SLE, Lupus-like Syndrome,

Sjogren’s Syndrome, MCTD,

CREST and Antiphospholipid
Syndrome 2020
Mark Stillwell, MD, FACP
 World of Pain (Where you may feel you are with a
rheumatologic disease)
• Cream (supergroup of Eric Clapton, Ginger Baker, Jack Bruce…..Rolling Stone
Magazine’s #2 guitarist, #3 drummer and #8 bassist of all time respectively)
• Released- 1967
• Album- Disraeli Gears (#1 US album in 1968)
• Active- 1966-1968
• Genre- Blues/Psychedelic/Hard Rock
• Honors- Inducted into the Rock and Roll Hall of Fame in 1993. The group has 2
Grammys and one nomination……all despite being together for only 2
years……currently Eric Clapton has 17 Grammys and 37 nominations himself
• First hit- I’m So Glad 1966
• Other hits: Sunshine of Your Love, Born Under a Bad Sign, Strange Brew, I Feel
Free, Crossroads, Badge, Tales of Brave Ulysses, Wheels of Fire, Spoonful, Toad,
White Room, Take It Back
Disraeli Gears album
Source: wikipedia.org
You all are about at the end of the hardest semester of your life. Hang in there, soon to be over!
Source: pinterest.com
 The BECOM-3 final is December 14

• Make a study plan now, don’t waste your upcoming holidays……..all a

great opportunity to practice Board questions and review areas you
don’t feel confident in.

• Life gets a lot nicer after this semester ends....... then only a little more
than 3 rigorous months in early 2020, a short semester, and finally the
fun really starts (just ask the OMS-IIIs and -IVs!).
 OMS-II students toward the end of their first semester ......Edvard Munch’s “The Scream” 1893.....one of four versions of this
sold at a Sotheby’s auction for $120 million a few years ago Source: edvardmunch.org
OMS-IIs come April.........from Charles Schulz, “Charlie Brown”
Source: weheartit.com
 Please study the pre-reading PowerPoints for the
Rheumatology section:
• A. Lab Testing For The Rheumatic Diseases
• B. Rheumatologic Drugs
• C. Behcet’s Disease
• D. Relapsing Polychondritis
• E. Rheumatology Practice questions

