Present address: Professor of Pathology, Bowman Gray School of Medicine, Winston-Salem, North Carolina. JOHN W. VESTER, M.D.: Associate Professor of Medicine, University of Pittsburgh, and Associate Chief of Staf, Oakland V. A. Hospital, Pittsburgh. Present address: Department of Research, Good Samaritan Hospital, Cincinnati, Ohio. 554 LINICAL ARTHRITIS AND RHEUMATISM,VOL. 11, No. 4 (AUGUST 1968) 555 SKELETAL MUSCLE INVOLVEMENT IN PSS RA,l6 and Pitkeathly and Coomes have recently described 3 cases of RA with polymyositis, in which serum enzyme and biopsy alterations were indistinguishable from those in polymyositis alone.'? Numerous accounts have indicated that untreated SLE may be associated with prominent myositis.ls Although there is general agreement that there may be conspicuous muscle wasting in severe scleroderma, the documented prevalence of skeletal muscle involvement in PSS has varied widely in published reports. Pearsonl9 has pointed out, however, that pathologic alterations are common in muscle biopsies from individuals with chronic disease states, and that these nonspecific lesions may well contribute to clinically observed muscle atrophy and weakness. To what extent the changes in PSS result from disuse atrophy and to what extent they represent primary myopathy has not been determined. In the present study, 53 patients with typical PSS were evaluated with respect to clinical, pathological, and biochemical features of skeletal muscle disease. The majority of these individuals was found to have evidence of a primary myopathy . MATERIALS AND METHODS Subjects The patients chosen for this study were designated as having PSS on the basis of two chief criteria: 1) Raynaud's phenomenon and/or typical sclerodermatous skin changes; and 2) involvement of the gastrointestinal tract documented by abnormal distal esophageal motility at fluoroscopy and/or classical radiographic small bowel or colon changes. Other evidence of systemic involvement in this group included arthritis, pulmonary fibrosis, and myocardial and renal disease typical of PSS. Ten patients are included who have Raynaud's phenomenon and extensive, diffuse dermal changes without demonstrable alimentary tract lesions; they have been followed for 2 to 12 years. Although we have encountered several patients who present combinations of features of scleroderma, SLE, RA, and dermatomyositis, these have been purposely excluded in order to limit the series as nearly as possible to classical PSS. The final list consists of 33 patients under current observation (Table 1, patients 1-33), 5 individuals who died during the period of the study (September, 196SJanuary, 1967) (patients 34-38), and 15 others followed at this center during the period 1955-65 who had autopsy samples of striated muscle available for review (patients 39-53 in Table 1). There were 20 men and 33 women, ranging from 17-75 years in age, who had clinical evidence of scleroderma for 1 3 1 years. Clinical Evaluation Weight loss was determined from each patient's weight at the time of study compared to his started weight prior to the onset of symptoms of scleroderma (including Raynaud's phenomenon). Individuals were carefully questioned regarding symptoms referable to myopathy, the interviewer attempting to separate those complaints of articular origin. Muscle groups were tested in the standard fashion (normal, good, fair, poor, trace, zero) described by Daniels, Williams, and Worthington.20 Thirty-eight patients were so examined; the remaining 15 were evaluated on the basis of previously recorded physical examinations. The muscles tested were those of the hip and shoulder girdles, and the muscle groups of the arm, forearm, hand, thigh, leg and foot. Combined judgments were made for proximal and distal musculature of both upper and lower extremities, and then a single rating was made for each patient, designed as an overall clinical estimation of muscle weakness. Atrophy of muscle groups, which was present in variable degree, was not included in this evaluation. Serum Enzymes Determinations of creatine phosphokinase (CPK), aldolase, lactic dehydrogenase (LDH), and glutamic oxalo-acetic transaminase ( SGOT ) were made on the fresh sera of 35 patients; LDH and SGOT values were included from the past records of 9 other individuals. CPK was determined by a modification of the method of Noda et a1.21 The normal range has been found to be 0-1.5 micromoles of phosphate/ml. serum/hr.*1-23 These units can be converted to International Units by multiplying by a factor of 16.6. Aldolase, measured by spectrophotometric assay originally described by Bruns, ranges from 0.9-2.5 milliunits/ ml. serum.21 The upper limit of normal in this study was taken as 3.0 milliunits. SGOT (0-45 Table l.