Re: 지독한 chronic synovitis와 osteoarthritis의 이해

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이 컨퍼런스 자료는 장은하 선생님이 햇수로 2년동안 읽은 논문을 정리한 귀한 자료입니다.

panic bird......

the source of pain in knee osteoarthritis

- 관절염에서 cartilage loss는 무릎관절염 증상수반없이도 발생한다. 그런데도 무릎관절염 연구는 cartilage loss에 초점이 맞추어져 있다. 실제로 cartilage는 pain fiber가 없다. 그래서 무릎관절염의 적절한 치료를 위해서는 통증의 원인의 이해가 반드시 필요하다.

knee pain이해를 위한 네가지 요소

1. 무릎안에서 어떤 구조물이 통증을 유발하는가?
2．joint로부터 pain impulse가 어떻게 흘러나와 신경계에 작용하는가?

3. 어떤 외부자극이 articular stimuli를 유도하여 nociceptor를 자극하는가?

4. 왜 그리고 어떻게 사람의 psychosocial feature 이 통증의 severity에 영향을 주는가?
 

Nociceptors in the knee

1. 통각 신경섬유는 활막，연골,　골막，연골하골，골수，지방패드，캡슐(capsule)，골－연골접합부에　분포．

２．마취하지　않은　상태에서　시행한　관절경　시술상　가장　통증에　민감한　구조물은　ligament insertion　부위，활막，　슬개골하　지방패드，bone  marrow lesion pain

** bone marrow lesion

　증상을　수반하지　않는　경우와　수반하는　경우를　비교한　MRI 결과에　대한　통계에　따르면　골수　내　부종을　동반한　병소(괴사，　골타박상，　microfracture(bone cyst）)는　무수신경섬유의　분포가　뚜렷하게　관찰되었으며　병소의　크기, 갯수와　통증강도는　비례．（intraosseous hypertension)

Intraosseous hypertension and pain in the knee.

INTRAOSSEOUS HYPERTENSION AND PAIN IN THE KNEE.pdf

 J Bone Joint Surg Br. 1975 Aug;57(3):360-3

The intraosseous pressure in the femur and tibia near the knee and in the internal saphenous vein at knee level was measured in fifty-three patients with suspected knee lesions. There were four groups: with and without degenerative osteoarthritis and with and without aching rest pain of the knee region. Low intraosseous pressures were found in patients with neither osteoarthritis nor rest pain, and in half the patients with osteoarthritis but without rest pain. Low pressures were found in the tibia, but very high intraosseous pressures were found in the femur in most patients with osteoarthritis and rest pain. Patients with no osteoarthritis but with rest pain mostly had high pressures in both the tibia and the femur.

Bone pain and pressure in osteoarthritic joints.

2004;260:179-86; discussion 186-90, 277-9.

Division of Rheumatology, Department of Medicine, University of Washington, Box 356428, Seattle, WA 98195, USA.

Intraosseous hypertension has been associated with a deep aching bone pain, particularly at rest, in subsets of patients with osteoarthritis of the hip and knee. The pathophysiology of this problem remains uncertain, but intraosseous phlebography implicates outflow impairment at relatively distal venous sites. Although the issue has been controversial, intraosseous pressures rise normally, and painlessly, when epiphyseal bone is loaded and these pulses may be mechanically meaningful in the distribution and transmission of impact energy. Increased outflow resistance may amplify the episodic pressure response with subsequent intravasation of epiphyseal fat leading to 'marrow oedema' and altered mechanics. The relationship between persisting pain and pressure is an old but convincing association. Its precise mechanism in osteoarthritis remains in need of an adequate explanation.

* knee effusion의　유무와　크기는　통증과　유관하다.

# 활막비후(synovial thickening)는　통증여부에　관련할　뿐아니라　통증강도와도　비례한다．　

# 통증이　있는　OA 환자　중　１５％가　건염，점액낭염을　가지고　있던　반면에　무릎통증이 없는　OA환자는 건염, 점액낭염이 없었다. 이는 soft tissue lesion은 통증과 약간의 연관성만 가지고 있다는 것을 의미.

#  증식성 활액막 소견인 Hoffa's fat  pad distortion은 knee effusion과 함께 통증강도와 비례.

From articular nociceptor to the central nervous system

- inflamation이 nociceptive input를 대뇌로 전달하는 역할을 하여 통증을 유발하는 주요 요인이다.

