Dna moczanowa – Patofizjologia i mechanizm

Dna moczanowa
Patofizjologia i mechanizm

Dna moczanowa jest przewlekłym zapaleniem stawów wywołanym przez odkładanie kryształów moczanu jednosodowego (MSU) w tkankach, z patogenezą obejmującą hiperurykemię (>6,8 mg/dl), czynniki genetyczne, metaboliczne i środowiskowe. Hiperurykemia wynika głównie ze zmniejszonego wydalania kwasu moczowego przez nerki (90% przypadków) lub zwiększonej produkcji (10%), a czynniki takie jak alkohol i choroby hematologiczne nasilają ten proces. Kryształy MSU indukują zapalenie poprzez aktywację inflamasomu NLRP3, co prowadzi do uwolnienia IL-1β i innych cytokin prozapalnych. Neutrofile odgrywają kluczową rolę zarówno w inicjacji, jak i samoograniczeniu zapalenia poprzez formowanie pułapek NETs i aggNETs, które modulują odpowiedź zapalną. Przewlekłe odkładanie kryształów prowadzi do powstawania guzków dnawych (tophi) i uszkodzenia stawów, z udziałem IL-1β w procesach osteoklastogenezy i degradacji chrząstki. Genetyka dny moczanowej wskazuje na mutacje w genach transporterów kwasu moczowego, a badania epigenetyczne sugerują, że zmiany w regulacji genów odporności wrodzonej wpływają na przebieg choroby.

Patofizjologia dny moczanowej

Dna moczanowa jest jedną z najczęstszych przyczyn przewlekłego zapalenia stawów, charakteryzującą się odkładaniem kryształów moczanu jednosodowego (MSU) w tkankach. Choroba ta ma złożone podłoże patogenetyczne obejmujące predyspozycje genetyczne, choroby współistniejące oraz czynniki dietetyczne.¹ Proces patogenetyczny dny moczanowej obejmuje kilka kluczowych etapów: hiperurykemię, odkładanie kryształów MSU w strukturach stawowych oraz odpowiedź immunologiczną na te kryształy.²

Hiperurykemia – podstawowy mechanizm dny

Hiperurykemia, definiowana jako stężenie kwasu moczowego w surowicy przekraczające 6,8 mg/dl (około 400 μmol/l), stanowi biochemiczną podstawę rozwoju dny moczanowej. To stężenie odpowiada przybliżonej granicy rozpuszczalności moczanu w płynach biologicznych.¹ Kwas moczowy jest końcowym produktem metabolizmu puryn, a jego stężenie w surowicy jest wynikiem równowagi między produkcją a wydalaniem.³

Hiperurykemia może być spowodowana:

Zmniejszonym wydalaniem kwasu moczowego (90% przypadków)⁴
Zwiększoną produkcją kwasu moczowego (10% przypadków)⁴
Zwiększonym spożyciem puryn (zwykle w połączeniu ze zmniejszonym wydalaniem)⁴

Zmniejszone wydalanie kwasu moczowego przez nerki jest najczęstszą przyczyną hiperurykemii. Etanol zwiększa katabolizm puryn w wątrobie, zwiększa powstawanie kwasu mlekowego, który blokuje wydzielanie moczanu przez kanaliki nerkowe, i może również stymulować syntezę kwasu moczowego w wątrobie.⁴ Z kolei zwiększona produkcja kwasu moczowego może wynikać ze zwiększonego obrotu nukleoproteiny w chorobach hematologicznych (np. chłoniak, białaczka, niedokrwistość hemolityczna) oraz w stanach zwiększonej proliferacji komórkowej i śmierci komórek.⁵

Tworzenie kryształów MSU

Formowanie kryształów MSU wymaga utrzymującego się przesycenia stężenia moczanu. Czynniki wpływające na tworzenie kryształów obejmują obecność cząstek zarodkowych, lokalne stężenie kationów, pH, temperaturę i odwodnienie.⁶ Kryształy MSU precipitują jako igłopodobne struktury, które są odkładane pozakomórkowo w tkankach beznaczyniowych (np. chrząstka) lub w tkankach stosunkowo beznaczyniowych (np. ścięgna, pochewki ścięgniste, więzadła, ściany kaletki) oraz skórze wokół chłodniejszych stawów dystalnych i tkanek.⁵

Niższe temperatury sprzyjają odkładaniu kryształów, co może wyjaśniać, dlaczego małżowina ucha i stopa są często miejscami odkładania kryształów i rozwoju guzków dnawych (tophi).⁷ Badania wykazały, że u pacjentów z hiperurykemią kryształy moczanu jednosodowego często odkładają się w miejscach urazu lub podrażnienia.⁷

Inicjacja procesu zapalnego

Inicjacja zapalenia w dnie moczanowej obejmuje mikrokryształy zwykle uwalniane z istniejących wcześniej guzków dnawych w błonie maziowej.⁸ Kryształy są uwalniane albo przez jakąś zmianę metaboliczną, taką jak wzrost lub spadek poziomu kwasu moczowego w surowicy, albo przez uraz mechaniczny.⁹

Kryształy MSU aktywują makrofagi i monocyty poprzez receptory Toll-podobne (TLR) 2 i 4, powodując transdukcję sygnału przez My88, kinazy związane z receptorem interleukiny-1 (IRAK1 i IRAK4).⁸ Zmiany konformacyjne IgG sprzyjają fagocytozie przez komórki posiadające receptory Fc-y, takie jak neutrofile i makrofagi.⁸

Aktywacja inflamasomu NLRP3

Kluczowym mechanizmem w patogenezie dny moczanowej jest aktywacja inflamasomu NLRP3 (receptora NOD-, LRR- i zawierającego domenę pirynu 3), która prowadzi do uwolnienia IL-1β i innych cytokin prozapalnych.¹⁰ Aktywacja inflamasomu NLRP3 przez kryształy MSU jest procesem dwuetapowym:¹¹

Sygnał 1 (pobudzenie): Proces pobudzenia jest mediowany przez receptory TLR (TLR2 lub TLR4) lub receptory cytokin poprzez szlaki aktywujące NF-kB. Ten proces kontroluje ekspresję genów pro-IL-1 i komponentów inflamasomu NLRP3 poprzez regulację w górę poziomu transkrypcyjnego i modyfikacje potranslacyjne, przygotowując komórki do montażu inflamasomu.¹²

Sygnał 2 (aktywacja): Fagocytoza kryształów MSU wyzwala montaż kompleksu inflamasomu NLRP3 i aktywuje kaspazę-1. Kilka mechanizmów, w tym wypływ jonów K+, sygnalizacja Ca2+, zaburzenia lizosomalne i generowanie reaktywnych form tlenu w mitochondriach, jest znanych jako zaangażowane w ten proces.¹²

Aktywowana kaspaza-1 rozcina pro-IL-1β do IL-1β i również rozcina GSDMD do jego fragmentu N-końcowego (GSDMD N-term), który tworzy pory ułatwiające uwalnianie IL-1β i pyroptozę.¹² IL-1β jest kluczowym mediatorem zapalnym, który reguluje proliferację komórek, różnicowanie i apoptozę w dnie moczanowej.¹³

Rola neutrofili w zapaleniu i jego rozwiązaniu

Neutrofile odgrywają podwójną rolę w patogenezie dny – uczestniczą zarówno w produkcji ostrego zapalenia, jak i w jego samoograniczeniu.¹⁴ Po fagocytozie kryształów MSU, neutrofile przechodzą proces formowania pułapek zewnątrzkomórkowych neutrofili (NETs), znany jako NEToza, i uwalniają cytokiny zapalne.¹⁴

