Rheumatology

Question 1

Describe the symptoms and signs, synovial fluid analysis, and x-ray features of osteoarthritis

Answer 1

tbd

Question 2

Discuss the risk factors for getting OA

Answer 2

tbd

Question 3

Explain the various theories on the pathogenesis of OA

Answer 3

tbd

Question 4

Discuss the treatment of OA as it relates to the pathophysiology

Answer 4

tbd

Question 5

Describe the general clinical features of rheumatoid arthritis (RA), including joint distribution, and extra-articular manifestations

Answer 5

Joint Distribution: peripheral symmetric synovial joints, small joints of hands and feet (DIP spared), and some medium/large joints; cervical spine (C1-2); cricoarytenoid, ossicles of inner ear, TMJ Symptoms: morning stiffness, soft tissue swelling and warmth, pain/tenderness to palpation, deformities and loss ROM/fxn Extra-articular Manifestations: Fatigue, malaise, anorexia, weight loss, low-grade fever, rheumatoid nodules over extensor surfaces and tendon sheaths and in the lungs, scleritis, neuropathy

Question 6

Describe the general laboratory features of rheumatoid arthritis (RA), including synovial fluid analysis and serologies

Answer 6

Serology: Rheumatoid Factor present in 85%, elevated ESR and CRP, anemia, hypergammaglobulinemia, Anti-cyclic citrullinated peptide (CCP) antibodies present in 70% Synovial Fluid: Inflammatory (WBC >2,000; primarily neutrophils), complement and glucose levels are low

Question 7

Describe the x-ray features of rheumatoid arthritis (RA)

Answer 7

Soft tissue swelling Juxta-articular osteopenia Symmetric loss of joint space Erosions in marginal distribution

Question 8

Discuss the genetic factors that may determine the severity of RA

Answer 8

Polygenic w/ different implicating genes in different populations 1. Concordance rate ~30% in monozygotic twins and 3% in dizygotic. 2. HLA-DR4 present in 50% or more (Class II MHC) A short sequence within the third hypervariable portion of the DRB1 gene determines susceptibility and severity (QKRAA, termed the shared epitope) - results in anti-CCP antibody. Disease-associated alleles include: Caucasians HLA-DRB1*0401, *0404, and *0101, HLA-DRB1*0405 in Asians and *1402 in Indians

Question 9

Explain the pathogenesis of RA in the synovial fluid, including cell types, cytokines, and proteolytic enzymes

Answer 9

Neutrophils comprise the major cellular component of the synovial fluid. They are chemotactically attracted via cytokines, IL-8 and TGF-beta, and adhesion molecules expressed on endothelial cells. Neutrophils may contribute to tissue damage by release of prostoglandins, leukotrienes, cytokines, oxygen radicals, and enzymes.

Question 10

Explain the pathogenesis of RA in the synovial tissue, including cell types,and proteolytic enzymes

Answer 10

Pannus tissue (abnormal fibrovascular tissue) is responsible for most of the joint damage. Infiltrating cells are mononuclear (lymphocytes and macrophages), with intense proliferation of local fibroblasts. Neutrophils are rare in the tissue. Lymphocytes: CD4+ T cells, B cells and plasma cells present, though not activated. Th 17 cells secrete IL-17 Macrophages: release pro-inflammatory cytokines (IL-1, TNF-alpha, and IL-6) and proteolytic enzymes.

Question 11

Explain the pathogenesis of RA in the synovial tissue, in regards to cytokines

Answer 11

Cytokines: IL-1, TNFα, IL-6, and IL-17 systemic effects (IL-6) - anorexia, fever, and stimulation of acute phase proteins (ie CRP); local effects (IL-1 and TNF) - chemotaxis of inflammatory cells, release of prostoglandins, AND induction of collagenase and neutral proteinase production (CARTILAGE AND BONE DESTRUCTION); TNF-alpha, IL-1, and IL-17 induce osteocyte lineage cells to express Receptor Activator of Nuclear Factor kB Ligand (RANKL) that osteoclast resorption of bone. Rheumatoid Factor: IgM antibody that recognize Fc portion of IgG. Form immune complexes that lead to compliment activation via classical pathway

