sign in sign up
<<
Home , Polyarthritis, Spinal disease, Spondyloarthropathy, Spondylopathy

REVIEW

SIWAT KIRATISEAVEE, MD LAWRENCE H. BRENT Department of Medicine, Albert Einstein Department of Medicine, Albert Einstein Medical Center, Philadelphia, Pa Medical Center, Philadelphia, Pa

Spondyloarthropathies: Using presentation to make the diagnosis

■ ABSTRACT PONDYLITIS IS EASY TO MISS and is often S just assumed to be “.” Physicians Diagnosing the —chronic should suspect a in a inflammatory diseases of the spine and peripheral joints young man or woman with morning stiffness that share several distinctive features—is challenging and lasting more than 30 minutes; or in a patient depends on careful evaluation of the history, physical who has back pain and a history of , pso- examination, and radiographs. The recent use of tumor riasis, or inflammatory bowel disease; or in a necrosis factor inhibitors is exciting and may represent patient with back pain that improves dramati- true disease-modifying drugs for these conditions. cally when the patient takes prednisone or a nonsteroidal anti-inflammatory drug (NSAID) ■ KEY POINTS for another reason. Spondyloarthropathy is a family of arthri- Common features of the spondyloathropathies are tides that includes: of the axial and peripheral skeleton and • Ankylosing variable involvement of the peripheral joints, gut, skin, • Reactive (including Reiter syn- eye, or aorta. drome) • • Enteropathic spondyloarthropathy (ie, Human leukocyte antigen B27 is strongly associated with spondyloarthropathy associated with spondyloarthropathy but is not a diagnostic test. inflammatory bowel disease) • Undifferentiated spondyloarthropathy Serologic tests for and antinuclear (forms that fail to meet the clinical crite- antibody are usually negative in patients with a ria for the other categories).1 spondyloarthropathy. The erythrocyte sedimentation The spondyloarthropathies are linked by rate and the C-reactive protein concentration are often association with the class 1 human leukocyte elevated, but elevations do not always correlate with antigen (HLA)-B27 and by a common clini- disease activity. copathologic lesion—enthesitis. There is no serologic test to aid in the Tumor necrosis factor inhibitors have recently been diagnosis. Rather, the diagnosis is made by analyzing a constellation of factors, such as approved for the treatment of spondyloarthropathy and axial and peripheral joint and skeletal involve- may have disease-modifying effects. Clinical experience ment, associated clinical features, and genetic with these drugs in patients with spondyloarthropathies predisposing factors.2 has been limited, but quite positive. Treatment has been focused on the relief of symptoms with drugs such as nonsteroidal anti- inflammatory drugs. The new tumor necrosis factor inhibitors may have a role in modifying

This paper discusses therapies that are experimental or are not approved by the US Food and the course of this family of conditions, but expe- Drug Administration for the use under discussion. rience with these drugs is limited.

184 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 71 • NUMBER 3 MARCH 2004 Downloaded from www.ccjm.org on September 26, 2021. For personal use only. All other uses require permission. T ABLE 1 Demographic features of the spondyloarthropathies

GENERAL RELATIVE PERCENTAGE OF MEAN AGE POSITIVE FOR PREVALENCE PREVALENCE* MALE PATIENTS (YEARS) AT B27 ANTIGEN DIAGNOSIS

Ankylosing spondylitis 0.86% 42% 75% 41 86% 0.1% 17% 75% 33 69% Psoriatic arthritis 0.29% 10% 43% 47 20%-34% Enteropathic NA 4% 67% 38 50%-75% Undifferentiated 0.67% 27% 31% 53 18%

*Based on the European Spondyloarthropathy Study Group data from seven centers, including 403 patients diagnosed with spondyloarthropathy.

In this article, we review the clinical presen- pathogenesis of the spondyloarthropathies, tation of the spondyloarthropathies to help guide but the exact cause and pathogenesis remain the clinician through diagnosis and treatment. unclear.

■ EPIDEMIOLOGY The role of the human histocompatibility complex An epidemiologic assessment of blood donors in The spondyloarthropathies are variably associ- Berlin, Germany,3 found that 1.9% had a ated with the HLA class I antigen B27.3 The spondyloarthropathy: 0.86% had ankylosing histocompatibility or HLA complex is respon- spondylitis, 0.67% had undifferentiated spondy- sible for antigen recognition, allowing the dis- Genetic loarthropathy, and 0.29% had psoriatic arthritis. tinction between self and nonself. In humans, immunologic, Reactive arthritis and enteropathic spondylitis the HLA complex is located on chromosome were much less common.3 6 and is made up of genes that code for HLAs. and The prevalence of spondyloarthropathy, HLA class I genes code for HLA-A, HLA-B, environmental particularly of , correlates and HLA-C molecules, which are expressed most strongly with the prevalence of HLA-B27 on all nucleated cells. HLA class II genes code factors appear in the general population. The percentage of for HLA-DR, HLA-DQ, and HLA-DP mole- to work spondyloarthropathy patients with this gene cules, found on antigen-presenting cells such varies from about 90% in those with ankylosing as macrophages and dendritic cells. together in spondylitis to 20% in those with psoriatic An important biologic role of the HLA spondylo- arthritis or undifferentiated spondyloarthropa- molecules is to present antigenic peptides in a thy (TABLE 1).4–9 Ankylosing spondylitis and manner that enables appropriate T-cell recep- reactive arthritis are more common in men, but tors to engage them while simultaneously dis- are likely underdiagnosed in women. The mean criminating self from nonself, leading to T-cell age at diagnosis is generally in the 30s and 40s. activation. HLA class I molecules generally Most people with the HLA-B27 gene do not present antigen to CD8-positive T cells, develop ankylosing spondylitis. whereas HLA class II molecules generally pre- TABLE 13–11 provides the key demographic sent antigen to CD4-positive T cells. characteristics of the spondyloarthropathies. Only a minority of people with the B27 gene develop spondylitis. While 90% of ■ THEORIES OF PATHOGENESIS Caucasian patients with ankylosing spondyli- tis are B27-positive, far fewer African Genetic, immunologic, and environmental Americans or Asians with this disease have factors appear to work in concert in the this antigen.

CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 71 • NUMBER 3 MARCH 2004 185 Downloaded from www.ccjm.org on September 26, 2021. For personal use only. All other uses require permission. Molecular mimicry T ABLE 2 and an environmental stimulus The shared amino acid sequence between the Common features of the antigen-binding region of HLA B*2705 and spondyloarthropathies nitrogenase from Klebsiella pneumoniae sup- Inflammatory back pain ports molecular mimicry as a possible mecha- Morning stiffness that is reduced nism for the induction of spondyloarthropathy with activity in genetically susceptible hosts by an environ- mental stimulus, such as bacteria in the gas- Peripheral arthritis 12 Typically asymmetric, occurring trointestinal tract. Another possible mecha- predominantly in the lower limbs nism is presentation of an arthritogenic pep- tide from enteric bacteria by specific HLA Enthesitis molecules. Many patients with ankylosing insertion spondylitis have subclinical gastrointestinal Plantar fascia insertion on calcaneus tract and elevated serum Patella, superior and inferior aspects Tibial tuberosity immunoglobulin A antibodies directed against Metatarsal heads Klebsiella. The bacteria may invade the gas- Base of fifth metatarsal joint trointestinal tract of a genetically susceptible Iliac spine, iliac crest host, leading to chronic inflammation and Ischial tuberosity increased permeability. Over time, bacterial Tarsal region antigens containing arthritogenic peptides Greater trochanter enter the blood stream. Bacterial antigens are Lateral epicondyle thought to play a role in the pathogenesis of Distal scapula reactive arthritis.13 Further studies are needed Distal ulna to establish their exact role in the pathogene- sis of reactive arthritis and related arthritides. Experimental work with transgenic mice and Radiographic evidence of reactive proliferation of new bone at the site The ESSG rats transfected with human HLA-B27 and of enthesitis beta-2-microglobulin has shown that certain criteria are strains develop a multisystemic illness resem- Radiographic bling spondyloarthropathy, whereas identical Characteristic extra-articular features commonly animals raised in a germ-free environment (eg, anterior uveitis) used to remain healthy.14,15 Significant family history facilitate ■ CLASSIFICATION AND DIAGNOSIS Presence of human leukocyte antigen B27 the diagnosis The system most commonly used to classify spondyloarthropathies for diagnostic purpos- es10 is the European Spondyloarthropathy • Alternating buttock pain Study Group (ESSG) criteria,10 which have a • Enthesitis sensitivity of 83.5% and a specificity of 95.2%. • Sacroiliitis. Diagnosis is based on the presence of one of According to the Amor criteria,16 which two major criteria (inflammatory spinal pain are less commonly used, the diagnosis is based or synovitis) plus one or more of the following: on a total score derived from consideration of • Positive family history of ankylosing 12 weighted criteria, which include history, spondylitis, psoriasis, acute uveitis, reactive clinical presentation, radiologic findings, arthritis, or inflammatory bowel disease (all genetic background, and response to treat- linked to the presence of B27 and spondylitis) ment. This method is less convenient than • Psoriasis the ESSG criteria. Its rates of sensitivity • Inflammatory bowel disease (90.8%) and specificity (96.2%) are statisti- • Urethritis, cervicitis, or acute diarrhea cally comparable to those of the ESSG less than 1 month before arthritis method.17

CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 71 • NUMBER 3 MARCH 2004 189 Downloaded from www.ccjm.org on September 26, 2021. For personal use only. All other uses require permission. SPONDYLOARTHROPATHIES KIRATISEAVEE AND BRENT

T ABLE 3 Characteristics of spine and eye disease in the spondyloarthropathies

SACROILIITIS SPONDYLITIS SYNDESMOPHYTES UVEITIS

Ankylosing spondylitis Symmetric Continuous, ascending Delicate, marginal Acute, unilateral, recurrent Reactive arthritis Asymmetric Discontinuous* Bulky, nonmarginal Acute, unilateral, recurrent Psoriatic arthritis Asymmetric Discontinuous Bulky, nonmarginal Chronic, bilateral Enteropathic Symmetric Continuous, ascending Delicate, marginal Chronic, bilateral spondyloarthropathy Undifferentiated None Minimal Occasional Uncommon, usually acute spondyloarthropathy unilateral

*Areas of spinal involvement are not continuous or contiguous with areas of normal-appearing spine between areas of spondylitis.

