Best Practices in Skin Care for the
`Multiple Sclerosis Patient Receiving
`Injectable Therapies
`
`Lynn McEwan, NP, MScN, MSCN; Janet Brown, RN, MSCN; Josée Poirier, BSc, MSCN;
`Janene Spring, RN, BScN, MSCN; Judith Brouillette, RN, BSc, MScN, MSCN; Kathleen Carr, RN,
`MSCN; Christine Guérette, RN, BSc, MBA, MSCN; Colleen Harris, MN, NP, MSCN; Donna Howard,
`RN, BScN, MSCN; Diane Lowden, NMSc(A), MSCN; Nicolee Richard, BScN, MSCN
`
`Although a cure for multiple sclerosis (MS) has not yet been discovered, a number of treatment
`options are available to help control symptoms, slow disease progression, and improve quality of life
`in patients with relapsing-remitting MS (RRMS). These include disease-modifying therapies (DMTs)
`such as beta-interferons, glatiramer acetate, and natalizumab. Disease-modifying therapies requir-
`ing frequent, self-administered injections can be particularly troublesome for some patients, as they
`may result in localized skin reactions at the injection site. A variety of injection-site reactions (ISRs)
`have been reported, including pain and erythema, lipoatrophy, abscesses and infections, necrosis,
`rash, swelling, and lumps. In order to appropriately distinguish between normal and abnormal reac-
`tions and to determine when further intervention is required, nurses involved in the care of patients
`with MS should be knowledgeable about the potential ISRs associated with DMTs. This best practices
`document was developed by a panel of Canadian MS clinic nurses in order to increase recognition
`among nurses that MS patients are at high risk for skin-site reactions with injectable therapies, and
`to provide the basis for skin-care practices in these patients. It reviews the risk factors associated with
`adverse skin reactions in MS patients treated with injectable therapies; the current attitudes and
`beliefs of nurses with respect to skin care; and the optimal skin-care interventions for MS patients at
`risk for adverse skin reactions when treated with injectable therapies. Areas requiring further research
`are discussed. Int J MS Care. 2010;12:177–189.
`
`Multiple sclerosis (MS) is a chronic inflam-
`
`matory disease of the central nervous sys-
`tem characterized by the demyelination of
`nerve cells.1 The most common form of the disease is
`relapsing-remitting MS (RRMS), in which patients
`experience multiple exacerbations over time. At present,
`there is no cure for MS; however, a number of treat-
`ment options are available to help control symptoms,
`slow disease progression, and improve quality of life in
`patients with RRMS. These include disease-modifying
`therapies (DMTs), which act on the immune system
`and modulate the inflammatory processes involved in
`the disease pathology.2 Medications used for the treat-
`
`ment of RRMS include interferon beta-1a (IFNβ-1a;
`Avonex, Biogen Idec, Mississauga, Ontario, Canada,
`administered intramuscularly once weekly; or Rebif,
`EMD Serono, Mississauga, Ontario, Canada, admin-
`istered subcutaneously 3 times per week), interferon
`beta-1b (IFNβ-1b; Betaseron, Bayer Inc, Toronto,
`Ontario, Canada; or Extavia, Novartis Pharmaceuticals
`Canada Inc, Dorval, Quebec, Canada; administered
`subcutaneously every 48 hours), glatiramer acetate (GA;
`Copaxone, Teva Canada Innovation, Montreal, Quebec,
`Canada; administered subcutaneously once daily), and
`natalizumab (Tysabri, Biogen Idec; administered intrave-
`nously every 4 weeks). The subcutaneously administered
`
`From the London Health Sciences Centre Multiple Sclerosis Clinic, London, Ontario, Canada (LM); MS Clinic–Eastern Health, St. John’s,
`Newfoundland, Canada (J Brown); Clinique Sclérose en Plaques, Centre Hospitalier de l’Université de Montréal, Montreal, Quebec, Can-
`ada (JP); Fraser Health MS Clinic, Burnaby Hospital, Burnaby, British Columbia, Canada (JS); Jewish General Hospital, Montreal, Quebec,
`Canada (J Brouillette); Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada (KC); Clinique Neuro Rive-Sud and Hôpital Charles
`LeMoyne, Greenfield Park, Quebec, Canada (CG); Multiple Sclerosis Clinic, Foothills Medical Centre, Calgary, Alberta, Canada (CH);
`Teva Neuroscience, Montreal, Quebec, Canada (DH, NR); and Multiple Sclerosis Program, McGill University Health Centre, Montreal Neu-
`rological Hospital, Montreal, Quebec, Canada (DL). Correspondence: Lynn McEwan, NP, MScN, MSCN, LHSC University Hospital, Room
`A7008, 339 Windermere Rd., London, Ontario N6A 5A5, Canada; e-mail: lynn.mcewan@lhsc.on.ca.
