What Is Chondrocalcinosis 2

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Overview 

Chondrocalcinosis is a common pathological condition characterised by cartilage calcification because of the accumulation of calcium pyrophosphate dihydrate (CPPD) crystals in the joints. This crystal deposition phenomenon affects mostly fibrocartilage tissues, such as the menisci and hyaline cartilage, a translucent type of cartilage that coats and protects articulating surfaces within the joints. Also known as calcium pyrophosphate arthropathy, this disorder affects mostly the knees and wrists. 

With a prevalence of roughly 7% in the United Kingdom, the number of chondrocalcinosis cases presents a strong association with an increase in age.1 However, the low number of population-based studies, coupled with the relatively small number of subjects analysed, suggests that these estimations can be pretty conservative, rendering the condition under-recognised and under-studied. 

Understanding chondrocalcinosis

Chondrocalcinosis occurrence can be categorised into two different presentations: type 1 and type 2. These two condition subtypes differ in several important aspects, such as their underlying causes and clinical expression. 

Chondrocalcinosis type 1 is a primarily idiopathic disorder that occurs mainly in elderly individuals. Its prevalence progressively increases with population ageing.2 Chondrocalcinosis 2, on the other hand, is a hereditary form of the condition unrelated to the patient's age.

It is believed that this condition might also be correlated to the presence of metabolic disorders such as hemochromatosis and hypomagnesemia.3

Causes and risk factors

Genetic factors 

The first steps towards unveiling the genetic basis of chondrocalcinosis 2 manifestation were linked to changes observed in the cartilage extracellular matrix in joints, leading to clues towards genes encoding proteins involved in this tissue microenvironment.4 The gene ANKH, which encodes the inorganic pyrophosphate transport regulator protein responsible for controlling pyrophosphate levels, is a genetic factor that plays a key role in disease manifestation.5 

ANKH expression is governed by a model of autosomal dominant inheritance, meaning that the presence of a single copy of the mutant altered gene allele can drive phenotype expression – a person with chondrocalcinosis type 2 can inherit the condition from an affected parent and is also likely to transmit the disorder to a child with a risk of 50%.6

Age-related factors

While the sporadic form of chondrocalcinosis affects middle-aged and elderly individuals, the hereditary form and forms linked to other conditions might present a precocious onset at an earlier age. 

Other contributing factors

Several metabolic disorders, such as hemochromatosis, hypomagnesemia, hyperparathyroidism, and hypophosphatasia, are risk factors strongly associated with higher chondrocalcinosis prevalence. 

Clinical presentation

The variable clinical presentation associated with this disorder can be placed within a wide spectrum of outcomes. Even though the deposition of the calcium pyrophosphate dihydrate crystals may be asymptomatic, the condition might manifest in chronic or acute pain and recurrent episodes. The most affected joints are the knee menisci, symphysis pubis, and wrist triangular cartilage. 

In general, a handful of symptoms that add up from an inflammatory state in the joints are reported by patients affected. These symptoms range from joint pain and swelling to stiffness and limited range of motion, leading to cartilage weakening and a higher chance of breaking.

This set of symptoms described for Chondrocalcinosis resembles that of arthritis or gout, which explains the association of this condition with “pseudoarthritis” or “pseudogout”.

Complications are likely to occur in the long run as the joint damage progresses over time.

Diagnosis

A key factor in the differential diagnosis that separates chondrocalcinosis from gout is the composition of the crystal deposition patterns. Briefly, while chondrocalcinosis is governed by calcium pyrophosphate dihydrate crystals, the gout pathophysiology is established when sodium urate crystals are deposited instead. 

Different techniques can be employed for the diagnosis of chondrocalcinosis:

Physical examination

A physical evaluation of external aspects of the affected joints, like redness, stiffness, and higher temperature, and even testing on moving ability and pain reflexes, might give the physician a clue on the presence of chondrocalcinosis. This diagnosis, however, cannot be confirmed by physical examination alone. 