• ***Material on these PPs will come back to haunt you on Boards I, II and III, along with
specialty boards, the rest of your life (not to mention tests here too……for many of them
you will unlikely get further didactic lectures on during the rest of your training…….so it
would be a good time to learn and understand them well now)
• ***Many of these diseases share symptoms/signs/lab results…..pay particular attention
to how each one is unique. Making these diagnoses is difficult, and most of these
diseases develop slowly over the years. For a long time, many patients may be
categorized as having an “undifferentiated connective tissue disorder” before they
eventually declare themselves as having a specific rheumatologic disease.
 Learning Objectives for this Session
• Describe genetic and environmental factors involved in predisposition
to SLE.
• Explain the clinical and classification criteria for SLE, including organ
involvement.
• Distinguish between SLE, Sjogren’s syndrome, CREST and MCTD.
• Describe Lupus-like syndrome and Antiphospholipid syndrome.
• Discuss diagnosis and treatment of the diseases above.
The doctor called Mrs. Smith saying, “Mrs. Smith,
your check came back.” Mrs. Smith answered, “So
did my arthritis!”
Henny Youngman (standup comedian from the mid 1900s)
“If I woke up in the morning and nothing hurt,
I would think I was dead”
Many of your senior faculty
 Case ........real one, early 1990s, Ft. Smith
• CC- Fever x 4 weeks in 60 yo male in the summer
• HPI-
• O- Gradual onset, intermittent initially, now daily
• L- Diffuse
• D- Lasts a few hours
• C- Quick spikes to 102 with chills, sweats when breaks
• A- Better with antipyretics, nothing makes it worse
• R- None
• T- Comes on late afternoon/early evening, resolves by midnight
• S- 7/10
• A- Positive- chills, sweats, bilateral pleuritic chest pain, central sharp chest pain
worse supine and better sitting forward, dry cough, rash, myalgias, arthralgias,
symmetric arthritis in hands
• Negative- hemoptysis, dysphagia, hematuria, new meds, palpatations, syncope
or TIA sx
 Case
• PHx- Medical- HBP, atrial tachyarrhythmias, BPH
• Surgical- None
• Transfusions- None
• Childhood- Had Measles, Mumps, Rubella, Chicken pox, Roseola, Parvovirus
• Immunizations- Td 5 yr ago
• Screening- PSA normal, stool OB and prostate exam c/w BPH in last year, colono
nl 9 years ago
• SHx- Lives in town, no EtOH/Tob/Illicit drug/Caffeine use
• Fam Hx- Mother 80 with HBP, Father 81 with OA, bro with HBP, children healthy
• All- None to meds, latex, food or environment
• Meds- Digoxin 0.125 mg/d, Procainamide SR 750 mg QID, Nicardipine 20 mg TID,
Prazosin 1 mg BID
• ROS- unremarkable except HPI
 Case
• PE- T 101, P 110 regular, RR 22, BP 138/90
• Skin- see picture
• HEENT, Neck, Abd, Spine, GU, Lymph unremarkable
• Cardiac- distant heart sounds, 2 component rub, PMI not
palpable, JVP 6 cm, Kussmaul’s sign negative, no murmur/gallop
• Chest- decreased BS and dullness to percussion in the bases and
pleural friction rubs bilaterally, no rales/rhonchi/wheezes, no pain
to palp
• Ext- see pictures
Skin exam
Source: flickr.com
Hand exam bilat
Source: hss.edu
 Case
• Lab-
• CBC- WBC 3.2 (nl diff), HCT 36, MCV 88, Plt 122k
• CMP- elevated globulin, nl albumin.....SPEP-polyclonal gammopathy
• ESR- 95 (nl < 20)
• TSH/FT4 normal
• CPK total and MB negative x3, LDH isoenzymes nl (LDH isoenzyme 2 > 1,
normal pattern) x 3, troponins weren’t done back then
• Hepatitis ABC panel negative, RPR negative, HIV negative
• Blood culture neg x 4 sets
• UA unremarkable with negative urine culture
• Sputum Gram stain- no polys, no organisms, culture negative
• Sputum AFB stain negative x 3
• PPD 0 mm induration
• Venous duplex showed no DVTs and pulmonary angiogram showed no PEs
Chest X-ray
Source: omicsonline.com
Chest X-ray (R lateral decubitus)
Source: wikipedia.org
EKG
Source: litfl.com
Echo......nl EF and wall motion, no vegetations
Source: mdedge.com
 Case
• I was asked to consult on the patient for fever, after they had
been admitted to the hospital ...............a diagnostic procedure
was ordered.
• This case will be continued at the end of the hour.
SLE/Lupus
Source: wikipedia.org
 There is lupus, and there is lupus, and there is
lupus
• It can be an occasional annoyance......it can be a bad disease.....or
it can be life threatening.
• No organ escapes its attack
 Systemic Lupus Erythematosis (SLE)- Intro
• SLE- also known simply as “lupus”
• A. It is one of many multisystem, autoimmune disorders that are
categorized as “collagen vascular diseases” or “connective tissue
diseases.” These diseases develop due to cellular damage caused by
tissue-binding autoantibodies and immune complexes.
• B. **Like many autoimmune diseases, SLE does not develop overnight,
but rather is often diagnosed after a patient has progressive symptoms
that are nondescript for years. It is almost never an acute-presenting
illness initially. *It is also a “different disease” in every person it affects.
• C. *These illnesses may, at times, be hard to characterize into just one
disorder creating “overlap syndromes” (e.g. “rhupus”) or
“undifferentiated connective tissue disease” (UCTD.....especially early
on).
 SLE- Intro
• SLE- also known simply as “lupus”
• D. SLE is thought to involve both genetic (multigenic) and environmental factors.
In identical twins there is only a 24% chance that the sibling will also have the
disease. Siblings are at 29-fold risk c/w the general population.
• 1. *Female sex is permissive for SLE (adult women are at 7 to 15-fold risk c/w
males, female children are at 3-fold risk).
• a. Females of many mammalian species make higher autoantibody
responses than males.
• b. Women exposed to estrogen-containing oral contraceptives or hormone
replacement have increased risk for developing SLE.
• 2. Ethnicity- higher risk in Asian, Latino and African-American populations.
• 3. Environmental stimuli such as UV light (70% of patients) can cause lupus
flares, as can EBV infection and Vitamin D deficiency.
Incidence by age in men (left) and women (right) in a German study of 2.3 million people
Source: lupus.bmj.com
Incidence by age in African-American vs Caucasian women in the Michigan Lupus Surveillance Program Registry
Source: researchgate.net
 SLE- Path
• SLE- Path
• A. *Skin- immunoglobulin deposition and T-lymphocyte inflammation at the
dermal-epithelial junction, keratinocyte injury and vasculitic abnormalities.
• B. *Various forms of lupus nephritis may show mesangial immune complex
deposits and subepithelial or subendothelial glomerulonephritis (focal or global,
proliferative +/- membranous sometimes with wire loops) associated with
immune deposits or glomerulosclerosis. Immune complex deposition can activate
complement injury. Antibodies are *predominately IgG, but may also be IgM.
• C. *Blood vessels often show nonspecific leukocytoclastic vasculitis, and may
involve small, medium-sized and large vessels. There can be immune complex
formation (against endothelial cells) or deposition in the vessel walls.
*Accelerated atherosclerotic disease can also be seen. *Cryoglobulinemia and
antiphospholipid syndrome causing clot formation in both veins and arteries can
develop.....i.e. hypercoagulable.
 SLE- Path
• SLE- Path