`
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`McEwan et al.
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`drugs requiring frequent, self-administered injections can
`be particularly troublesome for some patients, as they
`may result in localized skin reactions at the injection site.
`The skin, or integument, is the largest organ, provid-
`ing the body with protection against ultraviolet light,
`injury, and infection and helping to regulate body tem-
`perature. The skin receives about 30% of the body’s
`cardiac output of oxygenated blood and contains nerve
`receptors to help the body adapt to an ever-changing
`environment. It is made up of two main layers—the
`outer epidermis, which constantly regenerates by shed-
`ding dead cells and bringing new cells up from the der-
`mis layer, and the inner dermis, a thicker layer of dense
`connective tissue (Figure 1). When skin is normal and
`healthy, the surface does not differ from surrounding
`skin and is smooth to the touch. When the skin barrier
`is broken through injection, the door is opened to harm-
`ful environmental factors.
`A variety of injection-site reactions (ISRs) have been
`reported with the DMTs, including pain and erythema,
`lipoatrophy, abscesses and infections, necrosis, rash,
`swelling, and lumps. Subcutaneous interferon beta
`(IFNβ) injections result in ISRs in 85% to 92% of MS
`patients during the early phase of treatment, as seen
`in the large pivotal trials.3 In a prospective study of 60
`patients on IFNβ therapy, 24% never experienced ISRs,
`57% had an occasional reaction, and 19% had a reaction
`with each injection.4 Women and smokers undergoing
`interferon therapy are reported to be more susceptible
`to adverse skin reactions, although the reason for this is
`not clear.5,6 Mild erythema, induration, and pain are the
`most common adverse events associated with subcutane-
`ous injection of GA.7 Among 251 patients with RRMS
`randomly assigned to treatment with GA or placebo for
`2 years, 66% to 90% of patients given GA developed
`an ISR, compared with 37% to 59% of patients who
`received the placebo.7,8
`
`Figure 1. Normal skin
`
`Although ISRs are rarely serious, they can promote
`negative attitudes about injection therapy and reduce
`adherence to therapy, particularly in the early stages of
`treatment. In addition to providing MS patients with
`appropriate instruction on the preparation and admin-
`istration of injectable therapies, health-care professionals
`must inquire about ongoing issues, assess skin reactions,
`and periodically review the injection technique.
`In May 2009, a panel of Canadian MS clinic nurses
`convened to discuss the scope of a best practices docu-
`ment in order to increase recognition among nurses that
`MS patients are at high risk for skin-site reactions with
`injectable therapies, and to provide the basis for skin-
`care practices in these patients. Subsequently, a search of
`the literature for clinical practice guidelines, systematic
`reviews, relevant research studies, and other types of evi-
`dence was conducted. Where applicable, recommenda-
`tions were made and categorized according to the levels
`of evidence outlined in the “Summary of Recommenda-
`tions.” Anecdotal practices that were identified by the
`MS nurses through consensus but have not been studied
`are identified as “good practices.”
`This best practices document addresses the risk fac-
`tors associated with adverse skin reactions in MS patients
`treated with injectable therapies; the current attitudes
`and beliefs of nurses with respect to skin care; and opti-
`mal skin-care interventions for MS patients at risk for
`adverse skin reactions when treated with injectable thera-
`pies. Areas requiring further research are also discussed.
`
`ISRs Associated with DMTs for MS
`Erythema and Pain
`Erythema is characterized by redness of the skin due
`to inflammation and may involve dilated or congested
`capillaries (Figure 2). It may be localized or generalized
`and may occur suddenly or gradually. Skin color can
`range from bright red in patients with acute conditions
`to pale violet or brown in those with chronic problems.
