Inflammatory myositis associated with anti-U1-small nuclear ribonucleoprotein antibodies: a subset of myositis associated with a favourable outcome

P. Coppo, J. P. Clauvel, D. Bengoufa1, E. Oksenhendler, C. Lacroix2 and K. Lassoued

1 Service d'Immuno-Hématologie, Laboratoire d'Immunologie, Hôpital Saint-Louis, Paris and
2 Laboratoire d'Anatomo-Pathologie, Hôpital de Bicêtre, le Kremlin Bicêtre, France


    Abstract
 Top
 Abstract
 Introduction
 Material and methods
 Results
 Discussion
 References
 
Objectives. Inflammatory myositides are rare chronic disorders which may be either isolated or associated with other conditions such as connective tissue diseases or neoplasia. A large variety of autoantibodies can be detected in patients with myositis, some of which have a diagnostic and/or a prognostic value. Myositis associated with anti-U1-small nuclear ribonucleoprotein antibodies (anti-U1-snRNP Abs) are usually considered as overlapping syndromes, mainly mixed connective tissue diseases (MCTD) in which muscle symptoms occur insidiously during the disease course and are characterized by a favourable outcome.

Methods. The clinical, biological, immunological and pathological findings as well as the outcome of five patients with anti-U1-snRNP-associated myositis were retrospectively analysed.

Results. Patients were mainly black females. In all five patients, myositis was the predominant manifestation at presentation. Associated conditions consisted of interstitial lung disease (ILD) (three), arthritis (three) and neurological symptoms (two). No patient presented Raynaud's phenomenon nor met criteria for MCTD. Biological inflammatory features, rheumatoid factor and polyclonal hypergammaglobulinaemia were present in all cases. Besides anti-U1-snRNP Abs, one patient had anti-Ro/SSA and anti-La/SSB Abs at presentation and one additional patient developed anti-double-stranded-DNA and anti-Sm Abs after a follow-up of more than 4 yr. No patient had anti-PM/sclerosis (Scl) nor anti-aminoacyl-tRNA synthetase Abs. All patients dramatically improved with steroids, and reached complete remission (CR) within 3 weeks. Two patients relapsed 18 months after CR. They both reached rapidly second CR using steroids associated or not with oral methotrexate.

Conclusion. Our data suggest that anti-U1-snRNP Abs may define a subset of myositis characterized by a favourable outcome, though often associated with ILD and/or neurological manifestations.

KEY WORDS: Inflammatory myositis, Anti-ribonucleoprotein antibodies, Autoantibodies.


    Introduction
 Top
 Abstract
 Introduction
 Material and methods
 Results
 Discussion
 References
 
Inflammatory myositides are rare disorders in which the skeletal muscle is damaged by a non-suppurative inflammatory process, with lymphocytes, macrophages, plasma cells, rare eosinophils and neutrophils displaying a perivascular distribution [13]. Polymyositis (PM) refers to the condition that spares the skin and dermatomyositis (DM) to the one associated with characteristic cutaneous lesions [4]. PM/DM may be either isolated or associated in 20–30% of cases with other connective tissue disorders [5], such as systemic lupus erythematosus (SLE) [6, 7], mixed connective tissue disease (MCTD) [8], rheumatoid arthritis (RA) [9] and systemic sclerosis (SScl) [10]. They also can be associated with neoplastic diseases [11] or thymoma [12].

Myositides are associated with high morbidity and mortality rates, mainly due to both life-threatening muscle weakness and cardio-pulmonary complications [1318].

