ACR CONVERGENCE 2020—Calcium pyrophosphate (CPP) arthritis was initially described over 50 years ago, and new information continues to emerge about its underlying pathogenesis and clinical presentations over time, according to Ann Rosenthal, MD, Will and Cava Ross Professor of Medicine in the Division of Rheumatology, Medical College of Wisconsin and chief of rheumatology and associate chief of staff for research at the Clement J. Zablocki Veterans Affairs Medical Center, Milwaukee, Wis.
During the session, State of the Art: Looking at the Crystal Ball: CPP Arthritis, Dr. Rosenthal shared the latest information on the pathogenesis of CPP arthritis and its clinical presentation, diagnosis and treatment. She is a recognized leader in the research and treatment of CPP arthritis, as well as a member of the ACR/EULAR working group drafting classification criteria for CPP deposition disease.
Although no FDA-approved drugs for the treatment of CPP arthritis currently exist, Dr. Rosenthal hopes that will change in the near future as novel pathogenic paradigms emerge that may “improve our ability to treat this disease.”
Nomenclature & Classification Criteria
Dr. Rosenthal began the session with a brief discussion on the current nomenclature for CPP arthritis, noting the term pseudogout is outdated. She described common terms used to discuss CPP arthritis. The term CPP crystals refers to calcium pyrophosphate crystals, while the term CPP deposition is used to discuss the presence of crystals in joints. The term CPP deposition disease (CPDD) is used to talk about the clinical syndromes caused by CPP crystals. Acute CPP arthritis is now used to describe what used to be called pseudogout, and chronic CPDD refers to other forms of this arthritis that have a more chronic presentation.
She expressed excitement about the ideas being raised by the ACR/EULAR Classification Criteria working group. “This will really improve our ability to accurately make this diagnosis, as well as to generate uniform populations of patients for clinical trials,” said Dr. Rosenthal.
Rheumatologists are currently aware that CPP deposition has variable clinical presentations that are not mutually exclusive, including asymptomatic chondrocalcinosis and acute CPP crystal arthritis—the most commonly recognized form of CPP arthritis. CPP deposition may present as a chronic arthritis similar to rheumatoid arthritis (RA) or osteoarthritis (OA). CPP crystals are also associated with less common syndromes, such as spinal involvement, Charcot-like arthropathy and soft tissue deposition.
Several clinical features make clinicians suspect CPDD, she said, with the most obvious being aged 60 and older, as well as presence of one of the four Hs associated with the disease (e.g., hyperparathyroidism, hemochromatosis, hypomagnemesia and hypophosphatasia). Specific joint involvement patterns characterize CPP deposition, including involvement of the wrists, second and third metacarpophalangeal joints and the knee. Subcutaneous nodules are not characteristic of CPP deposition and would be more common in gout. Also, compared with RA, the inflammatory pattern in CPDD is not symmetrical, and a sudden onset of symptoms may occur. Often, CPDD presents similarly to OA, but in unusual joints and with radiographic clues, such as chondrocalcinosis and tendon calcification, she explained.
Dr. Rosenthal shared an update on the association of osteoporosis with CPP deposition. In a study from her team evaluating 25,000 patients with CPP deposition, the relative risk of osteoporosis was increased compared with an age-matched population.1
“Interestingly, some of the well-known metabolic syndromes associated with CPP deposition, including hemochromatosis and hypophosphatasia, are also associated with osteoporosis, and hyperparathyroidism causes increased bone remodeling,” she said. These associations emphasize the burgeoning importance of bone in CPP deposition.
Other key clinical observations in the form of case reports have demonstrated that CPP deposition can occur in weird places, Dr. Rosenthal said, such as soft tissue deposits in the spine, and in the temporomandibular joint. Common triggers of acute CPP attacks include illness or surgery.
Medications may also trigger CPP attacks, including, somewhat controversially, diuretics, as well as tacrolimus and immunomodulatory chemotherapies. She said a fairly robust collection of articles has evaluated bisphosphonates as potential triggers in acute CPP arthritis, but considering the increased prevalence of osteoporosis in the population with CPP deposition, one wonders if this could be confounding by indication.2
Diagnostic Modalities to Identify CPP Deposition
There’s some light on the horizon, with diagnostics that may help rheumatologists better manage CPP arthritis, Dr. Rosenthal noted.
CPP crystals are hard to see and many lack birefringence, including needle-shaped CPP crystals, as discussed in research from Andrés et al.3 Dr. Rosenthal shared several microscopy tips to better identify CPP crystals, such as:
- Avoid collecting synovial fluid in ethylenediamine tetraacetic acid (EDTA)-containing collecting tubes;
- Turn off the polarizer and turn up the light;
- Use oil or the highest power available;
- Use phase contrast if possible; and
- Take your time.
“Newer crystal identification modalities are on the horizon, such as a lens-free holographic polarized microscope system that is getting better for identifying CPP crystals and may eventually be an app on your cell phone,” she said.
Dr. Rosenthal also reviewed patient imaging modalities in order of usefulness for identifying CPP deposition. Conventional radiography can identify tendon calcifications that show important clues to identifying CPP deposition. Ultrasound may be slightly more sensitive than plain radiographs for diagnosing chondrocalcinosis, but requires a trained eye to distinguish the changes from those of gout. Additionally, conventional computed tomography (CT) scanning and dual-energy CT scanning hold promise for identifying CPP deposition. A study by Pascart et al. demonstrated the ability of dual-energy CT to differentiate CPP crystals from the calcium phosphate crystals that appear in bone.5
“Magnetic resonance imaging [MRI] is not very useful for CPP deposition right now,” she said, but hopes gradient echo or ultrashort echo time MRI may be useful in the future.
