Modern Rheumatology

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2019 Diagnostic criteria for mixed connective

tissue disease (MCTD): From the Japan research
committee of the ministry of health, labor, and
welfare for systemic autoimmune diseases

Yoshiya Tanaka, Masataka Kuwana, Takao Fujii, Hideto Kameda, Yoshinao

Muro, Keishi Fujio, Yasuhiko Itoh, Hidekata Yasuoka, Shusaku Fukaya,
Konomi Ashihara, Daisuke Hirano, Koichiro Ohmura, Yuya Tabuchi, Hisanori
Hasegawa, Ryo Matsumiya, Yuichiro Shirai, Takehisa Ogura, Yumi Tsuchida,
Mariko Ogawa-Momohara, Hidehiko Narazaki, Yoshino Inoue, Ippei
Miyagawa, Kazuhisa Nakano, Shintaro Hirata & Masaaki Mori

To cite this article: Yoshiya Tanaka, Masataka Kuwana, Takao Fujii, Hideto Kameda, Yoshinao
Muro, Keishi Fujio, Yasuhiko Itoh, Hidekata Yasuoka, Shusaku Fukaya, Konomi Ashihara, Daisuke
Hirano, Koichiro Ohmura, Yuya Tabuchi, Hisanori Hasegawa, Ryo Matsumiya, Yuichiro Shirai,
Takehisa Ogura, Yumi Tsuchida, Mariko Ogawa-Momohara, Hidehiko Narazaki, Yoshino Inoue,
Ippei Miyagawa, Kazuhisa Nakano, Shintaro Hirata & Masaaki Mori (2020): 2019 Diagnostic criteria
for mixed connective tissue disease (MCTD): From the Japan research committee of the ministry
of health, labor, and welfare for systemic autoimmune diseases, Modern Rheumatology, DOI:
10.1080/14397595.2019.1709944

To link to this article: https://doi.org/10.1080/14397595.2019.1709944

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MODERN RHEUMATOLOGY
https://doi.org/10.1080/14397595.2019.1709944

ORIGINAL ARTICLE

2019 Diagnostic criteria for mixed connective tissue disease (MCTD): From the
Japan research committee of the ministry of health, labor, and welfare for
systemic autoimmune diseases
Yoshiya Tanakaa, Masataka Kuwanab, Takao Fujiic, Hideto Kamedad, Yoshinao Muroe, Keishi Fujiof,
Yasuhiko Itohg, Hidekata Yasuokah, Shusaku Fukayah, Konomi Ashiharah, Daisuke Hiranoh, Koichiro Ohmurai,
Yuya Tabuchii, Hisanori Hasegawaj, Ryo Matsumiyac, Yuichiro Shiraib, Takehisa Ogurad, Yumi Tsuchidaf,
Mariko Ogawa-Momoharae, Hidehiko Narazakig, Yoshino Inouea, Ippei Miyagawaa, Kazuhisa Nakanoa,
Shintaro Hiratak and Masaaki Moril
a
The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan;
b
Department of Allergy and Rheumatology, Nippon Medical School, Graduate School of Medicine, Tokyo, Japan; cDepartment of
Rheumatology and Clinical Immunology, Wakayama Medical University, Wakayama, Japan; dDivision of Rheumatology, Toho University,
Tokyo, Japan; eDepartment of Dermatology, Nagoya University Graduate School of Medicine, Nagoya, Japan; fDepartment of Allergy and
Rheumatology, Graduation School of Medicine, The University of Tokyo, Tokyo, Japan; gDepartment of Pediatrics, Graduate School of
Medicine, Nippon Medical School, Tokyo, Japan; hDivision of Rheumatology, Department of Internal Medicine, Fujita Health University
School of Medicine, Aichi, Japan; iDepartment of Rheumatology and Clinical Immunology, Graduate School of Medicine, Kyoto University,
Kyoto, Japan; jDepartment of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo,
Japan; kDepartment of Clinical Immunology and Rheumatology, Hiroshima University Hospital, Hiroshima, Japan; lDepartment of Lifetime
Clinical Immunology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan

ABSTRACT ARTICLE HISTORY

Objective: To update and revise the diagnostic criteria for mixed connective tissue disease (MCTD) Received 23 October 2019
issued by the Japan Research Committee of the Ministry of Health, Labor, and Welfare (MHLW), a Accepted 25 December 2019
round table discussion by experts from rheumatology, dermatology, and pediatric medicine was con-
ducted in multiple occasions. KEYWORDS
Diagnosis; criteria; mixed
Methods: The definition of MCTD, and items included in the diagnostic criteria were generated by connective tissue disease
consensus method and evaluation using clinical data of typical and borderline cases of MCTD, by
applying to the diagnostic criteria for MCTD proposed in 1996 and 2004 by the Research Committee
of MHLW.
Results: To the end, all committee members reached consensus. Then, the criteria were assessed in
an independent validation cohort and tested against preexisting criteria. The revised criteria facilitate
an understanding of the overall picture of this disease by describing the concept of MCTD, common
manifestations, immunological manifestation and characteristic organ involvement. Conditions with
characteristic organ involvement include pulmonary arterial hypertension, aseptic meningitis and trige-
minal neuropathy. Even if the overlapping manifestations are absent, MCTD can be diagnosed based
on the presence of the characteristic organ involvement. Furthermore, the criteria were validated for
applicability in actual clinical cases, and public comments were solicited from the Japan College of
Rheumatology and other associated societies.
Conclusion: After being reviewed through public comments, the revised diagnostic criteria have
been finalized.

Introduction
In 1972, Sharp et al. proposed mixed connective tissue dis-
ease (MCTD) as a disease entity characterized by overlap-
ping clinical features of systemic lupus erythematosus (SLE),
systemic sclerosis, and polymyositis, as well as high titers of
serum anti-U1 ribonucleoprotein (U1-RNP) antibody [1].
Although MCTD was previously considered a subtype of
systemic sclerosis, it has recently been recognized as an
independent disease entity in terms of organ involvement
because of its characteristic association with conditions such
as pulmonary arterial hypertension, aseptic meningitis, and
trigeminal neuropathy [2–9].
In 1986, the MCTD criteria was first proposed by
Kasukawa et al., as representatives of the research committee
for MCTD of the Ministry of Health and Welfare in Japan
during an International Symposium on Mixed Connective
Tissue Disease and Anti-nuclear Antibodies [6]. MCTD was
designated as a specified disease by the Ministry of Health,
Labor, and Welfare (MHLW) in Japan in 1993. At present,
it is a designated intractable disease affecting 11,000

