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Welcome to Ed's Pathology Notes, placed here originally for the convenience of medical students at my school. You need to check the accuracy of any information, from any source, against other credible sources. I cannot diagnose or treat over the web, I cannot comment on the health care you have already received, and these notes cannot substitute for your own doctor's care. I am good at helping people find resources and answers. If you need me, send me an E-mail at scalpel_blade@yahoo.com Your confidentiality is completely respected. No texting or chat messages, please. Ordinary e-mails are welcome.

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Especially if you're looking for information on a disease with a name that you know, here are a couple of great places for you to go right now and use Medline, which will allow you to find every relevant current scientific publication. You owe it to yourself to learn to use this invaluable internet resource. Not only will you find some information immediately, but you'll have references to journal articles that you can obtain by interlibrary loan, plus the names of the world's foremost experts and their institutions.

Clinical Queries -- PubMed from the National Institutes of Health. Take your questions here first.
HealthWorld
Yahoo! Medline lists other sites that may work well for you

Alternative (complementary) medicine has made real progress since my generally-unfavorable 1983 review. If you are interested in complementary medicine, then I would urge you to visit my new Alternative Medicine page. If you are looking for something on complementary medicine, please go first to the American Association of Naturopathic Physicians. And for your enjoyment... here are some of my old pathology exams for medical school undergraduates.

I cannot examine every claim that my correspondents share with me. Sometimes the independent thinkers prove to be correct, and paradigms shift as a result. You also know that extraordinary claims require extraordinary evidence. When a discovery proves to square with the observable world, scientists make reputations by confirming it, and corporations are soon making profits from it. When a decades-old claim by a "persecuted genius" finds no acceptance from mainstream science, it probably failed some basic experimental tests designed to eliminate self-deception. If you ask me about something like this, I will simply invite you to do some tests yourself, perhaps as a high-school science project. Who knows? Perhaps it'll be you who makes the next great discovery!

Our world is full of people who have found peace, fulfillment, and friendship by suspending their own reasoning and simply accepting a single authority that seems wise and good. I've learned that they leave the movements when, and only when, they discover they have been maliciously deceived. In the meantime, nothing that I can say or do will convince such people that I am a decent human being. I no longer answer my crank mail.

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Describe some theoretical mechanisms of autoimmune disease. Give examples of known or suspected triggers for autoimmune disease.

List the common autoimmune diseases -- both those included in this lecture, and related disorders.

Give the predisposing factors, typical symptoms, signs, laboratory findings (especially autoantibodies), and pathologic anatomy for each of the following:

systemic lupus
discoid lupus
drug induced lupus
Sjogren's syndrome
progressive systemic sclerosis (scleroderma)
polymyositis and dermatomyositis
fibromyalgia syndrome ("fibrositis" -- not an autoimmune disease)
graft vs. host disease

Give the distinguishing features for each of the following:

CREST syndrome (anti-centromere disease)
mixed connective tissue disease (anti-ribonucleoprotein disease)

Recognize the following using the microscope:

acanthosis
parakeratosis
keratin plugs
hydropic change of basal cells
lupus dermal inflammatory infiltrate
Sjogren's changes in salivary gland
scleroderma skin changes
intimal proliferation ("onion-skinning") in the renal arteries
rheumatoid nodule (characteristic features)
polymyositis

Recognize lupus as today's "great imposter", and keep a high index of suspicion for all the common autoimmune diseases.

Immune Disease Iowa Virtual Microscopy Have fun

Immuno Pathology Photos, explanations, and quiz Indiana U.

Autoimmunity From Chile In Spanish

Immunopathology Great pathology images Indiana Med School

INTRODUCTION TO AUTOIMMUNE DISEASE

Autoimmune disease in humans can involve any of the types of "immunologic injury". (Type I injury is rare.)

The mechanisms of autoimmunity remain speculative, despite the elaborate discussion in "Big Robbins". Review: Nat. Med. 7: 899, 2001. Yet another: Nat. Med. 8: 899, 2002. To begin with, nobody really understands why our immune system doesn't attack ourselves more often. You'll hear about CLONAL DELETION, CLONAL ANERGY, and SUPPRESSION OF AUTOREACTIVE CLONES (by such things as anti-idiotype networks, etc.)

Whatever the "cause" of autoimmunity, infectious agents may be involved as triggers. For example:

Coxsackie B virus apparently shares an antigen with myocardium, and infection with this virus can trigger a lethal myocarditis ("Barney Clark's disease", etc.)

Measles virus shares an antigen with T-cells, and people with measles have greatly diminished T-cell function (anergy).

The Lyme bacillus flagellum protein ("flagellin") is a mimic for axon protein, and one of the most dread effects of Lyme infection is toxicity to the nerves; despite a decade of discussion, whether this is clinically important remains unsettled (Infect. Immun. 65: 1722, 1997). An outer surface protein is a mimic for one of the HLA types that, when present, results in Lyme patients developing an arthritis that does not resolve after the micro-organisms are killed (J. Immuno. 166: 5286, 2001).

Beta-hemolytic streptococci share an antigen with myocardium (causes the myocarditis of rheumatic fever) and basal ganglia ("St. Vitus Dance", "Sydenham's chorea", PANDAS -- "pediatric acquired neurotic disorder after strep").

* During the 1990's, several gram-negative bacilli were "usual suspects" in autoimmune disease. Again, the area's hard to study; the one link that seems to be holding up is klebsiella and ankylosing spondylitis. The molecular biology of gram-negative bacterial-induced molecular mimicry: Nat. Med. 6: 215, 2000.

Molecular mimicry seems to be the way helicobacter triggers autoimmune chronic atrophic gastritis (classic paper Inf. Imm. 64: 2031, 1996).

* Molecular mimicry to bacteria probably causes the production of the autoantibodies that cause Guillain-Barre syndrome (Neurology 54: 1453, 2000; Lancet 352: 635, 1998; Neurology 57: 736, 2001).

* Molecular mimicry is the cause of post-herpes corneal interstitial inflammation in mice (Science 279: 1344, 1998).

* Behçet's (aphthous-style ulcers in the mouth, maybe genitals, elsewhere, plus maybe vasculitis-thrombosis, plus maybe iridocyclitis) seems to be caused by T-cell autoimmunity / molecular mimicry against the heat-shock proteins (Lancet 347: 789, 1996; Lancet 350: 28, 1997).

* Molecular mimicry by several different proteins of the trypanosome is now cited as the cause of the variable autoimmune diseases seen after acute Chagas disease (Circulation 115: 1109, 2007).

AIDS virus infection can simulate (trigger?) lupus, rheumatoid arthritis, Sjogren's, or polymyositis and dermatomyositis.

Other triggers are also becoming apparent.

Thymomas express something very much like acetyl choline receptor, thereby triggering myasthenia gravis (Lancet 339: 707, 1992). Oat cell carcinoma (a lung cancer that simulates nerve cells in several respects) is notorious for exciting autoantibodies against cerebellum, retina, synapse, and/or amygdala. Stay tuned for more of these.

* There is one report of a new anti-neutrophil cytoplasmic antibody (pauci-immmune focal necrotizing glomerulonephritis) recognizing lysosomal membrane protein-2, produced after a bacterial flagellar protein to which they cross-react. Watch this one (Nat. Med. 14: 1088, 2008).

Foreign materials may alter the body enough that it begins attacking itself. Decide for yourself whether breast implants ever cause lupus and scleroderma (I'm unimpressed). But it's been held that there's a link between coal and rock dust exposure and several autoimmune diseases ("Caplan's").

More generally, since the autoimmune diseases exacerbate and remit (until fibrosis / gliosis dominate the picture, of course), it's easy to believe that they result from modulation problems within complex feedback networks.

In Sjogren's, insulin-dependent diabetes, and some other autoimmune diseases of glands, part of the pathogenesis seems to be inappropriate expression of HLA-D (i.e., class II) proteins on the target organ's cells. More about this later.

Even more curious, the T-cells of lupus patients evidently attack monocytes and cause them to undergo apoptosis, both providing more antigen and failing to clear apoptotic debris (J. Immunol. 167: 5963, 2001; J. Immunol. 169: 6020, 2002; Arth. Rheum. 46: 191, 2002).

