localized panniculitis secondary to subcutaneous

Localized panniculitis secondary to subcutaneousglatiramer acetate injections for the treatment

of multiple sclerosis: A clinicopathologicand immunohistochemical study

Luis Miguel Soares Almeida, MD,a Luis Requena, MD,b Heinz Kutzner, MD,c

Jorge Angulo, MD,b Joao de Sa, MD,d and Joao Pignatelli, MDa

Lisbon, Portugal; Madrid, Spain; and Friedrichshafen, Germany

Background: Glatiramer acetate has been shown to be effective in reducing the relapse and improving thedisability of patients with multiple sclerosis. The most common adverse effects at the injection sites includepain, inflammation, and induration that spontaneously disappear within hours or a few days.

Objective: We sought to characterize the histopathologic findings of localized panniculitis induced byglatiramer acetate at the injection sites.

Methods: Seven patients receiving daily glatiramer acetate injections for treatment of multiple sclerosisdeveloped localized panniculitis at the injection sites. The lesions were histopathologically and immuno-histochemically studied.

Results: The lesions consisted of a mostly lobular panniculitis, with lipophagic granuloma, namelyhistiocytes engulfing the lipids from necrotic adipocytes. In many areas, scattered neutrophils andeosinophils were seen both in the septa and in the fat lobules. Connective tissue septa showed wideningand fibrosis in conjunction with many lymphoid follicles, presenting with germinal center formation.Immunohistochemically, the inflammatory infiltrate of the fat lobule consisted of CD681 histiocytes andsuppressor/cytotoxic T lymphocytes. In contrast, the lymphoid follicles in the septa and at the interfacebetween septum and fat lobule were mainly composed of B lymphocytes.

Limitations: Only one biopsy was performed in each patient and, therefore, it was not possible to studythe histopathologic evolution of the panniculitic process.

Conclusions: Localized panniculitis at the sites of subcutaneous injections of glatiramer acetate fortreatment of multiple sclerosis seems to be a rare, but characteristic side effect of this therapy. Thehistopathologic pattern of these lesions consists of a mostly lobular panniculitis, with histiocytes andT lymphocytes in the fat lobule and thickened septa with scattered lymphoid follicles, which are mostlycomposed of B lymphocytes. ( J Am Acad Dermatol 2006;55:968-74.)

Glatiramer acetate consists of the acetatesalts of a mixture of synthetic polypeptides,containing 4 naturally occurring amino

acids: L-glutamic acid, L-alanine, L-tyrosine, andL-lysine. It simulates the myelin basic protein andis currently used for treatment of multiple sclerosisbecause it has been shown to be effective in reducingthe relapse and improving the disability of patientswith relapsing-remitting multiple sclerosis.1,2 Thedrug is administered in daily subcutaneous injectionsof 20 mg. The most common adverse effects, whichoccur in approximately 20% to 60% of the patients,include pain, inflammation, and induration at the

From the Departments of Dermatologya and Neurology,d Hospital

de Santa Maria, Universidade de Lisboa, Portugal; Department

of Dermatology, Fundacion Jimenez Dıaz, Universidad Auton-

oma, Madrid, Spainb; and Dermatohistopathologische Gemein-

schaftspraxis, Friedrichshafen, Germany.c

Funding sources: None.

Conflicts of interest: None identified.

Accepted for publication April 24, 2006.

Reprint requests: Luis Requena, MD, Department of Dermatology,

Fundacion Jimenez Dıaz, Avda. Reyes Catolicos 2, 28040-Madrid,

Spain. E-mail: [email protected].

Published online June 23, 2006.

0190-9622/$32.00

ª 2006 by the American Academy of Dermatology, Inc.

doi:10.1016/j.jaad.2006.04.069

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injection site, all of which spontaneously disappearwithin hours or a fewdays. Amore rare adverse effectis a frank panniculitis followed by localized lipoat-rophy at the injection sites, which has been describedonly in a few patients receiving treatment withglatiramer acetate injections.3-7 In those reports, theauthors only described ‘‘lipoatrophy,’’ in some caseseven without histopathologic study of the lesions,5,7

and in others with vague histopathologic descrip-tions of ‘‘inflammatory infiltrate involving the subcu-taneous tissue.’’3,4,6

We report a series of 7 patients who developedlocalized panniculitis at the sites of subcutaneousinjections of glatiramer acetate for treatment ofmultiple sclerosis. Our goal was to characterize thehistopathologic and immunohistochemical featuresof this drug-induced panniculitis. We also discussthe histopathologic differential diagnosis with othertypes of panniculitis showing similar histopathologicfeatures.

