SciELO - Scientific Electronic Library Online

 
vol.13 número1Hipercalcemia y enfermedades autoinmunesAsociación de parámetros bioquímicos del metabolismo óseo con progresión y/o desarrollo de nuevas calcificaciones aórticas índice de autoresíndice de materiabúsqueda de artículos
Home Pagelista alfabética de revistas  

Servicios Personalizados

Revista

Articulo

Indicadores

Links relacionados

  • En proceso de indezaciónCitado por Google
  • No hay articulos similaresSimilares en SciELO
  • En proceso de indezaciónSimilares en Google

Compartir


Revista de Osteoporosis y Metabolismo Mineral

versión On-line ISSN 2173-2345versión impresa ISSN 1889-836X

Rev Osteoporos Metab Miner vol.13 no.1 Madrid ene./mar. 2021  Epub 17-Mayo-2021

https://dx.doi.org/10.4321/s1889-836x2021000100002 

ORIGINALS

Hypercalcemia in patients with rheumatoid arthritis: a retrospective study

A Cordoba1a  1b  , MT García-Unzueta2  , L Riancho-Zarrabeitia3a  3b  4  , A Corrales3a  3b  , V Martínez-Taboada3a  3b  , JA Riancho1a  1b 

1aInternal Medicine Service. Marqués de Valdecilla University Hospital. Santander (Spain)

1bDepartment of Medicine and Psychiatry, University of Cantabria-Valdecilla Health Research Institute (IDIVAL). Santander (Spain)

2Clinical Analysis Service. Marqués de Valdecilla University Hospital. Santander (Spain)

3aRheumatology Service. Marqués de Valdecilla University Hospital. Santander (Spain)

3bDepartment of Medicine and Psychiatry. University of Cantabria-IDIVAL. Santander (Spain)

4Rheumatology Service. Sierrallana Hospital. Torrelavega (Spain)

Summary

Objetive

To investigate the prevalence of hypercalcemia in patients with rheumatoid arthritis (RA) and analyze the clinical features and causes of hypercalcemia.

Material and methods

Retrospective case-based review study that included 500 patients with RA. Patients with increased calcium levels on at least two occasions were identified.

Results

Hypercalcemia was present in 24 of the 500 RA patients (4.8%). The age ranged between 50 and 80 years, with a mean of 68±10 years. The mean duration of the disease was 10±7 years. Of the patients with hypercalcemia, 22 were postmenopausal women (92%) and only two were men (8%). Hyperparathyroidism was found in 9 patients in the series; only one patient had malignant hypercalcemia due to multiple myeloma, and one case was a consequence of vitamin D intoxication. In one patient, hypercalcemia appeared to be related to calcium-alkali syndrome. In the remaining patients, hypercalcemia was idiopathic (8/24) or the study was incomplete (4/24). No obvious relationship was found between disease activity and the appearance of hypercalcemia.

Conclusion

As in the general population, primary hyperparathyroidism is the most common cause of hypercalcemia in patients with RA. In some patients, no other disorders causing hypercalcemia were identified, raising the possibility of a causal relationship between RA and hypercalcemia.

Key words hypercalcemia; rheumatoid arthritis; hyperparathyroidism; vitamin D

INTRODUCTION

Hypercalcemia is a relatively common clinical problem and a frequent laboratory finding, both in hospital and out‐of‐hospital practice. Calcium ions play a critical role in many cellular functions. Parathyroid hormone (PTH) and vitamin D are the most important hormones for regulating calcium. The main sources of serum calcium are intestinal absorption, stimulated by active vitamin D metabolites, and bone resorption, usually stimulated by PTH. Therefore, hypercalcemia can be classified as PTHdependent (due to increased secretion of PTH by the parathyroid glands) and independent of PTH. The latter cases are attributable to increased bone resorption and/or increased intestinal absorption of calcium, induced by factors other than PTH. Among them, PTH‐related protein (PTHrP) and locally produced cytokines are factors that often cause hypercalcemia in cancer patients1. Unregulated extrarenal synthesis of 1,25‐dihydroxyvitamin D can also cause hypercalcemia, particularly in patients with chronic granulomatous disorders and in some patients with lymphoma2.

