adult-onset polymyositis-dermatomyositis: description of 25 patients with emphasis on treatment

Adult-Onset Polymyositis-Dermatomyositis: Description of 25 Patients With Emphasis on Treatment

By Gerard0 Ramirez, Ronald A. Asherson, Munther A. Khamashta, Ricard Cervera,

David D’Cruz, Graham R.V. Hughes

A retrospective study of 25 patients with poly-

myositis-dermatomyositis (PM-DM) is analyzed

with special attention to the effects of therapy

and follow-up. All patients (100%) complained

of muscle weakness and 66% of these demon-

strated typical skin changes of DM. All patients,

except 2, received corticosteroids at the onset

of the disease, 23 were treated with azathio-

prine, 7 received cyclophosphamide, 4 meth-

otrexate, and 1 had total body irradiation.

Among the patients adequately treated with

azathioprine, 75% had a good response, but 5

patients did not improve. Cyclophosphamide

was used subsequently in 2, with a satisfactory

response in 1. Another patient had a striking

response to oral methotrexate, and total body

irradiation helped to improve another patient.

Although high dose corticosteroids were the

preferred starting medication for the treatment

of PM-DM, it is important to detect those

patients who do not respond adequately and/or

develop side effects. In these circumstances,

the prompt use of immunosuppressive agents

appears justified.

@ 1990 by W.B. Saunders Company.

INDEX WORDS: Polymyositis: dermatomyosi-

tis: myositis; corticosteroids; immunosuppres-

sive therapy.

From the Lupus Arthritis Research Unit, The Rayne

Institute, St Thomas' Hospital, London, UK. Supported by the British Council, the British SLE Aid

Group, and the Jean Shanks Foundation. Gerard0 Ramirez, MD, FRCP(C): Visiting Clinical Re-

search Fellow; Ronald A. Asherson MD, FACP, FCP (SA):

Deputy Director of Clinical Research; Munther A. Kha-

mashta, MD: Deputy Director of Laboratory Research.

Ricard Cervera, MD, PhD: Visiting Laboratory Research Fellow; David D’Cruz MB, MRCP: Research Fellow; Gra-

ham R.V. Hughes, MD, FRCP: Head of Unit, Consultant

Rheumatologist, Lupus Arthritis Research Unit. The Rayne

Institute, St Thomas’ Hospital, London, UK. Address reprint requests to RA Asherson, MD, FACP,

FCP(SA): Lupus Arthritis Research Unit, The Rayne Insti- tute, St. Thomas’ Hospital. London SE1 7EH. UK.

o 1990 by W.B. Saunders Company. 0049-0172/90/2002-0006$5.00/O

P OLYMYOSITIS (PM) is an inflammatory disease of striated muscle, characterized by

the presence of inflammatory infiltrates in the skeletal muscle and associated with muscle fibre

necrosis and/or degeneration. When accompa- nied by typical skin changes it is called dermato-

myositis (DM). Although its etiology is un- known, a number of studies have suggested that

cellular and humoral immune disturbances play a pathogenic role. l-3 The mainstay of therapy in

PM-DM is corticosteroids, although there have not been any controlled studies of this form of therapy. 4-8 In some patients who failed to respond

to the recommended doses of corticosteroids or

who have required very high doses, resulting in nonacceptable side effects,g various immuno-

suppressive agents have been tried. These include methotrexate (MTX),‘0-14 azathioprine

(AZA),“-” chlorambucil,” cyclophosphamide,1g-2’ and cyclosporine.22s24 Thymectomy,25

intravenous gammaglobulin, plasmapheresis,27

total body and total lymph node irradiation” also have been used. We present the clinical and laboratory features of 25 patients with PM-DM,

extending retrospectively over a 12-year period. The stepwise approach to the management of

these patients, with greater emphasis on the early

use of immunosuppressive agents, is discussed.

PATIENTS AND METHODS

Twenty-five patients (18 women and 7 men, female/male

ratio, 2S:l) seen consecutively at the Rheumatology Depart-

ment, St. Thomas’ Hospital, London, were studied. The

patients’ ages ranged from 19 to 56 years (mean age 37), and

the disease duration ranged from 4 months to 41 years (mean,

7 years).