CONTACT Yoshiya Tanaka tanaka@med.uoeh-u.ac.jp The First Department of Internal Medicine, School of Medicine, University of Occupational and
Environmental Health, 1-1 Iseigaoka, Yahata-nishi, Kitakyushu 807-8555, Japan
ß 2020 Japan College of Rheumatology
2 Y. TANAKA ET AL.
registered patients and one of typical systemic autoimmune
diseases. However, in Europe and the United States, the dis-
ease concept of MCTD is sometimes far from being suffi-
ciently acknowledged. Also, in cases of changing
pathological conditions over the clinical course, no consen-
sus has been reached on to what extent pathological changes
are included in the concept of MCTD, and whether the
overlapping manifestations of SLE and MCTD are accept-
able [10].
Thus, in 2017, in order to understand the views of
Japanese experts and to establish a consensus on MCTD,
the MCTD Subcommittee of the Autoimmune Disease
Research Committee, as part of the Research Project on
Intractable Disease supported by the MHLW, collected typ-
ical and borderline cases of MCTD from each institution in
this study. A round table meeting was held to review the
definition of MCTD and to update the diagnostic criteria
for MCTD issued by the Japan Research Committee of the
MHLW in 1996 and 2004, by multiple rounds of discussions
and consensus generation based on analysis of detailed clin-
ical findings of the derivation and validation cohorts.
Methods
The development and testing of the diagnostic criteria for
MCTD was based on both data and expert clinical judg-
ment. First, a subcommittee was organized by experts in
connective tissue diseases, including MCTD, from different
specialties, rheumatology, dermatology, and pediatric medi-
cine. To review the definition of MCTD and to establish the
consensus of committee members, a total of 66 typical and
borderline cases of MCTD were collected from all 11 insti-
tutions of co-investigators and collaborators. Through ana-
lysis of these cases, the definition of MCTD was discussed,
and the diagnostic criteria for MCTD issued in 1996 and
2004 was updated and revised through a round table meet-
ing held repeatedly and final consensus by experts. The
2004 diagnostic criteria were also compared with the
Alarcon-Segovia criteria and Sharp criteria [5–8,11,12].
Finally, the validity of the revised diagnostic criteria was
tested in 51 cases accumulated by the MCTD Research
Committee of the MHLW in 2008, as a validation cohort.
In addition, an on-line questionnaire-based survey was
conducted on the conventional diagnostic criteria for
MCTD in children to identify problems with the criteria
and to explore measures to solve them. Furthermore, public
comments were solicited on the proposal for the revised
diagnostic criteria from the Japan College of Rheumatology
(JCR), the Japanese Dermatological Association and other
associated societies. Based on the results of these analyses,
as well as the public comments, a proposal for the 2019
revised diagnostic criteria for MCTD was developed.
Results
Based on a review of the definition of MCTD in the detailed
clinical findings of 66 cases of typical and borderline MCTD
provided by the committee members, the update and
revision of the 2004 diagnostic criteria for MCTD was dis-
cussed. In 33 typical cases of MCTD, the diagnostic con-
cordance rate for the diagnosis of MCTD was high, and
there were few deviations from the criteria. On the other
hand, the investigators were divided over the diagnosis in
33 borderline cases. As for the reasons for this, problems
were found with how they understood the common and
overlapping manifestations. Thus, the subcommittee deter-
mined that a diagnosis should be made while the basic con-
cept of the disease is adhered and while the characteristic
common manifestations, organ impairment, severity, and
therapeutic strategies are kept in mind. Moreover, in the
opening sections, the revised criteria facilitate an under-
standing of the overall picture of this disease by providing
descriptions of the concept of MCTD, common manifesta-
tions, immunological manifestation and characteristic organ
involvement (Table 1).
The common manifestations include those observed in
the majority of MCTD cases. Although pulmonary arterial
hypertension had been regarded as a common manifest-
ation, its prevalence is only 10%–20%. Thus, it was excluded
from the list of common manifestations. This exclusion had
a small effect on the sensitivity and specificity of the diagno-
sis. Meanwhile, conditions with characteristic organ involve-
ment include pulmonary arterial hypertension, aseptic
meningitis, and trigeminal neuropathy. Even if the overlap-
ping manifestations are absent, MCTD can be diagnosed
based on the presence of a characteristic organ involvement.
The items in the overlapping manifestations were origin-
ally selected depending upon their prevalence and relevance
to MCTD in the Sharp criteria (1). The overlapping mani-
festations were also partially revised. In the systemic scler-
osis-like manifestations, the designation of pulmonary
fibrosis was changed to interstitial lung disease. Because sen-
sitivity of restrictive ventilatory impairment by spirometry
for detection of interstitial lung disease is low, and decline
of diffusing capacity of lung for carbon monoxide is indica-
tive of the presence of advanced interstitial lung disease
and/or pulmonary arterial hypertension, which is included
in the characteristic organ involvement in the criteria, the
items of the respiratory function test were removed. Digital
ulcer and nail-fold capillaroscopic abnormalities were not
included in the criteria because they are essential items for
diagnosing systemic sclerosis. As for dermatomyositis-like
manifestations, Gottron’s papules/sign and heliotrope rash
were determined to be irrelevant to the criteria because they
are characteristic features of dermatomyositis and do not
contribute to improved sensitivity of this criteria.
Based on these findings, the subcommittee reached con-
sensus on the conventional criteria requiring a careful diag-
nosis of MCTD in patients diagnosed as having SLE,
systemic sclerosis, or polymyositis/dermatomyositis. A note
was added on the following disease marker antibodies char-
acteristic to SLE, systemic sclerosis, and polymyositis/derm-
atomyositis: (1) anti-double-stranded DNA antibody and
ant-Smith antibody, (2) anti-topoisomerase I antibody (anti-
Scl-70 antibody) and anti-RNA polymerase III antibody,
and (3) anti-aminoacyl-transfer RNA synthetase antibody

