In the United States (U.S.), osteoarthritis (OA) is the most common type of
arthritis and joint disorder, with the knee being the most frequently involved
symptomatic joint.7

Degenerative joint disease (usually termed OA) of the knee is a condition
characterized by the progressive destruction of the articular cartilage that
lines the knee joints, the subchondral bone surfaces, and synovium,
accompanied by pain, immobility, and reduction in function and the ability to
complete activities of daily living (ADL).1 Knee OA is a chronic debilitating
condition - predominantly occurring among the elderly - that affects a large
share of the population worldwide. It is the predominant form of arthritis and
the leading cause of disability in the U.S.5

Hyaluronic acid (HA) is a component of synovial fluid, which lubricates the
joint and absorbs shock. HA is a glycosaminoglycan molecule within the knee
joint where it provides viscoelastic properties to synovial fluid.3 HA is a
glycosaminoglycan that occurs naturally within the synovial fluid of the knee,
providing lubrication of the joint and protecting the cartilage from
mechanical degradation. HA has been shown to provide anti-inflammatory and
chondroprotective effects, increase proteoglycan and HA synthesis, and reduce
nerve impulses and nerve sensitivity associated with OA pain.16 HA production
is generally reduced and may be of poorer quality with OA, which may
exacerbate inflammation. Intra-articular HA aims to replace depleted or poor-
quality HA in the joint. HA is available commercially prepared and ready for
injection. HA products differ by molecular weight and cross-linkage.

HA injections reduce cartilage breakdown that results from a loss of cartilage
oligomeric matrix protein and also reduces inflammatory cytokines such as
interleukin-1.7

HA is also known as Hyaluronan or Hyaluronate. Intra-articular injection of HA
is also known as viscosupplementation. Viscosupplementation is the injection
of an intra-articular compound made of high molecular weight fluid containing
hylan products (derivative of hyaluronan) that essentially functions as a
viscoelastic glycosaminoglycan.8

Patients with OA of the knee who are not responsive to conservative
treatments, may be candidates for intra-articular HA for treatment of knee OA.
There are several viscosupplementation products (such as Euflexxa, Durolane,
Gel-One, GenVisc 850, Gelsyn-3, Hyalgan, Hymovis, Monovisc, Orthovisc,
Supartz FX, Synvisc, Synvisc-One, SynoJoyntTM, Visco-3TM, TriVisc, and
Triluron) that have been approved by the U.S. Food and Drug Administration
(FDA) for the treatment of pain associated with OA of the knee who have failed
to respond adequately to conservative non-pharmacologic therapy and simple
analgesics (e.g., acetaminophen).

**Covered Indications**

Various Hyaluronan preparations (viscosupplementation) for intra-articular
injections of the knee are considered reasonable and necessary when ALL of the
following criteria documented in the medical record are met:

1. Symptomatic OA of the knee. Pain that interferes with functional activities (such as, ambulation and prolonged standing).

2\. The diagnosis is supported by radiographic evidence of OA of the knee, for
example, joint space narrowing, subchondral sclerosis, osteophytes, and
subchondral cysts.

3\. Trial and failure or contraindication of at least 3 months of conservative
therapy:

  * Non-pharmacologic therapy (e.g., physical therapy, exercise, weight management, self-management programs, knee brace, cane)
  * Pharmacologic therapy (e.g., acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs) (oral, topical), topical capsaicin)

4\. Failure of or contraindication to intra-articular glucocorticoid
injections.

For patients who have responded to a prior series, a REPEAT* series of
viscosupplement therapy is considered reasonable and necessary when ALL of the
following are met:

  * Patient continues to meet initial criteria
  * Symptoms have recurred
  * Patient has experienced improvement in pain and functional capacity following the previous series of injections
  * At least 6 months have elapsed since the prior series of injections

* A series is defined as a set of injections for each joint and each treatment as per the FDA prescribing information

**Limitations**

****

Services that are not reasonable and necessary and cannot be covered by
Medicare are the following:

1\. The dose and frequency of administration should be consistent with the FDA
approved labeling. Doses and frequencies that exceed the FDA recommended
dosage/frequency as per the prescribing information, are considered not
reasonable and necessary and not covered by Medicare.

