Seronegative and septic arthritis: Pathology review

Definitions & Key takeaways

Seronegative and septic arthritis are two different forms of arthritis, each with its causes and symptoms. Seronegative arthritis refers to a type of arthritis in which a person tests negative for rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) antibodies, which are markers commonly associated with rheumatoid arthritis. Seronegative arthritis can be caused by a variety of conditions, including psoriatic arthritis, ankylosing spondylitis, reactive arthritis, etc.

Septic arthritis, on the other hand, is a severe form of arthritis, often caused by bacterial infections. The infection can enter the joint through a break in the skin, or from an infection in another part of the body that spreads through the bloodstream. Septic arthritis is a medical emergency and requires prompt treatment with antibiotics to prevent joint damage and systemic spread of the infection.

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Case Study0:00–1:02

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.

Physiology1:02–1:50

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.

Pathology1:50–2:47

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.

Psoriatic Arthritis2:47–5:14

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.

Diagnosis5:14–5:36

Treatment5:36–6:02

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.

Ankylosing Spondylitis6:02–9:11

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.

Diagnosis9:11–9:38

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.

Treatment9:38–10:04

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-associated arthritis10:04–11:09

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.

Reactive Arthritis11:09–13:23

The most common microorganisms that are associated with reactive arthritis include Shigella, Yersinia, Chlamydia, Campylobacter, and Salmonella.
An easy way to remember them is to think of the mnemonic ‘SHY chiCS'. These are all gram negative bacteria, so they have molecules on their outer surface called lipopolysaccharides, also known as endotoxins, which produce a strong immune response.
Just how exactly reactive arthritis develops is unclear, but it probably has to do with the way endotoxins react with the MHC molecules on a normal cell surface, making them appear foreign.Symptoms of reactive arthritis take up to three weeks to develop after the initial infection because the immune system takes a while to present foreign antigens and kick T cells into action.
Symptoms mainly involve pain and swelling of a single large joint like the knee. Less often, it can involve other joints like the ankles, hips, and small joints in the feet, or affect multiple joints.
Now, besides joint pain, there are 2 other symptoms that's very high yield for this disease. When the urethra is involved, it can lead to urethritis, which can cause pain with urination, and when the conjunctiva of the eye is affected it leads to conjunctivitis, which can cause redness of the eyes.
This is the classic triad of arthritis, urethritis, and conjunctivitis that should help you identify reactive arthritis in your exams.
So a helpful mnemonic is that these individuals can't see, can't pee, can't climb a tree. Rarely, reactive arthritis can cause a skin rash called keratoderma blenorrhagicum on the soles and the palm, which looks like vesico-pustular waxy lesion with a yellow brown color.
And finally, if you have a cervix, there can be cervicitis, which will cause pain with sexual intercourse, called dyspareunia.Reactive arthritis is usually diagnosed based on a history of previous infection and a complete clinical examination.

Diagnosis13:23–13:51

In arthrocentesis, the synovial fluid is usually clear and sterile since the bacteria producing the endotoxin do not invade the joints.
Genetic testing for the HLA-B27 gene is often positive. Finally, throat and genital swabs might be used to look for Chlamydia.
In terms of treatment, NSAIDs like ibuprofen can be used for symptom relief, and if this doesn't work, then corticosteroids can be given to dampen the inflammation.All right, let's switch to septic arthritis, also called infectious arthritis.

Treatment13:51–14:02

This too is associated with an infection, but unlike reactive arthritis, it isn't autoimmune. Septic arthritis refers to any joint inflammation caused by a microbe that's actually invading the bones causing damage.

Septic Arthritis14:02–17:10

Now, there are various ways for bacteria to get into a joint. For example, it can spread from a preexisting osteomyelitis, or infection in the adjacent bone.
It can also develop from hematogenous spread, meaning that bacteria from an infectious site elsewhere in the body might travel through the bloodstream and reach the joint.
And finally, it can occur by direct inoculation, which is when bacteria reach the joint directly. This can occur as a complication of orthopedic surgery, or if someone happens to fall on some dirty planks of wood and a nail pierces through their knee.Now, there are two main types of septic arthritis; gonococcal arthritis, which is caused by Neisseria gonorrhoeae that typically spreads hematogenously from an initial infection of the cervix, urethra, or pharynx.
For your exams, remember that this is more common in sexually active adolescents. On the other hand, non- gonococcal arthritis includes all of the other pathogens, especially Staphylococcus aureus, but it can also be due to multiple Streptococcus species, as well as Mycobacterium tuberculosis, and Borrelia species, which cause lyme disease.Once bacteria get into the synovial cavity, they start destroying the articular cartilage with their toxins, and attract inflammatory cells such as macrophages to the site.
Macrophages then release cytokines such as interleukin-1 and TNF-alpha that recruit even more immune cells to the site of infection.
These may include mast cells, which release histamine to trigger vasodilation and increase vascular permeability. The final result is an increased influx of blood and inflammatory cells into the area, which creates a strong inflammatory response.
Moreover, because vascular permeability increases, fluid starts to leak out of the capillaries and accumulate in the joint space, increasing intra-articular pressure, which compresses the blood vessels that supply the joint.
Ultimately, this leads to necrosis of the affected bones and cartilage, damaging the joint even further.And because it is an infectious process, individuals present with inflammatory symptoms.
Most often, the affected joint is red, swollen, warm, and very painful. Sometimes, the joint's mobility might be limited, and individuals might develop a fever too.
Now, gonococcal arthritis typically affects multiple joints, and it's also accompanied by skin lesions like pustules, as well as tenosynovitis, which is inflammation of the tendons.
On the other hand, non- gonococcal arthritis usually affects a single joint, typically the knee, but it tends to be more severe than gonococcal arthritis.
Diagnosis of septic arthritis starts with arthrocentesis. The important thing to keep in mind here is that typically, there's purulent synovial fluid with a high white blood cell count, over 50.000 cells per microliter; positive gram stain; and a positive culture, which identifies the exact causative bacteria.
In addition, imaging including an X-ray, ultrasound, CT scan, or MRI can also be very useful to see bone erosion and joint effusions, especially for hip and sacroiliac joints, where synovial fluid aspiration is difficult.

