0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
The Cutting Edge |

Response of Dystrophic Calcification to Intravenous Immunoglobulin FREE

Stefan Schanz, MD; Anja Ulmer, MD; Gerhard Fierlbeck, MD
[+] Author Affiliations

Assistant Section Editor: Michael P. Heffernan, MD
Assistant Section Editor: Christie Ammirati, MD

More Author Information
Arch Dermatol. 2008;144(5):585-587. doi:10.1001/archderm.144.5.585.
Text Size: A A A
Published online

REPORT OF A CASE

A 56-year-old woman with an 8-year history of CREST syndrome, a variant of scleroderma, presented with increasing calcium deposits that were causing inflammation and swelling of the index finger of her left hand (Figure 1), as well as Raynaud phenomenon, telangiectasia, and mild sclerosis of her fingers. She had intense pain and extreme morbidity and was severely handicapped in her office job. A barium swallow test revealed moderate esophageal dysmotility, and a computed tomographic scan demonstrated mild pulmonary fibrosis. Spirometry revealed normal values, particularly for carbon monoxide diffusing capacity and inspiratory vital capacity. There was no evidence of pulmonary hypertension, cardiac or renal manifestations, or systemic metabolic abnormalities in calcium regulation. Serologic tests were positive for antinuclear antibodies and anti–Scl-70 antibodies. Long-term treatment with D-penicillamine (30 weeks), warfarin sodium (13 weeks), and extracorporeal shock wave lithotripsy did not result in any improvement in the cutaneous calcifications or inflammation. The plastic surgeons refused to consider a surgical approach because of the risk of protracted and complicated wound healing.

Place holder to copy figure label and caption
Figure 1.

Pretreatment photographs show debilitating swelling of the left index finger as well as large, severely painful calcifications and inflammation (A), particularly involving the left index finger (B).

Graphic Jump Location

THERAPEUTIC CHALLENGE

Dystrophic calcification is known as a condition that is difficult to treat. Various therapies have been tried. Pharmacological approaches include warfarin, colchicine, probenecid, bisphosphonates, and diltiazem, all of which have been used with variable success.1,2 In selected cases, patients may benefit from the surgical removal of larger lesions.2 In cases involving small superficial lesions, treatment with carbon dioxide laser therapy may be helpful.3 Recently, reports of treatment with extracorporeal shock wave lithotripsy have been published.4 However, to date, no reliable treatment has been established, and most treatment efforts have been fruitless and frustrating.

SOLUTION

Years ago, we observed the resolution of large dystrophic calcifications in a patient with dermatomyositis who was treated with intravenous (IV) immunoglobulin. Therefore, we decided to initiate therapy with IV immunoglobulin in this case. According to established treatment regimens in autoimmune diseases,57 we administered IV immunoglobulin at a dosage of 2 g/d in a 4-day protocol once a month. After 2 cycles, the patient's pain and inflammation subsided. After 3 more courses, she was free of symptoms and was able to use her left hand without impairment (Figure 2). Her Rodnan skin score8 improved from 12 points before treatment to 9 points after treatment. The IV immunoglobulin therapy was well tolerated, without adverse effects. Some new lesions began to develop 6 months after the therapy was discontinued.

Place holder to copy figure label and caption
Figure 2.

Posttreatment photographs show a reduction in finger size (A) and an absence of inflammation (B) after 5 series of intravenous immunoglobulin therapy.

Graphic Jump Location

COMMENT

Dystrophic calcification occurs in the presence of normal calcium metabolism, presumably in sites of trauma such as elbows, knees, and fingers. Extrusion of calcium causes extreme inflammation, with pain, morbidity, secondary infection, and ulceration. It is often found in scleroderma, systemic lupus erythematosus, and dermatomyositis, especially in juvenile dermatomyositis. The mechanisms that lead to cutaneous calcification in connective tissue diseases are poorly understood, but tissue damage, hypovascularity, and hypoxia have been suggested to play a role in its development.1 Furthermore, it has been proposed that increased levels of the calcium-binding amino acid and γ-carboxyglutamic acid can promote calcification.9,10 Also, activated macrophages are thought to play a central role in the development of dystrophic calcification.11