• D. Heart- **Libman-Sacks endocarditis (non-bacterial, verrucous

endocarditis on the lines of closure of the heart valves, only 1-3 mm
in size, smaller than those seen in infective endocarditis),
**fibrinous or exudative pericarditis and myocarditis.
• E. Lymph nodes tend to show nonspecific chronic inflammation
(reactive hyperplasia) +/- areas of focal necrosis (with purple-
basophilic **hematoxylin bodies/LE bodies in necrotic regions,
made up of degraded nuclear material from injured cells plus
autoantibodies).
Immunofluorescence of skin biopsy in SLE- epidermal basement membrane and apoptotic nuclei of epidermal cells light up
Source: wikipedia.org
Multi-pronged attack in SLE nephritis
Source: nature.com
“Wire-loops” in SLE nephritis are due to thickened glomerular capillaries due to subendothelial immune complex deposition
Source: twitter.com
“Wire-loops” and mesangial proliferation in SLE nephritis
Source: archivesofpathology.org
SLE nephritis with WHO class I findings of mesangial immunoglobulin deposition only, however H&E light microscopy is normal
Source: kidneypathology.com
SLE nephritis with WHO class II (a,b) mesangial proliferation and class III (c, d) focal, segmental necrosis disease
Source: jasn.ssnjournals.org
SLE nephritis with WHO class IV (a,b) diffuse and class V(c, d) membranous disease
Source: jasn.ssnjournals.org
SLE nephritis with WHO class VI diffuse glomerulosclerosis
Source: slideshare.net
Summary of SLE nephritis classification
Source: scielo.br
SLE with leukocytoclastic vasculitis
Source: linkspringer.com
SLE with Libman-Sacks endocarditis (in this case causing MR, picture taken intra-op during MVR)
Source: cardiothoracicsurgery.biomedcentral.com
SLE with Libman-Sacks endocarditis (more extensive, at autopsy), vegetations are smaller than in infective endocarditis
Source: researchgate.net
Fibrinous or exudative pericarditis is common in SLE
Source: webpathology.com
Acute fibrinous (a), organizing (b) and finally scarred, thickened pericarditis with myocardial adhesions in SLE
Source: sciencedirect.com
SLE may have lymphadenopathy, usually reactive hyperplasia on histopath (follicular hypertrophy, prominent mantle regions in
the follicle periphery) Source: semanticscholar.org
 SLE may have lymphadenopathy, may have regions of necrosis (pink/eosinophilia with decreased cellularity) with
purple/basophilic **hematoxylin bodies = LE bodies in those areas Source: librepathology.org
 SLE- Clinical
• SLE- Clinical manifestations
• A. General- symptoms of SLE vary from mild and intermittent to severe,
fulminant and persistent. *Most patients have exacerbations (“flares”)
interspersed with periods of relative quiescence. Permanent complete
remissions are rare, unlike RA that can just “burn out.” Constitutional symptoms
include:
• 1. Fatigue (80-100% of patients) that can be disabling and not clearly related
to flares. This is often associated with fibromyalgia symptoms (myalgia is
common, myositis or severe muscle weakness is uncommon), depression and
sleep disturbances.
• 2. Fever (> 50% of patients) and tends to be present during times of disease
activity. This may resolve with to antipyretics. ***Fevers that resolve with
Acetaminophen, NSAID or steroids, then think autoimmune disease and
malignancy.......**fevers that do not resolve, or only partially improve, on such
drugs then think infection or drug-related fever.
• 3. Weight loss- due to the disease, med side effects (e.g.
Hydroxychloroquine), and associated GI disease (e.g. pancreatitis).
Clinical manifestations of SLE- also, oral/nasal ulcers (45%), nasal perforation, dry eyes/mouth (33%) and Raynaud’s phen (10-
50%)........another great imitator disease (like Syphilis, TB, porphyria, lymphoma, Celiac, MS) Source: prescriber.co.uk
 SLE- Clinical
• SLE- Clinical manifestations
• B. Musculoskeletal-
• 1. **Inflammatory arthritis- in 65-70%, migratory, polyarticular,
symmetrical.......*less disabling than RA and usually does not cause
severe destruction of the joints (occurs in only 10%)........>90% have
arthralgias.
• C. Mucosal-
• 1. **Mucosal and nasal septal ulcers (*often painless) can develop in
45% of patients, may be related to flares.
• 2. Nasal perforation.....think SLE, Wegener’s granulomatosis,
Cocaine/Methamphetamine, sarcoidosis, leprosy, syphilis, TB and other
treponemes, use of nasal steroids and decongestants, malignancy, and
invasive opportunistic infections.
Oral ulcer with SLE, often painless
Source: fidanowski.ca
 SLE- Clinical
• SLE- Clinical manifestations
• D. Cutaneous-
• 1. **Butterfly rash- in 40%, an erythematous rash in a malar
distribution over cheeks and nose, but sparing the nasolabial folds and
worsens or develops with sun exposure.
• 2. **Skin photosensitivity
• 3. **Discoid lupus- red-purple, inflamed coin-shaped patches or
plaques of skin with a scaling and crusty appearance......most often on the
scalp, cheeks, nose and ears. On healing there may be significant scars,
hyperpigmented peripherally and hypopigmented in the center. (*note-
discoid lupus can occur alone, without SLE, called just DLE- discoid lupus
erythematosis). On immunofluorescence, there is IgG and IgM deposition
at the dermal-epidermal junction, +/- dermal vasculitis.
 SLE- Clinical
• SLE- Clinical manifestations
• D. Cutaneous-
• 4. Livido reticularis- reddish-blue discoloration of skin,
netlike/lacy/blotchy pattern, blanching on pressure. Caused by
cutaneous venule and arteriole obstruction from clots, vasospasm
and sometimes vasculitis........often indicating an associated
antiphospholipid syndrome.
• 5. Leukocytoclastic vasculitis- causing non-blanching, palpable
purpura.
• 6. Alopecia- can manifest as diffuse thinning or can be patchy (like
with Syphilis).
Mild malar rash
Source: medscape.com
Moderate malar rash
Source: medicalnewstoday.com
Severe malar rash
Source: researchgate.net
Skin photosensitivity common in SLE
Source: sciencedirect.com
Discoid lupus lesion
Source: accd.org
Discoid lupus lesion
Source: ncbi.nlm.nih.gov
Old discoid lupus scars along with active, acute lesions
Source: empendium.com
Immunofluorescence of discoid lupus skin biopsy, lupus band test
Source: slideshare.net
Deeper biopsy also lights up areas of dermal vasculitis
Source: ijdvl.com
Livido reticularis in SLE
Source: medicaljournals.se
Livido reticularis in SLE.....more extensive......think associated antiphospholipid syndrome
Source: healthsurgical.com
SLE with leukocytoclastic vasculitis (palpable purpura that doesn’t blanch)
Source: hss.edu
SLE can cause alopecia due to diffuse thinning of hair
Source: lupus.bmj.com
SLE can also cause alopecia due to patchy losses, often in areas of previous discoid lupus
Source: lupus.bmj.com
 SLE- Clinical
• SLE- Clinical manifestations
• E. Renal disease- clinically apparent in 50-60% of patients, often the
most serious manifestation of SLE. Mainly due to anti-dsDNA antibody
formation of immune complexes, that deposit in this region, and direct
anti-dsDNA antibody attack on glomerular cells, including and mesangial,
subendothelial and subepithelial regions.
• 1. Multiple types of glomerulonephritis can be seen in SLE, leading to
proteinuria/nephrotic syndrome, hematuria and RBC casts, and
sometimes ESRD.
• 2. There are also extra-glomerular immune deposits that form in the
tubular basement membrane, interstitium (interstitial nephritis) and blood