These general diagnostic criteria are use- Enthesitis and dactylitis ful for the diagnosis of spondyloarthropathies, Enthesitis is inflammation at the site of including atypical, undifferentiated forms. attachment of ligaments, tendons, and other structures onto bone. It is a common clinical ■ GENERAL FEATURES OF ALL feature of spondyloarthropathy and is found SPONDYLOARTHROPATHIES most often in the heel or knee (TABLE 2). It may occasionally be seen in , The features shared by all spondyloarthrop- systemic , or sarcoidosis Elevated ESR, athies (TABLE 2, TABLE 3) are inflammatory back but is rare in other diseases. and CRP are pain, peripheral arthritis, enthesitis, dactylitis, Dactylitis, or “sausage digit,” is less com- and uveitis. But even though all types of mon than enthesitis and is found more often common, spondyloarthropathy can exhibit these fea- in reactive arthritis and psoriatic arthritis than but often not tures, the pattern of these features helps define in the other spondyloarthropathies. It is occa- the distinct form of spondyloarthropathy. sionally seen in sarcoidosis but is rare in other correlated with For example, symmetric sacroiliitis, grad- rheumatic diseases. disease activity ually ascending spondylitis, and delicate, marginal syndesmophytes (intervertebral Uveitis bony bridges) are seen more commonly in Uveitis in ankylosing spondylitis and reactive ankylosing spondylitis, whereas asymmetric arthritis is usually acute, unilateral, and recur- sacroiliitis, discontinuous spondylitis, and rent and rarely involves posterior elements. In bulky, nonmarginal syndesmophytes are more contrast, uveitis in patients with psoriatic common in reactive arthritis and psoriatic arthritis and associated with arthritis. Sacroiliac and lumbar spine disease inflammatory bowel disease is often chronic are not typically found in rheumatoid arthri- and bilateral and more often involves posteri- tis. or elements.

Peripheral arthritis Laboratory features of the peripheral joints Patients with a spondyloarthropathy are often can occur in patients with spondyloarthropa- found to have the B27 antigen, but B27 anti- thy. However, the arthritis is usually asymmet- gen status lacks specificity and therefore is not ric, distinguishing it from the typical symmet- itself diagnostic. Serologic tests for rheuma- ric of rheumatoid arthritis and toid factor and antinuclear antibody are usual- other connective tissue diseases. ly negative in patients with a spondy-

192 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 71 • NUMBER 3 MARCH 2004 Downloaded from www.ccjm.org on September 26, 2021. For personal use only. All other uses require permission. T ABLE 4 Inflammatory vs degenerative : A comparison of features

FEATURE INFLAMMATORY SPINAL DISEASE DEGENERATIVE SPINAL DISEASE

Age at onset Younger than age 40 From age 20 to age 90 Type of onset Insidious Variable Duration Longer than 3 months Variable Morning stiffness Longer than 30 minutes Less than 30 minutes Effect of physical activity Improves symptoms Worsens symptoms Radiation of pain Diffuse Radicular Multisystem disease Yes No Family history Often Variable

loarthropathy. The erythrocyte sedimentation Peripheral skeletal involvement rate (ESR) and the C-reactive protein (CRP) Tenderness may occur over sites of enthesitis, concentration are often elevated, but eleva- including costosternal junctions, spinous tions may not correlate with disease activity. processes, iliac crests, greater trochanters, ischial tuberosities, tibial tuberosities, or heels ■ ANKYLOSING SPONDYLITIS at the insertion of the Achilles tendon or plantar fascia. Axial skeletal involvement Hips and shoulders are the most fre- Back pain is an extremely common complaint quently involved peripheral joints in anky- Back pain in medical practice, occurring in up to 80% of losing spondylitis. Asymmetric peripheral in early the general population, and the pain is most arthritis occurs in 35% of patients, whereas commonly due to a mechanical problem. enthesitis occurs in 20%. Hip and ankle ankylosing In ankylosing spondylitis, however, the pain are more common initial presentations spondylitis is back pain is due to inflammation (TABLE 4).18 if the disease starts in childhood. The patient may first feel pain from the Temporomandibular joint involvement not mechanical sacroiliac joints deep in the gluteal regions. occurs in about 10% of patients. but due to This pain is insidious in onset. It is dull and difficult to localize and is often worse on Extra-articular manifestations inflammation awakening. Anterior uveitis or iridocyclitis (inflamma- The Schober test measures spinal mobili- tion of the iris and ciliary body) is the most ty with bending, although a positive test is not common extra-articular manifestation of specific for ankylosing spondylitis. Spinal ankylosing spondylitis, occurring in 25% to mobility with bending can be seen to improve 30% of patients at some time during the with treatment. course of the disease. Anterior uveitis in the Buttock pain is typically either unilateral absence of spondylitis is also associated with or alternating from side to side. With subse- the B27 antigen. quent involvement of the thoracic spine, Other extra-articular manifestations are including costovertebral, costosternal, and uncommon and usually occur late in the manubriosternal joints, patients may experi- course of the disease: ence chest pain that is accentuated by cough- Cardiac involvement may include ing or sneezing and is sometimes characterized ascending aortitis, aortic insufficiency, con- as “pleuritic.” Mild to moderate reduction of duction abnormalities, cardiomegaly, and chest expansion may occur. pericarditis.

CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 71 • NUMBER 3 MARCH 2004 193 Downloaded from www.ccjm.org on September 26, 2021. For personal use only. All other uses require permission. SPONDYLOARTHROPATHIES KIRATISEAVEE AND BRENT

Key feature FIGURE 2. Radiograph of the lumbar spine in a patient with ankylosing spondylitis of ankylosing showing syndesmophyte formation spondylitis: including bridging (arrow) due to FIGURE 1. Radiograph of the lumbar spine ossification of the annulus fibrosus. inflammatory- in a patient with ankylosing spondylitis showing reactive sclerosis and erosions pattern back at the corners of the vertebral bodies, or begin after age 40 or in childhood. Two fea- pain with “shiny corners”(arrow). tures of the history are critically important: inflammatory-pattern back pain with stiff- stiffness and Lung involvement is characterized by ness and a family history of ankylosing a family history slowly progressive fibrosis of the upper lobes spondylitis. that appears, on average, 2 decades after the The diagnosis is usually established by of the disease onset of ankylosing spondylitis. The lesions radiographic evidence of bilateral sacroili- may cavitate and be colonized by Aspergillus itis,19,20 in addition to a clinical feature such species. as inflammatory back pain, limitation of lum- Neurologic complications can be caused bar spine motion, or decreased chest expan- by fracture, instability, or compression of the sion. Testing for the B27 antigen has no value spine. is a rare but in routine screening and should not be regard- serious complication of long-standing ankylos- ed as diagnostic or confirmatory in patients ing spondylitis. with back pain.21

