PROGNOSTIC FACTORS IN POLYMY OSITIS/DERMATOMY OSITIS

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1 PROGNOSTIC FACTORS IN POLYMY OSITIS/DERMATOMY OSITIS A Computer-Assisted Analysis of Ninety-Two Cases JOCHANAN BENBASSAT, DOV GEFEL, KEREN LARHOLT, SHAUL SUKENIK, VLADIMIR MORGENSTERN, and AVlNOAM ZLOTNlCK An effort was made to identify all patients with polymyositis/dermatomyositis (PM/DM) admitted to hospitals in Israel from The diagnosis of PM/DM was retrospectively reviewed in 92 (46 definite, 26 probable, and 20 possible) cases. The most common complaints and physical findings in the course of the disease were muscle weakness (86 patients), rash (53 patients), arthritis or arthralgia (39 patients), and dysphagia (35 patients). Elevated serum aldolase levels were found in 64% of the patients for whom data were available; 92% had abnormal electromyogram results, and 60.9% had muscle histopathology consistent with PM/DM. Malignancy was diagnosed in 13 patients. Malignancy, ischemic heart disease, and pulmonary complications were the most common causes of death. The actuarial survival curve was heterogeneous, with an accelerated mortality during the first year after diagnosis and a slower mortality during the following 7 years. Independent unfavorable prognostic signs were: failure to induce remission, leukocytosis, fever, older age, a shorter disease history, and dysphagia. ~ From the Department of Medicine and the Medical Computing Unit, Hadassah University Hospital, Jerusalem: and the Department of Medicine and Medical Computing Unit, Soroka Medical Center, Beer Sheva, Israel. Jochanan Benbassat, MD: Department of Medicine, Hadassah University Hospital; Dov Gefel, MD: Department of Medicine, Hadassah University Hospital; Keren Larholt, BA: Medical Computing Unit, Soroka Medical Center: Shad Sukenik, MD: Department of Medicine, Soroka Medical Center; Vladimir Morgenstern: Medical Computing Unit, Hadassah University Hospital; Avinoam Zlotnick, MSc, MD: Department of Medicine, Hadassah University Hospital. Address reprint requests to J. Benbassat, MD, Department of Medicine, Hadassah University Hospital, Mt. Scopus, PO Box 24035, Jerusalem, 91240, Israel. Submitted for publication August 29, 1983; accepted in revised form September 7, There are several studies of survival in polymyositis/dermatomyositis (PM/DM) (1-5). Mortality in this disorder has been reported to be between 13.7% (6) and 50% (7) within an unspecified length of followup period. Associated autoimmune disease (433) and malignancy (4,6,8), the length and severity of the illness (5,8), age (2,4), and childhood onset of polymyositis (9) have been reported to be predictive of a reduced length of survival. On the other hand, Bohan et a1 (6) reported favorable survival statistics for all groups of patients with PM/DM, with the exception of those with associated malignancy, and there were no deaths among the patients with childhood DM reported by Sullivan et a1 (10). The differences in the reported mortality in PM/ DM, and the conflicting conclusions on the prognostic significance of the various manifestations of the disease could be because of limited interpretation of followup data. We know of only one study (3) of the actuarial survival of patients with PM/DM. This report is a retrospective computer-assisted analysis of all the hospital records we were able to collect, between 1956 and 1976, of PMlDM patients in Israel. An attempt is made to determine the effect of the various manifestations of PM/DM on the actuarial survival of the patients in order to identify factors of possible prognostic significance. METHODS The archives of the general hospitals in Israel, all of which maintain medical research indexing systems, were searched for patients discharged between 1956 and 1976 with diagnoses of polymyositis, dermatomyositis, or myositis. Each chart was evaluated according to the criteria of Bohan et a1 (6): (a) symmetric muscle weakness; (b) typical histologic Arthritis and Rheumatism, Vol. 28, No. 3 (March 1985)

2 250 BENBASSAT ET AL findings on muscle biopsy; (c) increased levels of muscle enzymes in the serum; (d) compatible electromyographic (EMG) findings; and (e) characteristic dermatologic manifestations. Patients suspected of having muscular dystrophy, endocrinopathy, alcoholism, muscle infections, or evidence of a central or peripheral nervous system disease were excluded from the study. One hundred sixty charts were reviewed, and 92 cases partially or completely fulfilled the diagnostic criteria. PMlDM was considered definite in 46 patients who presented at least 4 manifestations, probable in 26 patients with 3, and possible in 20 patients with 2 of the 5 manifestations. There were 30 known deaths with 16 autopsies. Classification by diagnostic