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Seronegative and septic arthritis: Pathology review




Musculoskeletal system

Pediatric musculoskeletal conditions
Musculoskeletal injuries and trauma
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Joint disorders
Muscular disorders
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Musculoskeletal system pathology review

Seronegative and septic arthritis: Pathology review


1 / 9 complete

USMLE® Step 1 style questions USMLE

9 questions

A 35-year-old man presents to his primary care physician’s office for evaluation of right knee and ankle pain for the past 2 days. He had similar pain over the left wrist and shoulder joints in the past year that self resolved. The patient has a painless rash on his hands which appeared around the same time. Past medical history is significant for a urinary tract infection 2 months ago which was treated with antibiotics. He has had 7 sexual partners over the past year and is currently sexually active. He uses condoms inconsistently. He denies any recent travel. His temperature is 38.2 °C (100.8°F), pulse is 80/minute, respirations are 16/minute, and blood pressure is 130/80 mmHg. Physical examination shows multiple nontender papulovesicular lesions on his hands. Passive flexion of wrists elicits a sharp pain. Which best describes the route of transmission regarding the causative organism resulting in this patient’s clinical condition?  


Content Reviewers:

Yifan Xiao, MD

Maurice is a 28 year old male who presents with a 2 year history of gradually progressive low back pain and stiffness.

He mentions that the pain wakes him up several times at night, and that the stiffness tends to be worse when he wakes up and improves as he moves.

Examination shows mild deformity of the spine and hip, as well as tenderness over the buttock.

Then you see Clint, a 63 year old male shows up with a red, warm and swollen left knee, which hurts so much he can barely walk.

Clint tells you that symptoms started a few days ago, after he tripped and cut his knee.

His body temperature is 38 celsius degrees or 100.4 degrees Fahrenheit.

X-rays are ordered in both cases, showing, in Maurice’s case, erosion of the sacroiliac joint.

On the other hand, in Clint’s case, X-rays look pretty normal, so an arthrocentesis is performed, revealing that synovial fluid is purulent.

Based on the initial presentation, both cases seem to have some form of arthritis.

But first, a bit of physiology real quick.

There are many types of joints, including fibrous, cartilaginous, and synovial joints. synovial joints, like those of the wrist, elbow, knees, shoulders, and hips, are mobile joints that connect two bones via a fibrous capsule that is continuous with the periosteum, which is the outer layer of bones.

The fibrous capsule is lined with a synovial membrane, which has cells that remove debris and produce synovial fluid.

This is a viscous fluid found inside the joint capsule which lubricates joint.

Together, the synovial membrane and articular cartilage form the inner lining of the joint space.

Now, arthritis refers to a group of diseases that cause destruction of one or more joints.

First, we have seronegative arthritis, which is called seronegative because there’s an absence of both rheumatoid factor or RF, and anti-cyclic citrullinated peptide antibody or anti-CCP, which are commonly found in rheumatoid arthritis.

Something specific to note is that seronegative spondyloarthropathies have a strong association with the gene HLA-B27, which encodes for a specific type of MHC class I molecule.

Now there are several subtypes of seronegative spondyloarthropathies and you can remember them by a mnemonic PAIR, where P stands for Psoriatic arthritis; A for Ankylosing spondylitis; I for Inflammatory bowel disease-associated arthritis; and R for Reactive arthritis.

Let’s start with psoriatic arthritis, which occurs in some individuals with psoriasis or with a family history of psoriasis.

It is an autoimmune disease characterized by joint inflammation.

Exactly what causes the immune system to go haywire and attack the joints is unclear.

Although the HLA-B27 gene is linked to the disease, it’s not enough to trigger psoriatic arthritis on its own, and environmental factors like physical trauma or an infection seem to play a role as well.

Now, it all starts with psoriasis, which is an autoimmune condition where skin self antigens are seen as foreign.

When that happens, T cells start releasing cytokines that recruit and activate other immune cells to release TNF, IL-12, and IL-23.

This triggers keratinocytes and fibroblasts to proliferate, which leads to the formation of psoriatic plaques.

These are red, raised patches with silvery scales made up of dead skin cells.

In some individuals with psoriasis, T cells also go to the joints and trigger the activation of osteoblasts and osteoclasts, leading to joint erosion and ossification, which can ultimately cause arthritis and severe deformities.

Now, arthritis usually occurs after the psoriatic plaques have appeared, but it can sometimes precede them, which makes diagnosis that much harder.

For your exam, it’s important to note that less than 30% of individuals with psoriasis develop psoriatic arthritis.

Symptoms of psoriatic arthritis typically include pain, swelling, and stiffness of the affected joints.

There are several types of psoriatic arthritis, depending on which joint is affected.

The most common one is the distal interphalangeal predominant type, which generally affects the joints nearest to the ends of the fingers and toes, leading to dactylitis, which is the inflammation of the fingers, also known as sausage fingers and nail abnormalities like ridging or pitting.

Over time, some individuals with distal interphalangeal predominant type can also develop severe bone erosions and finger deformities.

In severe cases, this can evolve into another type of psoriatic arthritis, which is arthritis mutilans.

In arthritis mutilans, extensive bone erosion at the fingers creates a telescopic digit appearance that results in a person having what’s called the opera-glass hand.

Diagnosis of psoriatic arthritis involves an X-ray, which may show joint erosion and osteopenia.

The most characteristic feature though is the pencil-in-cup radiographic sign, which arises from the periarticular erosions and resorption of the bone, making it look slimmer than the soft tissue around it, sort of like a pencil in a cup.

Treatment of mild cases of psoriatic arthritis includes NSAIDs.

In more severe cases, non-biologic DMARDs can be helpful, especially leflunomide.