METHODSThe clinical characteristics of our series are sum-

marized in Table I. Briefly, all 7 patients were female,with age range between 28 and 51 years (median:38 years). All patients had been instructed in self-injection techniques to assure the safe administrationof a daily subcutaneous injection of 20 mg ofglatiramer acetate. The commercially available formis a white, sterile, lyophilized powder containing 20mg of glatiramer acetate and 40 mg of mannitolsupplied in refrigerated single-use vials for subcuta-neous administration after reconstitution with sterilewater.8 As a regular procedure, prefilled syringepackages from the refrigerator were kept at roomtemperature for 20 minutes before the injection toallow the solution to warm to room temperature. Thepatients injected the drug into the subcutaneous fatat the recommended sites (periumbilical skin, upperside aspects of arms, hips, and front of thighs) andthey did not use any site more than once each week.The patients denied constitutional symptoms,trauma, or other skin problems, and they were nottaking any other medications at the time. Fivepatients received previous treatment with subcuta-neous injections of interferon beta, but this therapyhad been withdrawn at least 1 month beforetreatment with glatiramer acetate injections wasinitiated.

RESULTSThe lesions were located at the injection sites, and

all patients developed subcutaneous erythematousnodules in several areas (periumbilical skin, upperside aspects of arms, hips, and front of thighs) (Fig 1)

during the treatment. The duration of glatirameracetate treatment before localized panniculitis at theinjection sites was 1 to 2 months. When glatirameracetate injections were withdrawn, the cutaneouslesions disappeared within 2 to 3 months, but in 5 ofthe 7 patients, subcutaneous erythematous nodulesat the injection sites developed again when glatir-amer acetate injections were reintroduced. In allpatients, residual lesions of lipoatrophy (Fig 1) andhyperpigmentation developed in previously in-flamed sites.

Histopathologic studies were performed in allcases. Although the histopathologic findings variedfrom case to case, there were some common fea-tures. These features consisted of a mostly lobularpanniculitis, with a papillary and reticular dermalperivascular infiltrate, mainly composed of lympho-cytes. In the subcutaneous fat, the so-called lipo-phagic granuloma was the main histopathologicfinding, showing macrophages with large foamycytoplasm engulfing the lipids from necrotic adipo-cytes (Fig 2). In addition, small mature lymphocyteshad infiltrated the necrotic fat lobules. In many areas,scattered neutrophils and eosinophils were seenboth in the septa and the fat lobules. Connectivetissue septa showed widening and fibrosis. Manylymphoid follicles, with prominent germinal centerformation, were seen both in the septa and at theinterface between the septum and the fat lobule(Fig 3). These lymphoid nodules were uniformlycomposed of small mature lymphocytes at the centerand abundant plasma cells at the periphery. In 3cases, some of the septal blood vessels showedswollen endothelial cells and small lymphocytesinvolving the vessel walls, suggesting lymphocyticvasculitis, albeit without nuclear dust and fibrinoidnecrosis (Figs 4 and 5). Examination of the histologicsections under polarized light failed to discloserefractile foreign bodies.

Immunohistochemical studies were performed inall biopsy specimens of the 7 cases. The antibodiesused, their sources, dilutions, and results are sum-marized in Table II. Briefly, the inflammatory infil-trate of the fat lobule was mainly composed ofCD681 histiocytes (Fig 6), whereas the lobular lym-phocytes were mainly suppressor/cytotoxic T lym-phocytes, expressing CD45, CD3 (Fig 6), CD8 (Fig 7),and TIA-1 (Fig 8). Only a few lymphocytes involvingthe fat lobule showed a CD4 immunophenotype(Fig 7). TIA-1 expressionwas also seen in neutrophils,with coexpression of myeloperoxidase and neutro-philic elastase. In contrast, the lymphoid follicles inthe septa and at the interface between septa and thefat lobule were mainly composed of B lymphocytes,expressing CD20 and CD79a (Fig 8). Only a few

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scattered lymphocytes showed weak positivity forCD30. The proliferative index was low, with only5% of the nuclei of the inflammatory infiltrate cellsexpressing MIB-1 immunoreactivity. The remainingantibody stains were negative.

