Cases #4 Arthritis (SAQ) Flashcards
Why is articular cartilage and the synovial membrane important?
Normal articular cartilage
performs two functions:
(1) Along with the synovial fluid, it
provides virtually friction-free movement within the joint; and
(2) in weight-bearing joints, it spreads the load across the
joint surface in a manner that allows the underlying bones to
absorb shock and weight.
Synovial membrane:
Provides nutrients and lubrications. Nutrients because cartilage is avascular and lubrication bc reduce friction. Also, the synovial fluid is constant volume and it acts as a shock absorber
What is the role of these three in autoimmune arthritis
- T cells
- B cells
- Macrophages
- Cytokines produced by the activated T cells recruit leukocytes such as macrophages, whose products cause tissue injury, and also activate resident synovial cells to produce proteolytic enzymes, such as collagenase, that mediate destruction of the cartilage, ligaments, and tendons of the joint
- Macrophage-derived cytokines, particularly interleukin-1 (IL-1) and tumor necrosis factor-α (TNF-α), play central roles in this ongoing inflammatory process
- B cells will form plasma cells and produce IgM which are antibodies for your own IgG and that’s RF. They may form immune complexes with self-IgG that deposit in joints and other tissues, leading to inflammation and tissue damage. “B cells serve as antigen presenting cells, activating T cells, and producing RF”
Outline the changes that primarily affect the synovial membrane and articular cartiage, respectively in RA and OA
-What are the 4 main symptoms seen of OA in x-rays
RA:
So in the synovium, you’ll find macrophages, fibroblasts, activated leukocytes, dendritic cells, B cells, T cells, mast cells and NK + NKT cells. There are coordinated moleuclar signals (chemokines, adhesion molecules, cytokines and growth factors) and cellular events (apoptosis, proliferation, cell migration, survival) that reuslts in thickening of the synovium. This makes the tissue hypoxic (even through heaps of angiogenesis bringing the cells), because increasing metabolic demands for expanding synovial tissue - pannus invades the underlying cartilage and bone. In response to many of these cytokines, as well as immune complexes, destructive enzymes are released and result in cartilage damage. Once the cartilage has been compromised, mechanical stress enhances the cartilage damage. Bone erosion is driven by osteoclasts - RANKL is a ligand expressed on T cells and fibroblast-like synoviocytes. It will bind to RANK receptor - expressed in monocyte-macrophage lineage osteoclast precursor cells (so causes them to differentiate).
OA:
There is a loss of homeostatic mechanisms within the cartialge. There’s an imbalance of anabolic and catabolic activity that leads to eventual degeneration of the joint. This process is driven by cytokines, which in turn leads to a decrease in collagen synthesis and an increase in catabolic mediators (eg metalloprotinases). This results in the degradation and loss of matrix - loss of proteoglycans so change from blue to pink. The type-2 collagen network is diminished; chondrocyte apoptosis is increased (superficial chondrocytes die and deeper ones proliferate to form clusters - hyperplasia). Overall, cartialge tensile strenght and resilience is compromised. In response to these degenerative changes, chondrocytes proliferate and attempt to ‘repair’ the damage by synthesising new collagen and proteoglycans (doesn’t outweight tho). Cartialge becomes dehydrated (probs bc loss of proteoglycan to hold H2O) so superficial layers crack (fibrilliation) and the fragements break off to form loose bodies within joint (joint mice). Cartilage eventually lost in areas of greatest stress: the articulating areas. Leads to exposure of bone with movement leading to polishing of the exposed subchondral bone surface – called eburnation
1. Loss of joint space:
-Loss of articular cartilage which causes a loss of articular space
2. Sclerosis of bone
-Eburnated surface is sclerotic (hardened) because loss of protection of cartilage on top
3. Subchondral cysts
-It is possible for small fractures to occur through the articulating bone. Joint fluid is forced under pressure into the subarticular area in a one-way direction. The fluid incites a host response and becomes surrounded by a fibrous capsule.
4. Osteophyte formation
-Develop as a reparative response by remaining cartialge at the edges of a damaged joint.
