sign in sign up
<<
Home , Rheumatology, Scleromyositis

Anti-PM/Scl antibodies in connective tissue disease: Clinical and biological assessment of 14 patients F. Vandergheynst1, A. Ocmant2, C. Sordet3, R.L. Humbel4, J. Goetz5, F. Roufosse1, E. Cogan1, J. Sibilia3

1Internal Department and 2Immunology- Department, C.H.U. Erasme (Université Libre de Bruxelles), Bruxelles, Belgium; 4Immunopathology Department, C.H. Luxembourg, Luxembourg; 3Rheumatology Department and 5Immunology Laboratory C.H.U. Hautepierre, Strasbourg, France. Abstract Introduction Anti-PM/Scl antibodies (Anti-PM/Scl) represent a rarely encountered type of antinuclear antibodies. They have mainly been reported in association with idiopathic inflammatory – systemic sclerosis overlap syndromes (also called or sclerodermatomyositis) but also with , and systemic sclerosis without features of overlap syndromes. Studies concerning characteristics of patients with anti-PM/SCl are rare and include small numbers of patients.

Patients and methods Retrospective review of clinical and biological characteristics of 14 patients with anti-PM/Scl in two University : one in Belgium (Erasme , Bruxelles) and one in France (Hautepierre Hospital, Strasbourg).

Results Seven patients were identified in Erasme and 7 in Strasbourg: 5 with systemic sclerosis – (dermato)myositis over- lap syndromes, 4 with dermatomyositis, 1 with polymyositis, 3 with systemic sclerosis, 1 with primary Sjögren’s syndrome. The most frequently observed clinical characteristics (85% of patients) were: pulmonary interstitial dis- ease and or . No patient of our series died or developed cancer (mean follow-up: 6.1 years).

Conclusions Our study failed to identify an homogeneous clinical pattern in patients with anti-PM/Scl, except for 2 characteris- tics shared by 85% of the patients. This lack of homogeneity is in agreement with preceding literature. We confirm the favourable prognosis associated with the presence of anti-PM/Scl, despite the high incidence of interstitial pul- monary disease. The absence of cancer associated with presence of anti-PM/Scl represents a partial explanation. Finally, we report herein the second case of primary Sjögren’s syndrome associated with anti-PM/Scl.

Key words Anti-PM/Scl antibodies, polymyositis, dermatomyositis, systemic sclerosis, overlap syndromes, primary Sjögren’s syndrome.

Clinical and Experimental 2006; 24: 129-133. Anti-PM/Scl antibodies in connective tissue disease / F. Vandergheynst et al.

