Journal of Autoimmunity xxx (2014) 1e4
Contents lists available at ScienceDirect
Journal of Autoimmunity journal homepage: www.elsevier.com/locate/jautimm
The diagnosis and classification of mixed connective tissue disease Chiara Tani a, Linda Carli a, b, Sabrina Vagnani a, Rosaria Talarico a, Chiara Baldini a, Marta Mosca a, Stefano Bombardieri a, * a b
Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Italy Dottorato Genomec, University of Siena, Italy
a r t i c l e i n f o
a b s t r a c t
Article history: Received 7 October 2013 Accepted 13 November 2013
The term “mixed connective tissue disease” (MCTD) concerns a systemic autoimmune disease typified by overlapping features between two or more systemic autoimmune diseases and the presence of antibodies against the U1 small nuclear ribonucleoprotein autoantigen (U1snRNP). Since the first description of this condition in 1972, the understanding of clinical manifestations and long-term outcome of MCTD have significantly advanced. Polyarthritis, Raynaud’s phenomenon, puffy fingers, lung involvement and esophageal dysmotility are the most frequently reported symptoms among the different cohorts during the course of the disease. Moreover, in recent years a growing interest has been focused on severe organ involvement such as pulmonary arterial hypertension and interstitial lung disease which can accrue during the long-term follow-up and can still significantly influence disease prognosis. Over the last years, significant advances have been made also in disease pathogenesis understanding and a central pathogenetic role of anti-U1RNP autoantibodies has clearly emerged. Although controversies on disease definition and classification still persist, MCTD identifies a group of patients in whom increased surveillance for specific manifestations and prognostic stratification became mandatory to improve patient’s outcomes. Ó 2014 Published by Elsevier Ltd.
Keywords: MCTD Anti-U1RNP autoantibodies Prognosis Classification
1. Introduction The term “mixed connective tissue disease” (MCTD) refers to a systemic autoimmune disease characterized by overlapping features between at least two systemic autoimmune diseases including Systemic Lupus Erythematosus (SLE), Systemic Sclerosis (Ssc), polymyositis/dermatomyositis (PM/DM) and Rheumatoid Arthritis (RA). The presence of antibodies against the U1 small nuclear ribonucleoprotein autoantigen (U1snRNP) is considered as the serological hallmark of this condition. Because of the similar clinical features and unique serologic pattern of the first patients described in 1972, Sharp et al. proposed that MCTD might represent a distinct rheumatic disease syndrome. According to the first descriptions of the disease, MCTD patients appeared to have an excellent response to corticosteroid therapy and a favorable prognosis [1]. Since the first description, our understanding of the classification, clinical manifestations, long-term outcome and pathogenesis of MCTD have all advanced considerably. In this review, we will focus on the recent relevant literature published in the last decade
* Corresponding author. E-mail address: [email protected] (S. Bombardieri).
and we will try to redefine the shape of the disease in the light of the new scientific advances. 2. The endless history of MCTD classification The classification of rheumatic diseases is challenging because of the protean and frequently overlapping clinical and laboratory manifestations [2e5]. This problem is typified by the difficulty of classification and differential diagnosis of MCTD. Indeed, since its first description in 1972 by Sharp et al., it is still a matter of debate whether this condition has to be considered a distinct clinical entity rather than an overlap syndrome between two or more CTDs. Even if the anti-RNP reactivity is considered as the serologic hallmark with a well recognized diagnostic value, it is not restricted to MCTD patients being present also in SLE, SS, SSc patients as well as in Undifferentiated Connective Tissue Diseases (UCTD). However, while antibodies specifically directed against U1e70K are found in 75e90% of MCTD patients representing the most commonly detected U1-snRNP component, they are found in only 20e50% of SLE patients whose serum reacts with anti-RNP, thus suggesting a distinct serologic sub-profile [6]. To date at least three classification criteria for MCTD have been published [7e9].
0896-8411/$ e see front matter Ó 2014 Published by Elsevier Ltd. http://dx.doi.org/10.1016/j.jaut.2014.01.008
Please cite this article in press as: Tani C, et al., The diagnosis and classification of mixed connective tissue disease, Journal of Autoimmunity (2014), http://dx.doi.org/10.1016/j.jaut.2014.01.008
2
C. Tani et al. / Journal of Autoimmunity xxx (2014) 1e4
Comparative studies have reported similar results in term of sensitivity and specificity in capturing MCTD patients [10] while a recent study by Cappelli et al. found that Kasukawa’s criteria were more sensitive (75%) in comparison to those of Alarcon-Segovia (73%) and Sharp (42%) in classifying MCTD patients over time [11]. The clinical need to define disease activity other than to classify them has clearly emerged over the years; in clinical practice, SLEspecific disease activity criteria have been also used in MCTD patients and experience-based activity criteria have been recently proposed by Carvalho JF et al. [12] but, similarly that for classification criteria, an international consensus on this matter is still lacking. 3. Epidemiology, clinical features and prognosis The lack of internationally accepted classification or diagnostic criteria for MCTD led to a scarcity of epidemiological studies over the years and discordant data on the real prevalence and clinical course of this condition [13]. However, in recent years large studies have been published providing important advances on disease epidemiology, clinical and laboratory as well as long term prognosis.
