HLA-B27 Syndromes

Updated: Apr 09, 2021
  • Author: Huy D Nguyen, MD, MBA; Chief Editor: Andrew A Dahl, MD, FACS  more...
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Overview

Overview

The first human leukocyte antigen (HLA) haplotype association with human inflammatory disease was discovered in 1972, correlating HLA-B27 with ankylosing spondylitis. This remains one of the strongest known associations of this disease with HLA-B27. Since then, more than 100 disease associations have been made, including many exclusively ocular diseases and also systemic diseases with specific ocular manifestations. [1] The most notable conditions among these include: ankylosing spondylitis, reactive arthritis (previously referred to as Reiter syndrome), Behçet's disease, inflammatory bowel disease, and psoriatic arthritis. These conditions fall under the umbrella of seronegative spondyloarthropathies. By definition, patients with these diseases do not have circulating rheumatoid factor, hence the term seronegative. [2]

Reactive arthritis. Involvement of knee (left) and Reactive arthritis. Involvement of knee (left) and conjunctivitis (right). Courtesy of Paul Dieppe, BSc, MD, FRCP, FFPHM.

In ophthalmology, HLA associations are strongest in diseases of the uvea. Of patients with uveitis, 19-88% have the HLA-B27 phenotype, depending upon the study population cited. Acute anterior uveitis (AAU) as depicted in the image below, may occur as a distinct clinical entity or in conjunction with the seronegative spondyloarthropathies. [3]

Acute anterior uveitis in ankylosing spondylitis. Acute anterior uveitis in ankylosing spondylitis. Courtesy of Paul Dieppe, BSc, MD, FRCP, FFPHM.

HLA-B27 haplotype prevalence varies between populations. In the United States, prevalence is estimated at 6.1%, however this is spread by ethnicity with an estimated 7.5% prevalence among non-Hispanic whites and 3.5% across all other ethnicities in the United States combined. The prevalence among Mexican Americans was 4.6%. [4]  HLA-B27 prevalence is non-existent in Australian Aborigines, while it measures at 50% of the Haida Indian population and rates reaching 34% in Russian Chukotka Natives. [5, 6]

An HLA disease association is defined as a statistically increased frequency of the HLA haplotype in individuals with the specific disease compared to the frequency in individuals without the disease. This is expressed as a relative risk. For example, 80-90% of patients with ankylosing spondylitis have HLA-B27. Expressed as a relative risk, an HLA-B27 positive individual is approximately 87 times more susceptible to developing ankylosing spondylitis compared to the general population.

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Pathophysiology

The HLA system is genetically encoded in humans by the major histocompatibility complex (MHC), which is found on chromosome 6, and plays a determining role in immunity and in self-recognition in virtually all cells and tissues, with the exception of erythrocytes. [7]

Three classes of gene products are encoded within the small region of the major histocompatibility complex (MHC). This group of genes code for proteins found on the surfaces of cells that help the immune system recognize foreign substances. Class I MHC molecules include HLA-A, HLA-B, or HLA-C and serve as the antigen-presenting platform for CD8 or suppressor T cells. Class I molecules are present on all nucleated cells. Class II MHC molecules, the HLA-D region, serve as the antigen-presenting cells for CD4 or helper T cells. Macrophages and dendritic cells are the important class II antigen-presenting cells. Class I and class II molecules allow antigen presentation to the specific T-cell receptor via a specific structural groove in its tertiary structure. Class III MHC molecules include several proteins with other immune functions, such as cytokines, heat shock proteins, and parts of complement system. Although all 3 classes have loci clustered on chromosome 6, the gene location of the third class is a result of translocation during evolution.

Autoimmune/inflammatory conditions can occur if mutations in the groove binding site of class I and II molecules occur, leading to inappropriate binding to self-peptides or certain environmental peptides. The actual role of HLA-B27 in triggering an inflammatory response causing disease is still not precisely known. The oldest theory is that of molecular mimicry, in which an autoimmune response initially is mounted against a peptide from an infectious agent and is subsequently directed against HLA-B27 itself due to epitopic similarities. At least 2 self-peptides have been identified in patients with ankylosing spondylitis, supporting this hypothesis.