A wide variety of autoantibodies can be detected in PM/DM patients' sera [1923], some of which may have a diagnostic and/or a prognostic value. These mainly include antinuclear antibodies (ANA) detected in 4–17% of cases, and anti-aminoacyl-tRNA synthetase antibodies (Abs) [17, 2427], with prevalence being as high as 37%. Anti-PM/scleroses (Scl) Abs are a subset of ANA that are typically detected in patients with myositis associated with scleroderma or interstitial lung disease (ILD), and characterized by a favourable outcome [10, 28]. Anti-aminoacyl tRNA synthetase (anti-Jo1, -PL7 and -PL12) Abs define a subset of myositides associated with ILD, a poor response to therapy and a high death rate [26, 27]. Anti-signal recognition particle (-SRP) Abs, seen in a small percentage of patients are also associated with a poor prognosis [21]. Myositides associated with anti-U1-small nuclear ribonucleoprotein (anti-U1-snRNP) Abs typically overlap with other connective tissue disorders and seem to better respond to corticosteroids [21, 29]. We report herein the main clinical features and laboratory findings of five patients who presented with PM/DM and anti-U1-snRNP Abs.


    Material and methods
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 Abstract
 Introduction
 Material and methods
 Results
 Discussion
 References
 
Patients, polymyositis and connective tissue disease criteria
Between 1990 and 1997, 91 patients were referred to Hôpital Saint-Louis (Paris, France) for PM/DM. Among them, five (5.5%) had anti-U1-snRNP Abs. PM was defined according to Peter and Bohan's criteria [4]. Sharp's criteria were used for diagnosis of MCTD [30]. SLE and Sjögren's syndrome (SS) were defined according to the revised ARA criteria for SLE diagnosis [31] and the criteria of the European Community for SS [32], respectively. The 1987 ACR criteria [33] and the 1980 ACR criteria [34] were used to define RA and SScl, respectively. Patients' clinical charts were retrospectively analysed. All patients had complete physical examination with particular attention for muscle, skin, rheumatological and neurological manifestations as well as for neoplastic diseases. Muscle function (legs, arms and neck) was assessed by manual strength and scored from I to V as previously described [35] and by standard questions concerning impairment of swallowing and breathing. It was evaluated repeatedly during follow-up, first once a week for 1 month, then every 2 weeks for 3 months, then every month. A relapse was defined as the reappearance or increase in muscle weakness combined with increasing muscle enzymes or changes in electromyography (EMG) compatible with myositis.

Biological tests
All patients had routine laboratory tests which included muscle enzyme analysis, i.e. creatine phosphokinase (CPK), aldolase, lactic acid dehydrogenase (LDH), alanine aminotransferase (ALAT) and aspartate aminotransferase (ASAT). Normal values were <215, <8, <150, <40 and <37 IU/l, respectively.

Immunological investigations
Antinuclear Abs were detected by indirect immunofluorescence (IIF) on both HEP 2 cells and air-dried rat liver tissue sections. Anti-double-stranded DNA (ds-DNA) Abs were detected by ELISA [36]. The threshold positivity was 100 IU. Anti-extractable nuclear antigens (ENA) Abs (anti-Sm, -U1-snRNP, -Ro/SSA, -La/SSB) were detected by both ELISA (Profil Plus, BIO Advance, Emerainville, France) and counter-immunoelectrophoresis using purified antigens obtained from rabbit and bovine thymus powder (Pel Freez, Arkansas, USA), and from human spleen extract (Laboratoire d'Immuno-Pathologie, Hôpital Larrey, Angers, France) and reference sera. Sera were also analysed by dot-blotting using nuclear extracts from mammal cells (Anablot System II, Gull Diagnostics, Wavre, Belgium). Anti-aminoacyl-tRNA synthetase Abs [37] and anti-PM-Scl autoantibodies were detected by double immunodiffusion using reference sera. Anti-phospholipid antibodies (APLA) were assessed by ELISA (E.N. Harris, Louisville, USA). Other immunological tests included rheumatoid factor and complement level. Normal values for haemolytic complement activity (CH50), C3 and C4 components were 70–100%, 0.5–1.6 g/l and 0.2–0.6 g/l, respectively.

