Localized panniculitis secondary to subcutaneous
`glatiramer acetate injections for the treatment
`of multiple sclerosis: A clinicopathologic
`and 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 the
`disability of patients with multiple sclerosis. The most common adverse effects at the injection sites include
`pain, inflammation, and induration that spontaneously disappear within hours or a few days.
`
`Objective: We sought to characterize the histopathologic findings of localized panniculitis induced by
`glatiramer acetate at the injection sites.
`
`Methods: Seven patients receiving daily glatiramer acetate injections for treatment of multiple sclerosis
`developed 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, namely
`histiocytes engulfing the lipids from necrotic adipocytes. In many areas, scattered neutrophils and
`eosinophils were seen both in the septa and in the fat lobules. Connective tissue septa showed widening
`and fibrosis in conjunction with many lymphoid follicles, presenting with germinal center formation.
`Immunohistochemically, the inflammatory infiltrate of the fat lobule consisted of CD681 histiocytes and
`suppressor/cytotoxic T lymphocytes. In contrast, the lymphoid follicles in the septa and at the interface
`between 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 study
`the histopathologic evolution of the panniculitic process.
`
`Conclusions: Localized panniculitis at the sites of subcutaneous injections of glatiramer acetate for
`treatment of multiple sclerosis seems to be a rare, but characteristic side effect of this therapy. The
`histopathologic pattern of these lesions consists of a mostly lobular panniculitis, with histiocytes and
`T lymphocytes in the fat lobule and thickened septa with scattered lymphoid follicles, which are mostly
`composed of B lymphocytes. ( J Am Acad Dermatol 2006;55:968 74.)
`
`From the Departments of Dermatologya and Neurology,d Hospital
`de Santa Maria, Universidade de Lisboa, Portugal; Department
`of Dermatology, Fundacio´ n Jime´nez Dı´az, Universidad Auto´ n
`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,
`Fundacio´ n Jime´nez Dı´az, Avda. Reyes Cato´ licos 2, 28040 Madrid,
`Spain. E mail:
`lrequena@fjd.es.
`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
`
`968
`
`G latiramer acetate consists of
`
`the acetate
`salts of a mixture of synthetic polypeptides,
`containing 4 naturally occurring amino
`acids: L-glutamic acid, L-alanine, L-tyrosine, and
`L-lysine. It simulates the myelin basic protein and
`is currently used for treatment of multiple sclerosis
`because it has been shown to be effective in reducing
`the relapse and improving the disability of patients
`with relapsing-remitting multiple sclerosis.1,2 The
`drug is administered in daily subcutaneous injections
`of 20 mg. The most common adverse effects, which
`occur in approximately 20% to 60% of the patients,
`include pain, inflammation, and induration at the
`
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`Soares Almeida et al 969
`
`injection site, all of which spontaneously disappear
`within hours or a few days. A more rare adverse effect
`is a frank panniculitis followed by localized lipoat-
`rophy at the injection sites, which has been described
`only in a few patients receiving treatment with
`glatiramer acetate injections.3-7 In those reports, the
`authors only described ‘‘lipoatrophy,’’ in some cases
`even 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 developed
`localized panniculitis at the sites of subcutaneous
`injections of glatiramer acetate for treatment of
`multiple sclerosis. Our goal was to characterize the
`histopathologic and immunohistochemical features
`of this drug-induced panniculitis. We also discuss
`the histopathologic differential diagnosis with other
`types of panniculitis showing similar histopathologic
`features.
`
`METHODS
`The 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 administration
`of a daily subcutaneous injection of 20 mg of
`glatiramer acetate. The commercially available form
`is a white, sterile, lyophilized powder containing 20
`mg of glatiramer acetate and 40 mg of mannitol
`supplied in refrigerated single-use vials for subcuta-
`neous administration after reconstitution with sterile
`water.8 As a regular procedure, prefilled syringe
`packages from the refrigerator were kept at room
`temperature for 20 minutes before the injection to
`allow the solution to warm to room temperature. The
`patients injected the drug into the subcutaneous fat
`at the recommended sites (periumbilical skin, upper
`side aspects of arms, hips, and front of thighs) and
`they did not use any site more than once each week.