A second theory, referred to as the HLA-B27 misfolding hypothesis, is based on a peculiar biochemical property of the HLA-B27 molecule. These unfolded HLA-B27 proteins accumulate in the endoplasmic reticulum (ER). A proinflammatory stress response called the endoplasmic reticulum unfolded protein response (ERUPR) ensues. As a result, interleukin 23 (IL-23) is released, activating a proinflammatory response via interleukin-17+ T lymphocytes.

Another potential pathological mechanism of HLA-B27 is called the HLA-B27 heavy chain homodimer hypothesis. It is suggested that B27 heavy chains can form stable dimers, which tend to dimerize and accumulate in the endoplasmic reticulum. In turn, this initiates the proinflammatory ERUPR. In addition, these heavy chains and dimers can bind to other regulatory immune receptors such as the natural killer receptors (NKRs). This causes the expression and survival of more proinflammatory leukocytes and subsequent production of proinflammatory mediators; however, evidence indicates that this pathogenesis may not be responsible. [8]

Other theories suggest that the T-cell antigen is the true susceptibility factor or imply an innate etiology unrelated to HLA. Finally, HLA-B27 may simply represent a marker locus, closely linked to the as yet unidentified true immune response gene responsible for the inflammatory response. [9]

The amino acid sequencing of HLA-B27 has been known since 1985. The antigen consists of at least 100 subtypes, with associations existing between some subtypes and other HLA-B27 inflammatory diseases such as anterior uveitis. It is present in only 1.4-8% of the general population (higher in certain Native American groups and Scandinavians). Of patients with acute anterior uveitis, 50-60% may be HLA-B27 positive. Both racial background and national origin affect this rate of incidence. The frequency of HLA-B27 anterior uveitis is lowest in blacks, intermediate in Asians, and highest in whites. [10]

Several hypotheses with animal models have been proposed to explain the association of AAU and HLA-B27. Many cases of uveitis or reactive arthritis follow gram-negative bacillary dysentery or chlamydial infection. These gram-negative organisms include Ureaplasma, Shigella, Salmonella, Klebsiella, and Yersinia species. Similarities in the gram-negative cell wall lipopolysaccharide present in these microbes may explain their immunogenicity. Animal experiments with rodents that have been genetically altered to express human HLA-B27 molecules show that bacterial infection of the gut predisposes to arthritis and a reactive arthritis–like syndrome. Also, chronic intracellular chlamydial joint or eye infection might stimulate, via the HLA-B27 molecule, a CD8 T-cell effector mechanism activated to kill the infections, which coincidentally also indirectly injures the eye. [11]

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Clinical Features of HLA-B27 Syndromes - Acute Anterior Uveitis

HLA-B27 associated acute anterior uveitis (AAU) is the most frequent type of endogenous uveitis (see image below), accounting for 18-32% of all anterior uveitis cases in western countries and for 6-13% of all anterior uveitis cases in Asia. The relatively lower frequency in Asia is related to the lower frequency of HLA-B27 found in this population. As mentioned, there are varying global patterns of HLA-B27 associated AAU that may be attributed to different genetic factors, such as HLA-B27 polymorphisms and non-MHC genes. These geographic variations may also exist because of yet unidentified pathogenic environmental factors. [12, 13]

Acute anterior uveitis in ankylosing spondylitis. Acute anterior uveitis in ankylosing spondylitis. Courtesy of Paul Dieppe, BSc, MD, FRCP, FFPHM.

Studies indicate that HLA-B27 associated uveitis is a distinct entity characterized by a male predominance and frequent association with seronegative spondyloarthropathies, such as ankylosing spondylitis, reactive arthritis, psoriatic arthritis, and inflammatory bowel disease. [14] The first episode of HLA-B27 associated AAU most commonly occurs in patients aged 20-40 years, whereas the age of onset of HLA-B27-negative AAU tends to occur a decade later. Of patients with AAU, 50-60% may be HLA-B27 positive. It is generally an acute onset nongranulomatous unilateral disease presenting as a classic triad of pain, redness, and photophobia, which can be recurrent in either eye.

