Response to corticosteroids and alternative therapies in sarcoidosis-related hypercalcemia: A guideline-lacking retrospective analysis

Drew Robinson; Denver Crumpler; Guihua Zhai; Joseph Barney

doi:10.36141/svdld.vi.16239

Authors

Drew Robinson Division of Pulmonary, Allergy, and Critical Care Medicine, University of Alabama at Birmingham https://orcid.org/0009-0001-7355-8203
Denver Crumpler Division of Internal Medicine, University of Alabama at Birmingham
Guihua Zhai Center for Clinical and Translational Science, University of Alabama at Birmingham
Joseph Barney Division of Pulmonary, Allergy, and Critical Care Medicine, University of Alabama at Birmingham

Keywords:

retrospective study, sarcoidosis, hypercalcemia, steroid-sparing-therapy, retrospective studies

Abstract

Background and aim: Sarcoidosis is a systemic inflammatory disease of unknown etiology that can affect multiple organs including a known complication of hypercalcemia. Many therapies, both steroidal and nonsteroidal, have been employed. However, the optimal therapy for hypercalcemia in sarcoidosis is unknown, with most data from case reports and small case series. More information is needed to determine which nonsteroidal agents control hypercalcemia in sarcoidosis patients, particularly for populations in whom steroids should be avoided. We sought to answer the question, which pharmacological agents control hypercalcemia in patients diagnosed with sarcoidosis?

Methods: We performed a retrospective chart review on all adult patients at our hospital a diagnosis of Sarcoidosis and Hypercalcemia and a recorded calcium level of greater than 10.4 mg/dL. We then determined which agents were able to control their calcium to a level of 10.4 mg/dL or less for at least 6 months and 12 months.

Results: The most common efficacious treatments were prednisone, methotrexate, hydroxychloroquine, and prednisone + methotrexate. A positive linear relationship was found between ACE and highest calcium levels. No significant relationship between organ involvement or race and highest calcium levels were noted.

Conclusions: There is currently little data or guidelines to best guide the treatment of hypercalcemia in sarcoidosis. This study represents the first with the primary aim to compare treatment options for hypercalcemia in sarcoidosis across a large cohort. Several non-steroidal options were identified that controlled hypercalcemia as a single agent. In addition, this study further investigated potential biomarkers for abnormal calcium metabolism as well as the relationship between calcium levels and organ involvement/race. Further work is needed to determine the most effective steroid sparing therapy to control hypercalcemia in sarcoidosis.

Author Biography

Guihua Zhai, Center for Clinical and Translational Science, University of Alabama at Birmingham

References

1. Baughman RP, Janovcik J, Ray M, Sweiss N, Lower EE. Calcium and vitamin D metabolism in sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis. 2013;30(2):113-120.

2. Sharma OP. Vitamin D, calcium, and sarcoidosis. Chest. 1996;109(2):535-539. doi: 10.1378/chest.109.2.535.

3. Baughman RP, Teirstein AS, Judson MA, et al. Clinical characteristics of patients in a case control study of sarcoidosis. Am J Respir Crit Care Med. 2001;164(10 Pt 1):1885-1889. doi: 10.1164/ajrccm.164.10.2104046.

4. Lebacq E, Desmet V, Verhaegen H. Renal involvement in sarcoidosis. Postgrad Med J. 1970;46(538):526-529. doi: 10.1136/pgmj.46.538.526.

5. Gwadera L, Bialas AJ, Iwanski MA, Gorski P, Piotrowski WJ. Sarcoidosis and calcium homeostasis disturbances—do we know where we stand? Chron Respir Dis. 2019;16:1479973119878713. doi: 10.1177/1479973119878713.

6. Conron M, Young C, Beynon HL. Calcium metabolism in sarcoidosis and its clinical implications. Rheumatology (Oxford). 2000;39(7):707-713. doi: 10.1093/rheumatology/39.7.707.

7. Singha A, Liao SY, Herman DD, et al. Summary for clinicians: clinical practice guideline for the diagnosis and detection of sarcoidosis. Ann Am Thorac Soc. 2020;17(12):1510-1515. doi: 10.1513/annalsats.202007-874cme.

8. McEvoy CE, Niewoehner DE. Adverse effects of corticosteroid therapy for COPD: a critical review. Chest. 1997;111(3):732-743. doi: 10.1378/chest.111.3.732.

9. Keenan GF. Management of complications of glucocorticoid therapy. Clin Chest Med. 1997;18(3):507-520.

10. Matikainen N, Pekkarinen T, Ryhanen EM, Schalin-Jantti C. Physiology of calcium homeostasis: an overview. Endocrinol Metab Clin North Am. 2021;50(4):575-590. doi: 10.1016/j.ecl.2021.07.005.

11. Crouser ED, Maier LA, Wilson KC, et al. Diagnosis and detection of sarcoidosis: an official American Thoracic Society clinical practice guideline. Am J Respir Crit Care Med. 2020;201(8):e26-e51. doi: 10.1164/rccm.202002-0251st.