`Erythema and pain are common in patients receiv-
`ing injectable therapies. In a postmarketing review of
`1443 adverse event reports of ISRs with subcutaneous
`IFNβ-1b, erythema (57%) and pain (30%) were most
`frequently reported and often occurred together.6 An
`international cohort study of 445 patients comparing
`subcutaneous injection-site pain between IFNβ-1b and
`IFNβ-1a found a significant proportion of pain-free
`injections with IFNβ-1b regardless of needle size.9 How-
`ever, injection-site pain may occur with any agent and
`may even present 24 to 48 hours after injection. With
`glatiramer acetate injections, pain, inflammation, and
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`Best Practices in Skin Care for the MS Patient
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`needle (REGARD Study).17,23 In comparative studies
`of needle gauge size of 27 versus 29, the thinner needle
`size of 29 gauge demonstrated a significant reduction
`in injection-site pain for both subcutaneous IFNβ-1a
`and GA.16,18 Interferon beta-1b is now available with a
`30-gauge needle, but no studies to date have assessed
`the impact on injection-site pain or reactions. A study of
`patients’ perceptions of using a shorter, thinner needle
`(1 inch/25 gauge vs. 1.25 inch/23 gauge) when inject-
`ing intramuscular IFNβ-1a found that 70% of patients
`identified the 1-inch/25-gauge needle as being more
`comfortable and causing less pre-injection anxiety.15
`Although the use of a smaller, thinner needle (29 or
`30 gauge) and an auto-inject device has been shown to
`reduce pain and reactions,13,15-18 for intramuscular injec-
`tions the needle should be long enough to inject into the
`muscle rather than subcutaneous fat.15,24
`To avoid the development of erythema and pain
`following injection of a DMT, the site should be exam-
`ined before injection, with care taken to avoid injecting
`in damaged areas. The auto-injector and needle tips
`should be kept free of medication and the syringe held
`in an upright position when removing the needle cap to
`reduce the chances of medication adhering to the needle
`tip.13 Following an injection, the nurse should observe
`for redness and palpate the skin by gently pressing the
`fingers over the injection site to feel for lumps, hardness,
`or thickening of the skin. As erythema is commonly
`diagnosed through self-examination, the importance of
`self-examination should be emphasized to patients and
`caregivers, who should be encouraged to report and
`discuss their findings with their health-care professional.
`Depending on the type of erythema, treatment includes
`administration of nonsteroidal anti-inflammatory drugs
`(NSAIDs) or corticosteroids.
`Injection-site pain may be reduced by applying
`warm compresses before injection and cold compresses
`after injection for up to 5 minutes.25-27 The application
`of lidocaine/prilocaine cream has also been shown to
`reduce pain and the fear of pain after injection of IFNβ
`in a small cohort of patients with MS.28
`A topical cream with cortisone such as betamethasone
`valerate 0.1% can reduce erythema, as can gentle mas-
`sage for 15 to 30 seconds after IFNβ injection.29
`Lipoatrophy
`Lipoatrophy is a localized loss of subcutaneous adi-
`pose tissue at an injection site and appears as “dents”
`or depressions in the skin, which may range in size and
`severity (Figure 3). Although the exact mechanism lead-
`ing to lipoatrophy is unknown, theories include local
`immune reaction, mechanical injury over time, and
`
`Figure 2. Example of erythema associated
`with injectable DMTs for MS
`
`induration have been reported to occur in 20% to 60%
`of patients.10
`Erythema must be differentiated from purpura, which
`is caused by bleeding into the skin; application of pres-
`sure directly to the skin causes blanching of purpura but
`not erythema. The cause of erythema with DMTs is
`unclear. However, local chemokine induction is believed
`to be an underlying cause of inflammatory skin reactions
`seen in patients receiving subcutaneous IFNβ injec-
`tions.11 It has also been suggested that injection depth
`and injecting into sites with less subcutaneous fat (arms
`and thighs) are contributing factors in injection-site
`erythema.12 The use of auto-injectors and ensuring that
`needle tips are free of medication may reduce erythema.13
`A number of factors may contribute to injection-site
`pain, such as intrinsic drug properties and use of excipi-
`ents in formulation, as well as other formulary proper-
`ties, such as temperature, osmolarity, pH, concentration,
`and injection volume. Additional factors related to
`injection include needle size and shape, location, speed
`of injection and rate of drug administration, the person
`performing the injection, and the individual’s perception
`of pain.14
`Management of Erythema and Pain
`Recognition of formulary components and injection
`techniques contributing to ISRs and pain has led to
`changes in drug formulations and the use of smaller-
`gauge needles and auto-inject devices.9,13,15-21 A new for-
`mulation of subcutaneous IFNβ-1a without fetal bovine
`serum and human serum albumin showed a threefold
`reduction in ISRs compared with the original formula-
`tion (EVIDENCE Study),22 and there were also fewer
`ISRs using the new formulation and a smaller-gauge
`
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`Figure 3. Example of lipoatrophy
`associated with injectable DMTs for MS
`
`delayed inflammatory response.30 In severe lipoatrophy,
`depressions may measure up to 60 cm2 and be 1 to
`2 cm deep, with normal-appearing overlying skin. Mild
`lipoatrophy may be difficult to detect, and patients are
`sometimes unaware of the condition unless identified by
`a family member or a health-care professional.
