PBL 6: Inflammatory arthritis Flashcards
Discuss the basic epidemiology, presentation, investigation, management and prognosis of lyme disease
3 stages:
EARLY LOCALISED- bulls eye rash, possible fever, headache, lymph node swelling near bite
EARLY DISSEMINATED- bacteria spread around the body, possible: bells palsy, meningitis, severe headaches, heart palpitations, swelling in joints, severe muscle pain, red eyes
LATE DISEASE- lyme arthritis, irregular heart rhythm, pain, brain/cns damage, numbness, sleep disturbance, poor vision
Clinical diagnosis, antibody detection useful in late or disseminated stages
Oral antibiotics
carried by tics
reduce chance of tic bites
Lyme disease arthritis can occur when the lyme disease bacteria enter the joint and cause inflammation causing swelling and pain.
Treatment is the same as for the disseminated or late disease as this is a symptom of the spread of the overall disease.
Can fully recover following treatment but patients are at risk of permanent damage if the disease is not treated
Discuss the presentation, initial investigation, key differential diagnosis & initial management of polyarticular joint pain
Pain of more than more joint
History
Severity of joint
Pattern of joint involvement
Distribution of joint involvement
Physical exam
Lab tests
FBC
ESR/CRP
anti-CCP, HLAB27
Uric acid
Synovial fluid analysis
Imaging
X-ray
Ultrasound
MRI
Key differential diagnosis
osteoarthritis, spondyloarthritis, rheumatoid, psoriatic arthritis, juvenile idiopathic arthritis, crystal arthritis, and connective tissue disease
Initial management depends on diagnosis
Pain relief
Discuss the basic epidemiology, presentation, investigation, management and prognosis of spondyloarthropathies (e.g. psoriatic arthritis)
Spondyloarthropathy (SPA) → Autoimmune Inflammatory joint disorders affecting the spine
characterised by enthesitis (inflammation of the insertions of tendons, ligaments and capsules into bone), synovitis, and occurs in patients who are seronegative for rheumatoid factor.
Ankylosing Spondylitis
Psoriatic Arthropathy - 10% of people with psoriasis, especially with nail involvement. Disease severity does not correlate with skin disease.
Distal arthritis involving the distal interphalangeal joints (May have Pitting of the Nail)
Asymmetrical oligoarthritis
Symmetrical polyarthritis indistinguishable from rheumatoid arthritis
Spondylitis → Inflammation of the joints of the backbone.
Arthritis mutilans → Bad deformity
Peripheral joint disease is treated with NSAIDS, methotrexate, leflunomide and sulfasalazine. Anti-TNF therapies work well in selected patients where conventional synthetic disease-modifying anti-rheumatic drugs (DMARDs) have failed.
Axial disease is treated in a similar way to AS with physiotherapy, NSAIDs and biologic therapy as the mainstay. Anti-IL 12/23 and anti-IL17A are particularly effective in psoriatic arthritis with axial involvement and are licensed for first-line use alongside anti-tumour necrosis factor (TNF) treatment. Patients who fail to respond or who have contraindications to these may consider apremilast (anti-PDE4).
All patients benefit from a multidisciplinary team approach.
Enteropathic Arthritis - Arthritis occurring with inflammatory bowel disease (IBD). It occurs in approximately 10%–20% of patients with Crohn disease or ulcerative colitis. Treat IBD.
Reactive Arthritis - Arthritis in response to disease or necrotic tissue. Immune system goes into overdrive.
genetically associated (HLA) B27
Discuss the basic epidemiology, pathophysiology, presentation, investigation, management and prognosis of reactive arthritis
-Reactive arthritis is joint pain and swelling triggered by an infection in another part of the body
-inflammatory arthritis, autoimmune disease
-Usually lasts around 3 months to a year
-Relatively rare, however chlamydia associated ReA is endemic, especially in developed countries
-Caused by antigens which are similar to self antigens activate cytotoxic t-cells causing them to attack the cells at joints
-Painful swollen stiff joints
Swelling of fingers and toes
Conjunctivitis
Fatigue
-Check to see if history of infection in the past 2 weeks
Blood sample
Rules of other types of arthritis
FBC
ESR, CRP
X-ray to check state of joint inflammation
-Antibiotics - to treat the infection
Pain relief
NSAIDs
Steroids
Rest for the fatigue
Physio
DMARDs (disease-modifying anti-rheumatic drugs) - slow inflammation by restricting the immune system, may take a while to work
Discuss the basic epidemiology, pathophysiology, presentation, investigation, management, complications and prognosis of rheumatoid arthritis
-Onset usually between 40-60
-More prevalent in Female
-Stiff, swollen, painfull, warm, red joints
-May be systemically unwell
-usually the smaller joints
-autoimmune condition
-Extra fluid, normally used for fighting infection, is made in the joint, causing swelling. This stretches the joint capsule, pushing the joint out of shape, and causes damage to the joint
-Best prognosis if treated early
-Maintain an active lifestyle
-HLA genes are a predisposing RF for RA
Environmental factors not very well understood, however, some risk factors are:
Smoking, obesity, Blood transfusion, Prior termination of pregnancy
-normal tissue is attacked as if it were a pathogen
-In this process, cytokines are released. Namely, Interleukin-1 and Tumour Necrosis Factor Alpha.