category (group I: primary idiopathic polymyositis [PM]; group 11: primary idiopathic dermatomyositis [DM]; group 111: polymyositis with malignancy IPM/DM-Mall; group IV: polymyositis of childhood onset I PM/DM-Child]; group V: overlap syndromes [PM/DM- Osl) was according to the criteria of Bohan et al (6). PMBM-Child was defined as PMlDM in a subject age 18 or less. The available clinical, laboratory, and followup data were compiled according to a predesignated format, and a digital computer was used for their analysis. Followup information was limited to that found in the patients hospital and outpatient department records. In December 1980, information on additional deaths was obtained from the Ministry for Internal Affairs, which keeps a central registry of vital records. The large number of attending physicians and the heterogeneity of the clinical departments involved precluded standardization of the assessment of muscle strength and dysphagia. Therefore, muscle weakness and dysphagia were assumed to have been present whenever recorded as such in the patients charts. Remission was defined as an increase in muscle strength, or 2 or more of the following: disappearance of skin rash, normalization of muscle enzyme levels in serum, and normalization in EMG tracings. Survival functions were processed by the biomedical computer program P series of the University of California Press, 1979 (BMDP 79). The Berkson and Gage (1 1) option was selected for actuarial survivorship curves. The differences between curves were tested by the analogs of nonparametric rank tests provided by the program, the Breslow and Mantel-Cox tests (12,L3). Both statistics are asymptotically distributed as chi-square. The Breslow test gives greater weight to early observations and is less sensitive to late events which occur when few study patients remain alive (12,14). Independent risk factors were identified by stepwise logistic regression using the BMDP-8 I statistical software of the University of California. RESULTS Incidence. Data on the age-adjusted annual incidence rates of PM/DM in Israel derived from the patients in this series have been presented elsewhere (15). Briefly, there were 2.18 new cases annually per 1,000,000 population. The age distribution was heterogeneous, with modes in the second and seventh de- cades and with a relatively low incidence among subjects in their twenties. The male:female ratio among patients <60 years old was , while that among patients 2-60 was SO. DeVere and Bradley (4) have also found the female preponderance to be restricted to patients aged 55 or less. Clinical features. Patients with childhood polymyositis comprised 21.7% of our series. Another 31.5% were classified as having primary idiopathic dermatomyositis, and 19.6% had primary idiopathic polymyositis. The remaining patients had overlap syndromes (1 3.0%) and polymyositis with malignancy (14.1%). The time interval from first manifestation of the disease to diagnosis was 1 year or less in 69 patients, the average for the whole series being 13.0 months. Patients with PM/DM-Mal, PM/DM-Child, and PM/DM-0s presented with nonsignificantly shorter disease histories than did those with PM or DM. Skin rash was the most common presenting complaint in DM and PM/DM-Mal, muscle weakness in PM and PM/DM-Child, and arthralgia in PM/DM- 0s. The most common complaints throughout the duration of the disease were muscle weakness (93.5%), muscle pain (46.7%), rash (57.6%), and arthralgia (42.4%). By definition, skin rash characterized DM and was never present in PM. It was observed in 76.9% of the patients with PM/DM-Mal, in half of those with PM/DM-Child, and in one-third of the patients with PM/DM-0s. Dysphagia was reported by 38.0% of the patients and it was nonsignificantly more common in PM/DM-Ma1 and PM/DM-Child. Temperature above 38 C was found in 21.7%, while hepatomegaly, splenomegaly, and lymphadenopathy were found in 31.5, 20.7, and 10.9% of the patients, respectively. Laboratory findings. The EMG results were abnormal in 72 (92.3%) of the 78 patients examined. There were no differences in the frequency of EMG disturbances among the various diagnostic categories. Muscle biopsies were interpreted as compatible with polymyositis in 60.9% of the 80 cases that had available data. Abnormal histologic findings were seen in 85% of the muscle biopsies in PMIDM-Child, but only in 30.8% of those in PM/DM-Ma1 (P < 0.05). Serum aspartate aminotransferase (AST), creatine phosphokinase (CPK), aldolase (ALD), and lactic dehydrogenase (LDH) exceeded twice the upper level of normal in 39 of 83 (47.0%), 33 of 66 (50.0%, 29 of 45 (64.4%), and 34 of 59 (57.6%) cases with available data, respectively. The highest incidence of muscle enzyme abnormalities was observed in PM/DM-Child.