Describe the role of key inflammatory mediators (cytokines, IL-1, IL-6 and TNF) released from macrophages in RA
These cytokines stimulate synovial fibroblasts and chondrocytes in the nearby articular cartilage to secrete enzymes that degrade proteoglycans and collagen, leading to tissue destruction
Both IL-1 and TNF-a promote activation of T cells and induce synthesis of other pro-inflammatory proteins
TNF-a promotes activation of synovial fibroblasts and consequently production of CTGF, which promotes aberrant (abnormal) activation of osteoclasts and disturbs the homeostasis of cartialge, ultimately resulting in destruction of the joint. It will lead to (1) articualr destruction and bone reabsorption (osteocla and chondrocy), (2) pannus formation by inducing endothelial cell activation and amplification of chemokines and (c) induction of pain and fever (by PGE2 synthesis promotion and nociceptor sensitization)
IL-6: contradictory bc sometimes anti-inflammatory but it induces endothelial cells to express chemokines and activated T and B cells and osteoclasts
Show how autoantibodies such as rheumatoid factor, anti-CCP antibodies and anti-nuclear antibodies have a role in pathogenesis and therefore diagnosis of arthritis
STRONG INDICATOR: Anti-CCP antibodies: CCPs are derived from proteins in which arginine residues are converted to citrulline residues post-translationally. In RA, antibodies to citrullinated fibrinogen, type-2 collagen and alpha-enolase and vimentin may form immune complexes that deposit in joints. These ABs are a diagnostic marker for the disease and may be involved in tissue injruy
MODERATE INDICATOR: Rheumatoid factor: IgM (sometimes IgA) autoantibodies that bind to the Fc portions of their own IgG. They may form immune complexes with self-IgG that deposit in joints and other tissues, leading to inflammation and tissue damage.
Antinuclear antibodies: Autoantibodies start the cascade of inflammation, causing the body to attack itself. The antibodies that target “normal” proteins within the nucleus of a cell are called antinuclear antibodies (ANA). Most of us have autoantibodies, but typically in small amounts. The presence of large amount of autoantibodies or ANAs can indicate an autoimmune disease
Show how inflamamtion of the synovial joint leads to changes in joints
Enzymes that are involved in the inflammation will damage and eventually erode the underlying cartilage. That means the underlying bone is exposed and damaged so becomes irregular and pitted - RA (eburnation in OA - polishing due to movement). Inflammatory cytokines are also released from the pannus (RA) and result in loss of arti carti and damage to exposed bone. Destruction of the adjacent joint capsule and tendons leads to instability and deformity – results in radial and ulnar deviation of the wrists. Tendons may also rupture and result in deformity of fingers (RA)
The consequence of persistent joint inflammation is damage, deformity and disability.
In OA, you’ll have the four: : loss of joint space due to loss of cartilage, sclerosis of bone in the weight bearing areas (loss of protection of cartilage). Subchondrial bone cysts and osteophyte formation (reparative response by remaining cartilage at the edges of a damage joint)
Outline the main physical findings and symptoms in patients with RA or OA
Contrast the main differences in presentation of these two diseases e.g. stiffness/pain in morning for inflammatory arthritis and pain and stiffness later in the day after use in OA, peripheral joint involvement in RA, central joint involvement in OA and SpA
OA:
General symptoms: deep, aching pain exacerbated by use (better with rest), crepitus, limited range of movement, ABSENSE OF SYSTEMIC FEATURES (no fever),
Peculiar shit: osteophyte impingement on spinal foramina - nerve root compression, Herberden’s nodes: formation of osteophytes (calcific spurs) of the articular (joint) cartilage.
