Patient perspectives on health care provider practices leading to an axial spondyloarthritis diagnosis: an exploratory qualitative research study

BACKGROUND: The average time to a diagnosis for people with axial spondyloarthritis (axSpA) is 7-10 years. Delayed diagnosis may result in increased structural damage, worse physical function, and worse quality of life relative to patients with a timely axSpA diagnosis. Understanding patient experiences may provide insights for how to reduce diagnostic delays. OBJECTIVE: To provide foundational knowledge about patient experiences with healthcare providers leading to an axSpA diagnosis. METHODS: We conducted an exploratory qualitative research study with six focus groups interviews with participants recruited from three rheumatology clinics within the United States (MA (n = 3); CO (n = 2); PA (n = 1)) that included a total of 26 adults (10 females, 16 males) with rheumatologist confirmed diagnosis of axSpA in 2019. Focus groups were ~ 2 h, audio recorded, transcribed, and subject to dual coding. The codes reviewed were in relation to the patients\u27 diagnostic experiences. RESULTS: Patients described frustrating and lengthy diagnostic journeys. They recognized that the causes of diagnostic delays in axSpA are multifactorial (e.g., no definitive diagnostic test, disease characteristics, lack of primary care provider\u27s awareness about axSpA, trust). Patients described how doctors minimized or dismissed complaints about symptoms or told them that their issues were psychosomatic. Patients believed the healthcare system contributed to diagnostic delays (e.g., lack of time in clinical visits, difficulty accessing rheumatologists, health insurance challenges). Advice to physicians to reduce the diagnostic delay included allowing time for patients to give a complete picture of their illness experience, listening to, and believing patients, earlier referral to rheumatology, provision of HLA-B27 gene testing, and that physicians need to partner with their patients. CONCLUSIONS: Patients desire a definitive test that could be administered earlier in the course of axSpA. Until such a test is available, patients want clinicians who listen to, believe, and partner with them, and who will follow them until a diagnosis is reached. Educating primary care clinicians about guidelines and referral for diagnosis of axSpA could reduce diagnostic delay

IL-6 promoted intestinal epithelial proliferation in wound biopsy model.

<p>(A) WT mice were biopsy injured in the distal colon. Plot of the relative levels of IL-6 mRNA expression in the wound bed (relative to uninjured tissue) for various times after injury. N = 2–3 WT mice with a total of 4-6 wounds/time point. Data were shown as average ± SEM. One-way analysis of variance: F = 5.68, <i>P</i><0.01 (B) Cartoon depicting the microanatomy of a wound at day six post-biopsy; AC  =  adjacent crypts (green area); WC  =  wound channels (blue area); WAE  =  wound-associated epithelium overlying the wound bed (pink area). (C) Colonic sections of wounds from <i>IL-6^+/−</i> and <i>IL-6^-/-</i> mice at day six post-injury stained with mAb to BrdU (labels S-phase cells, red), mAb to β-catenin (labels epithelium, green), and bis-benzimide (nuclei, blue). Bars = 500 µm. (D) Quantification of the number of BrdU positive cells/wound adjacent crypts. Data were graphed as average ± SEM. One way analysis of variance: F = 10.5, p<0.0001. Means with different letters are significantly different by Bonferroni's multiple comparison test.</p

IL-6 expression was increased in human colons at sites of perforation.

<p>Tissue that was surgically resected from patients who suffered large bowel perforation was evaluated for IL-6 expression by <i>in situ</i> hybridization. Eleven cases were evaluated (8 males with trauma due to gun-shot wounds, ages 16–33; 1 female surgical trauma, age 45; and 2 females with diverticulitis, ages 72 and 79). (A) Representative staining from a patient with diverticulitis is shown at 20X and 100X, respectively. Bars = 100 µm. Arrows indicate IL-6+ cells with lymphocyte morphology. (B) Four high-powered fields with well-oriented crypts were evaluated for IL-6+ cells in the epithelial layer at the site of perforation and at the distal resection margin. The average ratio of IL-6+ cells in the perforation versus distal site ± SEM was shown. An unpaired student's t-test was used for statistical analysis; *, <i>P</i> = 0.02.</p

Inhibition of IL-6 resulted in more severe colitis and inhibition of intestinal epithelial proliferation.

<p>Colitis was induced in <i>dnKO</i> and <i>IL-10rb^+/-</i> littermate controls by co-housing. On day zero and three times weekly, mice were injected intraperitoneally with 500 µg of either anti-IL-6 mAb or control IgG mAb. Two independent experiments were performed with 8-9 mice/group. (A) Plot of the average percent of starting weight ± SEM shown for indicated groups of mice. Mice were weighed every three days. (B) Representative H+E stained sections of descending colons at day 9 post co-housing. Bars = 500 µm. Black dotted lines outline remaining crypts in the <i>dnKO</i> anti-IL-6 mAb treated mouse histology. (C) Graph of the average number of descending colonic crypts per high-powered field ± SEM. (D) At day 9 post-co-housing, mice were injected with BrdU one hour before sacrifice. Representative colonic sections stained with mAb to BrdU and detected with fluorescently conjugated antibodies were shown. The white dotted lines delineate crypts. Bars = 100 µm. (E) Graph of the average number ± SEM of BrdU positive cells per crypt. (F) Graph of the average ± SEM number of apoptotic bodies/crypt. One-way analysis of variance: (A) F = 3.5, <i>P</i><0.05 (for day 9 weights); (C) F = 57.36, <i>P</i><0.0001; (E) F = 17.92, <i>P</i><0.0001; (F) F = 10.87, <i>P</i><0.0001. Means with different letters are significantly different by Bonferroni's multiple comparison test.</p

Intraepithelial lymphocytes were a source of IL-6 early after injury.

<p>(A) Biopsy of the colon mucosa was performed in WT mice to create small wounds. IL-6 expression in the wound bed and adjacent tissue was evaluated by <i>in situ</i> hybridization one day after biopsy. Representative images were shown. Bars = 200 µm. Colored bars above wound images indicate areas of the wound bed as depicted in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0114195#pone-0114195-g004" target="_blank">Figure 4B</a>. (B) Co-localization by immunofluorescence was performed for IL-6 (red), CD3ε (green), and bis-benzimide (blue) on colon tissue from <i>dnKO</i> mice at day 6 after co-housing. Representative staining was shown at 63X. Bar = 200 µm. (C) Epithelial cells were harvested from <i>dnKO</i> mice on day 6 after co-housing, stained for T cell markers and IL-6, and assessed by flow cytometry. Representative dot plots were shown. (D, E) CD3+ CD4- CD8- IELs were harvested from WT mice and stimulated <i>ex vivo</i> with 10 ng/ml PMA and 1 µg/ml ionamycin for 5 hours. (D) RNA was collected and evaluated by qRT-PCR for IL-6 expression. (E) Culture supernatants were harvested and evaluated for secreted IL-6 by electrochemilluminescence. Data were shown as the average IL-6 expression or protein ± SEM. A paired student's t-test was used to determine significance; *, <i>P</i><0.05.</p