Skip to main content
Download PDF

A cohort study in HigAshi-nippon of Pulmonary hyPertensIoN in systEmic SclerosiS (HAPPINESS study): protocol and baseline data for an observational study

BMC Rheumatology volume 9, Article number: 25 (2025) Cite this article

Abstract

Background

Pulmonary hypertension (PH) is the leading cause of death among patients with systemic sclerosis (SSc). Recently, early therapeutic intervention to improve the prognosis was suggested, and the definition of PH was recently revised by lowering the cut-off value of mean pulmonary arterial pressure (mPAP) from ≥ 25 to > 20 mmHg. However, the optimal threshold for therapeutic intervention remains unclear. We aim to evaluate the prognosis of patients with SSc and its relationship with mPAP.

Methods

For this non-interventional retrospective and prospective cohort study, we enrolled patients with SSc or scleroderma spectrum disorders accompanied by other connective tissue diseases who underwent right heart catheterization (RHC) for suspected PH from 2010 to 2023. The date of the first RHC was defined as the baseline. Enrolled patients were classified into three groups based on their mPAP at the first RHC (≤ 20, 21-24, and ≥ 25 mmHg) and are being observed from baseline up to three years. The primary endpoint is the time between the first RHC and the first hospitalisation or death due to worsening PH.

Results

This study was approved by the Ethics Committee of Hokkaido University Hospital. A total of 229 patients were enrolled from 12 participating centres, with 41 prospectively followed up and 188 retrospectively followed up. The number of patients in each group (an mPAP of ≤ 20, 21–24, and ≥ 25 mmHg) is 79, 26, and 124, respectively. The observation is expected to be completed by December 2026. Findings will be disseminated at scientific conferences, peer-reviewed journals.

Conclusions

The findings of this study that we will obtain are expected to provide important information that will lead to improvements in the diagnosis of PH and the prognosis of patients.

Trial registration

This study was approved by the Ethics Committee of Hokkaido University Hospital (approval number 022-0109). It has been registered in the Japan Registry of Clinical Trials as jRCT1010220025 since November 7, 2022.

Peer Review reports

Background

Pulmonary hypertension (PH) often aggravates connective tissue diseases (CTDs) and negatively affects exercise capacity, quality of life, and survival. It is the leading cause of death in systemic sclerosis (SSc) and develops owing to pulmonary vascular disease (group 1 PH, pulmonary arterial hypertension [PAH]), left heart disease (group 2 PH), and/or interstitial lung disease (group 3 PH), complicating clarification of the underlying pathological condition and decision-making regarding therapeutic interventions [1,2,3,4,5]. Compared with PAH associated with other CTDs, such as systemic lupus erythematosus (SLE), SSc-PAH reportedly has a poorer response to immunosuppressive drugs and a worse prognosis [6, 7].

Although right heart catheterization (RHC) is a requisite for the diagnosis of PH, owing to its invasiveness it is exclusively performed in cases with a strong suspicion of PH based on other clinical examinations, such as N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, pulmonary function tests (such as the diffusing capacity of the lungs for carbon monoxide [DLCO]), ratio of forced vital capacity (FVC) to the DLCO, and tricuspid regurgitation velocity assessed via echocardiography [1, 8,9,10].

Recently, the definition of PH has been revised by lowering the cut-off value of mean pulmonary arterial pressure (mPAP) from ≥ 25 to > 20 mmHg [11]. Among patients with SSc, the mPAP = 21-24-mmHg group, traditionally referred to as those with borderline PH (or borderline PAP), is considered at risk of PAH, and cohort studies in different countries have revealed that 42-55% of these patients are classified as having overt PAH over time upon follow-up RHC [12, 13]. Furthermore, the mPAP = 21-24-mmHg group reportedly has similarly poor overall survival to the mPAP ≥ 25-mmHg group [14]. Therefore, early therapeutic interventions to improve prognosis have been suggested, particularly for patients with SSc-PAH [8, 15, 16], although the optimal threshold for therapeutic intervention remains unclear.

In this cohort study, we are aiming to evaluate the prognosis of patients with SSc and its relationship with the mPAP. We collected clinical data from patients with SSc who underwent RHC, dividing them into three groups based on their mPAP.

Methods

Study design

This is a non-interventional retrospective and prospective cohort study. We have enrolled patients with SSc or scleroderma spectrum disorders accompanying other CTDs who underwent RHC after 2010 for suspected PH. Patients were recruited from 12 specialized centers across eastern Japan (Table 1).