Medical and social histories and complete physical exami-

nations were obtained from all patients while in the hospital

or as outpatients. Hematologic, biochemical, and immuno-

logic investigations were carried out according to standard

procedures. These included complete blood count, creatine

kinase (CK), aspartate aminotransferase (AST), alanine

aminotransferase (ALT), and hydroxybutyrate dehydroge-

nase (HBD) levels, antinuclear antibodies (ANA), antibodies to double stranded DNA (anti-dsDNA), nuclear antigens

(anti-ENA), and organ specific antigens (antimitochondrial,

114 Seminars in Arthritis and Rheumatism, Vol20, No 2 (October), 1990: pp 114- 120

ADULT-ONSET POLYMYOSITIS-DERMATOMYOSITIS 115

antismooth muscle, antiparietal cells, and antithyroid antibodies) and latex test for rheumatoid factor (RF). Complement

levels (C3, C4) were determined by immunodiffusion (against

standard control sera), and immune-complexes by PEG immuno-

diffusion in some patients. Electromyography and muscle biopsy

were performed in 20 and 19 patients, respectively.

Sixteen patients (64%) received a definite diagnosis of

PM-DM and 9 (36%) had probable PM-DM according to

Bohan’s criteria. 29 Seventeen patients had adult primary

DM. 1 had primary PM, 6 had PM-DM with associated con-

nective tissue disease (3 with seropositive rheumatoid arthri-

tis [RA], 2 with seronegative RA, 1 with mixed connective

tissue disease), and 1 patient had PM with malignancy.

Polymyositis developed in 3 patients while taking penicil-

lamine. Patients who had developed a “secondary” PM

during the course of systemic lupus erythematosus (SLE),

Sjiigren’s syndrome, or progressive systemic sclerosis (PSS)

were excluded from the study as (A) the myositis was

incidental to their disease, and (B) it was relatively minor.

Six patients were evaluated for occult malignancy by

laboratory screening tests, chest roentgenograms, intrave-

nous pyelography, gastrointestinal contrast studies, endos-

copy, and abdominal ultrasound.

Table 2: Visceral Involvement of Patients With

PM-DM

I Clinical Features No. Patients %

Dysphagia

Crycopharyngeal dysfunction

Abnormal pulmonary function

studies

Interstitial fibrosis (chest roent-

genogram)

Tachyarrythmia (fibrillation/flut-

ter)

Ophthalmoplegia

Retinopathy (vasculitis)

Pericardial effusion

Osteonecrosis of hips

Malignancy

6 24

2 a

6 24

1 4

3 12

1 4

2 a

2 a

1 4

1 4

RESULTS

Clinical and Laboratory Findings

Clinical findings are summarized in Tables 1 and 2. All patients (100%) complained of muscle weakness, and 48% also experienced muscle tenderness. Sixty-eight percent of the patients dem- onstrated skin changes typical of DM. Raynaud’s phenomenon was a frequent finding, occurring in 36% of patients. Skin vasculitis was striking in 24% of the patients, all of whom showed other skin changes of DM. Severe intestinal vasculitis developed in one patient that led to necrosis,

bowel perforation, and death from peritonitis.

One patient had generalized erythroderma, initially diagnosed as a manifestation of psoriasis, and two other patients were believed to have generalized eczema until muscle weakness and laboratory abnormaIities confirmed the diagnosis

of DM. Although abnormal pulmonary function tests were evident in 24%, interstitial pulmonary fibrosis was detected in only one patient. Two

patients with crycopharyngeal dysfunction required myomectomy. Four patients needed intu-

bation or tracheostomy for temporary respira- tory failure due to muscle weakness and/or lung infection.

Table 1: Muscle and Skin Involvement of Pa-

tients With PM-DM

Clinical Features No. Patients %

Muscle weakness 25 100

Muscle tenderness 12 48 Muscle atrophy a 32

Arthralgias/arthritis 7 28

Typical skin changes 17 68

Disseminated skin eruption 12 48

Vasculitis (nail fold and dorsum of

hands) 6 24

Raynaud’s phenomena 9 36

Livedo reticularis 2 a

Poikiloderma 3 12

Sclerodactyly 2 a

Laboratory findings are summarized in Table 3. Of nine sera tested for anti-Jo- 1 antibody only one was positive. Three out of four patients with positive RF had long standing RA. One patient,

already described,” had a positive human immu- nodeficiency virus (HIV) test, detected 4 months after the initial visit to the hospital. In 95% ol patients tested (n = 20), the electromyography showed changes characteristic of myopathy and

78% of patients undergoing biopsy (n := 19) displayed abnormal muscle findings.

