Review
DERMATOMYOSITIS
JEFFREY P, CALLEN, M.D., F.A.C.P.
Dermatomyositis is a systemic disorder with prominent cutaneous features.^"^ With the exception of the characteristic rash and the association of dermatomyositis with malignancy, the condition is inseparable from polymyositis. Both of these conditions will be reviewed, stressing the importance of using the recent diagnostic criteria, the relationship of dermatomyositis to internal malignancy and a practical guide to the therapy of myositis. Criteria for Diagnosis'"^
The critieria for the diagnosis of myositis was first outlined systematically in 1975 by Bohanand Peter (Table 1).'The importance of these criteria cannot be overemphasized, particularly when evaluating study results from myositic patients. The patient with myositis has a progressive proximal muscle weakness over a period of months. Occasionally, the myositis may progress very rapidly. Symmetry of muscle involvement is present in almost all cases. The patient's initial complaint will usually be an inability to rise from a squatting position or an inability to raise the arms above the head. The distal muscles can become involved, but this only happens late in the disease course. Address for reprints: leffrey P. Callen, M.D., Department of Dermatology, University of Louisville School of Medicine, 323 East Chestnut Street, Louisville, KY 40202.
From the University of Louisville School of Medicine, Division of Dermatology, Louisville, Kentucky
Laboratory tests confirming muscle disease are necessary and also help to rule out other disease states. Muscle enzymes are usually elevated, most notably the creatinine phosphokinase (CPK), aldolase, serum glumateoxalate transaminase (SGOT) and/or latic dehydrogenase (LDH). These enzymes may be elevated in other neuromuscular disorders and provide sensitive but nonspecific evidence of myositis. Evidence of other organ involvement as a source of enzyme elevation must always be considered. Besides muscle, CPK may also be derived from the myocardium, LDH may come from the liver, red blood cells, or myocardium, and SGOT may be derived from the liver or myocardium. The muscle biopsy results should be consistent with dermatomyositis (DM) or polymyositis (PM). Typical features include fiber necrosis regeneration of fibers, centralization of nuclei and an inflammatory infiltrate. The muscle biopsy results may be relatively normal in the face of active disease, possibly related to sampling error. Also, the muscle biopsy helps to rule out other possible causes of myositis, such as sarcoidosis. Lastly, evidence of mus-
0011 -9059/79/0700/0423/$01.05 © International Society of Tropical Dermatology, Inc.
423
424
INTERNATIONAL JOURNAL OF DERMATOLOGY Table 1. Criteria for Diagnosis of Dermatomyositis—Polymyositis
1. Progressive symmetrical proximal muscle weakness 2. Musclf biopsy consistent with myosilis a. b. c. d. e.
Fiber necrosis Regeneration Sarcolemmal nuclei (centralization) Inflammatory infiltrate Perifascicular atrophy
3. Elevated muscle enzymes (CPK, SGOT, LDH, Aldolasel 4. Abnormal electromyogram a. b. c. d.
Positive or sharp waves Insertional Irritability Fibrillations Short polyphasic motor units
e. Lack of neuropathy 5. Culaneous disease a. b. c. d.
FHeliotrope Gottron's papules Pholodistribution of poikiloderma Periungual telangiectasias
cle disease may be seen on an electromyography (EMG). This study should always be accompanied by nerve conduction studies to rule out neuropathic disease. The typical EMG will show fibrillations, short polyphasic motor units, muscular irritability on insertion of the needles and positive waves. When the patient's condition is accompanied by cutaneous disease, the diagnosis of dermatomyositis should be considered. The typical changes are usually Gottron's papules and a heliotrope rash. Gottron's papules are atrophic papules or plaques over the knuckles (Fig. 1), and are believed to be pathognomonic of DM. The heliotrope rash is an edematous, violaceous to erythematous rash of the eyelids (Fig. 2), particularly the upper eyelids. Other cutaneous characteristics of DM include: a poikilodermatous rash in exposed areas (Fig. 3); periungual telangiectasias and cuticullar changes; a photosensitive eruption similar to that seen with lupus erythematous and urticaria. These conditions may also occur in other con-
|uly-August 1979
Vol. 18
nective tissue disorders or in cutaneous lymphomas. Other clinical features that commonly accompany dermatomyositis or polymyositis hut are not part of the criteria are Raynaud's phenomenon, arthralgias or occasionally arthritis. The presence of joint signs should alert the clinician to the possibility of an overlap syndrome. Raynaud's phenomenon is more commonly seen, and in some series, up to one-third of the patients experience this phenomenon. The criteria as outlined are helpful in establishing confidence limits for the diagnosis of myositis (Table 2). The diagnosis of dermatomyositis is based on the presence of compatible and/or typical cutaneous disease. The diagnosis is considered definite when all four criteria for muscle disease are present; probable with three criteria; possible with one or two criteria. In certain cases, the typical rash may occur without evidence of initial muscle disease, and these cases are referred to as dermatomyositis sine myositis (this diagnosis can only be made retrospectively). Children and adolescents with DM experience similar cutaneous and muscular manifestations as adults, but at times their disease may be more acute in its onset. The disease is often self-limited; however, profound muscle weakness and atrophy may develop, residual contractures may occur, or calcinosis of subcutaneum may develop, residual contractures may occur, or calcinosis of subcutaneum or muscles can be extensive. These complications may lead to prolonged, and in some cases, permanent disability. In addition, children often have other evidence of systemic disease such as bowel infarctions or perforations, and/or retinopathy. These findings rarely complicate the adult form of DM. Differential Diagnosis'-'' Before a diagnosis of dermatomyositis or polymyositis is confirmed, other causes ot muscle disease must be considered and ruled out. The tests used in the criteria are helpful, but additional historical and laboratory evi-
No. 6
DERMATOMYOSITIS
Callvn
425
dence are necessary. Neurologic disease is ruled out using nerve conduction studies. Muscular dystrophies may be ruled out by the patient's family history. Ingestion of drugs and toxic chemicals, particularly alcohol, must be looked for historically. Endocrine disorders such as thyrotoxicosis, Cushlng's disease, myxedema, or diabetes must be evaluated. Also myasthenia gravis should be ruled out. The EMG will usually be helpful in this case. Classification of DermatomyositisPolymyositis' ^
Separate classifications for DM and PM are necessary since the adult and childhood forms vary etiologically. I believe the adult form should be divided into dermatomyositis, polymyositis and overlap syndrome. Etiology
Childhood dermatomyositis.''-^'' In addition to the muscular and skin changes, children often demonstrate multiple organ Involvement. Bowel infarctions with perforation have been reported on several occasions, and are probably caused by a necrotlzing vasculitis.^""'" Occasionally such bowel involvement is fatal. Retinopathy has also been reported in childhood D M . " - ' ^ The retinopathy may lead to a loss of vision, believed to be a result of retinal vasculitis. Although the etiology of childhood DM is unknown, immune complex disease and viral disease have been postulated as causes. Dermatomyositis in children is believed by Banker to be a Type III hypersensitivity reaction (Gel-Coombs classification), with manifestations thought to be due to vasculitis. Other authors have found multiple types of viral particles in the muscle of patients with Q/y^ 13-17 Possibly, the disease is due to an immunecomplexreaction toa viral infection. Adult dermatomyositis-polymyositis. The cause and pathogenesis of adult myositis is not fully understood. Multiple factors may be involved, and alterations in the immune system are probably essential to the understanding of the disease process.
Fig. I. Top, Gottron's papules. Fig, 2. Bottom, heliotrof>e rash in dermatomyosilis.
Immune complex disease may be active in cases associated with hepatitis B "*• '^ or other collagen disorders, particularly lupus ery-
Flg, 3. Poikiloderma seen w i t h a flare of dermatomyositis on the patient's chest.
426
INTERNATIONAL lOURNAL OF DERMATOLOGY
Table 2, Confidence Limits for Diagnosis Dermatomyositis Definite—3 or 4 criteria + rash Probable—2 criteria + rash Possible^! criterion + rash Sinmyositis—rash only Polymyositis Definite—4 criteria Probable^3 criteria Possible—2 criteria
thematosus,^ vasculitis^" (urticarial or polyarteritis) and rheumatoid arthritis. There have been reports of antimyoglobin antibodies and occasionally immune complexes, but the levels do not correlate with disease Cell mediated immunity probably has a much more important role in adult disease than in the childhood form of DM.""3** Dawkins has pointed out the similarities of myositis to ex peri mental-a u toa llergic myositis, which is seen when animals are immunized with muscle and Freund's adjuvant.^^ In experimental autoallergic myositis weakness, enzyme elevation, typical histoiogical and typical electromyographic changes are found. Development of the disease may be blocked by immunosuppressive agents. Antimuscle antibodies are formed secondarily in this process. Others have shown altered cell mediated immunity in polymyositis and dermatomyositis. A lymphotoxin directed against muscle was found by Johnson et al.^' Although internal malignancy is seen in dermatomyositis, the pathogenesis of this re-
July-August 1979
Vol. 18
lationship is not clear. Neither immune complex or cell mediated immune phenomenon has been demonstrated adequately. Internal Manifestations of Myositis
Patients with dermatomyositis or polymyositis may have other manifestations of their disease besides those occurring in the muscle and skin. In addition to the relationship of internal malignancy (which will be discussed later), DM/PM has also been associated with pulmonary disease, hepatitis, vasculitis, glomerulonephritis, cardiac disease, esophageal dysfunction and eye disease. Each of these conditions occurs in isolated cases, but a complete knowledge of the complications is necessary in the care of the DM-PM patient. The incidence of pulmonary disease in DM-PM is not known.^'"^^ Pulmonary disease can be caused by one of several mechanisms (Table 3). Only the diffuse interstitial lung disease is a primary process.^^-^^ It may be manifested by dyspnea, cough or hypoxemia. The pathology is that of diffuse interstitial fibrosis, similar to that seen in other collagen-vascular disorders (particularly rheumatoid arthritis). The mechanism of interstitial lung disease is not known, but a cell mediated immune reaction against lung tissue may be involved.^^ Schwarz et al. have recently reviewed interstitial lung disease in patients with DM-PM and found that corticosteroids
Table 3. Causes of Pulmonary disease with Myositis 1. 2. 3. 4. 5.
