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MDTI - Rheumatology (Autoimmune disorders (Seropositive (autoantibodies…

- - - - Psoriatic arthritis (PA)
      - Enteropathic arthritis
      - Reactive arthritis (ReA)
      - Ankylosing spondylitis (AS)
      - Clinical features of all spondyloarthropathies
        
        Axial disease: spondylitis - inflammation of the vertebra (or intervertebral joints). Can form syndesmophytes. Also can manifest as sacroilitis - low back or buttock pain with morning stiffness and "rest" stiffness.
        
        Peripheral arthritis: inflammation within the joints causing swelling, pain, and sometimes redness, warmth, and stiffness. Typically asymmetric, oligoarticular (2-5 joints) or polyarticular (>5 joints).
        
        Enthesitis: tenderness at sites where tendons, ligaments or oint capsules attach to the bone. Achilles tendon is one of the most common sites.
        
        Dactylitis: otherwise known as "sausage digit" -- inflammation in synovium, tendon and surrounding tissue.
        
        Extra-articular manifestations: uveitis, constitutional (fever, weight loss, fatigue), gut inflammation/IBD, cardiovascular disease, psoriasis, aorta root dilatation/aortic insufficiency, interstitial lung disease, depression.
      - Pathogenesis of SpA:
        
        Altered bone remodeling
        
        Osteoclasts are responsible for erosion:
        
        Erosion - osteoclasts - RANK-RANKL
        
        HLA-B27
  - - - Clinical features: often heterogeneous
        
        Classification criteria (need four of eleven for research): malar rash, discoid rash, photosensitivity, oral ulcers, arthritis, neurologic disorder, renal disorder, serositis, hematologic disorder, antinuclear antibody, immunologic disorder (other antibodies).
        
        Malar rash: butterfly rash on cheeks and nose.
        
        Discoid rash: red raised disc-shaped patches, often scarring
        
        Oral ulcers: palate, tongue, nasal -- usually painless
        
        Non-scarring alopecia: diffuse thinning or hair fragility with visible broken hairs, in the absence of other causes.
        
        Arthritis: at least 2 joints, usually symmetric, tenderness or swelling +/- warmth, erythema (dolor, turgor, rubor, calor), non-erosive -- Jaccoud's arthritis.
        
        Neurologic: central and peripheral nervous system; e.g. seizures, pyschosis, stroke, neuropathy, cognitive dysfunction, mood and anxiety disorders.
        
        Nephritis: kidney inflammation - protein in the urine (> 500 mg/24 hrs and/or cellular casts (e.g. red cells surrounded by proteinaceous matrix).
        
        Serositis: inflammation around the lining of the lung or heart --> chest pain when taking a deep breath. In lung, pleuritis, for heart, pericarditis.
        
        Hematologic: hemolytic anemia, leukopenia (<4000/mm3) or lymphopenia (<1000 mm3), thrombocytopenia (<100,000/mm3).
        
        Immunologic: anti-nuclear activity (ANA) -- anti-dsDNA, anti-Smith. Antiphospholipid antibody -- lupus anticoagulant, anti-cardiolipin, false-positive RPR.
      - Epidemiology
        
        Who gets SLE? Rare: 20-150 cases/100,000 population. More common in females (7:1 in adults, 3:1 in children), non-European ancestry. More severe in non-European ancestry, males, children.
      - Factors influencing SLE pathogenesis
        
        Environmental
        
        UV light, viruses, smoking, medications --> drug-induced lupus (limited variant of SLE, resolves with withdrawal of medication)
        
        Hormonal
        
        Role of hormones unclear: estrogen and prolactin promote survival, activation of autoreactive B cells. Decreased estrogen and progesterone surge in pregnant SLE patients vs healthy controls during 2nd and 3rd trimesters.
        
        Female predominance, but unclear why. X chromosome itself may contribute independently. Increase SLE severity in transgenic mice expressing XX. Increased risk of SLE in Klinefelter's syndrome (XXY).
        
        Genetic
        
        Single gene mutation (1-3%)
        
        TREX1 codes from DNA exonuclease --> decreased production. CNS involvement, skin lesions.
        
        C2 (most common, mild, skin features), C1q, C4 (severe, early-onset, CNS involvement), C3 (nephritis).
        