Numerous mechanisms have been postulated to explain the effects of IV immunoglobulin therapy. They include passive inhibitory effects such as competition of IgG monomers with autoantibodies in the occupancy of Fc receptors, resulting in a faster clearance of pathogenetic antibodies; blockage of the immune activation by pathogenetic immunocomplexes; and binding of complement factors.12,13 Recent studies focus more intensively on macrophages as targets of IV immunoglobulin therapy. Siragam et al14 and Bruhns et al15 proposed that an interaction of IV immunoglobulin with dendritic cells or sensor macrophages could result in the suppression of effector macrophages. Also, Park-Min et al16 demonstrated that IV immunoglobulin therapy may suppress the expression of the interferon gamma receptor in macrophages and thereby inhibit interferon gamma–mediated macrophage activation. Kaneko et al17 showed that the anti-inflammatory effect of IV immunoglobulin depends on the sialylation of the Fc core polysaccharide, whereas nonsialylated IgG antibodies mediate proinflammatory activities. This leads to the most interesting hypothesis, ie, that the anti-inflammatory effect of IV immunoglobulin is nothing but the manifestation of a physiologic anti-inflammatory response to IgG antibodies produced in times of health.12 Yet we could not find a precise explanation as to how IV immunoglobulin may induce a resolution of calcium deposits. On the other hand, we did not find any evidence for spontaneous resolution of such extensive calcifications. We hypothesize that the impressive effect we saw in our patient was based mainly on anti-inflammatory effects, possibly owing to suppression of activated macrophages.

The clinical use of immunoglobulin for the treatment of immunodeficiencies and autoimmune disorders has increased rapidly in the last decades. Today, IV immunoglobulin is used to treat idiopathic thrombocytopenic purpura, Kawasaki disease, Guillain-Barré syndrome, myasthenia gravis, and other therapy-refractory chronic autoimmune diseases. Dermatomyositis and systemic lupus erythematosus were the first autoimmune diseases with skin involvement to be successfully treated with IV immunoglobulin.

Systemic sclerosis represents an autoimmune disease in which the skin and other organs undergo damage by excessive deposition of collagen and other matrix proteins. In an uncontrolled trial, Levy et al7 reported a decrease in the Rodnan skin score after treatment with IV immunoglobulin. The improvement in the Rodnan skin score in our patient corroborates their experience. However, our patient had CREST syndrome and was mainly impaired by debilitating dystrophic calcinosis that had been refractory to several therapies. Intravenous immunoglobulin as a single agent resulted in a remarkable reduction of the inflammation, tissue damage, and firm masses of the left index finger. This expensive treatment may be warranted to avoid serious complications and functional impairment in selected patients with cutaneous calcifications.

Box Section Ref ID

Submissions

Clinicians, residents, and fellows are invited to submit cases of challenges in management and therapeutics to this section. Cases should follow the established pattern. Manuscripts should be prepared double-spaced with right margins nonjustified. Pages should be numbered consecutively with the title page separated from the text (see Instructions for Authors [http://archderm.ama-assn.org/misc/ifora.dtl] for information about preparation of the title page). Clinical photographs, photomicrographs, and illustrations must be sharply focused and submitted as separate JPG files with each file numbered with the figure number. Material must be accompanied by the required copyright transfer statement (see authorship form [http://archderm.ama-assn.org/misc/auinst_crit.pdf]). Preliminary inquiries regarding submissions for this feature may be submitted to George J. Hruza, MD (ghruza@aol.com). Manuscripts should be submitted via our online manuscript submission and review system (http://manuscripts.archdermatol.com).

ARTICLE INFORMATION

Correspondence: Stefan Schanz, MD, University of Tuebingen, Liebermeisterstrasse 25, Tuebingen 72076, Germany (Stefan.schanz@med.uni-tuebingen.de).

Accepted for Publication: July 16, 2007.

Author Contributions: Drs Schanz and Fierlbeck had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Schanz and Fierlbeck. Acquisition of data: Schanz. Analysis and interpretation of data: Schanz, Ulmer, and Fierlbeck. Drafting of the manuscript: Schanz. Critical revision of the manuscript for important intellectual content: Schanz, Ulmer, and Fierlbeck. Administrative, technical, and material support: Ulmer. Study supervision: Ulmer and Fierlbeck.