Diffuse interstitial fibrosis Aspiration pneumonia Hypoventilation due to weakness Opportunistic infections Drug-related pneumonitis
Fig. 4, Cuticular changes in dermatomyositis. Noli the prominent periungual telangiectasias.
No. 6
DERMATOMyoSITIS
Callen
427
Table 4, Dermatomyositis and Malignancy
Patienl
Year of Diagnosis of DM
Localion and Type of Malignancy
Year ol Diagnosis ol' Malignancy
Date and Cause of Death
1
1962
Colon adenocarcinoma
1962
1962—metastatic disease
2
1967
Breast adencxarcinoma
!965
1967—metastatic disease
3
1971
unknown primary
1972
1972—metastatic disease
4
1974
unknown primary adenocarcinoma
1974
1974—meningitis
5
1960
unknown primary adenocarcinoma
1960
1960—metastatic disease
Adapted from reference 43,
seem beneficial in .50% of the patients.^^ other causes of pulmonary disease are secondary to weakness {aspiration, or hypoventilation), or secondary to therapeutic agents (opportunistic infections, or drug-induced pneumonitis), Hepatitis B has been associated with dermatomyositis or polymyositis."*-'" In one case, immune complexes of hepatitis associated antigen and antibody may have been involved in the initiation of dermatomyositis. In the other case, the authors believed that the hepatitis symptoms simulated those of DM.^^ This is an extremely rare situation, and the relationship may suggest that some cases of adult DM are related to vasculitis. As mentioned earlier, vasculitis has occasionally been reported in patients with DM-PM. Callen and Dubin reported a case of uticarial vasculitis that preceded the symptoms of PM.^" This rare association also suggests that in certain cases immune complex vasculitis may be involved in the pathogenesis of DM-PM. Recently Dyck et al.^* have reported five patients with PM who had focal glomerulonephritis, with asymptomatic proteinuria present in each case. Immunoglobulins were present in the renal biopsy specimen, suggesting that immune complex disease may be a factor. They also suggested that the incidence
of renal disease may be as high as 12% in patients with PM. Patients with myositis (DM-PM) may also demonstrate cardiac abnormalities.^-^'^^-^^ Gottdiener et al.^^ have recently reported 21 cases of dermatomyositis or polymyositis with evidence of cardiac dysfunction. Using noninvasive studies, they found increased cardiac performance similar to a high out-put state. Also mitral valve prolapse was found in 65% of the patients examined—this may be asymptomatic. Lastly, electrocardiographic abnormalities were found in 52% of cases and included conduction abnormalities and arrhythmias. In contrast, Pearson and Bohan have reported a 23% incidence rate of cardiac disease usually associated with polymyositis.^ The pathophysiology of cardiac involvement is unknown. Although death rarely occurs, the high incidence of cardiac abnormalities should be recognized.^^ Esophageal dysfunction may occur in patients with pure DM-PM, although rarely. Esophageal involvement is much more common in patients with myositis and overlap syndrome. Decreased motility appears to be theonly significant finding, and corticosteroid therapy rarely benefits this complication. Lastly, DM-PM has been associated on many occasions with retinopathy that may progress to blindness."-'^ Most cases of re-
428
INTERNATIONAL IOURNAL OF DERMATOLOGY
tinopathy occur in children or adolescents and probably represent a manifestation of diffuse vasculitis. This complication may be steroid resjionsive. Myositis and Malignancy'""^^
Dermatomyositis has long been recognized to be associated with internal malignancy.'''^"'"' There does not appear to be an increased incidence of malignancy in cases of myositis overlapped with other connective tissue disorders.••^'•*^ However, the relationship of polymyositis and malignancy is less certain. In 1975, Bohan and Peter suggested that the relationship be re-examined since many of the reported cases failed to meet the criteria for the diagnosis of myositis. In 1976, Barnes extensively reviewed the world's literature concerning this relationship'*'; however, she failed to use any predefined criteria for inclusion ot cases in her study. She speculated that the patients were older than those with uncomplicated DM and that ovarian and gastric tumors were more common,and that there was a significant relationship between DM and malignancy. Callen etal."'^ pointedout some of the fallacies of her study, particularly since there are many cases of DM and malignancy that go unreported, and since there were polymyositic patients included in her study. In a recent paper by Bohan et al.^ 153 cases of DM-PM were analyzed and and 8.5% incidence rate of internal malignancy was found.^ In their review, however, they included 11 patients with childhood DM, and 32 patients with overlap syndromes. Therefore, the true incidence in adults with DM-PM is closer to 12%. Also in their study, the DM to PM ratio of associated malignancy was equal. This is contrary to all previously published studies. In my recent study of 58 cases of definite or probable DM-PM (27 DM, 31 PM), the incidence of malignancy was found to be significantly higher in DM patients (25%) than that found in PM patients (< 3%).""-^ These patients were carefully reviewed according to the
luly-Augiist 1979
Vol. 18
criteria and exclusions suggested by Bohan and Peter. The nature of the relationship of malignancy and DM is not known. The malignancy may precede, coincide with, or follow the onset of the myositis; also the myositis may resolve when the tumor is removed. Many cases of late onset of malignancy have been reported (up to 13 years).•""^•' This type of distant relationship may not be more than coincidental. In five of our cases, the malignancy or metastatic disease occurred at the time ofthe diagnosis ofthe myositis (Table 4). No latecasesof malignancy were found in our study,•'^ which included average follow-up of 8.3 years. It is important to address the problem ofthe malignancy evaluation in patients with myositis. First, the patients should be carefully examined for evidence of cutaneous disease. When this is lacking, the association with malignancy is so tenuous that workup is not indicated. In the presence of a rash, the resolution of the problem is still controversial. Several authors have reported malignancies in myositic patients that are discovered by specialized tests.-^ Moss and Hanetin-'-* have addressed this problem by analyzing 28 patients with dermatomyositis (diagnosed by criteria of Bohan and Peter). None of their patients was found to have a malignancy by the use of radiographic "screening" tests including upper gastrointestinal series (UGI), barium enema (BE), intravenous pyelogram (IVP), chest x-ray, liver scans, or pancreatic scans. The patients with malignancy in their group either had a history of malignancy or were discovered based on symptomatology. In our seriesof 58 patients, none was found on the basis of similar screening tests.^^ In one case, the diagnosis of malignancy was found on the basis of a positive stool examination for blood. Similarly, Rowland et al.*^ have concluded that "if the patient has been properly examined (including pelvis and rectum) and if chest film and routine blood studies have been performed, the 'search' is almost never
No. 6
DERMATOMYOSITIS
fruitful in the absence ot appropriate symptoms. . . ." Complete history and physical examination with "routine" admission laboratory evaluation are probably sufficient evaluation. However, certain authors still teel compelled to suggest full evaluation, since they have seen cases that were otherwise undetectable.^ Another disturbing factor is the continued reporting of cases claiming that occult malignancy may be discovered by radiographic evaluation in the supposed abscence of symptoms. Marsh reported a case of polymyositis associated with carcinoma of the cecum, which he suggests was discovered by barium enema.'** However, in his case report, the man was noted to have had a recent change in bowel habits. In actuality, these symptoms vvouid have suggested that a coIonic x-ray should have been performed. In conclusion, DM is associated with malignancy in adults, whereas polymyositis is not. The myositis may be more resistant to therajjy in cases associated with malignancy. Spec ialized tests are of limited value tor detection of occult malignancy, Careful history and physical examination should direct the tests ordered. In patients who do not respond to therapy, a more extensive evaluation may be indicated, and in patients with a history of previous malignancy who develop DM, a thorough evaluation for recurrence is indicated. Prognosis o f D M - P M ^'••"
Prognosis of DM-PM is altered by several factors, including the age of the patient, the presence of severe muscular disease, the presence of malignancy, and/or the presence of complicating factors. In a recent report on survival of patients with polymyositis (including dermatomyositis). Carpenter et al.^" showed that the severity of initial disease and the presence of dysphagia were poor prognostic signs. Children with DM may have a better prognosis than adults, since often the disease is
Calhn
429
"^-' However, in children, severe weakness may lead to residual weakness, or contractures. Also the higher incidence of calcinosis can lead to more severe involvement. Corticosteroids appear to be prognostically beneficial in children, because they may decrease the calcinosis and improve the weakness. Reported prognosis varies depending on whether malignancy was present or not.'*'' Some studies have not shown differences due to the presence or absence of malignancy.^ In our study of 58 patients, there was no difference in survival between DM and PM when the cases ot" malignancy were excluded.''' However, there was a statistically significant lowering of survival in DM when malignancy was included. Malignancy appears to be a very poor prognostic sign. The presence of complicating factors also appears to affect adversely the survival rate of patients with DM-PM. Pulmonary involvement due to weakness or t'ibrosis is a poor prognostic factor,^" as is dysphagia,^^-^" possibly due to increased incidence of aspiration pneumonitis. There have not been enough cases of cardiac disease, nephritis and/or hepatitis to analyze their effects on survival. Gottdieneretal.^^ believe that the presence of cardiac abnormalities was common and probably did not alter survival. Evaluation of the Myositis Patient
Careful evaluation of the patient with myositis is necessary prior to institution of therapy. The physician must be certain that he/she is dealing with DM-PM and knows which complicating factors are involved. A thorough history is the key. The location ol the weakness and its functional extent should be noted. Other causes of myositis or myopathy should be ruled out, particularly toxic ingestants such as alcohol, clofibrate, etc; or familial disease. Historical evidence of other collagen-vascular disorders should be sought. Dyspnea and dysphagia should be
