Metastatic calcinosis cutis due to refractory hypercalcaemia responsive to denosumab in a patient with multiple sclerosis

Abstract

Metastatic calcinosis cutis results from abnormal calcium levels leading to the precipitation of insoluble calcium salts in the skin and subcutaneous tissue. Here, we present the case of a 67-year-old man with multiple sclerosis on chronic dexamethasone and concurrent supplementation of calcium and daily cholecalciferol presenting with painful calcified lesions. During initial presentation, corrected calcium was 13.8 mg/dL (reference range: 8.5–10.1 mg/dL), ionised calcium was 1.70 mg/dL (reference range: 1.13–1.32 mg/dL) and 25-hydroxyvitamin D was 41.6 ng/mL (reference range 30–100 ng/mL). Normocalcaemia was restored with the off-label use of denosumab, usually reserved for hypercalcaemia of malignancy and intractable osteoporosis. We discuss potential aetiologies of this patient’s hypercalcaemia, calcinosis cutis diagnosis and management and the off-label use of denosumab.

Background

Metastatic calcinosis cutis is a rare but potentially devastating consequence of hypercalcaemia. On the other hand, in patients suffering from multiple sclerosis (MS), low calcium and vitamin D levels have been shown to correlate with MS relapses, decreased anti-inflammatory effects and immunomodulation.^1–4 It is thus common practice among neurologists to recommend additional sources of vitamin D and calcium for this population.^{5 6} However, care should be taken, especially in patients concurrently taking steroids, to avoid a hypercalcaemic state. Such disarray in calcium metabolism can result in the precipitation of excess calcium into the subcutaneous tissue, also known as metastatic calcinosis cutis. This case report focuses on a patient with MS on a long-term, carefully monitored regimen of calcium and vitamin D, who presented with calcinosis cutis in the setting of hypercalcaemia of an aetiology that could not be elucidated despite extensive work-up.

Case presentation

A 67-year-old right-handed man with MS, osteoporosis and hypothyroidism presented with several weeks of left lower extremity cellulitis refractory to antibiotics. He complained of progressively worsening left thigh pain. He denied bone pain, abdominal discomfort and changes in mental status. Prior to this hospitalisation, he was able to walk with a cane and had an Expanded Disability Status Scale of 6. His relapsing remitting MS was diagnosed in 1978, after two distinct episodes in which he experienced a considerable loss of motor strength and visual function. Comparing historical MRI findings, described below, we can support the diagnosis of MS using the McDonald criteria.

The patient had been receiving 40 mg of copaxone three times per week as well as long-term dexamethasone, 1 mg, every 2 days 600 mg of elemental calcium (combined with 500 IU of vitamin D) two times per day and 2000 IU of cholecalciferol (vitamin D₃) two times per day for over 6 years after osteoporosis was diagnosed. His neurologist had intensively followed the patient, reporting normal calcium and vitamin D levels.

On presenting exam, vital signs were unremarkable and the patient was alert and oriented except to time. His neurological exam was notable for left upper quadranopsia, left upper and lower extremity weakness with a grade of 3/5 on the shoulder and hip muscles, and hyperreflexia at the left knee joint graded at 4+ (repetitive vibratory movements) toes flexed for a normal flexor plantar response bilaterally. Remaining neurological exam was unremarkable. He bore an erythaematous homogeneous patch with subcutaneous hardening involving the left proximal thigh extending to posterior left scrotal region. It was noticeably warm, non-tender, with no skin rupture and non-secreting; copaxone injection site was not coincident in location with these findings.

Cardiovascular exam was unremarkable. MRI showed no acute infarct, haemorrhage or mass but revealed multiple T2 bright foci distributed in pericallosal distribution with the size and distribution of demyelinating lesions remaining relatively unchanged when compared with MRI from 5 years prior. Abdominal and pelvic CT imaging revealed complex peripheral calcified masses with central hypodensity throughout the left pelvic area and proximal left lower extremity (figure 1A) not present in a previous CT scan performed in 2011. MRI of the left thigh was notable for a large heterogeneous collection with an enhancing rim indicating partial calcification in the subcutaneous soft tissue at the level of the ischial tuberosity, in the area medial to the obturator foramen, and in the intrapelvic region. Notable amounts of muscular and subcutaneous oedema were present throughout the thigh. A skin punch biopsy revealed innumerable calcium deposits (figure 1B) as well as fat necrosis throughout the left pelvic area including soft tissue and around both hip joints without lytic or blastic lesions; this finding, together with elevated systemic calcium levels, was felt to be most consistent with metastatic calcinosis cutis.

Figure 1.

(A) Contrasted CT axial view of the lower extremities showing complex peripheral and extensive calcification of subcutaneous fat in the upper medial thigh and buttocks regions. (B) Biopsy of the left thigh skin under x40 magnification with H&E stain showing the extent of calcium deposits and soft tissue reaction depicted as intensely basophilic deposits.

