Other Autoimmune Diseases 1

Question 1

Remember Rheumatoid Arthritis? How does this guy work?

Answer 1

Chronic, systemic inflammatory disorder that attacks mainly joints

inflammatory synovitis→ pannus (inflamed granulation tissue) formation: edematous synovium w/ inflammatory cells, granulation tissue and fibroblasts that grows over the articular cartilage→ cartilage erosion and ankylosis (fusion) of joint

Question 2

Discuss the pathology of rheumatoid arthritis, i.e., what is going on with the signals and cells

Answer 2

CD4+ T cells react to self-antigen including those in joints causing cytokine mediated inflammatory response.

INF-g: activates synovial cells and macrophages.

TNF and IL-1: cause synovial cells to secrete anti-cartilage proteases.

Increased RANKL expression (bone resorption)

Synovium contains germinal centers and 2’ follicles w/ plasma cells making antibodies against self-antigens. Effects synovium→ articular cartilage

Question 3

What histo/lab findings do we see with rheumatoid?

Answer 3

Histo: synovial cell hyperplasia (neutrophils and protein), dense inflammatory infiltrates, increased vascularity

Lab: anti-CCP antibodies, Rheumatoid factor (IgA/IgM autoantibodies against own Fc portion of IgG)

Question 4

What genes are linked to rheumatoid arthritis?

Answer 4

Genes: *HLA-DR4 is the main one, but also HLA-DRB1 and PTPN22

Question 5

What clinical findings will we see with rheumatoid arthritis?

Answer 5

• symmetrical arthritis of small joints (hands/feet), elbows, ankles and knees
• Rheumatoid nodules: large, subcutaneous nodules (25% of pts) with central necrosis surrounded by palisaded histiocytes
• Vasculitis – multiple organs may be involved
• Baker cysts (swelling of bursa behind knee)
• Fever, malaise, weight loss, myalgias
• Arthritis with morning stiffness that improves with activity

Question 6

What unique PE findings will we see for Rheumatoid Arthritis, including X-ray?

Answer 6

PE: radial deviation of wrist, PIP joints affected (swan neck or boutonniere deformity), DIP usually spared

Xray: Joint-space narrowing, loss of cartilage & osteopenia

Question 7

What type of hypersensitivity reaction is sjogren’s and what is going on with this guy?

Answer 7

Autoimmune destruction of salivary and lacrimal glands.

Type IV HS rxn (T-cell mediated) + fibrosis.

May be 1’(sicca syndrome) or 2’ to other autoimmune dz esp. RA. Classically seen in older women (50-60)

Question 8

Lab findings for Sjogren Syndrome

Answer 8

Lab: anti-ribonucleoprotein antibodies (anti-SSA/Ro and anti-SSB/La) *most sensitive
anti-SSA is marker for extraglandular sx like nephritis and vasculitis. Also seen in some SLE pts

Rheumatoid factor (even if RA absent), ANA (50-80%)

Question 9

Clinical picture of sjogren syndrome

Answer 9

Clinical: keratoconjunctivitis sicca (dry eyes), xerostomia (dry mouth), recurrent dental carries in older women=“can’t chew a cracker, dirt in my eyes”, lymphocytic sialadenitis of minor salivary glands on lip biopsy (diagnostic)

Question 10

What complications do we worry about with Sjogrens?

Answer 10

Complication: B-cell (marginal zone) lymphoma (parotid enlargement), ulceration of corneal epithelium and oral mucosa

Question 11

What is happening with systemic sclerosis?

Answer 11

Sclerosis of skin and visceral organs.

Classically seen in middle aged women (30-40)

Question 12

What is the pathology for systemic sclerosis?

Answer 12

1) autoimmunity
2) vascular damage
3) collagen deposition

1) CD4+ T-cell are activated and activate inflammatory response and fibroblasts

2/3) Autoimmune destruction of vessels→ endothelial dysfunction→ inflammation→ release of growth factors TGF-B and PDGF→ fibrosis, initially perivascular but eventually causing organ damage from narrowing of microvascular

Question 13

What lab values do we see with systemic sclerosis?

