Abstract
Objective:
IgG4-related disease (IgG4-RD), a multi-organ autoimmune disease, causes diverse manifestations that can lead to symptoms and distress. We developed and validated the Symptom Severity Index (SSI) to assess symptom burden.
Methods:
A pilot SSI was tested in n=5; several gaps were identified. Twenty semi-structured qualitative interviews were performed to expand the item set and identify missing symptoms. Subsequent changes resulted in the current SSI; it was administered with quality of life (QOL) measures to n=136. We assessed symptom burden and the construct validity of the SSI. A distress score for each symptom is calculated by multiplying symptom frequency (“Never” [0 points] to “Every Day” [3 points]) by associated distress (“None” [0 points] to “Very Much” [4 points]). Each distress score is summed to calculate a total SSI score.
Results:
The SSI assesses the frequency and distress of 24 symptoms. Among n=136 with ≥ 1 SSI, 90% experienced ≥ 1 symptom and 88% had distress. The median SSI score was 6.5 (IQR 3.0, 18.0). Fear of more severe disease was observed in 49%. The SSI inversely correlated with the SF-36 (r= - 0.51, p<0.001), the feeling thermometer (r= - 0.28, p<0.001), and the EQ-5D (r= - 0.28, p<0.001). The median SSI score was higher during active vs non-active disease among n=52 who completed >1 SSI (15 [6, 26] vs. 3 [2, 14], p=0.008).
Conclusions:
Symptoms and distress are common in IgG4-RD and associated with worse health-related QOL. The SSI has face, content, and construct validity; it corresponds with QOL measures.
Keywords: IgG4-Related Disease, Symptom Burden, Patient Reported Outcomes
INTRODUCTION
IgG4-related disease (IgG4-RD) is an immune-mediated fibro-inflammatory disease responsible for fibrotic, inflammatory lesions in nearly any organ or anatomic site (1). Organ involvement and disease severity can vary widely, including sialoadenitis and dacryoadenitis, pancreatitis, sclerosing cholangitis, and retroperitoneal fibrosis (2). Corresponding symptoms may include sicca symptoms, swelling of glands, abdominal pain, jaundice, weight loss, and constitutional symptoms. Given the myriad manifestations and symptoms that can occur, the patient experience with regard to symptoms and their associated severity and distress is likely to be diverse. The IgG4-RD Responder Index (RI) is a validated instrument that incorporates elements of the history, physical examination, and laboratory and imaging features with the goal of measuring disease activity accurately (3). However, there is no patient-reported outcome measure (PROM) specific for IgG4-RD. Further, no previous study has systematically assessed IgG4-RD symptoms among patients.
Given the frequent differences in patient and physician assessments of symptoms and their associated severity, PROMs are important to measure reliably the impact of disease activity, damage, and treatment from the patient’s perspective. Generic PROMs such as the SF-36 (4) and the EuroQOL-5D (5) are used commonly to measure the impact of disease on quality of life (QOL). However, such measures are not specific to symptoms or experiences associated with a condition and do not measure the severity or distress associated with disease-specific symptoms or manifestations. To facilitate efficacy trials and other patient-oriented studies in IgG4-RD, there is a need for a validated, disease-specific PROM. In addition to providing the patient’s perspective on disease activity and severity in clinical practice and pharmacologic trials, PROMs can inform the development and assessment of non-pharmacologic interventions to improve quality of life and alleviate distress.
We aimed to develop and to assess the clinical and content validity a PROM for IgG4-RD that assesses symptoms as well as their associated distress.
MATERIALS AND METHODS
Instrument Development
Forty common IgG4-RD symptoms were identified by three board-certified rheumatologists with expertise in IgG4-RD (ZSW, CAP, JHS) and grouped based on their associated IgG4-RD manifestation. The Symptom Severity Index (SSI) includes a list of potential symptoms of IgG4-RD for which respondents indicate the frequency of each symptom (ranging from “None” to “Daily”) and the degree of distress (ranging from “None” to “Very Much”) associated with that symptom. A draft version of the SSI was administered on paper to a convenience sample of five patients with confirmed IgG4-RD evaluated in an ambulatory rheumatology clinic. The goal was to test the usability of the instrument in a clinic setting and to obtain feedback on the symptom list. Based on these comments, several gaps and redundancies were identified. The study was approved by the Mass General Brigham Institutional Review Board.
