Rheumatoid and other inflammatory arthritis Flashcards
What does a synovial joint look like?
What is does the synovium, synovial fluid and articular cartilage consist. of
Synovium- 1-3 cell deep lining containing macrophage-like phagocytic cells (type A synoviocyte) and fibroblast-like cells that produce hyaluronic acid (type B synoviocyte), Type I collagen
Synovial fluid- Hyaluronic acid-rich viscous fluid
Articular cartilage-Type II collagen, Proteoglycan (aggrecan
What are the 2 major divisions of arthritis?
How does movement affect pain in each of these two types?
Osteoarthritis- pain usually worse on movement
Inflammatory arthritis- pain usually improves with movement
Radiographic signs of osteoarthritis?
Lossof articular cartilage leading to lack of space (bone in contact with bone)
Bony spurs (osteophytes
Causes of joint inflammation?
1) Infection- septic arthritis, tuberculosis
2) Crystal arthritis- gout, pseudo gout
3) Immune-mediated (“autoimmune”)
Which causes of joint inflammation are secondary in response to a noxious insult and which show primary inflammation?
Which show non-sterile and which show sterile inflammation?
secondary inflammation in response to a noxious insult- infection, crystal arthritis
primary inflammation- Immune-mediated (“autoimmune”)
Non-sterile- Infection
Sterile- Crystal arthritis, Immune-mediated (“autoimmune”)
Cause of septic arthritis (specify which organisms)
Bacterial infection of a joint (usually caused by spread from the blood)
Common organisms:
Staphylococcus aureus, Streptococci, Gonococcus
Risk factors for septic arthritis
immunosuppressed, pre-existing joint damage, intravenous drug use (IVDU)
Is septic arthritis a medical emergency?
Yes
Untreated, septic arthritis can rapidly destroy a joint
Clinical presentation of septic arthritis
-Acute red, hot, painful swollen joint
-Usually only 1 joint is affected* (monoarthritis)
-Typically fever. Patient often systemically unwell
Consider septic arthritis in any patient with an acute painful, red, hot, swelling of a joint, especially if there is fever
*gonococcal septic arthritis is an exception:
-It often affects multiple joints (polyarthritis)
-It is less likely to cause joint destruction
Diagnosis of septic arthritis
Joint aspiration. Send sample for urgent Gram stain and culture
Treatment for septic arthritis
Surgical wash-out (‘lavage’) and intravenous antibiotics
Cause of gout
Risk factor for gout
Risk factor for hyperuricaemia
Caused by deposition of monosodium urate (MSU) (aka uric acid) crystals in/around joints
-> inflammation
High uric acid levels (hyperuricaemia) = risk factor for gout
Causes of hyperuricaemia:
Genetic tendency
Increased intake of purine rich foods
Increased cell turn over eg chemotherapy
Reduced excretion (kidney failure)
Causes and risk factors for pseudo gout
Caused by deposition of calcium pyrophosphate dihydrate (CPPD) crystals
-> inflammation
Risk factors: background osteoarthritis, elderly patients, intercurrent infection
Other than gouty arthritis, what can tissue deposition of monosodium urate (MSU) crystals lead to?
Tophi: often develop around hands, feet, elbows, and ears
Clinical features of gout
Abrupt onset
Usually monoarthritis
Big toe 1st MTPJ (metatarsophalangeal joint) most commonly affected (podagra)
Can also affects other joints: most frequently joints in the foot, ankle, knee, wrist, finger, and elbow
Investigations for gout/ pseudo gout
Joint aspiration and synovial fluid analysis
Key investigation for any acute monoarthritis – NB SEPTIC joint!
Send to lab for
-Microbiology (gram stain, culture and sensivities)
-Polarising light microscopy to detect crystals
Difference between gout and pseudo gout crystals
What type of disease is rheumatoid arthritis and what is the primary site of pathology
RA = chronic autoimmune disease
Primary site of pathology is in the synovium
Synovitis = inflammation of the synovial membrane
Where is synovium found and what does inflammation at each of these sites lead to?
RA age of onset
Is it more common in females or males?
30-50
Females
Key features of RA
Chronic arthritis
Polyarthritis
Pain, swelling and early morning stiffness in and around joints
May lead to joint damage and destruction - ‘joint erosions’ on radiographs
Systemic disease with extra-articular manifestations
Auto-antibodies usually detected in blood
What does higher concordance of a trait in monozygotic than dizygotic twins indicate?
What would concordance rate of a purely genetic disease be in monozygotic twins?