--Clinical, Biochemical, and Histological Findings Relative t o Skeletal Muscle Involvement i n 53 Patients with Progressive Systemic Sclerosis Dogre of Age, sex Disease %Lnss duration in (yrs.) body wt. 33. I.L. 57-F 48-F 60--hI 61 24--F 24 49-hI 63-hf 75-F 62-F 62-F 53-F 53 37-F 70-M 59-F 47-M 49--F 27-F 28 17-F 20 36-ni 49-M 48-M 60-F 37-F 37 41 48-F 57-F 46-F 46-F 53-M 66-M 57-M 49-F 45-hI 55--M 40-F 31 39 8 13 2 15 3 20 3 17 3 27 4 7 0 10 29 6 2 6 0 10 3 0 3 4 3 0 8 20 12 35 2 18 3 3 2 0 3 2 4 2 7 2 18 1 24 2 5 12 2 15 0 16 16 0 2 0 7 12 0 13 26 2 0 5 0 7 22 2 0 10 8 4 0 18 10 17 3 4 29 34. IS. 57-F 20 23 29 1 1 13 3 20 22 6 7 30 ++ ++ ++++ 3 4 23 0 16 +++ ++ Patient 1. A.K. 2. E.P. 3. W.D. 4. S.B. 5. 6. 7. 8. 9. 10. G.W. M.A. E.H. H.H. S.T. E.B. 11. D.P. 12. J.H. 13. B.G. 14. J.F. 15. R.P. 16. B.C. 17. M.C. 18. 19. 20. 21. 22. R.L. J.H. C.W. A.P. A.Y. 23. 24. 25. 26. 27. G.R. M.K. E.B. D.McV. L.E. 28. A.E. 29. 30. 31. 32. G.B. M.B. J.S. J.T. 60 35. 36. 37. 38. A.R. M.B. P.S. C.P. 39. E.V. 40. M.W. il. L.0”. 66-F 65-41 3&F 53-F 46-F 44-F 48--M 1 muscle weakness (summary) ++++ ++ +++ +++ ++ ++++ ++ - ++ ++ + +++ +++ +++ + ++++ ++++ ++ + +++. + + + +++ ++ ++ + +++ ++ ++ + ++ ++ + +++ ++++ ++ *Based on “creatinine coefficient”24. tI3 = biopsy specimen; A = autopsy specimen. Urinary creatinine (Gm./24 h, Actual R Prcd.’ 0.52 0.77 0.63 1.01 1.07 0.71 1.29 1.57 0.80 0.79 0.96 0.87 0.84 1.19 0.61 0.47 1.48 1.00 0.79 0.86 0.63 0.42 0.53 0.46 1.14 0.72 1.00 0.83 0.45 0.78 0.49 0.71 0.80 1.01 1.03 0.73 0.73 1.67 0.90 0.65 82 102 45 78 82 79 74 90 71 93 63 105 106 82 58 107 127 87 92 93 77 54 31 39 82 75 95 89 50 106 68 94 74 70 59 53 47 91 75 86 1.04 0.60 0.43 Histopathologic abnormalities Inlerstitium Conn. a@e;. hluscle Muscle tissue Blood mg./24 h. (milliunits/ml.) snurcet fiber and fat vessels 165 47 48 98 74 259 34 55 77 142 24 184 179 110 45 255 61 1 44 34 51 2 65 8 20 51 42 29 55 49 237 44 134 44 102 R + + + B B - + + B - - - B B - - - B - - - R - - - 62 81 144 4.09 2.95 4.50 1.93 3.14 3.00 3.04 2.39 3.40 5.10 3.70 B - - - 80 61 75 43 355 2.44 6.13 0.77 0.43 74 47 100 :I A A B A + + + + + + + + + + + + 0.56 0.56 1.34 77 62 84 270 88 30 A A + + + - 4.13 2.50 3.72 7.40 12.00 2.20 2.45 2.35 2.72 2.70 3.65 3.22 3.40 3.07 2.12 3.22 2.29 - 2.56 3.29 2.80 3.60 4.50 2.84 - - - SKELETAL hfUSCLE INVOLVE-NT Patient Age. sex 50 42. A.A. 43. W.R. 44. n1.c. 45. 46. 42. 48. 49. 50. 51. 52. 53. A.J. B.S. R.M. S.C. H.G. I.K. W.W. .J.S. R.V. 51 38-A1 43--;\I 45 54-1; 55 63-1: 42-F 32-11 41-1: 71-F 35-F 4541 53--RI 36--hI Disease %,Loss duration in (yrs.) body wt. 3 4 1 1 3 2 2 3 6 3 2 1 5 2 1 4 21 21 15 5 5 9 11 38 18 0 4 5 8 4 13 14 557 IN PSS Degree of muscle weakness (summary) +++ +++ ++++ + + + + ++ ++ ++ Histopathologic abnormalities Interstitium Urinarv creatinihe urinary SCNm Conn. (Gm.124 h) creatine aldolase Muscle Muscle tissue Blood Actual % Pred.’ mg./24 h. (milliunits/ml.) sourcet fiber and fat v e ~ ~ e l s 1.03 0.90 1.29 1.17 0.95 0.73 0.56 + ++ ++ units/ml. serum)23 and LDH (100550 units/ml. serum)26 were determined by standard methods. Urine Creatine and Crcatinine Twenty-four hour urine samples were collected from 43 patients; 3 or more consecutive specimens were obtained in all but 6 cases. Most of these persons were in-patients on balanced, low protein, meat-free diet which was begun 48 hours prior to the first collection. Samples of volume less than 1000 cc. and those from patients with renal failure and elevated serum creatinine levels were omitted. Five patients (patients 14, 23, 42, 46, and 50 in Table 1) were taking corticosteroids (prednisone, 10 mg. or less per day) at the time of the collections, and one (No. 24) was receiving weekly intramuscular ACTH. Potassium aminobenzoate, epsilonaminocaproic acid, cortico-teroids, low molecular weight dextrans, and chloroquine were given for varying periods of time to others, but no reported data were obtained while these agents were being used. Urinary creatine and creatinine were determined by the method of MacFate et al.27 Opinion varies about normal daily creatine excretion; in this study we used 0-50 mg. for men and 0-100 mg. for women. Creatinine is relatively constant at 20-26 mg./Kg. body weight for males and 14-22 mg./Kg. for females. The “creatinine coe5cient,” as described by Shaffer, was calculated by adding urinary creatine and creatinine, and expressing this value in mg./Kg. body weight.28 The percentage of predicted creatinine coefficient (Table 1) was determined by coinparison of the actual and predicted 67 59 99 71 45 72 56 24 105 5 - + A A + + - A + + - A A A A A A A A A A + + - + + - - - - - - - coefficients (predicted based on 25 mg./Kg. for males and 20 mg./Kg. for females). In 6 patients, creatine excretion values were not available. Pathologic Materid Skeletal muscle was obtained in 36 cases, consisting of 18 open biopsies, (one case, patient No. 1, was biopsied in 2 areas, deltoid and gluteus), and 19 post-mortem specimens. Fifteen of the 18 biopsies were taken from the deltoid; no attempt was made to sample those muscle groups showing the most severe weakness or tenderness. Of the autopsied cases, only the 5 examined during the course of the study (patients 34-38) had multiple specimens available for review. The earlier postmortem materials frequently contained only 2 muscle samples, diaphragm and deltoid. All available autopsy samples were studied, including intercostal, diaphragm, rectus abdominis, tongue, anterior tibial, quadriceps femoris, and pectoral muscles. Sections were routinely fixed in 10 per cent formalin, embedded in para5n, and stained with hematoxylin and eosin; in some cases trichrome (Mallory and Masson) stains were done. Four biopsy specimens were fixed with 1 per cent osmium tetroxide and 5 per cent glutaraldehyde followed by 1 per cent osmium tetroxide, and prepared for electron microscopy. Microscopic diagnoses were made at two separate sittings without knowledge of the clinical features. In only 2 cases was there a difference in interpretation recorded, and in no case was a frankly abnormal diagnosis altered to normal or vice-versa. Pathologic changes were classified under the broad categories of muscle 558 MEDSGER, RODNAN, MOOSSY, WTER Fig. 1.-Extensive peri- and epimysial fibrosis in cross section in deltoid muscle; fibrosis mixed with scattered chronic inflammatory cells. Muscle fibers distorted and some with central nuclei. (Case No. 1) Hematoxylin and eosin, 2 7 0 ~ . fiber and interstitial tissue alterations, the latter being subdivided into lesions of connective tissue and fat and those of blood vessels. A word of caution in the interpretation of muscle biopsies has been raised by Engel, who points out that certain focal myopathic changes can be produced by electromyographic and hypodermic needles.29 That this is important in patients with chronic diseases such as PSS should be apparent when one considers the frequency with which the deltoid and gluteal areas are used for the injection of steroids and other drugs. We were aware of this possibility in our interpretations of the histopathologic features in these patients; no focal changes in the deltoid or gluteal muscles were described which had not also been detected in the quadriceps, anterior tibial, or other muscle groups. RESULTS( TABLE 1) Clinical Evaluation The average weight loss after onset of PSS was 12 per cent. Over 60 per cent of the patients were aware of easy fatigability and weakness, but those symptoms were usually poorly localized. Although marked weight loss (greater than 20 per cent body weight in 14 patients) and severe to marked objective muscle weakness (16 patients) were noted frequently, only 7 individuals presented specific symptoms related to muscle involvement. Six of these complained of generalized muscle aching and one of “cramps”; in only 2 was there evidence of muscle tenderness. Typically there was more marked weakness of the proximal muscle groups, especially the pectoral girdle, which was involved to some extent in 20 of 38 patients carefully examined. Forearm flexors and extensors and the intrinsic hand muscles were more commonly affected (26 of 38), but the most extensive dermal and articular changes were in proximity to these muscles. Loss of muscle mass was often seen around joints with synovial involvement, primarily knees, ankles, elbows, wrists, and MCP and PIP SKELETAL MUSCLE INVOLVEMENT IN PSS 559 Fig. 2.-Fibrosis, muscle fiber atrophy and abortive regeneration in longitudinal section in quadriceps muscle. (Case No. 35) Hematoxylin and eosin, 270 x . Urine Creatine and Creatinine The average creatine excretion for the entire group (38 patients, 234 urine specimens) was 110 mg.124 hours. 