3 PROGNOSTIC FACTORS IN POLYMYOSITIS 25 1 The levels of AST, CPK, ALD, and LDH correlated significantly (P < 0.005) with one another, although product-moment correlations were generally low ( ). Rheumatoid factor was found in the sera of 6 patients with PM/DM-0s and in 1 patient with PM. Rheumatoid arthritis was diagnosed in 6 of the patients with PM/DM-Os, scleroderma was diagnosed in 4, and Sjogren's syndrome in 2. Antinuclear antibodies (ANA) were found in the sera of 23.6% of the 55 patients with available data and were evenly distributed among the various diagnostic categories. In most cases the ANA titers were not recorded in the patients' charts. White blood cell counts exceeded 1O,OOO/~l in 12 (15.6%) of the 77 patients with available data. There were no marked abnormalities in red blood cell counts or in liver functions. Blood urea nitrogen (BUN) levels exceeded 50 mg/dl in 11.9%, and proteinuria was found in 14.5% of the patients. Cardiac and electrocardiographic abnormalities. Electrocardiogram (EKG) results were available for 73 patients. EKG abnormalities, including nonspecific ST-T changes, supraventricular arrhythmias, Q waves, and conduction disorders, were detected at the time of diagnosis in 23 patients (31.5%). In 11 of these 23 patients, the EKG abnormalities could be accounted for by an associated hypertensive (4 patients), ischemic (5 patients), or pulmonary (2 patients) heart disease. In the 4 patients with hypertensive heart disease, arterial hypertension preceded the diagnosis of PM/DM by 2, 3, 5, and 10 years. In 5 patients, ischemic and/or hypertensive heart disease was thought to be the primary cause of death. The abnormalities on the EKGs of the remaining 12 patients were paroxysmal atrial tachycardia (3 patients), ST-T changes (6 patients), and conduction disturbances (3 patients). None of the 16 autopsies revealed edema, lymphocytic infiltration, necrosis, or other inflammatory myocardial changes which have been described in PM/DM (16). However, the amount of effort invested in the search for such changes in the patients is unknown. Pulmonary manifestations. Twelve patients had lung involvement, and in 8 of these 12, pulmonary disease was thought to be the primary cause of death. Interstitial lung disease (17) was diagnosed in 2 patients and was confirmed at autopsy in l. Pulmonary emboli were the suspected cause of sudden death in 3 patients, and this was confirmed at autopsy in 1. The most common pulmonary involvement was pneumonia. It was found at autopsy in 7 patient3 and was the main cause of death in 4 of them. The extent to which aspiration contributed to the development of pneumonia was not recorded. Polymyositis with malignancy. Thirteen patients (14.1%; 3 with PM, 10 with DM) had malignancies, including Hodgkin's lymphoma, angiosarcoma, and carcinoma of the bronchus, stomach, colon, breast, ovary, and prostate. Malignant tumors were found in 6 (18%) of the 34 male patients in this series and in 7 (12%) of the 58 female patients. The diagnoses of PM/DM and malignancy were made simultaneously at Table 1. Recorded primary causes of death in 30 patients with polymyositisidermatomyositis, by diagnostic category* ~~ ~~ PMIDM- PMIDM- PMIDM- PM DM Ma1 Child 0s Total (n = 18) (n = 29) (n = 13) (n = 20) (n = 12) (n = 92) Uncontrolled activity 2 I 3 (10.0%) Pulmonary (26.7%) Cardiac 4 I 5 (16.7%) Cerebrovascular 1 I (3.3%') Malignancy 5 5 (16.7%) Uremia (10.0%') Not given 2 I I 1 5 (16.7%') All causes (1007~) Total mortality in diagnostic category (96) Length of followup (person years) Mortality per person years followup (X 100) ~ ~ * PM = polymyositis; DM = dermatomyositis; Ma1 = malignancy; Child = childhood onset; 0 s = overlap syndromes.

