adult-onset polymyositis-dermatomyositis: description of 25 patients with emphasis on treatment
TRANSCRIPT
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,” cyclophospha- mide,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), antibod- ies 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 antibod- ies) 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 ten- derness. 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, ini- tially 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 re- quired 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 start- ing 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 pa- tients were treated with AZA in doses of 1 to 2 mg/kg/d. Seven patients received cyclophospha- mide 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 cyclophospha- mide was lost to follow-up. Of the last three patients unresponsive to AZA, one received cy- closporine 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 devel- oped 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 ma- lignancy, 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 devel- oped 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 relation- ship. 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 syn- drome, 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 thera- peutic 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 tri- als 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 initi- ated 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 immunosup- pressive agents have been used to treat PM-DM. Malaviya lo first used MTX intravenously in three patients refractory to steroids, and in an- other 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 immuno- suppressives had failed. Three of five patients in our series treated with MTX responded favor- ably. In one, MTX was used after the consecutive failure of AZA, cyclosporine, and cyclophospha- mide. 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 be- tween the patients treated with AZA and ste- roids 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 cyclophos- phamide ineffective,6*‘9920 a recent report de- scribed 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 cyclophos- phamide. 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 recov- ered after the addition of chlorambucil.
The one patient in this series who received total body irradiation has already been de- scribed.28 More recently, cyclosporine has been
ADULT-ONSET POLYMYOSITIS-DERMATOMYOSITIS
tried with encouraging results.22-24 The only pa- tient 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 gammaglobu- lin in a patient unresponsive to several immuno- suppressive 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, pul- monary 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 med- ication 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, cyclos- porin 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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