The spondyloarthropathies are now recognized as a group of diseases that have a high incidence of associated ocular inflammatory disease. They include ankylosing spondylitis, Reiter’s syndrome (also called reactive arthritis), inflammatory bowel disease, psoriatic arthritis, and less well-defined, incomplete forms (Table 2). They are characterized by spondylitis or sacroiliitis, peripheral joint disease, and commonly increased incidence of the histocompatibility locus class I antigen HLA-B27. The presence of HLA-B27 is highly correlated with the occurrence of eye disease in these and other clinical conditions (Table 3).³ The spondyloarthropathies are seronegative (i.e., there is no rheumatoid factor). Onset of clinical disease occurs most frequently in the young adult years, between 16 and 40 years of age. Studies have shown radiographic evidence of spondylitis in up to 25% of HLA-B27-positive “normal” or asymptomatic first-degree relatives of HLA-B27–positive ankylosing spondylitis patients. Approximately 2% of the HLA-B27–positive white population will develop clinically significant ankylosing spondylitis. Incidence is equal in both sexes.⁴

HLA-B27 is a serologically identified allele of the HLA-B locus, which is one of the three recognized loci encoding the class I major histocompatibility complex (MHC) molecules on chromosome 6 in the human genome. The gene product that becomes the cell surface marker for HLA-B27–positive persons appears on certain cells and serves as one of the markers for the immune system to recognize these cells as self. It also acts as an antigen presentation molecule in cooperation with other molecules to facilitate antigen processing. The structure of the HLA-B27 surface molecule has been identified and characterized by serology testing into molecular subtypes of HLA-B27 (noted as B*2701 through B*2707). B*2705 is the more common subtype and is identified as that found in 90% of whites, Eskimos, and Native Americans. The different subtypes have not been shown to correlate with different types of spondyloarthropathies and vary by small differences in amino acid sequences.⁵

Identification and characterization of the crystalline structure and of the peptides that can bind in its binding groove have helped to clarify possible mechanisms involving molecules from bacterial cell wall, but these relationships seem far from being clearly established.^6,7,8,9,10

Clinical data seem to indicate that the HLA-B27 molecule or similar molecules are involved in the production of the disease process of the spondyloarthropathies. From the results of one study, transgenic rats appear to be a suitable animal model for human spondyloarthropathy.⁸ These rats were engineered to express the HLA-B27 gene and γ-macroglobulin gene; disease developed only in those rats with 50 to 150 copies of the HLA-B27 gene, and many of the clinical spondyloarthropathy findings developed even in a germ-free environment.⁸

Ankylosing spondylitis is characterized by inflammatory stiffening of the spine and rib cage by calcification of the nonsynovial (cartilaginous) synchondrosis of the intervertebral spaces; the apophyseal, costovertebral, neurocentral articulations; and the sacroiliac joints. The joints such as the cartilaginous manubriosternal and the symphysis pubis articulations and sternoclavicular joints are also sometimes involved. Involvement of peripheral synovial joints, such as hips, knees, and shoulders, although less frequent, does occur. Involvement of smaller joints is unusual. Nonarticular disease occurs in the aortic wall, lung, and anterior segment of the eye.¹¹ Diagnostic criteria are shown in Table 4.

Ankylosing spondylitis is distinctly different from rheumatoid arthritis, although earlier literature did not make this distinction. The sacroiliac joint is usually the most easily visible area of involvement and is best seen in oblique views on radiography of the sacroiliac joint as periarticular sclerosis and irregular loss of the joint space. These patients are seronegative for rheumatoid factor and may have an elevated erythrocyte sedimentation rate.^4,7

The presence of HLA-B27 antigen in 90% to 95% of white patients and 50% of black patients with ankylosing spondylitis is well documented, and the genetic predisposition to this disease has been recognized for many years. The relationship, however, is still incompletely understood at this point. HLA-B27 antigen is present in 6% to 14% of the white American population and 3% to 4% of the black American population. It is clear that people with this HLA type are at greater risk of developing one of the spondyloarthropathies; particularly ankylosing spondylitis, but as yet poorly defined environmental factors must be involved in triggering the development of the disease process.^4,11 The HLA-B27 antigen is even more strongly correlated with development of acute iridocyclitis than with joint changes. Of patients with HLA-B27 antigen, 20% to 25% will develop symptoms or radiographic evidence of spondylitis at some time in their life, and milder forms of the disease are commonly not diagnosed but believed to be due to back “strain” or injury. The incidence of clinical spondylitis is about equal between men and women, but the disease tends to be milder and more difficult to diagnose in women; its prevalence appears to approach 2% in those in the North American population who are HLA-B27 positive and who have been studied.