Financial Disclosure: None reported.

REFERENCES

Boulman  NSlobodin  GRozenbaum  MRosner  I Calcinosis in rheumatic diseases. Semin Arthritis Rheum 2005;34 (6) 805- 812
PubMed Link to Article
Dutz  J Treatment options for localized scleroderma. Skin Therapy Lett 2000;5 (2) 3- 5
PubMed
Bottomley  WWGoodfield  MJSheehan-Dare  RA Digital calcification in systemic sclerosis: effective treatment with good tissue preservation using the carbon dioxide laser. Br J Dermatol 1996;135 (2) 302- 304
PubMed Link to Article
Sparsa  ALesaux  NKessler  E  et al.  Treatment of cutaneous calcinosis in CREST syndrome by extracorporeal shock wave lithotripsy. J Am Acad Dermatol 2005;53 (5) ((suppl 1)) S263- S265
PubMed Link to Article
Cherin  PHerson  SWechsler  B  et al.  Efficacy of intravenous gammaglobulin therapy in chronic refractory polymyositis and dermatomyositis: an open study with 20 adult patients. Am J Med 1991;91 (2) 162- 168
PubMed Link to Article
Dalakas  MCIlla  IDambrosia  JM  et al.  A controlled trial of high-dose intravenous immune globulin infusions as treatment for dermatomyositis. N Engl J Med 1993;329 (27) 1993- 2000
PubMed Link to Article
Levy  YAmital  HLangevitz  P  et al.  Intravenous immunoglobulin modulates cutaneous involvement and reduces skin fibrosis in systemic sclerosis: an open-label study. Arthritis Rheum 2004;50 (3) 1005- 1007
PubMed Link to Article
Clements  PJLachenbruch  PASeibold  JR  et al.  Skin thickness score in systemic sclerosis: an assessment of interobserver variability in 3 independent studies. J Rheumatol 1993;20 (11) 1892- 1896
PubMed
Berger  RGFeatherstone  GLRaasch  RHMcCartney  WHHadler  NM Treatment of calcinosis universalis with low-dose warfarin. Am J Med 1987;83 (1) 72- 76
PubMed Link to Article
Moore  SEJump  AASmiley  JD Effect of warfarin sodium therapy on excretion of 4-carboxy-L-glutamic acid in scleroderma, dermatomyositis, and myositis ossificans progressiva. Arthritis Rheum 1986;29 (3) 344- 351
PubMed Link to Article
Mukamel  MHorev  GMimouni  M New insight into calcinosis of juvenile dermatomyositis: a study of composition and treatment. J Pediatr 2001;138 (5) 763- 766
PubMed Link to Article
Clynes  R IVIG therapy: interfering with interferon-gamma. Immunity 2007;26 (1) 4- 6
PubMed Link to Article
Ballow  M Mechanisms of action of intravenous immune serum globulin in autoimmune and inflammatory diseases. J Allergy Clin Immunol 1997;100 (2) 151- 157
PubMed Link to Article
Siragam  VCrow  ARBrinc  DSong  SFreedman  JLazarus  AH Intravenous immunoglobulin ameliorates ITP via activating Fc gamma receptors on dendritic cells. Nat Med 2006;12 (6) 688- 692
PubMed Link to Article
Bruhns  PSamuelsson  APollard  JWRavetch  JV Colony-stimulating factor-1–dependent macrophages are responsible for IVIG protection in antibody-induced autoimmune disease. Immunity 2003;18 (4) 573- 581
PubMed Link to Article
Park-Min  KHSerbina  NVYang  W  et al.  FcgammaRIII-dependent inhibition of interferon-gamma responses mediates suppressive effects of intravenous immune globulin. Immunity 2007;26 (1) 67- 78
PubMed Link to Article
Kaneko  YNimmerjahn  FRavetch  JV Anti-inflammatory activity of immunoglobulin G resulting from Fc sialylation. Science 2006;313 (5787) 670- 673
PubMed Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.

Pretreatment photographs show debilitating swelling of the left index finger as well as large, severely painful calcifications and inflammation (A), particularly involving the left index finger (B).

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Posttreatment photographs show a reduction in finger size (A) and an absence of inflammation (B) after 5 series of intravenous immunoglobulin therapy.