vessels in extra-glomerular regions (thrombotic and vasculitic lesions).
Also, a glomerular podocytopathy with foot process effacement, similar to
minimal change disease, can be seen independent of immune complex
disease (possibly from cytokine toxicity).
• 3. See earlier slides in this session for histopath.
 SLE- Clinical
• SLE- Clinical manifestations
• F. GI disease-
• 1. Dysphagia- 20-70% have esophageal dysmotility, and may be associated with
chest pain and GERD symptoms too.
• 2. Increased risk of peptic ulcer disease, not fully explained by just NSAID use.
• 3. Small or large bowel pseudo-obstruction- possibly due to immune complex
formation in the bowel (in smooth muscle cells) or due to vasculitis. This can be
associated with recurrent abdominal pain and distension/bloating.......can be
acute, recurrent or chronic......sometimes associated with hydronephrosis too.
• 4. Protein-losing enteropathy- leading to diarrhea, edema and
hypoalbuminemia.
• 5. Mild hepatitis is common, usually of no significance (this is distinct from
autoimmune or lupoid hepatitis, a different disease process).
• 6. Pancreatitis due to vasculitis can occur.
SLE with intestinal pseudo-obstruction and hydronephrosis
Source: researchgate.net
SLE with pancreatitis
Source: journalmc.org
 SLE- Clinical
• SLE- Clinical manifestations
• G. Cardiac disease-
• 1. Pericarditis (fibrinous, exudative, +/- effusion) is the most
common cardiac manifestation....seen in 25%.
• 2. Libman-Sacks endocarditis can lead to embolic phenomena or
valvular dysfunction (esp. regurgitation). *Most commonly involving
the MV/AV. Most common in those with antiphospholipid syndrome.
• 3. Increased risk for atherosclerotic heart disease and even
coronary artery vasculitis.
• 4. Myocarditis is uncommon.
Echo of Libman-Sacks endocarditis on MV
Source: emedicine.medscape.com
 Pt with SLE presenting with an acute inferior MI with coronary artery vasculitis/saccular aneurysms (a,b).....15 months later
(c,d) after treatment there is improvement. Source: ahajournals.org
 SLE- Clinical
• SLE- Clinical manifestations
• H. Pulmonary disease-
• 1. Pleural serositis- leading to pleurisy and pleural effusion
(exudative with elevated LDH).
• 2. Acute pneumonitis- acute onset cough, dyspnea +/- hemoptysis
with patchy changes on Chest X-ray and a ground-glass pattern on
Chest CT.
• 3. Pulmonary hemorrhage/diffuse alveolar hemorrhage-
associated with hemoptysis, hypoxemia and bilateral infiltrates.
• 4. Interstitial lung disease- in 3-9%, can be associated with chronic
SLE......diminished diffusion capacity is the hallmark with diffuse
ground-glass pattern on CT scan, +/- pulmonary hypertension.
Acute SLE pneumonitis. A- RUL infiltrate and R pleural effusion, B- 3 days into treatment with residual loculated R effusion, C- 2
months later with R pleural thickening and D- clear and nl CT scan 6 months later Source: archbronconeumol.org
Acute SLE pneumonitis of both lower lobes
Source: lungindia.com
Diffuse ground glass changes on CT of a SLE patient with chronic interstitial lung disease, eventually requiring lung transplants
Source: thorax.bmj.com
 SLE- Clinical
• SLE- Clinical manifestations
• I. Neuropsychiatric disease in > 50%-
• 1. Cognitive dysfunction +/- psychosis, depression and anxiety in 20-
80%
• 2. Vasculitis/cerebritis/meningitis/transverse myelitis
• 3. Stroke syndromes.....higher risk if there is associated
antiphospholipid syndrome
• 4. Accelerated atherosclerotic vasculopathy with ischemia
• 5. Seizures in 10-20%
• 6. Headaches in 57%, migraines in 40%
• 7. Peripheral neuropathy in 10-15%
• 8. Cranial neuropathy
 CNS lupus can be multifactorial, with cerebritis from autoimmune attack, immune complex deposition, vasculitis,
atherosclerotic/embolic disease and hypercoagulability from APLS. MRI with diffuse disease. Source: radiopaedia.org
CNS SLE vasculitis
Source: ajnr.org
Higher mag of CNS vasculitis with classic beaded pattern
Source: accessmedicine.mhmedical.com
 SLE- Clinical
• SLE- Clinical manifestations
• J. Hematologic disease- autoimmune diseases are often found when
a workup for a “penia” is undertaken
• 1. *Anemia of chronic disease is very common (75%)
• 2. Autoimmune hemolytic anemia (15%)
• 3. *Leukopenia (60%)
• 4. Thrombocytopenia (25%)
• 5. Lymphadenopathy (5-15%) with occasional splenomegaly,
especially with active disease
 SLE- Clinical
• SLE- Clinical manifestations
• K. Bone disease-
• 1. Osteonecrosis (aseptic necrosis)- present in 3-40%, due to
underlying disease +/- steroid treatments.
• 2. Osteoporosis- common, in 10%.....and 51% are *osteopenic
leading to increased fragility fractures
• L. ****Antiphospholipid syndrome- antiphospholipid antibodies are
present in 40%....the full antiphospholipid syndrome is less common
(20%).
• 1. DVT/PE/arterial thrombosis
• 2. Miscarriage/pre-eclampsia/pre-term delivery
• 3. CVA
 SLE- Clinical
• SLE- Clinical manifestations
• M. Eye disease-
• 1. Keratoconjunctivitis sicca is the most common.....dry eyes from
lacrimal gland involvement with hyposecretion
• 2. Ulcerative keratitis
• 3. Episcleritis and scleritis
• 4. Uveitis/iritis
• 5. Retinal vasculopathy/vasculitis....hemorrhage and cotton wool
spots
• 6. Optic neuropathy
• 7. Cataracts due to prolonged systemic steroid therapy for SLE
Discoid lupus of the eyelid
Source: scielo.br
Episcleritis- superficial, resolves with topical vasoconstrictors like Phenylephrine
Source: reviewofoptometry.com
Scleritis is deeper, causes eye pain and is serious, doesn’t resolve with topical vasoconstrictors
Source: slideshare.net
Keratitis
Source: semanticscholar.org
SLE retinopathy- hemorrhages and cotton wool spots
Source: tedmontgomery.com
 SLE retinal vasculitis on fluorescein angiogram with fluorescein leaks peripherally, beaded pattern of vessels and dark spots
reflecting old hemorrhages Source: researchgate.net
 SLE- Diagnosis
• SLE- Labs
• A. ***ANA (anti-nuclear antibody) test- detects autoantibodies targeting substances in
the nucleus of cells. The serum of the patient, in various dilutions, is added to a monolayer
of immortalized malignant human epithelial cells (such as HEp-2 cells). Anti-human
immunoglobulin (antibody to antibody) tagged to fluorescent stain is then added and
observed under an immunofluorescent microscope.
• 1. **Positive in > 95% (quite sensitive, but not specific, for SLE)
• 2. As 15% of the healthy population has a positive test of at least 1:80 titer..........most
of whom have no autoimmune disease at all......**A POSITIVE ANA ALONE DOES NOT
MEAN A PATIENT HAS SLE!!!........*only 11-13% of people with a positive ANA have
SLE........the higher the titer, the more likely a positive ANA is significant.....especially if >/=
1:160.
• 3. There are many subtypes of ANAs, various ones used to help differentiate between
different autoimmune diseases (e.g. anti-dsDNA, anti-RNP, anti-SCL-70, etc).
• 4. There are also different types of patterns of immunofluorescent ANA staining used
to differentiate autoimmune diseases, SLE most commonly has a **homogenous pattern,
see below:
ANA patterns.....an example of a positive test in a SLE patient = ANA positive at a titer of 1:1280 homogenous pattern
Source: emedicine.medscape.com
ANA test pattern schematic
Source: rxlist.com
Real ANA test patterns
Source: youtube.com
More real ANA test patterns
Source: education.questdiagnostics.com
Closeup of a speckled ANA pattern
Source: patterns.com
 SLE- Diagnosis

