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Can the Sarcoidosis Health Questionnaire predict the long-term outcomes in Japanese sarcoidosis patients?

Open ArchivePublished:January 11, 2019DOI:https://doi.org/10.1016/j.rmed.2019.01.001

      Highlights

      • Worse health status is a risk factor for 5-year deterioration of sarcoidosis.
      • The Sarcoidosis Health Questionnaire is predictive for long-term outcomes.
      • Systemic therapy at baseline is associated with long-term deterioration.
      • Light ventricular dysfunction is also a risk factor for 5-year deterioration.

      Abstract

      Rationale

      The Sarcoidosis Health Questionnaire (SHQ) is the first sarcoidosis-specific health status questionnaire ever developed. Worse health status, as evaluated by the SHQ, may indicate higher risk for deterioration in the following 5 years.

      Objectives

      To evaluate the association between SHQ scores and deterioration defined clinically at 5-year follow-up.

      Methods

      122 patients with biopsy-supported sarcoidosis completed the SHQ and underwent evaluation with respect to organ involvement, chest radiograph, electrocardiogram, serum biomarker measurements, pulmonary function tests, and echocardiogram. Of these 122, 88 (72.1%) were available for pulmonary, cardiac, and non-pulmonary, non-cardiac deterioration assessment during the following 5 years.

      Measurements and main results

      Five-year deterioration was observed in 20 patients (23%). The SHQ total score was significantly associated with 5-year deterioration, after adjusting for cardiac involvement at baseline, with adjusted odds ratio (OR) of 0.54 (95% confidence interval [95% CI], 0.29–0.99). The association of the total SHQ with 5-year outcome was not significant when adjusted for left ventricular ejection fraction (LVEF) at baseline (adjusted OR, 0.61 [0.32–1.16]), whereas LVEF was significantly associated with 5-year outcome (adjusted OR, 0.92 [0.86–0.99]). The association between total SHQ score and 5-year deterioration was marginal when adjusted for baseline usage of systemic corticosteroid (CS)/immunosuppressive (IS) agents (adjusted OR, 0.58 [0.31–1.10]), whereas systemic CS/IS usage significantly predicted 5-year deterioration (adjusted odds ratio [OR], 3.46 [1.12–10.7]). There was a marginal correlation between the total SHQ and LVEF (rho = 0.19, p = 0.07) and a weak association between the total SHQ and systemic CS/IS usage (rho = −0.23, p = 0.03). The Physical Functioning domain scores of the SHQ were significantly associated with 5-year deterioration (adjusted OR, 0.45–0.51).

      Conclusions

      Worse health status, as assessed by the SHQ score, can be a risk factor for 5-year deterioration of sarcoidosis, although usage of the CS/IS at baseline and lower LVEF at baseline are more predictive of 5-year deterioration.

      Keywords

      Abbreviations list

      ACCESS
      A Case-Control Epidemiologic Study of Sarcoidosis
      BHL
      bilateral hilar lymphadenopathy
      CES-D
      Center for Epidemiologic Study-Depression
      CI
      confidential interval
      COS
      clinical outcome status
      CS
      corticosteroid
      DF
      Daily Functioning
      EF
      Emotional Functioning
      18F-FDG PET
      18F-fluorodeoxyglucose positron emission tomography
      IS
      immunosuppressive agent
      KSQ
      King's Sarcoidosis Questionnaire
      LVEF
      left ventricular ejection fraction
      MCID
      minimal clinically important difference
      MRC
      Medical Research Council
      OR
      odds ratio
      PF
      Physical Functioning
      PFT
      pulmonary function test
      PRO
      patient-reported outcome
      SAT
      Sarcoidosis Assessment Tool
      SF-36
      Medical Outcomes Study 36-item short form
      SGRQ
      St. George's Respiratory Questionnaire
      SHQ
      Sarcoidosis Health Questionnaire
      WASOG
      World Association of Sarcoidosis and Other Granulomatous Disorders

      1. Introduction

      Sarcoidosis is a chronic and multisystem granulomatous disease of unknown etiology that can involve almost any organ system [
      Statement on sarcoidosis. Joint statement of the American thoracic society (ATS), the European respiratory society (ERS) and the World association of sarcoidosis and other granulomatous Disorders (WASOG) adopted by the ATS board of directors and by the ERS executive committee, February 1999.
      ]. The disease has a highly variable clinical outcome [
      • Nagai S.
      • Handa T.
      • Ito Y.
      • Ohta K.
      • Tamaya M.
      • Izumi T.
      Outcome of sarcoidosis.
      ,
      • Baughman R.P.
      • Nagai S.
      • Balter M.
      • Costabel U.
      • Drent M.
      • du Bois R.
      • Grutters J.C.
      • Judson M.A.
      • Lambiri I.
      • Lower E.E.
      • Muller-Quernheim J.
      • Prasse A.
      • Rizzato G.
      • Rottoli P.
      • Spagnolo P.
      • Teirstein A.
      Defining the clinical outcome status (COS) in sarcoidosis: results of WASOG Task Force.
      ] and often impairs the health status of patients [
      • Cox C.E.
      • Donohue J.F.
      • Brown C.D.
      • Kataria Y.P.
      • Judson M.A.
      Health-related quality of life of persons with sarcoidosis.
      ]. The correlation between physician assessment of sarcoidosis and patient self-assessment is relatively low. In consequence, patient-reported outcome (PRO) measures of sarcoidosis patients can reflect aspects of the disease that are divergent from objective measurements.
      The Sarcoidosis Health Questionnaire (SHQ) was developed by Cox and colleagues in the United States as the first questionnaire specifically focused on the health status of sarcoidosis patients [
      • Cox C.E.
      • Donohue J.F.
      • Brown C.D.
      • Kataria Y.P.
      • Judson M.A.
      The Sarcoidosis Health Questionnaire: a new measure of health-related quality of life.
      ,
      • Tanizawa K.
      • Handa T.
      • Nagai S.
      • Oga T.
      • Kubo T.
      • Ito Y.
      • Watanabe K.
      • Aihara K.
      • Chin K.
      • Mishima M.
      • Izumi T.
      Validation of the Japanese version of the sarcoidosis health questionnaire: a cross-sectional study.
      ]. Later, our group developed and validated a Japanese version of the SHQ. However, no previous study has evaluated whether the SHQ can predict outcomes in sarcoidosis patients.
      The objective of this study is to evaluate the association between health status, as assessed by the SHQ, and long-term deterioration of sarcoidosis. We hypothesize that worse health status is associated with higher frequency of deterioration. We also evaluated the associations between other PRO indices and objective variables, and deterioration.

      2. Methods

      2.1 Study population

      One-hundred twenty-two consecutive patients with biopsy-supported sarcoidosis who visited the Kyoto Central Clinic between June and December 2009 were enrolled in our previous study for validation of a Japanese version of the SHQ [
      • Tanizawa K.
      • Handa T.
      • Nagai S.
      • Oga T.
      • Kubo T.
      • Ito Y.
      • Watanabe K.
      • Aihara K.
      • Chin K.
      • Mishima M.
      • Izumi T.
      Validation of the Japanese version of the sarcoidosis health questionnaire: a cross-sectional study.
      ]. Grounds for exclusion were: 1) age <18 years; 2) presence of an active neoplasm; 3) failing to complete the questionnaire, or 4) no active organ involvement of sarcoidosis when filling out the questionnaire. Of these 122, 88 (72.1%) were available for 5-year follow-up and were analyzed in the present study. All patients provided written informed consent to participate in the prospective study approved by the ethics committees of Kyoto University Hospital (approval No. E679) and Kyoto Central Clinic.