Co istotne, neutrofile osiągają próg, po którym tworzą się duże struktury DNA/kryształów MSU, określane jako zagregowane pułapki zewnątrzkomórkowe neutrofili (aggNETs).¹⁵ AggNETs sekwestrują cytokiny prozapalne i chemokiny do degradacji przez proteazy serynowe, co prowadzi do złagodzenia ataków dny.¹⁵ Jest to możliwy mechanizm spontanicznej regresji dny.¹⁶

Aktywowane neutrofile, które fagocytują umierające neutrofile w późnych stadiach ataków dny, mogą promować produkcję TGF-β1 i eliminować odpowiedź zapalną.¹⁵ Ponadto, niezapalna fagocytoza umierających neutrofili przez makrofagi jest związana ze spontaniczną remisją zaostrzeń dny.¹⁵

Tophi i przewlekła dna moczanowa

Z czasem ostre zapalenie towarzyszące powtarzającym się atakom dny moczanowej może kulminować w patologicznym uszkodzeniu stawu. Przedłużone gromadzenie się kryształów MSU daje początek guzkom dnawym (tophi), które składają się z kryształów MSU w macierzy lipidów, białek i mukopolisacharydów.¹³

IL-1β jest kluczową cząsteczką w procesie uszkodzenia kości i chrząstki i odgrywa kluczową rolę w tworzeniu osteoklastów.¹⁷ Przewlekłe procesy zapalne w połączeniu z efektami komórek odpornościowych i kryształów na osteoblasty, chondrocyty i osteoklasty przyczyniają się do zaniku chrząstki, erozji kości, uszkodzenia stawów i tworzenia tophi.⁶

Mechanizmy molekularne i genetyczne w dnie moczanowej

Wpływ czynników genetycznych

Badania asocjacyjne całego genomu (GWAS) poziomu kwasu moczowego w surowicy wykazały, że warianty genetyczne o najsilniejszych efektach znajdują się głównie w genach kodujących transportery kwasu moczowego w nerkach i jelitach.² Wpływ czynników genetycznych na rozwój dny moczanowej obejmuje:¹⁸

Nadaktywność syntetazy fosforybozopirofosforanu (PRPP)
Częściowy niedobór fosforybozylotransferazy hipoksantynowo-guaninowej (HGPT)
Nadaktywność transportera kwasu moczowego w kanalikach nerkowych

Co ciekawe, geny powiązane z dną moczanową w badaniach GWAS nie obejmują tych kodujących składniki samego inflamasomu NLRP3, ale zamiast tego obejmują geny kodujące cząsteczki zaangażowane w jego regulację.¹⁹ Obecnie badania genetyczne są zdominowane przez uczestników pochodzenia europejskiego; jednak badania koncentrujące się na innych grupach populacyjnych odkrywają informatywne warianty specyficzne dla populacji związane z dną.¹⁹

Rola mechanizmów epigenetycznych

Badania genomowo-szerokie dny moczanowej podkreślają znaczenie szlaków epigenomicznych, sugerując, że epigenetyczne przeprogramowanie komórek odporności wrodzonej przez rozpuszczalny moczanu zwiększa ich reaktywność na kryształy MSU.²⁰ Mechanizmy epigenetyczne mogą odgrywać kluczową rolę w patogenezie dny, oferując potencjał zupełnie innych opcji terapeutycznych.²¹

Analiza mediatorów metabolicznych pozwoliła na szersze zrozumienie mechanizmów choroby. Podczas zaostrzeń dny kryształy MSU aktywują wyraźny profil metaboliczny i program transkrypcyjny w komórkach zapalnych.²² Zidentyfikowano szlak Clonal Hematopoiesis of Indeterminate Potential (CHIP) i nowe geny przyczynowe zaangażowane w patogenezę dny, w tym białka modyfikujące epigenom, takie jak TET2, EZH2, IDH2 i RUNX1.²³

Szlak purynowy i jego regulacja

Kwas moczowy jest produkowany głównie w wątrobie, jelitach i śródbłonku naczyniowym z egzogennych (głównie białko zwierzęce) i endogennych puryn i występuje głównie w postaci soli – moczanu.²⁴ Fruktoza również zwiększa wewnątrzkomórkową produkcję kwasu moczowego, a jej spożycie znacznie wzrosło w ciągu ostatnich kilku dekad, głównie z powodu zwiększonego wykorzystania syropu kukurydzianego jako słodzika komercyjnego.²⁴

Szlak sygnałowy purynowy wywiera różne efekty regulacyjne na zapalenie. Szlak signałowy ATP-P2X7R-NLRP3 może przyczyniać się do wzmocnienia zapalenia indukowanego przez MSU, wpływając na rozwój dny.²⁵

Kliniczne implikacje mechanizmów patogenetycznych

Związek z zespołem metabolicznym

Pacjenci z dną moczanową mają zwiększone ryzyko insulinooporności. Metaanaliza prospektywnych badań kohortowych wykazała, że hiperurykemia jest niezależnym czynnikiem ryzyka wystąpienia cukrzycy typu 2.²⁶ Liczne mechanizmy fizjologiczne mogą odgrywać rolę w związku między hiperurykemią a rozwojem cukrzycy typu 2. Hiperurykemia indukuje dysfunkcję śródbłonka, zmniejsza stężenie tlenku azotu (ważnego w stymulacji wychwytu glukozy) i jest związana ze stresem oksydacyjnym.²⁶

Insulinooporność również została powiązana z patogenezą dny moczanowej.²⁷ Hiperinsulinemia stymuluje nerkowy wymiennik sodowo-wodorowy do wchłaniania sodu i kwasu moczowego, powodując odpowiednio nadciśnienie i hiperurykemię.²⁸

Mechanizmy leków obniżających stężenie kwasu moczowego

Zrozumienie mechanizmów patogenetycznych dny moczanowej doprowadziło do opracowania różnych podejść terapeutycznych:

Leki urykostatyczne: Inhibitory oksydazy ksantynowej (allopurinol, febuksostat), które hamują produkcję kwasu moczowego²⁸
Leki urykozuryczne: Probenecyd, sulfinpirazon, lesinurad, które działają na nerkowy szlak transportu anionów kwasu moczowego, zwiększając wydalanie kwasu moczowego z moczem²⁸
Oksydaza moczanowa (urykaza): Peglotycase i rasburykaza, będące rekombinowanym enzymem urykazy, utleniają kwas moczowy do wysoce rozpuszczalnej allantoiny wydalanej w moczu²⁹
Inhibitory IL-1: Anakinra (Kineret) jest biologicznym lekiem, który blokuje białko zapalne (cytokinę) IL-1, odgrywające główną rolę w zapaleniu dnawym³⁰
Leki blokujące inflamasom: Kilka leków jest badanych, które blokują inflamasom, grupę białek współpracujących w celu aktywacji IL-1³⁰

Leki przeciwzapalne w ostrych napadach dny

Kolchicyna wywiera swoje działanie poprzez zmniejszenie produkcji kwasu mlekowego przez leukocyty, co z kolei zmniejsza odkładanie kwasu moczowego i zmniejsza fagocytozę, z ustąpieniem odpowiedzi zapalnej.³¹ Kolchicyna łagodzi zapalenie dnawowe, hamując aktywację kryształów MSU w inflamasomie NLRP3, blokując w ten sposób uwalnianie IL-1.³²