Table 1. Diagnostic criteria for mixed connective tissue disease 2019, from the
Japan research committee of the ministry of health, labor, and welfare for sys-
temic autoimmune diseases.
I. Common manifestations
1. Raynaud’s phenomenon
2. Puffy fingers and/or swollen hands
II. Immunological manifestation
Positivity for anti-U1 ribonucleoprotein antibody
III. Characteristic organ involvement
1. Pulmonary arterial hypertension
2. Aseptic meningitis
3. Trigeminal neuropathy
IV. Overlapping manifestations
A. Systemic lupus erythematosus-like manifestations
1. Polyarthritis
2. Lymphadenopathy
3. Malar rash
4. Pericarditis or pleuritis
5. Leukopenia (4,000/lL or less) or thrombocytopenia (100,000/lL or less)
B. Systemic sclerosis-like manifestations
1. Sclerodactyly
2. Interstitial lung disease
3. Esophageal dysmotility or dilatation
C. Polymyositis/Dermatomyositis-like manifestations
1. Muscle weakness
2. Elevated levels of myogenic enzymes
3. Myogenic abnormalities on electromyogram
Diagnosis: Mixed connective tissue disease is diagnosed when a patient meets
all the following: at least one common manifestation, immunological manifest-
ation, and at least one characteristic organ involvement; or when a patient
meets all the following: at least one common manifestation, immunological
manifestation, and at least one feature each in 2 or more from items A, B,
and C in overlapping manifestations.
Notes
1. Either double immunodiffusion or enzyme-linked immunosorbent assay
(ELISA) can be performed for detection of anti-U1 ribonucleoprotein anti-
body. When the result of double immunodiffusion is positive and incon-
sistent with that of the ELISA, the result of the double immunodiffusion
supersedes that of the ELISA.
2. When a patient is positive for one of the following disease marker anti-
bodies relatively specific to other connective tissue diseases, the diagnosis
of mixed connective tissue disease should be carefully made.
1. Anti-double-stranded DNA antibody or anti-Sm antibody
2. Anti-topoisomerase I antibody (anti-Scl-70 antibody) or anti-RNA
polymerase III antibody
3. Anti-aminoacyl-transfer RNA synthetase antibody or anti-melanoma
differentiation-associated gene 5 antibodies.
3. In children and adolescents, mixed connective tissue disease can also be
diagnosed when a patient meets all the following: at least one common
manifestation, immunological manifestation and at least one feature from
items A, B, or C in overlapping manifestations.
4. Differential diagnosis is prerequisite to decide “characteristic organ
involvement”. For instance, when aseptic meningitis is diagnosed, infec-
tious (mainly viral) meningitis, drug-induced meningitis, tumor-associated
meningitis should be carefully excluded. Differential diagnosis differ
among patients and an expert rheumatologist should be consulted if it is
unclear about the relevant differential diagnosis to consider.
and anti-melanoma differentiation-associated gene-5 anti-
body, respectively. These markers can be measured under
the current national health insurance scheme and appear to
be associated with prognosis and organ impairments.
The on-line questionnaire survey on the conventional
diagnostic criteria for MCTD in children revealed that posi-
tivity for anti-U1-RNP antibody and Raynaud’s phenom-
enon were emphasized as the common manifestations,
whereas half of the participating pediatricians did not agree
with inclusion of the overlapping manifestations in the diag-
nostic criteria. Because children with MCTD do not always
present with two or more overlapping manifestations [13], a
note was added, indicating that MCTD can be diagnosed if
MODERN RHEUMATOLOGY 3
children and adolescents present with one feature or more
of any item in the overlapping manifestations.
Based on these results, a proposal for the 2019 revised
diagnostic criteria for MCTD was developed (Table 1).
When its validity was tested in the 66 above-described cases
and an independent validation cohort of 51 cases accumu-
lated by the MCTD Research Committee of the MHLW in