Synovitis detected on magnetic resonance imaging and its relation to pain and cartilage loss in knee osteoarthritis

C L Hill　외

15~30개월 간 45세 이상의 퇴행성 관절염 환자 270명을 대상으로 장기적인 활막염 양상에 따른 통증과 연골손실의 변화를 관찰함.

the presence of MRI synovial thickening identified those with more severe pain.

An increase of one unit in summary synovitis score resulted in a 3.15-mm increase in VAS pain score (0–-100 scale).

Effusion change was not associated with pain change.

Of the 3 locations for synovitis, changes in the infrapatellar fat pad were most strongly related to pain change.

Despite cartilage loss occurring in over 50% of knees, synovitis was not associated with cartilage loss in either tibiofemoral or patellofemoral compartment.

슬관절의 증식성과 비증식성 삼출액의 자기공명영상 소견

비증식성 삼출액 （ 3 6 )　－　외상，슬내장증

증식성 삼출액 （29） － 색소 융모결절성 활액막염 (5), 류마치스 관절염 (6), 화농성 관절염 (6), 만성 활액막염 (5), 통풍성 관절염 (3), 결핵성 관절염 (2), 수지상 지방종 ( 2 )

슬관절강의　구분

1) 상부슬개와　２） 중앙부　３）후대퇴함요　４） 슬와하함요 4개 부위★★

슬관절강　내　지방츨

　전대퇴골지방층，　호파씨지방층，　대퇴사두근　지방층

- 이 그림에 대한 설명이 없네..

- ???

A.
  B.

The bland vs. proliferative joint effusion

A. Axial T2-weighted image shows smaller ratio of width of lateral recess

(L) / medial (M) recess in bland effusion .

B. Axial T2-weighted image shows larger ratio of width of lateral recess (L)

/medial recess (M) in proliferative effusion.

2) 시상면 영상에서 증식성 삼출액을 시사하는 관절내 지방층의 이상 소견

전대퇴골 지방층 (prefemoral fat pad)의 피지얼 스카의 상부3mm 이상의 절단(truncation), 전방의  부분적 미란이나 조개 모양의 결손 － 민감도　４％　특이도　１００％　

호파씨 지방층의 난원형　결손 이나 부분적인 전방　혹은　하방으로의 이동

　－　민감도　３２％　특이도　９５％

대퇴사두근 지방층 (Quadriceps fat　p a d )이 작고 불규칙하거나 보이지 않는 경우

　－　민감도　１４％　특이도　１００％

3) 조영증강을 실시한 경우에는, 활액막의 양상을 두께에 따라서는 얇거나 두껍게, 경계에 따라서는 평활 혹은 불규칙으로 구분하였다.　증식성 삼출액은 비증식성 삼출액에 비하여, 활액막이 두껍거나 불규칙한 경향을 보였고, 상부슬개와, 특히 외측 함요와 후대퇴함요에 좀 더 많이 분포하는 경향이　있다．

The role of joint innervarion in the pathogenesis of arthritis

Neurogenic origin of joint pain

슬관절 주변의 감각신경분포

20%; 유수신경 -mechanoreceptor

80% 무수신경 - 50% 교감신경, 50% 통각신경

neuronal contributions to inflammatory arthritis

염증성 관절염은 감각신경말단의 환경을 변질시켜 후근신경절을 통해 건측관절의 통각과민을 유발한다.　무수신경섬유 말단의 30%에서 substance P, CGRP가 관찰되는데 혈관확장을 통해 비만세포 유출을 유도하고 백혈구 화학주성이 있다.

IL-1β, TNF-α에 의해 활성화된 섬유모세포에 의해 자극된 nerve growth factor는 비만세포와 교감신경을 활성화시켜 염증을 조장한다. 국소적으로 증가된 NGF는 염증유발 물질의 증가를 야기하여 말초신경감작을 유도한다.

브라디키닌, 세로토닌의 증가는 교감신경말단에서 프로스타글란딘 방출을 유발하고 이를 통해 병소주변 혈류량 및 혈장삼출이 증가한다.

증가된 sensort traffic은 후각 국소의 Sp, CGRP, glutamate level을 높여 후각 심부의 2nd order neuron의 흥분을 유발한다. - Ex) contralateral effect

neurologic factors in degenerative arthritis

- agerelated loss of joint sensory innervation은 OA를 가속화한다.