Table 1 Number of enrolled patients
Full size table

The date of the first RHC was defined as the baseline. Enrolled patients were classified into three groups based on their mPAP at the first RHC (≤ 20, 21-24, and ≥ 25 mmHg) and were observed from baseline for three years. Patients who had undergone their first RHC more than three years before enrolment were followed up retrospectively (Fig. 1A). For patients who underwent the first RHC within three years of enrolment, prospective follow-up was initiated after they provided informed consent (Fig. 1B). For these patients, the prospective observation period is three years minus the retrospective period. Patients newly undergoing RHC after the start of this study are being followed up in a fully prospective manner for three years from baseline after they provided informed consent (Fig. 1C).

Fig. 1
figure 1

Study design. (A) Retrospective observation. (B) Prospective observation of patients who underwent RHC before inclusion. (C) Prospective observation of patients who underwent RHC at the same time as inclusion. SSc: systemic sclerosis; PH: pulmonary hypertension; RHC: right heart catheterisation; mPAP: mean pulmonary arterial pressure

Full size image

This study was approved by the Ethics Committee of Hokkaido University Hospital (approval number: 022–0109). It has been registered in the Japan Registry of Clinical Trials as jRCT1010220025 since November 7, 2022. All researchers involved in this study will comply with the Declaration of Helsinki and the Ethical Guidelines for Medical Research Involving Human Subjects.

Participants

Inclusion criteria

Patients who met the following criteria were included:

  1. 1.

    Aged 18 years or older at the time of inclusion.

  2. 2.

    Fulfilling the 2013 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria for SSc [17] or having scleroderma spectrum disorders (sclerodactyly or SSc-specific autoantibodies, including anti-Scl-70, anti-centromere, or anti-RNA polymerase III antibodies) and meeting one of the following criteria: the 2019 Japanese Ministry of Health, Labour, and Welfare diagnostic criteria for mixed connective tissue disease [18], the 1997 ACR classification criteria for SLE [19], the 2012 Systematic Lupus International Collaborating Clinics classification criteria for SLE [20], the Bohan and Peter criteria for the diagnosis of polymyositis and dermatomyositis [21], or the 2016 ACR/EULAR classification criteria for primary Sjögren’s syndrome [22].

  3. 3.

    Having had their first RHC later than 2010 for suspicion of PH owing to unexplained dyspnoea, increased NT-proBNP levels (more than twice the upper limit of the normal range), reduced pulmonary diffusing capacity (DLCO < 60% or FVC/DLCO > 1.6), or elevated tricuspid regurgitation velocity (> 2.8 m/s).

  4. 4.

    Voluntarily agreeing to participate in the study or not refusing to participate in the study.

Data collection

Schedules for data collection

Evaluation endpoints, treatment details, and outcomes will be collected regularly and registered in an anonymized database. Medical information, such as results of blood tests, skin evaluations, six-minute walk tests, pulmonary function tests, and transthoracic echocardiography, as well as RHC data, will be collected (Table 2). During the prospective observation period, participants will be followed up for up to three years. The clinical examinations and tests described below will be performed according to the schedule presented in Table 2. For the retrospective follow-up period, data will be extracted for each time point within the predefined time window, as described in Table 2.

Table 2 Study schedules
Full size table

Clinical information

Clinical information, including age, sex, date of first visit, the time from onset, diagnosis, social history, medical history, life history (such as smoking history), comorbidities, treatment up to the baseline, and classification of PH (groups 1, 2, 3, 4, and/or 5) will be collected at baseline. In addition, we will collected information on all immunosuppressive therapies, including mycophenolate mofetil (MMF), both at baseline and throughout follow-up. Details of concomitant medications will be regularly collected throughout the study. Information from physical examinations, such as the skin thickness, presence of skin ulcers, and vital signs, will also be collected regularly. When PH develops during the follow-up, each physician will determine the classification of PH based on the RHC results and other medical information.

In addition, patients’ subjective measures of breathlessness and quality of life will be assessed using the World Health Organization (WHO) functional classification and emPHasis-10 questionnaire, a useful, disease-specific, patient-reported assessment of the decline in quality of life due to PH [23, 24]. The 10-item questionnaire for the assessment of health-related quality of life in PH (emPHasis-10 questionnaire) will be administered during the prospective observational period.

Tests, imaging, and procedures

Blood immunological tests (Table 2), including those for autoantibodies, will be performed during the screening period. We will conduct blood tests every three months, and skin evaluation, six-minute walk tests, pulmonary function tests, and transthoracic echocardiography annually from the date of inclusion. The frequency and interval of RHC will be coordinated by the physician, considering the patient’s medical condition. During RHC, the mPAP, cardiac output, and pulmonary arterial wedge pressure will be measured, enabling us to calculate the pulmonary vascular resistance (PVR). For chest computed tomographic examinations, records of imaging conditions and equipment names will be preserved to enable future subgrouping.

