Nonuremic calciphylaxis in a patient with rheumatoid arthritis and osteoporosis treated with teriparatide
Authors: Arturo R. Dominguez, Shauna E. Goldman
Journal: Journal of the American Academy of Dermatology (2014)

To the Editor: Calciphylaxis is a devastating condition in which metastatic calcification of the microvasculature results in thrombosis and ischemic necrosis of target tissues.1Kalajian A.H. Malhotra P.S. Callen J.P. Parker L.P. Calciphylaxis with normal renal and parathyroid function not as rare as previously believed.Arch Dermatol. 2009; 145: 451-458Crossref PubMed Scopus (98) Google Scholar, 2Leis-Dosil V.M. Rubio-Flores C. Ruiz-Bravo Burguillos E. Diaz-Diaz R.M. Cutaneous vascular calcifications secondary to treatment with teriparatide.Actas Dermosifiliogr. 2013; 104: 89-90Crossref PubMed Scopus (7) Google Scholar, 3Weenig R.H. Pathogenesis of calciphylaxis: Hans Selye to nuclear factor κB.J Am Acad Dermatol. 2008; 58: 458-471Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar Calciphylaxis is well described in patients with chronic kidney disease and secondary hyperparathyroidism, however the literature describing it in the absence of these classic comorbidities is scant. A 66-year-old woman presented with a 3-month history of painful lower extremity nodules. Her medical history included obesity, pulmonary emboli, osteoporosis, and a 20-year history of well-controlled rheumatoid arthritis. Medications included leflunomide, prednisone (2 mg daily), warfarin, and teriparatide [recombinant human parathyroid hormone (1-34)], initiated 5 months prior. Physical examination revealed a 10- × 3-cm indurated subcutaneous plaque with livedoid erythema and retiform purpura on the bilateral thighs and scattered indurated subcutaneous nodules on the bilateral lower extremities (Fig 1). A lateral thigh lesion was biopsied at an outside facility 2 months prior, leaving a nonhealing ulcer despite appropriate wound care. The biopsy specimen was consistent with thrombotic vasculopathy; however, no additional workup was performed. Von Kossa stains were ordered and read by our pathologist, but no changes of early calciphylaxis were seen. Laboratory studies demonstrated normal renal function, parathyroid hormone levels, and calcium-phosphate product. Serum and urine protein electrophoresis, antineutrophil cytoplasmic antibodies, antinuclear antibodies, and antiphospholipid antibodies were all negative. Because of the patient's multiple risk factors, calciphylaxis was suspected clinically. Warfarin and teriparatide were discontinued and the patient was placed on low-molecular-weight heparin. Given her risk for poor wound healing, repeated biopsy was deferred. Bone scintigraphy of the thighs showed no abnormal uptake. Because of continued clinical suspicion and further lesion progression, the patient consented to repeated biopsy. Histopathology revealed intramural calcium deposition in subcutaneous arterioles with intimal hyperplasia and ischemic changes of the surrounding tissue consistent with calciphylaxis (Fig 2). Treatment with intravenous sodium thiosulfate therapy was initiated after surgical consultants determined the patient was a poor candidate for debridement. Unfortunately, her lesions progressed over the next month causing intractable pain despite management by pain specialists. Ultimately, she was transitioned to hospice care and died soon thereafter. This case underscores the importance of high clinical suspicion and prompt diagnosis in patients presenting with livedoid erythema, painful indurated subcutaneous plaques, and ulcerations in adipose-rich areas who have risk factors for nonuremic calciphylaxis including female gender, obesity, chronic inflammation, liver disease, rapid weight loss, malignancy, and primary hyperparathyroidism.1Kalajian A.H. Malhotra P.S. Callen J.P. Parker L.P. Calciphylaxis with normal renal and parathyroid function not as rare as previously believed.Arch Dermatol. 2009; 145: 451-458Crossref PubMed Scopus (98) Google Scholar Corticosteroids,1Kalajian A.H. Malhotra P.S. Callen J.P. Parker L.P. Calciphylaxis with normal renal and parathyroid function not as rare as previously believed.Arch Dermatol. 2009; 145: 451-458Crossref PubMed Scopus (98) Google Scholar warfarin,1Kalajian A.H. Malhotra P.S. Callen J.P. Parker L.P. Calciphylaxis with normal renal and parathyroid function not as rare as previously believed.Arch Dermatol. 2009; 145: 451-458Crossref PubMed Scopus (98) Google Scholar and teraparatide2Leis-Dosil V.M. Rubio-Flores C. Ruiz-Bravo Burguillos E. Diaz-Diaz R.M. Cutaneous vascular calcifications secondary to treatment with teriparatide.Actas Dermosifiliogr. 2013; 104: 89-90Crossref PubMed Scopus (7) Google Scholar have all been implicated as well. These factors are all thought to disrupt the balance between nuclear factor-kappa beta (NFκB)-mediated activation and fetuin-A and matrix Gla-protein-mediated (MGP) inhibition of endothelial cell calcification.3Weenig R.H. Pathogenesis of calciphylaxis: Hans Selye to nuclear factor κB.J Am Acad Dermatol. 2008; 58: 458-471Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar Because of the patient's multiple risk factors for calciphylaxis, the relationship to teriparatide cannot be stated with certainty, however previous cases exist.2Leis-Dosil V.M. Rubio-Flores C. Ruiz-Bravo Burguillos E. Diaz-Diaz R.M. Cutaneous vascular calcifications secondary to treatment with teriparatide.Actas Dermosifiliogr. 2013; 104: 89-90Crossref PubMed Scopus (7) Google Scholar, 4Spanakis E. Sellmeyer M.D. Nonuremic calciphylaxis precipitated by teriparatide [rhPTH(1-34)] therapy in the setting of chronic warfarin and glucocorticoid treatment.Endocr Rev. 2012; 33 (03_MeetingAbstracts): SAT-371Google Scholar Calciphylaxis may be diagnosed clinically in patients with typical skin findings and multiple risk factors. Because histopathology is often nondiagnostic in calciphylaxis, the benefits of a biopsy must be weighed against the risk of poor wound healing. If biopsy is performed, special stains may aid in diagnosis as histopathologic changes of early calciphylaxis are subtle.5Mochel M.C. Arakaki R.Y. Wang G. Kroshinsky D. Hoang M.P. Cutaneous calciphylaxis: a retrospective histopathologic evaluation.Am J Dermatopathol. 2013; 35: 582-586Crossref PubMed Scopus (85) Google Scholar Clearer definition of diagnostic criteria for calciphylaxis is needed.