      2.2 Patient-reported outcomes

      All patients completed the Japanese versions of the SHQ [
      • Cox C.E.
      • Donohue J.F.
      • Brown C.D.
      • Kataria Y.P.
      • Judson M.A.
      Health-related quality of life of persons with sarcoidosis.
      ,
      • Tanizawa K.
      • Handa T.
      • Nagai S.
      • Oga T.
      • Kubo T.
      • Ito Y.
      • Watanabe K.
      • Aihara K.
      • Chin K.
      • Mishima M.
      • Izumi T.
      Validation of the Japanese version of the sarcoidosis health questionnaire: a cross-sectional study.
      ], the generic Medical Outcomes Study 36-item short form (SF-36) [
      • Ware Jr., J.E.
      • Sherbourne C.D.
      The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection.
      ,
      • Fukuhara S.
      • Bito S.
      • Green J.
      • Hsiao A.
      • Kurokawa K.
      Translation, adaptation, and validation of the SF-36 Health Survey for use in Japan.
      ], and the respiratory-specific St. George's Respiratory Questionnaire (SGRQ) [
      • Jones P.W.
      • Quirk F.H.
      • Baveystock C.M.
      • Littlejohns P.
      A self-complete measure of health status for chronic airflow limitation. The St. George's Respiratory Questionnaire.
      ,
      • Hajiro T.
      • Nishimura K.
      • Tsukino M.
      • Ikeda A.
      • Koyama H.
      • Izumi T.
      Comparison of discriminative properties among disease-specific questionnaires for measuring health-related quality of life in patients with chronic obstructive pulmonary disease.
      ], to evaluate their health status at the time of enrollment (baseline). The SHQ consists of 29 items and three domains: Daily Functioning (DF), Physical Functioning (PF), and Emotional Functioning (EF). Each item was scored on a 7-point scale, and scores were calculated for each domain and for the total test by dividing the sums of the scores by the numbers of items. Higher scores indicate better health status on the SHQ and SF-36, but worse health status on the SGRQ. Dyspnea at baseline was self-evaluated using the Japanese version of the Medical Research Council (MRC) dyspnea scale, in which a higher score indicates a worse status [
      • National Institute for Clinical Excellence
      Chronic obstructive pulmonary disease: national clinical guideline for management of chronic obstructive pulmonary disease in adults in primary and secondary care.
      ]. Depressive symptoms at baseline were also self-evaluated by the Japanese version of the Center for Epidemiologic Study-Depression scale (CES-D, 20-item version), in which a higher score indicates more severe depression [
      • Radloff L.
      The CES-D Scale: a self-report depression scale for research in the general population.
      ,
      • Iwata N.
      • Okuyama Y.
      • Kawakami Y.
      • Saito K.
      Prevalence of depressive symptoms in a Japanese occupational setting: a preliminary study.
      ].

      2.3 Clinical variables

      Baseline clinical variables obtained on all patients and included in this analysis were organ involvement, chest radiograph, electrocardiogram, serum biomarkers (angiotensin converting enzyme activity, and soluble interleukin-2 receptor), pulmonary function tests (PFTs) [
      • Miller M.R.
      • Hankinson J.
      • Brusasco V.
      • Burgos F.
      • Casaburi R.
      • Coates A.
      • Crapo R.
      • Enright P.
      • van der Grinten C.P.
      • Gustafsson P.
      • Jensen R.
      • Johnson D.C.
      • MacIntyre N.
      • McKay R.
      • Navajas D.
      • Pedersen O.F.
      • Pellegrino R.
      • Viegi G.
      • Wanger J.
      Standardisation of spirometry.
      ,
      • The Committee of Pulmonary Physiology JRS
      Guidelines for Pulmonary Function Tests: Spirometry, Flow-Volume Curve, Diffusion Capacity of the Lung.
      ], and echocardiogram [
      • Handa T.
      • Nagai S.
      • Miki S.
      • Fushimi Y.
      • Ohta K.
      • Mishima M.
      • Izumi T.
      Incidence of pulmonary hypertension and its clinical relevance in patients with sarcoidosis.
      ]. The extent of organ involvement was assessed by the ACCESS (A Case-Control Epidemiologic Study of Sarcoidosis) Organ Involvement Index [
      • Judson M.A.
      • Baughman R.P.
      • Teirstein A.S.
      • Terrin M.L.
      • Yeager Jr., H.
      Defining organ involvement in sarcoidosis: the ACCESS proposed instrument. ACCESS research group. A case Control etiologic study of sarcoidosis.
      ]. Chest radiographs were classified according to standard radiographic staging: stage 0, normal; stage I, bilateral hilar lymphadenopathy (BHL); stage II, BHL with pulmonary infiltrates; stage III, pulmonary infiltrates without BHL; and stage IV, advanced pulmonary fibrosis [
      • DeRemee R.A.
      The roentgenographic staging of sarcoidosis. Historic and contemporary perspectives.
      ]. Serum angiotensin converting enzyme activity and soluble interleukin-2 receptor were measured by Kasahara's method [
      • Kasahara Y.
      • Ashihara Y.
      Colorimetry of angiotensin-I converting enzyme activity in serum.
      ] and chemiluminescence enzyme immunoassay, respectively.

      2.4 Outcome variables

      Evaluations at the 5-year follow-up after baseline included physician assessments, PFTs, and echocardiograms, but did not include any PRO measures. The long-term outcome was determined for this analysis from data during 5-year follow-up. Deterioration is defined in Fig. 1. All evaluations and decisions about treatment after baseline were made blinded to PRO indices at baseline.
      Fig. 1
      Fig. 1Definition of deterioration. *Systemic therapy is systemic corticosteroid or immunosuppressive agent. Abbreviation: LTOT, long-term oxygen therapy.

      2.5 Statistical analysis

      Clinical features and patient-oriented outcomes were summarized using mean (standard deviation) and number (percentage) as appropriate. Logistic regression was used to evaluate the association between SHQ scores, other PRO indices, and clinical variates with long-term deterioration. Candidate co-variates for multivariate models were identified based on the results of univariate analyses with P < 0.05. Since the number of patients with long-term deterioration was still small (20 with 5-year deterioration), only two variates were included in each model simultaneously. To overcome this paucity of outcome events, forward stepwise logistic regression analysis (removal from the model with P ≥ 0.2, and addition to the model with P < 0.1) was performed. Individual domain scores of the SHQ (DF, PF, and EF domains) were also analyzed in the same manner as were the SHQ total scores. Subgroup analyses were performed for the two subgroups: the subgroup of patients with lung involvement at baseline, and that of patients without cardiac involvement at baseline.
      Lungs are the most common involved organ system. Cardiac involvement was associated with both of worse prognosis and worse PRO measures in sarcoidosis [
      • Valeyre D.
      • Prasse A.
      • Nunes H.
      • Uzunhan Y.
      • Brillet P.Y.
      • Muller-Quernheim J.
      Sarcoidosis.
      ,
      • Judson M.A.
      • Chaudhry H.
      • Louis A.
      • Lee K.
      • Yucel R.
      The effect of corticosteroids on quality of life in a sarcoidosis clinic: the results of a propensity analysis.
      ]. In these subgroup analyses, multivariate analyses were not performed because of the small numbers of patients with deterioration (15 and 11, respectively). All data analyses were performed using STATA/IC 14.2 for Mac (Stata Corp., Lakeway, TX, USA). For all analyses, a P < 0.05 was considered statistically significant.