Diagnostic considerations Laboratory and radiologic evaluation Clinical manifestations of ankylosing An elevated ESR or CRP is seen in up to 75% spondylitis usually begin in late adoles- of patients with ankylosing spondylitis, but cence or early adulthood. In rare cases, they this may lack correlation with clinical disease

194 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 71 • NUMBER 3 MARCH 2004 Downloaded from www.ccjm.org on September 26, 2021. For personal use only. All other uses require permission. SPONDYLOARTHROPATHIES KIRATISEAVEE AND BRENT

with gradual ossification of the annulus fibro- sus and eventual “bridging” between vertebrae by syndesmophytes (FIGURE 2). This may ulti- mately result in a virtually complete fusion of the , resulting in the “bam- boo spine” (FIGURE 3). Bony erosion and osteitis at sites of osseous attachment of tendons and ligaments are common, particularly at the cal- caneus, ischial tuberosities, iliac crest, femoral trochanters, and spinous processes of verte- brae.

■ REACTIVE ARTHRITIS AND REITER SYNDROME

Reactive arthritis is an acute spondyloarthrop- athy that usually follows a urogenital or enteric infection, often in patients positive for the HLA-B27 antigen, although this is less fre- quent than in ankylosing spondylitis. Reiter syndrome22,23—arthritis, urethritis/cervicitis, and conjunctivitis—is now considered a subset of reactive arthritis. Diseases such as gonococcal arthritis and inflammatory bowel disease can mimic reactive arthritis and should be excluded before making the diagnosis of reactive Gonococcal FIGURE 3. Radiograph of the lumbar spine arthritis. arthritis and in a patient with late-stage ankylosing spondylitis showing extensive Articular manifestations inflammatory syndesmophyte formation with bridging The most distinctive musculoskeletal mani- ossification of the annulus fibrosus bowel disease (“bamboo spine”). festation of reactive arthritis is enthesitis, occurring in 70% of patients, most commonly can mimic in the heel or knee regions. reactive activity. A mild normochromic, normocytic In reactive arthritis, the arthritis typically anemia is present in 15% of patients. appears within 1 to 4 weeks of infectious arthritis Radiographic changes of the sacroiliac exposure. Constitutional symptoms are usual- joints are usually symmetric and consist of blur- ly mild, and fever, if present, is low-grade. ring of the subchondral bone plate, followed by and myalgias are prominent erosions and sclerosis of the adjacent bone. early symptoms. The pattern of arthritis is typ- Conventional plain radiography of the ically an acute, additive, asymmetric pelvis is a good screening tool for evaluation mainly involving the lower of sacroiliac joints in patients with inflamma- extremities. tory back pain. In the early stages of the evo- Axial skeletal involvement including lution of syndesmophytes, there is inflamma- sacroiliitis and spondylitis occurs clinically in tion of the superficial layers of the annulus about 50% of patients, although radiographic fibrosus with subsequent reactive sclerosis and changes are seen in only 20% initially. erosion of the adjacent corners of the verte- Occasionally, the upper extremities are bral bodies (called “shiny corners”) (FIGURE 1). involved in an asymmetric fashion, especially This combination of destructive osteitis and the hands and wrists. The knee can become repair leads to “squaring” of the vertebral bod- markedly swollen, with inflammatory synovial ies. The inflammatory process is associated fluid, popliteal cyst dissection, and rupture.

196 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 71 • NUMBER 3 MARCH 2004 Downloaded from www.ccjm.org on September 26, 2021. For personal use only. All other uses require permission. Exuberant calcaneal spurs may eventually develop due to ossification of the tendinous insertions. Dactylitis or sausage digits may occur due to flexor tenosynovitis in the fingers or toes.