2\. Initiation of a repeat series of treatment when at least 6 months have not
elapsed since the prior series of injections is considered not reasonable and
necessary and not covered.

3\. It is considered not reasonable and necessary as the initial treatment of
OA of the knee.

4\. It is contraindicated with infections or skin disease in the area of the
injection site or joint and considered not reasonable and necessary and not
covered by Medicare.

5\. It is contraindicated to administer these products if you are allergic to
hyaluronate products.

6\. A diagnosis other than OA is considered not reasonable and necessary and
not covered by Medicare.

7\. When there was no improvement in knee pain and functional improvement from
a previous series of injections, a repeat series of injections will be
considered not reasonable and necessary and will not be covered.

8\. Imaging procedures for the purpose of needle guidance that may be
considered reasonable and necessary are ultrasound or fluoroscopy. The
documentation must support why imaging is needed for needle guidance and
insertion. Other imaging modalities (e.g., computed tomography (CT) scan,
magnetic resonance imaging (MRI), arthrography) for the purpose of needle
guidance and insertion will be considered not reasonable and necessary and not
covered by Medicare.

Kolasinski, et al. (2020) developed guidelines and recommendations for
clinicians and patients in making treatment decisions for the management of
OA. Clinicians and patients should engage in shared decision-making that
accounts for patients' values, preferences, and comorbidities. Many providers
want the option of using HA injections when glucocorticoid injections or other
interventions fail to adequately control local joint symptoms. The conditional
recommendation is consistent with the use of HA injections, in the context of
shared decision-making that recognizes the limited evidence of benefit of this
treatment, when other alternatives have been exhausted or failed to provide
satisfactory benefit.2

Maheu, et al. (2019) conducted a literature review to determine the strength
of evidence in support of the efficacy and safety of intra-articular HA, from
randomized controlled trials (RCTs) and meta-analyses. The results of their
analysis showed that intra-articular HA provides a moderate symptomatic
benefit to knee OA patients and without major safety concerns. In fact, intra-
articular HA may offer 1 of the best benefit/risk ratios among pharmacologic
options, as measured by improvements in knee OA health outcomes, overall gain
in quality adjusted life years and substantial delays in time to total knee
replacement (TKR). They concluded by advocating for the consideration of
recommending intra-articular HA injection as a treatment option in the
management of knee OA, tailored by disease stage and patient phenotype.
Further research efforts should focus on identification of OA patient
subgroups that demonstrate a more robust response to intra-articular HA,
determination of long term effects of repeat intra-articular HA injections on
patient reported outcomes and TKR-sparing effect, further elucidation of
disease-modifying effects, and the potential for combination therapy with
other pharmacologic and non-pharmacologic therapies to optimize the management
of knee OA.3

Newberry, et al. (2015) conducted a review of the evidence that intra-
articular injections of HA in individuals with degenerative joint disease (OA)
of the knee improve function and quality of life (QoL) and that they delay or
prevent the need for TKR, specifically for individuals age 65 and over. They
concluded that RCTs enrolling older participants showed a small, statistically
significant effect of HA on function and relatively few serious adverse
events; however, no studies limited participation to those 65 years or older.
No conclusions can be drawn from the available literature on delay or
avoidance of TKR through the use of HA. Studies that can compare large numbers
of treated and untreated individuals, preferably with a randomized design, are
needed to answer this question.1