DISCUSSIONClinical trials have shown that glatiramer acetate is

effective in reducing the relapse rate and improvingdisability of patients with multiple sclerosis.1,2 Theprecise pharmacologic mechanism has not yet beenfully elucidated, but it was suggested that glatirameracetate alters T-cell immune function by inducingantigen-specific T-suppressor cells, interfering with

class II major histocompatibility binding,9 and mod-ifying cytokine profiles.10 A switch of the immunereaction from a T-helper 1 to a T-helper 2 cell typehas been observed during treatment with glatirameracetate, currently considered to be its main

Table I. Clinical characteristics of patients developing localized panniculitis at the sitesof glatiramer acetate injections

Case/age, y/sex 1/51/F 2/33/F 3/33/F 4/28/F 5/46/F 6/36/F 7/41/FRRMS duration, y 6 2 9 5 6 2 3Glatiramer acetatetreatment duration, y

3 1 1 2 1 2 1

Daily dosage, mg 20 20 20 20 20 20 20TI between firstinjections and developmentof panniculitis, mo

1 1.5 2 2 1 2 1.5

Regression of lesionsafter injections werewithdrawn, mo

2 3 2 3 2 3 3

Recurrent lesions withreintroduction of injections

No Yes Yes Yes Yes No Yes

Clinical features EN EN EN EN EN EN ENResidual lesions LA, HP LA, HP LA, HP LA, HP LA, HP LA, HP LA, HPAdministered treatment TCEs TCEs TCEs TCEs TCEs TCEs TCEsPrevious treatmentwith interferon beta

6 mo 2 mo 4 y 3 y 1 y No No

TI between interferonstopped and glatirameracetate introduced

2 mo 1 mo 1 mo I y I mo

EN, Erythematous nodules; F, female; HP, hyperpigmentation; LA, lipoatrophy; RRMS, relapsing-remitting multiple sclerosis; TCEs, topical

corticosteroids; TI, time interval.

Fig 1. Case 3. Clinical appearance of lesions. A, Erythe-matous subcutaneous nodule on site of injection ofglatiramer acetate at hip. B, Close-up view.

Fig 2. Case 3. Histopathologic features. A, Scanningmagnification showing involvement of subcutis. B, In-volvement of subcutaneous tissue consists of mostlylobular panniculitis. C, Center of fat lobule shows necroticadipocytes and inflammatory infiltrate. D, Lipophagicgranuloma. Most inflammatory cells consist of histiocytesengulfing lipids from necrotic adipocytes. (A to D, Hema-toxylin-eosin stain; original magnifications: A,35; B,340;C and D, 3400.)

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DECEMBER 2006970 Soares Almeida et al


mechanism of action.11 Stimulated glatiramer ace-tateereactive T-helper 2 lymphocytes can releaseanti-inflammatory cytokines, such as interleukin-4and -10, andneurotropic factor, such as brain-derivedneurotrophic factor.12

In controlled clinical trials the most commonlyobserved adverse effects were injection site reac-tions, vasodilatation, chest pain, asthenia, infection,pain, nausea, arthralgia, anxiety, and hypertonia.13

Concerning injection-site reactions, erythema (66%of patients), inflammation (49%), pain (73%), andpruritus (40%) are themost commonly described localside effects.8 In a few cases, lipoatrophy at the sites ofinjection has also been described.3-7 Drago et al3 werethe first authors pointing out localized lipoatrophyat the sites of subcutaneous injections in 6 femalepatients with multiple sclerosis receiving treatmentwith glatiramer acetate. They reported that the lesionsdeveloped without any preceding inflammation andthe overlying skin did not exhibit inflammation,sclerosis, or hyperpigmentation. Histopathologicfeatures of those cases were described as: ‘‘Normalepidermis and a perivascular infiltrate with lympho-cytes, neutrophils, and eosinophils throughout thedermis. There were fibroses of fat septa and occa-sionally a septal and perivascular inflammatory infil-trate.’’3 Mancardi et al4 reported 3 female patients andone male patient with well-circumscribed areas ofskin depression at the injection sites of glatirameracetate. Histopathologic studies were performed inthe 4 cases, with one patient showing erythematousnodules and the others presenting with depressedareas of skin. The histopathologic findings in the

