Immunopathology Associations Flashcards
Attacks synovial joints
Rheumatoid Arthritis, often progresses to synovial joint destruction. Also targets tendon sheathes and bursae
Autoimmune form of arthritis
Rheumatoid Arthritis
Arthritis that peaks age 40, but can become symp in 40’s
Rheumatoid Arthritis
Arthritis, more common in females than males
Rheumatoid Arthritis
HLAB4 is a haplotype of this arthritis.
Rheumatoid Arthritis
Type of arthritis that increase in prevalence with increase in latitute?
Rheumatoid Arthritis
Histological Pathogenesis of Rheumatoid Arthritis.
- Synovial edema and sparse mononuclear infiltrate.
- Synovial aggregates of mononuclear cells, CD4+ THELPER Cells, Plasma cells, Dendritic cells, Macrophages
- Synovial hyperplasia with villous change
- Increased synovial vascularity
- Organising fibrin on synovial surface and neurtophils on synovial surface and in joint space.
- Osteoclast activation = osteoporosis, junta-articular erosions, sub-chondral cysts.
- Mass of boggy inflammed synovium PANNUS, can erode cartilage, bone and ligament.
- Joint destroyed. Loss of articular cartilage. Fibrous ankylosis or Unstable
Mass of boggy inflammed synovium that can erode cartilage, known as what? Seen in What?
PANNUS
Rheumatoid Arthritis
Signs and symptoms of PANNUS/Rheumatoid Arth?
(4 basic signs of inflammation)
- Calor
- Rubor (
- Tumour (swelling)
- Dolar (pain)
Common site to observe synovial joint destruction
Metacarpal/interphalangeal joints
HLA-DRB1
Rheumatoid Arthritis.
TH17
Neutrophil recruitment – Rheumatoid Arthritis
TH1
Interferon Gamma (y) – Rheumatoid Arthritis
Cartilage Matric Metalloproteases
Rheumatoid Arthritis
Immune Complexes
Rheumatoid Arthritis
RANKL
Rheumatoid Arthritis
TNF
Rheumatoid Arthritis
Stiffness WORSE in the Morning
Rheumatoid Arthritis
Pain on movement of joint
Rheumatoid Arthritis
Small non-weight bearing joints (Hands and Feet, C-Spine)
Rheumatoid Arthritis
Important test pre-intubation
Sign of RA on the Neck = X-Ray, Lateral and an AP. Shows narrowing, bony erosions etc.
Treatment for Rheumatoid arthritis?
Total Joint Replacement
Joint Fusion.
Arthritis usually sparing hips and rest of spine?
Rheumatoid Arthritis
Symmetrical arthritis
Rheumatoid Arthritis
Z-deformities (thumb)
Sign of Joint Destruction in Rheumatoid Arthritis
Boutoniere deformities (V at interphalageal joint)
Sign of Joint Destruction in Rheumatoid Arthritis
Swan neck deformities
Sign of Joint Destruction in Rheumatoid Arthritis
Ulnar deviation (fingers towards little finger)
Sign of Joint Destruction in Rheumatoid Arthritis
Volar subluxation (enlargement at knuckles caused by tendon slip)
Sign of Joint Destruction in Rheumatoid Arthritis
Joint Effusions
Sign of Joint Destruction in Rheumatoid Arthritis
Juxta-articular osteopaenia
Sign of Joint Destruction in Rheumatoid Arthritis
Erosions
Sign of Joint Destruction in Rheumatoid Arthritis
Joint Space Narrowing
Sign of Joint Destruction in Rheumatoid Arthritis
Subluxations
Sign of Joint Destruction in Rheumatoid Arthritis
Secondary Amyloidosis
Protein Misfolding. Seen in…
Rheumatoid Arthritis.
Serosistitis
Inflammation of the serosa. Seen in…
Rheumatoid Arthritis
Caplans Syndrome
Rheumatoid arthritis (RA) and pneumoconiosis combination.
Manifests as intrapulmonary nodules, which appear homogenous and well-defined on chest X-Ray
Felty’s Syndrome
Combination of heumatoid arthritis, splenomegaly and neutropenia.
Sicca’s (Sjogrens) Syndrome
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.
Vasculitis
Rheumatoid Arthritis
Pneumonitis
Rheumatoid Arthritis
Rheumatoid Nodules
Rheumatoid Arthritis
Serology of Rheumatoid Arthritis
- Rheumatoid factor (80%)
non-specific
Antibodies (usually IgM) against IgG Fc portion
Marker for activity - APCA (anti-citrullinated peptide antibodies)
Specific for RA
Rheumatoid Factor
Seen in 80% of Rheumatoid Arthritis
non-specific
Antibodies (usually IgM) against IgG Fc portion
Marker for activity
Anti-Citrullinated Peptide Antibodies (ACPA) (AKA ACCP)
Rheumatoid Arthritis (Specific)
ACR/EULAR 2010 Criteria
Rheumatoid Arthritis Points for: Joint Involvement Serology Acute phase reactants Duration of symptoms
Degenerative arthritis
Osteoarthritis
Arthritis affecting articular cartilage, with a periarticular bone response
Osteoarthritis
Mechanical degradation of joints
Osteoarthritis
Arthritis associated with old age?