      3. Results

      3.1 Patient characteristics and patient-reported outcome (PRO) measures

      Clinical features and patient-reported outcomes at the time of enrollment are shown in Table 1, Table 2. Histograms of the SHQ scores are shown in Fig. 2.
      Table 1Demographics, organ involvement, radiographic stage, serum biomarkers, pulmonary function tests, echocardiogram, and treatment at enrollment (baseline).
      NumberAll enrolled patientsAvailable for 5-year follow-up
      12288
      Age, years56.8 ± 15.555.8 ± 14.1
      Male48 (39)35 (40)
      Duration of disease, months108.9 ± 86.2112.4 ± 82.9
      Number of organ systems involved1.8 ± 0.81.8 ± 0.8
       Pulmonary involvement98 (80)68 (77)
       Cardiac involvement27 (22)23 (26)
       Ocular involvement58 (48)42 (48)
       Skin involvement26 (22)23 (26)
       Radiographic stage, 0/I/II/III/IV37/31/33/14/531/18/23/13/3
       0/I/II/III/IV(31/26/28/12/4)(35/20/26/15/3)
      Serum biomarkers
       ACE, IU/L17.2 ± 6.517.2 ± 6.7
       sIL-2R, IU/mL639.9 ± 507.5676.7 ± 565.3
      Pulmonary function tests
       FVC, % predicted105.8 ± 18.5107.1 ± 16.8
       FEV1, % predicted105.8 ± 21.0106.0 ± 18.7
       DLCO, % predicted85.1 ± 17.285.1 ± 16.9
      Echocardiogram
       LVEF, %68.1 ± 11.467.9 ± 8.3
       PASP, mmHg29.4 ± 5.929.2 ± 5.8
      Treatment
       Systemic CS or IS26 [
      • Casanova N.
      • Zhou T.
      • Knox K.S.
      • Garcia J.G.
      Identifying novel biomarkers in sarcoidosis using genome-based approaches.
      ]
      20 [
      • Casanova N.
      • Zhou T.
      • Knox K.S.
      • Garcia J.G.
      Identifying novel biomarkers in sarcoidosis using genome-based approaches.
      ]
      Data represent mean ± standard deviation or number (percentage).
      Abbreviations: SD, standard deviation; ACE, angiotensin-converting enzyme; sIL-2R, soluble interleukin-2 receptor; FVC, forced vital capacity; FEV1, forced expiratory volume in one second; DLCO, diffusion capacity for carbon monoxide; LVEF, left ventricular ejection fraction; PASP, pulmonary arterial systolic pressure; CS, corticosteroid; IS, immunosuppressive agent.
      Table 2Patient-oriented outcomes at baseline.
      NumberAll enrolled patientsAvailable for five-year follow-up
      12288
      SHQ
       Daily Functioning [1–7]4.7 ± 1.04.7 ± 1.0
       Physical Functioning [1–7]5.4 ± 1.05.4 ± 0.9
       Emotional Functioning [1–7]4.8 ± 1.04.8 ± 1.0
       Total [1–7]4.9 ± 0.94.9 ± 0.8
      SF-36
       Physical functioning [0–100]79.2 ± 20.980.5 ± 20.5
       Role-physical [0–100]77.1 ± 27.079.2 ± 24.8
       Bodily pain [0–100]71.9 ± 26.774.2 ± 24.4
       General health perceptions [0–100]50.0 ± 19.749.5 ± 19.7
       Vitality [0–100]52.2 ± 23.153.4 ± 22.3
       Social functioning [0–100]78.6 ± 24.180.5 ± 22.7
       Role-emotional [0–100]77.7 ± 25.778.1 ± 25.7
       Mental health [0–100]66.6 ± 20.567.1 ± 21.4
      SGRQ
       Symptoms [0–100]39.8 ± 20.639.1 ± 20.3
       Activity [0–100]29.7 ± 24.927.6 ± 23.9
       Impact [0–100]14.6 ± 14.613.6 ± 14.0
       Total [0–100]23.4 ± 16.322.1 ± 15.4
       MRC [1–5]1.8 ± 0.81.5 ± 0.8
       CES-D [0–60]12.8 ± 9.311.6 ± 8.4
      Data represent mean ± standard deviation.
      The numbers in square brackets represent the theoretical score ranges.
      Better status is indicated by higher scores on the SHQ and SF-36, and by lower scores on the SGRQ, MRC, and CES-D.
      Abbreviations: SHQ, Sarcoidosis Health Questionnaire; SF-36, Medical Outcomes Study 36-item short form; SGRQ, St. George's Respiratory Questionnaire; MRC, Medical Research Council; CES-D, Center for Epidemiologic Study-Depression Scale.
      Fig. 2
      Fig. 2Distributions of the scores of the Sarcoidosis Health Questionnaire by five-year deterioration. Higher SHQ total and Physical Functioning domain scores represent better health status. A. Five-year deterioration in all patients (n = 88) and SHQ total scores. B. Five-year deterioration in all patients (n = 88) and SHQ Physical Functioning domain scores. C. Five-year deterioration in patients with lung involvement at baseline (n = 68). D. Five-year deterioration in patients without cardiac involvement at baseline (n = 65).