Joints: Hips, knees, L + C vertebrae, DIP joints, thumb’s saddle and big toe
RA:
General symptoms: morning stiffness (get this in OA too but it’s short lived in OA - in RA, it’s like 1h), it’s systemic so you have systemic signs (systemic inflammation) - fever, weight loss, fatigue, decreased appetite, wekaness (result from mediators like IL-1 and TNF), aching joints - could be incessant pain,
Peculiar shit: Radial deviation of wrist and ulnar deviation of fingers, Bouterinne and Swan neck deformities, rheumatoid nodules: painless lumps in subcutaneous tissue of skin in areas which are subject to pressure - fibronoid necrotic core which is surrounded by a palisade of macrophages, lymphocytes and plasma cells.
Joints: SYMMETRICAL AND POLYARTHRITIS - small joints of hands (MCP, PIP), wrist, toes, larger joints like knees and ankles (also elbow, shoulder, cervical spine)
- Differences:*
1. Morning stiffness big thing in RA and you get pain with use in OA
2. Examination: joint enlargement but soft vs hard - RA: tenderness at joint lines and symmetrical swelling (effusions) aka synovial thickening
- OA: the joint enlargement may be due to osteophytes
3. Clinical diagnosis: - RA: (1) Radiographic findings, (2) sterile, tubid synovial fluid (decreased viscosity + neutrophils), (3) anti-CCP and RF
- OA: use the symptoms and then use radiograph to confirm if need be
4. Fusion of the joint deformity or whatever doesn’t take place in OA (it does in RA)
SpA:
- Absense of RF, antinuclear AB and subcutaneous nodules
- When peripheral arthritis of spondyloarthritis occurs, it frequently begins as an episodic, asymmetrical, oligoarticular process that often involves the lower extremities. The arthritis can progress and may become chronic and disabling. A unique feature of spondyloarthritis is the appearance of fusiform swelling of an entire finger or toe, referred to as dactylitis or sausage digits.
- The diagnosis is suggested by inflammatory spine pain or chronic lower extremity asymmetric inflammatory oligoarthritis in two to four joints
- RA has RF, anti-CCP, antinuclear AB, systemic effects, symmetrical polyarthritis (all unlike SpA)
- Also use NSAIDs, TNF-a blockers (uveitis - might need methotrexate and glucocorticoids)
Outline the different genetic controbutions to RA, OA and SpA
RA:
- RA is a multigene disease with important contributions from both human leukocyte antigen (HLA) esp the HLA-DRB1 locus and non-HLA genes
- PTPN22 gene - polymorphism in this gene has a strong association with RA (it’s a gene which encodes a tyrosine phosphatase that is postulated to inhibit T cell activation)
OA
- The heritable component of OA has been estimated to be between 40 and 65%, stronger for hand and hip OA than for knee OA. Polymorphisms of GDF5 , LRCH1 , and a locus on chromosome 7q22 have been associated with OA of different joints in recent meta-analytic studies
- The “nodal” OA (Heberden’s nodes) appears to have a genetic component - associated with HLA-A1,B8 haplotypes
- COL2A1 gene — Proposed candidate osteoarthritic genes include the collagen genes that encode for type II collagen
SpA:
- Spondyloarthritis is strongly associated with human leukocyte antigen B27 (HLA-27), a specific allele of the B locus of the HLA-encoding class I major histocompatibility complex genes (whites with ankylosing spondylitis, reactive arthrtitis or juvenile spondyloarthritis ).
Outline the role of environmental factors and gender in aetiology of arthtiris, including smoking in RA
RA:
- Inflammatory and environmental insults such as smoking and infections may induce the citrullination of some self proteins, creating new epitopes that trigger autoimmune reactions
- Feamles less prevalance
OA:
- Gender has some influence; knees and hands are commonly affected in women, whereas hips are more commonly affected in men (so gender prevalance depends on joint affected)
- A prevailing theory is that abnormal force through the joint, either from a single traumatic event or from repeated microtrauma over time, can lead to damage to the articular structures of the joint and initiate a cascade of events resulting in the pathological changes recognized as “OA”.
SpA:
- Didn’t find anything on gender
- With the HLA-B27 allele, there is a key environmental factor that goes with it because when animal models, who were transgenic for HLA-B27, were raised in a germ-free environment, they reamined disease free
- Important associations exist between specific bacterial agents and disease pathogenesis: things like salmonella, campylobacter all appear to trigger an inflammatory response that results in misfolding of HLA-B27 in APC, generating a persistent inflammatory reaction.
