day 2 - immunology of joint disease Flashcards
define rheumatoid arthritis
Definition: Symmetrical autoimmune polyarthritis commonly affecting the peripheral joints. It is a severe inflammatory disorder which can affect men and women of any age
epitome of RA
Epidemiology:
Common disease (1-2% of population)
M:F ratio 1:3
Peak incidence: young adults and premenopausal women
RA diagnosis
Diagnosis is clinical: insidious, symmetrical arthritis, with painful, swollen joints.
A new diagnostic test for anti-cyclic citrullinated protein antibodies has been shown to be specific for rheumatoid arthritis
path of RA
Pathology:
Main target is the synovium: inflammation, vasculitis, oedema, villous hypertrophy, chronic inflammation, infiltration by lymphocytes and macrophages, proliferation of synovial cells and erosion of articular cartilage.
evidence of the role of the immune system in RA?
Evidence for role of the immune system in the disease:
High % have particular HLA type (DR4).
Associated with the presence in the blood of high titre of rheumatoid factor, an auto- antibody (usually IgM) reactive with altered autologous immunoglobulin (also anti- ribonucleoprotein and anti-perinuclear factor).
multi systems affected by RA
Multi-system disorder:
Marked by a variable course with exacerbations and remissions
• chronic inflammatory granulomatous lesions (rheumatoid nodules) at many sites,
especially subcutaneous.
• vasculitis: including skin, eyes (scleritis, keratoconjunctivitis) neuropathies.
• pulmonary disease: fibrosing alveolitis, effusions and pleuritis, Caplan’s syndrome.
• Sjogren’s syndrome.
• amyloidosis.
• haematological abnormalities: anaemia, lymphadenopathy, splenomegaly, hyperviscosity.
• local complications, e.g. tendon and nerve damage
what is • Sjogren’s syndrome.
Sjögren’s syndrome or Sjögren syndrome (pronounced /ˈʃoʊɡrɨn/ or /ˈʃʌrɡrɛn/[1] in English, the latter to approximate the Swedish pronounciation) is a chronic autoimmune disease in which the body’s white blood cells destroy the exocrine glands, specifically the salivary and lacrimal glands, that produce saliva and tears, respectively.[2] The immune-mediated attack on the salivary and lacrimal glands leads to the development of xerostomia (dry mouth) and keratoconjunctivitis sicca (dry eyes), which takes place in association with lymphocytic infiltration of the glands.[3] That inflammatory process eventually severely damages or destroys the glands.
Sjögren’s syndrome is usually classified by a clinician as either ‘primary’ or ‘secondary’. Primary Sjögren’s syndrome occurs by itself and secondary Sjögren’s syndrome occurs when another connective tissue disease is present
what is amyloidosis
Amyloidosis is a rare disease that results from accumulation of inappropriately folded proteins. These misfolded proteins are called amyloids. When proteins that are normally soluble in water, fold to become amyloids, they become insoluble and deposit in organs or tissues, disrupting normal function.[2][3] The type of protein that is misfolded and the organ or tissue in which the misfolded proteins are deposited determines the clinical manifestations of amyloidosis.
what is felty’s syndrome?
Felty’s syndrome, also called Felty syndrome,[1] is characterized by the combination of rheumatoid arthritis, splenomegaly and neutropenia. The condition is more common in those aged 50-70 years, and is more prevalent in females than males and more in Caucasians than blacks. It is a deforming but inactive disease and seropositive for RF
Felty’s syndrome:
• Destructive arthritis.
• High frequency of extra-articular manifestations especially vasculitis.
• Strong family history and HLA DR4 association.
• Lymphadenopathy and splenomegaly.
• Leucopenia, often neutropenia with increased susceptibility to infection.
role of T cells in RA
Role of T cells?
• Dense infiltrate of activated mature T cells (mainly CD4+ in synovium).
• Close association with particular MHC polymorphism HLA DR4.
• Therapy directed against T cells has been shown to be effective in treatment in some
cases.
• Most animal models are T cell dependent.
role of B cells in RA
Role of B cells and antibodies?
• Anti B cell therapy has proved successful.
• Some animal models are B cell dependent.
role of cytokines in RA
Role of cytokines?
• Evidence from both animal models and human studies that immunoregulatory cytokines are important
• Role of tumour necrosis factor (TNF): was shown to be pivotal (but not exclusive) cytokine, acting directly in both pro- and anti-inflammatory networks, and indirectly via effect on interleukins (IL), especially IL-1 and IL-6.
• Exploited to generate biological therapeutics (e.g. anti-TNF, soluble TNF receptor) which have proved to be of therapeutic value.
Possible components in the immunopathogenesis of rheumatoid arthritis:
Possible components in the immunopathogenesis of rheumatoid arthritis:
• Immune complex mediated disease.
• Dysregulation of T cells and/or macrophages in the synovium with persistent
production of pro-inflammatory mediators (e.g. TNF).
• Abnormal antigen presentation in synovium.
• Excess production of free radicals and matrix metalloproteases in the synovium.
Adverse prognostic factors in rheumatoid arthritis:
- High titre of serum rheumatoid factor.
- Presenting feature of insidious onset, > 50 years of age, symmetrical arthritis. • Joint erosions on X ray.
- Early appearance of nodules or vasculitis.
- Persistent disease activity in the first year after diagnosis.
current treatments for RA
Current treatments:
• NSAIDS / Steroids.
• DMARD: methotrextrate, ciclosporin, gold, penicillamine, azathioprine.
• Anti TNFalpha/soluble receptor/IL-1. • Anti CD20 antibodies.
Potential future treatments:
• Anti BAFF.
• Anti angiogenesis treatments? • Gene therapy?
