Acute anterior uveitis (AAU) and the spondyloarthritis (SpA) subtypes ankylosing spondylitis, reactive arthritis and psoriatic arthritis are among the inflammatory diseases affected by the biology of ...the intestinal microbiome. In this Review, the relationship between AAU, SpA and the microbiome is discussed, with a focus on the major SpA risk gene HLA-B*27 and how it is associated with both intestinal tolerance and the loss of ocular immune privilege that can accompany AAU. We provide four potential mechanisms to account for how dysbiosis, barrier function and immune response contribute to the development of ocular inflammation and the pathogenesis of AAU. Finally, potential therapeutic avenues to target the microbiota for the clinical management of AAU and SpA are outlined.
Ocular Sarcoidosis Pasadhika, Sirichai; Rosenbaum, James T
Clinics in chest medicine,
12/2015, Volume:
36, Issue:
4
Journal Article
Peer reviewed
Open access
Sarcoidosis is one of the leading causes of inflammatory eye disease. Ocular sarcoidosis can involve any part of the eye and its adnexal tissues and may cause uveitis, episcleritis/scleritis, eyelid ...abnormalities, conjunctival granuloma, optic neuropathy, lacrimal gland enlargement, and orbital inflammation. Glaucoma and cataract can be complications from inflammation itself or adverse effects from therapy. Ophthalmic manifestations can be isolated or associated with other organ involvement. Patients with ocular sarcoidosis can present with a wide range of clinical presentations and severity. Multidisciplinary approaches are required to achieve the best treatment outcomes for both ocular and systemic manifestations.
Uveitis is a common complication of spondyloarthritis. The “phenotype” of the uveitis characteristic of ankylosing spondylitis (sudden onset, anterior, unilateral, recurrent, more often male) may ...differ from the phenotype often seen with either psoriatic arthritis or inflammatory bowel disease (insidious onset, anterior and intermediate, bilateral, chronic, and/or more often female). The frequency of uveitis is also much greater in association with ankylosing spondylitis than with either inflammatory bowel disease or psoriasis. Uveitis may affect the choice of therapy and can rarely be a complication of therapy. Uveitis and arthritis also co-exist in several animal models.
Objective
To investigate whether HLA–B27–mediated experimental spondyloarthritis (SpA) is associated with a common gut microbial signature, in order to identify potential drivers of pathogenesis.
...Methods
The effects of HLA–B27 on 3 genetic backgrounds, dark agouti (DA), Lewis, and Fischer, were compared, using wild‐type littermates and HLA–B7–transgenic Lewis rats as controls. Cecum and colon tissue specimens or contents were collected from the rats at 2, 3–4, and 6–8 months of age, and histologic analysis was performed to assess inflammation, RNA sequencing was used to determine gene expression differences, and 16S ribosomal RNA gene sequencing was used to determine microbiota differences.
Results
Both HLA–B27–transgenic Lewis rats and HLA–B27–transgenic Fischer rats developed gut inflammation, while DA rats were resistant to the effects of HLA–B27, and HLA–B7–transgenic rats were not affected. Immune dysregulation was similar in affected Lewis and Fischer rats and was dominated by activation of interleukin‐23 (IL‐23)/IL‐17, interferon, tumor necrosis factor, and IL‐1 cytokines and pathways in the colon and cecum, while DA rats exhibited low‐level cytokine dysregulation without inflammation. Gut microbial changes in HLA–B27–transgenic rats were strikingly divergent on the 3 different host genetic backgrounds, including different patterns of dysbiosis in HLA–B27–transgenic Lewis and HLA–B27–transgenic Fischer rat strains, with some overlap. Interestingly, DA rats lacked segmented filamentous bacteria that promote CD4+ Th17 cell development, which may explain their resistance to disease.
Conclusion
The effects of HLA–B27 on gut microbiota and dysbiosis in SpA are highly dependent on the host genetic background and/or environment, despite convergence of dysregulated immune pathways. These results implicate an ecological model of dysbiosis, with the effects of multiple microbes contributing to the aberrant immune response, rather than a single or small number of microbes driving pathogenesis.