If the concordance rate for monozygotic twins > dizygotic twins, this indicates a genetic component.
If the disease was purely genetic, the concordance rate would be 100% for monozygotic twins.
Risk factors for rheumatoid arthritis
Genetics- higher concordance in monozygotic than dizygotic twins (but not 100%), therefore mix of genes and environment
Strongest genetic risk factor = HLA-DR
HLA-DRb chain amino acids 70-74 (‘shared epitope’). Smoking & shared epitope synergistically increase risk
Genome-wide association studies (GWAS):
>100 other genetic loci that contribute to RA risk (polygenic)
E.g. PTPN22, IL6R
Environment:
Smoking
Microbiome
Porphyromonas gingivalis
Poor oral health
Female sex
Rheumatoid arthritis: pattern of joint involvement
Symmetrical
Affects multiple joints (polyarthritis)
Affects small and large joints, but particularly hands, wrists and feet
Commonest affected joints:
Metacarpophalangeal joints (MCP)
Proximal interphalangeal joints (PIP)
Wrists
Knees
Ankles
Metatarsophalangeal joints (MTP)
Rheumatoid arthritis: extra-articular features
Common
Fever, weight loss
Subcutaneous nodules
Uncommon
Lung disease – nodules, fibrosis, pleuritis
Ocular inflammation e.g. episcleritis
Vasculitis
Neuropathies
Felty’s syndrome – triad of splenomegaly, leukopenia and rheumatoid arthritis
Amyloidosis
Rheumatoid arthritis: subcutaneous nodules
Describe the nodule
How common is it in RA
What is it associated with
Central area of fibrinoid necrosis surrounded by histiocytes and peripheral layer of connective tissue
Occur in ~30% of patients
Associated with:
Severe disease
Extra-articular manifestations
Rheumatoid factor
Rheumatoid arthritis: pathogenesis
Synovial membrane is abnormal in rheumatoid arthritis:
The synovium becomes a proliferated mass of tissue (pannus) due to:
Neovascularisation
Lymphangiogenesis
inflammatory cells:
activated B and T cells
plasma cells
mast cells
activated macrophages
Recruitment, activation and effector functions of these cells is controlled by a cytokine network
There is an excess of pro-inflammatory vs. anti-inflammatory cytokines (‘cytokine imbalance’)
The cytokine tumour necrosis factor-alpha (TNFα) is the dominant pro-inflammatory cytokine in the rheumatoid synovium
Its pleotropic actions are detrimental in this setting:
Osteoclasts - activate bone resorptions to cause bone erosion
Synoviocytes - activates joint inflammation to cause pain and joint swelling
Chondrocytes- hypertrophy and its expression of proteolytic enzymes leads to cartilage degradation to cause joint space narrowing
Can TNF alpha inhibition be used to treat RA?
How is this administered and what is administered?
Yes
Most commonly achieved through parenteral administration (most commonly sub-cutaneous injection) of antibodies or fusion proteins
How would blood Hb, MCV, white cell count, platelet count, ESRand CRP differ in RA, osteoarthritis and septic arthritis?
What antibodies are found in the blood of RA patients
- Rheumatoid factor
Antibodies that recognize the Fc portion of IgG as their target antigen
typically IgM antibodies i.e. IgM anti-IgG antibody
Positive in 70% at disease onset and further 10-15% become positive over the first 2 years of diagnosis - Antibodies to citrullinated protein antigens (Anti-citrullinated protein Antibodies ACPA)
Antibodies to citrullinated peptides are highly specific for rheumatoid arthritis
Citrullination of peptides is mediated by enzymes termed:
Peptidyl arginine deiminases (PADs)
Smoking causes citrullination of proteins in the lung epithelium therefore risk factor for RA
ACPAs predate first clinical symptoms of RA by a median of 4.5 years
X-ray features of RA
What is the limitation of this
Radiographic features of RA:
Soft tissue swelling
Peri-articular osteopenia
Bony erosions
NB erosions occur only in established disease. The aim of modern therapy is to treat EARLY before erosions (permanent damage) has occurred
Information from X-rays is limited to bony structures
Ultrasound features of RA
When is this performed
Disadvantage of using MRI
Ultrasound (US) is a much better test for detecting synovitis. US changes in RA:
Synovial hypertrophy (thickening)
Increased blood flow (seen as doppler signal)
May detect erosions not seen on plain X-ray
US (usually of hands and wrists) can be performed alongside clinical assessment in a dedicated early arthritis clinic
MRI can also be used but expensive and time-consuming
Principles of RA management
Treatment goal: prevent joint damage
Requires:
Early recognition of symptoms, referral and diagnosis
Prompt initiation of treatment: joint destruction = inflammation x time
Aggressive pharmacological treatment to suppress inflammation
Multidisciplinary input where needed e.g. physiotherapy, occupational therapy, surgery
Rheumatoid arthritis: pharmacological treatment
Glucocorticoid therapy (‘steroids’) useful acutely but avoid long-term use because of side-effects.
