Full Text: Correspondence

Aldolase Levels in Dermatomyositis and Polymyositis with Normal Creatine Kinase Levels

We read with interest the recent letters by Carter, et al¹and by Mercado², and would like to report our experience on the value of creatine kinase (CK), aldolase, aspartate aminotransferase (AST), and lactate dehydrogenase (LDH) levels in diagnosing adult polymyositis (PM) or dermatomyositis (DM).

Since 1978, we have seen in our internal medicine and dermatology departments, 48 consecutive patients with either DM (35 patients) or other inflammatory muscle disorder (11 with polymyositis, one with overlap syndrome, and one with inclusion myositis). CK, aldolase, and AST were simultaneously measured before treatment in 46 patients, with additional measurement of LDH in 38. As shown in Table 1, there was discrepancy between CK and aldolase in 6 patients: 2 had elevated CK with a normal aldolase level, and 4 had a normal CK level with high aldolase level. Noteworthy, one patient had on several instances an 8-fold increase in aldolase level along with a very low CK level. This 70-year-old woman had a definite PM, including the finding of a high aldolase level³ and 4 Bohan and Peter criteria⁴, associated with blood eosinophilia and subclinical relapse of cancer of the breast⁵. The other 3 patients had clinical diagnosis of DM with 3 to 5 Bohan and Peter criteria, but no associated malignancy. Overall, 3 out of 6 patients with discordant data on muscle enzyme levels were found to have a malignancy associated with DM or PM. Although aldolase may become elevated in serum with malignant tumors, the only patient in our series who had an isolated high aldolase level and concurrent malignancy had polymyositis. Moreover, the aldolase quickly normalized when glucocorticoid treatment was introduced, thereby substantiating its muscle origin in this patient. Finally, no condition that can give rise to aldolase in the serum, such as myocardial infarction, acute hepatitis, obstructive jaundice, or hemolytic anemia, were apparent in any of these patients.

Table 1. Clinical and laboratory findings in patients with polymyositis or dermatomyositis and discordant creatine kinase and aldolase levels.

We found using the Spearman rank correlation a strong correlation in the 46 patients between CK and aldolase (r = 0.69, p < 0.0001), AST (r = 0.79, p < 0.0001), and LDH (r = 0.66, p < 0.0001). These results indicate that, in agreement with Dr. Carter's statement, when evaluating patients for DM or PM, the initial blood test should be a CK measurement. However, the finding of a high aldolase level as the sole blood marker of muscle damage in PM with or without dermatological signs may not be anecdotal, since we observed this scenario in 4 patients (9.5%) with the disorder. Similarly, Vignos, et al found that 4 out of 20 patients with PM had normal CK. Of these 4 patients, 2 had elevated aldolase levels⁶. Further, the AST and LDH levels may also be normal in this setting, as observed in 3 of 4 patients in our series. We therefore fully agree with Carter, et al and Dr. Mercado's opinion that, in the appropriate clinical setting, normal levels of both CK and AST do not preclude active PM. In patients, particularly (but not only) those with malignancy, whose clinical picture strongly suggests PM, but who are found to have normal CK levels, it may be useful to control aldolase levels. However, whether aldolase may accurately serve to follow the efficacy of treatment in patients with PM and a normal CK level deserves further study.

ERIC LIOZON, MD; ELISABETH VIDAL, MD, Department of Internal Medicine; AGNES SPARSA, MD; Department of Dermatology, Dupuytren's University Hospital, Limoges, France. E-mail: eric.liozon@unilim.fr

1. Carter JD, Kanik KS, Vasey FB, Valeriano-Marcet J. Dermatomyositis with normal creatine kinase and elevated aldolase levels. J Rheumatol 2001;28:2366-7.

2. Mercado U. Dermatomyositis with normal creatine kinase and elevated aldolase levels. J Rheumatol 2002;29:2242-3.

3. Tanimoto K, Nakano K, Kano S, et al. Classification criteria for polymyositis and dermatomyositis. J Rheumatol 1995;22:668-74.

4. Bohan A, Peter JB, Bowman RL, Pearson CM. A computer-assisted analysis of 153 patients with polymyositis and dermatomyositis. Medicine (Baltimore) 1977;56:255-86.

5. Sparsa A, Liozon E, Herrmann F, et al. Routine vs extensive malignancy search for adult dermatomyositis and polymyositis. Arch Dermatol 2002;138:885-90.

6. Vignos PJ, Goldwyn J. Evaluation of laboratory tests in diagnosis and management of polymyositis. AM J Med Sci 1972;263:291-308.

Dr. Liozon and his colleagues are to be commended on their data regarding inflammatory muscle disorders. To our knowledge, their cohort of 46 patients with adult polymyositis or dermatomyositis represents the largest series of patients in which creatine kinase (CK), aldolase, and aspartate aminotransferase (AST) were measured on all patients prior to treatment.

In their series of 46 patients, 4 (9.5%) had normal CK in the setting of elevated aldolase concentrations. In the series reported by Vignos, et al, 2 out of 20 patients (10%) had a normal CK with elevated aldolase¹. Our group and Dr. Ulises Mercado described similar patients with definite dermatomyositis with elevated aldolase and normal CK levels in The Journal^2,3. While the numbers are still rather small, these data suggest that perhaps as many as 10% of patients with active myositis can present with normal CK and elevated aldolase levels.