Extra-articular manifestations Urethritis may be a principal feature of reac- tive arthritis, but genitourinary manifestations can also include cervicitis, salpingitis, vulvo- vaginitis, aseptic pyuria, and prostatitis. A sterile form of urethritis can be seen after Salmonella and Shigella infection, as well as after urogenital or chlamydial infection. FIGURE 4. Radiograph of the heel in a The precipitating episode of diarrhea is patient with Reiter syndrome, showing often mild, but occasionally it may be bloody lesions secondary to enthesitis including and prolonged. Patients with Yersinia enteritis erosions (insertion of the Achilles tendon often have mild, recurrent abdominal com- on the calcaneus) and periosteal new bone plaints. formation (insertion of the plantar fascia Small, shallow, painless ulcers of the glans on the calcaneus) (arrow). penis and urethral meatus (balanitis circinata) have been described and may precede symp- event due to the shared genetic susceptibility toms of arthritis. In uncircumcised patients, related to the B27 antigen. the lesions are moist and are asymptomatic Cardiac complications are reported as late unless secondarily infected. The foreskin has sequelae in 10% of patients with severe, long- to be retracted during the physical examina- standing disease including conduction abnor- tion to detect these lesions. On the circum- malities and aortic regurgitation. Conduction cised penis, the lesions harden to a crust, disturbances range from a prolonged PR inter- Often, the which may scar and cause pain. val to complete heart block.24 infection has Keratoderma blennorrhagica is a hyper- keratotic skin lesion that is seen in 12% to Laboratory evaluation resolved by the 14% of patients. It begins as clear vesicles on The infection triggering the reactive arthritis time reactive erythematous bases and progresses to macules, should be sought and treated as warranted. papules, and nodules. The lesions are often Often, however, the local infection has arthritis found on the soles of the feet, but they may resolved by the time features of reactive arthri- develops also be found on the toes, palms, scrotum, tis have developed. Prolonged antibiotic treat- penis, trunk, and scalp. The lesions are indis- ment courses have not been shown to reliably tinguishable clinically and microscopically influence the course of the arthritis. from pustular psoriasis. Onycholysis may occur. Radiographic evaluation Superficial oral ulcers are an early and The characteristic radiographic feature is not transient feature of the disease. Erythema joint erosion, as in rheumatoid arthritis, but nodosum is a feature of Yersinia enteritis, and reactive new bone formation at sites of enthe- can mimic inflammatory bowel disease. sitis (FIGURE 4). The presence of bony prolifera- Conjunctivitis is the most common ocular tion as seen in reactive arthritis, psoriatic complication of reactive arthritis. It occurs in arthritis, and ankylosing spondylitis is the the majority of patients with Shigella infections most helpful radiographic feature in distin- and is often the initial symptom. It also occurs guishing these diseases from rheumatoid after Salmonella and Campylobacter infections. arthritis. Linear periostitis along the About 35% of patients with postvenereal reac- metacarpal, metatarsal, and phalangeal shafts, tive arthritis develop conjunctivitis. Uveitis and exuberant periosteal spurs with indistinct may occur as an independent, asynchronous margins can be seen along the sites of tendi-

CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 71 • NUMBER 3 MARCH 2004 197 Downloaded from www.ccjm.org on September 26, 2021. For personal use only. All other uses require permission. SPONDYLOARTHROPATHIES KIRATISEAVEE AND BRENT

nous insertion onto bone. fuse swelling of the entire digit along with In the spine, asymmetric, paravertebral, arthritis of the distal interphalangeal, proxi- comma-shaped ossification is a characteristic mal interphalangeal, and metacarpopha- finding on plain radiography in reactive langeal or metatarsophalangeal joints. arthritis and psoriatic arthritis. It typically Dactylitis is not seen in rheumatoid arthritis. involves the lower three thoracic and upper three lumbar vertebrae. In contrast to anky- Extra-articular manifestations losing spondylitis, squaring of the vertebrae is The diagnosis of psoriatic arthritis cannot be uncommon. Plain radiographs of the spine are made with certainty in the absence of psoria- abnormal in up to 70% of cases of chronic sis. A physical examination for hidden psori- reactive arthritis. atic lesions, particularly in the ears, the hair- line, the umbilical area, the gluteal crease, ■ PSORIATIC ARTHRITIS and the nails is mandatory. Nail changes such as pitting, ridging, and onycholysis are often Psoriatic arthritis is defined as inflammatory seen. Onset of arthritis occurs before skin dis- arthritis associated with psoriasis and a nega- ease in up to 20% of patients. Uveitis has been tive rheumatoid factor. reported in 18% of patients.7

Articular manifestations Laboratory and radiographic evaluation Five general patterns of joint involvement Low titers of rheumatoid factor have been have been described.25 detected in 5% to 16% of patients, and anti- • Asymmetric oligoarthritis: most joints nuclear autoantibodies have been detected may be involved; small joints of hands and in 2% to 16% of the patients with psoriatic feet are often involved, including the distal arthritis.8,26,27 If high titers of rheumatoid interphalangeal joints. factor are present in the setting of symmetric • Symmetric polyarthritis indistinguishable polyarthritis, the patient is considered to from rheumatoid arthritis: similar to that seen have rheumatoid arthritis and concomitant Acute in rheumatoid arthritis, but with a negative psoriasis. peripheral rheumatoid factor. Patients with psoriasis, Characteristic radiographic features symmetric polyarthritis, and positive rheuma- include asymmetric distribution, involvement psoriatic toid factor are considered to have rheumatoid of distal interphalangeal joints, sacroiliitis, arthritis can arthritis and concomitant psoriasis. spondylitis, bone erosions and periosteal new • Arthritis of the distal interphalangeal bone formation, bony , and resorp- mimic joints: this form is commonly associated with tion of the distal phalanges. The typical late nail changes. Inflammation of these joints is change in the peripheral joint is the “pencil- not seen in rheumatoid arthritis. in-cup” erosion marked by lysis of the distal • Destructive arthritis (): end of the proximal phalanx, with remodeling severe deforming arthritis of small joints of of the proximal end of the more distal pha- the hands and feet, with osteolysis; patients lanx. Involvement of temporomandibular, may have constitutional symptoms, usually sternoclavicular, and manubriosternal joints is associated with severe skin disease and common. The presence of periosteal reaction sacroiliitis. is also characteristic of enthesitis seen in this • Spondylitis: may occur alone or with condition. Sacroiliitis tends to be asymmetric. other forms of psoriatic arthritis and is often In the spine, as in reactive arthritis, bulky, asymptomatic; sacroiliitis is usually asymmet- nonmarginal syndesmophytes are seen more ric, and syndesmophytes are usually bulky, frequently than marginal syndesmophytes. nonmarginal, and discontinuous, as in reac- tive arthritis. ■ ENTEROPATHIC SPONDYLOARTHROPATHY Other musculoskeletal features of psoriat- ic arthritis include dactylitis, tenosynovitis, Articular manifestations and enthesitis. Dactylitis occurs in more than Between 10% and 20% of patients with 30% of patients and is characterized by a dif- inflammatory bowel disease develop arthritis,

