MJBS 2024 Flashcards
Cathepsin K, abbreviated CTSK
Cathepsin K is a protease, which is defined by its high specificity for kinins, that is involved in bone resorption. The enzyme’s ability to catabolize elastin, collagen, and gelatin allows it to break down bone and cartilage. This catabolic activity is also partially responsible for the loss of lung elasticity and recoil in emphysema. Cathepsin K inhibitors show great potential in the treatment of osteoporosis. Cathepsin K is degraded by Cathepsin S, in a process referred to as Controlled Cathepsin Cannibalism.
Cathepsin K is expressed in a significant fraction of human breast cancers, where it could contribute to tumor invasiveness. Mutations in this gene are the cause of pycnodysostosis, an autosomal recessive disease characterized by osteosclerosis and short stature.
Legg–Calvé–Perthes disease (LCPD)
Legg believed the cause was impairment of blood supply to the femoral epiphysis, Calvé believed rickets, and Perthes deduced an infection possibly causing degenerative arthritis leads to LCP disease.
Perthes’ disease is one of the most common hip disorders in young children, occurring in roughly 5.5 of 100,000 children per year. The lifetime risk of a child developing the disease is about one per 1,200 individuals. Boys are affected about three to five times more often than girls.
The disease is theorized to include the artery of the ligamentum teres femoris being constricted or even blocked too early, not allowing for time when the medial circumflex femoral artery takes over. The medial circumflex femoral artery is the principal source of blood supply to the femoral head. LCP disease is a vascular restrictive condition of idiopathic nature. Symptoms like femoral head disfigurement, flattening, and collapse occur typically between ages four and ten, mostly male children of Caucasian descent. Children affected by LCP disease often display uneven gait and limited range of motion, and they experience mild to severe pain in the groin area.
Children younger than six have the best prognosis, since they have time for the dead bone to revascularize and remodel, with a good chance that the femoral head will recover and remain spherical after resolution of the disease. Children who have been diagnosed with Perthes’ disease after the age of ten are at a very high risk of developing osteoarthritis and coxa plana.
What is the principal source of blood supply to the femoral head?
The medial circumflex femoral artery is the principal source of blood supply to the femoral head.
What artery is impeded in Perthes disease? Legg-Calve-Perthes disease.
the artery of the ligamentum teres femoris being constricted or even blocked too early, not allowing for time when the medial circumflex femoral artery takes over.
Is anti-CCP always positive in RA?
Anti-CCP is not always positive in cases of RA. An older 2016 reviewTrusted Source by a team of medical experts and rheumatologists found that a positive anti-CCP result depends on how advanced the RA is. Positive anti-CCP results occurred in:
23% of people with early stage RA
50% of people at the time of their diagnosis
53–70% of people 2 years after their diagnosis
Is anti-CCP specific to RA?
The anti-CCP test has a 96%Trusted Source specificity, which is highly accurate in determining who does not have anti-CCP. A positive anti-CCP result likely means a person has RA, but it is not specific to RA alone. In a 2020 studyTrusted Source, researchers note that it is possible for anti-CCP to be present in people with other diseases, such as tuberculosis, autoimmune hepatitis, and systemic lupus.
Therefore, a positive anti-CCP alone may not confirm RA. Clinical evaluation is also necessary to determine which disease a person has.
(CCP)
Anti-cyclic citrullinated peptide (CCP) is an auto-antibody.
Rheumatoid factor (RF)
the autoantibody that was first found in rheumatoid arthritis. It is defined as an antibody against the Fc portion of IgG and different RFs can recognize different parts of the IgG-Fc. RF and IgG join to form immune complexes that contribute to the disease process such as chronic inflammation and joint destruction at the synovium and cartilage.
Rheumatoid factor can also be a cryoglobulin (antibody that precipitates on cooling of a blood sample); it can be either type 2 (monoclonal IgM to polyclonal IgG) or type 3 (polyclonal IgM to polyclonal IgG) cryoglobulin.
Although predominantly encountered as IgM, rheumatoid factor can be of any isotype of immunoglobulins; i.e., IgA, IgG, IgM, IgE, IgD.
Cryoglobulinemia
Defined by presence of serum cryoglobulins, which are immunoglobulin complexes that precipitate at 4°C and become soluble again at 30°C
Type I: cryoglobulin is single monoclonal immunoglobulin class, usually due to myeloma, Waldenström macroglobulinemia or other lymphoma
Type II: mixture of 2+ immunoglobulins, one a monoclonal antibody against polyclonal IgG; usually IgG-IgM, in which IgM is monoclonal and has rheumatoid factor activity
Type III: both immunoglobulin components are usually polyclonal IgG and IgM
PAD4
Protein-arginine deiminase type-4, is a human protein which in humans is encoded by the PADI4 gene. The protein as an enzyme, specifically protein-arginine deiminase, a type of hydrolase.
Molecular biology
The human gene is found on the short arm of Chromosome 1 near the telomere (1p36.13). It is located on the Watson (plus) strand and is 55,806 bases long. The protein is 663 amino acids long with a molecular weight of 74,095 Da.[5]
Function
This gene is a member of a gene family which encodes enzymes responsible for the conversion of arginine to citrulline residues (citrullination). This gene may play a role in granulocyte and macrophage development leading to inflammation and immune response. PADI4 plays a role in the epigenetics, the deimination of arginines on histones H3 and H4 can act antagonistically to arginine methylation.