Corneal manifestations may include fine keratitic precipitates and fibrin on the endothelium. Corneal edema may result from endothelial compromise and decompensation. Band keratopathy, an accumulation of calcium in the corneal epithelium, may be seen in chronic uveitis. The anterior chamber shows cells and flare, which is a haze seen on slit lamp examination, reflecting protein accumulation in the anterior chamber due to the breakdown of the blood-aqueous barrier, and, in severe inflammation, fibrinous exudate in the anterior chamber may occlude the pupil, causing iris bombe as depicted below. These findings may be mistaken for endogenous endophthalmitis. A hypopyon may be seen, and, rarely, a spontaneous hyphema can occur from the severely dilated iris vessels.

Anterior chamber fibrin collection in ankylosing s Anterior chamber fibrin collection in ankylosing spondylitis. Courtesy of Paul Dieppe, BSc, MD, FRCP, FFPHM.

Pigment dispersion, pupillary miosis, and iris nodules may be noted, and synechiae, both anterior and posterior, can occur. Posterior segment involvement is relatively rare, but cystoid macular edema, disc edema, pars plana exudates, or choroiditis may be seen. Intraocular pressure often is low, secondary to decreased aqueous production with inflammation of the ciliary body and trabecular meshwork. [15] Intraocular pressure also may be high if there is trabeculitis, pupillary block from a fibrin membrane, or clogging of trabecular meshwork by inflammatory debris.

AAU generally runs a short course of a few days to weeks but can last up to 3 months, with a tendency to recur in the same eye, especially in individuals who are HLA-B27 positive. Complications of AAU include cataract, glaucoma, hypotony, cystoid macular edema, papillitis, and synechiae formation. Some of these complications have a stronger association with HLA-B27 positive AAU, however no significant difference has been noted between HLA-B27 positive and negative AAU in measurement of final visual acuity and presence of posterior synechiae, cataract, and macular edema. [16, 17]

Classic AAU resolves completely when promptly and aggressively treated. Undertreated or misdiagnosed cases may progress to chronic iridocyclitis due to permanent damage of the blood-aqueous barrier.

Diagnosis

A careful history and physical examination usually helps distinguish between the uveitic entities associated with systemic disease and HLA-B27 from those that are not associated with HLA-B27. Disease entities causing AAU are varied and include traumatic iritis, post-intraocular surgery, juvenile rheumatoid arthritis, herpetic infection (both herpes simplex and herpes zoster), syphilis, sarcoidosis, Fuchs heterochromic iridocyclitis, glaucomatocyclitic crisis, Behcet disease, and low-grade endophthalmitis. [18]

The role of HLA-B27 testing in patients with unilateral AAU is important in the differential diagnosis. The lack of HLA-B27 antigen in unilateral AAU may be a clue for the clinician to search for other specific uveitis entities and other systemic diseases. It also may be useful in determining the prognosis of AAU, as AAU associated with HLA-B27, even in the absence of systemic disease, is less favorable and more likely to recur when compared with that of patients who are HLA-B27 negative.

Treatment

Medical management of AAU involves topical corticosteroids and topical cycloplegics. Periocular corticosteroid injections are useful in acute, recalcitrant, or noncompliant cases, particularly when posterior segment involvement occurs. Immunosuppressive therapy may be necessary in refractory cases or in those patients with corticosteroid-induced adverse effects. The primary goal is to eliminate all cells, thereby minimizing complications including cataracts, cystoid macular edema, hypotony, synechiae formation, or glaucoma.

Cycloplegics help relieve photophobia, secondary to ciliary spasm, and prevent or break synechiae formation. In most cases, short-acting drops, such as 1% cyclopentolate hydrochloride or 1% tropicamide, are sufficient. These allow pupillary motility and rapid recovery when discontinued. Longer acting cycloplegics, such as 5% homatropine, 0.25% scopolamine, and 1% atropine may also be useful. If the uveitis is more severe, more frequent dosing of cycloplegics may be necessary.

Corticosteroids may be administered by 4 routes, including topical, periocular, intraocular (intravitreal), and systemic. Topical corticosteroids are the mainstay of uveitis therapy. The goal is to use the minimum amount necessary to control inflammation and to prevent complications. Aggressive initial therapy may hasten recovery and limit the duration of therapy. Prednisolone acetate 1% given every hour is strongly recommended for acute presentations. Ointment form is available to those who cannot tolerate the preservative in the drops and may be particularly useful for a longer-acting bedtime dosage. Usually, 2-3 weeks at maximal frequency is all that is necessary to completely eliminate all cells, and a taper regiment is recommended when discontinuing therapy.

