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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.

DoctorGeorge.com is a larger, full-time service. There is also a fee site at myphysicians.com, and another at www.afraidtoask.com.

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I'm still doing my best to answer everybody. Sometimes I get backlogged, sometimes my E-mail crashes, and sometimes my literature search software crashes. If you've not heard from me in a week, post me again. I send my most challenging questions to the medical student pathology interest group, minus the name, but with your E-mail where you can receive a reply.

Numbers in {curly braces} are from the magnificent Slice of Life videodisk. No medical student should be without access to this wonderful resource. Someday you may be able to access these pictures directly from this page.

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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 linked below. 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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This page was last updated February 6, 2006.

During the ten years my site has been online, it's proved to be one of the most popular of all internet sites for undergraduate physician and allied-health education. It is so well-known that I'm not worried about borrowers. I never refuse requests from colleagues for permission to adapt or duplicate it for their own courses... and many do. So, fellow-teachers, help yourselves. Don't sell it for a profit, don't use it for a bad purpose, and at some time in your course, mention me as author and KCUMB as my institution. Drop me a note about your successes. And special thanks to everyone who's helped and encouraged me, and especially the people at KCUMB for making it possible, and my teaching assistants over the years.

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{49499} ochronosis ("alkaptonuria"), femoral head

You remember that alkaptonuria makes cartilage turn black and flake, causing bad osteoarthritis by early middle age. The pigment, of course, is homogentisic acid, a phenylalanine-tyrosine metabolite.

Also remember the various causes of clubbing (and its severe counterpart seen in non-oat-cell lung cancer, "hypertrophic osteoarthropathy") and neuropathic joint disease ("Charcot's joints").

Ankylosis of a joint is scarring that is sufficient to prevent movement in that joint.

"OSTEOARTHRITIS" ("osteoarthrosis", "degenerative joint disease"; Lancet 350: 503, 1997; Med. Clin. N.A. 81: 85, 122, 1997; Ann. Int. Med. 133: 635, 2000; Postgrad. Med. 114: 11, 2003).

A very common, slowly progressive, initially-noninflammatory process of unknown cause, normally occurring later in life.

Regardless of cause, the joint cartilage alters chemically and exhibits cracks perpendicular to the surface. Eventually, it becomes thinner.

* The biochemistry is complex and so far has not yielded any therapeutic triumphs. Stay tuned though.

In addition, the nearby perichondrium is activated, producing knobs off the side of the joint, and the synovium may undergo some thickening or transformation into scar, cartilage, and/or fat.

Most osteoarthritis fortunately never becomes symptomatic. When it does, victims experience the slow onset of stiffness, pain, minor deformity and limitation of motion without heat or effusion.

Most often involved are the great weight-bearing joints of spine, hips, and knees.

Especially troublesome is lipping in the cervical and lumbar spine ("osteophytes"), which can impinge on nerve roots of the spinal foramina.

For some reason, the phalangeal-metacarpal joint of the thumb, distal interphalangeal joints (spurs here are called "Heberden's nodes"), and TMJ are also common involved. (So much for the idea that "heavy weight-bearing" is the overriding cause of osteoarthritis....)

* Medical history buffs: This is the same Dr. Heberden who distinguished chickenpox from smallpox, described angina pectoris, and described night blindness.

"Bouchard's nodes" are similar, but on the proximal interphalangeal joints. * Wearing high-heeled shoes as a likely cause of knee osteoarthritis: Lancet 351: 1399, 1998. Makes sense.

The wrists, elbows and shoulders are generally spared.

Primary osteoarthritis is the common "arthritis" that affects most older people.

This is supposedly due to "wear-and-tear" (it's commoner in big people, especially in the overweight; see J. Rheumatol. 17: 283, 1990) and/or metabolic changes in cartilage (the bewildering array in "Big Robbins" is only the beginning, but they cannot all be primary.)

* The old notion that chondrocytes don't ordinarily divide is clearly not true; chondrocytes of the elderly show plenty of evidence of cell senescence, and this probably has something to do with osteoarthritis (J. Bone Joint Surg. 85-A (S2): 106, 2003).

Secondary osteoarthritis has an identifiable congenital or acquired predisposing factor (i.e., football knee, dancers, power drill operators, heavy people who do a lot of kneeling or squatting (Arth. Rheum. 43: 1443, 2000), congenital hip malformation, hemochromatosis, ochronosis, deposits, defective type II collagen gene COL2A1, now well-established and evidently extremely common (Arth. Rheum. 42: 39, 1999; Arth. Rheum. 51: 925, 2004), iron or copper overload, alkaptonuria, acromegaly, * other poorly-understood autosomal dominant syndromes, see J. Rheum. 18(S27): 7, 1991.) Most famous is post-traumatic osteoarthritis, yet at the level of pathophysiology it is almost entirely mysterious (Clin. Orth. Rel. Res. 423: 7, 2004).

