Pathophysiology Flashcards
What is pseudogout?
Aging cartilage degeneration: age related OA - calcium pyrophosphate crystals into joint cavity. Common in the elderly
Mineralisation around chondrocytes
Mainly asymptomatic
What is gout? and what causes it?
Crystal arthropathy, Hyperuricaemia
Presents with a acute red swollen joint and soft tissue lesions (similar to septic arthritis)
Multiple attacks lead to chronic damage
Uric acid is breakdown product of purines, gout if not excreting it or producing too much of it
Excreted by kidneys so gout in CKD, Taken in in diet - red meat
Acute leukemia - high turnover of cells so high levels of uric acid
What are Seronegative spondyloarthropathies?
Inflammatory systemic disease involving axial skeleton (spine and sacroilliac joints), also peripheral joints. Negative to rheumatoid factor
Oligoarthritis commonly involving large joints in lower limbs
Familial clustering, & linkage to HLA-B27
Characterized by inflammation at sites of attachment of ligament, tendon, fascia, or joint capsule to bone (enthesopathy)
Includes Reiter’s syndrome, ankylosing spondylitis, psoriatic arthritis, & arthritis of inflammatory bowel disease
Occurs more third decade, commonly young men
Genetic factors important role in susceptibility
Initial event involves interaction between genetic & environment factors, particularly bacterial infections
Reiter’s syndrome may follow GI/ GU infections
Bowel inflammation implicated in pathogenesis of Reiter’s syndrome, psoriatic arthritis, & ankylosing spondylitis
What is Ankylosing spondylitis?
Erosion of sites where ligaments and tendons attach to bone at sacroiliac joint and lumbar spine. Eventual posterior fusion of spine and possible involvement of upper spine and large joints. 5x more common in men. 90% have HLA-B27 antigen
What are Reactive arthropathies?
Inflammatory joint disorders with an infective cause but distant in time and place from the infection
What is Psoriatic arthritis?
Inflammation of the joints in 5-7% of psoriasis sufferers
Most have extra spinal disease
Silver/grey scaly spots on scalp, elbows, knees and lower spine
Pitting fingernails/toenails
Pain & swelling in one or more joints
Dactylitis of fingers/toes gives “sausage” appearance
What are 3 types of autoimmunity?
Organ-specific: type 1 diabetes
Tissue-specific: myesthenia gravis
Systemic: lupus
Which cells mainly mediate autoimmunity?
B cells
Why can diagnosis of autoimmunity be difficult?
Presence of auto-antibodies in healthy patients
What are the mechanisms underlying autoimmunity?
Inappropriate access to self- antigens by antigen presenting cells (normally immuno-priviledged site exposed)
Inappropriate/increased local expression of co-stimulatory molecules (infection or inflammation)
Alterations in way in which molecules are presented to immune system
(MHC changes)
Molecular mimicry (infective agent)
What are the types of arthropathy?
Degenerative: OA
Inflammatory: Seropositive e.g. RA, Seronegative e.g. Ank Spond, Psoriatic, Inflammatory bowel disease, Gout, Infection
What are risk factors for rheumatoid arthritis?
Genetic predisposition: HLA-DR4 associated
2-3x women than men
Increases with age
Caucasians
What are symptoms of rheumatoid arthritis?
Systemic: fatigue, anorexia, weight loss, low grade fever, anaemia
Articular- joint aching and stiffness
Extra-articular: pericarditis, valve problems, atherosclerosis, pleural effusions, rheumatoid nodules, pulmonary fibrosis, anaemia, splenomegaly, osteoporosis, rheumatoid nodules, vasculitis, leg ulcers, C1/C2 atlanto-axial subluxation, nerve compression scleritis, xerophthalmia
What are clinical features in the hands of a rheumatoid patient?
Metacarpophalangeal joint & proximal interphalangeal joint arthritis with ulnar deviation
Describe the pathogenesis of rheumatoid arthritis
Rheumatic factor autoantibodies attack synovium
Inflammation of synovium: angiogenesis, proliferation
Secondary changes occur in cartilage: enzymes and prostaglandins destroy articular cartilage and underlying bone, pannus invasion destroys cartilage at joint periphery
What can cause ankylosis of joints in rheumatoid arthritis?
Reduced movement of joint due to collagen scarring building up in the joint. This can mineralise and fix the joint
Describe visible differences in the joint between RA and OA
RA: inflammation, pannus, eroding cartilage, bony & fibrous ankylosis
OA: Osteophytes, bony spur, no ankylosis, subchondral cyst, subchondral sclerosis, thinned fibrillated cartilage
What investigations can be done to diagnose rheumatoid arthritis?