`Lipoatrophy can occur with prolonged injection
`therapy and has been observed with injection of GA and
`interferon as well as corticosteroids, insulin, vasopressin,
`growth hormone, dextran, diphtheria/tetanus vaccine,
`and antihistamines.31 Among MS patients, lipoatrophy
`occurs more frequently in those taking GA than in
`those on interferon therapy.32 The reported incidence
`of lipoatrophy among patients on GA has varied from
`15% in an Italian study of 27 patients33 to 64% in a US
`study of 14 patients.34 A retrospective Canadian study
`identified lipoatrophy in 34 of 76 (45%) MS patients, all
`of whom were female; in some, the condition appeared
`within 28 ± 14 months of therapy.30 Lipoatrophy was
`defined as severe in 5 patients, moderate in 9 patients,
`and mild in 20 patients; however, severity of lipoatrophy
`may be subjective and difficult to define. Interferon beta
`injections can also cause lipoatrophy, as found in 46% of
`patients in a study of 12 cases of panniculitis.35 Although
`longer treatment times are more strongly associated with
`development of lipoatrophy, a small number of cases
`occur within months of injection.
`Initial reports on the pathology of lipoatrophy
`described it as a noninflammatory condition, but sub-
`cutaneous localized panniculitis at the injection site has
`been described.10,36 More recent reports have noted as
`much as a 40% T-cell subcutaneous infiltration, more
`suggestive of lobular panniculitis.34 Lipoatrophy in
`
`patients on IFNβ often shows features of pancreatic
`panniculitis.35
`Lipoatrophy is more common in females, occurring
`predominantly on the anterolateral surface of the arms
`and thighs.33 It occurs more commonly in both men and
`women who are prone to cellulite formation. Uncer-
`tainty exists about whether lipoatrophy is permanent
`and how to treat it. The condition can be disfiguring
`and may adversely affect quality of life, including social
`functioning, emotional functioning, and mental health.30
`Management of Lipoatrophy
`As interventions to reduce the appearance of lipoat-
`rophy are limited, preventive measures should be rein-
`forced regularly with MS patients undergoing treatment
`with an injectable DMT. MS nurses should regularly
`review current injection preparation and site rotation
`procedures with MS patients and their care partners to
`ensure that they understand the rationale for injecting
`into healthy tissue—to avoid lipoatrophy and to ensure
`adequate absorption of medication. When therapy is ini-
`tiated, and at regular follow-up intervals, the MS nurse
`should ensure that patients are able to recognize lipoat-
`rophy through visual inspection and manual palpation.
`Patients and caregivers should be advised to report the
`appearance of lipoatrophy. Patients should be advised to
`rotate their injection sites regularly and to avoid inject-
`ing in or near an area of lipoatrophy.37-40 At scheduled
`follow-up visits, the MS nurse should inspect injection
`areas to identify any areas of pitting.
`If lipoatrophy occurs, the MS nurse should assess the
`injection and rotation practices and reinforce appropriate
`procedures, including the setup and appropriate depth
`selection of the auto-injector and preparation of the
`prefilled syringe. A ring left on the surface of the skin
`following the use of the auto-injector or syringe is an
`indication of excessive pressure being applied to the skin.
`Attempts to correct lipoatrophy through autologous
`fat transplantation or the use of commercial cosmetic
`fillers have achieved some benefits but are not commonly
`used in MS patients.41,42 Successful use of local injection
`of dexamethasone in insulin-related lipoatrophy has been
`reported, but no studies of this treatment have been con-
`ducted in MS patients.43
`Potential areas of exploration in the management of
`lipoatrophy include blocking the localized inflamma-
`tory reaction and thereby reducing the damage to the
`subcutaneous tissue, as well as the possibility that dam-
`aged subcutaneous tissue may decrease absorption and
`therefore efficacy.
