New Insights into CPPD

For recurrent acute arthritis and refractory chronic arthritis, there are possible benefits, described in small, inadequately controlled studies of hydroxychloroquine (presumably by decreasing phagolysosomal-mediated crystal-induced NLRP3 inflammasome activation) and methotrexate.^15,19 Conversely, rebound arthritis after tapering systemic corticosteroids could be an issue mediated by the known ability of corticosteroids to induce NLRP3 production in macrophages. There is no clear benefit of anti–tumor necrosis factor (TNF) therapy in CPPD. However, interleukin 1 antagonism clearly merits further investigation for refractory CPPD arthritis, as in gout.²⁰

It is not yet clear whether oral magnesium supplementation will have benefits in inhibiting crystal deposition in established CPPD.¹⁵ For example, promotion of crystal dissolution by recombinant alkaline phosphatase risks flares of acute arthritis by crystal shedding from cartilage.¹⁵ ENPP1 activity, and ANKH transport function (which is nonselectively inhibited by probenecid) represent compelling targets for future molecular therapeutics to suppress crystal deposition in severe, symptomatic CPPD.¹⁵

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Table 3: Developments in CPPD Hoped for in the Next Decade

Conclusion

Writer Hugh Prather described life as “a mixture of unsolved problems, ambiguous victories, and vague defeats with very few moments of clear peace.” So it is metaphorically in rheumatology, at present, with CPPD. The last decade has seen substantial advances in the disorder, but huge hurdles remain (see Table 3). A good starting point would be a multicenter, randomized, controlled clinical trial of symptomatic disease subsets driven by CPPD.

Acknowledgment

This work was supported by the Veteran’s Affairs Research Service and the National Institutes of Health grant PAG07996. Dr. Terkeltaub is a consultant to Takeda Pharmaceutical Company Ltd., Pfizer Inc., Regeneron Pharmaceuticals Inc., and Novartis Pharmaceuticals.

Dr. Terkeltaub is chief of the rheumatology section at the Veterans Affairs Medical Center in San Diego, and a professor of medicine at the University of California, San Diego School of Medicine.

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