CHICAGO—Diagnosis concerns and limited treatment options for calcium pyrophosphate deposition (CPPD) disease were the topic of a discussion at ACR Convergence 2025.
What Is CPPD?
CPPD occurs when calcium pyrophosphate crystals form around chondrocytes (chondrocalcinosis) and deposit in cartilage, tendon and joint capsules. In the long term, the condition has inflammatory and mechanical consequences.
Dr. Tedeschi
“Chondrocalcinosis is a radiographic finding and not the disease,” said Sara Tedeschi, MD, MPH, clinical investigator at Brigham and Women’s Hospital and an assistant professor of medicine at Harvard Medical School, Boston. “It becomes a disease when there are symptoms along with radiographic or tissue evidence of the crystals.”
CPPD disease typically affects adults older than 60. Joint trauma or surgery are risk factors, and CPPD disease can appear in conjunction with rheumatoid arthritis (RA), osteoarthritis (OA) and gout. Hemochromatosis, hyperparathyroidism, hypophospatasia and hypomagnesemia are risk factors, although they are uncommon. Genetic links have been found for early onset cases (i.e., younger than 30 years old). Just this year, a genome-wide association study identified ENPP1 as a causal pathway.
OA with CPPD is thought to be the most common symptomatic manifestation. In addition to the usual symptoms of OA, there is chondrocalcinosis on radiographs and effects seen in unusual joints, such as the shoulder.
Other manifestations include:
- Acute calcium pyrophosphate crystal arthritis, formerly called pseudogout;
- Chronic calcium pyrophosphate crystal arthritis, formerly called pseudo RA; and
- Crowned dens syndrome, which mimics meningitis.1
“These terms are an alphabet soup,” said Dr. Tedeschi. “We are hoping to standardize definitions across studies to identify groups of patients for enrollment in future clinical trials. Then we can develop targeted therapies for this condition that very much needs effective treatments.”
Diagnostic Difficulties
Radiology is important in treatment decisions. Conventional X-rays have a specificity of more than 90%, but the sensitivity is only about 50%. Ultrasound has a sensitivity of 85% and a specificity of 85%, allowing higher confidence the patient does have CPPD disease. Standard computed tomography (CT) and dual-energy CT have about twice the sensitivity of X-rays, plus the added advantage of quantifying the CPPD.
As of now, there is no validated clinical tool to diagnose CPPD disease. A 2016 study considered the probability of CPPD with combinations of synovial fluid crystals, chondrocalcinosis, acute monoarthritis and chronic arthritis. Patients were diagnosed as either definitely, probably or possibly having CPPD.2
“We know CPPD commonly exists with OA, but there are questions about whether CPPD causes arthritis or worsens OA,” said Dr. Tedeschi. “Before 2020, four large cohort studies produced conflicting results. These were looking at chnondrocalcinosis anywhere in the joint and OA progression as a whole.”
More recently, Wu, et al. found chondrocalcinosis in hyaline cartilage predicted further cartilage loss in the same knee compartment two years later, even without baseline cartilage damage. Dr. Tedeschi stressed that although it pointed toward a causal relationship, it was an observational study so causation could not be shown.3
The Rotterdam Study and Multicenter Osteoarthritis Study (MOST) looked at the association of chondrocalcinosis with incident OA, evaluating more than 6,000 knees. Although the studies themselves showed mixed results, a meta-analysis noted a 77% increase in risk, which was significant.
Treatment Options
Despite CPPD being a common cause of arthritis after age 60, well-researched treatment options are not available.
Dr. Pascart
“What I am going to talk about today is all off label,” said Tristan Pascart, MD, PhD, clinical researcher at Lille Catholic University in Lille, France. “There is certainly an urgent need for guidance in terms of managing CPPD.”
Some studies give us early indications of what may or may not work in these patients. The COLCHICORT trial compared colchicine with prednisone in a short-term equivalence setting.