12. Burke RR, Rybicki BA, Rao DS. Calcium and vitamin D in sarcoidosis: how to assess and manage. Semin Respir Crit Care Med. 2010;31(4):474-484. doi: 10.1055/s-0030-1262215.

13. Baraf L, Abu-Shakra M. Methotrexate treatment for sarcoidosis-induced hypercalcemia. AACE Clin Case Rep. 2020;6(6):e311-e314. doi: 10.4158/accr-2020-0120.

14. Saleh S, Ghodsian S, Yakimova V, Henderson J, Sharma OP. Effectiveness of infliximab in treating selected patients with sarcoidosis. Respir Med. 2006;100(11):2053-2059. doi: 10.1016/j.rmed.2006.02.017.

15. Antoniu SA. Infliximab for the therapy of chronic sarcoidosis. Expert Opin Investig Drugs. 2007;16(5):753-756. doi: 10.1517/13543784.16.5.753.

16. Baughman RP, Drent M, Kavuru M, et al. Infliximab therapy in patients with chronic sarcoidosis and pulmonary involvement. Am J Respir Crit Care Med. 2006;174(7):795-802.

17. Ioachimescu AG, Bauer TW, Licata A. Active Crohn disease and hypercalcemia treated with infliximab: case report and literature review. Endocr Pract. 2008;14(1):87-92. doi: 10.4158/ep.14.1.87.

18. Arkema EV, Cozier YC. Sarcoidosis epidemiology: recent estimates of incidence, prevalence and risk factors. Curr Opin Pulm Med. 2020;26(5):527-534. doi: 10.1097/mcp.0000000000000715.

19. Tana C, Drent M, Nunes H, Kouranos V, Cinetto F, Jessurun NT, Spagnolo P. Comorbidities of sarcoidosis. Ann Med. 2022;54(1):1014-1035. doi: 10.1080/07853890.2022.2063375.

20. Donovan PJ, Sundac L, Pretorius CJ, d’Emden MC, McLeod DSA. Calcitriol-mediated hypercalcemia: causes and course in 101 patients. J Clin Endocrinol Metab. 2013;98(10):4023-4029. doi: 10.1210/jc.2013-2016.

21. Israël-Biet D, Bernardinello N, Pastré J, Tana C, Spagnolo P. High-risk sarcoidosis: a focus on pulmonary, cardiac, hepatic and renal advanced diseases, as well as on calcium metabolism abnormalities. Diagnostics. 2024;14(4):395. doi: 10.3390/diagnostics14040395.

22. Huffstutter JG, Huffstutter JE. Hypercalcemia from sarcoidosis successfully treated with infliximab. Sarcoidosis Vasc Diffuse Lung Dis. 2012;29(1):51-52.

23. Walker MD, Shane E. Hypercalcemia: a review. JAMA. 2022;328(16):1624-1636. doi: 10.1001/jama.2022.18331.

24. Rossman MD, Thompson B, Frederick M, et al. HLA and environmental interactions in sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis. 2008;25(2):125-132.

25. Lang CC, McEwan SR, Ng AK. Co-existing hyperparathyroidism and sarcoidosis presenting with hypercalcaemia—a diagnostic challenge. Scott Med J. 1989;34(4):503-504. doi: 10.1177/003693308903400410.

26. Chaychi L, Chaidarun S, Golding A, Kinlaw WB, Memoli V, Siegel A. Unusual recurrence of hypercalcemia due to concurrent parathyroid adenoma and parathyroid sarcoidosis with lymph node involvement. Endocr Pract. 2010;16(3):463-467. doi: 10.4158/ep09325.cr.

27. Taylor RL, Lynch HJ Jr, Wysor WG Jr. Seasonal influence of sunlight on the hypercalcemia of sarcoidosis. Am J Med. 1963;34:221-227. doi: 10.1016/0002-9343(63)90055-x.

28. Rubin MR, Bruce JN, Khandji AG, et al. Sarcoidosis within a pituitary adenoma. Pituitary. 2001;4:195-202. doi: 10.1023/a:1015323208789.

29. Alsahwi N, Blavo D, Karanchi H. Systemic sarcoidosis with hypercalcaemia, hypothalamic–pituitary dysfunction and thyroid involvement. BMJ Case Rep. 2016;2016:bcr2016216696. doi: 10.1136/bcr-2016-216696.

30. Taibi L, Boursier C, Clodic G, Bolbach G, Béneteau-Burnat B, Vaubourdolle M, Baudin B. Search for biomarkers of neurosarcoidosis by proteomic analysis of cerebrospinal fluid. Ann Biol Clin (Paris). 2017;75(4):393-402. doi: 10.1684/abc.2017.1260.

31. Lawrence EC, Berger MB, Brousseau KP, et al. Elevated serum levels of soluble interleukin-2 receptors in active pulmonary sarcoidosis: relative specificity and association with hypercalcemia. Sarcoidosis. 1987;4(2):87-93.