Athletes probably do not have more osteoarthritis than others (for example, Am. J. Med. 88: 452, 1990), but there are many variables. Basketball players get osteoarthritis in the knees. Baseball pitchers get osteoarthritis in the shoulders and elbows. Soccer players who take trauma to the knees have a very high prevalence of osteoarthritis in later years, but longtime runners do not. And so forth. The key seems to be loading plus twisting the joint, which would seem to do the most damage to the cartilage.

Burned-out Lyme disease looks anatomically like osteoarthritis. (During the active phase, Lyme disease synovium looks like rheumatoid arthritis.)

Today, some pathologists and clinicians distinguish subtypes of osteoarthritis, and I think this is probably going to become standard:

• Generalized osteoarthritis: A systemic problem with the joint cartilages, with considerable spurring. Primarily genetic, expressing itself in later life; the most severe forms typically have the major mutation in COL2A1 but most have a normal gene.
• Large joint arthritis: Hips and knees, more in bigger people
• Superior pole osteoarthritis: The most common symptomatic osteoarthritis in the hip; probably due largely to minor anatomic variations that affect the distribution of weight-bearing
• Erosive osteoarthritis: Primarily the hands, with obvious inflammation and a fairly severe synovitis; thankfully the least common

Kashin-Beck disease is an ancient, endemic, deforming disease of bones and joints seen in Siberia, Mongolia, Tibet, and the remote areas of Mainland China. It begins in childhood and cripples up to 90% of people in some of the poorest communities. The underlying lesion is evidently non-formation of the little arteries that should supply the cartilage plates (Int. Ortho. 25: 151, 2001), explaining both the arthritis and the dwarfing of the limbs. The cause is almost certainly selenium deficiency plus vitamin E deficiency (Clin. Rheum 16: 441, 1997; NEJM 339: 1112, 1998) and maybe iodine deficiency (NEJM 339: 1156, 1998; epidemiologic link only, maybe not causal) coupled with fulvic acid (from rotting organic material; it poisons procollagen type II processing Eur. J. Biochem. 202: 1141, 1991, more) in the drinking water (J. Tox. 35: 79, 1992; Am. J. Clin. Nut. 57(S2): 259S, 1993). Animal model: Biochem. J. 289: 829, 1993. Histopathology Virch. Arch. A. 423: 483, 1993. Conference in Beijing Br. Med. J. 318; 485, 1999.

Regardless of whether osteoarthritis is "primary" or "secondary", the pathologist sees characteristic changes:

• cartilage "fibrillation" (collagen fibers within the cartilage become visible because they have lost their carbohydrate)
• cracking, erosion and flaking of articular cartilage
• subchondral sclerosis ("eburnation", ivory) and cyst formation
• osteophyte formation ("spurring", "lipping" -- outward growth of bone and cartilage at the margins of articular surfaces; this probably causes some of the pain)
• joint mice (sometimes; detached bits of cartilage and bone, resulting in pain or recurrent locking; real nature discovered by Virchow)
• sometimes a relatively mild synovitis (despite the conventional teaching that "osteoarthritis is non-inflammatory", it is now obvious that there is often considerable inflammation as the disease progresses: Rheumatology 44: 7, 2005)

The most interesting news in osteoarthritis is the evident effectiveness of the pop remedies glucosamine, s-adenosylmethionine, and chondroitin (JAMA 283: 1469 & 1483, 2000). The mechanism of action remains unknown.

Charcot's neuropathic change is a marked deformity of one or more joints in an area where sensation has been lost.

Histologically, it closely resembles the bony changes of classic osteoarthritis.

The old explanation that it represents the result of repeated injury obviously doesn't make sense, and there are cases in which it has developed very rapidly. Obviously there is a mechanism awaiting discovery -- it will involve unknown interactions between bone and nerve. (Osteopathic students take note!)

{10946} spurred spine
{24637} spur, histology
{24638} eburnation
{24639} "cyst" formation in articular bone
{24640} joint mouse
{40180} femoral head, eroded cartilage
{45612} x-ray, showing narrowed joint spaces

Osteoarthritis Great picture WebPath Case of the Week

"Osteoarthritic" lipping WebPath Tutorial

"Osteoarthritic" lipping WebPath Tutorial

Osteoarthritis Femoral heads

RHEUMATOID ARTHRITIS ("RA"; poem NEJM 320: 674, 1989; big review from Northwestern Med: Am. J. Med. 100(2A): 3-S, 1996; Med. Clin. NA 81: 29, 1997; Lancet 358: 903, 2001; molecules Ann. Int. Med. 136: 908, 2002)

A common, usually chronic, systemic, dread inflammatory disease (* probably a group of diseases) of unknown etiology. Its outstanding feature is progressive, symmetrical synovitis, with pain and morning stiffness, and which may lead to deformity and destruction of the joints.

Up to 3% of women and 1% of men worldwide will be affected; most cases arise in young or middle-aged adults. The American Indians have a very high prevalence of rheumatoid arthritis. Why women get more rheumatoid arthritis is mysterious; no doubt it has something to do with women's immune system being more powerful than men's. Going on the oral contraceptive pill has been said to help RA, and estrogen actually relieves some animal models.