430
INTERNATIONAL tOURNAL OF DERMATOLOGY
Table 5, The Relationship of Dermatomyositis to Malignan(y Coincidenlal Occurrences 1, DM may precede tumor by many years 2, DM may improve after tumor removal but may not relapse wiih tumor reappearance 3, DM may follow tumor Probable Related Eactors 1. DM may improve with tumor therapy and relapse when tumor recurs 2. DM mayoccurwith presence of tumor or metastatic disease 3. DM may improve with adjuvant therapy for tumor (i.e,, hypophysectomy in breast cancer)
noted, since both have adverse effects on survival. A previous history of malignancy should be noted since the presence of metastatic disease with the myositis can occur. Physicial examination should be thorough—it can determine the extent of muscular disease and the patient's functional capacity. Eurthermore, a careful cutaneous examination by a physician knowledgeable in the skin changes of DM should be performed. The presence of rash although it does not affect survival, does make the possibility of malignancy much greater. Laboratory evaluation should be more extensive in the presence of the following factors. The history of previous malignancy should alert the physician to possible metastases and a more extensive evaluation should be carried out. In addition, patients who fail to respond to therapy should have a more extensive evaluation. Lastly, certain patients may present with a typical rash only, in the absence of myositis (dermatomyositis sine myositis).^'' These patients must be reevaluated and examined for evidence of muscle involvement periodically.^'' Therapy 45.56-65 The therapy for DM-PM is at best controversial. A cornerstone in the therapy is the use of systemic corticosteroids; however, there is no prospectively controlled evaluation of this type of therapy. The myositis may have pe-
luly-Au^ust 1979
Vol, 18
riods of spontaneous remissions and exacerbations that cannot be analyzed without a controlled population. Observations made prior to the use of steroids are not valid since they do not take into account other therapeutic advances such as antibiotics, respirators, intensive care units, etc. The results with steroids have also varied greatly with each author. In a recent review. Carpenter et al.*** analyzed the differences between low and high dose steroid therapy in age, sex, muscle findings, presence of dysphagia and presence of skin rash matched groups. They found no differences based on the steroid dosage in these patients, and concluded that corticoids were symptomatically beneficial and should be used. Rowland et al."*^ have similarly concluded that corticoids were at least of symptomatic value, and no conclusions were drawn as to whether they were of prognostic value. Sullivan et al.^' have shown that in children, corticosterDids will improve symptoms, decrease residual weakness, improve survival and decrease the incidence of severity of calcinosis. This ispossibly related to the differing pathogenesis of DM in children (vasculitis of possible immune complex origin!. In patients who are steroid-resistant, immunosuppressive therapy has been advocated."'^•^'^"''^ Methotrexate, cyclophosphamide or azothioprine have been the most frequently used agents. As with corticosteroids, no controlled studies exist which confirm the benefits of immunosuppressives. Metzger et al.^** reported improvement in 17 of 22 patients, and in some of their patients, the steriod dosage could be lowered or withdrawn. The most common drug they used was methotrexate. Similarly, in a recent case reported by Giannini and Callen,^^ methotrexate appeared to allow lowering ofthe steroid dosage. Rowland et al.''^ in their review of this subject, found that 48 of the 66 patients reported had benefited from the immunosuppressive therapy. They concluded that in patients with severe disease (incapacitating or life-threatening) the use of immunosuppres-
No. 6
DERMATOMYOSITIS
sives was justified; however, it is not known whether these drugs are safer or more dangerous than corticosteroids. The association of malignancy with DM is well established. In several reports, tumor removal led to resolution of the DM.^'''*^-^^ In our study, tumor therapy did not benefit the myositisof any of the patients"; however, our group of tumor cases is small. Rowland etal.'*^ •have summarized the relationship of malignancy and myositis, and point out that the relationships may vary greatly. Tabie 5 indicates my experience with the possible relationship to tumor therapy. In summary, corticosteroids, although not of proven benefit, should be used to improve symptoms and possibly improve survival. The dosage should be dictated by the clinical situation—not by dogma. If improvement is not noted, then an immunosuppressive agent should be used. Although no agent is of proven benefit, my choice is methotrexate given orally. Tumor therapy should be directed accordingly. Physical therapy may be helpful to prevent contractures. In addition, complicating factors and other disorders such as collagen-vascular disease should be treated appropriately. Once therapy has been initiated, reevaluation of the disease activity is essential. Cutaneous disease may or may not reflect the course of the muscular disease. Weakness may persist in patients and may not indicate activity. EMG or muscle biopsy are cumbersome tests and on occasion can be negative with active myositis. The most reliable means of following the disease is by physical examination combined with the measurement of a muscle enzyme, usually the CPK. Vignos and Goldwyn^** have suggested that creatinuria is more sensitive in following patients; however, this test is much more cumbersome for the patient to carry out. When the CPK level decreases, the therapeutic agents may be tapered; when the CPK level increases, this may mean a relapse of the myositis and therapy should be more aggressive.
Callers
431
Summary
Dermatomyositis and polymyositis are diseases which must be carefully defined in each patient. Criteria such as those suggested by Bohan and Peter will help define the disease and exclude other possible causes of myositis. Immunological factors are probably involved in the pathogenesis of the disease, although varied types of injury may manifest in clinically similar disease. Dermatomyositis, not polymyositis, is related to internal malignancy in adults; however, an extensive malignancy evaluation is not indicated. Therapy with corticosteroids will improve the quality of life, will prevent contractures and calcinosis and may improve the chance of survival. In cases where steroids are ineffective, immunosuppressives may be helpful. Drug Names azathioprine: Imuran cyclophosphamide; Cytoxan
References 1, Bohan, A., and Peter, j . B.: Polymyositis and dermatomyositis (two partsi. N, Engl, |, Med, 292:344, 403, 1975. 2, Bohan, A., Peter, |. B,, Bowman, R, L., et al.: A computer-assisted analysis of 153 patients with polymyositis and dermatomyositis. Medicine 56:255, 1977, 3, Pearson, C, M.. and Bohan, A.: The spectrum of polymyosilis and dermatomyositis. Med. Clin. North Am. 61:439, 1977. 4, Pearson, C. M.: Polymyositis and dermatomyositis. Bull. Rheum. Dis. 12:269, 1962, 5, Tuffanelli, D, L,: Connective tissue diseases. In: Yearbook ot Dermatology, 1978, Edited by Malkinson, F. D., and Pearson, R, W, Chicago, Yearbook Medical Publishers. 1978, p. 9. b. Samitz. M, H.: Cuticular change in dermatomyositis; a clinical sign. Arch, Dermatol, 1 10:866, 1974, 7, Banker, B, C^,, and Victor, M,: Dermatomyositis (systemic angiopathy) of ( hildhood. Medicine 45:261, 1966, 8, Kornreich, H, K,, and Hanson, V.: The rheumatic diseases ol childhood. Curr, Prob, Pediatr, 4:14, 1974, 9, Banker, B, Q,: Dermatomyosilis of childhood, |, Neuropath, Exp, Neurol, 34:46, 1975. 10. Rose, A. I,: Childhood polymyositis. Am, |, Dis. Child. 127:318, 1974, 1 I. Harrison, S. M,, Frenkel, M,, Grossman, B. |., et al.:
432
INTERNATIONAL IOURNAL OE DERMATOLOGY
Retinopathy in childhood dermalomyositis. Am. ). Opthalmol. 76:786, 1973. 12. Eruman, L. S., Ragsdale, C. C , Sullivan, D. B., et al.: Relinopathy m juvenile dermatomyositis. j , Pediatr. 88:267, 1476. 1 3. Kimur.i, S,, and Eukuyama, Y.: Tubular ( ytoplasmic inclusions in a case of childhood dermatomyosilis with migratory subcutaneous nodules. Eur. J. Pediatr. 125:275. 1977, 14. Mastaglia, E, L,, and Walton, |. N.: Coxsackie viriisl/ke particles in skeletal muscle from a case of polymyositis. j . Neurol. Sci, 11:,'i93, 1970. 15. Hashimoto, K., Robinson, L,, Velayos, E., et al.: Dermatomyositis: electron microscopic, immunologic and tissue culture studies of paramyxovirus-like inc fusions. Art h. Dermatol 103:120, 1971. 16. Landry, M., and Winkelmann, R. K.: Tubular cytoplasmic inclusion in dermatomyositis. Proc, Mayo. Clin, 47:479, 1972. 17. Ben-Bassat, M., and Machtey. I.: Picornavirus-Iike structures in acute dermatomyositis. Am. j . Clin, Pathol. 58:245, 1972. 18. Pittsley,R. A,,Shearn, M. A., and Kaufman, L,: Acute hepatitis B simulating dermatomyositis, jAMA 239:959, 1978. 19. Mihas, A. A., Kirby, |. D.,and Kent, S. P.: Hepatitis B antigen and polymyositis. jAMA 239:221, 1978. 20. Callen, |, P., and Dubin, H. V.: Urticaria and polymyositis. Ar(h. Dc-rmatol. 114:1545, 1978. 21. Nishikai, M., and Homma, M.: Circulating autoantibody against human myoglobin in Polymyositis. )AMA 237:1842, 1977. 22. Reichlin, M., and Mattioli, M.: Description ot a serological reaction characteristic of polymyositis. Clin. Immunol. Immunopathol. 5:12, 1976. 23. Whitaker, j . N,, and Engel, W. K.: Vascular deposits of immunoglobulin and complement in idiopathic inflammatory myopathy. N, Engl. |. Med. 286:333, 1972. 24. Nishikai, M., and Homma, M.: Anti-myoglobin antibody in polymyositis. Lancet 2:1205, 1972, 25. Curie, S., Saunders, M., Knowles, M., et al.: Immunologltal aspects of potymyositis, (). |. Med 40:63, 1971. 26. Penn, A, S.: Myasthemia gravis, dermatomyositis and polymyositis; immunopathological diseases. Adv. Neurol.17:41, 1977. 27. lohnson, R. L., Eink, C. W., and Ziff, M.: Lymphotoxin formation by lymphocytes and muscle in polymyositis. (, Clin. Invest, 51:24,35, 1972. 28. Dawkins, R, L.: Experimental autoallergic myositis, polymyositis and myasthenia gravisacitoimmune muscle disease associated with immunodeficiency and neoplasia. Clin. Exp. Immunol. 21:185, 1975. 29. Dawkins, R. L., and Mastaglia, E. L.: Cellmediated cytotoxicity to muscle in polymyositis. N. Engl. ). Med. 288:434, 1973. 30. Lisak, R. P., andZweiman, B.:Mitogen and muscle extract induced in vitro proliferative responses in myasthenia gravis, dermatomyositis, and polymyositis. J. Neurol, Neurosurg. Psych. 38:512, 1975.