The mechanism of how HLA-B27 antigen is involved in this disease process is unclear. HLA determinants are located on chromosome 6. These determine cell surface markers that enable the immune system to recognize each cell as self. One theory that has been advanced suggests that the HLA-B27 antigen may be similar to antigens of the cell wall of certain exogenous agents or may be changed by the agents in a manner whereby the immune system has difficulty recognizing or responding appropriately to the agent or the altered HLA-B27 antigen. In one study, patients with ankylosing spondylitis had lower in vitro responsiveness of lymphocytes to Klebsiella antigens than HLA-B27–positive and HLA-B27–negative controls.¹² Antisera to certain isolates of Klebsiella lysed the lymphocytes of HLA-B27–positive patients with ankylosing spondylitis, but not the lymphocytes of HLA-B27–positive or HLA-B27–negative controls. This suggests that perhaps some Klebsiella antigens cross-react with a gene product closely associated with HLA-B27 or a Klebsiella-modified B27 antigen in patients with ankylosing spondylitis. Cross-reacting antigens have been identified in HLA-B27 and Klebsiella, Shigella, and Yersinia.¹³

The role of Klebsiella has not been clarified, and no other agent has been substantiated with respect to ankylosing spondylitis. Chlamydia has been suggested in some cases of Reiter’s syndrome, especially in instances of nonspecific urethritis.^14,15,16 Shigella, Salmonella, and Yersinia have been involved in clinical epidemics of postinfectious arthropathies.¹⁷ Additional theories involve HLA-B27 linkage with a specific immune response gene that predisposes patients to the disease, perhaps making them more susceptible to infection. The role of these factors remains to be clarified.^18,19

The acute iridocyclitis associated with ankylosing spondylitis is characterized by rapid onset of pain, photophobia, and blurred vision. Conjunctival, episcleral, and scleral injection and edema are seen. Poorly defined keratic precipitates are seen in the lower half of the corneal endothelium, and the anterior chamber has heavy flare that may be uneven. If the process is severe, there may be clot formation in the pupil space.^20,21 Cells in the anterior chamber may be so numerous that hypopyon will occur. Glaucoma can result from anterior chamber reaction blockage of the angle in the acute phase of inflammation and from pupil block from synechiae. Synechiae form early and, if not broken, will form lasting adhesions. Mydriatic and cycloplegic therapy is needed early in treatment. Spillover of inflammatory cells and inflammatory debris into the vitreous may occur, and the presence of disc blurring and macular edema is sometimes observed. This is sometimes also associated with hypotony. Posterior subcapsular cataracts and diffuse lens clouding are seen with severe prolonged episodes and repeated acute recurrences.^20,21

The typical episode lasts from 2 to 6 weeks. Aggressive suppression of the inflammatory reaction with topical corticosteroids is usually sufficient and reduces tissue damage, if an early intensive schedule is used, rather than increasing the drop schedule as the reaction increases. These patients may need to be seen daily when the condition is acutely active and may need to be seen every 2 to 3 days until the process is stable or clearly resolving. Treatment must be continued for several weeks as the process is resolving or reactivation will occur. Oral corticosteroids can be given for short periods of time. Some patients experience elevation of intraocular pressure with corticosteroid therapy, particularly as the eye improves and the ciliary body is again more able to produce aqueous humor. The long-acting effects of periocular injection of corticosteroids may become a more serious problem with persistent corticosteroid-induced glaucoma than the episode of acute iridocyclitis that was being treated.

