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HLA-B27 Syndromes

  • Author: Anna Luisa Di Lorenzo, MBBCh; Chief Editor: Hampton Roy, Sr, MD  more...
 
Updated: Apr 14, 2015
 

Overview

The first human leukocyte antigen (HLA) haplotype association with inflammatory disease was discovered in 1972, correlating HLA-B27 with ankylosing spondylitis. This remains one of the strongest known associations of disease with HLA-B27. Since then, more than 100 disease associations have been made, including many ocular diseases and systemic diseases with specific ocular manifestations.[1] These diseases also include reactive arthritis (previously referred to as Reiter syndrome), inflammatory bowel disease, and psoriatic arthritis.

Refer to the following image.

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 a group of autoimmune rheumatic diseases called seronegative spondyloarthropathies.[2] By definition, patients with these diseases have a negative rheumatoid factor, hence the term seronegative.[3, 4]

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

An HLA disease association is defined as a statistically increased frequency of the HLA haplotype in individuals with the disease compared to the frequency in individuals without the disease. This is expressed as a relative risk. For example, HLA-B27 appears in 80-90% of patients with ankylosing spondylitis. 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.[5]

Three classes of gene products are encoded within the small region of the major histocompatibility complex (MHC). 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 specific structural groove in its tertiary structure. 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 two self-peptides have been identified in patients with ankylosing spondylitis, which supports 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.

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.[6]

The sequence 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.[7]

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 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.[8]

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Clinical Features of HLA-B27 Syndromes - Acute Anterior Uveitis

HLA-B27 associated 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.

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 arthritic syndromes, such as ankylosing spondylitis, reactive arthritis, psoriatic arthritis, and inflammatory bowel disease.[9] 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 a benign nongranulomatous unilateral disease presenting as a classic triad of pain, redness, and photophobia.

Corneal manifestations may include fine keratitic precipitates and fibrin on the endothelium. Corneal edema may develop due to endothelial 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. This fibrin may be mistaken for endogenous endophthalmitis, cataract, or hypopyon. A hypopyon may be seen, and, rarely, even a spontaneous hyphema occurs as a result of 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.[10] Intraocular pressure also may be high if inflammatory cells and debris clog the trabecular meshwork, particularly in patients with preexisting poor facility of outflow.

AAU generally runs a short course of a few days to weeks 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, and synechiae formation. The prognosis of anterior uveitis associated with HLA-B27, either with or without systemic disease, is less favorable when compared with patients who are HLA-B27 negative with idiopathic anterior uveitis. Despite the potential for sequelae, the overall prognosis is good.[11]

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, postcataract extraction iritis, juvenile rheumatoid arthritis, herpetic infection (both herpes simplex and herpes zoster), syphilis, sarcoidosis, Fuchs heterochromic iridocyclitis, glaucomatocyclitic crisis, Behcet disease, and low-grade endophthalmitis.[12]

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 when compared with that of patients who are HLA-B27 negative.

Treatment

Medical management of AAU includes topical or systemic corticosteroids and topical cycloplegics. Periocular corticosteroid injections are extremely 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, or glaucoma.

Cycloplegics help relieve photophobia, secondary to ciliary spasm, and prevent and 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 and 0.25% scopolamine, also may be useful. If the uveitis is more severe, more frequent dosing of cycloplegics may be necessary.

Corticosteroids are the mainstay of uveitis therapy, but they should be used prudently owing to their adverse effects. 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. Usually, 2-3 weeks at maximal frequency is all that is necessary to completely eliminate all cells. Always discontinue corticosteroids by tapering the dose.

Corticosteroids may be administered by 4 routes, including topical, periocular, intraocular (intravitreal), and systemic. Topical therapy is used in anterior uveitis. The dosing varies from hourly to once daily. 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. 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 several years after implantation. This would allow reduction or elimination of systemic corticosteroids or immunosuppressive agents, thereby minimizing adverse effects related to treatment with these agents. As with any corticosteroid treatment, 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 useful starting dose.

More potent immunosuppression may be required in patients with vision-threatening inflammation interfering with activities of daily living, lack of response to corticosteroid treatment, and 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 typically are used in posterior uveitis or panuveitis, but they occasionally can be required in severe fibrinous anterior uveitis associated with reactive arthritis or ankylosing spondylitis.[13]

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 and monoclonal antibodies against the CD4 molecule.

Current therapies for uveitis remain nonspecific in their mode of action, and they have a number of adverse effects, as already mentioned. Owing to this, several therapies dealing with immunomodulation have been investigated. Two promising treatments involve 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 studies and human experimental studies. In view of this, investigations were carried out to examine the efficacy and safety of using anti-TNF-alpha in the treatment of various forms of uveitis with favorable results. 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 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 involves 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 success and few adverse effects from the treatment. A 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, and 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 based on a better understanding of the immune system and will include such substances as cytokines, chemokines, cell adhesion molecules, and T-cell subsets.

The role of the rheumatologist in the management of AAU is important in identifying underlying systemic diseases that may be present and in monitoring subsequent immunosuppressive therapy.

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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 has been established since the association of HLA-B27 in ankylosing spondylitis also has been found in families with more than one affected member.

Ankylosing spondylitis is a chronic, usually progressive, disease involving the articulations of the spine and adjacent soft tissues (see the image shown below). The sacroiliac joints usually are affected. Involvement of the hip and shoulders commonly occurs, and peripheral joints are affected less frequently. The disease predominantly affects young men and begins most often in the third decade.[14]

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. It is inherited in a Mendelian fashion, and it is found in 50% of first-degree relatives of those patients with spondyloarthropathies who are HLA-B27 positive. The chance that an HLA-B27 patient will develop spondyloarthritis or eye disease is 1 in 4.