Qualitative Interviews
Given the feedback from the convenience sample, semi-structured qualitative interviews were performed with patients with IgG4-RD to expand the item set and explore issues that were absent. Interviews were performed by a research coordinator (TH) trained and supervised by an expert in survey methodology (KD) using open-ended questions regarding symptoms they attributed to IgG4-RD, associated distress, and other concerns. Interviews were recorded and transcribed.
Survey Validation
The SSI was revised based on our findings from these interviews. Specific words and phrases identified in the interviews were added to the instrument and a new section in which patients could indicate fear of worsening disease was added. Redundant symptoms were removed. The revised version of the SSI was administered to five subjects for feedback regarding face validity. Minor changes resulted in the final SSI, which was administered at least once to a convenience sample of 136 patients. These patients were evaluated at routine visits in an ambulatory rheumatology clinic between June, 2018 and August, 2021. To be included, patients had to have definite, probable, or atypical IgG4-RD based on the ACR/EULAR Classification Criteria for IgG4-RD, as previously described (6–8). These classification criteria have a specificity of 97.8% and sensitivity of 82.0%. Definite cases fulfilled these criteria. Patients who were considered probable fulfilled two parts of the ACR/EULAR Classification Criteria (i.e., had clinical involvement of a typical organ and were rigorously evaluated to ensure that they did not meet any exclusion criteria) but did not reach the threshold of 20 inclusion points according to the criteria (frequently retroperitoneal fibrosis in a typical pattern because no biopsy could be safely obtained or the biopsy was not informative). Patients who were considered atypical met the previously established pathological and immunostaining criteria for diagnosing IgG4-RD but presented with involvement of an atypical organ (e.g., breast, prostate) that was not considered in the ACR/EULAR Classification Criteria; they did not fulfill any of the ACR/EULAR Classification Criteria exclusion criteria (2).
Standardized quality of life instruments, including the SF-36, EQ-5D-5L, and feeling thermometer surveys (i.e., a patient global assessment), were administered at the same time as the SSI. Disease activity (Active or Inactive) at each visit was determined based on the clinician’s assessment of symptoms, physical examination findings, and any associated laboratory or imaging results. Details regarding demographics and organ involvement were extracted from a prospective registry.
Scoring
The version of the SSI assessed for validation includes 24 symptoms divided across nine categories which correspond with clinical manifestation (e.g., salivary glands, sinus and nasal area, orbits and lacrimal glands). Participants report any of the symptoms included in the SSI that they experienced in the preceding 30 days, but only those that are associated with organ involvement in that participant are counted when scoring the SSI. A 30 day lookback period was included because of the frequency with which patients are typically evaluated in clinical trials of IgG4-RD and the typical time that it takes to note a change with treatment. Organ involvement is determined by the clinician prior to scoring based on the findings from the history, physical exam, imaging, and laboratory results. For each symptom, a symptom distress score is calculated by multiplying symptom frequency (range “Never” [0 points] to “Every Day” [3 points]) by associated distress (range “None” [0 points] to “Very Much” [4 points]). Each symptom distress score is then summed to determine a total SSI score (potential range: 0 to 288). In addition, a fear score is calculated which is measured by multiplying the symptom frequency for the question assessing fear by the amount of distress associated with that symptom. As part of the assessment, participants may report other symptoms but these are not scored. Participants also indicate which three symptoms in the SSI are the most important to them, but these rankings are not considered when scoring the SSI.