Osteoarthritis
COL2A1 gene
Familial Osteoarthritis
WNT signalling, Prostaglandin pathways
Osteoarthritis
Local factors affecting loading and wear (point loading) “Secondary Osteoarthritis” Injury Obesity Instability Hypermobility Joint dysplasia Neuropathy
Secondary Osteoarthritis
Chondrocyte Proliferation?
Osteoarthritis
Stages of osteoarthritis?
- Chondrocyte Proliferation
- Mediator Release
- Cartilage Remodelling
- Secondary Changes in Bone and Synovium
(Cystic Changes) - Loss of cartilage with subchondral bony change
Loss of cartilage with subchondral bony change
Osteoarthritis
Cystic Changes in Bone and Synovium
Osteoarthritis
Arthritis in PIP’s, 1sr MCP and 1st MTP joints
Osteoarthritis
Arthritis in Lumbar and Cervical Spine
Osteoarthritis
Deep, achy pain
Worsens with use
Short-lived morning stiffness
Osteoarthritis
Crepitus
Osteoarthritis
Decreased range of movement
Osteoarthritis
Subchondral Sclerosis
Osteoarthritis
Subchondral Cysts
Osteoarthritis
The Secondary Osteoarthritis.
Metabolic – Gout &
Pseudogout (Chondrocalcinosis)
Infectious / Septic Arthrits
The Seronegative immune mediated joint disorders
Ankylosing spondylitis
Reactive arthritis/Reiter syndrome
Enteropathic arthritis
Psoriatic arthritis
Joint disorder common in 6wks
Juvenile Idiopathic Arthritis
6wks affecting fewer than 4, mostly larger joints, ANA positive?
Oligoarthritis (Juvenile Idiopathic Arthritis Subtype)
6wks affecting more than 4, mostly smaller joints, RF+ positive? With poorer prognosis
Polyarthritis (Juvenile Idiopathic Arthritis Subtype)
ANA
Oligoarthritis (Juvenile Idiopathic Arthritis Subtype)
RF+
Polyarthritis (Juvenile Idiopathic Arthritis Subtype)
Ddx
10% of Psoriatic Arthritis
Sjogrens (75%)
Stills Disease
Systemic Onset JIA
Joint pain in 5yo
Systemic Onset JIA. Also... Fever Rash (salmon-pink) Lymphadenopathy Organomegaly Serositis / Hepatitis
Joint pain and inflammation Fever Rash (salmon-pink) Lymphadenopathy Organomegaly Serositis / Hepatitis
Patient 5yo and more likely female
Systemic Onset JIA or Stills Disease
Seronegative destruction of articular cartilage and bony ankylosis
Ankylosing spondylitis.
Usually affect sacro-iliac and apophysial joints
Arthropathy in sacro-iliac and apophysial (facet joints)
Ankylosing spondylitis
Ddx
HLA-B27+ Enteropathic Arthritis
Seronegative arthritis more common in males, average more common in mid-20’s
Ankylosing spondylitis
Question mark spine
Ankylosing spondylitis
Schober’s test (limited flexion (
Ankylosing spondylitis
Uveitis
Ankylosing spondylitis
Aortitis
Ankylosing spondylitis
HLA-B27
95% w/Ankylosing spondylitis are HLA-B27+
8% of Caucasian population = HLA-B27+
80% w/Reactive Arth/Reiters are HLA-B27+
Enteropathic Arthritis w/sacroiliitis or spondylitis
Psoriatic Arthritis
Arthritis (sausage finger, bony spurs) \+ Nongonococcal urethritis/cervicitis (+/- circinate balanitis) \+ Conjunctivitis
Reactive Arthritis/Reiter Syndrome
Also,
+/- oral ulceration, heart block, aortic regurgition
50% is chronic and resembles Ankylosing Spondylitis.
Arthritis within weeks after shigella, salmonella, yersinia, campylobacter or chlamydia.
Reactive Arthritis/Reiter Syndrome
Arthritis of mostly men 20-40
Reactive Arthritis/Reiter Syndrome
Or
Ankylosing Spondylitis
Ddx Possible Rheumatoid (early)
Less severe symptoms that reiter but nonetheless following infection?