`The patients denied constitutional
`symptoms,
`trauma, or other skin problems, and they were not
`taking any other medications at
`the time. Five
`patients received previous treatment with subcuta-
`neous injections of interferon beta, but this therapy
`had been withdrawn at
`least 1 month before
`treatment with glatiramer acetate injections was
`initiated.
`
`RESULTS
`The lesions were located at the injection sites, and
`all patients developed subcutaneous erythematous
`nodules in several areas (periumbilical skin, upper
`side aspects of arms, hips, and front of thighs) (Fig 1)
`
`during the treatment. The duration of glatiramer
`acetate treatment before localized panniculitis at the
`injection sites was 1 to 2 months. When glatiramer
`acetate injections were withdrawn, the cutaneous
`lesions disappeared within 2 to 3 months, but in 5 of
`the 7 patients, subcutaneous erythematous nodules
`at the injection sites developed again when glatir-
`amer acetate injections were reintroduced. In all
`patients, residual lesions of lipoatrophy (Fig 1) and
`hyperpigmentation developed in previously in-
`flamed sites.
`Histopathologic studies were performed in all
`cases. Although the histopathologic findings varied
`from case to case, there were some common fea-
`tures. These features consisted of a mostly lobular
`panniculitis, with a papillary and reticular dermal
`perivascular infiltrate, mainly composed of lympho-
`cytes. In the subcutaneous fat, the so-called lipo-
`phagic granuloma was the main histopathologic
`finding, showing macrophages with large foamy
`cytoplasm engulfing the lipids from necrotic adipo-
`cytes (Fig 2). In addition, small mature lymphocytes
`had infiltrated the necrotic fat lobules. In many areas,
`scattered neutrophils and eosinophils were seen
`both in the septa and the fat lobules. Connective
`tissue septa showed widening and fibrosis. Many
`lymphoid follicles, with prominent germinal center
`formation, were seen both in the septa and at the
`interface between the septum and the fat lobule
`(Fig 3). These lymphoid nodules were uniformly
`composed of small mature lymphocytes at the center
`and abundant plasma cells at the periphery. In 3
`cases, some of the septal blood vessels showed
`swollen endothelial cells and small
`lymphocytes
`involving the vessel walls, suggesting lymphocytic
`vasculitis, albeit without nuclear dust and fibrinoid
`necrosis (Figs 4 and 5). Examination of the histologic
`sections under polarized light
`failed to disclose
`refractile foreign bodies.
`Immunohistochemical studies were performed in
`all biopsy specimens of the 7 cases. The antibodies
`used, their sources, dilutions, and results are sum-
`marized in Table II. Briefly, the inflammatory infil-
`trate of the fat lobule was mainly composed of
`CD681 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 involving
`the fat lobule showed a CD4 immunophenotype
`(Fig 7). TIA-1 expression was also seen in neutrophils,
`with coexpression of myeloperoxidase and neutro-
`philic elastase. In contrast, the lymphoid follicles in
`the septa and at the interface between septa and the
`fat lobule were mainly composed of B lymphocytes,
`expressing CD20 and CD79a (Fig 8). Only a few
`
` EXHIBIT NO. 1042 Page 2
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`970 Soares Almeida et al
`
`J AM ACAD DERMATOL
`DECEMBER 2006
`
`Table I. Clinical characteristics of patients developing localized panniculitis at the sites
`of glatiramer acetate injections
`
`Case/age, y/sex
`RRMS duration, y
`Glatiramer acetate
`treatment duration, y
`Daily dosage, mg
`TI between first
`injections and development
`of panniculitis, mo
`Regression of lesions
`after injections were
`withdrawn, mo
`Recurrent lesions with
`reintroduction of injections
`Clinical features
`Residual lesions
`Administered treatment
`Previous treatment
`with interferon beta
`TI between interferon
`stopped and glatiramer
`acetate introduced
`
`1/51/F
`6
`3
`
`2/33/F
`2
`1
`
`3/33/F
`9
`1
`
`4/28/F
`5
`2
`
`5/46/F
`6
`1
`
`6/36/F
`2
`2
`
`7/41/F
`3
`1
`
`20
`1
`
`2
`
`20
`1.5
`
`3
`
`20
`2
`
`2
`
`20
`2
`
`3
`
`20
`1
`
`2
`
`20
`2
`
`3
`
`20
`1.5
`
`3
`
`No
`
`Yes
`
`Yes
`
`Yes
`
`Yes
`
`No
`
`Yes
`
`EN
`LA, HP
`TCEs
`6 mo
`
`EN
`LA, HP
`TCEs
`2 mo
`
`EN
`LA, HP
`TCEs
`4 y
`
`EN
`LA, HP
`TCEs
`3 y
`
`EN
`LA, HP
`TCEs
`1 y
`
`EN
`LA, HP
`TCEs
`No
`
`EN
`LA, HP
`TCEs
`No
`
`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 of
`glatiramer acetate at hip. B, Close up view.
