PBL Case 12 - Rheumatoid Arthritis

• What are the main forms of arthritis?

  Osteoarthritis (OA): The most common form of arthritis. It results from the gradual wear and tear of the joint cartilage over time...Rheumatoid Arthritis (RA): An autoimmune disease where the immune system attacks the synovium, the lining of the membranes surrounding the joints. This can lead to inflammation, joint damage, and deformities.Psoriatic Arthritis: This type of arthritis occurs in some people with psoriasis, a skin condition. Psoriatic arthritis can affect the joints, causing pain, stiffness, and swelling, and it may also affect the skin, nails, and eyes.Ankylosing Spondylitis: Ankylosing spondylitis primarily affects the spine. It causes inflammation of the spinal joints, leading to pain and stiffness. Over time, it can result in the fusion of the spine.Gout: Gout is a form of arthritis caused by the accumulation of uric acid crystals in the joints. It often affects the big toe, causing sudden and severe pain, swelling, and redness.Juvenile Idiopathic Arthritis (JIA): Formerly known as juvenile rheumatoid arthritis, JIA is a type of arthritis that occurs in children under the age of 16. It includes several subtypes, and symptoms can vary.Lupus Arthritis: Systemic lupus erythematosus (SLE or lupus) is an autoimmune disease that can affect various organs, including the joints. Lupus arthritis can cause joint pain, stiffness, and swelling.Reactive Arthritis: Reactive arthritis is a type of arthritis that occurs as a reaction to an infection in another part of the body, typically the gastrointestinal or genitourinary tract.

  
• What is osteoarthritis?

  Most common form of arthritis consisting of progressive cartilage loss due to particular risk factors which cause structural damage to the cartilage which leads to localised inflammation which accelerates this process --> joint pain and dysfunction"Wear and tear" --> local inflammation...

  
• What are the symptoms of OA?

  - Gradual onset - Joint pain worsens with use- Pain typically worse in the evening- Moring stiffness often minor for <30 mins (longer in RA)- Generally only affects a few joints- No accompanied systemic symptoms
• What are some clinical presentations of OA?

  - Genu varum or valgus if joint wears more on one side (valgus = knocked knees l before r so acute angle)- Heberden's or Bouchard's nodes - caused by formation of osteophytes in joints of the hands- Antalgic gait (limp) due to pain- Trendelenburg gait due to muscle weakening from limited use of joint of the hip abductors (gluteus medius and minimus and TFL)

  
• Describe the pathogenesis of OA (main cycle which leads to inc cartilage destruction)

  Viscious cycle!Risk factor --> structural damage of cartilage --> inc proliferation and altered chondrocyte activity to remove damaged cartilage = inc catabolic, reduced anabolic activity (release MMPs and ADAMTs proteinases which degrade ECM, upregulate NFkB in immune cells) --> inc DAMPs --> inc macrophage stimulation in synovial sublining (loose connective tissue with numerous blood and lymphatic vessels, nerves, scattered macrophages and fibroblasts) --> release of pro-inflammatory cytokines --> inc production of MMPs and ADAMTs by chondrocytes and type 2 fibroblast like synoviocytes --> inc destruction --> inc DAMPs....

  
• What are some risk factors which could lead to the initial damage of the cartilage in a joint in OA?

  AgeingMutationsSex (Female)ObesityPrevious joint injuryJoint abnormailityOccupation
• How does OA present on an X-ray?

  Subchondral sclerosisOsteophytes and bone cystsActivated macrophages release TGF-B which stimulates osteocytes which in turn stimulate osteoblasts to build new bone --> subchondral sclerosis and production of osteophytesThis also leads to the inc production of osteoclasts --> inc bone destruction and inc rate of bone remodelling = thicker bone trabeculae, less mineralised bone and inc number of lacunae

  
• What is the initial core management of OA that we use for all?

  Education, advice and access to infoExercise to strengthen muscles and limit inc load of joints = less initial damagePatients often think this will lead to more damage - actually helps - need to educate them why - not just "wear and tear"Weight loss - to limit load of joints and structural damage to cartilage which triggers alteration in chondrocyte function

  
• What further management options are there for RA?