Enteropathic Arthritis
Arthritis found in 10-15% of IBD patients
Enteropathic Arthritis
Asymmetrical arthritis of lower limb
Enteropathic Arthritis
Seronegative (in 90%) arthritis associated with psoriasis 20-40yo?
Psoriatic Arthritis (10% RF+)
HLA-CW6
Psoriatic Arthritis
Arthritis usually DIP, dactylitis, sausage finger/TOE 33%.
Also sometimes ankles, knees, hips, SI and facet joints
Asymetric, Histo resembling RA but not as destr.
Psoriatic Arthritis
“telescopic fingers” “whittling”
Arthritis mutilans due to osteolysis seen in 5% of Psoriatic Arthritis cases
“Pencil in cup”
Erosive but central not peripheral
Iritis and conjunctivitis
Psoriatic Arthritis
Hyperuricaemia
Gout (w/intraarticular sodium urate chrytals)
10% have hyperuricaemia, only 0.5% have gout
Intraarticular sodium urate chrystals
Gout (w/hyperuricaemia)
Arthritis of elderly with heavy male predominance.
Gout
Pathogenesis of Gout
Hyperuricemia
Urate precipitates in joints forming crystals
- Activation of complement and kinen system
Neutrophil chemotaxis
Release LTB4, prostaglandins and free radicals causes tissue inflamm.
Neutrophils phagocytose crystals, causing lysis of neutrophils .
Release of lysosomal enzymes leads to tissue inflaCammation. - Phagocytosis by macrophages
Leads to release of IL-1Beta and other cytokines in joint (resulting in further neutrophil chemotaxis)
Release of proteases leads to tissue inflammation.
Podgara
Acute Arthritis Gout
Gouty Tophi
Chronic Arthritis Gout
Large cause of mortality in gout?
Gouty nephropathy (20% of gout mortality)
Uurate overproduction due to:
Diet
Enzyme defects (known and unknown)
Decreased excretion
Primary Gout (90%)
Overproduction of Urate
- Increased cell turnover
- Inborn errors of metabolism
Reduced excretion
-Chronic renal failure
Secondary Gout (10%)
Chrystal Arthritides
Pseudogout
Calcium pyrophosphate dihydrate deposition disease
Pseudogout
Acute pain and swelling in knee, wrist or shoulder
Pseudogout
Chondrocalcinosis
(Calcification of fibro and hyaline cartilage)
= Pseudogout
Calcification of fibro and hyaline cartilage
Pseudogout
Low Phosphate
Pseudogout
Low Magnesium
Pseudogout
Increase PTH
Pseudogout
Arthropathy associated with Wilsons disease?
Pseudogout
Arthropathy associated with Haemachromatosis?
Pseudogout
Arthropathy associated with Alkaptonuria disease?
Pseudogout
Weakly positively birefringent rhomboid crystals on polarisation.
May be cloudy and associated with fever and ↑ peripheral WCC
Result from joint aspirate
=Pseudogout
Treatment for Pseudogout
Supportive
Should be excluded first in Dx of pseudogout?
Septic Arthritis
Negatitive birefringment
Gout
Hot, Red, one joint?
Septic Arthritis
Routes to septic arthritis?
Direct inoculation through injury
Direct spread from adjacent infection
Haematogenous spread
Common causative organisms in Septic Arthritis?
Haemophilus influenzaepredominates in children under age 2 years,
Staph. Aureus:older children and adults,
Gonococcus: young adulthood. mainly in sexually active women
Individuals with sickle cell disease are prone to infection withSalmonellaat any age.
Gram negative bacilli (elderly),
Tests in Septic Arthritis?
Aspirate
Stain
Culture
HLA-B8
Sjogrens
HLA-DR3
Sjogrens
Sjograns w/o RA?
Primary Sjogrens
Salivary gland enlargement F>M
Sjogrens
Risk lymphoma 1.16 (MALTOMA)
Sjogrens
Investigations in Sjogrens?
Lip biopsy
Lip Biopsy in Sjogrens
Periductal and perivascular CD4+ TH cells, B cells, plasma cells , fibrosis
Anti-Ro
Sjogrens (90%) also RF (75%)
Schirmer Tear Test
Sjogrens
Syndrome common in Turkey, Iran and Japan?