      3.2 Associations of the SHQ scores with long-term outcome

      Of 88 patients at the 5-year follow-up, 20 (23%) had five-year deterioration; this included pulmonary deterioration in two (2%), cardiac in nine (10%), and non-pulmonary, non-cardiac in nine (10%) patients. In univariate analysis, the total SHQ score was associated with 5-year deterioration: OR, 0.52 (0.28–0.94) (Table 3) (Fig. 2A). Total SHQ score was associated with 5-year deterioration after adjustment for cardiac involvement at enrollment, with adjusted OR of 0.54 (0.29–0.99) (Table 4, Model 1). The association of the total SHQ with 5-year outcome was not significant when adjusted for LVEF at baseline (Table 4, Model 2), and marginal when adjusted for the usage of systemic CS or IS at enrollment (Table 4, Model 3). There was a marginal correlation between the total SHQ and LVEF at baseline (rho = 0.19, p = 0.07) and a weak association between the total SHQ and systemic CS/IS usage at enrollment (rho = −0.23, p = 0.03). When the SHQ total scores, cardiac involvement, the usage of systemic CS or IS, and LVEF were entered into a forward stepwise logistic regression, none of these baseline indices were associated with 5-year deterioration (Table 4, Model 4).
      Table 3Univariate logistic regression analyses for long-term deterioration.
      Odds95% CIP
      Age, years1.00(0.96, 1.03)0.81
      Male1.01(0.37, 2.80)0.98
      Duration of disease1.00(1.00, 1.01)0.46
      Number of organ systems involved0.96(0.50, 1.83)0.91
      Pulmonary involvement0.85(0.27, 2.72)0.78
      Cardiac involvement3.16(1.09, 9.10)0.03
      Ocular involvement0.67(0.24, 1.84)0.43
      Skin involvement0.64(0.19, 2.18)0.48
      Radiographic stage1.14(0.75, 1.72)0.54
      Serum biomarkers
       ACE0.90(0.81, 1.00)0.06
       sIL-2R1.00(1.00, 1.00)0.26
      Pulmonary function tests
       % FVC1.00(0.97, 1.03)0.98
       % FEV11.00(0.97, 1.03)0.88
       % DLCO0.99(0.96, 1.02)0.52
      Echocardiogram
       LVEF0.91(0.86, 0.98)0.01
       PASP1.02(0.94, 1.11)0.68
       Systemic CS or IS4.24(1.42, 12.6)0.01
      SHQ
       Daily Functioning0.56(0.33, 0.96)0.04
       Physical Functioning0.48(0.27, 0.85)0.01
       Emotional Functioning0.69(0.41, 1.14)0.15
       Total0.52(0.28, 0.94)0.03
      SF-36
       Physical functioning0.99(0.97, 1.01)0.30
       Role-physical0.98(0.96, 1.00)0.04
       Bodily pain0.98(0.96, 1.00)0.05
       General health perceptions0.97(0.94, 0.99)0.02
       Vitality0.97(0.94, 0.99)0.01
       Social functioning0.99(0.97, 1.01)0.34
       Role-emotional0.98(0.96, 1.00)0.06
       Mental health0.98(0.96, 1.01)0.19
      SGRQ
       Symptoms1.00(0.97, 1.02)0.79
       Activity1.01(0.99, 1.03)0.33
       Impact1.01(0.98, 1.05)0.40
       Total1.01(0.98, 1.05)0.42
      MRC1.53(0.84, 2.78)0.16
      CES-D1.06(1.00, 1.12)0.06
      Abbreviations: Odds, odds ratio; CI, confidential interval.
      Table 4Multivariate logistic regression analyses with SHQ total score for long-term deterioration.
      Model 1Odds ratio95% CIP value
      SHQ total0.54(0.29, 0.99)0.047
      Cardiac involvement2.95(0.99, 8.81)0.053
      Model 2
      SHQ total0.61(0.32, 1.16)0.13
      LVEF0.92(0.86, 0.99)0.02
      Model 3
      SHQ total0.58(0.31, 1.10)0.09
      Systemic CS or IS3.46(1.12, 10.7)0.03
      Model 4 (forward stepwise)
      SHQ total0.63(0.33, 1.21)0.17
      Cardiac involvement1.37(0.35, 5.42)0.65
      LVEF0.95(0.87, 1.02)0.16
      Systemic CS or IS2.03(0.53, 7.69)0.30
      Among the SHQ domain scores, DF and PF scores were associated with 5-year deterioration in univariate analysis: DF with OR, 0.56 (0.33–0.96), and PF with OR, 0.48 (0.27–0.85) (Table 3) (Fig. 2B). PF scores of the SHQ were significantly associated with 5-year deterioration after adjustment for cardiac involvement at enrollment, the usage of systemic CS or IS at enrollment, and with baseline LVEF, respectively (Table 5, Model 1 to 3). No other domain score was associated with 5-year outcome in multivariate models, with the marginal association of the DF scores adjusted after cardiac involvement at enrollment (adjusted OR, 0.59 [0.34–1.00]). In the forward stepwise logistic regression model including the SHQ PF scores, cardiac involvement, the usage of systemic CS or IS, and LVEF, the SHQ PF scores was the only significant predictor for 5-year deterioration with adjusted OR of 0.48 (0.26–0.90). The SHQ PF scores were significantly associated with SF-36 physical functioning domain (rho = 0.570, p < 0.0001), SGRQ total scores (rho = −0.714, p < 0.0001), and MRC dyspnea scale (rho = −0.436, p < 0.0001).
      Table 5Multivariate logistic regression analyses with the SHQ Physical Functioning domain for long-term deterioration.
      Model 1Odds ratio95% CIP value
      SHQ Physical Functioning0.48(0.27, 0.87)0.02
      Cardiac involvement3.10(1.03, 9.37)0.045
      Model 2
      SHQ Physical Functioning0.51(0.28, 0.93)0.03
      LVEF0.92(0.86, 0.98)0.01
      Model 3
      SHQ Physical Functioning0.45(0.25, 0.83)0.01
      Systemic CS or IS4.66(1.46, 14.8)0.01
      Model 4 (forward stepwise)
      SHQ Physical Functioning0.48(0.26, 0.90)0.02
      Cardiac involvement1.23(0.30, 5.13)0.78
      LVEF0.95(0.87, 1.02)0.17
      Systemic CS or IS2.73(0.68, 10.9)0.16
      Of 68 patients who had lung involvement at enrollment and were available for 5-year follow-up, 15 (22%) had 5-year deterioration, including 2 (2%) with pulmonary deterioration, 7 (10%) with cardiac deterioration, and 6 (9%) with non-pulmonary, non-cardiac deterioration. In univariate analysis, total SHQ score was marginally associated with 5-year deterioration: OR, 0.51 (0.26–1.02) (Table 6) (Fig. 2C). The PF domain score was significantly associated with 5-year deterioration in this subgroup: OR, 0.45 (0.24–0.86) (Table 6).
      Table 6Univariate logistic regression analyses for the five-year deterioration.
      NumberWith lung involvementWithout cardiac involvement
      6865
      Long-term deteriorationsOdds15 (22)POdds11 (17)P
      95% CI95% CI
      Age, years1.01(0.96, 1.05)0.810.99(0.95, 1.04)0.70
      Male1.10(0.34, 3.55)0.870.51(0.12, 2.12)0.35
      Duration of disease1.00(1.00, 1.01)0.321.01(1.00, 1.01)0.09
      Number of organ systems involved0.89(0.42, 1.89)0.770.67(0.27, 1.67)0.39
      Pulmonary involvement1.15(0.22, 6.11)0.87
      Cardiac involvement2.87(0.83, 9.92)0.10
      Ocular involvement0.45(0.13, 1.48)0.190.42(0.11, 1.62)0.21
      Skin involvement0.63(0.16, 2.57)0.520.69(0.16, 2.91)0.62
      Radiographic stage1.23(0.74, 2.07)0.420.84(0.48, 1.47)0.54
      Blood laboratory tests
       ACE0.91(0.81, 1.01)0.080.90(0.78, 1.04)0.14
       sIL-2R1.00(1.00, 1.00)0.411.00(1.00, 1.00)0.49
      Pulmonary function tests
       %FVC1.01(0.97, 1.04)0.661.01(0.97, 1.05)0.54
       %FEV11.00(0.97, 1.03)0.931.01(0.97, 1.04)0.70
       %DLCO0.99(0.96, 1.03)0.730.98(0.94, 1.02)0.24
      Echocardiogram
       LVEF0.91(0.84, 0.98)0.010.95(0.84, 1.07)0.38
       PASP0.99(0.90, 1.10)0.911.08(0.95, 1.22)0.26
       Systemic CS or IS5.75(1.58, 20.9)0.017.14(1.45, 35.2)0.02
      SHQ
       Daily Functioning0.57(0.31, 1.06)0.080.34(0.14, 0.79)0.01
       Physical Functioning0.45(0.24, 0.86)0.020.49(0.24, 0.98)0.04
       Emotional Functioning0.68(0.38, 1.21)0.190.70(0.35, 1.38)0.30
       Total0.51(0.26, 1.02)0.0570.40(0.18, 0.93)0.03
      SF-36
       Physical functioning0.99(0.97, 1.02)0.440.97(0.94, 1.00)0.09
       Role-physical0.98(0.96, 1.00)0.040.96(0.94, 0.99)0.01
       Bodily pain0.98(0.95, 1.00)0.030.96(0.94, 0.99)0.02
       General health perceptions0.95(0.92, 0.99)0.010.95(0.91, 0.99)0.01
       Vitality0.97(0.94, 1.00)0.020.95(0.92, 0.99)0.01
       Social functioning0.99(0.96, 1.01)0.230.98(0.95, 1.01)0.17
       Role-emotional0.98(0.96, 1.00)0.0480.97(0.94, 0.99)0.01
       Mental health0.99(0.96, 1.01)0.280.97(0.94, 1.00)0.06
      SGRQ
       Symptoms1.00(0.97, 1.03)0.911.00(0.97, 1.04)0.86
       Activity1.01(0.99, 1.04)0.281.00(0.99, 1.03)0.87
       Impact1.02(0.98, 1.06)0.321.02(0.97, 1.07)0.41
       Total1.02(0.98, 1.05)0.311.01(0.97, 1.06)0.60
      MRC1.80(0.94, 3.43)0.082.17(1.00, 4.73)0.05
      CES-D1.06(0.99, 1.13)0.081.09(1.00, 1.19)0.06
      Of 65 patients who did not have cardiac involvement at enrollment, and were available for 5-year follow-up, 11 (17%) had five-year deterioration; this included pulmonary deterioration in 2 (3%), cardiac in 1(2%), and non-pulmonary, non-cardiac in 8 (12%). In univariate analysis, total SHQ score was associated with 5-year deterioration: OR, 0.40 (0.18–0.93) (Table 6) (Fig. 2D). The PF domain score was also associated with 5-year deterioration in this subgroup: OR, 0.49 (0.24–0.98) (Table 6).

