Anterior uveitis, inflammatory bowel disease, and ankylosing spondylitis in a HLA-B27-positive woman.

Abstract: A woman developed anterior uveitis at age 24, inflammatory bowel disease at age 29, and ankylosing spondylitis at age 45 by history. There were frequent recurrences. An HLA-B27 test was positive at age 53. The literature indicates that all of these conditions together in a HLA-B27-positive woman are uncommon. Physicians should be alert to the possibility that a patient might develop another of these associated diseases years after presentation of the first condition and educate their patients accordingly.

Key Words: acute anterior uveitis, inflammatory bowel disease, ankylosing spondylitis, HLA-B27

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The uncommon presence of anterior uveitis, inflammatory bowel disease, ankylosing spondylitis, and positive HLA-B27 serology in a single patient will be discussed with reference to the disparate specialty literature.

Case Report

A 36-year-old woman was seen with acute onset headache, photophobia, and a red right eye. There was a history of 6 previous episodes of acute anterior uveitis (AAU), or iritis, in one or the other eye since the age of 24. She had a past history of "ulcerative colitis" since the age of 29 that seemed to recur in winter parallel with recurrent anterior uveitis. She stated there had been only one or two Christmases without a simultaneous flare-up of anterior uveitis and inflammatory bowel disease (IBD).

She had 14 episodes of recurrent anterior uveitis over the next 22 years. During these episodes of AAU her visual acuity dropped as low as 6/15 but always recovered to 6/6 after appropriate treatment. Intraocular pressure was always normal except for brief elevations as a steroid responder.

Her anterior uveitis was characterized by +1 to +2 circulating microcells and +2 flare. Twice a heavy fibrin clot filled the pupil. There were no keratic precipitates. Iris adhesions to the lens were broken with vigorous cycloplegia. Episcleritis and/or scleritis were described on occasion. Dilated fundus examinations were always normal.

Her inflammatory bowel disease had periodic flare-ups. It was characterized by right upper quadrant pain, cramping, and diarrhea.

At age 53, she presented to her family practice physician with a 10-year history of chiropractic treatment for low back pain and a 1 1/2-year history of hip pain. She had morning stiffness and pain in her back and both hips. Plain film x-rays showed extensive sclerosis of sacroiliac joints with obliteration of the joint line consistent with ankylosing spondylitis (AS) in this clinical context. (Fig.). A human leukocyte antigen (HLA-B27) test was positive.

Discussion

Uveitis is inflammation of ocular uveal tissue, the pigmented and vascular tissue in the choroid and ciliary body. Anterior uveitis is the common form, originating in the ciliary body with inflammatory cells carried by aqueous humor circulation into the anterior chamber that are visible with a slit lamp. Acute and recurrent anterior uveitis is potentially vision-threatening because of adhesions of the iris to the lens (posterior synechiae), secondary glaucoma, cataract after multiple recurrences, and rarely cystoid macular edema.

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Acute anterior uveitis is associated with both AS, and to a lesser extent, IBD. Differences in presenting symptoms, rate of onset and duration, gender, and HLA-B27 reaction have been described in AAU patients to differentiate between IBD and AS associated with AAU. (1)

Inflammatory bowel disease includes disease in the small intestine (Crohn disease) and the colon (ulcerative colitis), with occasional overlap. Genetic linkages associated with IBD have been described, but they are neither diagnostic, nor consistent. Current knowledge of IBD pathogenesis requires a genetic propensity and an abnormal immune response to enteric Gram negative bacterial flora, resulting in damage to intestinal epithelial mucosal barrier. Enteric mucosal receptors for bacterial antigens and immune modulators, both up- and down-regulatory, are subjects of research. (2)

Seronegative spondyloarthritis involves the vertebral column and is seronegative for rheumatoid factor. Depending on the rigidity of criteria (eg, European Spondyloarthropathy Study Group), spondyloarthropathy includes varying proportions of patients with ankylosing spondylitis, Reiter's syndrome or reactive arthritis, psoriatic arthritis, arthritis associated with IBD, pauciarticular juvenile rheumatoid arthritis, and undifferentiated spondyloarthritis.

