Rheumatoid and other inflammatory arthritis

Question 1

What does a synovial joint look like?

Answer 1

Question 2

What is does the synovium, synovial fluid and articular cartilage consist. of

Answer 2

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

Question 3

What are the 2 major divisions of arthritis?
How does movement affect pain in each of these two types?

Answer 3

Osteoarthritis- pain usually worse on movement
Inflammatory arthritis- pain usually improves with movement

Question 4

Radiographic signs of osteoarthritis?

Answer 4

Lossof articular cartilage leading to lack of space (bone in contact with bone)
Bony spurs (osteophytes

Question 5

Causes of joint inflammation?

Answer 5

1) Infection- septic arthritis, tuberculosis
2) Crystal arthritis- gout, pseudo gout
3) Immune-mediated (“autoimmune”)

Question 6

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?

Answer 6

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”)

Question 7

Cause of septic arthritis (specify which organisms)

Answer 7

Bacterial infection of a joint (usually caused by spread from the blood)
Common organisms:
Staphylococcus aureus, Streptococci, Gonococcus

Question 8

Risk factors for septic arthritis

Answer 8

immunosuppressed, pre-existing joint damage, intravenous drug use (IVDU)

Question 9

Is septic arthritis a medical emergency?

Answer 9

Yes
Untreated, septic arthritis can rapidly destroy a joint

Question 10

Clinical presentation of septic arthritis

Answer 10

-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

Question 11

Diagnosis of septic arthritis

Answer 11

Joint aspiration. Send sample for urgent Gram stain and culture

Question 12

Treatment for septic arthritis

Answer 12

Surgical wash-out (‘lavage’) and intravenous antibiotics

Question 13

Cause of gout
Risk factor for gout
Risk factor for hyperuricaemia

Answer 13

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)

Question 14

Causes and risk factors for pseudo gout

Answer 14

Caused by deposition of calcium pyrophosphate dihydrate (CPPD) crystals
-> inflammation

Risk factors: background osteoarthritis, elderly patients, intercurrent infection

Question 15

Other than gouty arthritis, what can tissue deposition of monosodium urate (MSU) crystals lead to?

Answer 15

Tophi: often develop around hands, feet, elbows, and ears

Question 16

Clinical features of gout

Answer 16

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

Question 17

Investigations for gout/ pseudo gout

Answer 17

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

Question 18

Difference between gout and pseudo gout crystals

Answer 18

Question 19

What type of disease is rheumatoid arthritis and what is the primary site of pathology

Answer 19

RA = chronic autoimmune disease
Primary site of pathology is in the synovium
Synovitis = inflammation of the synovial membrane

Question 20

Where is synovium found and what does inflammation at each of these sites lead to?

Answer 20

Question 21

RA age of onset
Is it more common in females or males?

Answer 21

30-50
Females

Question 22

Key features of RA

Answer 22

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

Question 23

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?

Answer 23

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.

Question 24

Risk factors for rheumatoid arthritis

Answer 24

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

Question 25

Rheumatoid arthritis: pattern of joint involvement

Answer 25

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)

Question 26

Rheumatoid arthritis: extra-articular features

Answer 26

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

Question 27

Rheumatoid arthritis: subcutaneous nodules Describe the nodule How common is it in RA What is it associated with

Answer 27

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

Question 28

Rheumatoid arthritis: pathogenesis

Answer 28

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

Question 29

Can TNF alpha inhibition be used to treat RA? How is this administered and what is administered?

Answer 29

Yes Most commonly achieved through parenteral administration (most commonly sub-cutaneous injection) of antibodies or fusion proteins

Question 30

How would blood Hb, MCV, white cell count, platelet count, ESRand CRP differ in RA, osteoarthritis and septic arthritis?

Answer 30

Question 31

What antibodies are found in the blood of RA patients

Answer 31

1. 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 2. 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

Question 32

X-ray features of RA What is the limitation of this

Answer 32

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

Question 33

Ultrasound features of RA When is this performed Disadvantage of using MRI

Answer 33

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

Question 34

Principles of RA management

Answer 34

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

Question 35

Rheumatoid arthritis: pharmacological treatment

Answer 35

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

Question 36

What receptor does glucocorticoids bind Where is this receptor what happen on binding

Answer 36

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

Question 37

Methods of steroid administration

Answer 37

Oral prednisolone Intramuscular (IM) methyl prednisolone Intravenous (IV) Intra-articular (IA)

Question 38

Methotrexate mechanism of action

Answer 38

Inhibits dihydrofolate reductase (”folate antagonist”) Immunosuppressive/anti-inflammatory

Question 39

Methotrexate side effects

Answer 39

Nausea Hair loss Fall in WCC Abnormal liver function Pneumonitis Infection risk

Question 40

Biologicaltherapies for RA

Answer 40

Biological therapies are proteins (usually antibodies) that specifically target a protein such as an inflammatory cytokine 1. Inhibition of tumour necrosis factor-alpha (‘anti-TNF’) antibodies (infliximab, adalimumab, golimumab, certolizumab) fusion proteins (etanercept) 2. B cell depletion Rituximab – antibody against the B cell antigen, CD20 3. 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 4. Inhibition of interleukin-6 signalling Tocilizumab (RoActemra) – antibody against interleukin-6 receptor. Sarilumab (Kevzara) – antibody against interleukin-6 receptor.

Question 41

What is psoriasis?

Answer 41

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

Question 42

Is psoriatic arthritis seronegative?

Answer 42

Yes

Question 43

Dominant pathogenic pathway for psoriatic arthritis

Answer 43

Interleukin-17/interleukin-23 (IL17-IL23)

Question 44

Clinical presentation of psoriatic arthritis

Answer 44

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

Question 45

What is reative arthritis? What infections does it usually follow?

Answer 45

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

Question 46

Extra-articular manifestations of reactive arthritis?

Answer 46

Enthesitis (tendon inflammation) Skin inflammation Eye inflammation

Question 47

Who does this commonly occur in?

Answer 47

Commonly young adults with genetic predisposition (e.g. HLA-B27) and environmental trigger (e.g. Salmonella infection)

Question 48

Septic arthritis vs. reactive arthritis

Answer 48

Question 49

Inflammatory spondyloarthrits example What other diseases can manifest as this How does IS present

Answer 49

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)

Question 50

Classification of RA and key history/ examination points

Answer 50