{25016} rheumatoid arthritis, ulnar deviation
{25017} rheumatoid arthritis, ulnar deviation
{38225} rheumatoid arthritis, hand
{45602} rheumatoid arthritis, x-ray
{45648} rheumatoid arthritis, foot

Rhematoid Arthritis From Chile In Spanish

Rheumatoid arthritis WebPath Tutorial

Rheumatoid nodule Clickable WebPath Tutorial

Rheumatoid nodule WebPath Tutorial

Chronic synovitis in rheumatoid arthritis WebPath Tutorial

You will make the diagnosis clinically, based on the presence of four or more of these seven findings:
• morning stiffness
• arthritis in three or more areas
• arthritis in the hands
• symmetrical arthritis
• rheumatoid factor
• rheumatoid nodules
• characteristic x-ray findings

There is a hereditary component, but no simple pattern of inheritance.

The HLA associations of rheumatoid arthritis are just now starting to be worked out. HLA-DR4 is much-discussed ("the disease-associated antigen"); it correlates some with the disease in white people (70% of caucasian RA patients vs 28% of caucasian non-RA patients). In other populations, rheumatoid arthritis associates with HLA-DR1 instead; it now appears that, whatever number is assigned the actual high-risk tissue-type, they have a common five-amino-acid epitope (HLA-DRB1 shared epitope: Arth. Rheum. 42: 2698, 1999; Arth. Rheum. 43: 753, 2000).

Various alleles at the TNF locus also seem to be strongly linked to rheumatoid arthritis (Arth. Rheum. 43: 753, 2000). Strongest so far is a polymorphism at the gamma-interferon locus (Lancet 356: 783, 2000). The identical twin of a RA patient has only about a 30% chance of getting the disease.

An acute ("exudative", i.e., lots of neutrophils and fibrin, hyperplastic synovial cells, and obviously destructive) and chronic inflammatory synovitis leads to proliferation of a vascular connective tissue in the synovium, which later fills with polys, T-cells, and plasma cells ("pannus"). Venules assume the form and function (* "high endothelial", i.e., very permeable to lymphocytes) seen in lymphoid tissue. You won't see pus. On arthroscopy, pannus looks like a sea anemone.

Pannus spreads over and erodes the articular cartilage and even bone leading to fibrosis of the joint.

{49503} pannus, gross
{49504} pannus, gross
{46391} pannus, gross, up close
{24636} pannus, micro, eroding bone
{10313} pannus, micro, eroding bone
{19415} pannus, showing lymphocytes
{19418} pannus, showing lymphocytes

The etiology is obscure, but surely involves an immune system abnormality.

The first change is the homing of T-helper cells to the synovium, where they do not belong. No one knows why this happens. Perhaps some foreign agent -- EB virus? parvovirus? mycoplasma? dietary factor? something nasty from the gut (J. Rheumatol. 16: 1017 & 1061, 1990)? bacterial shock proteins? (Arthr. Rheum. 34: 486, 1991) -- initiates this immune response.

Mediators of inflammation that seem strongly involved in rheumatoid arthritis are macrophage-derived: IL-1, IL-6 (Br. J. Rheum. 34: 321, 1995), interleukin-8 (J. Lab. Cln. Med. 123: 183, 1994), leukotriene B4, complement components, and α-TNF (it abounds in rheumatoid fluids). Very likely the type synovial cells are among the "macrophages" that elaborate these. The cytokines summon the polys and cause other harmful things to happen. The factors produced primarily in lymphocytes do not seem to be involved.

Interleukin 1 (and more recently, α-TNF) have been shown stimulate production of collagenase and prostaglandin E₂ in rheumatoid joints. Currently a prime suspect is interleukin 6, produced by the synoviocycytes themselves (Am. J. Path. 152: 821, 1998). All of these wreck havoc.

There is also considerable interest in substance P, released from nerve terminals in joints. This is in keeping with observations that emotional stress triggers flare-ups, and that joints paralyzed by strokes are spared the effects of rheumatoid arthritis. Relate all this to the mouse model of scrambled neural circuitry, and the atypical depression of rheumatoid arthritis patients: JAMA 267: 910, 1992.

* Autoantibodies against type II collagen are often reported in rheumatoid arthritis. Whether these are primary, or the result of secondary sensitization to damaged cartilage in an area already overflowing with B-cells, is unclear (Arthr. Rheum. 42: 2569, 1999).

Food hypersensitivity is related anecdotally to some cases of rheumatoid arthritis, and some of the evidence is impressive. Patients may experiment with elimination diets. The value of a vegetarian diet (at least try it for a year) is now widely acclaimed: Br. J. Rheum. 33: 638 & 569, 1994; various modifications for which special success is claims are a vegan diet, a raw diet, a diet without gluten, and a diet full of lactobacilli. Consider the lack of controls when evaluating these studies, but don't dismiss them.