Frequent episodes of recurrent iridocyclitis may cause significant disability that results in loss of work, discomfort, and structural damage to the eye. These patients may benefit from longer-term treatment with oral nonsteroidal anti-inflammatory agents, such as indomethacin or naproxen. These medications may help to reduce the severity and frequency of recurrences, but the pain-decreasing effects of these medications may make it more difficult for the patient to recognize an acute recurrence of the iridocyclitis. Biologic agents such as infliximab (Remicade) and etanercept (Enbrel)^22,23,24,25 have been helpful. Patients should be examined for exacerbations of the inflammation if they note any change in vision—even minor symptoms.

Reiter’s syndrome is a clinical syndrome usually described as arthritis, conjunctivitis, or iridocyclitis and nonbacterial urethritis or cervicitis. A better definition may be needed, because not only may these not all be present, but also dysentery and mucocutaneous disease with balanitis, oral ulceration, or keratoderma blennorrhagicum may be part of the clinical picture. Enthesopathy of the plantar fascia or Achilles tendon is also suggestive of Reiter’s syndrome. It is more commonly identified in men, but may be more frequent in women than previously thought.¹⁷ The incidence reported by Noer²⁶ in U.S. Navy personnel over a 10-year period was 4 in 100,000 men per year. HLA-B27–positive persons have approximately a 25% risk for Reiter’s syndrome development after Shigella infection.²⁷ Although the cause is unknown, the high correlation with the presence of HLA-B27 (75%)²⁸ is clearly recognized. The previous discussion in the section on spondyloarthropathies concerning this HLA-B27 association demonstrates a genetic predisposition in a high percentage of these patients. In Reiter’s syndrome, infectious agents are suggested by reports of clinically indistinguishable acute disease after epidemic dysentery and sexually transmitted nongonococcal urethritis thought to be due to Chlamydia²⁹ or possibly Mycoplasma (Ureaplasma urealyticum).^30,31 Large epidemics of dysentery have been linked to multiple occurrences of arthritis, urethritis, and iridocyclitis.^26,32 Shigella, Campylobacter, Salmonella, and Yersinia have all been implicated.³³ Microbial antigens have been identified in the synovium after infectious with Chlamydia, Yersinia, and Salmonella.^34,35,36 Salmonella typhimurium is a frequently associated Salmonella pathogen causing reactive arthritis.

This seronegative arthritis usually involves larger joints and the weight-bearing joints of the lower extremities. The knees and ankles are most frequently involved, with redness and diffuse swelling. Multiple joint involvements are usual. Periostitis and tendinitis may occur, especially involving the Achilles tendon, producing heel pain. Sacroiliac radiographic changes are present in up to 32% of patients.¹⁷ Children may be affected rarely.³⁷ Reiter’s syndrome tends to affect young adults in the range of 16 to 40 years of age. The diagnosis is sometimes hard to establish because the urethritis or cervicitis may be forgotten or suppressed and the enteritis and other symptoms may have been mild or not identified as abnormal. If a urethritis or cervicitis is present, cultures should be considered to make sure no treatable organism is present, such as gonococcus. Serologic testing for syphilis will help to rule out this sometimes-associated venereal problem.

Low back pain due to insertional tendinitis and sacroiliitis is common. The dermal lesions typified by keratoderma blennorrhagicum, described as a hyperkeratotic erythematous dermatitis resembling pustular psoriasis, may not be present until later in the disease. It usually involves the hands and feet but may involve other areas. Superficial ulcers of the mucous membranes are frequent.³⁸ Enteritis is usually a prolonged diarrheal episode with frequent passage of bloody, loose stools, but it may be a 24-hour episode of increased bowel activity.³⁸