Question 12

Treatment options for Rheumatoid Arthritis

Answer 12

Anti-inflammatory/analgesic drugs Disease-modifying anti-rheumatic drugs (DMARDs) Physical Therapy Surgery - total joint replacements

Question 13

Discuss the treatment of RA as it relates to pathophysiology: Anti-inflammatory/analgesic drugs

Answer 13

Anti-inflammatory/analgesic drugs are used to relieve patient symptoms, but these do not prevent tissue destruction. These medications include aspirin, other NSAIDs, acetaminophen, and prednisone (oral or by intraarticular injection). The mechanisms of action include inhibition of production of inflammatory mediators.

Question 14

Discuss the treatment of RA as it relates to pathophysiology: Disease-modifying anti-rheumatic drugs (DMARDs)

Answer 14

medications include hydroxychloroquine, sulfasalazine, leflunomide, or methotrexate inhibit various macrophage and lymphocyte functions and actions of cytokines

Question 15

Contrast OA and RA on a clinical basis and discuss their differences in pathophysiology

Answer 15

Osteoarthritis does not have systemic involvement, whereas rheumatoid arthritis does. Osteoarthritis (OA) is a characterized by the destruction (degeneration) of articular cartilage and proliferation (hypertrophy) of the contiguous bone. Normally cartilage goes through a balanced remodeling process, in OA this balance is more destructive than constructive. Rheumatoid arthritis (RA) is a systemic, inflammatory, autoimmune disorder of unknown etiology that results predominantly in a peripheral, symmetric, inflammatory synovitis often leading to cartilage and bone destruction and joint deformities. Extra-articular manifestations also occur but are usually less extensive and severe than in the other “diffuse connective tissue diseases”.

Question 16

Review normal uric acid metabolism and identify secondary causes of hyperuricemia

Answer 16

Uric acid is a product of purine metabolism. Urinary uric acid excretion occurs through a four compartment model: 1) glomerular filtration (almost 100% of the filtered uric acid load) followed in the proximal tubule by 2) pre-secretory reabsorption, 3) secretion back into the tubule, and 4) post-secretory reabsorption. Net tubular reabsorption is about 90% of the filtered uric acid; thus only 10% of the filtered uric acid is excreted in the urine Hyperuricemia can result from increased production or decreased renal excretion of urate. A 24h urinary excretion of uric acid >750 mg on a regular diet suggests an overproduction of uric acid where a value <750 mg/24h would imply underexcretion of uric acid. The majority of patients (90%) with primary gout are underexcretors of uric acid.

Question 17

Describe the general clinical and synovial fluid analysis features of gout and calcium pyrophosphate dihyrate deposition disease (CPDD), including crystal morphology and birefringence

Answer 17

Gout: Fresh synovial fluid must be examined for the presence of monosodium urate (MSU) crystals. The intracellular crystals in PMNs are needle-shaped and negatively birefringent (yellow when parallel to the axis of the red compensator) on polarizing microscopy. The synovial fluid is inflammatory (typically 20,000-100,000 leukocytes/mm3 ) with a predominance of neutrophils. Hematological evaluation may show an elevated ESR, mild neutrophil leukocytosis, and possibly reactive thrombocytosis. CPDD: Fresh synovial fluid must be examined for the presence of CPPD crystals. CPPD crystals are rhomboid-shaped and positively birefringent (blue when parallel to the axis of the red compensator) on polarizing microscopy. The synovial fluid is inflammatory (typically 2,000-80,000 leukocytes/mm3) with a predominance of neutrophils. Peripheral blood WBC and ESR may be increased during acute attacks. Serum calcium, phosphorus, and iron studies are helpful in searching for associated metabolic causes of CPDD.