If both NSAIDs and non-biologic DMARDs fail, biologic DMARDs like TNF–inhibitors can be used to stop the disease from progressing.

Rarely, surgery is done to repair the damaged joints.

Next, ankylosing spondylitis is a chronic spondyloarthropathy that most often affects young and middle aged males, but its exact cause is unknown.

One theory suggests an underlying autoimmune reaction, where T cells mistake type I and type II collagen in the joints as foreign.

Now, ankylosing spondylitis typically affects the spine, making it really stiff.

Characteristically, there’s inflammation of the intervertebral joints, as well as the facet joints.

Remember that there are two types of joints between the vertebrae: the intervertebral joint, consisting of two vertebral bodies between which lays an intervertebral disc, which is made of type I and II collagen, and has an outer fibrous ring, called the annulus fibrosus, and an inner jelly-like substance, known as nucleus pulposus.

And then each vertebra also has four facet joints, one pair with the vertebra above and one with the vertebra below.

Sometimes, ankylosing spondylitis can also affect the sacroiliac joints, between the sacrum and the hip bones, or the joints of the cervical and thoracic region.

In any case, there’s destruction of the articular cartilage, so fibroblasts are activated and they start to replace the destroyed joint with fibrin.

Fibrin then deposits in layers to form a tough fibrous band around the joints, limiting their range of motion.

Eventually osteoblasts get activated too, triggering a process called ossification.

That’s when the fibrous tissue at the joint edges within the annulus fibrosus turns into small bony outgrowths called syndesmophytes.

Ankylosing spondylitis causes articular symptoms, such as morning stiffness and lower back pain, which is worse at night, lasts for more than 30 minutes, and improves with movement and exercise.

Individuals may also have kyphotic deformity where there’s an excessive outward curvature of the thoracic spine, as well as limited range of motion in the spine caused by both fibrin deposition and by syndesmophytes.

Things can get so bad that the affected part of the spine becomes completely immobile.

If ankylosing spondylitis affects the sacroiliac joints, it typically causes lower back or buttock pain and tenderness upon palpation, and if it affects the cervical or thoracic region it can cause neck or chest wall pain and stiffness.

Ankylosing spondylitis can also present extra-articular symptoms like weight loss, fever, and fatigue.

Other high-yield symptoms include uveitis and tendonitis, and, because the ribs and vertebrae are involved in breathing, spine stiffness can cause shortness of breath due to impaired chest expansion.

Another way ankylosing spondylitis can affect breathing is by causing restrictive lung disease, and specifically pulmonary fibrosis in the apical parts of the lungs.

In the heart, it can cause aortitis, or aortic wall inflammation, leading to dilation of the aortic ring and aortic insufficiency.

Diagnosis is usually based on an X-ray, CT scan, or MRI, which can detect erosion and narrowing of the joint spaces.

Another characteristic finding is the bamboo spine, which is caused by the ossification of the annulus fibrosus on the outside of a straightened spine, giving it a hollow appearance.

Finally, genetic testing for HLA-B27 can be done to confirm the diagnosis.

Inflammation and pain from ankylosing spondylitis are usually treated with NSAIDs like ibuprofen.

Pain and mobility issues can also be relieved by exercise or physical therapy.

Remember that these individuals also need frequent monitoring of their chest expansion.

In more severe cases, DMARDs like sulfasalazine and methotrexate can be taken to control symptoms and slow progression.

Moving on to the I in the PAIR acronym, seronegative arthritis may also be secondary to inflammatory bowel disease, including Crohn’s disease or ulcerative colitis.

Inflammatory bowel disease, or IBD for short, is characterized by chronic gastrointestinal tract inflammation, as well as systemic symptoms like fatigue, fever and unintentional weight loss.

Extraintestinal symptoms can include arthritis, most often affecting the knee or spine, eye manifestations like uveitis and episcleritis, and skin lesions like pyoderma gangrenosum and erythema nodosum.

IBD-associated arthritis should be suspected when an individual presents with gastrointestinal symptoms together with joint or back pain and stiffness.

To confirm the diagnosis of IBD, an endoscopy or colonoscopy with biopsy is needed.

Treatment often involves a step-up approach, where less potent anti-inflammatory medications are initiated, and if they fail, they’re changed to more potent medications like corticosteroids.

Then there’s reactive arthritis, previously known as Reiter’s syndrome.

This is an autoimmune condition that typically occurs after a bacterial infection of the gastrointestinal or urinary tract.

The most common microorganisms that are associated with reactive arthritis include Shigella, Yersinia, Chlamydia, Campylobacter, and Salmonella.

  1. "Robbins Basic Pathology" Elsevier (2017)
  2. "Harrison's Principles of Internal Medicine, Twentieth Edition (Vol.1 & Vol.2)" McGraw-Hill Education / Medical (2018)
  3. "Acute monoarthritis: What is the cause of my patient's painful swollen joint?" Canadian Medical Association Journal (2009)
  4. "Septic arthritis: current diagnostic and therapeutic algorithm" Curr Opin Rheumatol (2008)
  5. "2012 Update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis" Arthritis Care & Research (2012)
  6. "Rheumatoid arthritis: pathological mechanisms and modern pharmacologic therapies" Bone Research (2018)
  7. "Rheumatoid Arthritis: A Brief Overview of the Treatment" Medical Principles and Practice (2018)
  8. "Ankylosing spondylitis: etiology, pathogenesis, and treatments" Bone Research (2019)
  9. "Rheumatoid arthritis" The Lancet (2016)
  10. "The lifetime risk of adult-onset rheumatoid arthritis and other inflammatory autoimmune rheumatic diseases" Arthritis & Rheumatism (2011)