The conjunctivitis is usually described as mucopurulent and may be sterile. It may be accompanied by an iridocyclitis, episcleritis, or scleritis. Punctate and subepithelial corneal involvement has been reported. The iridocyclitis may be the presenting ocular manifestation. Recurrences are usually associated with an acute iridocyclitis, which is of rapid onset with conjunctival and episcleral edema and injection. The corneal endothelium has cellular debris and poorly defined, small-sized to medium-sized keratic precipitates.³⁹ Heavy flare, cells, and a very early tendency toward formation of posterior synechiae are characteristic, more so than in most other forms of acute iridocyclitis (Figs. 1,2,3). Even the most aggressive pupil dilation management is sometimes inadequate for preventing synechiae. A peripheral iridectomy may be necessary to prevent iris bombé and angle closure if the synechiae cannot be broken enough to establish an opening for aqueous through the pupil (Fig. 4). The heavy flare is sometimes so plasmoid that cells are immobile and a fibrinlike clot may be seen in the pupil opening as the inflammation resolves. Cells and inflammatory debris may be seen in the vitreous, and blurring of the disc margins and macular edema may occur with severe or prolonged episodes. Lens clouding and posterior subcapsular cataracts occur with prolonged or repeated episodes. Hypotony can occur after a severe or prolonged course and may persist after resolution. Occasionally, secondary glaucoma may occur, owing to the anterior chamber reaction, in which case it will resolve as the inflammation resolves. With repeated recurrences, damage to the trabecular meshwork may occur, and prolonged recalcitrant glaucoma may result that may be poorly responsive to any medical or surgical management. This can be a serious factor in permanent visual loss with this type of iridocyclitis.^20,21,39,40

The usual course is 2 to 6 weeks for acute iridocyclitis. Topical corticosteroids and mydriatics should be used early and aggressively to reduce tissue damage. Frequent follow-up visits are necessary until the process is clearly resolved. The use of systemic corticosteroids may be necessary and should be used with the same indications and precautions as in other inflammatory disease and for a short period of time. Prolonged topical treatment is necessary for several weeks after the inflammation has cleared, because early withdrawal of topical corticosteroids will frequently result in return of inflammatory changes.

Occasionally, this process will become chronically active or recur at frequent enough intervals to require long-term management. Oral nonsteroidal anti-inflammatory agents, such as indomethacin or naproxen, may be helpful and may be needed for many months for two reasons: (1) to help reduce the level of activity and the frequency of recurrences in the ocular inflammation, and (2) to allow decreasing the corticosteroid dosage to decrease the rate of cataract formation and other associated side effects of corticosteroids. The decreased awareness of pain sometimes seen with these medications may alter the patient’s recognition of recurrences. If they have any change in symptoms, they should be examined to evaluate for recurrence of an acute episode of inflammation.

Ulcerative colitis and regional enteritis, such as Crohn’s disease or granulomatous colitis, have been reported to be associated with acute iridocyclitis and scleritis. Ulcerative colitis is characterized by mucosal ulcerations of the rectal area, colon, and occasionally terminal ileum. The mucosa is inflamed and friable and may contain crypt abscesses. Toxic megacolon, hemorrhage, and spontaneous bowel perforation may occur with exacerbations. Carcinoma may be a late complication. Regional enteritis may variably involve large and small bowel with transmural inflammation, including granulomas, fissuring, discrete ulcerations, serositis, and mesenteric lymphadenitis. Strictures, fistulas, and inflammatory masses are seen as complications. The causes of these conditions are unknown.^41,42,43,44

The associated arthritis and iridocyclitis, however, are similar in both conditions. Peripheral arthritis is seen in approximately 12% of patients with ulcerative colitis and approximately 20% of patients with regional enteritis. Radiographic evidence of sacroiliitis has been reported to show an incidence of approximately 18% and to be equal in both sexes in both conditions. Clinical spondylitis is seen in association with bowel inflammation in 4% to 7% of these conditions. The overall incidence of HLA-B27 in these two conditions may be slightly elevated, but is more similar to that in the normal population. HLA-B27 is present in 53% to 75% of patients who have both spondylitis and inflammatory bowel disease. The sacroiliac involvement is frequently asymmetric (Fig. 5). It is not clear whether the spondylitis is secondary to the inflammatory bowel disease or to an overlap of the conditions. Spondylitis occurs before the bowel disease in 25% of patients, and there seems to be little correlation in the activity of symptoms between the sacroiliitis and the bowel disease. Colectomy does not affect the sacroiliitis, even when the bowel disease is improved. This is in contrast to the activity of the peripheral arthritis, which does seem to parallel the activity of the inflammatory bowel disease in 60% to 74% of patients. The peripheral arthritis also precedes the bowel disease in 7% to 11% of patients.^42,45,46 It is not clear how these relate to the associated iridocyclitis.