One of the best experimental models involves sensitizing the T-cells of various animals to type II collagen. This only works if they have a particular HLA sequence. Definitely stay tuned.

And it's now established that clones of autoreactive T4-cells, accumulating in the joints, are typical for rheumatoid arthritis (Science 253: 325. July 19, 1991; J. Imm. 164: 5788, 2000).

Despite the fact that the problem seems to begin with T-cells rather than B-cells, two autoantibodies are quite common in the disease.

Rheumatoid factor, present in most RA patients, is polyclonal antibody (mostly IgM, often IgA) against the Fc portion of IgG. When present, the patient is said to be "seropositive"; otherwise, "seronegative." Its presence means the disease is more likely to be familial, there is more likely to be vasculitis, there are more likely to be rheumatoid nodules, and there is more likely to be eye involvement. Contrary to older teaching, higher titers also suggest greater disease severity. See Arth. Rheum. 50: 2113, 2004, lots more.

Anti-CCP (antibodies against anticyclic citrullinated peptide) is the up-and-coming test for rheumatoid arthritis, with claims of 80% sensitivity and 99% specificity. It evidently turns positive a few years before disease onset, as do rheumatoid factors (Arth. Rheum. 48: 2741, 2003).

Small joints are most often affected, especially the proximal interphalangeal joints (swan-neck deformity, boutonniere deformity, sometimes ankylosis, more often subluxation), metacarpophalangeal joints (ulnar deviation), wrists, knees, ankles. Tendons may rupture, especially those that extend the last two fingers.

Whatever the cause, central to today's thinking about rheumatoid arthritis is the understanding that the irreversible destruction of the joints begins with the first symptoms, and is cumulative and progressive. Hence the emphasis on disease-modifying medications (methotrexate, many others from various classes) early-on, rather than just anti-inflammatories. See below.

{24635} rheumatoid arthritis, damaged joint
{24633} rheumatoid arthritis, mutilated joints
{46392} rheumatoid arthritis, x-ray showing erosions
{24634} destruction of finger joints in rheumatoid arthritis

Rheumatoid arthritis
WebPath Case of the Week

There's still debate as to whether rheumatoid joints really are stiffer in wet weather (Scand. J. Rheum. 15: 27, 1986 vs Proc. Nat. Acad. Sci. 93: 2895, 1996; J. Rheum 29: 335, 2002).

Rheumatoid subluxation of the cervical spine is a surgical emergency when the spinal cord is compressed.

"Geodes" are subchondral pseudocysts, in which the bone degenerates and fills with debris, as in one of the familiar hollow rocks with crystals inside. Usually in rheumatoid arthritis; you can see them in osteoarthritis, aseptic necrosis, gout or pseudogout too.

{30286} rheumatoid disease of axis
{30288} rheumatoid disease of axis

The rheumatoid arthritis patient has a systemic disease and many other problems:

Patients may develop splenomegaly (when this causes neutropenia / pancytopenia, this is the ominous Felty's syndrome), anemia of chronic disease, generalized lymphadenopathy (J. Clin. Path. 43: 106, 1990), and/or myopathy. Mild fever and severe malaise are common. Amyloidosis occurs in around 15%, especially the more severe cases (Br. J. Rheum. 35: 44, 1996). Most of these bad effects are probably due to interleukin 1 (IL-1) production.

Rheumatoid lung -- fibrosis of the alveolar septa, which make them impermeable to oxygen and decreases lung compliance -- occurs in around a quarter of these patients. RA patients must stop smoking. Fibrous tissue may also selectively obliterate the bronchioles and small vessels. Update, emphasizing speculative mechanisms: Am. J. Med. Sci. 321: 83, 2001.

Rheumatoid nodules occur in maybe 20% of patients with rheumatoid arthritis (and many patients with rheumatic fever, or with neither).

These consist of an acellular center of eosinophilic material ("fibrinoid", as before a mix of plasma proteins) surrounded by palisaded histiocytes and other cells, maybe with a rim of granulation tissue.

They may occur nearly anywhere; most often about extensor surfaces, sometimes the pericardium, aortic valve (thankfully rare), lung parenchyma (coal miners -- that's Caplan's syndrome, part of the "black lung" mess.)

{12473} rheumatoid nodule, patient
{09000} rheumatoid nodule, histology
{08999} rheumatoid nodule, histology

Osteoporosis of disuse develops around affected joints. Actually, it's not just disuse -- the process seems to melt bone.

Rheumatoid vasculitis (type III immune injury, no surprise in a disease in which antibodies can be directed against themselves) can and do cause MI, stroke, gangrene, finger and leg ulcers, Raynaud's, etc. Check these patients for cryoglobulins.

Sjogren's syndrome can develop (* 15%).

Pleurisy (painful inflammation of the pleural surfaces) can develop and produce effusions that compress the lungs. Pericarditis is less common.