Question 18

Contrast the differences in the pathophysiology of gout and pseudogout (CPDD)

Answer 18

Their inflammatory responses are similar. Gout is due to increased uric acid which results in crystals. This occurs b/c of increased uric acid production or lack of elimination. Crystals form due to decreased temp, dehydration, trauma, low pH (less soluble), and/or proteoglycans that solubilize MSU leading to precipitated gout attack CPDD is due to abnormal pyrophosphate metabolism and increased extracellular pyrophosphate that crystallizes in the presence of calcium, which are released into synovial fluid via “shedding”

Question 19

Discuss the treatments for acute crystal-related arthritis and chronic symptomatic hyperuricemia

Answer 19

Gout: Diet decreased in purines can help but is not the best tx modality. Acute gouty attack can be treated with NSAIDS (anti-inflammatory), colchicine (decreases inflammatory PMNs), or corticosteroids. Chronic treatment includes involve decreasing serum uric acid levels with medication. A uricoseric (Probenecid) increases renal excretion. A xanthine oxidase inhibitor (Allopurinol) decreases uric acid synthesis. CPDD: Anti-inflammatory drugs are used to treat acute pseudogout (see Gout, Treatment). Unlike gout, there is no way to remove CPPD crystals from the joints or to retard further progression of the disease.

Question 20

Describe the clinical, laboratory, and x-ray features of Ankylosing Spondylitis, including any extra-articular manifestations

Answer 20

• *Clinical history and physical examination**
  a. All patients have inflammatory back pain characterized by:
  1) Insidious onset of pain lasting > 3 months
  2) Prolonged morning stiffness (> 30-60 minutes)
  3) Improvement of pain with exercise
  4) No neurologic sequelae
  b. Physical examination of back shows:
  1) SI joint tenderness
  2) Global loss of spine range of motion
  3) Late in disease course may find back deformities and reduced chest expansion.
  c. Approximately 25% of AS patients have peripheral arthritis usually of hips and shoulders (i.e. joints close to spine).
  d. Unlike rheumatoid arthritis, ankylosing spondylitis frequently affects synchondroses which are areas of cartilaginous union with bone. This includes manubriosternal joint, costovertebral joints, and pubic ramis.
• *Extraarticular manifestations**
  1) Acute anterior uveitis - 25% (eye) irritation
  2) Osteoporosis-19-62%
  3) Microscopic colitis- 22-69%, Crohn’s-like lesions 7%
  4) Pulmonary apical fibrosis - 2%
  5) Cardiovascular disease with aortitis, aortic insufficiency, and varying degrees of heart block - up to 10% of patients with long-standing disease.
  6) Cauda equina syndrome - rare.
  7) Amyloidosis-rare
• *_ Laboratories and radiographs_**
  a. Elevated sedimentation rate (ESR); negative rheumatoid factor (RF), negative ANA (serologically negative)
  b. Radiographs show sacroiliitis characterized by bone erosion and sclerosis (+/- bony fusion) in 100% of patients with AS by age 45.
  c. Over 66% of AS patients develop radiographic spondylitis with thin, marginal syndesmophytes. Only 10% develop complete spinal fu-sion (bamboo spine).
  d. Peripheral joint radiographs can show inflammatory hip disease which can lead to bony fusion (20-25%).

Question 21

Discuss the epidemiology and genetics of the seronegative spondyloarthropathies.

Answer 21

Estimated incidence of ankylosing spondylitis in the general population is 0.1% to 0.2%.

The chance of developing AS is about 1-2% if you are HLA-B27 postive and incresases to 10-20% if a first-degree relative has ankylosing spondylitis. Identical twins have a concordance rate of up to 60%. Hence, these diseases tend to run in families. ERAP1 is another gene implicated in AS.

Strong relationship between the MHC class I antigen HLA - B27 and ankylosing spondylitis; 90% of the Caucasian ankylosing spondylitis population is HLA-B27 positive.

Since not all persons who possess HLA-B27 develop a spondyloarthropathy, it is proposed that a genetically susceptible individual develops the disease when exposed to an environmental trigger. Bacteria such as salmonella, shigella, yersinia, campylobacter, and chlamydia induce reactive arthritis in 20% of B27 positive individuals. The trigger for ankylosing spondylitis is unknown although normal bowel bacteria has been proposed.

