Treatment of Calcinosis Dr. Jonathan Stein

Treatment of Calcinosis Dr. Jonathan Stein July 19, 2005 Outline      Definition of calcinosis Epidemiology Clinical features Pathophysiology Treatment 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   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  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 Classification of Calcinosis Type of Calcification Serum Ca+/ PO4Normal Tissue status Injured Examples Dystrophic Scleroderma, DM, SLE Metastatic Calciphylaxis Idiopathic Elevated Elevated Normal Normal Normal or injured Normal Hyperparathyroidism Chronic renal failure Tumoral calcification Who Develops Dystrophic Calcinosis?  Adults: - SLE, scleroderma & overlap syndrome  Children: - dermatomyositis Epidemiology of Calcinosis  Scleroderma: 25% of patients in 10 years cutaneous SSc  anti-centromere antibody  Overlap  limited syndrome: no published data 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 Morbidity Associated with Calcinosis     Cosmetic Pain – inflammation and laceration Secondary infection Limited function Calcinosis in Scleroderma  In the elbow:  over olecrenon  In the finger:   well-defined deposit in fingertip tuft diffuse deposit, entire finger length  Calcinosis in Dermatomyositis  Small scattered nodules on extremities   Deep muscular deposits Diffuse deposits along myofascial planes Generalized superficial calcification forming exoskeleton  Calcinosis Universalis Calcinosis in SLE   Extremities and buttock Usually limited within dermis and subcutaneous fat tissue Calcinosis in SLE Mitochondria: Nidus of Calcification Pathophysiology Key concepts: i. tissue injury alters mitochondria cell membrane permeability increased mitochondria uptake of Ca+/PO4 areas of calcinosis ii. iii. high levels of gamma glutamic acid found in The Chronicle of Medical Therapy for Calcinosis EDTA - 1955 Etidronate - 1971 Steroids - 1978 Colchicine - 1986 *Warfarin - 1987 *Diltiazem - 1993 *Minocycline - 2003 ? - 2005 Chronic Tissue Inflammation Macrophage activity Tissue Damage Increased CBAA Increased apoptosis Increased Ca into cell Decreased renal Phos clearance Muscle alteration/ dysfunction Colchicine Warfarin Diltiazem, Minocycline Calcinosis Probenecid Laser Surgical excision 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. Warfarin Not 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    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 (t=0, 6m, 12m, 18m)  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   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   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.  Warfarin - Conclusions  May be beneficial if duration of calcinosis is short and small lesions Not effective in long standing disease, or extensive disease  Diltiazem Theory:  Diltiazem decreases the intracellular accumulation of Ca+ secondary to alteration of the cellular membrane 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   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 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 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?    From a Surgical Opinion  Cosmetic concern, painful mass, recurrent infection, ulceration, functional impairment  Options: i) ii) CO2 laser therapy Excision 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  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 Surgical Excision  Case studies: small localized lesions – good results, no reoccurrence Diffuse lesions – debulking procedure needed, reoccurrence  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   Surgical Excision   1 patient complete relief of tenderness Substantial calcinosis remained in 2 patients 1 patient required subsequent amputation of fingertip following calcinosis removal  Acetic Acid Iontophoresis  Shetty S. Rheumatology. 2005. A pilot study of acetic acid iontophoresis and ultrasound in the treatment of systemic sclerosis-related calcinosis. Risks vs. Benefits Risk Warfarin Diltiazem Bleeding Blood pressure Benefit <1 cm, <6 m duration Regression in small localized lesions Decrease ulceration Cosmetic, no bleeding Complete eradication Minocycline Skin darkening CO2 laser Excision Multiple treatments Infection, bleeding, damage to deep tissues 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  Thank You !