In 2011, Gunnarsson R et al. performed a nationwide retrospective study to assess prevalence and incidence of MCTD in Norway founding 147 adult Caucasian with a definite diagnosis of MCTD and for a point prevalence of 3.8 per 100 000 adults and an incidence 2.1 per million per year during the period from 1996 to 2005 with a female predominance (76.9%) [14]. Prevalence of the clinical findings during the course of the disease as reported by the most recent literature (years 2003e2013) is summarized in Table 1. Polyarthritis, Raynaud’s phenomenon (RP), puffy fingers, interstitial lung disease and esophageal dysmotility are the most frequently reported symptoms among the different cohorts (Table 1) during the course of the disease. The largest recent MCTD cohort has been described by Hajas A et al. in 2013; they found that at the time of diagnosis, polyarthritis, RP, puffy fingers and sclerodactily were the most prevalent symptoms reported in 65%, 53%, 50% and 35% respectively; however, during the 30 years of prospective follow-up patients tended to accrue over time new symptoms such as esophageal hypomotility, nervous system manifestations, pulmonary arterial hypertension (PAH), interstitial lung disease but no progression to other CTD was recorded. Interestingly, they also observed a significant progression
Table 1 Prevalence of the main clinical findings of MCTD as reported in the recent (2003e2013) literature. Author, year, Country
Arthritis-RP
Lung involvement (case definition)
Oesophageal involvement (case definition)
PAH (case definition)
e
ILD: 78% (on HRCT)
e
79%e99%
Self reported dispnea: 47%
Oesophageal dilatation: 56% Gastroesophageal reflux: 50% Oesophageal motor impairment: 83% Symptoms of oesophageal dysmotility: 50%
89.6%/59.5%
ILD: 47% (on HRCT and PFR)
17.8% (on DE right ventricle catheterization)
94.5%/78.6%
ILD: 52.7% (on HRCT and PFR)
e
ILD: 52% (on HRCT)
Oesophageal dysmotility (on radiographic barium passage or radionuclide transit scintigraphy): 49.6% Oesophageal dysmotility (on radiographic barium passage or radionuclide transit scintigraphy): 69.5% e
49.7%/85.1%
44.1% (on chest radiography or CT scan or PFR)
45.3% (on manometry or esophageal barium transit)
e
e/86%
e
Gastroesophafeal reflux: 52%
e
e
66.6% (on HRCT)
e
e
e
e
e
3.4% (on Doppler echocardiography right ventricle catheterization)
Type of study N of patients Classification criteria Fagundes MN, 2009, Brazil Prospective 50 Kasukawa’s Gunnarsson R, 2011, Norway Nationwide, retrospective survey 147 At least one (Sharp, Kasukawa or Alarcon-Segovia) Hajas A, 2013, Hungary Prospective observational 280 Alarcon-Segovia Szodoray P, 2012, Norway Prospective observational 201 Alarcon-Segovia Gunnarsson R 2012, Norway Nationwide, cross-sectional 126 At least one (Sharp, Kasukawa or Alarcon-Segovia) Cappelli 2011, Italy Retrospective 161 Expert opinion Maldonado ME, 2008, USA Cross-sectional 21 Alarcon-Segovia Bodolay E, 2005, Hungary Cross-sectional 144 Alarcon-Segovia Gunnarsson R 2012, Norway Nationwide, cross-sectional 147 At least one (Sharp, Kasukawa or Alarcon-Segovia)
e
23.8% (on DE right ventricle catheterization)
e
ILD: interstitial lung disease; HRCT: high resolution tomography; PFR: pulmonary function tests; RP: Raynaud’s phenomenon; PAH: pulmonary arterial hypertension; DE: Doppler echocardiography.
Please cite this article in press as: Tani C, et al., The diagnosis and classification of mixed connective tissue disease, Journal of Autoimmunity (2014), http://dx.doi.org/10.1016/j.jaut.2014.01.008
C. Tani et al. / Journal of Autoimmunity xxx (2014) 1e4
of vascular abnormalities on nailfold capillaroscopy in patients with RP during the course of the disease. Moreover, cardiovascular manifestations as well as thrombotic events have been reported to occur in up to 35% and 25% of the patients respectively [15]. Overall, they reported a better survival rate (98% at 5-year and 96% at 10-year respectively) with respect to earlier reports [16]; PAH and cardiovascular events were found to be the major contributors to a poor prognosis in this cohort [15]. Similarly to other CTDs, cardiovascular events due to accelerated atherosclerosis are an emerging issue in MCTD; traditional cardiovascular risk factors as well as the chronic inflammation, elevated levels of AECA, aCL, and anti-b2-GPI autoantibodies are important atherogenic factors in patients with MCTD [17e19]. In 2005, Bodolay E et al. found a prevalence of active interstitial lung disease in 66.6% of consecutive MCTD patients as detected by HRCT and ground glass shadowing and fibrosis were the most common findings [20]. In 2012, a systematic evaluation of lung fibrosis was performed on 126 consecutive MCTD patients from the Norwegian registry; at least one HRCT abnormality compatible with lung fibrosis was found in 52% of patients, being the most prevalent manifestations the reticular patterns; severe lung fibrosis was found in 19%. Most importantly, severe lung fibrosis was associated with poorer functional performances (as expressed by functional lung test, 6-min walking distance and NYHA functional class) and higher mortality after a mean follow-up of 4.2 years [21]. Pulmonary hypertension is the other major issue on MCTD management. Recently, the prevalence of this severe complication has been revisited by Gunnarsson et al.; in an unselected cohort of MCTD patients, they found a PH frequency in the cohort of 3.4% (5/147) over a period of 5.6 years of observation; in two cases PH was isolated while in three was associated with ILD [22]. In 2006, a prevalence of 25/179 was found by Vegh J et al.; they also found that the overall organ damage in our MCTD-PAH patients was much more serious than in MCTD-non-PAH patients during the same follow-up period. The probability of a 5-year survival in MCTD-PAH cases was 73% opposed to 96% in MCTD patients without PAH [18]. In conclusion, although there are growing numbers of reports on successfully treated MCTD-PAH, PAH is still considered as a severe complication of MCTD seriously worsening the prognosis of the disease. Interestingly, recently the presence of antib2GPI antibodies was associated with pulmonary arterial hypertension in a small cohort of MCTD patients [19]. Early atherosclerosis is another emerging issue in MCTD patients; similarly to what observed in other systemic autoimmune diseases, early signs of subclinical atherosclerosis have been described with respect to healthy controls [23]. Indeed, besides traditional cardiovascular risk factors, autoantibodies such as anti-U1RNP antibodies and AECA, as well as the up-regulation of pro-inflammatory cytokines, could play a crucial role in early atherosclerotic events in MCTD. 4. New advances in disease pathogenesis Over the last years, significant advances have been made in disease pathogenesis understanding and a central pathogenetic role of anti-U1RNP autoantibodies has clearly emerged. Indeed, recent experimental data demonstrated that components of the U1 snRNP complex may participate directly in provoking the anti-RNP responses; autoantibodies in MCTD recognize intact or modified individual U1 snRNP proteins as well as structures composed of multiple subunits of the U1 snRNP macromolecule. Moreover, an anti-U1RNP autoantibodies have been found to interact with lung tissue thus significantly contributing to disease features [24e27].