      4. Discussion

      In our cohort of well-characterized patients with sarcoidosis, the total SHQ score was associated with outcome after 5 years. This association is independent of cardiac involvement at baseline, while it is marginal and not significant after adjusting for the baseline usage of systemic CS/IS and LVEF, respectively. The Physical Functioning domain score is also associated with 5-year deterioration even after adjustment for these other confounders. These findings suggest that worse health status on the SHQ can be a risk for long-term deterioration in sarcoidosis patients.
      Evaluation of outcomes in sarcoidosis patients has not been standardized thus far [
      • Valeyre D.
      • Prasse A.
      • Nunes H.
      • Uzunhan Y.
      • Brillet P.Y.
      • Muller-Quernheim J.
      Sarcoidosis.
      ]. Sarcoidosis is a multisystem disease that can affect different organs with different severities and activities [
      • Nagai S.
      • Handa T.
      • Ito Y.
      • Ohta K.
      • Tamaya M.
      • Izumi T.
      Outcome of sarcoidosis.
      ,
      • Baughman R.P.
      • Nagai S.
      • Balter M.
      • Costabel U.
      • Drent M.
      • du Bois R.
      • Grutters J.C.
      • Judson M.A.
      • Lambiri I.
      • Lower E.E.
      • Muller-Quernheim J.
      • Prasse A.
      • Rizzato G.
      • Rottoli P.
      • Spagnolo P.
      • Teirstein A.
      Defining the clinical outcome status (COS) in sarcoidosis: results of WASOG Task Force.
      ,
      • Valeyre D.
      • Prasse A.
      • Nunes H.
      • Uzunhan Y.
      • Brillet P.Y.
      • Muller-Quernheim J.
      Sarcoidosis.
      ]. An objective assessment of a single organ system cannot reflect other organ system lesions or systemic symptoms. There has been also no blood biomarker established as a comprehensive index for disease activity in sarcoidosis [
      • Valeyre D.
      • Prasse A.
      • Nunes H.
      • Uzunhan Y.
      • Brillet P.Y.
      • Muller-Quernheim J.
      Sarcoidosis.
      ,
      • Keir G.
      • Wells A.U.
      Assessing pulmonary disease and response to therapy: which test?.
      ,
      • Casanova N.
      • Zhou T.
      • Knox K.S.
      • Garcia J.G.
      Identifying novel biomarkers in sarcoidosis using genome-based approaches.
      ,
      • Miyoshi S.
      • Hamada H.
      • Kadowaki T.
      • Hamaguchi N.
      • Ito R.
      • Irifune K.
      • Higaki J.
      Comparative evaluation of serum markers in pulmonary sarcoidosis.
      ]. The World Association of Sarcoidosis and Other Granulomatous Disorders (WASOG) recently defined the clinical outcome status (COS) based on examinations 5 years after diagnosis [
      • Baughman R.P.
      • Nagai S.
      • Balter M.
      • Costabel U.
      • Drent M.
      • du Bois R.
      • Grutters J.C.
      • Judson M.A.
      • Lambiri I.
      • Lower E.E.
      • Muller-Quernheim J.
      • Prasse A.
      • Rizzato G.
      • Rottoli P.
      • Spagnolo P.
      • Teirstein A.
      Defining the clinical outcome status (COS) in sarcoidosis: results of WASOG Task Force.
      ]. However, WASOG COS would not be appropriate in this study because our patients were enrolled at various phases of the disease course and were reevaluated not at 5 years after diagnosis, but at 5 years after enrollment. We, thus originally defined “deterioration” for this study to evaluate the 5-year outcome after baseline.
      The SHQ is the first disease-specific PRO instrument for sarcoidosis. Multidisciplinary properties of the SHQ were shown in Cox's original study and our previous one [
      • Cox C.E.
      • Donohue J.F.
      • Brown C.D.
      • Kataria Y.P.
      • Judson M.A.
      The Sarcoidosis Health Questionnaire: a new measure of health-related quality of life.
      ,
      • Tanizawa K.
      • Handa T.
      • Nagai S.
      • Oga T.
      • Kubo T.
      • Ito Y.
      • Watanabe K.
      • Aihara K.
      • Chin K.
      • Mishima M.
      • Izumi T.
      Validation of the Japanese version of the sarcoidosis health questionnaire: a cross-sectional study.
      ]. On the other hand, some limitations of the SHQ have been described. The SHQ is supposed to be almost entirely based on the SF-36 and contains standalone items for ocular, skin, and pulmonary involvement [
      • Victorson D.E.
      • Cella D.
      • Grund H.
      • Judson M.A.
      A conceptual model of health-related quality of life in sarcoidosis.
      ]. Indeed, the generic health status measured by the SF-36 was also associated with long-term outcome in our study. Additionally, the minimal clinically important difference (MCID) has not been established for the SHQ [
      • Judson M.A.
      • Mack M.
      • Beaumont J.L.
      • Watt R.
      • Barnathan E.S.
      • Victorson D.E.
      Validation and important differences for the Sarcoidosis Assessment Tool. A new patient-reported outcome measure.
      ]. The King's Sarcoidosis Questionnaire (KSQ) and the Sarcoidosis Assessment Tool (SAT), two assessments recently developed to overcome these limitations, have been validated as new sarcoidosis-specific PRO instruments [
      • Judson M.A.
      • Mack M.
      • Beaumont J.L.
      • Watt R.
      • Barnathan E.S.
      • Victorson D.E.
      Validation and important differences for the Sarcoidosis Assessment Tool. A new patient-reported outcome measure.
      ,
      • Patel A.S.
      • Siegert R.J.
      • Creamer D.
      • Larkin G.
      • Maher T.M.
      • Renzoni E.A.
      • Wells A.U.
      • Higginson I.J.
      • Birring S.S.
      The development and validation of the King's Sarcoidosis Questionnaire for the assessment of health status.
      ]. Both the KSQ and the SAT have several modules that reflect specific aspects of sarcoidosis, such as fatigue and skin involvement [
      • Judson M.A.
      • Mack M.
      • Beaumont J.L.
      • Watt R.
      • Barnathan E.S.
      • Victorson D.E.
      Validation and important differences for the Sarcoidosis Assessment Tool. A new patient-reported outcome measure.
      ,
      • Patel A.S.
      • Siegert R.J.
      • Creamer D.
      • Larkin G.
      • Maher T.M.
      • Renzoni E.A.
      • Wells A.U.
      • Higginson I.J.
      • Birring S.S.
      The development and validation of the King's Sarcoidosis Questionnaire for the assessment of health status.
      ], and an MCID has been established for the latter [
      • Judson M.A.
      • Mack M.
      • Beaumont J.L.
      • Watt R.
      • Barnathan E.S.
      • Victorson D.E.
      Validation and important differences for the Sarcoidosis Assessment Tool. A new patient-reported outcome measure.
      ]. The predictive properties of the KSQ and the SAT should be evaluated and compared to the SHQ in future studies.
      Of the PRO measures evaluated in this cohort, the MRC dyspnea scale and the CES-D tended to be associated with outcome, whereas the SGRQ was not. Dyspnea can be associated with both pulmonary and cardiac involvement, and also with fatigue in sarcoidosis [
      • Jastrzebski D.
      • Ziora D.
      • Lubecki M.
      • Zieleznik K.
      • Maksymiak M.
      • Hanzel J.
      • Poczatek A.
      • Kolczynska A.
      • Nguyen Thi L.
      • Zebrowska A.
      • Kozielski J.
      Fatigue in sarcoidosis and exercise tolerance, dyspnea, and quality of life.
      ]. Depressive symptoms have an association with organ involvement other than pulmonary and cardiac, such as muscles, nerves and bones [
      • Hinz A.
      • Brahler E.
      • Mode R.
      • Wirtz H.
      • Bosse-Henck A.
      Anxiety and depression in sarcoidosis: the influence of age, gender, affected organs, concomitant diseases and dyspnea.
      ]. On the other hand, the SGRQ is more specific for respiratory diseases. Although the SGRQ significantly correlates with the SHQ [
      • Cox C.E.
      • Donohue J.F.
      • Brown C.D.
      • Kataria Y.P.
      • Judson M.A.
      The Sarcoidosis Health Questionnaire: a new measure of health-related quality of life.
      ], the SHQ is superior in differentiating the number of organ systems involved [