F. Vandergheynst, MD; A. Ocmant, MD; Introduction were retrospectively analysed without C. Sordet, MD; R.L. Humbel, PhD; J. In 1977, Wolfe et al. (1) described a prior selection. Goetz, MD; F. Roufosse, PhD; E. Cogan, novel auto-antibody called anti-PM1. The 14 patients of the present study PhD; J. Sibilia, PhD. In a series of 18 patients with myositis have been followed from 1985 to 2004 Please address correspondence to: and/or systemic sclerosis, 12 presented in Erasme Hospital in Brussels (n = 7) Dr F. Vandergheynst, Department, C.H.U. Erasme, 808 route an between the two and in Hautepierre Hospital in Stras- de Lennik, 1070 Brussels, Belgium. diseases sometimes called scleromyos- bourg (n = 7) in the Departments of E-mail: [email protected] itis. A few years later, in 1984, Reichlin Internal Medicine, Rheumatology and Received on April 29, 2005; accepted in et al. described a new specific autoanti- . These two university hospi- revised form on October 28, 2005. body closely related to anti-PM1, anti- tals are referral centers for systemic © Copyright CLINICAL AND EXPERIMEN- PM/Scl antibody (2). Among the 22 inflammatory rheumatic diseases, but TAL RHEUMATOLOGY 2006. patients of this study, 21 presented with also practise highly diversified medical myositis and 10 with systemic sclero- activity allowing a very large recruit- sis, 9 of the 22 having an overlap syn- ment of patients. drome. Several other studies have con- firmed the association between anti- Methods PM/Scl and idiopathic inflammatory In Erasme Hospital, the search for anti- and/or systemic sclerosis (2- nuclear antibodies (ANA) was per- 5). Nevertheless, a homogeneous clini- formed by immunofluorescence (IF) on cal pattern associated with anti-PM/Scl HEP 2 cells (classical method, on has never been identified, except in human larynx carcinoma cells) for the Marguerie’s study (4). Among 32 pat- oldest sera, then on HEP 2000 cells, ients, 6 common clinical characteristics transfected to over-express SSA anti- were found in more than 50% of pat- gen, which improves the sensitivity for ients: Raynaud’s phenomenon (100 %), detection of anti-SSA antibodies. The (97%), arthritis (97%), search for anti-PM/Scl is performed in myositis (88%), restrictive syndrome every patient with an ANA associated or lung (78%) and dysphagia with nucleolar fluorescence on one (78%). hand and either an homogeneous or a Anti-PM/Scl are directed against a nuc- speckled fluorescence pattern on the leolar macromolecular complex of pep- other hand. The search for anti-PMScl tides of 75 (PM/Scl-75 protein) and was performed by immunodiffusion 100 kDa (PM/Scl-100 protein), with until 2001 and then by immunodot (kit PM/Scl-75 being considered the main ANA-Porfil 3 EUROLINE / BIOG- autoantigen (6). This autoantigenic NOST), which allowed improving the complex is the human homologue of sensitivity for anti-PMScl detection. the yeast exosome, which is an RNA- In Hautepierre Hospital, the search for processing complex (7). ANA is performed by IF on HEP 2 These are observed in cells. Search for anti-PM/Scl is per- 6% of isolated idiopathic inflammatory formed by immunodiffusion (kit Ingene myositis (dermatomyositis/polymyosi- 102) in every patient with an ANA and tis), 2% of isolated systemic sclerosis speckled / nucleolar pattern in IF. Posi- and 24% of overlap type scleromyositis tivity of anti-PM/Scl is confirmed by (4, 5). Among all patients with PM/Scl, immunodot in the department of auto- 43 to 88% have scleromyositis or scle- immunity in Centre Hospitalier de Lux- rodermatomyositis. embourg (Professor Humbel). The aim of our study was to analyse Diagnostic criteria for polymyositis clinical and biological characteristics (PM) and dermatomyositis (DM) are of Caucasian patients with anti-PM/Scl the classical criteria of Peter and Bohan detected in two University Hospitals: (8). Diagnostic criteria for systemic Erasme University Hospital in Brussels sclerosis are the classical criteria of the and Strasbourg University Hospitals. American Association (9). Patients and methods Every patient has been evaluated by Patients two senior who established The medical records of every patient the diagnosis in the setting of multi- with anti-PM/Scl in the two centers disciplinar discussions.