Leczenie pacjentów do docelowego stężenia kwasu moczowego w surowicy jest niezbędne do zmniejszenia zaostrzeń dny i rozwiązania guzków dnawych.³³ Wytyczne ACR zalecają podejście leczenia do celu, które kieruje dawkowaniem i utrzymaniem leków obniżających stężenie kwasu moczowego (ULT), aby osiągnąć stężenie kwasu moczowego w surowicy poniżej 6 mg/dl.³⁴

Rozpoczęcie ULT może wywołać zaostrzenie dny z powodu aktywacji kryształów wytrąconych w stawach. Ryzyko zaostrzenia dny zwiększa się wraz z większym zmniejszeniem poziomu kwasu moczowego w surowicy. Badania sugerują, że ataki dny związane z ULT mogą zmniejszyć przestrzeganie ULT przez pacjenta. Profilaktyka lekami przeciwzapalnymi zmniejsza ryzyko zaostrzenia dny po rozpoczęciu ULT.³⁴

Nowe kierunki badań i terapii

Wiedza o patogenezie dny i celach leczenia zmienia się. Wiele nowszych podejść terapeutycznych koncentruje się na wzajemnym oddziaływaniu między metabolizmem a zmianami epigenomicznymi w odpowiedzi zapalnej w dnie moczanowej.³⁵ Kilka nowych środków jest w fazie rozwoju, które bezpośrednio celują w inflamasom NLRP3.³⁵

AMPK, działający częściowo poprzez epigenom, odgrywa również rolę w pamięci odporności wrodzonej, wpływając na rozwój i przebieg dny, a także na bardzo zmienną odpowiedź objawów zaostrzenia dny na terapię obniżającą poziom kwasu moczowego.³⁵ Badacze są na drodze do opracowania większej liczby terapii i, co ważniejsze, bardziej zindywidualizowanych terapii wykorzystujących potencjalne biomarkery do przewidywania i zapobiegania zapaleniu dnawowemu.³⁵

Badania dotyczące specyficznego mechanizmu aktywacji inflamasomu NLRP3 w przebiegu dny moczanowej nadal pozostają tajemnicą, co poważnie ogranicza wczesną diagnostykę i terapię dny.³⁶ Lepsze zrozumienie wzajemnego oddziaływania między metabolitami a zmianami epigenetycznymi i aktywacją sieci czynników transkrypcyjnych w komórkach zapalnych może dostarczyć nowych spostrzeżeń na temat mechanizmów choroby podczas dny moczanowej.²²

Biomarkery w diagnostyce dny

Inflamasom NLRP3 może stanowić obiecujący biomarker diagnostyczny i cel terapeutyczny, co może pomóc we wczesnej diagnostyce i terapii, a także w rozwoju leków terapeutycznych.³⁷ Badania wykazały, że ekspresja NLRP3, ASC i kaspazy-1 była znacznie wyższa w grupach z dną moczanową i hiperurykemią niż w grupach kontrolnych.³⁷

Ceramid (Cer) jest związkiem rdzeniowym metabolizmu sfingolipidów i odgrywa ważną rolę w regulowaniu procesów wewnątrzkomórkowych, takich jak proliferacja, różnicowanie i apoptoza.³⁸ Wyniki badań wskazują, że całkowite poziomy SM i Cer u myszy modelowych były znacznie wyższe niż w kontroli, a poziomy Cer były dodatnio skorelowane z poziomami IL-6 i TNF-α.³⁹

Nowe potencjalne cele terapeutyczne

Odkryto, że kilka mechanizmów molekularnych jest zaangażowanych w samoograniczenie zapalenia dnawego:

CD14 jest proksymalnym punktem we wrodzonej odpowiedzi immunologicznej na wychwytywanie kryształów MSU, aktywację kaspazy-1 i produkcję IL-1 w makrofagach. Zmniejszona produkcja CD14 w zapaleniu indukowanym przez MSU może przyczyniać się do spontanicznej remisji, a blokada funkcji CD14 może być użyteczna w przypadku opornej dny.³²
Członkowie rodziny IL-1, IL-33 i IL-37, są znani jako negatywne regulatory sygnalizacji IL-1, a ich właściwości przeciwzapalne zostały wykazane w licznych modelach chorób.³²
Rola glikolitycznego przeprogramowania i jego efektów w zapaleniu mediowanym przez NLRP3 i ryzyku dny została niedawno opisana. Badania wykazały rolę mitochondrialnego nośnika pirogronianu (MPC) w aktywacji NLRP3. Niedobór MPC prowadził do podwyższonego wydzielania IL-1β w odpowiedzi na agonistów NLRP3 w makrofagach.⁴⁰

Struktury transportera URAT1 uzyskane przez naukowców rzucają światło na mechanizm, za pomocą którego URAT1 transportuje moczany, i oferują wgląd w przyszłe wysiłki w odkrywaniu leków.⁴¹ Leki działają poprzez blokowanie URAT1 w stanie skierowanym do wewnątrz.⁴¹

Odkryto, że rola kinaz rodziny Src mieloidalnych w chorobach autozapalnych, w tym dnie, sugeruje celowanie w szlaki fosforylacji tyrozyny jako potencjalną strategię terapeutyczną do zarządzania stanami charakteryzującymi się zwiększoną aktywnością neutrofili.⁴⁰

Chociaż nasze zrozumienie mechanizmów molekularnych dny moczanowej znacznie się poprawiło w ciągu ostatnich 20 lat, wiele fundamentalnych i klinicznie istotnych pytań pozostaje bez odpowiedzi.⁴² Przejście sygnałów genetycznych do wiedzy mechanistycznej wymaga badań eksperymentalnych, które są stopniowo prowadzone w loci takich jak ABCG2, PDZK1, MAF i HNF4A.²⁰