Diagnosis17:10–17:56

Additionally, blood tests can be performed, and they usually show findings consistent with inflammation, like raised ESR, CRP, and leukocytosis.Treatment of septic arthritis typically starts with antibiotic therapy and pain medication.
For suspected gonococcal infection, you need to know that empirical treatment usually consists of ceftriaxone, which can be switched once culture results come back.
If there are concerns about resistance or chlamydia co-infection, the individual is given dual therapy with ceftriaxone and azithromycin.
In addition, treatment may require joint aspiration and washout by either arthrocentesis or a surgical operation known as arthrotomy.All right, as a quick recap… Psoriatic arthritis is an autoimmune process that causes a T cell mediated attack of the joints in people with psoriasis.

Treatment17:56–18:32

The most common type is the distal interphalangeal predominant type, which can cause pain, swelling, and stiffness in the affected joints but also psoriatic plaques and hand deformities like opera-glass hand.
Diagnosis is based on a history of psoriasis, negative serology for RF and anti-CCP, and X-rays showing joint erosion, osteopenia, and the pencil-in-cup sign.

Review18:32–21:07

Treatment includes NSAIDS and DMARDs. Ankylosing spondylitis usually affects the intervertebral joints, facet joints, and sometimes, the sacroiliac or neck and thoracic joints.
Symptoms consist of morning stiffness and lower back pain, which is worse at night, lasts for more than 30 minutes, and improves with exercise.
Extra-articular manifestations include uveitis, aortitis, peripheral enthesitis, and shortness of breath. Diagnosis is usually based on an X-ray, which can detect erosion, narrowing of the joint spaces, and a bamboo spine.
Treatment consists of NSAIDs, exercise or physical therapy, and in more severe cases, DMARDs. Seronegative arthritis may also be associated with inflammatory bowel disease, which is characterized by chronic gastrointestinal tract inflammation together with joint or back pain and stiffness.
For diagnosis of IBD, an endoscopy or colonoscopy with biopsy is needed, and treatment involves anti-inflammatory medications.
Reactive arthritis is when an infection elsewhere in the body, typically in the genitourinary or gastrointestinal systems, triggers inflammation of a single large joint.
The condition can also be associated with urethritis and conjunctivitis. Diagnosis is clinical with history and examination, and treatment is with anti-inflammatory medications.
Finally, septic arthritis is caused by various bacterial infections. It can be gonococcal arthritis when it's caused by Neisseria gonorrhoeae, or more commonly, non-gonococcal arthritis when it's caused by Staphylococcus aureus or other bacteria.
It usually affects just one joint, which presents with signs of acute inflammation like pain, redness, warmth, and swelling.
Diagnosis requires arthrocentesis and imaging, and treatment includes antibiotics and surgical management.Going back to our cases, Maurice is a 28 year old male with a 2 year history of progressive low back pain and stiffness.
This is important since we know we're looking for a more chronic cause of arthritis. He says the pain gets worse at night and in the mornings, but improves with use.
The key clue is that Maurice presents deformity and limited range of movement of the spine and hip, as well as buttock tenderness.
In addition, X-rays reveal erosion of the sacroiliac joint. Given this information, Maurice most probably has ankylosing spondylitis.

Summary21:07–22:16

Since this is a chronic and progressive disease, Maurice will need periodic evaluation. Clint, on the other hand, is a 63 year old male with a 3 day history of pain in the left knee that's associated with redness, warmth, and swelling, and a fever, so based on this we're looking for something with an acute cause.
The biggest clue is that arthrocentesis reveals a purulent synovial fluid, and together with his symptoms, Clint most likely has septic arthritis.
Gram stain and culture of the synovial fluid should be done to find the specific pathogen before starting empirical treatment.
in the left knee that's associated with redness warmth and swelling and he has a fever So based on this we're looking for something with an acute cause The biggest clue is that arthrocentesis reveals a purulent synovial fluid and together with his symptoms clint most likely has septic arthritis gram stain and culture of the synovial fluid should be done to find the specific pathogen before starting empirical