130 Anti-PM/Scl antibodies in connective tissue disease / F. Vandergheynst et al. arthritis rheumatoid olymyositis and systemic sclerosis; S/N: Speckled/nucleolar; H/N: Homoge- FFF FF F MFF F Erasme Hospital (Bruxelles) (n = 7) (n = 7) Hautepierre Hospital (Strasbourg) of the hands < penicillamine < penicillamine of the hands seronegative renal crisis Sjogren myositis (DM) (DM/Scl) sclerosis (PM/Scl) sclerosis (PM/Scl) (DM/Scl) (PM/Scl) sclerosis Pulmonaryinvolvement Articularinvolvement Sicca syndrome +Renalinvolvement + +Dysphagia and/or +deglutition abnormalities +Cancer + + –Others + – + – – + – – –Antigenic + –specificity Hyperkeratosis – + –other than PM Scl –FR IgM –(>20U/ml) + – – –Anti-phospholipid + –Ab and/or lupic –anticoagulant – –cryoglobulinemia + – – – +Cryoglobulin + – Myositis + – + + + – – – – – – – – + – – – – – – – + NP Myasthenia – + – – – + – – – + NP – Hyperkeratosis NP Initial diagnosis NP + – + + – – – + + – NP Sclerodermic – – + + – – – – – – – – + – – – NP + NP – – – – + + – + – – – + – + + – – – + + RO/SS-A – – – – + – – – – – – – – – – – – NP – – Sex F F F F AgeDuration of follow-up (yrs) Diagnosis 4.5 46 Primary 1 Dermato- 34 Overlap 20 DM 70 Systemic 2.5 60 DM 11 Overlap 56 Systemic 7.5 Overlap 33 Overlap 2 33 PM 12 43 DM 3.5 Overlap 36 Systemic 3 34 8 71 3 25 14 75 57 3 Clinical and biological data of the patients. able I. T Clinical Data Raynaud + – +Biological +Data ANA: + fluorescence S/N – S/N +Overlap (DM/Scl): syndrome between dermatomyositis and systemic sclerosis; (PM/Scl): p H/Nneous/nucleolar; NP: Not performed; N: normal. + S/N S/N + S/N – H/N – S/N S/N + S/N + S/N + S/N S/N S/N Patients Data Patient 1 2 3 4 5 6 7 8 9 10 11 12 13 14