`
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`Injection-Site Infections
`Injection-site infections can include cellulitis (Figure
`4) and soft-tissue abscesses (Figure 5). Cellulitis is diffuse
`inflammation that involves the region from the stratum
`corneum to the subcutaneous fat. It occurs where the
`skin barrier has previously been broken through cuts,
`blisters, cracks in the skin, or insect bites, or by injecting
`drugs, either subcutaneous or intramuscular. Conditions
`such as diabetes, obesity, or others that affect circulation
`can also increase the risk of cellulitis. The patient may
`present with a spreading area of redness, superficial cuta-
`neous edema, warmth, and pain around the injection
`site,44 and the skin may have the appearance of orange
`peel (peau d’orange) (Figure 4). This may or may not
`be accompanied by systemic manifestations of fever,
`tachycardia, and leukocytosis. Cellulitis is often caused
`by streptococcal or staphylococcal bacteria, which are a
`part of the normal skin flora and do not cause infection
`unless the skin is broken. It can occur within 1 to several
`days after skin trauma. Cellulitis is usually a clinical diag-
`nosis, and local skin cultures may not identify causative
`bacteria.
`An abscess is a collection of liquid or pus in the subcu-
`taneous fat, fascia, or muscle and may be sterile or septic
`(Figure 5). A mass under the skin with redness, warmth,
`pain, swelling, and fluctuance is suggestive of an abscess.
`Sterile abscesses are caused by irritants such as drugs or
`foreign bodies (eg, splinter), whereas septic abscesses are
`caused by bacteria.45 When a medication is injected and
`not absorbed, it can cause irritation to the surrounding
`tissue, forming a sterile abscess with no infection. Over
`time, the sterile abscess may form a hard mass or lump.
`An abscess usually spreads beneath the skin rather than
`extending to the surface of the skin, thus encapsulating
`the collection of liquid or pus. This encapsulation may
`prevent spread to other sites but also prevents immune
`cells from attacking the bacteria. Localized signs of
`inflammation, erythema, pain, swelling, or warmth on
`touch are signs of both sterile and septic abscesses but are
`usually more severe with an infectious etiology. Septic
`abscesses may be accompanied by fever and/or regional
`lymphadenopathy, while sterile abscesses are not.45
`An infectious etiology of an abscess can be deter-
`mined by needle aspiration or surgical drainage of
`material from the mass, with laboratory confirmation of
`microbiological organisms through Gram stain or cul-
`ture. If a sample of material cannot be obtained, imaging
`techniques such as ultrasonography, computed tomog-
`raphy (CT), or magnetic resonance imaging (MRI)
`or clinical evidence of fluctuance (wavelike motion on
`palpation due to fluid) can also be used to diagnose an
`
`Best Practices in Skin Care for the MS Patient
`
`Figure 4. Appearance of cellulitis (ie,
`orange peel or peau d’orange)
`©2009 Logical Images, Inc. Used by permission.
`
`abscess, but not to differentiate between sterile and septic
`etiologies.45
`The literature contains little information on the
`prevalence of skin and soft-tissue infections associated
`with MS injectable therapies. However, premarketing
`controlled drug trials have demonstrated a low incidence
`of injection-site infections in patients on drug therapy,
`with a reported incidence of injection-site abscess of
`approximately 1% to 2.5%.37,46 A recent survey of MS
`nurse experts from 15 MS centers in North America also
`found a low incidence of injection-site infections—0%
`to 4.5% for cellulitis (mean, 1.01%) and 0% to 3.0%
`for abscess (mean, 0.37%). There were no reports of
`injection-site infections in the pediatric population (L
`McEwan, unpublished data).
`Predisposing factors for injection-site skin infections
`and abscesses identified in other populations undergoing
`treatment with injectable therapies have included mul-
`tidose vials, reuse of needles, poor hygiene, obesity, and
`immunodeficiency.47,48 However, no such factors in MS
`patients have been clearly identified. Suggested factors
`include poor injection technique, inadequate skin cleans-
`ing, excessively shallow injections, and repeated use of
`the same injection site.5 In a survey of MS nurses on
`
`Figure 5. Example of an abscess developing
`4 weeks after injection of IFNβ-1a
`(Courtesy of Colleen Harris, RN.)
`
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`injection-site infections, one nurse noted recurrent infec-
`tion after systemic corticosteroid treatment (L McEwan,
`unpublished data).
