Amyloidosis associated with dermatomyositis and features of multiple myeloma

Amyloidosis Associated with Dermatomyositis

and

Features of Multiple Myeloma The Progression of Amyloidosis Associated with Corticosteroid

and Cytotoxic Drug Therapy

Described here Is a 59 year old man with dermatomyositis and hypogammaglobulinemia. HIS muscle power improved after corticosteroid therapy, but extensive amyloidosis and repeated infections appeared. Bone marrow morphology suggested muttlple myeloma, but treatment with cytotoxlc drugs had no beneficial effect on the amyloldosls. Because of rapld progression of the amyloidosls and further lnfectlons, cytotoxlc drug therapy was stopped, cortlcosteroid dosage was decreased, and supplementary immunoglobulln therapy was instltuted. The infections occurred less frequently and the amyloidosis appeared to regress. This case suggests that Immunosuppressive therapy may exacerbate amyloidosis. The llterature is reviewed, and the possible role of humoral immunodeficlency In the pathogenesls of amyloidosis is discussed. It is suggested that supplementary lmmunoglobulin may be beneficial In amyloldosis.

PAUL J. ZILKO, M.B.’ ROGER L. DAWKINS,

M.D.

Perth, Western Australia

From the Clinical Immunology and Immunopathology Division, Department of Pathology, University of Western Australia, Perth, 6009 Western Australia. This study was supported by grants from the Western Australian Arthritis and Rheumatism Foundation, the Muscular Dystrophy Associations of America, and the National Health and Medical Research Council. Requests for reprints should be addressed to Dr. Paul J. Zilko, Department of Pathology, Perth Medical Centre, Shenton Park, 6008 Western Australia. Manuscript accepted November 1, 1974. Western Australian Arthritis and Rheumatism Foundation (Mercke Sharp & Dohme) Research Fellow. l

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Amyloidosis is known to be associated with plasma cell dyscrasias including multiple myeloma [ 11, but the diagnostic criteria for these conditions and the mechanisms of association are far from clear. Little is known about the therapy for amyloidosis and, in particular, what influence, if any, the treatment of myeloma has on the development of amyloid. The patient we describe suggests that therapy for dermatomyositis and myeloma can lead to the progression of amyloidosis. The possible significance of immunodeficiency in amyloidosis and dermatomyositis is discussed. CASE REPORT A 59 year old man presented in December 1972 with a 4 month history of swelling and stiffness of his fingers, and weakness and wasting of his upper arms. Following this he had a rash on his legs, and then hoarseness and mild dysphagia occurred in the 2 weeks before his admission to the hospital. Examination revealed weakness and wasting of the proximal muscles of the upper and lower limbs, most marked in the shoulder girdles. There

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AMYLOIDOSIS WITH DERMATOMYOSITIS AND MULTIPLE MYELOMA-ZILKO.

DAWKINS

was edema of the fingers and hands, and pitting edema of the legs and feet. Mild periorbital edema was evident with slight erythema of the cheeks and a psoriasiform rash was noted on the elbows, scalp and legs. Cardiovascular and respiratory systems were normal. The hemoglobin level was 10.6 g/100 ml, white blood cell count 7,400/mm3 with a normal differential and the sedimentation rate ranged from 12 to 20 mm/hour. Serum protein electrophoresis revealed an albumin of 3.5 g/100 ml and a globulin of 2.4 g/100 ml with a gamma globulin of 0.6 g/100 ml. Serum glutamic oxaloacetic transaminase and creatine phosphokinase were repeatedly normal.

streptokinase-streptodornase (Lederle) antigens and normal lymphocyte transformation response to phytohemagglutinin (PHA). Even though the immunoglobulin levels were low, there was an adequate response to tetanus toxoid 0.5 cc (Commonwealth Serum Laboratories, Victoria, Australia) and Salmonella typhi 0.1 cc (Commonwealth Serum Laboratories, Victoria, Australia) vaccination, with titers of these antibodies rising to 1:10,240 and 160, respectively. After 4 months of cytotoxic therapy, the tetanus antibody titer had fallen to a low level