Question 22

Explain the theories of the pathogenesis of the seronegative spondyloarthropathies.

Answer 22

Possible theories of how HLA-B27 can predispose a person to de-velop AS include:

1) Arthritogenic peptide hypothesis: The arthritogenic re-sponse might involve specific microbial peptides that bind to HLA-B27 and then are presented in a unique manner to CD8+ (cytotoxic) T cells resulting in disease.

2) Molecular mimicry: The induction of autoreactivity to self-antigens might develop as a result of “molecular mimicry” between sequences or epitopes on the infecting organism or antigen and a portion of the HLA-B27 molecule or other self-peptides.

3) Free heavy chain hypothesis: HLA-B27 heavy chains can form stable homodimers with no associated β-2 microglobu-lin on the cell surface. These homodimers can trigger direct activation of natural killer (NK) cells though recognition via killer cell immunoglobulin-like receptors (KIR).

*4) Unfolded protein hypothesis: HLA-B27 has a propensity to misfold in the endoplasmic reticulum causing an unfolded protein stress response. This results in the release of inflammatory cytokines such as IL-23 which can activate proin-flammatory Th 17 cells. Notably, endoplasmic reticulum aminopeptidase 1 (ERAP-1) is involved in the trimming of peptides for loading MHC molecules (ie HLA-B27) into the endoplasmic reticulum. Abnormal loading may contribute to misfolding of HLA-B27 resulting in an unfolded protein stress response and IL-23 production. ERAP-1 and IL-23 polymorphisms both contribute to the genetic risk of devel-oping AS.

Question 23

Discuss the treatment of the seronegative spondyloarthropathies as it relates to the pathogenesis

Answer 23

Treatment

A. In AS, specific back exercises and good posture should be emphasized; sleep with either no pillow or a small pillow.

B. Smoking should be avoided in AS patients as they can lose chest wall function secondary to the disease process.

C. Nonsteroidal anti-inflammatory (NSAIDS) agents are usually the first drugs used for spondyloarthropathies. The indole derivatives such as indomethacin or tolmetin are usually used first.

D. Steroid injections into the peripheral joints may be of benefit.

E. Sulfasalazine** has been useful in some cases of peripheral arthritis. Spondyloarthropathy patients (AS, reactive arthritis, psoriatic) who have refractory peripheral arthritis may benefit from **methotrexate.

F. Tetracycline early in the course of chlamydial-induced reactive arthritis may ameliorate the course of the arthritis. In cases of established arthritis, a three-month course of tetracycline or erythromycin may be beneficial, although usually it is not.

G. It is unclear if a three-month course of antibiotics (quinolone) in reactive arthritis secondary to enteric pathogens (Shigella, Salmonella, etc.) is beneficial, although usually it is not.

H. For patients with sacroiliitis, spondylitis, peripheral arthritis, and/or enthesitis who failed standard therapy, anti-TNF biologic agents (act to reduce inflammation) have been very effective therapies. Unfortunately, these agents do not stop the progression of bony erosions or the formation of syndesmophytes.

Question 24

Describe the clinical, laboratory, and X-ray features of systemic lupus erythematosis (SLE), including the organs involved and serologies

Answer 24

Clinical: 1. Malar rash, 2. Discoid rash, 3. Photosensitivity, 4. Oral ulcers, 5. Arthritis, 6. Serositis, 7. Renal involvement, 8. Central nervous system involvement (seizures or psychosis), 9. Hematologic disorders (hemolytic anemia, leukopenia, lymphopenia, thrombocytopenia), 10. Immunologic disorders (antibodies to native DNA, Smith antigen, anticardiolipin IgG or IgM, lupus anticoagulant, or a false-positive serologic test for syphilis), and 11. Antinuclear antibody (ANA). Positivity for at least 4 of the 11 criteria allows classification of a patient having SLE.