Graphic Jump Location

Tables

References

Boulman  NSlobodin  GRozenbaum  MRosner  I Calcinosis in rheumatic diseases. Semin Arthritis Rheum 2005;34 (6) 805- 812
PubMed Link to Article
Dutz  J Treatment options for localized scleroderma. Skin Therapy Lett 2000;5 (2) 3- 5
PubMed
Bottomley  WWGoodfield  MJSheehan-Dare  RA Digital calcification in systemic sclerosis: effective treatment with good tissue preservation using the carbon dioxide laser. Br J Dermatol 1996;135 (2) 302- 304
PubMed Link to Article
Sparsa  ALesaux  NKessler  E  et al.  Treatment of cutaneous calcinosis in CREST syndrome by extracorporeal shock wave lithotripsy. J Am Acad Dermatol 2005;53 (5) ((suppl 1)) S263- S265
PubMed Link to Article
Cherin  PHerson  SWechsler  B  et al.  Efficacy of intravenous gammaglobulin therapy in chronic refractory polymyositis and dermatomyositis: an open study with 20 adult patients. Am J Med 1991;91 (2) 162- 168
PubMed Link to Article
Dalakas  MCIlla  IDambrosia  JM  et al.  A controlled trial of high-dose intravenous immune globulin infusions as treatment for dermatomyositis. N Engl J Med 1993;329 (27) 1993- 2000
PubMed Link to Article
Levy  YAmital  HLangevitz  P  et al.  Intravenous immunoglobulin modulates cutaneous involvement and reduces skin fibrosis in systemic sclerosis: an open-label study. Arthritis Rheum 2004;50 (3) 1005- 1007
PubMed Link to Article
Clements  PJLachenbruch  PASeibold  JR  et al.  Skin thickness score in systemic sclerosis: an assessment of interobserver variability in 3 independent studies. J Rheumatol 1993;20 (11) 1892- 1896
PubMed
Berger  RGFeatherstone  GLRaasch  RHMcCartney  WHHadler  NM Treatment of calcinosis universalis with low-dose warfarin. Am J Med 1987;83 (1) 72- 76
PubMed Link to Article
Moore  SEJump  AASmiley  JD Effect of warfarin sodium therapy on excretion of 4-carboxy-L-glutamic acid in scleroderma, dermatomyositis, and myositis ossificans progressiva. Arthritis Rheum 1986;29 (3) 344- 351
PubMed Link to Article
Mukamel  MHorev  GMimouni  M New insight into calcinosis of juvenile dermatomyositis: a study of composition and treatment. J Pediatr 2001;138 (5) 763- 766
PubMed Link to Article
Clynes  R IVIG therapy: interfering with interferon-gamma. Immunity 2007;26 (1) 4- 6
PubMed Link to Article
Ballow  M Mechanisms of action of intravenous immune serum globulin in autoimmune and inflammatory diseases. J Allergy Clin Immunol 1997;100 (2) 151- 157
PubMed Link to Article
Siragam  VCrow  ARBrinc  DSong  SFreedman  JLazarus  AH Intravenous immunoglobulin ameliorates ITP via activating Fc gamma receptors on dendritic cells. Nat Med 2006;12 (6) 688- 692
PubMed Link to Article
Bruhns  PSamuelsson  APollard  JWRavetch  JV Colony-stimulating factor-1–dependent macrophages are responsible for IVIG protection in antibody-induced autoimmune disease. Immunity 2003;18 (4) 573- 581
PubMed Link to Article
Park-Min  KHSerbina  NVYang  W  et al.  FcgammaRIII-dependent inhibition of interferon-gamma responses mediates suppressive effects of intravenous immune globulin. Immunity 2007;26 (1) 67- 78
PubMed Link to Article
Kaneko  YNimmerjahn  FRavetch  JV Anti-inflammatory activity of immunoglobulin G resulting from Fc sialylation. Science 2006;313 (5787) 670- 673
PubMed Link to Article

Correspondence

CME
Also Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
Please click the checkbox indicating that you have read the full article in order to submit your answers.
Your answers have been saved for later.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.

Multimedia

Some tools below are only available to our subscribers or users with an online account.

1,636 Views
14 Citations
×

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Collections
PubMed Articles
Jobs