Systemic lupus erythematosus (SLE): Pathology review

Definitions & Key takeaways

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Case Study0:00–1:08

At the internal medicine department, a 42 year old female named Mary shows up. She complains of multiple skin lesions on the arms, chest and back.
She reports having these lesions for about 3 months. In the past, she had similar lesions.
She reports morning stiffness involving her fingers and knees, as well as a history of multiple miscarriages. Blood tests revealed pancytopenia as well as a very high ESR and CRP.
She was positive for ANA and antiphospholipid antibodies.Meanwhile, at the emergency department, a 25 year old man named Kyle shows up with flank pain and hematuria.
He has a history of migratory arthralgias and photosensitivity. He was positive for ANA and double-stranded DNA antibodies, and also had low complement levels.
Blood tests revealed very high ESR and CRP, as well as high creatinine, so a urinalysis was performed, showing proteinuria and red blood cell casts.
Both individuals actually have very different presentations of the same disease, called Systemic Lupus Erythematosus. This is a systemic, relapsing, and remitting autoimmune disease, where systemic means that essentially any tissue or organ can undergo inflammation; while relapsing and remitting, stands for periods of illness, called relapses or flares; and periods of remission during which there are few or no symptoms.

Pathophysiology1:08–3:17

Now, lupus develops when the person’s immune system starts recognizing nuclear antigens of the body’s own cells as foreign and tries to attack them.
Essentially, B cells start producing antibodies which bind to nuclear antigens in our own cells. Normally, these B cells are destroyed before they fully mature in a process called self tolerance, but in people with lupus this process is impaired.
The antibodies released by these B cells form antigen-antibody complexes and these complexes drift around in the blood until they deposit or stick to the vessel wall in all sorts of different organs and tissues like the kidneys, skin, joints, heart.Deposited complexes then initiate a local inflammatory reaction, which causes damage through the activation of the complement system, which, after a huge cascade of enzyme activation, causes the cell to burst and die.
Eventually, this gets complement factors like C3 and C4 all used up. A very high yield fact to remember is that this is a kind of type III hypersensitivity reaction.
Another high-yield fact is that because early complement proteins like C1q, C2 and C4 are all involved in removing those antigen-antibody complexes, individuals that lack any of these proteins are more likely to experience lupus.
Now, many patients also develop antibodies targeting other cells like red, white blood cells and platelets, leading to pancytopenia.
This is considered a type II hypersensitivity reaction. Okay, the classic scenario involves a female of reproductive age, especially of African-American or Hispanic descent.

Key Symptoms & Findings3:17–8:15

There are 11 key symptoms and findings you need to remember for lupus and we can divide them into 4 groups. The first group are 3 symptoms that have to do with the skin.
The first is a malar rash, sometimes just called a “butterfly rash”, which is a rash over the cheeks that spares the nasolabial folds and appears after sun exposure.
Second is a discoid rash, which is a chronic erythematous rash in sun-exposed areas like the arms and legs that are plaque-like or patchy redness that’s scaly and can cause severe scarring or hair loss.
Third, is a general photosensitivity of the skin, essentially a catch-all category for other rashes that happen to sun-exposed areas, typically only lasting a couple of days.
The next group involves 2 symptoms affecting the membranes. Lupus can also damage the inner membrane or mucosa of various tissues, causing ulcers in the mouth or nose.
Next, there’s serositis which is inflammation of the serosa, which is like the outer membrane of an organ or tissue. It can manifest as pleuritis, which is inflammation of the lining around the lungs and chest cavity; as peritonitis, which is the inflammation of the lining of the abdomen, or as pericarditis, which is inflammation of the lining of the heart.
It’s worth noting that in addition to pericarditis, lupus can also cause inflammation of the myocardium, leading to myocarditis, or the endocardium, leading to Libman-Sacks endocarditis, where clumps of fibrin and immune cells form vegetations on the mitral or aortic valve.
What makes these vegetations special is that they can be present on either surface of the valve, but are usually on the undersurface.
The third group includes 3 extraglandular manifestations. First up is arthritis, two or more joints have to be inflamed.
The next one is evidence of kidney damage based on protein or cells in the urine. It’s generally caused by diffuse proliferative glomerulonephritis, which is the most common and severe type of glomerulonephritis caused by immune complex deposition along the glomerular basement membrane.
The test question might show you or describe a light microscopy image with diffuse thickening of the glomerular capillary walls with characteristic "wire-loop" structures.
Lupus nephritis can ultimately lead to end-stage kidney failure.A high yield fact to remember is the end stage kidney failure is the number one cause of morbidity and mortality among individuals with lupus, followed by infections and cardiovascular disease.
The last one is neuropsychiatric conditions like headaches, seizures, psychosis, and mood disorders like depression.The final three are lab findings related to blood.
One of these is having autoantibodies against blood components causing cell destruction, and leading to conditions like anemia, thrombocytopenia, or leukopenia; while the tenth and eleventh findings have to do with having specific antibodies in the blood.
The next one is having positive serology for antinuclear antibodies or ANA, which targets nuclear antigens. Now a large proportion of patients with lupus have these, meaning this test is very sensitive, but it isn’t very specific, because it can be found in other autoimmune diseases.The final lab finding is having one of three other autoantibodies.
The first is anti-Smith, which is an antibody against small ribonucleoproteins. The second is anti-dsDNA, which is against double stranded DNA and is often seen more during flares, especially in individuals with kidney involvement.
These two are relatively specific for lupus. The third type of antibody is antiphospholipid, which is actually an antibody that targets proteins bound to phospholipids, and is less specific for lupus, meaning that it can pop up in other situations.
There are three types of antiphospholipid antibodies. The first is anticardiolipin.
The other two antiphospholipid antibodies are lupus anticoagulant, also called lupus antibody, and anti-beta2 glycoprotein I.
Sometimes individuals with lupus develop antiphospholipid syndrome, where the antiphospholipid antibodies cause a hypercoagulable state, meaning they’re more prone to developing clots and having complications like deep vein thrombosis, stroke, and recurrent miscarriages.

