Dr' Jonathan Stein

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Treatment of Calcinosis
Dr. Jonathan Stein July 19, 2005
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Outline

• Definition of calcinosis
• Epidemiology
• Clinical features
• Pathophysiology
• Treatment

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Mrs. M

• 32F, SLE dx in 1994
• Polyarthritis hands, knees bilaterally,
  concordant anti- DS DNA
• Complications
• DVT Oct 1994, anticardiolipin antibody
• Myositis Nov 1994
• Small bowel vasculitis 1995
• Phlebitis 1996
• Calcinosis right leg 1996

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Mrs. M

• Imuran 75, MTX 12.5, coumadin, prednisone 7.5
• 1999-2005 multiple treatments for cellulitis
• Sick kids 2001 recommended diltiazem 120 and
  alendronate
• Calcinosis remained, but no skin breakdown for 3
  yrs
• Cellulitis in April 2004
• Non resolving ulcers Dec. 2004, seen by ID,
  plastics
• Multiple rounds of IV antibiotics
• Seen in June 2005, new erythmea, purulent
  discharge

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What is Calcinosis?

• Deposition of hydroxyapatite Ca PO4 in soft
  tissues
• Normal vs. abnormal Ca PO4 metabolism
• Calcinosis circumscripta few deposits
• Calcinosis universalis generalized deposits in
  the skin, subcut. tissue, muscles

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Classification of Calcinosis
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Who Develops Dystrophic Calcinosis?

• Adults
• - SLE, scleroderma overlap syndrome
• Children
• - dermatomyositis

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Epidemiology of Calcinosis

• Scleroderma 25 of patients in 10 years
• limited cutaneous SSc
• anti-centromere antibody
• Overlap syndrome no published data

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Epidemiology of Calcinosis

• Dermatomyositis
• 40 of JDM, 20 of adults
• duration of disease 3.8 years prior to the
  diagnosis of calcinosis
• SLE
• women with severe/long standing disease

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Morbidity Associated with Calcinosis

• Cosmetic
• Pain inflammation and laceration
• Secondary infection
• Limited function

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Calcinosis in Scleroderma

• In the elbow
• over olecrenon
• In the finger
• well-defined deposit in fingertip tuft
• diffuse deposit, entire finger length

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Calcinosis in Dermatomyositis

• Small scattered nodules on extremities
• Deep muscular deposits
• Diffuse deposits along myofascial planes
• Generalized superficial calcification forming
  exoskeleton  

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Calcinosis Universalis
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Calcinosis in SLE

• Extremities and buttock
• Usually limited within dermis and subcutaneous
  fat tissue

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Calcinosis in SLE
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Mitochondria Nidus of Calcification
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Pathophysiology

• Key concepts
• tissue injury alters mitochondria cell membrane
  permeability
• increased mitochondria uptake of Ca/PO4
• high levels of gamma glutamic acid found in areas
  of calcinosis

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The Chronicle of Medical Therapy for Calcinosis
EDTA - 1955
Etidronate - 1971
Steroids - 1978
Colchicine - 1986

• Warfarin - 1987

Diltiazem - 1993
Minocycline - 2003
? - 2005
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Chronic Tissue Inflammation
Structural Defects
Macrophage activity
hypovascularity
Age related changes
hypoxemia
Tissue Damage
Increased CBAA
Increased apoptosis
Increased Ca into cell
Decreased renal Phos clearance
Muscle alteration/ dysfunction
Diltiazem, Minocycline
Probenecid
Colchicine
Laser Surgical excision
Warfarin
Calcinosis
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Disodium Etidronate

• 1) Cram R, et al. Diphosphonate treatment of
  calcinosis universalis. NEJM, 1971.
• 2) Metzger A, et al. Failure of disodium
  etidronate in calcinosis due to dermatomyositis
  and scleroderma. NEJM, 1974.