      • Cox C.E.
      • Donohue J.F.
      • Brown C.D.
      • Kataria Y.P.
      • Judson M.A.
      The Sarcoidosis Health Questionnaire: a new measure of health-related quality of life.
      ]. In addition, any PFT parameters were not associated with outcome in this study. This may be because respiratory specific indices cannot predict worsening of extrapulmonary organ involvement. Another possible reason is that pulmonary deterioration was seen only in two patients (2%).
      Among the three domains of the SHQ, the scores from the PF domain were the strongest predictor for 5-year deterioration. The PF domain was significantly associated with the SF-36 physical functioning (PF) subscale, the SGRQ score and dyspnea. The original report as well as our previous study also showed stronger associations of the PF domain with the SGRQ score, dyspnea, and physiological measurements, compared to the other SHQ domains [
      • Cox C.E.
      • Donohue J.F.
      • Brown C.D.
      • Kataria Y.P.
      • Judson M.A.
      The Sarcoidosis Health Questionnaire: a new measure of health-related quality of life.
      ,
      • Tanizawa K.
      • Handa T.
      • Nagai S.
      • Oga T.
      • Kubo T.
      • Ito Y.
      • Watanabe K.
      • Aihara K.
      • Chin K.
      • Mishima M.
      • Izumi T.
      Validation of the Japanese version of the sarcoidosis health questionnaire: a cross-sectional study.
      ]. However, the SF-36 PF subscale, the SGRQ score or any physiological measurement other than LVEF was not predictive for 5-year deterioration in this study.
      The PF domain is composed of six questions, four of which deal with respiratory and/or cardiac symptoms (easy breathing; shortness of breath; cough; wheezing), and two with pain (headache; arthralgia) [
      • Cox C.E.
      • Donohue J.F.
      • Brown C.D.
      • Kataria Y.P.
      • Judson M.A.
      The Sarcoidosis Health Questionnaire: a new measure of health-related quality of life.
      ]. Of these six questions, the scores on the two questions for pain were associated with the long-term outcome (unadjusted OR of 0.79 [95%CI, 0.58–0.89]), whereas those on the four questions for respiratory and/or cardiac symptoms were not (unadjusted OR of 0.90 [95%CI, 0.80–1.03]). The SF-36 bodily pain subscale was also marginally associated with five-year deterioration. On the other hand, the SF-36 PF subscale addresses the restriction of several daily activities, but not painful symptoms. The SGRQ also includes no question about pain. Thus, painful symptoms, rather than respiratory and/or cardiac ones and general physical activity, may be predictive of long-term deterioration of patients with sarcoidosis.
      It should be also noted that, in this study cohort, most events of 5-year deterioration were cardiac (9/20), or non-pulmonary, non-cardiac (9/20). The predictive properties of these PRO instruments may be altered in other sarcoidosis populations with different outcomes (e.g. more frequent pulmonary deteriorations). In addition, the SF-36 PF subscale shows the ceiling effect in this study (Figure e1), which may affect its association with long-term outcome.
      Reported indicators for poor prognosis in sarcoidosis include disease onset >40 years old, involvement of the central nervous system (beyond an isolated central nerve palsy), heart, bone, or sino-nasal organ involvement, radiographic stage IV, bronchial stenosis, and pulmonary hypertension [
      • Valeyre D.
      • Prasse A.
      • Nunes H.
      • Uzunhan Y.
      • Brillet P.Y.
      • Muller-Quernheim J.
      Sarcoidosis.
      ]. Composite physiological index and high-resolution computed tomography parameters were recently reported to predict mortality in patients with pulmonary sarcoidosis [
      • Walsh S.L.
      • Wells A.U.
      • Sverzellati N.
      • Keir G.J.
      • Calandriello L.
      • Antoniou K.M.
      • Copley S.J.
      • Devaraj A.
      • Maher T.M.
      • Renzoni E.
      • Nicholson A.G.
      • Hansell D.M.
      An integrated clinicoradiological staging system for pulmonary sarcoidosis: a case-cohort study.
      ]. Our data suggest that some PRO measures, including SHQ scores, should also be considered as potential predictors of outcomes. Different results on organ involvement and physiological impairment may be associated with different study populations and definitions of outcomes.
      Decreased LVEF and cardiac involvement at baseline are significant and marginal risks for 5-year deterioration after adjustment for total SHQ scores, respectively. Japanese sarcoidosis patients have a higher prevalence of cardiac involvement than do Western patients, with cardiac involvement being a major cause of mortality [
      • Morimoto T.
      • Azuma A.
      • Abe S.
      • Usuki J.
      • Kudoh S.
      • Sugisaki K.
      • Oritsu M.
      • Nukiwa T.
      Epidemiology of sarcoidosis in Japan.
      ,
      • Rybicki B.A.
      • Maliarik M.J.
      • Major M.
      • Popovich Jr., J.
      • Iannuzzi M.C.
      Epidemiology, demographics, and genetics of sarcoidosis.
      ,
      • Iwai K.
      • Sekiguti M.
      • Hosoda Y.
      • DeRemee R.A.
      • Tazelaar H.D.
      • Sharma O.P.
      • Maheshwari A.
      • Noguchi T.I.
      Racial difference in cardiac sarcoidosis incidence observed at autopsy.
      ]. In fact, 45% of the cases of 5-year deterioration in this study were cardiac. Another significant predictor of deterioration is the usage of systemic CS/IS at baseline. It is reasonable because the usage of systemic CS/IS can be a surrogate marker for active disease at baseline, whatever organ systems are predominantly affected. Usage of systemic CS is also associated with health status of sarcoidosis patients [
      • Judson M.A.
      • Chaudhry H.
      • Louis A.
      • Lee K.
      • Yucel R.
      The effect of corticosteroids on quality of life in a sarcoidosis clinic: the results of a propensity analysis.
      ].
      There are several limitations of our study to consider. There were only 20 events of deterioration at the 5-year follow-up. We were too underpowered to construct multivariate models that included all potential covariates. Analysis in larger multi-center cohorts and enrichment of more severe cases would be more definitive. None of the questionnaires used in this study specifically addresses fatigue, although fatigue impairs the health status of sarcoidosis patients [
      • Drent M.
      • Lower E.E.
      • De Vries J.
      Sarcoidosis-associated fatigue.
      ,
      • Judson M.A.
      Quality of life assessment in sarcoidosis.
      ,
      • Drent M.
      • Marcellis R.
      • Lenssen A.
      • De Vries J.
      Association between physical functions and quality of life in sarcoidosis.
      ]. In fact, the SF-36 vitality subscale score was predictive for 5-year deterioration in this study. Assessment of fatigue, vitality, and energy by the SF-36 and other PRO instruments may provide additional predictive information to the SHQ.
      Baseline evaluation does not include 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET). 18F-FDG PET at diagnosis is reported to be a predictor of pulmonary deterioration within one year [
      • Umeda Y.
      • Demura Y.
      • Morikawa M.
      • Ameshima S.
      • Tsuchida T.
      • Fujibayashi Y.
      • Okazawa H.
      • Ishizaki T.
      Prognostic value of dual-time-point 18F-fluorodeoxyglucose positron emission tomography in patients with pulmonary sarcoidosis.
      ], although 18F-FDG PET has not been widely used at regular follow-ups.
      In conclusion, we demonstrate that worse health status, as assessed by the SHQ, is a risk for deterioration during the following 5 years, although the usage of systemic CS/IS and LVEF at baseline are stronger risks. If validated in other cohorts and with other questionnaires such as the KSQ and the SAT, this suggests that health status should be evaluated to address both subjective disease burdens for sarcoidosis patients and patients’ risks for future deterioration, in addition to common objective measures.