3
Interestingly, in animal models the immunization with U1e70kd small nuclear RNP (70K) lead to MCTD-like features while mice deficient in Toll-like receptor 3 (TLR-3) failed to develop MCTD-like lung disease when immunized with the same antigen but they developed an autoimmune syndrome characterized by severe glomerulonephritis similar to SLE features, thus suggesting that exposure to 70K in a susceptible background is the key factor to induce autoimmunity and target organ injury consistent with MCTD [28]. For classification purpose, the presence of anti-U1RNP autoantibodies is mandatory; however, the coexistence of other autoantibodies is a common clinical experience in MCTD with significant influence on disease expression and clinical course suggesting a potential pathogenetic role. Other autoantibodies frequently observed in MCTD patients are anti-phospholipids (aCL, antib2GPI), anti-Ro, AECA, rheumatoid factor (RF) as well as anti-cyclic citrullinated peptides (anti-CCP). On these basis, several sub-phenotype have been described among MCTD patients; by cluster analysis, at least three clinical and serological patterns have been proposed by Szodoray P et al. [29,30]. In detail, one subgroup of patients is characterized by predominant vascular involvement (PAH, RP, livedo reticularis and vascular thrombosis) and higher prevalence of AEC and antiphospholipids in some cases satisfying the classification criteria for secondary antiphospholipid syndrome. Sensorineural hearing loss has been also reported as an emerging issue in up to 50% of MCTD patients and a significant association with anti-phospholipids antibodies other than higher anti-U1RNP titers have been found [31]. In the second cluster identified by Szodoray et al. patients with predominant lung involvement (ILD) esophageal dysmotility and myositis were grouped; the immunohistochemical analysis of the lung biopsy showed C3 complement and IgM type immunoglobulin deposition in the alveolar epithelial cells thus suggesting that a ICmediated damage might play a role in the pathogenesis of ILD. Similarly, in a histopathological study on esophageal lesions of MCTD patients, most severe changes including atrophy, loss of smooth muscle cells and fibrosis were observed in the muscular layer of the lower esophagus and immunoglobulin and complement deposition were found [32]. An association between ILD and esophageal dysfunction has also been observed by Fagundes MN et al. to support the hypothesis of a common pathogenetic pathway [33]. The third cluster identified by Szodoray P et al. recognizes patients with higher prevalence of erosive arthritis and anti-CCP autoantibodies. Non-erosive inflammatory arthritis is frequently described as a presenting feature in MCTD and bone erosions are rarely reported in the traditional literature [34]; with respect to previous reports, erosions accrual over time and deformities developing have been described in up to 30% of patients in more recent studies with long-term follow-up [35]. Indeed, it is well known that some clinical features of MCTD may change over time, and that the disease may evolve from predominant inflammatory manifestations to a sclerotic disease [36,37]. Recent observational studies highlighted the importance of a long-term follow-up to better define the natural course of the disease and potential evolution to other CTDs. It has been recently reported that roughly 20% of patients initially diagnosed with MCTD at disease onset evolved to another CTD over a period of 5 years but this percentage tends to significantly increase up to 50% of patients (depending on the classification criteria adopted) over a period of 10 years [11,38]. The presence of anti-DNA antibodies was associated with evolution into SLE, while esophageal dysmotility and sclerodactyly with evolution into SSc.
Please cite this article in press as: Tani C, et al., The diagnosis and classification of mixed connective tissue disease, Journal of Autoimmunity (2014), http://dx.doi.org/10.1016/j.jaut.2014.01.008
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The importance of humoral immunity in disease pathogenesis has been recently highlighted; several B cell subsets abnormalities were demonstrated in peripheral blood of MCTD patients and significant associations between disease activity and of anti-U1RNP autoantibodies titers were found [39]. 5. Conclusions In last decade, several advances in the knowledge of disease course and pathogenesis of MCTD have been reached. Recent longterm multicentre observational studies have been published, significantly contributing to this progress overcoming the limitations related with the disease rarity. Although controversies on disease definition and classification still persist, it appears that the concept of MCTD is useful to the clinician regardless of the controversy over nomenclature, as because MCTD identifies a group of patients in whom severe and lifethreatening organ involvement can occur especially during the follow-up. Increased surveillance for specific manifestations and prognostic stratification according to different clinical and serological features became mandatory to improve patient’s survival and quality of care. References [1] Sharp GC, Irvin WS, Tan EM, Gould RG, Holman HR. Mixed connective tissue disease: an apparently distinct rheumatic disease syndrome associated with a specific antibody to an extractable nuclear antigen (ENA). Am J Med 1972;52: 148e59. [2] Baldini C, Mosca M, Della Rossa A, Pepe P, Notarstefano C, Ferro F, et al. Overlap of ACA-positive systemic sclerosis and Sjögren’s syndrome: a distinct clinical entity with mild organ involvement but at high risk of lymphoma. Clin Exp Rheumatol 2013;31:272e80. [3] Tani C, D’Aniello D, Delle Sedie A, Carli L, Cagnoni M, Possemato N, et al. Rhupus syndrome: assessment of its prevalence and its clinical and instrumental characteristics in a prospective cohort of 103 SLE patients. Autoimmun Rev 2013;12:537e41. [4] Mosca M, Tani C, Carli L, Bombardieri S, Undifferentiated CTD. a wide spectrum of autoimmune diseases. Best Pract Res Clin Rheumatol 2012;26:73e7. [5] Agmon-Levin N, Mosca M, Petri M, Shoenfeld Y. Systemic lupus erythematosus one disease or many? Autoimmun Rev 2012;11:593e5. [6] Habets WJ, de Rooij DJ, Salden MH, Verhagen AP, van Eekelen CA, van de Putte LB, et al. Antibodies against distinct nuclear matrix proteins are characteristic for mixed connective tissue disease. Clin Exp Immunol 1983;54: 265e76. [7] Sharp GC. Diagnostic criteria for classification of MCTD. In: Kasukawa R, Sharp GC, editors. Mixed connective tissue diseases and anti-nuclear antibodies. Amsterdam: Elsevier; 1987. pp. 23e32. [8] Kasukawa R, Too T, Miyawaki S, Yoshida H, Tanimoto K, Nobunaga M, et al. Preliminary diagnostic criteria for classification of mixed connective tissue disease. In: Kasukawa R, Sharp GC, editors. Mixed connective tissue diseases and anti-nuclear antibodies. Amsterdam: Elsevier; 1987. pp. 41e7. [9] Alarcon-Segovia D, Villareal M. Classification and diagnostic criteria for mixed connective tissue disease. In: Kasukawa R, Sharps GC, editors. Mixed connective tissue diseases and anti- nuclear antibodies. Amsterdam: Elsevier; 1987. pp. 33e40. [10] Alarcon-Segovia D, Cardiel MH. Comparison between 3 diagnostic criteria for mixed connective tissue disease. Study of 593 patients. J Rheumatol 1989;16: 328e34. [11] Cappelli S, Bellando Randone S, Martinovi c D, Tamas MM, Pasali c K, Allanore Y, et al. “To be or not to be,” ten years after: evidence for mixed connective tissue disease as a distinct entity. Semin Arthritis Rheum 2012;41: 589e98. [12] Lage LV, Caleiro MT, Carvalho JF. Proposed disease activity criteria for mixed connective tissue disease. Lupus 2010;19:223e4. [13] Gaubitz M. Epidemiology of connective tissue disorders. Rheumatology 2006;45(Suppl. 3):iii3e4. [14] Gunnarsson R, Molberg Ø, Gilboe IM, Gran JT, PAHNOR1 Study Group*. The prevalence and incidence of mixed connective tissue disease: a national multicentre survey of Norwegian patients. Ann Rheum Dis 2011;70:1047e51. [15] Hajas A, Szodoray P, Nakken B, Gaal J, Zöld E, Laczik R, et al. Clinical course, prognosis, and causes of death in mixed connective tissue diseases. J Rheumatol 2013;40:1134e42.
