Raising Awareness of an Underdiagnosed Disease

For a disease that was discovered more than 50 years ago, Calcium Pyrophosphate Deposition (CPPD) disease, a form of arthritis caused by calcium pyrophosphate crystals, remains relatively misunderstood and underdiagnosed.

Lawrence Ryan, MD and Ann Rosenthal, MD
Drs. Ann Rosenthal and Lawrence Ryan authored a review article in the June 2016 issue of the New England Journal of Medicine which reflects more than 40 years of research on Calcium Pyrophosphate Deposition disease.

As major contributors to our understanding of this disease, Ann Rosenthal, MD, FEL '89, Will & Cava Ross Professor of Medicine, chief of rheumatology and director of the Medical College of Wisconsin Arthritis Institute, and Lawrence Ryan, MD, GME '75, FEL '77, professor emeritus of medicine (rheumatology), were invited to author a review article in the June 2016 issue of the New England Journal of Medicine which reflects more than 40 years of research on CPPD disease conducted at the Medical College of Wisconsin.

"Why do we study CPPD disease and arthritis in general? As people live longer, healthier lives, rates of CPPD disease and arthritis will rise and become even greater threats to independence," Dr. Ryan says. "Plus, these maladies hurt!"

One contributing factor to CPPD disease's lack of exposure is the thorny issue of its name. Since it was first described in 1962, the disease has had a number of nomenclature changes, including the popular name of "pseudogout," which was coined due to clinical similarity of one form of CPPD disease to gout. It subsequently was noted by Daniel McCarty, MD, former chair of medicine at MCW, that the crystals were composed of calcium pyrophosphate rather than uric acid. In 2011, experts from the European League Against Rheumatism recommended that specialists use the term "CPPD disease" and categorized clinical involvement as either acute or chronic arthritis.

"Looking back, the naming issue makes sense from a historical progression, but it also has been a major problem in the field," Dr. Rosenthal shares. "We have to agree on uniform naming criteria so that we are all talking about the same thing."

In the early stages of this disease, calcium pyrophosphate crystals develop inside cartilage. Once present, these crystals begin to damage cartilage tissue by inducing inflammation, along with other harmful changes. Untreated CPPD disease may lead to severe, painful attacks or chronic pain and inflammation. Over time, joints may degenerate or break down, resulting in long-term disability.

The crystals themselves are the key to diagnosis, and researchers have shown that their presence can be most accurately assessed in the fluid inside the arthritic joint, known as synovial fluid.

Ann Rosenthal, MD"Identifying these crystals with a microscope requires patience and experience, and our field needs to get better at it," Dr. Rosenthal remarks. "Our best estimate is that between four and seven percent of adults in the US and Europe have CPPD disease, so it appears to be a relatively common disease that we are not consistently diagnosing," Dr. Ryan adds.

Once diagnosed, treatment of the acute form of CPPD disease focuses on reducing inflammation until symptoms stop – which can be a matter of weeks or months. Symptoms are particularly persistent in the chronic form, and strategies to reduce inflammation and pain can improve quality of life, but they also must be balanced against side effects. In contrast to gout, which has long-term therapies to reduce urate crystal formation, no drug has yet been proven to remove calcium pyrophosphate crystals or reduce their formation in CPPD disease.

"We’re looking for better treatments," Dr. Rosenthal comments. "Rather than targeting systemic inflammation, we’d like to focus on preventing or dissolving the crystals."

In addition to committing themselves to uncovering new potential treatments for CPPD disease and other forms of arthritis, Drs. Ryan and Rosenthal have dedicated their careers to treating patients and mentoring promising rheumatologists.

After blazing a trail as MCW's first rheumatology fellow and Wisconsin's first rheumatology trainee, Dr. Ryan served as chief of rheumatology at MCW for more than 20 years – receiving the institution's highest honor in 1999: the Distinguished Service Award.

When he had the opportunity to speak at the Commencement Ceremony for the MCW Medical School Class of 1999, he asked the graduates to recall all of the family members, friends and other mentors who had helped them along the way.

Dr. Ryan recommended that the graduates return these many favors by assisting other promising physicians and scientists.

Lawrence M. Ryan, MD "It feels like a completely different world in medicine and rheumatology than when I started, and it has been incredible to watch how these fields have transformed over time."

– Dr. Lawrence M. Ryan

"While we both feel passionately about CPPD disease, I am most grateful for Dr. Ryan's dedication as a mentor, colleague and friend," Dr. Rosenthal says. "He has had a huge influence on my career."

Another pivotal experience came when Dr. Rosenthal was selected in 2013 to participate in the Hedwig van Ameringen Executive Leadership in Academic Medicine® (ELAM) program, run by Drexel University College of Medicine, which focuses on helping senior women faculty members at academic medical centers enhance their leadership skills. "It was a great opportunity to gain further education into the nuts and bolts of how academic medical centers operate," Dr. Rosenthal shares. "The best part was developing a new network of aspirational women leaders across the nation."

Dr. Rosenthal is poised to continue what Dr. Ryan and his contemporaries began more than 40 years ago by treating arthritis in all its forms – while also leading research into better therapies for CPPD disease. "With age being the biggest risk factor for CPPD disease, and an aging population on the horizon, this research is more important than ever," Dr. Rosenthal notes.

– Greg Calhoun

MCW Magazine: Alumni story MCW Magazine: Clinical story MCW Magazine: Discovery story MCW Magazine: Philanthropy story

The Lawrence M. Ryan, MD, Endowed Education Fund in Rheumatology has been established to permanently honor Dr. Ryan's contributions. Through this endowed fund, donors will help residents, fellows and medical students travel to rheumatology conferences, sponsor external expert speakers to discuss clinical and research topics, and support other educational opportunities that enhance the vitality of MCW's division of rheumatology.

For more information, please contact Angela Nelson, senior director of development and alumni giving, at (414) 955-4708 or annelson@mcw.edu.

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