A group of 112 patients with an average age of 87 were treated the first day with a standard analgesic. One arm was given 1.5 mg colchicine on day one and 1 mg on the second, compared with 30 mg of prednisone on both days. This study showed equivalency to the main end point of visual analog scale pain on the first day.4 Despite that equivalency, a post hoc analysis looked at the need for additional doses of either study medication or interarticular injections. In this instance, colchicine was associated with poorer response on day three.5
“The general guidance gives you two options in treating acute flares,” said Dr. Pascart. “From this trial in most cases, it is better to favor prednisone.”
Longer term options include blocking crystal formation or dissolving the crystals. Multiple studies looking at probenecid and magnesium supplementation have not shown efficacy in dissolving the crystals.
“That leaves us with blocking inflammation,” said Dr. Pascart. “The trials we do have are both very old. A crossover pilot study of hydrochloricone showed a reduction in recurrent flares. We are still waiting 30 years for the conformational study that never came.”
Dr. Pascart said the “exciting part” is targeted therapy in CPPD. A Nature study from 20 years ago showed CPP crystal formation involved the NALP3 inflammasone resulting in high interleuken 1 (IL-1). If you block that cytokine, you could also stop the huge production of IL-6.6
In 2020, Latourte and others undertook a pilot study looking at tolcizumab in CPPD. Those who had very refractory disease and had anakinra in their treatment improved using tolcilizumab.7
“This was a great promise to open doors in using biologics and particularly IL-6 inhibitors,” said Dr. Pascart. “Basically everyone seems to agree a trial of colchicine is the first line that should be proposed in all cases,” said Pascart. “When it fails or is not tolerated, you think of methotrexate and then biologics. We don’t now have enough evidence to support the use of hydrochloricone.”
The research is expanding. Two trials are ongoing comparing colchicine with placebo. One study is looking at toclizumab vs. placebo. A fourth is comparing baricitnib and usual care.
“In terms of management of CPPD disease, there is an urgent need for guidance,” said Dr. Pascart. “The only available recommendations are 15 years old from the European Alliance of Associations for Rheumatology with nothing from the ACR. I am not aware of any national recommendations either. Hopefully we’ll be able to formulate these in the next few years.”
Kurt Ullman is a freelance writer based in Indiana.
Disclosures
Dr. Tedeschi: Consultant with Alexion, Avalo and Novartis. Consultant Merck/MSD (terminated).
Dr. Pascart: Consultant with Avalo.
References
- Cai K, Fuller A, Zhang Y, et. al. Towards development of core domain sets for short term and long term studies of calcium pyrophosphate crystal deposition (CPPD) disease: A framework paper by the OMERACT CPPD working group. Semin Athritis Rheum. 2024 Aug;51(4):946–950.
- Rosenthal AK, Ryan LM. Calcium pyrophosphate deposition disease. N Eng J Med. 2016 Jun 30;374(26):2575–2584.
- Wu Y, Liew JW, Boer JD et. al. Chondocalcinosis and incident knee arthritis: findings from 2 large prospective cohorts with 20 year follow-up. Ann Rheum Dis. 2025 Oct;84(10):1743–1751.
- Pascart T, Robinet P, Ottaviani S, et al. Evaluating the safety and short-term equivalence of cholchicine versus prednisone in older patients with acute calcium pyrophosphate crystal arthritis (COLCHICORT): an open-label, multicentre, randomized trial. Lancet Rheumatol. 2023 Sept;5(9):e523–e531.
- Pascart T, Norberciak L, Richette P, et. al. Exploring patient profiles associated with resolution of acute calcium pyrophosphate arthritis treated with colchicine and prednisone: post hoc analysis of a randomized controlled trial. Arthritis Care Research (Hoboken). 2025 Sept. Online ahead of print.
- Martinon F, Petrill V, Mayor A, et al. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature. 2006 Mar 9;440(7081):237–241.
- Latourte A, Ea HK, Frazier A, et. al. Tocilizumab in symptomatic calcium pyrophosphate deposition disease: A pilot study. Ann Rheum Dis. 2020 Aug;79(8):1126–1128.