)uly-August 1979
Vol. 18
31, Erazier, A. R., and Miller, R, D.: Interstitial pneumonitis in association with polymyositis and dermatomyositis. Chest 65:403, 1974. i2. Schwarz, M., Matthay, R. A., Sahn, S. A., et al.: Interstitial lung disease in polymyositis and dermatomyositis: analysis ot six cases and review of the literature. Medicine 55:89, 1976. 33. Webb, D, R., and Currie, G. D,: Pulmonary fibrosis masking fwlymyositis. jAMA 222:1146, 1972, 34. Dyck, R, E., Gordon, D. A., Cardella, C. |,, et al.: The glomerulonephritis of polymyositis. ARA Abstract, 1978. 35. Gottdiener, |. S,, Sherber, H. S., Hawley, |.,etal.: Cardiac manifestations in polymyositis. Am. J. Cardiol. 41:1141, 1978. ,36. Lightfoot, P, R., Bharati, S., and Lev M.: Chronic dermatomyositis with intermittent trifasicular block. Chest 71:4t3, 1977, 37. Williams, R. C: Dermatomyositis and malignancy: a review of the literature. Ann. Intern. Med. 50:1174, 1959. 38. Curtis, A. C, Biaylock, H. C, and Harrell, E. R.: Malignant lesions associated with dermatomyositis. jAMA 150:844, 1952. 39. Arundell, E. D.,yyilkinson, R. D., and Haserick, |. R.: Dermatomyositis and malignant neoplasms in adults. Arch. Dermatol, 82:772, 1960. 40. Talbott, |, H.: Acute dermatomyositi spolymyositis and malignancy. Sem, Arthritis Rheum, 6:305, 1977. 41. Barnes, B. E.: Dermatomyositis and malignancy. Ann. Intern. Med. 84:68, 1976. 42. Callen, ), P., Chanda, |. )., and Slawiski, M. S.: Dermatomyositis and malignancy: a contrary viewpoint. Ann, Inlern. Med. 84:751, 1976 (letter). 43. Callen, |. P., Hyla, |. E., Boles, G. G., and Kay, D. R.: The relationship of dermatomyositis and polymyositis to internal malignancy. Submitted for publication. 44. Moss, A, A,, and Hanelin, L. G.: Occult malignant tumors in dermalologic disease. Radiology 123:69, 1977. 45. Rowland, L. P., Clark, C, and Olarle, M.: Therapy for dermatomyositis and poiymyositi s. Adv. Neurol. 17:63, 1977. 46. Marsh, C. B. C: Polymyositis leading to diagnosis and resection of occult localized carcinoma ofthe cecum. South, Med. |. 71:1441, 1978, 47. Logan, R. G,, Bandera, |. M., Mikkelsen, W. M., et al.: Polymyositis: a clinical study, Ann. Intern. Med. 6,5:996, 1966. 48. Medsger, T. A., Dawson, W. N., and Masi, A. T.; The epidemiology Cif polymyositis. Am, |. Med. 715, 1970. 49. Medsger, T. A., Robinson, H., and Masi, A. T.: Eaclors affecting survivorship in polymyositis. Arth, Rheum, 14:249, 1971. 50. Carpenter, |. R., Bunch, T.W., Engel, A. G., et al.: Survival in polymyositis: corticosteroids and risk factors. ). Rheum. 4:207, 1977. 51. Sullivan, D. B., Cassidy, |. T., Petty, R. E., et al.: Prognosis in childhood dermatomyositis, ). Pediatr. 80:555, 1972. 52. Carpenter, S., Karpati, G,, Rothman, S., et al.: The
No. 6
53. 54. 55. 56.
57. 58.
59.
60.
Callvn
DERMATOMYOSITIS
childhood type of dermatomyositis. Neurology 26:9,52, 1976. Lell,M. E., and Swerdlow, M. L.: Dermatomyosilis of c:hildhood. Pediatr, Ann. 203:115, 1977. Krain, L. S.: Dermatomyositis in six patients without initial muscle involvement. Arch, Dermatol. 111:241, 1975, Callen, J. P.; Dermatomyositis-sine-myositis: late occurrence of muscle disease. Submitted for publication. 1979. Winkelmann, R.K., Mulder, D. W., Lambert, E. H.,et al.: Course of dermatomyositis-polymyositis, comparison of untreated and cortisone-treated patients. Proc. Mayo. Clin. 43:545, 1968. Grob, D.: Use of drugs in myopathies. Ann. Rev. Pharm. Toxicol. 16:215, 1976. Metzger, A. L,, Bohan, A,, Goldberg, L, S,, et al,: Polymyositis and dermatomyositis: combined methotrexate and corticosteroid therapy, Ann, Intern, Med. 81:182, 1974, Arnetl, E. C, Whelton, ). C, Zizic, T. M., et al.: Methotrexate tberapy in |X)lymyositis. Ann. Rheum. Dis. 32:536, 1973. Benson, M. D., and Aldo, M. A.: Azathioprine
61. 62. 63. 64. 65. 66. 67.
68.
433
therapy in polymyositis. Arch. Intern. Med. 132:547, 1973. Haas, D. C : Treatment of polymyositis with immunosuppressive drugs. Neurology 23:55, 1973. Currie, S,, and Walton, |. N,: Immunosuppressive therapy in dermatomyositis. |, Neurol. Neurosurg. Psychiatr. 34:447, 1971. lacobs, |. C: Methotrexate and azothioprine treatmen! of childhood dermatomyositis. Pediatrics 59:212, 1977. Dubowitz, V.: Treatment of dermatomyositis in childhood. Arch, Dis, Child. 51:494, 1976. Schaller, ), G,: Dermatomyositis. |. Pediatr. 83:699, 1973. GiannJni, ). M., and Callen, |. P.: Methotrexate therapy of dermatomyositis. Arch. Dermatol. In press. Allan, R. M,, Dykes, P. W,, Harris, O, D,, et al.: Dermatomyositis associated with hepatic secondaries from carcinoma of the colon. Gastroenlerology 62:1227, 1972. Vignos, P. |., and Goldwyn, |.: Evaluation of laboratory tests in diagnosis and management of polymyositis. Am. J. Med. Sci. 263:291, 1972.
The Aniline Dye Problem
The statement has been made that aniline dyes will not cause irritation ofthe skin, even in workmen whose face and hands are constantly covered with them, that the dyes are then in a soluble form; the conclusion follows that dyed stockings, etc., will not cause inflammation ofthe skin, for the colors are then in as insoluble a form as the dyer can make them. It is further said, in the year 1872, arsenic was found in magenta, with which the hosiery was dyed in 6.5%, but that the highest quantity is now under 0.09%. This may betrueof hosiery manufactured at Nottingham and Leicester, to which Mr. Ashwell refers, but it certainly is not true of all dyed stockings. Dr. Edson, ofthe New York Health Department, has called attention to the danger of wearing certain kinds of colored stockings. The dye, on analysis, was found to contain poison—quantities of arsenic and antimony. It has occurred in the experience of nearly every physician to meet with cases of skin irritation directly traceable to the dye in the patient's clothing; but every one is not equally susceptible to the influence of these irritants; because a certain dye-stuff will cause a dermatitis in one individual, it does not follow it will cause it in every case. I opine there must exist a condition ofthe skin that is predisposed to take on inflammation from certain kinds of external irritants. A number of individuals may be exposed to the same influence, a few will be affected, while the others may subject themselves to such irritants with impunity. This is known to be true in the cases of eczema, the parasitic diseases, and dermatoses produced by rhus poisoning.— McCuire, j. C: Dermatoses produced by dyestuffs. j. Cutan. Dis. 5:59, 1887.