`
`scattered lymphocytes showed weak positivity for
`CD30. The proliferative index was low, with only
`5% of the nuclei of the inflammatory infiltrate cells
`expressing MIB-1 immunoreactivity. The remaining
`antibody stains were negative.
`
`DISCUSSION
`Clinical trials have shown that glatiramer acetate is
`effective in reducing the relapse rate and improving
`disability of patients with multiple sclerosis.1,2 The
`precise pharmacologic mechanism has not yet been
`fully elucidated, but it was suggested that glatiramer
`acetate alters T-cell immune function by inducing
`antigen-specific T-suppressor cells, interfering with
`
`Fig 2. Case 3. Histopathologic features. A, Scanning
`magnification showing involvement of subcutis. B, In
`volvement of subcutaneous tissue consists of mostly
`lobular panniculitis. C, Center of fat lobule shows necrotic
`adipocytes and inflammatory infiltrate. D, Lipophagic
`granuloma. Most inflammatory cells consist of histiocytes
`engulfing lipids from necrotic adipocytes. (A to D, Hema
`toxylin eosin stain; original magnifications: A, 35; B, 340;
`C and D, 3400.)
`
`class II major histocompatibility binding,9 and mod-
`ifying cytokine profiles.10 A switch of the immune
`reaction from a T-helper 1 to a T-helper 2 cell type
`has been observed during treatment with glatiramer
`acetate,
`currently considered to be its main
`
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`Soares Almeida et al 971
`
`Fig 3. Case 3. Additional histopathologic features of
`case 3. A, Many lymphoid follicles are seen at septa and
`periphery of fat lobules. B, Center of lymphoid follicles is
`small mature lymphocytes. C, Numerous plasma cells are
`lymphoid follicles. (A to C,
`present at periphery of
`Hematoxylin eosin stain; original magnifications: A, 340;
`B, 3200; C, 3400.)
`
`Fig 4. Case 4. Histopathologic features. A, Scanning
`power showing mostly lobular panniculitis. B, Septa are
`thickened, but most
`infiltrate is within fat
`lobule.
`C, Necrotic adipocytes and histiocytic infiltrate. D, Foamy
`histiocytes as expression of
`lipophagic granulomas.
`(A to D, Hematoxylin eosin stain; original magnifications:
`A, 35; B, 340; C, 3200; D, 3400.)