Most reported cases of hypercalcemia are due to primary hyperparathyroidism or malignant neoplasms; together, these causes account for more than 90 percent of cases. Less common causes include granulomatous disorders, vitamin D poisoning, lithium or thiazide therapy, familial hypocalciuric hypercalcemia, etc. Among musculoskeletal diseases, sarcoidosis and metastatic bone tumors are well‐known causes of hypercalcemia. However, the relationship between rheumatoid arthritis (RA) and hypercalcemia is unclear and conflicting results have been reported35. Thus, while Ralston et al. found only 1 patient with hypercalcemia among 102 patients with RA5, a much higher frequency, up to 30%, has been reported in some series3. Therefore, our study aims to determine the frequency of hypercalcemia and its origin in unselected patients with RA.

PATIENTS AND METHODS

We investigated 500 unselected patients with a diagnosis of RA6, seen in the Rheumatology consultation of the Marqués de Valdecilla Hospital. This tertiary hospital serves a population of about 350,000 people.

A computerized search of the blood tests carried out on these patients over a 15‐year period (2002‐2016) allowed us to identify total and ionized calcium values. Hypercalcemia was defined as a total serum calcium concentration greater than 10.4 mg/dl, and/or ionized calcium greater than 1.35 mmol/l (the limits of the normal range), in at least two determinations. The clinical records of patients with hypercalcemia were reviewed and clinical and biochemical data were extracted according to a standard protocol. The protocol was approved by the Cantabria Clinical Research Ethics Committee, which did not consider the written consent of the patients necessary due to the retrospective observational nature of the study.

A Pubmed search was done on the terms "rheumatoid arthritis" and "hypercalcemia". Secondary references of relevant documents were also checked.

RESULTS

Patients’ characteristics

A total of 476 patients (95.2%) presented normal serum calcium levels, while 24 patients (4.8%) had hypercalcemia, according to the definition above.

The demographic, clinical and laboratory characteristics are listed in table 1. In summary, the RA sample with hypercalcemia (n=24) showed a preponderance of female gender (22 of 24, 92%) and had a mean age of 68±10 years (50‐80). Most of the patients had long‐standing RA (mean duration of the disease at the time of identification of hypercalcemia, 10±7 years; range 2‐21), but in 5 cases the diagnosis of RA and hypercalcemia were simultaneous. Globally, 72% patients had positive rheumatoid factor and/or positive anti‐citrullinated peptides. Not unexpectedly, the clinical spectrum was quite varied. Globally, 11 of the 24 patients with hypercalcemia (46%) had elevated inflammatory markers (CRP or ESR) at that time. Only 10 patients (42%) had evidence of arthritis at the time of hypercalcemia, and only 6 of them had arthritis and increased inflammatory markers. Four patients were taking vitamin D supplements and 9 were receiving calcium supplements. In all but one case, the doses were low and could not be considered as the cause of hypercalcemia.

Table 1.  Characteristics of patients with hypercalcemia 

Variables expressed as mean ± standard deviation (SD) or number and percentage. RA: rheumatoid arthritis; RF: rheumatoid factor; ACCP: anti-citrullinated cyclic peptide antibodies.

Causes of hypercalcemia

After diagnostic studies, primary hyperparathyroidism was found in 9 patients (Figure 1). This represents 1.8% of the 500 RA patients, and 37% of the 24 hypercalcemia patients. Serum PTH levels ranged between 73 and 283 pg/ml (normal range <65 pg/ml). In 6 patients, a parathyroid adenoma was identified by scintigraphy or during surgical exploration. Three patients rejected the imaging studies. Two patients underwent surgery, 4 received antiresorptives and 3 did not receive any specific therapy.

