Calcinosis Universalis Complicating Juvenile Dermatomyositis: Resolution During Probenecid Therapy1

Mark C. Eddy, Rattana Leelawattana, William H. McAlister and Michael P. Whyte

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 Children’s Hospital; St. Louis, Missouri 63110; Mallinckrodt Institute of Radiology (W.H.McA.), Washington University School of Medicine, St. Louis Children’s 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.


    Introduction
 Top
 Introduction
 Case Report
 Discussion
 References
 
JUVENILE dermatomyositis (JDM) is a multisystem disease characterized by acute and chronic nonsuppurative inflammation of skin and striated muscle (1). Ectopic calcification has been reported in 25–50% of JDM patients (1). This complication can cause significant debility (2) with severe pain, skin ulceration, muscle atrophy, joint contracture, and acroosteolysis (3). Spontaneous regression of the aberrant mineralization over years has been reported in 14 cases but not quantified (1, 2, 3, 4, 5). Although aggressive medical management with immunosuppressive therapy may prevent this problem (6), there is no established medical treatment (1). Surgical excision can be used for extensive areas of calcification (7, 8).

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.


    Case Report
 Top
 Introduction
 Case Report
 Discussion
 References
 
History and physical findings

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, 30–220 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. 1Go). 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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Figure 1. Patient, age 18 yr, before probenecid therapy showing arm contractures caused by ectopic calcifications.

 
Probenecid treatment

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. 2AGo-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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Figure 2. Left shoulder. A, Age 18 yr, extensive deep calcareal deposits are seen about the shoulder (arrows) extending into the arm. B, Age 19 yr, soft tissue calcifications have significantly diminished.

 
Laboratory

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 1Go.


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Table 1. Biochemical parameters of mineral homeostasis before and during probenecid theapy

 
Initial biochemical investigations revealed an elevated serum phosphate, uric acid, lactate dehydrogenase (LDH) and maximum tubular phosphate reabsorption/glomerular filtration rate (TmP/GFR) with suppressed serum levels of intact PTH (intact PTH RIA-immunoradiometric assay, Nichols Diagnostics, San Juan Capistrano, CA). Of note, serum total and ionized calcium (Vitros Chemical System, Division of Johnson & Johnson Clinical Diagnostics, Rochester, NY), 1,25-dihydroxy vitamin D, creatinine, alkaline phosphatase, magnesium, and CPK were normal before (and during) probenecid therapy.

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. 2AGo, 3AGo, and 4AGo). In his upper extremities, deep calcareal and deep linear (left more severe than right) calcifications extended from each axilla to the elbow (Fig. 3AGo) 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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Figure 3. AP pelvis. A, Age 18 yr, extensive deep calcareal deposits are seen about each hip and extending into the thighs. B, Age 19 yr, after a 7-month course of dietary modification, probenecid treatment, and continued antacid administration a dramatic decrease in soft tissue calcifications was demonstated with normal bone mineral content. Arrow, Residual calcified area.

 


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Figure 4. Right knee. A, Age 18 yr, large deep linear calcifications seen at the distal thigh with extension over the knee. B, Age 19 yr, minimal residual calcifications remain with normal bone mineral content.

 
At each hip, a mixed pattern of deep linear and deep calcareal calcifications extended into his thighs. In his lower legs, a modest, lacy, reticular, subcutaneous pattern of calcification was noted in the left midcalf with scattered deep linear calcifications.

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. 2BGo, 3BGo, and 4BGo). 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.


    Discussion
 Top
 Introduction
 Case Report
 Discussion
 References
 
Improvement in ectopic calcification during probenecid therapy was last described in 1981 (13). Other than the study of Dent and Stamp in 1972 (14), previous reports have been without metabolic testing that would elucidate any therapeutic efficacy (3, 13, 14, 15, 16, 17). All of these patients had some form of connective tissue disease (Table 2Go). Ours is the seventh description (10 cases) of a favorable response to probenecid, but the first with detailed pre- and posttherapy investigation.


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Table 2. Probenecid therapy for ectopic calcification

 
In 1972, Dent and Stamp (14) described a 23 yr-old woman with Still’s disease whose phalangeal calcifications improved following 3 yr of 2 g probenecid daily. Studies of her mineral homeostasis demonstrated a decline of serum phosphate and urate levels during treatment. Renal phosphate handling was reportedly normal throughout her course of probenecid therapy; however, pretreatment investigation was not performed. Of interest, our patient did not show significant reduction of his serum urate levels; however, the magnitude of the decline of serum phosphate level was similar (1 mg/dL) to that documented in Dent and Stamp’s report.

Table 2Go 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 diltiazem’s 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 diltiazem’s success, detailed biochemical exploration of these patients has not been forthcoming.

Dent and Stamp (14) were aware of probenecid’s 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 1750–1250 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 patient’s 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 patient’s 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 probenecid’s mechanism of action and to fully document probenecid’s efficacy. Calcinosis universalis can be a devastating complication of JDM, and further investigation and therapeutic trials are important.


    Acknowledgments
 
We are grateful to the Dietary, Laboratory, and Nursing Staff of the MRU, Shriners Hospitals for Children, for making this study possible. Darlene Harmon provided expert secretarial help. We would like to thank Dr. Ernesto Levy for his assistance in managing this patient’s connective tissue disorder.


    Footnotes
 
1 This work was supported by Grant 15958 from the Shriners Hospitals for Children. Presented in part at the 19th annual scientific meeting of The American Society for Bone and Mineral Research, September 10–14, 1997, Cincinnati, Ohio [J Bone Miner Res 12:(Suppl 1) S-393, 1997]. Back

Received April 23, 1997.

Revised June 27, 1997.

Accepted July 14, 1997.


    References
 Top
 Introduction
 Case Report
 Discussion
 References
 

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