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AMYLOIDOSIS WITH DERMATOMYOSITIS AND MULTIPLE MYELOMA-ZILKO,

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Figure 1. lmmunoglobulin levels, Bence Jones protein and clinical features are shown in relation to prednisone, cytotoxic drug and immunoglobulin therapy. (1:160) and there was no significant response to further tetanus toxoid vaccination. The percentage of 6 lymphocytes detected by surface immunofluorescence, using anti-immunoglobulin conjugate [3], was 16.5 per cent before therapy and fell over the ensuing months; it finally reached a level of 1.5 per cent after the sixth course of cytotoxic drugs. Percentage of T lymphocytes, as determined by the sheep red blood cell rosette method [4], ranged from 51 to 58 per cent, which is well within our normal range. Lymphocyte transformation response to PHA also remained normal. Since February 1974, there has been slow improvement in the appearance of the skin amyloid with regression of both the waxy and purpuric lesions. When the prednisone dose reached 7.5 mg/day the rash over the shins, which had previously regressed, became more evident. At this time the patient complained of increased fatigue, and examination demonstrated a return of muscle weakness.

COMMENTS

The clinical diagnosis of dermatomyositis in our patient was made on the grounds of proximal myopathy, typical skin rash, edema of the hands and legs and myopathic electromyographic findings. The absence of elevated muscle enzyme levels and histologic evidence of muscle necrosis does not exclude this diagnosis. The presence of small amounts of amyloid in the muscle interstitium might suggest that the proximal myopathy was similar to that referred to by Osserman in connection with myeloma and other plasma cell dyscrasias [5]. However, the rapid improvement in muscle power and esophageal function

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following corticosteroid therapy, and the recurrence of these features as well as the skin rash and edema when steroid dosage was reduced below 10 mg/day, would favor the diagnosis of dermatomyositis rather than amyloid or myeloma myopathy. Amyloidosis with dermatomyositis has been the subject of one previous case report [6]. This case differed in that the dermatomyositis was longstanding and unresponsive to corticosteroid therapy, but it was possible that the steroids contributed to the development of the amyloidosis. Dermatomyositis has also been reported in association with myelomatosis [7]. The present case is very similar to that described by Osserman et al. [8]. They described a middle-aged man who presented with hoarseness and evidence of skin amyloid and in whom extensive amyloidosis involving the bowel, heart, laryngotracheobronchial and periarticular tissues later developed. This patient also had an overt plasma cell dyscrasia with 30 per cent plasma cells including immature forms in the bone marrow, hypogammaglobulinemia, abnormal urinary protein and no obvious lytic lesions of the bones. Such cases provide real problems in the interpretation of bone marrow morphology. When osteolytic lesions are present, the case fulfills the criteria for overt multiple myeloma with associated amyloidosis [9]. However, when osteolytic lesions are absent, the diagnosis is much more difficult especially when a marked plasma cell dyscrasia is present. In some series of amyloidosis, results of bone marrow examinations which show less than 20 per cent plasma cells without immature or blast cells [lo] are reported, but it is possible that cases with

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more abnormal bone marrow morphology were arbitrarily classified as myeloma with associated amyloid. Some investigators have suggested that primary amyloktosis and myeloma may be part of the same spectrum with a certain amount of overlapping occuring in some cases [ 11,121. However this proposition is contradicted in some animal studies [ 131 in which there is a lack of correlation between rates of amyloid production and degrees of plasma cell hyperplasia. Such a proposition is also supported by the findings of lsobe and Osserman [l] that light chains in amyloid and myeloma differ, particularly in terms of their electrophoretic motility. Thus, although plasma cell dyscrasias may be common to both conditions, there appear to be some basic differences between myeloma and amyloidosis. The conceptual difficulties referred to are especially important in relation to therapy, particularly when therapy for one condition may be contraindicated in the other. The rapid onset and progression of the cutaneous amyloidosis soon after starting corticosteroid therapy and the later progression of the bowel amyloid would seem to indicate that the corticosteroid and cytotoxic drugs may have encouraged the progression of the amyloidosis in our patient. The gastric biopsy in January 1973 and the rectal biopsy in May 1973, at the time of diagnosis of the cutaneous amyloidosis, were negative for amyloid. Biopsy specimens obtained in November 1973, after the episode of pseudoobstruction of the colon and rectal bleeding, indicated extensive amyloid deposition in the stomach, duodenum, jejunum, colon and rectum. Since stopping cytotoxic drug therapy in January 1974. and reducing the prednisone dosage quite markedly, there is clinical evidence that the cutaneous amyloid regressed. Despite this and the eventual disappearance of Bence Jones proteinuria, other parameters of the plasma cell dyscrasia, such as bone marrow morphology and the immunoglobulin levels, have remained approximately unchanged. Such a clinical course must raise the possibility that corticosteroids and cytotoxic drugs may lead to a stimulation of amyloid production and deposition. Some investigators believe that steroids contributed to the onset of amyloidosis, especially in patients with rheumatoid arthritis [ 141. In general, however, the prevailing view is that steroids have little if any beneficial or detrimental effect on amyloidosis, but that they should be avoided in patients who are debilitated and prone to other steroid complications [ 151. However, some investigators have claimed that regression of amyloid occurred with corticosteroids [ 161 or cytotoxic drugs [ 17,161. The hypothesis that amyloidosis may be exacerbated by steroids or cytotoxic drugs is supported by