On admission, corrected serum calcium level was elevated to 13.8 mg/dL (reference range: 8.5–10.1 mg/dL), ionised calcium level was 1.70 mg/dL (reference range: 1.13–1.32 mg/dL), 25-hydroxyvitamin D level was 41.6 ng/mL (reference range: 18–72 ng/mL) and parathyroid hormone level (PTH) was <5.0 (reference range: 10–70 pg/mL). White blood cell count was 15.9×10⁹/L (reference range: 4–11.3×10⁹/L), haemoglobin 108 g/L (reference range: 140–175 g/L), haematocrit 32.9% (reference range: 42%–50%), MCV 95.9 fL (reference range: 80–100 fL), reticulocyte count was 1.7% (reference range: 0.5%–1.5%), segmented neutrophil was 10.5×10³/L (reference range: 1.8–7.9×10⁹/L), and his total iron binding capacity was 208 ncg/dL. Erythrocyte sedimentation rate, C-reactive protein, liver function, viral hepatitis, muscle enzyme, lactate and 24 hours urine sample testing were unremarkable. Serum urea nitrogen, creatinine, phosphorus, magnesium, iron and ferritin were within normal levels. Free kappa and free lambda light chain, serum protein electrophoresis, urine protein electrophoresis and ACE levels were unremarkable. Skeletal survey revealed diffuse osteopaenia but no lytic or blastic lesions.

Throughout the first 10 days of hospitalisation, calcium levels remained elevated, (figure 2), despite aggressive and constant intravenous fluid administration, calcitonin and pamidronate (given on day 2). Four milligrams of zalendronic acid was added on day 11 which resulted in a reduction in his ionised calcium to normal levels. From admission, his white blood cell count fluctuated from 15–25×10⁹/L and was attributed to chronic steroid use. Low haemoglobin count was suspected from anaemia of chronic disease with malignancy unlikely. The abscess resolved after 12 days of vancomycin and pipercillin/tazobactam. Minocycline was administered to modulate inflammatory response of the calcinosis cutis. The left thigh rash decreased substantially in size and colour over his hospitalisation, but remained indurated. The patient was discharged on day 18.

Figure 2.

The patient’s serum corrected calcium (circles), calcium (squares) and ionised calcium (triangles) levels over his first and second hospitalisation course. Dotted lines indicate normal levels, respectively. Second hospitalisation course started 9 days after initial discharge.

He was readmitted 9 days after discharge for worsening thigh pain and erythaema and was found to have an ionised calcium of 1.48 mg/dL as shown in figure 2; the hypercalcaemia was again refractory to intravenous fluid administration. Bisphosphonates were discontinued in favour of denosumab, 120 mg, two doses, 1 month apart and he was given his first dose on day 5 of his second hospital stay. His ionised calcium stabilised within normal levels on day 7 and patient was discharged on day 8. Remarkably, it remained in the normal range on follow-ups. For the calcinosis cutis, extracorporeal shock-wave lithotripsy therapy was recommended.

Differential diagnosis

Differential diagnosis for hypercalcaemia:

Primary, secondary and tertiary hyperparathyroidism.

Malignancy (eg, Multiple Myeloma, PTH-rp mediated hyperparathyroidism).

Thyrotoxicosis.

Immobilisation.

Hypervitaminosis A.

Drugs (vitamin D, lithium, thiazides, milk of alkali).

Dehydration.

Renal disease.

Adrenal insufficiency.

Familiar hypocalciuric hpercalcaemia.

Rare (HIV-lymphadenopathy, granulomatosis with polyangitis, Crohn’s disease).

Differential diagnosis for calcinosis cutis:

Dystrophic (deposition of calcium into damaged tissue, normal serum calcium levels).

Metastatic (abnormal calcium levels leading to precipitations in the skin and subcutaneous tissue).

Calciphylaxis (abnormal calcium levels with depositions in blood vessels).

Idiopathic and Iatrogenic.

Treatment

Intravenous fluids.

Calcitonin.

Pamidronate.

Zalendronic acid.

Denosumab.

Outcome and follow-up

Normocalcaemia after two doses of denosumab. No abnormal calcium laboratory levels after a year of close follow-ups. Several months of symptomology due to calcinosis cutis.