This causes:
Stimulation of inflammation
Attraction of other immune cells (chemotaxis)
Excess synovial fluid production
Cartilage destruction
Bone resorption
Stimulation of B lymphocyte differentiation and maturation
Increased antibody production, including production of rheumatoid factor
synovitis:
Inflammatory cells infiltrate synovium and it proliferates
Macrophages and osteoclasts create a layer of chronically inflamed tissue and erodes articular cartilage
This can lead to joint deformity
Ligament insertions are a common site of inflammation
FBC
ESR and CRP
RF- 70-90% of RA patients have it in their serum, BUT, 5-10% have RF and no RA
Radiologically:
Soft tissue swelling
Periarticular osteoporosis
Juxta Articular erosions
Narrowing of joint space
RA diagnosis can be made on clinical grounds, following a history, examination and application of diagnostic criteria. You may not be able to see changes on X Ray at diagnosis.
MDT & Shared care
Drug Treatments
To reduce symptoms
To Prevent further damage by controlling the disease
NSAIDs and DMARDS
NSAIDs: Improve joint pain and stiffness but no effect on disease progression
DMARDs:
Suppress inflammation and slow progression of joint disease
Commence by 6 weeks of onset
Mechanism of drugs not exactly understood. Some suppress immune system, some inhibit cell replication
Act slowly, DMARDs can be added or substituted if still no effect after a long time
Methotrexate, Sulfasalazine, Hydroxychloroquine
Describe the role of the MDT and the concept of shared care in the management of RA
Group of healthcare professionals that meet on a regular basis to discuss the care, progress, and treatment of a patient
Agreement between all parties (GP, hospital, patient) which enables there to be an understanding regarding the care/treatment/medications of a patient from all sides
· Decisions should be made in a patient’s best interest so healthcare professionals must be able to take full responsibility for any choices they make => e.g., GPs signing-off prescriptions for patients
· Clinical responsibilities:
o Keeping up to date with the prescribed medications of a patient
o Recognising side effects caused by medication
o Ensuring patients are clinically monitored and are aware of this => e.g., medication reviews
o Staying informed about the guidance of medications and on the management of a patient’s conditions
Consultant Rheumatologist
Rheumatology Nurse Practitioner
GP
Physiotherapist
Occupational Therapist
Podiatrist
Radiographer
Phlebotomist
Pharmacist
Pain Management Team
Clinical & Health Psychologists
Orthopaedic Surgeon
Discuss inflammatory markers and their use in diagnosing musculoskeletal disease
Inflammatory markers are Complexes that can increase or decrease and indicate inflammation in a patient
Different inflammatory markers will suggest different MSK diagnoses. Use all types of appropriate inflammatory markers as evidence to diagnose suspected disease.