Other investigations
Muscle biopsy of clinically affected muscles was performed in four patients prior to steroid therapy. Samples were embedded in paraffin and coloured with haematoxylin–eosin, and Masson trichrome. Degeneration, regeneration and atrophy of muscle fibres were systematically evaluated. Immunophenotyping analysis of the inflammatory infiltrating cells was performed using Abs to CD20 (L 26), CD3, HLA-DR (LN 3), myeloid/macrophage (Mac 387), CD45RO (UCHL 1) (Dako S.A., USA). EMG was not systematically performed if characteristic clinical, histological and biochemical findings were present. It was performed in patient 1 who did not undergo muscular biopsy, and in patient 3. Oesophagus motility was studied by radiography with video-recording in patients 1 and 3. Hands soft tissue X-rays were obtained in all patients. Pulmonary vital capacity and carbon oxide (CO) diffusion capacity testing were analysed in patients 1, 3 and 4 who had clinical and/or chest radiography evidence of ILD (normal values >75 and >70%, respectively). Thymoma was sought for in all patients using chest X-rays and chest computerized tomography.

Follow-up
The mean follow-up of the patients reported here was 35.8 months (range 19–67).


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 Material and methods
 Results
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 References
 
Patients
Clinical findings are summarized in Table 1Go. Patients were mainly females (four out of five) aged from 29 to 49 yr (mean 36.4) at first symptoms. Four patients were black.


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TABLE 1. Main clinical features at presentation and outcome

 
Muscle weakness was present at onset in all patients. Three patients (1, 2 and 4) had severe muscle weakness (grade V) involving proximal limbs muscles. Dysphagia was present in patient 1. Patients 3 and 5 had severe myalgias and cramps with moderate muscle weakness (grade III).

Pulmonary manifestations were present in three patients, all of whom had an ILD on chest X-rays and computerized tomography (patients 1, 3 and 4). Dyspnoea was present in patients 1 and 4. Vital capacity was reduced in all three patients (50, 40 and 63%, respectively), as well as CO diffusion (45, 44 and 10%, respectively). Echocardiography and a right cardiac catheterism disclosed a pulmonary hypertension in patient 4.

Neurologic manifestations were noticed in patients 1 and 2, and consisted of an unexplained febrile lymphocytic meningitis without evidence of infection in both of them. Patient 2 also developed confusion and peripheral neuropathy associated with hyporeflexia, and a vesical sphincter paresia.

Three patients (1, 3 and 5) had evidence of a symmetrical non-destructive arthritis involving distal joints. Skin manifestations were observed in patient 1 who developed necrotizing lesions of fingers and patchy alopecia. No patient had Raynaud's phenomenon. Severe calcinosis universalis was found in patient 3. Patients 1 and 3 had diffuse mild lymph node enlargement. Histological examination of a cervical lymph node in patient 1 revealed necrotizing histiocytic lymphadenitis, consistent with the diagnosis of Kikuchi–Fujimoto's disease. Fever and weight loss were present in patients 1, 2 and 4, all three who experienced severe muscle weakness.

Patients 2 and 4 had typical pathological features of SS on salivary gland biopsy. No patient had evidence of neoplastic disorder or thymoma.

Laboratory findings
Biochemical and immunological findings are summarized in Table 2Go.


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TABLE 2. Main biological and immunological data at presentation

 
All patients had increased levels of serum muscle enzymes. CPK and LDH ranged from 565 to 14 000 IU/l (mean 5735), and from 162 to 1310 IU/l (mean 611), respectively. Aldolase was elevated in patient 3 (39 IU/l). ASAT and ALAT were elevated in all patients, ranging from 55 to 370 IU/l (mean 166), and from 60 to 240 IU/l (mean 124), respectively. All patients had biological features of inflammation at presentation, i.e. hyperfibrinaemia (>4 g/l), elevated C-reactive protein (>7 mg/l), and/or increased serum alpha2 globulins (>9 g/l). All patients had a serum polyclonal hypergammaglobulinaemia, ranging from 23 to 61 g/l (mean 38). Patients 3 and 4 had an isolated and transient elevated proteinuria (1.60 and 2.90 g/24 h, respectively) with normal serum creatinine clearance and urine sediment. Renal biopsy was performed in patient 3 and revealed a mesangial glomerulonephritis with IgG and C3 deposits in mesangium and in vascular walls. Analysis of cerebrospinal fluid disclosed low glucose (2.1 mmol/l) and high protein levels (0.77 g/l) associated with lymphocytosis (50.106/l) in patient 1, normal glucose and high protein levels (0.88 g/l) together with lymphocytosis (20.106/l) in patient 2. In both patients, no infectious agent was found. All patients had negative serology for HTLV-1 and HIV.