[16] Miyawaki S, Onodera H. Clinical course and prognosis of patients with mixed connective tissue disease. In: Kasukawa R, Sharp GC, editors. Mixed connective tissue disease and anti-nuclear antibodies. Amsterdam: Elsevier Science Publishers B.V. Biomedical Division; 1987. pp. 331e6. } I, Jakab Z, Vegh J, et al. The evaluation of [17] Bodolay E, Seres I, Szodoray P, Csipo paraoxonase (PON) activity in patients with mixed connective tissue disease. J Rheumatol 2008;35:237e43. } I, Udvardy M, Lakos G, et al. Clinical [18] Vegh J, Szodoray P, Kappelmayer J, Csipo and immunoserological characteristics of mixed connective tissue disease associated with pulmonary arterial hypertension. Scand J Immunol 2006;64: 69e76. [19] Hasegawa EM, Caleiro MT, Fuller R, Carvalho JF. The frequency of anti-beta 2glycoprotein I antibodies is low and these antibodies are associated with pulmonary hypertension in mixed connective tissue disease. Lupus 2009;18: 618e21. [20] Bodolay E, Szekanecz Z, Dévényi K, Galuska L, Csípo I, Vègh J, et al. Evaluation of interstitial lung disease in mixed connective tissue disease (MCTD). Rheumatology 2005;44:656e61. [21] Gunnarsson R, Aaløkken TM, Molberg Ø, Lund MB, Mynarek GK, Lexberg AS, et al. Prevalence and severity of interstitial lung disease in mixed connective tissue disease: a nationwide, cross-sectional study. Ann Rheum Dis 2012;71: 1966e72. [22] Gunnarsson R, Andreassen AK, Molberg Ø, Lexberg ÅS, Time K, Dhainaut AS, et al. Prevalence of pulmonary hypertension in an unselected, mixed connective tissue disease cohort: results of a nationwide, Norwegian crosssectional multicentre study and review of current literature. Rheumatology 2013;52:1208e13. [23] Soltesz P, Bereczki D, Szodoray P, Magyar MT, Der H, Csipo I, et al. Endothelial cell markers reflecting endothelial cell dysfunction in patients with mixed connective tissue disease. Arthritis Res Ther 2010;12:R78. [24] Greidinger EL, Foecking MF, Ranatunga S, Hoffman RW. Apoptotic U1e70 kd is antigenically distinct from the intact form of the U1e70-kd molecule. Arthritis Rheum 2002;46:1264e9. [25] Hof D, Cheung K, de Rooij DJ, van den Hoogen FH, Pruijn GJ, van Venrooij WJ, et al. Autoantibodies specific for apoptotic U1-70K are superior serological markers for mixed connective tissue disease. Arthritis Res Ther 2005;7:R302e9. [26] Murakami A, Kojima K, Ohya K, Imamura K, Takasaki Y. A new conformational epitope generated by the binding of recombinant 70-kD protein and U1 RNA to anti-U1 RNP autoantibodies in sera from patients with mixed connective tissue disease. Arthritis Rheum 2002;46:3273e82. [27] Okawa-Takatsuji M, Aotsuka S, Uwatoko S, Takaono M, Iwasaki K, Kinoshita M, et al. Endothelial cell-binding activity of anti-U1-ribonucleoprotein antibodies in patients with connective tissue diseases. Clin Exp Immunol 2001;126:345e54. [28] Greidinger EL, Zang Y, Jaimes K, Hogenmiller S, Nassiri M, Bejarano P, et al. A murine model of mixed connective tissue disease induced with U1 small nuclear RNP autoantigen. Arthritis Rheum 2006;54:661e9. [29] Szodoray P, Hajas A, Kardos L, Dezso B, Soos G, Zold E, et al. Distinct phenotypes in mixed connective tissue disease: subgroups and survival. Lupus 2012;21:1412. [30] Setty YN, Pittman CB, Mahale AS, Greidinger EL, Hoffman RW. Sicca symptoms and anti-SSA/Ro antibodies are common in mixed connective tissue disease. J Rheumatol 2002;29:487e9. [31] Hajas A, Szodoray P, Barath S, Sipka S, Rezes S, Zeher M, et al. Sensorineural hearing loss in patients with mixed connective tissue disease: immunological markers and cytokine levels. J Rheumatol 2009;36:1930e6. [32] Uzuki M, Kamataki A, Watanabe M, Sasaki N, Miura Y, Sawai T. Histological analysis of esophageal muscular layers from 27 autopsy cases with mixed connective tissue disease (MCTD). Pathol Res Pract 2011;15(207):383e90. [33] Fagundes MN, Caleiro MTC, Navarro-Rodriguez T, Baldi BG, Kavakama J, Salge JM, et al. Esophageal involvement and interstitial lung disease in mixed connective tissue disease. Respir Med 2009;103:854e60. [34] Halla JT, Hardin JG. Clinical features of the arthritis of mixed connective tissue disease. Arthritis Rheum 1978;21:497e503. [35] Takasaki Y, Yamanaka K, Takasaki C, Matsushita M, Yamada H, Nawata M, et al. Anticyclic citrullinated peptide antibodies in patients in mixed connective tissue disease. Mod Rheumatol 2004;14:367e75. [36] Burdt MA, Hoffman RW, Deutscher SL, Wang GS, Johnson JC, Sharp GC. Longterm outcome in mixed connective tissue disease. Arthritis Rheum 1999;42: 899e909. [37] Nimelstein SH, Brody ST, McShane D, Holman HR. Mixed connective tissue disease: a subsequent evaluation of the original 25 patients. Medicine 1980;59:239e48. [38] Mosca M, Tani C, Carli L, Della Rossa A, Talarico R, Baldini C, et al. Analysis of the evolution of UCTD to defined CTD after a long term follow-up. Clin Exp Rheumatol 2013;31:471. [39] Hajas S, Barath P, Szodoray B, Nakken P, Gogolak Z, Szekanecz E, et al. Derailed B cell homeostasis in patients with mixed connective tissue disease. Hum Immunol 2013;74:833e41.
