Metabolic Research Unit, Shriners Hospital for Children (M.C.E., R.L., M.P.W.), St. Louis, Missouri 63131; Department of Pediatrics (M.C.E.), Division of Endocrinology and Metabolism, Washington University School of Medicine, St. Louis Childrens Hospital; St. Louis, Missouri 63110; Mallinckrodt Institute of Radiology (W.H.McA.), Washington University School of Medicine, St. Louis Childrens Hospital; St. Louis, Missouri 63110; and Division of Bone and Mineral Diseases, Departments of Medicine, Pediatrics, and Genetics (M.P.W.), Washington University School of Medicine at Barnes-Jewish Hospital; St. Louis, Missouri 63110
Address all correspondence and requests for reprints to: Michael P. Whyte, Metabolic Research Unit, Shriners Hospital for Children, 2001 South Lindbergh Boulevard, St. Louis, Missouri 63131-3597.
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Introduction |
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Ectopic calcification in JDM is thought to develop through a dystrophic mechanism, whereby damaged muscle releases mitochondrial calcium into matrix vesicles, which then promote mineralization (9). Histological study of the lesions shows hydroxyapatite accumulation rather than bone (10). Serum calcium and phosphate levels are reported to be normal.
We report a young man with JDM and calcinosis universalis whose ectopic calcifications resolved during 7 months of uncomplicated probenecid therapy.
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Case Report |
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This 19-yr-old black college student was referred at age 18 yr to the Metabolic Research Unit (MRU) at Shriners Hospital for Children, St. Louis for evaluation of diffuse, progressive, and disabling areas of periarticular calcification complicating JDM.
Our review of his medical records revealed that he presented to a local medical facility at age 9 yr following a 1-month history of progressive weakness and leg pains. At age 10 yr, muscle biopsy showed an inflammatory myopathy. Serum creatine phosphokinase (CPK) level was approximately 12,600 U/L (normal, 30220 U/L). Despite low-dose prednisone therapy and brief courses of azathioprine and cyclosporine treatment for JDM, serum CPK levels reportedly remained elevated for 7 yr. Subcutaneous calcifications first appeared at age 14 yr on his shoulders, elbows, and knees and progressed despite 1 yr of phosphate-binding antacid therapy [Al(OH)3]. He suffered significant pain and stiffness from the lesions that prevented him from sitting. He could only walk short distances. Hospitalization was necessary on several occasions to treat cutaneous abscesses at calcified sites. Biopsy of a mass near a scapula was interpreted as nodular calcinosis cutis.
At age 16 yr, he began an aggressive course of antiinflammatory therapy including weekly doses of methotrexate, monthly intravenous immunoglobulin, and daily plaquenil, and larger daily doses of Al(OH)3 (7.5 g/day) were prescribed for his calcinosis. Serum CPK levels reportedly normalized, however, the areas of calcinosis progressed. Surgical excision of the larger calcified areas was recommended (but not performed) to enhance his mobility.
During initial MRU evaluation at age 18 yr, our research dietician estimated his daily calcium and phosphorus intake to be 800 mg [recommended daily allowance 1200 mg/day (11)] and 1750 mg [recommended daily allowance 1200 mg/day (11)], respectively. He consumed a great deal of meat products.
His height was 172 cm, weight 61 kg, blood pressure120/78, and pulse
76. He was a slender, Tanner V, pleasant young man in no acute distress
(Fig. 1). Head, eyes, ears, nose, throat,
cardiorespiratory, abdominal, genitourinary, and neurological
examinations were unremarkable. However, diffuse, rock-hard
enlargements of both shoulders extended anteriorly and posteriorly into
the pectoral and infrascapular areas that completely prevented
adduction of his arms. Gluteal areas were similarly enlarged and hard
with extension of masses into both thighs. Circular white, hard,
nodular lesions erupted from the skin over both elbows, tips of the 3rd
and 4th digits of his right hand, knees, and right Achilles tendon.