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the epidemiologic survey of Lehner [ 191. In a study of autopsy cases over a period from 1935 to 1962 he showed that there was a doubling of the incidence of amyloidosis after the introduction of corticosteroids, cytotoxic drugs and antibiotics. He also demonstrated that, although the number of primary amyloid cases did not increase, there was a considerable increase in amyloidosis associated with carcinoma, myeloma, lymphoma and rheumatoid arthritis. Such an hypothesis has also received strong support from animal experiments in which immunosuppression with cytotoxic drugs or irradiation during the amyloid induction period has led to more rapid and overt tissue deposition [ 20-221. Such evidence has led Telium [ 141 to propose a two-stage theory for the development of amyloid. He suggested that the initial stage involves hyperplasia of the plasma cell precursors due to some type of prolonged antigen stimulus. This is followed by a second stage of immune suppression during which amyloid deposition occurs. Such a theory relating amyloidosis to immunologic deficiency would be compatible with many of the facts in the present case. Polymyositis is associated with normal cell-mediated immunity, myotoxic T lymphocytes and yet humoral deficiency [23,24]. It is suggested that an initial imbalance of immune mechanisms, as may occur in dermatomyositis, may lead to the development of amyloid deposition. In our patient this imbalance may have been further exacerbated by the corticosteroid and later cytotoxic drug therapy, leading to rapid progression of the amyloidosis. We show that the cyclical cytotoxic therapy led to selective suppression of B cell numbers and humoral function leaving T cell numbers and function relatively intact. Thus it seems quite likely that therapy, by increasing a humoral defect, may have exaggerated a preexisting deficiency or imbalance. The gamma globulin therapy was initially started in an attempt to control the severe and life-threatening infections this patient was experiencing at frequent intervals. The therapy appears to have been successful in that there have been no significant infectious episodes over a 6 month period since starting gamma globulin therapy. The temporal relationship of this therapy to the improvement in cutaneous amyloid may suggest that the gamma globulin could play a role by virtue of a feedback mechanism which inhibits plasma cell production of the excess light chains and thus amyloid deposition. This case illustrated the difficulty in categorizing the amyloidosis when the major diagnostic tool is bone marrow morphology. It also highlights the possible deleterious effects that corticosteroid and cytotoxic drug therapy may have on amyloidosis. It is suggested that these drugs may be contraindicated in

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the absence of overt myeloma, but much more information is required in view of the difficulty in drawing a clear distinction between amyloidosis and multiple myeloma. The possible beneficial effect of gamma globulin therapy on the course of the amyloidosis warrants more attention, especially when it is associated with hypogammaglobulinemia.

ADDENDUM

ACKNOWLEDGMENT

We have recently seen a newly diagnosed case of polymyositis with similar features of amyloidosis and myeloma. In this instance, skeletal muscle showed evidence of myofiber necrosis and mononuclear inflammatory infiltration thereby confirming the diagnosis of polymyositis. In addition, amyloid was seen in intramuscular vessels.

We are grateful to Dr. J. D. Wetherall, Mr. G. Grimsley, Mr. R. McKenna and Miss J. Johnstone for their assistance and to Dr. M. J. Byrne for helpful discussions. Dr. K. B. Shilkin kindly provided the histopathologic details.