Analysis
Continuous data are reported using mean and standard deviation (SD) or median and interquartile range (IQR), as appropriate. Categorical variables are reported as N (%). We analyzed the first SSI completed by each participant. In those who had at least one survey available at a time of inactive disease and a time of active disease, we assessed the difference in scores between these two times. Convergent validity was tested using Pearson correlation coefficients. Known-group validity was determined using a paired Wilcoxon-Sign Rank Test. SAS version 9.4 was used for all analyses. A p < 0.05 was considered to be statistically significant.
RESULTS
Survey Development and Qualitative Interviews
Semi-structured qualitative interviews with twenty subjects with IgG4-RD were conducted and transcribed between August, 2018 and January, 2019. Subjects were predominantly male (13, 65.0%), White (16, 80.0%), and had a mean (SD) age of 62.8 (14.0) years (Supplemental Table 1). Of the 40 symptoms included in the original version of the SSI, subjects recounted experiencing 24. Thematic saturation was reached once n=20 subjects were interviewed as the content of discussion became repetitive in the final n=5 interviews and agreement was reached among investigators. In addition to these symptoms, subjects expressed several additional sources of distress which were not captured in the draft SSI, including fear of worsening disease, diagnostic uncertainty, and fear of malignancy (Table 1).
Table 1.
Insights and Quotations from Qualitative Interviews
| Insights | Quotations |
|---|---|
| Patients have fear of worsening disease, comorbidities, or disease progression | “I guess the frustrating thing as a patient about the disease, or other diseases that probably carry the same frustration, is the not knowing when it’s going to come back and the fear of not catching it in time to prevent some other catastrophic problem.” (60–65-year-old Male; involvement: pancreas, prostate, lungs, sinuses, lymph nodes, salivary gland, thyroid, renal) |
| “I’m always curious about IgG4 and what might happen to me. Will I have whatever you call it, a relapse? Or will my IgG4 level go back up, I don’t know.” (75–80-year-old Male; involvement: cholangitis, pancreas, prostate, salivary, LAD) | |
| “And they know IgG4 is a disease that can disappear just as well as it appears, and who knows why that is? I do know that-- I always felt it was from the rash, but we'll tell as time goes by if it comes back.” (65–70-year-old Male; involvement: orbital) | |
| “[Regarding what is most important to him about his IgG4-RD] Definitely the pains and the worry that it would expand and then get into your organs” (65–70-year-old Male; involvement: orbital) | |
| “[T]he more education you can offer to the medical world and the more education you can offer to patients, it takes the fear factor out of it” (60–65-year-old Male; involvement: pancreas, prostate, lungs, sinuses, lymph nodes, salivary gland, thyroid, renal) | |
|
| |
| There is diagnostic uncertainty and misdiagnosis among IgG4-RD patients. | “I really think that the […] process, the way it went, go get a … poke a hole in your eye and poke a hole and take out lymph [nodes], and then, ‘Oh none of that worked, [laughter] so go to the rheumatologist.’ I don’t know.” (65–70-year-old Male; involvement: orbital) |
| “prior to [my diagnosis], I had been pursuing this for 30 years. 3–0 years. So it wasn’t just something that happened recently” (60–65-year-old Male; involvement: orbital) | |
| “I just was concerned. I knew something. I knew my body was trying to tell me something. […] So I was concerned because I just didn’t know what was happening. I didn’t know what was wrong.” (60–65-year-old Female; involvement: retroperitoneal fibrosis) | |
|
| |
| Patients and physicians, including most rheumatologists, are unfamiliar with what IgG4-RD is. | “I think the only reason I was diagnosed is I had the right doctor and had the right conversation. […] My rheumatologist had heard of it, had never had a patient who had it. All my previous doctors didn’t even know to test for it” (60–65-year-old Male; involvement: pancreas, prostate, lungs, sinuses, lymph nodes, salivary gland, thyroid, renal) |
| “I go online and google IgG4 and whatever it is just to see whether there’s any kind of relationship.” (60–65-year-old Male; involvement: pancreas, prostate, lungs, sinuses, lymph nodes, salivary gland, thyroid, renal) | |
