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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_2745_Библиотеки_им_академика_М_И_Перельмана
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10 years of IFNβ-1b therapy. 42 Histopathologically, these
cases were consistent with morphea, with thickened collagen
bundles extending into the subcutaneous fat, paucity of
adnexal structures, and a deep reticular lymphocytic infiltrate
(Figure 9.3). 41 The authors proposed a possible dysregulation
of inflammatory cytokines, trauma, or a combination of both
as the underlying cause.
FIGURE 9.2 Clinical presentation of morphea showing
multiple hyperpigmented atrophic plaques with an
erythematous border. Also pictured are a few scattered cherry
angiomas and seborrheic keratoses. See eBook for color
figure.
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FIGURE 9.3 Morphea. Sclerotic eosinophilic collagen
throughout the dermis with a dense perivascular and
periadnexal infiltrate composed of lymphocytes and plasma
cells and trapping of adnexal structures (hematoxylin and
eosin, 3×). See eBook for color figure.
Cutaneous Ulceration and Necrosis
Injection site ulceration and necrosis typically occur within the
first 4 months of therapy but have been reported greater than
1 year after initiating therapy. Necrosis is generally limited to
an area 3 cm or less in diameter with extension into the
subcutaneous fat, although larger lesions with involvement of
the fascia overlying muscle have been reported. 29 Healing is
usually associated with scarring. In rare cases, debridement
with subsequent skin grafting may be required. Histologically,
perivascular and interstitial lymphohistiocytic infiltrates,
panniculitis, and thrombosis of deeper vessels have been
reported.
13,29,43-50
Proposed mechanisms include thrombosis
and necrosis of dermal vessels secondary to abnormal
aggregation of platelets as well as a hypersensitivity reaction
within blood vessels.
43,51-53
Incorrect injection technique and
improper depth of injection have been identified as risk
factors. 54 The decision of whether to continue treatment
depends on the extent of necrosis. Some patients have
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experienced healing of necrotic skin lesions while continuing
therapy. Patients should be advised not to administer therapy
into the affected area. 23 If multiple lesions are present, the
general consensus is that therapy should be discontinued.
29
Pathogenesis
The pathogenesis of injection site reactions with IFN-β
therapy is not fully understood. Direct toxic and
proinflammatory mechanisms, as well as IgE-mediated and
delayed hypersensitivity reactions have been proposed as
potential causes. Furthermore, immune-mediated necrotizing
vasculitis and platelet-dependent thrombosis may play a role.
Patients with MS have clotting abnormalities at baseline
secondary to abnormal platelet activation, which may be
further exacerbated by the immunomodulatory treatments used
in MS.
37,51,55
IFN-β administered subcutaneously can induce
inflammatory skin reactions due to local chemokine induction
with immune cell extravasation. More specifically, studies
have demonstrated an upregulation of chemokines (CCL2 and
CXCL10), with recruitment of circulating T cells to evolving
skin lesions. 56 Histologically, reports have demonstrated a
lupuslike reaction with superficial and deep perivascular and
periadnexal lymphocytic infiltrate with focal interface damage
and interstitial mucin.
23,57,58
In severe cases, thrombosis of
deeper vessels may be seen.
13,29,43-49
Systemic Reactions
Rare systemic reactions have been reported with the use of
IFN-β therapy in patients with MS, although a direct
correlation between disease onset and the use of IFN therapy
could not be proven in all cases. Twelve cases of sclerosing
skin disorders, including both limited and diffuse cutaneous
sclerosis, have been reported in patients with MS. 59 In five of
these patients, IFN-β had been administered between 1 and
8 years before the onset of sclerosis, which the authors
suggested may have been the trigger. 59 One case of cutaneous
vasculitis with renal impairment was reported in a patient
injecting IFN-β for 10 weeks who developed purpura,
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proteinuria, and hematuria after an injection. 18 In another case,
a middle-aged female developed disseminated cutaneous
lesions after her third IFN-β injection, which reappeared after
a subsequent injection and resolved upon discontinuation of
therapy. 60 A diffuse maculopapular rash was reported in one
patient after her second IFN-β injection, which resolved with
antihistamines and corticosteroids but reappeared after the
third injection. 61 In addition, there was one report of severe,
new-onset dermatomyositis in a male patient after 5 years of
IFN-β therapy. There was a temporal association between
exacerbation of symptoms and repeated injections, with in
vitro studies revealing enhanced type I IFN signaling in
lymphoid cells in response to IFN-β. 62 Furthermore, IFN-
induced sarcoidosis is a rare reaction but has been reported in
seven patients with MS, as well as one with multiple myeloma
and one patient with renal cell carcinoma.
