To the Editor:
Calcium pyrophosphate deposition (CPPD) disease predominantly affects older individuals and is more common in men.1 It can manifest in various forms, including acute monoarthritis, polyarthritis mimicking osteoarthritis with intermittent flares, and a polyarticular presentation resembling rheumatoid arthritis.2 In younger patients with CPPD, a thorough metabolic evaluation is recommended to identify potential secondary causes.
A 40-year-old woman with a history of Graves disease, managed with thyroid replacement therapy following radioactive iodine treatment, presented with a 3-day history of left wrist monoarthritis. She had been under the care of a community rheumatologist for intermittent, self-limited monoarthritis affecting the ankles, wrists, knees, and shoulders over the past 5 years. Each episode lasted 4 to 5 days, with completely asymptomatic intervals between flares.
The patient had no signs of connective tissue disease such as rashes, photosensitivity, oral ulcers, or Raynaud phenomenon, and had no personal or family history of psoriasis or inflammatory bowel disease. Despite treatment with nonsteroidal antiinflammatory drugs and combination therapy with colchicine and hydroxychloroquine, she continued to experience frequent flares that occurred at least twice per month. Although prednisone provided temporary relief, its use was limited due to debilitating anxiety with each course.
On examination, she was afebrile (36.2 °C) with elevated blood pressure (152/96 mmHg) and heart rate (104 beats per minute). The cardiorespiratory exam was normal, and there was no evidence of tophi or psoriatic lesions on the skin, nails, or scalp. She had a left wrist effusion without associated erythema or lymphangitic streaking. Palpation elicited pain, which was exacerbated by movement, resulting in a limited range of motion.
Laboratory evaluation revealed a normal complete blood count, with a mildly elevated erythrocyte sedimentation rate (22 mm/h; normal < 20 mm/h). Renal function, rheumatoid factor, anticitrullinated peptide antibodies, and serum urate levels were all within normal limits. Antinuclear antibody testing showed a titer of 1:320 with a homogeneous pattern; however, the extractable nuclear antigen panel was negative.
Radiographic imaging of the left wrist (Figure 1A) demonstrated chondrocalcinosis, characterized by dense mineralization of the ulnocarpal space and mild mineralization of the intercarpal hyaline cartilage. Ultrasound findings revealed active synovitis with hyperemia and synovial thickening in the left radiocarpal joint (Figure 1B).
(A) Posterior-anterior radiograph demonstrating dense chondrocalcinosis of the ulnocarpal space (arrow) with associated ulnar styloid cysts and soft tissue swelling over the ulnar side of the wrist. (B) Ultrasound of the left wrist highlighting heterogenous, hypoechoic collection localized to the region of the radiocarpal joint (arrow), with increased vascularity showing active synovitis.
Synovial fluid analysis from the left wrist showed a total nucleated cell count of 14,500 cells/mm³ (normal < 2000 cells/mm³) with neutrophil predominance (86%). However, no crystals were visualized under polarized light microscopy.
Additional laboratory testing was performed to investigate potential secondary causes of CPPD. Calcium and phosphate levels were within normal limits. Notably, the patient had significant hypomagnesemia, with a serum magnesium level of 0.45 mmol/L (normal 0.66-1.07 mmol/L). Thyroid function tests revealed an elevated thyroid-stimulating hormone level of 31.2 mIU/L (normal 0.27-4.20 mIU/L). Additionally, vitamin D was 56 nmol/L (normal 75-250 nmol/L), and parathyroid hormone was mildly elevated at 7.5 pmol/L (normal 1.6-6.9 pmol/L). Despite ongoing oral magnesium supplementation, the patient’s hypomagnesemia persisted. The patient was referred to nephrology, and 24-hour urine analysis demonstrated renal magnesium wasting, with a fractional excretion of magnesium of 3.9% (normal < 1% in patients with hypomagnesemia). Genetic testing for hypomagnesemia confirmed a heterozygous pathogenic variant in hepatocyte nuclear factor 1β (HNF-1β), a monogenic cause of cystic kidney disease and antecedent isolated renal magnesium wasting.3
Thyroid hormone titration corrected her hypothyroidism, whereas vitamin D supplementation effectively normalized both vitamin D and parathyroid hormone levels. The nephrology team initiated intravenous magnesium infusion and added amiloride and dapagliflozin to reduce renal magnesium wasting. Unfortunately, the patient remained hypomagnesemic (Figure 2) and had frequent flares of monoarthritis. She was initially started on anakinra, an interleukin (IL)-1 receptor antagonist, on an as-needed basis, reducing flare duration from 5 days to 1-2 days. Transition to daily anakinra (100 mg subcutaneous) achieved near-complete resolution of monoarthritis episodes.
Line chart illustrating persistent hypomagnesemia despite oral and IV magnesium supplementation, as well as the addition of amiloride and dapagliflozin. IV: intravenous.
CPPD is rare in individuals under 60 years of age, warranting a full metabolic panel in younger patients.4 This case underscores hypomagnesemia as a significant contributor to CPPD pathogenesis. Magnesium serves as a cofactor for pyrophosphatase that facilitates pyrophosphate hydrolysis. Magnesium deficiency, therefore, can lead to pyrophosphate accumulation and calcium pyrophosphate crystal deposition. In this patient, her hypomagnesemia was linked to a pathogenic variant in HNF-1β, disrupting renal magnesium reabsorption.3 This variant is associated with renal magnesium wasting syndromes resembling Gitelman syndrome.4 Fortunately, IL-1 inhibition with anakinra proved to be efficacious, highlighting the role of IL-1 in refractory CPPD.
This case emphasizes the importance of investigating secondary causes in young patients with CPPD. Persistent hypomagnesemia due to renal magnesium wasting contributes to refractory disease. Oral and intravenous replacement are ineffective due to the renal wasting, and many patients do not respond to amiloride. Daily anakinra significantly reduced her disease burden, demonstrating its potential in the treatment of refractory CPPD acute monoarthritis. Future studies are needed to explore the long-term benefits of targeted IL-1 blockade for the management of refractory CPPD arthritis.
Footnotes
CONTRIBUTIONS
BSM: writing – original draft, validation, visualization; PAB: writing – reviewing & editing; KSR: writing – reviewing & editing, resources; SHM: Supervision, writing – reviewing & editing.
FUNDING
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
COMPETING INTERESTS
The authors declare no conflicts of interest in preparing this article.
ETHICS AND PATIENT CONSENT
The patient provided written informed consent to publish her medical information online and in print. Institutional review board approval was not required for this case report, in accordance with the policies of the authors’ institutions.
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