Laboratory tests

The gold standard and more assertive tool for Chondrocalcinosis diagnosis is the identification of CPPD crystals in the synovial fluid, a collection of thick fluids located between joints that cushions bone ends and reduces friction and wear. Observed under light microscopy, the crystals are characteristically rectangular, square or rhomboid-shaped.7

Imaging tests

  • X-rays: Radiologic screenings are an important tool for the identification of patterns of Chondrocalcinosis in important condition-related joints such as the hands, knees, and pelvis. The crystal deposition is observed in the X-ray as punctate and linear densities in the cartilages affected, like the hyaline or the fibrocartilage. Its low cost and wide availability make radiography a suitable option for diagnosis. However, the low sensitivity of this imaging technique might lead to missing crystal deposition identification in small joints. 
  • Ultrasound: Recent studies suggest that the application of ultrasound can lead to more sensitive results in the identification of Chondrocalcinosis when compared to plain radiologic imaging.8 This higher sensitivity, however, is heavily dependent on the machine operator's experience, as the distinction between chondrocalcinosis and gout signal patterns may confuse result interpretation and final diagnosis.
  • MRI: Chondrocalcinosis diagnosis using MRI can be tricky, as the calcium mineralisation in the crystal-deposited areas might lead to areas of signal heterogeneity in the cartilage. This poor specificity of MRI for crystal deposition imaging justifies the little utility of this technique alone for diagnosis completion.

Treatment 

The pillar of Chondrocalcinosis treatment and management is centred on inflammation and symptom control, as no drug is known to prevent progressive articular destruction.9 

  • Pain management through medications is based on nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin and/or ibuprofen and Colchicine – the latter also indicate prophylaxis. The paucity of evidence-based treatment guidelines has led to these two therapy avenues having been extrapolated to Chondrocalcinosis treatment based on their proven efficacy in gout treatment.

    Even though reductions in both diseases can be achieved, flare-ups and pain episodes have been reported. The considerable toxicity of Colchicine needs to be taken into the equation of modulating dosing in its prescription.10
  • Surgical interventions can be suggested when treatment has proven ineffective. As for the joint aspiration procedure, also named arthrocentesis, the fluid is drained through a needle from the sore joint. The removal of crystals contained in the fluid alleviates pain and swelling in the area.

    In more extreme cases, joint surgery can repair unstable and strongly damaged joints or even replace joints with artificial ones – especially in the knees or hip. 

Prognosis and outlook

The prognosis for Chondrocalcinosis can be variable due to the variable nature of its symptoms. In the long run, patients might experience progressive joint damage, significantly limiting its function. For better condition management, lifestyle changes such as weight reduction, exercising, and physical therapy can reduce joint stiffness and increase mobility.11 A healthier lifestyle can drive a better quality of life for individuals affected. 

Prevention and risk reduction

The hereditary character of chondrocalcinosis 2 suggests the follow-up of relatives in family nuclei in which diagnosis has been confirmed. A handful of different genetic tests to evaluate alterations in the ANHK gene are available to assess the disorder's establishment.12

Moreover, there is significant relevance in evaluating chondrocalcinosis development in patients affected by metabolic diseases known to be associated with this disorder, like hemochromatosis and hypomagnesemia. 

In the case of chondrocalcinosis-diagnosed patients, regular medical checkups help monitor the condition's development and aid in assessing the most suitable treatment and/or management options for the current disease status of the individual. 

Summary

Chondrocalcinosis 2 is a hereditary form of joint calcification with a precocious onset in young patients It is important to note that Chondrocalcinosis has many causes – CPPD deposition among them. However, the opposite is not true: not all patients with CPPD deposition are chondrocalcinosis-diagnosed. Population-based studies are scarce and highlight the conservative prevalence estimates, likely linked to sensitivity problems in diagnostic tools or even misdiagnosis given the set of symptoms like other joint-related disorders. 

The research agenda on chondrocalcinosis points towards a promising future, especially when it comes to novel therapeutic options: (I) Anakinra, an IL-1R antagonist efficacious against auto-inflammatory disease13, (II) Oral NLRP3 inflammasome inhibitors14, and (III) Tocilizumab, an IL-6 receptor antibody.15