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Materiały źródłowe

#1 Gout – StatPearls – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK546606/
Gout is one of the most common causes of chronic inflammatory arthritis in the United States, characterized by monosodium urate (MSU) monohydrate crystals deposition in the tissues. […] Gout is characterized biochemically by extracellular fluid urate saturation, which is reflected by hyperuricemia in the blood, with plasma or serum urate concentrations exceeding 6.8 mg/dL (approximately 400 mol/L); this level is the approximate limit of urate solubility. […] The etiology of gout is usually multifactorial, including genetic predisposition, medical comorbidities, and dietary factors. […] Hyperuricemia is the leading cause of gout, a condition where uric acid crystals accumulate in joints, causing inflammation and pain. […] Hyperuricemia plays a pivotal role in developing gout as it facilitates the nucleation and growth of MSU crystals by reducing urate solubility.
#2 The pathogenesis of gout: molecular insights from genetic, epigenomic and transcriptomic studies – University of Otago
https://ourarchive.otago.ac.nz/esploro/outputs/journalArticle/The-pathogenesis-of-gout-molecular-insights/9926554890101891
The pathogenesis of gout involves a series of steps beginning with hyperuricaemia, followed by the deposition of monosodium urate crystal in articular structures and culminating in an innate immune response, mediated by the NLRP3 inflammasome, to the deposited crystals. […] Large genome-wide association studies (GWAS) of serum urate levels initially identified the genetic variants with the strongest effects, mapping mainly to genes that encode urate transporters in the kidney and gut. […] More recently, genetic and epigenetic genome-wide studies have revealed new pathways in the inflammatory process of gout, including genetic associations with epigenomic modifiers. […] Epigenome-wide association studies are also implicating epigenomic remodelling in gout, which perhaps regulates the responsiveness of the innate immune system to monosodium urate crystals.
#3 Etiology and pathogenesis of gout – Clinical Tree
https://clinicalpub.com/etiology-and-pathogenesis-of-gout/
Gout is a chronic disease of monosodium urate crystal deposition, which typically presents as recurrent episodes of severe, painful inflammatory arthritis. Monosodium urate crystals form from extracellular fluids saturated with urate, the endproduct of human purine metabolism. […] The gout flare is a severe but self-limited arthritis caused by an inflammatory response to monosodium urate crystals. Repeated gout flares and persistent crystal deposition can lead to chronic gouty arthritis, tophi, and erosive gout. […] Hyperuricemia (elevated serum urate concentration) is the central biochemical precursor for gout. It is generally classified as a serum urate concentration exceeding about 6.8 mg/dL (400 M). […] Hyperuricemia results from an imbalance between urate production and excretion. In most patients with gout, hyperuricemia results from impairment of renal and gut excretion.
#4 Gout – Musculoskeletal and Connective Tissue Disorders – Merck Manual Professional Edition
https://www.merckmanuals.com/professional/musculoskeletal-and-connective-tissue-disorders/crystal-induced-arthritides/gout
Gout is a disorder caused by hyperuricemia (serum urate 6.8 mg/dL [ 0.4 mmol/L]) that results in the precipitation of monosodium urate crystals in and around joints, most often causing recurrent acute or chronic arthritis. […] The greater the degree and duration of hyperuricemia, the greater is the likelihood that gout will develop. Urate levels can be elevated because of […] Decreased renal (most common) or gastrointestinal excretion […] Increased production (rare) […] Increased purine intake (usually in combination with decreased excretion). […] Decreased renal excretion is by far the most common cause of hyperuricemia. […] Ethanol increases purine catabolism in the liver and increases the formation of lactic acid, which blocks urate secretion by the renal tubules, and ethanol may also stimulate liver urate synthesis.
#5 Gout – Musculoskeletal and Connective Tissue Disorders – Merck Manual Professional Edition
https://www.merckmanuals.com/professional/musculoskeletal-and-connective-tissue-disorders/crystal-induced-arthritides/gout
Increased production of urate may be caused by increased nucleoprotein turnover in hematologic conditions (eg, lymphoma, leukemia, hemolytic anemia) and in conditions with increased rates of cellular proliferation and cell death (eg, psoriasis, cytotoxic cancer therapy, radiation therapy). […] Increased intake of purine-rich foods (eg, liver, kidney, anchovies, asparagus, consomm, herring, meat gravies and broths, mushrooms, mussels, sardines, sweetbreads) can contribute to hyperuricemia. […] Urate precipitates as needle-shaped monosodium urate (MSU) crystals, which are deposited extracellularly in avascular tissues (eg, cartilage) or in relatively avascular tissues (eg, tendons, tendon sheaths, ligaments, walls of bursae) and skin around cooler distal joints and tissues (eg, ears, finger pads).
#6 Gout – StatPearls – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK546606/
The pathophysiology of gout involves a series of complex and interacting processes as follows: Various genetic and metabolic factors contribute to hyperuricemia in the bloodstream. […] Metabolic, physiologic, and other characteristics are responsible for MSU crystal formation. […] Soluble inflammatory factors, cellular elements, innate immune processes, along with the characteristics of MSU crystals, promote an acute inflammatory response. […] Chronic inflammatory processes coupled with the effects of immune cells and crystals on osteoblasts, chondrocytes, and osteoclasts contribute to cartilage attrition, bone erosion, joint injury, and the formation of tophi. […] The formation of MSU crystals requires sustained supersaturated concentrations of urate. Factors like the presence of particulate seed, local cation concentrations, pH, temperature, and dehydration influence crystal formation.
#7 The pathogenesis of gout | MDedge
https://medauth2.mdedge.com/content/pathogenesis-gout
In the Normative Aging Study, 22% of men who had serum urate levels greater than 9 mg/dL developed gout during a 5-year perioda much higher rate than among men with serum urate levels less than 9 mg/dL. Nevertheless, a full 78% of the men in this study with serum urate levels greater than 9 mg/dL did not develop gout over the 5-year period, illustrating that while hyperuricemia predisposes to gout, it does not automatically cause gout. […] Other factors, when combined with hyperuricemia, contribute to crystal deposition and the development of gout. […] Patients with hyperuricemia tend to have monosodium urate crystal deposition at sites of trauma or irritation. […] Lower temperatures favor crystal deposition, which may explain why the helix of the ear and the foot are often sites of crystal deposition and tophus development.
#8 Gout – StatPearls – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK546606/
The initiation of inflammation in gout involves microcrystals usually shed from preexisting synovial tophi. […] The IgG conformational changes encourage phagocytosis by cells possessing Fc-y receptors, such as neutrophils and macrophages. […] The predominant pathway of cytosolic protein complex activation involves the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome. MSU crystals activate macrophages and monocytes via toll-like receptors (TLR) 2 and 4, resulting in signal transduction by My88, interleukin-1 receptor-associated kinase 1 (IRAK1), and IRAK4.
#9 The pathogenesis of gout | MDedge
https://medauth2.mdedge.com/content/pathogenesis-gout
Crystals are believed to be released either by some metabolic change, such as an increase or decrease in serum urate level, or by mechanical trauma. […] This sets into motion the formation of a complex called the inflammasome, which releases IL-1 beta, one of the most important mediators of the acute attack. […] Following an acute attack, the symptoms of gouty arthritis may be gone, but the crystals are still present in the joint. Therefore, the patient remains at risk for continued flares and progressive disease. […] The key point is that low-grade inflammation persists and crystals remain in the joint, which can lead to progressive disease. […] Acute gout attacks can be treated with anti-inflammatory drugs, but the disease can and often will continue to progress unless the serum urate level is normalized. […] Two studies of patients whose serum urate levels were successfully reduced to less than 6 mg/dL showed that crystals began to be depleted from the patients joint fluid, which should ultimately prevent the risk of progressive gouty arthritis.