Traditionally, the urinary tract has been thought to be sterile in the absence of a clinically identifiable infection. However, recent evidence suggests that the urinary tract harbors a variety of ...bacterial species, known collectively as the urinary microbiome, even when clinical cultures are negative. Whether these bacteria promote urinary health or contribute to urinary tract disease remains unknown. Emerging evidence indicates that a shift in the urinary microbiome may play an important role in urgency urinary incontinence (UUI). The goal of this prospective pilot study was to determine how the urinary microbiome is different between women with and without UUI. We also sought to identify if characteristics of the urinary microbiome are associated with UUI severity.
We collected urine from clinically well-characterized women with UUI (n = 10) and normal bladder function (n = 10) using a transurethral catheter to avoid bacterial contamination from external tissue. To characterize the resident microbial community, we amplified the bacterial 16S rRNA gene by PCR and performed sequencing using Illumina MiSeq. Sequences were processed using the workflow package QIIME. We identified bacteria that had differential relative abundance between UUI and controls using DESeq2 to fit generalized linear models based on the negative binomial distribution. We also identified relationships between the diversity of the urinary microbiome and severity of UUI symptoms with Pearson's correlation coefficient.
We successfully extracted and sequenced bacterial DNA from 95% of the urine samples and identified that there is a polymicrobial community in the female bladder in both healthy controls and women with UUI. We found the relative abundance of 14 bacteria significantly differed between control and UUI samples. Furthermore, we established that an increase in UUI symptom severity is associated with a decrease in microbial diversity in women with UUI.
Our study provides further characterization of the urinary microbiome in both healthy controls and extensively phenotyped women with UUI. Our results also suggest that the urinary microbiome may play an important role in the pathophysiology of UUI and that the loss of microbial diversity may be associated with clinical severity.
Uveitis is the most common, clinically apparent, extra-articular manifestation of axial spondyloarthritis. This review summarizes recent publications related to this form of uveitis.
Studies ...published since the start of 2015 address the worldwide prevalence of human leukocyte antigen (HLA) B27-associated uveitis, the prevalence of axial spondyloarthritis among patients with B27-associated acute anterior uveitis (AAU), the genetics of AAU and some of the clinical implications of AAU. Progress has been made in the treatment of uveitis in general and in the treatment of uveitis in association with spondyloarthropathy in particular. The pathogenesis of AAU might derive clues from the above as well as from an understanding of the microbiome and possibly from knowledge derived from uveitis in association with Ebola.
Although HLA B27-associated uveitis has been recognized since 1973, a variety of recent observations shed new light on this common clinical association with spondyloarthritis.
Objective
The HLA–B27/β2‐microglobulin (β2m)–transgenic (Tg) rat is a leading model of B27‐associated spondyloarthritis (SpA), and the disease is dependent on the presence of intestinal bacteria. ...Previous studies have shown that adult HLA–B27/β2m–Tg rats have an altered intestinal microbiota. This study sought to better define the age‐dependent changes to both mucosal immune function and dysbiosis in this rat model of SpA.
Methods
Intestinal contents were collected from wild‐type and HLA–B27/β2m–Tg rats postweaning (ages 3 and 6 weeks), at disease onset (age 10 weeks), and after the establishment of disease (ages ≥16 weeks). The microbial community structure was determined by 16S ribosomal RNA sequencing and quantitative reverse transcription–polymerase chain reaction (qRT‐PCR). Mucosal and systemic Th1, Th17, and Treg cell responses were analyzed by flow cytometry, as was the frequency of IgA‐coated intestinal bacteria. Intestinal expression of inflammatory cytokines and antimicrobial peptides (AMPs) was determined by qRT‐PCR.