Discussion

Physiological serum calcium levels are maintained through a multitude of regulatory pathways in the body including calcium absorption in the intestines, excretion in the urine, bone homeostasis and reabsorption in the kidneys. These processes are in turn subjected to interactions between various regulatory substances such as vitamin D and PTH. In the case of our patient, we explored and ruled out based on the case presentation multiple common and rare causes of hypercalcaemia as listed on the Differential Diagnosis section. Additionally, we considered that our patient’s intake of multiple medications for treatment of his comorbidities could have caused an idiosyncratic medication interaction; for example, with the use of omeprazole and foscarnet, but this was also felt to be unlikely.⁶

In a similar case report of a patient with MS and refractory hypercalcaemia, the authors concluded that their patient’s hypercalcaemia was due to the cumulative effects of vitamin D and calcium supplementation over the course of multiple years.⁷ Contrastingly, our patient’s unremarkable vitamin D levels and well-supported calcium intake excludes this aetiology. The Institute of Medicine recommends a tolerable upper limit of vitamin D intake equal to 4000 IU/day and up to 2000 mg/day of calcium for healthy adults.⁸ Most sources recommend additional calcium and vitamin D supplementation for patients on long-term glucocorticoid therapy and, in addition, daily doses of up to 10000 IU for patients with MS are not uncommon.⁹ For these reasons, our patient’s intake of 1200 mg of calcium and 5000 IU of vitamin D supplementation is not uncommonly high, even when accounting for diet sources and endogenous production, respectively. Moreover, 25-hydroxyvitamin D level (a surrogate for vitamin D sufficiency) measured 41.6 ng/mL, not elevated. Although debatable, experts recommend a range between 20 and 50 ng/mL with reservations for concentrations above 50 ng/mL.⁸

In regards to the patient’s calcifications, we considered different types of calcinosis cutis as listed in the Differential Diagnosis section. We concluded that metastatic calcinosis cutis was the culprit after considering calcium levels and biopsy results. Treatments considered, apart from correcting calcium levels, included intradermal sodium thiosulfate, calcium channel blockers and lithotripsy. Sodium thiosulfate is used to dissolve calcium complexes, and while its mechanism has not been fully identified, it is thought to effect improvement by chelating calcium and reducing calcium extravasation.¹⁰ Calcium channel blockers (eg, diltiazem) inhibit cell calcium influx and are commonly used for dystrophic calcinosis cutis associated with autoimmune diseases.¹¹ Treatments such as colchicine and minocycline are also viable options to reduce inflammation. Finally, extracorporeal shock-wave lithotripsy is an effective treatment for calcinosis cutis that can rapidly alleviate pain caused by calcified lesions.¹² We recommended lithotripsy due to size and pain associated with these calcifications.

Finally, the use of denosumab after failure of intravenous fluids, calcitonin, pamidronate and zalendronic acid is of interest in this case. This monoclonal antibody binds to nuclear factor-kappa ligand (RANKL), a protein that promotes osteolysis and is secreted by osteoblasts, in turn blocking it from interacting with its receptor ultimately leading to decreased bone resorption and osteoclastic activity.¹³ Denosumab is usually reserved for the treatment of hypercalcaemia of malignancy or complicated osteoporosis.¹³ Scarce reports where this monoclonal antibody was used ‘off-label’ included conditions such as end-stage renal disease or parathyrotoxicosis.¹⁴ It is true that denosumab, apart from aggressively treating this patient’s hypercalcaemia, could potentially alleviate his osteoporosis. Nonetheless, the use of denosumab is associated with two particular adverse reactions that, although rare, are of concern in this case. The first is an increased risk of atypical femur fractures mediated by a delay in bone remodelling especially with concomitant glucocorticosteroid use.¹⁵ The second is immune dysfunction and an increase in the incidence of infections, mediated by the inhibition of the RANKL/RANK expressed in monocytes and macrophages.¹⁴

We were unable to define a specific mechanism that accounted for the refractory hypercalcaemia and resultant metastatic calcinosis cutis in this case after extensive investigation. Our patient has recuperated from his hypercalcaemia but has experienced sequelae from the resultant protracted calcinosis cutis. Remarkably, he has had no derangement in his calcium on close follow-up. Calcinosis cutis is a rare phenomenon and has not been well studied, particularly in patients with MS. However, there have been case studies establishing the association of hypercalcaemia with metastatic calcinosis cutis.^{16 17} Of particular significance is the unprecedented use of denosumab to treat a case of bisphosphonate-resistant hypercalcaemia resulting in the patient’s complete remission after two doses. This off-label use is of clinical significance and a unique application in the literature.

Learning points.

• Patients with multiple sclerosis taking calcium and vitamin D supplements are at an increased risk for hypercalcaemia and should be carefully monitored.

• Denosumab is a monoclonal antibody that blocks nuclear factor-kappa ligand (RANKL), a protein secreted by osteoblasts that promotes osteolysis. Denosumab is used for the treatment of pathologies where bone homeostasis is imbalanced (eg, label use: bone metastases, hypercalcaemia of malignancy, multiple myeloma, osteoporosis; off-label use: rheumatoid arthritis).

• The off-label use of denosumab is warranted and should be promptly considered after other options have been exhausted in a patient with signs and symptoms of hypercalcaemia without contraindications.

• Calcinosis cutis is a rare but devastating sequela of hypercalcaemia, causing prolonged painful inflammation.