Pseudogout Causes

Exactly why some people get pseudogout and others do not is unknown. Experts do know several factors can increase and decrease a person’s risk for the disease, which can occur when calcium pyrophosphate (CPP) crystals collect in the soft tissues of a joint.

See What Is Calcium Pyrophosphate Crystals Deposition (CPPD)?

Risk Factors for Pseudogout

The following risk factors are associated with higher rates of pseudogout, which may be called CPPD disease or acute CPP crystal inflammatory arthritis. Unlike gout, pseudogout is not influenced by diet, ¹ Rosenthal AK, Ryan LM. Calcium Pyrophosphate Deposition Disease. N Engl J Med. 2016;374(26):2575-2584. doi: 10.1056/NEJMra1511117 sex, or ethnicity. ² Zhang Y, Brown MA. Genetic studies of chondrocalcinosis. Curr Opin Rheumatol. 2005, 17: 330-335.

Most of these risk factors, such as age and genetics, cannot be changed. Underlying conditions that increase risk may be addressed with treatment.

Age

Estimates vary regarding how many people have calcium pyrophosphate crystal deposition, but researchers know for certain that risk increases dramatically with age.

Most people who develop pseudogout are 60 or older. In fact, after age 60, the likelihood of developing pseudogout doubles with each decade of life. ¹ Rosenthal AK, Ryan LM. Calcium Pyrophosphate Deposition Disease. N Engl J Med. 2016;374(26):2575-2584. doi: 10.1056/NEJMra1511117 One often-cited study ³ Wilkins E, Dieppe P, Maddison P, Evison G. Osteoarthritis and articular chondrocalcinosis in the elderly. Ann Rheum Dis. 1983;42(3):280-284. doi:10.1136/ard.42.3.280 of 100 people admitted to a geriatric unit found signs of pseudogout in the joints of 44% of people aged 84 or older, though not all the people noticed symptoms.

Joint trauma

A joint injury or surgery can trigger a pseudogout flare-up. ⁴ Slobodonick A, Toprover M, Pillinger M. Crystal Arthritis. In: Efthimiou P, ed. Absolute Rheumatology Review. Springer Nature Switzerland AG; 2020; chap 15. Accessed September 15, 2020. https://doi.org/10.1007/978-3-030-23022-7_15 ^{, 5} Doherty M, Watt I, Dieppe PA. Localised chondrocalcinosis in post-meniscectomy knees. Lancet. 1982;1(8283):1207-1210. doi: 10.1016/s0140-6736(82)92336-4 Experts theorize this happens because trauma can cause joint cartilage to release the calcium phosphate crystals that have accumulated within it. Once released, the crystals activate an immune system response that leads to swelling and other pseudogout symptoms. ⁶ Ivory & Velázquez. The forgotten crystal arthritis. Mo Med. 2012 Jan-Feb;109(1):64-8. Review. PubMed PMID: 22428450.

Family history

Genetics plays a role, making some people more prone to accumulating calcium pyrophosphate crystals in their joints.

Recent research suggests that certain mutations in the ANKH gene, which helps regulate metabolism, increases the risk for developing pseudogout. People with these genetic mutations are:

• More likely to develop pseudogout at an earlier age ⁷ Netter P, Bardin T, Bianchi A, Richette P, Loeuille D. The ANKH gene and familial calcium pyrophosphate dihydrate deposition disease. Joint Bone Spine. 2004 Sep;71(5):365-8. Review. PubMed PMID: 15474385. ^{, 8} US National Library of Medicine. Genetics Home Reference. Reviewed June 2018. Published July 7, 2020. Accessed July 23, 2020. http://ghr.nlm.nih.gov/gene/ANKH
• More likely to experience CPPD-related back pain and problems in the spine ⁹ Genetic and Rare Diseases Information Center, National Institute for Advancing Translational Sciences. Chondrocalcinosis 2. Last updated January 12, 2018. Accessed August 4, 2020. https://rarediseases.info.nih.gov/diseases/1292/chondrocalcinosis-2

While CPPD disease is fairly common, CPPD disease caused by the ANKH gene is considered rare. ⁹ Genetic and Rare Diseases Information Center, National Institute for Advancing Translational Sciences. Chondrocalcinosis 2. Last updated January 12, 2018. Accessed August 4, 2020. https://rarediseases.info.nih.gov/diseases/1292/chondrocalcinosis-2 Other genes may also play a role in the development of CPPD disease. ¹ Rosenthal AK, Ryan LM. Calcium Pyrophosphate Deposition Disease. N Engl J Med. 2016;374(26):2575-2584. doi: 10.1056/NEJMra1511117

Gout

People who are diagnosed with gout are about 2.5 times more likely to develop pseudogout. ⁴ Slobodonick A, Toprover M, Pillinger M. Crystal Arthritis. In: Efthimiou P, ed. Absolute Rheumatology Review. Springer Nature Switzerland AG; 2020; chap 15. Accessed September 15, 2020. https://doi.org/10.1007/978-3-030-23022-7_15

