Scleromyxedema: A multicenter studyof characteristics, comorbidities, course, and therapy

in 30 patients

Franco Rongioletti, MD,a Giulia Merlo, MD,a Elisa Cinotti, MD,a Valentina Fausti, MD,a

Emanuele Cozzani, MD,a Bernard Cribier, MD,b Dieter Metze, MD,c Eduardo Calonje, MD,d

Jean Kanitakis, MD,e Werner Kempf, MD,f Catherine M. Stefanato, MD,d Eduardo Marinho, MD,g

and Aurora Parodi, MDa

Genoa, Italy; Strasbourg, Lyon, and Paris, France; M€unster, Germany; London, United Kingdom; and

Z€urich, Switzerland

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66

Background: Scleromyxedema is associated with a monoclonal gammopathy and other comorbidities. Itsprognostic and therapeutic features are poorly documented because most reports deal with single cases orsmall series.

Objective: We sought to describe the characteristics of patients with scleromyxedema regardingdemographics, clinical characteristics, comorbidities, therapeutic interventions, and course.

Methods: We conducted a retrospective and prospective multicenter study.

Results: We identified 30 patients with scleromyxedema (17 men and 13 women). The mean age atdiagnosis was 59 years. The mean delay between disease onset and diagnosis was 9 months. Monoclonalgammopathy was detected in 27 patients. Extracutaneous manifestations were present in 19 patientsincluding neurologic (30%), rheumatologic (23.3%), and cardiac (20%) manifestations. Two patientsdeveloped hematologic malignancies. The most common therapies included oral steroids and intravenousimmunoglobulins. Although corticosteroids were ineffective, intravenous immunoglobulins (alone or incombination with other drugs) induced complete remission in 4 and partial remission in 9 patients with amean treatment duration of 2 years. In all, 21 patients were followed up for a mean period of 33.5 months,at which time 16 patients were alive, 12 with and 4 without skin disease. Five patients died: 2 withdermatoneuro syndrome and 1 each with myeloid leukemia, Hodgkin lymphoma, and myocardialinsufficiency.

Limitations: This is mainly a retrospective study.

Conclusions: Our study confirms that scleromyxedema is a chronic and unpredictable disease with severesystemic manifestations leading to a guarded prognosis. There is no specific definitive treatment. Our datasupport the contention that intravenous immunoglobulin is a relatively effective and safe treatment. Theresponse is not permanent and maintenance infusions are required. ( J Am Acad Dermatol 2013;69:66-72.)

Keywords: dermatoneuro syndrome; intravenous immunoglobulin; monoclonal gammopathy; mucinoses;scleromyxedema.

the Section of Dermatology, Dipartimento di Scienze della

lute (DISSAL), University of Genoa and S. Martino University

ospitala; Department of Dermatology, Universit�e Louis Pas-

ur, Hopitaux Universitaires, Strasbourgb; Department of Der-

atology, University Hospital, M€unsterc; St John’s Institute of

ermatology, St Thomas’ Hospital, Londond; Department of

ermatology, Edouard Herriot Hospital Group, Lyone; Kempf

d Pfaltz, Histological Diagnostics, and Department of Der-

atology, University Hospital Z€urichf; and Service de Derma-

logie et Anatomie Pathologique de l’Hopital Bichat, Paris.g

Funding sources: None.

Conflicts of interest: None declared.

Accepted for publication January 11, 2013.

Reprint requests: Franco Rongioletti, MD, Clinica Dermatologica,

Universit�a di Genova, Viale Benedetto XV, 7, 16132 Genova,

Italy. E-mail: franco.rongioletti@unige.it.

Published online February 28, 2013.

