Healthcare utilization and unmet needs of patients with antisynthetase syndrome: An international patient survey

Antisynthease syndrome (ASSD) is a rare, complex and understudied autoimmune disease. Internet-based studies can overcome barriers of traditional on-site research and are therefore very appealing for rare diseases. The aim of this study was to investigate patient-reported symptoms, diagnostic delay, symptoms, medical care, health status, working status, disease knowledge and willingness to participate in research of ASSD patients by conducting an international web-based survey. The multilingual questionnaire was created by an international group of rheumatologists and patients and distributed online. 236 participants from 22 countries completed the survey. 184/236 (78.0%) were female, mean age (SD) was 49.6 years (11.3) and most common antisynthetase antibody was Jo-1 (169/236, 71.6%). 79/236 (33.5%) reported to work full-time. Median diagnostic delay was one year. The most common symptom at disease onset was fatigue 159/236 (67.4%), followed by myalgia 130/236 (55.1%). The complete triad of myositis, arthritis and lung involvement verified by a clinician was present in 42/236 (17.8%) at disease onset and in 88/236 (37.3%) during the disease course. 36/236 (15.3%) reported to have been diagnosed with fibromyalgia and 40/236 (16.3%) with depression. The most reported immunosuppressive treatments were oral corticosteroids 179/236 (75.9%), followed by rituximab 85/236 (36.0%). 73/236 (30.9%) had received physiotherapy treatment. 71/236 (30.1%) reported to know useful online information sources related to ASSD. 223/236 (94.5%) were willing to share health data for research purposes once a year. Our results reiterate that internet-based research is invaluable for cooperating with patients to foster knowledge in rare diseases. Supplementary Information The online version contains supplementary material available at 10.1007/s00296-023-05372-9.


Introduction
Antisynthetase-syndrome (ASSD) as one of the idiopathic inflammatory myopathy (IIM) subtypes is a rare disease, with an estimated global prevalence of 1-9/100.000 [1]. In an analysis within the EuroMyositis registry, ASSD was the third most common IIM subtype (17% of analyzed patients) after dermatomyositis and polymyositis [2]. The defining diagnostic cornerstone is the presence of autoantibodies against one of the aminoacyl transfer RNA (tRNA) synthetases. Anti-Jo1 auto-antibodies were the first described antibodies of this disease spectrum [3]. Furthermore, they are the only myositis specific autoantibodies used in the latest EULAR/ACR criteria for IIM [4]. Other antibodies defining ASSD are anti-PL-7, anti-PL-12, anti-EJ, anti-OJ, anti-KS, anti-Ha and anti-Zo [5]. In addition to muscle involvement, the main clinical features are Raynaud's phenomenon, mechanic's hands, arthritis, and interstitial lung disease (ILD) [5]. Although classified as IIM, myositis might be clinically absent in some cases [6] and symptoms vary remarkably between patients [7]. Prognosis mainly depends on pulmonary involvement, often seen in anti-PL-7/-12 patients [8]. Therapy is established depending on organ involvement [9] and mainly includes methotrexate, azathioprine, cyclophosphamide, rituximab or IVIG [10]. Especially in ASSD with concomitant ILD, B-cell-directed therapy with rituximab is increasingly used [11] and was M. Weiss and M. T. Holzer share first authorship.
Extended author information available on the last page of the article 1 3 associated with a significant glucocorticoid-sparing effect [12].
Digital crowdsourcing promises to overcome barriers of traditional on-site research [13]. The validity of patient-reported diagnoses has been underlined in previous publications [14][15][16] and lead to first patient-powered, internet-based studies in rheumatology [17][18][19][20]. Despite the increasing research regarding ASSD in the last few years, aspects such as disease knowledge, quality of life, burden of disease, healthcare utilization and willingness to participate in research remained largely unexplored. Elucidating these questions may help to improve the health care situation of ASSD patients.
The aim of this study was to investigate patient-reported symptoms, diagnostic delay, medical care, health and working status, disease knowledge and willingness to participate in research of ASSD patients by conducting an international web-based survey.

Survey development
The survey was initially drafted in German by JK and DS and was then adopted to the suggestions of all authors including rheumatologists treating ASSD patients and three patients' representatives to ensure meaningfulness and clarity of the questions asked. The questionnaire was translated to five additional languages (English, Swedish, Spanish, French, Italian) by native speakers to guarantee equivalence. The final multilingual online questionnaire (Supplementary Material 1) included 4 general questions and 33 different items and took approximately 10 min to complete. The group decided to investigate: (1) Symptoms and diagnostic delay -9 items (2) medical care -9 items (3) health and working status -7 items (4) disease knowledge -6 items and (5) research participation -2 items.