DERMATOMYOSITIS
JEFFREY P, CALLEN, M.D., F.A.C.P.
Dermatomyositis is a systemic disorder with prominent cutaneous features.^"^ With the exception of the characteristic rash and the association of dermatomyositis with malignancy, the condition is inseparable from polymyositis. Both of these conditions will be reviewed, stressing the importance of using the recent diagnostic criteria, the relationship of dermatomyositis to internal malignancy and a practical guide to the therapy of myositis. Criteria for Diagnosis'"^
The critieria for the diagnosis of myositis was first outlined systematically in 1975 by Bohanand Peter (Table 1).'The importance of these criteria cannot be overemphasized, particularly when evaluating study results from myositic patients. The patient with myositis has a progressive proximal muscle weakness over a period of months. Occasionally, the myositis may progress very rapidly. Symmetry of muscle involvement is present in almost all cases. The patient's initial complaint will usually be an inability to rise from a squatting position or an inability to raise the arms above the head. The distal muscles can become involved, but this only happens late in the disease course. Address for reprints: leffrey P. Callen, M.D., Department of Dermatology, University of Louisville School of Medicine, 323 East Chestnut Street, Louisville, KY 40202.
From the University of Louisville School of Medicine, Division of Dermatology, Louisville, Kentucky
Laboratory tests confirming muscle disease are necessary and also help to rule out other disease states. Muscle enzymes are usually elevated, most notably the creatinine phosphokinase (CPK), aldolase, serum glumateoxalate transaminase (SGOT) and/or latic dehydrogenase (LDH). These enzymes may be elevated in other neuromuscular disorders and provide sensitive but nonspecific evidence of myositis. Evidence of other organ involvement as a source of enzyme elevation must always be considered. Besides muscle, CPK may also be derived from the myocardium, LDH may come from the liver, red blood cells, or myocardium, and SGOT may be derived from the liver or myocardium. The muscle biopsy results should be consistent with dermatomyositis (DM) or polymyositis (PM). Typical features include fiber necrosis regeneration of fibers, centralization of nuclei and an inflammatory infiltrate. The muscle biopsy results may be relatively normal in the face of active disease, possibly related to sampling error. Also, the muscle biopsy helps to rule out other possible causes of myositis, such as sarcoidosis. Lastly, evidence of mus-
0011 -9059/79/0700/0423/$01.05 © International Society of Tropical Dermatology, Inc.
423
424
INTERNATIONAL JOURNAL OF DERMATOLOGY Table 1. Criteria for Diagnosis of Dermatomyositis—Polymyositis
1. Progressive symmetrical proximal muscle weakness 2. Musclf biopsy consistent with myosilis a. b. c. d. e.
Fiber necrosis Regeneration Sarcolemmal nuclei (centralization) Inflammatory infiltrate Perifascicular atrophy
3. Elevated muscle enzymes (CPK, SGOT, LDH, Aldolasel 4. Abnormal electromyogram a. b. c. d.
Positive or sharp waves Insertional Irritability Fibrillations Short polyphasic motor units
e. Lack of neuropathy 5. Culaneous disease a. b. c. d.
FHeliotrope Gottron's papules Pholodistribution of poikiloderma Periungual telangiectasias
cle disease may be seen on an electromyography (EMG). This study should always be accompanied by nerve conduction studies to rule out neuropathic disease. The typical EMG will show fibrillations, short polyphasic motor units, muscular irritability on insertion of the needles and positive waves. When the patient's condition is accompanied by cutaneous disease, the diagnosis of dermatomyositis should be considered. The typical changes are usually Gottron's papules and a heliotrope rash. Gottron's papules are atrophic papules or plaques over the knuckles (Fig. 1), and are believed to be pathognomonic of DM. The heliotrope rash is an edematous, violaceous to erythematous rash of the eyelids (Fig. 2), particularly the upper eyelids. Other cutaneous characteristics of DM include: a poikilodermatous rash in exposed areas (Fig. 3); periungual telangiectasias and cuticullar changes; a photosensitive eruption similar to that seen with lupus erythematous and urticaria. These conditions may also occur in other con-
|uly-August 1979
Vol. 18
nective tissue disorders or in cutaneous lymphomas. Other clinical features that commonly accompany dermatomyositis or polymyositis hut are not part of the criteria are Raynaud's phenomenon, arthralgias or occasionally arthritis. The presence of joint signs should alert the clinician to the possibility of an overlap syndrome. Raynaud's phenomenon is more commonly seen, and in some series, up to one-third of the patients experience this phenomenon. The criteria as outlined are helpful in establishing confidence limits for the diagnosis of myositis (Table 2). The diagnosis of dermatomyositis is based on the presence of compatible and/or typical cutaneous disease. The diagnosis is considered definite when all four criteria for muscle disease are present; probable with three criteria; possible with one or two criteria. In certain cases, the typical rash may occur without evidence of initial muscle disease, and these cases are referred to as dermatomyositis sine myositis (this diagnosis can only be made retrospectively). Children and adolescents with DM experience similar cutaneous and muscular manifestations as adults, but at times their disease may be more acute in its onset. The disease is often self-limited; however, profound muscle weakness and atrophy may develop, residual contractures may occur, or calcinosis of subcutaneum may develop, residual contractures may occur, or calcinosis of subcutaneum or muscles can be extensive. These complications may lead to prolonged, and in some cases, permanent disability. In addition, children often have other evidence of systemic disease such as bowel infarctions or perforations, and/or retinopathy. These findings rarely complicate the adult form of DM. Differential Diagnosis'-'' Before a diagnosis of dermatomyositis or polymyositis is confirmed, other causes ot muscle disease must be considered and ruled out. The tests used in the criteria are helpful, but additional historical and laboratory evi-
No. 6
DERMATOMYOSITIS
Callvn
425
dence are necessary. Neurologic disease is ruled out using nerve conduction studies. Muscular dystrophies may be ruled out by the patient's family history. Ingestion of drugs and toxic chemicals, particularly alcohol, must be looked for historically. Endocrine disorders such as thyrotoxicosis, Cushlng's disease, myxedema, or diabetes must be evaluated. Also myasthenia gravis should be ruled out. The EMG will usually be helpful in this case. Classification of DermatomyositisPolymyositis' ^
Separate classifications for DM and PM are necessary since the adult and childhood forms vary etiologically. I believe the adult form should be divided into dermatomyositis, polymyositis and overlap syndrome. Etiology
Childhood dermatomyositis.''-^'' In addition to the muscular and skin changes, children often demonstrate multiple organ Involvement. Bowel infarctions with perforation have been reported on several occasions, and are probably caused by a necrotlzing vasculitis.^""'" Occasionally such bowel involvement is fatal. Retinopathy has also been reported in childhood D M . " - ' ^ The retinopathy may lead to a loss of vision, believed to be a result of retinal vasculitis. Although the etiology of childhood DM is unknown, immune complex disease and viral disease have been postulated as causes. Dermatomyositis in children is believed by Banker to be a Type III hypersensitivity reaction (Gel-Coombs classification), with manifestations thought to be due to vasculitis. Other authors have found multiple types of viral particles in the muscle of patients with Q/y^ 13-17 Possibly, the disease is due to an immunecomplexreaction toa viral infection. Adult dermatomyositis-polymyositis. The cause and pathogenesis of adult myositis is not fully understood. Multiple factors may be involved, and alterations in the immune system are probably essential to the understanding of the disease process.
Fig. I. Top, Gottron's papules. Fig, 2. Bottom, heliotrof>e rash in dermatomyosilis.
Immune complex disease may be active in cases associated with hepatitis B "*• '^ or other collagen disorders, particularly lupus ery-
Flg, 3. Poikiloderma seen w i t h a flare of dermatomyositis on the patient's chest.
426
INTERNATIONAL lOURNAL OF DERMATOLOGY
Table 2, Confidence Limits for Diagnosis Dermatomyositis Definite—3 or 4 criteria + rash Probable—2 criteria + rash Possible^! criterion + rash Sinmyositis—rash only Polymyositis Definite—4 criteria Probable^3 criteria Possible—2 criteria
thematosus,^ vasculitis^" (urticarial or polyarteritis) and rheumatoid arthritis. There have been reports of antimyoglobin antibodies and occasionally immune complexes, but the levels do not correlate with disease Cell mediated immunity probably has a much more important role in adult disease than in the childhood form of DM.""3** Dawkins has pointed out the similarities of myositis to ex peri mental-a u toa llergic myositis, which is seen when animals are immunized with muscle and Freund's adjuvant.^^ In experimental autoallergic myositis weakness, enzyme elevation, typical histoiogical and typical electromyographic changes are found. Development of the disease may be blocked by immunosuppressive agents. Antimuscle antibodies are formed secondarily in this process. Others have shown altered cell mediated immunity in polymyositis and dermatomyositis. A lymphotoxin directed against muscle was found by Johnson et al.^' Although internal malignancy is seen in dermatomyositis, the pathogenesis of this re-
July-August 1979
Vol. 18
lationship is not clear. Neither immune complex or cell mediated immune phenomenon has been demonstrated adequately. Internal Manifestations of Myositis
Patients with dermatomyositis or polymyositis may have other manifestations of their disease besides those occurring in the muscle and skin. In addition to the relationship of internal malignancy (which will be discussed later), DM/PM has also been associated with pulmonary disease, hepatitis, vasculitis, glomerulonephritis, cardiac disease, esophageal dysfunction and eye disease. Each of these conditions occurs in isolated cases, but a complete knowledge of the complications is necessary in the care of the DM-PM patient. The incidence of pulmonary disease in DM-PM is not known.^'"^^ Pulmonary disease can be caused by one of several mechanisms (Table 3). Only the diffuse interstitial lung disease is a primary process.^^-^^ It may be manifested by dyspnea, cough or hypoxemia. The pathology is that of diffuse interstitial fibrosis, similar to that seen in other collagen-vascular disorders (particularly rheumatoid arthritis). The mechanism of interstitial lung disease is not known, but a cell mediated immune reaction against lung tissue may be involved.^^ Schwarz et al. have recently reviewed interstitial lung disease in patients with DM-PM and found that corticosteroids
Table 3. Causes of Pulmonary disease with Myositis 1. 2. 3. 4. 5.