Behcet’s Syndrome
HLA-B51
Behcet’s Syndrome
Genital ulcers
Eye: Uveitis (anterior or posterior) Retinal vasculitis
Skin: Erythema nodosum, Pseudofolliculitis, Papulopustular lesions
Pathergy
Minor skin injury precipitates pustules in a couple of days
±Constitutional symptoms
Behcet’s Syndrome
Anti-La
Sjogrens (60-90%)
SLE (10-15%)
MPO-ANCA
Anti-myeloperoxidase ANCA
=Microscopic PolyAngiitis & =Churg-Strauss Δ - necrotising vasculitis - asthma - allergic rhinitis - pulmonary infiltrates - increased circulating eosinophils - necrotizing granulomas (extrvascular)
- necrotising vasculitis
- asthma
- allergic rhinitis
- pulmonary infiltrates
- increased circulating eosinophils
- necrotizing granulomas (extrvascular)
Churg Strauss Syndrome
PR3-ANCA
Anti-proteinase-3 ANCA = Wegener’s Granulomatosis - Upper airways (necrotising granulomas) - Necrotising granulomatous vasculitis (small-medium vessels) - Necrotising glomerulonephritis
- Upper airways (necrotising granulomas)
- Necrotising granulomatous vasculitis (small-medium vessels)
- Necrotising glomerulonephritis
Wegners Granulomatosis
Autologous
Self Organ Donation (graft etc)
Syngeneic
Monozygotic (identical) siblings
Allogeneic
Living or Cadaveric (Another genetically different person donor)
Umbilical Cord Blood
Cord blood is collected because it contains stem cells, which can be used to treat hematopoietic and genetic disorders.
Xenograft
From animal e.g. Pig heart valves
Issues in Organ Transplant besides rejection
Technical
Cold ischaemia time
Reperfusion injury
Functional status and co-morbidity of recipient
Rejection/Immunosuppression (Infection, Post-transplant-lymphoproliferative disease PTLD (EBV- mediated), Neoplasia - HPV SCC, HHV8 -Kaposi, Lymphoma)
Recurrence (viral, primary FSGS, mesangiocapillary GN, diabetic and IgA nephropathy)
Rate of 5-10y graft survival?
(80%)
Rate of 10-20y graft survival?
(50%)
Definition of transplant rejection?
Aka HOST versus graft
“A process whereby the transplant recipient’s immune system recognizes the graft as foreign and attacks it with potential adverse effects on its viability and function”
Rejection Antigens?
MHC (Minor HC antigens account for GVHD in Human Leucocyte Antigen - identical Bone Marrow Transplant)
ABO
Others
MHC
Major Histocompatability Complex
Mediated Graft Versus Host disease in HLV identical BMT
Seen in Hyperacute rejection (MHC1)
ABO
Most important blood type system (or blood group system) in human blood transfusion. The associated anti-A and anti-B antibodies are usually IgM antibodies, which are produced in the first years of life by sensitization to environmental substances, such as food, bacteria, and viruses.
No HLA, but ABO compatibility required?
Cardiac and Liver transplant
HLA and ABO compatibility min requirement?
Pancreas Transplant
Extensively matched ABO (ABO mismatched are possible) \+ HLA (mostly DR) \+ X-matched for preformed antibodies
Kidney Transplant
ABO Compatibility Essential
HLA as possible
Bone Marrow Transplant
T-Cell Mediated Rejection?
Cellular Rejection (as opposed to humeral)
Cytotoxic T-Cells \+ Cytokine Sectreting CD4+ T-Cells \+ Activated Microphages.
Role of Cytotoxic T-cells in transplant rejection (HVGD)
Kill cells in the grafted tissue, causing parenchymal and, perhaps more importantly, endothelial cell death (resulting in thrombosis and graft ischemia).
Role of Cytokine Secreting CD4+ T-Cells in transplant rejection (HVGD)?
Trigger DTH (delayed type hypersensitivity), with increased vascular permeability and local accumulation of mononuclear cells (lymphocytes and macrophages).
Role of Activated Macrophages in transplant rejection (HVGD)?
Injure graft cells and vasculature.
DTH
Trigger DTH (delayed type hypersensitivity), with increased vascular permeability and local accumulation of mononuclear cells (lymphocytes and macrophages).
Autoimmune reaction resulting in rejection of graft?
Humeral Rejection Type II (Autoantibody) immune response.
Classification of Transplant Rejection?
Hyperacute
(Accelerated Acute)
Acute
Chronic
Cyanotic, mottled and flacid graft on removal of vascular clamps in Operating Room?
Hyperacute Rejection
Rejection involving complement fixing
Hyperacute Rejection
Graft rejection in less
Hyperacute Rejection
Treatment or hyperacute rejection?
Organ Removal
Rejection involving preformed antibodies? Name the antibody types?
MHC 1 or ABO, mothers, previous transfusions and transplants)
Fibrinoid necrosis of vessels and Cortical Infarction in transplant rejection?
Hyperacute Rejection
Process which has reduced the incidence of hyperacute transplant rejection?
Cross Matching
Monitoring of query “Hyperacute rejection’?