`Management of Injection-Site Infections
`Cleansing of the injection site with alcohol is con-
`sidered to be the optimal skin preparation to avoid
`infection.49 Cleansing the skin with 70% alcohol for
`5 seconds can reduce bacteria counts by 82% to 91%.
`However, diabetic patients who did not use skin prepa-
`ration before insulin injection every other week for 3 to
`5 months had no incidence of injection-site infection.49
`Similar results were found for patients receiving botuli-
`num toxin type A injections without alcohol skin prepa-
`ration.50 In the use of insulin, infection is more likely to
`be caused by contaminated needles, syringes, and solu-
`tions than by lack of skin preparation.51
`Treatment for mild or typical cases of infection
`should include use of an appropriate oral antimicro-
`bial agent.52 Severe cases may require hospitalization
`and intravenous antimicrobial therapy. Although the
`usual course of therapy is 10 to 14 days, a 5-day course
`of antibiotic treatment has been shown to be as effective
`as a 10-day course in uncomplicated cellulitis.53 In some
`cases, cutaneous inflammation may worsen during the
`first 24 hours of antimicrobial treatment because of the
`sudden destruction of pathogens, releasing inflammatory
`enzymes. Administration of adjunct corticosteroids may
`reduce inflammation but does not alter outcome.54,55
`Elevation of the affected site may promote drainage of
`edema and inflammatory substances.
`Generally, sterile abscesses resolve spontaneously
`and do not require treatment. Use of warm compresses
`over the abscess may hasten drainage or reabsorption
`of the abscess. Treatment for septic abscesses should
`include incision and removal of collected material and
`pus. Adjunct antimicrobial therapy varies and should be
`based on Gram stain, culture, and symptoms. Currently,
`there is insufficient evidence to support abscess cav-
`ity packing or wound closure, and the former has been
`associated with increased pain.56-60 However, in a ran-
`domized trial comparing primary closure of superficial
`abscesses with conventional packing, duration of healing
`was significantly decreased with primary closure.60 Clini-
`cal trials are lacking on the appropriate management of
`abscesses.
`Proper diagnosis is the key to effective management
`of patients with injection-site infections. Although nurs-
`es may not be responsible for prescribing drug therapy,
`they should have knowledge of the signs and symptoms
`of cellulitis and soft-tissue abscesses and be familiar with
`treatment recommendations. Nurses also have a funda-
`
`mental role in the prevention of injection-site infections
`by educating patients on correct injection technique and
`skin care.
`Induration, Swelling, Lumps, Rash, and
`Necrosis
`Although swelling and induration are sometimes used
`interchangeably, an induration is a localized hardening
`around the injection site that is usually well demarcated
`with palpable borders (Figure 6), while swelling is typi-
`cally caused by fluid accumulation in tissue and may be
`soft or firm.61 Induration may appear several hours after
`injection and last from 24 to 72 hours, causing a feel-
`ing of warmth, itching, hypersensitivity to touch, and
`swelling, and forming a round or elliptical lump less
`than 5 cm2 in size. Thirteen percent of the 1443 ISRs
`reported over 30 months of postmarketing surveillance
`of IFNβ-1b were of induration.6 The mechanisms of
`injection-site inflammation in patients on interferon
`therapy are unknown but are thought to involve an
`inflammatory response to interferon influenced by the
`injection path and depth, with inflammation less likely
`to occur in areas with a higher proportion of subcutane-
`ous fat such as the abdomen or buttocks.12 In the phase
`3 clinical trial of GA, induration affected 19% of 125
`subjects treated with GA.7 In some cases, these reactions
`persisted for several days.
`In some patients, erythematous patches develop
`around injection sites, leading to necrotic ulcers (Fig-
`ure 7).62 Necrosis has been reported in 3% to 5% of
`patients on IFNβ-1b therapy3,6; however, necrosis is
`probably underreported, as many adverse event report-
`ing systems rely on passive reporting by clinicians.6
`Cutaneous necrosis has also been described in patients
`on intramuscular IFNβ-1a.63 One case of subcutaneous
`injection giving rise to persistent erythematous plaques
`has been reported.64 Risk factors for necrosis include
`
`Figure 6. Induration associated with
`injectable DMTs for MS
`(Courtesy of Stanley Hashimoto, MD, Division of Neurology,
`Department of Medicine, University of British Columbia.)
`
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`Best Practices in Skin Care for the MS Patient
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`Figure 7. Necrosis associated with
`injectable DMTs for MS
`(Courtesy of Colleen Harris, RN.)
