Other Autoimmune Diseases 1 Flashcards
Remember Rheumatoid Arthritis? How does this guy work?
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
Discuss the pathology of rheumatoid arthritis, i.e., what is going on with the signals and cells
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
What histo/lab findings do we see with rheumatoid?
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)
What genes are linked to rheumatoid arthritis?
Genes: *HLA-DR4 is the main one, but also HLA-DRB1 and PTPN22
What clinical findings will we see with rheumatoid arthritis?
- 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
What unique PE findings will we see for Rheumatoid Arthritis, including X-ray?
PE: radial deviation of wrist, PIP joints affected (swan neck or boutonniere deformity), DIP usually spared
Xray: Joint-space narrowing, loss of cartilage & osteopenia
What type of hypersensitivity reaction is sjogren’s and what is going on with this guy?
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)
Lab findings for Sjogren Syndrome
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%)
Clinical picture of sjogren syndrome
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)
What complications do we worry about with Sjogrens?
Complication: B-cell (marginal zone) lymphoma (parotid enlargement), ulceration of corneal epithelium and oral mucosa
What is happening with systemic sclerosis?
Sclerosis of skin and visceral organs.
Classically seen in middle aged women (30-40)
What is the pathology for systemic sclerosis?
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
What lab values do we see with systemic sclerosis?
Lab: Anti-Scl-70, anticentromere antibody
Compare limited vs diffuse systemic sclerosis
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
What are inflammatory myopathies in general, and how do we commonly treat them?
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)
What is going on with the inflammatory myopathy dermatomyositis?
Patho: Damage to small blood vessels leading to muscle injury. Type 1 Interferon upregulates certain genes leading to advanced inflammatory response.
How will dermatomyositis present?
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
What labs do we see with dermatomyositis and what clinic signs are associated with them?
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
Compare polymyositis to dermatomyositis and what causes it
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.
What histology do we note for polymyositis?
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.
Discuss the clinic and lab findings for inclusion-body myositis
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.
What histology will we see with inclusion-body myositis?
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.
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?
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
As you might infer, Non-alcoholic Fatty Liver Disease is NOT caused by Alcohol. What is it caused by?
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.
What histology and labs do we see with NAFLD?
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
Who is at risk for NAFLD and what does it lead to?
Most common metabolic disorder!
at risk: obesity, metabolic syndrome, type 2 DM
leads to: fatty change, hepatitis, cirrhosis, cryptogenic cirrhosis
What causes hemochromocytosis and what labs will we see because of this?
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)
How does hemochromatosis present?
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)
Discuss the morphology and histology of hemochromatosis
gross: large, dark brown liver → small and cirrhosis
histo: brown granules in hepatocytes/Kupffer cells, prussian blue shows iron in blue
How do we treat hemochromatosis and what happens if we don’t
leads to: hepatocellular carcinoma, Micronodular cirrhosis (pigment cirrhosis), portal HTN (bleeding/varices)
tx: phlebotomy to remove RBC
In hereditary (primary) hemochromatosis, what genes cause it?
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.
What causes secondary hemochromatosis?
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
What causes Wilson Disease?
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
How does Wilson’s present?
presents in childhood
sx: cirrhosis, neuro sx, kayser-fleischer rings in cornea
labs: inc copper
How do we treat Wilson disease and what can it lead to?
leads to hepatocellular carcinoma
tx: D-penicillamine
Discuss α1-Antitrypsin Deficiency
inherited AR
Serine protease inhibitor
sx: emphysema and liver disease
histo: Cytoplasmic globular inclusions- PAS positive