Bloods
FBC : anaemia (chronic disease / haemolytic)
ESR : raised
CRP : moderately raised
Immunology: RhF : raised in ~70% of cases (also some healthy people), Anti CCP more specific marker
Radiology :
US, MR or isotope bone scans (early changes)
Radiographs of hands & feet (later changes), soft tissue swelling, juxta-articular osteopenia, joint space narrowing, periarticular erosions, subluxation, deformity
What are treatment options for rheumatoid arthritis?
Symptomatic relief: Pain killers, Glucocorticosteroids
Treatment of underlying disease process: DMARDS (Disease modifying anti-rheumatic drugs), Normally at least two
Biological agents after DMARDS have been unsuccessful
How do corticosteroids help to treat rheumatoid?
Inhibition of transcription factors
Reduced transcription of many cytokine genes e.g. ↓IL1, IL2 and TNF
Reduced clonal proliferation of T helper Cells
What are DMARDs?
Mimic endogenous compounds, Anti-cancer and immunosuppressant effects
Anti-proliferatives: Methotrexate (against folate activity), azathioprine (against purine synthesis)
Suppressive: sulphasalazine (against IL-1 & TNF), penicillamine (against MΦs, T cells, IL-1)
Gold injections = uncertain mechanism
Describe how methotrexate works
Folic acid antagonists. Inhibits dihydrofolate reductase activity which prevents conversion of dihydrofolate to tetrahydrofolate which is not all used for the production of purines and amino acids and therefore DNA and protein synthesis
Inhibits S phase
Renal excretion
Side effects - mainly affects tissues which are highly proliferative - Gi tract, liver due to anti proliferative effects
Describe how azathioprine works
Anti proliferative effects
Purine analogue
Reduce DNA & RNA synthesis so can’t go through cell cycle
Reduce guanine and adenine synthesis
Adverse effects: cholestasis, liver necrosis
What Biological Agents can be used to treat rheumatoid arthritis?
mAbs (monoclonal antibodies): infliximab = anti-TNF cytokine, rituximab = anti-CD20 on B lymphocytes
What is the prognosis for rheumatoid arthritis patients?
10% will become severely disabled, majority of damage in first 5 years
70% will have variable symptoms with flair ups requiring drug therapy 20% mild disability and symptoms
Complications: Reduced immunity, Complications of drug treatments
What questions need to be asked in a history addressing lumps and bumps?
How long have you had this? Exacerbating/alleviating factors Pain in swelling location or elsewhere History of trauma Any previous or recent treatment/intervention/surgery Site-dependent questions Neurological disturbance/distribution Temporally-associated systemic symptoms
What additional factors need to be considered when forming a diagnosis on lumps and bumps?
Age Gender Social history Occupation Medical history
What are 2 methods for lump examination?
SSSCCATTTT Site, Size, Shape, Consistency, Colour, Auscultate, Tenderness, Tissue layer, Thrills/Fluctuance, Transillumination SPACE TIT Size, Shape, Surface Position Attachments Consistency & Colour Edge Thrills/pulsation/fluctuance Inflammation Transillumination
What are methods for determining the origin/content of a lump?
Transillumination - fluid filled
Fluctuance - fluid filled
Auscultate - air, bowel sounds, pulsation, bruits
What does annular mean in relation to lumps?
Ring shaped
What does arcuate mean in relation to lumps?
Curved
What does nodule or papule mean in relation to lumps?
Palpable mass of specific size
What does macule mean in relation to lumps?
Flat region of surface colour change
What does pustule mean in relation to lumps?
Small pocket of pus
What techniques can be used to determine the tissue layer location of a mass?
Bone masses are immobile
Muscle/tendon masses can be moved, or have their movement limited, by muscle contraction
Neural masses only tend to move left-to-right
Pressing on a neural mass can cause pain/tingling/sensory loss
Lumps within the skin can be moved with the skin
What ways can you describe a skin cancer?
A – Asymmetry
B – Borders
C – Colour
D - Dimensions
How does lymphadenopathy present?
Palpable relatively non-mobile mass
Enlargement can be unilateral during cancer or infection
What are Sister Mary Joseph Nodules?
Cancer metastasis in umbilicus
Spread up urachus from bladder
What needs to be considered with groin lumps?