Pathogenesis
Shifting to pathogenesis of CPP arthritis, Dr. Rosenthal shared the slow and steady progress being made to better understand the disease’s involved pathways. She reviewed the two phases of CPDD, beginning with crystal formation in cartilage, which remains poorly understood. After crystals are formed, joint damage is mediated. This damage classically occurs when crystals break off from cartilage and produce an inflammatory response through pathways similar to those of gout.
Dr. Rosenthal has focused her research on understanding the crystal formation phase of this disease. The current thinking builds off of the past 60 years of CPP deposition research, which has focused largely on pyrophosphate.
Taking a different approach, Dr. Rosenthal became interested in hereditary forms of CPDD, because she thinks they have a lot to teach us about potential pathogenic pathways relevant to age-related CPP deposition. It’s well known that hereditary CPP deposition clusters at one of two genetic loci, CCAL1 on chromosome 8q and CCAL2 on chromosome 5p.
“We’ve known for about 20 years now the identity of CCAL2. CCAL2 is the protein ANKH [ankylosis protein homolog human gene], which is a multi-pass transmembrane protein that likely transports ATP [adenosine triphosphate] or pyrophosphate from the inside of the cell to the outside of the cell,” she said.
The ANKH mutations associated with CPP deposition are gain-of-function mutations in ANKH, so chondrocytes with too much ANKH overproduce pyrophosphate.
In the lab, when ANKH is silenced in chondrocytes, Dr. Rosenthal and colleagues have seen a significant reduction in ATP that is elaborated by these cells, as well as a significant reduction in pyrophosphate. She says, “So we’ve asked why some metabolic disease associations and hereditary forms of CPP deposition due to CCAL1 can’t easily be explained by alterations of cartilage pyrophosphate.”
A new potential pathway was proposed by a discovery by Dr. Rosenthal and her team showing that osteoprotegerin accounts for the CCAL1 locus in CPDD.6 Osteoprotegerin is a decoy receptor for RANK ligand, a key mediator of bone remodeling. When osteoprotegerin is in excess, it prevents osteoclastogenesis, and when it is scarce, it encourages osteoclastogenesis.
They showed that cartilage is not the primary target of osteoprotegerin or RANK ligand. They hypothesized that a loss of osteoprotegerin function causes increased osteoclasts in subchondral bone.7 Osteoclasts secrete a yet-to-be identified substance that increases pyrophosphate production in the adjacent cartilage. Excess pyrophosphate forms CPP crystals, but also leaks back into subchondral bone and perpetuates a cycle of joint damage.
The ANKH and osteoprotegerin mutations suggest two pathogenic pathways, Dr. Rosenthal said, one beginning with increased pyrophosphate production by cartilage, such as one may see with ANKH mutations, hypophosphatasia and hypomagnemesia. The second possible pathway involves disordered bone remodeling caused by osteoprotegerin mutations, hyperparathyroidism, hemochromatosis, injury, OA and age.
Treatment Opportunities
Dr. Rosenthal concluded the session with a brief discussion of CPDD treatment. She reviewed the many current options for managing acute CPP arthritis and lamented the lack of studies showing a role for drugs currently used for chronic CPDD. She hopes improved understanding of CPP arthritis pathophysiology will lead to new potential therapies.
“ANKH is a druggable target and probably belongs to the category of organic anion transporters,” Dr. Rosenthal said. She notes many drugs are organic anion inhibitors, such as probenecid, which, in large quantities, decreases the amount of extracellular ATP secreted by chondrocytes. The RANK-ligand pathway is also “eminently targetable,” she says, noting denosumab mimics the effects of functional osteoprotegerin.
Dr. Rosenthal concluded with enthusiasm that there is much to look forward to in the world of CPP deposition, including the new set of classification criteria coming shortly, very exciting diagnostic modalities on the horizon and an improved mechanistic understanding of the pathogenesis.
“I’m hoping that all of this leads to better management of our patients, which is our ultimate goal,” she said.
Carina Stanton is a freelance science journalist based in Denver.
References
- Balderrama CK, Rosenthal AK, Lans D, et al. Calcium pyrophosphate deposition disease and associated medical comorbidities: A national cross‐sectional study of U.S. veterans. Arthritis Care Res (Hoboken). 2017 Sep;69(9):1400–1406.
- Roddy E, Muller S, Paskins Z, et al. Incident acute pseudogout and prior bisphosphonate use: Matched case-control study in the U.K.-Clinical Practice Research Datalink. Medicine (Baltimore). 2017 Mar;96(12):e6177.
- Andrés M, Vela P, Vega Jovaní V, et al. Most needle-shaped calcium pyrophosphate crystals lack birefringence. Rheumatology (Oxford). 2019 Jun 1;58(6):1095–1098.
- Zhang Y, Lee SY, Zhang Y, et al. Wide-field imaging of birefringent synovial fluid crystals using lens-free polarized microscopy for gout diagnosis. Sci Rep. 2016 Jun 30;6:28793.
- Pascart T, Norberciak L, Legrand J, et al. Dual-energy computed tomography in calcium pyrophosphate deposition: Initial clinical experience. Osteoarthritis Cartilage. 2019 Sep;27(9):1309–1314.
- Williams CJ, Qazi U, Bernstein M, et al. Mutations in osteoprotegerin account for the CCAL1 locus in calcium pyrophosphate deposition disease. Osteoarthritis Cartilage. 2018 Jun;26(6):797–806.