Occasionally, severe inflammation may not respond and may require periocular, intraocular, or systemic corticosteroids, especially if the posterior segment is involved. Periocular corticosteroids are usually given as depot injections in the sub-Tenon space. Intravitreal corticosteroids by injection or by implantation of a sustained released device have been shown to be useful in the treatment of both chronic uveitis and uveitic cystoid macular edema. These sustained devices are particularly promising in treating long-standing inflammation, as they can release medications for as long as several years after implantation. This would allow reduction or elimination of systemic corticosteroids or immunosuppressive agents, thereby minimizing systemic effects related to treatment with these agents. Notable ocular side effects include accelerated cataract development and steroid-induced glaucoma, therefore intraocular pressures should be monitored on a regular basis.

Systemic corticosteroids can be administered orally or intravenously. These are especially beneficial when the systemic disease requires therapy as well. It is important to discuss the adverse effects of corticosteroids with the patient and to have these monitored by the patient's primary care physician. Prednisone at 1 mg/kg/d is a common starting dose and is titrated based on comorbidities and response.

More potent immunosuppression may be required in patients with vision-threatening inflammation interfering with activities of daily living, lack of response to corticosteroid treatment, or intolerance of corticosteroids. Patients taking 10 mg or more to control their symptoms may benefit from an antimetabolite as a safer long-term treatment. Drugs used in these situations include azathioprine, mycophenolate mofetil, cyclophosphamide, chlorambucil, methotrexate, tacrolimus, and cyclosporine. These agents are more commonly used in posterior uveitis or panuveitis, but they occasionally can be required in severe fibrinous anterior uveitis associated with reactive arthritis or ankylosing spondylitis. [19]

Cyclosporine is becoming increasingly useful as an adjunct to systemic corticosteroids. It may allow the physician to decrease or totally withdraw the corticosteroids once the remission is achieved. The usual dose is 2.5-5 mg/kg/d. Careful monitoring of blood pressure and renal function is required. Investigational therapies include a sustained-release device containing cyclosporin or the highly lipid-soluble steroid fluocinolone, or monoclonal antibodies against the CD4 molecule.

Therapies for uveitis remain nonspecific in their mode of action, and they have a number of adverse effects leading to increased interest in immunomodulatory therapies such as antitumor necrosis factor alpha (anti-TNF-alpha) and the use of HLA-B27 oral tolerance therapy. TNF-alpha has been shown to be a critical inflammatory instigator in the pathogenesis of various forms of uveitis, including AAU, in both animal and human experimental studies. Anti-TNF-alpha infliximab is a murine-human chimeric monoclonal antibody directed against human TNF-alpha. It has been shown to be a rapid, effective, and safe therapy of vision-threatening ocular inflammation in Behcet disease and refractory posterior uveitis. Etanercept is a genetically engineered fusion protein, which binds and inactivates both TNF-alpha and TNF-beta. One study showed the efficacy of this protein in improving both ocular inflammation and articular inflammation when injected subcutaneously twice a week for at least 3 months in the treatment of resistant chronic uveitis, including chronic anterior uveitis in children with juvenile rheumatoid uveitis and idiopathic uveitis. This allowed the reduction of both systemic corticosteroids and/or systemic methotrexate.

Oral tolerance therapy involves administering an antigen orally to induce a specific peripheral immune tolerance. The mechanisms of oral tolerance are unclear, but it is believed that it revolves around a specific antigen and the generation of active suppression or clonal anergy dependent on the antigen dose. Oral tolerance has been shown to be successful in experimental models dealing with multiple sclerosis, arthritis, diabetes, myasthenia gravis, and uveitis. Based on this, clinical studies have been initiated using such antigens as myelin in multiple sclerosis, collagen in rheumatoid arthritis, and uveitogenic peptides in intermediate and posterior uveitis, again with signs of success and few adverse effects from the treatment. An HLA-B27-derived peptide (B27PD) mimicking retinal autoantigen has been found to be effective in both animal models and patients with uveitis.