Can you get above the swelling? Yes: not a hernia, No: likely a hernia
Reduce a hernia and test cough impulse
Is it solid or fluid-filled? - fluid, hydrocele
Where is the lump relative to the testicle? - above: spermatocele, on testicle: Cancer
Where is the testicle? - within swelling: hydrocele
Does it look/feel like a ‘Bag of worms’? - varicocele
What is testicular pain?
Torsion until proven otherwise
What is a hydrocele? And how can you diagnose it?
Fluid in tunica vaginalis
Will transilluminate and sits at the level of the testicle
May not be able to palpate the testicle
How would a patent processus vaginalis present?
Young boy
Swelling not there in the morning but appears during the day, then disappears when lying down
Swelling transilluminates but can’t get hand above it
Peritoneal fluid communicating, gravity means it accumulates through the day
What is a hernia?
Protrusion of a tissue or organ through its retaining tissue
What are the 4 abdominal wall area hernias?
Inguinal: Males more than females, Above & medial to pubic tubercle
Femoral: Females more than males, Below & lateral to pubic tubercle
Incisional (post operative)
Umbilical: Normally in newborn / young
What is Lumbar (Petit) triangle?
Site for herniation
Bordered by iliac crest, latissimus dorsi and external oblique
What is the inguinal canal?
Passageway through anterior abdominal wall
What is the deep inguinal ring?
Invagination of transversalis fascia
Lies between the midpoint of inguinal ligament & the midinguinal point (1cm above the inguinal ligament)
What is the superficial inguinal ring?
Lies supero-lateral to the pubic tubercle
Point of emergence of spermatic cord (male) or round ligament of uterus and coverings (female)
What are the contents of the female inguinal canal?
Round ligament of uterus
Lymphatics from uterus
Ilioinguinal nerve
Genital branch of genitofemoral nerve
What are the contents of the male inguinal canal?
Spermatic cord & contents
Ilioinguinal nerve
Genital branch of genitofemoral nerve
What is a direct inguinal hernia?
Medial to inferior epigastric artery
Weakness of conjoint tendon
Presses on the superficial inguinal ring
What is an indirect inguinal hernia?
Lateral to inferior epigastric artery Passes through processus vaginalis via deep & superficial inguinal rings Travels into scrotum Congenital type Common in males
What is Hesselbach’s triangle?
Region of bulging with a direct inguinal hernia
Bordered by rectus abdominis, inguinal ligament and inferior epigastric artery
Describe the examination of an inguinal herniae
Patient lying down & standing Observe site and direction Make other regional observations Compare sides Test cough impulse Reducible/irreducible Pressure over alternate inguinal rings May need to stand Auscultate for bowel sounds
What types of groin swelling can occur in females?
Canal of Nuck (female equivalent of processus vaginalis)
Bartholin gland cyst
Femoral hernia
What swellings can occur in femoral triangle?
Saphenous vein pierces roof (can dilate here saphena varix)
Inguinal lymph nodes sit in triangle (lymphadenopathy)
Femoral hernia presents as swelling in the triangle
Where are superficial inguinal lymph nodes?
Sit in two groups, proximal & distal
Gross lymphadenopathy can present as a groin lump
Which structure lies outside femoral sheath & deep to iliac fascia?
Femoral nerve
Femoral artery, vein & lymphatics located inside the fascia
Artery and vein sit in femoral sheath & lymphatics sit in femoral canal
What is the femoral canal?
Fascial compartment for lymphatics (weak spot)
Why are women at higher risk of femoral hernia?
Wider pelvic girdle so femoral canal larger
What forms the femoral ring?
Lacunar ligament
Inguinal ligament
Pectineal ligament
High chance of hernial sac contents strangulation due to rigid borders of femoral ring
What are Branchial cysts?
Remnants of the embryological branchial sinus which should obliterate
If it remains open it can form a branchial fistula that opens & discharges onto the lower neck
What are rheumatological diseases?
Characterized by pain & inflammation in joints & connective tissues
Sometimes referred to as collagen-vascular diseases
May affect many different parts of the body
Over 200 different conditions
What are Non Immunological Inflammatory Diseases?
Osteoarthritis (OA)
Gout
Pseudogout
What form of immunity underlies the non inflammatory rheumatological diseases?
Innate
What are Immunologically-Mediated rheumatological Diseases?
Rheumatoid Arthritis (RA) Systemic Lupus Erythematosus (SLE/ Lupus) Spondyloarthropathies Ankylosing spondylitis Reactive Arthritis (Reiter’s Syndrome) Psoriatic Arthritis Spondylitis associated with Inflammatory Bowel Disease Sjogren’s Syndrome Polymyositis/Dermatomyositis Behcet’s Syndrome Systemic Sclerosis (Scleroderma) Giant Cell Arteritis
What is the Function of Normal Synovium?