| “I was concerned about why this was happening and to just figure out what’s causing it because something has to be causing it” (40–45-year-old Female; involvement: salivary and lacrimal glands) | |
|
| |
| IgG4-RD may raise concern for malignancy or be misdiagnosed as malignancy which causes distress for patients. | “The surgeon said that effectively it was so bad that he could not operate and do anything. And then the oncologist said I immediately need[ed] to get chemo.” (75–80-year-old Male; involvement: cholangitis, pancreas, prostate, salivary, LAD) |
| “Because my oncologist was apologetic that we diagnosed 10 years ago that I had [lymphoma], where[as] now, that was probably not the case. That it was probably IgG4 that was just misdiagnosed as [lymphoma]” (60–65-year-old Male; involvement: submandibular glands, retro-orbital space, lacrimal glands, lymph nodes, paravertebral masses, RPF, renal cortical lesions, prostate) | |
| “I had a lot of distress because I really thought that I had pancreatic cancer. ” (60–65-year-old Male; involvement: pancreas, prostate, lungs, sinuses, lymph nodes, salivary gland, thyroid, renal) | |
Fear of worsening disease
Subjects expressed fear that their disease would worsen, progress, or, for those patients in remission, relapse. Concern about the unpredictability of IgG4-RD was articulated by 8 subjects, resulting in the addition of a question for patients to indicate fear of worsening disease. The addition of the fear score allows for further understanding of distress associated with IgG4-RD.
“I guess the frustrating thing as a patient about the disease, or other diseases that probably carry the same frustration, is the not knowing when it’s going to come back and the fear of not catching it in time to prevent some other catastrophic problem.” (60–65-year-old Male; involvement: pancreas, prostate, lungs, sinuses, lymph nodes, salivary gland, thyroid, renal)
“[Regarding what is most important to him about his IgG4-RD] Definitely the pains and the worry that it would expand and then get into your organs” (65–70-year-old Male; involvement: orbital) (Table 1).
Diagnostic uncertainty
Subjects often recounted delays in the time it took for their providers to consider or diagnose IgG4-RD. From their perspectives, subjects felt that the diagnostic process was delayed by a lack of awareness among their providers of IgG4-RD.
“I think the only reason I was diagnosed is I had the right doctor and had the right conversation. […] My rheumatologist had heard of it, had never had a patient who had it. All my previous doctors didn’t even know to test for it” (60–65-year-old Male; involvement: pancreas, prostate, lungs, sinuses, lymph nodes, salivary gland, thyroid, renal)
“prior to [my diagnosis], I had been pursuing this for 30 years. 3–0 years. So it wasn’t just something that happened recently” (65–70-year-old Male; involvement: orbital) (Table 1).
Fear of malignancy
In particular, many subjects recounted experiences of having had suspected or even having been diagnosed with a malignancy, contributing to distress.
“The surgeon said that effectively it was so bad that he could not operate and do anything. And then the oncologist said I immediately need[ed] to get chemo.” (75–80-year-old Male; involvement: cholangitis, pancreas, prostate, salivary, LAD)
“I had a lot of distress because I really thought that I had pancreatic cancer. “ (60–65-year-old Male; involvement: pancreas, prostate, lungs, sinuses, lymph nodes, salivary gland, thyroid, renal) (Table 1).
Symptom and Distress Burden
The final version of the SSI (Supplemental Material) was administered at routine clinic visits between June, 2018 and August, 2021 to 136 participants, who were predominantly male (88, 65%) and white (109, 80%), and had a mean (SD) age of 59 (14) years (Table 2). Of the 136 participants, 98 (72%) had definite IgG4-RD, 28 (21%) had probable IgG4-RD, and 10 (7%) had atypical IgG4-RD. Common organ involvement observed in participants included pancreas or biliary tract (73, 54%), salivary gland (57,42%), kidney (54, 40%), orbit (40, 29%), retroperitoneal fibrosis (31, 23%), lung (20, 15%), sinus (14, 10%), and prostate (9, 7%). Multi-organ involvement, defined as at least 3 organs, was observed in 80 (59%) participants, while 56 (41%) had only one or two organs involved. There were 84 (62%) participants with active disease at the time of their first survey and 48 (35%) participants with inactive disease at the time of their first survey. The survey was taken more than once by 52 (38%) participants.