200 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 71 • NUMBER 3 MARCH 2004 Downloaded from www.ccjm.org on September 26, 2021. For personal use only. All other uses require permission. slightly more often in Crohn disease than in . This enteropathic arthritis is usually nondestructive and reversible. Enteric spondyloarthropathy can occur in one of three patterns. One is a peripheral asymmetric arthritis with fewer than five joints involved. Second is a peripheral sym- metric polyarthritis with five or more joints involved. And the third pattern is character- ized by spinal involvement with sacroiliitis and spondylitis, sometimes with peripheral joint involvement.28,29 The peripheral arthritis may precede the diagnosis of inflammatory bowel disease and, once established, often parallels the activity of the inflammatory bowel disease. Spondylitis FIGURE 5. Dactylitis involving the left fourth toe in a patient with rarely occurs prior to the diagnosis of inflam- undifferentiated spondyloarthropathy. matory bowel disease and does not correlate with the disease activity of the underlying bowel disease. sitis, or dactylitis (FIGURE 5) should raise the sus- picion of a spondyloarthropathy. Often, the Extra-articular manifestations passage of time with repeated history and Clubbing of fingers, uveitis, erythema examinations will clarify the nature of any nodosum, and are also underlying disease. observed in inflammatory bowel disease, with a higher frequency in Crohn disease.4 ■ TREATMENT Subclinical inflammatory lesions in the gut OF SPONDYLOARTHROPATHIES are common, as observed on colonoscopic 10%–20% of mucosal biopsy studies in patients with It is difficult to test treatments for the patients with spondyloarthropathy but no gastrointestinal spondyloarthropathies because the disease— symptoms. Follow-up studies of such patients especially the spinal involvement—progress- inflammatory indicate that 6% develop inflammatory bowel es slowly. In the absence of specific treat- bowel disease disease and, of those with inflammatory gut ments, the general goals of therapy are to lesions, 15% to 25% develop clinical Crohn control symptoms of morning stiffness and develop disease.30 This suggests that patients with sub- pain, to slow or stop disease progression, and arthritis clinical inflammatory bowel disease can pre- to help the patient maintain erect posture sent with extraintestinal manifestations, mak- and functional ability. ing diagnosis more challenging. Drug therapy ■ UNDIFFERENTIATED NSAIDs have been the mainstay of therapy, but SPONDYLOARTHROPATHY they have not been shown to slow or stop dis- ease progression. Cyclooxygenase-2 inhibitors “Undifferentiated spondyloarthropathy” rep- are likely effective and have an improved gastric resents a working diagnosis for patients who safety profile compared with nonselective have manifestations consistent with a NSAIDs. Nonselective NSAIDs are often spondyloarthropathy but who do not meet avoided in spondyloarthropathy associated with the criteria for its well-defined forms. At pre- inflammatory bowel disease. NSAIDs are often sent, it is unclear if these patients have an very beneficial in patients with undifferentiated early, incomplete form of a defined spondy- spondyloarthropathy.31,32 loarthropathy. If patients do not response to NSAIDs, A good history and physical examination one of the following second-line therapies documenting inflammatory back pain, enthe- should be considered.

CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 71 • NUMBER 3 MARCH 2004 201 Downloaded from www.ccjm.org on September 26, 2021. For personal use only. All other uses require permission. Sulfasalazine patients’ axial or peripheral arthritis may Sulfasalazine has been shown to be effective respond dramatically to a therapeutic course for controlling inflammatory symptoms of of corticosteroids. spondyloarthropathy over the short term, especially peripheral musculoskeletal involve- Tumor necrosis factor inhibitors ment.33–35 Sulfasalazine was effective in Infliximab has been used in the treatment of reducing synovitis in patients with peripheral spondyloarthropathies, including ankylosing polyarticular involvement but had no effect spondylitis43,44 and psoriatic arthritis,45,46 in on axial involvement.36 Although sul- relatively small studies that showed benefit. fasalazine has disease-modifying activity in has been shown to effectively rheumatoid arthritis, this has not been docu- control the articular and cutaneous manifes- mented for spondyloarthropathy.37 tations of psoriatic arthritis47,48 and can inhibit radiographic progression as well.49 A Methotrexate recent double-blind, placebo-controlled trial Methotrexate has been shown to be effective showed etanercept to be effective in treating in the treatment of the articular and skin the musculoskeletal symptoms of ankylosing manifestations of psoriatic arthritis.38 In small spondylitis.50 Etanercept recently was studies of patients with ankylosing spondylitis, approved by the US Food and Drug there was apparent benefit for peripheral but Administration for the treatment of active not axial involvement.39–42 ankylosing spondylitis.

Corticosteroids Other therapies Oral corticosteroids are occasionally used in Physical therapy, especially extension exer- patients with a spondyloarthropathy who cises for the spine, is believed to help the have severe polyarticular symptoms unre- patient maintain erect posture. Orthopedic sponsive to other treatments, especially surgery—including total joint arthroplasty of patients with psoriatic arthritis. Intra-articu- the hips and knees and, in rare cases, correc- lar injections are used for monoarticular or tive spinal surgery—may be beneficial. Studies of TNF oligoarticular flares. In our experience, However, heterotopic bone formation may inhibitors are spondyloarthropathy does not respond as occur after total joint arthroplasty, especially well to oral or injected corticosteroids as at the hip joint, and prophylactic treatment small but does rheumatoid arthritis. However, some should be considered. encouraging