U/S Doppler ofr BF or Duplex
Transplant rejection over 1-5 days
Accelerated Acute Rejection
Non-complement fixing rejection
Accelerated Acute Rejection
FcR-bearing cells (T-Cells – primarily Cytotoxic)
Accelerated Acute Rejection
Rejection, can be humeral or cell mediated, but is more commonly cell mediated?
Accelerated Acute Rejection
Rejection that often relapses?
Accelerated Acute Rejection
Treatment for Accelerated Acute Rejection?
Immosuppression, but only partially effective.
Transplant removal often required.
Rejection between 6-90 days?
Acute Rejection
Type of rejection, common (10-30%) in Kidney transplants?
Acute Rejection
Anti-CD20
Treatment used in humoral acute rejection.
On CD4 staining.
Also seen = Polyconal Immunoglobulin, Plasmapharesis
Plamaphaesis
Treatment in humoral acute rejection. On CD4 staining. Also used = Plasmapharesis and Anti-CD20
Polyconal Immunoglobulin
Treatment in humoral acute rejection.
On CD4 staining.
Also used = Polygonal Immunoglobulin and Anti-CD20
ATG (Anti-Thymocyte Globulin)
Anti-thymocyte globulin is used in the treatment of vascular acute rejection. Along with ALG.
ALG (Anti-lymphocyte globulin)
ALG is used as a treatment for vascular acute transplant rejection. Along with ATG
Treatment for acute transplant rejection?
Cellular Steroids Vascular ATG, ALG Humoral C4 staining Polyconal immunoglobulin, plasmapharesis, antiCD20
Rejection characterised by loss of function w/o fever?
Acute Rejection.
Pathogenesis an Tx targets of Acute Rejection?
Endothelium is main target of pathology
CD4+ and CD8+ infiltrate (glomerular and tubular damage and endothelitis)
Necrosis
Heart: Lymphocyte infiltrate and myocyte damage
Vascular response may be subacute proliferation and fibrosis
Responds to aggressive immunosuppression (particularly anti-T cell strategies)
Progression to chronic rejection common
Rejection marked by an interstitial mononuclear cell infiltrate with associated edema and parenchymal injury,
Cellular Acute Rejection
Rejection marked by necrotizing vasculitis with thrombosis (when less acute mimics arterioscleotic thickening)
Humeral Acute Rejection (Antibody medicated)
Rejection over months/years
Chronic Rejection
Obliterative intimal fibrosis
Glomeruli
Coronary arteries
Vascular damage associated with Chronic Rejection
Interstitial fibrosis Tubular atrophy Vanishing bile duct syndrome Bronchiolitis obliterans Gross scarring and shrinkage
Chronic Rejection
Relatively refractory with progressive loss of graft function
Chronic Rejection
Why are chronic rejections the most common?
Immunosuppresents so good it drags rejection out
Suspected mechanism behind chronic rejection?
Recipient cells present MHC from the recipient organs
Difference between direct and indirect cellular rejection?
Own (indirect) versus donor (direct) antigen presenting cells (APC’s) which are presenting the MHC (always from donor).
Indirect cellular rejection
Usually chronic rejection
Methods for improving graft survival?
- Better Matching
2. Immunosuppression
Better HLA matching improves Graft survival?
Yes but….
As drugs for immunosuppression have improved, HLA matching is not even attempted in some situations, such as heart, lung, and liver transplantation; in these cases, the recipient often needs a transplant urgently.
Cyclosporine (FK506)
Immunosuppressant
Anti lymphocyte Globulins
Immunosuppressant
Monoclonal Antibodies (e.g. Monoclonal Anti-CD3)
Immunosuppressant
Squamous cell carinoma a side effect of which type of drug?
Immunosuppressants
Kaposi sarcoma a s/e of what drugs? Where else seen?
Immunosuppressants/HIV progression to AID’s
Lymphomas as s/e?
Immunosuppressants
Presensitisation?
Now Countered by cross-matching
Irradiated to leucocyte deplete
Questionable increase in tolerance
Tx for Aplasia/neoplasias/Herediatary immunodeficineies or metablic abnormalities?
Bone Marrow Transplantation
Mortality in BMT patients?
20-40%
BMT graft sources
Allogenic (Match sibling or unrelated doner)
Autologous
BMT graft types
Bone Marrow
Peripheral Stem Cells (mat. T-cells)
Cord Stem Cells
Graft manipulation for BMT
- T-Cell Depletion (less GVHD, Less successful engraftment, Less graft v tumour)
- Stem Cell (CD34+) Enrichment
Sequence for BMT Transplantation
- Matchining (fully matched sibling can be used whole)
- Viral Status (esp. CMV)
- Conditioning of Recipient (eliminate residual immune system. Note: not required in Sever Combined Immune Deficiency (SCID).
