94Overlap of ACA-positive systemic sclerosis and Sj
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94Overlap of ACA-positive systemic sclerosis and Sj
OverlapofACA-positivesys；riskoflymphoma；C.Baldini,M.Mosca,A.Dell；N.Luciano,R.Talarico,C.T；RheumatologyUnit,Univers；Objectives；Weaimedtoassessthepreval；ofpatientsaffectedby“ACA；Inth
　Overlap of ACA-positive systemic sclerosis and Sj?gren’s syndrome: a distinct clinical entity with mild organ involvement but at highrisk of lymphomaC. Baldini, M. Mosca, A. Della Rossa, P. Pepe, C. Notarstefano, F. Ferro,N. Luciano, R. Talarico, C. Tani, A.G. Tavoni, S. BombardieriRheumatology Unit, University of Pisa, Pisa, Italy.ObjectivesWe aimed to assess the prevalence of patients with either primary Sj?gren’s syndrome (pSS) and positive anticentromere antibodies (ACA) and secondary Sj?gren’s syndrome (sSS) and limited cutaneous ACA-positive systemic sclerosis (SSc) in two large cohorts of patients with pSS and SSc? and also to compare the clinical features of these two subsets with thoseof patients affected by “ACA-positive SSc without sicca symptoms” and “pSS”.MethodsIn this retrospective monocentric study, the case records of “overlap” patients ful?lling both the classi?cation criteria for SS and the LeRoy criteria for early SSc were identi?ed from two datasets of patients with limited cutaneous ACA-positive SSc (209 subjects) and with pSS (402 subjects) who attended our Rheumatology Unit in the years between 1989 and 2011. Control groups were represented by SSc subjects without sicca symptoms (“SSc group”) and ACA-negative pSS patients(“pSS group”). SSc patients with sicca symptoms (“Sicca-SSc group”) who did not complete the diagnosticalgorithm for SS were excluded from the analysis. Demographic, clinical and immunological data of the patients enrolledwere collected cumulatively over the entire follow-up period. Statistical analysis was performed using SPSS 13(SPSS Inc., Chicago IL, USA)ResultsOut of the two datasets 41 “overlap” patients were selected. The control groups were represented by 102/209 SSc subjects without sicca symptoms (“SSc group”) and 387/402 pSS patients (“pSS group”). Eighty-one “sicca-SSc” with an incomplete work-up for SS were excluded from the analysis. The prevalence of ACA-positive pSS patients among pSS was 3.7% (15/402), while the frequency of patients with de?nite sSS in the SSc cohort was 20% (26/128). No differences were detected between “overlap” patients and control groups, relatively to demographic characteristics. “Overlap patients” were characterised by a milder SSc disease (i.e. lower frequency of sclerodactily, negative evolution of the capillaroscopy pattern or absence of severe systemic involvement) whereas, as far as the SS-related manifestations were concerned, although often lacking in speci?c autoantibodies (i.e. rheumatoid factor, anti-Ro/SSA, anti-La/SSB), the “overlap patients” displayed a full blown SS phenotype with recurrent salivary gland enlargement, purpura, fatigue, arthralgias, and leukocytopenia. It is noteworthy that the prevalence of non-Hodgkin’s lymphoma in the “overlap patients”was higher than in pSS.ConclusionsTaken together, the results of our work emphasise the existence of a novel distinct clinical entity which might tentatively be called “ACA-positive limited scleroderma/SS overlap syndrome” characterised by a benign SSc clinical course butat a high risk of non-Hodgkin’s lymphoma.Key wordssystemic sclerosis, Sj?gren’s syndrome, lymphomaChiara Baldini, MD Marta Mosca, MDAlessandra Della Rossa, MD Patrizia Pepe, MDChiara Notarstefano, MD Francesco Ferro, MD Nicoletta Luciano, MD Rosaria Talarico, MD Chiara Tani, MDAntonio G. Tavoni, MDStefano Bombardieri, MD, PhDPlease address correspondence to:Chiara Baldini, MD,Dipartimento di Reumatologia, Università di Pisa, Via Roma 67, 56126 Pisa, Italy.E-mail: chiara.Received on September 25, 2012; accepted in revised form on November 5, 2012.? Copyright EXPERIMENTALCLINICAL RHEUMATOLOGY AND2013.Competing interests: none declared.IntroductionSystemic present from with autoimmune a clinical picture diseases varying may diseases (1-6). Sj?gren’s syndrome (SS) undifferentiated to overlapping is a systemic autoimmune disease char-acterised by a progressive hypofunction of frequently the salivary and lachrymal glands, extra-glandular associated with a variety of ing manifestations, includ-orders malignant alone with as (7, primary 8). lymphoproliferative The SS disease dis-or in may association occur as sociation secondary other connective SS. In particular, tissue disorders the as-(SSc) and SS has been described since between systemic sclerosis 1965 when Bloch the cases of three patients with SS and et al. (9) ?rst reported progressive studies have con?rmed the existence of SSc. Afterwards, several a full SS clinical phenotype in patients with ing a limited SSc with positive anticen-SSc, especially in those present-tromere antibodies (ACA) (10-20). On the other hand, an increasing number of reports have described the existence of a subgroup of SS patients with positive ACA regarded as a distinct clinical vari-ant of pSS (13, 17, 18, 21-24). Thus, the interplay between SS and SSc seems to be quite complex encompassing a wide spectrum overlapping of clinical intermediate and make it challenging to differentiate one phenotypes which might from the others in the absence of novel biomarkers (25-36). In the present study we analysed the prevalence and clinical pro?le of patients classi?ed as affected by either “ACA-positive limited cutane-ous SSc and concomitant sSS” or “ACA-positive pSS”. The features of these pa-tients were compared with those of both the patients affected by “ACA-positive SSc SSc) and the “ACA-negative pSS” pa-without SS” (from now on called tients (from now on called pSS). Patients and methodsThis spective, study was a single-centre, retro-out at a tertiary-referral Rheumatology observational study carried centre.Patient selectionThe case records of all the patients with a diagnosis of limited cutaneous ACA-273positive SSc and/or pSS attending the Rheumatology of Pisa in the years between 1999 and Unit of the University 2011 were reviewed in order to identify patients ful?lling both the classi?cation criteria SS. The diagnosis of SSc was made ac-for ACA-positive SSc and for cording to the “American Rheumatism Association criteria” (37) and LeRoy alsis of SS followed the “American-Eu- “early SSc criteria” (38); the diagno-et ropean consensus group” (AECG) cri-teria (39). Criteria for pre-scleroderma or very early SSc, as recently put for-ward by the European League Against Rheumatism Research Scleroderma Trials and also Group (EUSTAR) (40) was all, study: 209 with a diagnosis of limited 611 assessed patients in were all the enrolled cases. in Over-this cutaneous ACA-positive with a diagnosis of pSS.SSc and 402 Data collectionDemographic, clinical and immunolog-ical over the entire follow-up period for all data were collected cumulatively patients the ease most of each group. According to ance of Raynaud’s Phenomenon, sicca onset recent was de?ned literature by studies, the appear-dis-manifestations, salivary gland enlarge-ment, sclerodactily, digital ulcers, calcinosis, arthritis, purpura, puffy ?ngers, dysphagia, pulmonary arterial hypertension or lung gastroesophageal re?ux, ?brosis (41-43).Clinical for and laboratory assessment on subjective dry eyes and mouth, pa-the SS component included data rotid or gland enlargement and previous tions present lished as de?ned extra-glandular manifesta-for series the activity in the recently pub-jective of disease and damage criteria the literature and in the (8, 44-48). largest case Ob-tivitis xerostomia and keratoconjunc-to the AECG criteria. Biopsy results of sicca were assessed according minor according salivary and/or the Chisholm and Mason score to the glands focus were scoring classi?ed system (39, quired 49). Diagnosis of lymphoma re-the on SSc histological component con?rmation. For naud’s the presence we collected data phenomenon, of sclerodactily, telangiectasia,Ray-Subsets included in the studynal variables. Chi-Square, ANOVA and Logistic regression were performed. Patients with missing data were ex-cluded from the respective analysis.