Study endpoints

Primary endpoint

The primary endpoint is the time between the first RHC and first hospitalization or death due to worsening PH. The relationship between hospitalisation or death and PH will be determined by each physician, considering symptoms (e.g. WHO functional class) and the need for additional treatment for PH [25].

Secondary endpoints

  1. 1.

    Change in the parameters of RHC, including the mPAP and PVR (measured one or more times during follow-up).

  2. 2.

    WHO functional class.

  3. 3.

    emPHasis-10 score.

  4. 4.

    Six-minute walk distance.

  5. 5.

    Plasma and serum biochemical markers, including BNP, NT-proBNP, haemoglobin, uric acid, haptoglobin, and KL-6.

  6. 6.

    Pulmonary function tests, including DLCO and FVC/DLCO ratio.

  7. 7.

    Transthoracic echocardiography parameters, including the tricuspid regurgitation velocity, left ventricular ejection fraction, ratio of the transmitral early peak velocity to the early diastolic mitral annulus velocity, septal early diastolic mitral annulus velocity, lateral early diastolic mitral annulus velocity, and left atrial volume index.

  8. 8.

    Modified Rodnan total skin thickness score.

The above evaluations will be performed within the predefined time window described in Table 2.

In addition, to explore indicators to discriminate the spectrum/phenotype of PH between groups 1, 2, and 3 from an early stage, factors affecting secondary endpoints, such as the time from onset and detail of therapies, will be examined in the baseline data.

Data management

Information related to the study will be managed by replacing personal information, such as names and addresses, with control numbers (research IDs) to prevent participant identification. The principal investigator will supervise the strict storage of the corresponding chart. No identifying information will be included in the publication of the information obtained in this study. This study is being monitored by the Clinical Research and Medical Innovation Center of Hokkaido University Hospital.

Statistical analysis

Statistical analyses are conducted by a statistician using SAS software version 9.4 (SAS Institute Inc., Cary, NC, USA). Continuous data are presented as means with standard deviations or medians with interquartile ranges, and categorical data are presented as frequencies and percentages. Survival analysis with comparison of different subgroups according to the mPAP at the first RHC (≤ 20, 21-24, and ≥ 25 mmHg) as the primary endpoint will be performed using Kaplan–Meier analysis, log-rank tests, and covariate-adjusted Cox regression analysis. The primary analysis will be the comparison between the group with an mPAP of ≤ 20 mmHg and that with an mPAP of 21‐24 mmHg. Other comparisons will be performed as secondary endpoints. Cox regression analysis will be performed for baseline parameters, including age, sex, the time from onset, social history, medical history, comorbidities, mPAP, PVR, WHO functional class, the emPHasis-10 score, the six-minute walk distance, DLCO, FCV/DLCO ratio, and immunosuppressive therapies, including MMF. We will analyze whether patients receiving long-term MMF differ in terms of mPAP, progression to PH, or survival compared to those who never received it or received it only for a short period. Survival may also be analyzed by dividing the participants into two groups, that with an mPAP of ≤ 20 mmHg and that with an mPAP of ≥ 21 mmHg. In addition, we will also perform the analysis comparing between the group with an mPAP of < 25 mmHg and that with ≥ 25 mmHg.

Statistical power calculations

Based on other literature [14, 26] and our previous study [27], the enrolled patients are expected to be classified into three groups in a 2:1:2 ratio based on the mPAP (≤ 20, 21–24, and ≥ 25 mmHg). The primary comparison groups will be the mPAP ≤ 20-mmHg group and the mPAP = 21-24-mmHg group. In a previous multicentre study involving patients with SSc, the three-year incidence rates of PH were 4.2% in the group with normal haemodynamics (mPAP ≤ 20 mmHg) and 18.5% in the mPAP = 21-24-mmHg group [12]. Assuming that 10% of participants who underwent RHC owing to suspected PH were not diagnosed with the condition, the estimated three-year incidence rates of hospitalization owing to suspected PH are 4.7% and 20.6% for these groups, respectively. Based on these figures, the sample size required to achieve 80% power with a log-rank test at a 5% significance level, considering a 12-month enrolment period and a 36-month follow-up period, was calculated as 85 patients for the mPAP ≤ 20-mmHg group and 43 patients for the mPAP = 21-24-mmHg group. Including the mPAP ≥ 25-mmHg group, the total required sample size is 213 (85 + 43 + 85) patients. Considering an anticipated dropout rate of approximately 10%, the target sample size was set at 230 patients.