0190-9622/$36.00

� 2013 by the American Academy of Dermatology, Inc.

http://dx.doi.org/10.1016/j.jaad.2013.01.007

J AM ACAD DERMATOL

VOLUME 69, NUMBER 1Rongioletti et al 67

Scleromyxedema, the generalized papular andsclerodermoid form of lichen myxedematosus, isa fairly uncommon disease associated with mon-oclonal gammopathy and systemic manifesta-tions.1,2 There are limited data regarding itscourse and prognosis. No consensus on the op-timal therapy of this potentially fatal disease

CAPSULE SUMMARY

d Scleromyxedema is a chronic andunpredictable disease associated withmonoclonal gammopathy and severesystemic implications includingneurologic, hematologic, and cardiologicinvolvement leading to a guardedprognosis.

d There is no specific definitive treatmentand the therapeutic response variesamong different patients.

d Our data support the contention thatintravenous immunoglobulin is arelatively effective and safe treatment forboth cutaneous and extracutaneousmanifestations of scleromyxedema,although the therapeutic response is notpermanent.

exists, because of itsrarity and the limited num-ber of cases, the lackof randomized, controlledtrials, and poorly under-stood pathogenesis. Theaim of our study is to de-scribe the characteristicsof patients with scleromyx-edema presenting to 6medical centers, in termsof demographics, clinicalcharacteristics, comorbid-ities, therapeutic interven-tions and course.

METHODSAll patients seen from

January 1, 2000, to April 1,2012, and given a diagnosisof scleromyxedema at theparticipating centers wereevaluated retrospectively by

chart review and prospectively. The diagnosis ofscleromyxedema was made on the basis of thefollowing criteria: (1) a generalized papular andsclerodermoid eruption; (2) microscopic evidenceof mucin deposition, fibroblast proliferation, andfibrosis; (3) detection of monoclonal gammopathy;and (4) absence of a concomitant thyroid disorder.1

If monoclonal gammopathy was lacking at the timeof diagnosis, the case was also included, but wasconsidered atypical. Data collected from all theparticipating centers included demographics, his-tory, clinical characteristics, laboratory examina-tions, systemic associations, treatment, response,follow-up, and outcome. Treatment data includeddocumentation of therapies used for each patient,including dosage of the medication, number ofcycles, and side effects, as available. The clinicalresponse was evaluated according the followingparameters: (1) flattening of the papules; (2) soften-ing of skin induration; (3) reduction of skin thick-ness; (4) improvement of joint mobility; (5)improvement of mouth opening; and (6) improve-ment of systemic symptoms. Partial response wasdefined as decrease in skin changes and improve-ment in systemic symptoms, and complete response

as disappearance of symptoms and no detectableskin findings on examination.

RESULTSA total of 30 patients meeting our clinicopatho-

logic criteria for scleromyxedema were included inthis study. In all, 27 patients fulfilled all 4 criteria for

diagnosing scleromyxedemaand 3 were classified as atyp-ical because they lackedmonoclonal gammopathy.There were 17 men and 13women. The mean age was59 years (range, 34-86). Themean duration of the skindisease at diagnosis was 9months (range, 1-60).History was not contributoryfor most of them, except for 4patients who presented withthe following diseases:Kaposi sarcoma (classictype), Raynaud phenome-non, rheumatoid arthritis,and tuberculosis. Moreover,a female patient had under-gone mammoplasty with sil-icone breast implants andanother had several sessionsof esthetic microimplants

(including hyaluronic acid) 9 years and 8months, respectively, before the diagnosis ofscleromyxedema.

The characteristic skin findings were those of ageneralized sclerodermoid eruption studded withmultiple, firm papules of 1 to 3 mm in diameterinvolving the face (Fig 1), trunk, and all limbs (Fig 2)in 23 patients. In 5 patients the lower limbs were notaffected whereas the face was spared in 2 men.Edema and erythemawere often present. Six patientsexhibited a red-brown discoloration of the involvedskin. Seven patients reported pruritus and 1 reportedpain and dysesthesia; 12 patients exhibited a‘‘doughnut sign,’’ ie, a central depression surroundedby an elevated rim on the extended proximal inter-phalangeal joint. Involvement of the ears with pap-ular thickening and deep furrows on the glabellawere a constant finding in all patients, producing aleonine facies in 6 of them (Figs 1 and 3). Fourpatients exhibited features more similar to sclero-derma (sclerodermoid face). The deep furrowingwas also typically evident on the back and may becalled ‘‘Shar-Pei sign’’ because of its resemblance tothe dog of that name (Fig 4). Reduced articularmobility and difficulty in opening the mouth were

Fig 2. Scleromyxedema. Involvement of hand, which isstudded with multiple, firm, closely spaced papules.