58 per cent (8 of 14 men and 14 of 24 women) showed clearly elevated values at some stage in their clinical course, ranging as high as 611 mg.124 hours (patient 14). At the time of most recent examination, the average daily urinary creatinine was 0.817 Gm. When compared with their predicted excretion of creatinine, plus creatine, calcuSerum Enzymes lated as creatinine coefficient, most patients CPK levels were normal in all but 3 pa- produced subnormal amounts, ranging from tients, who showed mild elevations (1.80- 31-127 per cent and averaging 74 per cent 2.50 units). LDH and SGOT were raised of predicted values. In 10 instances, pain only one instance (case No. 4) and this tients were re-evaluated after an interval woman displayed elevation of all enzymes. of 6 months or longer; 6 of these showed The most common abnormality was aldo- significant decreases in urinary creatinine lase activity, which was high in 20 of 35 in- excretion over time (patients 17, 22, 34, 41, stances, and ranged as high as 12 milli- 43, 44), indicating disproportionate loss of units/ml. serum (again, case No. 4). muscle mass. joints of the hands. The shoulder girdle, however, was frequently atrophic and weak without evidence of articular disease. Clinical estimation of the degree of muscle weakness revealed the following distribution: none 10 patients 9 minimal (+) moderate (++) 18 severe (+++) 10 marked(++++) 6 560 MEDSGER, RODNAN, MOOSSY, VESTER Fig. 3.-Interstitial collection of lymphocytes in quadriceps. (Case No. 35) Hematoxylin 270 x . and eosin, Pathologic Findings No gross abnormality of the freshly obtained muscle was found. Significant histological abnormalities were noted in skeletal muscle from 14 of 36 patients. These alterations occurred more often in tissue obtained at autopsy (10 of 19) than by biopsy ( 4 of 17). The muscles most commonly affected were those most often sampled at autopsy (deltoid, pectoral, forearm groups, and diaphragm) but tongue and anterior tibia1 musculature occasionally showed histopathologic changes. These lesions appeared to be independent of overlying dermal thickening. In 3 instances deltoid biopsies were normal despite considerable involvement of the skin of the upper arm (patients 3,4, and 14). The most common change was interstitial and perivascular fibrosis ( 13 cases), followed in frequency by interstitial and perivascular inflammatory infiltrates (8 cases) and myofibril atrophy, necrosis, and degeneration (10 cases). It was unusual to see muscle fiber lesions without interstitial reaction, and vice-versa. However, skip areas, in which these two processes were spatially separated, were often present in the same muscle specimen. A wide spectrum of muscle fiber abnormalities was found, including atrophy, necrosis, and eosinophilic floccular degeneration. A few cases showed patchy foci in which muscle fibers were intensely necrotic, with abundant nuclear debris, obliteration of the usual myofibrilIar Iandmarks, and little or no adjacent inflammatory reaction. Changes in the interstitial tissue were characterized chiefly by irregularly distributed islands of peri- and epimysial fibrosis (Figs. 1 and 2) and increased interstitial fat. These lesions occurred both SKELETAL MUSCLE INVOLVEMENT I N PSS Fig. 4.-Perivascular 561 fibrosis. (Case No. 41) Hematoxylin and eosin, 270 x . DISCUSSION early and late in the clinicalcourseof PSS. Scattered cellular infiltrates (mainly Clinical Evaluation lymphocytes with occasional plasma cells Evaluation of muscle strength is particuand, more rarely, neutrophilic leucocytes ) larly difficult in the presence of articular were most often located in the interstitiurn disease, and atrophy in such circumstances (Fig. 3), and in only 2 instances were these aggregates distinctly nodular in ap- may not reflect primary myopathy. In fact, pearance. Perivascular inflammatory infil- it was our impression that a considerable trates were present in 3 cases. Perivascular portion of muscle wasting in these patients and perineural fibrosis were seen in vary- with PSS was the result of disuse. Furthering degrees, usually mild, in 5 specimens more, other more ominous features of (Figs. 4 and 5). Fibrinoid degeneration, as scleroderma leading to general debility also illustrated in the perineural connective tis- contributed to loss of muscle mass. Malabsue in Fig. 5, was noticed only once. No sorption, renal failure, and congestive heart primary vascular inflammation was seen in failure due to myocardial and/or pulmonary this material, in the sense of a cellular in- fibrosis thus resulted in atrophy out of profiltration of blood vessel walls. In one case, portion to objective evidence of active vessel wall calcification was present in the muscle cell injury. We were impressed by the frequency anterior tibia1 musculature, but it was not possible to determine the exact type of ves- with which severe muscle atrophy and 011sel from the sections available. Electron jectively measured weakness were found microscopic examination of 4 specimens despite an absence of specific complaints. failed to reveal any significant alteration in The muscle disease in these patients was usually insidious, in contrast to the more capillaries or myofibrils. MEDSGER, RODNAN, MOOSSY, VESTER 562 Fig. 5.