Results

Baseline characteristics

A total of 229 patients were enrolled from 12 participating centres, with 41 patients prospectively followed up and 188 retrospectively followed up. Seven of 41 patients are observed prospectively for a full 3 years (Table 1). The clinical characteristics of the patients in each group are summarised in Table 3. The number of patients in each group (an mPAP of ≤ 20, 21–24, and ≥ 25 mmHg) was 79, 26 and 124, respectively (Table 4).

Table 3 Clinical characteristics at the baseline
Full size table
Table 4 Result of baseline right heart catheterization
Full size table

Discussion

In this non-interventional retrospective and prospective cohort study, we are collecting clinical data of patients with SSc who underwent RHC for suspected PH to evaluate the life prognosis and its relationship with mPAP. We achieved registration of more patients than the required number, which has been calculated in advance. Patients were recruited from 12 hospitals associated with connective tissue diseases across eastern Japan. By enrolling patients from different regions, environments and backgrounds, we increase the diversity of the geographical and demographic statistics. This would increase the potential for generalizing the results of the analysis. In addition, this study can reduce the influence and bias of the practices of individual physicians and centers.

In contrast to PAH associated with CTDs other than SSc, SSc-PAH often develops chronically, and has been reported to have a poorer response to immunosuppressive drugs and a worse prognosis [6, 7]. In non-SSc CTD-related PAH, vasculitis with thickening of the tunica media, plexiform lesions, and fibrinoid necrosis with proliferation of vascular smooth muscle cells is seen in the pulmonary arteries, whereas in SSc-PAH, inflammatory cell infiltration has been reported to be scarce, but fibrous intimal thickening and luminal narrowing have been observed in a wide range of pulmonary vessels, including pulmonary arteries, pulmonary capillaries, and pulmonary veins [28]. These histological features may explain differences in clinical presentation and response to immunosuppressive drugs, and may be associated with poorer life expectancy. We cannot evaluate histologically in each patients, but we can estimate the pathological condition by regularly assessing the clinical data such as echocardiography and pulmonary function tests.

In recent years, there have been reports on the prognosis of mPAP = 21-24-mmHg patients [14]. In this study, we will further analyze the changes in subjective symptoms, each parameter including follow-up RHC after enrolment, and treatment information. The findings of this study that we will obtain are expected to provide important information that will lead to improvements in the diagnosis of PH and the prognosis of patients.

Trial status

The HAPPINESS study received ethical approval on September 27, 2022. Recruitment started on October 19, 2022 and finished on November 8, 2023. Observation is expected to be completed by December 2026.

Data availability

The data underlying this article will be shared on reasonable request to the corresponding author.

Abbreviations

ACR:

American College of Rheumatology

CTD:

Connective tissue disease

DLCO:

Diffusing capacity of the lungs for carbon monoxide

EULAR:

European League Against Rheumatism

FVC:

Forced vital capacity

mPAP:

Mean pulmonary arterial pressure

MMF:

Mycophenolate mofetil

NT-proBNP:

N-terminal pro-brain natriuretic peptide

PAH:

Pulmonary arterial hypertension

PH:

Pulmonary hypertension

PVR:

Pulmonary vascular resistance

RHC:

Right heart catheterization

SLE:

Systemic lupus erythematosus

SSc:

Systemic sclerosis

USA:

The United States of America

WHO:

World Health Organization

References

  1. Humbert M, Kovacs G, Hoeper MM, Badagliacca R, Berger RMF, Brida M, et al. 2022 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J. 2022;43:3618–731. https://doiorg.publicaciones.saludcastillayleon.es/10.1093/eurheartj/ehac237.

    Article  CAS  PubMed  Google Scholar 

  2. Kato M, Sugimoto A, Atsumi T. Diagnostic and prognostic markers and treatment of connective tissue disease-associated pulmonary arterial hypertension: current recommendations and recent advances. Expert Rev Clin Immunol. 2020;16:993–1004. https://doiorg.publicaciones.saludcastillayleon.es/10.1080/1744666x.2021.1825940.

    Article  CAS  PubMed  Google Scholar 

  3. Ninagawa K, Kato M, Kikuchi Y, Sugimori H, Kono M, Fujieda Y, et al. Predicting the response to pulmonary vasodilator therapy in systemic sclerosis with pulmonary hypertension by using quantitative chest CT. Mod Rheumatol. 2023;33:758–67. https://doiorg.publicaciones.saludcastillayleon.es/10.1093/mr/roac102.

