Seronegative Spondyloarthropathies
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[edit] Seronegative Spondyloarthropathies
Nancy Y.N. Liu
Bruce R. Weinstein
The term seronegative spondyloarthropathies refers to a group of rheumatic diseases that share a number of clinical, radiologic, and pathogenetic features.These disorders are characterized by (1) inflammatory arthritis with a predilectionfor involvement of the axial skeleton and sacroiliac (SI) joints; (2) enthesopathy, defined as inflammation at sites of insertion of tendon, ligament, or fascia to bone; (3) asymmetric, peripheral oligoarthritis; (4) extraarticular features, most notably ophthalmologic, mucocutaneous, and urogenital involvement; (5) familial predisposition; (6) strong association with the class I HLA-B27 antigen; and (7) absence of rheumatoid factor.This group of disorders includes ankylosing spondylitis, reactive arthritis, Reiter's syndrome, psoriatic arthritis, arthropathy of inflammatory bowel disease (IBD), juvenile-onset ankylosing spondylitis, undifferentiated spondyloarthropathies, and uveitis associated with the HLA-B27 haplotype.
[edit] PATHOGENESIS
The pathogenesis of the seronegative spondyloarthropathies is unclear.The prevalence of HLA-B27 in the Caucasian population is 8%, but almost 90% of white patients with ankylosing spondylitis, Reiter's syndrome, reactive arthritis, or juvenile ankylosing spondylitis are HLA-B27 positive.The significance of this association, however, remains to be elucidated.Researchers have developed several hypotheses based on the HLA-B27 association and other clinical observations.[1] The first hypothesis is that molecular mimicry between HLA-B27 antigen and bacterial peptides results in cross-reactivity with self-peptides.In the second hypothesis, HLA-B27 binds arthritogenic bacterial peptides and elicits a cytotoxic T-cell response; subsequently the cytotoxic T cell cross-reacts with structurally similar self-peptides in articular tissue, which are also presented by HLA-B27.The third and most likely theory is that the presence of B27 molecules lacking β2-microglobulin results in binding of B27 to exogenous bacterial peptides, which are presented to T cells.Researchers reported the spontaneous development of colitis, arthritis, psoriasiform skin lesions, and genitourinary inflammation in B27 transgenic rats.Other groups developed transgenic mice lacking β2-microglobulin that experienced skin and joint changes in the presence of bacterial infections.Both these experiments support the direct role of HLA-B27 in the manifestation of disease.
The onset of arthritis after a urogenital or enteric infection by particular organisms (Chlamydia, Salmonella, Shigella, Yersinia, and Campylobacter) suggests that bacterial agents can initiate arthritis in a genetically susceptible host.Viable organisms are difficult to culture from joint fluid or synovium.With more sensitive polymerase chain reaction (PCR) techniques, however, bacterial ribonucleic acid (RNA) has been detected in the synovial white blood cells or tissue.Therefore the persistence of infection may induce specific synovial immune responses, particularly a cell-mediated one.
The close association of the gastrointestinal (GI) tract with the spondyloarthropathies has been supported by the presence of asymptomatic, microscopic intestinal inflammation in patients with ankylosing spondylitis, reactive arthritis, and undifferentiated spondyloarthropathies.Ileocolonoscopies and random biopsies performed on patients with these diseases revealed that 65% had subclinical IBD.Researchers therefore postulate that chronic inflammation in the intestinal tract may increase mucosal permeability and facilitate entrance of exogenous antigens into the circulation.Subsequently, these antigens initiate joint inflammation through various immune mechanisms.
It is likely that genetics (particularly HLA-B27), bacterial infections, and increased intestinal mucosa permeability make variable contributions to the pathogenesis of the spondyloarthropathies.Other possible pathogenetic mechanisms are mentioned in the following sections on specific disorders.
[edit] ANKYLOSING SPONDYLITIS
[edit] Epidemiology
Ankylosing spondylitis (AS) is often considered the prototype of the seronegative spondyloarthropathies.Although often unrecognized, AS has an overall prevalence of approximately 0.2%.[2] AS usually begins in adolescence or young adulthood, with a threefold greater incidence in men than women.Men often experience more severe axial manifestations.AS is a race-related disease, affecting whites and some Native Americans more frequently than African-Americans.Approximately 90% of patients with AS have the HLA-B27 antigen, although only 2% of B27-positive individuals have clinically detectable disease.Familial aggregation is quite pronounced.About 10% to 20% of B27-positive first-degree relatives of B27-positive patients with AS have or will develop AS.
[edit] Pathophysiology
AS is characterized by symmetric sacroiliitis and a progressive inflammatory arthritis of the axial skeleton and is often accompanied by enthesitis or inflammation at ligamentous insertions into bone.In 90% of patients the spine tends to be involved in an ascending manner, from the lumbar to the cervical region.Inflammation is followed by the formation of granulation tissue, calcification, and eventual ossification around the intervertebral disk margins, the apophyseal joint capsule insertion on bone, and the ligamentous insertions on the spine (e.g., flaval, interspinal, and supraspinal ligaments; costovertebral joints), referred to as enthesopathy.
[edit] Patient Evaluation
[edit] History.
The earliest complaint in patients with AS corresponds to SI and lower axial skeleton pathology and consists of chronic, insidious low back pain and stiffness.The pain is dull and often localized in the gluteal or lower lumbar region and proximal posterior thigh.Other patients may have difficulty localizing the back pain.Morning back stiffness for more than 60 minutes is an important feature.In contrast to low back syndromes from mechanical causes, this stiffness tends to be exacerbated by inactivity and immobility and improved with exercise (see Chapter 127 ).Discomfort and stiffness may interrupt sleep, and the patient must arise to stretch and walk.
