The Pathologic Human Joint

=Objectives= All the objectives for this lecture are student supplied.

Different categories of "Arthritis", aka Musculoskeletal Pain

 * Nonarticular: Away from the joint, this is due to muscle, bone or bursa.
 * Referred: This has a source away from the musculoskeletal system. It is due to visceral pain, neurological or central sensitization.
 * Periarticular: This is due to things around the joint. It could be a muscle, tendon, tenosynovium, bursa or ligament.
 * Arthritis: And this is due to stuff in the joint. It can be due to processes affecting the subchondral bone, cartilage, synovial fluid or synovium.
 * Splitting of Arthritis: Arthritis is classically classified as either inflammatory or non-inflammatory. This does not mean that inflammatory processes are not taking place in non-inflammatory arthritis!  It is just a convenient, if outdated, classification system.  Non-inflammatory, the smaller category, is either due to: trauma, avascular necrosis, neuropathic/charcot marie tooth, or endocrine/metabolic/other...
 * Splitting of Inflammatory Arthritis: Inflammatory arthritis typically presents as clinically appreciable (i.e. to the naked eye and touch) inflammation. It is red, hot, tender, and/or swollen.  It is split into three categories: polyarticular, oligoarticular and monoarticular.  Polyarticular is most likely rheumatoid arthritis.  It could also be SLE related, vasculitis, or due to viral causes such as Hep B/C or parvovirus.  Oligoarticular (meaning "a few" joints) arthritis are the spondyloarhtropathies.  These are: ankylosing spondylitis, reactive arthritis (formerly called Reiter syndrome), Psoriatic arthritis and SpA associated with Chron's disease or ulcerative colitis.  I believe polymyalgia rheumatica should be here as well, but it isn't in the slides.  Finally, under monoarticular arthritis, there is septic arthritis, gout and pseudogout.

Changing Understanding of Osteoarthritis

 * Historically, OA is primarily a disease of the cartilage. However, science is moving towards the conclusion that it is a pathologic response of the entire joint with cartilage eburnation & fissure, subchondral bone changes, synovial hypertrophy, and systemic hormones/cytokines.
 * It was previously recognized that weight and joint malalignment contribute to OA. It is now recognized that chondrocytes serve as mechano-sensors and alter their metabolism in response to loading.  In response to mechanical stress, chondrocytes change gene expression and increase production of inflammatory cytokines and matrix-degrading enzymes.  So, there seems to be a systemic response which correlates to the observation that obesity associated OA occurs in this descending frequency: knee > hand > hip.
 * It is not just degeneration, it is an active process. It is due to ineffective repair, chondrocyte dysfunction, protease activation and cytokine/growth factor elaboration.

Pathogenesis of Osteoarthritis

 * Cartilage quality declines. There is collagen fragmentation, hyperhydration, and increased extractability of proteoglycans.  This all leads to matrix disorganization.
 * In the abnormal joint, there is cartilage matrix disorganization and defective chondrocyte function in response to mechanical loading and damage. Both of these lead to ineffective degradation, impaired synthetic function, loss of normal matrix, and an increasing amount of cartilage susceptible to further damage.
 * Specifically, chondrocytes in OA exhibit: increased metabolism and protein synthesis; increased mitosis and formation of clones; increased degradation of proteins/collagen; and changes in cytokine profile and responsiveness.
 * CARTILAGE DOES NOT JUST WEAR AWAY!
 * Proteinases: metalloproteinases, serineproteases and cysteineproteases are all degrading the extracellular matrix.
 * Cytokines: These include CSFs, GFs, ILs and IFNs. In OA and increase is seen in IL1, IL6 and TNF-alpha which means an increase in degradation and a decrease in synthesis.  A decrease is seen in TGF, PDGF, IGF-1, IFN-gamma, FGF and EGF which would normally work to slow degradation and increase synthesis.
 * There is a potential link between obesity and OA via: leptin, estrogen, IL-6, IL-beta and TNF-alpha.
 * In post-menopausal women, the decline in estrogen is associated with an increase in IL-6 and TNF-alpha (Robbins).
 * Other potential contributors to OA are: the synovium through cartilage nutrition, as a cytokine source and via synovitis; the synovial fluid (roles are uncertain); and through bone via proliferation, sclerosis and osteophytes.

