Gout and comorbidity: a nominal group study of people with gout

Background Comorbidities are common in patients with gout, yet qualitative research is lacking. The study objective was to examine the impact of gout on comorbidities. Methods Nine nominal groups were conducted. Patients with gout discussed and rank-ordered their concerns in response to the question, “How does gout or its treatment affect your other conditions and their treatment?” Results Nine nominal groups had 45 gout patients, with mean age 61 years (standard deviation (SD) 10.7) and mean gout duration 14.9 years (SD 12). Of these, 62% were men, 45% African-American, 51% married and 63% were currently using allopurinol. The most frequently cited highly ranked concerns among the nine nominal groups were: (1) interaction of gout medication with medications for other medical conditions (three groups); (2) worsening of other medical comorbidities, including hospitalizations (seven groups); (3) worsening of anxiety and depression (three groups); (4) significant dietary changes for gout that contrasted with diet for other conditions (three groups); (5) new diseases diagnosed due to gout (three groups); (6) irreversible joint damage (three groups); (7) inability to exercise and weight gain (four groups); and (8) gout misdiagnosed as another health condition (three groups). Other domains ranked highly were: (1) impact of gout on daily life and activities, including the ability to work and social activities (six groups); (2) medication side effects, real and perceived (nine groups); (3) weight loss due to gout related to frequent flares (one group); and (4) cost and burden (three groups). Conclusions Gout and the medications used for its treatment have a significant effect on comorbidities and their management. These findings provide insights into potential targets for improving outcomes in patients with gout.

Corbin and Strauss developed the trajectory model further refined by Charmaz and others that includes three componentsbody (organ system and function), biographical time (explicit narrative that gives meaning and purpose to a person's life) and conceptions of self (role identity, social identity, etc.), i.e., the BBC chain [21,22]. A person enjoys a sense of health and wellbeing only when body, biographical time, and conceptions of self are in balance, interactively stabilizing and reinforcing one another [21][22][23]. By its effect on comorbidities, I hypothesized that gout might destabilize this BBC chain due to associated progressive loss of self from body failures (worsening of kidney or heart disease), failed performance and social isolation (suboptimal management of multiple comorbidities leading to an inability to function normally) [24]. Therefore, the aim of this formative study was to assess the effect of gout (and its treatment) on comorbidity, considering all aspects, using the nominal group technique (NGT), and assessing if this fits our proposed theoretical model, the trajectory model.

Study sample, NGT sessions, and analyses
Consecutive patients with at least one visit to the community-based clinic at the University of Alabama at Birmingham (UAB) between January 2016 and February 2017 for gout, identified by the presence of an International Classification of Diseases, ninth revision, common modification (ICD-9-CM) code, 274.xx, were invited for study participation. African-Americans and women were oversampled. Free parking, refreshments during the session, and a US$30 check were provided to each participant. The UAB Institutional Review Board (IRB) approved the study.
The NGT is a variant of the traditional focus group that taps the experiences, skills, and views of the participants. NGT has been used successfully in understanding participant views in several medical conditions and allows an in-depth examination of a single question [25][26][27][28][29][30][31]. NGT promotes even participation. NGT methods help in developing an inclusive list of issues related to a specific question followed by soliciting participant feedback on the relative importance of this list using a rank-ordering procedure [28,32]. This exercise facilitates representation of the implicit views of the group.
Patient nominal group sessions were conducted to understand the impact of gout on comorbidity. Each nominal group session was led by an experienced NGT moderator (JAS) [12,33] and lasted 1-1.5 hours. After informed consent, everyone gave brief introductions. Each participant was provided with the study question printed on top of a blank sheet of paper, which was also written on a flipchart: "How does gout or its treatment affect your other conditions and their treatment?" Participants were asked if the main question was clear and if they had any questions about it, which were addressed by the NGT moderator before starting each session. The NGT participants independently generated as many words or short phrases as possible in response to the question on a sheet of paper. All responses identified by each participant were recorded verbatim on a flip chart in large letters by the NGT moderator (JAS), so that they were visible to participants. Participants discussed and elaborated each response and combined responses that were similar, where appropriate. All participants rank-ordered the three responses deemed most important with scores from 1 to 3 on index cards, 3 being the highest rank score. A rank order was created for each nominal group based on total scores, with the highest score corresponding to the top rank.
All NGT discussions were recorded and fully transcribed by an administrative assistant (DF) and transcriptions were examined to identify discussion related to each response, which led to the creation of a comprehensive list of statements. Responses were compared to determine overlap and saturation of themes was confirmed.