Your lecturer predicts that in the near future, clones of lymphocytes in patients with autoimmune diseases will be identified bearing mutatations that are signatures for particular diseases.

Perhaps the first is the mutated perforin that seems to be etiologic in common autoimmune aplastic anemia (Blood 109: 5234, 2007).

Also watch microchimerism, reactions between the cells that pass between mother and child during pregnancy and may linger for decades (Sci. Am. 298(2): 72, 2008).

It's hard to study, but I've been able to find nothing at all published recently to support the "pop" notion that emotional stress precipitates autoimmune disease.

* If you are very interested in the molecular basis of the immunogen-toleragen seesaw, check out Lancet 357: 2115, 2001.

Rules that almost always work:

Autoimmune diseases typically are linked to particular Class I (A, B, or C) or Class II (D) HLA antigens, but not both. Those linked to particular class I antigens (i.e., ankylosing spondylitis, reactive arthritis after a bacterial infection, common psoriasis) are more common in men, while those linked to class II antigens (the rest of the autoimmune diseases) show a slight to striking female preponderance. (Type I diabetes favors neither males nor females.) Patients inherit the same HLA antigens as many of their healthy counterparts.

Again, "because they reflect deviations in complex control networks", the autoimmune diseases are diseases of exacerbations and remissions. Don't try to understand this yet. The immune system is a chaotic system, with tiny tweaks able to cause large changes. For example, in lupus there are antibodies that bind antibodies that bind antibodies ("idiotype network": Nat. Med. 10: 17, 2004).

Monozygotic twins of patients are at increased risk, but it is never >30% (i.e., the risk is greatest with juvenile onset diabetes).

Selection of T-cells after antigenic stimulation has been studied in identical twins; if both are sick with a particular T-cell mediated disease, the clones they select tend to be identical; if only one is sick, responses tend to be different. (See Nature 364: 243, 1993.)

Siblings not inheriting the same HLA's that are linked to the immune disease are still at slightly increased risk.

The systemic autoimmune diseases are a family of chronic illnesses of generally unknown etiology. Their older name, "the collagen vascular diseases", is meaningless today. Except for DM-PM and the enthesopathies, all are more common in women.

They include systemic lupus, rheumatoid arthritis, juvenile rheumatoid arthritis, the enthesopathies (probably), scleroderma, DM-PM, Sjogren's syndrome, rheumatic fever, variants of all these, and overlap syndromes. (* We will save some of them for later.)

Each shows some familial tendency but no clear-cut pattern of inheritance.

There is a link between HLA antigens and various autoimmune diseases. The strongest link is between HLA-B27 and spondylitis.

Remember that all these diseases are likely to overlap, and that each is probably a syndrome with several possible causes.

"Lupoid chronic-active hepatitis" (several types) and "primary biliary cirrhosis" overlap with this family also, and may be seen with any "systemic autoimmune disease".

The autoimmune diseases all involve abnormal cellular proliferations (lymphocytes in systemic lupus, synovial lining cells in rheumatoid arthritis, fibroblasts in scleroderma and primary biliary cirrhosis, etc.)

Remember also that many apparently healthy people, especially older people, have autoantibodies in relatively high titers. No one knows why.

In the 1990's, we found we could treat some autoimmune diseases by feeding (later injecting) the autoantigen.

There's precedent for this kind of tolerization The First Americans fed poison ivy to their babies, imparting a tolerance to the rhus hapten. The mechanisms (then and now) include suppression of immunity by TH2 cells, and depletion/anergy of TH1 cells.

Injecting a peptide that mimics myelin basic protein is now a mainstay of the management of multiple sclerosis. Stay tuned for more amazing successes.

* Using oral bovine type I collagen for scleroderma -- maybe helps, no miracles Arth. Rheum. 58: 1810, 2008.

In the future, watch for autologous hemopoietic stem-cell transplantation as therapy for refractory autoimmune disease (Lancet 353: 550, 1999).

* Here are the famous HLA linkages for diseases. This information is not very useful clinically, but has a way of popping up on exams (though not mine).

B8 & DR3

autoimmune Addisonism myasthenia gravis Sjogren's

B27

ankylosing spondylitis Reiter's syndrome enteropathic arthropathy autoimmune uveitis

B35

DeQuervain's

B38

psoriatic arthritis

B51

Behçet's

B47

21-hydroxylase deficiency (gene is in the allele)

Cw6

common psoriasis

DR2

Goodpasture's multiple sclerosis

DR3

celiac sprue / dermatitis herpetiformis lupoid hepatitis lupus (weak)

DR3, DR4

autoimmune diabetes

DR4

pemphigus rheumatoid arthritis

DR5

autoimmune pernicious anemia Hashimoto's autoimmune thyroiditis

THE AUTOANTIBODIES (Am. J. Med. 100(2A): 16S, 1996)

When you order an "ANA" ("anti-nuclear antibodies") screen, the patient's serum will be placed on some mammalian cells and counterstained to stain green any patient antibodies that may have stuck.

The pattern may give you a hint of which antibody is present! (With today's newer tests, these don't work so well as they once did.)

RIM PATTERN

Probably anti-dsDNA. Your patient probably has SYSTEMIC LUPUS.

HOMOGENEOUS PATTERN

Probably anti-histones. Your patient probably has DRUG-INDUCED LUPUS.

SPECKLED PATTERN

Could be anti-Sm and/or anti-Ro/SSA and/or anti-La/SSB and/or anti-U1RNP and/or any of several others. You'll certainly want to continue your workup!

CENTROMERE PATTERN

An especially fine speckling with little background staining. This is anti-centromere, the marker for CREST / pulmonary hypertension.

NUCLEOLAR PATTERN

anti-Th/To or anti-fibrillarin / anti-U3RNP or anti-U17RNP. Think of SCLERODERMA, though most scleroderma patients don't show the nucleolar pattern.

Notice the titer. If it's 1:40 or less, it probably means nothing. If it's 1:160 or more, your patient probably has something going on.

You can also order these tests for individual autoantibodies.

anti-dsDNA

Anti-double stranded DNA. A misnomer, of course. Your patient has systemic lupus. About half of lupus patients have these antibodies.

anti-ssDNA

Anti-single stranded DNA. Think of drug-induced lupus.

anti-histone

Think of drug-induced lupus.

anti-Sm

Anti-Smith. Your patient has systemic lupus. About a third of lupus patients have these antibodies.

anti-Ro/SSA

Lupus, Sjogren's, neonatal lupus, or some mix of these.

anti-La/SSB

Lupus, Sjogren's, or some mix of these

anti-U1RNP

Anti-ribonucleoprotein. When this is the main autoantibody, your patient has mixed connective tissue disease.

Anti-Scl70

Anti-topoisomerase I. Your patient has the bad kind of scleroderma. A large minority of people with the bad kind of scleroderma have this autoantibody.

Anti-centromere

Sensitive and specific for CREST, the limited scleroderma variant.

Anti-Jo

Antibody against transfer-RNA synthetase. Your patient probably has polymyositis. About half of these patients have this autoantibody.

In the future, watch for cheap autoantibody assays to screen for impending (within a few years) disease. Anti-citrulline to predict who's going to get rheumatoid arthritis: Lancet 363: 1544, 2004. Autoantibodies in lupus are there years before symptoms: NEJM 349: 1499 & 1526, 2003.

SYSTEMIC LUPUS ERYTHEMATOSUS (SLE, "the red wolf"; NIH review Ann. Int. Med. 123: 42, 1995; Med. Clin. N.A. 81: 113, 1997).

Lupus From Chile In Spanish

Lupus Text and pictures From "Big Robbins"

{08403} lupus immune complexes (green) trapped in the glomerulus
{28142} discoid lupus on the face (what features do you see?)

Lupus is a common, dread, remitting and relapsing illness defined by clinical criteria that you will learn on Internal Medicine. (You can find them in Arthr. Rheumatol. 25: 1271, 1982 or in "Big Robbins".)

Lupus usually manifests as arthritis, skin changes, kidney damage, inflamed serosal membranes, fever, and mental changes. Most lupus victims look healthy, but they are very sick.

Lupus is mostly a disease of young women, though no one is immune; it is slightly more common in blacks. At least one woman in 1000 in the US and worldwide has overt lupus. (* The pediatric disease is essentially the same as the adult form: Pediatrics 83: 325, 1989).

