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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
Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Italy
b
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: The term “mixed connective tissue disease” (MCTD) concerns a systemic autoimmune disease typified by
Received 7 October 2013 overlapping features between two or more systemic autoimmune diseases and the presence of
Accepted 13 November 2013 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
Keywords: outcome of MCTD have significantly advanced. Polyarthritis, Raynaud’s phenomenon, puffy fingers,
MCTD
lung involvement and esophageal dysmotility are the most frequently reported symptoms among the
Anti-U1RNP autoantibodies
different cohorts during the course of the disease. Moreover, in recent years a growing interest has been
Prognosis
Classification
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 un-
derstanding 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.

1. Introduction and we will try to redefine the shape of the disease in the light of
the new scientific advances.
The term “mixed connective tissue disease” (MCTD) refers to a
systemic autoimmune disease characterized by overlapping fea- 2. The endless history of MCTD classification
tures between at least two systemic autoimmune diseases
including Systemic Lupus Erythematosus (SLE), Systemic Sclerosis The classification of rheumatic diseases is challenging because
(Ssc), polymyositis/dermatomyositis (PM/DM) and Rheumatoid of the protean and frequently overlapping clinical and laboratory
Arthritis (RA). The presence of antibodies against the U1 small manifestations [2e5]. This problem is typified by the difficulty of
nuclear ribonucleoprotein autoantigen (U1snRNP) is considered as classification and differential diagnosis of MCTD.
the serological hallmark of this condition. Indeed, since its first description in 1972 by Sharp et al., it is still
Because of the similar clinical features and unique serologic a matter of debate whether this condition has to be considered a
pattern of the first patients described in 1972, Sharp et al. proposed distinct clinical entity rather than an overlap syndrome between
that MCTD might represent a distinct rheumatic disease syndrome. two or more CTDs.
According to the first descriptions of the disease, MCTD patients Even if the anti-RNP reactivity is considered as the serologic
appeared to have an excellent response to corticosteroid therapy hallmark with a well recognized diagnostic value, it is not restricted
and a favorable prognosis [1]. to MCTD patients being present also in SLE, SS, SSc patients as well
Since the first description, our understanding of the classifica- as in Undifferentiated Connective Tissue Diseases (UCTD). However,
tion, clinical manifestations, long-term outcome and pathogenesis while antibodies specifically directed against U1e70K are found in
of MCTD have all advanced considerably. In this review, we will 75e90% of MCTD patients representing the most commonly
focus on the recent relevant literature published in the last decade 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].
* Corresponding author. To date at least three classification criteria for MCTD have been
E-mail address: s.bombardieri@med.unipi.it (S. Bombardieri). 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 In 2011, Gunnarsson R et al. performed a nationwide retro-
sensitivity and specificity in capturing MCTD patients [10] while a spective study to assess prevalence and incidence of MCTD in
recent study by Cappelli et al. found that Kasukawa’s criteria were Norway founding 147 adult Caucasian with a definite diagnosis of
more sensitive (75%) in comparison to those of Alarcon-Segovia MCTD and for a point prevalence of 3.8 per 100 000 adults and an
(73%) and Sharp (42%) in classifying MCTD patients over time [11]. incidence 2.1 per million per year during the period from 1996 to
The clinical need to define disease activity other than to classify 2005 with a female predominance (76.9%) [14].
them has clearly emerged over the years; in clinical practice, SLE- Prevalence of the clinical findings during the course of the dis-
specific disease activity criteria have been also used in MCTD pa- ease as reported by the most recent literature (years 2003e2013) is
tients and experience-based activity criteria have been recently summarized in Table 1.
proposed by Carvalho JF et al. [12] but, similarly that for classifi- Polyarthritis, Raynaud’s phenomenon (RP), puffy fingers, inter-
cation criteria, an international consensus on this matter is still stitial lung disease and esophageal dysmotility are the most
lacking. frequently reported symptoms among the different cohorts
(Table 1) during the course of the disease.
3. Epidemiology, clinical features and prognosis The largest recent MCTD cohort has been described by Hajas A
et al. in 2013; they found that at the time of diagnosis, polyarthritis,
The lack of internationally accepted classification or diagnostic RP, puffy fingers and sclerodactily were the most prevalent symp-
criteria for MCTD led to a scarcity of epidemiological studies over toms reported in 65%, 53%, 50% and 35% respectively; however,
the years and discordant data on the real prevalence and clinical during the 30 years of prospective follow-up patients tended to
course of this condition [13]. accrue over time new symptoms such as esophageal hypomotility,
However, in recent years large studies have been published nervous system manifestations, pulmonary arterial hypertension
providing important advances on disease epidemiology, clinical (PAH), interstitial lung disease but no progression to other CTD was
and laboratory as well as long term prognosis. 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 Oesophageal involvement PAH (case definition)
(case definition) (case definition)
Type of study