Results
An inflammatory cytokine signature and elevated AMP expression during the postweaning period preceded the development of clinical bowel inflammation and dysbiosis in HLA–B27/β2m–Tg rats. An early and sustained expansion of the Th17 cell pool was specifically observed in the cecal and colonic mucosa of HLA–B27/β2m–Tg rats. Strongly elevated intestinal colonization of Akkermansia muciniphila and an increased frequency of IgA‐coated fecal bacteria were significantly associated with expression of HLA–B27 and arthritis development.
Conclusion
HLA–B27/β2m expression in this rat model renders the host hyperresponsive to microbial antigens from infancy. Early activation of innate immunity and expansion of a mucosal Th17 signature are soon followed by dysbiosis in HLA–B27/β2m–Tg animals. The pathologic processes of perturbed mucosal immunity and dysbiosis strongly merit further study in both prediseased and diseased populations of patients with SpA.
To provide recommendations for the use of anti-tumor necrosis factor α (TNF-α) biologic agents in patients with ocular inflammatory disorders.
Ocular inflammatory diseases remain a leading cause of ...vision loss worldwide. Anti-TNF-α agents are used widely in treatment of rheumatologic diseases. A committee of the American Uveitis Society performed a systematic review of literature to generate guidelines for use of these agents in ocular inflammatory conditions.
A systematic review of published studies was performed. Recommendations were generated using the Grading of Recommendations Assessment, Development, and Evaluation group criteria.
Numerous studies including controlled clinical trials have demonstrated that anti-TNF-α biologic agents (in particular infliximab and adalimumab) are effective in the treatment of severe ocular inflammatory disease. Based on these studies, the expert panel makes the following recommendations.
Infliximab and adalimumab can be considered as first-line immunomodulatory agents for the treatment of ocular manifestations of Behçet's disease. Infliximab and adalimumab can be considered as second-line immunomodulatory agents for the treatment of uveitis associated with juvenile arthritis. Infliximab and adalimumab can be considered as potential second-line immunomodulatory agents for the treatment of severe ocular inflammatory conditions including posterior uveitis, panuveitis, severe uveitis associated with seronegative spondyloarthropathy, and scleritis in patients requiring immunomodulation in patients who have failed or who are not candidates for antimetabolite or calcineurin inhibitor immunomodulation. Infliximab and adalimumab can be considered in these patients in preference to etanercept, which seems to be associated with lower rates of treatment success.
Four major medical societies involved with hydroxychloroquine (HCQ) therapy concur on the need for common principles and cooperation to minimize the risk of ocular toxicity. At a daily dosage of ≤5 ...mg/kg/day actual body weight, the risk of retinal toxicity from HCQ is <2% for usage up to 10 years. Widespread adoption of more sensitive testing techniques, such as optical coherence tomography and automated visual fields, by eye care providers will allow the detection of early toxicity and thus preserve the patient’s visual function. Baseline testing is advised to rule out confounding disease when a patient is started on HCQ. Annual screening with sensitive tests should begin no more than 5 years after treatment initiation. Providers should be sensitive to the medical value of HCQ, and not stop the drug for uncertain indications. It is important to note that effective communication among prescribing physicians, patients, and eye care providers will optimize the utility and safety of HCQ.
PURPOSE OF REVIEWThe term spondyloarthritis (SpA) encompasses a group of chronic inflammatory disorders of the joints, including ankylosing spondylitis, psoriatic arthritis, reactive arthritis, ...inflammatory bowel disease, juvenile SpA and undifferentiated SpA. These diseases can also present with uveitis, or intraocular inflammation, which can be controlled with biologics.
RECENT FINDINGSProfound success has occurred with the tumor necrosis factor-α inhibitors infliximab and adalimumab, moderate success with certolizumab pegol and golimumab and less encouraging results with etanercept. Promising results have also been demonstrated with interleukin-17 (IL-17) antagonists, such as secukinumab ixekizumab or combined IL-12 and 23 medications, such as ustekinumab.
SUMMARYIn cases of uveitis that require long-term control, biologics are an emerging and valuable class of medications for these patients, and may provide avenues to control both their underlying SpA and uveitis manifestations.
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