FeV1 and BMI influence King’s Sarcoidosis Questionnaire score in sarcoidosis patients

Sarcoidosis is rare granulomatous disease that can affect virtually any organ [1, 2]. Besides measurable organ impairment (e.g. lung function defects) sarcoidosis affects quality of life (QoL) [3, 4] by organ-associated symptoms (e.g. cough) on the one hand and constitutional complaints (e.g. fatigue) on the other hand [1].

Several clinical trials in sarcoidosis have failed to meet primary endpoints based on improvement of measurable function impairment (e.g. forced vital capacity [FVC]) [5] even though patients experienced subjective improvement. Therefore, besides organ impairment, quality of life has been awarded an important endpoint for clinical studies in sarcoidosis [6]. To assess quality of life, Patel et al. presented a sarcoidosis-specific questionnaire [7] (King’s Sarcoidosis Questionnaire, KSQ) which has been translated and validated to Dutch and German [8, 9]. The questionnaire has 29 items covering general health status (GHS) as well as subdomains for lung (LUNG), skin (SKIN), eye (EYE), and medication (MED) associated QoL. Each subdomain can take a score between 0 and 100 and scores can be combined to integrate different subdomains in one score. In the initial analysis by Patel et al. [7], LUNG subdomain correlated well with lung function and the other subdomains correlated with respective organ involvement.

We have recently translated KSQ to German and validated its translated version in a cohort of sarcoidosis patients [8]. We hypothesized that KSQ offers additional information on patients’ well-being and that KSQ scores are only partially influenced by serological or lung function parameters routinely used to follow-up sarcoidosis patients.

Sarcoidosis is a granulomatous disease of unknown origin and, beyond its acute presentation, can take a chronic course and thereby may affect virtually every organ while favoring lung involvement [1, 2, 13, 14]. Organ involvement often requires immunosuppressive therapy. In addition to direct organ involvement, constitutional complaints like dyspnea on exertion (DOE), fatigue, pain and weakness may limit patients’ wellbeing even in the absence of direct organ manifestation [15, 16], however, these complaints are difficult to assess and especially to measure e.g. for clinical trials. The King’s Sarcoidosis Questionnaire is a relatively new health status measure to assess the patients’ perspective on their disease [7] and recently was validated for Dutch and German [8, 9]. For this questionnaire, there is a lack of knowledge, how disease assessment by routine follow-up parameters explains KSQ as a surrogate of health perceptation by affected persons.

In this study, we analyzed to which extent follow-up parameters in sarcoidosis can explain KSQ values and whether there are independent and supplementary information obtained by using the KSQ. We therefore analyzed KSQ values obtained in the validation cohort taking clinical data in consideration, focusing on the GHS and the LUNG scores because most of the patients had pulmonary manifestation of sarcoidosis (Additional file 1: Table S1).

There are three main observations. First, the questionnaire adds significant information about the patients’ health status beyond classical parameters obtained in routine follow-up; second, BMI impacts patients’ reported well-being; and third, of all lung function parameters, FeV1 correlates most strongly with KSQ scores, both, for female and male..

In our cohort, GHS adds information of patients’ health perceptation beyond other clinical parameters assessed in routine follow-up. As could be expected, GHS is influenced by the subdomain scores, which were generally lower in patients with respective organ manifestation or drug therapy. However, the influence of each subdomain or any organ manifestation only partially explained GHS and organ manifestations did not fully explain respective subdomain scores either. Importantly, single organ involvement did not influence GHS apart from bone involvement (Table 4), which can be considered as a surrogate of multiple organ involvement [17] affecting GHS (Additional file 1: Table S4). Additionally, we did not observe that serological parameters correlate with GHS or LUNG scores (Table 3 and Fig. 3) besides ACE, which slightly associated with GHS score (Fig. 3C). This is noteworthy, because reduced quality of life of sarcoidosis is often hypothesized to relate to inflammatory activity. The effect of ACE in this context is against the expectations, as higher ACE values signify higher GHS scores. However, one has to consider that ACE values were not genotype-corrected [18‐20] and were the most missing data in the cohort, because they were not routinely measured since there is no generally accepted standardization of the test. Inflammatory parameters from bronchoalveolar lavage and peripheral blood gauge pathological mechanism and may reflect inflammatory activity of sarcoidosis, allowing identification of patients at risk for progression and therapeutic need [21‐26]. Most interestingly, these mechanisms and inflammatory activity do not hamper general health as shown in Fig. 3 and Additional file 1: Figure S5.

Patel et al. [7] demonstrated that lung function parameters influence LUNG score, which we could reproduce in our cohort. FVC, FeV1, TLC and DLCO all correlate with LUNG score (Fig. 1). Of note, correlation differs between male and female and was stronger for the latter one. We did not observe any other difference between male and female in our cohort, neither for questionnaire score nor for clinical, serological or lung function parameter.