Answer 13

Lab: Anti-Scl-70, anticentromere antibody

Question 14

Compare limited vs diffuse systemic sclerosis

Answer 14

Limited:
limited skin involvement with late visceral involvement.
CREST syndrome (Calcinosis/Centromere antibodies, Raynaud phenomenon, Esophageal dysmotility, Sclerodactylyl, Telangiectasias); generally affects skin from elbows down to fingers; pulmonary HTN

Diffuse:
Diffuse skin involvement and early visceral involvement (commonly involving vessels, GIT, Lungs (interstitial lung disease), Kidneys); generally affects skin from the elbows up; renal failure can be the first symptom

Question 15

What are inflammatory myopathies in general, and how do we commonly treat them?

Answer 15

Immune mediated injury and inflammation of skeletal muscles

a/w: systemic sclerosis

Tx: Corticosteroids. If resistant, immunosuppressives methotrexate or azathioprine.

Third line: IVIG, cyclophosphamide, cyclosporine, or rituximad (antibody that targets B cells)

Question 16

What is going on with the inflammatory myopathy dermatomyositis?

Answer 16

Patho: Damage to small blood vessels leading to muscle injury. Type 1 Interferon upregulates certain genes leading to advanced inflammatory response.

Question 17

How will dermatomyositis present?

Answer 17

Clinic: Telangiectasias in nail folds, gums, eyelids.Slow onset symmetrical proximal muscle weakness, heliotrope rash eyelids, Gottron papules (dark red rash on knuckles), 1/3 with dysphagia from muscle involvement, 10% with interstitial lung disease.

Kids get calcinosis and lipodystrophy, not myositis antibodies = no cardiac or lung involvement = better than adult

Question 18

What labs do we see with dermatomyositis and what clinic signs are associated with them?

Answer 18

Lab/Clinic:

• Anti-Mi2 antibodies (attack helicase for nucleosome remodeling) (presents with heliotrope rash and Gottron papules)
• Anti Jo-1 antibodies (attacks t-RNA synthetase) (interstitial lung disease, nonerosive arthritis, “mechanics hands” skin rash
• Anti P155/P140 antibodies (attack transcription regulators) (paraneoplastic and juvenile cases of dermato).

We will also see an elevated CK due to muscle damage

Question 19

Compare polymyositis to dermatomyositis and what causes it

Answer 19

Shares myalgias and weakness with dermatomyositis but with no cutaneous features

Patho: Unknown. Theory: CD8-positive cytotoxic T cells mediate tissue damage Not linked to vascular injury like dermato.

Question 20

What histology do we note for polymyositis?

Answer 20

Histology: Patchy endomysial mononuclear inflammatory cell infiltrates with lots of CD8+ T cells, increased sarcolemma expression of MHC Class I antigens,focal invasion of normal appearing myofibers by inflammatory cells.

Question 21

Discuss the clinic and lab findings for inclusion-body myositis

Answer 21

Clinic: Muscle weakness in the quadriceps and distal upper extremities with dysphagia due to esophageal musculature involvement.

Lab: Modestly elevated creatinine kinase levels; most myositis related antibodies absent.

Question 22

What histology will we see with inclusion-body myositis?

Answer 22

Histology: Exact same as Polymyositis! In addition, we see abnormal cytoplasmic inclusions described as “rimmed vacuoles,” tubulofilamentous inclusions in myofibers seen by electron microscopy, protein inclusions (beta-amyloid, TDP-43, ubiquitin), and endomysial fibrosis with fatty infiltrate reflective of chronic disease course.

Question 23

With mixed connective tissue disorder, we see features of SLE, polymyositis, and systemic sclerosis.

How does this typically present and what lab findings do we see?