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 who are HLA-B27 positive with iritis, and not all patients who are HLA-B27 positive develop disease.[15]

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 findings may first appear on one side.

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. The patient also should be informed of the risk of deformity and involvement of other organ systems, including the lungs, causing pulmonary apical fibrosis, and the heart, causing aortitis and aortic insufficiency.

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Clinical Features of HLA-B27 Syndromes - Reactive Arthritis

Reactive arthritis refers to an acute nonpurulent arthritis complicating an infection elsewhere in the body. The term has been used primarily to refer to spondyloarthropathies following enteric or urogenital infections and occurring in individuals who are HLA-B27 positive. Included in this category is what was once referred to as Reiter syndrome and is now referred to as reactive arthritis, which originally was described as a triad of arthritis, nonspecific urethritis, and conjunctivitis, often accompanied by iritis. Refer to the following image.

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

Reactive arthritis occurs like ankylosing spondylitis in individuals who are HLA-B27 positive; in fact, 60-85% of patients 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.

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 conjunctivitis is usually minimal and lasts for only a few days or weeks. It is mucopurulent and papillary. See the image depicted below.

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 recurs frequently in this condition. It may become bilateral and chronic and may result in blindness. Mucocutaneous lesions are common and appear in the mouth and palate and on the glans penis and palms and soles.

Two such conditions considered to be major diagnostic criteria, according to the American Rheumatological Association (ARA) guidelines, are as follows: (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 include sacroiliitis, plantar fasciitis, Achilles tendonitis, nail bed pitting, palate 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.[16]

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 periocular or systemic corticosteroids depending on the severity of the condition. The molecular mechanisms of HLA-B27-associated arthritis and uveitis are becoming better understood and may someday soon contribute to specific targeted immunotherapy.[17]

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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 do 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 the association of HLA-B27 in peripheral psoriatic arthritis is weak. 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, very few abnormal lab results occur. Elevated erythrocyte sedimentation rates, C reactive proteins, and complement levels reflect inflammation. 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 and is less likely to be progressive and destructive. It 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. However, it can exacerbate skin involvement. In extensive skin involvement, methotrexate can be used, which relieves both skin lesions and arthritis. Renal and liver function tests and a complete blood cell (CBC) count should be performed frequently, adjusting dosage as necessary. Other effective drugs include sulfasalazine, intramuscular gold, cyclosporine, etretinate, and azathioprine.

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Contributor Information and Disclosures
Author

Anna Luisa Di Lorenzo, MBBCh Clinical Assistant Professor, Department of Ophthalmology, Kresge Eye Institute, Wayne State University School of Medicine; Consulting Staff, Somerset Ophthalmology

Anna Luisa Di Lorenzo, MBBCh is a member of the following medical societies: American Academy of Ophthalmology, American College of Physicians, American Medical Association, American Society of Cataract and Refractive Surgery, Association for Research in Vision and Ophthalmology, Michigan Society of Eye Physicians & Surgeons, Michigan State Medical Society, Oakland County Medical Society, Women in Ophthalmology, Inc

Disclosure: Nothing to disclose.

Specialty Editor Board

Simon K Law, MD, PharmD Clinical Professor of Health Sciences, Department of Ophthalmology, Jules Stein Eye Institute, University of California, Los Angeles, David Geffen School of Medicine

Simon K Law, MD, PharmD is a member of the following medical societies: American Academy of Ophthalmology, Association for Research in Vision and Ophthalmology, American Glaucoma Society

Disclosure: Nothing to disclose.

R Christopher Walton, MD Professor, Director of Uveitis and Ocular Inflammatory Disease Service, Department of Ophthalmology, University of Tennessee College of Medicine

R Christopher Walton, MD is a member of the following medical societies: American Academy of Ophthalmology, Association for Research in Vision and Ophthalmology, Retina Society, American College of Healthcare Executives, American Uveitis Society

Disclosure: Nothing to disclose.

Chief Editor

Hampton Roy, Sr, MD Associate Clinical Professor, Department of Ophthalmology, University of Arkansas for Medical Sciences

Hampton Roy, Sr, MD is a member of the following medical societies: American Academy of Ophthalmology, American College of Surgeons, Pan-American Association of Ophthalmology

Disclosure: Nothing to disclose.

Additional Contributors

John D Sheppard, Jr, MD, MMSc Professor of Ophthalmology, Microbiology and Molecular Biology, Clinical Director, Thomas R Lee Center for Ocular Pharmacology, Ophthalmology Residency Research Program Director, Eastern Virginia Medical School; President, Virginia Eye Consultants

John D Sheppard, Jr, MD, MMSc is a member of the following medical societies: American Academy of Ophthalmology, American Society for Microbiology, American Society of Cataract and Refractive Surgery, Association for Research in Vision and Ophthalmology, American Uveitis Society

Disclosure: Nothing to disclose.

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Reactive arthritis, acute conjunctivitis. Courtesy of Paul Dieppe, BSc, MD, FRCP, FFPHM.
Anterior chamber fibrin collection in ankylosing spondylitis. Courtesy of Paul Dieppe, BSc, MD, FRCP, FFPHM.
Acute anterior uveitis in ankylosing spondylitis. Courtesy of Paul Dieppe, BSc, MD, FRCP, FFPHM.
Ankylosing spondylitis disease progression. Courtesy of Paul Dieppe, BSc, MD, FRCP, FFPHM.
Reactive arthritis. Involvement of knee (left) and conjunctivitis (right). Courtesy of Paul Dieppe, BSc, MD, FRCP, FFPHM.
 
 
 
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