`
`mechanism of action.11 Stimulated glatiramer ace-
`tate reactive T-helper 2 lymphocytes can release
`anti-inflammatory cytokines, such as interleukin-4
`and -10, and neurotropic factor, such as brain-derived
`neurotrophic factor.12
`In controlled clinical trials the most commonly
`observed 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%), and
`pruritus (40%) are the most commonly described local
`side effects.8 In a few cases, lipoatrophy at the sites of
`injection has also been described.3-7 Drago et al3 were
`the first authors pointing out localized lipoatrophy
`at the sites of subcutaneous injections in 6 female
`patients with multiple sclerosis receiving treatment
`with glatiramer acetate. They reported that the lesions
`developed without any preceding inflammation and
`the overlying skin did not exhibit
`inflammation,
`sclerosis, or hyperpigmentation. Histopathologic
`features of those cases were described as: ‘‘Normal
`epidermis and a perivascular infiltrate with lympho-
`cytes, neutrophils, and eosinophils throughout the
`dermis. There were fibroses of fat septa and occa-
`sionally a septal and perivascular inflammatory infil-
`trate.’’3 Mancardi et al4 reported 3 female patients and
`one male patient with well-circumscribed areas of
`skin depression at the injection sites of glatiramer
`acetate. Histopathologic studies were performed in
`the 4 cases, with one patient showing erythematous
`nodules and the others presenting with depressed
`areas of skin. The histopathologic findings in the
`
`Fig 5. Additional histopathologic features of case 4.
`A, Septa contain dense lypmphocytic infiltrate. B, Some
`septal blood vessels showed swollen endothelial cells
`and small lymphocytes involving vessel walls, suggesting
`lymphocytic 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.)
`
`erythematous nodule were described as follows:
`‘‘Inflammation was present in the subcutis with a
`septal and perivascular pattern. The morphological
`appearance of the vessels was normal, and no throm-
`bosis was detected.’’ In contrast, the biopsy specimens
`from depressed areas of the skin showed ‘‘fibrosis of
`the dermis and subcutis with reduction in the size of
`the fat lobules and minimal mononuclear infiltrates.’’4
`Hwang and Orengo5 reported a 35-year-old woman
`
` EXHIBIT NO. 1042 Page 4
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`972 Soares Almeida et al
`
`J AM ACAD DERMATOL
`DECEMBER 2006
`
`Table II. Immunohistochemical study of 7 cases of localized panniculitis secondary to subcutaneous
`injections of glatiramer acetate for treatment of multiple sclerosis
`
`Clone
`
`Source m/p
`
`HIER
`
`Dilution
`
`Specificity
`
`Results
`
`Antibody
`
`CD15
`
`Leu-M1
`
`CD34
`
`HPCA1/My10
`
`CD43
`CD45 (LCA)
`
`DF-T1
`PD7/26
`
`UCHL1
`CD45RO
`PGM-1
`CD68
`Myeloperoxidase MPO-7
`
`Neutrophilic
`elastase
`CD3
`CD4
`CD8
`TIA-1
`
`CD20
`
`CD79a
`
`CD30
`
`MIB-1
`
`NP57
`
`F7.2.38
`1F6
`DK25
`2G9
`
`L26
`
`JCB117
`
`Ber-H2
`
`Ki-67
`
`BD
`
`BD
`
`DG
`DG
`
`DG
`DG
`DG
`
`DG
`
`DG
`DG
`DG
`IK
`
`DG
`
`DG
`
`DG
`
`DG
`
`m
`
`m
`
`m
`m
`
`m
`m
`p
`
`m
`
`p
`m
`m
`m
`
`m
`
`m
`
`m
`
`m
`
`1
`
`1
`
`1
`1
`
`1
`1
`1
`ÿ
`
`1
`1
`1
`1
`
`1
`
`1
`
`1
`
`1
`
`ÿ/1 (neutrophils)
`Mature neutrophils,
`monocytes, myeloid cells
`ÿ
`Hematopoietic precursor/
`stem cells
`ÿ
`Myeloid cells, macrophages
`11 (lymphocytes
`Granulocytes, monocytes,
`and
`macrophages, all
`histiocytes)
`hematolymphoid cells
`11 (lymphocytes)
`T lymphocytes
`1:400
`Monocytes and macrophages 111 (histiocytes)
`1:200
`1 (neutrophils)
`1:2000 Myeloid cells, granulocytes
`and their precursors
`Myeloid cells, granulocytes
`and their precursors
`Pan T-cell marker
`T-helper/inducer cells
`T-suppressor/cytotoxic cells
`T-suppressor/cytotoxic cells,
`neutrophils
`Pan B-cell marker
`
`1:400
`
`1:100
`
`1:100
`1:400
`
`1:100
`
`1:200
`1:10
`1:50
`1:600
`
`1:500
`
`1:50
`
`1:10
`
`1:40
`
`Pan B-cell marker, including
`plasma cells
`Ki-1 marker: activated T and
`B cells, Reed-Sternberg cells
`Proliferation marker
`
`1 (neutrophils)
`
`11 (lymphocytes)
`1 (lymphocytes)
`11 (lymphocytes)
`11 (granulocytes)
`
`11 (lymphoid
`nodules)
`11 (lymphoid
`nodules)
`ÿ/1 (lymphocytes)
`ÿ/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.