4 252 BENBASSAT ET AL 3 aro Years Figure 1. Actuarial survival since diagnosis of 92 patients with polymyositis/dermatornyositis, by sex. After 6 years followup, only 1 man and 7 women remained in the study. presentation in 8 patients. In 2 patients, the malignant neoplasm was detected 1 month and 8 months prior to diagnosis of PM/DM. In the remaining 3 patients, the diagnosis of PM/DM preceded that of malignancy by 6, 18, and 24 months. The frequency of malignancy increased with age. Malignant tumors were found in 1 (3%) of the 34 patients aged 40 years or less, 5 (16%) of the 32 patients aged 41-59, and in 7 (27%) of the 26 patients aged 60 or more. Survival and factors of possible prognostic significance. Malignancy, ischemic heart disease, and pulmonary complications were the most common causes of the 30 known deaths. Three patients died of uremia and 3 died from uncontrolled activity of PM/DM (Table 1). Actuarial survival depicted a heterogeneous curve, which revealed an accelerated mortality the first year after diagnosis and a slower mortality over the following 7 years. There were no Table 2. Factors affecting actuarial survival of 92 patients since diagnosis of polymyositisi dermatomvositis Cumulative proportion surviving after (months) P Variable* Breslow test Mantel-Cox test to diagnosis Sex Men (34) <7 months (53) Women (58) >7 months (37) Interval from first manifestation Diagnostic category PM (18) DM (29) PMIDM-Ma1 ( 13) PMiDM-Child (20) PM/DM-Os (12) Age at diagnosis (years) <20 (23) (46) >61 (23) Temperature ("C) <38 (72) >38 (20) Remission achieved Yes (57) No (17) White blood cells < 10,000/~1 (65) >10,00O/F1'(12) Dysphagia No (57) Yes (35) Rash Yes (53) No (39) ' * Figures in parentheses indicate the number of patients with available data. See Table 1 for diagnostic category abbreviation definitions.

5 PROGNOSTIC FACTORS IN POLYMYOSITIS 253 Table 3. Stepwise logistic regression analysis of the effect of variables on actuarial survival of 92 patients with polymyositisidermatomyositis diagnosed in Israel between 1956 and 1976 Improvement Global Step Variable Entered no. entered as XZ P X2 P 1 Clinical remission Yesino Leukocyte count Number Temperature "C 9. I Age Years Time since first manifestation Months Dvsuhaeia Yesino differences in length of survival time for male and female patients (Figure 1). Patients with PM/DM-Ma1 had a higher mortality rate than those in the remaining diagnostic categories (Table 1). The mortality of patients with PM/DM- Ma1 was 44.0 per 100 person years of followup, but it was only in the remaining diagnostic categories. There were no significant differences in actuarial survival among the various diagnostic categories, probably because of the small numbers of patients (Table 2). A shorter disease history, rash, dysphagia, temperature above 38T, older age, leukocyte counts exceeding 1O,OOO/pl at diagnosis, and failure to induce a clinical remission were associated with a significantly reduced actuarial survival (Table 2). BUN levels >30 mg/dl, proteinuria, and elevated serum aldolase levels were associated with a nonsignificantly shorter actuarial survival. Stepwise logistic regression revealed that failure to induce a clinical remission, leukocyte counts of 2 10,0001~1 at diagnosis, temperature above 38 C at diagnosis, and older age were independent risk factors. A shorter disease history and dysphagia contributed to mortality with borderline significance (Table 3). Stepwise logistic regression using entry variables only (i.e., excluding clinical remission) showed that white blood count, temperature, and age remained independent significant risk indicators (P = 0.004, 0.002, and 0.01 I, respectively). Repeated analysis after excluding 12 patients with pulmonary involvement identified only white blood cell count (P = 0.001) and age (P = 0.005) as independent