14,63-70
In one case, a
patient developed noncaseating granulomas in her skin and in
pulmonary lymph nodes after 3 years of therapy. The authors
proposed that the development of sarcoidosis was due to a
dysregulation in the modulatory role of IFN-β (and more
generally type I interferon) expression in chronic
inflammation. 64 In addition, multiple reports of new-onset
psoriasis, psoriatic arthritis, and psoriasis exacerbations have
been reported with the use of IFN therapy, with some lesions
lasting as long as 6 years after the cessation of IFN-β.
13,71-74
The mechanism is thought to be due to IFN-β’s
proinflammatory effect in psoriasis, with upregulation of the
interleukin (IL)-23/ T helper cell (Th)17 pathway.
72,75
Glatiramer Acetate
Injection site reactions have been reported in 20% to 80% of
patients taking glatiramer acetate, including erythema (66%),
inflammation (49%), pain (73%), and pruritus (40%).
76-78
These injection site reactions are generally mild or moderate in
severity and disappear spontaneously in hours to days. Similar
rates of injection site reactions are seen with the 20- and 40mg dosing regimens. 76 Aviv et al recently proposed three
distinct histologic responses to glatiramer acetate injections:
(1) erythematous plaques and nodules with superficial and
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sometimes deep inflammatory infiltrates seen in an acute
response, (2) morpheaform plaques with perivascular and
interstitial dermatitis and thick collagen bundles seen in
chronic cases, and (3) lipoatrophy initially present as deep
infiltrates of lymphocytes, neutrophils, eosinophils, and
plasma cells, leading to a more chronic infiltration, loss of
subcutaneous adipose tissue, and delicate fibrosis. 79 Average
onset of injection site reactions after glatiramer acetate therapy
is 1.75 years, but reactions may occur as early as the first
injection. 79 Possible causes of injection site reactions include
the high immunogenicity of glatiramer acetate, repeated
trauma to the fat inciting an inflammatory reaction, as well as
an allergic reaction to glatiramer acetate components.
80,81
Panniculitis and Lipoatrophy
Glatiramer acetate is characteristically associated with frank
panniculitis and subsequent lipoatrophy.
33,82-86
Of all the
injectable disease-modifying therapies for MS, glatiramer
acetate is associated with the highest prevalence of
lipoatrophy. This occurrence was originally reported to be
rare, occurring in 2% of patients in clinical studies, but in a
recent study involving full skin examinations in patients taking
glatiramer acetate, prevalence was as high as 45%.
84,87
Trauma
alone can cause lipoatrophy, such as the lipoatrophy seen with
acupuncture. It is thought that this type of lipoatrophy is
caused by the activation of macrophages and release of
cytokines such as tumor necrosis factor (TNF) and IL-1.
82
Histologically, acupuncture-induced lipoatrophy is
characterized by an involutional pattern with thin and
elongated fat lobules, with only a few surrounding
macrophages. However, on histopathologic examination of
glatiramer acetate–associated lipoatrophy, a lobar panniculitis
predominates with histiocytes engulfing lipids from necrotic
adipocytes and T lymphocytes in the fat lobules. Thickened
septa with scattered lymphoid follicles composed of B
lymphocytes may also be seen. 33 This type of adverse event
appears to be independent of injection technique. 84 Glatiramer
acetate panniculitis is thought to be secondary to the drug’s
high immunogenicity, as a robust immune response is required
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for glatiramer acetate to be therapeutic in MS treatment.
33,80,85
In mild cases, cutaneous lesions may resolve with treatment
discontinuation but can reappear if injections are restarted.
However, two recent reports suggested that glatiramer acetate–
associated lipoatrophy can persist and even progress despite
discontinuing treatment.
80,88
Nicolau syndrome (embolia cutis medicamentosa) is a rare
complication of the injection of several drugs, leading to
cutaneous, subcutaneous, or muscular aseptic necrosis. There
are multiple cases of Nicolau syndrome reported in the
literature secondary to glatiramer acetate injections.