Fig 3. Scleromyxedema. Involvement of ear with thick-ening of skin and papules.

Fig 4. Scleromyxedema. Deep furrowing was also typi-cally evident on back and may be called ‘‘Shar-Pei sign’’.

Fig 1. Scleromyxedema. Typical involvement of face withdeep furrows on glabella and confluent papules on chinproducing leonine facies.

Table I. Extracutaneous manifestations in 30patients with scleromyxedema

Neurologic involvement 9 (30%)

Dermatoneuro syndrome (leading tocoma in 3)

4

Alzheimer disease 1Sensitive and/or motor neuropathy(2 carpal tunnel syndrome)

4

Joint involvement 7 (23.3%)Arthralgias (with or without arthritis) 7

Cardiac involvement 6 (20%)Myocardial ischemia 3Congestive cardiomyopathy 2Specific inflammatory cardiomyopathywith mucin deposition (biopsy) leadingto death

1

Muscle involvement 3Myositis 2Fibromyalgia 1

Respiratory involvement 2Lung fibrosis 1Lung fibrosis with perivascular mucin(biopsy)

1

Hematologic involvement 2Hodgkin lymphoma 1Myelodysplastic syndrome leading tomyeloid leukemia

1

Gastrointestinal involvement 1Reduced esophageal motility 1

Ocular involvement 1Bilateral macular edema 1

Miscellaneous 2Raynaud phenomenon 1Sj€ogren syndrome 1

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JULY 201368 Rongioletti et al

the most frequent symptoms associated with skininvolvement.

The monoclonal spike was IgG l chain in 18patients and IgG k in 4 patients. In 5 patients the typeof paraproteinwas not specified.Additional laboratoryexaminations were noncontributory in most patients.

Extracutaneous manifestations were present in 19patients (Table I).

Information on therapy was available in 25 of 30patients. Different therapeutic regimens were used(Table II). Thirteen patients received high-doseintravenous immunoglobulins (IVIG) both as first(in 6 patients) and as second to fifth line of treatment,usually administered at the dose of 2 g/kg/mo. IVIG

were combined once with oral steroids and oncewith lenalidomide. The duration of treatment rangedfrom 2 to 84months (mean, 22). Four patients (3 withIVIG alone and 1 in association with lenalidomide)

Table II. Treatment modalities in 25 patients with scleromyxedema

Treatments Patients

Complete

response

Partial

response Failure

Tried 1: 14IVIG alone 3 3Steroids alone (PS/dexamethasone) 2Thalidomide 1Acitretin 1Melphalan 1Mycophenolate mofetil 1PS 1 thalidomide 1PS 1 hydroxychloroquine 1

Tried 2: 3PS, followed by IVIG 2*Hydroxychloroquine, followed by phototherapy 1

Tried 3: 5PSL, followed by photopheresis, followed by IVIG 1*MTX, followed by PS, followed by IVIG 1*Phototherapy, followed by radiotherapy, followed by isotretinoin 1Chloroquine, followed by etretinate, followed by interferon alfa-2b 1Melphalan 1 PS, followed by photopheresis 1 PS 1 MTX, followed byradiotherapy

1

Tried 4: 2Hydroxychloroquine, followed by PS, followed by thalidomide, followedby IVIG 1 lenalidomide

1y

Thalidomide, followed by bath PUVA, followed by photopheresis, followedby PSL 1 IVIG

1z

Tried 5: 1Cyclosporine, followed by azathioprine, followed by cyclophosphamide, followedby MTX 1 PS, followed by IVIG

1*

IVIG, Intravenous immunoglobulins; MTX, methotrexate; PS, prednisone; PSL, prednisolone; PUVA, psoralen plus ultraviolet A.