* The biopsychosocial impact of lupus: Arthr. Rheumatol. 27: 13, 1984; J. Rheumatol. 13: 570, 1986. Probably little has changed.

Lupus is a disease of many curious autoantibodies directed against antigens that are common to most or all cells.

The etiology is unknown and surely differs from case to case.

Most of today's work focus on defective apoptosis and immune reaction to the products of apoptosis (for example, in the famous NZBxNZW mouse model: J. Imm. 181: 5264, 2008).

There is much discussion nowadays, but still little hard evidence, of defective clearance of apoptotic cells as "the cause of lupus" (Rheum. Dis. Clin. N.A. 26: 215, 2000; Arth. Rheum. 46: 191, 2002; Arth. Rheum. 48: 2888, 2003; Rheumatology 44: 1101, 2005). This fits with the photosensitivity (why?), and might explain the lupus-like syndrome in complement component deficiencies (uh, maybe these are required to clear apoptotic bodies -- update with a focus on what's unknown Arth. Rheum. 54: 1543, 2006). However, excessive numbers or appearances of apoptotic bodies themselves is not seen in lupus under the microscope.

* Alfalfa, which contains L-canavanine, a bizarre amino acid, causes lupus in monkeys and sometimes in humans.

* For the classic review of the molecular biology of the principal lupus autoantigens, see Arthr. Rheumatol. 29: 457, 1986. These include nucleosomes (by far the most important -- J. Immuno 174: 3326, 2005; Am. J. Path. 172: 275, 2008) and the cytoplasmic Ro antigens; the mechanisms of immune activation appear to be novel for lupus (J. Clin. Invest. 115: 407, 2005).

An environmental agent may contribute. One group claims that dogs belonging to lupus patients are more likely than others to have autoantibodies (Lancet 339: 1378, 1992).

Which autoantibodies are harmful, and how they do their damage, is not always clear.

Most lupus patients make antibodies against their own DNA (mega-review NEJM 338: 1359, 1998). Double-stranded DNA ("native-DNA", * "peripheral" or "rim pattern antibodies") gets trapped in the glomeruli, where it complexes with anti-nDNA (see J. Rheumatol. 13: 512, 1986). The complexes cause damage by a Type III mechanism. (Of course, anti-nuclear antibodies of any sort should be harmless to living cells.)

Other anti-nuclear antibodies are responsible for the "hematoxylin bodies" seen occasionally in tissues, and for the "LE cell phenomenon".

Hematoxylin bodies, pathognomonic of lupus, are altered remnants of nuclei. (* You will not be expected to recognize hematoxylin bodies.)

The LE body is a white blood cell nucleus that has been stripped of its cytoplasm during the phlebotomy, homogenized and opsonized by anti-nuclear antibodies (* typically anti-histone H1: Arth. Rheum. 41: 1446, 1998), and then eaten by a poly or mono. The cell that has eaten the LE body is then called the "LE cell".

LE cell
WebPath photo

{08394} LE cell; Giemsa stained preparation {29440} LE cells, Papanicolaou stain

Anti-Ro ("anti-SSA", an autoantibody against an RNA polymerase) crosses the placenta and causes heart block and discoid rash in newborns (probably by a type II immunologic injury). It also binds to the epidermis, and probably causes some of the photosensitivity.

* More than you want to know about Ro and La: Arth. Rheum. 42: 199, 1999.

Antibodies against neurons are thought to cause the psychosis and convulsions often seen in lupus (Type II immunologic injury)

Antibodies against blood cells are known to cause the hemolytic anemia, neutropenia, and thrombocytopenia often seen (together or separately) in lupus (Type II immunologic injury).

Antigen-antibody complexes probably cause most of the arthritis and vasculitis (Type III immunologic injury).

Lupus vasculitis
The histopathology is nonspecific
WebPath photo


Because of the vasculitis (?), lupus patients have accelerated atherosclerosis (NEJM 349: 2399, 2003).

Update on lupus vasculitis: Medicine 85: 95, 2006. The types are very diverse; having anti-Ro/SSA and/or anti-La/SSB on board puts you at risk.

Antibodies to the phospholipids involved in initiating thrombosis is the troublesome "lupus anticoagulant" (an antiphospholipid antibody that inactivates a freely-floating molecule). This causes paradoxical deep-vein thrombosis, thrombocytopenia, and abortion. See below.

Antibodies against other clotting factors also can cause trouble.

Lupus patients make many other weird antibodies. (You will learn how and when to test for these sometime.) For example, they tend to develop false-positive syphilis tests (* "biologic false positives", BFP's).

Genetic factors:

* Lupus patients often have HLA-DR2, DR3, A1, and/or B8. The DR2 locus is often linked to a null allele for C4 (there's a mouse model for this now too).

Lupus runs in families, and there's been a great deal of work in the past ten years, mostly people trying to figure out what alleles for what immune molecules ("candidate genes") run with the disease. There's been a lot of data, but no unifying ideas.

Monozygous twins are 25% concordant for lupus, dizygous only 2% (Arth. Rheum. 35: 311, 1992).

Patients with hereditary C2, C4, * C1q (Arth. Rheum. 39: 663, 1996), * C1r, * C1s, * C5, * C7, or * C9 deficiencies get a lupus-like syndrome (Ann. Rheum. Dis. 46: 153, 1987).

* The search for a virus in lupus has been unrewarding. The "myxovirus-like particles" ("tubular arrays") seen in endothelium are a non-specific alpha-interferon effect (Arthr. Rheum. 29: 501, 1986).

Lupus kidney
These are tubular arrays
WebPath photo


Blood vessels:

Lupus vasculitis typically involves the small arteries and arterioles. Type III immune complex injury is usually implicated.

When acute vasculitis is bad, plasma proteins that have gelled in the walls are called "fibrinoid". If the walls are dead, "fibrinoid necrosis" is said to be present.

More chronic vasculitis leads to fibrosis and narrowing of vessels.

A reasonably specific change for lupus vasculitis is concentric adventitial fibrosis ("adventitial onionskinning") around the splenic arteries.

Spleen onionskinning
Lupus
WebPath photo


Kidney: ("The kidney is never really normal in ANA-positive systemic lupus.")

The glomerulus traps antigens or pre-formed immune complexes as the strainer does in a sink. Several different glomerular syndromes can result.

Lupus glomerulonephritis The dark pink is immune complexes WebPath photo

Lupus glomerulonephritis Lots of immune complexes WebPath photo

Lupus glomerulonephritis
Lots of immune complexes
WebPath photo

In addition, anti-tubular antibodies ("lupus interstitial nephritis") and vasculitis can impair kidney function.

Skin:

Patients must avoid sunlight. The famous "butterfly rash" results (at least in part) from sunlight on the malar area of the face.

Systemic lupus Butterfly rash KU Collection

Butterfly rash WebPath photo

Butterfly rash WebPath photo

Butterfly Rash
Patient photo
Brazilian Medical Students

{08388} butterfly rash {12273} butterfly rash {12274} butterfly rash {25551} butterfly rash {33208} lupus butterfly

The "discoid rash" is also exacerbated by sun exposure.

Involved areas are sharply demarcated ("discoid"), depigmented (the edges are likely to be hyperpigmented), hairless, scaly, and shiny. The microscopic picture shows:

• areas of acanthosis and parakeratosis of the epidermis, with keratin plugging of follicles, alternating with areas of thinning and loss of adnexa
• hydropic change of the basal cells, which may lead to necrosis
• hyperemia and edema of the dermal papillae
• a T-cell infiltrate in the upper dermis, especially around the adnexa

{14316} discoid lupus
{08376} discoid rash of lupus, histology (nice local hydropic change in basal layer)
{11985} discoid lupus
{28868} discoid lupus
{28877} discoid lupus (good plugs)
{28880} discoid lupus (good atrophy / hyperkeratosis of epidermis)

Discoid lupus
WebPath photo


Deposits of immunoglobulins and complement components ("fibrinoid") are found just below the basement membrane of both involved and uninvolved skin in the majority of lupus patients. These are detected by the "lupus band test" -- more on this when you see us again, or see Clin. Exp. Rheum. 17: 427, 1999.

