For many years the seronegative spondyloarthropathies were confused understandably with rheumatoid arthritis due to common features of significant morning gel and inflammatory peripheral arthritis. This led to confusion in terminology with names such as rheumatoid spondylitis, rheumatoid variants, and so on. With better understanding of the histocompatibility genes, though, they are known now to be a clinically and etiologically distinct cluster of diseases with shared common features and clinical characteristics that distinguish them from each other. This chapter discusses the four main types of seronegative spondyloarthropathies: ankylosing spondylitis, reactive arthritis or Reiter’s disease, psoriatic arthritis, and enteropathic arthritis associated with inflammatory bowel disease (IBD). As a group, they are rheumatoid factor negative, hence the name seronegative, and have radiographic and/or clinical sacroiliitis, typical vertebral abnormalities, inflammatory peripheral arthritis, enthesopathy, uveal tract involvement, familial clustering, and the frequent presence of human leukocyte antigen B27 (HLA-B27).

All of these conditions are a form of an inflammatory arthritis and significant morning gel phenomenon is expected during times of active inflammation. Stiffness requiring over an hour to resolve after prolonged periods of inactivity, such as immediately after awakening in the morning, is a common feature and the duration required for resolution often correlates with the severity of the condition. Morning gel or morning stiffness is a common feature with all inflammatory arthritides and likely led to the early confusion with rheumatoid arthritis. Similarly, activity helps to improve the sensation of stiffness and patients with any inflammatory arthritis will report improvement with activity as opposed to worsening with activity, as is common in mechanical disorders and osteoarthritis. The pattern of peripheral joint
involvement in the seronegative spondyloarthropathies is asymmetric and oligoarticular, or may have no peripheral joint involvement with only axial involvement as often happens in ankylosing spondylitis, unlike the symmetrical distal small joint involvement seen in rheumatoid arthritis.

A seronegative spondyloarthropathy should be considered in a person with significant morning gel phenomenon of over an hour in duration, who does not have symmetrical small joint polyarthritis, but may have low back pain or asymmetric oligoarthritis, especially with inflammatory hip or shoulder involvement. Enthesopathies such as tendinitis or bursitis are common in all the seronegative spondyloarthropathies. At this point, nonarticular features can help make the correct diagnosis. In ankylosing spondylitis and reactive arthritis, the male-to-female ratio is strongly male dominant, hence female sex makes those conditions possible, but statistically less likely. The presence of certain extra-articular manifestations can assist the clinician in narrowing the differential diagnosis and lead to the correct diagnosis. Skin lesions that are papulosquamous in morphology, well demarcated, erythematous, and scaly suggestive of psoriasis will make psoriatic arthritis the most likely diagnosis, although it can reflect keratoderma blenorrhagicum seen in reactive arthritis. Mucous membrane lesions that may be painless such as urethritis and oral ulcers make reactive arthritis most likely, but can be seen in ankylosing spondylitis and enteropathic arthritis. Mucosal ulcers seen in the rectum or colon strongly suggest an enteropathic arthritis, but are also seen in reactive arthritis and ankylosing spondylitis. The overlap in clinical presentation of these diseases reflects that these conditions represent a spectrum of diseases that differ phenotypically, but have a common, albeit complex, genotypic pathogenic basis. When the clinician suspects the diagnosis of one of the seronegative spondyloarthropathies, closer examination of the extra-articular features will be more fruitful in identifying the specific disease.

The classic patient with ankylosing spondylitis will be a male with an onset in his late teens or early twenties with morning stiffness, low back pain, and radiographic bilateral sacroiliitis. The duration of stiffness will be over an hour and usually 3 to 4 hours, varying directly with the severity of the disease. Physical activity will improve his stiffness and back pain unlike the pain and stiffness from a mechanical back disorder or osteoarthritis that worsens with activity. Nonsteroidal anti-inflammatory drugs, even over-the-counter products will provide relief although it may be incomplete relief of pain and stiffness.

Pain and stiffness reflect the inflammatory nature of the condition and an onset of pain or stiffness after the age of 40 years is very unusual. While the disease is more common in men, women are not immune from developing ankylosing spondylitis and often have less back symptoms and more peripheral asymmetric oligoarthritis. The pain from sacroiliitis is commonly reported as low back pain by the patient, but may be felt as buttock or gluteal pain, or pain in the anterior and/or lateral thighs. Extra-articular features are less common in ankylosing spondylitis than the other seronegative spondyloarthropathies, but do occur in a minority of patients. Iritis or anterior uveitis, occurring in up to 20% patients, is one of the more common extra-articular features often predating the development of the musculoskeletal manifestation. Oral mucosal ulcerations and shallow rectal or colonic ulcerations can be seen less frequently than iritis and uveitis. Finally, an IgA nephritis and leukocytoclastic cutaneous vasculitis resembling Henoch–Schönlein purpura has been reported.

Although commonly associated with Reiter’s syndrome and the classic triad of arthritis, urethritis, and uveitis, reactive arthritis includes many more extra-articular manifestations than the classic triad, especially involving the skin and the mucosal membranes. The arthritis is usually an acute, additive, and asymmetric one with enthesitis and/or axial arthritis commonly seen and combined with keratoderma blenorrhagicum, diarrhea, cervicitis, urethritis, conjunctivitis, painless oral ulcers, and/or circinate balanitis. Identifying a prior recent infectious event is not always possible, but reactive arthritis is known to occur after dysenteric type illness or genitourinary infections. Typically, reactive arthritis follows the infection within 1 to 4 weeks, with fever being common and arthritis being the last clinical feature to present. Reactive arthritis is the most common musculoskeletal condition seen in active HIV infection and HIV should be considered in any new diagnosis of reactive arthritis, or worsening reactive arthritis. Finally, reactive arthritis is reported to occur after treatment of infections or immunization.

Psoriasis is a chronic autoimmune skin condition that has a higher prevalence of a coexisting chronic inflammatory arthritis than is seen in the general population. The skin disease usually predates the onset of arthritis, although the converse relationship is seen and the concurrent onset of psoriasis and arthritis is the least common mode of presentation. The pattern of joint involvement is variable but typically follows five different patterns: symmetric polyarthritis, distal interphalangeal joint involvement, oligoarthritis, arthritis mutilans, and axial involvement.

The inclusion of IBD in this group of diseases emphasizes the relationship between gut inflammation and joint inflammation. Other gastrointestinal conditions, such as celiac disease, and intestinal bypass surgery are occasionally accompanied by joint inflammation, but these are not considered as spondyloarthropathies. Crohn’s disease and ulcerative colitis are discussed together since the musculoskeletal and gastrointestinal features cannot be easily differentiated. Musculoskeletal issues are the most common extraintestinal manifestations of IBD and appear in 2% to 20% of patients with either ulcerative colitis or Crohn’s disease, with peripheral arthritis seen more frequently in patients with colonic involvement and more extensive bowel disease. The frequency of peripheral arthritis in IBD ranges up to 20% of patients, with a higher prevalence in Crohn’s disease. In both Crohn’s disease and ulcerative colitis, the arthritis generally is pauciarticular, asymmetric, frequently transient or migratory, and typically nondestructive with common recurrences. Infrequently, the peripheral arthritis becomes chronic and destructive. Enthesopathies can cause sausage digit deformities, Achilles tendinitis, and plantar fasciitis. Axial involvement involving the sacroiliac joints or spine occurs in both diseases with prevalence rates of 10% to 20% for sacroiliitis and 7% to 12% for spondylitis reported, although the actual figures are probably higher because of the existence of subclinical axial involvement.