Describe the principles underlying the treatment of patients with inflammatory joint disease citing evidence base e.g. TARGET TO TREAT
Describe the treatment regime for RA
FROM THE BOOKLET, TARGET TO TREAT: TREATMENT NEEDS TO BE TARGETED TO THE INDIVIDUAL AND REGULARLY REVIWED IN RELATION TO THEIR RESPONSE TO THE THERAPY CHOSEN
TTT is generally defined as a treatment strategy in which the clinician treats the patient aggressively enough to reach and maintain explicitly specified and sequentially measured goals, such as remission or low disease activity. TTT is proactive, has a clear endpoint (the “target”), and can be operationalized as a specific treatment algorithm, simplifying the multitude of complex medication sequences that can be used to treat active RA
Treatment regime for RA:
- First if you are suspected of having RA, you used NSAIDs and either from there on, you get RA diagnosis confirmed or alternative diagnosis
- Then after the diagnosis is confirmed, you go into the DMARD (consider glucocorticoids) and you can continue NSAIDs for bridging
- Then after some months, you can either have remission or no remission.
- If remission, you can sustain the remission and maybe taper if glucocorticoids were used
- If you didn’t have remission, then you can use therapy with biological agents or combination of DMARDs or both
- If have refractory disease then you:
- Therapy started with biological agents if not started
- Consider abtacept or rituximab
- Consider switching to another biological agent
List the different classes of drugs used in the treatment of inflammatory joint disease, including those used in the management of pain. Outline their mechanisms of action and the site(s) at which they are thought to act
RA:
- Pain: paracetamol and NSAIDs
- Inflammation: NSAIDs, COX-2 inhibitors, glucocorticids
- Disease progression: DMARDS and biological agents
__________________________________________________
Paracetamol (opoid analgesic, antipyeretic, anti-inflammatory): Thought to inhibit COX prostaglandin synthesis and it can cross the BBB. One effect of it is that it reduces peripheral pain sensation ____________________________________________________
NSAIDS:
- COX enzymes turn arachdonic acid to prostaglandins. We target these enzymes with inhibitors - they aren’t streoids! They don’t alter disease progression
1. Aspirin (non-opoid analgesic, NSAID, anti-platelet agent): irreveribly binds to COXs
2. Ibuprofen (NSAID): more potent than aspirin
3. Diclofenac (NSAID): more potent than ibuprofen. This one is highly selective for COX-2 (which is 50x more produced in inflammatory process - it’s inducible).
Coxibs like Celebrex (NSAID)
-They are COX-2 inhibitors
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Glucocorticoids (cortecosteroids)
- Anti-inflammatory but also immunosuppressive
- NOT DISEASE MODIFYING!