`ÿ, Negative; ÿ/1, single scattered cells; 1, 15 % positive cells; 11, 15% to 50% positive cells; 111, more than 50% positive cells.
`
`with symmetric soft-tissue depressions on the peri-
`umbilical skin, upper back aspect of arms, side of
`hips, and front of thighs that correlated exactly to the
`injection sites of glatiramer acetate. Unfortunately
`these lesions were not histopathologically studied.
`Soo´s et al6 described an additional female patient
`developing localized panniculitis and subsequent
`lipoatrophy at the sites of subcutaneous glatiramer
`acetate injections for the treatment of multiple sclero-
`sis. The patient had several areas of circumscribed
`cutaneous atrophy on the skin of the abdominal
`wall and thighs. Histopathologic study of these le-
`sions demonstrated ‘‘normal epidermis and dermis. A
`marked lymphohistiocytic infiltrate was seen as well
`as swollen vessels with monocytic cells both subcu-
`taneously and in the fatty tissue septa.’’ In spite of
`the absence of inflammatory clinical features on the
`overlying skin, Soo´s et al6 were the first authors who
`recognized a panniculitic stage previous to the lipo-
`atrophy induced by the glatiramer acetate injections.
`Finally, Edgar et al7 described 5 female patients with
`lipoatrophy at the sites of glatiramer acetate injections
`and biopsy was performed only in two of them. These
`
`authors described ‘‘normal immunofluorescence and
`no inflammatory infiltrate’’ in one patient, whereas in
`the other one the ‘‘skin punch biopsy was normal.’’
`The panniculitis secondary to glatiramer acetate in-
`jections seems to be much more frequent in female
`than in male patients. In our literature review we have
`found that only 1 of the 17 described patients was
`male and our 7 patients were also women. After
`reviewing the literature it also becomes clear that a
`thorough histopathologic study of localized pannicu-
`litis secondary to glatiramer acetate injections has yet
`to be done.
`Lipoatrophy secondary to subcutaneous injec-
`tions has been described in conjunction with several
`drugs, including insulin, corticosteroids, vasopressin,
`antibiotics, human growth hormone, iron dextran,
`diphtheria-pertussis-tetanus immunization serum,
`and antihistamines.14 Although different pathogenic
`mechanisms have been proposed for each of these
`drugs, lipoatrophy most probably is the common late
`or residual stage of a previous drug-induced local-
`ized panniculitis. In the described cases of localized
`lipoatrophy at the sites of subcutaneous glatiramer
`
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`Fig 6. Case 3. Immunohistochemical staining for CD68 (A
`and 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 necrotic
`adipocytes. C, Immunoexpression for CD3 is seen in
`inflammatory cells with lymphoid appearance. D, Higher
`magnification showing CD3 immunoreactivity of some
`inflammatory cells involving fat lobule. (A to D, Avidin
`biotin immunoperoxidase, original magnifications: A and
`C, 3200; B and D, 3400.)
`
`the drug
`is very likely that
`acetate injections it
`itself induced a local inflammatory response. The
`histopathologic features of lipophagic granulomas
`and scattered neutrophils and eosinophils within the
`fat lobule, in addition to the presence of lymphoid
`follicles with germinal center formation at the septa,
`support the idea that both a direct toxic effect on the
`adipocytes and a hypersensitivity reaction might be
`involved in the pathogenesis of the localized pan-
`niculitis. Subsequent septal fibrosis and fat lobule
`atrophy cause residual lipoatrophy.