N of patients

Classification criteria

Fagundes MN, 2009, Brazil e ILD: 78% (on HRCT) Oesophageal dilatation: 56% e
Prospective Gastroesophageal reflux: 50%
50 Oesophageal motor
Kasukawa’s impairment: 83%
Gunnarsson R, 2011, Norway 79%e99% Self reported Symptoms of oesophageal e
Nationwide, retrospective survey dispnea: 47% dysmotility: 50%
147
At least one (Sharp, Kasukawa
or Alarcon-Segovia)
Hajas A, 2013, Hungary 89.6%/59.5% ILD: 47% (on HRCT Oesophageal dysmotility 17.8% (on DE  right
Prospective observational and PFR) (on radiographic barium ventricle catheterization)
280 passage or radionuclide
Alarcon-Segovia transit scintigraphy): 49.6%
Szodoray P, 2012, Norway 94.5%/78.6% ILD: 52.7% (on HRCT Oesophageal dysmotility 23.8% (on DE  right
Prospective observational and PFR) (on radiographic barium ventricle catheterization)
201 passage or radionuclide
Alarcon-Segovia transit scintigraphy): 69.5%
Gunnarsson R 2012, Norway e ILD: 52% (on HRCT) e e
Nationwide, cross-sectional
126
At least one (Sharp, Kasukawa
or Alarcon-Segovia)
Cappelli 2011, Italy 49.7%/85.1% 44.1% (on chest 45.3% (on manometry or e
Retrospective radiography or esophageal barium transit)
161 CT scan or PFR)
Expert opinion
Maldonado ME, 2008, USA e/86% e Gastroesophafeal reflux: 52% e
Cross-sectional
21
Alarcon-Segovia
Bodolay E, 2005, Hungary e 66.6% (on HRCT) e e
Cross-sectional
144
Alarcon-Segovia
Gunnarsson R 2012, Norway e e e 3.4% (on Doppler
Nationwide, cross-sectional echocardiography  right
147 ventricle catheterization)
At least one (Sharp, Kasukawa
or Alarcon-Segovia)