Mainly measured from blood, but also urine and synovial fluid
Haemoglobin (Hb) (FBC) - Chronic inflammation indication / Autoinflammatory disease indication
White Cell count (FBC)- Infection and inflammation
ESR (Erythrocyte sedimentation rate) - increases with higher levels of plasma proteins /inflammation
CRP - inflammation
Urea and electrolytes (U&Es) - Renal impairment/ could indicate gout and connective tissue disease
Uric acid - High in gouty patients
Calcium - Hypo/hyper calcaemia - hypo - osteomalacia
Hyper - malignancy
Alkaline Phosphatase (liver function test) - high indicates paget’s disease
Creatine kinase - a muscle enzyme, increases on muscle injury /can show inflammation
Procalcitonin - when high = joint infection/inflammation (Measure in hot joints) bacterial infection and sepsis
Rheumatoid factor -
Cyclic citrullinated peptide antibody (antiCCP) - antibody found in RA pts / more specific than Rheumatoid factor. V predictive of more aggressive RA
Complement - C3 and C4 increase in inflammatory responses (low serum levels of them)
Lupus and vasculitis
Describe the commonly used drugs to treat rheumatoid arthritis
Painkillers- Relieve pain. Some OTC and some prescribed
NSAIDs
DMARDs
Steroids
Biologics
DMARDs:
E.g Methotrexate
Halt/Reverse the underlying disease
Most commonly used:
Methotrexate- Also a chemo drug, first choice to treat RA, moderate to severe RA
Salazopyrin
Hydroxychloroquine- Moderate RA
Leflunomide- Moderate to severe RA
DMARDs take several weeks to show effect
More than one can be taken
Suppress inflammation and slow progression of erosive joint disease
NSAIDs:
Improve pain and stiffness, but have no impact on disease activity or progression
Describe the key features of acute inflammation including the vascular reaction, leukocyte recruitment-activation, actions of the principal mediators of inflammation and outcomes
A response by vascularized tissue to infections and necrotic tissue damage.
It brings leukocytes & plasma proteins from the circulation to the site of infection
Acts as a protective response to remove the cause of cell injury e.g. microbes and the consequences of injury e.g. necrotic cells.
Caused by necrosis (DAMPs) or infection (PAMPs/MAMPs)
Neutrophils characterise the inflammation
Heat (Calor)
Redness (Rubor)
Swelling (Tumour)
Pain (Dolor)
Loss of function (Functio Laesa)
Stimulus: PAMPs or DAMPs are produced
Recognition by Sentinel Cells: Macrophages, dendritic cells and mast cells have toll-like receptors that recognise DAMPs or PAMPs
Cytokines produced by sentinel cells when the inflammasome complex is activated
Recruitment of Leukocytes: Neutrophils and monocytes
Inflammation Induced: Vasodilation and increased vascular permeability, leading to oedema
Phagocytosis: by neutrophils and macrophages
Regulation: Cytokines switch from inflammatory to healing and growth factors
Resolution: Where homeostasis is restored
Vascular changes:
Changes in blood flow - Vasodilation:
Induced by histamine & prostaglandins I2 & D2 (& other mediators e.g. Bradykinin & Serotonin) on vascular smooth muscle
First involves arterioles & then capillaries
Slows blood
Results in increased blood flow to affected area, causing heat & redness of site of inflammation
Increased Permeability:
Causes an outpouring of exudate
Exudate is high in proteins, including immunoglobulins and coagulation factors e.g. fibrin
Inflammatory oedema - the increase in hydrostatic pressure and decrease in plasma oncotic pressure causes net movement of fluid from the blood plasma into tissues
Changes in permeability of vessels - Retraction of endothelial cells:
Results in the opening of interendothelial spaces
Initiated by histamine, bradykinin, leukotriene B4 & nitric oxide
Mainly occurs in post capillary venules
Fast (15-30 mins) & short lived
Endothelial injury:
Leakage due to damage by burns or induced by microbes/microbial toxins
Starts immediately after damage and is sustained for several hours until damage is repaired
Maximises movement of plasma proteins & leukocytes (WBCs)
Advantages of inflammatory oedema:
Brings antibodies and fibrin to site of infection
Fibrin mesh provides a scaffold for WBCs and prevents spread of microorganisms
Contains non-specific immune cells that oponise pathogens for neutrophil-mediated phagocytosis
Fluid dilutes and modifies the actions of toxins
The exudate circulates in the lymphatic system, aiding antigen presentation
Leukocyte recruitment and activation:
Margination:
Vasodilation slows blood in the post-capillary venules
Cells marginate from the centre of the vessel to the periphery
Rolling:
Endothelial cells activated by cytokines express adhesion molecules called selectins
Leukocytes attach to selectins (via sialyl Lewis-X)
The leukocytes bind & detaching makes them ‘roll’ along endothelial surface
Adhesion:
Chemokines activate integrins which are on the surface of neutrophils
This increases their affinity for the selectins that are present on the surface of endothelial cells, causing firm adhesion between the neutrophil and the endothelial cell
Transmigration:
Leukocytes migrate through the endothelial surface by squeezing between cells at intercellular junctions. Mainly occurs in post-capillary venules. Platelet endothelial cell adhesion molecule-1 (PECAM-1) mediates the transmigration of leukocytes.