Diffuse interstitial fibrosis Aspiration pneumonia Hypoventilation due to weakness Opportunistic infections Drug-related pneumonitis
Fig. 4, Cuticular changes in dermatomyositis. Noli the prominent periungual telangiectasias.
No. 6
DERMATOMyoSITIS
Callen
427
Table 4, Dermatomyositis and Malignancy
Patienl
Year of Diagnosis of DM
Localion and Type of Malignancy
Year ol Diagnosis ol' Malignancy
Date and Cause of Death
1
1962
Colon adenocarcinoma
1962
1962—metastatic disease
2
1967
Breast adencxarcinoma
!965
1967—metastatic disease
3
1971
unknown primary
1972
1972—metastatic disease
4
1974
unknown primary adenocarcinoma
1974
1974—meningitis
5
1960
unknown primary adenocarcinoma
1960
1960—metastatic disease
Adapted from reference 43,
seem beneficial in .50% of the patients.^^ other causes of pulmonary disease are secondary to weakness {aspiration, or hypoventilation), or secondary to therapeutic agents (opportunistic infections, or drug-induced pneumonitis), Hepatitis B has been associated with dermatomyositis or polymyositis."*-'" In one case, immune complexes of hepatitis associated antigen and antibody may have been involved in the initiation of dermatomyositis. In the other case, the authors believed that the hepatitis symptoms simulated those of DM.^^ This is an extremely rare situation, and the relationship may suggest that some cases of adult DM are related to vasculitis. As mentioned earlier, vasculitis has occasionally been reported in patients with DM-PM. Callen and Dubin reported a case of uticarial vasculitis that preceded the symptoms of PM.^" This rare association also suggests that in certain cases immune complex vasculitis may be involved in the pathogenesis of DM-PM. Recently Dyck et al.^* have reported five patients with PM who had focal glomerulonephritis, with asymptomatic proteinuria present in each case. Immunoglobulins were present in the renal biopsy specimen, suggesting that immune complex disease may be a factor. They also suggested that the incidence
of renal disease may be as high as 12% in patients with PM. Patients with myositis (DM-PM) may also demonstrate cardiac abnormalities.^-^'^^-^^ Gottdiener et al.^^ have recently reported 21 cases of dermatomyositis or polymyositis with evidence of cardiac dysfunction. Using noninvasive studies, they found increased cardiac performance similar to a high out-put state. Also mitral valve prolapse was found in 65% of the patients examined—this may be asymptomatic. Lastly, electrocardiographic abnormalities were found in 52% of cases and included conduction abnormalities and arrhythmias. In contrast, Pearson and Bohan have reported a 23% incidence rate of cardiac disease usually associated with polymyositis.^ The pathophysiology of cardiac involvement is unknown. Although death rarely occurs, the high incidence of cardiac abnormalities should be recognized.^^ Esophageal dysfunction may occur in patients with pure DM-PM, although rarely. Esophageal involvement is much more common in patients with myositis and overlap syndrome. Decreased motility appears to be theonly significant finding, and corticosteroid therapy rarely benefits this complication. Lastly, DM-PM has been associated on many occasions with retinopathy that may progress to blindness."-'^ Most cases of re-
428
INTERNATIONAL IOURNAL OF DERMATOLOGY
tinopathy occur in children or adolescents and probably represent a manifestation of diffuse vasculitis. This complication may be steroid resjionsive. Myositis and Malignancy'""^^
Dermatomyositis has long been recognized to be associated with internal malignancy.'''^"'"' There does not appear to be an increased incidence of malignancy in cases of myositis overlapped with other connective tissue disorders.••^'•*^ However, the relationship of polymyositis and malignancy is less certain. In 1975, Bohan and Peter suggested that the relationship be re-examined since many of the reported cases failed to meet the criteria for the diagnosis of myositis. In 1976, Barnes extensively reviewed the world's literature concerning this relationship'*'; however, she failed to use any predefined criteria for inclusion ot cases in her study. She speculated that the patients were older than those with uncomplicated DM and that ovarian and gastric tumors were more common,and that there was a significant relationship between DM and malignancy. Callen etal."'^ pointedout some of the fallacies of her study, particularly since there are many cases of DM and malignancy that go unreported, and since there were polymyositic patients included in her study. In a recent paper by Bohan et al.^ 153 cases of DM-PM were analyzed and and 8.5% incidence rate of internal malignancy was found.^ In their review, however, they included 11 patients with childhood DM, and 32 patients with overlap syndromes. Therefore, the true incidence in adults with DM-PM is closer to 12%. Also in their study, the DM to PM ratio of associated malignancy was equal. This is contrary to all previously published studies. In my recent study of 58 cases of definite or probable DM-PM (27 DM, 31 PM), the incidence of malignancy was found to be significantly higher in DM patients (25%) than that found in PM patients (< 3%).""-^ These patients were carefully reviewed according to the
luly-Augiist 1979
Vol. 18
criteria and exclusions suggested by Bohan and Peter. The nature of the relationship of malignancy and DM is not known. The malignancy may precede, coincide with, or follow the onset of the myositis; also the myositis may resolve when the tumor is removed. Many cases of late onset of malignancy have been reported (up to 13 years).•""^•' This type of distant relationship may not be more than coincidental. In five of our cases, the malignancy or metastatic disease occurred at the time ofthe diagnosis ofthe myositis (Table 4). No latecasesof malignancy were found in our study,•'^ which included average follow-up of 8.3 years. It is important to address the problem ofthe malignancy evaluation in patients with myositis. First, the patients should be carefully examined for evidence of cutaneous disease. When this is lacking, the association with malignancy is so tenuous that workup is not indicated. In the presence of a rash, the resolution of the problem is still controversial. Several authors have reported malignancies in myositic patients that are discovered by specialized tests.-^ Moss and Hanetin-'-* have addressed this problem by analyzing 28 patients with dermatomyositis (diagnosed by criteria of Bohan and Peter). None of their patients was found to have a malignancy by the use of radiographic "screening" tests including upper gastrointestinal series (UGI), barium enema (BE), intravenous pyelogram (IVP), chest x-ray, liver scans, or pancreatic scans. The patients with malignancy in their group either had a history of malignancy or were discovered based on symptomatology. In our seriesof 58 patients, none was found on the basis of similar screening tests.^^ In one case, the diagnosis of malignancy was found on the basis of a positive stool examination for blood. Similarly, Rowland et al.*^ have concluded that "if the patient has been properly examined (including pelvis and rectum) and if chest film and routine blood studies have been performed, the 'search' is almost never
No. 6
DERMATOMYOSITIS
fruitful in the absence ot appropriate symptoms. . . ." Complete history and physical examination with "routine" admission laboratory evaluation are probably sufficient evaluation. However, certain authors still teel compelled to suggest full evaluation, since they have seen cases that were otherwise undetectable.^ Another disturbing factor is the continued reporting of cases claiming that occult malignancy may be discovered by radiographic evaluation in the supposed abscence of symptoms. Marsh reported a case of polymyositis associated with carcinoma of the cecum, which he suggests was discovered by barium enema.'** However, in his case report, the man was noted to have had a recent change in bowel habits. In actuality, these symptoms vvouid have suggested that a coIonic x-ray should have been performed. In conclusion, DM is associated with malignancy in adults, whereas polymyositis is not. The myositis may be more resistant to therajjy in cases associated with malignancy. Spec ialized tests are of limited value tor detection of occult malignancy, Careful history and physical examination should direct the tests ordered. In patients who do not respond to therapy, a more extensive evaluation may be indicated, and in patients with a history of previous malignancy who develop DM, a thorough evaluation for recurrence is indicated. Prognosis o f D M - P M ^'••"
Prognosis of DM-PM is altered by several factors, including the age of the patient, the presence of severe muscular disease, the presence of malignancy, and/or the presence of complicating factors. In a recent report on survival of patients with polymyositis (including dermatomyositis). Carpenter et al.^" showed that the severity of initial disease and the presence of dysphagia were poor prognostic signs. Children with DM may have a better prognosis than adults, since often the disease is
Calhn
429
"^-' However, in children, severe weakness may lead to residual weakness, or contractures. Also the higher incidence of calcinosis can lead to more severe involvement. Corticosteroids appear to be prognostically beneficial in children, because they may decrease the calcinosis and improve the weakness. Reported prognosis varies depending on whether malignancy was present or not.'*'' Some studies have not shown differences due to the presence or absence of malignancy.^ In our study of 58 patients, there was no difference in survival between DM and PM when the cases ot" malignancy were excluded.''' However, there was a statistically significant lowering of survival in DM when malignancy was included. Malignancy appears to be a very poor prognostic sign. The presence of complicating factors also appears to affect adversely the survival rate of patients with DM-PM. Pulmonary involvement due to weakness or t'ibrosis is a poor prognostic factor,^" as is dysphagia,^^-^" possibly due to increased incidence of aspiration pneumonitis. There have not been enough cases of cardiac disease, nephritis and/or hepatitis to analyze their effects on survival. Gottdieneretal.^^ believe that the presence of cardiac abnormalities was common and probably did not alter survival. Evaluation of the Myositis Patient
Careful evaluation of the patient with myositis is necessary prior to institution of therapy. The physician must be certain that he/she is dealing with DM-PM and knows which complicating factors are involved. A thorough history is the key. The location ol the weakness and its functional extent should be noted. Other causes of myositis or myopathy should be ruled out, particularly toxic ingestants such as alcohol, clofibrate, etc; or familial disease. Historical evidence of other collagen-vascular disorders should be sought. Dyspnea and dysphagia should be