Treatment and Follow-Up

All but two patients received prednisolone at the onset of the disease, the dosage ranging from 20 to 80 mg/d (Fig 1). In four patients, a bolus of methylprednisolone was used either as the starting medication or to control a relapse. One patient did not receive steroids because of a history of chronic gastritis and ulcer. Polymyosi-

116

Table 3: Laboratory Findings in Patients With

PM-DM

Patients With

Abnormal Results/

No. of Patients

Laboratory Features Tasted %

Raised ESR 1 l/23 47

Elevated CK (n i 250 lU/l) 21125 a4

Elevated ALT (n < 45 IU/I) 7113 53

Elevated AST (n < 38 IU/I) 13123 56

Elevated HBD (n < 182 IU/I) 20123 86

ANA l3/22 59

Anti-DNA l/20 5

Anti-ENA 3117 17

Anti-Jo-l 119 11

Organ-specific antibodies 3/l 1 27

Rheumatoid factor 4/19 21

Low c3 o/11 0

Low c4 l/l 1 7

Immune complexes 216 33

tis developed in another patient shortly after she started penicillamine and improved rapidly

when this agent was stopped. Twenty-three patients were treated with AZA in doses of 1 to 2 mg/kg/d. Seven patients received cyclophosphamide and four, MTX. One patient had total body

irradiation, 200 rads over 5 weeks, and has been described separately.28

Among the 23 patients treated with AZA, 20

had an adequate trial (more than two months),

RAMiREZ ET AL

and 1.5 of these 20 (75%) had a good response. In

7 of the 15 patients with a good response, AZA was initiated at the same time as steroids, and in

another 7 it was started after beginning steroid

treatment with an interval ranging from 6 weeks to 18 months, either because of lack of improve-

ment with steroids alone, or as a steroid-sparing agent. One patient with chronic gastritis and ulcer was treated with AZA alone. Two patients

received cyclophosphamide pulses intravenously (3 pulses weekly of 500 mg each) at the begin-

ning of AZA treatment. Five patients did not improve with AZA treat-

ment. Cyclophosphamide was used subsequently in two with a satisfactory response in one. The patient who did not improve with cyclophosphamide was lost to follow-up. Of the last three patients unresponsive to AZA, one received cyclosporine and subsequently cyclophosphamide without effect, but responded strikingly to oral

MTX (maximum dose 25 mg/wk). Another patient treated with MTX did not improve; total body irradiation was then used, which resulted in steady improvement over the following months without further therapy. Six years after treatment this patient remains well. The only death was the patient who failed to respond to AZA, MTX, and cyclophosphamide pulses and plasmapheresis.

Two patients did not tolerate AZA; one developed severe mouth ulcers and the other severe

shaking chills after each dose. Both responded to

Fig 1: Therapy in 25 pa-

tients with PM-DM. Ab-

breviations: CS, cortico-

steroids; RX, treatment;

R, favorable response: F,

failure to respond: MisDx,

Misdiagnosis; Cph, Cyclo-

phosphamide; CyA, Cy-

closporin A: TBI, total

body irradiation; MP, bo-

lus methylprednisolone.

ADULT-ONSET POLYMYOSITIS-DERMATOMYOSITIS 117

MTX. Another patient, who received a diagnosis of DM in another center, was initially started on steroids and later on AZA. On admission to St Thomas’ Hospital, muscle weakness was moder- ate. Pulmonary involvement, vasculitis of the retina and skin, and antibodies to neutrophil cytoplasm suggested Wegener’s granulomatosis,

and therapy was changed to cyclophosphamide. During hospitalization muscular weakness be- came prominent and a florid rash typical of DM

appeared, making the diagnosis of DM clear. Eventually this patient improved.

Two patients did not receive AZA. One had

PM induced by penicillamine and recovered after stopping this drug. The other patient with

only four months of follow-up is recovering with steroids alone.

Patient follow-up ranges from 4 months to 122

months, with a mean of 42 months (4 years). Eighteen patients are still taking prednisone with a mean dose of 7.5 mg/d and 3 have stopped prednisone. The survival rate in our series is 96%.

Six patients developed secondary infections as

complications of therapy. Two had pulmonary infections, including the patient who died. Infec- tious arthritis of the third right interphalangeal joint (one patient), skin infections (one patient) and severe candidiasis (two patients) were ob-

served and treated accordingly.