erythematous nodule were described as follows:‘‘Inflammation was present in the subcutis with aseptal and perivascular pattern. The morphologicalappearance of the vessels was normal, and no throm-bosiswas detected.’’ In contrast, the biopsy specimensfrom depressed areas of the skin showed ‘‘fibrosis ofthe dermis and subcutis with reduction in the size ofthe fat lobules and minimal mononuclear infiltrates.’’4

Hwang and Orengo5 reported a 35-year-old woman

Fig 4. Case 4. Histopathologic features. A, Scanningpower showing mostly lobular panniculitis. B, Septa arethickened, but most infiltrate is within fat lobule.C, Necrotic adipocytes and histiocytic infiltrate. D, Foamyhistiocytes as expression of lipophagic granulomas.(A to D, Hematoxylin-eosin stain; original magnifications:A, 35; B, 340; C, 3200; D, 3400.)

Fig 3. Case 3. Additional histopathologic features ofcase 3. A, Many lymphoid follicles are seen at septa andperiphery of fat lobules. B, Center of lymphoid follicles issmall mature lymphocytes. C, Numerous plasma cells arepresent at periphery of lymphoid follicles. (A to C,Hematoxylin-eosin stain; original magnifications: A, 340;B, 3200; C, 3400.)

Fig 5. Additional histopathologic features of case 4.A, Septa contain dense lypmphocytic infiltrate. B, Someseptal blood vessels showed swollen endothelial cellsand small lymphocytes involving vessel walls, suggestinglymphocytic vasculitis. C, Higher magnification demon-strates that nuclear dust and fibrinoid necrosis are absent.Note presence of numerous eosinophils among lympho-cytes. (A to C, Hematoxylin-eosin stain; original magnifi-cations: A, 340; B, 3200; C, 3400.)

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with symmetric soft-tissue depressions on the peri-umbilical skin, upper back aspect of arms, side ofhips, and front of thighs that correlated exactly to theinjection sites of glatiramer acetate. Unfortunatelythese lesions were not histopathologically studied.Soos et al6 described an additional female patientdeveloping localized panniculitis and subsequentlipoatrophy at the sites of subcutaneous glatirameracetate injections for the treatment of multiple sclero-sis. The patient had several areas of circumscribedcutaneous atrophy on the skin of the abdominalwall and thighs. Histopathologic study of these le-sions demonstrated ‘‘normal epidermis and dermis. Amarked lymphohistiocytic infiltrate was seen as wellas swollen vessels with monocytic cells both subcu-taneously and in the fatty tissue septa.’’ In spite ofthe absence of inflammatory clinical features on theoverlying skin, Soos et al6 were the first authors whorecognized a panniculitic stage previous to the lipo-atrophy induced by the glatiramer acetate injections.Finally, Edgar et al7 described 5 female patients withlipoatrophy at the sites of glatiramer acetate injectionsand biopsywas performed only in two of them. These

authors described ‘‘normal immunofluorescence andno inflammatory infiltrate’’ in one patient, whereas inthe other one the ‘‘skin punch biopsy was normal.’’The panniculitis secondary to glatiramer acetate in-jections seems to be much more frequent in femalethan inmale patients. In our literature reviewwe havefound that only 1 of the 17 described patients wasmale and our 7 patients were also women. Afterreviewing the literature it also becomes clear that athorough histopathologic study of localized pannicu-litis secondary to glatiramer acetate injections has yetto be done.