Figure 1.  Causes of hypercalcemia in this series 

Only one of the patients had a malignant hypercalcemia, due to multiple myeloma. In another patient, the hypercalcemia was due to vitamin D intoxication. In one patient, hypercalcemia could be due to the calcium‐alkaline syndrome, a situation similar to the milk‐alkaline syndrome. This diagnosis was based on the fact that hypercalcemia was associated with renal failure and the patient had been treated with calcium carbonate and thiazide supplements.

In the other patients in our series (8/24), the cause of hypercalcemia was unknown and, therefore, it can be considered idiopathic. Among this group, hypercalcemia was fluctuating (alternating normal and increased levels) in 5 patients, while in the other 3 it was transient. Hypercalcemia was always mild and asymptomatic. Although some patients showed elevated markers of inflammation, review of the cases did not reveal a relationship between calcaemia and clinical outbreaks of the disease. In 4 patients, follow‐up studies and follow‐up excluded disorders known to be associated with hypercalcemia (such as cancer, hyperparathyroidism, hyperthyroidism, adrenal insufficiency, etc.). However, in 4 other patients the study was limited, insufficient to establish with certainty the etiology of hypercalcemia.

None of the patients presented hypercalcemia secondary to granulomatous diseases (such as tuberculosis and sarcoidosis) or solid organ neoplasia. However, one patient had hypercalcemia mediated by increased 1,25dihydroxyvitamin D levels, with suppressed PTH and increased angiotensin converting enzyme (ACE). Neither in the initial study (which included CT, PET and bone marrow biopsy), nor during follow‐up were signs of neoplasia, adenopathy or granulomatous disease found. Corticosteroid treatment achieved full normalization of biochemical parameters, but the source of 1,25‐dihydroxyvitamin D could not be identified.

DISCUSSION

RA is a chronic systemic inflammatory disorder. Although joint tissues are the main target of the inflammatory process, the disease also has consequences for bone tissue, both locally and systemically. In particular, RA causes increased bone resorption, which results locally in erosions and juxta‐articular osteopenia, and systemically in reduced bone mass and increased risk of osteoporotic fractures. However, the association of RA with hypercalcemia is discussed (Table 2).

Table 2.  Hypercalcemia studies in patients with rheumatoid arthritis (RA) 

NI: not included.

Almost 4 decades ago, Kennedy et al. noted the presence of hypercalcemia in 23 of 50 patients with RA (46%). In 7 cases (14%) the hypercalcemia was permanent. The cause was unclear. Many patients had active disease and some biochemical characteristics that suggested hyperparathyroidism, but serum PTH levels were within the normal range4. However, Scott et al. reported a very low frequency of hypercalcemia among RA patients, 0.5% among outpatients and 0‐2% among hospitalized patients7. These findings are similar to those of Ralston et al., who found only one case of hypercalcemia in a group of 102 RA patients studied over a 3‐month period5. On the other hand, in a more recent study by Oelzner et al. which included 146 German RA patients, the frequency of hypercalcemia was 30%. Since high calcium levels were correlated with higher ESR and CRP values, as well as lower levels of PTH and 1,25‐dihydroxyvitamin D, they suggested that hypercalcemia was probably due to increased bone resorption related to disease activity3.

In our study, the frequency of hypercalcemia among RA patients was 4.8%, which is intermediate between those reported in previous studies. It is interesting to note that, unlike previous studies, we did not observe a clear association between RA activity and hypercalcemia. However, differences in patient characteristics, and specifically the availability of more potent disease‐modifying drugs in recent years, make it difficult to compare the older series with the more recent ones.

Regarding the etiology of hypercalcemia, primary hyperparathyroidism seems to be the most common cause in patients with RA, similar to what happens in the general population. The prevalence of hyperparathyroidism in the Caucasian population is approximately 0.20.9%8,9. Therefore, the 1.8% frequency that we found in RA may be somewhat higher than expected. However, the limited sample size does not allow us to firmly establish that the frequency of primary hyperparathyroidism is higher in RA than in the general population. However, a higher prevalence of hyperparathyroidism has recently been published in other RA cohorts, with a mean frequency of around 2.8%10. On the other hand, it is worth mentioning that patients with hyperparathyroidism can have a variety of musculoskeletal manifestations, including pain and chondrocalcinosis1113, which must be properly interpreted and not be confused with the consequences of RA or other rheumatic disorders.