Aging and Osteoarthritis

 * Aging cartilage does not equal OA. This is a pathogenic state.  However, the incidence of OA does increase with age as well as genetics, obesity, congenital factors, vocation/avocation, trauma and other secondary factors.
 * There is a difference between use and overuse. NFL football players get OA early.  Runners have not been shown to have any greater incidence of OA.

Clinical Findings in Osteoarthritis

 * There is pain with use and a limited but painful ROM. There is joint line tenderness.
 * It is slowly progressive. The pain is increased with use and decreased at night and with rest.
 * There is some slight morning stiffness. There is "gelling": stiffness after use.  There is also crepitus in the joint.
 * Grossly, there is joint enlargement due to bone, effusion and ligaments.
 * Nodules on the DIP are referred to as Heberden's nodes. Those on the PIP are Bouchard's nodes.  Both of these are found in primary OA.
 * Secondary OA occurs at the knee/hip or due to trauma.
 * The other type of OA is spinal OA/degenerative disc disease.
 * Radiographic changes are: joint space narrowing, subchondral sclerosis, subchondral discs and the presence of osteophytes.

Treating Osteoarthritis

 * Goals: prevent the disease, prevent the progression, and reverse the progression.
 * There are a number of challenges surrounding OA clinical trials. It is uncertain who is best to study (early OA? Late OA?), or what exactly should be studied (clinical symptoms? x-ray changes? Biomarkers?.)
 * There are non-modifiable risk factors for OA: age, sex (the ladies get it more) and genetics.
 * There are modifiable risk factors for OA: obesity, overuse and trauma.
 * Pain is can be due to a number of factors including: subchondral bone ischemia and repair, osteophytes, synovium/bursa inflammation, capsule distention and growth, muscle spasm, CNS problems, cartilage fragmentation, and synovial fluid.
 * Treatment is predicated on: correct dx, psychological factors, physical factors. It can be in the form of analgesia (acetaminophen, NSAIDs or opiods), intraarticular injection of steroids or surgery.

Fibromylagia

 * A constellation of symptoms including wide-spread, chronic pain.
 * Characterized by: wide spread pain for at least 3 months, pain to palpation of typical tender points, and can co-exist with inflammatory disease (RA, SLE)
 * Female:male ratio of 7:1
 * Associated with: sleep disorder, MDD, anxiety, migraines, IBS, panic disorder and lack of aerobic exercise.
 * Current scientific data points to a central sensitization of pain (ie descending pathways of pain) occurring in the absence of tissue damage.

Gouty Arthritis
=Links=
 * On arthrocentesis, there is the presence of negatively birefringement crystals. These are needle shaped, and "CUB", i.e. Cross Urate Blue.  They are uric acid crystals that are indicative of gouty arthritis.
 * In pseudogout, the culprit is the calcium pyrophoshate dihydrate crystal. This is thick, rhomboid or square and is a weakly positive birefringement crystal.
 * Gout is classically an acute, mono-articular, inflammatory, self-limited arthritis. 90% of first gout attacks occur at the 1st MTP or ankle.  Over time, oligo-articular or even polyarticular attacks occur including the upper extremities.
 * Serum uric acid is soluble ~7 mg/dL, but can remain soluble in serum in a supersaturated state depending on temp, pH and proteins. Precipitation out of serum into crystals occurs in gout and results in gouty tophi.
 * The cause of the gout attack is innate immunity. This is the rapid immune response to danger and tissue damage.
 * PAMPs (remember them?) are the extracellular receptors to invariant patterns found on common pathogens. They activate an innate immune response and neutrophils and macrophages rapidly respond.
 * DAMPs (danger/damage associated molecular pattern) are activated in the presence of uric acid, among other things. Uric acid binds the DAMP, triggering catalytic activity leading to cleavage of inactive pro-IL-1-beta to active IL-1-beta.  IL-1 drives the inflammation response.
 * Uric acid metabolism and production is dependent upon xanthine oxidase. This enzyme catalyzes the last 2 steps in the purine to uric acid pathway.  URAT1 handles urate excretion/resorption in kidney.
 * Gout is treated with inhibitor of xanthine oxidase (Allupurinol, Fexuxostat, and Oxipurinol) to decrease uric acid production. Inhibitors of URAT1 (Probenicid, benzbromarone, losartan, and fenofibrate) can reduce renal resorption of uric acid promoting excretion in urine.
 * Radiology references for arthritis (OA, gout, RA)
 * Pseudogout case by European Society of Radiology
 * Gout case by European Society of Radiology