Maintenance of intact non-adherent tissue surface
Lubrication of cartilage
Control of synovial fluid volume & composition (plasma & hyaluronan)
Nutrition of chondrocytes within joint
What is athralgia?
Joint pain
What are characteristics of joint Arthritis?
Pain Redness Swelling Increased warmth Fluid accumulation (synovial effusion) Stiffness (especially in morning/ inactivity)
Describe the Pathogenesis of Rheumatoid Arthritis
Inflammed synovial tissue (synovitis) Villous hyperplasia Intimal cell proliferation Inflammatory cell infiltration: T & B cells, macrophages & plasma cells Production of cytokines & proteases Increased vascularity Self-amplifying process
What are Key cytokines in Chronic Inflammatory Arthritis?
TNF-alpha IL-1 IFN-gamma IL-6 OPGL (RANK-ligand) IL-17 IL-23
What T cell subtypes contribute to pathogenesis of RA?
Synovial naive T cells
Regulatory T cells
T helper cells: release cytokines to activate leukocytes and mesenchymal cells, recruit B cell help, cytotoxicity CD8 cells, cell contact mediated activation of macrophages, fibroblasts & endothelium
What signs of RA can be seen on xray?
Early Arthritis - soft tissue swelling, especially around PIP joints Chronic inflammation in joint leads to bone destruction evident as erosions
Prolonged severe chronic arthritis leads to deformity & disability
What is the Immune Response Directed Against in RA?
Type II collagen
IgG (rheumatoid factor)
Citrullinated proteins (arginine residues modified)
What is the immune response targeted against in SLE?
Nuclear: Ribonuclear proteins, Histones, dsDNA
Leukocyte cell surface antigens
Cardiolipin
What are Susceptibility genes for rheumatological conditions?
MHC class II in RA, HLA DR4 MHC class I in seronegative spondyloarthropathy Complement deficiency genes in SLE Gender due to oestrogen involvement
Describe Genetic Basis of Rheumatic Diseases
Genotype contributes to rheumatic disease susceptibility
Rheumatic diseases are polygenic
Genotype predisposes an individual to disease, but does not make disease development certain
What Environmental factors may contribute to rheumatological disease?
Viral (hepatitis B and C, mumps, EBV)
Bacterial (Streptococci, Salmonella, Shigella)
UV light in SLE
What factors of Immune System Status are important in the development of rheumatological conditions?
Relative state of activation Relative balance of Th1:Th2 cells History of previous immune responses Level of expression of autoantigen Level of expression of MHC Co-stimulatory molecules Ongoing inflammation
Describe the 3 phases of RA development
Environment and genetics feed into this
Pre-articular phase: autoimmunity, anti CCP, RhF, collagen specific response
Transition phase: microbial insult, biomechanical events, neurological events, microvascular dysfunction
Articular phase: articular localisation, CV disease, osteoporosis, functional decline
Describe differences between acute and chronic inflammatory arthritis
Acute Arthritis: Rapid onset (hours/days), Severe symptoms, innate immune response, neutrophils (proteases, leukotrienes, prostaglandins)
rapid joint destruction, Can evolve into chronic disease
Examples: Gout & Infectious Arthritis
Chronic Arthritis: gradual onset (days/weeks), Symptoms more moderate, adaptive immune response, T cells & macrophages, Cytokines & chronic inflammation lead to joint remodeling &
destruction via erosion
Examples: Rheumatoid Arthritis, Ankylosing Spondylitis
Give examples of monoarticular inflammatory arthritis
Gout
Infection
Reactive
Give examples of polyarticular inflammatory arthritis
RA
SLE
Which joints are affected in RA and SLE?
PIPs and MCPs
Which joints are affected in Osteoarthritis and Psoriatic arthritis?
DIPs
Which joint is affected in gout?
MTP - big toe
Give examples of symmetrical inflammatory arthritis
RA and SLE
Give examples of asymmetrical inflammatory arthritis
Psoriatic and reactive
What is the clinical picture of someone presenting with RA?
Morning stiffness Arthritis of 3 or more joints Arthritis of hand joints Symmetrical Rheumatoid nodules Anti CCP/RhF Radiographic changes Diagnostic criteria: 4 of 7 present for at least 6 weeks
What can be complications of RA?
