AssessmentsRheumatoid arthritis and osteoarthritis: Pathology review
USMLE® Step 1 style questions USMLE
A 65-year-old man comes to his primary care provider for evaluation of pain in both knees. His symptoms worsen with activity and improve with rest and ibuprofen. The patient had previously been an avid runner but had to stop due to the joint pain. Past medical history is notable for hypertension and a right fibular fracture, which occurred after a biking accident. Vitals are within normal limits. Examination of the affected joints reveals crepitus and mildly reduced range of motion. The remainder of the patient’s physical examination is noncontributory. Knee imaging is ordered, and the results are as follows:
Reproduced from: Radiopedia
Which of the following additional findings, if present, would best support the patient’s diagnosis?
Jody is a 55 year old woman who presents with a 6 month history of bilateral hand and wrist stiffness.
She mentions that the stiffness lasts for more than an hour a day but tends to improve as she uses the affected joints.
Examination shows swelling, limited range of movement, and subcutaneous nodules over the proximal interphalangeal joints, but no redness.
Then you see Kerry, a 60 year old woman who comes in with a 1 year history of pain in the right knee that has gotten progressively worse.
The pain is worse in the evening or with use of the affected limb and is associated with stiffness, which typically occurs at rest and lasts around 10 to 15 minutes.
Examination reveals Kerry is obese, has bowing of the right knee, and that the affected joint has a limited range of motion.
Blood tests are ordered in both cases, showing in Jody’s case high levels of rheumatoid factor (RF) and anti-citrullinated peptide antibody (ACPA), whereas in Kerry’s case both antibodies were absent.
Both people have arthritis.
Now, a healthy joint usually consists of two bones, each with its own layer of articular cartilage.
Articular cartilage is a type of connective tissue with a lubricated surface that acts like a protective cushion for bones to smoothly glide against.
For example, 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 that has cells that remove debris and produce synovial fluid, which is a viscous fluid found inside the joint capsule to lubricate the 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, and it can be classified as inflammatory or non-inflammatory.
Inflammatory arthritis is caused by an )immune response attacking the joints.
On the other hand, non-inflammatory arthritis is caused by mechanical wear and tear, and it is mostly represented by osteoarthritis.
Generally, in terms of symptoms, there are a few differences between inflammatory and non-inflammatory arthritis.
Ok so inflammatory conditions are usually accompanied by joint swelling, erythema, prolonged morning stiffness lasting more than one hour, and symmetric pain that improves with use.
Most of these conditions are also associated with extra-articular symptoms, like fever and fatigue.
On the other hand, non-inflammatory arthritis is usually suggested by asymmetric pain that gets worse with use and affects weight bearing joints, like the knee and the hip, and morning stiffness that lasts less than one hour.
Extra-articular symptoms are usually absent in non-inflammatory arthritis.
Let’s begin with the most common type of inflammatory arthritis.
Rheumatoid arthritis is a chronic, progressive, and inflammatory disorder that affects synovial joints and, sometimes, other parts of the body like the skin and the lungs.
It is thought to be an autoimmune reaction, however, the exact cause is unknown.
Generally speaking, it seems to be associated with environmental risk factors like infections and smoking, and with a genetic predisposition, like in biologically female individuals, and having the alleles HLA-DR1 and HLA–DR4.
So basically, it is believed that environmental risk factors in those with genetic predisposition end up modifying normal articular proteins in synovial joints.
As a consequence, the modified proteins end up confusing the cells of our immune system, which fail to recognize them as being self, or part of the normal human body, so at this point this protein is now a self antigen.
Antigen presenting cells then pick up the self antigen and take them to the lymph nodes, where they activate CD4+ T helper cells.
T helper cells then stimulate the nearby B cells to proliferate and differentiate into plasma cells, which produce specific autoantibodies against these self antigens, namely rheumatoid factor or RF, and anti-cyclic citrullinated peptide antibody or anti-CCP.
Soon after, both T helper cells and antibodies enter the circulation and reach the joints.
Macrophages will also produce inflammatory cytokines, like tumor necrosis factor, or TNF-α, interleukin- 1 or IL-1, and interleukin- 6, IL-6, which, together with the cytokines released by T cells, stimulate synovial cells to proliferate.
This increase in synovial cells and immune cells in the joint creates a pannus, which is a thick, swollen synovial membrane with granulation or scar tissue, made up of fibroblasts, myofibroblasts, and inflammatory cells.
Over time, the cytokines released in the pannus start to break down the articular cartilage, so the underlying bones are exposed and can directly rub against one another, leading to bone erosion.
