Background: Multiple sclerosis (MS) is one of the neuroinflammatory disorders that commonly affect the young. Injectable interferons beta-1a (Rebif 22-44, Betaseron 250 and Avonex 30) are one of the most important first line disease modifying therapies with less side effects compared to others. But the injection site reaction (ISR) is an important side effect, which can decrease the patient’s compliance to the medications that will lead to the disease progression.
Objective: The purpose of this study was to compare the ISR in the three types of interferon (2 subcutaneous  Rebif 22-44, Betaseron 250 and one intramuscular Avonex 30) and determine whether the route of administration (subcutaneous versus intramuscular) affects the frequency of ISR, and to reduce this side effect and ensure compliance. 
Methods: This was a single center, prospective observational study of 300 patients at King Fahad University Hospital (Al Khobar, Saudi Arabia) form September 2015 to August 2016 with a relapsing remitting form of multiple sclerosis for which 114 patents were receiving injectable interferon. A questionnaire was filled out by the participants including type of interferon, type of ISR and pain severity. Patients were then evaluated in our MS clinic and dermatology clinic after 1 week and 3 months. Data were analyzed by IBM-SPSS version 21. Appropriate statistical tests will be mandated per the collected data. Statistical significance is determined at p-value<0.05 with a confidence interval of 0.95. Frequency and proportion, and relative risks (RR) were calculated and Chi-square test was used.
Results: ISRs in the form of erythema were reported by fewer patients on Avonex group 21.1% compared to the other two injectables, Betaseron group (77.8%, p<0.0001, RR=2.6) and Rebif groups (69.8%, p<0.0001, RR=2.3). Similar observations were noticed 3 months later, where the Avonex group had statistically significant less ISRs with no abnormality in 89.9% compared to (52.3%, p<0.0001, RR=3.5) and (44.4%, p<0.0001, RR=4.2) in Rebif and Betaseron respectively. Only patients on Rebif had skin ulceration 3.5% (n=3) at initial assessment; however, there was insignificant difference and none of the patients had skin ulceration at the 3 months’ evaluation. 
Conclusions: Interferon beta-1a (Avonex) found to be the least to cause ISR compared to Rebif and Betaseron.
Keywords: Multiple sclerosis, Injection site reaction (ISR), Interferon beta


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