Please cite this article in press as: Tani C, et al., The diagnosis and classification of mixed connective tissue disease, Journal of Autoimmunity (2014), http://dx.doi.org/10.1016/j.jaut.2014.01.008
Contents lists available at ScienceDirect
Journal of Autoimmunity journal homepage: www.elsevier.com/locate/jautimm
The diagnosis and classification of mixed connective tissue disease Chiara Tani a, Linda Carli a, b, Sabrina Vagnani a, Rosaria Talarico a, Chiara Baldini a, Marta Mosca a, Stefano Bombardieri a, * a b
Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Italy Dottorato Genomec, University of Siena, Italy
a r t i c l e i n f o
a b s t r a c t
Article history: Received 7 October 2013 Accepted 13 November 2013
The term “mixed connective tissue disease” (MCTD) concerns a systemic autoimmune disease typified by overlapping features between two or more systemic autoimmune diseases and the presence of antibodies against the U1 small nuclear ribonucleoprotein autoantigen (U1snRNP). Since the first description of this condition in 1972, the understanding of clinical manifestations and long-term outcome of MCTD have significantly advanced. Polyarthritis, Raynaud’s phenomenon, puffy fingers, lung involvement and esophageal dysmotility are the most frequently reported symptoms among the different cohorts during the course of the disease. Moreover, in recent years a growing interest has been focused on severe organ involvement such as pulmonary arterial hypertension and interstitial lung disease which can accrue during the long-term follow-up and can still significantly influence disease prognosis. Over the last years, significant advances have been made also in disease pathogenesis understanding and a central pathogenetic role of anti-U1RNP autoantibodies has clearly emerged. Although controversies on disease definition and classification still persist, MCTD identifies a group of patients in whom increased surveillance for specific manifestations and prognostic stratification became mandatory to improve patient’s outcomes. Ó 2014 Published by Elsevier Ltd.
Keywords: MCTD Anti-U1RNP autoantibodies Prognosis Classification
1. Introduction The term “mixed connective tissue disease” (MCTD) refers to a systemic autoimmune disease characterized by overlapping features between at least two systemic autoimmune diseases including Systemic Lupus Erythematosus (SLE), Systemic Sclerosis (Ssc), polymyositis/dermatomyositis (PM/DM) and Rheumatoid Arthritis (RA). The presence of antibodies against the U1 small nuclear ribonucleoprotein autoantigen (U1snRNP) is considered as the serological hallmark of this condition. Because of the similar clinical features and unique serologic pattern of the first patients described in 1972, Sharp et al. proposed that MCTD might represent a distinct rheumatic disease syndrome. According to the first descriptions of the disease, MCTD patients appeared to have an excellent response to corticosteroid therapy and a favorable prognosis [1]. Since the first description, our understanding of the classification, clinical manifestations, long-term outcome and pathogenesis of MCTD have all advanced considerably. In this review, we will focus on the recent relevant literature published in the last decade
* Corresponding author. E-mail address: [email protected] (S. Bombardieri).
and we will try to redefine the shape of the disease in the light of the new scientific advances. 2. The endless history of MCTD classification The classification of rheumatic diseases is challenging because of the protean and frequently overlapping clinical and laboratory manifestations [2e5]. This problem is typified by the difficulty of classification and differential diagnosis of MCTD. Indeed, since its first description in 1972 by Sharp et al., it is still a matter of debate whether this condition has to be considered a distinct clinical entity rather than an overlap syndrome between two or more CTDs. Even if the anti-RNP reactivity is considered as the serologic hallmark with a well recognized diagnostic value, it is not restricted to MCTD patients being present also in SLE, SS, SSc patients as well as in Undifferentiated Connective Tissue Diseases (UCTD). However, while antibodies specifically directed against U1e70K are found in 75e90% of MCTD patients representing the most commonly detected U1-snRNP component, they are found in only 20e50% of SLE patients whose serum reacts with anti-RNP, thus suggesting a distinct serologic sub-profile [6]. To date at least three classification criteria for MCTD have been published [7e9].
0896-8411/$ e see front matter Ó 2014 Published by Elsevier Ltd. http://dx.doi.org/10.1016/j.jaut.2014.01.008
Please cite this article in press as: Tani C, et al., The diagnosis and classification of mixed connective tissue disease, Journal of Autoimmunity (2014), http://dx.doi.org/10.1016/j.jaut.2014.01.008
2
C. Tani et al. / Journal of Autoimmunity xxx (2014) 1e4
Comparative studies have reported similar results in term of sensitivity and specificity in capturing MCTD patients [10] while a recent study by Cappelli et al. found that Kasukawa’s criteria were more sensitive (75%) in comparison to those of Alarcon-Segovia (73%) and Sharp (42%) in classifying MCTD patients over time [11]. The clinical need to define disease activity other than to classify them has clearly emerged over the years; in clinical practice, SLEspecific disease activity criteria have been also used in MCTD patients and experience-based activity criteria have been recently proposed by Carvalho JF et al. [12] but, similarly that for classification criteria, an international consensus on this matter is still lacking. 3. Epidemiology, clinical features and prognosis The lack of internationally accepted classification or diagnostic criteria for MCTD led to a scarcity of epidemiological studies over the years and discordant data on the real prevalence and clinical course of this condition [13]. However, in recent years large studies have been published providing important advances on disease epidemiology, clinical and laboratory as well as long term prognosis.