2008, there was only discordant case, which did not meet
2004 criteria, but satisfied new criteria. Specifically, this
patient had pulmonary arterial hypertension in the absence
of overlapping features. Thus, in the validation cohort, the
revised diagnostic criteria had a sensitivity of 90.6% and
specificity of 98.4%, compared to 88.7% sensitivity and
98.4% specificity of the diagnostic criteria 2004. In addition,
the revised criteria were also generally highly valued,
according to the public comments solicited from the JCR
and other associated societies.
Discussion
The subcommittee discussed how to update and revise the
diagnostic criteria for MCTD and reached consensus on the
basic concept of the disease entity, by considering character-
istic common manifestations, organ impairment, severity,
and therapeutic strategies in comparison with other con-
nective tissue diseases. The new criteria were validated in an
independent cohort, and was likely to increase sensitivity
without lowering specificity. It was also generally highly val-
ued, according to the public comments solicited from the
JCR and other associated societies. After being peer
reviewed, the revised diagnostic criteria have been finalized.
This new guideline should be used in epidemiological stud-
ies in the future.
The treatment of MCTD shares many aspects in common
with that of SLE, systemic sclerosis, and polymyositis/derm-
atomyositis, such that therapeutic components specific to
MCTD are limited [2–6]. This is also attributable to the
small number of articles on MCTD because some rheuma-
tologists in Europe and the United States do not acknow-
ledge the disease concept of MCTD [10]. Thus, the
diagnosis of MCTD is often made in clinical setting by
judgement based on expertise of physicians. By reaffirming
of the disease concept and development of the diagnostic
criteria, studies for evaluating efficacy of treatment regimens
could be done in the future by using unified patients
defined by the criteria.
Moreover, in the opening sections, the revised criteria
facilitate an understanding of the overall picture of this dis-
ease by providing descriptions of the concept of MCTD,
common manifestations, immunological manifestation and
characteristic organ impairments. Pulmonary arterial hyper-
tension, aseptic meningitis and trigeminal neuropathy are
included in characteristic organ involvement, because they
are well known to be characteristic to MCTD and are often
significant prognosis factors, but their prevalence is 10–20%
or less [14–17]. In cases diagnosed as SLE, systemic scler-
osis, or polymyositis/dermatomyositis, the subcommittee
decided that MCTD should be carefully diagnosed as
4 Y. TANAKA ET AL.
indicated by the conventional diagnostic criteria. By provid-
ing a note on specific disease marker antibodies characteris-
tic to each disease, the revised diagnostic criteria facilitate
differential diagnosis. Furthermore, a description that differ-
ential diagnosis is prerequisite to decide characteristic organ
involvement and that an expert rheumatologist should be
consulted if it is unclear has been added to the notes.
Meanwhile, with the exception of pulmonary arterial
hypertension, the prognosis of MCTD is better than that of
SLE and polymyositis/dermatomyositis associated with inter-
stitial pneumonitis. There are even some cases in which
bolus corticosteroid therapy is not essential. The treatment
of MCTD also shares many aspects with other connective
tissue diseases. However, because the number of relevant
articles is small, it is difficult to develop treatment guide-
lines and diagnostic criteria based on systematic literature
review. The revised diagnostic criteria cannot be assured to
be based on sufficient scientific evidence. This study was
conducted as part of the Research Project on Intractable
Disease supported by the MHLW and primarily aimed to
develop diagnostic criteria that would accurately identify
patients with intractable disease eligible for medical benefits.
For this reason, the revised diagnostic criteria should pro-