• SLE- Labs
• B. ***Anti-double stranded DNA antibody (anti-dsDNA)- very specific
for SLE, seen in 70%, but less sensitive
• C. **Anti-Smith antibody (anti-Sm)- very specific for SLE, but not
sensitive....only seen in 30%.
• D. Anti-ribonucleoprotein antibody (anti-RNP)- aims at the U1 particle
of the extractible nuclear antigen (ENA) called
ribonucleoprotein.....almost always present in MCTD, but seen in only
25% of those with SLE.
• E. Anti-Ro/SSA and anti-La/SSB antibodies- most characteristic of
Sjogren’s syndrome, but found in 20-30% of patients with SLE.
 SLE- Diagnosis
• SLE- Labs
• F. Rheumatoid factor (RF), seen in 20-30% with SLE, and anti-cyclic citrullinated
peptide (anti-CCP), seen in 6% with SLE, have much higher sensitivity and specificity
for RA. RF is usually an IgM antibody directed against the constant Fc portion of IgG
(an antibody to an antibody).
• G. False-positive RPR or VDRL (= positive non-treponemal syphilis test with a
negative treponemal test) is seen in 20% of those with SLE......as it detects antibody to
cardiolipin antigen, found in syphilis and is also a phospholipid itself, and many SLE
patients have anti-phospholipid syndrome, or at least make anti-cardiolipin
antibodies.
• H. SPEP- SLE, *like most autoimmune diseases, tends to have elevated globulins
(globulin > albumin ratio , rather than the normal albumin > globulin) on a CMP and it
gives a polyclonal hyperglobulinemia pattern on SPEP.......a pattern also seen in many
chronic inflammatory diseases like HIV, subacute and chronic infections (e.g.
osteomyelitis, TB), chronic liver disease/cirrhosis, IBD.......monoclonal findings on SPEP
would be most suggestive of multiple myeloma, MGUS/benign monoclonal
gammopathy, lymphoma, amyloidosis and Waldenstrom’s macroglobulinemia.
 SLE- Diagnosis
• SLE- Labs
• I. *Complement- C3, C4 and CH50 (total hemolytic complement) all tend to go
down with active SLE, due to consumption of complement during immune
complex formation.....they improve as activity improves….(while with
inflammation alone, without immune complex formation, all three tend to be
elevated)
• J. Acute phase reactants- significantly go up with activity of most autoimmune
diseases and inflammatory processes, along with many bacterial infections:
• 1. **Erythrocyte sedimentation rate (ESR)- measures the sedimentation of
RBCs in a tube over 1 hour, measured in millimeters....inflammation causes
*fibrinogen and other acute phase reactants to increase and bind to RBC
membranes, causing RBCs to stick to each other forming rouleaux, which settle
faster. A normal ESR is < 20 mm/hr.....active autoimmune disease often has ESRs
significantly > 50 mm/hr.....sometimes > 100 mm/hr. This is, therefore, an
indirect measure of acute phase reactants.
ESR testing.....read at 1 hour
Source: slideplayer.com
 SLE- Diagnosis
• SLE- Labs
• J. Acute phase reactants-
• 2. Most positive acute phase reactants are proteins synthesized in
the liver, and increase during acute and chronic inflammation, including:
• a. **C-reactive protein (CRP)- changes occur quicker to reflect
increasing or decreasing inflammation than with the ESR (nl < 3.0 mg/L)
• b. *Fibrinogen
• c. Ferritin- *unreliable as an indicator of body iron stores during an
inflammatory process (falsely elevated)
• d. *D-dimer
• e. Complement
• f. Ceruloplasmin, haptoglobin, alpha-1 antitrypsin, alpha-2
macroglobulin, mannin-binding lectin, prothrombin, factor VIII
• 3. Negative acute phase reactants go down with inflammation- such
as albumin, transferrin and antithrombin.
 SLE- Diagnosis
• SLE- Labs
• K. Antiphospholipid tests- see Antiphospholipid section for details
• 1. Lupus anticoagulant assay
• 2. Anti-cardiolipin antibodies
• L. Lupus erythematosus cells (LE cells) [LE prep to find them is made
from buffy coat cells]- a neutrophil or macrophage/monocyte that has
phagocytized the denatured nuclear material of another cell in blood or
bone marrow (requiring ANA). This denatured material is an absorbed
hematoxylin body (LE body). Seen in SLE (76% sensitive, 97% specific),
but sometimes also in other autoimmune diseases such as RA and drug-
induced lupus. RARELY USED ANYMORE GIVEN INCREASED SENSITIVITY
OF THE ANA TEST.....DON’T CONSIDER THIS IN CURRENT CRITERIA FOR
SLE DIAGNOSIS.........distinguish from Tart cells (monocyte/macrophage
that has phagocytized an intact nucleus of another cell)
 LE cells- here are monocytes with digested nuclear material (nucleus no longer intact) peripherally in their cytoplasm, seen
in SLE Source: imagebank.hematology.org
Another LE cell
Source: askhematologist.com
LE cell with LE/hematoxylin body of ingested nuclear material in the periphery
Source: peir.path.uab.edu
Tart cell (monocyte with ingested intact, preserved nucleus).....NOT C/W SLE, and of no significance
Source: reddit.com
 SLE- Diagnosis