- Immunosuppression
- Growth factor support.
- Supportive blood products (CMV-)
Low Risk CMV group in BMT
CMV- Recipient, CMV- Donor
High Risk CMV group in BMT
CMV+ Recipient
w/wo CMV+ Donor
Lenght of post BMT neutropenia?
Should lift be 21 days
Time to NK cells post BMT?
1 month
Time to T-Cells post BMT?
Depends on T-Cell
1-24 for most.
Some never return.
Depends too on immunosuppression
Time to B-Cells post BMT?
Slow production for 1st 3months
If rapid in 1st 3mts then suspect autologous reconstitution or lymphoproliferative disease.
Plateaus out at between 6-9 months
IgM, IgG, IgA normalisation post BMT?
6-24 months
Vaccination post BMT?
Follow guidelines
No BMT.
Immunocompetent donor T-cells recognize a mismatch with recipient HLA and initiate an immune response against an immunologically vulnerable host
Graft Versus Host Disease (GVHD)
Rate of GVHD in BMT?
30-50%
Transplants associated with GVHD?
BMT (30-50%)
Blood Transfusion
Solid Organs, commonly LIVER (immune organ CD4+8 cells, transplanted a lot) (others =occasionally)
Minor histocompatibility antigens
Non-MHC encoded polymorphisms
Cytokine polymorphisms
Mechanism of GVHD which avoid “Matching”
Occasionally seen in autologous transplants die t re-emergence of autoreactive t-cells
Rejection in
Acute GVHD
Maculopapular rash +
Hepatosplenomegaly
Acute GVHD
Treatment for Acute GVHD?
Aggressive and early
Steroids + Anti-T-Cell agents + Anti-TNFalpha
Types of Chronic GVHD?
Progressive (worst Px)
Interrupted
De novo (best Px)
Similar in appearance to systemic scleosis and Sjogrens?
Chronic GVHD
Tightening of skin around the mouth
Portal system of the liver
White out lung disease (acute vascular information)
GI fibrosis and dysmotilty
Chronic GVHD
Granulomatous arteritis of the aorta and larger vessels with a predilection for the extracranial branches of the carotids
Giant Cell Arthritis
Older person
Unilateral Headache, facial pain and scalp tenderness.
Giant Cell Arthritis
Arteritis far more common in the elderly (>50) and affect F>M, 2:1?
Giant Cell Arthritis
Commonest primary systemic vasculitis
Giant Cell Arthritis
ESR adjusted for age and CRP if this condition is suspected.
Giant Cell Arthritis
25% of those with this go blind?
Giant Cell Arthritis
Tx in Giant Cell Arthritis affecting eye
Corticosteroids can reduce initial inflammation.
Skip Lesions
Often associated with polymyalgia rheumatica
Giant Cell Arthritis
Bilateral neck, shoulder and low back pain and stiffness. Worse in the morning Malaise, tiredness, weight loss, depression and fever. Elevated ESR and CRP.
Polymyalgia Rheumatica
Tx for Polymyalgia rheumatica?
Responsive to steroids
HLA-DRB1*04
Polymyalgia Rheumatica
HLA-DRB1*01
Polymyalgia Rheumatica
Arthritis with temporal relationship to outbreaks of…
Parainfluenza
Parvovirus B19
Mycoplasma
Chlamydia
Polymyalgia Rheumatica
Association between GCA and polymyalgia rheumatica?
50% of patients with Giant Cell Arteritis have symptoms of PMR and up to 20% of PMR patients have biopsy findings of GCA
Pulseless Syndrome
Takayasu Arteritis
Patient in upper limbs may have a weak or absent pulse
Takayasu Arteritis
Granulomatous thickening of the aortic arch, which primarily affects the brachial artery yeilding a pulsless upper limb
Takayasu Arteritis
Arthritis affecting young adults?
Polyarteritis Nodosa
Artritis affecting mostly small and medium arteries?
Polyarteritis Nodosa
Artritis associated with
Abdo pain and melaena
Renal Disease (renal artery affected)
Rash
Polyarteritis Nodosa
Virus associated with Polyartritis Nodosa?
Hepatitis B
Necrotising Vasculitis?
Polyartrirs Nodosa
Histological signs of Polyartritis Nodosa?
Fibrinoid Necrosis
Multiple Thrombosis
Erythema of hands and fee (cutaneous) and of eyes and mouth (muco) t, e in children?
Query Kawasaki disease.
Artritis affecting large, small and medium arteries in children?
Kawakaski
Sex affected more by kawasaki?
Male
Lymph and Cardiac Signs of Kawasaki Disease?