Nonaxial symptoms may provide the first clue to diagnosis.A young man with synovitis in a large lower extremity joint, tenosynovitis, or enthesopathy of the Achilles or supraspinatus tendon unrelated to mechanical causes should prompt the physician to consider AS in the differential diagnosis.The temporomandibular or sternoclavicular joints are less often involved.The patient may describe a pleuritic chest pain, which represents the enthesopathy at the costosternal and costovertebral joints.
Acute anterior uveitis, the most frequent and important extraarticular manifestation, is present in 25% of AS patients and is more common in patients who are HLA-B27 positive.Conversely, 50% of patients with uveitis are HLA-B27 positive; of these, one half or more have AS or reactivearthritis.[3] The onset is usually acute, starting with mild prodrome of eye discomfort or headache, followed by severe eye pain, redness, photophobia, blurry vision, and increased lacrimation.The episodes are usually unilateral, lasting several weeks to several months.Recurrences can occur in either eye.
Cardiac, pulmonary, renal, and neurologic involvement is less common in AS.Aortic regurgitation and conduction abnormalities, such as complete heart block, occur in less than 5% of patients.Restrictive lung disease, documented on pulmonary function tests, is secondary to ossification of rib and sternal articulations but is rarely clinically significant.Upper lobe pulmonary fibrosis, interstitial lung disease, and cavitation occur in less than 1% of patients.Chest radiographs are insensitive to early interstitial disease, and high-resolution computed tomography (HRCT) may be needed to evaluate AS patients with symptoms of dyspnea.Cauda equina syndrome, atlantoaxial subluxation, spinal stenosis, and spinal fractures affect less than 5% of all AS patients.
Although usually not prominent, constitutional symptoms may develop, consisting of fatigue, weight loss, and low-grade fever.A family history of spondyloarthropathy or HLA-B27 positivity should be sought.
[edit] Physical Examination.
Physical findings reflect the predilection of this disease for the axial skeleton, including the SI joints, large peripheral joints, and the entheses.The apophyseal joints, which have the principal role in spinal flexion, are involved early in AS.The Shober test can detect limitation in flexion of the lumbar spine (Fig.137-1).Lateral flexion, extension, and rotation of the back are also diminished; these measurements are part of the initial evaluation and subsequent follow-up.Limitation of neck movement tends to occur later in AS.Chest expansion, normally greater than 5 cm from full inspiration to end expiration, is often diminished.Inflammation of the SI joints can be assessed in several ways (Fig.137-2).Palpation of inflamed entheses over the spinous processes, ischial tuberosities, greater trochanters, iliac crest, costovertebral and costochondral junctions, Achilles tendons, and plantar fascia may elicit pain.Since the hips or shoulders are involved in one third of patients, range of motion (ROM) measurements of these joints should be part of the physical examination.
Symptoms of uveitis are usually more helpful than the physical examination in differentiating uveitis from conjunctivitis.A slit-lamp examination is required to make the definitive diagnosis.The other extraarticular manifestations are relatively uncommon and are usually seen after AS is well established.The history and physical examination need to be directed toward these potential complications during routine follow-up.The most catastrophic but fortunately rare complication of AS involves neurologic sequelae.Minor trauma can fracture the cervical spine; the cervical region is the most vulnerable.Spinal cord compression and cauda equina syndrome may start with urinary and fecal incontinence.Similar to rheumatoid arthritis, general anesthesia canpose some risk for neurologic injury if cervical spine disease is present.Lateral x-ray studies of the neck in flexion and extension are useful to evaluate ROM and infrequent cervical subluxations.The anesthesiologist should be informed regarding mode of intubation.
[edit] Laboratory and Radiologic Studies
No laboratory tests are diagnostic.Nonspecific evidence of systemic inflammatory disease frequently includes an elevated erythrocyte sedimentation rate (ESR) and a normochromic normocytic anemia.HLA-B27 testing is most useful as a diagnostic adjunct or when a patient presents with uveitis but is generally not indicated as a screening or routine diagnostic test because of this antigen's prevalence in the general population as well as the prevalence of AS.
Routine anteroposterior (AP) x-ray study of the pelvis often demonstrates symmetric sacroiliitis (Fig.137-3).In early disease, radiologic abnormalities may be unilateral, subtle, or inapparent.SI joint views can better demonstrate these findings in mild cases.Computed tomography (CT) and magnetic resonance imaging (MRI) scans have the greater sensitivities.Both plain SI joint views and CT scans are associated with greater radiation exposure to the gonads than are routine pelvic x-ray studies.X-ray studies of the spine and inflamed entheses can reveal bony erosions, osteitis, ossification, or syndesmophytes (Fig.137-4).Bony ankylosis is a characteristic but late finding.Osteoporosis of the spine, kyphosis, and symmetric joint space narrowing of the hips and shoulders may be present.
[edit] Clinical Course
Expression of AS is highly variable.The course tends to progress slowly, punctuated with acute flares.Severe, unrelenting AS resulting in complete ankylosis of the spine and hips is uncommon.Life expectancy is not reduced.Most patients maintain good functional capacity and continue to work.[4] Frequently the first 10 years of AS can serve as a rough barometer of disease severity over a patient's lifetime.If the hips and other peripheral joints are not involved within the first decade of disease, they are unlikely to become affected later.
[edit] REITER'S SYNDROME AND REACTIVE ARTHRITIS
Reiter's syndrome is probably the most common cause of asymmetric inflammatory arthritis of the lower extremities in young men.The term Reiter's syndrome is gradually being supplanted by reactive arthritis(ReA).This latter termencompasses a broader group of patients, in whom inflammatory arthritis develops after an infection, usually in the genitourinary (GU) or GI tract; reactive arthritides are also distinguished on the basis of antecedent infection sites by referring to them as postvenereal (GU) and postenteric (GI).The term B27-associated ReA is used to emphasize the heterogeneity of these diseases and to differentiate them from other postinfectious diseases, such as rheumatic fever.[2] Reiter's syndrome is still used to describe postvenereal ReA.