Lipoatrophy secondary to subcutaneous injec-tions has been described in conjunction with severaldrugs, including insulin, corticosteroids, vasopressin,antibiotics, human growth hormone, iron dextran,diphtheria-pertussis-tetanus immunization serum,and antihistamines.14 Although different pathogenicmechanisms have been proposed for each of thesedrugs, lipoatrophymost probably is the common lateor residual stage of a previous drug-induced local-ized panniculitis. In the described cases of localizedlipoatrophy at the sites of subcutaneous glatiramer

Table II. Immunohistochemical study of 7 cases of localized panniculitis secondary to subcutaneousinjections of glatiramer acetate for treatment of multiple sclerosis

Antibody Clone Source m/p HIER Dilution Specificity Results

CD15 Leu-M1 BD m 1 1:400 Mature neutrophils,monocytes, myeloid cells

�/1 (neutrophils)

CD34 HPCA1/My10 BD m 1 1:100 Hematopoietic precursor/stem cells

�

CD43 DF-T1 DG m 1 1:100 Myeloid cells, macrophages �CD45 (LCA) PD7/26 DG m 1 1:400 Granulocytes, monocytes,

macrophages, allhematolymphoid cells

11 (lymphocytesandhistiocytes)

CD45RO UCHL1 DG m 1 1:400 T lymphocytes 11 (lymphocytes)CD68 PGM-1 DG m 1 1:200 Monocytes and macrophages 111 (histiocytes)Myeloperoxidase MPO-7 DG p 1 1:2000 Myeloid cells, granulocytes

and their precursors1 (neutrophils)

Neutrophilicelastase

NP57 DG m � 1:100 Myeloid cells, granulocytesand their precursors

1 (neutrophils)

CD3 F7.2.38 DG p 1 1:200 Pan T-cell marker 11 (lymphocytes)CD4 1F6 DG m 1 1:10 T-helper/inducer cells 1 (lymphocytes)CD8 DK25 DG m 1 1:50 T-suppressor/cytotoxic cells 11 (lymphocytes)TIA-1 2G9 IK m 1 1:600 T-suppressor/cytotoxic cells,

neutrophils11 (granulocytes)

CD20 L26 DG m 1 1:500 Pan B-cell marker 11 (lymphoidnodules)

CD79a JCB117 DG m 1 1:50 Pan B-cell marker, includingplasma cells

11 (lymphoidnodules)

CD30 Ber-H2 DG m 1 1:10 Ki-1 marker: activated T andB cells, Reed-Sternberg cells

�/1 (lymphocytes)

MIB-1 Ki-67 DG m 1 1:40 Proliferation marker �/1 (lymphocytes)

BD, Becton Dickinson, San Jose, Calif; DG, Dako, Glostrup, Denmark; HIER, heat-induced epitope retrieval; IK, Immunotech, Krefeld, Germany;

m, monoclonal; p, polyclonal.

�, Negative; �/1, single scattered cells; 1, 15 % positive cells; 11, 15% to 50% positive cells; 111, more than 50% positive cells.

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acetate injections it is very likely that the drugitself induced a local inflammatory response. Thehistopathologic features of lipophagic granulomasand scattered neutrophils and eosinophils within thefat lobule, in addition to the presence of lymphoidfollicles with germinal center formation at the septa,support the idea that both a direct toxic effect on theadipocytes and a hypersensitivity reaction might beinvolved in the pathogenesis of the localized pan-niculitis. Subsequent septal fibrosis and fat lobuleatrophy cause residual lipoatrophy.

From a histopathologic point of view, the differ-ential diagnosis of panniculitis induced by glatirameracetate injections includes all panniculitides show-ing lymphoid follicles, with distinct germinal centerformation. These histopathologic features are mainlyseen in panniculitis associated with connective tissuedisease, including deep morphea and lupus pannic-ulitis.14 The most characteristic histopathologic find-ing in deep morphea is the presence of a markedfibrous thickening of the septa of subcutaneous fat.As a consequence of thickening, collagen also re-places the fat normally present around the eccrinecoils and below them, giving the misimpression thatsweat glands have ascended into the dermis. Whenthe sclerotic process involves both dermis and sub-cutis, the full thickness of the specimen appearshomogeneously eosinophilic. The spaces betweencollagen bundles disappear, with atrophy of theadnexal structures, blood vessels, and nerves,

leaving only the muscle fibers of arrectores pilorum.An inflammatory infiltrate is only present in activelesions and it consists of aggregations of lympho-cytes surrounded by plasma cells at the junctionof the thickened septa and the fat lobules. Plasmacells may also be arranged interstitially between