DISCUSSION

Clinical and Serological Findings

The sex ratio, mean age, and clinical features

of patients in this series were similar to other

reports.5-8 There was a predominance of the DM group (68%), higher than that observed by Bo- han et al (29%),* Ochsberg et al (28%),3’ and Banbassat et al (29%),32 which may simply reflect a specific referral pattern within our hospital.

The presence of vasculitis in adult-onset PM-DM has only recently been emphasized. Feldman et al noted vasculitis in 7 of 76 patients (9%), seen over a 1 l-year period.33 As in our experience, all patients with vasculitis had a rash typical of DM. These authors also suggested an association between cutaneous vasculitis and malignancy, which we were unable to confirm. We found cutaneous vasculitis in 6 (24%) patients. one of whom also developed severe intestinal vasculitis leading to intestinal perforation and

death. Gastrointestinal vasculitis is a recognized feature of childhood DM,34,35 but to our knowl-

edge has not been reported in adult PM-DM. Besides the typical DM rash, 12 (48%) had a

diffuse erythematous eruption similar to that noted by Bohan et a1.8 In some patients the rash

was severe and present for months to years before

the other features of PM-DM appeared. Often the rash was misdiagnosed as atypical psoriasis

or disseminated eczema. Dysphagia was noted in 24% of our patients

and has been reported in other series.8,3’*36-38

Interstitial lung fibrosis has been detected radio- graphically in 10% of patients described39 but

was observed in only one (4%) of our patients. However, abnormalities in pulmonary function

studies were found in 24%. Ophthalmoplegia is a

rare feature of PM-DM.8,40 Prominent ophthal-

moplegia (paralysis of medial eye movements and upward gaze) was present in one of our

patients. A brain scan did not show abnormalities of the brain stem, and the eye movements slowly

improved with steroid therapy. The frequency of abnormalities in serum en-

zymes, electromyography, and muscle biopsies is

comparable with other reports.8,3’ An association between anti-Jo-l antibody and the presence of pulmonary fibrosis was reported by Yoshida et

a14’ and others.42,43 Of nine patients tested, only one was positive for the antibody and its presence

was unassociated with pulmonary fibrosis. Two

patients were positive for RNP antibodies, one of whom had mixed connective tissue disease. Or-

gan specific antibodies were found in 3 of 11

patients, one with antithyroid antibodies was clinically hypothyroid. Recently, both hyper- and

hypothyroidism have been reported in patients with myositis.44

Penicillamine is associated with diverse autoim-

mune diseases including PM, myasthenia gravis

and SLE. Up to 1986, 25 cases of penicillamine- induced PM-DM have been documented.45*46 No correlation between previous therapy, penicil-

lamine dose, or duration of treatment has been detected. The majority had RA and recovered after discontinuation of the drug, or after a short course of steroids. Three of our patients developed PM while on penicillamine. In one, the symptoms started after only 4 weeks of treatment and improved after discontinuing the drug. An- other patient recovered after treatment with

118 RAMiREZ ET AL

prednisone and AZA. The response was slow, but 1 year later she was completely well. The third patient, with primary biliary cirrhosis, developed PM after 5 years of treatment with penicillamine but did not recover completely after combined treatment with steroids and immunosuppressive agents.

An association of PM-DM with malignant disease, specifically in men over 50 years of age, has been suggested.47T48 Two recent reports have cast doubts on the significance of this relationship. 49*50 Only one of our patients had cancer, an in situ carcinoma of her left breast, which was successfully excised two years before the onset of PM-DM.

Several musculoskeletal syndromes have been described in association with HIV infection, including Reiter’s syndrome, Sjogren’s syndrome, vasculitis, psoriatic and septic arthritis.” An association with PM was first reported by Dalakas,‘* and another patient with DM was recently described.s3 One of our patients who was HIV positive developed DMs3’

Response to Therapy and Follow-up

The best treatment for PM-DM is unclear for many reasons: the availability of different therapeutic interventions; the difficulty in performing controlled studies; the low frequency of the disease; and inaccuracies in assessing disease activity.4*29

Corticosteroids are considered the treatment of choice, although prospective, randomized trials have never been carried out.6,7’54 Most authors recommend beginning with high-dose steroids (1 to 2 mg/kg/d).4*s4*SS Others, however, have initiated therapy at lower doses in patients with milder symptoms. Carpenters6 did not find dif- fering survival patterns between the high-dose and low-dose steroid-treated groups. Alternate- day steroid therapy was proposed by Uchino et a1.57 Intravenous methylprednisolone has been reported as more effective than high-dose oral therapy in one study.58