[edit] Epidemiology
Approximately 1% of patients develop ReA after nongonococcal urethritis associated with Chlamydia trachomatis. Similarly, 2% to 3% of patients develop ReA after an enteric infection with one of the Salmonella species, Shigella flexneri, Campylobacter jejuni, or Yersinia.[5]Yersinia- associated ReA is reported more often in other countries and is rare in the United States.Approximately 60% to 80% of patients who develop ReA have HLA-B27 antigen, and conversely, approximately 20% of B27-positive individuals will develop ReA after exposure to the organisms listed.The postenteric form displays equal gender distribution, whereas the postvenereal type has a male predominance.
[edit] Patient Evaluation
ReA is a multisystem disorder and often unrecognized.The classic Reiter's syndrome triad of arthritis, urethritis, and conjunctivitis is frequently not present or is not identified.Arthritis typically develops 1 to 3 weeks after the GU or GI infection.Urethritis symptoms may be quite subtle and in women are often absent.Constitutional symptoms of fever and weight loss may be present, particularly during the acute phase, but are usually mild.
The hallmark of ReA is the development of a sterile synovitis and enthesitis similar to that seen in AS.Although ReA favors the joints of the lower extremities, especially the knees, ankles, and feet, the upper extremities may also be affected.Early in the illness, the patient complains of joint stiffness, myalgias, and low back pain.Initial physical findings may be scant.The combination of tenosynovitis, periostitis, and arthritis affecting the fingers or toes may give rise to a characteristic diffuse swelling known as sausage digits(Fig.137-5).Sacroiliitis and axial involvement occur less often in ReA than in AS.Sacroiliitis is frequently unilateral and often is not identified by conventional radiology early in the illness.True spinal ankylosis occurs much less frequently than in AS.A B27-positive individual is more likely to develop inflammatory back symptoms.Urethritis, the primary feature of postvenereal ReA, can be a secondary feature in the postenteric form.Dysuria, urinary frequency, urethral erythema, and prostatitis are common in males, whereas urethritis and cervicitis are often undetected in females.
Approximately 20% of patients with the postvenereal form of ReA develop the classic skin lesion, keratoderma blennorrhagicum(Fig.137-6).It is strikingly similar topustular psoriasis and typically affects the soles of the feet but can also involve the genitalia, scalp, and trunk.Nails may show onycholysis and thickening. Circinate balanitis produces small, usually painless superficial erosions on the glans penis (Fig.137-7).The oral mucosa is also frequently affected by painless, superficial ulcerations.Conjunctivitis, which can be mild and asymptomatic, occurs often, whereas acute anterior uveitis, another ocular manifestation, is strongly associated with B27-positive patients.Cardiac, pulmonary, renal, and neurologic complications may occur in similar pattern and frequency as in AS.
[edit] Laboratory and Radiologic Studies
No definitive tests can establish a diagnosis of ReA.Since aggressive treatment with antibiotics may improve the natural history of postchlamydial ReA, Chlamydia organisms should be identified and treated accordingly.[6] It is still not clear whether aggressive treatment of the responsible bowel pathogens has the same beneficial effect on the natural history of the postenteric form.
The synovial fluid from an inflamed joint is usually inflammatory but is otherwise nondiagnostic.Analysis of the fluid is important to exclude infection and crystal disease.The ESR is often elevated.Leukocytosis and normochromic normocytic anemia may occur.HLA-B27 determination may help diagnostically in difficult cases, particularly in the evaluation of an uncharacterized chronic monoarticular or pauciarticular arthritis without other distinguishing features.This antigen can also provide prognostic information about the development of uveitis and axial disease.
The enthesopathic features of ReA may cause periostitis, erosions, and reactive new bone formation.Periosteal spurs occur most frequently in the feet and heels.Axial disease, including sacroiliitis, may be seen, although it is often not radiographically evident early in the disease.
[edit] Clinical Course
ReA is marked by bouts of exacerbation and remission.Typically, the first episode subsides in 3 to 6 months.Skin manifestations may persist longer.Severity varies considerably.The postvenereal form has a greater propensity for chronic arthritis, enthesitis, uveitis, and other extraarticular manifestations than the postenteric form.This difference may be related to degrees of arthritogenicity of the various organisms, the difficulty in completely eradicating Chlamydia organisms from the GU tract, or recurrent antigen exposure.A significant minority of patients develop persistent joint symptoms and chronic axial involvement similar to AS.
[edit] Human Immunodeficiency Virus
Human immunodeficiency virus (HIV) infection has been associated with a broad spectrum of cutaneous and musculoskeletal disorders, including arthritis and enthesopathies (see Chapter 32 ).The significance of these rheumatic associations, however, is still controversial.ReA, the first rheumatic disease associated with HIV infection, can develop before, simultaneously with, or after signs of immunodeficiency.ReA associated with HIV disease is often more severe, with pronounced constitutional symptoms and aggressive arthritis and enthesitis.[7] Involvement of the foot and ankle is common and often debilitating, altering the gait, interfering with ambulation, and leading to the “AIDS foot.” Enthesopathy also affects the upper extremities.Hip and axial skeleton involvement is uncommon.Severe muscle atrophy may be prominent.Standard therapy with nonsteroidal antiinflammatory drugs (NSAIDs) is often inadequate.
The importance of HIV's association with ReA is twofold.First, the physician must consider early HIV infection in a patient presenting with Reiter's syndrome, psoriatic arthritis, or other unexplained monoarticular or pauciarticular arthritis.Second, HIV infection should be excluded before administering immunosuppressive therapy for refractory disease.Because of the severity of clinical manifestations and difficult treatment issues, a rheumatologist, a dermatologist, and infectious disease experts may be consulted to help coordinate management.