Other emerging therapeutic options include antibiotic therapy in view of the implicated role of gram-negative bacterial infections on triggering HLA-B27 associated AAU. Sulfasalazine treatment has been investigated for its potential role in reducing the number of recurrent attacks of AAU. Prophylactic ciprofloxacin has also been investigated but was not found to be beneficial in view of its adverse effects and cost.

Future novel potential treatments will be based on a better understanding of the immune system and the modulation of cytokines, chemokines, cell adhesion molecules, and T-cell subsets.

The role of the rheumatologist in the management of AAU is important in identifying and managing underlying systemic diseases that may be co-involved, especially with the use of systemic immunomodulatory therapies. About 1% of HLA-B27 positive individuals develop AAU, and 84% of HLA-B27 positive patients with AAU will have Reiter's syndrome, ankylosing spondylitis, or psoriatic arthritis. [20] It is also notable that 20-30% of patients diagnosed with Reiter's or AS develop AAU, putting importance on the identification of ophthalmologic conditions in existing rheumatology patients. [21]

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Clinical Features of HLA-B27 Syndromes - Ankylosing Spondylitis

Initial observations of HLA-B27 association with ankylosing spondylitis were made in Whites. Subsequent studies have established the presence of HLA-B27 in patients with ankylosing spondylitis from nearly every ethnic group. A genetic linkage to HLA-B27 is suspected as HLA-B27 associated ankylosing spondylitis has been found to have a familial predisposition. [22]

Ankylosing spondylitis is a chronic, usually progressive, disease involving the articulations of the spine and adjacent soft tissues. The sacroiliac joints and proximal joints (hips and shoulders) are frequently affected while peripheral joints are seldomly affected. The disease predominantly affects young men and begins most often in the third decade. [23]

Ankylosing spondylitis disease progression. Courte Ankylosing spondylitis disease progression. Courtesy of Paul Dieppe, BSc, MD, FRCP, FFPHM.

HLA-B27 is found in 88% of patients with ankylosing spondylitis. [24] The chance that an HLA-B27 patient will develop spondyloarthritis or eye disease is 1 in 4. [1]

Symptoms of ankylosing spondylitis include lower back pain and stiffness after inactivity. The disorder can be totally asymptomatic or severe and crippling. Often, symptoms of back disease are lacking in patients with iritis who are HLA-B27 positive, and not all patients who are HLA-B27 positive develop arthritic spinal or sacroiliac disease. [25]

Diagnosis

Radiographs of sacroiliac joints show sclerosis and narrowing of the joint space. This is followed by ligamentous ossification, and osteoporosis. Both sacroiliac joints usually are involved but can be asymmetric initially.

Ankylosing spondylitis may first present to an ophthalmologist in the form of AAU. A family history or symptoms of back problems and a positive HLA-B27 are highly suggestive of the diagnosis. Sacroiliac films should be obtained, and the patient should be referred to an internist or a rheumatologist to monitor and manage the risk of deformity and systemic complications such as pulmonary apical fibrosis, aortitis, and aortic insufficiency.

Treatment

First-line treatments for active cases of ankylosing spondylitis include NSAIDs, however, there is no evidence to suggest the increased efficacy of any one NSAID over another. TNF inhibitors are recommended in refractory cases. Treatment with physical therapy is also highly recommended in both active and stable cases of ankylosing spondylitis. There is little evidence to support the use of systemic glucocorticoids in the management of AS at this time. [26]

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Clinical Features of HLA-B27 Syndromes - Reactive Arthritis

Reactive arthritis refers to spondyloarthropathies following enteric or urogenital infections and occurring in individuals who are HLA-B27 positive, formerly known as Reiter syndrome. Reiter syndrome originally was described as a triad of arthritis, nonspecific urethritis, and conjunctivitis, often accompanied by iritis. Reactive arthritis includes Reiter syndrome's classic triad of symptoms plus other major diagnostic criteria discussed below. .

Reactive arthritis, acute conjunctivitis. Courtesy Reactive arthritis, acute conjunctivitis. Courtesy of Paul Dieppe, BSc, MD, FRCP, FFPHM.