In 2011, Gunnarsson R et al. performed a nationwide retrospective study to assess prevalence and incidence of MCTD in Norway founding 147 adult Caucasian with a definite diagnosis of MCTD and for a point prevalence of 3.8 per 100 000 adults and an incidence 2.1 per million per year during the period from 1996 to 2005 with a female predominance (76.9%) [14]. Prevalence of the clinical findings during the course of the disease as reported by the most recent literature (years 2003e2013) is summarized in Table 1. Polyarthritis, Raynaud’s phenomenon (RP), puffy fingers, interstitial lung disease and esophageal dysmotility are the most frequently reported symptoms among the different cohorts (Table 1) during the course of the disease. The largest recent MCTD cohort has been described by Hajas A et al. in 2013; they found that at the time of diagnosis, polyarthritis, RP, puffy fingers and sclerodactily were the most prevalent symptoms reported in 65%, 53%, 50% and 35% respectively; however, during the 30 years of prospective follow-up patients tended to accrue over time new symptoms such as esophageal hypomotility, nervous system manifestations, pulmonary arterial hypertension (PAH), interstitial lung disease but no progression to other CTD was recorded. Interestingly, they also observed a significant progression
Table 1 Prevalence of the main clinical findings of MCTD as reported in the recent (2003e2013) literature. Author, year, Country
Arthritis-RP
Lung involvement (case definition)
Oesophageal involvement (case definition)
PAH (case definition)
e
ILD: 78% (on HRCT)
e
79%e99%
Self reported dispnea: 47%
Oesophageal dilatation: 56% Gastroesophageal reflux: 50% Oesophageal motor impairment: 83% Symptoms of oesophageal dysmotility: 50%
89.6%/59.5%
ILD: 47% (on HRCT and PFR)
17.8% (on DE right ventricle catheterization)
94.5%/78.6%
ILD: 52.7% (on HRCT and PFR)
e
ILD: 52% (on HRCT)
Oesophageal dysmotility (on radiographic barium passage or radionuclide transit scintigraphy): 49.6% Oesophageal dysmotility (on radiographic barium passage or radionuclide transit scintigraphy): 69.5% e
49.7%/85.1%
44.1% (on chest radiography or CT scan or PFR)
45.3% (on manometry or esophageal barium transit)
e
e/86%
e
Gastroesophafeal reflux: 52%
e
e
66.6% (on HRCT)
e
e
e
e
e
3.4% (on Doppler echocardiography right ventricle catheterization)
Type of study N of patients Classification criteria Fagundes MN, 2009, Brazil Prospective 50 Kasukawa’s Gunnarsson R, 2011, Norway Nationwide, retrospective survey 147 At least one (Sharp, Kasukawa or Alarcon-Segovia) Hajas A, 2013, Hungary Prospective observational 280 Alarcon-Segovia Szodoray P, 2012, Norway Prospective observational 201 Alarcon-Segovia Gunnarsson R 2012, Norway Nationwide, cross-sectional 126 At least one (Sharp, Kasukawa or Alarcon-Segovia) Cappelli 2011, Italy Retrospective 161 Expert opinion Maldonado ME, 2008, USA Cross-sectional 21 Alarcon-Segovia Bodolay E, 2005, Hungary Cross-sectional 144 Alarcon-Segovia Gunnarsson R 2012, Norway Nationwide, cross-sectional 147 At least one (Sharp, Kasukawa or Alarcon-Segovia)
e
23.8% (on DE right ventricle catheterization)
e
ILD: interstitial lung disease; HRCT: high resolution tomography; PFR: pulmonary function tests; RP: Raynaud’s phenomenon; PAH: pulmonary arterial hypertension; DE: Doppler echocardiography.
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C. Tani et al. / Journal of Autoimmunity xxx (2014) 1e4
of vascular abnormalities on nailfold capillaroscopy in patients with RP during the course of the disease. Moreover, cardiovascular manifestations as well as thrombotic events have been reported to occur in up to 35% and 25% of the patients respectively [15]. Overall, they reported a better survival rate (98% at 5-year and 96% at 10-year respectively) with respect to earlier reports [16]; PAH and cardiovascular events were found to be the major contributors to a poor prognosis in this cohort [15]. Similarly to other CTDs, cardiovascular events due to accelerated atherosclerosis are an emerging issue in MCTD; traditional cardiovascular risk factors as well as the chronic inflammation, elevated levels of AECA, aCL, and anti-b2-GPI autoantibodies are important atherogenic factors in patients with MCTD [17e19]. In 2005, Bodolay E et al. found a prevalence of active interstitial lung disease in 66.6% of consecutive MCTD patients as detected by HRCT and ground glass shadowing and fibrosis were the most common findings [20]. In 2012, a systematic evaluation of lung fibrosis was performed on 126 consecutive MCTD patients from the Norwegian registry; at least one HRCT abnormality compatible with lung fibrosis was found in 52% of patients, being the most prevalent manifestations the reticular patterns; severe lung fibrosis was found in 19%. Most importantly, severe lung fibrosis was associated with poorer functional performances (as expressed by functional lung test, 6-min walking distance and NYHA functional class) and higher mortality after a mean follow-up of 4.2 years [21]. Pulmonary hypertension is the other major issue on MCTD management. Recently, the prevalence of this severe complication has been revisited by Gunnarsson et al.; in an unselected cohort of MCTD patients, they found a PH frequency in the cohort of 3.4% (5/147) over a period of 5.6 years of observation; in two cases PH was isolated while in three was associated with ILD [22]. In 2006, a prevalence of 25/179 was found by Vegh J et al.; they also found that the overall organ damage in our MCTD-PAH patients was much more serious than in MCTD-non-PAH patients during the same follow-up period. The probability of a 5-year survival in MCTD-PAH cases was 73% opposed to 96% in MCTD patients without PAH [18]. In conclusion, although there are growing numbers of reports on successfully treated MCTD-PAH, PAH is still considered as a severe complication of MCTD seriously worsening the prognosis of the disease. Interestingly, recently the presence of antib2GPI antibodies was associated with pulmonary arterial hypertension in a small cohort of MCTD patients [19]. Early atherosclerosis is another emerging issue in MCTD patients; similarly to what observed in other systemic autoimmune diseases, early signs of subclinical atherosclerosis have been described with respect to healthy controls [23]. Indeed, besides traditional cardiovascular risk factors, autoantibodies such as anti-U1RNP antibodies and AECA, as well as the up-regulation of pro-inflammatory cytokines, could play a crucial role in early atherosclerotic events in MCTD. 4. New advances in disease pathogenesis Over the last years, significant advances have been made in disease pathogenesis understanding and a central pathogenetic role of anti-U1RNP autoantibodies has clearly emerged. Indeed, recent experimental data demonstrated that components of the U1 snRNP complex may participate directly in provoking the anti-RNP responses; autoantibodies in MCTD recognize intact or modified individual U1 snRNP proteins as well as structures composed of multiple subunits of the U1 snRNP macromolecule. Moreover, an anti-U1RNP autoantibodies have been found to interact with lung tissue thus significantly contributing to disease features [24e27].