430
INTERNATIONAL tOURNAL OF DERMATOLOGY
Table 5, The Relationship of Dermatomyositis to Malignan(y Coincidenlal Occurrences 1, DM may precede tumor by many years 2, DM may improve after tumor removal but may not relapse wiih tumor reappearance 3, DM may follow tumor Probable Related Eactors 1. DM may improve with tumor therapy and relapse when tumor recurs 2. DM mayoccurwith presence of tumor or metastatic disease 3. DM may improve with adjuvant therapy for tumor (i.e,, hypophysectomy in breast cancer)
noted, since both have adverse effects on survival. A previous history of malignancy should be noted since the presence of metastatic disease with the myositis can occur. Physicial examination should be thorough—it can determine the extent of muscular disease and the patient's functional capacity. Eurthermore, a careful cutaneous examination by a physician knowledgeable in the skin changes of DM should be performed. The presence of rash although it does not affect survival, does make the possibility of malignancy much greater. Laboratory evaluation should be more extensive in the presence of the following factors. The history of previous malignancy should alert the physician to possible metastases and a more extensive evaluation should be carried out. In addition, patients who fail to respond to therapy should have a more extensive evaluation. Lastly, certain patients may present with a typical rash only, in the absence of myositis (dermatomyositis sine myositis).^'' These patients must be reevaluated and examined for evidence of muscle involvement periodically.^'' Therapy 45.56-65 The therapy for DM-PM is at best controversial. A cornerstone in the therapy is the use of systemic corticosteroids; however, there is no prospectively controlled evaluation of this type of therapy. The myositis may have pe-
luly-Au^ust 1979
Vol, 18
riods of spontaneous remissions and exacerbations that cannot be analyzed without a controlled population. Observations made prior to the use of steroids are not valid since they do not take into account other therapeutic advances such as antibiotics, respirators, intensive care units, etc. The results with steroids have also varied greatly with each author. In a recent review. Carpenter et al.*** analyzed the differences between low and high dose steroid therapy in age, sex, muscle findings, presence of dysphagia and presence of skin rash matched groups. They found no differences based on the steroid dosage in these patients, and concluded that corticoids were symptomatically beneficial and should be used. Rowland et al."*^ have similarly concluded that corticoids were at least of symptomatic value, and no conclusions were drawn as to whether they were of prognostic value. Sullivan et al.^' have shown that in children, corticosterDids will improve symptoms, decrease residual weakness, improve survival and decrease the incidence of severity of calcinosis. This ispossibly related to the differing pathogenesis of DM in children (vasculitis of possible immune complex origin!. In patients who are steroid-resistant, immunosuppressive therapy has been advocated."'^•^'^"''^ Methotrexate, cyclophosphamide or azothioprine have been the most frequently used agents. As with corticosteroids, no controlled studies exist which confirm the benefits of immunosuppressives. Metzger et al.^** reported improvement in 17 of 22 patients, and in some of their patients, the steriod dosage could be lowered or withdrawn. The most common drug they used was methotrexate. Similarly, in a recent case reported by Giannini and Callen,^^ methotrexate appeared to allow lowering ofthe steroid dosage. Rowland et al.''^ in their review of this subject, found that 48 of the 66 patients reported had benefited from the immunosuppressive therapy. They concluded that in patients with severe disease (incapacitating or life-threatening) the use of immunosuppres-
No. 6
DERMATOMYOSITIS
sives was justified; however, it is not known whether these drugs are safer or more dangerous than corticosteroids. The association of malignancy with DM is well established. In several reports, tumor removal led to resolution of the DM.^'''*^-^^ In our study, tumor therapy did not benefit the myositisof any of the patients"; however, our group of tumor cases is small. Rowland etal.'*^ •have summarized the relationship of malignancy and myositis, and point out that the relationships may vary greatly. Tabie 5 indicates my experience with the possible relationship to tumor therapy. In summary, corticosteroids, although not of proven benefit, should be used to improve symptoms and possibly improve survival. The dosage should be dictated by the clinical situation—not by dogma. If improvement is not noted, then an immunosuppressive agent should be used. Although no agent is of proven benefit, my choice is methotrexate given orally. Tumor therapy should be directed accordingly. Physical therapy may be helpful to prevent contractures. In addition, complicating factors and other disorders such as collagen-vascular disease should be treated appropriately. Once therapy has been initiated, reevaluation of the disease activity is essential. Cutaneous disease may or may not reflect the course of the muscular disease. Weakness may persist in patients and may not indicate activity. EMG or muscle biopsy are cumbersome tests and on occasion can be negative with active myositis. The most reliable means of following the disease is by physical examination combined with the measurement of a muscle enzyme, usually the CPK. Vignos and Goldwyn^** have suggested that creatinuria is more sensitive in following patients; however, this test is much more cumbersome for the patient to carry out. When the CPK level decreases, the therapeutic agents may be tapered; when the CPK level increases, this may mean a relapse of the myositis and therapy should be more aggressive.
Callers
431
Summary
Dermatomyositis and polymyositis are diseases which must be carefully defined in each patient. Criteria such as those suggested by Bohan and Peter will help define the disease and exclude other possible causes of myositis. Immunological factors are probably involved in the pathogenesis of the disease, although varied types of injury may manifest in clinically similar disease. Dermatomyositis, not polymyositis, is related to internal malignancy in adults; however, an extensive malignancy evaluation is not indicated. Therapy with corticosteroids will improve the quality of life, will prevent contractures and calcinosis and may improve the chance of survival. In cases where steroids are ineffective, immunosuppressives may be helpful. Drug Names azathioprine: Imuran cyclophosphamide; Cytoxan
References 1, Bohan, A., and Peter, j . B.: Polymyositis and dermatomyositis (two partsi. N, Engl, |, Med, 292:344, 403, 1975. 2, Bohan, A., Peter, |. B,, Bowman, R, L., et al.: A computer-assisted analysis of 153 patients with polymyositis and dermatomyositis. Medicine 56:255, 1977, 3, Pearson, C, M.. and Bohan, A.: The spectrum of polymyosilis and dermatomyositis. Med. Clin. North Am. 61:439, 1977. 4, Pearson, C. M.: Polymyositis and dermatomyositis. Bull. Rheum. Dis. 12:269, 1962, 5, Tuffanelli, D, L,: Connective tissue diseases. In: Yearbook ot Dermatology, 1978, Edited by Malkinson, F. D., and Pearson, R, W, Chicago, Yearbook Medical Publishers. 1978, p. 9. b. Samitz. M, H.: Cuticular change in dermatomyositis; a clinical sign. Arch, Dermatol, 1 10:866, 1974, 7, Banker, B, C^,, and Victor, M,: Dermatomyositis (systemic angiopathy) of ( hildhood. Medicine 45:261, 1966, 8, Kornreich, H, K,, and Hanson, V.: The rheumatic diseases ol childhood. Curr, Prob, Pediatr, 4:14, 1974, 9, Banker, B, Q,: Dermatomyosilis of childhood, |, Neuropath, Exp, Neurol, 34:46, 1975. 10. Rose, A. I,: Childhood polymyositis. Am, |, Dis. Child. 127:318, 1974, 1 I. Harrison, S. M,, Frenkel, M,, Grossman, B. |., et al.:
432
INTERNATIONAL IOURNAL OE DERMATOLOGY
Retinopathy in childhood dermalomyositis. Am. ). Opthalmol. 76:786, 1973. 12. Eruman, L. S., Ragsdale, C. C , Sullivan, D. B., et al.: Relinopathy m juvenile dermatomyositis. j , Pediatr. 88:267, 1476. 1 3. Kimur.i, S,, and Eukuyama, Y.: Tubular ( ytoplasmic inclusions in a case of childhood dermatomyosilis with migratory subcutaneous nodules. Eur. J. Pediatr. 125:275. 1977, 14. Mastaglia, E, L,, and Walton, |. N.: Coxsackie viriisl/ke particles in skeletal muscle from a case of polymyositis. j . Neurol. Sci, 11:,'i93, 1970. 15. Hashimoto, K., Robinson, L,, Velayos, E., et al.: Dermatomyositis: electron microscopic, immunologic and tissue culture studies of paramyxovirus-like inc fusions. Art h. Dermatol 103:120, 1971. 16. Landry, M., and Winkelmann, R. K.: Tubular cytoplasmic inclusion in dermatomyositis. Proc, Mayo. Clin, 47:479, 1972. 17. Ben-Bassat, M., and Machtey. I.: Picornavirus-Iike structures in acute dermatomyositis. Am. j . Clin, Pathol. 58:245, 1972. 18. Pittsley,R. A,,Shearn, M. A., and Kaufman, L,: Acute hepatitis B simulating dermatomyositis, jAMA 239:959, 1978. 19. Mihas, A. A., Kirby, |. D.,and Kent, S. P.: Hepatitis B antigen and polymyositis. jAMA 239:221, 1978. 20. Callen, |, P., and Dubin, H. V.: Urticaria and polymyositis. Ar(h. Dc-rmatol. 114:1545, 1978. 21. Nishikai, M., and Homma, M.: Circulating autoantibody against human myoglobin in Polymyositis. )AMA 237:1842, 1977. 22. Reichlin, M., and Mattioli, M.: Description ot a serological reaction characteristic of polymyositis. Clin. Immunol. Immunopathol. 5:12, 1976. 23. Whitaker, j . N,, and Engel, W. K.: Vascular deposits of immunoglobulin and complement in idiopathic inflammatory myopathy. N, Engl. |. Med. 286:333, 1972. 24. Nishikai, M., and Homma, M.: Anti-myoglobin antibody in polymyositis. Lancet 2:1205, 1972, 25. Curie, S., Saunders, M., Knowles, M., et al.: Immunologltal aspects of potymyositis, (). |. Med 40:63, 1971. 26. Penn, A, S.: Myasthemia gravis, dermatomyositis and polymyositis; immunopathological diseases. Adv. Neurol.17:41, 1977. 27. lohnson, R. L., Eink, C. W., and Ziff, M.: Lymphotoxin formation by lymphocytes and muscle in polymyositis. (, Clin. Invest, 51:24,35, 1972. 28. Dawkins, R, L.: Experimental autoallergic myositis, polymyositis and myasthenia gravisacitoimmune muscle disease associated with immunodeficiency and neoplasia. Clin. Exp. Immunol. 21:185, 1975. 29. Dawkins, R. L., and Mastaglia, E. L.: Cellmediated cytotoxicity to muscle in polymyositis. N. Engl. ). Med. 288:434, 1973. 30. Lisak, R. P., andZweiman, B.:Mitogen and muscle extract induced in vitro proliferative responses in myasthenia gravis, dermatomyositis, and polymyositis. J. Neurol, Neurosurg. Psych. 38:512, 1975.