JOHN D. CARTER, MD; JOANNE VALERIANO, MD; FRANK B. VASEY, MD, Division of Rheumatology, University of South Florida, Tampa, Florida, USA. E-mail: joshcart01@hotmail.com

1. Vignos PJ, Goldwyn J. Evaluation of laboratory tests in the diagnosis and management of polymyositis. Am J Med Sci 1972;263:291-308.

2. Carter JD, Kanik KS, Vasey FB, Valeriano-Marcet J. Dermatomyositis with normal creatine kinase and elevated aldolase levels. J Rheumatol 2001;28:2366-7.

3. Mercado U. Dermatomyositis with normal creatine kinase and elevated aldolase levels. J Rheumatol 2002;29:2242-3.

The interest in my report in The Journal is much appreciated. Three cases described by Dr. Liozon and colleagues are examples of idiopathic dermatomyositis (DM) with normal creatine kinase (CK) and elevated aldolase concentrations, while the other 3 cases are DM or polymyositis (PM) associated with malignancy.

As noted, the most useful enzymes in diagnosis and prognosis of inflammatory disorders of muscle are serum CK and aldolase. The aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lactic dehydrogenase (LDH) enzymes may appear in increased amounts as well. These 3 enzymes share a site of origin in both muscle and liver. Aldolase, which catalyzes the breakdown of fructose 1,6-bisphosphate, is often thought to be a muscle-specific enzyme, but is also present in the liver. Therefore an increase of AST, ALT, and LDH enzymes obligates us to test for gammaglutamyl-transferase (GGT) to determine a liver origin, since this enzyme is not found in muscle¹.

Patients with myositis and malignancy who improved with therapy despite the presence of tumor have been described. In 1980, Perlman and Barth² reported a case of myositis, with elevated serum CK, breast cancer, and interstitial lung disease in a 47-year-old woman. She received corticosteroids and a cytotoxic agent. Despite the presence of tumor her CK level returned to normal. The tumor was then resected, but it recurred 4 months later. At that time muscle symptoms became more prominent, but her CK remained normal. She died of disseminated carcinomatosis. In their letter, Liozon, et al describe a 70-year-old woman with myositis, breast cancer, normal CK and elevated aldolase, and blood eosinophilia, who had relapse of the breast cancer. When she received corticosteroids, the aldolase rapidly normalized. While the blood eosinophilia could be explained by a hypersensitivity mechanism to tumor antigens, the high aldolase level may have been the result of involvement of both liver and muscle.

According to Pearson³, metastatic tumors are rarely seen in skeletal muscle. However, they may be more common than is believed. In 1959, he found 6 cases of metastatic tumor out of 38 cases of malignant disease surveyed at autopsy.

Much has been learned about inflammatory disorders of muscle since the pioneer works by Carl M. Pearson. But what initiates muscle fiber destruction in idiopathic DM/PM? It continues to be a mystery.

ULISES MERCADO, MD, MS, FACR, Hospital General Mexicali y Universidad Autonoma de Baja California, Mexicali, Mexico. E-mail: ulisesmercado@uabc.mx

1. Mendell JR. Approach to the patient with muscle disease. In: Braunwald E, Fauci AS, Kasper DL, et al, editors. Harrison's principles of internal medicine. 15th ed. New York: McGraw-Hill; 2001:2520-4.

2. Perlman SG, Barth WF. Polymyositis, breast carcinoma, and interstitial lung disease. J Rheumatol 1980;7:348-52.

3. Pearson CM. The incidence and type of pathological alterations observed in muscles in routine autopsy survey. Neurology 1959;9:757-66.

We read with interest the article of Ruffatti, et al concerning autoantibodies to proteinase 3 and myeloperoxidase in systemic sclerosis (SSc)¹. In their study of 115 patients with SSc, they found that antibodies to proteinase 3 (PR3-antineutrophil cytoplasmic antibodies) as well as antibodies to myeloperoxidase (MPO-ANCA) might be detected in some SSc sera. Recently we also investigated SSc, and we now confirm this finding.

Sera from 11 patients with SSc were assayed by indirect immunofluorescence (IIF) on in-house ethanol-fixed normal human neutrophils and commercial formalin-fixed neutrophils, and on HEp-2 cells (The Binding Site, Birmingham, UK). All sera were tested by direct ELISA kits (The Binding Site) against PR3, MPO, bactericidal/permeability increasing protein (BPI). In-house ELISA against lactoferrin and human neutrophil elastase were also performed as described².

Table 1 gives the results. Three of the 11 sera produced perinuclear/ nuclear staining pattern on ethanol-fixed neutrophils. When these sera were retested on formalin-fixed neutrophils granular cytoplasmic fluorescence was observed in 2 sera, and these sera were defined as p-ANCA positive. ELISA results revealed that 5 of the 11 sera contained ANCA directed specifically against the following neutrophil antigens: MPO (n = 2), PR3 (n = 2), BPI (n = 1), and human neutrophil elastase (n = 1). One serum contained ANCA against PR3 and BPI simultaneously. Only MPO-ANCA positive sera were p-ANCA positive by IIF.