• SLE- Classification criteria for SLE

• A. 2019 ACR (American college of Rheumatology)/EULAR
(European League Against Rheumatism) criteria
• 1. Developed to improve detection of early- or new onset-
SLE as well as to improve the sensitivity and specificity
compared with previous criteria. *A positive ANA >/= 1:80 is
required as an entry criterion. **Diagnosis requires both clinical
and lab/immunological criteria.
Source: mdedge.com
 SLE- Diagnosis

• SLE- Classification criteria for SLE

• B. *ANA-negative SLE- is now felt to occur in only 2% of
patients, given more standardized testing these days. Those
patients often do have anti-Ro/SSA, anti-La/SSB, anti-Sm or
antiphospholipid/cardiolipin antibodies......and such patients
sometimes may be on immunosuppressive therapy for other
diseases, attenuating their ability to form appropriate
antibodies to give a positive ANA test.
 Lupus-like Syndrome/Drug-induced Lupus
• Lupus-like syndrome/drug-induced lupus- 10% of lupus cases
• A. An autoimmune response triggered by drugs that presents with myalgias,
arthralgias/arthritis, *serositis (pericardial/pleural effusions) +/- fever or
rash/photosensitivity......coming on after people have been on certain drugs usually for
months or years......*rarely affects CNS or kidneys
• 1. Higher risk drugs- ***Hydralazine (happens in 5-10% of patients),
***Procainamide (happens in 15-33% of patients, if on it a long time), **Quinidine
• 2. Low-to-moderate risk- *TNF-alpha inhibitors (Eternacept, Infliximab, Adalimab),
*INH, *Minocycline, *Methyldopa, Carbamazepine, Sulfsalazine, ACE inhibitors,
Penicillamine, Phenytoin, Minoxidil, Propafenone, HCTZ, Nitrofurantoin, statins,
Chlopromazine, Acebutolol and PTU.
• B. Male:female 1:1 (unlike typical SLE).....more common in Caucasians
• C. Treatment is inducing drug withdrawal +/- NSAIDs or steroids......may take weeks-
months to resolve.

• ***Since the high-risk drugs are used much less these days, incidence is lower
Source: slideshare.net
 Lupus-like Syndrome/Drug-induced Lupus

• Lupus-like syndrome/drug-induced lupus

• D. *95% ANA-positive with homogenous pattern (often high-
titer) and **95% anti-histone antibody-positive is the marker for
this problem [THINK BOARDS HERE] (can be seen in many other
rheum diseases however, including SLE and RA).........*anti-
dsDNA, characteristic of SLE, is usually negative.
• E. *Mechanism- the predisposing factor for this disease is
being a “slow-acetylator” of these drugs, that are metabolized
by acetylation in the liver.
 Sjogren’s Syndrome