Lab: Indicative of Renal involvment (BUN, creatinine irregularities), anemia, thrombocytopenia, leukopenia, antibodies to dsDNA and phospholipid, ANA tes positive (antinuclear antibodies)

X-ray: Normal

Question 25

Explain the difference between organ specific autoimmunity and systemic autoimmunity.

Answer 25

Organ specific autoimmunity is defined as an immune response directed against a single autoantigen or a restricted group of autoantigens within a given organ. The result is autoimmune destruction of only those organs expressing the relevant autoantigens. Examples of organ-specific autoimmunity include myasthenia gravis (antibodies to acetylcholine receptors), Goodpasture’s syndrome (antibodies to basement membrane type IV collagen of the kidney and lung), autoimmune thyroiditis, and type I diabetes mellitus.

Systemic autoimmunity is defined as an immune response against multiple autoantigens rather than to autoantigens of a given organ. The resulting disease affects multiple organs both on the basis of circulating immune complexes and direct immune attack against organs. The prototype systemic autoimmune disease is systemic lupus erythematosus (SLE). Many of the rheumatic diseases have features of systemic autoimmunity, including Sjögren’s syndrome and mixed connective tissue disease. Other rheumatic diseases are felt to be autoimmune in origin and have features of systemic autoimmune disease although they may focus on specific organs. Examples of this include polymyositis (muscle) and rheumatoid arthritis (synovium of the joints).

Question 26

Discuss the epidemiology and genetics of SLE including the predisposing factors and environmental factors that can modulate disease.

Answer 26

Epidemiology

SLE is a disease primarily of the young women with a female to male ratio of 9:1, with onset after puberty reaching a peak during the childbearing years. The prevalence varies in different populations and varies from 0.5 to 5 per thousand and is more common in certain ethnic groups, particularly African Americans, Asians, and Hispanic Americans.

Predisposing Factors

Genetics: Although the etiology of SLE is unclear, there is overwhelming evidence for a genetic predisposition.

a. Increased incidence of SLE among relatives of patients. (relative risk 2-3).
b. Twin studies showing a concordance rate of about 35% in monozygotic twins compared to ≈ 2% in dizygotic twins.
c. Association of SLE with HLA-DR3; and C4A null alleles (strongest association, complement deficiency).
d. Other genes associated with innate immunity and interferon alpha pathways may predispose to developing SLE. Interferon (IFN)-α and IFN-β upregulate the expression of a variety of genes in lymphocytes. This “IFN signature” of gene expression is more prevalent in patients with active SLE.
e. In the murine models of SLE, multiple gene loci appear to be involved in a complex fashion. In the NZB/NZW mouse model of lupus, one involved locus is linked to the MHC and another to an IFN-inducible gene. Other involved loci are being studied.

Environmental:: The expression of disease manifestations can be greatly affected by environmental factors.

a. Sex hormones. There is a markedly increased incidence of SLE in women of childbearing age. The female to male ratio is approximately 9 to 1. This strongly suggests that sex hormones affect the expression of disease. The disease-accelerating effect of estrogens and the protective effect of androgens have been elegantly demonstrated in the NZB/NZW murine lupus model.
b. Sun exposure. SLE skin disease can be exacerbated by exposure to U.V. light (photosensitivity). Ultraviolet light may stimulate keratinocytes to express more snRNAs on their cell surface and secrete more inflammatory cytokines resulting in B cell activation with antibody production. Patients can sometimes have marked systemic or generalized flares of disease after excessive sun exposure.

Question 27

Explain the pathophysiology of SLE and the various theories used to explain autoimmunity.

Answer 27

Type II manifestations (direct antibodies against self): Hemolytic anemias, anti-phospholipid antibodies, CNS stuff.
Type III manifestations (immune complex damage): Lupus nephritis, antinuclear antibodies.

Theories: Essentially see under “Autoimmunity: Immunopathology Type II.”