[edit] PSORIATIC ARTHRITIS
Psoriasis affects 1% to 2% of the North American white population but is less prevalent in the African-American and Native American populations.Since psoriasis is a common disease, inflammatory or noninflammatory arthritis may coexist in psoriatic patients and may not be directly related to psoriasis.Thus the true incidence of psoriatic arthritis (PsA) in patients with psoriasis is unknown, and estimates have ranged widely, from 6% to 42%.In addition, a small percentage of patients (approximately 15%) develop arthritis that may precede the onset of skin disease.PsA affects an estimated 5% to 8% of patients with psoriasis.Men and women are equally affected, but in the subsets of PsA, male predominance occurs in the spondylitic form, whereas female predominance occurs in the rheumatoid form.Onset occurs usually in the second or third decade of life but can be as late as the sixth decade.In the subset of psoriatic patients who develop spondylitis or sacroiliitis, HLA-B27 is present in 50%.The etiology of psoriasis and PsA is unknown.The causes are likely multifactorial and include genetic predisposition, with humoral and cellular abnormalities.Trauma and other environmental factors may exacerbate joint disease with the development of acroosteolysis.Infections, whether related to streptococci in the skin or to HIV, may also have some role in the pathogenesis of PsA.
[edit] Patient Evaluation
Skin disease precedes the onset of articular manifestation in 75% of patients with PsA.Concomitant presentation of skin and joint disease occurs in 10% to 15%.The remaining patients develop skin disease after the onset of inflammatory arthritis.
Five major forms of PsA have been described (Box 137-1).The most common form is an asymmetric, oligoarticular(i.e., fewer than five joints)arthritis, which affects 60% to 70% of PsA patients.Large and small joints may be affected.Dactylitis, or sausage digits, is another common feature (see Fig.137-5).Although the majority of patients are initially categorized into this group, many progress to develop asymmetric polyarthritis.
| Box 137-1 - Patterns of Psoriatic Arthritis |
|
Symmetric polyarthritis, clinically indistinguishable from rheumatoid arthritis (RA), is the second most common form, affecting 15% to 25% of PsA patients.Patients are rheumatoid factor (RF) negative and have no rheumatoid nodules.Distal interphalangeal (DIP) joint involvement, not typically described in RA, occurs in this form of PsA.In addition, radiographic evidence of proximal interphalangeal (PIP) or DIP joint ankylosis helps to differentiate the two diseases.
Isolated DIP joint involvement occurs in only 5% of PsA patients.This form of arthritis is associated with nail bed changes, including multiple nail pits and onycholysis (Fig.137-8).
Arthritis mutilans, a progressively destructive form of arthritis, also occurs in 5% of patients.Starting as DIP joint disease, the arthritis progresses with osteolysis of the phalanges, resulting in telescoping of digits or pencil-in-cup deformities on radiographs.Many of these patients also have sacroiliitis and severe skin involvement.
Isolated spondylitis/sacroiliitis also affects only about 5% of PsA patients.Inflammatory back symptoms are present.Psoriatic spondylitis may be difficult to distinguish from AS except for the presence of psoriasis.Sacroiliitis is more often radiographically asymmetric than AS.In addition, the syndesmophytes are usually nonmarginal and asymmetric, in contrast to the marginal, symmetric pattern of AS.
As with all classification schemes, some patients may not be categorized easily into one of the five subsets.Others may evolve from one pattern to another or may overlap between subsets.Often, axial involvement is silent.About 20% to 40% of PA patients have sacroiliitis on plain radiographs, but almost two thirds of these patients are asymptomatic.Enthesitis also occurs in PsA, contributing to the sausage deformities, plantar fasciitis, heel spurs, and syndesmophyte formation in the axial spine.
Skin involvement is the predominant extraarticular feature of PsA.Since most patients have skin diseases that antedate or parallel the onset of their arthritis, the diagnosis is not difficult.Patients who present with only asymmetric arthritis, tenosynovitis, or inflammatory back pain, however, require a careful search for occult skin lesions, with examination of the scalp, umbilicus, intergluteal fold, groin, external acousticmeatus, and perineum.Extensive nail pitting (greater than 20 pits per nail) and subungual hyperkeratosis are present in 80% of PsA patients; similar nail changes are found in only 20% to 30% of patients with isolated skin disease.
Aortic insufficiency and apical pulmonary fibrosis are rare complications and are associated only with patients who have spondylitis.Inflammatory eye disease occurs in approximately 30% but usually consists of conjunctivitis rather than nongranulomatous uveitis.
[edit] Laboratory and Radiologic Studies
No specific laboratory studies can confirm the diagnosis of PsA.Nonspecific indicators of inflammation are present.RF or positive antinuclear antibodies (ANAs) are present in a small percentage of patients, but these findings are likely to reflect the baseline positive rate in the general population.
Radiographic features help distinguish PsA from some of the other inflammatory arthritides (Box 137-2).In the peripheral joints the asymmetric pattern of joint involvement, along with DIP disease, are important clues.Periarticular osteopenia, a classic finding in RA, is absent in PsA despite erosive changes.Tuft resorption, bony ankylosis, and periostitis are other common features of PsA that are uncommon in RA.Axial involvement in PsA is similar to that of ReA and can usually be distinguished from AS (Table 137-1).Asymmetric, nonmarginal syndesmophytes in the thoracolumbar region, paravertebral ossification, vertebral fusion, and disk space calcification are features of psoriatic spondylitis.
Table 137-1 Radiographic Features of the Spondyloarthropathies
| Feature | AS/IBD | ReA/PsA |
|---|---|---|
| Sacroiliitis | Bilateral | Unilateral |
| Syndesmophytes | Marginal | Nonmarginal |
| Symmetric | Asymmetric | |
| Continuous | Skip levels | |
| Vertebral bodies | Squaring | Less squaring |
| Apophyseal fusion | Common | Less common |
| Box 137-2 - Radiographic Findings Common to Psoriatic Arthritis and Reactive Arthritis |
|
[edit] Clinical Course
Initially described as being relatively benign, PsA may be as severe and deforming as RA.Development of deformities may depend on severity of initial presentation.Poor prognostic indicators include multiple joint effusions (greater than five) at presentation, high level of medication use, low ESR, and presence of particular HLA antigens.