-Perineural fibrosis with fibrinoid alteration in connective tissue. (Case No. 41) Hematoxylin and eosin, 270 x . acute exacerbations characteristic of dermatomyositis. Both diseases preferentially involve proximal musculature, but in PSS the muscles of the forearms and hands are frequently affected, together with adjacent skin and joints. Only 12 individuals showed completely normal distal upper extremity function, and in these acral skin changes were minimal or Raynaud's phenomenon alone was present. More akin to dermatomyositis was the frequent shoulder girdle weakness, which was most often unassociated with articular or para-articular disorders. Urine Creatine and Creatinine Under normal conditions, 2 per cent of muscle creatine is hydrolyzed and excreted daily as creatinine. The amount of urinary creatinine has long been recognized as a reflection of body creatine stores, and is thus considered a measure of body muscle mass. Christianson et al., in their discussion of polymyositis, reported 11 cases of scleroderma with an average daily creatinine excretion of 857 mg., far below their figures for patients with other diseases not usually . ~ ~ also obassociated with m y ~ p a t h y We served a low average daily urine creatinine of 817 mg.; however, there was no correlation between the decrease in creatinine and degree of muscle weakness for each patient. The 6 patients considered to have the most marked functional impairment of muscle (patients 1, 4, 17, 35, 38, and 42) excreted close to the average weight-based predicted amounts of creatinine. On the other hand, 6 of 10 restudied after intervals of 6 months or more did show disease progression, increasing muscle weakness, and concomitant decline in the creatinine output. It should be cautioned that this index cannot provide an accurate reflection of primary myopathy since disuse atrophy may contribute an important share in the 563 SKELETAL MUSCLE INVOLVEMENT IN PSS 25 t T i WEIGMT LOSS, % O F NORYAL BODY WEIGHT 5th 0 8.00 SERUM ALDOLASE 6.00 4.00 Yillirnitr I ml. m II 1 t 2.00 200 150 URINARY CREATINE mqml24hn. 100 1 1 - r- Fig. 6.-Correlation of degree of muscle weakness with 1 percentage weight loss, serum aldolase level, and urinary creatine excretion. The figures in parenthesis indicate the number of patients in each category with respect 3 to muscle weakness. The values represented are the mean and standard error of the mean. - 50 n CLINICAL ESTIMATION OF DEGREE OF MUSCLE WEAKNESS loss of muscle mass. It may, however, be a rough guide to the severity and rate of progression of PSS. Creatine is thought to be synthesized primarily in the liver and stored in voluntary skeletal muscle, where it exists chiefly as phosph~creatine.~~ Creatine itself is excreted in large auantities only when muscle cells are unable to incorporate properly and/or store pho~phocreatine.~~ In this study, the average urinary creatine was 107 mg.124 hours, only one-third the average amount found by Christianson et al. in their patients with s~leroderma.~O These abnormalities in creatine excretion are less frequent and more modest in degree than those found in polymyositis, yet the results suggest a fair correlation with disease activity. Our 6 patients with marked clinical myopathy excreted an average of 161 mg.1 day, while those with minimal or no atrophy or weakness excreted an average of 74 mg./day (Fig. 6). Of the 8 men and 14 women considered to have excessive creatinuria, 16 (73 per cent) were felt to have active progression of scleroderma, rather than stable courses, at the time of study. Fifteen of 19 (79 per cent) with high creutine excretion had aldolase elevations, and 5 of 9 abnormal histopathologic findings. We found no direct correlation between creatinuria, decreased urinary creatinine, and weight loss as Christianson et al. showed with their dermatomyositis group. Serum Enzymes In primary inflammatory and degenerative myopathies, abnormal amounts of many enzymes are released across sarcolemmal membranes of injured or dying muscle cells.33 The high percentage of nldolase elevations in the present group of patients with scleroderma was unexpected, especially in view of the low frequency of CPK, LDH, and SGOT abnormalities. Although 15 to 18 patients (83 per cent) with high serum aldoIase levels were found to have creatinuria of excessive degree, only 4 of 10 showed histopathological changes in muscle. Both aldolase elevation and amount 564 of creatinuria correlated well with the dcgree of muscle weakness (Fig. 6). There are reports of increased serum aldolase levels in disorders of myometrium and myo~ardium."-~5 Thus it is possible that cardiac and/or smooth muscle involvement may contribute to the observed serum aldolase changes in our patients with PSS. Pathologic Findings Surprisingly little has been added to the exhaustive histological descriptions of Dinkler and M61-y.