Treatment of Dermatomyositis With Intravenous Gammaglobulin BIANCA A. LANG, M.D., Halifax, NovaScotia, Canada, RONALD M. LAXER, M.D., GORDON MURPHY, M.D., EARL D. SILVERMAN, M.D., CHAIM M. ROIFMAN, M.D., Toronto, Ontario, Canada

PURPOSJQ The main&y of pharmacologic ther- apy in patients with dermatomyositis is cortico- steroids. However, becausq patients so~etimea become refractory to these drugs and ?WXUUW these drugs have potential short- and long-term toxicities, alternate therapy is higW &&able. Therefor0, a pilot study was initiated using highdose intravenous gammaglobulin (IVGG) in the treatment of dermatomyositia

PA- AND MEI’EODS: IVGG was adminis-

tered to five patients with juvenile dermatomyo- sitis. Prior to IVGG treatment, all patients had persistent muscle weakness despite daily corti- costeroids and three patients had developed un- acceptable st&oid toxicity. Two of the patients had previously developed toxicity while receiv- ing immunosuppressive therapy.

RE9UL.m IVGG therapy resulted in improved musclestrengthandameliorat8dskinrashinall patients The perc8ntage increase hi muscle strength as measured by sphygmomanometry following the g-month cow of IVGG ranged from 66% to 666% iq the proxhnal lower ex- tremities and from 30% to 166% in the proximal upper extremitiea Following IVGG therapy, prednisone could be discontinued or the dose re- duced in all patients.

CONCLUSION: This study susgegts that IVGG may allow steroid sparing in dermatomyositis and may pvvide a safe alternative to cytotoxic therapy.

From the Divisions of Immunology/Allergy. Rheumatology. and Neu- rology, Department of Pediatrics (RML. GM. EDS, CMR), The Hospital for Sick Children, Toronto, Ontario, Canada, and the Department of Pediat- rics (SAL), lzaak Walton Killam Hospital for Children, Dalhousie Universi- ty, Halifax, Nova Scotia, Canada.

This work was supported by lmmuno Canada and the Leah Reichmann lmmunodeficiency Fund.

Requests for reprints should be addressed to Chaim M. Roifman. M.D., Division of Immunology/Allergy. The Hospital for Sick Children, 555 Uni- versity Avenue, Toronto, Ontario, M5G 1X8, Canada.

Manuscript submitted January 29, 1990, and accepted in revised form May 10.1991.

T he mainstay of pharmacologic therapy in der- matomyositis is corticosteroids. Most recom-

mended treatment regimens consist of initial high- dose prednisone followed by low doses for extended periods of time. This treatment has resulted in a significantly improved outcome in dermatomyositis [1,2]. However, some patients are refractory to ste- roid therapy, demonstrate only a partial response, or remain steroid dependent, while others develop complications of corticosteroid therapy [3,4]. In pa- tients who are either resistant to or intolerant of corticosteroids, or who are dependent on large doses of prednisone, treatment with immunosuppressive agents has been advocated. The use of agents such as methotrexate, axathioprine, cyclophosphamide, chlorambucil, and cyclosporin A has been reported in dermatomyositis; however, results have been variable and unpredictable [4-6]. In addition, po- tential short- and long-term toxicity remains of great concern, particularly in the pediatric age group.

Alternate therapy is therefore desirable. High- dose intravenous gammaglobulin (IVGG) has proved to be effective in a number of disorders in which immune mechanisms are believed to ‘play a pathogenetic role [7-91. Although the etiology of dermatomyositis is unknown, a number of immu- nologic abnormalities appear to contribute to its pathogenesis [lo-121. We have previously de- scribed a patient with infantile polymyositis who improved with IVGG treatment despite prior fail- ure of prednisone, methotrexate, and cyclophos- phamide [13]. We now report the results of a pilot study of IVGG therapy in five patients with dermatomyositis.