3
Interestingly, in animal models the immunization with U1e70kd small nuclear RNP (70K) lead to MCTD-like features while mice deficient in Toll-like receptor 3 (TLR-3) failed to develop MCTD-like lung disease when immunized with the same antigen but they developed an autoimmune syndrome characterized by severe glomerulonephritis similar to SLE features, thus suggesting that exposure to 70K in a susceptible background is the key factor to induce autoimmunity and target organ injury consistent with MCTD [28]. For classification purpose, the presence of anti-U1RNP autoantibodies is mandatory; however, the coexistence of other autoantibodies is a common clinical experience in MCTD with significant influence on disease expression and clinical course suggesting a potential pathogenetic role. Other autoantibodies frequently observed in MCTD patients are anti-phospholipids (aCL, antib2GPI), anti-Ro, AECA, rheumatoid factor (RF) as well as anti-cyclic citrullinated peptides (anti-CCP). On these basis, several sub-phenotype have been described among MCTD patients; by cluster analysis, at least three clinical and serological patterns have been proposed by Szodoray P et al. [29,30]. In detail, one subgroup of patients is characterized by predominant vascular involvement (PAH, RP, livedo reticularis and vascular thrombosis) and higher prevalence of AEC and antiphospholipids in some cases satisfying the classification criteria for secondary antiphospholipid syndrome. Sensorineural hearing loss has been also reported as an emerging issue in up to 50% of MCTD patients and a significant association with anti-phospholipids antibodies other than higher anti-U1RNP titers have been found [31]. In the second cluster identified by Szodoray et al. patients with predominant lung involvement (ILD) esophageal dysmotility and myositis were grouped; the immunohistochemical analysis of the lung biopsy showed C3 complement and IgM type immunoglobulin deposition in the alveolar epithelial cells thus suggesting that a ICmediated damage might play a role in the pathogenesis of ILD. Similarly, in a histopathological study on esophageal lesions of MCTD patients, most severe changes including atrophy, loss of smooth muscle cells and fibrosis were observed in the muscular layer of the lower esophagus and immunoglobulin and complement deposition were found [32]. An association between ILD and esophageal dysfunction has also been observed by Fagundes MN et al. to support the hypothesis of a common pathogenetic pathway [33]. The third cluster identified by Szodoray P et al. recognizes patients with higher prevalence of erosive arthritis and anti-CCP autoantibodies. Non-erosive inflammatory arthritis is frequently described as a presenting feature in MCTD and bone erosions are rarely reported in the traditional literature [34]; with respect to previous reports, erosions accrual over time and deformities developing have been described in up to 30% of patients in more recent studies with long-term follow-up [35]. Indeed, it is well known that some clinical features of MCTD may change over time, and that the disease may evolve from predominant inflammatory manifestations to a sclerotic disease [36,37]. Recent observational studies highlighted the importance of a long-term follow-up to better define the natural course of the disease and potential evolution to other CTDs. It has been recently reported that roughly 20% of patients initially diagnosed with MCTD at disease onset evolved to another CTD over a period of 5 years but this percentage tends to significantly increase up to 50% of patients (depending on the classification criteria adopted) over a period of 10 years [11,38]. The presence of anti-DNA antibodies was associated with evolution into SLE, while esophageal dysmotility and sclerodactyly with evolution into SSc.
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The importance of humoral immunity in disease pathogenesis has been recently highlighted; several B cell subsets abnormalities were demonstrated in peripheral blood of MCTD patients and significant associations between disease activity and of anti-U1RNP autoantibodies titers were found [39]. 5. Conclusions In last decade, several advances in the knowledge of disease course and pathogenesis of MCTD have been reached. Recent longterm multicentre observational studies have been published, significantly contributing to this progress overcoming the limitations related with the disease rarity. Although controversies on disease definition and classification still persist, it appears that the concept of MCTD is useful to the clinician regardless of the controversy over nomenclature, as because MCTD identifies a group of patients in whom severe and lifethreatening organ involvement can occur especially during the follow-up. Increased surveillance for specific manifestations and prognostic stratification according to different clinical and serological features became mandatory to improve patient’s survival and quality of care. References [1] Sharp GC, Irvin WS, Tan EM, Gould RG, Holman HR. Mixed connective tissue disease: an apparently distinct rheumatic disease syndrome associated with a specific antibody to an extractable nuclear antigen (ENA). Am J Med 1972;52: 148e59. [2] Baldini C, Mosca M, Della Rossa A, Pepe P, Notarstefano C, Ferro F, et al. Overlap of ACA-positive systemic sclerosis and Sjögren’s syndrome: a distinct clinical entity with mild organ involvement but at high risk of lymphoma. Clin Exp Rheumatol 2013;31:272e80. [3] Tani C, D’Aniello D, Delle Sedie A, Carli L, Cagnoni M, Possemato N, et al. Rhupus syndrome: assessment of its prevalence and its clinical and instrumental characteristics in a prospective cohort of 103 SLE patients. Autoimmun Rev 2013;12:537e41. [4] Mosca M, Tani C, Carli L, Bombardieri S, Undifferentiated CTD. a wide spectrum of autoimmune diseases. Best Pract Res Clin Rheumatol 2012;26:73e7. [5] Agmon-Levin N, Mosca M, Petri M, Shoenfeld Y. Systemic lupus erythematosus one disease or many? Autoimmun Rev 2012;11:593e5. [6] Habets WJ, de Rooij DJ, Salden MH, Verhagen AP, van Eekelen CA, van de Putte LB, et al. Antibodies against distinct nuclear matrix proteins are characteristic for mixed connective tissue disease. Clin Exp Immunol 1983;54: 265e76. [7] Sharp GC. Diagnostic criteria for classification of MCTD. In: Kasukawa R, Sharp GC, editors. Mixed connective tissue diseases and anti-nuclear antibodies. Amsterdam: Elsevier; 1987. pp. 23e32. [8] Kasukawa R, Too T, Miyawaki S, Yoshida H, Tanimoto K, Nobunaga M, et al. Preliminary diagnostic criteria for classification of mixed connective tissue disease. In: Kasukawa R, Sharp GC, editors. Mixed connective tissue diseases and anti-nuclear antibodies. Amsterdam: Elsevier; 1987. pp. 41e7. [9] Alarcon-Segovia D, Villareal M. Classification and diagnostic criteria for mixed connective tissue disease. In: Kasukawa R, Sharps GC, editors. Mixed connective tissue diseases and anti- nuclear antibodies. Amsterdam: Elsevier; 1987. pp. 33e40. [10] Alarcon-Segovia D, Cardiel MH. Comparison between 3 diagnostic criteria for mixed connective tissue disease. Study of 593 patients. J Rheumatol 1989;16: 328e34. [11] Cappelli S, Bellando Randone S, Martinovi c D, Tamas MM, Pasali c K, Allanore Y, et al. “To be or not to be,” ten years after: evidence for mixed connective tissue disease as a distinct entity. Semin Arthritis Rheum 2012;41: 589e98. [12] Lage LV, Caleiro MT, Carvalho JF. Proposed disease activity criteria for mixed connective tissue disease. Lupus 2010;19:223e4. [13] Gaubitz M. Epidemiology of connective tissue disorders. Rheumatology 2006;45(Suppl. 3):iii3e4. [14] Gunnarsson R, Molberg Ø, Gilboe IM, Gran JT, PAHNOR1 Study Group*. The prevalence and incidence of mixed connective tissue disease: a national multicentre survey of Norwegian patients. Ann Rheum Dis 2011;70:1047e51. [15] Hajas A, Szodoray P, Nakken B, Gaal J, Zöld E, Laczik R, et al. Clinical course, prognosis, and causes of death in mixed connective tissue diseases. J Rheumatol 2013;40:1134e42.