    Article  PubMed  Google Scholar 

  4. Moriya H, Kato M, Hisada R, Ninagawa K, Tada M, Sakiyama K, et al. The chest CT signs for pulmonary veno-occlusive disease correlate with pulmonary haemodynamics in systemic sclerosis. Rheumatology (Oxford). 2023;00:1–6. https://doiorg.publicaciones.saludcastillayleon.es/10.1093/rheumatology/kead485.

    Article  CAS  Google Scholar 

  5. Tokushige N, Hayashi Y, Omura J, Jinnai T, Atsumi T. Patient characteristics, diagnostic testing, and initial treatment profiles of patients with connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) using a Japanese claims database. Mod Rheumatol. 2024. https://doiorg.publicaciones.saludcastillayleon.es/10.1093/mr/roae033.

    Article  PubMed  Google Scholar 

  6. Sanchez O, Sitbon O, Jaïs X, Simonneau G, Humbert M. Immunosuppressive therapy in connective tissue diseases-associated pulmonary arterial hypertension. Chest. 2006;130:182–9. https://doiorg.publicaciones.saludcastillayleon.es/10.1378/chest.130.1.182.

    Article  CAS  PubMed  Google Scholar 

  7. Condliffe R, Kiely DG, Peacock AJ, Corris PA, Gibbs JS, Vrapi F, et al. Connective tissue disease-associated pulmonary arterial hypertension in the modern treatment era. Am J Respir Crit Care Med. 2009;179:151–7. https://doiorg.publicaciones.saludcastillayleon.es/10.1164/rccm.200806-953OC.

    Article  PubMed  Google Scholar 

  8. Humbert M, Yaici A, de Groote P, Montani D, Sitbon O, Launay D, et al. Screening for pulmonary arterial hypertension in patients with systemic sclerosis: clinical characteristics at diagnosis and long-term survival. Arthritis Rheum. 2011;63:3522–30. https://doiorg.publicaciones.saludcastillayleon.es/10.1002/art.30541.

    Article  PubMed  Google Scholar 

  9. Gladue H, Steen V, Allanore Y, Saggar R, Saggar R, Maranian P, et al. Combination of echocardiographic and pulmonary function test measures improves sensitivity for diagnosis of systemic sclerosis-associated pulmonary arterial hypertension: analysis of 2 cohorts. J Rheumatol. 2013;40:1706–11. https://doiorg.publicaciones.saludcastillayleon.es/10.3899/jrheum.130400.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Coghlan JG, Denton CP, Grunig E, Bonderman D, Distler O, Khanna D, et al. Evidence-based detection of pulmonary arterial hypertension in systemic sclerosis: the DETECT study. Ann Rheum Dis. 2014;73:1340–9. https://doiorg.publicaciones.saludcastillayleon.es/10.1136/annrheumdis-2013-203301.

    Article  PubMed  Google Scholar 

  11. Simonneau G, Montani D, Celermajer DS, Denton CP, Gatzoulis MA, Krowka M, et al. Haemodynamic definitions and updated clinical classification of pulmonary hypertension. Eur Respir J. 2019;53:1801913. https://doiorg.publicaciones.saludcastillayleon.es/10.1183/13993003.01913-2018.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Valerio CJ, Schreiber BE, Handler CE, Denton CP, Coghlan JG. Borderline mean pulmonary artery pressure in patients with systemic sclerosis: transpulmonary gradient predicts risk of developing pulmonary hypertension. Arthritis Rheum. 2013;65:1074–84. https://doiorg.publicaciones.saludcastillayleon.es/10.1002/art.37838.

    Article  CAS  PubMed  Google Scholar 

  13. Bae S, Saggar R, Bolster MB, Chung L, Csuka ME, Derk C, et al. Baseline characteristics and follow-up in patients with normal haemodynamics versus borderline mean pulmonary arterial pressure in systemic sclerosis: results from the PHAROS registry. Ann Rheum Dis. 2012;71:1335–42. https://doiorg.publicaciones.saludcastillayleon.es/10.1136/annrheumdis-2011-200546.

    Article  PubMed  Google Scholar 

  14. Xanthouli P, Jordan S, Milde N, Marra A, Blank N, Egenlauf B, et al. Haemodynamic phenotypes and survival in patients with systemic sclerosis: the impact of the new definition of pulmonary arterial hypertension. Ann Rheum Dis. 2020;79:370–8. https://doiorg.publicaciones.saludcastillayleon.es/10.1136/annrheumdis-2019-216476.