Other Features8:15–9:49

Now, although it’s not included in the 11 key findings, other types of autoantibodies called anti-SSA or anti-Ro can be present.
The reason that these are important is that pregnant individuals with lupus who are also positive for anti-SSA autoantibodies are at risk of having a newborn with neonatal lupus erythematosus.
This may classically manifest as congenital heart block, periorbital or diffuse rash, transaminitis or increased liver transaminases, and cytopenias at birth.Another type of auto-antibodies not counting as a criterion is anti-histone antibodies.
For your exams, positive ANA and anti-histone antibodies with negative anti-dsDNA antibodies is a clue for drug-induced lupus erythematosus which develops as a reaction to certain medications metabolized by N-acetylation in the liver.
You can remember these with the mnemonic SHIPP, where S stands for Sulfonamide, H for Hydralazine, I for Isoniazid and P for Procainamide and Phenytoin.
So, genetically predisposed individuals who are slow acetylators are at risk for drug-induced lupus. This is characterized by abrupt onset of lupus symptoms, like fever, arthralgias and pleuritis.
For your test, it’s important to know that unlike idiopathic lupus, drug-induced lupus typically does not affect the oral mucosa, CNS, or kidneys.
Now, because lupus can affect any organ, differential diagnosis can be difficult. Starting off from the skin, an important differential is dermatomyositis, which is an autoimmune disorder that causes muscle inflammation, leading to progressive muscle weakness and wasting.

Differential Diagnosis9:49–12:38

Individuals typically present the heliotrope or lilac rash, which is a pruritic purplish rash that can appear on or around the eyelids.
This rash is similar to the malar rash of individuals with lupus, but a key hint on your test is that it typically extends beyond the nasolabial folds, which is a region that’s usually spared in lupus.
On the other hand, individuals presenting a discoid rash may require a skin biopsy showing autoantibody deposition. Differential diagnosis includes skin cancer, psoriasis, lichen planus, sarcoidosis, or syphilis.The arthritis in lupus can be difficult to distinguish from rheumatoid arthritis.
However a key distinguishing feature is that the joint deformities in lupus are usually non-erosive, which can be seen on an X ray.
Serology showing the presence of anti-cyclic citrullinated peptides are more supportive of the diagnosis of rheumatoid arthritis, and can help distinguish the diseases.
Now, the term “rhupus” is used to describe patients with overlapping features of both lupus and rheumatoid arthritis, which usually has serologies consistent with both diseases, as well as erosive arthritis.Individuals with Sjögren's syndrome may have the same extraglandular manifestations that can be observed in lupus.
Also, individuals with Sjögren's syndrome often have Ro and La antibodies. The distinction here is that Sjögren's syndrome should also present with glandular manifestations like keratoconjunctivitis, sicca, and xerostomia, so use that as a hint to distinguish between the two.
Finally, cytopenias can be caused by a wide spectrum of diseases, ranging from hematologic to infectious and autoimmune diseases.
In addition, sometimes serological results are misleading, since these autoantibodies are often positive in a wide variety of diseases.
A particularly high yield one is anticardiolipin antibodies which are also present in people with syphilis, and that can cause a false-positive test, and some cases of lupus may resemble the maculopapular rash of the palms and soles that’s typical of secondary syphilis.
On your exam, remember that treponemal antibody testing should be negative in lupus. The treatment of lupus often depends on the severity of the symptoms and what organ systems are affected.

Treatment12:38–13:12

Hydroxychloroquine and chloroquine can be helpful for arthritis and mucocutaneous symptoms. Short term, low doses of a glucocorticoid like prednisone can be used in conjunction to treat acute flares with less severe symptoms and high doses are needed for serious or life threatening cases, often with other immunosuppressant medications like cyclophosphamide, azathioprine, or mycophenolate mofetil.All right, as a quick recap...Systemic lupus erythematosus is diagnosed based on 11 key symptoms and lab findings.

Review13:12–14:01

We can divide them into 4 groups; 3 for skin, 3 for blood, 3 extraglandular and 2 mucosal related.For skin, there’s malar rash, discoid rash, and photosensitivity; for blood, there’s hematologic conditions like anemia, leukopenia, and thrombocytopenia, antinuclear antibodies, and another type of autoantibody like anti-double-stranded DNA, anti-Smith, or antiphospholipid antibodies; for extraglandular, we have arthritis in two or more joints, renal involvement, and neuropsychiatric conditions; finally, for mucosal, there’s oral or nasal ulcers, and serositis.Coming back to our individuals, Mary’s multiple skin lesions on the arms, chest and back are consistent with a discoid rash.

Summary14:01–15:07

She also presents with arthritis involving her fingers and knees, and she was positive for ANA and antiphospholipid antibodies, which in turn led to her multiple miscarriages and pancytopenia.
On the other hand, there’s Kyle, who has a history of photosensitivity, and presented to the emergency department with lupus nephritis.
In addition he was positive for ANA and double-stranded DNA antibodies. As you can see, these two individuals have very different presentations of what ended up being the same disease.
So for treatment, Mary should be treated as an outpatient with hydroxychloroquine or chloroquine and short-term glucocorticoids, while Kyle needs a more aggressive approach, getting in-hospital treatment with short-term high-dose glucocorticoids, and he may get other immunosuppressive medications like cyclophosphamide.