Chemotaxis:
Chemoattractants (IL-8, C5a, leukotriene B4) activate the contractile protein actin within the leukocyte, causing the cell to move
Phagocytosis and O2 Dependent Killing:
Pathogen Recognition Receptors (PRRs) e.g. toll-like receptors on the phagocyte bind to PAMPs
Bacterium becomes attached to membrane evaginations called pseudopodia which are part of the cytoplasm
Phagocyte engulf the bacterium forming a phagosome
Destruction of Phagocytosed Material
Phagosome fuses with a lysosome (phagolysosome), which contains digestive enzymes (lysosomal proteases)
The lysosomal enzymes break down bacteria into particles
In activated neutrophils, cytoplasmic components of the phagocyte oxidase enzyme assemble in the membrane of the phagosome to form an active enzyme
This enzyme catalyses the conversion of oxygen to superoxide + hydrogen peroxide
Myeloperoxidase (enzyme present in granules of neutrophils) then converts hydrogen peroxide into hypochlorite (bleach)
Reactive oxygen species, acid and nitric oxide kill the ingested microbes
Those digestion products are exocytosed from the cell and some are used for antigen presentation.
Resolution:
Neutrophils die by apoptosis and disappear within 24 hours after the stimulus has been eliminated
Important mediators of acute inflammation:
Hageman factor- Clotting factor found in blood & produced the liver, Activates the coagulation cascade, complement system and kinin system
Bradykinin- Increases vascular permeability, dilates blood vessels, contraction of smooth muscle, pain
Histamine- Vasodilation, Increased vascular permeability, Endothelial activation
Cytokines- TNF, IL-1 & IL-6 - increase COX activity in hypothalamus, raising temp, causing fever. IL-1&6 increase ACP in liver, they all increase leukocyte production in bone marrow, TNF accelerates atherosclerosis and promotes thrombosis
Chemokines - Chemotaxis, Leukocyte Activation
Complement System - See more seperately
4 Possible outcomes:
Resolution & Healing
Continued Acute Inflammation
Abscess Formation
Chronic Inflammation
Describe the causes of chronic (including granulomatous) inflammation, the cells-mediators which are involved and the processes of regeneration and repair
Outcomes of acute inflammation
· Resolution and healing
· Continued acute inflammation
· Abscess formation
· Chronic Inflammation
What is chronic inflammation
· Prolonged inflammation due to persistence of stimulus
· Characterised by macrophages lymphocytes and plasma cells
· Delayed response but more specific
Causes of chronic
· Persistent infection
· Infection with viruses, mycobacteria, parasites + fungi
· Autoimmune disease
· Foreign material
· Carcinoma
Macrophage – master controller
· Dominant cell in most chronic inflammatory reactions
· Derived from haematopoietic stem cells and circulate as monocytes
· Found in connective tissue, spleen, lymph nodes, CNS and Lungs
· Half-life of monocytes is about a day whereas the lifespan of tissue macrophages is several months or years
· Often become dominant within 2 days post-insult
· M1 stimulate inflammation
· M2 Stimulate repair
Lymphocytes
· T-cells and B-cells
· All produced in the bone marrow, T-cells mature in thymus
· In thymus T-cells differentiate into CD4+ helper T-cell or CD8+ cytotoxic T-cell
· T cells – CD4 use TCR to bind to antigen presented on MHC II
Helper T-cell
T cell receptor complex binds to MHC II antigen and CD28 binds to B7
Becomes TH-1 cells and TH-2 cells
TH-1 cells secrete interferon gamma to recruit macrophages
TH-2 cells recruit eosinophils and cause B-lymphocytes to produce IgE
B-lymphocytes
· Undergo Ig rearrangement to become naïve B-cells, expressing IgM and IgD
· Antigen binds to IgM or IgD, causing maturation to plasma cells
Granulomatous inflammation
· A collection of activated macrophages / epithelioid histiocytes
· Non-caseating or caseating (Cheese like necrosis caused by Tb)
· Mycobacterial infection, fungal infection
· Foreign material – Crohn’s disease, Sarcoidosis
How do granulomas form
· Macrophage’s process and present antigen on the surface in association with MHC II molecules to CD4+ helper T-cells.
· Macrophages secrete IL-12 causing CD4+ helper T-cells to differentiate into the TH1 subtype
· TH1 cells secrete interferon gamma, which converts macrophages into epithelioid histiocytes and giant cells
Wound healing
· Healing is initiated when inflammation begins
· Occurs via a combination of regeneration and repair
How do wounds heal?
· Replacement of damaged tissue with native tissue is dependent on its capacity to regenerate
· Types of tissues can be classified into three types based on their regenerative capacity
· Labile – able to regenerate
· Stable – liver (hyperplasia – increase cell number)
· Permanent – lack significant regenerative potential
What is involved in repair?