Meanwhile, the antibodies that enter the joint space bind to their targets and form immune complexes that accumulate in the synovial fluid, activating the complement system, which further contributes to joint inflammation and injury.
Now, when it comes to articular symptoms, rheumatoid arthritis typically involves three or more joints symmetrically, meaning the same joint groups on both sides of the body, like the finger joints in both hands for instance.
The hallmark symptom of rheumatoid arthritis is chronic morning stiffness that lasts for over an hour, improves with use, and has lasted for more than 6 weeks.
The most frequent sites are the proximal interphalangeal joints of the hand, the metacarpo-phalangeal joints of the hand, and the wrists.
By contrast, the first carpometacarpal joint and the distal interphalangeal joints are rarely involved because they contain very little synovium.
Associated symptoms include reduced grip strength and range of motion, pain, and swelling.
As a particularity, swelling in rheumatoid arthritis is different from the one in osteoarthritis.
In rheumatoid arthritis, the swelling is caused by soft tissue edema secondary to inflammation, whereas in osteoarthritis swelling is secondary to bony overgrowth that makes the joint look larger.
Another distinction to help you out is that rheumatoid arthritis doesn’t usually cause redness or warmth because the inflammatory process is so gradual and chronic.
However, sometimes it can present with acute inflammatory signs such as edema, redness, warmth, and pain when there’s an acute episode of rheumatoid arthritis, also called a flare.
Now, other joints of the body besides the hands can be affected.
For example, in the feet, it’s usually the metatarsophalangeal joints, causing the individual to bear more weight on the heels and hyperextend their toes.
Hip involvement usually happens later in the disease, causing pain in the groin, thigh, or low back.
One very dangerous spot is the C1-C2 joint, or the atlantoaxial joint, which is the only synovial joint in the spine.
When it’s affected, it can cause neck pain, and sometimes extension of the neck during endotracheal intubation can worsen the subluxation, leading to acute compression of the spinal cord or vertebral arteries.
This can lead to spinal cord compression and tetraplegia, which is paralysis of all four limbs and torso.
As the disease progresses, there are also a series of deformities that can occur due to joint destruction.
One of them is swan-neck deformity, which doesn’t occur in the neck but in the fingers, causing them to deform and resemble the shape of a swan’s neck.
Specifically, the distal interphalangeal joint of the affected finger is in flexion or bent, while the proximal interphalangeal joint is in hyperextension or bent beyond its normal range of motion. There’s also the Boutonniere deformity, where roles reverse, meaning the proximal interphalangeal joint flexes to face the palm, and the distal interphalangeal joint is in hyperextension facing away from the palm.
Sometimes, when the metacarpophalangeal joints are severely affected, an ulnar drift can occur, where the fingers lean away from the thumb and toward the pinky.
This is due to the weakened radiocarpal ligaments that cause radial rotation of the metacarpals and carpus on the radius, which results in ulnar deviation of the joint.
Another important deformity is the Z-deformity, where the thumb flexes at the metacarpophalangeal joint and hyperextends at the interphalangeal joint.
This makes the finger look as if the individual is trying to hitch a ride, which is why it is also called the hitchhiker thumb deformity.
Now, if the spine is involved, cervical joint destruction can lead to vertebral misalignment or subluxation, causing pain, neurologic deficits, and deformity.
Finally, there can also be toe deformities like the claw toe deformity, where the metatarsophalangeal joint is hyperextended, while the proximal and distal interphalangeal joints are flexed.
This makes affected toes to look like bird claws.
Unfortunately, the cytokines released by the immune system don’t stay in just one place.
Instead, they can reach multiple organ systems, causing extra-articular symptoms.
For example, interleukin- 1 and 6 travel to the brain, where they act as pyrogens, inducing fever, fatigue, loss of appetite and, ultimately, weight loss.
They can also lead to inflammation of the uvea, which is the layer of tissue beneath the white of the eye or sclera, causing uveitis.
Some signs of uveitis include eye pain, conjunctival redness, blurry vision, miosis, and rarely with hypopyon or accumulation of pus in the anterior chamber of the eye.
If the sclera is involved, it can cause scleritis.
Now, in the skin, as well as in many visceral organs, the inflammatory cytokines lead to the formation of rheumatoid nodules, which are bumps with a central area of fibrinoid necrosis that’s surrounded by palisading histiocytes, a type of macrophage.
Palisading means the cells are arranged in layers around the necrotic area, parallel with each other, almost like a picket fence.
On examination, these are seen as singular or multiple subcutaneous nodules that are firm to the touch, non painful, and distributed around the affected joint.
In the soft tissue, the disease can lead to carpal tunnel syndrome.