Left forearm extension was limited to approximately 150 degrees by
elbow calcifications. Flexion, as well as internal and external
rotation of the hips was significantly impaired because of
periarticular calcifications. He walked with a shuffling gait secondary
to limited range of motion at his hips and knees.
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After initial MRU investigation (see below), we recommended a restricted calcium (500 mg) and phosphorus (600 mg) diet, by decreasing dairy product as well as meat intake, and advised that he continue A1(OH)3 therapy. He agreed to a trial of probenecid treatment 6 months afterwards, and followed our instructions to gradually increase the dose from 250 mg po daily to 500 mg po thrice daily over 2 months. Estimated medication compliance was nearly 100%.
Within 3 months of beginning probenecid therapy, the patient noticed less pain while sitting. One month later, he began to feel better. Bumps of ectopic calcification began to disappear 2 months later (shoulders, elbows, and knees). A physician elsewhere prescribed alendronate therapy to prevent bone demineralization 2 months before his second MRU evaluation; however, we stopped the alendronate treatment 3 weeks before this hospitalization for reevaluation.
Inpatient MRU follow-up at age 19 yr (7 months after probenecid was
initiated) demonstrated remarkable physical and radiographic
improvement of his calcifications (Figs. 2A-4B). Concurrent with resolution of the
calcinosis was an improved sense of well-being and a 16.5-kg weight
gain. Range of motion improved in all joints, except internal rotation
of his hips. A large 10-cm diameter, ball-shaped, soft, apparently
fluid-filled pouch with a firm center remained at the medial aspect of
his right arm. His dietary calcium and phosphorus intakes were
estimated to be 450 mg and 1250 mg, respectively.
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Mean values of fasting serum and 24-h urine biochemistries
obtained during inpatient evaluations at the MRU, while we matched his
ad libitum and then modified diet with a constant calcium
intake, are summarized in Table 1.
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Following 7 months of probenecid therapy, serum phosphate was normal, however, serum uric acid remained elevated. Intact PTH levels became measurable in the normal range, and urinary tubular reabsorption of phosphate (TRP) and TmP/GFR decreased.
Radiographic description
Calcifications of JDM have been categorized into: 1) deep linear, 2) deep calcareal, 3) superficial calcareal, and 4) superficial lacy reticular patterns (12). Both superficial and deep calcareal types typically have a coalescent and mottled appearance. Deep linear calcifications traverse fascial/muscle planes.
Skeletal survey at age 18 yr demonstrated normal bone mineral
content with extensive soft tissue calcifications, especially about the
axillary and hip regions (Figs. 2A, 3A
, and 4A
). In his upper
extremities, deep calcareal and deep linear (left more severe than
right) calcifications extended from each axilla to the elbow (Fig. 3A
) with scattered deep calcareal lesions
in his forearms. Nodular calcifications were present at the tips of
digits 3 and 4 of his right hand. Additionally, the left distal
interphalangeal joint of his right 4th digit was obliterated.
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Radiographs at age 19 yr, after 7 months of probenecid therapy,
demonstrated a dramatic reduction of soft tissue calcifications, most
impressive in the axillae and hips (Figs. 2B, 3B
, and 4B
). The bony structures and mineral
content remained normal appearing. Calcifications in the arms and
thighs were also dramatically improved. No new calcifications were
noted.
Renal sonogram (sector array using 3.5 MHZ transducers; Acuson 128 XP, Mountain View, CA) after the probenecid therapy, demonstrated normal-appearing kidneys with the exception of a small cyst in the left lower pole. Despite the resolution of calcinosis universalis, there was no evidence of nephrocalcinosis or of nephrolithiasis.