  
  

  Paracetamol Topical NSAIDs. If ineffective, 3rd line options include: Oral NSAIDs, Opioids, Topical capsaicin, Supports, Walking aids, Intra-articular corticosteroid injections. If all fails, joint replacement is suggested if condition is having a drastic impact on QoL

  
• What is rheumatoid arthritis?

  A systemic autoimmune disease characterised by chronic symmetrical inflammation of the small and large synovial joints, sparing the DIP joints
• Which joints does RA primarily affect?

  Small joints of hands and feet (MC/TPs and PIPs), wrists, knees and ankles

  
• What does RA result in?

  Progressive destruction of the synovial joints through loss of cartilage and bone --> pain, loss of function and deformity
• Who does RA primarily affect?

  American and european women aged 40 to 60 (but can develop at any age)
• How does RA typically present?

  Acute onset of pain and stiffness in hands, wrists or feet (like walking on marbles) with or without larger joint involvement affecting daily activities Joint pain usually eases with use. Pain and stiffness typically worse in the morning. Morning stiffness for >30 mins. Affects symmetrically. Accompanied by additional systemic symptoms e.g. malaise, fever, weight loss+/- extra-articular manifestations
• What is inflammation driven by in RA?

  Self-reactive Th cells towards proteins of the synovium (often citrullinated proteins) --> release of cytokines including IFN-gamma and IL-17 --> destruction of bone and cartilage and activation of B cells --> production of autoreactive antibodies
• What is required for the development of RA?

  Autoimmune disease - requires breakdown of tolerance, genetic predisposition and environmental triggers to develop
• What is necessary for the initiation of RA?

  Initial inflammation of the synovial tissue
• What can cause initial inflammation of the synovium? What does this lead to?

  Interaction of genetic and environmental factors --> production of self-reactive antibodies e.g. IgM Rheumatoid factor or Anti-CPP --> activation of the complement system via classical pathway (via bound antibodies) --> conversion of resident macrophages to M1 macrophages via the binding of C3a and C5a to complement receptors and direct interaction of immune complexes themselves --> release of PIC and chemokines --> extraversion of leukocytes into the synovium including SR Th cells
• What is IgM rheumatoid factor?

  An IgM autoantibody against the Fc portion of IgG - low levels usually produced to help clear immune complexes Individuals with RA produce higher levels with higher affinity to IgG by synovial B cells - not sure why...

  
• How can macrophages be activated?

  Via phagacytosis, DAMPs, PAMPs, PIC, immune complexes, complement and oxidative stress
• How does high levels of RF lead to the development of RA?

  RF binds with IgG to form immune complexes RF is primarily produced by synovial B cells so deposited in the synovium --> classical activation of complement --> production of C3a and C5a --> activation of M1 macrophages --> production of PIC and chemokines --> extraversion of leukocytes into the synovium including SR Th cells

  
• What is anti-CPP? How do they lead to the development of RA?

  Anti-cyclic citrullinated peptides are antibodies that target cyclic citrullinated peptides and form immune complexes, typically in the synovium --> classical activation of complement and direct activation of macs and neutrophils --> production of PIC and chemokines --> extraversion of leukocytes into the synovium including SR Th cells
• What can cause the production of anti-CCP?

  The inheritance of certain HLA alleles --> inc liklihood of citrullinated proteins being presented of APCs --> activation of SR Th cells in the lymph nodes --> production of anti-CPP by synovial B cells
• What are citrullinated peptides?

  Peptides that contain citrulline, a modified form of the amino acid arginine due to conversion by PAD enzymes - high levels present in joints
• Which HLA genes are associated with RA?

  HLA-DRB1 gene - higher affinity for citrullinated proteins Allows for activation of SR Th cells towards citrullinated proteins --> sustained inflammation
• Why are anti-CPP immune complexes typically formed in the synovium?

  The synovium contains high levels of PAD1 which catalyses the local citrullination of synovial proteins, such as fibrin and collagen 2 - higher levels of citrullinated proteins found here --> inc formation of anti-CPP complexes
• What environmental factors can inc the liklihood of an individual producing anti-CPP?

  Smoking and certain bacterial infections - contain citrullinated peptides. Genetic predisposition inc likelihood of these being presented on APC --> activation of SR Th cells and production of anti-CPP Anti-CPP can trigger the development of RA and/or be produced as a result of activation of SR Th cells as a result of extraversion of leukocytes in RA --> activation of B cells
• How does the activation of SR Th cells lead to destruction and further inflammation within the joint in RA?