`
`incorrect injection techniques, insufficient needle length,
`cold drug, repeated use of the same injection site, and
`excessive exposure of recent injection sites to sunlight or
`ultraviolet rays.12
`Although rash is not a common ISR, all DMTs have
`had isolated reports of either localized or systemic “rash-
`like” reactions (Figure 8). A cutaneous lesion resembling
`lupus erythematosus has been described in MS patients
`receiving IFNβ injections.65-67 A more widespread ery-
`thematous, maculopapular rash occurring on the trunk
`and extremities following intramuscular injection of
`IFNβ-1a has also been reported.68 In one report, red,
`vascular, itchy lesions developed after injection of IFNβ
`in the arms or abdomen but not in the thighs, and the
`problem resolved after the patient used the correct injec-
`tion technique with a longer needle.69 Interferon beta
`has also been associated with limited or diffuse systemic
`cutaneous sclerosis.62,70 There have been case reports of
`focal and diffuse urticaria and pruritus occurring within
`30 minutes to several months after the initiation of GA,
`as well as a single case of urticarial vasculitis.71,72
`The reason for rash formation is unknown, but it has
`been suggested that MS patients have abnormalities of
`platelet activation and that IFNβ may enhance platelet
`aggregation in these patients, causing a platelet-depen-
`dent thrombosis.62
`The literature contains little information on lumps,
`swelling, and redness associated with DMTs in MS.
`These symptoms alone may occur often, possibly disap-
`pearing and then reappearing.
`Management of Induration, Swelling, Lumps, Rash,
`and Necrosis
`As with other ISRs, proper injection-site rotation
`practices are important in preventing induration, swell-
`ing, rash, and necrosis. On scheduled visits, MS nurses
`should review injection preparation procedures with the
`patient and caregivers and inspect injection areas to iden-
`tify any problems. Between visits, patients and caregivers
`
`Figure 8. Example of a rash associated
`with injectable DMTs for MS
`(Courtesy of Stanley Hashimoto, MD, Division of Neurology,
`Department of Medicine, University of British Columbia.)
`
`should be advised to perform regular visual inspection
`and manual palpation of the skin to identify these prob-
`lems.
`To prevent inflammation, the area should be warmed
`sufficiently before injection. Warming also serves to relax
`the tissue, improve medication absorption, and improve
`circulation to allow the medication to be more easily dis-
`persed from the area.29
`If indurations are present, alcohol should not be used
`to clean the skin because it can cause irritation; soap and
`water should be used instead.73 The indurated site may
`be massaged with moisturizing cream, either immedi-
`ately following injection in the case of IFNβ or 24 hours
`after injection in the case of GA. Local application of ice
`has been shown to reduce inflammation due to injec-
`tion, with the effect being most beneficial when per-
`formed immediately after injection.73,74 In cases of pro-
`longed inflammation, local application of heat may be
`useful.73 Antihistamines may also be effective in reducing
`inflammation; however, recent studies have shown no
`significant effect of antihistamine on ISRs associated
`with GA injection.27,75 Subcutaneous desensitization with
`GA has been shown to be effective in patients with focal
`and systemic reactions, enabling them to return to thera-
`py without further reactions.71
`Indurations, swelling, and rashes may respond to
`cortisone cream; however, in cases of necrosis, cortisone
`can delay the healing process and increase the likelihood
`of secondary infections. Betamethasone valerate 0.1%
`cream is recommended for ISRs because the level of
`cortisone is high enough to manage inflammation but
`low enough to prevent additional problems. However,
`betamethasone should not be used on thin, fragile areas.
`Hydrocortisone 1% is insufficient to manage inflamma-
`tion and should not be used.29
`Areas of necrosis must be evaluated for signs and
`symptoms of infection. As incorrect injection practices
`are common causes of necrosis,12 patients who develop
`
`International Journal of MS Care
`183
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`MYLAN PHARMS. INC. EXHIBIT 1095 PAGE 7
`
`

`
`McEwan et al.
`
`necrosis at a DMT injection site may require an evalu-
`ation of their cognitive ability in order to validate their
`understanding of proper self-injection procedures. Treat-
`ment of necrosis generally includes antibiotics or surgery,
`including incision and drainage, debridement, excision,
`and/or skin grafting.6
`
`Overall Good Practices in DMT Injection
`for MS
`Both health-care providers and patients self-adminis-