In contrast to the findings from Patel et al. [7], FeV1 and DLCO were the most important drivers for LUNG score in our cohort (Additional file 1: Table S3). Their effect was still detectable in multivariate models integrating serological parameters, age, sex, BMI, and radiological type (Table 3). Notably, VIF below 10 indicates that multicollinearity is not mainly causative of these findings [12]. VIF values 5.85 and 4.42 for FVC and FeV1 respectively can be easily anticipated by the fact that in restrictive lung diseases FeV1 depends on FVC. However, the importance of FeV1 for LUNG and GHS score is an interesting observation in regard of a recent description of different ventilatory defects in a large cohort of sarcoidosis patients [27]; an obstructive ventilator defect was found in approximately 15% of patients in our cohort. Especially in obstructive and mixed ventilatory defects, FeV1 may better reflect airway involvement and thereby explain reduced quality of life. The importance of FeV1 for patients’ perception of sarcoidosis-associated well-beings further emphasized by the fact that FeV1 remained the only significant lung function parameter that influenced GHS in the univariable linear regression analysis (Table 5). This effect remained robust after including serological, radiological or clinical parameters as independent variables. Considering a minimal clinical important difference for the GHS domain of 8 and the LUNG domain of 4 [28], an absolute increase or decrease in FeV1 of 6% or 12% will result in better or worse quality of life as assessed by the LUNG or GHS score, respectively.

The third important point of the analysis is the role of BMI for patients’ quality of life. Our analysis of the cohort does not allow to conclude, whether obesity is a reason for or consequence of reduced quality of life, however obesity has been recognized as prevalent in sarcoidosis patients [29] and affecting quality of life [30, 31]. Vice versa reduced quality of life may result in inactivity and obesity resulting in a vicious circle. Obesity additionally affects lung function parameters and sensation of dyspnea [32, 33], but effect of BMI on LUNG and GHS score was independent of lung function impairment (Tables 3 and 4) and remains robust in all analyses. We did not observe differences in BMI between patients with and without immunosuppressive therapy (Additional file 1: Fig. S4), but our analysis could not rule out that obesity resulted from previous corticosteroid therapy with its immanent side effect of weight gain [34]. In this context one may interpret the observation that worries about medication correlate with BMI (R = − 0.16, p = 0.06), demonstrating an interplay between weight and concerns about drug therapy. The robust influence of obesity on sarcoidosis-associated quality of life is noteworthy in the context that several data support an influence of obesity on the inflammatory environment [35‐37] which may propagate autoimmune diseases like sarcoidosis [38, 39]. In this context, one might speculate whether life style modifications like diet may alter the inflammatory milieu and patients’ reported quality of life [40, 41].

In summary, our study shows that GHS gauges an aspect of patients’ suffering from sarcoidosis, which is not captured by the clinical parameters in use and is of relevance for patients monitoring and clinical decisionmaking.

There are several limitations of this study. First, most of the patients included in the study were recruited in a tertiary pneumological center, which may bias the cohort towards more severely and chronically diseased patients. However, especially in this cohort of patients, the use of questionnaires to assess patients’ health status and to adapt therapy is especially useful, whereas its role in patients presenting with acute or uncomplicated sarcoidosis is debatable. Second, KSQ values were determined at a single time point, which does not allow answering the question about its value in therapeutic decisions. A recent publication analysed the KSQ score in the follow-up of patients underscoring its use in patient care [28]. Third, the application of multivariable linear models to assess factors that influence patient-reported outcomes represent an exploratory and artificial mathematical approach, that leaves out a certain amount of unmeasurable information. Accordingly, the adjusted r-squares in our analysis only demonstrated a moderate fitting of the applied models, which was confirmed in cross-validation strategies. Nevertheless, the effect of BMI and FeV1 remained robust over all multivariable models. However, as we outlined before, clinical data only explain partially patient-reported health-related quality of life.

Even with these limitations in mind, the study contributes some important insights. Most importantly, we could demonstrate that KSQ adds important additional information to routinely monitored parameters in sarcoidosis care. Therefore, the questionnaire may represent a tool in patient care and also a relevant instrument for clinical studies in sarcoidosis. Furthermore, our data suggest an important role of FeV1 at least for the patients’ self-perception of well-being. Interestingly, there seems to be a slight difference in the perception between male and female, as female LUNG scores correlate better with lung function compared to male. Lastly, the role of BMI in sarcoidosis and associated quality of life is emphasized by our study and raises the question, whether addressing body weight may be a treatable trait for sarcoidosis-associated constitutional complaints.