* The old claim that the lupus band test on non-sun-exposed skin being positive in systemic lupus and negative in discoid lupus is discredited.

Hives, ulcers, blisters all result from immune injury.

* Future dermatologists: Try topical tacrolimus (Rheumatology 43: 1383, 2004).

{08385} positive lupus band test (granules along basement membrane are immune complexes)
{33205} positive lupus band test, better example

Positive lupus band test WebPath photo

Positive lupus band test WebPath photo

Mouth ulcers ("aphthae", little infarcts) are another annoying problem for many lupus patients.

Joints:

Arthritis (inflammation of joint tissues) is common in lupus. It resembles rheumatoid arthritis, though it is seldom mutilating.

It is probably due to type III immune injury. The histology is acute and chronic synovitis.

"Serositis":

Pleural and pericardial inflammation creates pain and small fibrinous effusions. By autopsy time, all lupus patients have pleural scarring.

Heart (Mayo Clin. Proc. 74: 275, 1999):

The best-known and most typical change is "nonbacterial verrucous endocarditis" (verrucous means warty), also called "Libman-Sacks endocarditis". Update Am. J. Med. 120: 636, 2007; maybe one lupus patient out of 10 will be affected sometime.

Many small vegetations ("verrucae") occur on all parts of the valves (most often mitral, but any can be involved). They are made up of necrotic debris with acute and chronic inflammation; they may organize. Now that lupus patients are surviving longer, it's clear that Libman-Sacks endocarditis is a major problem.

Despite old claims to the contrary, valves do in fact become mutilated in lupus, probably from fibrin organizing on their surfaces (NEJM 319: 861 & 877, 1988). There is a strong correlation between Libman-Sacks and the presence of antiphospholipid and anticardiolipin antibody (classic paper Am. J. Med. 89: 411, 1990).

{06962} Libman-Sacks endocarditis in lupus

Coronary vasculitis occasionally causes sudden death in lupus patients. In addition, these patients have accelerated coronary artery atherosclerosis for some reason, independent of the Framingham risk factors.

* Current work looks at the presence of apoptotic endothelial cells as a marker for coronary disease and abnormal vascular tone, and an explanation for the vascular lesions generally. Stay tuned. Blood 103: 3677, 2004.

"Neonatal lupus" is due to maternal anti-Ro(SSA) (* rarely anti-La/SSB or anti-U₁-nRNP -- NEJM 316: 1135, 1987). These children have a rash and a serious heart block (anti-Ro attacks their AV node tissue). Anti-Ro is blamed for some loss of pregnancies, though evidence is conflicting (Br. J. Rheum. 37: 740, 1998). (Q. J. Med. 66: 125, 1988).

* Lupus myocarditis is thankfully rarely apparent clinically, but today's high-powered cardiac investigations are picking up some subclinical cases (Am. J. Med. 113: 419, 2002).

Blood:

Patients with lupus have increased total serum gamma globulins ("polyclonal gammopathy"; a lab test result).

Antibodies against red cells, neutrophils, and/or platelets can cause the corresponding cytopenias.

Patients with "lupus anticoagulant" tend to have paradoxical thrombosis rather than hemorrhage. More about this soon.

* This autoantibody is also common in people who do not have lupus, and if it is the presenting problem, the vast majority of patients do not develop systemic lupus (Medicine 84: 225, 2005).

This was a subject for intensive investigation in the late 1980's. Closely akin to -- but not identical with -- lupus anticoagulant are anticardiolipin antibodies that cause spontaneous abortion (thrombosis and infarction of the placenta, or more plausibly, improper implantation Proc. Nat. Acad. Sci. 90: 6464, 1993) & thrombosis and are present in many patients with lupus. Both are related to false-positive tests for syphilis.

And lupus patients can develop a bleeding tendency due to antibodies against clotting factors (especially factor VIII), thrombocytopenia, and/or vasculitis.

* Thrombocytopenia with platelet counts under 50,000 is ominous: Arth. Rheum. 56: 614, 2007.

Or they can just get deep vein thrombosis, without the anticoagulant (Arch. Int. Med. 154: 164, 1994).

Autoimmune thrombotic thrombocytopenic purpura is well-known in lupus and caused by an antibody against the serum factor that handles used vWF.

* Fulminating lupus hemophagocytic syndrome: Ann. Int. Med. 114: 387, 1991.

Lungs:

Only a few patients get pulmonary lesions directly attributable to lupus (Chest 88: 265, 1985).

* In severe pulmonary lupus, the alveolar walls undergo fibrosis, probably as the result of type III immune complex injury. In bad cases, the vasculitis causes bleeding into the alveoli (Am. J. Clin. Path. 85: 552, 1986).

Liver:

Despite the existence of an ANA-positive autoimmune disease called "lupoid hepatitis", involvement of the liver in true lupus is uncommon, at least in adults.
* Childhood autoimmune hepatitis may herald future lupus (Rheumatology 46: 1171, 2007).

Brain:

Fatigue is a major problem for most lupus patients, and is often the presenting complaint (Arch. Neurol. 46: 1121, 1989).

Antibodies against neurons probably cause the psychosis and convulsions often seen in lupus.

Brain infarcts (strokes) are a serious problem in many lupus victims.

* In the past, lupus cerebral vasculitis (few inflammatory cells, much intimal proliferation) has been blamed for most infarcts (strokes) in these patients. It now appears that lupus anti-cardiolipin antibody is present in most lupus patients with strokes, and the problem may be thrombosis instead (Am. J. Med. 86: 391, 1989).

NMR studies show evanescent inflammatory lesions and/or generalized atrophy (Arthr. Rheum. 31: 159, 1988; J. Rheumatol. 15: 601, 1988).

Anti-ribosomal P protein antibodies in the blood and anti-neuronal antibodies in the spinal fluid have been closely linked to lupus psychosis (but not other CNS problems): Arth. Rheum. 41: 1819, 1998. Whether the test (which can be ordered) is useful clinically, or the relationship is even true, is now under serious question (South. Med. J. 98: 704, 2005).

You will learn a great deal about working up lupus in advanced courses and on your internal medicine rotations.

Most lupus patients have anti-native (i.e., anti-double stranded) DNA, and this antibody is unusual except in lupus patents. These usually also react with some ribonucleoproteins, which may drive their production (J. Clin. Invest. 93: 443, 1994).

The few that don't have anti-native DNA will usually have anti-Ro/SSA (not specific for lupus), or anti-Sm ("Smith" antigen, a nuclear RNP, specific for lupus, though present in only 30%).

* Molecular biology of Smith, which has some distinctive epitopes: J. Immuno. 167: 562, 2001.

Remember that many healthy people have low titers of anti-nuclear antibodies. I would not think twice about a titer of 1:40 or less.

Clinical course and treatment:

Lupus still kills people. This is usually the result of kidney failure, iatrogenic immunosuppression (infections), bleeding, heart failure, or brain damage. When I was in medical school in the 1970's, we were told that 25% of patients would die of the disease within the five years after diagnosis. Thankfully, the mortality is much less today.

After several years, the incidence of myocardial infarction becomes very high in these patients, probably because of steroid therapy (Am. J. Med. 83: 503, 1987). Iatrogenic disease in lupus patients: JAMA 263: 1812, 1990.

You will learn about various low-tech (* Omega-3 fish oil) treatments and high-tech (total lymphoid radiation, pulsed cyclophosphamide, super-high-chemo and stem-cell rescue Lancet 356: 701, 2000; TNF-receptor blockers Arth. Rheum. 56: 274, 2007, autologous stem cells JAMA 295: 527, 2006; lots more) treatments for lupus on rotations.

* The most interesting work right now on lupus therapy is on atacicept (TACI-Ig), which binds TNF-family cytokines (BLyS and APRIL) thereby allowing B-cell apoptosis instead of stimulation. Big study Arth. Rheum. 56: 4142, 2007. Of course rituximab is under study (Rheum. 47: 821, 2008).

* Medical history buffs: Queen Anne and lupus. Br. Med. J. 304: 1365, 1992.