        Predisposing gene polymorphisms (18%)
        
        ~50 gene loci identified on GWAS. Most common = MHC class II alleles. HLA-DR2 and HLA-DR3 are associated with 2x increased risk.
        
        SLE susceptibility gene loci and pathways: three implicated pathways are immune-complex processing, immune signal transduction, and TLR-type I IFN pathway (TREX1).
        
        Epigenetic
        
        Heritable changes in gene function that do not entail change in DNA sequence: DNA hypomethylation -- increased gene activation, triggered by UV light, medications, viruses, smoking (SLE environmental triggers), abnormal regulation may induce autoreactivity
        
        Immunoregulatory
        
        Defective phagocytosis and clearing of apoptotic cells, DNA from apoptotic cells is hypomethylated (vs. necrotic cells) --> may induce autoreactivity, nuclear autoAg within membrane blebs persist --> formation of immune complexes.
      - Treatment & Therapeutic Targets
        
        (TLRs) Antimalarial agents to inhibit increased TLR activity in autoreactive B cells. e.g. hydroxychloroquinine.
        
        (Cytokines) Belimumab blocks the action of B-cell lymphocyte stimulator (BLyS) protein, which B-cells require for survival. By blocking BLyS, belimumab reduces the number of B-cells available to produce antibodies that contribute to SLE. In clinical studies, belimumab-treated patients experienced less activity of their SLE than those who received other SLE therapies. Belimumab was approved by the FDA in March 2011.
        
        (T cells) Mycophenolate mofetil - inhibits T and B cell proliferation, immune responses and Ab formation.
        
        Glucocorticoids seem standard
      - SLE pathogenesis: antibodies and immune complexes
        
        Immune complexes
        
        Immune complexes (IC) activate the complement system, causing cytokine release & recruitment of inflammatory cells, resulting in tissue damage. ICs are normally cleared by phagocytosis; this clearance is defective in SLE, resulting in more inflammatory cytokine release.
        
        Autoantibodies
        
        Anti-nuclear antibodies: Present in >90% of SLE patients, but poor specificity (up to 20% of healthy individuals), may not correlated with SLE disease activity, pathogenic mechanism unclear. ANA becomes more of a confirmatory test when all other indicators of lupus exist.
        
        Anti-RNP
        
        Seen in SLE and mixed connective tissue disease (overlapping features of SLE, scleroderma, RA and other autoimmune diseases).
        
        Anti-Smith
        
        Also specific for SLE
        
        Anti dsDNA
        
        97% specific for SLE, associated with active glomerulonephritis, may correlate with disease activity
        
        Anti-Ro/La (SSA/SSB)
        
        Seen in SLE and Sjogren's syndrome (autoimmune disease affecting exocrine glands causing dry eyes and mouth). Pathogenic in neonatal lupus.
        
        Antiphospholipid antibodies
        
        Ab to cell membrane components, associated with thrombosis of arteries and veins, SLE - anti-cardiolipin (immunologic criteria)
        
        Ab that recognize self Ag. These are generated during antibody assembly -- immature B cells can harbor auto-reactive antibodies, B cell check points are abnormal in SLE. In SLE, autoreactive Ab which should be deleted persist. This abnormal immune regulation causes a loss of self-tolerance.
        
        Cytokines
        
        B lymphocyte stimulator (BLyS/BAFF) promotes increased B-cell survival. SLE patients have elevated BLyS levels, extended periods of high BLyS levels increase likelihood of autoreactive cells reaching maturity. Type 1 IFN is a potent promotor of inflammatory response. For innate immune system, stimulates gene expression of TLRs upregulated on B cells, for adaptive immunity IFN1 promotes T cell survival and increases Ab secretion by B cells. SLE patients have higher IFN - IFN release by pDCs stimulated by immune complexes.
        
        T cells
        
        Indirect damage: T cells stimulate B cells via inflammatory cytokines. Stimulate B ell division, promote high affiinity of B cells for Ag, promote Ab class switching (IgM to IgG).
        
        Direct damage: T cells infiltrate tissues, including skin and kidneys contributing to inflammatory tissue damage.
        
        Hypomethylated DNA can make T cells more autoreactive. Inhibitors of T-cell methylation in mice induce glomerulonephritis. DNA extracted form T cells of SLE patients is hypomethylated compared to controls.