• Loss of T cell tolerance (emergence of autoimmune T cells)
• Polyclonal B cell activation (kind of a mitogen B cell effect by certain agents)
• Cross-reaction of antibodies with ‘self’ tissues
• “Illicit help” model (self-antigen coupled to foreign-antigen)
• Sequestered antigen
• Immunodeficiency (complement deficiencies or Fc deficiencies)

Note also a great article in the NEJM this week that Scott Koski mailed out earlier that postulates that some kind of macrophage dysfunction means that apoptotic cells - instead of being properly engulfed before they can spill their contents - spill out some DNA into the extracellular space, thus potentially sensitizing the immune system to dsDNA.

Question 28

Discuss the treatment of SLE as it relates to the pathophysiology.

Answer 28

Decrease exposure to triggers (wear lots of clothing + sunblock)
Decrease inflammatory response (NSAIDs, steroids)
Decrease cell-mediated (T) immune response (anti-malarials, immunosuppressive)
Also now using anti-B cell drugs (rituximab: CD20 antibody)
Administer IVIg (no clear mechanism of action)

Question 29

Systemic Lupus Erythematous

acronym of symtpoms

Answer 29

Acronym: MD SOAPBRAIN

Mallor Rash (spares nasolabial folds, sun sensitive)

Discoid Rash (anular, raised edges, scarring)

Serositis (pericarditis/pleuritis- chest pain, dyspnea)

Oral ulcers

ANA test positive (found 95-98% in SLE patients)

Photosensitivity

Blood (hemolytic anemia, leukopenia, thrombocytopenia)

Renal involvement (immune complex Type III cause kidney disease, lumpy bumpy)

Arthritis (immune complex Type III arthritis)

Immune (anti-dsDNA antibodies, anti-phospholipid antibodies, bind beta-2 glycoprotein 1 (on endothelial cells) stimulating thrombosis causing clot/stroke)

Neuro

Question 30

Name the different types of vasculitis according to the Chapel Hill Consensus Conference classification.

Answer 30

Classified based on the size of the involved vessel and the clinical presentation.

Large-vessel vasculitis:

• Giant-cell arteritis (anything off coronary arteries or carotids outside the brain)
• Takayasu’s arteritis (anything off the aortic arch)

Medium-vessel vasculitis:

• Polyarteritis nodosa
• Kawasaki’s disease

Small-vessel vasculitis:

• Antineutrophil cytoplasmic antibody (ANCA)-positive vasculitides:
  
  • Wegener’s
  • Churg-Strauss
• ANCA-negative:
  
  • Henoch-Schonlein Purpura
  • Essential cryoglobulinemic vasculitis
  • Cutaneous leukocytoclastic angiitis

(Probably don’t need to know all the names but for completeness’ sake:)

Question 31

Describe the clinical features and the laboratory abnormalities suggestive of vasculitis.

Answer 31

In a nutshell: clinically you feel crappy. Fever, pain. Lab values suggest lots of inflammation. That’s about it. Think Type III immunopath with an option on focal ischemia.

Clinical features:

• Skin lesions
• “Constitutional:” Fever, anorexia/weight loss, weakness/fatigue.
• Musculoskeletal: arthralgias (joint pains), arthritis, myalgias, peripheral neuropathy.

Lab features:

• Indicative of systemic inflammation.
• Anemia
• Thrombocytosis
• Low albumin
• Elevated sedimentation rate + C-reactive protein
• Low complement levels
• &c.

Keep an eye out for stuff that’s indicative of Type III immunopathology– cryoglobulins (immune complex precipitate in serum samples stored in the fridge overnight), renal failure, etc.

Question 32

Discuss the different immunopathogenic mechanisms that mediate vasculitis.

Answer 32

(1) Immune complexes:

• Note that the immune complexes do not magically (or stochastically if you prefer) get stuck in random endothelia (recall that they get preferentially stuck in serous filters). It takes some manner of pre-existing inflammation of the endothelium first– this activates Platelet Activating Factor (PAF), resulting in vascular permeability, which is what permits the immune complexes to attach and cause complement.
• Again that immune complexes are not the precipitating event– it’s inflammation activating PAF.