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WarfarinNot Just a Blood Thinner

• G-carboxyglutamic acid (GCA) high in areas of
  calcinosis
• GCA binds large amounts of calcium
• Carboxylation of glutamine leads to formation of
  GCA is coupled with vitamin K cycle
• Warfarin inhibits vitamin K cycle

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Warfarin Success

• Berger et al. Am J Med. 1987. Treatment of
  calcinosis universalis with low-dose warfarin.
• Double blind placebo, 8 patients, 18 months, 1mg
  warfarin
• Measures clinical, labs, radiographic, bone scan
  (t0, 6m, 12m, 18m)

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Berger Classification for Grading Calcinosis

• 1 x-ray evidence, not palpable
• 2 multiple small areas of palpable deposits, no
  tumoral calcification
• 3 widespread, extensive deposition, no tumoral
  calcification
• 4 widespread, with tumoral areas and/or skin
  breakdown

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Warfarin

• Results
• 1 patient had reduction in size of lesions
• 2 patients had improvement in bone scan
• No improvement in patients who had 3 or 4 grade
  calcinosis

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Warfarin - Failure

• Lassoued K, et al. Am J Med. 1988. Failure of
  warfarin in treatment of calcinosis universalis.
• Cukierman T, et al. Ann Rheum Dis. 2004. Low dose
  warfarin treatment for calcinosis in patients
  with systemic sclerosis.

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Warfarin - Conclusions

• May be beneficial if duration of calcinosis is
  short and small lesions
• Not effective in long standing disease, or
  extensive disease

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Diltiazem

• Theory
• Diltiazem decreases the intracellular
  accumulation of Ca secondary to alteration of
  the cellular membrane

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Diltiazem

• Vayssairat M, et al. Ann Rheum Dis. 1998.
  Clinical significance of subcutaneous calcinosis
  in patients with systemic sclerosis. Does
  diltiazem induce its regression?
• Retrospective study, n 47
• 23 treated with diltiazem, 180mg/d, 12 with
  serial hand radiographs

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Role of Diltiazem - Limited

• Findings
• Of 12 treated with Diltiazem who had serial
  radiographs
• 3 slight regression, 3 worsening condition, 6
  unchanged
• Conclusion Diltiazem has limited role
• Limitations under dosage

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Minocycline

• Robertson L. et al. Ann Rheum Dis. 2003.
• Treatment of cutaneous calcinosis in limited
  systemic sclerosis with minocycline
• Open label study, 50 or 100mg
• Clinical and radiograph follow up
• 9 patients, limited scleroderma, mean disease of
  11.9 years
• Length of treatment 3.5 years

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Minocycline

• 8 had reduction in ulceration and inflammation
• Only 1 had reduction in size on x-ray
• Deposits turned blue/black colour
• Limitations extent of calcinosis?

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From a Surgical Opinion

• Cosmetic concern, painful mass, recurrent
  infection, ulceration, functional impairment
• Options
• CO2 laser therapy
• Excision

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Carbon Dioxide Laser

• Bottomley W. Br J Dermatol 1996.
• Digital calcification in systemic sclerosis
  effective treatment with good tissue preservation
  using the carbon dioxide laser.
• 6 females, systemic sclerosis, digital
  calcification
• Mean disease activity 7 years, calcinosis
  minimum 6 months
• Total number of digital calcinoses treated 21

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Carbon Dioxide Laser

• Results
• In total, 3 patients good response (pain free), 2
  moderate response, 1 partial relief of pain
• Healing took 4-10 weeks
• Post op infection in 2 patients

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Surgical Excision

• Case studies small localized lesions good
  results, no reoccurrence
• Diffuse lesions debulking procedure needed,
  reoccurrence

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Surgical Excision

• Gilbart M. J Hand Surg. 2004. Surgery of the
  hand in severe systemic sclerosis.
• 10 patients, 4 had calcinosis
• Treated with debulking, via small stab incision
  with a high-speed dental burr

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Surgical Excision

• 1 patient complete relief of tenderness
• Substantial calcinosis remained in 2 patients
• 1 patient required subsequent amputation of
  fingertip following calcinosis removal

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Acetic Acid Iontophoresis

• Shetty S. Rheumatology. 2005.
• A pilot study of acetic acid iontophoresis and
  ultrasound in the treatment of systemic
  sclerosis-related calcinosis.

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Risks vs. Benefits
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Summary

• Calcinosis is not uncommon
• Occurs in long standing severe disease
• Significant associated morbidity
• Medical and surgical treatment benefit shown in
  small, localized nodules
• Risks vs. benefits

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Thank You !