The major histocompatibility complex on the short arm of chromosome 6 contains some 220 genes in 3 gene clusters. Within the first cluster are >500 human leukocyte antigens type B. There are at least 24 HLA-B27 subtypes. Class I molecules, including HLA-B types, present endogenous/intracellular antigen peptides to cytotoxic (CD8+) T-lymphocytes. The three-dimensional structure of HLA-B27 has a unique stereospecific antigen-binding site. (3) There is a strong statistical interrelationship between AAU, IBD, AS, and HLA-B27 depicted in the Table. HLA-B27 is thought to be a marker for an immune abnormality, rather than an etiologic factor.

Current knowledge of all three entities found in this patient, AAU, IBD, and AS, requires a genetic predisposition and an abnormal immune response that damages the respective tissues. A wide variety of abnormal inflammatory mediators have been identified in these diseases: cytokines, chemokines, growth factors, tissue necrosis factors, interferon, interleukins, leukotrienes, nitrous oxides, and prostaglandins. Intestinal abnormalities may be related in AAU and AS, as Reiter's syndrome is known to be precipitated by Gram negative intestinal flora bacteria, as well as genitourinary tract flora. Some two-thirds of AAU patients without gastrointestinal symptoms had microscopic inflammation of blind intestinal biopsies. (4)

This patient developed AAU before IBD and AS, as often occurs. (1) If 3% of AAU patients develop IBD, and 56% of female HLA-B27-positive AAU patients develop AS, (5) the product of their probabilities is 0.0168, or less than 1/50 chance of a woman with anterior uveitis having all three conditions and a positive HLA-B27 serology. Chance favors a prepared mind informed by a thorough past medical history.

Conclusion

This case illustrates the need for all physicians to be aware of multi-system disease. All patients diagnosed with AAU, IBD, or AS should be questioned specifically if they or their relatives have symptoms of eye, gut, or joint inflammation. They should be educated that these other systems might be involved in the future, if not present initially, and that they have a familial tendency. (6) It may not be cost-effective to test for HLA-B27 if any single disease complex initially responds to treatment. However, if there are recurrences or more than one organ system involved, the HLA-B27 test might contribute to prognosis or treatment. All physicians, and especially specialists, should remember they were trained initially as "head to toe" doctors and not lose sight of the whole patient.

References

1. Lyons JL, Rosenbaum JT. Uveitis associated with inflammatory bowel disease compared with uveitis associated with spondyloarthropathy. Arch Ophthalmol 1997;115:61-64.

2. Podolsky DK. Inflammatory bowel disease. N Engl J Med 2002;347:417-429.

3. Chang JH, McCluskey PJ, Wakefield D. Acute anterior uveitis and HLA-B27. Surv Ophthalmol 2005;50:364-388.

4. Banares AA, Jover JA, Fernandez-Gutierrez B, et al. Bowel inflammation in anterior uveitis and spondyloarthropathy. J Rheumatol 1995;22:1112-1117.

5. Linssen A, Meenken C. Outcomes of HLA-B27-positive and HLA-B27-negative acute anterior uveitis. Am J Ophthalmol 1995;120:351-361.

6. van der Linden SM, Rentsch HU, Gerber N, et al. The association between ankylosing spondylitis, acute anterior uveitis and HLA-B27: the results of a Swiss family study. Br J Rheumatol 1988;27(suppl 2):39-41.

7. Banares A, Hernandez-Garcia C, Fernandez-Guitierrez B, et al. Eye involvement in the spondyloarthropathies. Rheum Dis Clin North Am 1998;24:771-784.

E. Mitchell Singleton, MD, FACS, and Sanford E. Hutson, MD, FAAFP

Department of Ophthalmology, University of Arkansas for Medical, Sciences, Area Health Education Center--Northwest, Fayetteville, Arkansas

Reprint requests to E. Mitchell Singleton, MD, FACS, 1793 E. Manchester Drive, Fayetteville, AR 72703. Email: [e-mail]

Accepted January 26, 2006.

RELATED ARTICLE: Key Points

* Statistics from the literature indicate that the presence of all three conditions in a HLA-B27-positive woman is uncommon.

* Anyone presenting with any of these entities should be questioned specifically and warned about the possibility of the other associated conditions they or their family may experience in future years.

Table. HLA-B27 and Associated Inflammatory Diseases (1,3,7)

                                                   % AAU patients
Inflammatory     HLA-B27 %   % presenting disease  developing specific
disease          prevalence  developing AAU        systemic disease

Inflammatory     46          2-9                   2-3
  bowel disease
Ankylosing       90          20-30                 * 84-90 if + HLA-B27
  spondylitis                                      * 30-55 if - HLA-B27