[edit] ARTHROPATHY OF INFLAMMATORY BOWEL DISEASE
The first associations between bowel disease and arthritis were described in the early 1900s.Despite these descriptions, however, the distinct entity of inflammatory arthritis occurring in patients with IBD was not accepted in the medical community until after 1960.Currently, musculoskeletal involvement is the most common extraarticular manifestation of IBD.
The etiology of IBD arthropathy is unknown (see Chapter 108 ).No HLA-B27 association has been established in patients with peripheral arthritis or asymptomatic sacroiliitis.In contrast, 50% to 75% of IBD patients with symptomatic spondylitis are HLA-B27 positive.Given these genetic and clinical differences, researchers believe that a different pathogenesis may exist for each group.Since HLA-B27 is associated with spondylitis patients, the pathogenesis in this group may be similar to theories for idiopathic AS.In the peripheral arthritis subset, since clinical disease parallels bowel disease, mechanisms directly related to gut inflammation might be more applicable.
[edit] Patient Evaluation
[edit] Peripheral Arthritis.
The incidence of peripheral arthropathy in IBD patients is 15% to 20%, with a more frequent occurrence in Crohn's disease (20%) than in ulcerative colitis (12%) patients.In addition, peripheral arthritis is more frequently associated with colonic than with ileal involvement in Crohn's disease.Peripheral joint involvement classically begins with or after the onset of bowel disease.[8] Subsequent flares also parallel disease activity in the bowel.Males and females are equally affected.Joint involvement is typically asymmetric, oligoarticular, often migratory, and lasts for weeks to months but rarely becomes chronic.The most common joint affected is the knee, followed by the ankle, elbow, and wrist.Smaller joint involvement occurs less often.Enthesopathy, such as tendinitis and plantar fasciitis, may develop.Other extraarticular features of IBD, including the skin, mucous membranes, and eyes, often are concurrently active.Erosive deformities rarely develop (less than 10%) but seem to involve large joints, particularly hips and shoulders.In the few cases of erosive arthropathy, granulomatous synovitis may be responsible.
[edit] Axial Arthropathy.
Two subsets of IBD-associated axial arthropathy exist: (1) asymptomatic sacroiliitis noted on plain radiographs and (2) symptomatic axial disease clinically indistinguishable from idiopathic AS.The incidence of asymptomatic sacroiliitis may be as high as 29%, but frank AS occurs in only 2% to 8% of IBD patients.In contrast to peripheral arthropathy, axial skeletal disease does not correlate with IBD activity.Spondylitis often precedes the development of active bowel disease by many years, thus making the diagnosis difficult.Unfortunately, even when IBD is under control or in remission, axial disease may persist or progress.Men are affected more often than women, but not to the degree in idiopathic AS.Classically, the symptoms of inflammatory back pain develop insidiously.Peripheral arthritis may coexist with axial disease and extraarticular features.
[edit] Laboratory and Radiologic Studies
Laboratory tests are nonspecific.RF is usually negative, and ESR and other indicators of inflammation are elevated.Chronic anemia may exist.Synovial fluid is inflammatory, with white blood cell counts varying from 5000 to 50,000/mm3.
Radiographs of peripheral joints usually reveal only soft tissue swelling without erosive changes.The axial findings may include shoulder and hip joint space narrowing, vertebral body squaring, symmetric sacroiliitis, osteitis pubis, marginal syndesmophytes, and progressive bony bridging cephalad, beginning in the lumbar region.All these features are indistinguishable from idiopathic AS (see Figs.137-3 and 137-4 and Table 137-1).
[edit] UNDIFFERENTIATED SPONDYLOARTHROPATHY
The current categories of spondyloarthropathies are often inadequate to encompass a spectrum of patients who may have oligoarthritis, enthesopathy, dactylitis, or inflammatory back symptoms without antecedent infection, GI symptoms, or dermatologic abnormalities.Thus the term undifferentiated spondyloarthropathies encompasses those patients with one or more of the features of spondyloarthropathy but who do not fulfill the criteria for established disease categories.The European Spondyloarthropathy Study Group developed criteria to broaden the definition of spondyloarthropathy (Box 137-3).Long-term follow-up of these patients reveals that 50% develop a defined spondyloarthropathy, 40% obtain remission, and only 10% continue with recurrent oligoarticular arthritis.
| Box 137-3 - Criteria for Spondyloarthropathy✢ |
| Rights were not granted to include this data in electronic media. Please refer to the printed book. ✢From Dougados M, van der Linden S, Nakache J: European Spondyloarthropathy Study Group (ESSG): Preliminary criteria for the classification of spondyloarthropathy, Arthritis Rheum 34:1218, 1991. |
[edit] DIFFERENTIAL DIAGNOSIS
When a patient presents with classic inflammatory back symptoms and extraarticular features, the primary care physician can easily establish the diagnosis.If the disease presents insidiously and the various symptoms and signs span many years, however, the diagnosis is less obvious and may elude the physician.The differential diagnosis of spondyloarthropathies can be separated into three categories: back pain, peripheral arthritis, and peripheral arthritis with back pain (Box 137-4).Low back pain is extremely common and has a broad differential (see earlier and Chapter 127 ).Osteoarthritis, infection (particularly in injection drug users), hyperparathyroidism, paraplegia and quadriplegia, and osteitis condensans ilii (primarily in multiparous women) can affect SI joints.These can usually be distinguished clinically and radiologically.Diffuse idiopathic skeletal hyperostosis (DISH) may be initially confused with AS, but DISH is a condition of older individuals, and both disorders have characteristic radiographic features.
| Box 137-4 - Differential Diagnosis for Spondyloarthropathies |
Axial Arthritis
|
Peripheral arthritis may be the initial or only manifestation of a spondyloarthropathy.The arthritis is classically monoarticular or oligoarticular but is sometimes polyarticular.Early RA, acute crystal disease (e.g., gout, pseudogout), acute or chronic infections (e.g., Lyme disease arthritis), osteoarthritis, sarcoidosis, and synovial neoplasm are within the differential diagnosis.Synovial fluid analysis includes crystal studies and cultures.Serologies may be helpful in the evaluation.Occasionally, synovial biopsy is necessary to exclude atypical infectious arthritis.
