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

Abstract

Objective

To update and revise the diagnostic criteria for mixed connective tissue disease (MCTD) issued by the Japan Research Committee of the Ministry of Health, Labor, and Welfare (MHLW), a round table discussion by experts from rheumatology, dermatology, and pediatric medicine was conducted in multiple occasions.

Methods

The definition of MCTD, and items included in the diagnostic criteria were generated by 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 trigeminal 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.

Keywords:

• Diagnosis
• criteria
• mixed connective tissue disease

Introduction

In 1972, Sharp et al. proposed mixed connective tissue disease (MCTD) as a disease entity characterized by overlapping 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 registered patients and one of typical systemic autoimmune diseases. However, in Europe and the United States, the disease concept of MCTD is sometimes far from being sufficiently acknowledged. Also, in cases of changing pathological conditions over the clinical course, no consensus 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 acceptable [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 typical 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 clinical 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 judgment. First, a subcommittee was organized by experts in connective tissue diseases, including MCTD, from different specialties, rheumatology, dermatology, and pediatric medicine. 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 institutions of co-investigators and collaborators. Through analysis 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 meeting 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 discussed. In 33 typical cases of MCTD, the diagnostic concordance 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 determined that a diagnosis should be made while the basic concept 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 understanding of the overall picture of this disease by providing descriptions of the concept of MCTD, common manifestations, immunological manifestation and characteristic organ involvement (Table 1).

Table 1. Diagnostic criteria for mixed connective tissue disease 2019, from the Japan research committee of the ministry of health, labor, and welfare for systemic 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/μL or less) or thrombocytopenia (100,000/μL 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 manifestation, 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 antibody. When the result of double immunodiffusion is positive and inconsistent 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 antibodies 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, infectious (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.

The common manifestations include those observed in the majority of MCTD cases. Although pulmonary arterial hypertension had been regarded as a common manifestation, 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 diagnosis. Meanwhile, conditions with characteristic organ involvement include pulmonary arterial hypertension, aseptic meningitis, and trigeminal neuropathy. Even if the overlapping manifestations are absent, MCTD can be diagnosed based on the presence of a characteristic organ involvement.

The items in the overlapping manifestations were originally selected depending upon their prevalence and relevance to MCTD in the Sharp criteria (1). The overlapping manifestations were also partially revised. In the systemic sclerosis-like manifestations, the designation of pulmonary fibrosis was changed to interstitial lung disease. Because sensitivity 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 indicative 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 consensus on the conventional criteria requiring a careful diagnosis of MCTD in patients diagnosed as having SLE, systemic sclerosis, or polymyositis/dermatomyositis. A note was added on the following disease marker antibodies characteristic to SLE, systemic sclerosis, and polymyositis/dermatomyositis: (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 and anti-melanoma differentiation-associated gene-5 antibody, 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 positivity for anti-U1-RNP antibody and Raynaud’s phenomenon were emphasized as the common manifestations, whereas half of the participating pediatricians did not agree with inclusion of the overlapping manifestations in the diagnostic 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 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 accumulated 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 characteristic common manifestations, organ impairment, severity, and therapeutic strategies in comparison with other connective 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 valued, 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 studies in the future.

The treatment of MCTD shares many aspects in common with that of SLE, systemic sclerosis, and polymyositis/dermatomyositis, 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 rheumatologists in Europe and the United States do not acknowledge 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 disease by providing descriptions of the concept of MCTD, common manifestations, immunological manifestation and characteristic organ impairments. Pulmonary arterial hypertension, 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 sclerosis, or polymyositis/dermatomyositis, the subcommittee decided that MCTD should be carefully diagnosed as indicated by the conventional diagnostic criteria. By providing a note on specific disease marker antibodies characteristic to each disease, the revised diagnostic criteria facilitate differential diagnosis. Furthermore, a description that differential 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 interstitial 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 guidelines 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 provide 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 diagnostic criteria incorporating clinical and social background 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 subsequent validation using independent cohort, we have established 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 providing 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.