· Replacement of damaged tissue with a fibrous scar
· Occurs if stem cells are lost + in permanent tissues
· Granulation tissue forms initially – contain myofibroblast – smooth muscle cells and fibroblast overlap – Fibroblast produces collagen – muscle cells contract
· Myofibroblasts contract and pull edges of the wound together
Phase of wound healing
· Coagulation phase (blood going from liquid to solid) - clotting system activates due to collagen and blood contact, the hageman factor is the clotting factor linking the clotting and inflammatory system.
· Inflammatory phase - neutrophils, macrophages and platelets, they provide a scaffold and growth factors needed.
· Proliferative/ granulation tissue phase - granulation tissue formation, the formation of new capillaries and fibroblasts
· Remodelling phase - myofibroblasts remodel the extracellular matrix and this remodelling is followed by apoptosis leading to the formation of an acellular scar.
Wound healing
· Primary Intention – wound edges brought together leading to minimal scarring
· Secondary intention – Edges not brought together, Granulation tissue fills the gap, then myofibroblasts contract the wound. Scar forms
Types of scarring
· Hypertrophic scar – excess production of scar tissue that is localised to the wound
· Keloid scar – Exuberant production of the scar tissue out of proportion to the wound size. Excess type III collagen
Cause of delayed wound healing
· Infection
· Ischaemia
· Foreign bodies
· Diabetes
· Malnutrition
Discuss the mechanisms of acute and chronic inflammation
Inflammation serves to destroy, dilute and trap injurious agents
Acute Inflammation
Typically a short duration (minutes, hours or a few days)
Triggered by a range of insults (chemical, thermal damage or infection)
Infection is sensed by macrophages which release chemokines and cytokines attracting neutrophils to the site of infection
In other instances, inflammation is initiated by resident mast cells, which attract eosinophils
Once inflammation is initiated, several changes occur in vascular endothelium to allow attachment and the ‘leaking’ of monocytes - primarily neutrophils but also monocytes and lymphocytes
This results in vascular changes (vasodilation, slowing of circulation, and entry of inflammatory cells), leukocyte extravasation and chemical mediators of inflammation (histamine, cytokines, coagulation system, complement system)
Four possible outcomes: regrowth and resolution, healing by collagenous scar formation, abscess formation, chronic inflammation
Chronic Inflammation
When the causative agent cannot be eliminated and antigenic persistence occurs
Key cells of chronic inflammation are macrophages and T-cells which control infection, and lymphocytes and plasma cells which are present at the infection site
Macrophage secretory products meditate characteristic features of chronic inflammation:
Tissue damage via proteases and oxygen radicals
Revascularisation by angiogenic factors
Fibroblast Migration
Collagen Synthesis
Remodelling via Collagenases
Simulation of T-cell Activity by Secretion of IL-12
Chronic Inflammation V Acute Inflammation:
Chronic inflammation has a longer life span
Tissue destruction, inflammation and healing all happen simultaneously in chronic inflammation, but take place in stages in acute
Predominant inflammatory cells involved are different
Discuss the role of the major histocompatibility complex (MHC) in the concept of immune tolerance and how this relates to autoimmunity
Role of MHC in immune tolerance
MHC are glycoproteins that control how the immune system detects and responds to specific antigens
Pathogen recognition:
The MHC presents peptides normally inside the cell to the immune system so it can present pathogens to T-cells.
T-cells become activated if the MHC peptide is recognised as foreign
T-Cell activation leads to B-Cell proliferation
Immune Tolerance
Tolerance → the recognition of self antigens to avoid the immune system from attacking itself.
Epithelium of thymus contains MHC proteins, to present self antigens to immature T-cells (MHC also contains self-peptides)
Immunological tolerance can develop through two mechanisms: central + peripheral
Central:
Eliminates self-reactive lymphocytes in bone marrow + thymus
Positive selection → If immature T-cells have weak binding for MHC self-peptide, they survive.
Negative selection→ If immature T-cells have strong binding for MHC self-peptide, they don’t survive
Peripheral:
Eliminates self-reactive lymphocytes that escape the radar of central mechanisms in peripheral tissues + secondary lymphoid organs
Some self-reactive T-cells escape the periphery leading to the production of antibodies by B-cells to self-antigens → autoimmunity
Discuss the concept of shared care with regard to people with chronic illness and discuss the differing roles of primary, secondary and intermediate care professionals.