The carpal tunnel is a narrow passageway formed by the carpal bones and the transverse carpal ligament at the wrist, which gives passage to the median nerve and muscle tendons.
Because rheumatoid arthritis causes tendon inflammation, these swell up and compress the median nerve, causing carpal tunnel syndrome and symptoms such as paresthesia or tingling sensation, pain, and numbness of the hand.
Blood vessels can also be affected, causing wall inflammation resulting and in various forms of vasculitis, which can make blood vessels more prone to developing atheromatous or fibrofatty plaques.
These can lead to cardiovascular disease like myocardial infarction and stroke.
In fact, cardiovascular disease is the primary cause of mortality associated with rheumatoid arthritis.
Meanwhile, within the lung interstitium, fibroblasts get activated and proliferate, causing pulmonary fibrosis that impairs the alveolar gas exchange.
The pleural cavities surrounding the lungs can get inflamed as well, causing them to fill up with fluid, which is known as pleural effusion, and it can impair lung expansion too, interfering even more with gas exchange.
Additionally, there’s Caplan's syndrome, which is when the individual has both pneumoconiosis and rheumatoid arthritis, and this tends to manifest as intrapulmonary nodules.
The liver can start producing high amounts of hepcidin in response to inflammatory cytokines.
Hepcidin decreases serum iron levels by inhibiting its absorption by the gut and trapping it into macrophages or liver cells, leading to anemia of chronic disease.
In the spleen, rheumatoid arthritis can lead to splenomegaly and neutropenia, a combination called Felty syndrome.
It can also be associated with Sjogren syndrome, which is an autoimmune disease that primarily attacks the lacrimal and salivary glands, impairing their ability to secrete their fluids and resulting in dry eyes, mouth, and skin among many other symptoms.
And finally, rheumatoid arthritis can lead to AA amyloidosis, which is a type of amyloidosis that occurs as a reaction to another illness.
In short, rheumatoid arthritis causes the liver to produce a protein called SAA or serum amyloid A protein in high levels, which is a normal reaction.
However, if inflammation persists, a small portion of the SAA protein, called AA protein, will separate from SAA and deposit in organs as AA amyloid, especially in the kidneys, where it causes organ damage.
Diagnosis of rheumatoid arthritis is based on a complete clinical evaluation, followed by a series of tests, since some conditions like Parvovirus B19 infection may mimic the symptoms of rheumatoid arthritis.
Okay, so when it comes to blood tests, there might be signs of anemia, thrombocytosis, mild leukocytosis, and elevated erythrocyte sedimentation rate or ESR and C-reactive protein or CRP, all of which are caused by the chronic inflammation associated with the disease.
It’s also important to test for autoantibodies like RF and anti-CCP.
For your exam, you should remember that rheumatoid factor is an IgM antibody that targets the constant Fc component of human IgG antibodies.
Anti-cyclic citrullinated peptide antibody is an antibody that targets citrullinated proteins, which are proteins whose arginine residues have been chemically modified to citrulline through a process called citrullination.
A high-yield fact you should know is that although RF is associated with rheumatoid arthritis, it is not highly specific, as it is positive in just 70% of cases.
On the other hand, anti-CCP is more specific of rheumatoid arthritis, as it has a specificity of almost 96%.
This means that there are cases of rheumatoid arthritis with negative serology.
In these cases, diagnosis is based solely on clinical findings and imaging.
A minority of individuals could also present antinuclear antibodies or ANA, which are formed against the normal proteins of a cell’s nucleus.
Radiographs of the affected joint are also important for diagnosis.
Over time, some possible changes might include juxta-articular osteopenia, or decreased bone density around affected joints that shows as areas with increased transparency on an x-ray; soft tissue swelling, which is seen as a thick halo around the bone; narrowing of the joint space; bone erosions, which look like someone bit into the bone; and rarely, subchondral cysts, which are sacs of hyaluronic acid that form in the subchondral bone, the layer of bone just under the cartilage.
On an x-ray, subchondral cysts look like dark, round, and fairly well delimited areas inside the bone.
In some cases, arthrocentesis can be done, where synovial fluid is collected from an affected joint and examined under a microscope and sent for Gram stain and cultures, especially during a flare, to make sure there’s no evidence of crystals like in gout or pseudogout, or signs of infection like in septic arthritis.
There’s no cure for rheumatoid arthritis, but there are ways to keep the disease under control.
The main treatment consists of long term medications called disease modifying antirheumatic drugs or DMARDs, which can be non-biological or biological.
Most individuals with an acute rheumatoid arthritis flare are started on non-biological DMARDs, like methotrexate, leflunomide, hydroxychloroquine, and sulfasalazine.
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