PATIENTS AND METHODS Patient Criteria

Five patients with dermatomyositis, one male and four females ranging in age from 2l/2 years to 15 years, were entered in a prospective study protocol for treatment with IVGG. Eligibility for entry into the study required that patients met Bohan and Peter’s [14] criteria for definite juvenile dermato- myositis, were between the ages of 6 months and 18 years, had no evidence of hypogammaglobulinemia,

August 1991 The American Journal of Medicine Volume 91 169

GAMMAGLOBULIN FOR DERMATOMYOSITIS / LANG ET AL

TABLE I

Characteristics of Five Patients with Juvenile Dermatomyositis Treated with IVGG I

Age at Disease Patient Diagnosis Duration Treatment Steroid Number (years) Sex Prior to IVGG Prior to IVGG Toxicity

: 7 F 1 month Prednisone Stemid-induced diabetes mellitus 7 years Prednisone, methotrexate, azathioprine, cyclophosphamide, None

hydroxychloroquine, IV methylprednlsolone 3 4 2” ri

3 years Prednisone, IV methylprednisolone, methotrexate 4 months Prednisone

Cushingoid, cataracts,,vertebral fracture, hypertension

5 5 F 2.5 yean Prednisone, IV methylprednisolone ro;l$@d, hypertension

IV = intravenous

and either failed to improve after initial therapy with corticosteroids, remained steroid dependent after 4 months of therapy, or developed unaccept- able steroid toxicity. Patient characteristics are summarized in Table I. All five patients were tak- ing corticosteroids at the time of enrollment into the study. Two patients had received immuno- suppressivedrugs prior to the study; however, these drugs were not permitted during the study and had not been used within 6 months of the study’s onset. Hydroxychloroquine had been used for 3 years pri- or to the study in Patient 2.

IVGG Administration Patients received IVGG (IVEEGAM, Immuno

Corporation, Vienna, Austria) at a dose of 1 g/ kg/day, given over 6 to 8 hours on 2 consecutive days once every 4 weeks for a period of 9 months (total dose 2 g/kg/month). Treatment was administered in an outpatient facility. All adverse reactions were noted.

Clinical and Laboratory Evaluations Patients were examined by one of the investiga-

tors prior to the initiation of the study and monthly before IVGG infusions. Each patient was assigned one physiotherapist who assessed muscle strength according to the British Medical Research Coun- cil’s (BMRC) system (O-5) and by sphygmomanom- etry [13] prior to each monthly IVGG infusion. Cre- atine kinase activity, aspartate aminotransferase, quantitative immunoglobulins, and erythrocyte

TABLE II Patient 1 Patient 2 Patient 3 Patient 5 Percentage Increase in Strength as Measured by Sphygmomanometry Muscle Before After Before After Before After Before Alter Following the g-Month Course of IVGG Group IVGG IVGG IVGG IVGG IVGG IVGG IVGG IVGG

Patient Number

:

3 (course 1) 3 (come 2) 5

Left Hip Abductors (%I

606 34

1:; 80

Left Shoulder Abductors (%)

186

3’: 104 150

Shoulder 4-15 515 4+/5 515 4-15 515 315 415 abductor

Shoulder 4-15 515 4+/5 515 4-15 515 315 515 flexors

Hip 4-15 515 515 515 415 4+15 315 515 abductor

Hip 315 515 515 515 415 4+15 415 515 flexors

sedimentation rate were measured at the time of entry into the study and monthly prior to IVGG infusions. Patients were screened for hepatitis B surface antigen and antibody to human immunode- ficiency virus at enrollment and every 4 months during the study. Muscle biopsy examination and electromyography were performed in four of the five patients immediately prior to entry into the study.

RESULTS IVGG treatment administered for 9 consecutive

months resulted in resolution of skin lesions in all four patients who had skin involvement prior to entry into the study. At the start of the investiga- tion, four patienta had extensive scaly, erythema- tous rashes and vasculitic lesions at various sites. One patient had, in addition, calcinosis in multiple sites. Within 2 to 4 months after starting IVGG infusions, a dramatic improvement of skin lesions was noticed in all patients. Amelioration and subse- quent clearing of the diffuse erythematous rash oc- curred first. Subsequently, the vasculitic lesions re- solved, and calcinosis markedly improved.

In parallel to the improvement of skin lesions, muscle strength gradually increased. Increments in the strength of various muscle groups ranged from 34% to 606% as measured by sphygmomanometry in

TABLE Ill

Comparison of Muscle Strength in Proximal Upper and lower Extremities Before and at Completion of the g-Month Course of IVGG*

ssessed by the British Medical Research Council’s system 10-5).