■ REFERENCES 9. Marsal S, Armadans-Gil L, Martinez M, Gallardo D, Ribera A, Lience E. Clinical, radiographic and HLA association as markers for different 1. Olivieri I, Salvarani C, Cantini F, Ciancio G, Padula A. Ankylosing patterns of psoriatic arthritis. Rheumatology 1999; 38:332–337. spondylitis and undifferentiated spondyloarthropathies: a clinical 10. Dougados M, van der Linden S, Juhlin R, et al. The European review and description of a disease subset with older age at onset. Spondyloarthropathy Study Group preliminary criteria for the classifi- Curr Opin Rheumatol 2001; 13:280–284. cation of spondylarthropathy. Arthritis Rheum 1991; 34:1218–1227. 2. Zeidler H, Mau W, Khan MA. Undifferentiated spondy- 11. Boyer SG, Lanier PA, Templin WD, Bulkow L. Spondyloarthropathy loarthropathies. Rheum Dis Clin North Am 1992; 18:187–202. and rheumatoid arthritis in Alaskan Yupik Eskimos. J Rheumatol 3. Braun J, Bollow M, Remlinger G, et al. Prevalence of spondylo- 1990; 17:489–496. arthropathies in HLA-B27 positive and negative blood donors. 12. Sieper J, Braun J. Pathogenesis of spondylarthropathies. Persistent Arthritis Rheum 1998; 41:58–67. bacterial antigen, , or both? Arthritis Rheum 1995; 4. de Keyser F, Elewaut D, de Vos M, et al. Bowel inflammation and the 38:1547–1554. spondyloarthropathies. Rheum Dis Clin North Am 1998; 24:785–813. 13. Cuchacovich R, Japa S, Huang WQ, et al. Detection of bacterial DNA 5. Zeidler H. Undifferentiated arthritis and spondyloarthropathy as a in Latin American patients with reactive arthritis by polymerase major problem of diagnosis and classification. Scand J Rheumatol chain reaction and sequencing analysis. J Rheumatol 2002; 1987; 65(suppl):54–62. 29:1426–1429. 6. Rezaian MM, Aquino ML, Brent LH. Undifferentiated spondylo- 14. Hammer RE, Maika SD, Richardson JA. Spontaneous inflammatory : comparison of clinical manifestations and outcome on disease in transgenic rats expressing HLA-B27 and human beta2 HLA-B27 negative and positive patients. Ann Rheum Dis 2000; microglobulin: an animal model of HLA-B27-associated human disor- 59(suppl 1):199. ders. Cell 1990; 63:1099–1112. 7. Queiro R, Torre JC, Belzunegui J, et al. Clinical features and predic- 15. Taurog JD, Richardson JA, Croft JT. The germ-free state prevents tive factors in psoriatic arthritis-related uveitis. Semin Arthritis development of gut and joint inflammatory disease in HLA-B27 Rheum 2002; 31:264–270. transgenic rats. J Exp Med 1994; 180:2359–2364. 8. Gladman DD, Farewell VT, Kopciuk KA, Cook RJ. HLA markers and 16. Amor B. Reiter’s syndrome. Rheum Dis Clin North Am 1998; progression in psoriatic arthritis. J Rheumatol 1998; 25:730–733. 24:677–695.

CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 71 • NUMBER 3 MARCH 2004 205 Downloaded from www.ccjm.org on September 26, 2021. For personal use only. All other uses require permission. SPONDYLOARTHROPATHIES KIRATISEAVEE AND BRENT