#10 Inflammation in gout: mechanisms and therapeutic targets | Nature Reviews Rheumatology
https://www.nature.com/articles/nrrheum.2017.155
Inflammatory cytokines, in particular IL-1, are the key mediators of gouty inflammation. […] The NLRP3 inflammasome is the major pathway by which MSU crystals trigger the cellular inflammatory response. […] Multiple regulatory pathways modulate the activity of the inflammasome and the release of IL-1; this may explain in part the clinical origins of gouty inflammation. […] The acute symptoms of gout are triggered by the inflammatory response to monosodium urate crystals, mediated principally by macrophages and neutrophils. […] Innate immune pathways are of key importance in the pathogenesis of gout, in particular the activation of the NLRP3 inflammasome, which leads to the release of IL-1 and other pro-inflammatory cytokines. […] The orchestration of this pro-inflammatory cascade involves multiple intracellular and extracellular receptors and enzymes interacting with environmental influences that modulate the inflammatory state. […] Furthermore, the resolution of inflammation in gout is becoming better understood. […] Some of these pathways can be manipulated and present novel therapeutic opportunities for the treatment of acute gout attacks.
#11 Frontiers | Role of NLRP3 in the pathogenesis and treatment of gout arthritis
https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2023.1137822/full
Mechanistically, the NLRP3 inflammasome activation is a two-step process that requires initiation and activation signals from a variety of exogenous and endogenous activators. […] It has also been suggested that neutrophil-derived serine proteases such as myeloblastin, elastase and cathepsin G, metalloproteinases and granzyme A may be responsible for IL-1Î² maturation, thereby contributing to the occurrence and development of GA. […] Despite the elaborate knowledge on the pathophysiology of GA and the activation of NLRP3 inflammasome, the functional roles of NLRP3 inflammasome and its-mediated biological mechanisms in GA remain unclear. […] Given that MSU crystals function as NLRP3 inflammasome agonists, it is plausible to believe that NLRP3 inflammasome plays a key role in the pathogenesis of GA.
#12 The pathogenesis of gout
https://www.jrd.or.kr/journal/view.html?uid=1605&vmd=Full
Priming and activation of the NLRP3 inflammasome in gout. Signal 1, the priming process, is mediated by TLRs (TLR2 or TLR4) or cytokine receptors through NF-kB activating pathways. This process controls the gene expression of pro-IL-1 and components of the NLRP3 inflammasome through upregulation of transcriptional level and PTM, preparing cells for inflammasome assembly. In Signal 2, phagocytosis of MSU crystals trigger the assembly of the NLRP3 inflammasome complex and activates caspase-1. Several mechanisms, including ionic K+ efflux, Ca2+ signaling, lysosomal disruption and mitochondrial reactive oxygen generation are known to involve in this process. Activated caspase-1 cleaves pro-IL-1 into IL-1 and also cleaves GSDMD into its amino-terminal fragment (GSDMD N-term) forms pores which facilitates IL-1 release and pyroptosis.
#13
https://link.springer.com/article/10.1007/s10067-011-1877-0
IL-1 is the pivotal inflammatory mediator that regulates cell proliferation, differentiation, and apoptosis in gouty arthritis. This proinflammatory cytokine can induce the expression of a wide range of inflammatory mediators that are directly responsible for neutrophil influx to the synovium, a hallmark of gouty arthritis. […] Activation of the IL-1 receptor on endothelial cells by IL-1 has been shown to be a fundamentally critical step in the development of MSU-induced inflammation using genetic knockout rodent models. […] Furthermore, neutrophil influx results in further phagocytosis of MSU crystals and the perpetuation of both IL-1 release and its associated inflammatory processes. […] Over time, the acute inflammation accompanying repeated flares of gouty arthritis can culminate in pathologic joint damage. Prolonged accumulation of MSU crystals gives rise to tophi which consist of MSU crystals in a matrix of lipids, protein, and mucopolysaccharides.
#14 Spontaneous resolution of acute gout: mechanisms and therapeutic targets | RMD Open
https://rmdopen.bmj.com/content/9/3/e003586
Gout is a common inflammatory arthritis that has been increasing in both prevalence and incidence. […] Onset of gout is related to the deposition of monosodium urate crystals under hyperuricaemia. […] However, the underlying mechanism for spontaneous remission of gout requires further elucidation. […] In this article, we summarise the roles and mechanisms related to spontaneous remission of gout, which are essential for understanding its pathogenesis and developing potential targeted therapies. […] Research has shown that neutrophils are involved in not only the production of acute inflammation but also its self-remission. […] After phagocytosis of MSU crystals, neutrophils undergo the formation of neutrophil extracellular traps (NETs), a process known as NETosis, and release inflammatory cytokines.
#15 Spontaneous resolution of acute gout: mechanisms and therapeutic targets | RMD Open
https://rmdopen.bmj.com/content/9/3/e003586
It is worth noting that neutrophils reach a threshold and that large DNA/MSU crystal structures, designated aggregation neutrophil extracellular traps (aggNETs), are subsequently formed. […] AggNETs sequester proinflammatory cytokines and chemokines for degradation by serine proteases, resulting in the relief of gout attacks. […] Activated neutrophils that engulf dying neutrophils by phagocytosis in the late stages of gout attacks can promote the production of TGF1 and eliminate the inflammatory response. […] Furthermore, non-inflammatory phagocytosis of dying neutrophils by macrophages is associated with spontaneous remission of gout flares. […] IL-1 is an inflammatory cytokine secreted by macrophages that also plays a crucial role in gout. […] Uptake of MSU crystals by macrophages induces activation of NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasomes, which in turn leads to activation of caspase-1 precursor (procaspase 1) that converts pro-IL-1 to biologically active IL-1.
#16 Mechanism of neutrophil extracellular traps in the pathogenesis of gout
https://www.clinexprheumatol.org/abstract.asp?a=20818
Gout is a self-limited inflammatory disease caused by the deposition of monosodium urate (MSU) crystals in joints and surrounding tissues due to abnormal purine metabolism. […] During gout, NETs induced by MSU crystals exacerbate inflammation, and aggregated NETs (aggNETs) promote the resolution of gout-associated inflammation by encapsulating MSU crystals, degrading cytokines and chemokines, and blocking the recruitment and activation of neutrophils. […] With disease progression, NETs participate in the formation of tophi. […] Therefore, aggNETs are a possible mechanism of spontaneous gout regression. […] Studying the specific mechanism by which NETs affect inflammatory bursts and spontaneous regression in gout patients is important. […] This review summarises the role of NETs in different stages of gout and the specific pathogenesis of NETs in gout to provide new ideas for the diagnosis and treatment of gout.
#17
https://link.springer.com/article/10.1007/s10067-011-1877-0
IL-1 is a key molecule in the process of bone and cartilage damage and plays a critical role in osteoclast formation. […] This ineligibility for current treatment that exists among a large number of patients with gout has resulted in the need for alternative treatment options. One such therapeutic alternative has arisen from the increasing understanding of the role of IL-1 in the underlying inflammatory response seen in gouty arthritis. Treatment strategies that aim to interrupt the IL-1 molecular pathway will theoretically reduce the inflammation and pain experienced by patients during flares of gouty arthritis, and clinically, this treatment approach has shown considerable early promise. […] Agents that interfere with IL-1 signaling therefore appear to represent an important therapeutic class in the future treatment of gouty arthritis; however, clinical experience with these agents in patients with rheumatoid arthritis suggests that their use may be associated with an increased risk of infection.
#18 The Pathogenesis and Treatment of Gout
https://touroscholar.touro.edu/sjlcas/vol6/iss2/9/