170 August 1991 The American Journal of Medicine Volume 91

the four patients in whom these measurements could be accurately obtained (Table II). Support- ing these measurements are estimates of muscle weakness according to the BMRC scale (Table III). In Patients 1 and 3, measurements demonstrated at least two muscle groups that scored Z/5 at the onset of the study. After nine infusions of IVGG, all mus- cle groups scored 5/5 according to the BMRC scale. Patient 2 had predominant skin involvement with only mild muscle weakness (4/5) at the beginning of the study. After administration of IVGG therapy, strength increased to normal (5/5). In Patient 5, upper extremity strength increased by 150% as measured by sphygmomanometry and proximal lower extremity strength increased by 80%. Muscle strength graded by the BMRC scale increased from 3/5 to 4/5 or 5/5. Reliable measurements could not be obtained in Patient 4 because of his young age. However, functional assessment of strength showed dramatic improvement as outlined in the case summary.

Serum creatine kinase activity was abnormally elevated in two of five patients prior to their enroll- ment in the study. Concomitantly with the im- provement of skin and muscle strength, levels of serum creatine kinase activity gradually declined in one patient and returned to within normal levels in the remaining patient.

The marked amelioration of clinical symptoms and laboratory abnormalities permitted corticoste- roid therapy to be gradually decreased in all pa- tients and even discontinued in two of five patients. These patients have now been followed for more than 18 months. Patient 3 experienced a relapse 2 months after discontinuation of IVGG. Reintroduc- tion of IVGG infusions and a transient increase in the prednisone dose resulted in improvement of muscle strength. IVGG infusions were given for an additional 12 months and were then stopped. The patient remains well since the second discontinua- tion of IVGG therapy.

COMMENTS Although the prognosis for dermatomyositis has

improved over the past 30 years, therapy remains suboptimal. On the basis of previous success in treating other autoimmune diseases with IVGG and our success in treating a patient with infantile poly- myositis, we undertook this study of IVGG in der- matomyositis. Administration of IVGG therapy in five patients with dermatomyositis resulted in im- provement in muscle strength and amelioration of the skin rash. These patients received IVGG be- cause of either steroid failure, steroid dependence, or significant steroid toxicity. One patient had been given previous trials of successive immunosuppres-

sive therapy without success, and one patient was unable to tolerate immunosuppressive therapy.

Evaluation of treatment in patients with derma- tomyositis is complicated by the heterogeneous na- ture of the disease and by the fact that the disorder may follow one of a number of clinical courses [3]. Patient 1 may have been destined to follow a mono- cyclic course; nevertheless, her well-being was jeop- ardized by steroid-induced diabetes mellitus early in the course of her disease. IVGG had a marked steroid-sparing effect and her improvement with this therapy allowed us to avoid the potential toxic- ity of cytotoxic drugs. Significant steroid-sparing was also seen in Patient 3 whose disease had previ- ously followed a chronic continuous course. Follow- ing treatment with IVGG, this patient’s strength returned to normal for the first time since diagnosis and her prednisone dose was the lowest since diag- nosis. A similar steroid-sparing effect was obtained in Patients 4 and 5.

IVGG also appeared to have a beneficial effect on the skin manifestations in all patients studied. In Patient 2, a vasculitic rash was the most prominent complaint at the beginning of the study, and signifi- cant improvement was seen after treatment. Rashes resolved completely in Patients 1, 3, and 4 after administration of IVGG, although in Patient 3, the heliotrope recurred along with muscle weakness 2 months after IVGG was stopped.

The rationale for the use of IVGG in dermato- myositis is based on the hypothesis that an alter- ation in immune function is of primary importance in the pathogenesis of the disease. IVGG has been found to be effective in a number of disparate disor- ders that appear to involve immune mechanisms, including idiopathic thrombocytopenia purpura, myasthenia gravis, and Kawasaki disease [N-12]. Similar to Kawasaki disease, where the etiology is unknown but a vasculitis appears to be the hall- mark of the disease, a vasculopathy is seen in der- matomyositis [lo]. Elevated levels of factor VIII- related antigen have supported the concept of damaged vascular endothelium [ll]. The findings of circulating immune complexes and complement and the deposition of immunoglobulin within blood vessel walls from muscle biopsies of patients with dermatomyositis [l&12] add further support to the concept of the importance of an immunologic basis for the pathogenesis of this disorder.