Antinuclear Abs were detected by IIF in all patients, and displayed a speckled fluorescent pattern at high dilution (<1:1000). Anti-ds-DNA and anti-Sm Abs were absent at onset in all five patients. Anti-Scl 70, anti-centromere and anti-PM/Scl Abs were found negative. Anti-U1-snRNP Abs were detected in all patients. Immunoblotting analysis revealed reactivity with the RNP-70 kDa and the RNP-A (33 kDa) polypeptides in all five patients and with RNP-C (22 kDa) in two patients (patients 1 and 3) (data not shown). Anti-aminoacyl tRNA synthetase Abs (anti-Jo 1, -PL7, -PL12) were found negative in all patients.

Patients 3 and 5 had a Coombs' test positive for IgG that was associated with an Evans' syndrome in patient 5 (Table 2Go). Other autoantibodies are indicated in Table 2Go. Hypocomplementaemia was present in patients 3 and 4. CH50, C3 and C4 levels were 0.13 g/l, 0.95 g/l and 68.6%, respectively, in patient 3, and 0.3 g/l, 0.1 g/l and 15.9%, respectively, in patient 4.

Electromyography
EMG was performed in patients 1 and 3 and disclosed positive sharp waves, fibrillations, and spontaneous discharges of high frequency, consistent with myositis, as well as short, small polyphasic motor units, consistent with myopathy. In patient 1, EMG also found a decrease in sensitive nerve conductivity, consistent with a sensitive neuropathy.

Pathological findings
Analysis of a muscle biopsy specimen revealed lymphocyte infiltrates in all patients but one (patient 2). In patient 3, lymphocytes were predominantly confined to the endomysium. In patient 5, lymphocytes were predominantly confined to the interstitium, whereas in patient 4, lymphocytes and plasma cells infiltrated striated muscular fibres and vessel walls. Degenerative fibres were present in three patients (patients 2, 3 and 4) and were associated with necrotic fibres in patient 2 and in patient 4 (Fig. 1Go). Atrophy of nerve fibres was present in patient 2. Immunophenotyping analysis was performed in patient 4 and revealed a dense perivascular infiltrate made of CD3+ CD45RO+ lymphocytes and macrophages (stained with both Mac387 and LN3 Abs).



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FIG. 1. Striated muscle biopsy performed in patient 4, showing necrotic fibres and a large infiltrate of mononuclear inflammatory cells (magnification x40).

 

Diagnosis at presentation
The patients reported here were classified as having definite PM (three cases) or probable PM (two cases), according to Peter and Bohan's criteria [4]. Myositis was associated with SS in patients 2 and 4. Two additional patients met three of the ARA's criteria for SLE diagnosis (patients 3 and 5) (Tables 1Go and 2Go). No patient fulfilled the four major criteria for MCTD diagnosis. However, using Sharp's set of criteria, patients 1 and 4 met the diagnosis of probable MCTD. Both developed severe myositis and ILD associated with anti-U1-snRNP Abs, and no anti-Sm Abs.

Treatment and outcome (Table 1Go)
All patients responded promptly to steroids (1–2 mg/kg/day) with a dramatic improvement of muscle weakness within 48 h. Patient 1 also received one course of intravenous immunoglobulins (IvIg) (0.4 g/kg/day, 3 days). Complete clinical and biological remission of the myositis was reached within 3 weeks in all patients. Non-muscle manifestations, i.e. arthritis, skin lesions, lymphadenopathy and lymphocytic meningitis, also quickly resolved. After 4 weeks of treatment, steroids were tapered and a maintenance posology of 5–10 mg/day could be reached at 3 months.

