Seronegative arthritis: Clinical practice

Seronegative arthritis refers to a group of four chronic diseases - ankylosing spondylitis, psoriatic arthritis, reactive arthritis, and enteropathic arthritis.

All of them are negative for rheumatoid factor, they’re all positive for HLA-B27, and they typically all run in families.

Another feature they share is that they usually affect the bones in the spine and nearby joints. That’s why they’re sometimes called seronegative spondyloarthritides, where spondylo means vertebra.

Other features include inflammatory back pain that causes morning stiffness which improves after 30 minutes of movement.

These diseases also cause peripheral arthritis that’s generally asymmetric, and axial arthritis like sacroiliitis and spondylitis, affecting the sacroiliac and vertebral joints, respectively.

Individuals also present enthesitis – meaning inflammation at the sites where tendons or ligaments insert into the bone and dactylitis, also known as sausage fingers.

They also cause extra-articular symptoms like involvement of the eyes with anterior uveitis, skin with psoriasis, the heart with aortic regurgitation or pericarditis, genitourinary involvement due to nerve compression at the spinal cord, and gastrointestinal involvement with inflammatory bowel disease - both Crohn's disease or ulcerative colitis.

Seronegative spondyloarthritides typically have a good response to NSAIDs and an elevated CRP in blood tests.

To meet the diagnostic criteria for seronegative spondyloarthritis, an individual has to have evidence of sacroiliitis on imaging plus one of these spondyloarthritis features, or HLA-B27 positivity plus two additional spondyloarthritis features.

Once the criteria for a seronegative spondyloarthritis have been met, it’s time to figure out which one it is.

First up is ankylosing spondylitis. It typically affects young males, causing fever and pain and stiffness in the low back, hips, buttocks, and thighs, especially in the mornings or after sitting still for a long time.

Initially, individuals have relapsing-remitting pain, meaning that the symptoms are at times worse - relapsing, and at other times they’re improved or gone - remitting.

The pain also has an asymmetric distribution, often affecting unpaired joints.

And over time, there’s joint destruction and bony growth on top of the destroyed joint, which can lead to ankylosis, meaning joint stiffness, and ultimately a loss of mobility.

In the spine, the gentle lordosis, or swayback, of the lower spine and the neck are balanced by a gentle kyphosis, or hunchback, in the upper spine. These curves work in harmony to keep the body’s center of gravity aligned over the pelvis.

But in ankylosing spondylitis, ongoing inflammation can lead to loss of the normal lumbar lordosis, with thoracic kyphosis and compensatory cervical hyperextension.

In time, individuals start developing a question mark posture where they look like a question mark rather than an exclamation point.

In fact, the pain paradoxically improves over time because the inflammatory process dies down as the joint gets completely obliterated.

If ankylosing spondylitis is suspected, spinal involvement must be assessed with physical exam maneuvers.

In the cervical spine, flexion deformity is measured through the occiput-to-wall test. That’s where an individual is asked to stand erect with heels and buttocks against a wall and to try and extend his or her neck and touch the wall, while keeping the chin horizontal.

Healthy individuals can do this without any trouble, so if there’s distance between the occiput and the wall, that reflects the degree of cervical deformity.

In the thoracic spine, the range of motion of the costovertebral joints is measured by the degree of chest expansion at the level of the xiphoid.

The individual is asked to raise their arms above their heads and exert a maximal forced expiration, followed by a maximal inspiration, and measurements are taken at the end of both expiration and inspiration.

The difference between the two measurements is the degree of expansion, and is usually greater than 2 centimeters, while decreased expansion may be observed in individuals with ankylosing spondylitis due to reduced chest wall mobility.

In the lumbar spine, range of motion is tested in the sagittal plane by the Schober test, and in the coronal plane by the extent of lateral spinal flexion.

The Schober test measures forward flexion of the lumbar spine. To do it, the individual has to stand straight up, and the examiner makes a mark approximately at the level of the fifth lumbar vertebra or L5. Then, two more points are marked, one 5 centimeters below and another one 10 centimeters above this point, for a total of 15 centimeters distance. The individual must then bend forward maximally without bending the knees and the distance is measured again.