Like ankylosing spondylitis, reactive arthritis occurs in individuals who are HLA-B27 positive; in fact, 60-85% of patients with reactive arthritis are HLA-B27 positive. The disease is most common in persons aged 18-40 years, but it has been known to occur in children and older adults. The sex ratio varies depending on whether the infection is enteric or venereally acquired. The sex ratio following gastrointestinal infection is 1:1, whereas the genitourinary disease primarily affects males. Prevalence of the disease also is high in homosexual and bisexual men, owing to the high rate of genitourinary and gastrointestinal infections in this group. A particular severe form of peripheral spondyloarthropathy following an infection has been described in patients with AIDS.

Etiology

The first bacterial infection noted to be causally related to reactive arthritis was Shigella flexneri. Other bacteria that have been implicated in reactive arthritis include several Salmonella species, Yersinia enterocolitica, Campylobacter jejuni, Chlamydia trachomatis, Chlamydia pneumoniae, Clostridium difficile, and Ureaplasma urealyticum.

COVID-19 may be linked to reactive arthritis pending continued research to clarify the relationship and mechanism. [27, 28, 29]

Symptoms

The syndrome usually begins with urethritis followed by conjunctivitis and rheumatological findings. Arthritis begins within 1 month of infection in 80% of patients. It is usually acute, asymmetric, and oligoarticular and predominantly involves the joints of the lower extremities (eg, knees, ankles, feet, wrists). The arthritis is usually quite painful. Dactylitis or sausage digit is a diffuse swelling of a solitary finger or toe. This is a distinct feature of both reactive arthritis and psoriatic arthritis. Plantar fasciitis and Achilles tendonitis also are common. Sacroiliitis is present in as many as 70% of patients. The eye is involved in 20% of patients, most commonly manifesting as papillary and mucopurulent conjunctivitis that is usually minimal and lasts for only a few days or weeks. 

Reactive arthritis. Involvement of knee (left) and Reactive arthritis. Involvement of knee (left) and conjunctivitis (right). Courtesy of Paul Dieppe, BSc, MD, FRCP, FFPHM.

Punctate and subepithelial keratitis may occur rarely, leading to permanent corneal scars. Acute nongranulomatous iritis occurs in 10% of these patients and may become bilateral and chronic. Mucocutaneous lesions are common and appear in the mouth and palate and on the glans penis and palms and soles.

In addition to the Reiter triad, two other mucocutaneous conditions are part of the major diagnostic criteria for reactive arthritis, according to the American Rheumatological Association (ARA) guidelines: (1) keratoderma blennorrhagicum, a scaly, erythematous, irritating disorder of the palms and soles of the feet, and (2) circinate balanitis, a persistent, scaly, erythematous circumferential rash of the distal penis. Keratoderma blennorrhagicum may resemble pustular psoriasis, which can make it difficult to distinguish between these two seronegative arthropathies. Minor diagnostic criteria of reactive arthritis include sacroiliitis, plantar fasciitis, Achilles tendonitis, nail bed pitting, palatal ulcers, and tongue ulcers.

Diagnosis

Reactive arthritis is a clinical diagnosis without definitive laboratory or radiographic findings. The diagnosis should be considered when an acute asymmetric inflammatory arthritis or tendonitis follows an episode of diarrhea or dysuria. These diseases are also spondyloarthropathies involving the tendon insertion, not the synovium, primarily of weightbearing joints. HLA-B27 testing is not essential to confirm the diagnosis, but it may determine the eventual severity and chronicity of the condition. [30]

Treatment

Treatment is empirical and aimed at relieving symptoms. Patient education, reassurance, and physical therapy are of paramount importance. Acute arthritis is treated with analgesics and nonsteroidal anti-inflammatory drugs, such as indomethacin. Whether antibiotics help in reactive arthritis is unclear; however, it is known that treatment of acute chlamydial urethritis may prevent subsequent reactive arthritis.