~.*The frequency of muscle lesions reported by different observers has vaned widely. Steiner and Chason found no changes in 4 patients at autopsy,30 while Piper and Helwig noted abnormalities in all of 25 post-mortem cases?' Morrison and co-workers reported perivascular lymphocytic infiltrations, mainly endomysial and perimysial in location, in several patients with PSS.38 LeCoulant and Texier, in n discussion of 2 cases with pathologic alterations in muscles far distant from areas of classic dermal change, emphasized both severe atrophy of muscle fibers and interstitial dense cellular "nodules" separating and infiltrating fibers and bundles.39Pende and DeCarlo stressed the occurrence of myofibril fragmentation and degeneration, with loss of striations, eosinophilic homogenization, and sarcolemmal nuclear prolifera t i ~ n . ~ "Infiltrative changes were less prominent in their cases, but areas of fibrosis appeared in all 8 samples studied. The striated muscle changes in PSS, although similar in quality to those of other connective tissue disorders, were felt by Walton and Adams to be characterized primarily by increase in interstitial connective tissue with fibrosis.41 Of the total of 36 patients in this series with tissue specimens available, one would have predicted from clinical and/or laboratory findings that 26 would show some histologic changes in skeletal muscle; how- MEDSGER, RODNAN, MOOSSY, VESTER ever, as previously noted, only 14 were abnormal. The most striking discrepancy was in the low yield of biopsy changes ( 4 of 17) . This difference may be explainecl by 2 factors: 1) Those individuals who succumb to PSS have more serious disease; thus autopsy material would be expected to have more histopathologic abnormalities; and 2) The single muscle biopsy has limited reliability. Thirteen of these biopsied patients had moderate to severe muscle weakness, and of 15 completely studied, 12 had elevated serum aldolase values and 9 showed excessive urinary creatine. These findings support the concept that a single muscle specimen is frequently not histologically representative. Electron microscope evaluation of ultrastructural abnormalities in skeletal muscle (abductor pollicis brevis and brachioradialis) from 2 patients with PSS has been reported by Michalowski and K~dejko.*~ Decreased numbers of mitochondria, their vacuolization, and granular degeneration, and vascular changes including capillary wall thickening and lumen obliteration were described. Norton, Hurd, and Ziff found abnormal capillary ultrastructure in studying quadriceps muscles from scleroderma patients.43 We have processed 4 specimens for electron microscopy, but no conclusive changes could be demonstrated in capillaries or myofibrils when compared with control material. The frequency of elevated aldolase levels and creatinuria in this group of patients with PSS confirms that in most instances muscle cell degeneration is occurring. These findings correlate well with clinical evidence of muscle weakness and loss of muscle mass (Fig. 6), and we believe that, taken in the aggregate, they are a more reliable index of muscle disease than the results of an isolated muscle biopsy. Quantitatively, the frequency of lesions found in PSS (39 per cent) in this study 565 SKELFTAL MUSCLE INVOLVEMENT I N PSS is in keeping with 45 per cent reported by C r ~ i c k s h a n kin~ ~“rheumatic diseases” and 34 per cent by Sokoloff et a l j 5 in 202 cases, 57 of which were rheumatoid arthritis. It should be noted that we had available for study only 2 to 4 muscle groups in the majority of necropsies, compared to the 7 to 9 sampled by Cruickshank. We observed muscle lesions in 6 patients who had little or no weight loss ( 8 per cent or less of original weight) or general debility and in 7 individuals who had PSS 3 years or less. Three of the most striking examples of myositis were patients ill less than 12 months (patients 32, 34, 50). These findings emphasize that an important active myopathy is present in PSS, apart from the changes which can be attributed to chronic debilitation. The finding of various combinations of myofibril and interstitial involvement demonstrated in our patients supports the currently accepted concept that there is no specific primary muscle lesion in scleroderma. Histopathologic criteria alone could thus lead to confusion with polymyositis and other diseases of connective tissue. Accumulations of chronic idammatory cells, nodular or otherwise, have no recognizable specificity, and, alone, will not distinguish PSS, SLE, RA, polymyositis, dermatomyositis