Ocular inflammatory changes include conjunctivitis, episcleritis, keratitis, acute and chronic iridocyclitis, and posterior changes as well.^{47,48,49,50,51,52} The acute iridocyclitis is milder and frequently not accompanied by as much pain, photophobia, and redness as in the acute iridocyclitis associated with other spondyloarthropathies. Mild injection of the conjunctival and episcleral vessels and blurred vision may be the only symptoms of an acute flare of activity. The endothelium of the cornea usually has cellular debris and poorly formed keratic precipitates in the lower cornea. The anterior chamber contains cells and moderate flare, and a protein clot is not infrequent in the pupil, with early formation of posterior synechiae (Fig. 6); however, the synechiae are usually more easily broken than in ankylosing spondylitis and Reiter’s syndrome.⁵³ Treatment with topical corticosteroids and mydriatics is usually effective. The activity of the iridocyclitis has been reported to follow the activity course of the inflammatory bowel disease. Systemic treatment of inflammatory bowel disease has been noted to help the ocular inflammation. Decreasing the systemic treatment occasionally allows ocular inflammation to become visible and requires close observation and appropriate increase in local therapy.^48,53,54,55 Surgical resection of inflamed bowel for other medical reasons has sometimes been reported to coincide with lessening of ocular inflammation,^53,55 but these observations need better evaluation.⁵¹ Posterior segment manifestations, including retinal and choroidal vascular disease, are also sometimes noted.^56,57

Acute and chronic iridocyclitis occurs with psoriatic arthritis. Psoriatic arthritis is sometimes confused with Reiter’s syndrome because of the similarity of skin lesions (i.e., pustular psoriasis and keratoderma blennorrhagicum). In patients with keratoderma blennorrhagicum, other psoriatic lesions develop as well.^58,59 In psoriatic arthritis, distal interphalangeal joints may be involved and nail lesions are common. The correlation of widespread ankylosis with spondylitis (40%) and sacroiliitis (21%) is frequently observed,⁶⁰ but the presence of HLA-B27 has a higher correlation with these associated complications.⁶¹ Psoriatic arthritis is found in approximately 20% to 34% of patients with psoriasis, and estimates of 0.10% in the general population are considered reasonable.⁶⁰

Conjunctivitis is seen in approximately 20%, scleritis in approximately 2%, and an association between HLA-B27 and iridocyclitis in approximately 10% of patients.⁶² The iridocyclitis seen in connection with this condition tends to be similar to that seen with ankylosing spondylitis and is managed in a similar manner. It is however different in being more recalcitrant to treatment and last longer. The skin must play a role in prolonging the stimulus for inflammation. Its course is different from the other spondyloarthropathies.⁶³ There may be multiple recurrences, and the iridocyclitis may become chronic, unrelenting, and, at times, difficult to control.

Sarcoidosis remains a systemic granulomatous condition of unknown etiology. It is recognized by histologic appearance and clinical features and sometimes by exclusion of other etiologies. The granuloma formation is probably a final common tissue response pathway to many different antigens that are not readily cleared from the tissue. The histologic pictures of diseases associated with a number of environmental agents, such as beryllium, pine dust, or peanut dust are similar to those of sarcoidosis.^64,65 This seems to be a reasonable explanation for the inability to find one specific causative agent despite the relative frequency of the disease, which is estimated to be between 30 and 64 per 100,000 based on clinical examination. Autopsy studies, however, show that the true incidence may be 10 times this rate, suggesting that most cases go undiagnosed.^66,67 Fatigue is sometimes the only symptom of systemic involvement. Skin lesions, conjunctival granulomas (Fig. 7), lymph node biopsy specimens, and other involved tissues show high CD4+ T-cell concentrations in epithelioid cell noncaseating granulomas. Certain body compartments may be more involved, and systemic circulating T-cell populations or other systemic indicators of inflammatory activity may show no abnormality. The diagnosis may be easier when the chest x-ray shows the typical mediastinal lymph node enlargement, or when systemic levels of angiotensin-converting enzyme or serum lysozyme are elevated.^68,69,70 Genetic factors apparently play a role, and immune complexes have been noted; however, these influences remain to be clarified.⁷¹