Lupus variants:

* SUBACUTE CUTANEOUS LUPUS ERYTHEMATOSUS: Anti-Ro, HLA-DR3, skin photosensitivity with papules, no scarring, sparing of the kidneys (Med. Clin. N.A. 73: 1073, 1989). Subclassifying the histopathology for dermatopathologists: Arch. Derm. 130: 54, 1994. There's been little since; thalidomide is now used for treatment (Am. J. Med. 118: 246, 2005).

CHRONIC DISCOID LUPUS ERYTHEMATOSUS (the usual form of "chronic cutaneous lupus") shows only the discoid skin changes. It is limited to sun-exposed skin. Around 10% of these patients eventually get the systemic disease, but most remain ds-DNA-negative and otherwise healthy. When severe, cyclosporine, methotrexate, and thalidomide have all proved helpful, and the new monoclonal efalizumab (anti-CD11a on the T-cells) has proved most promising (Arch. Derm. 143: 873, 2007).

Most DRUG-INDUCED LUPUS ERYTHEMATOSUS is precipitated by hydralazine, procainamide, isoniazid, penicillamine, or phenytoin (* Lovastatin lupus: Arch. Int. Med. 151: 1667, 1991).

The patients have anti-nuclear antibodies just as in lupus. Anti-histone antibodies (* "homogeneous pattern") are very characteristic, and the ones that actually make a person sick are anti-H2A-H2B antiguanosine autoantibodies (NEJM 318: 1431 & 1460, 1988).

The drug is of course acting as a hapten. The disease resolves when the drug is withdrawn.

* The anti-TNF agents such as etanercept occasionally precipitate classic (anti-dsDNA) lupus: Chest 134: 850, 2008.

Most of these patients are "slow acetylators"; you'll learn about them in Pharm.

* The linkage is with HLA-DR4.

* INCOMPLETE LUPUS: patients with suggestive findings but who do not meet the criteria for SLE. Prognosis is good (Arch. Int. Med. 149: 2473, 1989; the huge Dutch study reaches the same conclusion Rheumatology 40: 89, 2001).

* CANINE LUPUS is an important cause of morbidity in pet dogs ("Millie Bush's disease).

SJOGREN'S SYNDROME (Mikulicz's disease, "autoimmune exocrinopathy", "autoimmune epithelitis", etc. Review Br. J. Rheum. 35: 204, 1996.

A common, usually mild illness characterized by autoimmune damage to the salivary and lacrimal glands, plus arthritis.

Sometimes the vulvar and other glands are affected, and occasionally the renal tubules are ruined.

Most patients are middle-aged women. Sjogren's affects perhaps 2 million people in the US, though most probably do not know it.

The terminology is a little loose. This seems to be the common usage:

* "Mikulicz's syndrome" is large salivary and lacrimal glands infiltrated with lymphocytes, from any cause (Sjogren's, sarcoid, leukemia, lymphoma, AIDS, GVH-disease). Any of these diseases can cause dryness, and so can many common drugs, notably antihistamines, antipsychotic drugs, and antidepressants.

"Sicca syndrome" is unexplained dry eyes ("keratoconjunctivitis sicca") and dry mouth ("xerostomia") together.

* "Mikulicz's disease" or "autoimmune exocrinopathy" (neither in common use now) describe "sicca syndrome" due to autoimmune destruction.

"Primary Sjogren's syndrome" is autoimmune exocrinopathy by itself, or with mild arthritis. Biopsy of a minor salivary gland (usually from normal-appearing lower lip) is now required for research subjects.

"Secondary Sjogren's syndrome" is diagnosed when there is associated autoimmune disease: "Sjogren's with lupus", "Sjogren's with scleroderma", "Sjogren's with polymyositis", or "Sjogren's with rheumatoid arthritis". Very common -- perhaps a majority of these patients have it: Ann. Rheum. Dis. 46: 286, 1987.

* One known "underlying disease" that causes Sjogren's is chronic hepatitis C infection. No one knows why (Am. J. Med. Sci. 325: 135, 2003).

* "The benign lymphoepithelial lesion" is an anatomic pathologist's description of the glandular enlargement due to Sjogren's; it may present as a mass.

{35591} Sjogren's histology, minor salivary gland, fibrosis and lymphocytes
{35594} Sjogren's histology
{35597} Sjogren's histology; note lots and lots of lymphocytes

Sjogren's
Histopathology
WebPath photo

Sjogren's
Minor salivary gland
Wikimedia Commons

The autoantigens in Sjogren's (primary or secondary) seems to be ALPHA-FODRIN, a cytoskeleton component found in the salivary, lacrimal, and bronchial glands and rearranged when they secrete rapidly (Am. J. Path. 155: 173, 1999; Arch. Derm. 135: 535, 1999, Science 276: 604, 1997; Am. J. Path. 165: 53, 2004; Am. J. Path. 167: 1051, 2005; Rheumatology 46: 479, 2007) and the TYPE 3 MUSCARINIC ACETYLCHOLINE RECEPTOR (makes sense; Arth. Rheum. 44: 2376, 2001; Arth. Rheum. 54: 1165, 2006).

* Don't expect either antoantibody to come into widespread use in clinical diagnosis. My reading suggests to me that they are primarily T-cell autoantigens, which makes testing for sensitivity difficult.

T-cells (mostly helpers; see Semin. Arthr. Rheumatol. 14: 77, 1984) infiltrate and destroy the glands.

The lymphocytic infiltration is patchy but dense, B-cells enter and germinal follicles may appear, and the acini and (later) ducts eventually are wrecked.

Lip biopsy has been widely used, and biopsy of the parotid seems to be about equally good (Rheumatology 46: 335, 2007). Minor salivary gland biopsy is especially helpful is amyloidosis is also in your "differential diagnosis": (Arth. Rheum. 59: 714, 2008).

The epithelial cells in these glands show abnormal expression of HLA-DR's on their epithelial cells (Hum. Path. 19: 932, 1988). Obviously something's really scrambled.

Primary or secondary, most Sjogren's patients have autoantibodies of one sort or another.

Almost all female Sjogren's patients have antibodies against two "cytoplasmic" antigens, anti-Ro/SSA and anti-La/SSB (Ann. Rheum. Dis. 45: 732, 1986; Arthr. Rheum 29: 1223, 1986).

Anti-Ro/SSA is found in many autoimmune diseases (remember it is the cause of neonatal lupus). * It is especially seen with type III immune-injury vasculitis, which can be devastating (Arthr. Rheumatol. 28: 1251, 1985; Am. J. Clin. Path. 88: 26, 1987).

Anti-La/SSB is more specific for Sjogren's. (* Anti-RANA, described in Big Robbins, isn't proving very useful.)

* The histo-compatibility antigens HLA-B8, Dw3, and DRw52 are markers for Sjogren's (Am. J. Med. 80: 23, 1986).

Manifestations

In "sicca syndrome", patients eventually get damage to the eyes, nasal and oral mucosa from dryness. Cracker sign: "Would you like to eat a dry cracker right now?" "NO!!" Ask whether the patient keeps a glass of water at the bedside to sip at night. Do you see lipstick on her front teeth? The unpleasant, official "dryness test" (* "Schirmer's") involves hanging a strip of filter paper out of the lower conjunctival sac for fifteen minutes and watching it not wet beyond 1 cm or so. This sounds like it violates the Geneva convention.

"Sjogren's is an abnormal proliferation of lymphocytes". Patients with diagnosed primary Sjogren's often develop B-cell malignant lymphomas (around 10% of primary Sjogren's patients eventually get lymphoma (J. Rheum 24: 2376 1998, Rheumatology 45: 1012, 2006 & many others.) Oncogenes and chromosomal rearrangements in "benign Sjogren's": Arth. Rheum. 40: 318, 1998.

* Up to 40% of patients have an interstitial nephritis, and this is occasionally a problem (severe distal renal tubular acidosis, potassium wasting; Ann. Int. Med. 110: 405, 1989).

Dr. Sjogren observed that these patients often develop chronic shortness of breath, and we now know that many of these patients get a lymphocytic bronchiolitis which can progress to pulmonary fibrosis. The histology is variable. Update Chest 130: 1489, 2006.

* Rituximab (anti-CD20) for Sjogren's: Arth. Rheum. 57: 310, 2007 (optimistic). Etanercept fails: Arth. Rheum. 50: 2240, 2004.