    Article  PubMed  Google Scholar 

  15. Kolstad KD, Li S, Steen V, Chung L. Long-Term outcomes in systemic Sclerosis-Associated pulmonary arterial hypertension from the pulmonary hypertension assessment and recognition of outcomes in scleroderma registry (PHAROS). Chest. 2018;154:862–71. https://doiorg.publicaciones.saludcastillayleon.es/10.1016/j.chest.2018.05.002.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Kovacs G, Maier R, Aberer E, Brodmann M, Graninger W, Kqiku X, et al. Pulmonary arterial hypertension therapy May be safe and effective in patients with systemic sclerosis and borderline pulmonary artery pressure. Arthritis Rheum. 2012;64:1257–62. https://doiorg.publicaciones.saludcastillayleon.es/10.1002/art.33460.

    Article  PubMed  Google Scholar 

  17. van den Hoogen F, Khanna D, Fransen J, Johnson SR, Baron M, Tyndall A, et al. 2013 Classification criteria for systemic sclerosis: an American college of rheumatology/european league against rheumatism collaborative initiative. Ann Rheum Dis. 2013;72:1747–55. https://doiorg.publicaciones.saludcastillayleon.es/10.1136/annrheumdis-2013-204424.

    Article  PubMed  Google Scholar 

  18. Tanaka Y, Kuwana M, Fujii T, Kameda H, Muro Y, Fujio K, et al. 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. Mod Rheumatol. 2021;31:29–33. https://doiorg.publicaciones.saludcastillayleon.es/10.1080/14397595.2019.1709944.

    Article  PubMed  Google Scholar 

  19. Hochberg MC. Updating the American college of rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1997;40:1725. https://doiorg.publicaciones.saludcastillayleon.es/10.1002/art.1780400928.

    Article  CAS  PubMed  Google Scholar 

  20. Petri M, Orbai AM, Alarcón GS, Gordon C, Merrill JT, Fortin PR, et al. Derivation and validation of the systemic lupus international collaborating clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum. 2012;64:2677–86. https://doiorg.publicaciones.saludcastillayleon.es/10.1002/art.34473.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Bohan A, Peter JB. Polymyositis and dermatomyositis (first of two parts). N Engl J Med. 1975;292:344–7. https://doiorg.publicaciones.saludcastillayleon.es/10.1056/nejm197502132920706.

    Article  CAS  PubMed  Google Scholar 

  22. Shiboski CH, Shiboski SC, Seror R, Criswell LA, Labetoulle M, Lietman TM, et al. 2016 American college of rheumatology/european league against rheumatism classification criteria for primary Sjögren’s syndrome: A consensus and data-driven methodology involving three international patient cohorts. Ann Rheum Dis. 2017;76:9–16. https://doiorg.publicaciones.saludcastillayleon.es/10.1136/annrheumdis-2016-210571.

    Article  PubMed  Google Scholar 

  23. Yorke J, Corris P, Gaine S, Gibbs JS, Kiely DG, Harries C, et al. emPHasis-10: development of a health-related quality of life measure in pulmonary hypertension. Eur Respir J. 2014;43:1106–13. https://doiorg.publicaciones.saludcastillayleon.es/10.1183/09031936.00127113.

    Article  PubMed  Google Scholar 

  24. Takeyasu R, Tamura Y, Abe K, Goda A, Satoh T, Suda R, et al. Psychometric validation of a Japanese version of the emPHasis-10 questionnaire, a Patient-Reported outcome measure for pulmonary Hypertension　- multicenter study in Japan. Circ Rep. 2020;2:255–9. https://doiorg.publicaciones.saludcastillayleon.es/10.1253/circrep.CR-20-0014.

    Article  PubMed  PubMed Central  Google Scholar 

  25. McLaughlin VV, Hoeper MM, Channick RN, Chin KM, Delcroix M, Gaine S, et al. Pulmonary arterial Hypertension-Related morbidity is prognostic for mortality. J Am Coll Cardiol. 2018;71:752–63. https://doiorg.publicaciones.saludcastillayleon.es/10.1016/j.jacc.2017.12.010.

    Article  PubMed  Google Scholar 

  26. Jaafar S, Visovatti S, Young A, Huang S, Cronin P, Vummidi D, et al. Impact of the revised haemodynamic definition on the diagnosis of pulmonary hypertension in patients with systemic sclerosis. Eur Respir J. 2019;54:1900586. https://doiorg.publicaciones.saludcastillayleon.es/10.1183/13993003.00586-2019.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Ninagawa K, Kato M, Ohira H, Tsuneta S, Iwano H, Kono M et al. The assessment of left heart disease in patients with systemic sclerosis and pulmonary hypertension. Clin Exp Rheumatol. 2021;39 Suppl 131:103– 10.