      Funding

      This study was supported in part by a grant from the Ministry of Health, Labour and Welfare of Japan awarded to the Study Group on Diffuse Pulmonary Disorders and the Respiratory Failure Study Group, Scientific Research/Research on Intractable Diseases. Other support includes the Japan Society for the Promotion of Science KAKENHI (Grant Numbers JJP25860642, JJP16K09534, and JJP26461187); a grant from the Japan Intractable Diseases Research Foundation; and the Ms. Mieko Sonoda Memorial Research Fund for Interstitial Lung Diseases.

      Acknowledgements

      We thank Ms. Y. Sato, Ms. M. Yokota, and Ms. S. Yoshida (Kyoto Central Clinic) for their help with outpatient clinical practice, Ms. H. Inoue, Ms. Y. Kubo, Ms. A. Kita, Ms. I. Morioka, Ms. S. Shima, and Ms. N. Chaki (Kyoto Central Clinic) for their secretarial help, and Mr. S. Ueda, Ms. N. Matsuzaki, and Ms. M. Nakatsuji (Kyoto Central Clinic) for their technical assistance. We also thank Ms. T. Toki, Ms. S. Tamura, and Ms. N. Kimura (Department of Respiratory Care and Sleep Control Medicine, Graduate School of Medicine, Kyoto University) for their secretarial work.

      Appendix A. Supplementary data

      The following is the supplementary data to this article:
      Figs1
      Figs1Figure 1e. Distributions of the scores of the SF-36 physical functioning subscale by 5-year deterioration (n = 88). Higher scores on the SF-36 physical functioning subscale represent better health status.