  Results in the production of a pannus in the joint

  
• What does the activation of macrophages to M1 macrophages in the synovium lead to in RA?

  Release PIC and chemokines --> extraversion of leukocytes into the synovium including SR Th cells as well as hyperplasia and hypertrophy of the synovium --> thickeningSynovial hyperplasia --> hypoxia --> activation of HIF Tf --> release of VEGF --> angiogenesis --> inc leukocyte extraversion...

  
• How are SR Th cells activated in RA? What do they do?

  Genetic predisposition inc liklihood of self antigens such as citrullinated peptides (high production in synovium) being presented on APCAPC present these to and activate SR Th cells --> production of cytokines IL-17 and IFN-gamma
• Which leukocytes are extraversed into the synvium in RA?

  Neutrophils, monocytes, SR Th cells and SR B cells via PIC and chemokines released from activated macrophages and synovial fibroblasts

  
• Describe the formation of a pannus in RA

  SR Th cells release IL-17 and IFN-gamma which enhances the innate IR by acting as a chemotaxant for neutrophils and stimulating the production of PIC by macrophages and synovial fibroblasts --> inflammation, production of MMPs and ADAMTs by chondrocytes and synovial fibroblasts as well as production of RANKL --> stimulation of osteoclasts --> erosion of bone Result in erosion of bone and cartilage destruction

  
• What is a pannus?

  A hyperproliferative, inflammatory invasive vascularised tissue mass - a hallmark feature of the joint in RAConsists of M1 macs, MMP and ADAMT producing synovial fibroblasts and chondrocytes and infiltrating leukocytes (including SR Th cells)

  
• How does the formation of a pannus lead to chronic inflammation of a joint?

  Results in release of DAMPs --> release of PIC by macs --> cardinal signs of inflammation, pain and extraversion of leukocytes --> further damage and activation of SR Th cells...SR Th cells sustain inflammation due to presence of self-antigens

  
• What are some risk factors for developing RA?

  Smoking (contains citrullinated peptides) Age - risk inc with age as more time for "perfect storm" to occur Sex - women produce higher levels of antibodies as eostrogen stimulates IS (3:1 ratio)Obesity - AT produces PIC and adipokines which can stimulate macrophages in joints to produce PIC and chemokines and attract SR Th cells Diet - Mediterranean diet reduces risk as rich in foods with anti-inflammatory propertiesInfections - can activate SR Th cells via molecular mimicry
• What is the thought process when you have a patient presenting with joint symptoms?

  Is the problem arising from the joint(s) or not? - could be referred pain e.g. chest and upper limb pain from a heart attackIs it acute or chronic?Is it inflammatory or non-inflammatory?What is the pattern of joint involvement?
• What are some other differentials to be aware of when diagnosing RA?

  - OA- Psoriatic Arthritis- Lupus Arthritis- Gout- Sjögren's Syndrome- Other forms of arthritis Important to ask specific questions in history to help rule these out..

  
• How does RA differ from OA? How is it distinguished from RA?

  While it can cause joint pain and stiffness, OA is distinguished from RA by its gradual onset, involvement of weight-bearing joints, and absence of significant systemic inflammationOA can affect hands too BUT DIP joints are NOT SPARED

  
• How can psoriasis result in arthritis? How is it distinguished from RA?

  Both psoriasis and psoriatic arthritis are autoimmune conditionsIn psoriasis, this immune response primarily targets the skin cells, leading to the characteristic skin lesions.This is why suspected RA patients are asked about skin problems during diagnosis as PsA symptoms mimic those of RAIn psoriatic arthritis, the immune system's attack extends to the joints --> pain, swelling, and damageThis is why suspected RA patients are asked about skin problems during diagnosis as PsA symptoms mimic those of RA

  
• How can LSE result in arthritis? How is it distinguished from other forms of arthritis, including RA?

  It is a systemic autoimmune disease that can affect the joints as well as various other symptoms BUT joint pain due to lupus arthritis tends to be migratory and mainly affects large joints, helping us to differentiate it from RA This is why suspected RA and OA patients are asked about a photosensitive or malar rash during diagnosis