Statistical analysis was performed us-ing SPSS 13 (SPSS Inc., Chicago IL, USA)ResultsStudy populationTwo hundred and nine patients with a diagnosis of limited cutaneous ACA-positive SSc and 402 patients with pSS attended our Rheumatology Unit from 1989 to 2011. Out of the two datasets, we selected 102/209 subjects with lim-ited cutaneous SSc without sicca symp-toms (SSc group), 387/402 patients with ACA-negative pSS (pSS group) and 41 patients who ful?lled both the LeRoy early SSc diagnostic criteria and the diagnostic criteria for SS (from now on called “overlap” group). Eighty-one SSc patients with sicca symptoms were excluded from the analysis since either the diagnosis of sSS was not substanti-ated by a minor salivary gland biopsy or they did not complete the algorithm for sSS diagnosis as required by the AECG criteria 2002 (from now on called “sic-ca SSc”). Figure 1 summarises the dif-ferent subsets included in the study. It can be observed that the prevalence of ACA(+) SS patients was 3.7% (15/402) while the frequency of patients with sicca symptoms and/or de?nite sSS in the SSc cohort were 51.2% (107/209) and 20% (26/128), respectively. Table I summarises the epidemiologic features of the three subgroups of patients en-rolled and namely:
the “overlap group” (n=41), the “SSc group” (n=102) and the “pSS group” (n=387). Nodiffer-Unit from 1989 to 2011. Out of the two datasets of patients with a diagnosis of limited cutaneous ACA-positive SSc (n=209) and with pSS (n=402) we selected 102/209 subjects with limited cutaneous SSc without sicca symptoms (SSc group), 387/402 patients with ACA-negative pSS (pSS group) and 41 patients who ful?lled both the LeRoy early SSc diagnostic criteria and the diagnostic criteria for SS (“overlap” group). This “overlap” group consisted of 26 patients originally classi?ed among the 209 SSc patients and of 15 patients previously included in the pSS dataset. Eighty-one SSc patients with sicca symptoms (“sicca SSc”).were excluded from the analysis since either the diagnosis of sSS was not substantiated by a minor salivary gland biopsy or they did not complete the algorithm for sSS diagnosis as required by the AECG criteria 2002.Note: SSc: patients with ACA(+)SSc a Sicca-SSc: SSc patients with sicca symp-toms an incomplete work up SS; Overlap: patients ful?lling both the criteria for SSc and SS; pSS: patients with primary SS.Fig. 1. Displays the subsets included in the study. Two hundred and nine from our Rheumatologyeosophageal involvement, lung intersti-tial ?brosis, pulmonary hypertension, and digital ulcerations. In particular pulmonary hypertension was de?ned by an increase in mean pulmonary ar-terial pressure (PAP) 25 mmHg at rest as assessed by right heart catheterisa-tion (50); if a right heart catheterisation had not been performed, a pulmonary artery systolic pressure &40 mmHg on the heart Doppler echocardiography was considered diagnostic. Lung inter-stitial involvement was documented by chest x-ray and when required by high resolution computed tomography. As far as laboratory tests were concerned, white blood cell count &4000/mm3, C3 &80 mg/dl, C4 &10 mg/dl, IgG globu-lin &1.6 g/dl, creatinine clearence &60 ml/min, proteinuria &300 mg/day and urinary pH &6 were considered abnor-mal. Immunological data included anti-nuclear antibodies (detected by indirect immuno?uorescence), anti Ro/SSA, La/SSB antibodies (by counterimmuno-electrophoresis), and