Participant recruitment
The cross-sectional questionnaire (SurveyMonkey Inc) was available in six languages (English, German, Swedish, Spanish, French, Italian) and accessible from 4th of July 2020 until 23rd April 2021. No specific sample size was targeted. The survey was distributed via social media (Twitter, Instagram, Facebook), QR codes and email. All patients with self-reported ASSD diagnosis confirmed by a physician were eligible. This survey was based on patient reported aspects, as the questions were answered anonymously the gained information based solely on patients' answers and not on information of the treating physician. Prior to completing the survey patients were required to give consent via the platform.

Statistical analysis
Descriptive and summary statistics were used and depicted in tabular and graphical form using mean, median, percentage or minimum/maximum to enable comparison e.g. between ASSD subtypes. Participants, who did not complete the whole survey were excluded from statistics. Regression analyses were performed to investigate correlations. The analyses were performed using IBM SPSS Statistics V.22 Windows (SPSS Inc, Chicago, Illinois, USA). Results and methodology was reported according to the Checklist for Reporting Results of Internet E-Surveys [21]. Graphs were depicted with Microsoft Excel. The study was approved by the ethics committee of the medical faculty of the university of Erlangen-Nürnberg, Germany (20-104-B; date: 16.03.2020).

Diagnostic delay
Mean age (SD) at diagnosis was 49.5 years (11.3 years) with a median (IQR) diagnostic delay of 1 year (0-2 years). Maximal diagnostic delay was 31 years. A median (IQR) of 3 (2-4) and a maximum of 30 specialist doctors were seen until the diagnosis ASSD was established. Diagnostic delay for patients with EJ-antibodies was shortest and PL-7-antibodies longest with a median of 0 years (0-1 years) and 2 years (0-5 years), respectively.

Research participation
223/236 (94.5%) of the patients reported to be willing to regularly share data about their health for research purposes

Discussion
To our knowledge, this is the first large international survey among patients with a self-reported diagnosis of ASSD.
The results depict the current healthcare situation of ASSD patients, pointing out unmet needs and may guide further research. Furthermore, this web-based study underlines how technology may facilitate and accelerate research in rare diseases. The median diagnostic delay was similar to the previous study of Cavagna et al. with one year, and anti-PL-7/12 patients reporting longer delays compared to anti-Jo-1 patients [7]. The recently published systematic review on diagnostic delay of myositis patients revealed a mean delay of 17 months in diagnosis of ASSD with very varying study results [22]. As possible reasons for the delay in diagnosis many factors like health care service-related aspects or complex clinical characteristics were discussed. Classification criteria for ASSD are currently being developed in a collaborative project (CLASS) to further improve collaborative research but also aid diagnosis. Levi et al. demonstrated the value of a multidisciplinary team and especially including rheumatologists to increase diagnostic accuracy [23].
In this study the large majority of patients (91.5%) was seen regularly by rheumatologists, however this could be due to selection bias, as rheumatologists mainly helped to share the survey. Interestingly, less than half of patients (46.6%) reported to have a main physician contact working at a university center. This could also partly explain the relatively low number of tests reported to establish the diagnosis (i.e. 39.0% reporting a muscle strength test). A recent survey among physicians treating IIM patients revealed the inconsistent state of knowledge and clinical practice [24].
In line with previous studies [17,25,26], we observed fatigue (60.7%) and pain (33.5%) being frequently reported. These symptoms should be frequently assessed and could be added to the currently used IMACS Disease Activity Core Set Measures [27]. The major effect of fatigue on overall quality of life of myositis patients has been recently pointed out [28]. Additionally, in our survey 16.3% of the patients described depression as comorbidity. A recent German study of health insurance data found comparable results with slightly elevated depression rates in myositis patients compared to the control group [29]. Hence, fatigue and depression should be actively screened for by physicians in clinical routine.