Carpal tunnel syndrome Baker’s cyst Vasculitis Subcutaneous nodules Secondary Sjögren’s syndrome Peripheral neuropathy Cardiac & pulmonary involvement Felty’s syndrome Anaemia of chronic disease
What are therapeutic strategies for RA?
Reduce inflammation: NSAIDs, Steroids (prednisolone)
Disease Modifying Anti-Rheumatic Drugs (DMARDs): Sulfasalazine, Methotrexate, Hydroxychloroquine, Steroids, Azathioprine, Cyclosporine, Cyclophosphamide
More selective biologics: TNF antagonists, IL-6R antagonists, anti-B cell (CD20) therapy, costimulatory inhibitors (CTLA4-Ig), (IL-1R antagonists)
How does etanercept exert its therapeutic effects?
Binding of inflammatory cytokines like TNF to its receptor leads to the production of inflammatory effector molecules. Soluble TNF receptor fusion proteins like etanercept prevent this binding
MAbs have similar effect by binding directly to the cytokine
What are surgical options for RA treatment?
Removal of inflamed synovium
Arthroplasty
What systems can be effected in RA?
Joints (arthritis) Vessels (vasculitis) Eyes (scleritis & episcleritis) Haematologic (anaemia, thrombocytosis) Pulmonary (pleurisy, alveolitis)
Which systems are involved in SLE?
Joints (arthritis) Skin (photosensitive rash) Serosa (pericardium & pleura) Haematology (anaemia, thrombocytopenia) Kidneys (glomerulonephritis) Lungs (interstitial disease, alveolitis) CNS (cognitive dysfunction, seizures)
What is SLE?
Autoimmune connective tissue disease, immune system primarily attacks parts of the cell nucleus
Affects tissues throughout body M:F 1: 9 Most often develops between 15 & 40yrs , although can develop any age
More common in afrocarribean and Asian populations
What risk does pregnancy pose to someone with SLE?
Chances of miscarriage, premature birth, & inter-uterine death high if disease poorly controlled
Ro or La positive mother - pass to baby and cause heart problems, baby can be born with malar rash which settles 3-6 months
What are treatment options for Seronegative spondyloarthropathies?
Early diagnosis & treatment, pain, stiffness & fusion controlled
In women, AS often mild &hard to diagnose
Exercise
Medications: NSAIDs, Sulfasalazine, MTX, Biologics
Posture management
What is Reiter’s Syndrome?
Inflammatory Arthritis can affect spine, joints of spine & sacroiliac joints
Characteristic inflammation of joints, urinary tract, eyes, & ulceration of skin &mouth
Fever, weight loss, skin rash
Often begins following inflammation of the intestinal or urinary
tract. Sets off a disease process involving joints, eyes, urinary tract, & skin. Many people have periodic attacks that last from 3-6 months Some have repeated attacks, usually followed by symptom-free periods
What are treatments for psoriatic arthritis?
Skin care Light treatment (UVB or PUVA) Corrective cosmetics Medications: NSAIDs, DMARDs Biologics IL- 23 Exercise Splints Surgery (rarely)
What is Inflammatory Bowel Disease? And how does it link to arthritis?
2 separate diseases: inflammation of bowel & can cause arthritis
Crohn’s Disease: inflammation of colon or small intestines
Ulcerative Colitis: ulcers & inflammation of lining of the colon
Severity IBD influences severity of arthritis
Other areas affected by IBD include spine, hips ankles, knees, liver, skin, eyes
Describe osteoarthrititis
Most common rheumatic disease
Progressive loss of cartilage & reactive changes at margins of joint & in subchondral bone
Begins at 40/50, increases with age; mainly aged 65 & older
Affects weight-bearing joints eg knees, hips, & lumbosacral spine
May be consequence of earlier damage or overuse of joint
Obesity frequently associated, Genetic factors play a role in development, Dominant in females, incidence 10x greater than in men
Final outcome is full-thickness loss of cartilage down to bone
What is treatment for osteoarthrititis?
Joint Replacement Surgery -Primarily of knee & hip, also available in hands, shoulders,& elbows
Indications: pain at rest, instability, patients benefit from aggressive PT before & after surgery
What are treatment options for IBD?
Diet
Exercise
Medication: Corticosteroids, Immunosuppressants, NSAIDs, Sulfasalazine, Biologics (anti- TNF)
Surgery
Who would be in the MDT of a rheumatology patient?
Consultants & trainees Rheumatology Nurse practitioner Biologics Nurse practitioner Occupational Therapist Physiotherapist
Why are cutaneous nerve innervation areas different to dermatomes?
Named nerve can carry several root values and innervate parts of several dermatomes