SCLERODERMA ("[Progressive] Systemic Sclerosis"): NEJM 360: 1989, 2009.

A family of mild-to-miserable, usually slowly-progressive diseases with excessive fibrosis throughout the body. The skin is always involved; death is due to damage to the kidneys, lungs, heart, or GI tract. About one person in 4000 has scleroderma (Mayo Clin. Proc. 60: 105, 1985).

The diagnosis of scleroderma is made on physical exam. It has never been a biopsy or lab doctor's disease.

The etiology and pathogenesis of scleroderma remain obscure.

* You'll hear reports of fibroblasts from these patients making too much collagen in tissue cultures, various cytokines (notably the newly-discovered CTGF, "connective tissue growth factor") causing excess collagen proliferation in the skin, and downregulation of proteins that prevent overcollagenization (Am. J. Path. 163: 571, 2003). However, no clear picture of the pathogenesis of scleroderma has emerged.

Autoimmunity appears to be a factor, as these patients often have autoantibodies. Human graft-vs.-host disease resembles scleroderma's skin, lung, and vascular lesions, and the best animal model uses B- and T-cells from one mouse strain to attack the tissues of another (Arth. Rheum. 50: 1319, 2004).

* There is a susceptability allele at the connective tissue growth factor locus, but the effect is not striking (NEJM 357: 1210, 2007).

Researchers need a definition of scleroderma to know who to include in studies. One big study (Medicine 87: 131, 2008) said anyone who (1) has Raynaud's phenomenon and (2) has at least one of the scleroderma-related autoantibodies:

• anti-Scl-70 / anti-topoisomerase I


• anti-PM-Scl (polymyositis-scleroderma overlap sydrome; calcinosis)


• * anti-fibrillarin


• * anti-RNA polymerase I (skin, kidney involvement)


• * anti-RNA polymerase III


• * anti-fibrillin / anti-U₃RNP



"Anti-nucleolar antibodies" (* anti-fibrillarin and some others) are worth remembering as they give the "nucleolar" pattern on the old anti-nuclear antibody screening test.

{33248} anti-nuclear antibody preparation in scleroderma, with each of the thousand points of light a different nucleolus

Anti-topoisomerase I (* formerly Scl-86, etc.) is a marker for severe, diffuse disease, especially with lung involvement; more about the antibody and what keeps it going Arth. Rheum. 36: 1580, 1993; the epitope recognized determines the severity Arth. Rheum. 36: 1406, 1993). The antigen Scl-70, mentioned in Big Robbins, is a breakdown product of anti-topoisomerase I; today it's a common name for this "scleroderma test".

* This topoisomerase is a DNA-modifying enzyme that seems to work particularly well at the collagen gene, causing cells to produce too much collagen (Lancet 2: 475, 1988). This idea is supported by the discovery that the skin-tight mouse, the genetic model for scleroderma, has high topoisomerase, and if you can get the mouse to make fewer antibodies, it doesn't get so sick (Cell Immuno 167: 135, 1996). More on the mouse: Am. J. Path. 165: 641, 2004.

Apoptosis of endothelium is seen early in the disease.

* Claims in the mid-1990's that anti-endothelial antibodies mediated much of the damage in scleroderma have failed to find confirmation.

More likely, the deadly onionskinning results from a complex interplay of molecules. Watch for abnormal fibrous responses to endothelial damage: J. Imm. 174: 5740, 2005.

Anti-centromere antibody in high titer more or less defines the milder CREST syndrome, a scleroderma variant (see below; Br. J. Derm. 113: 381, 1985; Am. J. Med. 77: 812, 1984).

* Anti-Th/To antibodies correlate with a milder, perhaps distinct, disease similar to CREST but with less gastrointestinal involvement and worse pulmonary fibrosis (Arth. Rheum. 41: 74, 1998). Stay tuned.

* Anti-fibrillarin antibodies correlate a severe, probably distinct scleroderma variant (Arth. Rheum. 39: 1151, 1996; J. Imm. 163: 1066, 1999).

* Antibodies against RNA polymerases I and III (distinct from Ro and La) seem to define a separate scleroderma variant that is especially rough on the kidneys. (Br. J. Rheum. 37: 15, 1998). Antibodies against RNA polymerase II tend to occur with anti-topoisomerase I (Chest 114: 801, 1998). This has held up well.

Fetal cells are found in the skin lesions of about half of women with scleroderma, raising the possibility that it's often a variant of graft-vs.-host disease (which it resembles): NEJM 338(17):1186, 1998. This is holding up: Rheumatology 43: 965, 2004. Watch for more on "microchimerism"; no one knows how common it is even in healthy mothers. Today, it seems likely that we all have some of our mother's cells, and that women carry cells from their children (Sci. Am. 298(2): 72, Feb 2008).

In addition, there are vessel abnormalities.

A vasculitis and monocytic infiltrate precedes the fibrosis as it progresses.

Small vessels in many parts of the body show intimal proliferation. The histology is concentric fibrosis "onionskinning", but involving the intima this time) and/or myxoid proliferation.

{08466} onion-skinning of intima of small artery in scleroderma
{08469} intimal proliferation in scleroderma (elastic stain, kidney)
{24854} intimal proliferation in scleroderma demonstrated with PAS stain
{33259} intimal proliferation in small artery of the scleroderma kidney; the tubules are atrophic because of the longstanding lack of blood flow
{17124} kidney vascular changes in scleroderma

Scleroderma From Chile In Spanish

Scleroderma Note the sclerodactyly and facial changes WebPath photo

Scleroderma Malnutrition or physical effect? You decide. Webpath.

Scleroderma Intimal onionskinning WebPath photo

A clinician can detect scleroderma by observing that only a few large capillaries remain in the nail folds. ("How to": Arch. Derm. 139: 1027, 2003).

Skin and cutaneous vessels (Med. Clin. N.A. 73: 1167, 1989):

Visible skin changes are preceded in almost all cases by Raynaud's phenomenon (fingers blanching on exposure to cold; the color sequence is white-blue-red), and then by swelling. (Gangrene of the fingertips is the result of severe Raynaud's.)

The skin eventually becomes tight and firm. This usually begins on the fingers ("sclerodactyly", "acrosclerosis") and hands.

The dermis becomes increasingly collagenized, the epidermis thins and loses its adnexa ("atrophy"), and it may progress to immobility.

{14335} scleroderma, hands (notice calcium in knuckles)
{14336} scleroderma, finger (notice that the thin epidermis makes the skin shiny, and that the vessels are bunched at the nail root)
{25460} scleroderma, acrosclerosis
{24626} scleroderma, hands
{24917} scleroderma, histology of skin
{08460} scleroderma, histology of skin

Scleroderma Skin changes WebPath photo

Scleroderma Skin changes WebPath photo

The altered dermis may calcify (feel for this in the finger pads). The calcium binds to gamma carboxyglutamic acid residues, so one can treat it with a low dose of coumarin.

Onionskinning of the intima of the digital vessels is present, and probably explains the Raynaud's.

The skin disease may never get farther than the hands, or may cause microstomia, bedsores, etc.

Alimentary tract (Dig. Dis. Sci. 53: 1163, 2008):

The smooth muscle of the gut, especially the esophagus, is replaced by collagen. "Rubber hose esophagus" is a serious problem, causing difficulty swallowing, reflux and aspiration of food. Gastroparesis is common, and pseudo-obstruction, bacterial overgrowth, and malabsorption may result from intestinal involvement.

Scleroderma
Stomach -- trichrome for collagen
WebPath photo


Musculoskeletal system:

There is a mild chronic synovitis, and about 15% of patients get some chronic myositis with elevated creatine kinase levels, and collagenization and weakness in proximal extremities.

Kidneys:

The classic lesion in the kidneys is intimal proliferation ("onion-skinning") of the interlobular arteries in the kidneys.

Intimal onionskinning in the kidney is also typical of "malignant high blood pressure", where it is accompanied by necrosis and thrombosis of the arteries. One third of patients with scleroderma get high blood pressure due to the kidney changes, and one third of these get frank "malignant high blood pressure" ("scleroderma hypertensive crisis"). Great pictures: Am. J. Kid. Dis. 14: 236, 1989.