and other diseases of connective tissue.46 Similarly, the vascular lesions, including those associated with fibrinoid change, have no unequivocal interpretat i ~ n . ~Morphological ? alterations of the muscle fiber, formerly given much weight in other areas of muscle pathology, have themselves been questioned, even as a means for distinguishing denervation or neurogenic atrophy from m y ~ p a t h y . ~ ~ There is one histopathologic feature which appears more consistently in PSS than in other diseases affecting connective tissue. Fibrosis, with increase in interstitial, perivascular, and perineural connective tissue, is noted by Walton and Adams4’ to be most frequent in scleroderma and RA. Fibrosis was present in 13 of the 14 abnormal specimens in our study. Since muscle fiber degenerative changes and cellular infiltrations are indistinguishable from those of other disorders, it would be incorrect to conclude that this fibrosis represents a unique type of myopathy. Rather it should be viewed as a type of local response found more commonly in PSS than in other causes of myositis. CASEREPORTS Case N o . 1 . A. K. is a 57-year-old woman who developed Raynaud’s phenomenon in 1936. In 1962, she noted pain, heat, and swelling of the knees, wrists, and PIP joints bilaterally. Subsequently there was tightening of the skin over the fingers, arms, face, and feet, shortening of the distal phalanges, and flexion contractures leading to limited mobility of the hands, elbows, shoulders, and knees. She lost 66 pounds (39 per cent of previous weight) but did not complain of dysphagia or diarrhea. Painful ulcers appeared over both medial and lateral malleoli. She was able to feed herself, but required assistance for all other activities; she denied muscle weakness, tenderness, and cramps. When admitted to Presbyterian-University Hospital in September, 1965 the patient’s blood pressure was 95/60 mm.Hg and the pulse 88/min. Her face was “pinched,” with thickened, taut skin over the nose, cheeks, and neck; similar changes were noted over the chest, a r m s and hands, and multiple telangiectatic lesions were present. The lungs were normal. An apical systolic ejection murmur was present, and the pulmonic component of the second heart sound was accentuated. There was no hepato- or splenomegaly. Flexion contractures involved the DIP and MCP joints, wrists, elbows, shoulders, hips, and knees. Pronounced tendon rubs were palpable over both knees. There was profound weakness and wasting of the shoulder girdle, forearm muscles, and intrinsic muscles of the hands. The pelvic girdle was also weak, and marked quadriceps atrophy was evident. She was given an overall rating of muscle weakness. The hemoglobin was 10.0 Gm. per cent, hematocrit 33 per cent, WBC 8100/cu.mm. with a ++++ 566 normal differential count. The L.E. cell test was negative. The latex agglutination reaction for rheumatoid factor was positive in a titer of 1:320. Total serum protein was 6.8 Gm. per cent with 3.2 Gm. per cent albumin and 1.3 Gm. per cent gamma globulin. Roentgenographic examination revealed markedly decreased esophageal motility, and small bowel hypomotility typical of PSS. Interstitial fibrosis was present on chest x-ray. ECG was unremarkable. SGOT was 12, LDH 360, and CPK 1.24. The serum aldolase was elevated to 4.13 milliunits/ ml. Persistent creutinuriu, averaging 165 mg./24 h, was present on numerous determinations. The creatinine excretion was 0.52 Gm./24 h, and the creatinine coefficient was 82 per cent of that predicted for her new weight. Muscle biopsy was obtained from the deltoid, through definitely thickened skin of the upper arm. Microscopically there was irregular myofibril atrophy and necrosis and some collagenization of muscle fibers. Marked fibrosis of the interstitium was seen, with increased fat, and there were scattered lymphocytic infiltrations. (Fig. 1). Five months later the patient was readmitted because of pain in the right hip, and found to have avascular necrosis of the femoral head. There were no changes in creutine and creatinine excretion, and aldolase remained the only serum enzyme elevated. An Austin-Moore prosthesis was inserted, and at surgery the gluteus medius muscle was biopsied. Muscle fiber degeneration was present and several areas of calcification were seen. Interstitial changes were less marked but similar to those illustrated in Fig. 1. Case No. 35. A. R., a housewife, was first examined in 1960, at age 60, when she complained of a 20-year history of Raynaud's phenomenon. At that time she noted arm and shoulder weakness, and tight, thick, hyperpigmented skin over the fingers, neck, face, and chest. Blood pressure was 145/95 