rheumatoid factor (RF, by nephelometry). ACA were de-tected by indirect immuno?uorescence. Data on mixed cryoglobulinemia and monoclonal antibodies were not avail-able for many of the patients enrolled in this study and so were not included in the analysis.Statistical analysisData were expressed as mean±SD for continuous variables and as absolute frequencies and percentages for nomi-Table I. Epidemiologic features of the patients enrolled in the study.Epidemiologic featuresSexAge at the onset (mean ±SD, yrs)Age at diagnosis of SSc (mean ±SD, yrs) Age at the inclusion (mean ±SD, yrs)Disease duration from the onset (mean ±SD, yrs) Length of follow-up (mean ±SD, yrs) Menopausal status (+)Overlap* (n=41) 41 F:0 M 45 ± 13 52 ± 12 59 ± 12 13.6 ± 9.4 6 ± 5 32 (78%)SSc (n=102) 95 F:7 M 46 ± 15 54 ± 14 60 ± 14 15 ± 1.6 6 ± 7 78 (77%)pSS (n=387) 376F:11 M 49 ± 14 n.a. 59 ± 14 14 ± 10 7 ± 7 270 (75%)p-value
NS NS NS NS NS NS NSsicca-SSc** (n=81)80F:1M48 ± 1658 ± 1264 ± 1116 ± 136 ± 760 (74%)Notes.*overlap: patients with both SSc and SS; **sicca-SSc: SSc patients with sicca symptoms for whom the diagnosis of sSS was not substantiated by a minor salivary gland biopsy or by a complete diagnostic algorithm as required by the AECG criteria 2002.274ences were detected between the three groups as far as the epidemiologic and demographic characteristics were con-cerned. did not differ for sex ratio, age at the In particular, the three groups onset of the disease, age at the diagno-sis of SSc, age at the inclusion, meno-pausal status and follow-up length.SSc-related manifestation in“overlap patients” vs. “SSc patients”The cal Table manifestations” frequency of “SSc-related is clini-the study satis?ed the Le Roy criteria III. All the patients summarised included in in and the VEDOSS criteria whereas the ARA criteria were ful?lled by 88% of the “SSc patients” and by 61% of the “overlap signi?cant difference between the two patients” with a statistically groups “overlap patients” ful?lled at least the (p&0.0001). Although all the classi?cation criteria for early SSc, the comparative analysis shows that these patients involvement had Raynaud’s than a less severe systemic the ity of both “SSc patients” and “overlap ?rst symptom phenomenon the “SSc for the represented patients”. vast major-patients” ptype =0.07). (96% Nonetheless, vs. 85% scleroderma-respectively, detected more frequently in the former nailfold capillary patterns were subgroup rather than in the latter (Fig. 2). ci?c In particular, we found in vs.the abnormal 32% of capillaroscopy an the “overlap pattern unspe-ue=0.05) and an active pattern in 18%
15% of the “SSc patients” patients” (p-val-of the “SSc patients” (the “overlap patients” vs. 44% of onset p-value=0.03). The was naud’s apparently of subjective sicca symptoms of phenomenon concomitant in to Ray-eye and dry mouth were referred later the “overlap patients” 21/41 whereas (51%) dry during patients, with a mean latency from the the follow-up by 18/41 (44%) ?rst in 2/41 (5%) of the cases sicca symp-symptom of 7.9±7.3 years. Only toms preceded the diagnosis of SSc. As far as internal organ involvement was related, with subgroup SSc when alone, compared the “overlap with patients patient” serious SSc disease. More speci?cally, seemed to evolve to a less “overlap patients” presented a higherTable II. Clinical pattern of the “SSc-related manifestations”.FeaturesOverlap (n=41) * (n=102) SSc