Lungs:

Scleroderma patients commonly get a diffuse interstitial-alveolar fibrosis. This limits the ability to breathe ("restrictive lung disease") and to get oxygen into the bloodstream ("alveolar-capillary block", "diffusion barrier"). This is most common in the generalized disease, but can occur in the limited forms as well (Chest 134: 601, 2008). Don't wory about the subtypes.

A few scleroderma patients have severe pulmonary hypertension, with intimal onionskinning of the pulmonary arteries. This is more common in the CREST syndrome, where perhaps 10% are affected.

{33274} scleroderma lung; trichrome stain shows collagen/scar blue

* Scleroderma patients often die during cold weather from chest colds.

* Other organs:

In unusual cases of scleroderma, there are cardiac arrhythmias, cardiomyopathy, polyneuropathy.

Scleroderma variants:

CREST SYNDROME ("limited cutaneous scleroderma") -- a milder variant of scleroderma, distinguished by the presence of anti-centromere antibody.

Calcinosis, Raynaud's phenomenon, Esophageal dysfunction, Sclerodactyly, and Telangiectasias (groups of dilated vessels in the skin)

Pulmonary hypertension and/or primary biliary cirrhosis (J. Derm. 26: 18, 1999) are common in CREST. The kidneys are usually spared.

* For some reason, these people are also prone to bad periodontal disease and/or corneal ulcers and/or inner ear troubles (Medicine 87: 131, 2008).

Confirmation and titer of anti-centromere antibody is now a tube test ("anti-centromere protein B").

MORPHEA is "a form of scleroderma" confined to one area of the skin (Med. Clin. N.A. 73: 1143, 1989). Remember Lyme disease as one known cause of morphea (surprise!) Classic morphea does not turn into scleroderma and does not require any lab work beyond (probably) a Lyme check.

Exactly what morphea has to do with scleroderma has always been debatable.

Morphea patients tend to be positive for anti-Th/To, and negative for other scleroderma markers (Rheumatology 40: 683, 2001).

* Future pathologists: The localized scleroderma variants feature inflammation and fibrosis of the papillary dermis; this is spared in regular scleroderma.

{12187} morphea
{14333} morphea
{15358} morphea

Morphea (localized scleroderma) Prize photograph Institute of Medical Illustrators

"Maybe not really scleroderma...."

LOCALIZED LINEAR SCLERODERMA ("sabre-cut scleroderma") is rare and follows a dermatome (Ann. Int. Med. 104: 849, 1986) and may involve the underlying muscle. It's the common form of morphea/scleroderma in children.

* Parry-Romberg involves half of the face ("facial hemiatrophy"). Since patients often have local linear scleroderma as well, it's probably another morphea variant (J. Amer. Acad. Derm. 56: 257, 2007); curiously, it may involve bone as well, and nowadays it seems that neither this illness nor local linear scleroderma typically have any positive labs suggesting any known autoimmune disease (J. Amer. Acad. Derm. 54: 227, 2006).

* EOSINOPHILIC FASCIITIS / "the Fasciitis-Panniculitis Syndromes" are yet another supposed systemic variant of scleroderma (though without skin involvement or Raynaud's or telangiectasias).

In these illnesses, the septa of the deep fat, and sometimes other collagen, thicken diffusely or locally for no obvious reason. Eosinophils may or may not be present. The mainstay of therapy (which evidently works more often than not) is cimetadine (Medicine 75: 6, 1996 -- still the major review).

One model for this was the L-tryptophan fiasco (NEJM 322: 874, 1990). Another known cause is Lyme disease (JAMA 272: 1283, 1994). A third was the toxic-oil fiasco in Spain.

There's been little study of this recently; fibroblsts from victims of this illness do not express the proteins that are likely to be overexpressed in classic scleroderma (J. Imm. 167: 7126, 2001).

* Scleroderma-like changes developed on the hands of vinyl chloride workers, and some cases have been linked to industrial solvent exposures (J. Occup. Med. 29: 493, 1987). If augmentation mammoplasty is an additional cause, it is vanishingly rare (Ann. Int. Med. 111: 377, 1989; the article that sparked all the lawsuits).

There is at present no highly-effective treatment for scleroderma.

Historically, around 50% of scleroderma patients have ben alive five years after diagnosis (Arthr. Rheum. 34: 403, 1991); maybe half the time, the disease gets somewhat better by itself (Arth. Rheum. 44: 2828, 2001).

Penicillamine is often administered, which makes sense because it inhibits collagen synthesis.

Imatinib, which inhibits both TGF-beta and PDGF, helps in the experimental models; watch for it to be tried clinically (Arth. Rheum. 56: 311, 2007).

Bosentan, the endothelin receptor antagonist, for scleroderma: Arth. Rheum. 56: 1985, 2007.

Cyclophosphamide, especially for the lung disease: NEJM 354: 2655, 2006; Arth. Rheum. 56: 1676, 2007.

Interferon gamma and relaxin have proved disappointing (Lancet 367: 1683, 2006).

* Halofuginone is often suggested as a proposed drug for scleroderma; it prevents laying-down of the very-dense collagen, but not of normal collagen: J. Inv. Derm. 106: 84, 1996; Autoimmunity 35: 277, 2002.

Serendipity: Patients given Iloprost for their Raynaud's report that this greatly helps the skin tightening; perhaps this modulates the CTFG effect (J. Clin. Invest. 108: 241, 2001)

The most encouraging work on scleroderma suggests that high-dose immunosuppression followed by infusion of your own adult stem cells arrests and even reverses the severe systemic disease (Blood 110: 1388, 2007; JAMA 299: 925, 2008).

* Medical history buffs: The most picturesque (and horrifying) Raynaud's syndrome is ergotism (intoxication with Claviceps purpura fungus from wet rye. Lysergic acid causes LSD-related psychosis as well as gangrene of the extremities and "St. Anthony's flame" neuropathy. Mass outbreaks are memorable and have occurred even in the mid-20th century.

POLYMYOSITIS and DERMATOMYOSITIS": Lancet 355: 53, 2000; immunology review from Harvard Neurology 69: 2008, 2007).

Polymyositis is an inflammatory disease that damages skeletal muscle.

Groups of muscle cells degenerate, and there is a chronic inflammatory infiltrate in the muscle. Pure polymyositis is mediated by T-cells attacking muscle.

Dermatomyositis is another inflammatory disease in which antibodies involve the capillaries at the edges of muscle cell groups, and also skin involvement

* It's uncommon for the rash of dermatomyositis to occur without muscle involvement: "amyopathic dermatomyositis" Arch. Derm. 131: 1458, 1996) -- when it runs with lung disease, it is especially ominous (Rheumatology 44: 1282, 2005).

Various rashes occur, the characteristic ones being a lupus-like "butterfly rash", "heliotrope eyelids", and purple bumps on the knuckles (Gottron's sign). Others may mimic seborrhea.

{13120} Gottron's sign
{14342} heliotrope eyelids
{14338} Gottron's sign (easier to see on the left hand than on the right hand)
{14339} Gottron's sign
{14340} Gottron's sign
{15346} butterfly rash (closely resembles lupus)

Muscle biopsy in dermatomyositis
Text and photomicrographs
Dr. Warnock's Collection

The etiology and pathogenesis of polymyositis-dermatomyositis are obscure. There is strong circumstantial evidence that autoimmunity is somehow involved, but you should ignore any elegant or complete descriptions of its pathogenesis.

Polymyositis and dermatomyositis tend to occur with evidence of any of the other collagen-vascular diseases, or with rheumatic fever, sarcoidosis or cancer.

Skeletal muscle ground up and injected with Freund's adjuvant is the basis for the induced animal models.

ANTISYNTHETASE SYNDROME, a subcategory of polymyositis, features antibodies against several of t-RNA synthetases (J. Immunol. 144: 1737, 1990; Clin. Exp. Rheumatol. 8: 259, 1990). Anti-Jo-1 (anti-histidyl-tRNA synthetase) was the first of these antibodies, which are markers for polymyositis-dermatomyositis (anti-Jo-1 is quite specific: Arth. Rheum. 39: 292, 1996) and also pulmonary fibrosis; some accounts say they predict a good response to glucocorticoid. Many more anti-tRNA-synthetases have been found (Arth. Rheum. 56: 1295, 2007).