The older "treatment pyramid" had as its base aspirin or non-steroidal anti-inflammatory drugs, muscle-strengthening, and rest.

The next line of attack was gold.

Immunosuppression used to be reserved for resistant cases, but there was never any shortage of such patients. Today, disease-modifying treatments are typically started much earlier. Methods include glucocorticoids, antimetabolites such as azathioprine, methotrexate cyclophosphamide, cyclosporine, others. Also tried are total lymphoid radiation, gamma interferon, anti-CD4 monoclonal antibody and more. Strong medicine -- but certainly worth trying before your RA patient commits suicide. The most bizarre new therapy is oral administration of altered type II collagen to "tolerize" the T-cells (however that works, and it seems to, at least for a minority of patients: Science 261: 1727, 1993; Arth. Rheum. 39: 41, 1996; some small studies with variable results since. Watch the simple carbohydrate amiprilose (J. Rheum. 25: 30, 1998).

Omega-3's (fish oil) probably help in controlling symptoms of rheumatoid arthritis (Arthr. Rheum. 37: 824, 1994) by blocking production of leukotriene B4 and interleukin 1.

The BIG news in rheumatoid arthritis is the spectacular success of the new biotech antibodies against TNF, or bits of receptor to soak the stuff up. Etanercept is a fusion product of Fc and TNF receptor, binds both α-TNF and β-TNF, and results are extremely impressive: NEJM 342: 763, 2000; infliximab is another that binds only beta TNF. Beware of opportunistic infections of course.

Rituximab (B-cell depleter): NEJM 350: 2546 & 2572, 2004. Anakinra, the interleukin-1 receptor antagonist: Rheum. Dis. Clin. N.A. 30: 365, 2004.

The rate of malignant lymphomas is somewhat increased (maybe doubled) in rheumatoid arthritis patients; contrary to older concerns, this does not seem to be due to therapy, but to some intrinsic property of the disease (i.e., all the divisions of those lymphocytes).

There is an increased tendency to B-cell lymphoma; Arth. Rheum. 50: 1740, 2004.

Manipulation failed in one study when applied for rheumatoid arthritis: J. Musculoskel. Med., June 1990. In evaluating any therapeutic claim you may hear for rheumatoid arthritis, remember that it is a disease of exacerbations and remissions, many cases just go away, and only a minority lead to profound deformity and disability ("arthritis mutilans"). Flagrant arthritis quackery is a * $3 billion-a-year business in the U.S. alone (see also Med. J. Aust. 143: 516, 1985.) Folk cures are less disturbing (Arthr. Rheum. 32: 1604, 1989).

JUVENILE RHEUMATOID ARTHRITIS ("Still's disease")

Apparent rheumatoid arthritis in one or more joints beginning under age 16 (peak incidence 1-3 years). Probably this is several different diseases.

A febrile prodrome for weeks or months, big lymph nodes and liver, pleuritis, pericarditis, iridocyclitis, and/or skin rash may appear.

Rheumatoid factor is usually absent, while ANA is often positive. Don't worry about the subtypes now. Many cases remit.

The immunopathology remains poorly understood. The most robust finding is probably the elevated levels of alpha-TNF (Curr. Op. Rheum. 11: 377, 1999).

Despite the obvious differences between Still's disease and classical rheumatoid arthritis, the joint changes appear to be the same.

There is often talk of an infectious agent as the cause of JRA, but despite various reports, there's still nothing solid.

* Autologous stemcell transplantation for cure of refractory JRA: Lancet 353: 550, 1999.

Remember parvo 19 as a cause of sudden horrendous multi-joint disease in anybody. It may hang on for a long, long time.

Of course, Lyme disease is in the "differential" of any kid with "JRA".

"THE REACTIVE ENTHESOPATHIES" (seronegative spondyloarthropathies, HLA-B27 family; these are not "variants of rheumatoid arthritis")

This is a curious family of common, overlapping illnesses that include ankylosing spondylitis (Marie-Strumpell disease, "bamboo spine", "poker-back"), Reiter's syndrome, enteropathic arthropathy (shigella, salmonella, campylobacter, yersinia; the tendency is to lump these with Reiter's as "reactive arthritis": see Clin. Exp. Rheum. 11S8: S29, 1993), ulcerative colitis / Crohn's, and the joint disease of psoriasis (big review Postgrad. Med. 97(4): 97, April 1995). All are more common and more severe in men.

{46390} ankylosing spondylitis
{49505} ankylosing spondylitis
{49506} ankylosing spondylitis

An "enthesis" is the point at which a ligament attaches to bone. The axial entheses are involved. Joints do not erode, but ankylose (fuse solid), with bone actually connecting to bone (even marrow to marrow) around joints and disks.

Remember they are all much more common in people with HLA-B27; the link is strongest in white people. Rheumatoid factor is not present and synovial membranes are usually not inflamed.