1.

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10. 11. 12.

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In September 1974, the patient died of cardiac arrest. Autopsy revealed extensive amyloid infiltration of the heart, skin and bowel. Amyloid was also seen in the vessels of the liver, spleen, kidney, lung and adrenal glands. The bone marrow was hyperplastic and showed the features seen on the previous examinations. In skeletal muscle there was amyloid in the interstitium but there were no inflammatory changes.

lsobe T, Osserman EF: Amyloidosis, plasma-cell dyscrasia, monoclonal immunoglobulins and BenceJones proteins. N Engl J Med 290: 473, 1974. Alexanian R, Bonnet J. Gerham E, l-taut A, Hewlett J, Lane M, Monks R, Wilson H: Combination chemotherapy for multiple myeloma. Cancer 30: 382, 1972. Papamichail M, Brown JC, Holborow EJ: lmmunoglobulin on the surface of human lymphocytes. Lancet 2: 850, 1971. Papamichail M, Holborow EJ, Keith H, Currey HLF: Subpopulations of human peripheral blood lymphocytes distinguished by combined rosetter formation and membrane immunofluorescence. Lancet 2: 64, 1972. Osserman EJ: Multiple myeloma and related plasma cell dyscrasias, Immunological Disease. 2nd ed (Sampter M, ed), Boston, Little, Brown 8 Co., 1971, p 520. Gelderman AH, Levine RA, Arndt KA: Dermatomyositis complicated by generalised amyloidosis. N Engl J Med 267: 858, 1962. Beck P: Myelomatosis presenting as dermatomyositis. Br Med J 1: 747. 1988. Osserman EF, Takatsuki K, Talal N: The pathogenesis of amylokfosis. Semin Hematol 1: 3, 1964. Bergsagel DE, Carbone PP. Costa G, et al.: Proposed guidelines for protocol studies. II. Plasma cell myeloma. Cancer Chemother Rep 4 (pt 3): 145. 1973. Cathcart ES, Ritchie RF. Cohen AS, Brandt K: Immunoglobulins and amylokfosis. Am J Med 52: 93, 1972. Kyle RA, Bayrd ED: Primary systemic amyloidosis and myeloma. Arch Intern Med 107: 344, 1971. Glenner GG, Terry WD, lsersky C: Amyloidosis. its nature

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and pathogenesis. Semin Hematol 10: 65, 1973. Huitgren MK, Druet RL, Janigan DT: Experimental amyloidosis in isogeneic X-irradiated recipients of sensitized spleen tissue. Am J Pathol 50: 943. 1967. Teilum G: Pathogenesis of amyloidosis. Acta Pathol Microbiol Stand 61: 21, 1964. Cohen AS: Amylokiosis. N Engl J Med 277: 635, 1967. McCall JW, Fisher WR: Primary amyloidosis of the larynx. Ann Dtol Rhino1 Laryngol 62: 316. 1953. Jones NF, Hilton PJ, Tighe JR, Hobbs JR: Treatment of primary renal amyloidosis with melphalan. Lancet 2: 616, 1972. Ansell BM, Eghtedari A, Bywaters EGL: Chlorambucil in the management of juvenile chronic polyarthrftis complicated by amyloidosis. Ann Rheum Dis 30: 331, 197 1. Lehner T: Changing trends in amyloidosis since the introduction of modern chemotherapy. Pathol Microbial (Basel) 27: 855, 1964. Druet RL, Janigan DT: Experimental amyloidosis. Am J Pathol 49: 1103, 1968. Clerici E, Mocarelli P, Smeraldi E, Villa ML: Amylokiosis in neonatally thymectomised and antilymphocytic serum treated mice. Clin Exp lmmunol 5: 163, 1969. Hardt F: Acceleration of casein induced amyloidosis in mice by immunosuppressive agents. Acta Pathol Microbial Stand (A) 79: 61, 1971. Dawkins RL, Zilko PJ: Polymyositis and myasthenia gravis: immunodeficiency disorders involving skeletal muscle. The Lancet I: 200, 1975. Dawkins RL, Mastaglia FL: Cell-mediated cytotoxicity to muscle in polymyositis. N Engl J Med 288: 433, 1973.