In the general population, cancer is the second most common cause of hypercalcemia14,15. In our RA series, only one patient had hypercalcemia related to a malignancy, which is reassuring in the context of the increased cancer risk reported in RA16.

The calcium‐alkaline syndrome, an update of the picture previously known as milk‐alkaline syndrome, characterized by the triad of hypercalcemia, metabolic alkalosis and kidney failure, secondary to the ingestion of variable amounts of calcium together with an absorbable alkaline, represents, according to data recent, the third most common cause of hypercalcemia1719. One patient in our cohort presented a picture consistent with this syndrome.

In a significant proportion of patients, the cause of hypercalcemia remained unclear. Patients with lymphoma and granulomatous disorders (such as tuberculosis or sarcoidosis) may have hypercalcemia due to unregulated extrarenal synthesis of 1,25‐dihydroxyvitamin D20,21. In the current series, one patient had recurrent hypercalcemia associated with high levels of 1,25‐dihydroxyvitamin D. Consistent with an extrarenal source, 1,25‐dihydroxyvitamin D and calcium levels normalized with glucocorticoid therapy. However, after a large study, which included repeated PET scans, CT scans, and bone marrow biopsies, no evidence of granulomatous disorder or cancer could be found. On the other hand, the patient's age and the time course of serum calcium and 1,25‐dihydroxyvitamin D levels do not fit within the spectrum of genetic deficiency of CYP24A1, an enzyme that metabolizes 25 and 1,25‐dihydroxyvitamin D22,23. Therefore, RA, although inactive, was the most likely explanation for the abnormal synthesis of 1,25‐dihydroxyvitamin D. It should be noted that Gates published the case of a patient similar to this24. The mechanisms that relate RA to 1,25‐dihydroxyvitamin D synthesis are unclear, but could depend on cytokine‐mediated macrophage activation. Whatever the mechanisms involved, these appear to be very rare cases. In fact, RA was not among the underlying disorders in a series of 101 patients with 1,25‐dihydroxyvitamin D25 mediated hypercalcemia.

Future epidemiological studies, with larger cohorts of RA patients, would help to clarify whether the frequency of hyperparathyroidism increases in RA. Furthermore, careful clinical studies of patients in whom diagnostic analysis does not reveal causes of hypercalcemia other than RA can help to better understand the pathophysiology of these rare cases.

Treatment of hypercalcemia in RA must take into account the cause and the mechanisms responsible for the increase in serum calcium. General measures should include the withdrawal of calcium supplements and other drugs that induce hypercalcemia (such as lithium or thiazides) and maintaining adequate hydration. In acute severe cases, intravenous fluids, bisphosphonates such as zoledronic acid, and sometimes calcitonin are indicated26. For patients with a parathyroid adenoma, surgical removal is the therapy of choice, but non‐invasive procedures can be useful in patients with very high surgical risk27,28. In these patients, drug treatment with cinacalcet or antiresorptive agents can help control hypercalcemia9. In 1,25‐dihydroxyvitamin D‐mediated hypercalcemia, corticosteroids are usually very effective, but ketoconazole or antimalarials can also help control extrarenal vitamin D hydroxylation and, consequently, normalize levels2,29.

CONCLUSION

In this study of a cohort of 500 RA patients, hypercalcemia was present in 4.8%. As in the general population, primary hyperparathyroidism was the most common cause. In some patients, no other disorders causing hypercalcemia were identified, raising the possibility of a causal relationship between RA and hypercalcemia. However, in these cases we did not find a clear link between disease activity and calcium levels.

Although limited by its retrospective nature, our study thus adds useful information on the epidemiology of hypercalcemia and RA. These results suggest that hypercalcemia has a similar frequency in RA and in the general population and that the causes are similar. Although the study was incomplete in some cases, our data support that most patients have another underlying diagnosis as the cause of hypercalcemia. Therefore, if hypercalcemia is discovered in a patient with RA, a search should be made for underlying causes, particularly hyperparathyroidism and cancer.