• Sjogren’s syndrome (SS)- a long-term autoimmune disease with

primary symptoms causing dry eyes (xerophthalmia), dry mouth
(xerostomia), dry skin (xerosis) and vaginal
dryness/dyspareunia.....***called “sicca syndrome.”.........only
10% with dry-eye syndrome truly have SS.
• A. Epidemiology- More common in women (9-20:1 female-to-
male), Caucasians and tends to develop in the 30s-40s age
group.
• 1. 5-10% at risk to develop non-Hodgkin’s lymphoma.
• 2. Can be primary, or secondary associated with RA/SLE
 Sjogren’s Syndrome
• Sjogren’s syndrome (SS)-
• B. Signs/symptoms-
• 1. Constitutional- fatigue
• 2. Eyes- *keratoconjunctivitis sicca due to decreased tear formation
(*Schirmer’s test- filter paper strip put inside eyelids for 5 minutes....normal
moistness is 15 mm, SS is </= 5 mm) +/- lacrimal gland enlargement.
• 3. Mouth- salivary hypofunction leading to increased caries and periodontal
disease, Candida infections (oral and angular cheilitis) and changes in taste
(dysgeusia)
• 4. Salivary gland- diffuse enlargement of parotid, submandibular and other
salivary glands (30-50%).
• 5. Dry airways- causing a chronic dry cough.
• 6. Vagina- dryness with dyspareunia, increased BV and Candida infections.
• 7. Skin- dryness/xerosis, 13-30% get Raynaud’s phenomena, 10% get vasculitis
 Sjogren’s Syndrome
• Sjogren’s syndrome (SS)-
• B. Signs/symptoms-
• 8. Joints- 50% have arthralgias +/- arthritis (symmetric and non-
erosive).....if erosive then usually associated with RA
• 9. Muscles- there may be a mild, inflammatory myopathy with insidious
proximal muscle weakness......sometimes inclusion body myositis
• 10. Autoimmune thyroiditis is common....10-70%
• 11. Peripheral neuropathy in 10% and depression in 33-49%.
• 12. Hematologic- 20% with anemia of chronic disease and 20% with
leukopenia, 10% with thrombocytopenia. Cryoglobulinemia in 16%.
 Sjogren’s Syndrome