In the three patients who presented with ILD, chest X-rays and computerized tomography were performed 3–4 months after the onset of disease and showed a dramatic improvement in all three cases. Pulmonary function evaluated in patient 4 after 4 months of treatment, showed an improvement of both vital capacity and CO diffusion (84 and 45%, respectively).

Patients 4 and 5 experienced a relapse of myositis 2 yr and 1 yr after the initial diagnosis, respectively. Patient 4 was treated with steroids (1 mg/kg/day) and oral methotrexate (10 mg/week), and reached a durable second complete remission (CR). However, in this patient, ILD relapsed 6 yr after the myositis was diagnosed, without further muscle manifestation, while he was receiving steroids 10 mg/day as maintenance therapy. Chest X-rays and computerized tomography revealed a severe fibrosis that was associated with a worsening of vital capacity (37%). Bronchoalveolar lavage ruled out a methotrexate-induced pneumopathy. An increase in steroid dosage (0.5 mg/kg/day) allowed a slight but durable improvement of vital capacity (56%). One year after relapse, this patient was still in CR of myositis under 10 mg/day of steroids. In patient 5, a second CR was obtained after the steroid dosage was increased from 8 to 16 mg/day, with no additional immunosuppressive therapy.

Steroids were well tolerated in all patients with the exception of patient 4 who presented a severe amyotrophy and a femoral aseptic osteonecrosis.

Patient 3 developed anti-Sm and anti-ds-DNA Abs (350 IU/l) 4 and 6 yr, respectively, after myositis was diagnosed, fulfilling therefore sufficient criteria for SLE diagnosis. In contrast, none of the four other patients developed additional manifestations which could have led to reconsider the initial diagnosis, after a mean follow-up period of 35.8 months (range 19–67). Anti-U1-snRNP Abs remained positive in all patients.


    Discussion
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 Abstract
 Introduction
 Material and methods
 Results
 Discussion
 References
 
PM/DM are rare idiopathic disorders characterized by an inflammatory damage of skeletal muscles [4]. Patients with PM/DM usually share muscle weakness involving the proximal limbs, pharynx and upper oesophagus. A firm diagnosis is based upon the presence of a typical clinical picture, elevated serum levels of skeletal muscle enzymes, typical EMG changes and a diagnostic muscle biopsy [4]. In most cases, treatment is initiated when a diagnosis of a possible PM/DM is made, even though all four criteria are not simultaneously satisfied. Interestingly, a subset of patients with PM/DM develop non-muscle symptoms that may or not overlap with other connective tissue disorders [5]. For instance, 20–40% of patients with PM also develop an ILD that is often associated with anti-aminoacyl tRNA synthetase Abs and a poor outcome unless anti-PM/Scl Abs are present [16, 24, 28]. In rare cases, patients with PM/DM develop neurological manifestations, usually a peripheral neuropathy, defining the so-called neuromyositis [38].

The pathophysiology of PM/DM is poorly understood. There is a body of evidence suggesting that an autoimmune process may be involved in the aetiology of these disorders [39]. Indeed, PM/DM are often associated with autoimmune diseases and with a large variety of autoantibodies [2022] but there is little evidence that these autoantibodies may play any direct role in the induction of muscle damage. In contrast, both CD8+ and CD4+ T lymphocytes which are abundantly present in tissue lesions, are thought to be implicated in the pathogenesis of PM/DM [3, 40]. Infiltrating T lymphocytes are usually supposed to be self-reactive, though the autoantigens that they may recognize still remain unknown. Such antigens, presented to the autoinvasive CD8+ T cells by the class I major histocompatibility complex molecules on the sarcolemma, are expected to be either endogenous muscle peptides or viruses. However, the failure by several laboratories to amplify known viral RNA from muscles affected by PM points to endogenous muscle proteins, rather than viruses, as the likely candidate autoantigens [40]. A cytotoxicity that was mediated by {gamma}{delta} T lymphocytes, and which specificity was targeted to heat shock protein(s), has been reported in an unique patient with PM [41]. In other rare patients, muscle disease may be triggered by infectious agents, for instance coxsackie virus or echovirus, particularly in patients with hypogammaglobulinaemia [42].