Bibliografía

1 Bollerslev J, Pretorius M, Heck A. Parathyroid hormone independent hypercalcemia in adults. Best Pract Res Clin Endocrinol Metab. 2018;32 (5):621-638. [ Links ]

2 Tebben PJ, Singh RJ, Kumar R. Vitamin D-mediated hypercalcemia: mechanisms, diagnosis, and treatment. Endocr Rev. 2016;37(5):521-547. [ Links ]

3 Oelzner P, Lehmann G, Eidner T, Franke S, Müller A, Wolf G, et al. Hypercalcemia in rheumatoid arthritis: relationship with disease activity and bone metabolism. Rheumatol Int. 2006;26(10):908-915. [ Links ]

4 Kennedy AC, Allam RF, Rooney PJ, Watson ME, Fairney A, Buchanan KD, et al. Hypercalcaemia in rheumatoid arthritis: investigation of its causes and implications. Ann Rheum Dis. 1979;38(5):401-412. [ Links ]

5 Ralston SH, Fraser WD, Jankowski J, Richards IM, Cowan RA, Capell HA, et al. Hypercalcaemia in rheumatoid arthritis revisited. Ann Rheum Dis. 1990;49(1):22-24. [ Links ]

6 Van Der Linden MPM, Knevel R, Huizinga TWJ, Van Der Helm-Van Mil AHM. Classification of rheumatoid arthritis: Comparison of the 1987 American College of Rheumatology criteria and the 2010 American College of Rheumatology/European League Against Rheumatism criteria. Arthritis Rheum. 2011;63(1):37-42. [ Links ]

7 Scott DL, Farr M, Hawkins CF, Wilkinson R, Bold AM. Serum calcium levels in rheumatoid arthritis. Ann Rheum Dis. 1981;40(6):580-583. [ Links ]

8 Minisola S, Pepe J, Scillitani A, Cipriani C. Explaining geographical variation in the presentation of primary hyperparathyroidism. Lancet Diabetes Endocrinol. 2016;4(8):641-643. [ Links ]

9 Bilezikian JP, Bandeira L, Khan A, Cusano NE. Hyperparathyroidism. Lancet. 2018;391(10116):168-178. [ Links ]

10 Emamifar A, Jensen Hansen IM. The influence of thyroid diseases, diabetes mellitus, primary hyperparathyroidism, vitamin B12 deficiency and other comorbid autoimmune diseases on treatment outcome in patients with rheumatoid arthritis. Medicine (Baltimore). 2018;97(21):e10865. [ Links ]

11 Rubin MR, Silverberg SJ. Rheumatic manifestations of primary hyperparathyroidism and parathyroid hormone therapy. Curr Rheumatol Rep. 2002;4(2):179-185. [ Links ]

12 Reginato AJ, Falasca GF, Pappu R, McKnight B, Agha A. Muscoloeskeletal manifestations of osteomalacia:report of 26 cases and literature review. Semin Arthritis Rheum. 1999;28:287-304. [ Links ]

13 Bilezikian JP, Cusano NE, Khan AA, Liu J-M, Marcocci C, Bandeira F. Primary hyperparathyroidism. Nat Rev Dis Prim. 2016;2:16033. [ Links ]

14 Meng QH, Wagar EA. Laboratory approaches for the diagnosis and assessment of hypercalcemia. Crit Rev Clin Lab Sci. 2015;52(3):107-119. [ Links ]

15 Goldner W. Cancer-Related Hypercalcemia. J Oncol Pract. 2016;12(5):426-432. [ Links ]

16 Simon TA, Thompson A, Gandhi KK, Hochberg MC, Suissa S. Incidence of malignancy in adult patients with rheumatoid arthritis: a meta-analysis. Arthritis Res Ther. 2015;17(1):212. [ Links ]