  28. Overbeek MJ, Vonk MC, Boonstra A, Voskuyl AE, Vonk-Noordegraaf A, Smit EF, et al. Pulmonary arterial hypertension in limited cutaneous systemic sclerosis: a distinctive vasculopathy. Eur Respir J. 2009;34:371–9. https://doiorg.publicaciones.saludcastillayleon.es/10.1183/09031936.00106008.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We appreciate all the member of the Department of Respiratory Medicine of Hokkaido University Hospital, and Department of Cardiovascular Medicine of Hokkaido University Hospital for performing RHC and transthoracic echocardiography in the enrolled patients. We thank all the members of the HAPPINESS study group and the Department of Rheumatology, Endocrinology, and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University. This work was partly supported by a junior scientist promotion project at Hokkaido University.

Funding

The study received financial support for the research by Janssen Pharmaceutical K.K.

Author information

Authors and Affiliations

  1. Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan

    Shuhei Takeyama, Ryo Hisada, Kazuro Kamada, Tatsuya Atsumi & Masaru Kato

  2. Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan

    Hironari Hanaoka & Sho Ishigaki

  3. Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University, Sapporo, Japan

    Akiyoshi Hashimoto

  4. Department of Rheumatology, Tohoku University Hospital, Sendai, Japan

    Yusho Ishii

  5. Third Department of Internal Medicine, Obihiro-Kosei Hospital, Obihiro, Japan

    Yuka Shimizu

  6. Division of Cardiology, Nephrology, Pulmonology and Neurology, Department of Internal Medicine, Asahikawa Medical University, Asahikawa, Japan

    Toshiharu Takeuchi

  7. Department of Internal Medicine, Tomakomai City Hospital, Tomakomai, Japan

    Shuhei Shimoyama & Tetsuya Horita

  8. Department of Allergy and Rheumatology, Nippon Medical School Graduate School of Medicine, Tokyo, Japan

    Masataka Kuwana

  9. Division of Rheumatology, Department of Internal Medicine, Tokyo Women’s Medical University School of Medicine, Tokyo, Japan

    Tomoaki Higuchi

  10. Department of Internal Medicine, Japanese Red Cross Kitami Hospital, Kitami, Japan

    Masaru Yoshimura

  11. Department of Rheumatology and Clinical Immunology, Sapporo City General Hospital, Sapporo, Japan

    Hiroshi Kataoka

  12. Department of Hematology and Rheumatology, Tohoku Medical and Pharmaceutical University, Sendai, Japan

    Yuko Shirota

  13. Data Science Center, Promotion Unit, Institute of Health Science Innovation for Medical Care, Hokkaido University Hospital, Sapporo, Japan

    Kazufumi Okada & Yoichi M. Ito

  14. The First Department of Internal Medicine, University of Toyama Faculty of Medicine, Toyama, Japan

    Masaru Kato

Authors
  1. Shuhei Takeyama
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Hironari Hanaoka
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Akiyoshi Hashimoto
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Yusho Ishii
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Yuka Shimizu
    View author publications

    You can also search for this author inPubMed Google Scholar

  6. Toshiharu Takeuchi
    View author publications

    You can also search for this author inPubMed Google Scholar

  7. Shuhei Shimoyama
    View author publications

    You can also search for this author inPubMed Google Scholar

  8. Masataka Kuwana
    View author publications

    You can also search for this author inPubMed Google Scholar

  9. Tomoaki Higuchi
    View author publications

    You can also search for this author inPubMed Google Scholar

  10. Masaru Yoshimura
    View author publications

    You can also search for this author inPubMed Google Scholar

  11. Hiroshi Kataoka
    View author publications

    You can also search for this author inPubMed Google Scholar

  12. Yuko Shirota
    View author publications

    You can also search for this author inPubMed Google Scholar

  13. Kazufumi Okada
    View author publications

    You can also search for this author inPubMed Google Scholar

  14. Yoichi M. Ito
    View author publications

    You can also search for this author inPubMed Google Scholar

  15. Ryo Hisada
    View author publications

    You can also search for this author inPubMed Google Scholar

  16. Kazuro Kamada
    View author publications

    You can also search for this author inPubMed Google Scholar

  17. Sho Ishigaki
    View author publications

    You can also search for this author inPubMed Google Scholar

  18. Tetsuya Horita
    View author publications

    You can also search for this author inPubMed Google Scholar

  19. Tatsuya Atsumi
    View author publications

    You can also search for this author inPubMed Google Scholar

  20. Masaru Kato
    View author publications

    You can also search for this author inPubMed Google Scholar

Consortia

the HAPPINESS study group

Contributions

ST, HH, AH, YI, YS, TT, SS, MK, TH, MY, HK, YS, RH, KK, SI, TH, TA, MK contributed to data interpretation and manuscript development, critique and revision for important intellectual content by providing comment, reading, editing and approving the final version of the manuscript. KO and YMI were involved in the statistical planning of this study and carried out sample size calculations.