Table 2.
Demographics and Disease-Specific Features
| At least one survey | One survey during active and inactive disease | |
|---|---|---|
|
| ||
| N | 136 | 52* |
| Classification Criteria (N, %) | ||
| IgG4-RD | 98 (72) | 40 (77) |
| Probable IgG4-RD | 28 (21) | 10 (19) |
| Atypical IgG4-RD | 10 (7) | 2 (4) |
| Male | 88 (65) | 36 (69) |
| Age at SSI Completion (mean, SD) | 59 (14) | 57 (13) |
| Race (N, %) | ||
| White | 109 (80) | 32 (62) |
| Black | 8 (6) | 1 (2) |
| Asian | 13 (10) | 4 (8) |
| Other | 3 (2) | 2 (4) |
| Unknown | 3 (2) | 13 (25) |
| Hispanic or Latino | 16 (12) | 8 (15) |
| Organ Involvement | ||
| Single or Two Organs | 56 (41) | 23 (44) |
| Three or More Organs | 80 (59) | 29 (56) |
| Selected Organ Involvement | ||
| Orbit | 40 (29) | 14 (27) |
| Sinus | 14 (10) | 5 (10) |
| Salivary | 57 (42) | 25 (48) |
| Lung | 20 (15) | 7 (13) |
| Pancreas or Biliary | 73 (54) | 29 (56) |
| Prostate | 9 (7) | 3 (6) |
| Retroperitoneal Fibrosis | 31 (23) | 10 (19) |
| Kidney | 54 (40) | 22 (42) |
| Disease Activity at First Survey | ||
| Active Disease | 84 (62) | N/A |
| Remission | 48 (35) | N/A |
At the time of the first survey, 123 (90%) participants reported at least one symptom and 120 (88%) reported experiencing any distress associated with a symptom (Figures 1A and 1B). Of these participants, 19 (14%) experienced the symptoms a few days a month, 38 (28%) a few days a week, and 66 (49%) every day. Levels of distress were characterized as a little bit (45, 36%), somewhat (29, 23%), quite a bit (27, 22%), and very much (20, 16%). The burden of symptoms and distress varied across disease sites (Figure 2). Participants with orbital involvement experienced the greatest burden of symptoms with 18 (81.82%) of participants with orbit involvement reporting any symptom, followed by those with sinus (6, 75%) and respiratory (11, 79%) involvement (Figure 2A, Supplementary Figure 1A). Among those with salivary or gastrointestinal involvement, two of the most commonly affected organs in this cohort, 25 (71%) and 36 (72%) participants reported symptoms. Among all participants, constitutional symptoms were common (70, 83%). With regard to distress (Figure 2B, Supplementary Figure 1B), all participants with sinus or prostate symptoms found them distressing and, similarly, most participants with any symptom associated with other manifestations experienced any amount of distress. The greatest levels of distress (“Very Much”) were observed in participants with orbital (4, 22%), sinus (1, 17%), or respiratory involvement (2, 18%). High levels of distress were also observed among patients with constitutional symptoms (9, 13%). Fear of worsening disease was reported by 67 (49%) participants.
Figure 1.
Symptom frequency (1A) and distress (1B) at the time of the first survey
Figure 2.
Distribution of Symptom (2A) and Distress (2B) by Organ at First Survey
Survey Validity
At the time of the first survey, the median (IQR) SSI score was 6.5 and the range was 3.0 to 18.0 (Supplementary Figure 2). Those with active disease at the time of their first survey had a higher score than those with inactive disease, though this did not achieve statistical significance (9 [3,19] vs 4 [3,16], respectively, p=0.1, Figure 3A). Among those who completed the survey during a period of active disease and during a period of inactive disease, the median SSI score during active disease was significantly higher than the score during inactive disease (15 [6,26] vs 3 [2,14], respectively, p=0.008, Figure 3B). In the same group of participants, the fear score during periods of active disease and inactive disease was similar (4 [2,8] vs 3 [1.5,5], p=0.6, Figure 3C).