17. Collantes-Estevez E, Cisnal del Mazo A, Muñoz-Gomariz E. 38:618–627. Assessment of 2 systems of spondyloarthropathy diagnostic and clas- 36. Clegg DO, Reda DJ, Weisman MH, et al. Comparison of sulfasalazine sification criteria (Amor and ESSG) by a Spanish multicenter study. J and placebo in the treatment of reactive arthritis (Reiter’s syn- Rheumatol 1995; 22:246–251. drome). A Department of Veterans Affairs Cooperative Study. 18. Calin A. Seronegative spondyloarthritides. Med Clin North Am 1986; Arthritis Rheum 1996; 39:2021–2027. 70:323–336. 37. Thomson GT, Thomson BR, Thomson KS, Ducharme JS. Clinical effi- 19. van der Linden S, Valkenburg HA, Cats A. Evaluation of diagnostic cacy of mesalamine in the treatment of the spondyloarthropathies. J criteria for ankylosing spondylitis. Arthritis Rheum 1984; 27:361–368. Rheumatol 2000; 27:714–718. 20. van der Linden S, van der Heijde D. Ankylosing spondylitis. 38. Cuellar ML, Espinoza LR. Methotrexate use in psoriasis and psoriatic In: Ruddy S, Harris J, Sledge CM, editors. Kelley’s Textbook of arthritis. Rheum Dis Clin North Am 1997; 23:797–809. Rheumatology. Philadelphia: WB Saunders, 2001:1039–1053. 39. Sampiao-Barros PD, Costallat LT, Bertolo MB, Neto JF, Samara AM. 21. Khan MA, Khan MK. Diagnostic value of HLA-B27 testing ankylosing Methotrexate in the treatment of ankylosing spondylitis. Scand J spondylitis and Reiter’s syndrome. Ann Intern Med 1982; 96:70–76. Rheumatol 2000; 29:160–162. 22. Reiter H. Über eine bisher unerkannte Spirochateninfektion 40. Biasi D, Carletto A, Caramaschi P, Pacor ML, Maleknia T, Bambara (Spirochaetosis arthritica). Dtsch Med Wochenschr 1916; 42:1535. LM. Efficacy of methotrexate in the treatment of ankylosing 23. Wilkens RF, Arnett FC, Bitter T, et al. Reiter’s syndrome. Evaluation of spondylitis: a three-year open study. Clin Rheumatol 2000; preliminary criteria for definitive disease. Arthritis Rheum 1981; 19:114–117. 24:844–849. 41. Marshall RW, Kirwan JR. Methotrexate in the treatment of ankylos- 24. Deer T, Rosencrance JG, Chillag SA. Cardiac conduction manifesta- ing spondylitis. Scand J Rheumatol 2001; 30:313–314. tions of Reiter’s syndrome. South Med J 1991; 84:799–800. 42. Roychaudhry B, Bintley-Bagot S, Hunt J, Tunn EJ. Methotrexate in 25. Gladman DD, Rahman P. Psoriatic arthritis. In: Ruddy S, Harris J, severe ankylosing spondylitis: a randomized placebo controlled, dou- Sledge CM, editors. Kelly’s Textbook of Rheumatology. Philadelphia: ble-blind observer study [abstract]. Rheumatology 2001; 40(suppl WB Saunders, 2001:1071–1079. 1):43. 26. Torre Alonso JC, Rodriguez Perez A, Arribas Castrillo JM, Ballina 43. Van den Bosch F, Kruithof E, Baeten D, de Keyser F, Mielants H, Veys Garcia J, Riestra Noriega JL, Lopez Larrea C. Psoriatic arthritis: a clini- EM. Effects of a loading dose regimen of three infusions of chimeric cal, immunological and radiological study of 180 patients. Br J monoclonal antibody to tumour necrosis factor alpha (infliximab) in Rheumatol 1991; 30:245–250. spondyloarthropathy: an open pilot study. Ann Rheum Dis 2000; 27. Jones SM, Armas JB, Cohen MG, Lovell CR, Evison G, McHugh NJ. 59:428–433. Psoriatic arthritis: outcome of disease subsets and relationship of 44. Brandt J, Haibel H, Cornely D, et al. Successful treatment of active joint disease to nail and skin disease. Br J Rheumatol 1994; ankylosing spondylitis with the anti-tumor necrosis factor alpha 33:834–839. monoclonal antibody infliximab. Arthritis Rheum 2000; 28. Orchard TR, Wordsworth P, Jewell DP. Peripheral arthropathies in 43:1346–1352. inflammatory bowel disease: their articular distribution and natural 45. Antoni C, Kavanaugh A, Kirkham B, et al. The infliximab multina- history. Gut 1998; 42:387–391. tional psoriatic arthritis controlled trial (IMPACT) [abstract]. Arthritis 29. Wollheim FA. Enteropathic arthritis. In: Ruddy S, Harris J, Sledge CM, Rheum 2002; 46(suppl):S381. editors. Kelly’s Textbook of Rheumatology. Philadelphia: WB 46. Feletar MH, Brockbank JE, Schentag CT, Lapp V, Gladman DD. Saunders, 2001:1081–1088. Treatment of recalcitrant psoriatic arthritis patients with inflix- 30. Smale S, Natt RS, Orchard TR, Russell AS, Bjarnason I. Inflammatory imab—a 12-month observational study of 16 patients [abstract]. bowel disease and spondyloarthropathy. Arthritis Rheum 2001; ACR/ARHP Annual Scientific Meeting, New Orleans, Louisiana, 44:2728–2736. 2002. 31. Rezaian MM, Brent LH. Undifferentiated spondyloarthropathy: 47. Mease PJ, Goffe BS, Metz J, van der Stoep A, Finck B, Burge DJ. seven-year follow-up study of 357 patients. Arthritis Rheum 2001; Etanercept in the treatment of psoriatic arthritis and psoriasis: a ran- 44(suppl):S93. domised trial. Lancet 2000; 356:385–390. 32. Dougados M, Maetzel A, Mijiyawa M, Amor B. Evaluation of sul- 48. Mease PJ. Improvement in disease activity in patients with psoriat- phasalazine in the treatment of spondyloarthropathies. Ann Rheum ic arthritis receiving etanercept (Enbrel): results of a phase 3 mul- Dis 1992; 51:955–958. ticenter clinical trial [abstract]. Arthritis Rheum 2001; 33. Clegg DO, Reda DJ, Abdellatif M. Comparison of sulfasalazine and 44(suppl):S90. placebo for the treatement of axial and peripheral articular manifes- 49. Ory P, Sharp JT, Salonen D, et al. Etanercept (Enbrel) inhibits radio- tations of the seronegative spondyloarthropathies: a Department of graphic progression in patients with psoriatic arthritis [abstract]. Veterans Affairs cooperative study. Arthritis Rheum 1999; Arthritis Rheum 2002; 46(suppl):S196. 42:2325–2329. 50. Gladman DD, Sack KE, Davis JC. Treatment of ankylosing spondylitis 34. Clegg DO, Reda DJ, Weisman MH, et al. Comparison of sulfasalazine and by inhibition of tumor necrotic factor alpha. N Engl J Med 2002; placebo in the treatment of ankylosing spondylitis. A Department of 346:1349–1356. Veterans Affairs cooperative study. Arthritis Rheum 1996; 39:2004–2012. 35. Dougados M, van der Linden S, Leirisalo-Repo M, et al. Sulfasalazine ADDRESS: Lawrence H. Brent, MD, Einstein Arthritis Center, 5501 Old in the treatment of spondyloparthropathy. A randomized, multicen- York Road, Korman 103, Philadelphia, PA 19141; ter, double-blind, placebo-controlled study. Arthritis Rheum 1995; e-mail [email protected].

206 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 71 • NUMBER 3 MARCH 2004 Downloaded from www.ccjm.org on September 26, 2021. For personal use only. All other uses require permission.