Crystalline Arthritis Flashcards
There is evidence that the use of a biologic IL-1B inhibitor may be an option for severe and refractory gouty arthritis attack. Why?
Monosodium urate crystal actviate the inflammasome and induce release of IL-1B.
What are some drugs against Il-1B?
- Anakinra (recombinant human Il-1 receptor anatagonist)
- Canakinumab (Il-1B Ab)
- reilonacept (decoy IL-1B receptor)
What is gout?
Gout is marked by transient attacks of acute arthritis initiated by crystallization of monosodium urate (MSU) within and around joints.
It develops after many years of hyperuricemia. Hyperuricemia is defined as a plasma urate level greater than 7.0 mg/dL.
How does gout typically begin?
Gout typically begins as an acute monoarticular arthritis most often a joint (such as 1st MTP) in the distal lower extremity. It is a severe painful arthritis but usually resolves within 5-7 days.
Gout may also in later stages become polyarticular and can be confused with rheumatoid arthritis.
In some patients, the accumulation of MSU in the body results in what?
tophi (or large deposits of MSU) typically over extensor surface of upper or lower extremity joints. MSU can also deposit in the interstitium of the kidney leading to renal functional impairment.
Urinary stones of uric acid may also form (urolithiasis).
What are the major causes of PRIMARY gout?
Decreased renal uric acid excretion in more than 90% and overproduction of urate in less than 10% of affected patients.
What are the major causes of secondary gout?
Secondary hyperuricemia and gout are usually related to decreased renal urate clearance as a direct or indirect consequence of the primary disease process.
Four known specific inborn errors of purine metabolism with overproduction of urate account for less than 1% of cases of secondary hyperuricemia and gout
How is uric acid made in humans?
Uric acid synthesis and purine salvage. Catabolism of purines, especially inosine monophosphate (IMP) and guanosine monophosphate (GMP), results in urate synthesis via the common substrate xanthine. Xanthine oxidase is necessary for urate synthesis from any purine and so serves as a target for agents that inhibit uric acid synthesis (e.g., allopurinol, febuxostat). Purine salvage via hypoxanthine guanine phosphoribosyl transferase (HGPRT) returns hypoxanthine and guanine to IMP and GMP, respectively.
Denoted in bold, mammals other than primates and some monkeys possess uricase, which converts uric acid to allantoic acid for further degradation. APRT, adenine phosphoribosyl transferase; AMP, adenosine monophosphate; PNP, purine nucleotide phosphorylase; XMP, xanthine monophosphate.
What does HGPRT deficiency result in?
partial loss not only increases in hypoxanthine and guanine and subsequent uric acid synthesis but also in the depletion of nucleotides that provide feedback inhibition on purine biosynthesis.
NOTE:
Complete absence of HGPRT also results in hyperuricemia, but the significant neurologic manifestations of this condition (Lesch-Nyhan syndrome) dominate the clinical picture so it is classified as secondary gout.
How is urate/uric acid handled by the kidneys?
freely filtered 100% at the glomeruli into the PT where it is almost (98-100%) completely reabsorbed
What happens to the reabsorbed urate?
50% of the reabsorbed urate is then secreted back into the proximal tubules where once again it is largely reabsorbed such that in the final analysis, 8-12% of the urate originally filtered by the glomeruli winds up excreted into the urine as uric acid.
What are the transporters of urate resorption in the kidneys? secretion?
reabsorption- URAT1, OAT4, OAT10
secretion- OAT1, OAT3, ABCG1, MRP4, NPT1,4
Why do men have more serum urate than women?
The normal adult male has a total body urate pool of ~1200 mg, twice that of the adult female. This gender difference may be explained by an enhancement of renal urate excretion due to the effects of estrogenic compounds in premenopausal women.
How does urate enter the intestine?
The entry of urate into the intestine is most likely a passive process that varies with serum urate concentration.
What is another way urate enters the urine?
Intestinal tract bacteria are able to degrade uric acid. This breakdown process (intestinal uricolysis) is responsible for approximately one-third of total urate metabolism, and accounts for nearly all urate disposed of by extrarenal routes. Under normal conditions, uric acid is almost completely degraded by colonic bacteria with little being found in the stool.
Individuals with high serum value levels may deposit urate either occultly or in the form of appreciable masses (tophi) with the consequence that the total body urate pool may be significantly higher than in nonhyperuremics.
Such occult deposition of uric acid (total body urate burden) may have implications for treatment because they may form a “buffering reservoir” of urate that that resists initial treatment with urate-lowering agents
Primary hyperuricemia in men frequently begins when?
at puberty, when the lower serum urate levels characteristic of children rise into the adult male range.
WHY GOUT AFFECT MORE MALES THAN females before menopause?
Due to an enhancing effect of estrogenic compounds on renal urate clearance. Thus, hyperuricemia in women is usually delayed until after menopause; at that point serum urate values in normal women increase, and approximate those in normal men of corresponding age.