Figure 3.
SSI in Active Disease vs Inactive Disease Between Individuals (A) and Within Individuals (B). Fear Score in Active Disease vs Inactive Disease Within Individuals (C)
There were strong inverse correlations between the SSI score and the SF-36 (r= −0.51, p<0.001), EQ-5D (r= −0.48 p<0.001), and the feeling thermometer (r= −0.53, p<0.001), indicating that having more symptoms and distress associated with manifestations of IgG4-RD was associated with lower health-related quality of life. In addition, the SSI score correlated moderately with the SF-36 scales for role limitations due to physical health (r= −0.39, p<0.001) and emotional problems (r= −0.23, p=0.0098). Findings regarding the correlation of SSI scores with generic measures of quality of life were similar when these correlations were assessed after stratifying the cohort into tertiles. The fear score had modest correlations with the SF-36 (r= −0.25, p<0.001), EQ-5D (r= 0.31, p=0.01), and the feeling thermometer (r= −0.28, p=0.02). The fear score did not have strong correlations with the role limitations due to physical (r= −0.18, p=0.1) and emotional problems (r= −0.21, p=0.08).
DISCUSSION
This is the first study to develop and assess the clinical and content validity of a patient-reported outcome measure that assesses symptoms and distress in IgG4-RD. Approximately 9 out of 10 patients with IgG4-RD experience symptoms and distress related to their condition and many identify fear as a common experience during their journey. The Symptom Severity Index (SSI) has face validity among patients and experts. In addition, SSI scores strongly correlate with generic measures of health-related quality of life and are different among those with active as opposed to inactive disease.
The frequent burden of symptoms and associated distress in IgG4-RD probably reflects a combination of effects from active disease as well as potential damage from the disease and its treatment (9, 10). For instance, patients with pancreatobiliary disease may experience jaundice during active disease but have symptoms of pancreatic insufficiency during active and inactive disease because of damage to the pancreas from prior inflammation or even a Whipple procedure. Even during periods of inactive disease, many patients reported symptoms and distress at sites affected by their IgG4-RD. Differentiating active disease from damage remains challenging in IgG4-RD but the improvement in the SSI between active and inactive disease states suggests that some portion of symptoms and distress measured by the SSI are impacted by treatment. Though this has been previously demonstrated in clinical trials using the IgG4-RD Responder Index as an outcome measure (11–13), it has not been assessed systematically from the perspective of the patient, as in this study. These findings highlight the need for more effective treatment and management strategies in IgG4-RD as well as the potential utility of the SSI as a patient-reported outcome measure for use in future clinical trials assessing treatments.
An unexpected finding during the development of the SSI was the frequency with which patients reported fear associated with IgG4-RD. It is important to note that fear per se was not queried specifically in interviews with patients; rather, patients voiced their experience with fear without prompting. When collected prospectively, 49% of patients at the time of their first survey reported fear of developing more serious or severe disease in the previous 30 days. This finding highlights the burden of this experience among patients with IgG4-RD and the importance of identifying novel strategies to address fear and its associated distress. Indeed, though the SSI score associated with fear decreased between active and inactive disease, the difference was minimal and did not reach statistical significance. Therefore, treatment of IgG4-RD alone may be insufficient in many for addressing fear and the associated distress. In addition to considering mental health interventions, education about IgG4-RD and the enhancement of patient-focused resources may alleviate some fear.