Corresponding author

Correspondence to Masaru Kato.

Ethics declarations

Ethics approval and consent to participate

This study was approved by the Ethics Committee of Hokkaido University Hospital (approval number: 022–0109). It has been registered in the Japan Registry of Clinical Trials as jRCT1010220025 since November 7, 2022. All researchers involved in this study will comply with the Declaration of Helsinki and the Ethical Guidelines for Medical Research Involving Human Subjects. For retrospective observation (Fig. 1A), participants have the opportunity to opt out of the study. Information regarding the study is disclosed on the webpage of each participating facility. For the prospective observation (Fig. 1B C), written informed consent was obtained from all patients before prospective study procedures were performed.

Consent for publication

Study participants are informed that their anonymized data will be published in academic journals and provide the written consent form for publication.

Competing interests

This study will be conducted fairly by the principal researcher (and group) of this university and will be funded by Janssen Pharmaceutical K.K. Approval for conflicts of interest in this study has been obtained from the Conflict-of-Interest Committee of Hokkaido University Hospital, ensuring fairness. H Hanaoka has received speaking fees from Asahi-Kasei, Chugai, Astellas, and Eli Lilly. A Hashimoto has received speaking fees from Eisai, Janssen, Mochida Pharmaceutical, Nippon Shinyaku, Daiichi Sankyo Company. M Kuwana has received research grants from MBL, consultant/speaking fees from Asahi-Kasei, AstraZeneca, Boehringer-Ingelheim, Chugai, GSK, Janssen, Kissei, MBL, Mochida, and Ono Pharmaceuticals. T Higuchi has received speaking fees or consulting fees from Chugai, Pfizer, Boehringer, Asahi Kasei, Gilead, Eli Lilly, Janssen, and RIBOMIC, and belongs to an endowment department that is supported with an unrestricted grant from Ayumi, Asahi Kasei, Taisho, Mochida, Chugai, and AbbVie. YM Ito is a member of Independent Data Monitoring Committee of Janssen Pharmaceutical K.K. R. Hisada has received speaking fees from AbbVie Inc., Asahi-Kasei Co., Astellas Pharma Inc., Ayumi Pharmaceutical Co., Bristol-Myers Squibb Co., Chugai Pharmaceutical Co., Ltd.; Daiichi Sankyo Co., Ltd., Eisai Co. Ltd., Janssen Pharmaceutical K.K., Nippon Boehringer Ingelheim Co., Mitsubishi Tanabe Pharma Co., Otsuka Pharmaceutical Co., Ltd., Pfizer Inc. T Atsumi has received research grants from Astellas, Takeda, Mitsubishi Tanabe, Chugai, Daiichi-Sankyo, Otsuka, Pfizer, Alexion, Bayer, Otsuka, Chugai, Takeda, Eisai, Bristol-Myers Squibb, Daiichi Sankyo, Mitsubishi Tanabe, and Asahi Kasei; consultant fees from Ono, Sanofi, Daiichi Sankyo, and Pfizer; and speaking fees from Mitsubishi Tanabe, Chugai, Astellas, Takeda, Pfizer, Daiichi Sankyo, Bristol-Myers Squibb, and Eli Lilly. M Kato has received research grants from AbbVie, Actelion, GlaxoSmithKline, Janssen, Nippon Shinyaku, and Novartis, and speaking fees from Astellas, Boehringer, Eisai, Eli Lilly, Janssen, Mitsubishi Tanabe, and Pfizer. The other authors have nothing to declare.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Takeyama, S., Hanaoka, H., Hashimoto, A. et al. A cohort study in HigAshi-nippon of Pulmonary hyPertensIoN in systEmic SclerosiS (HAPPINESS study): protocol and baseline data for an observational study. BMC Rheumatol 9, 25 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s41927-025-00474-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s41927-025-00474-2

Keywords

BMC Rheumatology

ISSN: 2520-1026

Contact us