*There is a lesser rise in urate levels in postmenopausal women treated with estrogen replacement therapy*
Normal age of onset of gout for men? women?
men- 30-45
women- 55-70
Thus, the clinical manifestations of hyperuricemia occur, on average, about two decades later than the initial physiologic increase in serum urate concentration. This observation suggests that there is a lengthy period of asymptomatic hyperuricemia preceding the occurrence of gout in both men and women.
How does a gout attack develop?
The inflammation in gout is triggered by precipitation of monosodium urate (MSU) crystals into the joints, which result in the production of cytokines that recruit leukocytes. Macrophages phagocytose the MSU and the intracellular sensor, the inflammasome, recognizes the crystals. The inflammasomeactivates caspase-1, which is involved in the production of some biologically active cytokines, most notably IL-1. IL-1 is proinflammatory, and promotes accumulation of neutrophils and macrophages in the joint. These cells, in turn, release other cytokines, free radicals, proteases and arachidonic acid metabolites, all of which recruit more leukocytes and damage the joint.
Urate crystals may also activate the complement system, leading to the generation of chemotactic complement byproducts. These cascades trigger an acute arthritis, which typically remits spontaneously in days to weeks.
How is a gout attack propagated?
Propagation of the acute gouty response by activated neutrophils. Neutrophils that enter the joint migrate toward and phagocytose crystals. In the case of crystals coated with immunoglobulins and complement, the resultant activation results in synthesis and/or release of inflammatory mediators such as interleukin (IL)-1β, IL-8, and TNF, as well as proteases and reactive oxygen species. In the case of uncoated crystals, the crystal frequently interacts with, and lyses the membrane of the phagolysosome, spilling toxic contents and leading to cell lysis. In both cases, the result is local tissue damage and recruitment of additional neutrophils from the bloodstream in an explosive inflammatory cycle. LTB4, leukotriene B4.
Why does gout occur in synovium over plasma?
Gout
NOTE:
Synovial fluid is inherently a poorer solvent for monosodium urate than plasma. The lower temperature of the peripheral joints also favors precipitation. Gout attacks also commonly occur in the morning due to decreasing pH that occurs during rest and in the big toe begin blood pools there.
What is this showing?
Radiographs demonstrating severe destructive changes in tophaceous gout.
Repeated attacks of acute arthritis lead eventually to chronic tophaceous arthritis and the formation of tophi in the inflamed synovial membranes and periarticular tissue.
Radiographs show changes typical of bony tophi including soft tissue distortion, erosions with sclerotic margins, and overhanging edges. Joint space narrowing is minimal, despite the large erosions.
As mentioned, primary overproduction of uric acid can be due either enzyme abnormalities or increased purine biosynthesis. What are some enzyme abnormalities assoicated with primary hyperuricemia?
PRPP synthetase increased activity- X linked
HPRT deficiency- X- linked
What are the effects of partial HPRT deficiency?
Increased purine biosynthesis de novo driven by surplus PRPP; overproduction of uric acid
Kelley-Seegmiller syndrome
What are the effects of virtually complete HPRT deficiency?
X-linked condition called Lesch-Nyhan associated with increased purine biosynthesis de novo driven by surplus PRPP
Other enzyme abnormalities assoicated with increased purine biosynthesis de novo?
1) Glucose-6-phosphatase deficiency or absence
2) Fructose-1-phosphate aldoade deficiency
What are the effects of Glucose-6-phosphatase deficiency or absence?
Von Gierke’s disease- an AR disease characterized by overproduction PLUS UNDEREXCRETION OF URIC ACID
glycogen storage disease type 1
What are the effects of Fructose-1-phosphate aldolase deficiency?
Overproduction PLUS underexcretion of uric acid (also AR)
What are some systemic conditions causing OVERPRODUCTION of uric acid?
- Hemolytic anemia
- SCD
- Thalassemia
- Polycythmia vera
- Megaloblastic anemia
- MM/Waldenstroms macroglobulinemia
- Tumor lysis syndrome
- Psoriasis and Sarcoidosis
- Leukemia and Lymphoma
others
What are some systemic conditions causing UNDEREXCRETION of uric acid?
- Renal insufficiency
- Dehydration/volume depletion
- Lactic acidosis
- Ketoacidosis
What are some systemic conditions causing BOTH OVERPRODUCTION AND UNDEREXCRETION of uric acid?
- MI
- CHF
- SEPSIS
What are some metablic states associated with hyperuricemia?
- Hyper- and hypothyroidism
- Hyper and hypoPTHism
- Obesity
What is this?