The burden of symptoms and distress varied across manifestations of IgG4-RD but in nearly every category, more than half of patients with an associated disease manifestation in that category had symptoms at least a few days a month. Among those with symptoms, far more than half experienced distress associated with their symptoms. Moreover, the overall burden of symptoms and distress as measured by the SSI correlated strongly with generic health-related quality of life measures, highlighting the negative impact of symptoms on quality of life. In a previous study, we found that patients with IgG4-RD frequently endorsed symptoms of depression and distress, the need for resources to help address emotional concerns and improve self-care, as well as the impact of their disease on their life (14). Additional studies are needed to determine the degree to which such targeted interventions may improve the burden of symptom distress and to understand their associations with quality of life in this vulnerable population.
The SSI queries patients regarding symptoms related to common manifestations of IgG4-RD. In earlier versions of the survey, patient feedback indicated that the length of the survey was an obstacle which prompted us to focus on the more common manifestations reported during individual interviews and in our clinical experience. Symptoms and distress experienced by patients with more rare or atypical manifestations of IgG4-RD (e.g., pachymeningitis, breast mass) may therefore not be captured effectively by the SSI. In future steps, the SSI may be adapted to extract symptoms and distress associated with rare or atypical manifestations, as needed. In the current version of the SSI, other symptoms can be reported by patients but require adjudication for association with a manifestation of IgG4-RD which may limit the usability of the SSI in large clinical trials and other studies. As such, they are not currently considered when scoring the SSI. The SSI also asks patients to rank their most bothersome symptoms which can be used by clinicians to prioritize specific symptoms or sources of distress; these responses are not scored.
Our study has a number of important strengths. We followed sequential steps to develop and validate a novel patient-reported outcome measure, incorporating patient input and feedback in the development of the instrument in addition to that of experts in the field. To develop and validate the SSI, we included patients from a large clinical center of excellence which manages patients with diverse IgG4-RD manifestations. In contrast to generic health-related quality of life measures, the SSI is disease-specific and can be used to track symptoms and distress attributable to IgG4-RD manifestations. While the IgG4-RD Responder Index assesses disease activity from the physician’s perspective, the SSI reflects the patient experience and can be used to assess the burden and impact of active disease, disease- or treatment-related damage, as well fear on patients.
Despite these strengths, our study has important limitations. First, the development and validation of the SSI was performed at a single center which may limit its generalizability. However, our center has one of the largest cohorts of IgG4-RD patients in the world and manages patients with diverse manifestations. The single center nature of the study may select for patients with more severe symptoms or disease. Second, as discussed, common symptoms and associated distress are queried in the SSI. In future versions, adaptations to assess the burden of symptom and distress related to less common manifestations may be considered. Third, we investigated the validity of the SSI, in part, by comparing the SSI during periods of active disease to that measured during periods of inactive disease but not necessarily prior to and after treatment.
Additional studies are needed prior to the routine use of the SSI in clinical trials. First, prospectively administering the SSI prior to and after treatment initiation to investigate its ability to discriminate between treatment arms (e.g., effective treatments vs placebos) as well as its longitudinal validity when compared with generic measures of quality of life will be important. . Second, an assessment of the reliability of the SSI is an important avenue for future investigation. Third, as more patients complete the SSI, including those with less common manifestations, additional analyses (e.g., factor analysis, weighting) will be helpful for optimizing the approach to scoring and identifying potential subscales.
In conclusion, we developed and assessed the clinical and content validity of the SSI, a novel patient-reported outcome measure. Using the SSI, we found that symptoms and associated distress are common in a large cohort of patients with diverse IgG4-RD manifestations and varying stages of disease activity. The SSI can be used to systematically measure and monitor the burden of symptoms and distress in IgG4-RD in day-to-day practice and clinical trials. Effective management strategies, including both pharmacologic therapies and mental health interventions, may improve the burden of symptoms and distress in IgG4-RD.
Supplementary Material
Acknowledgements:
The authors would like to thank Dr. Michael Putman for sharing code to create some of the figures used in this manuscript.
Financial Disclosures:
ZSW reports research support from Bristol-Myers Squibb and Principia/Sanofi and consulting fees or advisory board fees from Viela Bio, Zenas BioPharma, Horizon, Novartis, Visterra/Otsuka, Shionogi, and MedPace. ZSW and JHS receive royalties for use of the Symptom Severity Index.