Read more: All About Gout - Symptoms, Diagnosis, Treatment

Osteoarthritis

Research suggests that CPP crystals are 2 to 3 times more common in patients who have osteoarthritis than those who do not. ⁴ Slobodonick A, Toprover M, Pillinger M. Crystal Arthritis. In: Efthimiou P, ed. Absolute Rheumatology Review. Springer Nature Switzerland AG; 2020; chap 15. Accessed September 15, 2020. https://doi.org/10.1007/978-3-030-23022-7_15 ^{, 10} Zhang W, Doherty M, Bardin T, Barskova V, Guerne PA, Jansen TL, Leeb BF, Perez-Ruiz F, Pimentao J, Punzi L, Richette P, Sivera F, Uhlig T, Watt I, Pascual E. European League Against Rheumatism recommendations for calcium pyrophosphate deposition. Part I: terminology and diagnosis. Ann Rheum Dis. 2011 Apr;70(4):563-70. Epub 2011 Jan 7. PubMed PMID: 21216817. Some experts believe that people who have osteoarthritis with calcium pyrophosphate deposition may experience more swelling and inflammation than people who have osteoarthritis without crystals. ¹¹ Ledingham J, Regan M, Jones A, Doherty M. Factors affecting radiographic progression of knee osteoarthritis. Ann Rheum Dis. 1995 Jan;54(1):53-8. PubMed PMID: 7880123; PubMed Central PMCID: PMC1005513. ^{, 12} Rosenthal AK. Crystals, inflammation, and osteoarthritis. Curr Opin Rheumatol. 2011 Mar;23(2):170-3. Review. PubMed PMID: 21169842; PubMed Central PMCID: PMC3154781.

Read more: What Is Osteoarthritis?

Rheumatoid arthritis

Experts estimate people with rheumatoid arthritis are 2 times as likely to get pseudogout. ⁴ Slobodonick A, Toprover M, Pillinger M. Crystal Arthritis. In: Efthimiou P, ed. Absolute Rheumatology Review. Springer Nature Switzerland AG; 2020; chap 15. Accessed September 15, 2020. https://doi.org/10.1007/978-3-030-23022-7_15

Read more: What Is Rheumatoid Arthritis (RA)?

Underlying conditions

There are several metabolic and endocrine disorders that can predispose a person to pseudogout (CPPD), including:

• Hemochromatosis, ¹ Rosenthal AK, Ryan LM. Calcium Pyrophosphate Deposition Disease. N Engl J Med. 2016;374(26):2575-2584. doi: 10.1056/NEJMra1511117 ^{, 4} Slobodonick A, Toprover M, Pillinger M. Crystal Arthritis. In: Efthimiou P, ed. Absolute Rheumatology Review. Springer Nature Switzerland AG; 2020; chap 15. Accessed September 15, 2020. https://doi.org/10.1007/978-3-030-23022-7_15 an inherited disorder that causes the body to store excess iron in the organs and tissues around the joints.
• Hyperparathyroidism, ¹ Rosenthal AK, Ryan LM. Calcium Pyrophosphate Deposition Disease. N Engl J Med. 2016;374(26):2575-2584. doi: 10.1056/NEJMra1511117 which can cause abnormal amounts of calcium in the blood, and perhaps other thyroid conditions that affect the body’s metabolism.
• Hypophosphatasia, ¹ Rosenthal AK, Ryan LM. Calcium Pyrophosphate Deposition Disease. N Engl J Med. 2016;374(26):2575-2584. doi: 10.1056/NEJMra1511117 a metabolic disorder that affects bones and teeth.
• Hypomagnesemia, ¹ Rosenthal AK, Ryan LM. Calcium Pyrophosphate Deposition Disease. N Engl J Med. 2016;374(26):2575-2584. doi: 10.1056/NEJMra1511117 ^{, 4} Slobodonick A, Toprover M, Pillinger M. Crystal Arthritis. In: Efthimiou P, ed. Absolute Rheumatology Review. Springer Nature Switzerland AG; 2020; chap 15. Accessed September 15, 2020. https://doi.org/10.1007/978-3-030-23022-7_15 a condition in which there is abnormally low magnesium levels in the blood.

Experts recommend that patients with pseudogout be screened for underlying conditions if they are younger than 60 and have no genetic risk of CPPD disease. ¹ Rosenthal AK, Ryan LM. Calcium Pyrophosphate Deposition Disease. N Engl J Med. 2016;374(26):2575-2584. doi: 10.1056/NEJMra1511117

Factors that Reduce Risk

Alcohol and tobacco abuse disorders, coronary artery disease, congestive heart failure, diabetes, and hypertension seem to lower the risk of developing CPPD disease, including pseudogout. ⁴ Slobodonick A, Toprover M, Pillinger M. Crystal Arthritis. In: Efthimiou P, ed. Absolute Rheumatology Review. Springer Nature Switzerland AG; 2020; chap 15. Accessed September 15, 2020. https://doi.org/10.1007/978-3-030-23022-7_15 While these conditions are associated with a lower risk of pseudogout and other forms of CPPD disease, their negative effects on health and well-being are significant and therefore not desirable.

Similarly, certain medications, such as proton pump inhibitors, thiazide diuretics, and loop diuretics have been associated with a lower risk of CPPD disease, including pseudogout. ⁴ Slobodonick A, Toprover M, Pillinger M. Crystal Arthritis. In: Efthimiou P, ed. Absolute Rheumatology Review. Springer Nature Switzerland AG; 2020; chap 15. Accessed September 15, 2020. https://doi.org/10.1007/978-3-030-23022-7_15 However, these medications carry potential side effects and are not recommended for lowering the risk of CPPD disease.