53,89,90
One
patient who had been given 20 mg glatiramer acetate for
7 years experienced severe, lancinating pain with injection into
her lower abdomen after recently increasing the dosage and
decreasing the frequency of her injections. 90 Histological
examination of the excised specimen revealed predominately
lobar panniculitis with lymphocytes and plasma cells
surrounding necrotic adipocytes as well as diffuse
subcutaneous sclerosis. The authors proposed that this
morphealike sclerosis is likely an underreported aspect of
glatiramer acetate injection site reactions.
90
Management
Prompt treatment of injection site reactions is important, as it
may contribute to continued patient compliance. For the
management of injection site reactions, ibuprofen and topical
corticosteroids or calcineurin inhibitors have been shown to be
beneficial in decreasing inflammation.
Adherence to proper injection protocol can help reduce the
risk, including prewarming the injection solution, sterile
technique, proper needle length, subcutaneous injection (vs.
intradermal injection), and regularly changing injection sites.
91
Therefore, the injection technique should be regularly
reviewed with patients to ensure competence and reduce the
incidence of secondary complications.
Injection site care is another important aspect in preventing
complications. Warm compress application before injection
has been shown to be effective in decreasing injection site
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reactions. 87 The use of firm pressure and ice packs after
injections can also help minimize swelling and bruising. If
swelling persists for longer than a day, warm compresses can
be applied to the site. If swelling continues to persist, the
patient should be instructed to consult a physician to rule out
possible infection.
91
In the case of mild to moderate injection site reactions,
disease-modifying therapy should not be discontinued. For
injection site necrosis, temporary dose reduction or
discontinuation may be indicated depending on the severity.
26,29
Local treatment may include topical antibacterials, but it is
important to avoid topical corticosteroids in the case of
necrosis, as they can prolong wound healing and increase the
risk of infection. 91 Surgical excision and grafting may be
indicated in more severe cases. It is important to note that
some injection site reactions (i.e., postinflammatory
hyperpigmentation, scars, and disfiguring lipoatrophy) may
persist.
Infusion Therapies (Alemtuzumab,
Natalizumab, Ocrelizumab, Rituximab)
Cutaneous Infusion-Associated Reactions
Alemtuzumab
Alemtuzumab (Lemtrada, Campath-1H®, Genzyme
Corporation, Cambridge, MA, USA) is a humanized
monoclonal antibody directed against cluster of differentiation
(CD)52, which is present on the surface of B and T cells. In
two phase 3 trials of alemtuzumab in relapsing remitting MS
(12 mg on 5 consecutive days and 3 consecutive days 12 mo
later), cutaneous infusion-associated reactions occurred in
66% of patients, including rash (47%), urticaria (13%),
pruritus (11%), and erythema (4%). 92 Two subsequent studies
including a retrospective chart review and a prospective cohort
study reported lower rates of cutaneous side effects in 34.2%
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and 33.3% of patients, respectively.
93,94
This difference was
attributed to a higher dose of corticosteroids and suggests that
pretreatment with corticosteroids and antihistamines may help
ameliorate the cutaneous side effects of alemtuzumab infusion.
93
The histopathologic spectrum of hypersensitivity reactions
associated with alemtuzumab was recently described.
95
Biopsies of five patients with cutaneous T cell lymphoma or
chronic lymphocytic leukemia who were treated with
alemtuzumab and developed pruritic, erythematous papules,
and plaques were reviewed. Histopathologic examination
revealed subacute spongiotic dermatitis with multifocal
parakeratosis, endothelial activation, and perivascular
lymphocytic infiltrate, without prominent eosinophils. The
authors hypothesize that the cutaneous reaction may be due to
an immunologic response secondary to resident memory T
cells in the skin.
95
One case report demonstrated severe generalized bullous drug
eruption occurring 10 days after infusion of alemtuzumab. The
rash resolved with high-dose oral corticosteroids. A
subsequent infusion was given 1 year later with concomitant
intravenous and postinfusion corticosteroids. Following the
second infusion, the patient developed a more limited,
asymptomatic macular dermatitis. 96 Alopecia is another
reported adverse effect of alemtuzumab, with two cases of
alopecia universalis and three cases of alopecia areata in the
literature.
97-99
Immune thrombocytopenic purpura was initially
reported in six patients in a 2008 study, including a fatal case
in a patient receiving alemtuzumab 24 mg.
100-103
Across all
clinical trials, immune thrombocytopenic purpura incidence
was 2% in patients receiving alemtuzumab 12 or 24 mg.
Therefore, patients should be advised to monitor for the
development of petechiae, increased bleeding, or easy
bruising.