`From a histopathologic point of view, the differ-
`ential diagnosis of panniculitis induced by glatiramer
`acetate injections includes all panniculitides show-
`ing lymphoid follicles, with distinct germinal center
`formation. These histopathologic features are mainly
`seen in panniculitis associated with connective tissue
`disease, including deep morphea and lupus pannic-
`ulitis.14 The most characteristic histopathologic find-
`ing in deep morphea is the presence of a marked
`fibrous thickening of the septa of subcutaneous fat.
`As a consequence of thickening, collagen also re-
`places the fat normally present around the eccrine
`coils and below them, giving the misimpression that
`sweat glands have ascended into the dermis. When
`the sclerotic process involves both dermis and sub-
`cutis, the full thickness of the specimen appears
`homogeneously eosinophilic. The spaces between
`collagen bundles disappear, with atrophy of the
`adnexal
`structures, blood vessels, and nerves,
`
`Fig 7. Case 3. Immunohistochemical staining for CD4 (A
`and B) and CD8 (C and D). A, Immunoexpression for CD4
`is seen in inflammatory cells with lymphoid appearance.
`B, Higher magnification showing CD4 immunoreactivity
`of some lymphocytes involving fat lobule. C, Immunoex
`pression for CD8 in lymphoid cells exceeds that for CD3
`and 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 lymphoid
`cells expressing immunoreactivity for TIA 1. B, Higher
`magnification 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.)
`
`leaving only the muscle fibers of arrectores pilorum.
`An inflammatory infiltrate is only present in active
`lesions and it consists of aggregations of lympho-
`cytes surrounded by plasma cells at the junction
`of the thickened septa and the fat lobules. Plasma
`cells may also be arranged interstitially between
`
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`DECEMBER 2006
`
`the sclerotic collagen bundles. In contrast to the
`panniculitis induced by the injections of glatiramer
`acetate, the fat lobule in deep morphea is spared and
`devoid of any inflammatory infiltrate. Histopatho-
`logic findings in lupus panniculitis are also charac-
`teristic. In more than half of the cases there are
`typical epidermal and dermal changes of discoid
`lupus erythematosus. These include atrophy of the
`epidermis, vacuolar change at the dermoepidermal
`junction, thickened basement membrane, interstitial
`mucin between collagen bundles of the dermis, and
`superficial and deep perivascular inflammatory in-
`filtrate of lymphocytes involving the dermis. In the
`other half of the cases, the changes are confined to
`the subcutaneous fat, with no anomalies in the
`dermis or epidermis. There is a mostly lobular
`panniculitis with inflammatory infiltrate predomi-
`nantly composed of lymphocytes. A characteristic
`feature, found in more than half of the patients, is the
`presence of lymphoid follicles. Often, these lym-
`phoid follicles show germinal centers and numerous
`plasma cells at the periphery that also extend inter-
`stitially between collagen bundles of the septa of the
`subcutis. In contrast to glatiramer acetate induced
`panniculitis, necrosis of adipocytes is usually sparse
`or absent
`in lupus panniculitis and there is no
`significant 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 between
`collagen bundles of the reticular dermis and con-
`nective tissue septa of the subcutaneous fat, are
`absent in glatiramer acetate induced panniculitis.
`In summary,
`localized panniculitis at the sites
`of subcutaneous injections of glatiramer acetate for
`treatment of multiple sclerosis seems to be a rare but
`characteristic side effect. It consists of a mostly
`lobular panniculitis followed by lipoatrophy. From
`a histopathologic point of view, the lesions show
`lipophagic granulomas involving the fat lobules with
`lymphoid follicles at the septa of the subcutaneous
`tissue. It is likely that the drug itself induces a local
`inflammatory response as a result of a direct toxic
`effect on the adipocytes, and this inflammatory stage
`is 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 are
`reintroduced.
`
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` AMNEAL