In normal individuals, the difference between the two measurements should exceed 5 centimeters, with the total distance greater than 20 centimeters. If the distance of the two points doesn’t increase by at least 5 centimeters, this is a sign of restriction in the lumbar flexion.

In addition to physical exam maneuvers, an X-ray of the spine should be done.

In the early stages of ankylosing spondylitis there may be small erosions at the corners of the vertebral bodies, which become square-shaped.

Over time, long-standing inflammation causes complete ossification of the space between the vertebral borders, resulting in a bamboo spine due to fusion of the vertebrae.

These X-ray findings typically occur long after the inflammatory process started, so an MRI is better for detecting early signs of spinal inflammation.

In individuals with sacroiliitis seen on plain radiography, additional imaging, such as an MRI, is not necessary for diagnosis. However, if plain radiographs don’t reveal sacroiliitis, and when there’s still a high suspicion for ankylosing spondylitis, an MRI can be done to reveal inflammatory changes and more subtle structural abnormalities.

The next disease is psoriatic arthritis which specifically affects individuals with psoriasis.

Most of the time, psoriasis precedes the onset of arthritis by a few years, but occasionally both can develop together.

On rare occasions the arthritis can precede the skin rash, which means that some individuals develop psoriatic arthritis even without having psoriasis.

To further complicated things, having psoriasis and arthritis doesn’t always mean psoriatic arthritis, because individuals with psoriasis, can get other types of arthritis like rheumatoid arthritis, osteoarthritis, gout, reactive arthritis, and the arthritis of inflammatory bowel disease.

So psoriatic arthritis has to fit the classic pattern, and it has to occur in a person that typically has psoriatic skin changes like pitting or onycholysis, and scaly skin lesions.

There are five main patterns of psoriatic arthritis.

The most frequent presentation asymmetric oligoarticular arthritis, which doesn’t affect the same joints on both sides of the body and usually involves fewer than three joints.

Next is symmetric polyarticular arthritis, which affects five or more joints on both sides of the body simultaneously, mainly the hands and feet, similar to rheumatoid arthritis.

Then there’s the spondylitis presentation, characterized by stiffness of the neck or the sacroiliac joint of the spine.

Next is the distal interphalangeal predominant presentation, which is characterized by inflammation and stiffness in the joints nearest to the ends of the fingers and toes.

And finally, the least common but most severe presentation is arthritis mutilans, characterized by deforming and destructive arthritis that can progress over months to years and causes severe joint damage.

Next up is reactive arthritis, which is an arthritis that most commonly arises a few days to weeks after an infection, most commonly affecting the urogenital or gastrointestinal tracts.

Now, this is not a septic arthritis because it’s thought to be an autoimmune process triggered by molecular mimicry, rather than a pathogen directly infecting the joint.

The most frequent pathogen associated to reactive arthritis is Chlamydia trachomatis, which causes urethritis.

But other pathogens include enteric bacteria like Salmonella, Shigella, Yersinia, Campylobacter, and Clostridium difficile, all of which cause gastroenteritis or colitis.

Reactive arthritis most often causes a monoarticular or oligoarticular pattern of the arthritis, typically affecting the large joints like the knees and sacroiliac spine, with associated dactylitis, enthesitis, conjunctivitis, and urethritis that causes burning pain on urination.

It can recur in months or years, but often fades over the course of a year and doesn’t cause permanent joint deformity or immobility.

The physical examination is aimed at excluding other arthritic disorders, and identifying if there’s a preceding or concomitant condition like urethritis or diarrhea that may be associated to the arthritis.

In individuals with a joint effusion, an arthrocentesis should be done to examine the synovial fluid. It would show an increased white blood cell count, and a Gram stain and culture should be done to exclude septic arthritis, since in reactive arthritis no microorganisms are recovered from the joint Cultures may also be carried out on stool samples to look for enteric bacteria, as well as urine samples and swabs from the urethra, cervix and the throat to look for Chlamydia.

There is no single definitive test for reactive arthritis, so ultimately, the diagnosis of reactive arthritis is made in an individual with evidence of a prior enteric or genitourinary infection from a likely pathogen like Chlamydia trachomatis, and subsequent arthritis without an alternative cause of the arthritis.