Neurogenic Inflammation and Arthritis

JON D. LEVINE

　“　Inflammation is more than a product of an immune response; its severity is

also powerfully controlled by the nervous and endocrine systems〃

adrenal medulla- via release of epinephrine

vagus-mediated modulation of nociceptive threshold에　관여

inflammatory mediator　－induced　hyperalgesia

plasma extravasation

염증　반응　및　통증양상에　대한　 sexual dimorphism을　야기

sympathoadrenal axis와　vagal afferent에　의해　조절되는　 neural-immune mechanisms that underlie sexual dimorphism을　— plasma extravasation, neutrophil

function, inflammatory hyperalgesia의　측면에서　분석함．

＜Plasma extravasation＞

－　first line of defense required for several other aspects of　the inflammatory response

－　tissue- protective component of the inflammatory response

magnitude of bradykin－ininduced　plasma extravasation in the rat knee joint is inversely related to　the severity of joint injury　．．．swelling - joint destruction　의　불일치

－　bradykinin-induced plasma extravasation　is powerfully affected by stress, 25 activity in the subdiaphragmatic vagus,　and by noxious stimulation.

☉　Endocrine modulation of inflammation

the release of glucocorticoid from the adrenal cortex

the release of epinephrine，endogenous opioids from the adrenal medulla,

decrease plasma extravasation

＜HYPERALGESIA＞

pain은　plasma extravasation, neutrophil　function에　대하여　feedback을　가지는데　이러한　피드백은　vagal afferent　activity의　큰　영향을　받는다．　

염증에　따른　직접적인　통각과민　유발기전과　별도로　브라디키닌은　교감신경　말단에　작용하여　PG의　분비를　촉진　－＞　vagal afferent　activity에　의해　조절되며　 sexual dimorphism을　보인다．

＜ SEXUAL DIMORPHISM IN CLINICAL AND EXPERIMENTAL　INFLAMMA TORY PAIN>

　 기전은　아직까지　불명확．．

- marked female predominance for inflammatory disease begins at menarche and continues up until menopause

- Sex differences in the development of experimental arthritis are abolished following castration in male rats

- principal female gonadal hormone, 17-estradiol, can exacerbate experimental arthritis in intact males

- severity of rheumatoid arthritis is markedly suppressed during pregnancy

- Rheumatoid arthritis is also suppressed in women taking oral contraceptive pills.

hypothesis>

sexually dimorphic mechanisms in adrenal medullary function, and that these differences are substantially attributable to the effects of sex steroids.

<MODULATION OF INFLAMMATION BY THE ADRENAL

MEDULLA>

- the effector organ of the sympatho-adrenal neuroendocrine axis　and

　hypothalamic-pituitary-adrenal axis

↳ modulation of baseline nociceptive threshold and bradykinin-induced hyper algesia by vagal afferent activity

↳ bradykinin-induced plasma extravasation 조절．

↳　epinephrine ; plasma levels의 pro- and anti-inflammatory cytokine　분비에　관여．β-adrenergic receptor에　작용하여　macrophage， inflammatory protein　생산을　억제．；sexually dimorphic effect of isoproterenol, a-adrenergic agonist is less in females than in males

adrenal medulla dependent background inhibition of bradykinin-induced plasma extravasation occurs in normal female but not in male rats; it is enhanced by estrogen and suppressed by testosterone

repeated stress did not affect lipopolysaccharide (LPS)-induced neutrophil recruitment in males but significantly inhibited it in females.

<VAGAL MODULATION OF INFLAMMATION AND

INFLAMMATORY HYPERALGESIA>

intraplantar capsaicin in a paw acts to modestly inhibit bradykinin-induced plasma extravasation in the knee joint of the rat, but when the vagus nerve is cut below the level of the diaphragm, this inhibition is markedly increased.

- ongoing activity in the subdiaphragmatic vagus nerve potently antagonizes

the ability of noxious stimuli to inhibit inflammation.

Stimulation of vagal afferents can raise or lower baseline nociceptive

thresholds, depending on the strength of stimulation

vagus nerve, at the subdiaphragmatic level, can either increase or decrease the

magnitude of hyperalgesia produced by inflammatory mediators, depending on

the agent.

vagotomy decreases tonic inflammatory hyperalgesia (nociceptive behavior in phase 2 of the formalin test) in male but not in female rats, 83 but does not affect inflammatory hyperalgesia caused by PGE 2 . 42