RANK & RANKL
RANKL plays a critical role for adequate bone metabolism. This surface-bound molecule (also known as CD254), found on osteoblasts, serves to activate osteoclasts, which are critically involved in bone resorption. Osteoclastic activity is triggered via the osteoblasts’ surface-bound RANKL activating the osteoclasts’ surface-bound receptor activator of nuclear factor kappa-B (RANK). Recent studies suggest that in postnatal bones, the osteocyte is the major source of RANKL regulating bone remodeling. RANKL derived from other cell types contributes to bone loss in conditions involving inflammation such as rheumatoid arthritis, and in lytic lesions caused by cancer, such as in multiple myeloma.
What are inflammasomes?
As part of the innate immune system, inflammasomes play an important role in the induction of inflammatory cascades and coordination of host defenses, both via the activation and secretion of pro-inflammatory cytokines and the induction of a specialized form of immune-stimulatory programmed cell death termed pyroptosis. Inflammasomes and their components can also be involved in PANoptosis, a unique form of inflammatory cell death that cannot be individually accounted for by pyroptosis, apoptosis, or necroptosis alone.
(PAMPs)
Pathogen‐associated molecular pattern molecules (PAMPs) are derived from microorganisms and recognized by pattern recognition receptor (PRR)‐bearing cells of the innate immune system as well as many epithelial cells. In contrast, damage‐associated molecular pattern molecules (DAMPs) are cell‐derived and initiate and perpetuate immunity in response to trauma, ischemia, and tissue damage, either in the absence or presence of pathogenic infection. Most PAMPs and DAMPs serve as so‐called ‘Signal 0s’ that bind specific receptors [Toll‐like receptors, NOD‐like receptors, RIG‐I‐like receptors, AIM2‐like receptors, and the receptor for advanced glycation end products (RAGE)] to promote autophagy.
What is NLR? Hint: related to inflammasome family
NLRP1, NLRP3, NLRP6 and NLRC4 are subsets of the NLR family and thus have two common features: the first is a nucleotide-binding oligomerization domain (NOD) which is bound by ribonucleotide-phosphates (rNTP) and is important for self-oligomerization. The second is a C-terminal leucine-rich repeat (LRR), which serves as a ligand-recognition domain for other receptors (e.g. TLR) or microbial ligands.
Undifferentiated spondyloarthritis (uSpA)
Undifferentiated spondyloarthritis (uSpA), also known as undifferentiated arthritis, is a non-specific mono- or polyarthropathy that lacks the clinical, serological and radiological features that would allow specific diagnosis. It often turns out to be an early presentation of a more well-known form of arthritis.
Enthesitis
inflammation of the entheses, the sites where tendons or ligaments insert into the bone.[1][2] It is an enthesopathy, a pathologic condition of the entheses. Early clinical manifestations are an aching sensation akin to “working out too much”, and it gets better with activity. It is worse in the morning (after sleeping and not moving). The muscle insertion hurts very focally as it joins into the bone, but there is little to no pain at all with passive motion. There are some cases of isolated, primary enthesitis which are very poorly studied and understood. It is known to be associated with other autoimmune diseases, like spondyloarthropathies and psoriasis (thought to often precede psoriatic arthritis). A common autoimmune enthesitis is at the heel, where the Achilles tendon attaches to the calcaneus.
Classification of Juvenile idiopathic arthritis (JIA), formerly known as juvenile rheumatoid arthritis (JRA)
The current classification system by the International League of Associations for Rheumatology (ILAR) recognizes seven distinct subtypes of JIA, based on their presentation within the first six months:
1. Oligoarticular 2. Polyarticular (RF negative)
3. Polyarticular (RF positive) 4. Systemic Onset 5. Psoriatic 6. Enthesitis Related Arthritis 7. ‘Undifferentiated’.
Toxic epidermal necrolysis (TEN) vs Stevens-Johnson syndrome (SJS).
In people with SJS, TEN is diagnosed when more than 30% of the skin surface is affected and the moist linings of the body (mucous membranes) have extensive damage. Less than 10% is SJS.
Causes of Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN).
SJS/TEN is usually caused by a skin reaction to medicine. The symptoms are likely to start showing up one to four weeks after you start taking a new drug.
The most common drug triggers of SJS/TEN include antibiotics, epilepsy drugs, sulfa drugs and allopurinol (Aloprim, Zyloprim).
Risk factors of Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN).
- HIV infection. Among people with HIV, the incidence of SJS/TEN is about 100 times greater than that among the general population.
- A weakened immune system. The immune system can be affected by an organ transplant, HIV/AIDS and autoimmune diseases.
- Cancer. People with cancer, especially blood cancers (hematologic malignancies), are at increased risk of SJS/TEN.
- A history of SJS/TEN. If you’ve had a medication-related form of this condition, you are at risk of a recurrence if you use that drug again.
- A family history of SJS/TEN. If a first-degree relative, such as a parent or sibling, has had SJS/TEN, you may be more susceptible to developing it too.
- Genetic factors. Having certain genetic variations puts you at increased risk of SJS/TEN, especially if you’re also taking drugs for seizures, gout or mental illness.