risk factors. Temperature contributed to mortality with borderline significance (P = 0.07). Survival was not affected by the presence of arthritis or arthralgia, abnormal histologic findings on muscle biopsy, increased levels of 1 or more of the remaining muscle enzymes, erythrocyte sedimentation rate, abnormalities revealed in the EMG tracing, hemoglobin level, presence of Raynaud's phenomenon, antinuclear antibodies in the serum, blood pressure at diagnosis, abnormalities shown in the EKG, splenomegaly, or degree of certainty in the diagnosis. DISCUSSION The presented data should be interpreted with caution. They are based on a retrospective study of a relatively small number of patients seen over a long period of time at a large number of institutions. The degree of evaluation varied, and evaluations of serum levels of muscle enzymes, EMG, and biopsies were missing in many cases; hence the relatively high proportion of probable and possible cases of PM/DM in the series. However, our study was unique in employing a stepwise logistic regression. which combined multivariate analytic techniques and actuarial Table 4. Mortality in published series of patients with poly myositisidermatom yosit is Number of Surveyed patients time Mortality Reference at risk interval 93 O'Leary and Waisman (7) Sheard (19) Wedgewood et a1 (9)* 26 Not given 40.0 Pearson (20) 48 Not given 25.0 Logan et al (2) Winkelman et a1 (8) 289 Not given 27.6 Medsger et al (3) Sullivan et a1 (lo)* Riddoch and Morgan-Hughes (5) DeVere and Bradley (4) Bohan et a1 (6) Carpenter et a1 (21)t Henriksson and Sandstedt (18) 107 Not given 23.0 This series * Including cases of polymyositis/dermatomyositis of childhood only. 'I Including cases of polymyositis and dermatomyositis only.

6 254 BENBASSAT ET AL Table 5. Prognostic factors in published series of patients with polymyositis/dermatomyositis (PM/DM)* Number Unfavorable prognostic Signs with no prognostic Reference of cases signs significance Riddoch and Morgan-Hughes (5) Winkelman et al (8) Logan et al (2) DeVere and Bradley (4) Medsger et al (3) I I8 124 Prolonged disease history, low serum CPK levels Raynaud s phenomenon, severity of activity, malignancy, scleroderma, pharyngeal and chest muscle weakness Older age, fulminating type of PMiDM Prolonged duration prior to Rx, overlap syndrome, malignancy, older age Older age, degree of muscle weakness, dysphagia, pneumonitis Skin rash, routine test results, sex, duration of disease, age Severity of activity, ESR Sex, skin rash, ESR, EMG abnormalities, hematocrit. abnormal muscle histopathology Bohan et a1 (6) Carpenter et a1 (21) Henriksson and Sandstedt (18) This series I Malignancy, older age, prolonged duration prior to Rx Dysphagia, severe proximal muscle weakness Older age, prolonged duration prior to Rx, cardiac manifestations, malignancy, no response to Rx Independent risk factors Older age Fever Leukocytosis Failure to induce remission Comorbid factors Malignancy Skin rash Dysphagia Shorter disease historv Severity of activity, scleroderma, Raynaud s phenomenon Corticosteroid Rx, degree of inflammation on muscle biopsy Arthritis, ESR, abnormal muscle histopathology, EMG abnormalities, Raynaud s phenomenon, hemoglobin level, blood pressure, EKG abnormalities, splenomegaly, sex, ANF, level of muscle enzymes *CPK = creatine phosphokinase; Rx = treatment: ESR = erythrocyte sedimentation rate: EMG = electromyogram; EKG = electrocardiogram; ANF = antinuclear factor. survival rates. Using these methods, failure to induce remission, leukocytosis of lo,ooo/pi or more, temperature above 38 C, and older age, and to a lesser degree, a shorter history and dysphagia, were identified as independent risk factors for mortality. Pneumonia was the main reason fever was identified as a risk. After exclusion of the remission variable and of pneumonia patients, the