Lymph = Cervical Lymphadenopathy
Coronary Arteries = Aneurysm and MI
Anti-endothelial and smooth muscle antibodies
Kawakaski
Young men
Buerger’s Disease(Thromboangitis Obliteran)
Small Vesses Vasculitis?
Microscopic Polyangitis
Wegner’s Granulomatosis
Churg-Straus
Henoch-Schonlein Purpura
P-ANCA, purpura, lungs, kidneys, cvs, git, necrotizing glomerular nephritis, exogenous antigens from drugs , blood and infections.
Microscopic Polyangitis
Triad:
Renal Disease
Chronic Sinusitis
Pneumonitis
ANCA+
Wegner’s Granulomatosis (Tx = Rapid Immunosup)
Typically affects vessels of respiratory tract, strongly associated with asthma, eosinophilia and pulmonary infiltrates. May also have GI Sx (e.g. colitis, bleeding) +/- cardiac +/- peripheral neuropathy Sx’s.
P-ANCA+ and IgE
Churg-Straus Syndrome (Tx = Glucocortiocids +Support)
Small vessel IgA & immune complex mediated vasculits often following upper-RTI in young children
Giveaway is lesions on the buttocks and legs
Henoch-Schonlein Purpura
Ability of a test to indicate a negative result in the absence
of disease.
Specificity
Ability of a test to indicate a positive result in the presence
of disease.
Sensitivity
Immune complex mediated disease affecting any organ with diverse manifestations and variable prognosis?
Systemic Lupus Erythematous
SLE affects who?
Females x9 more
20-30’s
60% Concordance in Twins.
Varients of SLE limited only to the skin?
Discoid lupus erythematosus
Subacute cutaneous lupus
Butterfly rash
Systemic Lupus Erythematous
Arthralgia and arthritis with skin and haematological abnormalities?
Systemic Lupus Erythematous
Haematological features of SLE?
Immune thrombocytopaenia
Haemolytic anaemia
Autoimmune neutropaenia
Anti-nuclear antibody (ANA) Anti-dsDNA antibody ENA antibodies Anti-RBC antibody Anti-cardiolipin & lupus anticoagulant
All auto-antibodies of Systemic Lupus Erythematous
Inflammation & organ dysfunction due to Immune Complex deposition in the vasculature of affected organs
SLE
Dx for SLE?
Clinical Hx & examination
Urinalysis & urine microscopy
Assess function of potentially involved organs.
Autoantibodies (Indirect immunofluoresence)
DIFF= Skin /Renal
Detection of Anti-Nuclear Antibodies?
Indirect Immunofluoresence
ANA patterns
Homogenous
Speckled
Centromere
Nucleolar
ANA reactivity clarification?
ELISA, RIA and Immunoblotting
Anti-bodies to double stranded DNA?
Highly Specific for SLE
Anti-Sm (30%)
Anti-Ro (30%)
Anti-La
30% specific (except La) each for SLE
All are anti-ENA (extractable nuclear antigen).
ELISA meaning?
Enzyme Linked ImmunoSorbant Assay
Jo-1
30% of Polymyosistitis
RNP
100% Mixed Connective Tissue Disease
Scl-70
A poor prognostic indicator for Scleroderma.
Most common glomerular disease?
IgA nephropathy.
IgA immune complexes deposited in mesangium.
IgA nephropathy.
Anti-GBM antibody
Goodpastures
Anti-CCP
Rheumatoid Arthritis
DR4 and DR1
Rheumatoid Arthritis
Citrulline
Rheumatoid Arthritis
Principle Antibodies in Rheumatoid Arthritis
Anti CCP (Specific 97%, sensitive 88%) RF (Specific 65%, Sensitive 50-90%)
Anti-PR3+
Granulomatosis with Polyangitis (GPA)
Treatment for Granulomatosis with Polyangitis?
Cyclophosphamide
Anti-ACHr (receptor)
Myasthenia Gravis
Anti-MUSK (muscle specific tyrosine kinase)
Found in some anti-AchR negative MG
IgA EMA
Coeliac (90-100% sensitive and specific) Dermatitis herpetiformis (50-70% sensitive, 90-100 specific)
False negative – gluten free diet
Commonest malignant disorder of plasma cells
Multiple Myeloma
Age of onset in Multiple Myeloma?
After age 50 yrs
> 20% Abnormal looking BM plasma cells
Multiple Myeloma
Paraprotein in blood and/or urine
Multiple Myeloma
Bone destruction with osteoporosis or lytic lesions
Often seen in Multiple Myeloma
Test for paraproteins?
Electrophoresis
Dx of Multiple Myeloma
Monoclonal expansion of paraprotein secreting plasma cells in bone marrow
IgG 60% of cases
IgA 20% of cases
Light chains alone 15-20% of cases
X-Chromosome (males) defect in B-Cell Maturation. Presents in early childhood.