vide precise criteria but not contain any criteria that lead to
different decisions between physicians or institutions or that
differ from those in the current diagnostic criteria. In other
words, the subcommittee assumes that it developed diagnos-
tic criteria incorporating clinical and social back-
ground factors.
Keeping in mind the disease concept of MCTD and the
revised diagnostic criteria for MCTD accepted in this study,
the subcommittee will aim to develop treatment guidelines
in the future.
Conclusion
Using consensus methods using patients’ database and sub-
sequent validation using independent cohort, we have estab-
lished a common view on disease entity of MCTD, and
updated and revised the diagnostic criteria.
Acknowledgments
The authors wish to thank all the patients for their contribution to the
study. The authors thank all medical staff in all institutions for provid-
ing the data. This work was supported in part by a Grant-In-Aid for
Scientific Research from the Ministry of Health, Labor and Welfare
of Japan.
Conflict of interest
Yoshiya Tanaka has received speaking fees and/or honoraria from
Daiichi-Sankyo, Astellas, Chugai, Eli Lilly, Pfizer, Abbvie, YL Biologics,
Bristol-Myers, Takeda, Mitsubishi-Tanabe, Novartis, Eisai, Janssen,
Teijin and has received research grants from Asahi-kasei, Mitsubishi-
Tanabe, Chugai, Takeda, Sanofi, Bristol-Myers, UCB, Daiichi-Sankyo,
Eisai and Ono. Masataka Kuwana has received speaking fees and/or
honoraria from Abbvie, Actelion, Astellas, Ayumi, Bayer, Boehringer-
ingelheim, Chugai, Eisai, Janssen, GSK, Mitsubishi Tanabe, Novartis,
Ono, Pfizer, Nippon Shinyaku, and Takeda, and has received research
grants from Actelion, Asahi-kasei, Mitsubishi-Tanabe, Chugai, Eisai,
Nippon-Kayaku, and Ono. Takao Fujii has received speaking fees and/
or honoraria from Abbvie, Astellas, Asahi-kasei, Chugai, Eli Lilly,
Eisai, Janssen, Kissei, Mitsubishi-Tanabe, Ono, Pfizer, Sanofi, Taisho
Toyama, Takeda, and UCB, and has received research grants from
AbbVie, Ayumi, Asahi-kasei, Astellas, Chugai, Daiichi-Sankyo, Eli
Lilly, Eisai, Kissei, Mitsubishi-Tanabe, Pfizer, Nippon-Kayaku, Ono,
Takeda, and UCB. Hideto Kameda has received speaking fees and/or
honoraria from AbbVie GK, Asahi-Kasei, Astellas, Bristol-Myers,
Chugai, Eli Lilly, Janssen, Mitsubishi-Tanabe, Novartis and Pfizer, and
has received research grants from AbbVie GK, Asahi-Kasei, Astellas,
Chugai, Eisai, Mitsubishi-Tanabe and Novartis. Keishi Fujio has
received speaking fees and/or honoraria from Tanabe Mitsubishi,
Bristol Myers, Eli Lilly, Chugai, Jansen, Pfizer, Ono, Abbie, Ayumi,
Astellas, Sanofi, Novartis, Daiichi Sankyo, Eisai, Asahi Kasei, Japan
Blood Products Organization, and Kowa, and has received research
grants from Tanabe Mitsubishi, Bristol Myers, Eli Lilly, Chugai, Abbie,
Ayumi, Astellas, Sanofi, Eisai, and Asahi Kasei. Koichiro Ohmura has
received speaking fees and/or honoraria from Abbvie, Actelion,
Astellas, Ayumi, Asahikasei-Pharma, Bristol-Myers, Eisai, Eli Lilly,
GSK, Janssen, Mitsubishi Tanabe, Novartis, Sanofi and has received
research grants from Bristol-Myers, Eisai, Eli Lilly, GSK, Mitsubishi-
Tanabe, Nippon-Kayaku. Hisanori Hasegawa has received speaking
fees and/or honoraria from Astellas, Chugai, Eli Lilly, Pfizer, Bristol-
Myers, Eisai, Janssen, Teijin, Asahi-kasei, Nihon Pharmaceutical, Ono
and has received research grants from Mitsubishi-Tanabe. Yuichiro
Shirai has received a research grant from Actelion. Shintaro Hirata has
received consultancy fee, advisory fee, or speaker bureau from AbbVie,
Asahi-Kasei Pharma, Asahi-Kasei Medical, Astellas, Ayumi, Bristol-
Myers Squibb, Celgene, Chugai, Eisai, Eli Lilly, Janssen, Kissei,
Novartis, Pfizer, Sanofi, Takeda, Tanabe-Mitsubishi, and UCB. Tokyo
Medical and Dental University received unrestricted research grants
for Department of Lifetime Clinical Immunology from AbbVie,
Ayumi, Chugai, CSL Behring, Japan Blood Products Organization,
Nippon Kayaku, UCB Japan, Asahi-Kasei. Others do not have conflict
of interests.
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