Disseminated gonorrheal infection (DGI) can closely resemble ReA in its articular and nonarticular features.The epidemiology of the two diseases is similar, occurring in the sexually active population.The rash of DGI is usually vesiculopustular, however, and can be easily distinguished from keratoderma blennorrhagicum.Appropriate sites (blood, joint, skin, vagina, urethra, throat, rectum) should be cultured if DGI is suspected.The diseases also may coexist in the same patient.
The symmetric pattern of PsA may be confused with RA, but PsA lacks RF, rheumatoid nodules, and swan-neck or boutonnière deformities.The involvement of DIP joints, absence of periarticular osteopenia, presence of bony ankylosis, periostitis, acroosteolysis, and bony resorption are typical for PsA or ReA but are unusual for RA.Osteoarthritis of the DIP or PIP joints, especially erosive osteoarthritis, maybe confused with PsA or ReA.Bouchard's nodes (osteoarthritic involvement of PIP joints) and carpometacarpal joint disease are more consistent with osteoarthritis.Radiographically, osteophyte formation or the central erosions of erosive osteoarthritis help distinguish osteoarthritis from PsA and ReA.
The physician may not initially suspect enthesitis when a patient complains of pain or swelling in a tendon or ligamentous area.Tender areas are common in fibromyalgia.Mechanical overuse or calcific tendinitis resembles enthesopathy, particularly in the shoulder, Achilles tendon, and plantar fascia.Drugs such as retinoids or fluorides may produce plantar fasciitis or ossification, respectively.Achilles tendinitis has been associated with fluoroquinolone therapy.Recurrent or persistent tenosynovitis with inflammatory features or in atypical locations (e.g., toes, fingers, heels) should alert the physician to include spondyloarthropathies in the differential diagnosis.
Osteoarthritis and RA are common diagnoses for low back pain and peripheral joint disease.More unusual diseases that can involve both areas include Whipple's disease, Behçet's syndrome, relapsing polychondritis, and familial Mediterranean fever.Acquired immunodeficiency syndrome (AIDS) must be considered in the differential diagnosis of patients with ReA or PsA who also have risk factors for HIV infection.Fulminant psoriasis with or without arthritis and ReA has been reported as an initial presentation of HIV infections.
Finally, given the similarities among the spondyloarthropathies, each disease must be included in the differential diagnosis of the other.The separation of Reiter's syndrome (ReA) from PsA can be extremely difficult because the skin lesions and pattern of joint involvement are clinically indistinguishable.However, oral lesions, circinate balanitis, and urethritis are not features of PsA.Reports of an evolution of one spondyloarthropathy into another with time (e.g., the patient with urethritis and arthritis who later develops the skin disease of psoriasis) make the distinction between diseases less clear.
[edit] TREATMENT
Treatment for spondyloarthropathies begins with educating patients, since many of these diseases are chronic, often affecting young people during their most active and productive years.Although the pathogenesis of the disease is unknown, patients' understanding of the disease course, the potential factors that may aggravate and improve their arthritis, and the prevention measures are of utmost importance.National associations, patient newsletters, and support groups can provide educational, social, and emotional support.The Spondylitis Association of America provides mutual support, promotes research and education, and publishes useful quarterly newsletters.
Control of the associated medical conditions may have a direct benefit for the various spondyloarthropathies.Since the peripheral arthritis of IBD parallels the activity of bowel disease, treatment of the underlying bowel disease with corticosteroids, sulfasalazine, and other medications is the primary therapy.If a total colectomy is necessary for ulcerative colitis, the peripheral arthritis completely disappears.Joint disease may not resolve after total colectomy in Crohn's disease, however, perhaps because of residual or occult disease in the small intestine.Since the axial arthropathy does not correlate with bowel disease activity, management is very similar to that of idiopathic AS (see following section).Some studies on psoriasis suggest a correlation between improvement of joint disease when the skin disease is aggressively treated.
Appropriate antibiotic therapy should be instituted for patients with acute chlamydial urethritis, but antibiotics do not prevent the development of ReA.Enteric infections usually have cleared when arthritis occurs.Patients with ReA caused by Chlamydia may benefit from long-term therapy (3 months) with lymecycline, an antibiotic similar to tetracycline or doxycycline.It is not clear, however, if this beneficial effect results from lymecycline's antibacterial actions or another mechanism.
[edit] Nonsteroidal Antiinflammatory Drugs
NSAIDs are the mainstay of pharmacologic intervention in the spondyloarthropathies.More than 20 NSAIDs are available and differ in their half-life, routes of excretion, and interaction with other drugs (Table 137-2).The mechanism of action for all NSAIDs is based on the inhibition of both prostaglandin synthesis and neutrophil function.