If the underlying infection is still present, individuals must be given the appropriate antibiotics for treatment, such as a short course of tetracyclines.

Finally, there’s enteropathic arthritis, also called inflammatory bowel disease-related arthritis, which is when the arthritis is an extra-intestinal manifestation of inflammatory bowel disease.

Enteropathic arthritis is more likely in individuals with disease involving the large intestine, and it should be suspected whenever an individual with an inflammatory bowel disease develops joint pain or stiffness.

But like psoriatic arthritis, individuals with inflammatory bowel disease can develop arthritis from other causes as well, so this remains a diagnosis of exclusion.

The main clue for diagnosis is that treating the inflammatory bowel disease usually makes enteropathic arthritis improve.

Seronegative arthritis symptoms generally improve with exercise as well as medications.

Initial therapy for all of them are nonsteroidal antiinflammatory drugs or NSAIDs.

Individuals who do not respond adequately to NSAIDs may get injection of major affected joints with intra-articular glucocorticoids.

In addition, individuals with ankylosing spondylitis may be given low-potency opioids for short periods of time, if NSAIDs are contraindicated or aren’t sufficient at controlling the pain.

If that doesn’t suffice, then disease modifying antirheumatic drugs or DMARDs can be used for individuals that don’t respond to any other treatment.

Rather than just reducing pain and inflammation, DMARDs help limit the amount of joint damage and disease progression.

Individuals with moderate to severe peripheral arthritis without erosions or substantial functional limitations are started on non-biological DMARDs, like sulfasalazine, methotrexate, leflunomide, or hydroxychloroquine.

And individuals with severe peripheral arthritis who already have erosions and functional limitation, or those with axial arthritis, are started on biological DMARDs, also called biologics.

Specifically for seronegative arthritis, biologics that are TNF inhibitors are chosen, like adalimumab, etanercept, and infliximab.

These medications are immunosuppressive and have serious side effects, so it’s important to monitoring with lab tests like a CBC to check for pancytopenia, AST, ALT, albumin to assess liver function, and a BUN and creatinine to assess kidney function.

In extreme cases of seronegative arthritis, there are surgical interventions like a total joint replacement which can be done if a joint is already destroyed, particularly the knees or hips.

In individuals with severe spinal deformities, a surgical procedure called a wedge osteotomy of the spine can be done. During this procedure, a surgeon removes a wedge-shaped section of bones at the back of the spine.

Finally, fusion of the atlantoaxial joint of the cervical spine is done when there’s significant neck or occipital pain or evidence of neurologic dysfunction.

Summary

Alright, as a quick recap… Seronegative arthritis or spondyloarthritis refers to ankylosing spondylitis, psoriatic arthritis, reactive arthritis, and enteropathic arthritis.

These diseases are negative for rheumatoid factor, positive for HLA-B27, cause back pain, peripheral and/or axial arthritis, enthesitis, dactylitis, extra-articular manifestations, have a good response to NSAIDs, show a family history of spondyloarthritis, and cause an elevated CRP.

For diagnosis, an individual must have sacroiliitis plus one of these features, or HLA-B27 positivity plus two other features.

Ankylosing spondylitis typically affects young males, and causes stiffness in the low back, thigh, hip, or buttocks.

Psoriatic arthritis occurs in individuals with psoriasis, which classically causes nail bed pitting or onycholysis, and scaly silver skin lesions.

Reactive arthritis arises soon after or during an infection, typically of the urogenital or gastrointestinal tracts.

Finally, enteropathic arthritis is when the arthritis is secondary to an inflammatory bowel disease.

In general, initial therapy of seronegative arthritis should involve the use of an NSAID to relieve the pain.

Some individuals may get injection of affected joints with intra-articular glucocorticoids. If that doesn’t suffice, then individuals may be started on DMARDs.

Individuals with moderate to severe peripheral arthritis without erosions or substantial functional limitations are started on non-biological DMARDs, while individuals with severe peripheral arthritis who already have erosions and functional limitation, or those with axial arthritis, get biological DMARDs called TNF inhibitors.