The mechanism of action of IVGG in autoim- mune disorders or vasculopathies is unknown, al- though a number of hypotheses exist. There is some evidence from animal models [15] and human stud- ies [16] to suggest that coxsackievirus may play a role in the pathogenesis of dermatomyositis. If a virus or bacterial toxin plays a role in the etiology of

GAMMAGLOBULIN FOR DERMATOMYOSITIS / LANG ET AL

August 1991 The American Journal of Medicine Volume 91 171

GAMMAGLOBULIN FOR DERYATOMYOSITIS / LANG ET AL

dermatomyositis, gammaglobulin may provide neu- tralizing antibody or antitoxin. Alternatively, many autoantibodies bear cross-reactive idiotypes, and IVGG may exert its effect by supplying anti- idiotypic antibodies. It has been demonstrated in experimental animal models that autoantibody production by B cells can be suppressed by admin- istering specific anti-idiotypic antibodies [i7]. By selectively reducing the concentration of pathogen- ic antibodies, autoimmune disease may be effec- tively treated.

Our study suggests that IVGG allows steroid sparing in dermatomyositis, provides an alternative treatment to cytotoxic therapy, and results in im- provement of both muscle strength and skin rash in patients who have shown refractoriness to conven- tional steroid or immunosuppressive therapy. As seen in other diseases, IVGG appears to be a safe drug in dermatomyositis. Further studies with larg- er numbers of patients will be required to establish the role of IVGG in dermatomyositis.

ACKNOWLEDGMENT We thank Brenda Reid and Denise Purcell for technical and secretarial assistance.

REFERENCES 1. Sullivan DB, Cassidy JT, Petty RE. Burt A. Prognosis in childhood dermato- myositis. J Pediatr 1972; 80: 55563.

2. Dubowitz V. Treatment of dermatomyositis in childhood. Arch Dis Child 1976; 51: 494500. 3. Spencer CH. Hanson V, Singsen BH, Bernstein BH. Kornreich HK. King KK. Course of treated juvenile dermatomyositis. J Pediatr 1984; 105: 399-408. 4. Jacobs JC. Methotrexate and azathioprine treatment of childhood dermato- myositis. Pediatrics 1977; 59: 212-8. 5. Niakan E. Pitner SE, Whitaker JN. Bertorini TE. Immunosuppressive agents in corticosteroid-refractory childhood dermatomyositis. Neurology 1980, 30: 286-91. 6. Heckmatt J. Saunders C. Peters AM, et al. Cyclosporin in juvenile dermato- myositis. Lancet 1989; 1: 1063-6. 7. Newburger JW, Takahashi M, Burns JC, et al. The treatment of Kawasaki syndrome with intravenous gammaglobulin. N Engl J Med 1986; 315: 341-7. 8. Gajdos PH. Outin H, Elkharrat D. et a/. High-dose intravenous gammaglobulin for myasthenia gravis. Lancet 1984; 1: 406. 9. Shahar E, Murphy EG, Roifman CM. Benefit of intravenously administered immune serum globulin in patients with Guillain-Barre syndrome. J Pediatr 1990; 116: 141-4. l$ Banker BQ, Victor M. Dermatomyositis (systemic angiopathy of childhood). Medicine (Baltimore) 1966; 45: 261-89. 11. Scott JP, Arroyave C. Activation of complement and coagulation in juvenile dermatomyositis. Arthritis Rheum 1987; 30: 572-6. 12. Whitaker JN. Engel WK. Vascular deposits of immunoglobulin and comple- ment in idiopathic inflammatory myopathy. N Engl J Med 1972; 286: 333-8. 13. Roifman CM, Schaffer FM, Wachsmuth SE, et a/. Reversal of chronic poly- myositis following intravenous immune serum globulin therapy. JAMA 1987; 258: 513-5. 14. Bohan A, Peter JB. Polymyositis and dermatomyositis. N Engl J Med 1975; 292: 344-7. 15. Strongwater SL, Dorovini-Zis K. Ball RD. Schnitzer TJ. A murine model of polymyositis induced by coxsackievirus Bl (Tuscan strain). Arthritis Rheum 1984; 27: 433-42. 16. Bowles NE, Sewry CA, DubowitzV. Archard LD. Dermatomyositis, polymyo- sitis. and coxsackie-B-virus infection. Lancet 1987; 1: 1004-7. 17. Zanetti M, Bigaui PE. Anti-idiotypic immunity and autoimmunity. Eur J Im- munol 1981; 11: 187-95.

172 August 1991 The American Journal of Medicine Volume 91