Table 137-2 Nonsteroidal Antiinflammatory Drugs (NSAIDs) Used to Treat Seronegative Spondyloarthropathies
| Rights were not granted to include this data in electronic media. Please refer to the printed book. |
Various factors influence the choice of an NSAID in a particular patient (Box 137-5).NSAIDs are contraindicated for patients with active peptic ulcer disease or chronic anticoagulation (nonacetylated salicylates can be used in some patients, if needed, and possibly the new COX-II inhibitor).Concurrent medical problems, such as history of peptic ulcer disease, congestive heart failure, renal insufficiency, hepatic insufficiency, or bleeding diathesis, make NSAIDs relatively contraindicated.The need for the NSAID must be weighed against the patient's other medical problems.Some NSAIDs interact with sulfonylureas, antihypertensives, and anticoagulants.Asthmatic patients or patients with a known allergy to aspirin can develop allergic reactions to NSAIDs.Patients' lifestyles and drug costs are other major factors to consider.Specific cyclooxygenase II (COX-II) inhibitors, which do not interfere with the constitutive effects of cyclooxygenase I on the GI mucosa, are now available (see Chapters 102 and 132 ).Although rheumatologists traditionally prefer indomethacin to aspirin for ReA, many other NSAIDs are equally effective.High dosages are typically necessary to control the inflammatory process (e.g., indomethacin, 150 to 200 mg/day; naproxen, 1500 mg/day).
| Box 137-5 - Factors in Choice of NSAID |
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Treatment with one NSAID should continue for at least 2 to 4 weeks before the drug is discontinued for a lack of efficacy.When one NSAID fails, another should be chosen from a different chemical class.Frequently, several different NSAIDs are prescribed before the most effective one is established for an individual.Patients should be informed of this rationale, since they often perceive this method as haphazard.
NSAIDs' toxicities are secondary to their antiprostaglandin effects; GI intolerance is the most common. NSAID gastropathy, a term that includes superficial gastric erosions, diffuse gastritis, and frank ulcer craters, has great morbidity.Approximately 2% to 5% of patients taking NSAIDs for more than a year may develop ulcers, bleeding, or perforation.Advanced age, additional medical problems, and a history of peptic ulcer disease are risk factors for NSAID gastropathy.Misoprostol, a prostaglandin E1, was developed to prevent it.Proton pump inhibitors appear to be equally effective in prevention of gastric ulcers and better than misoprostol for duodenal ulcers.Thus guidelines for prevention include use of either drug in high-risk patients.[9] NSAID-induced small bowel and colon injury has also been reported.Renal toxicities include renal insufficiency from decreased renal blood flow, interstitial nephritis, and hyperkalemia.Reversible impairment of platelet aggregation may result in prolonged bleeding.Central nervous system toxicities include headaches, dizziness, mental status changes, and depression.Aseptic meningitis has been reported with ibuprofen, sulindac, naproxen, and tolmetin.Cutaneous reactions are varied.Certain NSAIDs have been reported to exacerbate psoriasis, particularly ibuprofen, indomethacin, and meclofenamate.
[edit] Corticosteroids
Intraarticular corticosteroids may be judiciously used in the peripheral joints of patients with spondyloarthropathies.Occasionally, injection of the plantar fascia, tendon sheath, or deep bursa is helpful if rest, NSAIDs, and orthoses have been ineffective.Systemic steroids have been used for short-term control of severe AS; however, this therapy is not recommended for routine treatment.
[edit] Second-line Agents
When NSAIDs and physical measures are ineffective in controlling symptoms or if progressive erosive disease develops in the peripheral joints, a rheumatologic referral to assist with decisions for second-line agents and monitoring for potential toxicities should be considered.Unfortunately, effective therapy to prevent ankylosis in the axial arthropathy has not been established.
Sulfasalazine, a drug initially developed for RA and subsequently used for IBD, has been studied for treatment of patients with AS, ReA, and undifferentiated spondyloarthropathies.[10] Results reveal some benefit for spondylitic symptoms in the short term, but whether the drug modifies the long-term outcome of AS is unknown.Sulfasalazine appears to be more effective for peripheral arthritis of AS or for ReA.[11] Its mechanism of actions may include reduction of intestinal mucosal inflammation and permeability or direct reduction of mediators of inflammation.Sulfasalazine has also been used in psoriasis and PsA with success.Doses range from 2 to 3 gm daily.Enteric-coated tablets given with food may reduce GI intolerance (see Chapter 133 ).
Methotrexate, a folate antagonist, has been used effectively for PsA since the 1960s.Initially, dermatologists used methotrexate for skin diseases, but beneficial effects on joints were coincidentally noted.Methotrexate is administered orally, subcutaneously, or intramuscularly on a weekly basis, beginning with 7.5 to 15 mg per week and titrated up to 20 to 30 mg based on response.Methotrexate has also been used for intractable Reiter's syndrome.Before instituting methotrexate, HIV infection must be excluded.Onset of AIDS has occurred in patients after methotrexate was started for severe psoriasis or ReA.Trimethoprim is contraindicated for patients who take methotrexate because of its additive antifolate effects (see Chapter 133 ).
Parenteral gold is also effective in the treatment of PsA.Although most studies have not been prospectivelycontrolled, 60% to 75% of the patients improved on parenteral gold therapy.When compared with a rheumatoid population, drug intolerance was less in PsA.Patients with peripheral arthritis responded best.Gold had no effect on the spondylitic patients.It also had no beneficial effects on the skin, although gold did not exacerbate underlying skin disease.
Hydroxychloroquine, a drug often used to treat RA and systemic lupus erythematosus (SLE), has been prescribed for PsA and Reiter's syndrome.Exacerbation of psoriasis has been reported anecdotally with hydroxychloroquine use.In recent studies, skin reaction has not been a significant problem, but any antimalarial agent should be used cautiously in psoriatic patients (see Chapters 85 and 133 ).
Retinoid (vitamin A) derivatives, particularly etretinate, have been studied extensively for the treatment of psoriasis; smaller studies have demonstrated etretinate's effectiveness in treating PsA.Low-dose cyclosporine can successfully andsafely treat psoriatic arthritis unresponsive to other drugs.Etretinate and cyclosporine are additional therapies to consider when methotrexate is ineffective.