It's now generally agreed that these are the result of T-cell sensitization to some component of the enthesis. Right now, the principal suspect is aggrecan (Rheumatology 42: 846, 2003, Ann. Rheum. Dis. 62: 561, 2003, others).

The pathology mostly involves ligamentous attachments, with a mix of acute and chronic inflammation and scarring. Concurrent inflammation of the urethra, conjunctiva, iris, and aortic valve ring are common. As you would expect, exercise usually helps the symptoms.

* Infliximab and etanercept have been used off-label for ankylosing spondylitis and obviously work; the FDA has now approved this use. Stay tuned.

Reiter's syndrome is arthritis, eye problems, and a horny rash on the glans, trunk, and especially palms and soles, all following an episode of urethritis or infectious gastroenteritis (* "Can't see, can't pee, can't go out with me!"). Most patients are men; most are HLA-B27 positive. Chlamydial antigens may abound in the pannus: Arthr. Rheum. 31: 937, 1988. The symptoms come and go, and generally vanish for good after a few months. This disease is not rare.

{12289} Reiter's, scaly rash
{12290} Reiter's, scaly rash

Spondylitis patients tend to get better by themselves, especially after the spine is no longer mobile. * Holist Norman Cousins got relief from his ankylosing spondylitis by watching Marx Brothers' and Three Stooges movies. (Is this possible?? Reasonable people will differ.... Of course, ankylosing spondylitis stops hurting when the spine is fully ankylosed, and there are no photos of Mr. Cousins with his spine mobility restored.)

LOW BACK PAIN (remember there's also "neck pain"). Review Br. Med. J. 310: 929, 1995.

This ubiquitous clinical problem has baffled the scientific medical profession until recently:

(1) Imaginary etiologies (notably "muscle spasm") are routinely invoked to explain it, resulting in a whole class of drugs ("muscle relaxants") that are used very questionably. (I hope you enjoy reading "The Myth of Skeletal Muscle Spasm", Am. J. Phys. Med. Rehab. 68: 1, 1989, as much as I did.)

(2) Bulges and protrusions (but not extrusions) seen on MRI scans were considered etiologic, until it turned out that folks without back pain have indistinguishable "pathology" (NEJM 331: 69, 1994).

(3) Anecdotal evidence of better results from treatment through "systems of alternative medicine" (osteopathy, chiropractic), which treat back pain using empirical techniques. See West. J. Med. 150: 351, 1989. This has found recent support in a few pretty good controlled studies: Br. Med. J. 300: 1431, 1990; Lancet, July 28, 1990, p. 220, others.

(4) Recent discovery by the medical profession of such common-sense processes as facet syndrome (Hosp. Pract. 23: 41, Oct. 30, 1988), which is probably the most common cause of back pain without sciatica; and little tears in the annulus fibrosus (which is innervated and doesn't heal well; Br. Med. J. 312: 169, 1996)

Risk factors for low back pain are tall stature, overweight, large breast size, slouching, lack of physical conditioning, cigaret smoking (Lancet 1: 1305, 1989), and drunkenness. Truck drivers and nurses have more than their share of back troubles.

* Mutations of collagen IX and disk disease: JAMA 285: 1843, 2001.

Mechanical problems that give rise to low back pain are only now being elucidated.

It has been known for centuries that the nucleus pulposus has dried up and the annulus has cracked in most discs by age 60. These cause a variety of problems (Hosp. Pract. 24: 135, Sept. 1989).

When a nucleus pulposus herniates through the annulus and impinges on a nerve root, the pain can be severe. (You'll learn about the "straight leg raising test" and other techniques in clinic).

In "facet syndrome", we think that the posterior inter-laminar facet joints sublux as a result of disc space narrowing. Patients typically report sudden onset on bending or twisting, have negative straight leg raising tests, and have relief when a local anesthetic is injected into the joint.

Another plausible-sounding theory of the origin of this kind of pain is herniation of a bit of synovium into the space around the nerve -- it's easy to see how manipulation could relieve this problem immediately. Stay tuned.

* Yet another idea -- nerves growing deeper than their usual stopping-point in the outer third of the annulus fibrosus. Lancet 350: 178, 1997.

Magnetic resonance imaging is elucidating the more subtle mechanical problems that have previously eluded radiologists: South. Med. J. 81: 1487, 1988.

Please remember that there are many non-mechanical causes of low back pain. These patient may have rupturing aortic aneurysms, metastatic cancer, epidural abscesses, Pott's disease (i.e. TB of the spine), etc., etc.

* No surprise: Magnetotherapy flops for low back pain JAMA 283: 1322, 2000, also JAMA 284: 564, 2000.

{11449} Pott's disease

Joint TB Pittsburgh Pathology Cases

Richard Hallgren PhD Guide to Osteopathic Manipulation

"Science is self-correcting". Just as mechanical explanations are finally being figured out, mechanical therapies are finally being appreciated by scientific physicians.

Flaws in previous studies, pro and con: Br. Med. J. 303: 1298, 1991. However, no less a figure that the chief of Harvard's pain clinic teaches physicians (M.D.'s, that is) to perform manipulations Hosp. Pract. 24: 89, March 1989.