      References

      1. Statement on sarcoidosis. Joint statement of the American thoracic society (ATS), the European respiratory society (ERS) and the World association of sarcoidosis and other granulomatous Disorders (WASOG) adopted by the ATS board of directors and by the ERS executive committee, February 1999.
        Am. J. Respir. Crit. Care Med. 1999; 160: 736-755
        • Nagai S.
        • Handa T.
        • Ito Y.
        • Ohta K.
        • Tamaya M.
        • Izumi T.
        Outcome of sarcoidosis.
        Clin. Chest Med. 2008; 29: 565-574
        • Baughman R.P.
        • Nagai S.
        • Balter M.
        • Costabel U.
        • Drent M.
        • du Bois R.
        • Grutters J.C.
        • Judson M.A.
        • Lambiri I.
        • Lower E.E.
        • Muller-Quernheim J.
        • Prasse A.
        • Rizzato G.
        • Rottoli P.
        • Spagnolo P.
        • Teirstein A.
        Defining the clinical outcome status (COS) in sarcoidosis: results of WASOG Task Force.
        Sarcoidosis Vasc. Diffuse Lung Dis. 2011; 28: 56-64
        • Cox C.E.
        • Donohue J.F.
        • Brown C.D.
        • Kataria Y.P.
        • Judson M.A.
        Health-related quality of life of persons with sarcoidosis.
        Chest. 2004; 125: 997-1004
        • Cox C.E.
        • Donohue J.F.
        • Brown C.D.
        • Kataria Y.P.
        • Judson M.A.
        The Sarcoidosis Health Questionnaire: a new measure of health-related quality of life.
        Am. J. Respir. Crit. Care Med. 2003; 168: 323-329
        • Tanizawa K.
        • Handa T.
        • Nagai S.
        • Oga T.
        • Kubo T.
        • Ito Y.
        • Watanabe K.
        • Aihara K.
        • Chin K.
        • Mishima M.
        • Izumi T.
        Validation of the Japanese version of the sarcoidosis health questionnaire: a cross-sectional study.
        Health Qual. Life Outcomes. 2011; 9: 34
        • Ware Jr., J.E.
        • Sherbourne C.D.
        The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection.
        Med. Care. 1992; 30: 473-483
        • Fukuhara S.
        • Bito S.
        • Green J.
        • Hsiao A.
        • Kurokawa K.
        Translation, adaptation, and validation of the SF-36 Health Survey for use in Japan.
        J. Clin. Epidemiol. 1998; 51: 1037-1044
        • Jones P.W.
        • Quirk F.H.
        • Baveystock C.M.
        • Littlejohns P.
        A self-complete measure of health status for chronic airflow limitation. The St. George's Respiratory Questionnaire.
        Am. Rev. Respir. Dis. 1992; 145: 1321-1327
        • Hajiro T.
        • Nishimura K.
        • Tsukino M.
        • Ikeda A.
        • Koyama H.
        • Izumi T.
        Comparison of discriminative properties among disease-specific questionnaires for measuring health-related quality of life in patients with chronic obstructive pulmonary disease.
        Am. J. Respir. Crit. Care Med. 1998; 157: 785-790
        • National Institute for Clinical Excellence
        Chronic obstructive pulmonary disease: national clinical guideline for management of chronic obstructive pulmonary disease in adults in primary and secondary care.
        Thorax. 2004; 59 (1-232)
        • Radloff L.
        The CES-D Scale: a self-report depression scale for research in the general population.
        Appl. Psychol. Meas. 1977; 1: 385-401
        • Iwata N.
        • Okuyama Y.
        • Kawakami Y.
        • Saito K.
        Prevalence of depressive symptoms in a Japanese occupational setting: a preliminary study.
        Am. J. Public Health. 1989; 79: 1486-1489
        • Miller M.R.
        • Hankinson J.
        • Brusasco V.
        • Burgos F.
        • Casaburi R.
        • Coates A.
        • Crapo R.
        • Enright P.
        • van der Grinten C.P.
        • Gustafsson P.
        • Jensen R.
        • Johnson D.C.
        • MacIntyre N.
        • McKay R.
        • Navajas D.
        • Pedersen O.F.
        • Pellegrino R.
        • Viegi G.
        • Wanger J.
        Standardisation of spirometry.
        Eur. Respir. J. 2005; 26: 319-338
        • The Committee of Pulmonary Physiology JRS
        Guidelines for Pulmonary Function Tests: Spirometry, Flow-Volume Curve, Diffusion Capacity of the Lung.
        The Japanese Respiratory Society, Tokyo2004
        • Handa T.
        • Nagai S.
        • Miki S.
        • Fushimi Y.
        • Ohta K.
        • Mishima M.
        • Izumi T.
        Incidence of pulmonary hypertension and its clinical relevance in patients with sarcoidosis.
        Chest. 2006; 129: 1246-1252
        • Judson M.A.
        • Baughman R.P.
        • Teirstein A.S.
        • Terrin M.L.
        • Yeager Jr., H.
        Defining organ involvement in sarcoidosis: the ACCESS proposed instrument. ACCESS research group. A case Control etiologic study of sarcoidosis.
        Sarcoidosis Vasc. Diffuse Lung Dis. 1999; 16: 75-86
        • DeRemee R.A.
        The roentgenographic staging of sarcoidosis. Historic and contemporary perspectives.
        Chest. 1983; 83: 128-133
        • Kasahara Y.
        • Ashihara Y.
        Colorimetry of angiotensin-I converting enzyme activity in serum.
        Clin. Chem. 1981; 27: 1922-1925
        • Valeyre D.
        • Prasse A.
        • Nunes H.
        • Uzunhan Y.
        • Brillet P.Y.
        • Muller-Quernheim J.
        Sarcoidosis.
        Lancet. 2014; 383: 1155-1167
        • Judson M.A.
        • Chaudhry H.
        • Louis A.
        • Lee K.
        • Yucel R.
        The effect of corticosteroids on quality of life in a sarcoidosis clinic: the results of a propensity analysis.
        Respir. Med. 2015; 109: 526-531
        • Keir G.
        • Wells A.U.
        Assessing pulmonary disease and response to therapy: which test?.
        Semin. Respir. Crit. Care Med. 2010; 31: 409-418
        • Casanova N.
        • Zhou T.
        • Knox K.S.
        • Garcia J.G.
        Identifying novel biomarkers in sarcoidosis using genome-based approaches.
        Clin. Chest Med. 2015; 36: 621-630
        • Miyoshi S.
        • Hamada H.
        • Kadowaki T.
        • Hamaguchi N.
        • Ito R.
        • Irifune K.
        • Higaki J.
        Comparative evaluation of serum markers in pulmonary sarcoidosis.
        Chest. 2010; 137: 1391-1397
        • Victorson D.E.
        • Cella D.
        • Grund H.
        • Judson M.A.
        A conceptual model of health-related quality of life in sarcoidosis.
        Qual. Life Res. 2014; 23: 89-101
        • Judson M.A.
        • Mack M.
        • Beaumont J.L.
        • Watt R.
        • Barnathan E.S.
        • Victorson D.E.
        Validation and important differences for the Sarcoidosis Assessment Tool. A new patient-reported outcome measure.
        Am. J. Respir. Crit. Care Med. 2015; 191: 786-795
        • Patel A.S.
        • Siegert R.J.
        • Creamer D.
        • Larkin G.
        • Maher T.M.
        • Renzoni E.A.
        • Wells A.U.
        • Higginson I.J.
        • Birring S.S.
        The development and validation of the King's Sarcoidosis Questionnaire for the assessment of health status.
        Thorax. 2013; 68: 57-65
        • Jastrzebski D.
        • Ziora D.
        • Lubecki M.
        • Zieleznik K.
        • Maksymiak M.
        • Hanzel J.
        • Poczatek A.
        • Kolczynska A.
        • Nguyen Thi L.
        • Zebrowska A.
        • Kozielski J.
        Fatigue in sarcoidosis and exercise tolerance, dyspnea, and quality of life.
        Adv. Exp. Med. Biol. 2015; 833: 31-36
        • Hinz A.
        • Brahler E.
        • Mode R.
        • Wirtz H.
        • Bosse-Henck A.
        Anxiety and depression in sarcoidosis: the influence of age, gender, affected organs, concomitant diseases and dyspnea.
        Sarcoidosis Vasc. Diffuse Lung Dis. 2012; 29: 139-146
        • Walsh S.L.
        • Wells A.U.
        • Sverzellati N.
        • Keir G.J.
        • Calandriello L.
        • Antoniou K.M.
        • Copley S.J.
        • Devaraj A.
        • Maher T.M.
        • Renzoni E.
        • Nicholson A.G.
        • Hansell D.M.
        An integrated clinicoradiological staging system for pulmonary sarcoidosis: a case-cohort study.
        Lancet Respir. Med. 2014; 2: 123-130
        • Morimoto T.
        • Azuma A.
        • Abe S.
        • Usuki J.
        • Kudoh S.
        • Sugisaki K.
        • Oritsu M.
        • Nukiwa T.
        Epidemiology of sarcoidosis in Japan.
        Eur. Respir. J. 2008; 31: 372-379
        • Rybicki B.A.
        • Maliarik M.J.
        • Major M.
        • Popovich Jr., J.
        • Iannuzzi M.C.
        Epidemiology, demographics, and genetics of sarcoidosis.
        Semin. Respir. Infect. 1998; 13: 166-173
        • Iwai K.
        • Sekiguti M.
        • Hosoda Y.
        • DeRemee R.A.
        • Tazelaar H.D.
        • Sharma O.P.
        • Maheshwari A.
        • Noguchi T.I.
        Racial difference in cardiac sarcoidosis incidence observed at autopsy.
        Sarcoidosis. 1994; 11: 26-31
        • Drent M.
        • Lower E.E.
        • De Vries J.
        Sarcoidosis-associated fatigue.
        Eur. Respir. J. 2012; 40: 255-263
        • Judson M.A.
        Quality of life assessment in sarcoidosis.
        Clin. Chest Med. 2015; 36: 739-750
        • Drent M.
        • Marcellis R.
        • Lenssen A.
        • De Vries J.
        Association between physical functions and quality of life in sarcoidosis.
        Sarcoidosis Vasc. Diffuse Lung Dis. 2014; 31: 117-128
        • Umeda Y.
        • Demura Y.
        • Morikawa M.
        • Ameshima S.
        • Tsuchida T.
        • Fujibayashi Y.
        • Okazawa H.
        • Ishizaki T.
        Prognostic value of dual-time-point 18F-fluorodeoxyglucose positron emission tomography in patients with pulmonary sarcoidosis.
        Respirology. 2011; 16: 713-720