Calcium Pyrophosphate Dihydrateand Basic Calcium Phosphate Crystalinduced Arthropathies

[그리운시절]

Calcium Pyrophosphate Dihydrateand Basic Calcium Phosphate Crystalinduced

Arthropathies : Update on Pathogenesis, Clinical Features, and Therapy

Introduction

Often asymptomatic, calcium-crystal deposition can cause acute attacks of inflammatory arthritis, such as pseudogout, erosive arthritis, or periarthritis, and is associated with an exaggerated form of OA.

Calcification Mechanism: Role of Extracellular Inorganic Pyrophosphate

Articular calcification results from an imbalance between physiologic calcification inhibitors and mediators.

Extracellular inorganic pyrophosphate (ePPi) is now recognized as an important factor for controlling calcium crystal formation [4,5].

1) excess ePPi generation via the chondrocytes-->calcium pyrophosphate dihydrate (CPPD) deposition

2) ePPi deficiency --> HA(carbonated-substituted hydroxyapatite) crystal deposition.

-The primary stimulus of ePPi production : transforming growth factor (TGF)

-Other stimuli for ePPi production : ascorbate, retinoic acide, and thyroid hormone

-Negative regulators for ePPi production : interleukin-1–beta, tumor necrosis factor–alpha, some isoforms of parathyroid hormone–related peptide, and insulin-like growth factor–1

Pathogenesis of Calcium-containing Crystal Deposition Disease

Clinical observations support the hypothesis that crystal deposition causes cartilage degeneration and differs from primary OA by the distribution of involved joints and

the severity of the disease. Unusual sites of OA, such as the elbow, the shoulder, or the ankle joint, should lead to further investigation for evidence of CPPD or BCP

crystal disease

BCP crystals are mainly responsible for acute periarthritis that involves all possible tendon or capsular sites.

1. 기존의 연구

calcium-containing crystal deposition --> synovial lining cell stimulation --> synovial cell proliferation, matrix-degrading molecule release and secretion of inflammatory mediators and cytokines--> chondrocytes to generate matrix-degrading molecules

2. 최근 연구결과

1) chondrocytes 가 BCP crystals을 endocytosis하면서 prostaglandin E2 and collagenase secretion

2) BCP crystals stimulated production of matrix metalloproteinase (MMP)-1 and MMP-

13 by articular porcine chondrocytes.

3) crystal type에 따라서 작용기전이 다름

- BCP crystals --> chondrocytes inducible nitric oxide (NO) synthase messenger RNA expression‎ and NO production.

- OCP crystals induced two times more NO production than carbonated-substituted HA crystals,

- HA crystals had no effect on NO stimulation

4) The inflammatory potential 은 BCP(basic calcium phosphate) crystals의 surface area에 의존

--> a large crystal surface allowed a greater amount of proteins to bound leading to an increased crystal-cell membrane contact. This could trigger intracellular signaling via a cell surface receptor–like receptor, or could modify the cell membrane properties,

5) Other studies have recently confirmed this biologic variability of BCP crystals on monocyte activation on cytokine release, such as tumor necrosis factor–alpha, interleukin-6, and interleukin-10 , or MMP stimulation

3. 감별진단 : acute inflammatory articular or periarticular

--> septic arthritic or abscess, acute HA attack

4. 진단요점 : the knowledge of para-articular tendons, capsulae, and bursae, with the typical aspects of plain radiographs showing calcifications of varying size.

1) at the very beginning or in asymptomatic joints ->calcifications can be unfragmented. and dense, with a round shape,

2) inflammation has started --> start to be fragmented, with fluffy edges

3) They can vanish within days or weeks

4) Unusual sites에서도 발병 -> toes (pseudo-pseudo-podagra), wrists, elbows, ankles, coccygeal pain

5) chronic pain도 가능

6) Basic calcium phosphate crystals can cause acute synovitis of small or large joints.

7) BCP crystals appeared with joint degeneration.

8) 확진이 어렵다(BCP crystal은 검출하기 힘듬)

5. Treatment of calcific tendinitis

The management of crystal-associated OA remains identical to primary OA because the prevention of calcification is yet unavailable.

1) symptomatic treatment (nonsteroidal anti-inflammatory drugs, local corticosteroid injection, physical modalities including heat application, and range of movement exercises)

2) specific treatment (needle aspiration, surgical or arthroscopic removal, shock-wave, and ultrasound).

The capacity of ultrasound to promote resorption of calcification is noteworthy

Clinical Expression‎ of Calcium Pyrophosphate Dihydrate Deposition

1) pseudogout attacks (25% of patients with CPPD deposition exhibit this pattern),

2) pseudo-rheumatoid presentation (5% of cases) with multiple joint involvement,

3) progressive OAlike joint degradation of numerous joints, especially at unusual sites,

4) asymptomatic but radiologic disease;

5) chronic destructive arthropathies presenting with geodes of various size.

spine은 잘 침범하지 않지만

1. the periodontoid region

2. cervicothoracic spine, are prone to CPPD deposits

한 논문에 의하면 ligamentum flavum of the cervical and thoracic spine에 침착