NSAIDs (non-steroidal anti-inflammatory drugs e.g. ibuprofen): symptom relief but increasingly less important and unfavourable long-term safety profile ((renal function, cardiovascular risk))
‘DMARDs’ (disease-modifying anti-rheumatic drugs) =
drugs that control the disease process (usually immunosuppressive)
1st line treatment regime:
IM or short course of oral steroids
Start combination DMARD therapy (usually Methotrexate + hydroxychloroquine &/or sulfasalazine)
2nd line regime:
Biological therapies: potent and targeted
New therapies include Janus Kinase (JAK) inhibitors : Tofacitinib & Baricitinib
What receptor does glucocorticoids bind
Where is this receptor
what happen on binding
Glucocorticoids bind the glucocorticoid receptor (GR)
GR resides in cytoplasm
On binding by glucocorticoids, steroid-GR complex translocates to the nucleus and binds DNA response elements, affecting transcription
Methods of steroid administration
Oral prednisolone
Intramuscular (IM) methyl prednisolone
Intravenous (IV)
Intra-articular (IA)
Methotrexate mechanism of action
Inhibits dihydrofolate reductase (”folate antagonist”)
Immunosuppressive/anti-inflammatory
Methotrexate side effects
Nausea
Hair loss
Fall in WCC
Abnormal liver function
Pneumonitis
Infection risk
Biologicaltherapies for RA
Biological therapies are proteins (usually antibodies) that specifically target a protein such as an inflammatory cytokine
- Inhibition of tumour necrosis factor-alpha (‘anti-TNF’)
antibodies (infliximab, adalimumab, golimumab, certolizumab)
fusion proteins (etanercept) - B cell depletion
Rituximab – antibody against the B cell antigen, CD20 - Modulation of T cell co-stimulation
Abatacept - fusion protein - extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to modified Fc (hinge, CH2, and CH3 domains) of human immunoglobulin G1 - Inhibition of interleukin-6 signalling
Tocilizumab (RoActemra) – antibody against interleukin-6 receptor.
Sarilumab (Kevzara) – antibody against interleukin-6 receptor.
What is psoriasis?
Psoriasis is an immune-mediated disease affecting the skin
Scaly red plaques on extensor surfaces (eg elbows and knees)
~10% of psoriasis patients also have joint inflammation
Is psoriatic arthritis seronegative?
Yes
Dominant pathogenic pathway for psoriatic arthritis
Interleukin-17/interleukin-23
(IL17-IL23)
Clinical presentation of psoriatic arthritis
Varied clinical presentations:
-Classically asymmetrical arthritis affecting IPJs
But also can manifest as:
-Symmetrical involvement of small joints (rheumatoid pattern)
-Oligoarthritis of large joints
-Arthritis mutilans
-Spinal and sacroiliac joint inflammation
What is reative arthritis?
What infections does it usually follow?
Sterile inflammation in joints following infection elsewhere in the body
Symptoms follow 1-4 weeks after infection and this infection may be mild
Common infections:
urogenital (e.g. Chlamydia trachomatis)
gastrointestinal (e.g. Salmonella, Shigella, Campylobacter infections)
Reactive arthritis may be first manifestation of HIV or hepatitis C infection
Extra-articular manifestations of reactive arthritis?
Enthesitis (tendon inflammation)
Skin inflammation
Eye inflammation
Who does this commonly occur in?
Commonly young adults with genetic predisposition (e.g. HLA-B27) and environmental trigger (e.g. Salmonella infection)
Septic arthritis vs. reactive arthritis
Inflammatory spondyloarthrits example
What other diseases can manifest as this
How does IS present
Classic example is Ankylosing spondylitis (AS)
SpA can also occur as a manifestation of psoriatic arthritis and inflammatory bowel disease (IBD)
Primarily inflammation of the spine (spondylitis) and sacro-iliac joints (sacro-iliitis)
Peripheral joints, esp. tendon insertions (entheses), can also be affected
Extra-articular manifestations including anterior uveitis (iritis)
Classification of RA and key history/ examination points