Manipulation for neck pain: Br. Med. J. 313: 1291, 1996. Manual therapy ("as performed by osteopaths", though not HVLA manipulation) seems to be better than regular physical therapy for neck pain: Br. Med. J. 326: 911, 2003, By now there are dozens of studies of manipulation for low back pain, and most are coming up with "worth considering". I predict that a subgroup will be found (those with facet syndrome?) for which manipulation will be the treatment of choice. Stay tuned.

* We learn with hope of the formation of the National Association for Chiropractic Medicine (P.O. Box 794, Middleton WI 53562; phone 608-233-8991, http://www.chiromed.org/), dedicated to upgrading the profession's scientific and ethical standards.

This is welcome news, but these reformers continue to meet much resistance from ideologues and antiscientific practitioners. You'll have a chance to find out about this yourselves.

Terms: "radiculopathy", "lumbago" and "sciatica" indicate nerve root involvement, typically with radiating pain. The most common cause, of course, is a bad disc. "Cauda equina syndrome", from compression of the cauda equina by a midline herniated nucleus pulposus, tumor or abscess is a surgical emergency.

Practical management of low back pain for generalists: Prim. Care 15: 827, 1988. Remember there's still malingerers out there.

SUPPURATIVE ARTHRITIS ("septic arthritis", i.e., bacterial infection in a joint)

The most common agents are gonococcus, gram positive cocci (Staph, Strep), and gram negative rods (E. coli, H. 'flu, Pseudomonas; Salmonella in sickle cell disease).

These organisms arrive by hematogenous spread.

Suppurative arthritis is uncommon in children (think of H. 'flu or spread from contiguous osteomyelitis).

Bacterial arthritis is usually monarticular and involves large joints. (Gonococcal arthritis often involves a series of joints.)

The cartilage is quickly ruined by hydrolytic enzymes from polys. In bad cases, the joint may be ankylosed.

Gonococcal arthritis WebPath Tutorial

Septic arthritis EMBBS

Septic arthritis Closer view EMBBS

Tuberculous arthritis follows primary pulmonary infection. It is likely to be bad and chronic, with pannus and ankylosis.

SYNOVIAL BIOPSY

Especially if there is a single diseased joint, you may consider synovial biopsy. Nowadays it is easy and safe. You may detect:
• mycobacteria and caseating granulomas (tuberculosis)


• cancer cells (metastatic cancer


• iron pigment and hyperplastic synoviocytes (pigmented villonodular synovitis)


• nothing but mature fat (arborescent lipoma)


• lots of neutrophils (bacterial infection, Behcet's, familial mediterranen fever


• Whipple cells (Whipple's)


• noncaseating granulomas (probably sarcoidosis)


• copper overload (Wilson's)


• amyloid (amyloidosis)


• iron overload (hemochromatosis)


• uric acid crystals (gout)


• germinal centers and lots of synovial cells (probably rheumatoid arthritis)


* For the truly hard-core: Pathology of the synovium Am. J. Clin. Path. 114: 773, 2000.

RELAPSING POLYCHONDRITIS (Ann. Int. Med. 129: 114, 1998)

A serious, hard-to-spot (especially if you don't think of it) disease of all forms of cartilages.

This is now known to be an autoimmune disease mediated by T-cell sensitization to the collagens in cartilage.

There is a superb mouse model (J. Clin. Invest. 112: 1843, 2003), produced when mice with HLA-DQ8 (the human HLA association) are injected with chicken type II collagen. The mice mount a T-cell reaction against their own collagen II and IX.

In both animals and humans, there are usually antibodies against type II collagen; whether they are pathogenic or secondary to cartilage damage is unknown. As with most autoimmune diseases in humans, it often runs with other autoimmune diseases and responds to immunosuppression. Oral tolerization by feeding type II collagen: Am. J. Med. Sci. 324: 101, 2002.

The onset is sudden and spectacular, but it is a disease of exacerbations and remissions, and it often takes a long time for physicians to consider it.

Symptoms and signs are caused by inflammation of the perichondrium of the ears (very typical), nose (can produce saddle nose) large airways (can be lethal) and joints (painful).

You would rather not biopsy the disease, since cartilage does not heal, If you find the characteristic lesion (degenerating cartilage cells under very inflamed perichondrium), you've exacerbated the damage. If not, you'll find only granulation tissue. Make the call on the physical exam.

CALCIUM CRYSTAL DEPOSITION DISEASE:

"Pseudogout" ("chondrocalcinosis") involves deposition of calcium phosphates, usually in the knees. The process is poorly understood, but is very common, especially in older folks.

There is a hereditary form (Gene Arth. Rheum. 48: 2627, 2003). If you have hypercalcemia, hypophosphatemia, or hypomagnesemia, you're at extra risk. By age 80, a majority of people will have some calcium pyrophosphate in the knees. This is especially true if the joints have already been damaged by diabetes, iron overload, or something else.