Study participant characteristics
Nine nominal groups were conducted with 45 gout patients (range between 2 and 10 people per nominal group) with a mean age of 61 years (standard deviation 10.7), of which 62% were men, 45% African-American, 51% were married and 45% had a college degree (Table 1). Most patients also had at least one additional comorbidity (specific data not collected). Only 9% were on colchicine only and 2% were not receiving any gout medication; the remaining patients were using allopurinol, febuxostat or both. Almost two thirds were currently using natural supplements and 39% had had two or more gout flares in the last 6 months. Of the nine nominal groups, three consisted of all men, and one consisted of five women and one man (female predominant). There were no significant differences in mean age (standard deviation) and gout duration by race/ethnicity or gender, respectively: whites vs. African-Americans, 62.9 (11.0) vs. 61.8 (5.2) (p = 0.68) and 17.9 (11.6) vs. 12.3 years (9.3) (p = 0.09); men vs. women, 60.1 (11.8) vs. 62.3 (8.4) (p = 0.50) and 17.0 (11.1) vs. 11.2 years (9.5) (p = 0.08). A saturation of themes was achieved.
The top themes/concerns that emerged from each nominal group are listed in Table 2 (also see Appendix 1 for details). These themes mapped to body failure, the limitation of identity-relevant performances with a progressive loss of self and/or to social isolation. Despite specification of the question relating to the effect of gout or its treatment on their comorbid conditions and their treatments, several patients and groups chose to rank the overall effect of gout or its treatment on daily life, since they considered the overall wellbeing just as important as (or more important than) a specific disease, i.e., heart disease or hypertension. For the sake of clarity, the themes from nominal groups were divided into (1) the effect of gout/treatments on comorbidity and their treatment and (2) the general effect on overall wellbeing (in the subsequent sections). Letters (A to L) at the beginning of each theme correspond to those identified in the consecutive nominal groups (see Table 2), and therefore are not in a sequential order in each section.
The impact of gout or gout treatment on comorbidities and their management Interaction of gout medications with medications for other medical conditions (C) Three nominal groups ranked this among their top concerns. Participants reported interaction of gout medications with: (1) medications for their hypertension, making them less effective; (2) Gleevec (the market name for imatinib, an anti-cancer medication), with an inability to take Gleevec and colchicine together; (3) medications for concomitant diseases, leading to more fatigue; (4) grapefruit juice, since they were instructed not to take gout medications with grapefruit juice.

Worsening of other medical comorbidities, including hospitalizations (E)
Seven patient groups listed this among their top concerns. Patients described that gout flare and associated pain increased their blood pressure and heart rate and worsened their heart condition, eczema, and other medical conditions. Pain medications such as ibuprofen worsened heart conditions; and allopurinol interfered with diabetes mellitus control. Participants were hospitalized with gout flares that also affected their other conditions.   H. Gout crystals caused me the "kidney problem"-kidney damage -"They are like razor knives, they cut your tissueyour kidney, other organs"

Worsening of anxiety and depression (F)
Three patient groups listed this among their top concerns. Participants experienced worsening of depression and anxiety due to gout. Acute gout flare interfered with the ability to stay focused and increased the risk of depression.

Significant changes in diet with dietary restrictions that contrast with diet for other chronic conditions (G)
Three patient nominal groups listed this among their top concerns. Patients wanted to go on high protein diet for weight loss to help diabetes mellitus and heart conditions, or eat more fish or take fish oil for heart disease prevention, but these diets seemed to worsen gout. Many believed that the cabbage or dry beans that they wanted to eat for a heart-healthy diet increased the risk of gout flare, therefore the presence of gout interfered with the intake of the "healthy" foods that they liked for better comorbidity management and/or prevention of associated compliations.

New disease diagnosis due to gout (H)
Three patient nominal groups listed this among their top concerns. Patients had new diagnoses of kidney disease, hypertension, heart disease, sleep apnea, and kidney stone disease (urate stones and calcium stones), which they did not have before the diagnosis of gout. They believed that gout was the reason for them to have these new diseases.
Patients likened the urate crystals to "razor knives that cut through the tissues".
Irreversible joint damage due to arthritis and joint/tendon problems (I) Two patient nominal groups listed this among their top concerns. Patients experienced progressive joint symptoms and joint destruction, which put people at risk of joint replacement surgery, and led to progressive symptoms over time, sometimes leading to long hospitalizations.