Answer 23

Lab: Antibodies to ribonucleoprotein particle-containing U1 ribonucleoprotein

Clinic: Synovitis of fingers, Raynaud, mild myositis with mild renal involvement that responds well to corticosteroids

Complications: Pulmonary HTN, interstitial lung disease, renal disease

Question 24

As you might infer, Non-alcoholic Fatty Liver Disease is NOT caused by Alcohol. What is it caused by?

Answer 24

Different causes:

1) insulin resistance→ hepatic steatosis.
2) Cytochrome P450 metabolism going on in liver produces ROS, and lipid laden cells are more sensitive to lipid peroxidation→ apoptosis.
3) Less autophagy of apoptosed cells→ mitochondrial injury and Mallory-Denk body formation. Inflammatory response by Kupffer cells leads to scar tissue.

Question 25

What histology and labs do we see with NAFLD?

Answer 25

histo: May see Mallory-Denk bodies (tangled intermediate filaments in ballooned hepatocytes), but more common in alcoholic liver dz.
labs: ALT>AST; AST/ALT ratio

Question 26

Who is at risk for NAFLD and what does it lead to?

Answer 26

Most common metabolic disorder!

at risk: obesity, metabolic syndrome, type 2 DM

leads to: fatty change, hepatitis, cirrhosis, cryptogenic cirrhosis

Question 27

What causes hemochromocytosis and what labs will we see because of this?

Answer 27

inc iron= deposition in tissues (hemosiderin)= free radical organ damage

path: ^iron→ tissue damage→1) lipid peroxidation 2) stimulation of collagen deposition 3)direct DNA damage from iron
labs: inc serum ferritin, dec TIBC, inc serum iron, inc serum saturation, high HC, guaiac + stool (bleeding from hemorrhoids)

Question 28

How does hemochromatosis present?

Answer 28

presents in adulthood, females present 1-2 decades behind males

triad: cirrhosis, diabetes mellitus, bronze skin
sx: Hepatomegaly, Abdominal pain, Cardiac dysfunction, Arthritis, Hypogonadism (due to higher estrogen from cirrhosis)

Question 29

Discuss the morphology and histology of hemochromatosis

Answer 29

gross: large, dark brown liver → small and cirrhosis
histo: brown granules in hepatocytes/Kupffer cells, prussian blue shows iron in blue

Question 30

How do we treat hemochromatosis and what happens if we don’t

Answer 30

leads to: hepatocellular carcinoma, Micronodular cirrhosis (pigment cirrhosis), portal HTN (bleeding/varices)

tx: phlebotomy to remove RBC

Question 31

In hereditary (primary) hemochromatosis, what genes cause it?

Answer 31

AR: inc enterocyte iron absorption

mutation: HFE gene (chr 6) (mutations=C282Y, H63D) transferrin receptor 2 (TfR2) or hepcidin (HAMP) → epithelial cells can’t sense circulating Fe2+ levels → can’t tell you have enough iron → excessive intestinal absorption
deposition of iron in liver, pancreas, heart, joints and endocrine organs leading to cell injury.

Question 32

What causes secondary hemochromatosis?

Answer 32

cause: inc iron 2* chronic transfusions. hemodialysis, anemia, sickle cell, leukemia, PO overload, ineffective erythropoiesis

accumulation of iron in tissues, usually within the reticuloendothelial system

Question 33

What causes Wilson Disease?

Answer 33

inherited AR defect (ATP7B gene) in ATP mediated hepatocyte copper transport→ less copper in bile and less copper incorporation into ceruloplasmin

patho: copper deposits in tissue, free radicals damage tissues

Question 34

How does Wilson’s present?

Answer 34

presents in childhood

sx: cirrhosis, neuro sx, kayser-fleischer rings in cornea
labs: inc copper

Question 35

How do we treat Wilson disease and what can it lead to?

Answer 35

leads to hepatocellular carcinoma

tx: D-penicillamine

Question 36

Discuss α1-Antitrypsin Deficiency

Answer 36

inherited AR

Serine protease inhibitor

sx: emphysema and liver disease
histo: Cytoplasmic globular inclusions- PAS positive