(2) T cell-mediated: I think he’s trying to say you can have antigens in your endothelia that piss off your T cells. Beyond that and some scrambled discussion on giant cell arteritis and association with HLA-DR4, I got nothing.
(3) Antineutrophil cytoplasmic antibodies (ANCAs) (see below)
(4) Anti-endothelial antibodies (type II immunopathology)
(5) Infection of vascular endothelial cells: promote immune complex binding and PMN adhesion (also probably ANCA-related problems), drive inflammatory response.

Note that these seem to break up into two categories:

• Root causes of endothelial inflammation (type II immunopath, infection, T cells)
• Exacerbating factors of endothelial inflammation (ANCAs, immune complexes)

Question 33

Distinguish the different types of ANCAs and discuss their role in the pathogensis of vasculitis.

Answer 33

• This is a little tricky. Just to keep this straight: ANCAs are endogenous antibodies that bind to certain granulatory enzymes that are released to the surface of neutrophils when activated by certain inflammatory cytokines (like those at the site of vascular inflammation). Antibody binding further activates the neutrophil to induce greater inflammation. So if your neutrophils aren’t activated, ANCA isn’t going to do much. Once they’re activated, though, ANCA is going to take the inflammation up a notch.
• Thus: ANCAs do not seem to precipitate inflammation, but they exacerbate the inflammation that is already extant.
• The two types of ANCAs are named for where they stain in the lab; this has nothing to do with their involvement in the inflammatory process.
• Anti-neutrophilic cytoplasmic antibodies (types of ANCAs):
  
  • (1) Cytoplasmic (c-ANCA): entire cytoplasm stains in the lab.
    
    • Antigen = Proteinase-3 (PR3) in primary granules in PMNs.
    • c-ANCA is associated with Wegener’s granulomatosis.
  • (2) Perinuclear (p-ANCA): only stains around the nucleus in the lab.
    
    • Antigen = myeloperoxidase (MPO) in primary granules in PMNs.
    • p-ANCA is associated with microscopic polyangiitis.
  • These amplify the inflammatory response in endothelium– once the granule contents are released onto the endothelial surface, circulating ANCAs can bind to their targets and cause further damage.

Question 34

Discuss the treatment of vasculitis as it relates to the extent of organ involvement.

Answer 34

• Treat the antigen that’s either causing the underlying inflammation or forming the immune complexes: Drugs, bugs, connective tissue disease, malignancies.
• Manage inflammation with steroids.
• Treat rapidly progressing disease with high-dose steroids and chemo drugs. Plasmapheresis can be helpful with immune complexes (partic. vs. hepatitis C) and ANCA problems.

Question 35

Mechanisms of Vasculitis

Answer 35

Mechanisms of vasculitis

Primary causes:

Type II immunopath (B-cell mediated)
T-cell mediated
Infection
Secondary to inflammation
Immune complexes
ANCAs

Question 36

Review the classification scheme for inflammatory myopathies.

Answer 36

Group I: Primary idiopathic polymyositis
Group II: Primary idiopathic dermatomyositis
Group III: PM/DM associated with neoplasia (in DM, incidence 4%-40%)
Group IV: Childhood DM (more rarely PM)
Group V: PM/DM associated with another rheumatic/connective tissue disease

Other: Inclusion body myositis (IBM): Men > women; age > 50 years; insidious onset of muscle weakness predominantly involving finger flexors and thigh muscles; negative autoantibodies; classic histopathologic changes of rimmed vacuoles and inclusion; resistant to treatment with immunosuppressive drugs

Question 37

Describe the clinical and laboratory features of polymyositis and dermatomyositis including EMG and MRI findings.

Question 38

Discuss the clinical and laboratory features of the Anti-synthetase Syndrome including anti-synthetase antibodies.

Question 39

Contrast the cellular differences in the pathology of polymyositis and dermatomyositis.

Question 40

List the evidence suggesting viral infections as a cause or triggering factor in polymyositis or dermatomyositis.

Question 41

Discuss the treatment of inflammatory myopathies as it relates to pathophysiology.