significant risk indicators identified were white blood cell count and age. Our findings are similar to those in other series with regard to the overall proportion of patients with PM/DM who died during followup (2-5,8,9) (Table 41, main causes of death (3-6,8,18) (Table I), and shape of the actuarial survival curve (3) (Figure 1). Similarly to other series of patients with PM/DM, older age (2,4,6), dysphagia (3,8), and acute progressive onset of the disease (2,s) with fever and leukocytosis predicted poorer survival. Surprisingly, malignancy, which has been reported to be associated with reduced survival in PM/DM (4,6,8,18), was not independently found to affect survival in our subjects (Table 5). We could not confirm that the overlap syn-

7 PROGNOSTIC FACTORS IN POLYMYOSITIS 255 dromes (4,8), a prolonged disease history (5,6), the degree of elevation of serum CPK (3, cardiac manifestations (18), or Raynaud s phenomenon (8) had any effect on survival. In agreement with other studies, sex (3,6,8), sedimentation rate (3,4), hemoglobin level (31, and EMG abnormalities (3) had no prognostic significance. Additional parameters which did not affect survival were arthritis, splenomegaly, high blood pressure levels at diagnosis, antinuclear antibodies in the serum, or abnormal histologic findings on muscle biopsy (Table 5). REFERENCES I. Rose AL, Walton JN: Polymyositis: a survey of 89 cases with particular reference to treatment and prognosis. Brain 89: , Logan RL, Bandera JM, Mikkelsen WM, Duff IF: Polymyositis: a clinical study. Ann Intern Med 65: , Medsger TA, Robinson H, Masi AT: Factors affecting survivorship in polymyositis: a life table study of 124 patients. Arthritis Rheum 14: , DeVere R, Bradley WG: Polymyositis: its presentation, morbidity and mortality. Brain 98: , Riddoch D, Morgan-Hughes JA: Prognosis in adult polymyositis. J Neurol Sci 26:71-80, Bohan A, Peter JB, Bowman RL, Pearson CM: A computer assisted analysis of 153 patients with polymyositis-dermatomyositis. Medicine (Baltimore) 56: , O Leary PA, Waisman M: Dermatomyositis: a study of 40 cases. Arch Dermatol Syphilol 41:lOOl-1009, Winkelman RK, Mulder DW, Lambert EH, Howard EH, Diessner RG: Course of dermatomyositis and polymyositis: comparison of untreated and cortisone treated patients. Mayo Clin Proc , Wedgewood RJP, Cook CD, Cohen J: Dermatomyositis: report of 26 cases in children with discussion of endocrine therapy. Pediatrics 12: , Sullivan DB, Cassidy JT, Petty RE, Burt A: Prognosis in childhood dermatomyositis. J Pediatr 80: , Berkson J, Gage RP: Calculation of survival rates for cancer. Mayo Clin Proc 25: Breslow NE: Analysis of survival data under the proportional hazard model. Intern Stat Rev 43:45-52, Mantel N: Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 50: , Peto R, Pike MC, Armitage P, Breslow NE, Cox DR, Howard SV, Mantel N, McPherson K, Peto J. Smith PG: Design and analysis of randomized clinical trials requiring prolonged clinical observation of each patient. Br J Cancer 35:l-27, Benbassat J, Gefel D, Zlotnick A: Epidemiology of polymyositis-dermatomyositis in Israel ( ). Isr J Med Sci 16: , Denbow CE, Lie JT, Tancredi RG, Bunch TW: Cardiac involvement in polymyositis: a clinicopathologic study of 20 autopsied patients. Arthritis Rheum 22: , Schwartz MI, Matthay RA, Sahn SA, Stanford RE, Marmostein BL, Steinhorn DJ: Interstitial lung disease in polymyositis-dermatomyositis: analysis of six cases and a review of the literature. Medicine (Baltimore) , Henriksson KG, Sandstedt P: Polymyositis: treatment and prognosis: a study of 107 patients. Acta Neurol Scand , Sheard C: Dermatomyositis. Arch Intern Med 88: , Pearson CM: Patterns of polymyositis and their responses to treatment. Ann Intern Med , Carpenter JR, Bunch TW, Engel AG, O Brien PC: Survival in polymyositis: corticosteroids and risk factors. J Rheumatol 4: , 1977