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 3

of vascular abnormalities on nailfold capillaroscopy in patients with Interestingly, in animal models the immunization with U1e70-
RP during the course of the disease. Moreover, cardiovascular kd small nuclear RNP (70K) lead to MCTD-like features while
manifestations as well as thrombotic events have been reported to mice deficient in Toll-like receptor 3 (TLR-3) failed to develop
occur in up to 35% and 25% of the patients respectively [15]. MCTD-like lung disease when immunized with the same antigen
Overall, they reported a better survival rate (98% at 5-year and but they developed an autoimmune syndrome characterized by
96% at 10-year respectively) with respect to earlier reports [16]; severe glomerulonephritis similar to SLE features, thus suggesting
PAH and cardiovascular events were found to be the major con- that exposure to 70K in a susceptible background is the key factor to
tributors to a poor prognosis in this cohort [15]. induce autoimmunity and target organ injury consistent with
Similarly to other CTDs, cardiovascular events due to accelerated MCTD [28].
atherosclerosis are an emerging issue in MCTD; traditional car- For classification purpose, the presence of anti-U1RNP auto-
diovascular risk factors as well as the chronic inflammation, antibodies is mandatory; however, the coexistence of other
elevated levels of AECA, aCL, and anti-b2-GPI autoantibodies are autoantibodies is a common clinical experience in MCTD with
important atherogenic factors in patients with MCTD [17e19]. significant influence on disease expression and clinical course
In 2005, Bodolay E et al. found a prevalence of active interstitial suggesting a potential pathogenetic role. Other autoantibodies
lung disease in 66.6% of consecutive MCTD patients as detected by frequently observed in MCTD patients are anti-phospholipids
HRCT and ground glass shadowing and fibrosis were the most (aCL, antib2GPI), anti-Ro, AECA, rheumatoid factor (RF) as well
common findings [20]. as anti-cyclic citrullinated peptides (anti-CCP). On these basis,
In 2012, a systematic evaluation of lung fibrosis was performed several sub-phenotype have been described among MCTD pa-
on 126 consecutive MCTD patients from the Norwegian registry; at tients; by cluster analysis, at least three clinical and serological
least one HRCT abnormality compatible with lung fibrosis was patterns have been proposed by Szodoray P et al. [29,30].
found in 52% of patients, being the most prevalent manifestations In detail, one subgroup of patients is characterized by pre-
the reticular patterns; severe lung fibrosis was found in 19%. Most dominant vascular involvement (PAH, RP, livedo reticularis and
importantly, severe lung fibrosis was associated with poorer func- vascular thrombosis) and higher prevalence of AEC and anti-
tional performances (as expressed by functional lung test, 6-min phospholipids in some cases satisfying the classification criteria
walking distance and NYHA functional class) and higher mortality for secondary antiphospholipid syndrome.
after a mean follow-up of 4.2 years [21]. Sensorineural hearing loss has been also reported as an
Pulmonary hypertension is the other major issue on MCTD emerging issue in up to 50% of MCTD patients and a significant
management. Recently, the prevalence of this severe complication association with anti-phospholipids antibodies other than higher
has been revisited by Gunnarsson et al.; in an unselected cohort of anti-U1RNP titers have been found [31].
MCTD patients, they found a PH frequency in the cohort of 3.4% In the second cluster identified by Szodoray et al. patients with
(5/147) over a period of 5.6 years of observation; in two cases PH predominant lung involvement (ILD) esophageal dysmotility and
was isolated while in three was associated with ILD [22]. myositis were grouped; the immunohistochemical analysis of the
In 2006, a prevalence of 25/179 was found by Vegh J et al.; they lung biopsy showed C3 complement and IgM type immunoglobulin
also found that the overall organ damage in our MCTD-PAH pa- deposition in the alveolar epithelial cells thus suggesting that a IC-
tients was much more serious than in MCTD-non-PAH patients mediated damage might play a role in the pathogenesis of ILD.
during the same follow-up period. The probability of a 5-year Similarly, in a histopathological study on esophageal lesions of
survival in MCTD-PAH cases was 73% opposed to 96% in MCTD MCTD patients, most severe changes including atrophy, loss of
patients without PAH [18]. smooth muscle cells and fibrosis were observed in the muscular
In conclusion, although there are growing numbers of reports layer of the lower esophagus and immunoglobulin and comple-
on successfully treated MCTD-PAH, PAH is still considered as a se- ment deposition were found [32].
vere complication of MCTD seriously worsening the prognosis of An association between ILD and esophageal dysfunction has also
the disease. Interestingly, recently the presence of antib2GPI anti- been observed by Fagundes MN et al. to support the hypothesis of a
bodies was associated with pulmonary arterial hypertension in a common pathogenetic pathway [33].
small cohort of MCTD patients [19]. The third cluster identified by Szodoray P et al. recognizes pa-
Early atherosclerosis is another emerging issue in MCTD tients with higher prevalence of erosive arthritis and anti-CCP au-
patients; similarly to what observed in other systemic autoimmune toantibodies. Non-erosive inflammatory arthritis is frequently
diseases, early signs of subclinical atherosclerosis have been described as a presenting feature in MCTD and bone erosions are
described with respect to healthy controls [23]. Indeed, besides rarely reported in the traditional literature [34]; with respect to
traditional cardiovascular risk factors, autoantibodies such as previous reports, erosions accrual over time and deformities
anti-U1RNP antibodies and AECA, as well as the up-regulation of developing have been described in up to 30% of patients in more
pro-inflammatory cytokines, could play a crucial role in early recent studies with long-term follow-up [35].
atherosclerotic events in MCTD. Indeed, it is well known that some clinical features of MCTD
may change over time, and that the disease may evolve from
4. New advances in disease pathogenesis predominant inflammatory manifestations to a sclerotic disease
[36,37]. Recent observational studies highlighted the importance
Over the last years, significant advances have been made in of a long-term follow-up to better define the natural course of
disease pathogenesis understanding and a central pathogenetic the disease and potential evolution to other CTDs. It has been
role of anti-U1RNP autoantibodies has clearly emerged. Indeed, recently reported that roughly 20% of patients initially diagnosed
recent experimental data demonstrated that components of the U1 with MCTD at disease onset evolved to another CTD over a
snRNP complex may participate directly in provoking the anti-RNP period of 5 years but this percentage tends to significantly in-
responses; autoantibodies in MCTD recognize intact or modified crease up to 50% of patients (depending on the classification
individual U1 snRNP proteins as well as structures composed of criteria adopted) over a period of 10 years [11,38]. The presence
multiple subunits of the U1 snRNP macromolecule. Moreover, an of anti-DNA antibodies was associated with evolution into SLE,
anti-U1RNP autoantibodies have been found to interact with lung while esophageal dysmotility and sclerodactyly with evolution
tissue thus significantly contributing to disease features [24e27]. 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
4 C. Tani et al. / Journal of Autoimmunity xxx (2014) 1e4

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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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