[16] Miyawaki S, Onodera H. Clinical course and prognosis of patients with mixed connective tissue disease. In: Kasukawa R, Sharp GC, editors. Mixed connective tissue disease and anti-nuclear antibodies. Amsterdam: Elsevier Science Publishers B.V. Biomedical Division; 1987. pp. 331e6. } I, Jakab Z, Vegh J, et al. The evaluation of [17] Bodolay E, Seres I, Szodoray P, Csipo paraoxonase (PON) activity in patients with mixed connective tissue disease. J Rheumatol 2008;35:237e43. } I, Udvardy M, Lakos G, et al. Clinical [18] Vegh J, Szodoray P, Kappelmayer J, Csipo and immunoserological characteristics of mixed connective tissue disease associated with pulmonary arterial hypertension. Scand J Immunol 2006;64: 69e76. [19] Hasegawa EM, Caleiro MT, Fuller R, Carvalho JF. The frequency of anti-beta 2glycoprotein I antibodies is low and these antibodies are associated with pulmonary hypertension in mixed connective tissue disease. Lupus 2009;18: 618e21. [20] Bodolay E, Szekanecz Z, Dévényi K, Galuska L, Csípo I, Vègh J, et al. Evaluation of interstitial lung disease in mixed connective tissue disease (MCTD). Rheumatology 2005;44:656e61. [21] Gunnarsson R, Aaløkken TM, Molberg Ø, Lund MB, Mynarek GK, Lexberg AS, et al. Prevalence and severity of interstitial lung disease in mixed connective tissue disease: a nationwide, cross-sectional study. Ann Rheum Dis 2012;71: 1966e72. [22] Gunnarsson R, Andreassen AK, Molberg Ø, Lexberg ÅS, Time K, Dhainaut AS, et al. Prevalence of pulmonary hypertension in an unselected, mixed connective tissue disease cohort: results of a nationwide, Norwegian crosssectional multicentre study and review of current literature. Rheumatology 2013;52:1208e13. [23] Soltesz P, Bereczki D, Szodoray P, Magyar MT, Der H, Csipo I, et al. Endothelial cell markers reflecting endothelial cell dysfunction in patients with mixed connective tissue disease. Arthritis Res Ther 2010;12:R78. [24] Greidinger EL, Foecking MF, Ranatunga S, Hoffman RW. Apoptotic U1e70 kd is antigenically distinct from the intact form of the U1e70-kd molecule. Arthritis Rheum 2002;46:1264e9. [25] Hof D, Cheung K, de Rooij DJ, van den Hoogen FH, Pruijn GJ, van Venrooij WJ, et al. Autoantibodies specific for apoptotic U1-70K are superior serological markers for mixed connective tissue disease. Arthritis Res Ther 2005;7:R302e9. [26] Murakami A, Kojima K, Ohya K, Imamura K, Takasaki Y. A new conformational epitope generated by the binding of recombinant 70-kD protein and U1 RNA to anti-U1 RNP autoantibodies in sera from patients with mixed connective tissue disease. Arthritis Rheum 2002;46:3273e82. [27] Okawa-Takatsuji M, Aotsuka S, Uwatoko S, Takaono M, Iwasaki K, Kinoshita M, et al. Endothelial cell-binding activity of anti-U1-ribonucleoprotein antibodies in patients with connective tissue diseases. Clin Exp Immunol 2001;126:345e54. [28] Greidinger EL, Zang Y, Jaimes K, Hogenmiller S, Nassiri M, Bejarano P, et al. A murine model of mixed connective tissue disease induced with U1 small nuclear RNP autoantigen. Arthritis Rheum 2006;54:661e9. [29] Szodoray P, Hajas A, Kardos L, Dezso B, Soos G, Zold E, et al. Distinct phenotypes in mixed connective tissue disease: subgroups and survival. Lupus 2012;21:1412. [30] Setty YN, Pittman CB, Mahale AS, Greidinger EL, Hoffman RW. Sicca symptoms and anti-SSA/Ro antibodies are common in mixed connective tissue disease. J Rheumatol 2002;29:487e9. [31] Hajas A, Szodoray P, Barath S, Sipka S, Rezes S, Zeher M, et al. Sensorineural hearing loss in patients with mixed connective tissue disease: immunological markers and cytokine levels. J Rheumatol 2009;36:1930e6. [32] Uzuki M, Kamataki A, Watanabe M, Sasaki N, Miura Y, Sawai T. Histological analysis of esophageal muscular layers from 27 autopsy cases with mixed connective tissue disease (MCTD). Pathol Res Pract 2011;15(207):383e90. [33] Fagundes MN, Caleiro MTC, Navarro-Rodriguez T, Baldi BG, Kavakama J, Salge JM, et al. Esophageal involvement and interstitial lung disease in mixed connective tissue disease. Respir Med 2009;103:854e60. [34] Halla JT, Hardin JG. Clinical features of the arthritis of mixed connective tissue disease. Arthritis Rheum 1978;21:497e503. [35] Takasaki Y, Yamanaka K, Takasaki C, Matsushita M, Yamada H, Nawata M, et al. Anticyclic citrullinated peptide antibodies in patients in mixed connective tissue disease. Mod Rheumatol 2004;14:367e75. [36] Burdt MA, Hoffman RW, Deutscher SL, Wang GS, Johnson JC, Sharp GC. Longterm outcome in mixed connective tissue disease. Arthritis Rheum 1999;42: 899e909. [37] Nimelstein SH, Brody ST, McShane D, Holman HR. Mixed connective tissue disease: a subsequent evaluation of the original 25 patients. Medicine 1980;59:239e48. [38] Mosca M, Tani C, Carli L, Della Rossa A, Talarico R, Baldini C, et al. Analysis of the evolution of UCTD to defined CTD after a long term follow-up. Clin Exp Rheumatol 2013;31:471. [39] Hajas S, Barath P, Szodoray B, Nakken P, Gogolak Z, Szekanecz E, et al. Derailed B cell homeostasis in patients with mixed connective tissue disease. Hum Immunol 2013;74:833e41.
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