131 Anti-PM/Scl antibodies in connective tissue disease / F. Vandergheynst et al.

Clinical abnomalities Table II. Characteristics of patients with anti-PM/Scl antibodies. Diagnosis of lung involvement is made on the basis of interstitial infiltrates Reichlin Genth Marguerie Oddis Present series n = 20 n = 12 n = 32 n = 23 n = 14 demonstrated by tomodensitometry and/or abnormality of diffusion capaci- Clinical features ty for carbon monoxide (DLCO). Joint Raynaud 55% 92% 100% 65% 71% Interstitial pulmonary disease 35% 42% 78% 30% 85% involvement is diagnosed on the basis Arthralgia/arthritis 50% 58% 97% 83% 85% of arhralgias or arthritis. Renal involve- Dysphagia/Deglutition ? 36% 78% ? 21% ment is diagnosed when proteinuria (> abnormalities 0.15 g per day), elevation of serum cre- Renal involvement ? 0% 3% 0% 21% Sicca syndrome ? 25% 34% ? 43% atinin (> 1.2 mg/dl) or decrease in crea- tinin clearance are observed repeatedly Diagnosis and are not related to drug toxicity (e.g. Idiopathic inflammatory 55% 8% 3% 26% 38% D-penicillamine) or an associated dis- myopathy Systemic sclerosis 4% 50% 12% 30% 15% ease (e.g. diabetes mellitus or hyper- Scleromyositis or 41% 42% 85% 43% 38% tension). Diagnosis of esophageal in- sclerodermatomyositis volvement is made on the basis of an Primary Sjo¨gren’s syndrome - - - - 1 patient abnormal barium swallow or manome- out of 14 try or a history of dysphagia, laryngeal aspiration or aspiration pneumonia. Previous series of patients with anti- ing to Chisholm’s classification) was PM/Scl have shown that this autoanti- identified in 2 of them. Results body is associated with myositis and/or The large majority of patients with Mean duration of follow-up of the 14 systemic sclerosis, which is confirmed anti-PM/Scl are diagnosed as myositis patients with anti-PM/Scl was 6.1 years by our study. Nevertheless, we identi- and/or systemic sclerosis, but the pre- after the diagnosis (1-20 years). Clini- fied one patient with primary Sjög- valence of the different clinical mani- cal and biological characteristics of rens’s syndrome associated - at time of festations is highly variable from one these patients are detailed in Table I. diagnosis - with interstitial lung disease series to another (Table II). This can be were administered to and lacking any feature of systemic explained by the variability of criteria all patients, among whom 4 underwent sclerosis or myositis. Only one other used to identify these complications. In methylprednisolone pulses. case of isolated primary Sjögren’s syn- our series, prevalence of renal involve- Immunosuppressive drugs were given drome associated with presence of anti- ment (defined as renal failure or pro- to the majority of patients: hydroxy- PM/Scl has been reported in the litera- teinuria of more than 0.15 g per day) is chloroquine (1/14), azathioprine (2/14), ture (11). In the largest series of pat- of 23% (n = 3), whereas Genth - defin- (3/14), cyclophosphamide ients with anti-PMScl, Schnitz found ing renal involvement as rapidly pro- (1/14), intravenous immunoglobulins only 5 patients among 55 without gressive renal failure or malignant arte- (2/14), γ interferon (1/14), D-penicil- clearly identified systemic sclerosis rial hypertension - found a prevalence lamine (3/14) and (1/14), and/or myositis. Nevertheless, except of 0%. With such a definition, only one the latter of which was used in the set- for the case of primary SS, the 4 other of our patients would have been con- ting of a clinical trial for the patient patients had clinical features typically sidered as having renal involvement . with primary Sjögren’s syndrome (10). observed in these disorders. These 4 In the 3 patients in our series with renal In our retrospective study - given the patients had signs and symptoms not involvement, we considered it was re- diversity of disease course and clinical sufficiently evolved to fulfill classifica- lated to systemic sclerosis, and there- manifestations - we were unable to tion criteria for a well-defined connec- fore did not perform biopsy. The freq- evaluate the efficacy of these treatment tive tissue disease. Hence they could be uency and the severity of pulmonary options. Of the 4 patients treated with considered as having undifferentiated involvement differ between series reac- D-penicillamine for systemic sclerosis, connective tissue disease (UCTD) (12). hing 85% in our series. 2 had to interrupt the treatment because To the best of our knowledge, the pre- Diagnostic value of anti-PM/Scl is of new-onset autoimmune manifesta- valence of anti-PM/Scl in UCTD has interesting because, in the literature, 43 tions (1 case of myasthenia, 1 case of not been defined. to 88% of anti-PMScl positive patients myositis) which regressed after cessa- The prevalence of sicca syndrome in have overlap syndromes (scleromyosi- tion of D-penicillamine. other series of anti-PM/Scl patients tis or sclerodermatomyositis). varies from 0 to 45% depending on the Nevertheless, other autoimmune mark- Discussion diagnostic tools that are used . In our 6 ers for these overlap syndromes have This retrospective analysis of 14 pat- patients presenting with sicca syn- been described depending on genetic ients with anti-PM/Scl largely confirms drome, 5 underwent a minor salivary factors. Among Japanese patients with previous published data. We further gland biopsy. A lymphoid infiltrate scleromyositis, 50% have anti-Ku anti- underline several points as follows: suggestive of SS (grade 3 or 4 accord- bodies, whereas anti-PMScl are very