*Caused by IVIG.yCaused by IVIG 1 lenalidomide.zCaused by IVIG 1 steroids.

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VOLUME 69, NUMBER 1Rongioletti et al 69

achieved complete clinical remission. Ultrasoundskin examination confirmed the clinical response in2 patients with reduction of dermal thickness. Apartial significant remission was seen in 9 patientswith general improvement but focal persistence ofareas of papular induration. The improvement inskin tightness and thickness usually began after thefirst or second cycle of IVIG. Extracutaneous mani-festations that improved included arthralgias in 2patients. The treatment modestly reduced the para-protein levels in only 1 patient. There were nosubstantial side effects leading to discontinuation ofIVIG therapy except in 1 case in which the therapywas stopped because of myocardial ischemia.

Systemic steroids alone were given to 2 patientswhereas systemic steroids in associationwithdifferentregimen treatments such asmelphalan,methotrexate,thalidomide, hydroxychloroquine, cyclophospha-mide, bortezomib, and cycles of photopheresis wereadministered to 11 patients. The results were usuallyunsatisfactory because only 4 patients had a partial

response with prednisone (dosage 25-75 mg) associ-ated, respectively,with IVIG (2patients), thalidomide,and hydroxychloroquine. The association of methyl-prednisolone (1 g/d for 3 days) followed by cyclo-phosphamide (200 mg/d for 7 days) and 11 cycles ofplasmapheresis induced a complete remission asemergency treatment in a patient who developedcoma in the setting of dermatoneuro syndrome.

Alternative therapies alone that offered partialbenefit in single cases of our series included: thalid-omide (100 mg/d) that, however, was totally inef-fective in another one and acitretin (1 mg/kg/d) thatwas discontinued because of side effects. Melphalanalone induced significant reduction of paraproteinlevels from 18.7 to 4.7 g/L in 1 patient but withoutclinical improvement.

Twenty one patients were available for follow-upevaluation. The mean follow-up time was 33.5months (range, 2 months-11 years). At end offollow-up, 16 patients were alive, 12 with and 4without detectable skin disease. Five patients died:

Fig 5. Histopathology of scleromyxedema with typicaltriad of mucin, fibroblast proliferation, and fibrosis.

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JULY 201370 Rongioletti et al

1 each of myeloid leukemia (11 years after diagnosisof scleromyxedema), Hodgkin lymphoma (22months after diagnosis of skin disease), myocardialinsufficiency related to biopsy-proven endocardialmucin deposition, and 2 of coma in the setting ofdermatoneuro syndrome.

DISCUSSIONMost information about scleromyxedema has

been retrieved from anecdotal or single case reports.The largest series on scleromyxedema comparablewith ours, published in 1995,3 included 26 patients.This series was an update to the Mayo Clinic medicalrecords including a number of patients who hadbeen previously reported. Only small collections ofpublished cases are further available for comparisonincluding another retrospective series of 10 patientsfrom the Johns Hopkins University4 and a retrospec-tive French study of 8 patients.5 Our study, which isone of the largest scleromyxedema case series todate, confirms the previously described features ofthe classic scleromyxedema patient profile, includ-ing no significant gender predominance, main in-volvement of adults in their fifties or sixties,prevalence of monoclonal gammopathy of the Ig ltype, and frequent association with various comor-bidities (70%). In fact, the Mayo Clinic study reportedextracutaneous manifestations in 77% of patients.Extracutaneous symptoms in our series were mainlyneurologic (30%), rheumatologic (25%), and cardiac(22%) ones. Our findings differ from the results ofboth the Mayo Clinic and the John Hopkins series,where gastrointestinal and pulmonary involvementswere the most common systemic manifestations.This may reflect that the disease is extremely unpre-dictable. In the latter study, however, a high per-centage of musculoskeletal symptoms (9 of 10patients) and cardiovascular involvement (6 of 10patients) similar to our series was also found.Peripheral neuropathy was the most frequent(50%) extracutaneous involvement in the Frenchseries of 8 patients.