In the past, the etiology of gout was simplistically believed to be based in the generous indulgence of rich foods and alcohol. However, research has revealed that gout has complex environmental and genetic origins. Specifically, researchers have begun to focus attention on the molecular basis of gout and its related features. These features include hyperuricemia, the stages of gout, and the decreased solubility of uric acid. […] The results of the research conducted revealed that there are three features that are genetically induced that independently contribute to the onset of gout: phosphoribosyl pyrophosphate (PRPP) synthetase hyperactivity, partial deficiency of hypoxanthine-guanine phosphoribosyltransferase (HGPT), and hyperactivity of the uric acid transporter in the renal tubule. […] In addition, diets rich in meat and seafood and devoid of dairy products substantially increase the risk of developing gout. […] From a research perspective, the elucidation of the pathophysiology of gout can lead to the development of even more effective therapeutic options.
#19 The pathogenesis of gout: molecular insights from genetic, epigenomic and transcriptomic studies – University of Otago
https://ourarchive.otago.ac.nz/esploro/outputs/journalArticle/The-pathogenesis-of-gout-molecular-insights/9926554890101891
Notably, genes implicated in gout GWAS do not include those encoding components of the NLRP3 inflammasome itself, but instead include genes encoding molecules involved in its regulation. […] Knowledge of the molecular mechanisms underlying gout has advanced through the translation of genetic associations into specific molecular mechanisms. […] Current genetic studies are dominated by participants of European ancestry; however, studies focusing on other population groups are discovering informative population-specific variants associated with gout. […] Genetic, epigenetic and transcriptomic studies in hyperuricaemia and gout have, in the past 6 years, provided important insights into the underlying molecular mechanisms, revealing new inflammatory pathways and epigenetic factors and expanding research beyond European populations.
#20 The pathogenesis of gout: molecular insights from genetic, epigenomic and transcriptomic studies | Nature Reviews Rheumatology
https://www.nature.com/articles/s41584-024-01137-1
Genome-wide association studies of gout highlight the importance of epigenomic pathways, suggesting that epigenetic reprogramming of innate immune cells by soluble urate increases their responsiveness to monosodium urate crystals. […] The translation of genetic signals into mechanistic knowledge requires experimental studies, which are gradually being conducted in loci such as ABCG2, PDZK1, MAF and HNF4A.
#21 Editorial: Advances in Pathogenesis and Therapies of Gout
https://pmc.ncbi.nlm.nih.gov/articles/PMC9010866/
Gout is one of the most common metabolic disorders in human caused by inflammatory responses to the deposition of monosodium urate (MSU) crystals, which form in the presence of increased urate concentrations. The pathogenesis of gout is that MSU crystal triggers a strong inflammatory response by activating macrophages in tissues and promoting the collection of neutrophils to tissues or organs. […] However, activation of the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome by monosodium urate crystals with release of IL-1 plays a major role in the initiation of the gout flare. […] The activation of NLRP3 inflammasome and subsequent induction of the release of IL-1 exerts a central role in the initiation of gout flares. […] Given that the purine signaling pathway exerts different regulatory effects on inflammation, Tao et al. reviewed the role of purinergic receptor-mediated signaling pathways in the regulation of gout flare and resolution. […] The possibility that epigenetic mechanisms may contribute to gout pathogenesis offers the potential of a set of completely different therapeutic options.
#22 Epigenetic and Metabolic Regulation of Macrophages during Gout
https://www.mdpi.com/2813-4583/1/3/13
The analysis of metabolite mediators has allowed a broader understanding of disease mechanisms. […] During gout flares, monosodium urate crystals activate a distinct metabolic profile and inflammatory transcriptional program in inflammatory cells. […] The interplay between metabolic changes by MSUc, the regulation of epigenetic changes and the activation of transcription factor networks in inflammatory cells remains unknown. […] A better understanding of the interplay between metabolites and how it alters inflammatory response may provide novel insights into disease mechanisms during gout. […] Gout is caused by the deposition of monosodium urate crystals in the joints in patients with persistent hyperuricaemia (HU). […] Since the deregulation of urate metabolism is at the heart of gout, it is vital to understand genetic conditions and environmental or behavioural exposures such as diet that modify blood urate levels and underlying molecular mechanisms.
#23 New Causal Genes, Pathways Implicated in Gout Pathogenesis – Rheumatology Advisor
https://www.rheumatologyadvisor.com/reports/new-causal-genes-pathways-implicated-in-gout-pathogenesis/
More than 93 genetic variants were identified in the 500FG cohort previously unassociated with urate that may be linked to gout inflammation. […] The Clonal Hematopoiesis of Indeterminate Potential (CHIP) pathway and new casual genes have been identified and implicated in gout pathogenesis, according to results presented at the American College of Rheumatology (ACR) Convergence 2022, held from November 10 to 14, in Philadelphia, Pennsylvania. […] Researchers identified 339 loci associated with gout encompassing 515 independently-associated variants, of which 123 loci were not among any previously loci reported in urate or gout; 1657 cis- and 267 trans-eQTLs were identified for 252 of the 339 loci. […] Genes mutated in the CHIP pathway a new pathway identified in the study including epigenome modification proteins such as TET2, EZH2, IDH2, and RUNX1, were implicated in gout pathogenesis. […] The researchers implicated new causal genes and pathways in gout, including genes that regulate urate, NLRP3 inflammasome activity and autophagy, and the identification of the CHIP pathway.
#24 Examining the Connection Between Gout and Metabolic Syndrome – Rheumatology Advisor
https://www.rheumatologyadvisor.com/features/examining-the-connection-between-gout-and-metabolic-syndrome/
Uric acid is mainly synthesized in the liver, intestines, and vascular endothelium from exogenous (mostly animal protein) and endogenous purines and is mainly found in its salt form, urate. Fructose also increases intracellular uric acid production. Its consumption has increased substantially over the last few decades, primarily due to the increased use of corn syrup as a commercial sweetener. […] Serum urate levels also depend on the degree of excretion by the kidneys, and low excretion is the main factor contributing to high urate levels. […] Hyperuricemia increases the risk of gout from monosodium urate crystal formation, which can occur spontaneously at a concentration of 6.8 mg/dL. Hyperuricemia may also increase the risk of urolithiasis in the form of uric acid precipitation in the renal collecting system. Urate and uric acid solubility decrease with increasing pH.
#25
https://journals.lww.com/ahm/fulltext/2022/03000/the_development_from_hyperuricemia_to_gout__key.3.aspx
The noninflammatory removal of MSU by mature macrophages may explain why most individuals with AHUA and MSU deposition will not develop gout eventually. […] Thus, as MSU crystals precipitate in the synovial fluid, the noninflammatory uptake of crystals by synovial resident macrophages may be a crucial mechanism for joints to maintain a non-inflammatory state. […] We suggest that in addition to MSU-induced inflammation, there may exist other auxiliary inflammatory pathways required for the amplification of MSU-induced inflammation. […] P2X7R is a member of the P2X receptor subfamily of P2 receptors. […] It remains unclear how the nonselective pore forms and what its physiologic significance is, although pannexin-1 (Panx-1) has been suggested to be involved. […] Thus, while MSU initiates inflammation, the ATP-P2X7R-NLRP3 pathway may cause inflammation amplification.
#26 Examining the Connection Between Gout and Metabolic Syndrome – Rheumatology Advisor
https://www.rheumatologyadvisor.com/features/examining-the-connection-between-gout-and-metabolic-syndrome/