{14258} pseudogout (or so they tell me...)
{14261} pseudogout (ditto)

"Osteoarthritic" lipping
WebPath Tutorial

SYNOVIAL SARCOMA

Biphasic (usually, spindle cell and epithelial-like "synovioblast") sarcoma that usually arises in or about Hunter's canal in young adults. (These tumors usually does not arise in synovium.)

It metastasizes either by blood or lymphatics. (The latter fact is unusual for sarcomas.)

Prognosis is fair, with 50% ten-year survival.

Pigmented villonodular synovitis is a localized, destructive lesion within a single joint (usually the knee), with proliferation of synovium, hemosiderin pigmentation, and destruction of the joint. Whether it is a true clonal tumor is unknown. Excision is usually curative though it may recur.

{09655} pigmented villonodular synovitis, gross

FIBROUS HISTIOCYTOMAS

The cell of origin for all of these curious tumors is the "macrophage acting as a fibroblast". Don't worry about such arcane stuff; leave that to pathologists. We can talk about these here, because several of them affect joints or tendons.

Dermatofibroma ("sclerosing hemangioma"): skin and elsewhere

This is a solitary, hard nodule. The phagocytes contain lipid, making them yellow on cross-section. They also contain hemosiderin, imparting a brown color, and this also causes melanocytic pigmentation of the overlying skin, particularly around the edges, so these appear as brown bumps.

{25592} dermatofibroma, gross
{12203} dermatofibroma, darkly pigmented
{12774} dermatofibroma, gross
{12775} dermatofibroma, gross; this one was quite vascular
{12777} dermatofibroma, gross
{39954} dermatofibroma, section
{24260} dermatofibroma, histology (good spindle-cell histiocytes)

Giant cell tumor of tendon sheath ("fingeroma", "xanthofibroma"): quasi-neoplastic benign yellow mass

Malignant fibrous histiocytoma: the commonest sarcoma, develops deep in limbs or in retroperitoneum.

{21145} malignant fibrous histiocytoma, buttock; you need only recognize this is a deep soft-tissue cancer (i.e., probably a sarcoma)

{09019} malignant fibrous histiocytoma, histology; you need only recognize this is a spindle-cell malignancy

{09021} malignant fibrous histiocytoma; you need only recognize this is a malignancy; the cells do remind me of those in a granuloma

TENDONS AND BURSAE

Tenosynovitis and bursitis result from injury (usually mild and repeated). Syndromes includes housemaid's knee (* an occupational hazard of certain monastics as well) and tennis elbow.

{12025} bursitis

Osgood-Schlatter's disease is a banal but uncomfortable, very common local necrosis-and-healing lesion involving the anterior tibial tuberosity of athletically-active, rapidly-growing teens. The cause is probably repeated, tiny avulsions of the periosteum from the pull of the quadriceps tendon. See Am. Fam. Phys. 41: 173, 1990.

Carpal tunnel syndrome: annular fibrosis of the flexor retinaculum, impinging on the median nerve. Very common. Most cases are idiopathic, but remember amyloidosis.

Ganglion cyst: a blob on wrist or fingers, formed by myxoid degeneration of connective tissue. It is neither a "ganglion" nor a "cyst", and it does not communicate with the joint. The home remedy -- smash it with a holy book -- is about as successful as surgery.

Ganglion cyst, wrist
Prize photograph
Institute of Medical Illustrators


Dupuytren's contracture: fibrosis of the palmar aponeurosis. The relationships to alcoholism and diabetes are probably overstated. A similar lesion can involve the plantar aponeurosis. * Ronald Reagan had a "Dupuytren's" removed while president. "Peter Pan" originator James Barrie had right hand disabled by "tendonitis", maybe Dupuytren's; this became the inspiration for his self-parody as "Captain Hook". (The clock-ticking crocodile who pursues Captain Hook is also allegorical -- the symbol of his own approaching death.)

{49523} Dupuytren's contracture

Famous arthritics (Clin. Rheum. 8: 442, 1989): John Madison (rheumatoid arthritis); Renoir (rheumatoid arthritis); Rubens (rheumatoid arthritis); Columbus (Reiter's; also Arch. Int. Med. 152: 274, 1992).

Bunion Hallux valgus WebPath Tutorial

Gout WebPath Tutorial

Gout X-ray WebPath Tutorial

Gout Tophus WebPath Tutorial

Gout Uric acid crystals WebPath Tutorial

Gout Photomicrograph of tophus KU Collection

Dislocated knee Tom Demark's Site Dislocated knee Ischemic complications Tom Demark's Site

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Teaching Pathology

PathMax -- Shawn E. Cowper MD's pathology education links
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Notes for Good Lecturers
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Classroom Control
"I Hate Histology!"
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Rudolf Virchow on Pathology Education -- humor
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The Pathology Blues
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Pathological Chess

Taser Video 83.4 MB 7:26 min