* Suspected triggers include toxoplasmosis, parvoviruses, immunizations, "stress". The drug D-penicillamine (useful for rheumatoid arthritis and scleroderma) commonly causes DM-PM. * Simian AIDS features DM-PM in 50% of cases.

* C2-deficient people get a polymyositis-like syndrome in addition to their lupus.... The idiopathic disease is often associated with HLA-DR3/B8. Attempts to isolate a virus have failed.

* Dermatomyositis is a very common disease of collie and shelty puppies (Am. J. Path. 123: 465 & 480, 1986).

Whatever the cause(s), the muscle changes on physical exam and biopsy are characteristic.

Polymyositis affects the proximal muscles of the extremities most severely (weak hips and shoulders, weak neck flexors).

It spares the extra-ocular muscles (making it easy to distinguish from myasthenia gravis).

The muscles are at first sore, tender, swollen (edematous), and weak. (Patients may complain of "fatigue" instead).

Perivascular (think dermatomyositis) and endomysial (think polymyositis) inflammation, and muscle cell necrosis, are usually present on biopsy but may be subtle.

The pathologist also looks for decreased muscle cell diameter at the edge of the bundles (perifascicular atrophy), which is basically diagnostic for dermatomyositis.

* Guessing from the biopsy whether it's polymyositis or dermatomyositis isn't altogether reliable. If you must...

Polymyositis
• more T-CTL killer cells among the muscle fibers



Dermatomyositis

• more vasculitis


• immune complex deposits


• single-fiber necrosis


• fibrosis


• really striking perifascicular atrophy

{05780} dermatomyositis, histology; note the lymphocytes in this particular case
{05789} dermatomyositis, late, trichrome stain; muscle cells (red) are largely replaced by scar tissue (blue)
{09039} polymyositis, histology in muscle; note lymphocytes
{14358} polymyositis, histology; good perifascicular atrophy
{29501} polymyositis; find a few examples each of muscle fibers undergoing necrosis, atrophy, and regeneration

Later, in severe disease, weakness is profound, and the muscles are fibrotic, there may be calcium deposits (often extensive in childhood dermatomyositis -- chemistry Arth. Rheum. 54: 3345, 2006), etc.

You will learn about the diagnosis of polymyositis-dermatomyositis in clinics.

There are often increased circulating eosinophils, especially in dermatomyositis.

Serum muscle enzymes are greatly increased (check creatine kinase, * aldolase is measured less often)

* Electromyography and muscle biopsy are also used.

When you suspect dermatomyositis, rule out cancer, especially in older patients, especially of the ovary. In a large minority of cases, the disease is the first sign of an internal malignancy (Ann. Int. Med. 134: 1087, 2001; NEJM 326: 363, 1992).

Polymyositis and dermatomyositis are miserable diseases, and are difficult to treat even today (Rheum. 44: 83, 2005).

Rituximab seems to help the muscle and skin disease in dermatomyositis only slightly: Arch. Derm. 143: 763, 2007.

MIXED CONNECTIVE TISSUE DISEASE (MCTD, "anti-U₁-RNP disease")

A mixed picture with features of lupus, polymyositis, and scleroderma. Patients have severe Raynaud's phenomenon, swollen fingers, mild myositis, and severe joint pain. The rest of the "mix" is more variable.

The kidneys are spared. The brain is usually spared. Response to glucocorticoids is often good.

High titers of antibodies against ribonucleoprotein (U₁-RNP, one of the "speckled pattern" antibodies) are characteristic. Old questions about whether this is "really a separate disease" seem to be moot nowadays, and there's a mouse model produced by immunizing against U₁-RNP (Arth. Rheum. 54: 661, 2006).

Regardless, when U₁RNP titers are high, the patient will likely have arthritis / myositis (Br. J. Rheum. 37: 39, 1998).

Lately, it's become clear that about half of MCTD patients have pulmonary fibrosis on today's imaging studies (Rheumatology 44: 656, 2005); however, it lacks honeycombing and does not interfere much with one's health. And a large minority of MCTD patients have damage to the lining of the lung vessels ("pulmonary hypertension"), and treatment should probably be undertaken (Arth. Rheum. 52: 2125, 2005).

MCTD Weird bowel lesion Pittsburgh Pathology Cases

MCTD Pittsburgh Pathology Cases

Mixed Connective Tissue Disease Pittsburgh Illustrated Case

Anti-nuclear antibodies Homogeneous pattern WebPath photo

Anti-nuclear antibodies Homogeneous pattern WebPath photo

Anti-nuclear antibodies Peripheral pattern WebPath photo

Anti-nuclear antibodies Speckled pattern WebPath photo

Anti-nuclear antibodies Nucleolar pattern WebPath photo

Anti-nuclear antibodies
Nucleolar pattern
WebPath photo

* FIBROMYALGIA SYNDROME ("allodynia", "fibrositis", "rheumatic pain modulation disorder"; "muscular rheumatism", not an autoimmune disease: Big current review Ann. Int. Med. 146: 726, 2007.

Fibrositis is the most common diagnosis made by consulting rheumatologists today. This is an extremely common, distinct disease without any known anatomic or laboratory correlates. (Just like today's oh-so-organic migraine was in the pre-1990's era, remember? It is a mysterious pain syndrome with morning stiffness, deep tenderness at predictable locations ("trigger points" -- to learn where and how to poke, see Arthr. Rheum. 31: 182, 1988). Patients are often disabled. There are EEG abnormalities in deep sleep, and probably some kind of disturbance in brain serotonin metabolism. By now, it's clear that there is a central problem with pain modulation ("nociception") in these patients: Arth. Rheum. 36: 642, 1993; Arth. Rheum. 40: 98, 1997.

Typical victims are young, effective women who dislike alcohol and Valium, and complain of nonrestorative sleep. There may be as many as 6 million patients with this illness in the U.S. I remember these patients being ridiculed (in the 1970's) as "total body pain" cases -- malingerers or neurotics. (Presently the "personality problems" of these patients are attributed to chronic pain.) Fibromyalgia syndrome is not presently considered to be an autoimmune disease. (This pathologist questions the experience of clinicians who have published photos of "positive lupus band tests" from these patients -- they look like classic negative studies. See RDCNA above.) The 1992 Copenhagen Conference declared this to be a real entity (Lancet 340: 1103, 1992) and attempts a better definition. Doubt about the syndrome's reality seems to have ended.

Treating fibrositis is complex; aerobic exercise is important (swimming, being non-impact, is often helpful), and certain drugs seem to help (try cyclobenzoprine 10 mg q HS, helps a large minority of patients; or nowadays the newer antidepressants). Acupuncture at the trigger points has been reported as useful, as is injection of anesthetics. Acupuncture gets a "definite maybe" from the Maryland Complementary Medicine Program: J. Fam. Pract. 48: 213, 1999. In 1987, I predicted the selective serotonin uptake inhibitors would be successful in treating fibromyalgia, and this has now been nicely confirmed. Guaifenesin, a current "pop" remedy, has a devoted following among self-help groups, and the drug seems to have some poorly-understood muscle-relaxant and analgesic properties (JABFP 17: 240, 2004; there was a small study for fibromyalgia yielding negative results in 1996 and nothing real since). Stay tuned.

* Reminder: You will study osteoarthritis ("wear and tear arthritis"), rheumatoid arthritis, the enthesopathies, and rheumatic fever later in the course. Another important cause of multi-joint arthritis is iron overload -- fairly common, and very preventable.

BIBLIOGRAPHY / FURTHER READING

I urge anyone interested in learning more about the autoimmune diseases to consult these standard textbooks.

Roitt's Essential Immunology
Robbins and Cotran Pathologic Basis of Disease
Rosai and Ackerman's Surgical Pathology
Rubin's Pathology: Clinicopathologic Foundations of Medicine
Silverberg's Surgical Pathology


In my notes, the most helpful current journal references are embedded in the text. Students using these during lecture strongly prefer this. And because the site is constantly being updated, numbered endnotes would be unmanageable. What's available online, and for whom, is always changing. Most public libraries will be happy to help you get an article that you need. Good luck on your own searches, and again, if there is any way in which I can help you, please contact me at scalpel_blade@yahoo.com. No texting or chat messages, please. Ordinary e-mails are welcome. Health and friendship!

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