Systemic corticosteroids should be avoided because they can aggravate the cutaneous manifestations of the disease, but local administration can help persistent monoarthritis, fasciitis, and tendonitis. In chronic destructive arthritis, cytotoxic drugs, such as methotrexate or azathioprine, may be beneficial. Uveitis usually is treated with topical steroids. Periocular steroids, systemic corticosteroids, and steroid-sparing immunomodulatory therapies can be used depending on the severity and response to treatment. [31]

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Clinical Features of HLA-B27 Syndromes - Inflammatory Bowel Disease

Ulcerative colitis and Crohn disease are associated with AAU. Specifically, 2.4% of patients with Crohn disease and 5-12% of patients with ulcerative colitis develop AAU. Sometimes, the iritis predates the bowel disease, which may sometimes be asymptomatic. Approximately 50-75% of patients with spondylitis in association with inflammatory bowel disease have HLA-B27. In contrast, patients who develop sclerouveitis in the presence of inflammatory bowel disease tend to be HLA-B27 negative, and these patients tend not develop sacroiliitis.

Diagnosis

Radiograph findings of involved peripheral joints are usually normal except for soft tissue swelling. An occasional patient with recurrent disease may show small bony erosions and joint space narrowing. Spine films show changes indistinguishable from ankylosing spondylitis. Blood work, including white blood cell (WBC) count, red blood cell (RBC) count, and erythrocyte sedimentation rate, usually reflect the intestinal disease.

Treatment

Treatment should be directed at the underlying inflammatory bowel disease. Nonsteroidal anti-inflammatory drugs can effectively treat the joint symptoms. Glucocorticoids, which are used for the control of colitis and extraintestinal manifestations, including uveitis, also may suppress the arthritis. Physical therapy is beneficial for posture maintenance in spondylitis and for prevention of contractures in peripheral arthritis.

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Clinical Features of HLA-B27 Syndromes - Psoriatic Arthritis

The prevalence of arthritis in patients with psoriasis is higher than that found in the general population. It occurs in about 5-42% of patients with psoriasis. HLA-B27 is associated with the pustular form of psoriasis and weakly associated with peripheral psoriatic arthritis. In the presence of spondylitis-associated with psoriasis, 60-70% of these cases are HLA-B27 positive.

The age of onset of psoriatic arthritis is usually in the third or fourth decade and occurs equally in both sexes.

Psoriasis precedes the onset of arthritis by months or years. The prognosis of psoriatic arthritis is more favorable than that of rheumatoid arthritis unless it is the severe destructive form called arthritis mutilans. The course of the disease is mild, intermittent, and affects only a few joints. The proximal interphalangeal joints and distal interphalangeal joints are commonly involved with characteristic sausage-shaped digits. Knees, hips, ankles, temporomandibular joints, and wrists are less frequently involved. Most patients have onychodystrophy, which includes onycholysis and ridging and pitting of nail beds. Twenty-five percent of patients develop a more severe symmetrical arthritis resembling rheumatoid arthritis. Twenty-three percent develop psoriatic spondylitis, which differs from that in ankylosing spondylitis because it is less progressive and debilitating.

Workup

Like most spondyloarthropathies, most serum labs are normal except for nonspecific inflammatory markers such as erythrocyte sedimentation rate, C reactive protein, and complement level. Radiographic investigation shows findings similar to rheumatoid arthritis, but unique findings include erosions at the distal interphalangeal joints, expansion of the base of the terminal phalanx, pencil-in-cup appearance, and asymmetric or unilateral sacroiliitis.

Diagnosis

Psoriatic arthritis should be considered in individuals with arthritis and psoriasis. Psoriatic skin lesions can look like eczema and seborrheic dermatitis. Both reactive arthritis and psoriatic arthritis have dactylitis, but reactive arthritis usually occurs in younger males, is less likely to be progressive and destructive, and is more likely to be associated with characteristic skin lesions, urethritis, and conjunctivitis.

Gout can look like psoriatic arthritis, except for the presence of intra-articular sodium urate crystals. It is distinguished from rheumatoid arthritis by the lack of (1) rheumatoid factors, (2) the tendency for asymmetry, dactylitis, iritis, enthesopathy, and onychodystrophy, and (3) the high frequency of HLA-B27 in patients with spondylitis and sacroiliitis.

Treatment

The mainstay of treatment is patient education with physical and occupational therapy. Nonsteroidal anti-inflammatory drugs reduce joint inflammation and pain. In more severe cases, hydrochloroquine can be beneficial in inducing disease remission but also exacerbate skin involvement. In extensive skin involvement, methotrexate can be used to relieve both skin lesions and arthritis. Renal function, liver function, and a complete blood cell (CBC) count should be performed regularly and titrated as necessary. Other effective drugs include sulfasalazine, intramuscular gold, cyclosporine, etretinate, and azathioprine.

