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Calcium crystal deposition diseases — beyond gout

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From Nature Reviews Rheumatology

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Abstract

The most common types of calcium-containing crystals that are associated with joint and periarticular disorders are calcium pyrophosphate dihydrate (CPP) and basic calcium phosphate (BCP) crystals. Several diverse but difficult-to-treat acute and chronic arthropathies and other clinical syndromes are associated with the deposition of these crystals. Although the pathogenic mechanism of calcium crystal deposition is partially understood, much remains to be investigated, as no drug is available to prevent crystal deposition, permit crystal dissolution or specifically target the pathogenic effects that result in the clinical manifestations. In this Review, the main clinical manifestations of CPP and BCP crystal deposition are discussed, along with the biological effects of these crystals, current therapeutic approaches and future directions in therapy.

Key points

  • Deposition of calcium-containing crystals, including calcium pyrophosphate dihydrate (CPP) and basic calcium phosphate (BCP), results in a wide variety of articular and periarticular disorders.

  • Calcium-containing crystal deposition diseases are common but underdiagnosed conditions, and the treatment options are limited; no drug is available to prevent crystal deposition or permit crystal dissolution.

  • CPP crystal deposition (CPPD) diseases can be accurately diagnosed using compensated polarized microscopy to detect CPP crystals in the synovial fluid, whereas identifying BCP crystals in the synovial fluid is difficult.

  • BCP crystals are found in 100% of cartilage samples from patients with osteoarthritis (OA) undergoing joint replacement surgery and probably represent a therapeutic target in OA.

  • BCP crystals exert potentially pathogenic effects on a number of articular cell types including fibroblasts, chondrocytes and synovial macrophages.

  • Drugs targeting the NOD-, LRR- and pyrin domain-containing 3 (NLRP3) inflammasome, membrane-proximal kinases, IL-6 and crystal deposition represent potential future therapeutics for arthropathies related to CPP and BCP crystals.

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Fig. 1: Clinical outcomes of calcium-containing crystal deposition.
Fig. 2: Features of calcium crystal deposition disease on imaging.
Fig. 3: Cellular processes and inflammation driven by BCP and CPP crystals.
Fig. 4: Cellular mechanism leading to crystal-induced tissue damage in the joint.

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Acknowledgements

A.D. is funded by the Health Research Board, Ireland. The authors thank O. Mahon for assistance with illustrations and for critical reviewing of the manuscript.

Reviewer information

Nature Reviews Rheumatology thanks E. Pascual, A. K. Rosenthal and B. Rothschild and for their contribution to the peer review of this work.

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Authors and Affiliations

  1. School of Medicine and Medical Science, University College Dublin, Dublin, Ireland

    Geraldine M. McCarthy

  2. Mater Misericordiae University Hospital, Dublin, Ireland

    Geraldine M. McCarthy

  3. School of Biochemistry and Immunology and School of Medicine, Trinity College Dublin, The University of Dublin, Dublin, Ireland

    Aisling Dunne

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Glossary

Chondrocalcinosis

Calcification of articular fibrocartilage or hyaline cartilage, most commonly owing to calcium pyrophosphate dihydrate crystal deposition.

Hypophosphatasia

A rare genetic disorder characterized by defective mineralization of bone and/or teeth caused by a deficiency of serum and bone alkaline phosphatase.

Gitelman variant of Bartter syndrome

A genetic renal disorder characterized by hypokalaemic alkalosis (low serum potassium levels) caused by inactivating mutations in a gene encoding a thiazide-sensitive sodium–chloride cotransporter (SLC12A3).

Birefringent

A state that enables a material of ordered structure to split a single ray of unpolarized light into two rays; the colour of the birefringent material changes as its orientation changes in relation to the light source.

Acetabular labrum

A ring of fibrous cartilage that surrounds the acetabulum (cup) of the hip joint.

Symphysis pubis

A cartilaginous joint located between the left and right pubic bones.

Annulus fibrosus

The outer layer of the intervertebral disc composed of strong layers of collagen fibres that surrounds the soft inner core of the disc.

Calciphylaxis

A rare and potentially fatal disease cause by the accumulation of calcium in small blood vessels of the fat and skin.

Crepitus

A medical term used to describe the cracking or popping sensation or sound that occurs when moving a joint; it is caused by the presence of air in the subcutaneous tissue.

Barbotage

Needle aspiration and lavage; it is used in the treatment of calcific tendinitis.

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McCarthy, G.M., Dunne, A. Calcium crystal deposition diseases — beyond gout. Nat Rev Rheumatol 14, 592–602 (2018). https://doi.org/10.1038/s41584-018-0078-5

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