Anti-U1-snRNP Abs are a subset of autoantibodies directed to snRNP which are important components in pre-messenger RNA processing [43, 44]. snRNP are made of at least 11 polypeptides with molecular weights ranging from 11 to 70 kDa (termed 70K, A, A', B, B', B'', C, D, E, F and G) and five snRNA molecules (U1, U2, U4, U5 and U6). Anti-U1-snRNP typically react by western blot on nuclear extracts with the 70 kDa protein, the A protein (33 kDa) and occasionally the C protein (22 kDa) [45]. This specificity is strongly associated with MCTD, an overlap syndrome combining features of SLE, SScl and PM together with a Raynaud's phenomenon and anti-U1-snRNP Abs [30]. However, these Abs can also be detected in up to 30–40% of patients with SLE [46] or other connective tissue diseases, such as SScl, in particular in those with limited skin sclerosis, lung fibrosis, joint involvement and high sedimentation rate [47]. According to Lundberg et al. [29], patients with PM and anti-U1-snRNP Abs are typically white females who fulfil the required criteria for MCTD diagnosis. In these patients, myositis is rarely the initial manifestation but rather appears insidiously during the disease course. Histopathological muscle changes are generally mild as compared with patients without anti-U1-snRNP Abs. In addition, these patients were reported to have a rapid favourable response to steroids, suggesting that anti-U1-snRNP Abs may constitute a good prognosis marker of PM.

We report here five patients, mostly black women, who presented with inflammatory myositis associated with anti-U1-snRNP Abs as an initial manifestation. Diagnosis of PM could be ascertained in three of them, whereas the other two presented probable PM. All patients had associated non-muscle manifestations, that included neurological symptoms and/or ILD in four cases. Interestingly, lung manifestations were not associated with anti-aminoacyl-tRNA synthetase nor anti-PM-Scl Abs. In contrast to Lundberg's patients, myositis was present at onset in all cases, and was severe in three of them. Moreover, four of our patients were black and none of them presented a Raynaud's phenomenon, nor met sufficient criteria for MCTD, though myositis was associated with SS, lupus or lupus-like disease in four cases. In addition, all five patients had rheumatoid factor and serum hypergammaglobulinaemia, that have not been reported in Lundberg's series. However, as in Lundberg's report, all patients described herein improved dramatically with steroids, with a durable CR in three cases. Two patients relapsed but reached rapidly second CR using steroids, associated or not with methotrexate.

Altogether, these findings strongly suggest that anti-U1-snRNP autoantibodies may define a subset of patients with PM/DM, who favourably respond to steroids in spite of a severe initial condition and associated manifestations (ILD, neurological symptoms, fever and female gender) that so far have been considered as bad prognosis markers [13, 18, 48]. However, a prospective analysis of a larger series of patients is needed to better evaluate the clinical significance and the prognostic value of anti-U1-snRNP Abs in patients with PM/DM. Whether or not these Abs are more frequently detected in black female patients also needs to be evaluated in such a study.


    Acknowledgments
 
The authors thank M. Bargis-Touchard for technical assistance.


    Notes
 
Correspondence to: K. Lassoued, Service d'Immuno-Hématologie, Hôpital Saint-Louis, 1 Avenue Claude Vellefaux, 75475 Paris cedex 10, France. Back


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 Abstract
 Introduction
 Material and methods
 Results
 Discussion
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Submitted 15 November 2001; Accepted 25 March 2002





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