• Sjogren’s syndrome (SS)-

• C. Labs-
• 1. ANA >/= 1:320 in 64%, usually speckled pattern
• 2. RF-positive in 40% with anti-CCP positive in 5-22%
• 3. **anti-Ro/SSA and anti-La/SSB antibodies are found in the
majority of SS patients (60-80%)
• 4. Focal lymphocytic sialadenitis on lower lip salivary gland
biopsy
Bilateral parotid enlargement in Sjogren’s syndrome
Source: emedicine.medscape.com
Path of lip biopsy in Sjogren’s
Source: memorangapp.com
Path of lip biopsy in Sjogren’s- focal lymphocytic infiltrates
Source: umedicine.uiowa.com
 Mixed Connective Tissue Disease (MCTD)
• Mixed Connective Tissue Disease (MCTD)-
• A. Epidemiology-
• 1. Most with this disease are female and present in the second and third
decades of life
• B. Signs/symptoms-
• 1. In the early phases, prior to diagnosis patients complain of easy fatigability,
along with poorly defined myalgias and arthralgias.....and may be labelled as
having undifferentiated connective tissue disorder.
• 2. **Raynaud’s phenomenon/syndrome- a syndrome with vasospasm of the
digital arteries (fingers > toes) and occasionally nose, ears and lips. It may or may
not be associated with numbness or pain. Lasts minutes to hours and may be
precipitated by cold exposure or stress. *There may be burning with return of
bloodflow. Distal cyanosis can be present, with proximal pallor. *Rubor initially
develops with resolution. May be aggravated by estrogen supplementation,
caffeine, smoking and beta blockers and it is treated with calcium channel blockers
or topical nitrates or use of gloves. **Swollen hands or digits are common, and
peripheral vasculitic lesions and digital ulcers may develop.
 Mixed Connective Tissue Disease (MCTD)
• Mixed Connective Tissue Disease (MCTD)-
• B. Signs/symptoms-
• 3. Fever- can be intermittently present
• 4. Arthritis- *60% develop arthritis with synovitis that can be deforming like RA.
• 5. Sjogren’s syndrome in 32%
• 6. Inflammatory myopathy- while most have myalgias, true myositis with
elevated CPK or muscle weakness is uncommon (except possibly in flares).
• 7. 70% have cardiac disease involving one of the three layers....only 30% are
symptomatic. 40% may have pericarditis at some time. Accelerated atherosclerosis
has been noted.
• 8. Lung involvement is seen in 75%, and may manifest as serositis
(pleurisy/pleural effusions), pulmonary hypertension or ILD (in 50-65%).
• 9. Renal disease is uncommon, occasional membranous GN/proteinuria.
 Mixed Connective Tissue Disease (MCTD)
• Mixed Connective Tissue Disease (MCTD)-
• B. Signs/symptoms-
• 10. GI- 60-80% have GI issues such as dysmotility, abdominal pain,
malabsorption, pancreatitis or bleeding issues.
• 11. CNS- trigeminal neuropathy, headaches and sensorineural
hearing loss are the most common manifestations......otherwise CNS
disease is uncommon.
• 12. Hematologic- 75% have anemia and leukopenia is common.
• 13. Pregnancy- causes flare in 40%, low birthweight infants and
increased fetal demise.
 Mixed Connective Tissue Disease (MCTD)
• Mixed Connective Tissue Disease (MCTD)-
• C. Diagnosis-
• 1. *ANA-positivity with high titer and speckled pattern is common
• 2. **Anti-RNP antibodies at high titer are the hallmark, present in
95-100% of cases
• 3. **In the face of other issues such as Raynaud’s phenomena,
edematous hands/swollen fingers, significant arthritis/synovitis +/-
pulmonary hypertension/ILD with minimal to no renal/CNS
involvement.
Raynaud’s phenomena with pallor
Source: merckmanuals.com
Raynaud’s phenomena with cyanosis
Source: merckmanuals.com
Digital ischemic ulcers in MCTD
Source: ard.bmj.com
Classic swollen hands and fingers in MCTD
Source: bindevevssykdommer.no
 CREST Syndrome
• CREST- [BOARDS love this disease]
• A. Also known as a limited cutaneous form of scleroderma, or progressive systemic sclerosis.....also
occurs in 10% of those with primary biliary cirrhosis.
• B. 5 main features (>/= 2 features gives the diagnosis):
• 1. C- Calcinosis cutis......dystrophic calcium deposits/nodules in the skin and subcutaneous
tissues.....25-40% of CREST patients. Often seen on the finger tips/elbows and can be quite painful.
Lesions can ulcerate and even leak whitish material.
• 2. R- Raynaud’s phenomenon.....often the first manifestation of CREST.
• 3. E- Esophageal dysmotility......causing dysphagia or atypical chest pain.
• 4. S- Sclerodactyly.....early on there may be edematous and inflamed fingers and toes, followed by
thickening and tightening of the skin (becomes hard and shiny) distal to the MCP joints due to
excessive collagen deposition. Distal digital ischemic ulcers form in 30-50% of these patients. With
time the fingers/toes curve inward, develop contractures and lose range of motion.
• 5. T-Telangiectasia.........widened venules (spider veins) developing externally in the skin. In CREST
they develop on the hands, palms, periungual regions, face, lips, forearms and mucous membranes
 CREST Syndrome
• CREST- [BOARDS love this disease]
• C. Chronic fatigue and pulmonary hypertension, without
pulmonary fibrosis, but with cor pulmonale may develop.
• D. Diagnosis-
• 1. Characteristically have a positive anti-centromere antibody
(82-96%) and most are ANA-positive.
• 2. Anti-Scl-70, characteristic of scleroderma, is positive in only
13%
Calcinosis cutis in CREST
Source: healthline.com
Calcinosis cutis in CREST
Source: consultqd.clevelandclinic.org
Sclerodactyly plus Raynaud’s phenomenon in CREST
Source: medscape.com
Sclerodactyly in CREST
Source: aocd.org
Facial telangiectasias in CREST
Source: aocd.org
Lip telangiectasias in CREST
Source: medscape.com
Palm telangiectasias in CREST
Source:bestpractice.bmj.com
Periungual telangiectasias in CREST
Source:semanticscholar.org
 Antiphospholipid Syndrome (APLS)
• Antiphospholipid syndrome- an autoimmune hypercoagulable state due
to antiphospholipid antibody formation. It can be either primary or
secondary (due to autoimmune disease such as SLE). More common in
women.
• A. Clinical problems- arterial (CVA) and venous blood clots (DVT/PE),
recurrent miscarriages, pre-eclampsia, intrauterine growth retardation,
pre-term birth, stillbirth, placental infarction, migraine headache, livido
reticularis.....occasionally multi-system organ failure due to small vessel
occlusions.
• B. Mechanism- APLS antibodies bind/inhibit protein C and S, plus bind
to prothrombin increasing its cleavage to thrombin.....creating a
hypercoagulable state.
 Antiphospholipid Syndrome (APLS)
• Antiphospholipid syndrome-
• C. Diagnosis- **often an elevated aPTT is present......diagnosis requires at least
one clinical and one laboratory criterion.
• 1. Clinical criteria-
• a. An arterial or deep venous clot
• b. 1 fetal demise >/= 10 weeks into pregnancy or >/= 3 spontaneous
abortions before 10 weeks
• 2. Lab criteria-......on 2 occasions >/= 12 weeks apart
• a. Anti-cardiolipin IgM and/or IgG
• b. Anti-beta2 glycoprotein 1 IgG and/or IgM
• c. Lupus anticoagulant
• D. Treatment- ASA and/or Warfarin......heparin if pregnant
Lupus anticoagulant
Source: flipper.diff.org
Lupus anticoagulant
Source: presentica.com
Lupus anticoagulant test mechanism
Source: captodayonline.com
 Case
• ANA positive 1:1280, RF positive 1:80
• Further serology shows anti-CCP/dsDNA/Sm/Ro/La/Jo-1/RNP/ANCA
negative
• *****and anti-histone 1:640
 Case
• Dx- Serositis (pericardial/pleural effusion, pleurisy/pericarditis, arthritis)
with FUO, pancytopenia, polyclonal hyperglobulinemia and high sed rate
due to Procainamide-induced lupus-like syndrome

• Tx- Procainamide stopped and a 2 week course of Prednisone plus 3 month

course of Naproxen sodium was given.......fever rapidly resolved.....all other
symptoms slowly resolved over the next 3 months
 Hurts So Good (how you feel with a rheumatologic
disease.........but after a binge)
• John “Cougar” Mellencamp
• Released- 1982 (1st released by Little Anthony and the Imperials in 1965)
• Album- American Fool
• This song peaked at #2 on Billboard’s weekly top 100 songs.........was #8 on the top 100
songs of the year
• Active- 1976-present
• Genre- Heartland and Country Rock
• Honors- 1 Grammy (12 nominations), Songwriter’s Hall of Fame 2018. Inducted into the
Rock and Roll Hall of Fame in 2008. Started Farm Aid along with Willie Nelson and Neil
Young, in 1985.
• First hit- I Need a Lover in 1979
• Other hits: Jack and Diane, Pink Houses, Small Town, Ain’t Even Done With the Night,
R.O.C.K. in the USA, Rain on the Scarecrow, Paper in Fire, Authority Song, Wild Night,
Cherry Bomb, Lonely Ol’ Night, Crumblin’ Down, Hand To Hold On To, Check It Out
Source: wikipedia.org