The mean time from primary symptoms to diag-nosis was relatively short (10 months) comparedwith the previous data of 36 months3 or 41.6months.4 This could be related to the more precisedefinition of the diagnostic criteria and the increasedawareness of the disease as a result of publicationson scleromyxedema that appeared in recent years. In4 patients the delay was also a result of a previoushistopathological diagnosis of interstitial granulomaannulare because of larger numbers of CD681

macrophages in addition to the classic microscopictriad of mucin, fibroblast proliferation, and fibrosis(Fig 5).6

There is no evidence to support a specific treat-ment for scleromyxedema. In the past, monthlycourses of melphalan were often the therapy ofchoice, targeting the plasma-cell dyscrasia. Thisalkylating agent can result in some clinical improve-ment, but it has also been implicated in 30% of thedeaths secondary to its induction of hematologicmalignancies and septic complications.3

The most commonly used therapies in our pa-tients were IVIG and systemic steroids. IVIG therapyproved to be effective as first-line therapy both alonein 3 patients and in conjunction with lenalidomide inanother one, and partially effective in at least 9patients who failed to respond to other modalitiessuch as steroids, hydroxychloroquine, photophere-sis, retinoids, and chemotherapeutic agents. IVIGhas been usually administered at the dose of 2 g/kg/mo, divided into 4 to 5 consecutive doses4; however,cycles every 6 to 8 weeks were generally required tomaintain remission.4,7 In fact, any attempt to dis-continue the administration of IVIG led to a slowrecurrence of skin lesions. Drawbacks of IVIG arerelated to their high cost and the time-consumingadministration. No significant side effects were ob-served except in 1 patient with previous congestiveheart failure who developed myocardial ischemiaafter the fourth cycle of IVIG, an uncommon eventthat has already been signaled.8

The successful use of IVIG in scleromyxedema hasbeen documented in the literature,4,7 although themechanism of action is unclear. An immunomodula-tory action including neutralization of circulatingautoantibodies by anti-idiotype antibodies, func-tional blockade of fragment crystallizable receptorson macrophages, modulation of the production ofcytokines, and cytokine antagonists with an antifi-brotic mechanism have been suggested.9 On thecontrary, systemic steroids, used alone or in combi-nation with chemotherapeutic agents, did not pro-duce satisfactory results.10 Only 2 patients showed apartial improvement with prednisone plus

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thalidomide and prednisone plus hydroxychloro-quine, respectively. Most of our patients, however,were treated with prolonged daily steroid therapy.Recently, anecdotal cases that responded well tohigh-dose dexamethasone alone or in associationwith melphalan, bortezomib, and thalidomide(which are well-established antimyeloma treat-ments) were reported.11,12 Thalidomide alone hasalso been described to give marked improvement inpatients with recalcitrant disease.13 In 14 individuals,2 or more different systemic treatment regimenswereused, confirming thatmanydrugswere ineffective, orhighlighting the fact that the same drug may produceheterogeneous results in different patients and thetreatment of scleromyxedema often required a mul-timodal and stepwise approach. However, after theintroduction of IVIG, most cases were treated withthis single drug as a first-line treatment, and the use ofcombination or sequential therapeutic modalitiestended to decrease. No patient was treated withhigh doses of alkylating agents including melphalan,followed by autologous blood stem cell transplanta-tion, which has been described as effective in scle-romyxedema on an anecdotal basis.14

Our study confirms that the prognosis in patientswith scleromyxedema is guarded. Five of 21 patients(23.8%) who were followed up died, whereas 12were alive with disease. Death was caused by com-plications related to scleromyxedema in 3 patients,ie, dermatoneuro syndrome leading to coma in 2 andmyocardial insufficiency as a result of inflammatorymucinous cardiomyopathy in 1, whereas hemato-logic malignancies were the cause of death in theremaining 2 patients. In the Mayo Clinic series, thedisease has proven fatal in 10 of 26 patients (38%).The higher percentage of deaths, however, was aresult of hematologic malignancies and septic com-plications related to melphalan treatment that hasbeen only occasionally used in our series.Dermatoneuro syndrome is a rare and occasionallylethal neurologic complication of scleromyxedemacharacterized by fever, confusion, dysarthria,lethargy, convulsions, and coma, often precededby flu-like symptoms.15 Treatment is difficult; plas-mapheresis,16 dexamethasone and bortezomib,17