)uly-August 1979
Vol. 18
31, Erazier, A. R., and Miller, R, D.: Interstitial pneumonitis in association with polymyositis and dermatomyositis. Chest 65:403, 1974. i2. Schwarz, M., Matthay, R. A., Sahn, S. A., et al.: Interstitial lung disease in polymyositis and dermatomyositis: analysis ot six cases and review of the literature. Medicine 55:89, 1976. 33. Webb, D, R., and Currie, G. D,: Pulmonary fibrosis masking fwlymyositis. jAMA 222:1146, 1972, 34. Dyck, R, E., Gordon, D. A., Cardella, C. |,, et al.: The glomerulonephritis of polymyositis. ARA Abstract, 1978. 35. Gottdiener, |. S,, Sherber, H. S., Hawley, |.,etal.: Cardiac manifestations in polymyositis. Am. J. Cardiol. 41:1141, 1978. ,36. Lightfoot, P, R., Bharati, S., and Lev M.: Chronic dermatomyositis with intermittent trifasicular block. Chest 71:4t3, 1977, 37. Williams, R. C: Dermatomyositis and malignancy: a review of the literature. Ann. Intern. Med. 50:1174, 1959. 38. Curtis, A. C, Biaylock, H. C, and Harrell, E. R.: Malignant lesions associated with dermatomyositis. jAMA 150:844, 1952. 39. Arundell, E. D.,yyilkinson, R. D., and Haserick, |. R.: Dermatomyositis and malignant neoplasms in adults. Arch. Dermatol, 82:772, 1960. 40. Talbott, |, H.: Acute dermatomyositi spolymyositis and malignancy. Sem, Arthritis Rheum, 6:305, 1977. 41. Barnes, B. E.: Dermatomyositis and malignancy. Ann. Intern. Med. 84:68, 1976. 42. Callen, ), P., Chanda, |. )., and Slawiski, M. S.: Dermatomyositis and malignancy: a contrary viewpoint. Ann, Inlern. Med. 84:751, 1976 (letter). 43. Callen, |. P., Hyla, |. E., Boles, G. G., and Kay, D. R.: The relationship of dermatomyositis and polymyositis to internal malignancy. Submitted for publication. 44. Moss, A, A,, and Hanelin, L. G.: Occult malignant tumors in dermalologic disease. Radiology 123:69, 1977. 45. Rowland, L. P., Clark, C, and Olarle, M.: Therapy for dermatomyositis and poiymyositi s. Adv. Neurol. 17:63, 1977. 46. Marsh, C. B. C: Polymyositis leading to diagnosis and resection of occult localized carcinoma ofthe cecum. South, Med. |. 71:1441, 1978, 47. Logan, R. G,, Bandera, |. M., Mikkelsen, W. M., et al.: Polymyositis: a clinical study, Ann. Intern. Med. 6,5:996, 1966. 48. Medsger, T. A., Dawson, W. N., and Masi, A. T.; The epidemiology Cif polymyositis. Am, |. Med. 715, 1970. 49. Medsger, T. A., Robinson, H., and Masi, A. T.: Eaclors affecting survivorship in polymyositis. Arth, Rheum, 14:249, 1971. 50. Carpenter, |. R., Bunch, T.W., Engel, A. G., et al.: Survival in polymyositis: corticosteroids and risk factors. ). Rheum. 4:207, 1977. 51. Sullivan, D. B., Cassidy, |. T., Petty, R. E., et al.: Prognosis in childhood dermatomyositis, ). Pediatr. 80:555, 1972. 52. Carpenter, S., Karpati, G,, Rothman, S., et al.: The
No. 6
53. 54. 55. 56.
57. 58.
59.
60.
Callvn
DERMATOMYOSITIS
childhood type of dermatomyositis. Neurology 26:9,52, 1976. Lell,M. E., and Swerdlow, M. L.: Dermatomyosilis of c:hildhood. Pediatr, Ann. 203:115, 1977. Krain, L. S.: Dermatomyositis in six patients without initial muscle involvement. Arch, Dermatol. 111:241, 1975, Callen, J. P.; Dermatomyositis-sine-myositis: late occurrence of muscle disease. Submitted for publication. 1979. Winkelmann, R.K., Mulder, D. W., Lambert, E. H.,et al.: Course of dermatomyositis-polymyositis, comparison of untreated and cortisone-treated patients. Proc. Mayo. Clin. 43:545, 1968. Grob, D.: Use of drugs in myopathies. Ann. Rev. Pharm. Toxicol. 16:215, 1976. Metzger, A. L,, Bohan, A,, Goldberg, L, S,, et al,: Polymyositis and dermatomyositis: combined methotrexate and corticosteroid therapy, Ann, Intern, Med. 81:182, 1974, Arnetl, E. C, Whelton, ). C, Zizic, T. M., et al.: Methotrexate tberapy in |X)lymyositis. Ann. Rheum. Dis. 32:536, 1973. Benson, M. D., and Aldo, M. A.: Azathioprine
61. 62. 63. 64. 65. 66. 67.
68.
433
therapy in polymyositis. Arch. Intern. Med. 132:547, 1973. Haas, D. C : Treatment of polymyositis with immunosuppressive drugs. Neurology 23:55, 1973. Currie, S,, and Walton, |. N,: Immunosuppressive therapy in dermatomyositis. |, Neurol. Neurosurg. Psychiatr. 34:447, 1971. lacobs, |. C: Methotrexate and azothioprine treatmen! of childhood dermatomyositis. Pediatrics 59:212, 1977. Dubowitz, V.: Treatment of dermatomyositis in childhood. Arch, Dis, Child. 51:494, 1976. Schaller, ), G,: Dermatomyositis. |. Pediatr. 83:699, 1973. GiannJni, ). M., and Callen, |. P.: Methotrexate therapy of dermatomyositis. Arch. Dermatol. In press. Allan, R. M,, Dykes, P. W,, Harris, O, D,, et al.: Dermatomyositis associated with hepatic secondaries from carcinoma of the colon. Gastroenlerology 62:1227, 1972. Vignos, P. |., and Goldwyn, |.: Evaluation of laboratory tests in diagnosis and management of polymyositis. Am. J. Med. Sci. 263:291, 1972.
The Aniline Dye Problem
The statement has been made that aniline dyes will not cause irritation ofthe skin, even in workmen whose face and hands are constantly covered with them, that the dyes are then in a soluble form; the conclusion follows that dyed stockings, etc., will not cause inflammation ofthe skin, for the colors are then in as insoluble a form as the dyer can make them. It is further said, in the year 1872, arsenic was found in magenta, with which the hosiery was dyed in 6.5%, but that the highest quantity is now under 0.09%. This may betrueof hosiery manufactured at Nottingham and Leicester, to which Mr. Ashwell refers, but it certainly is not true of all dyed stockings. Dr. Edson, ofthe New York Health Department, has called attention to the danger of wearing certain kinds of colored stockings. The dye, on analysis, was found to contain poison—quantities of arsenic and antimony. It has occurred in the experience of nearly every physician to meet with cases of skin irritation directly traceable to the dye in the patient's clothing; but every one is not equally susceptible to the influence of these irritants; because a certain dye-stuff will cause a dermatitis in one individual, it does not follow it will cause it in every case. I opine there must exist a condition ofthe skin that is predisposed to take on inflammation from certain kinds of external irritants. A number of individuals may be exposed to the same influence, a few will be affected, while the others may subject themselves to such irritants with impunity. This is known to be true in the cases of eczema, the parasitic diseases, and dermatoses produced by rhus poisoning.— McCuire, j. C: Dermatoses produced by dyestuffs. j. Cutan. Dis. 5:59, 1887.