Fig 7. Case 3. Immunohistochemical staining for CD4 (Aand B) and CD8 (C and D). A, Immunoexpression for CD4is seen in inflammatory cells with lymphoid appearance.B, Higher magnification showing CD4 immunoreactivityof some lymphocytes involving fat lobule. C, Immunoex-pression for CD8 in lymphoid cells exceeds that for CD3and CD4. D, Higher magnification showing CD8 immu-noreactivity of many lymphocytes involving fat lobule.(A to D, Avidin-biotin immunoperoxidase, original mag-nifications: A and C, 3200; B and D, 3400.)

Fig 8. Case 3. Immunohistochemical staining for TIA-1(A and B) and CD79a (C and D). A, Scattered lymphoidcells expressing immunoreactivity for TIA-1. B, Highermagnification showing TIA-1 immunoreactivity of scat-tered lymphocytes involving fat lobule. C, CD79a immu-noreactivity is stronger at periphery of lymphoid follicles.D, Higher magnification showing CD79a immunoreactiv-ity of lymphoid cells. (A to D, Avidin-biotin immunoper-oxidase, original magnifications: A and C, 3200; B and D,3400.)

Fig 6. Case 3. Immunohistochemical staining for CD68 (Aand B) and CD3 (C and D). A, Strong immunohistochem-ical stain for CD68 of inflammatory cells within fat lobules.B, Higher magnification showing CD68 immunoexpres-sion within cytoplasm of histiocytes around necroticadipocytes. C, Immunoexpression for CD3 is seen ininflammatory cells with lymphoid appearance. D, Highermagnification showing CD3 immunoreactivity of someinflammatory cells involving fat lobule. (A to D, Avidin-biotin immunoperoxidase, original magnifications: A andC, 3200; B and D, 3400.)

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the sclerotic collagen bundles. In contrast to thepanniculitis induced by the injections of glatirameracetate, the fat lobule in deep morphea is spared anddevoid of any inflammatory infiltrate. Histopatho-logic findings in lupus panniculitis are also charac-teristic. In more than half of the cases there aretypical epidermal and dermal changes of discoidlupus erythematosus. These include atrophy of theepidermis, vacuolar change at the dermoepidermaljunction, thickened basement membrane, interstitialmucin between collagen bundles of the dermis, andsuperficial and deep perivascular inflammatory in-filtrate of lymphocytes involving the dermis. In theother half of the cases, the changes are confined tothe subcutaneous fat, with no anomalies in thedermis or epidermis. There is a mostly lobularpanniculitis with inflammatory infiltrate predomi-nantly composed of lymphocytes. A characteristicfeature, found in more than half of the patients, is thepresence of lymphoid follicles. Often, these lym-phoid follicles show germinal centers and numerousplasma cells at the periphery that also extend inter-stitially between collagen bundles of the septa of thesubcutis. In contrast to glatiramer acetateeinducedpanniculitis, necrosis of adipocytes is usually sparseor absent in lupus panniculitis and there is nosignificant neutrophilic infiltrate. Additional histo-pathologic features usually seen in lupus panniculi-tis, such as sclerotic collagen bundles at the septa,hyaline necrosis of the adipocytes at the fat lobule,and mucin deposits interstitially arranged betweencollagen bundles of the reticular dermis and con-nective tissue septa of the subcutaneous fat, areabsent in glatiramer acetate induced panniculitis.

In summary, localized panniculitis at the sitesof subcutaneous injections of glatiramer acetate fortreatment of multiple sclerosis seems to be a rare butcharacteristic side effect. It consists of a mostlylobular panniculitis followed by lipoatrophy. Froma histopathologic point of view, the lesions showlipophagic granulomas involving the fat lobules withlymphoid follicles at the septa of the subcutaneoustissue. It is likely that the drug itself induces a localinflammatory response as a result of a direct toxiceffect on the adipocytes, and this inflammatory stageis followed by a hypersensitivity reaction and

residual lipoatrophy. When glatiramer acetate injec-tions are withdrawn, the cutaneous lesions disap-pear, but they recur when the injections arereintroduced.

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