Unfortunately, many patients do not respond to steroids alone or require unacceptably high doses to control the disease. Various immunosuppressive agents have been used to treat PM-DM. Malaviya lo first used MTX intravenously in three patients refractory to steroids, and in another patient who had received no other previous

treatment, with improvement in all. Favorable results have been also reported by other investigators. ‘*-14 Medzger et al” reported 17 of 22 (77%) patients who responded to MTX, including five who improved after other immunosuppressives had failed. Three of five patients in our series treated with MTX responded favorably. In one, MTX was used after the consecutive failure of AZA, cyclosporine, and cyclophosphamide. In the two other patients, MTX was used after AZA resulted in intolerable side effects.

Azathioprine is the only immunosuppressive agent assessed in controlled, double-blinded trials.15’16 Three months after initiation, strength and histopathologic features were similar between the patients treated with AZA and steroids and those receiving prednisone alone. How- ever, the same authors noted that AZA plus steroid resulted in a greater improvement with respect to functional disability after 3 years. Additionally, these patients required lesser amounts of corticosteroids.‘6 Azathioprine was the most frequently used immunosuppressive in this series. Fifteen (75%) of the patients with adequate trials improved. It should be stressed that delay in starting immunosuppressive drug therapy may result in significant steroid toxicity or the development of muscle atrophy that might limit the future response to other agents. The lack of response to immunosuppressives in some series might be due to their use in burn-out chronic cases with a little chance of response.”

Although some authors have found cyclophosphamide ineffective,6*‘9920 a recent report described 10 patients who responded favorably to intravenous pulses of cyclophosphamide.2’ In three patients, this was the only treatment given. Seven of our patients were treated with cyclophosphamide. In two, it was given as the initial immunosuppressive therapy followed by AZA as maintenance therapy with a good response. How- ever, in only two of the other patients did cyclophosphamide have a beneficial effect.

Few reports document the use of combined immunosuppressive therapy in the treatment of PM-DM. Wallace’8 described two patients who did not respond to steroids and MTX but recovered after the addition of chlorambucil.

The one patient in this series who received total body irradiation has already been described.28 More recently, cyclosporine has been

ADULT-ONSET POLYMYOSITIS-DERMATOMYOSITIS

tried with encouraging results.22-24 The only patient in our series who received cyclosporine did not respond to this drug. Plasmapheresis is an alternative therapy whose efficacy needs to be confirmed.*’ In our series, plasmapheresis was used in conjunction with cyclophosphamide in a desperately ill patient with vasculitis to no avail. A striking response to intravenous gammaglobulin in a patient unresponsive to several immunosuppressive agents was noted by Roifman,26 sug- gesting a possible role for this treatment in the

future. Our mortality rate (4%) is substantially lower

than other reported series.8’31’5g Even in Baron’s

small series, the mortality rate was 31K6’ Im- provements in general medical care, ie, medica- tions to prevent drug-induced complications, such as H2 receptor blockers and alkalis in the case of

steroids, adequate nutritional management, pulmonary toilet, and aggressive control of infec-

tion, may have reduced the mortality in our series. Also the mean age of our patients, 38 years, is slightly lower than in other series

reported. Younger ages have been shown previ- ouely to be associated with greater survival rates.sg It is our impression, however, that an aggressive

119

therapeutic approach to the management of this disease was a contributory factor in the lower mortality observed.

CONCLUSION

High-dose steroids is the preferred initial medication for the treatment of PM-DM in this series. However, it is important to the early

detection of those patients who do not respond adequately, require high doses of steroids to maintain the response, or experience side effects. Because of the danger of muscle atrophy, with consequent diminution of response, the early use of immunosuppressive therapy is justified. Our

data shows that prompt and concomitant use of AZA results in satisfactory responses for the majority of patients. Nevertheless, there still

remains a small number of patients who are resistant or unable to tolerate AZA. It is unclear which of the second line therapies offer the best alternative option, although MTX appears to be a reasonable choice. Cyclophosphamide, cyclosporin A, and total body irradiation, among oth-

ers, also may be effective. Failure to respond to one of these latter agents does not imply lack of response to another.

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