Inability to exercise and weight gain (J)
Four patient nominal groups listed this among their top concerns. The gout flare pain immobilized people, and made it impossible for them to exercise and work out, which they needed to do regularly for a better management of other chronic conditions.
Gout confused with and diagnosed as another health condition (K) Three patient nominal groups listed this among their top concerns. Patients reported that their gout had been misdiagnosed as muscle sprain, rotator cuff tendinitis, or a leg clot. I. Joints wear out quicker because of gout-I had two joints repaired, in wrist and ankle 0 Each patient gave 3 points to the highest rank, 2 points to the second highest and 1 point to the third highest rank. In most cases, the number of total votes is the number of patients × 6, except in one case when the patient left before voting, due to transportation issues (NGT9) Domains C, E, F, G, H, and K mapped to body failure. Domains I and J mapped to body failure and failed performances.
The impact of gout or its treatment on daily life Impact of gout on daily life and activities, including the ability to work and social activities (A) Six of the nine groups listed this among their top concerns. Participants reported that gout interfered with mobility and independence and affected their ability to function, go shopping, doing yard work, housekeeping, driving, going out, or doing physical therapy for back pain or after joint replacement. Gout also influenced the ability to work, making patients immobile during a flare and making them need a cane and other assistive devices: "Nobody goes to work with gout". Gout made it difficult for participants to play with grandchildren, limited social life, made them quit hobbies, and forced some to not take long vacations or travel far.

Medication side effects, real and perceived (B)
All nine groups listed this among their top concerns. Most groups reported real side effects of treatments they experienced, and in many cases, the medication had to be discontinued due to the occurrence of the side effect. Side effects associated with medication reported by participants were: (1) allopurinol: nausea, allergic reaction, itching, rash, headache, or brain fog; (2) colchicine: problems with calcium levels, kidney function, diverticulitis, brain fog, dry mouth, stomach upset, or sun sensitivity; (3) non-steroidal anti-inflammatory drugs (NSAIDs): diverticulitis, leg swelling, acid reflux, kidney disease, gastrointestinal (GI) bleed, liver problems, or diarrhea; and (4) corticosteroids: weight gain, GI upset, leg swelling, or hip necrosis. One group also ranked high the worry about long-term side effects of various gout medications even in the absence of any experienced side effects.
Weight loss due to gout, not related to flares (D) One patient group listed this among their top concerns. Active gout with frequent flares was associated with weight loss.

Cost and burden (L)
Three patient nominal groups listed this among their top concerns. Patients complained that some medications for gout, such as Colcyrs (the market name for colchicine) were very expensive. They also found frequent physician and laboratory visits for monitoring burdensome.
Domains B, D, and L mapped to body failure. Domain A mapped to body failure, failed performances and social isolation.

Gender differences in the impact of gout on the lives of patients
No observable differences in ranking of themes by gender were noted, since similar themes were ranked highly by male vs. female-predominant nominal groups.

