{'fraction_non_alphanumeric': 0.026039942623855235, 'fraction_numerical': 0.016330133509875316, 'mean_word_length': 4.928057553956834, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 1, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Potential Impact of Biologically Derived Hyaluronic Acid on Quality of Life in Patients with Knee Osteoarthritis in the United States

Introduction Knee osteoarthritis is one of the leading causes of disability in the world. Intra-articular hyaluronic acid (IA-HA) is a treatment modality that provides a minimally invasive treatment option for the management of osteoarthritis-related symptoms. This study examined the current and potential economic impact of using a biologically derived, high molecular weight hyaluronic acid preparation (Euflexxa) on the US population for the management of knee osteoarthritis. Methods A model was developed to estimate the total number of patients with symptomatic knee osteoarthritis in the US in 2015, distributed by Kellgren–Lawrence (K–L) grade, and the number of people living with total knee arthroplasty (TKA). The potential utility of Euflexxa was applied to this model population to determine the current and potential impact of the treatment as the total number of quality adjusted life years (QALY) saved within the US population. Results There are approximately 12 million people currently suffering from symptomatic knee osteoarthritis in the US, and approximately 5 million living with TKA. It was estimated that, with a target treatment group of K–L grades 2–3, there are approximately 4 million patients eligible for treatment with a high molecular weight intra-articular hyaluronic acid injection. With current use, it is estimated that Euflexxa can save 36,730 QALY/year among the US population, and has the potential to save an additional 369,181 QALY/year if used by all eligible patients. Conclusions This study demonstrates that more widely used, biologically derived, high molecular weight IA-HAs, such as Euflexxa, have the potential to save a substantial number of QALYs among the US population with symptomatic knee osteoarthritis. Funding: Ferring Pharmaceuticals Inc.


INTRODUCTION
Knee osteoarthritis (OA) is a chronic, progressive disease that continues to be one of the leading causes of disability among active patients in the USA. Knee OA results in a decrease in quality of life for those suffering from the disease, as well as a large financial burden on health care systems and society [1,2]. The prevalence of symptomatic knee OA in the USA was estimated to be 9.9 million in 2010, and it is estimated that among older adults in the USA, there are over 10 million quality of life years lost annually because of knee OA [3,4].
A number of treatment methods are available for managing the symptoms of knee OA. Non-surgical treatments may incorporate changes in diet and exercise, ambulatory aids, simple analgesics, and non-steroidal anti-inflammatory drugs (NSAIDs), while more invasive treatments may include intra-articular injections and surgical interventions like total knee arthroplasty (TKA). Many patients diagnosed with OA may have comorbidities precluding them from some of the available treatment options [5]. There are also patients that may not demonstrate an adequate response to non-surgical treatments and are unwilling or medically unsuitable to undergo surgical interventions [6]. Experts argue that it is essential to prolong the period of time between the decline of conservative treatment efficacy and surgical intervention, as having TKA at a younger age may increase the likelihood of requiring a revision, leading to increased costs and possible complications [7]. It is therefore important to consider treatment options available that may alleviate symptoms related to knee OA and delay the need for primary TKA in order to reduce the likelihood of requiring a revision TKA.
The use of intra-articular hyaluronic acid (IA-HA) as a treatment method for knee OA presents a non-surgical option for symptom relief which may provide better results than other conservative treatment options [8,9]. Evidence also suggests that the use of IA-HA

Ethics Statement
This article does not contain any new studies with human or animal subjects performed by any of the authors.

Study Scope and Model Generation
We modelled the total number of patients in the USA (2015) with symptomatic knee OA, distributed across Kellgren-Lawrence (K-L) OA severity grades, and the current number of patients with TKA. Using these estimates, we projected the total number of eligible patients who may benefit from the use of Euflexxa versus conventional care in the USA.
The model was developed to provide an estimate for the prevalence of symptomatic knee OA in the USA in 2015. Estimates for the prevalence of symptomatic knee OA in the USA were obtained from the American Academy of Orthopaedic Surgeons (AAOS) [3], and estimates on the incidence of knee OA, prevalence of TKA, and incidence of TKA were obtained from the published literature [13][14][15] (Table 1). The portion of the population who have undergone a TKA was omitted from the model, given that they have already received definitive knee OA treatment and would no longer be eligible to benefit from an IA-HA injection. As incidence data was sourced from 1995, the prevalence per 100,000 person/years was taken and adjusted for the age and sex distribution for 2015 [13]. It was estimated that there were 9.9 million people with symptomatic knee OA in the USA in 2010, and that the annual incidence of symptomatic knee OA in the US is approximately 770,000 ( Table 1).
The distribution of patients with knee OA by K-L severity grades was obtained from a large observational study on knee OA involving 3021 people surveyed in the US population [16]. The majority of studies examining IA-HA involved participants with K-L grades of 2-3, so the percentage of the symptomatic OA population with K-L grades 2 and 3 was calculated to determine the total number of patients eligible to benefit from IA-HA injections. Patients across all K-L levels who had not received a TKA or were currently using IA-HA were considered eligible to receive appropriate conventional care. The current use of Euflexxa and other IA-HA products was obtained through the IMS claims data for 2014 [17].
The mortality rate corresponding to the demographics of the model population was used, under the previously validated assumption that mortality amongst the OA population is similar to that of the general US population [18][19][20]. Data on utility scores for the healthy US population was obtained from the literature [21].
The changes in health state of patients receiving treatment was reported in terms of a utility score, represented in QALYs, a frequently used quality of life measurement in health economic analyses. QALYs are determined by using utility values that represent desired health states which, for a single patient, vary from 0 (indicating death) to 1 (indicating perfect health) [22]. In order to determine the impact of a treatment, the number of eligible patients for the treatment was multiplied by the increase in utility score resultant from that treatment.

OA Prevalence and TKA Prevalence Calculations
The prevalence of symptomatic knee OA in the USA for the year 2015 was estimated according to the formula where x is the 2010 symptomatic knee OA prevalence, y is the symptomatic knee OA incidence, and z is the US death rate for adults over 35.
A similar formula was used to estimate the prevalence of TKA in the US population: where a is the 2013 TKA prevalence, b is the TKA incidence, and z is the US death rate for adults over 35.
Both of these formulas are nested formulas, where the number of times the formula is nested corresponds to the superscript number.
The nested formula takes the preliminary prevalence, adds the incidence, and subtracts the death rate to gain the prevalence for the following year. This new prevalence is then the starting point for the next iteration of the formula, which is repeated for the number of times specified.

Treatment
The treatment option examined in this study is the high molecular weight IA-HA injection Euflexxa. In a randomized controlled trial (the FLEXX trial), Altman et al. examined this preparation over two courses of three injections, with 6 months between each course of treatment [23]. As a comparator, we used appropriate

Economic Impact Calculation
The current and potential impact of each treatment was calculated by multiplying the however, as this value may have either increased or decreased in 2015, a two-way sensitivity analysis was performed on the current use of Euflexxa. In addition, there is some uncertainty as to whether the mortality rate of persons with OA is similar to or higher than that in the general population [18][19][20]25]. In order to consider this uncertainty, a two-way sensitivity analysis was performed adjusting the mortality rate.    [26,27], and the impact of OA treatments in European countries [28]. To our knowledge, this is the first study to measure the current and potential impact of a symptomatic knee OA treatment modality with respect to the total number of QALYs saved per year across the entire US population.