mm. Hg, and decreased range of motion of the PIP and MCP joints was observed. The hemoglobin was 14.2 Gm. per cent and the hematocrit 43 per cent, and blood urea nitrogen 8 mg. per cent. The L.E. cell test was negative. Total protein was 6.5 Gm. per cent with 3.8 Gm. per cent albumin and 1.1 Gm. per cent gamma globulin. Pulmonary hypertension with exercise was demonstrated on right heart catheterization. In January, 1966, she began to have headaches and was found to be hypertensive. At this time there was an increase in generalized weakness and MEDSGER, RODNAN, MOOSSY, WTER fatigability, as well as anorexia and dysphagia. Three weeks after beginning to take prednisone (20 mg./day), the patient, suddenly became restless, obtunded, and comatose. She was transferred to Presbyterian-University Hospital. She had lost 22 per cent of her previous weight. On admission the blood pressure was 210/120, and the pulse 100/min. The respiration was Cheyne-Stokes in character. There was nuchal rigidity, blurring of the left optic disc, decreased deep tendon reflexes in the left arm and leg, and bilateral Babinski signs. The hemoglobin was 14.2 Gm. per cent, hematocrit 45 per cent, and white cell count 14,000/cu.mm. with 93 per cent neutrophilic leukocytes. Lumbar puncture yielded xanthochromic cerebrospinal fluid containing many red blood cells, confirming the clinical impression of subarachnoid hemorrhage. The blood urea nitrogen was 25 mg. per cent and serum creatinine 1.5 mg. per cent. Arteriograms and brain scan were normal. There was a gradual increase in responsiveness, and the localizing neurologic signs disappeared. Blood pressure was controlled with alpha methyldopa. After the patient had improved considerably, muscle evaluation was performed. She complained of no aching or tenderness. There was profound weakness of shoulder and pelvic girdles, and she was unable to perform work against any resistance with these muscle groups. Quadriceps atrophy was present, but anterior tibial and posterior tibial functions were fair. Forearm muscles were fair but interossei and thenar muscles were weak. weakness. The overall rating was Serum transaminase (SGOT), LDH, and CPK values were normal. The serum aldolase activity was 6.13 milliunits/ml. Urine creatinine was 0.43 Gm./24 hours, urine creutine 355 mg., and the creatinine coefficient 75 per cent of that predicted for her new weight (at this time the patient had been off corticosteroids for 4 weeks). The blood urea nitrogen was 20 mg. per cent. During the sixth hospital week, she became oliguric and lapsed into congestive heart failure. She did not respond to digitalis and diuretics, developed refractory pulmonary edema, and expired. At post-mortem examination, the chief finding was that of renal vascular lesions indistinguishable from those seen in malignant hypertension. There was pulmonary and myocardial fibrosis and extensive disease of the esophagus characteristic of PSS. The diaphragm, deltoid, and quadriceps muscles all showed pathologic changes. Frank muscle necrosis and eosinophilic floccular changes ++++ 567 SKELETAL MUSCLE INVOLVEMENT IN PSS were present (Fig. 2). In the interstitium, fat and connective tissue were increased, with extensive fibrosis and some areas of calcification. Chronic inflammatory cells were scattered throughout, and there were small perivascular cellular collections (Fig. 3). SUMMARIO IN INTERLINGUA Cinquanta-tres patientes con typic sclerosis systemic progressive (SSP) esseva examinate pro evidentia de myoasthenia, anormal enzymas seral, disturbation del creatina e creatinina urinari, e alterationes histopathologic in tissu de musculo skeletic. In le majoritate del casos, characteristicas clinic e biochimic de myopathia primari esseva notate. Affection microscopic de fibras o de interstito muscular esseva presente in 14 de 36 casos. Le anormalitate le plus uniformemente presente esseva fibrosis interstitial. Le affection muscular es reguardate como un importante characteristica del curso clinic de SSP. REFERENCES 1. Westphal, C. F. 0.: Zwei F d e von Schlerodermie. Charitb-Annalen. (Berlin) 3:341, 360, 1876. 2. Lewin, G., and Heller, J.: Die Sclerodermie. Berlin, A. Hirschwald, 1895. pp. 169-171. 3. Dinkler, M.: Zur Lehre von der Sklerodermie. Deutch. Arch. Klin. Med. 48:514, 1891. 4. Mbry, H.: Anatomie Pathologique et Nature de la Sclbrodermie. Paris, G. Steinheil, 1889. 5. Hutchinson, J.: On morphoea, diffuse scleroderma, and allied diseases. Arch. Surg. (London) 2:25, 1890. 6. Wolters, M.: Beitrag zur Kenntriss des Sclerodermie. Arch. Derm. Syph. (Paris) 24:695, 943,1892. 7. Nixon, J. A.: Sclerodermia and myositis. 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