Fig. 3 Current and previous treatments
It is important to note, that lack of physical activity comprises a higher risk of depression [30]. On the other hand, there are studies pointing out the potential effect of physical therapy on pain and functional outcome in myositis patients [31]. Bhashyam et al. recently described the high percentage of opioid users among myositis patients [17]. Noteworthy, our results show higher frequency of pain medication therapy than physiotherapy in ASSD patients. Given the abovementioned aspects of physical activity, there might be an unmet need to improve especially physiotherapy and physical activity in ASSD. The recently published letter by Gupta et al. addresses this need and suggests online solutions and tools to improve self-managed physical activity [32].
Regarding the clinical symptoms we observed highest involvement of joints in Jo-1-positive patients which is congruent to the findings of Cavagna et al. [7]. The complete triad of symptoms was also mainly present in Jo-1-positive, also confirming the results of Cavagna et al.
Regarding lung involvement differences between our study and the study of Cavagna et al. can be found. All of the EJpositive patients had physician proven ILD, which reflects also the initial symptoms of dyspnoe/cough mentioned by the patients. Overall lung involvement in our study (67.8%) confirms the high ILD frequency in ASSD, also observed in the EuroMyositis registry (71%) [2].
In our cohort, rituximab was the most applied therapy, except for oral prednisolone and pain medication (36% of the patients). The increase of this therapeutic concept may depict the latest achievements in immunology, suggesting a potential pathogenic role of ASSD-autoantibodies such as Jo-1 in pathogenesis of the disease [33][34][35] and therefore giving underlining indications for B-cell-directed treatment approaches in ASSD. Recently a first case of CD-19-targeted CAR T Cells was published demonstrating a novel effective and safe treatment option for refractory cases [36]. The impaired health status of the majority of patients is in line with previous work [37] and prevented the majority of patients from working. Only one third of the patients were able to work full-time. These results confirm the Swedish results by Leclair et al. [38], which demonstrated that costs related to IIM start to increase already two years before diagnosis and mean annual costs were 3 to 5 times higher than in the general population. A German study showed that sick leave and early retirement decreased in the last decades [25].
Patients reported a very high willingness to participate in research activities. Simple patient-centered tests to measure muscle endurance [39] and self-sampling of capillary blood [40] have recently been validated. They could complement wearable [41] and smartphone data [42] to enable remote monitoring [43] and decentralized clinical trials.
Similar to previous studies [19,44,45], patients expressed interest for further information and only a third reported to know useful online information regarding ASSD. Reported useful online material was collected (supplementary table 5) and should be proactively discussed especially with newly diagnosed patients. Low interest in local community workshops could be explained by the large burden to participate in such meetings and have been increasingly carried out virtually due to the COVID pandemic.
The large number of international patients and involvement of patient research partners are strengths of this study. The digital nature of the study, recall bias, lack of ability to confirm disease and focus on rheumatologists could introduce a selection bias. Furthermore, not having differentiated between current and previous treatments limit the results. The survey was only evaluated by rheumatologists and the three patient research partners prior to distribution.

Conclusion
This survey enabled a detailed overview of the current healthcare situation of ASSD patients and unmet needs. The study highlights the great burden of disease, its heterogenous appearance and treatments. The results prompt physicians to evaluate currently neglected symptoms such as fatigue and myalgia and make more usage of physiotherapy. Online information is welcomed by patients however patients are mostly not aware of useful content. The large majority of patients would be willing to share health related data for research purposes. Our results reiterate that internet-based research is invaluable for cooperating with patients to foster knowledge in rare diseases.

Supplementary Information
The online version contains supplementary material available at https:// doi. org/ 10. 1007/ s00296-023-05372-9. obtaining the degree "Dr. med." for Michaela Weiss. JS is member of the European Reference Network for Rare Neuromuscular Disorders (ERN EURO-NMD). This research was supported by the NIHR Manchester Biomedical Research Centre (NIHR203308). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care.
Author contributions All authors contributed to design of the study and questionnaire and were responsible for data acquisition. Data analyzation and interpretation was performed by MW, MTH and MK. The manuscript draft was written by MW, MTH and JK. All authors revised the manuscript and gave substantial contributions. All authors gave final approval of the version to be published and take full responsibility for the integrity and accuracy of all aspects of the work.
Funding Open Access funding enabled and organized by Projekt DEAL. Open Access funding enabled and organized by Project DEAL. This study was partially supported by the Deutsche Forschungsgemeinschaft (DFG) by project PANDORA (FOR2886).
Data availability Data are available on reasonable request from the corresponding author.

Conflict of interest
The authors report no competing interests.

Ethical approval
The study was approved by the ethics committee of the medical faculty of the university of Erlangen-Nürnberg, Germany (20-104-B; date: 16.03.2020). Informed consent was obtained from all subjects involved in the study. Written informed consent has been obtained from the patients to publish this paper.
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, 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 changes were made. 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:// creat iveco mmons. org/ licen ses/ by/4. 0/.