[edit] Rehabilitative Management
Exercise to maintain muscle tone and function is important for patients with inflammatory arthritis.A programmed routine set by a physical therapist should be the initial step.Often, because of lower extremity disease, even low-impact weight-bearing exercises are not possible.Performing exercises in a heated pool or walking in a pool may be ideal alternatives.Judicious use of splints during acute inflammatory periods may preserve function and alignment of involved joints.Referral to an occupational therapist for splints and assessment of activities of daily living are important for patients with upper extremity involvement.
Patients with ReA or PsA often have foot and ankle involvement.Dactylitis and other small-toe joint involvement result in foot deformities that cannot be accommodated by regular shoes.Prescription shoes with extra depth or a toe box can help.Soft shoe inserts with metatarsal bars redistribute weight away from the metatarsophalangeal joints.Plantar fasciitis may also respond to soft inserts or to local corticosteroid injections.Heel cups provide extra cushioning for symptomatic heel spurs.If multiple midfoot or hindfoot joints are involved, limited periods of casting (less than 7 days) for immobilization can be ordered.Since these patients tend to ankylose joints rapidly, however, prolonged immobilization without diligent ROM exercises is not advisable.Management of Achilles tendinitis is difficult.NSAIDs are the mainstay, with cautious corticosteroid injections.Ice and immobilization may also help.
Axial involvement in any of the spondyloarthropathies should begin with referral to a physical therapist to maintain functional capacity.However, daily back and chest expansion exercises must become ingrained in patients' routines (Fig.137-9).To minimize spinal flexion deformities, patients should sleep on a firm mattress and thin pillows.Patients should also be instructed to lie for at least 30 minutes each day or night in a prone position (belly down).In addition, protection from injury should be emphasized, since spinal fractures with minimal trauma occur in the osteoporotic spondylitic spine.Thus patients need to avoid prolonged periods of non–weight bearing, maintain adequate dietary intake of calcium and vitamin D, and refrain from sports that can result in spinal injury.
[edit] Surgery
Orthopedic intervention may be necessary for patients who have persistent peripheral arthritis despite the various interventions described.Arthroscopic or surgical synovectomy is an option in persistent synovitis of the knee.Totaljoint replacement for severe hip or knee arthritis can be successful, although heterotopic bone formation may influence surgical outcome.Psoriatic patients with aggressive, small-joint arthritis should be referred to hand surgeons early for possible procedures to prevent the mutilans state.Surgical fusion of the wrist may reduce pain and preserve limited function.Persistent tendinitis of the fingers or synovitis at the wrist despite medical therapy may require synovectomy.In AS, cervical fractures at C6-7 and other levels may require stabilization.Rarely, severe flexion deformities of the spine can be corrected by osteotomies, but the procedure carries great risk.
[edit] Consultation and Referral
The seronegative spondyloarthropathies are multisystem disorders.The need for consultation depends on such factors as questions about the diagnosis, severity of the clinical manifestations, response to treatment, particular organ system involvement, and physician's familiarity and proficiency in treating these disorders (Box 137-6).Rheumatology consultation remains the cornerstone referral and should usually be sought if the diagnosis is established or suspected.The primary care physician, however, may provide most of the day-to-day management, as well as the long-term follow-up.If the disease is refractory to standard treatment with physical therapy and NSAIDs, or if second-line agents are being considered, a rheumatologist's input becomes even more important.
| Box 137-6 - Managed Care Guide: Pointers on Management of Seronegative Spondyloarthropathies |
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Patient education, exercise, and physical therapy are mainstays of therapy.A physical therapy consultation is highly recommended when the diagnosis is made.Most programs can be performed at home.A single consultation may be all that is needed.
Acute anterior uveitis, if unrecognized and untreated, can lead to severe ocular sequelae, including blindness.Urgent referral to an ophthalmologist should be made if patients have symptoms.The primary care physician must educate patients about uveitis symptoms so that medical attention is sought promptly.
Consultations with an orthopedist, podiatrist, dermatologist, cardiologist, or pulmonologist may be necessary, depending on each patient's disease manifestations.
[edit] REFERENCES
- ↑ SD Khare, HS Luthra, CS David: HLA-B27 and the other predisposing factors in spondyloarthropathies. Curr Opin Rheum 1998; 10:282.
- ↑ 2.0 2.1 MA Khan, SM van der Linden: Ankylosing spondylitis and other spondyloarthropathies. Rheum Dis Clin North Am 1990; 16:551.
- ↑ TE Feltkamp, JH Ringrose: Acute anterior uveitis and spondyloarthropathy. Curr Opin Rheum 1998; 10:314.
- ↑ MM Ward: Quality of life in patients with ankylosing spondylitis. Rheum Dis Clin North Am 1998; 24:815.
- ↑ A Keat: Reiter's syndrome and reactive arthritis in perspective. N Engl J Med 1983; 309:1606.
- ↑ M Leirisalo-Repo: Prognosis, course of disease, and treatment of the spondyloarthropathies. Rheum Dis Clin North Am 1998; 24:737.
- ↑ ML Cuellar: HIV infections: associated inflammatory musculoskeletal disorders. Rheum Dis Clin North Am 1998; 24:403.
- ↑ SR Weiner, J Clarke, NA Taggart, PD Utsinger: Rheumatic manifestations of inflammatory bowel disease. Semin Arthritis Rheum 1991; 20:353.
- ↑ FL Lanze: A guideline for the treatment and prevention of NSAID-induced ulcers. Am J Gastroenterol 1998; 93:2037.
- ↑ M Dougados, S van der Linden, M Leirisalo-Repo: Sulfasalazine in the treatment of spondyloarthropathy: a randomized, multicenter, double-blind, placebo-controlled study. Arthritis Rheum 1995; 38:618.
- ↑ DO Clegg, DJ Reda, MH Weissman,et al.: Comparison of sulfasalazine and placebo in the treatment of ankylosing spondylitis: a Department of Veterans Affairs cooperative study. Arthritis Rheum 1996; 39:2004.