p-valuesicca-SSc(n=81)**
ARA criteria Le Roy criteria25 &0.0001 66 Capillaroscopy (speci?c pattern) 41 (61%) 102 90 (88%) Dif?culty in swallowing/Dysphagia 29 (100%) 90 (100%) 0.004 NS 81 (81%)Esophageal involvement 28 (72.5%) 76 (92.8%) NS 62 (100%)50 (76%)Sclerodactyly 22 (68.3%) 72 (74.5%) Teleangiectasia 21 (53.7%) 89 (70.6%) &0. 43 (61%)Melanoderma 22 (51.2%) 32 (87.3%) 0.02 65 (53%)Calcinosis 3 (43.7%) 9 (31.4%) (8.8%) NS 28 (81%)10 (34%)Digital ulcers1 (7.3%) Pulmonary arterial hypertension 5 (2.4%) 2 (12%) 50 7 (6.9%) &0.0001 NS Heart involvement 0.09 29 3 (13%)(4%)Lung ?brosis4 (4.9%) 16 (49%) NS 12 6 (36%)(8%)Renal involvement 6 (9.8%) 18 (15.7%) NS Primary Biliary cirrosis 0 (14.6%) (0%) 26 (17.6%) 2 (25.5%) (2%) NS 8 (14%)0 (10%)Thyroiditis15 2 (4.9%) (36.6%)34 3 (3%) (33.3%)NS NS30 5 (0%)(6%)(37%)Notes.whom the diagnosis of sSS was not substantiated by a minor salivary gland biopsy or by a complete*overlap: patients with both SSc and SS; **sicca-SSc: SSc patients with sicca symptoms for diagnostic algorithm as required by the AECG criteria 2002.Nailfold capillaroscopy patternsFig. 2.Scleroderma-type nailfold capillary patterns were detected more frequently in the SSc group rather
Shows capillaroscopy patterns in the SSc group and in the overlap group.than in the overlap group.prevalence of teleangectasia (43.7% 3.4%, p=0.02) but a lower prevalence of vs. vs.both digital necrosis and ulcers (12.2%(51.2%
49%, p&0.0001) and sclerodactily out of the 41 the “overlap patients” notvs. 87.3%, p&0.0001), with 20 275Table III. A. Clinical pattern of the “SS-related manifestations”.FeaturesOverlap(n=41)*
(n=102)SSc
p-valuesicca-SSc(n=81)** Xerophtalmia Xerostomia41 0 &0.0001 Parotid enlargement 40 (100%) 0&0.0001 75 Articular involvement 13 (97.5%) (1%) &0.%)(92%)Purpura 19 (31.7) &0.0001 PNS 6 (46.3%) (14.6%) 17 1 (16.7%) 0. (4%)2 (29%)(3%)Fatigue (2.4%) 0
Lymphoma 16 1 (39%) 0&0.0001 NS Low C3 levels 6 (14.6%) 3 (2.9%) 0.002 17 1 (1%)Low C4 levels 7 (17.9%) (1%) NS 19 1 (21%)(1%)Leukocytopenia3 (7.7%) 22 1 (22%) Hypergammaglobulinaemia 8 (19.5%) 4 &0.0001 NS ESR8 (20%) 1 (4%) 0.001 11 4 (24%)(5%)(13%)Anti-Ro/SSA 7 (17.1%) 2 (1%) Anti-La/SSB9 (22%) 6 (2%) &0. 15 6 (8%)0 (18%)Rheumatoid factor (RF)173 (7.3%) 0 (6%) (0%) (41.5%)110 (0%) (11.3%)&0.00010.02 19 0 (0%)(0%)(24%)Notes.whom the diagnosis of sSS was not substantiated by a minor salivary gland biopsy or by a complete *overlap: patients with both SSc and SS; **sicca-SSc: SSc patients with sicca symptoms for diagnostic algorithm as required by the AECG criteria 2002.Table III. B. Clinical pattern of the “SS-related manifestations”.FeaturesOverlap(n=41) *
(n=387) pSS
p-valueSicca-SSc(n 81)** Xerophtalmia Xerostomia41 346 Parotid enlargement 40 (100%) 344 (89.4%) 0.02 75 Articular involvement 13 (97.5%) Purpura 19 (31.7) 233 52 (89) (13.6%) 0.005 NS 74 (93%)PNS 6 (46.3%) 20 (60%) 0.02 NS 24 3 (92%)(4%)Fatigue 0.02 2 (29%)Lymphoma 16 1 (14.6%) (2.4%) Low C3 levels 6 (39%) 85 2 (5%) (0.5%) Low C4 levels 7 (14.6%) 12 (22%) 0.004 0.01 17 1 (3%)(1%)Leukocytopenia3 (17.9%) 44 (3%) NS Hypergammaglobulinaemia 8 (7.7%) 23 (14%) (7%) NS 19 1 (21%)(1%)(24%)Anti-Ro/SSA 8 (19.5%) Anti-La/SSB9 (20%) 211 80 (21%) 292 (56%) &0.0001 NS 11 4 (5%)&0.0001 Rheumatoid factor (RF)17 3 (22%) (7.3%) (41.5%)139 (75%) 241 (36%) (64%)&0. (13%)(8%)0.010 (18%)0 (0%)(0%)Notes.whom the diagnosis of sSS was not substantiated by a minor salivary gland biopsy