Table 1. ELISA and IIF results for ANCA testing in 11 patients with SSc. IIF used ethanol-fixed (EF) and formalin-fixed (FF) neutrophils as substrates for detection of ANCA and HEp-2 cells for detection of ANA.

Of note, the patient with PR3- and BPI-ANCA was repeatedly positive for these antibodies and clinically showed lung fibrosis and pulmonary hypertension, but no renal involvement. No study patient had any symptom or sign of secondary renal disease.

Our small study indicates that the IIF results did not appear to predict the occurrence of specific ANCA in patients with SSc, in agreement with the findings of Ruffatti, et al¹. Further studies are needed to determine whether autoantibodies to several neutrophil antigens are present in SSc and whether these antibodies are associated with some clinical features.

IRENA M. MANOLOVA, MD; MARIA DANCHEVA, MD, University Hospital, Faculty of Medicine, Thracian University, 6000 Stara Zagora, Bulgaria.

1. Ruffatti A, Sinico RA, Radice A, et al. Autoantibodies to proteinase 3 and myeloperoxidase in systemic sclerosis. J Rheumatol 2002;29:918-23.

2. Manolova I, Dancheva M, Halacheva K. Antineutrophil cytoplasmic antibodies in patients with systemic lupus erythematosus: Prevalence, antigen specificity and clinical associations. Rheumatol Int 2001;20:197-204.

We thank Dr. Manolova and Dr. Dancheva for their interest in our article¹. The results they report confirm that proteinase 3 (PR3)-antineutrophil cytoplasmic antibodies (ANCA) as well as myeloperoxidase (MPO)-ANCA may be detected in some patients with systemic sclerosis (SSc). Moreover, the lack of correlation between their ELISA and indirect immunofluorescence (IIF) findings is in agreement with our data. Further, in addition to the classical p-ANCA pattern, a perinuclear/nuclear staining pattern on ethanol-fixed and negative staining on formalin-fixed neutrophils was found in their scleroderma sera. This too is in keeping with our findings when SSc sera were recently reexamined with IIF on ethanol- and formalin-fixed human neutrophils (Menarini, Inova Diagnostics, San Diego, CA, USA)^2,3. Indeed, matched interpretations by 3 different observers resulted in the same ANCA pattern in 18 out of 115 SSc sera (15.65%). To our knowledge that particular ANCA staining, defined as an atypical p-ANCA pattern, has never been described in scleroderma sera. Its coarse perinuclear fluorescence on ethanol-fixed neutrophils was difficult to make out, because it was always associated with nuclear fluorescence and in particular with a fine speckled pattern in 16 out of 18 positive sera (88.89%) and with a speckled staining in 2 (11.11%). The high titer of anti-topoisomerase I antibody causing a fine speckled pattern on ethanol-fixed neutrophils prevented our observing the perinuclear fluorescence of the atypical p-ANCA pattern, which was more evident in the diluted sera and when it was associated with speckled staining of anticentromere antibody (Figure 1).

Figure 1. IIF test on ethanol-fixed neutrophils shows an atypical p-ANCA pattern, characterized by a coarse fluorescent ring confined to the perinuclear zone. Speckled nuclear fluorescence due to anticentromere antibodies is also evident (original magnification ´1000).

Prevalences or mean values of some clinical and serological features of atypical p-ANCA positive patients were compared by Fisher's exact test and the Mann-Whitney U test with those of atypical p-ANCA negative patients, and no significant difference was found between the 2 groups (Table 1). In particular, no statistically significant association was observed between the atypical p-ANCA pattern and antibodies to PR3, MPO, and cathepsin G antigens. The relationship between atypical p-ANCA staining and antibodies to other neutrophil antigens and well defined clinical features in scleroderma patients needs further investigation if the significance of this particular ANCA fluorescence pattern is to be determined.

Table 1. Comparison of clinical and serological features of patients with an atypical p-ANCA positive pattern and those with atypical negative pattern.

AMELIA RUFFATTI, MD, Associate Professor of Rheumatology; PANAGIOTIS GRYPIOTIS, PhD, Research Biologist; SILVANO TODESCO, MD, Professor of Rheumatology, Department of Medical and Surgical Sciences, Rheumatology Unit, University of Padova, Via Giustiniani 2, 35128 Padova, Italy. E-mail: amelia.ruffatti@unipd.it

1. Ruffatti A, Sinico RA, Radice A, et al. Autoantibodies to proteinase 3 and myeloperoxidase in systemic sclerosis. J Rheumatol 2002;29:918-23.

2. Wiik A. Delineation of a standard procedure for indirect immunofluorescence detection of ANCA. Acta Pathol Microbiol Immunol Scand 1989;97 Suppl:12-3.

3. Radice A, Vecchi M, Bianchi MB, Sinico RA. Contribution of immunofluorescence to the identification and characterization of anti-neutrophil cytoplasmic autoantibodies. The role of different fixatives. Clin Exp Rheumatol 2000;18:707-12.