In uncontrolled studies of alemtuzumab for MS, melanoma
occurred in 4 of 1486 (0.3%) of alemtuzumab-treated patients.
One patient had evidence of locally advanced disease.
104
Postmarketing reports of melanoma include a 34-year-old
woman who developed superficial spreading melanoma in a
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long-standing nevus after 6 months of treatment with
alemtuzumab. The authors hypothesized that alemtuzumab led
to impairment of immunosurveillance predisposing to
tumorigenesis.
105
Two additional cases of melanoma with
alemtuzumab therapy have been reported in a retrospective
study of Austrian patients with B cell chronic lymphocytic
leukemia.
106
These findings have led the FDA to recommend
routine skin examination at the start of treatment and annually
thereafter to monitor for melanoma.
107
Natalizumab
Natalizumab (Tysabri®, Biogen Idec, Cambridge, MA, USA
and Elan Pharmaceuticals, Dublin, Ireland) is an adhesionmolecule inhibitor, specifically a humanized monoclonal
antibody targeting α4 integrins on the surface of lymphocytes.
As a result, natalizumab blocks leukocyte trafficking across
the blood-brain barrier.
108
Cutaneous side effects associated
with natalizumab infusions include urticaria, allergic
dermatitis, and hypersensitivity reactions, including serum
sickness reactions.
109-111
Less common reactions have been
reported in the literature. One patient reportedly developed
acquired perforating dermatosis after 6 infusions (300 mg per
month).
112
Skin lesions were temporally associated with
infusions, appearing 3 to 5 days after each infusion, resolving
15 days later. In another case, a patient with a 12-year history
of MS developed a generalized erythematous drug eruption,
edema, and nausea after 1 month of natalizumab.
113
Natalizumab may also induce or aggravate psoriasis in patients
with MS. One patient with a family history of psoriasis
developed plaque psoriasis 6 years after the initiation of
natalizumab. Her disease was well controlled with topical
therapies.
114
Another patient in her 30s with a history of mild
psoriasis in adolescence developed a severe disseminated
psoriasis eruption that was resistant to topical treatment and
phototherapy after six natalizumab infusions. The authors
hypothesized a paradoxical immune reaction due to
upregulation of other pathways after blocking the migration of
lymphocytes across the blood-brain barrier.
115
A middle-aged
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man without any history of psoriasis developed severe
psoriasis on his extremities after two doses of natalizumab.
Treatment was discontinued after six doses because of
persistent psoriasis and new-onset foot pain that made walking
difficult.
116
Finally, another patient without any prior history
of psoriasis developed biopsy-proven psoriasis on the scalp,
trunk, and extremities with associated arthralgias after 19
natalizumab infusions.
117
Treatment was switched to dimethyl
fumarate, and the plaques cleared within 3 months.
The role of natalizumab in the development of melanoma is
unclear. A meta-analysis of safety data from clinical trials on
natalizumab reported a similar incidence of melanoma among
patients who received natalizumab (3/4250; 0.07%) compared
with placebo (2/2059; 0.10%).
118
Multiple case reports of
melanoma have been reported with natalizumab therapy,
including a case of ocular melanoma as well as urethral
melanoma.
119-125
On review of the FDA’s Adverse Event
Reporting System database up until 2014, 137 cases of
natalizumab-associated melanoma were identified. The
median onset was 4 months after starting therapy, and there
were two mucosal melanomas, five ocular melanomas, and
nine melanoma-related deaths.
119
In normal melanocytes, α4
integrin is not expressed; however, it is expressed on
melanoma cells. Downregulation of α4 integrin has been
shown to be involved with melanoma invasion. Thus, one
proposed mechanism of natalizumab-potentiated melanoma
involves binding α4 integrin to directly promote melanoma
cell replication, invasion, and migration.
119
Conversely, the
role of natalizumab in inducing melanoma was challenged by
the results of a 4-year dermoscopic study following 74 patients
with MS with 775 monitored melanocytic skin lesions. This
investigation yielded substantial dermoscopic changes in only
1.54% of cases.
126
All excised lesions were benign, and
immunohistological studies and proliferation and invasion
assays revealed a lack of detectable levels of melanoma
progression markers (secreted protein acidic and rich in
cysteine [SPARC] and β3 integrin) in nevi. This study
concluded that natalizumab therapy does not increase the risk
for nevus transformation.
126
Nevertheless, further data are
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