or by a complete *overlap: patients with both SSc and SS; **sicca-SSc: SSc patients with sicca symptoms for diagnostic algorithm as required by the AECG criteria 2002.developing skin sclerosis over a mean follow-up nary arterial hypertension diagnosis in although of 3.3±3.5 yrs. In addition, 7/102 “SSc patients” and only in 1/41 heart involvement, gastrointestinal tract not statistically signi?cant, of the “overlap patients”. Noteworthy, involvement and lung ?brosis occurred the 81 sicca-SSc patients showed an in-more frequently in the group of patients termediate clinical pro?le between the with SSc alone rather than in the over-SSc and the “overlap patient” groups. lap patients. It is noteworthy that, pul-More monary arterial hypertension estimated “overlap speci?cally, on higher frequency of sclerodactily (81% patients” in they comparison presented with an observed the basis vs.and in 16/102 of echocardiography was 12%).
51.2%) and digital ulcers (36% vs.(15.7% solely vs. 4.9%, in 2/41 patients with SSc p”overlap” patients pared catheterisation con?rmed =0.09). Right heart a pulmo-presented to On patients the other with hand, when com- ?brosis (10% a lower SSc alone they vs. 25.5%) (Table II).prevalence of lung 276SS-related manifestation in“overlap patients” vs. “SSc patients” and “pSS patients”The frequency of the “SS-related clini-cal manifestations” in the three groups is summarised in Table III III tical B. Despite excluded from the statis-A and Table bles III analysis, “SS-related A and III we B the frequency of the also reported in Ta-of the 81 “sicca-SSc patients”. All the clinical manifestations”
“overlap patients” satis?ed the AECG criteria for SS and had a focus score ≥1 at the minor salivary gland biopsy. As far as glandular manifestations was re-lated, subjective and objective evidence of sicca syndrome was detected almost in all the patients. In addition, we also found parison to the “SSc patients” presented that “overlap patients” in com-a higher frequency of parotid swelling (31.7% (46.3% vs. 1% p&0.0001), arthralgias (14.6 (19.5% vs.vs. 16.7%, p&0.0001), purpura (39% ly, parotid salivary gland enlargement, vs.vs. 0,
1%, p=0.0004), leukocytopenia pp&0.0001). Surprising-&0.0001) and fatigue purpura, peripheral nervous system in-volvement and fatigue were also more common in the “overlap patient group” than in patients with pSS. Nonetheless, in when spite of their clinical “overlap compared to pSS presentation, patients, showed patients” more infrequently the (Ro/SSA p&0.0001) RF positivity (hypergammaglobulinaemia autoantibodies (p&0.0001) and p=0.01), anti SS-related (p&0.0001). anti-La/SSB Regarding 6/41 SSc ”overlap long-term patients” complications and 1 of the kin’s patients quency lymphoma developed (p&0.0001). a non-Hodg-The fre-patients was even higher than the one of lymphoma in the overlap detected 12/387, p=0.004).in the pSS group (6/41 vs. Prevalence and risk factors for non-Hodgkin’in overlap patientss lymphoma In of non-Hodgkin’s lymphoma: 6/20 cas-our series we documented 20 cases es occurred in the overlap subset, 1/20 in the the and group “SSc group” (p=0.002), 1/20 in tients. The histology features of the 12the remaining of the “sicca-SSc 12/20 in patients” pSS pa-包含各类专业文献、生活休闲娱乐、各类资格考试、幼儿教育、小学教育、高等教育、应用写作文书、外语学习资料、行业资料、专业论文、文学作品欣赏、中学教育、94Overlap of ACA-positive systemic sclerosis and Sj等内容。　
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