132 Anti-PM/Scl antibodies in connective tissue disease / F. Vandergheynst et al. rare. Inversely, only 10% of North a speckled / nucleolar pattern (13/14), patients with polymyositis overlap syn- American patients with scleromyositis or a homogeneous / nucleolar pattern dromes. J Clin Immunol 1984; 4: 40-4. 3. GENTH E, MIERAU R, GENETZKY P et al.: have anti-Ku (13). (1/14) in immunofluorescence. The Immunogenetic associations of scleroderma- None of the patients in our series died, only antigenic specificity observed related antinuclear antibodies. Arthritis in accordance with the favourable other than anti-PM/Scl was an anti- Rheum 1990; 33: 657-65. prognosis observed in the literature: Ro/SS-A identified in one patient 4. MARGUERIE C, BUNN C, COPIER J et al.: The clinical and immunogenetic features of only one death related to connective (patient N° 11 - Table I). In the litera- patients with autoantibodies to the nucleolar tissue disease is reported, due to pul- ture, detection of other auto-antibodies antigen PM-Scl. Medicine 1992; 71: 327-36. monary hypertension (4). Among all is rarely observed in patients with anti- 5. ODDIS C, OKANO Y, RUDERT W, TRUCCO M, auto-antibodies encountered in sys- PM/Scl: one patient with anti-dsDNA DUQUESNOY RJ, MEDSGER T: Serum autoantibodies to the nucleolar antigen PM- temic sclerosis, anti-PMScl is associat- (4) without feature and one Scl. Clinicals and immunogenetic associa- ed with the best prognosis, despite the patient with anti-JO1 (5). On the other tions. Arthritis Rheum 1992; 35: 1211-17. frequency of interstitial lung disease hand, positivity 6. RAIJMAKERS R, RENZ M, WIEMANN C et al.: PM-Scl 75 is the main autoantigen in patients and the frequent overlap with myositis. seems to be higher reaching 28% (n=4) with the polymyositis/scleroderma overlap This observation could be due to sever- in our study, 66% in Marguerie’s series syndrome. Arthritis Rheum 2004; 50: 565-9. al factors: and 50% in Genth’s series (3). 7. BROUWER R, VREE EGBERTS WT, HENGST- - Patients in our series with interstitial MAN GJ et al.: Autoantibodies directed to novel components of the PM/Scl complex, lung involvement responded well to Conclusion the human exosome. Arthritis Res 2002; 4: corticosteroids - as described in the Anti-PMScl antibodies are specific 134-8. literature - and none of them devel- markers of systemic sclerosis and myo- 8. BOHAN A, PETER JB: Polymyositis and der- oped severe respiratory failure. Such sitis and particularly of the overlap matomyositis. N Engl J Med 1975; 292: 344- 47, 403-7. patients, therefore, generally do not syndromes, scleromyositis or sclero- 9. SUBCOMMITTEE FOR SCLERODERMA CRITERIA require cyclophosphamide for pul- dermatomyositis. Presence of this anti- OF THE AMERICAN RHEUMATISM ASSOCIATION: monary involvement. body is a good prognostic factor as Diagnostic and Therapeutic Criteria Com- - No muscular or myocardial compli- there appears to be no association with mittee: Preliminary criteria for the classifica- tion of systemic sclerosis (scleroderma). cation occurred in patients with malignancy. Furthermore, the associat- Arthritis Rheum 1980; 23: 581-90. myositis . ed lung involvement is generally not 10. STEINFELD S, DEMOLS P, SALMON I, KISS R, -To the best of our knowledge, aggressive and responds well to corti- APPELBOOM T: Infliximab in patients with among all patients with anti-PM/Scl costeroids. primary Sjögren’s syndrome: a pilot study. Arthritis Rheum 2001; 44: 2371-75. described in the literature, an occur- Anti-PMScl - detected by immunofluo- 11. SCHNITZ W, TAYLOR-ALBERT E, TARGOFF I, rence of cancer has been reported rescence - must be identified by specif- REICHLIN M, SCOFIELD R: Anti-PM/Scl only once : a heavy smoker (more ic methods (immunodiffusion, immu- autoantibodies in patients without clinical polymyositis or scleroderma. J Rheumatol than 50 packets per year) died from noblot), justifying close collaboration 1996; 23: 1729-33. lung cancer, 15 years after the onset with a specialised laboratory. 12. MOSCA M, BALDINI C, BOMBARDIERI S: of connective tissue disease (5). The Undifferentiated connective tissue diseases delay between the onset of the two References in 2004. Clin Exp Rheumatol 2004; 22 (Suppl. 33): S14-S18. diseases makes a causal relationship 1. WOLFE JF, ADELSTEIN E, SHARP GC: Antinu- 13. FRANCHESCINI F, CAVAZZANA J, GENERALI very unlikely. clear antibody with distinct specificity for polymyositis. J Clin Invest 1977; 59: 176-8. D: Anti-Ku antibodies in connective tissue Every patient with anti-PM/Scl in our 2. REICHLIN M, MADDISON P, TARGOFF et al.: diseases: clinical and serological evaluation study had high ANA levels , with either Antibodies to a nuclear/nucleolar antigen in of 14 patients. J Rheumatol 2002; 29: 1393-7.

133