- They alter gene transcription
1. Dexamethasone (corticosteroid): Used for inflamamtion and overactive immune system conditions
2. Prednisone (corticosteroid): Main one used - widely used for inflammation and immune conditions. It prevents the formation of arachidonic acid - target the phospholipase that converts the phospholipids to arachdonic acids
______________________________________________
DMARDs:
- Cause immunosuppression, there’s no direct anti-inflammatory effects (take a long time to work)
1. Methotrexate (immunosuppressant [antimetabolite, antifolate]): folate antagonist (folate is required for production of nucelotides and hence DNA). Targets synthesis and replication of DNA through reducing production of nucleotides. Folic acid needed for nucleotides and what methotrexate is working as a competitive antagonist for folate - it is targetting dividing cells (bone marrow, progenitor cells in immune system, tumor cells)
2. Cyclosporine (immunosuppressant): inhibits calcineurin - a phosphatase that activates T-cells. So you’ll get decreased T-cell proliferation, inhibition of IL-2
Biological agents:
- Abtacept (immunosuppressant): blocks second signal between APC and T cell by binding to the CD80 and CD86 molecule (first signal is MHC) so T cell aint activated. It is a fusion protein composed of the IgG fragment fused to the extracellular domain of CTLA-4
- Rituximab (monoclonal AB): monoclonal AB against CD20, which is found on surface of B cells, which it destroys so it depletes B cells. Plasma cells and stem cells aren’t affected bc CD20 not present on them so need constant treatment since B cells will likely repopulate
- Infliximab (monoclonal AB againt TNF-a): anti-TNF chimeric monoclonal antibody (human IgG Fc) - works to reduce unbound TNF which could activate the receptor
- Etanercept: soluble TNF receptor so like, you’ll bind TNF-a and there will be less TNF to go around activating the receptor (like infliximab but ‘cept’ and ‘mab’). Used to treat RA, and some SpA
- Adalimumab: monoclonal AB that binds to TNF-alpha and stops bind to receptor so decrease inflammation and decrease immune response. Fully human mab and only works in moderate/severe arthritis. Also RA and some SpA
- Tocilizumab: binds IL-6 receptor and prevents the transduction of signals so can’t summon T and B cells = they don’t activate
Outline the major side effects associated with these drugs, providing a rationale
- Diclofenac: higher risk of GI effects (idk why bc like, it’s a COX-2 inhibitor but yolo…guess it also inhibits some COX-1 and with more potency so like, see th GI effects more with this). You stop the formation of prostaglandins. Prostaglandins that should have been produced are important in the mucosal membrane in the stomach etc so perhaps that’s why you get the oral effects (prostaglandins are imp in production of mucosal lining in stomach. So like, shouldn’t use too much
- Celebrex: they reduce incidence of GI effects (bc COX-1’s inhibition revolves around gastric and renal effects). But there’s increased risk of CV events (from thrombus formation) so it’s PRESCRIPTION ONLY
- Glucocorticoids are used as a bridging therapy but long term use can lead to Cushingoid effects (cataracts, ulcers, skin thinning and brusising, hypertension/hyperglycaemia, infections, osteoporosis/obesity, immunosuppression, diabetes). So once remission, you should taper glucocorticoid use
- Methotrexate: mucosal ulceration, hepatic, and renal toxicity, skin reactions, nausea, teratogenic
- Clycosporin: peptic ulcers, vommitting, high blood pressure, tingling, etc
Also, with symptom relief in glucocorticoids, your disease might be getting worse but you dont realise it
Outline the principles of non-pharmacological approaches to management
Management of OA consists of non-pharmacological and pharmacological treatment. Weight loss, exercise, physiotherapy, bracing in certain instances, acetaminophen, non-steroidal anti-inflammatory drugs, and local injections are the mainstays of treatment. Joint replacement is typically performed as a last option in late stages, with outcomes being better for hip than for knee replacement
RA: surgery can achieve pain relief, deformity correction, and fucntional improvement. This can include excisions, reconstructions, joint replacements or fusions. Physiotherapy is also a thing.
Explain why inflammatory joint disease produces systemic symptoms such as fatigue and weight loss
RA is a systemic disease, and therefore in addition to joint-specific symptoms, persons with RA may experience fever, weight loss, fatigue, myalgias, and decreased appetite because of the systemic inflammation
Although RA is basically a symmetric polyarticular arthritis,
there also may be constitutional symptoms such as
weakness, malaise, and low-grade fever. Many of the systemic
manifestations result from the same mediators that
cause joint inflammation (e.g., IL-1, TNF).
Can you get osteophytic projections in RA?
Yes in seronegative!
Seronegative rheumatoid arthritis is the diagnosis of rheumatoid arthritis without the presence of certain antibodies in the patient’s blood. It is one of two main types of rheumatoid arthritis diagnoses.
Fill in this table
Yolo
Find out the roles of the the following three auto-antibodies in the pathogenesis of arthritis and their usefullness in diagnosis
(a) Rheumatoid Factor (RF)
(b) Citrulline antibodies and the anti-Cyclic Citrullinated Peptide (anti-CCP) antibody test
(c) Anti-nuclear antibody (ANA)
Yeah