XLA/Brutons Tyrosine Kinase Defect/X-linked agammaglobulinaemia
btk
Brutons Tyrosine Kinase
Vital in maturation of Pro-BCell to Pre-Bcell
Defect = agammaglobulinaemia = IgA, IgG and IgM def
Recurrent infections – RTIs (lungs & ears chronic OM)
Meningitis and septic arthritis
Agammaglobinaemia.
Complications and Tx of X-linked Agammaglobinaemia?
IVIg and antibiotics
Complications…
Bronchiectasis
Chronic Sinus Damage
Antibody deficiencies
XLA CVID Hyper-IgM IgA Specific antibody deficiency Transient hypogammaglobulinaemia
Infections soon after birth
- Recurrent bacterial
- Persistent Viral
- Opportunistic
- Persistent Thrush
Severe Combined Immunodeficiency (SCID)
Absence of T cells (
Severe Combined Immunodeficiency (SCID)
Treatment of SCID?
Isolation in +pressure
Antibiotics
Bone Marrow Transplant, possibly gene therapy.
X-linked (young men) Typically presents as a skin infection with +ve organisms (staph aureus, fungi, tc) with deep abscess formation
Chronic Granulomatous Disease
NADPH oxidase (Phox)
Chronic Granulomatous Disease
Treatment for chronic granulomatous disease?
Prophylaxis (co-trimoxasole, itraconasole)
BMT
CD11a, 11b, 11c and CD18
Adhesion molecules (Neutrophil Function Disorder)
Failure in inactivation of complement and kinin systems
Angioedema (deep tissue swelling)
Any part of body
Airway & gut (recurrent abdominal pain)
No urticaria or itch (tingling described)
Late childhood or teenage years
Hereditary Angioedema.
Treatment for hereditary angioedema
Treatment
C1-Inh replacement (acute attacks)
Modified androgens (danazol or stanazol)
Bradykinin receptor anatagonists
Atophy
Type 1 IgE mediated allergy (most common allergy) 10% population. - Asthma - Hay Fever - Eczema - Foods - Urticaria and angioedema - Anaphylaxis
Type 2 Allergy
Autoantibody
Type 4
Patch Test (Angry Back Syndrome)
Important consideration in IgE allergies
Sensitisation does not mean necessarily mean clinical allergy!
Negative result does not exclude allergy
Patient may need a challenge test
Negative SPT does not exclude allergy
Investigation for Anaphylaxis?
Mast cell tryptase Demonstration of mast cell degranulation Elevated levels seen from 1-12 hrs after rxn 90% specific Sensitivity less good
Usually IgE-mediated
Food allergy
Other stimuli not excluded
Gold Standard in Allergen Dx
Allergen Challange
Tx for Allergens
Avoid allergen – if possible
Anti-histamines Self injectable adrenaline Steroids – onset of action 6hrs Individualised plan life threatening reaction? Chance of re-exposure?
Desensitisation – venoms, pollens
Indications for Glucocorticoids
Significant Acute Inflammation
Cortisol
Main Natural Glucocorticoid
Aldosterone
Main Natural Glucocorticoid
Prednisone and Cortisone
Biologically inactive synthetic
11 keto group requires activation to the 11-hydroxy group before having effect on cytosolic receptor.
Activated forms = Prednislone, Cortisol.
Long Acting Glucocorticoid?
Dexmethasone
Short Activng Glucocorticoid?
Prednisolone
Hydrocortisone
Methylprednisolone
Tramcinolone.
Steroid Dosing
High (20-40mg p/day)
Medium
Low (250mg given every 24-48 hrs
MEDICATION TO AVOID IN STEROIDS?
NSAIDS
Graft Rejection Pathophysiology
APC-TCR = CD4 proliferation, release of IL2 and recruitment of Cytotoxic CD8+Tcells
Agents used in Transplant Immunosuppression
Glucocorticoids
Calcineurin Inhibitors (Cyclosporine, Tacrolimus)
Antiproliferative/antimetabolic agents
Monclonal Antibody Therapies (cell specific)
Calcineurin Inhibitors
Cyclosporine, Tacrolimus (100x more potent).
Intracell signalling pathways to block IL2.
Mainstay of organ transplant.
S/E’s Nephrotoxicity, Neurotixcity.
Sirolimus
TOR (Target of Rapamycin) inhibition.
Thereby blocking IL2
Cell Cycle Inhibitors
Mycophenolate Mofetil
Inhibits Inosine, needed for nucleotide synthesis
Used in SLE
Azathioprine
Metabolised to 6MP in the liver.
Anti-IL2-Receptor Antibodies.
Daclizumab and Basiliximab
Prophylaxis against organ rejection.