Patients with gout are at increased risk for insulin resistance. A meta-analysis of prospective cohort studies with no evidence of heterogeneity found hyperuricemia to be an independent risk factor for incident type 2 diabetes. The authors stated that the evidence strongly supported hyperuricemia as a causal factor in the development of type 2 diabetes. […] Multiple physiologic mechanisms may play a role in the association between hyperuricemia and the development of type 2 diabetes. Hyperuricemia induces endothelial dysfunction, reduces nitric oxide (important in stimulating glucose uptake), and is associated with oxidative stress. […] However, can lowering serum urate improve insulin sensitivity? In a recent small study, Takir et al compared the effect of allopurinol 300 mg daily for 3 months vs observation only in patients with hyperuricemia but without diabetes. After 3 months, patients taking allopurinol showed reductions in serum urate, fasting blood glucose, fasting insulin, insulin resistance (measured by homeostatic model assessment of insulin resistance), and serum high-sensitivity C-reactive protein. The number of patients with impaired fasting glucose after 3 months compared with baseline was reduced (20% vs 75%; P < .001).
#27 Gout < Clinical Reference - MSK
https://clinref.com/rheumatology/gout/
Gout is a metabolic condition resulting from deposition of monosodium urate (MSU) crystals in and around the tissues of joints. […] Initially it was thought that gout happened due to excessive formation of uric acid but later on it became clear that it was mainly due to insufficient clearance by kidneys. […] Hyperuricemia however, is present in all gout patients at some stage. […] Urate crystals provoke inflammatory response from leukocytes and synovial cells. […] Insulin resistance has also been implicated in pathogenesis of gout. […] End product of protein metabolism is urea whereas purine metabolism produces uric acid as its end product.
#28 Understanding Treatments for Gout
https://www.ajmc.com/view/nov05-2218ps451-s458
Hyperinsulinemia stimulates the renal tubular sodium-hydrogen exchanger to reabsorb sodium and uric acid, resulting in hypertension and hyperuricemia, respectively. […] The most commonly used class of urate-lowering drug is the uricostatic agents, which inhibit xanthine oxidase and lead to decreased production of uric acid. […] A second class of urate-lowering drugs is the uricosuric agents, probenecid and sulfinpyrazone, which act on the renal uric acid anion transport pathway to increase uric acid excretion in urine. […] Febuxostat is a novel oral nonpurine selective inhibitor of xanthine oxidase. […] A second investigational agent is urate oxidase (uricase), which mediates the conversion of uric acid into a more soluble molecule allantoin.
#29 Pharmacology of the Therapeutic Approaches of Gout | IntechOpen
https://www.intechopen.com/chapters/66515
Chronic gout requires treatments with drugs that either promote excretion (e.g., probenecid, lesinurad) or prevent its synthesis through inhibition of enzyme xanthine oxidase (allopurinol, febuxostat, etc.). […] Colchicine has a unique mechanism action. […] Pegloticase and rasburicase, being a recombinant uricase enzyme, oxidize uric acid to highly soluble allantoin excreted in urine. […] Newer treatment options are being extensively studied especially interleukin-1 (IL-1) inhibitors but their approval is still pending. […] The quest for an optimally designed drug with desirable efficacy and acceptable safety profile is still on.
#30 Gout/Gouty Arthritis In Depth: Risk Factors, Treatment | HSS
https://www.hss.edu/conditions_gout-risk-factors-diagnosis-treatment.asp
The most common cause of gout (about 90% of cases) is the inability to excrete enough uric acid in the urine. This inability may occur for a number of reasons. The most common is a genetic defect in substances referred to as organic anion transporters in the kidney, which leads to an excessive reabsorption of uric acid from the kidney and thus too much uric acid in the blood. However, a defect in excretion of uric acid can also occur due to medications, such as diuretics, low dose aspirin, or alcohol. […] Anakinra (brand name Kineret) is a biologic medication that blocks the inflammatory protein (cytokine) IL1. IL1 plays a major role in gouty inflammation. This medication is injected subcutaneously by the patient once a day, usually for 3 days, but can be used longer if needed to resolve a flare. […] Medications that block the inflammasome: Several medications are under study which block the inflammasome, which is a group of proteins that work together to activate IL1, among other actions. As above, increased IL1 can stimulate gout flare, and blocking IL1 can quiet gout down.
#31 Pharmacologic Management of Gout
https://www.uspharmacist.com/article/pharmacologic-management-of-gout
The purpose of lowering serum urate concentrations is to prevent acute gout attacks and the development of tophi. According to the ACR, pharmacologic treatment of hyperuricemia is indicated for any patient with an established diagnosis of active gouty arthritis. ULT may be initiated during a gouty attack provided that effective anti-inflammatory management has been instituted. […] Colchicine exerts its effects by reducing lactic acid production by leukocytes, which in turn decreases uric acid deposition and reduces phagocytosis, with abatement of the inflammatory response.
#32 Spontaneous resolution of acute gout: mechanisms and therapeutic targets | RMD Open
https://rmdopen.bmj.com/content/9/3/e003586
In the clinic, colchicine relieves gout inflammation by inhibiting MSU crystal activation in the NLRP3 inflammasome, thereby blocking the release of IL-1. […] CD14 is a proximal point in the innate immune response to MSU crystal uptake, caspase-1 activation and IL-1 production in macrophages. […] Therefore, reduced CD14 production in MSU-induced inflammation may contribute to spontaneous remission, and blockade of CD14 function may be useful for refractory gout. […] The IL-1 family members IL-33 and IL-37 are known to be negative regulators of IL-1 signalling, and their anti-inflammatory properties have been demonstrated in numerous disease models. […] We have discovered many potential therapeutic targets by elucidating the pathogenesis and self-remission mechanisms of gout. […] We believe that targeted therapy for gout is coming soon, providing welcome relief for patients with refractory gout.
#33 The management of gout: Much has changed
https://www.racgp.org.au/afp/2016/may/the-management-of-gout-much-has-changed
Gout is a common problem that is increasing in prevalence in Australia. […] Accumulation of urate in the body occurs as a result of an imbalance in intake or intrinsic urate production and excretion through the kidneys and gastrointestinal tract (GIT). […] Gout is associated with a number of serious comorbidities such as hypertension, diabetes mellitus, ischaemic heart disease, kidney disease and obesity. […] Treating patients to a target serum urate is essential for reducing gout flares and resolving tophi. […] Allopurinol should not be stopped during acute flares of gout. […] Historically, there has been concern that starting urate-lowering therapy such as allopurinol could worsen or prolong the acute gout flare. […] Evidence suggests that it is the starting dose of allopurinol, not the maintenance dose, that increases the risk of allopurinol hypersensitivity syndrome (AHS).
#34 Treating Gout without Doubt | UConn School of Pharmacy
https://pharmacy.uconn.edu/course/gout/
The goal of chronic gout management is to lower the serum uric acid level with ULT, if indicated, and to prevent future attacks. ULT includes medications that decrease uric acid production or promote uric acid excretion. […] The 2020 ACR guideline recommends a treat-to-target approach that guides ULT dose titration and maintenance to achieve serum uric acid of less than 6 mg/dL. […] Initiation of ULT may trigger a gout flare due to activation of crystals precipitated in joints. The risk of gout flare increases with higher reduction in serum uric acid levels. Studies suggest that gout attacks associated with ULT may decrease patient adherence to ULT. Prophylaxis with anti-inflammatory medications decreases the risk of gout flare upon ULT initiation. The 2020 ACR guideline recommends prophylactic therapy upon initiating ULT and for at least three to six months. […] The pharmacy team plays a crucial role in identifying drug-induced hyperuricemia and educating patients about the importance of adherence to ULT. Gout flares are painful and debilitating. Pharmacists can recommend initiation of anti-inflammatory therapy for acute gout flares.
#35 New gout treatments are here, with more coming – ACR Convergence Today
https://www.acrconvergencetoday.org/new-gout-treatments-are-here-with-more-coming/
Knowledge about goutâs pathogenesis and treatment targets is changing. […] The disease is characterized by the deposition of urate crystals precipitated from uric acid. As part of the recent evolution in understanding of the pathogenesis of gout, experts recognize gout to be driven in large part by macrophages via the NLRP3 inflammasome-interleukin 1 pathway. […] Many newer therapeutic approaches focus on the interplay between metabolism and epigenomic changes in the inflammatory response in gout. […] Several new agents are in development that directly target the NLRP3 inflammasome, he added. […] AMPK, working partly through the epigenome, also plays a role in innate immune memory, affecting the development and course of gout as well as the highly variable response of gout flare symptoms to uric acid lowering therapy. […] We are on the path to more therapies and, more importantly, more individualized therapies using potential biomarkers to predict and prevent gouty inflammation.