References

  1. Neame R, Zhang W, Deighton C, Doherty M, Doherty S, Lanyon P, et al. Distribution of radiographic osteoarthritis between the right and left hands, hips, and knees. Arthritis & Rheumatism [Internet]. 2004 May [cited 2023 Sep 8];50(5):1487–94. Available from: https://onlinelibrary.wiley.com/doi/10.1002/art.20162
  2. Rosenthal AK, Ryan LM. Calcium pyrophosphate deposition disease. N Engl J Med [Internet]. 2016 Jun 30 [cited 2023 Sep 8];374(26):2575–84. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6240444/
  3. Richette P, Ayoub G, Bardin T, Bouvet S, Orcel P, Badran AM. Hypomagnesemia and chondrocalcinosis in short bowel syndrome. The Journal of Rheumatology [Internet]. 2005 Dec 1 [cited 2023 Sep 8];32(12):2434–6. Available from: https://www.jrheum.org/content/32/12/2434 
  4. Bjelle AO. Morphological study of articular cartilage in pyrophosphate arthropathy. (Chondrocalcinosis articularis or calcium pyrophosphate dihydrate crystal deposition diseases). Ann Rheum Dis [Internet]. 1972 Nov [cited 2023 Sep 8];31(6):449–56. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1005975/ 
  5. Pendleton A, Johnson MD, Hughes A, Gurley KA, Ho AM, Doherty M, et al. Mutations in ankh cause chondrocalcinosis. Am J Hum Genet [Internet]. 2002 Oct [cited 2023 Sep 8];71(4):933–40. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC378546/
  6. Zaka R, Williams CJ. Genetics of chondrocalcinosis. Osteoarthritis Cartilage [Internet]. 2005 Sep;13(9):745–50. Available from: https://www.oarsijournal.com/article/S1063-4584(05)00102-0/fulltext
  7. MacMullan P, McCarthy G. Treatment and management of pseudogout: insights for the clinician. Ther Adv Musculoskelet Dis [Internet]. 2012 Apr [cited 2023 Sep 8];4(2):121–31. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3383522/
  8. Frediani B, Filippou G, Falsetti P, Lorenzini S, Baldi F, Acciai C, et al. Diagnosis of calcium pyrophosphate dihydrate crystal deposition disease: ultrasonographic criteria proposed. Ann Rheum Dis [Internet]. 2005 Apr [cited 2023 Sep 8];64(4):638–40. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1755428/
  9. Announ N, Guerne PA. Treating difficult crystal pyrophosphate dihydrate deposition disease. Curr Rheumatol Rep [Internet]. 2008 Jun 1 [cited 2023 Sep 8];10(3):228–34. Available from: https://doi.org/10.1007/s11926-008-0037-2
  10. Kim ST, Bittar M, Kim HJ, Neelapu SS, Zurita AJ, Nurieva R, et al. Recurrent pseudogout after therapy with immune checkpoint inhibitors: a case report with immunoprofiling of synovial fluid at each flare. J Immunother Cancer [Internet]. 2019 May 14 [cited 2023 Sep 8];7:126. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518723/
  11. Cppd deposition disease [Internet]. [cited 2023 Sep 8]. Available from: https://orthop.washington.edu/patient-care/articles/arthritis/cppd-deposition-disease.html
  12. Clinical and research tests for 56172 - genetic testing registry (Gtr) - ncbi [Internet]. [cited 2023 Sep 8]. Available from: https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=56172%5bgeneid%5d&_ga=2.150598582.1615726797.1694178285-1829820665.1694178285
  13. Jesus AA, Goldbach-Mansky R. Il-1 blockade in autoinflammatory syndromes. Annu Rev Med [Internet]. 2014 [cited 2023 Sep 8];65:223–44. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4178953/
  14. Klück V, Jansen TLTA, Janssen M, Comarniceanu A, Efdé M, Tengesdal IW, et al. Dapansutrile, an oral selective NLRP3 inflammasome inhibitor, for treatment of gout flares: an open-label, dose-adaptive, proof-of-concept, phase 2a trial. Lancet Rheumatol. 2020 May;2(5):e270–80
  15. Ogata A, Kato Y, Higa S, Yoshizaki K. IL-6 inhibitor for the treatment of rheumatoid arthritis: A comprehensive review. Mod Rheumatol. 2019 Mar;29(2):258–67.

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This content is purely informational and isn’t medical guidance. It shouldn’t replace professional medical counsel. Always consult your physician regarding treatment risks and benefits. See our editorial standards for more details.

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Leticia Tiburcio Ferreira

PhD in Genetics and Molecular Biology – University of Campinas, Brazil

Letícia is an experienced researcher and passionate writer. Her solid background in molecular biology and infectious diseases has led her to experiences in renowned institutions like Columbia University, University of Campinas, and Texas A&M University. After years of academic writing and authoring research proposals and pieces in indexed and peer-reviewed scientific journals, she is now focused on broadening audiences within an intersection between science and communication. Driven by the desire to contribute to education through writing and constant learning, she is delving into medical communications and making health-related content accessible and relatable to the general public.

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