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 “back pain.” Physicians Diagnosing the spondyloarthropathies—chronic should suspect a spondyloarthropathy 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 uveitis, 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: enthesitis of the axial and peripheral skeleton and • Ankylosing spondylitis variable involvement of the peripheral joints, gut, skin, • Reactive arthritis (including Reiter syn- eye, or aorta. drome) • Psoriatic arthritis • 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 rheumatoid factor 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% Reactive arthritis 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 rheumatology 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 ankylosing spondylitis, 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 arthropathies 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 Achilles tendon insertion spondylitis have subclinical gastrointestinal Plantar fascia insertion on calcaneus tract inflammation 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- Dactylitis 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 sacroiliitis 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