and IVIG18 seem to achieve the best results, althoughmany patients appeared to recover spontaneously,and some who were given only supportive care diedof their disease.19 One of our 2 patients respondedwell to plasmapheresis, cyclophosphamide, andsteroids, but subsequently died of a second acuteneurologic episode, whereas the second one died ina few days while receiving IVIG treatment. Twoother patients with dermatoneuro syndrome com-pletely recovered from coma without apparent

residual deficits, one with steroids and the otherapparently spontaneously. In fact, both of them arealive and under treatment with IVIG with partialimprovement and relatively good control of theirdisease. The exact pathophysiology of dermato-neuro syndrome remains obscure, however, andeven brain autopsies gave varying and inconclusiveresults15; in particular, mucin deposition has neverbeen found, whereas gliosis and demyelinationseem to be a feature.20

Cardiovascular abnormalitieswith congestive heartfailure affect up to 10% of patients with scleromyxe-dema,21 andmucin deposition in themyocardiumandheart vessels has been previously reported as anautopsy finding.22 Finally, 2 patients died of Hodgkinlymphoma and myeloid leukemia, respectively.Anecdotal cases of hematologic malignancies includ-ing non-Hodgkin lymphoma, multiple myeloma, andmyelomonocytic leukemia in scleromyxedema havebeendescribed, and a triggering role ofmelphalan hasbeen considered.3,23 However, our patients in whomthe development of a hemolymphoproliferativedisorder could be related to scleromyxedema itselfdid not receive anychemotherapeutic regimen. Toourknowledge, this is also the first observation of thedevelopment of Hodgkin lymphoma associatedwith scleromyxedema. No patient developed overtmyeloma,which is not a commonevent, in spite of thepersistence of the serum monoclonal gammopathy(7% and 12% of cases in the Mayo Clinic and theFrench series, respectively).3,5

The pathogenesis of scleromyxedema remains tobe elucidated. Themain hypothesis is that circulatingcytokines, such as interleukin 1, tumor necrosisfactor, and transforming growth factor-b, known tostimulate glycosaminoglycan synthesis and fibroblastproliferation in the skin, could play a role.2 Manyauthors have also suggested that the paraproteinsthemselves might act as autoantibodies that stimulatefibroblasts to proliferate and overproduce mucin.24

However, although serum isolated frompatients withscleromyxedema does enhance fibroblast prolifera-tion in vitro, purified paraproteins (IgG) from thesame patients do not stimulate fibroblasts.25

Moreover, in our patients paraprotein levels did notcorrelate with the severity or the progression of thedisease or the response to treatment. Finally, theobservation of 2 cases of scleromyxedema occurring,respectively, after breast silicone implantation andinjections of dermal fillers including hyaluronic acidmay suggest that at least in some cases, scleromyx-edema could be triggered by adjuvants.26,27

Our findings emphasize that scleromyxedema is achronic and unpredictable disease with systemicimplications, especially neurologic, cardiologic, and

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JULY 201372 Rongioletti et al

hematologic ones, entailing a guarded prognosis.Although spontaneous clinical resolution, even after15 years, has been anecdotally described,28 none ofour patients were this lucky.

There is no specific definitive treatment and thetherapeutic response varies greatly between patients.Our data support theuseof IVIGas a first-line therapy,as it is relatively effective and safe for the treatment ofboth cutaneous and extracutaneous manifestations ofscleromyxedema. The therapeutic response, how-ever, is not permanent so that maintenance infusionsspaced out to every 2 months are required.

We thank Walter Burgdorf, MD, and Alfredo Rebora,MD, for their valuable suggestions and cooperation in thisstudy.

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