Idiopathic symmetric pseudorheumatoid calcium pyrophosphate dihydrate (CPPD) deposition arthropathy in an elderly female. This 84-year-old female presented with a history of past right carpal tunnel syndrome and with chronic symmetric proliferative synovitis of both wrists and second and third metacarpophalangeal (MCP) joints, with physical findings of synovial and dorsal extensor tenosynovial swelling of the wrists and synovial swelling at the second to third MCP joints (A). Changes on hand and wrist plain radiographs consistent with the diagnosis of CPPD deposition disease, presented for the right wrist (B), included cystic changes in multiple carpal bones including the scaphoid and lunate, linear calcification on the ulnar side of the carpus (arrow) typical for the chondrocalcinosis of CPPD deposition, and mild narrowing of the radiocarpal joint indicative of cartilage loss.
Chondrocalcinosis of the most commonly affected joints in calcium pyrophosphate dihydrate deposition disease. A, Linear calcifications observed in knee menisci and fibrocartilage. B, Lateral view showing calcification of the articular cartilage as a line parallel to the femoral condyles. C, Calcification of intercarpal joints and triangular ligament. D, Calcification of the symphysis pubis fibrocartilage associated with subchondral bone erosions and subchondral increased bone density.
Whats going on here?
Hydroxyapatite crystal-associated calcific bursitis of the shoulder in a patient with chronic renal failure and secondary hyperparathyroidism
A, Chronic soft tissue swelling involving the right shoulder due to calcific right shoulder subacromial bursitis in a middle-aged male with a history of chronic renal failure on hemodialysis. Note the convex contour of the right shoulder compared with the left.
B, Radiograph showing extensive calcification both within the rotator cuff and the expanded subacromial bursa surrounding the right shoulder joint. Incidental note is made of the resorption of the distal end of the clavicle consistent with the secondary hyperparathyroidism in this patient
Subacromial bursa fluid from the right shoulder. Note the milk-white appearance with a chalky sediment of the particulate material in the fluid after centrifugation consistent with crystal deposition disease
D, Microscopic appearance of bursa fluid aggregates of basic calcium phosphate crystals in the absence of special stains. The particles are irregular but have approximately spherical profiles. (Unstained. Magnification ×250.)
E, Appearance of the bursa fluid under polarized light microscopy. Importantly, the aggregated particles of basic calcium phosphate crystals demonstrate edge birefringence but do not display intrusive birefringence, as seen in the figure. (Unstained. Magnification ×250.)
Electron photomicrograph of a mononuclear phagocyte from this bursa fluid that contained phagocytosed electron dense (dark black) spherical aggregates of crystals of the basic calcium phosphate hydroxyapatite in three phagolysosomes oriented vertically to the right of the nucleus. Hundreds of tiny needle-shaped hydroxyapatite crystals are clumped in each of these dense aggregates. For perspective, the size of the mononuclear phagocyte is approximately 20 microns, and an individual (nonaggregated) hydroxyapatite crystal is approximately 0.04 × 0.01 × 0.01 microns in size. (Transmission electron microscopy. Magnification ×1000.)
What is this?
GOUT
- Development of tophi – white chalky aggregates of uric acid crystals
- Renal failure – urate crystals deposit in the kidney tubules
- Negative (needle shaped) birefringence (Negative birefringent crystals are blue when perpendicular and yellow when parallel.)
What is this?
A typical granuloma seen in gout. The central part is formed by urate crystals (u). The inflammatory cells surrounding the area of rystals typically include macrophages, lymphocytes, plasma cells, and giants cells.
What is this?
Gouty tophus
The urate deposits (amorphous pink areas) have been dissolved by formalin fixation. H&E
NOTE: preservation of the crystals for ID with polarized light microscopy REQUIRES the use of unstained sections because the aqueous dyes used in most staining techniques will dissolve the crystals. Crystal preservation is also improved using alcohol rather than formalin
What is this?
Gouty bursitis.
•The urate deposits (brownish areas) have been preserved by alcohol fixation. Silver stain
What is this?
Gout (black)
- Tophaceous deposits around joints erode into cartilage and subchondral bone and may cause marginal erosions of bone as seen in clinical x-rays.
- Gouty arthritis with urate deposits in subchondral bone. Alcohol fixation and silver stain.
What dis?
Pseudogout- calcium pyrophosphate crystals
- Presentation identical to gout, but caused by deposition of calcium pyrophosphate dihydrate crystals (CPPD).
- Aspiration reveals **POSITIVELY birefringent, rhomboid-shaped crystals. (Think Positive for Pyrophosphate in Pseudogout. )
NOTE: Positive birefringence refers to crystals appearing yellow when perpendicular and blue when parallel to the plane of light.
Identify left from right
Left: urate crystals
Right: CPPD
Cholesterol crystals in a synovial fluid sample (may be seen in RA)
What is happening here?
Calcium pyrophosphate dihydrate (CPPD) crystal deposition arthropathy of the knee joint
A. Femoral condyle. There are extensive foci of chalky white particulate deposits within the articular cartilage.
B. Histology = Hypertrophic chondrocytes adjacent to the crystal aggregates are within enlarged chondrons
C. Polarized light microscopy of CPPD crystal aggregates within the hyaline articular cartilage. The individual crystals have rod and rhomboid shapes and are positively birefringent