#36 Frontiers | Role of NLRP3 in the pathogenesis and treatment of gout arthritis
https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2023.1137822/full
Gout arthritis (GA) is a common and curable type of inflammatory arthritis that has been attributed to a combination of genetic, environmental and metabolic factors. Chronic deposition of monosodium urate (MSU) crystals in articular and periarticular spaces as well as subsequent activation of innate immune system in the condition of persistent hyperuricemia are the core mechanisms of GA. […] Although MSU crystals in articular cartilage detected by arthrosonography or in synovial fluid found by polarization microscopy are conclusive proofs for GA, the exact molecular mechanism of NLRP3 inflammasome activation in the course of GA still remains mysterious, severely restricting the early diagnosis and therapy of GA. […] On the one hand, the activation of Nod-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome requires nuclear factor kappa B (NF-ÎºB)-dependent transcriptional enhancement of NLRP3, precursor (pro)-caspase-1 and pro-IL-1Î², as well as the assembly of NLRP3 inflammasome complex and sustained release of inflammatory mediators and cytokines such as IL-1Î², IL-18 and caspase-1. On the other hand, NLRP3 inflammasome activated by MSU crystals is particularly relevant to the initiation and progression of GA, and thus may represent a prospective diagnostic biomarker and therapeutic target.
#37 Frontiers | Role of NLRP3 in the pathogenesis and treatment of gout arthritis
https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2023.1137822/full
Herein, we first introduced the functional role of NLRP3 inflammasome activation and relevant biological mechanisms in GA based on currently available evidence. […] It also should be noted that the NLRP3 inflammasome may also represent a promising diagnostic biomarker and therapeutic target, which might aid in early diagnosis and therapy, as well as the development of therapeutic drugs. […] The NLRP3 inflammasome is a critical component of the innate immune system, and its abnormal activation is of particular relevance to the pathogenesis of a variety of inflammatory diseases. […] Specifically, a previous study has demonstrated that the expression of NLRP3, ASC and caspase-1 was significantly higher in the GA groups and hyperuricaemia groups than those in control groups. […] The NLRP3 inflammasome is made up of a sensor, NLRP3 protein, ASC adaptor protein and pro-caspase-1, which can be significantly activated by extracellular adenosine triphosphate (ATP), certain bacterial toxins, mitochondrial damage, and various types of crystalline and particulate matter.
#38 The pathogenesis and treatments of gout and hyperlipidemia | JIR
https://www.dovepress.com/lipidomics-analysis-deepen-understanding-the-molecular-mechanisms-in-a-peer-reviewed-fulltext-article-JIR
These findings suggest that the development of gouty arthritis may contribute to the lipid metabolism disorders and that allopurinol treatment may exert beneficial effects on lipid homeostasis in individuals with gout. […] Gouty mice had the highest PI level and the lowest PE level, and allopurinol regulated the total PI and PE levels and some small aberrant lipid metabolism in gouty mice. […] The increase in the number of PI species in the model group may be due to altered signaling, as the dynamics of PI synthesis and accumulation are important for the level and availability of these signaling metabolites. […] Cer is the core compound of sphingolipid metabolism. This lipid plays an important role in regulating intracellular processes such as proliferation, differentiation, and apoptosis.
#39 The pathogenesis and treatments of gout and hyperlipidemia | JIR
https://www.dovepress.com/lipidomics-analysis-deepen-understanding-the-molecular-mechanisms-in-a-peer-reviewed-fulltext-article-JIR
In our results, the total levels of SM and Cer in model mice were significantly higher than in control, and the levels of Cer were positively correlated with the levels of IL-6 and TNF-. […] Allopurinol therapy, from the gouty symptoms to related inflammation mediators, from blood lipids to the lipoproteins and apolipoproteins, has a good effect on gouty arthritis. […] In summary, the present study successfully established an animal model of gout using MSU crystal injection and high-fat diet feeding, which exhibited gouty symptoms, inflammation, and aberrant lipid metabolism, particularly showing abnormalities in eight lipids in serum. The study demonstrated that Cer had strong correlations with IL-6, TNF, and SUA, indicating its potential as an early biomarker for gout. Furthermore, the study revealed that allopurinol treatment could inhibit the progression of gouty arthritis and regulate aberrant PI and PE lipids and PC/PE ratio.
#40 Gout Basic Research: 2023 in Review
https://www.mdpi.com/2813-4583/2/3/17
This paper identifies a role for myeloid Src family kinases in autoinflammatory diseases, including gout, and suggests targeting tyrosine phosphorylation pathways as a potential therapeutic strategy for managing conditions characterized by heightened neutrophil activity. […] The role of glycolytic reprogramming and its effects in NLRP3-mediated inflammation and the risk of gout has recently been described by Chen et al. This study investigated the role of the mitochondrial pyruvate carrier (MPC) in NLRP3 activation. MPC deficiency, achieved through genetic knockout in mice or pharmacological inhibition with antidiabetic drug pioglitazone in human THP1 cells, led to elevated IL-1Î² secretion in response to NLRP3 agonists in macrophages. […] This report studies the relationship between the MPC and NLRP3 activation in the context of pioglitazone treatment in diabetes mellitus and highlights that glycolytic reprogramming upon MPC modulation recapitulates the mechanism of NLRP3 activation and increases gout risk.
#41 Urate transporter structures reveal the mechanism behind important drug target for gout – St. Jude Childrenâs Research Hospital
https://www.stjude.org/media-resources/news-releases/2024-medicine-science-news/urate-transporter-structures-reveal-mechanism-behind-important-drug-target-for-gout.html
Ten structures of URAT1 obtained by scientists at St. Jude Childrens Research Hospital provide a deep understanding of the mechanism of urate transport to guide gout therapeutic design. […] URAT1 is a transporter that regulates urate levels, controlling its reabsorption in the kidneys. […] The new structures of URAT1, in combination with substrates and inhibitors, illuminate the mechanism by which URAT1 transports urate and offer insights for future drug discovery efforts. […] We can see the inhibitors very clearly, and in all three structures, URAT1 is in the inward-facing state. This clarity indicates that the inhibitors are very effective at keeping the protein in this conformation, Dai said. From these observations, we conclude that the drugs work by locking URAT1 in the inward-facing state. […] Without structural information, its challenging to understand how specific mutations affect the function of the transporter. Now we can map those genetic variations onto the structure and explain their effects, Lee said. This is a big step forward to understanding diseases linked to URAT1.
#42 Gout. Mechanisms of inflammation in gout | Arthritis Research & Therapy | Full Text
https://arthritis-research.biomedcentral.com/articles/10.1186/ar2952
Proinflammatory cytokines undoubtedly have a critical role in orchestrating the inflammatory reaction to MSU crystals. Recent attention has focused particularly on the role of IL-1. […] The inflammasome is a cytoplasmic protein complex composed of a protein of the NLRP (or NALP) family, an adapter ASC protein as well as an inflammatory caspase. […] The group of Tschopp discovered that many inorganic particles, including MSU and calcium pyrophosphate dihydrate crystals, are capable of activating the NLRP3 inflammasome to process and secrete active IL-1 as well as IL-18. […] The results show that MSU crystals initiate an inflammatory cascade, the starting point being the release of active IL-1 from monocytes and macrophages. […] Although our understanding of how MSU crystals trigger inflammation has advanced considerably in the past 20 years, a number of fundamental and clinically relevant questions remain unanswered.