Funding/Support:
ZSW is funded by NIH/NIAMS [K23AR073334, R03AR078938] and the Rheumatology Research Foundation [K Supplement]. This work was also conducted while ZSW was supported by a Scientist Development Award from the Rheumatology Research Foundation. GK is supported by T32 AR007258. ZSW, JHS, and CAP received support from NIH/NIAID [UM1 AI144295].
Footnotes
Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
REFERENCES
- 1.Stone JH, Zen Y, Deshpande V. IgG4-related disease. N Engl J Med. 2012;366:539–51. [DOI] [PubMed] [Google Scholar]
- 2.Wallace ZS, Zhang Y, Perugino CA, Naden RL, Choi HK, Stone JH, et al. Clinical phenotypes of IgG4-related disease: an analysis of two international cross-sectional cohorts. Ann Rheum Dis. 2019;78:406–12. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Wallace ZS, Khosroshahi A, Carruthers MD, Perugino CA, Choi H, Campochiaro C, et al. An international multispecialty validation study of the IgG4-related disease responder index. Arthritis Care Res (Hoboken). 2018;70:1671–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Ware JE Jr., Sherbourne CD. The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Med Care. 1992;30:473–83. [PubMed] [Google Scholar]
- 5.Herdman M, Gudex C, Lloyd A, Janssen M, Kind P, Parkin D, et al. Development and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L). Qual Life Res. 2011;20:1727–36. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Wallwork R, Perugino CA, Fu X, Harkness T, Zhang Y, Choi HK, et al. The association of smoking with IgG4-related disease: a case-control study. Rheumatology (Oxford). 2021;60:5310–17. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Sanders S, Fu X, Zhang Y, Perugino CA, Wallwork R, Della-Torre E, et al. Lifetime allergy symptoms in IgG4-related disease: a case-control study. Arthritis Care Res (Hoboken). 2022;74:1188–95. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Wallace ZS, Naden RP, Chari S, Choi HK, Della-Torre E, Dicaire JF, et al. The 2019 American College of Rheumatology/European League Against Rheumatism classification criteria for IgG4-related disease. Ann Rheum Dis. 2020;79:77–87. [DOI] [PubMed] [Google Scholar]
- 9.Katz G, Stone JH. Clinical perspectives on IgG4-related disease and its classification. Annu Rev Med. 2022;73:545–62. [DOI] [PubMed] [Google Scholar]
- 10.Wallace ZS, Deshpande V, Mattoo H, Mahajan VS, Kulikova M, Pillai S, et al. IgG4-related disease: clinical and laboratory features in one hundred twenty-five patients. Arthritis Rheumatol. 2015;67:2466–75. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Carruthers MN, Topazian MD, Khosroshahi A, Witzig TE, Wallace ZS, Hart PA, et al. Rituximab for IgG4-related disease: a prospective, open-label trial. Ann Rheum Dis. 2015;74:1171–7. [DOI] [PubMed] [Google Scholar]
- 12.Della-Torre E, Lanzillotta M, Campochiaro C, Di-Colo G, Mancuso G, Capurso G, et al. Efficacy and safety of rituximab biosimilar (CT-P10) in IgG4-related disease: an observational prospective open-label cohort study. Eur J Intern Med. 2021;84:63–7. [DOI] [PubMed] [Google Scholar]
- 13.Matza MA, Perugino CA, Harvey L, Fernandes AD, Wallace ZS, Liu H, et al. Abatacept in IgG4-related disease: a prospective, open-label, single-arm, single-centre, proof-of-concept study. The Lancet Rheumatology. 2022;4:e105–e12. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Wallace ZS, Cook C, Finkelstein-Fox L, Fu X, Castelino FV, Choi HK, et al. The association of illness-related uncertainty with mental health in systemic autoimmune rheumatic diseases. J Rheumatol. 2022;49:1058–66. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.