17 Kaklamanos M, Perros P. Milk alkali syndrome without the milk. BMJ. 2007;335(7616):397-398. [ Links ]

18 Beall DP, Henslee HB, Webb HR, Scofield RH. Milk-alkali syndrome: a historical review and description of the modern version of the syndrome. Am J Med Sci. 2006;331(5):233-242. [ Links ]

19 Fernández García M, Riancho Moral JA, Hernández Hernández JL. Síndrome calcio-alcalinos: actualización de un antiguo problema clínico. Med Clin (Barc). 2011;137(6):269-272. [ Links ]

20 Kallas M, Green F, Hewison M, White C, Kline G. Rare causes of calcitriol-mediated hypercalcemia: a case report and literature review. J Clin Endocrinol Metab. 2010;95(7):3111-3117. [ Links ]

21 Bikle DD, Patzek S, Wang Y. Physiologic and pathophysiologic roles of extra renal CYP27b1: Case report and review. Bone Reports. 2018;8:255-267. [ Links ]

22 Woods GN, Saitman A, Gao H, Clarke NJ, Fitzgerald RL, Chi N-W. A young woman with recurrent gestational hypercalcemia and acute pancreatitis caused by CYP24A1 deficiency. J Bone Miner Res. 2016;31(10):1841-1844. [ Links ]

23 Carpenter TO. CYP24A1 loss of function: Clinical phenotype of monoallelic and biallelic mutations. J Steroid Biochem Mol Biol. 2017;173:337-340. [ Links ]

24 Gates S, Shary J, Turner RT, Wallach S, Bell NH. Abnormal calcium metabolism caused by increased circulating 1,25-dihydroxyvitamin D in a patient with rheumatoid arthritis. J Bone Miner Res. 1986;1(2):221-226. [ Links ]

25 Donovan PJ, Sundac L, Pretorius CJ, d’Emden MC, McLeod DSA. Calcitriolmediated hypercalcemia: causes and course in 101 patients. J Clin Endocrinol Metab. 2013;98(10):4023-4029. [ Links ]

26 Carrick AI, Costner HB. Rapid Fire: Hypercalcemia. Emerg Med Clin North Am. 2018;36(3):549-555. [ Links ]

27 Sormaz IC, Poyanlı A, Açar S, İşcan AY, Ozgur İ, Tunca F, et al. The results of ultrasonography-guided percutaneous radiofrequency ablation in hyperparathyroid patients in whom surgery is not feasible. Cardiovasc Intervent Radiol. 2017;40(4):596-602. [ Links ]

28 Riancho JA, Lastra P, Amado JA. Alcoholization: An option for the treatment of hyperparathyroidism. Med Clin (Barc). 2009;132(17):682-683. [ Links ]

29 Sharma OP. Hypercalcemia in granulomatous disorders: a clinical review. Curr Opin Pulm Med. 2000;6(5):442-447. [ Links ]

30 Bramble MG, Blake DR, White T, Sly J, Kerr DN. Ionised calcium in rheumatoid arthritis: effect of non-steroidal anti-inflammatory drugs. Br Med J. 1980;281(6244):840-841. [ Links ]

31 Mudge CS, Yoo DC, Noto RB. Rheumatoid arthritis demonstrated on PET/CT as the etiology of hypercalcemia. Med Health R I. 2012;95(2):54-56. [ Links ]

32 Abrar-Ahmad Z. Rheumatoid arthritis and primary hyperparathyroidism. J Rheumatol Neuromuscul Syst. 2016; 1(1):002. [ Links ]

Received: October 31, 2020; Accepted: February 18, 2021

Correspondencia: José A. Riancho (rianchoj@unican.es)

Conflict of interests: The authors declare no conflict of interest.

Creative Commons License Este es un artículo publicado en acceso (Open Access) abierto bajo la licencia Creative Commons Attribution Non-Commercial, que permite su uso, distribución y reproducción en cualquier medio, sin restricciones siempre que sin fines comerciales y que el trabajo original sea debidamente citado.