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Questions & Answers

Overview

Which conditions are associated with HLA-B27?

Which ophthalmologic diseases have the strongest association with HLA-B27?

How is a human leukocyte antigen (HLA) disease association defined?

In humans, where is the human leukocyte antigen (HLA) system genetically encoded?

What is the role of the major histocompatibility complex (MHC) in the pathophysiology of human leukocyte antigen (HLA) system?

What is the role of human leukocyte antigen (HLA) B27 in triggering an inflammatory disease-causing response?

How many subtypes of human leukocyte antigen (HLA) B27 have been identified?

What is the basis for the association of acute anterior uveitis (AAU) with human leukocyte antigen (HLA) B27?

What is the prevalence of human leukocyte antigen (HLA) B27 associated acute anterior uveitis (AAU)?

What is the typical presentation of human leukocyte antigen (HLA) B27 associated acute anterior uveitis (AAU)?

What is the disease progression of human leukocyte antigen (HLA) B27 associated acute anterior uveitis (AAU)?

How is human leukocyte antigen (HLA) B27 associated acute anterior uveitis (AAU) diagnosed?

What are the treatment options for human leukocyte antigen (HLA) B27–associated acute anterior uveitis (AAU)?

What is the role of cycloplegics in the treatment of human leukocyte antigen (HLA) B27–associated acute anterior uveitis (AAU)?

What is the role of corticosteroids in the treatment of human leukocyte antigen (HLA) B27–associated acute anterior uveitis (AAU)?

What are the indications for aggressive immunosuppression therapy in human leukocyte antigen (HLA) B27–associated acute anterior uveitis (AAU)?

What is the role of cyclosporine in the treatment of human leukocyte antigen (HLA) B27–associated acute anterior uveitis (AAU)?

What novel therapies are being investigated for the treatment of human leukocyte antigen (HLA) B27–associated acute anterior uveitis (AAU)?

What is the role of etanercept in the treatment of human leukocyte antigen (HLA) B27–associated acute anterior uveitis (AAU)?

What is oral tolerance and how is it used in the treatment of human leukocyte antigen (HLA) B27–associated acute anterior uveitis (AAU)?

What is the role of antibiotics in the treatment of human leukocyte antigen (HLA) B27–associated acute anterior uveitis (AAU)?

What is the role of the rheumatologist in the management of human leukocyte antigen (HLA) B27–associated acute anterior uveitis (AAU)?

How does the prevalence of human leukocyte antigen (HLA) B27–associated ankylosing spondylitis vary among races?

What is human leukocyte antigen (HLA) B27–associated ankylosing spondylitis?

What is the prevalence of human leukocyte antigen (HLA) B27 in patients with ankylosing spondylitis?

What are the signs and symptoms of human leukocyte antigen (HLA) B27–associated ankylosing spondylitis?

How is human leukocyte antigen (HLA) B27–associated ankylosing spondylitis diagnosed?

What is human leukocyte antigen (HLA) B27–associated reactive arthritis?

Which bacteria are linked to human leukocyte antigen (HLA) B27–associated reactive arthritis?

What are the signs and symptoms of human leukocyte antigen (HLA) B27–associated reactive arthritis?

How is human leukocyte antigen (HLA) B27–associated reactive arthritis diagnosed?

What are the treatment options for human leukocyte antigen (HLA) B27–associated reactive arthritis?

How prevalent is human leukocyte antigen (HLA) B27–associated inflammatory bowel disease (IBD)?

How is human leukocyte antigen (HLA) B27–associated inflammatory bowel disease (IBD) diagnosed?

What are the treatment options for human leukocyte antigen (HLA) B27–associated inflammatory bowel disease (IBD)?

What is the prevalence of human leukocyte antigen (HLA) B27 in psoriasis?

What lab and imaging findings suggest human leukocyte antigen (HLA) B27–associated psoriatic arthritis?

How is human leukocyte antigen (HLA) B27–associated psoriatic arthritis diagnosed?

What are the treatment options for human leukocyte antigen (HLA) B27–associated psoriatic arthritis?

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