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Discussion |
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Table 2 summarizes the six additional reports (nine patients) of
improvement of calcinosis during probenecid therapy (3, 13, 14, 15, 16, 17) and two
reports of nonefficacy (18, 19). There is no discussion in these papers
whether calcinosis returned following cessation of successful
probenecid therapy. Mackie (15), Meyers (16), Ansell (17), Sewell and
colleagues (3), and Skuterud and co-workers (13), described improvement
of calcinosis within weeks to months without significant follow-up
or biochemical data. Hudson and Jones (18), commenting on three
additional unreported patients of Dent and Stamp and Ansell (19),
mention no significant improvement of calcinosis despite 1 yr of
probenecid treatment.
Despite the frequency of calcinosis in patients with collagen vascular diseases, trials of probenecid therapy apparently stopped in 1984. The limited studies of warfarin, colchicine, bisphosphonates, and phosphate-binding antacids that have been tried instead have not consistently proven beneficial for calcinosis of JDM (1, 20, 21). Intralesional glucocorticoid injections have been reported to improve cutaneous calcinosis (22, 23).
More recently, efficacy of diltiazem for calcinosis of JDM (24) and other collagen vascular diseases (25), idiopathic calcinosis (26), and intramuscular calcium accumulation in Duchenne muscular dystrophy (27) has been reported. Preliminary studies of diltiazems efficacy in reducing intramuscular calcium in dystrophic hamsters (28) lead Palmieri and co-workers (26) to suggest that intracellular calcium dishomeostasis contributed to ectopic calcium deposition in these animals. Further, they postulated that the calcium channel-blocking activity of diltiazem might diminish excess calcific deposits, enabling macrophages to scavenge the periphery of ectopic calcifications. However, despite diltiazems success, detailed biochemical exploration of these patients has not been forthcoming.
Dent and Stamp (14) were aware of probenecids induction of phosphaturia in patients with hypoparathyroidism, and that this effect was not observed in euparathyroid individuals. Remarkably, our patient repeatedly had subnormal serum levels of intact PTH together with hyperphosphatemia and increased TmP/GFR before probenecid therapy. However, normal PTH values were restored during probenecid and dietary therapy. The reason for the suppressed pretreatment PTH levels in our patient is unclear. Serum total and ionized calcium, magnesium, and 1,25-dihydroxyvitamin D levels were normal, and urine calcium levels were unremarkable in our patient before probenecid therapy, and together with his clinical status gave no indication that this ectopic calcification was spontaneously resolving.
Because of his hyperphosphatemia, we felt it prudent to advise our patient to diminish his seemingly excessive phosphorus intake. Despite the reduction in dietary phosphorus levels (from 17501250 mg daily), his TmP/GFR decreased with the concomitant administration of probenecid. Accordingly, reduction in blood phosphate levels appeared to be the result of the probenecid rather than dietary reduction in phosphorus content (which might be expected to increase TmP/GFR). We believe that renal-mediated decline in our patients blood phosphate levels resulted in reequilibration of complexed mineral phosphate with extracellular inorganic phosphate, thus favoring ectopic mineral dissociation (lowered extracellular calcium-phosphate product). Thus, the sustained phosphaturia lead to a progressive decrease in the mass of ectopic calcifications. We note, however, that normalization of circulating PTH levels would also be expected to correct an elevated TmP/GFR and hyperphosphatemia. Of interest, our patients serum LDH levels gradually decreased into the normal range during probenecid therapy. His serum CPK levels were consistently normal before and during probenecid treatment. Elevated LDH levels may have been a result of ectopic calcification causing muscle damage, rather than reflecting his myopathy. Whether the deposits will return with cessation of probenecid therapy is not known.
Additional detailed studies of the mineral homeostasis of patients with ectopic calcification from various disorders, followed by trials of probenecid treatment (if contraindications do not exist), must be completed to understand probenecids mechanism of action and to fully document probenecids efficacy. Calcinosis universalis can be a devastating complication of JDM, and further investigation and therapeutic trials are important.
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Acknowledgments |
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Footnotes |
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Received April 23, 1997.
Revised June 27, 1997.
Accepted July 14, 1997.
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References |
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