Discussion
This qualitative study focused on the impact of gout and its treatment on other health conditions (comorbidities) and their management. We achieved an adequate representation of African-Americans and women with gout, two understudied populations in gout. Several findings merit further discussion and add to the current knowledge, in the absence of previous qualitative work on this topic. We conducted nominal groups until saturation was achieved. We believe that the small sample size for three nominal groups (n = 2-3 people in each group), the global and broad nature of our question and the diverse socio-demographic composition of our sample with oversampling of African-Americans and women, may have led to the current need for more nominal groups (nine) than the usual number (4-5 nominal groups), before saturation of themes was achieved.
A majority of nominal groups (7/9) reported that gout was associated with worsening of other medical comorbidities, and hospitalizations. Gout flare was associated with worsening of blood pressure and heart conditions, and the use of gout medications was associated with lowered efficacy of medication for blood pressure control. Several patients were hospitalized with gout flares that also were associated with loss of optimal control of other comorbidities. A previous study reported that hospitalizations due to acute gout flares were longer in gout patients with renal failure, heart failure, osteoarthritis, or diabetes mellitus [34]. In addition, gaps in the inpatient management of gout [35] likely further contribute to a longer hospitalization. Thus, previous studies showed that there is a complex interaction of comorbidity and gout, which affect each other adversely and thus increase the risk of hospitalization and its duration. Nominal group participants noted that comorbidity management was affected adversely during an admission for gout flare, providing a further insight into mechanism of this problem/ challenge.
Three patient nominal groups listed new disease diagnoses due to gout among their top concerns. Patients reported that since their gout was diagnosed, they had received new diagnoses of kidney disease, hypertension, heart conditions, sleep apnea and kidney stone (urate stones and calcium) disease, which they did not have before the diagnosis of gout. They believed that gout was the reason for them to be developing these new diseases. A patient said: "Gout could lead to heart disease, diabetes, cholesterol problems and atherosclerosis". Hypertension, kidney disease, kidney stones, diabetes mellitus, heart disease and heart failure are common comorbidities in people with gout and hyperuricemia [8], as is metabolic syndrome [2]. Patients likened the urate crystals to "razor knives that cut through the tissues", a mechanism they thought could lead to some of these conditions. Three groups reported worsening of anxiety and depression due to gout. Patients reported both the negative effect of gout flares on anxiety and depression, their inability to concentrate during a gout flare, and the worry/ anxiety associated with having a gout flare at night. This study provides insight into why depression may be more prevalent in patients with gout who have frequent gout attacks or attacks in multiple joints [36].
The focus of our study was to assess the effect of gout or its treatment on other comorbidities and their treatment. Several groups ranked the overall effect of gout on general wellbeing, daily activities, and gout medicationrelated important issues, rather than the impact on a specific disease. Since our broad research objective was to truly assess the impact of gout or its treatment, we did not force patients or groups to only choose a specific disease when they felt more appropriate choosing the effect on overall wellbeing, function, and daily activities. General well-being is an extremely important aspect of patient exprience, and in most instances represents an overall summative and cumulative effect of various diseases, their treatments and complications, experienced by the patient at the current time.
All nine groups reported side effects, real and perceived, from gout medications. Cumulatively, patients had experienced side effects from each gout medication. These included the following adverse events: NSAID-associated renal failure, GI bleeding, leg swelling and heart problems; colchicine-associated GI upset, dry mouth and renal function problems; corticosteroid-associated weight gain, GI upset, leg swelling, hip necrosis; allopurinol-associated nausea, allergic reaction, itching, rash, headache and brain fog; and febuxostat-associated heart problems were reported as symptoms/comorbidities resulting from gout treatments. Many patients also worried about the longterm side effects of gout medications even in the absence of any current side effects. A majority of nominal groups (6/9) reported the impact of gout on daily life and activities, the ability to work, and social activities. It is interesting that this emerged as a theme, despite the fact that the question was focused on other (health) conditions and their treatment. When discussed explicitly with the patients, they indicated that their overall ability to perform daily activities and function is more important than discussing another health condition; and that this ability reflected the impact of all their health conditions. Patients not only had difficult with daily activities and the tasks they enjoyed, but they also had to take sick days due to gout flares. Patients also had difficulty with social activities, such as going out to eat (due to dietary restrictions), watch a ballgame with family and friends, or attend important family or social gatherings (due to the uncertainty of a gout flare). The significant impact of gout on patients' quality of life is well-known [12], and this study provides an in-depth insight into one mechanism for how and why this might actually happen.
These study findings must be interpreted considering the strengths and limitations of the study. Our findings may not be generalizable to all patients with gout, only those seeking health care. Over 80% of the patients were on urate-lowering therapy, a larger proportion than is reported in other gout cohorts, indicating that generalizability to populations with lower rates of treatment with ULTs may not be possible. The study sample more closely mirrors the epidemiology of gout in the USA [1] than many previous studies, which were focused on Caucasian men. Therefore, findings are generalizable to most patients with gout, who have a concomitant medical comorbidity. Another limitation is that patients described certain drug-disease interactions that have not been described previously such as allopurinol worsening diabetic control or gout medications (unspecified) rendering anti-hypertensive medication less effective, which are not consistent with previously known interactions/effects of these medications. These may represent the effect of other medications rather than the gout medications, i.e., patient misperception, or less likely, an unusual experience by a patient. We needed nine nominal groups to achieve theme saturation at least partially due to a small sample size for three nominal groups (n = 2-3 people in each group). Theme saturation can sometimes be achieved with a smaller number of groups. We conducted these small nominal groups realizing well that at least 4-5 people constitute a nominal group, since two of these three small nominal groups provided us with African-American patients, and the last nominal group helped us achieve saturation. The study strengths were the examination of a community clinic-based sample, inclusion of African-Americans and women with gout, and the focus on a single question.

Conclusions
In conclusion, this study assessed the impact of gout on comorbidity. We found that gout and its treatment affect patient comorbidities and their management and daily living in several ways. Most of the highly ranked related themes led to body failure and/ or negatively affecting patient's social role by limiting identity-relevant performances with a progressive loss of self, thus fitting the proposed theoretical model. This study provides insight into the effect of gout on comorbidity. Studies need to explore the interrelationships of gout and comorbidity, and whether comanagement can improve patient outcomes.  I. My joints are so sore now all the time, wondering if they are damaged due to (gout) flares 8 • Sometimes unable to do activities of daily living • Sometimes can't get to the doctor's appointment • Can't make it to the bathroom • I was off duty for 2 months due to gout flare B. Some of the gout medications such as prednisone can cause weight gain, diabetes and affect eyesight 8 • Bowel problems due to prednisone-pain in the belly • As far as the treatment goes, prednisone causes me to gain weight • I have been diagnosed with edema in the legs; I think medications (pain killers, prednisone) have something to do with it -could be the medication, doctor said • I had to take a lower dose of gout medication due to kidney problems • I am allergic to Neurontin, it caused face swelling and rash, when I was getting it for gout • NSAIDs cause bleeding • I was taking over the counter pain meds for gout, had kidney problems as a result E. I did not have high blood pressure until I was diagnosed with gout-not sure it caused it 9 • When you are having a flare, your BP goes way up • Indomethacin has contributed to my kidney disease-Indocin would reduce flares so I took it like candy • I would take it very day sometimes twice so that I could get to work in the military, started in 1983 and by 1993, they told me I had "shrunk kidneys"-I have been on dialysis since 2015 • Indocin caused 2 GI bleedings which cost me to need 4 units of blood • I tried taking Indocin but couldn't take it, it made me crazy • Having gout flares all the time, took Indocin, and was diagnosed with stomach ulcers twice • They tell you to take it (Naprosyn) on a full stomach, I took it once on empty stomach and had severe vomiting • Prednisone caused renal failure "stage 4 kidney disease: my doctor put me on the prednisone, and they couldn't get me off; every time they stop it, gout comes right back" Table 3 All themes and related main discussions for the effect of gout or its treatment on comorbidity or its treatment from all nominal groups (Continued) • Prednisone caused me to develop necrosis of both hip joints • Woke up 1 day, I could not walk, they x-rayed me told me I had arthritis. Then I went to see my rheumatologist, he sent me to the other doctor, and he told me I had hip necrosis. They had to do a hip replacement, it got infected with Staph, then they had to do it again-I was in hospital for months with that, a lot of antibiotics • I couldn't take Indocin due to stomach bleeds, so they put me on prednisone, and I had to have hip replacement for necrosis of the hip joint • Using medicines to subside gout has led to more arthritis which leads to taking more drugs and more side effects • If you have both gout and another type of arthritis, you have to take more drugs • I was put on Neurontin in addition to my gout medications H. Gout crystals caused me the "kidney problem"-kidney damage 3 • Crystals get filtered by your kidney • "They (crystals) are like razor knives, they cut your tissueyour kidney, other organs" L. The medication I take caused me to get my liver checked often 2 • I am on prednisone and also on cellcept for my scleroderma;

Availability of data and materials
We are ready to share the data with colleagues, after obtaining appropriate permissions from the UAB Ethics Committee, related to HIPAA and Privacy policies.
Authors' contributions JAS designed the study, developed the protocol and obtained IRB approval, conducted the nominal sessions, analyzed the voting by the participants and the data, wrote the first draft of the manuscript and revised it and made the decision to submit it. Table 3 All themes and related main discussions for the effect of gout or its treatment on comorbidity or its treatment from all nominal groups (Continued) • All medicine is designed to be one thing, but you know it could cause long-term side effects • That bothers me as well; I was on Uloric and I was worried about heart problems-They thought I was having a heart attack and I stopped it after that, and am not taking any medicine, just cherry extract now A. Limits going to work, activity and going out 5 • When my gout flares, I can not go to work • It's like age, "shuts you down" • Luckily, I am retired, but it interferes with going to other places • "Overall limits your experience of life" • It limits socializing • Used to enjoy going to Nashville, we cut down on the trips since my gout • Limits whether I can drive somewhere and go eat • Would always go with wife for shopping, now can't do that • Not going to the movies anymore, don't know when it will start • "It's like walking on glass to get to your car-would you do that, or would you rest at your home?" Each patient gave 3 points to the highest rank, 2 points to the second highest and 1 point to the third highest rank. In most cases, total votes is the number of patients × 6, except in one case when the patient left before voting, due to transportation issues Ethics approval and consent to participate The University of Alabama at Birmingham's Institutional Review Board approved this study (X120404005) and all investigations were conducted in conformity with ethical principles of research. All patients involved in the study gave consent to participate in the study.

Consent for publication
No individual person's data were presented in any form in this study and therefore no consent to publish is required.