The American Academy of Orthopaedic Surgeons (AAOS) Management of
Osteoarthritis of the Knee (Non-Arthroplasty) Evidence-Based Clinical Practice
Guideline adopted August 31, 2021 is based on a systemic review of the
available scientific and clinical information and accepted approaches to
treatment and/or diagnosis. Twenty-eight studies (17 high-strength and 11
moderate-strength) assessed intra-articular HA injections when compared to
controls. When we differentiated high-versus low-molecular weight
viscosupplementation our analyses demonstrated no significant differences
among different viscosupplementation formulations. Some studies demonstrated a
statistical benefit with the use of HA but could not reach the significance
for a minimally clinical meaningful difference, leading to the conclusion that
viscosupplementation can represent a viable option for some patients that
failed other treatments when appropriately indicated. The number needed to
treat to see a tangible benefit from HA was 17 patients. Furthermore, this
difference was most evident at 6 weeks and 3 months. This 2021 version of this
guideline found that statistically significant improvements were associated
with high-molecular cross-linked HA but when compared to mid-range molecular
weight, statistical significance was not maintained. This newer analysis did
not demonstrate clinically relevant differences when compared to controls.
However, as previous research reported benefits in their use, the group felt
that a specific subset of patients might benefit from its use. The HA
recommendation was downgraded to Moderate Strength of recommendation due to
lack of generalized results. HA intra-articular injection(s) is not
recommended for routine use in the treatment of symptomatic OA of the knee.
Currently intra-articular treatments are a commonly utilized approach in
treating symptomatic knee OA, hence there should be no issues implementing
this recommendation as it does not influence a major change in clinical
practice, and it provides further evidence to support and guide these
practices. Future research in this area should embrace detailed OA
characterization including sub-group analyses and OA severity stratification.4

Bannuru, et al. (2016) conducted a systemic review on RCTs and meta-analyses
to examine the risks of HA compared with intra-articular placebo and
investigated whether the risks vary among individual HA preparations. They
identified 74 studies involving 13,032 participants aged between 45 and 75
years. The overall incidence of local reactions reported across all products
was 8.5%. Commonly reported adverse events (AEs) were transient local
reactions, such as pain, swelling and arthralgia, which subsided rapidly. They
concluded that given the very low incidence of any particular AEs, that HA
products are relatively well tolerated. These products have a similar safety
profile compared to each other.5

Bannuru, et al. (2015) examined the efficacy of treatments of primary knee OA
using a network meta-analysis design, which estimates relative effects of all
treatments against each other. For pain, all interventions significantly
outperformed oral placebo, with effect sizes from 0.63 for the most
efficacious treatment (HA) to 0.18 for the least efficacious treatment
(acetaminophen). For function, all interventions except intra-articular
corticosteroids were significantly superior to oral placebo. For stiffness,
most of the treatments did not significantly differ from one another.6

Campbell, et al. (2015) conducted a systematic literature review of meta-
analyses comparing treatment of knee OA with intra-articular
viscosupplementation (intra-articular HA) versus oral NSAIDs, intra-articular
corticosteroids, intra-articular platelet-rich plasma, or intra-articular
placebo to determine which meta-analyses provide the best current evidence and
identify potential causes of discordance. The available evidence shows that
intra-articular HA provides small but clinically relevant improvements in knee
pain and function when compared with intra-articular placebo. Although there
were no major clinical differences in the efficacy of intra-articular HA
versus oral NSAIDs in relieving knee pain and restoring function, the fact
that intra-articular HA has a more favorable side-effect profile than oral
NSAIDs makes intra-articular HA a good option for patients unable to tolerate
oral NSAIDs. Both intra-articular HA and intra-articular corticosteroids were
effective in controlling pain, with steroids providing better short-term
relief and HA providing more long-term relief starting in the 5 to 13-week
post injection period and lasting for up to 26 weeks. Regarding intra-
articular HA versus intra-articular platelet-rich plasma, intra-articular HA
improved knee function at 2 and 6 months after injection but the effects were
less robust than those of intra-articular platelet-rich plasma. Intra-
articular HA in terms of pain and function may be a better treatment option as
more high quality randomized, double-blinded studies are needed to compare the
effects of platelet-rich plasma versus other treatments before it can be fully
endorsed as a viable universal option for patients with knee OA. They
concluded the current highest level of evidence suggests that intra-articular
HA is a viable option for patients with knee OA. Its use results in
improvements in knee pain and function that can persist for up to 26 weeks in
comparison with other treatment modalities. Intra-articular HA has been shown
to have a good safety profile, and its use should be considered in patients
with early knee OA.8

Berkoff, et al. (2012) conducted a peer-reviewed literature search to compare
the accuracy of intra-articular large joint injections with imaging guidance
versus conventional anatomical guidance. Numerous imaging modalities may be
used to aid the clinician in identifying the correct trajectory for intra-
articular injections including ultrasound, fluoroscopy, CT, and MRI. The
results of the current analysis demonstrate that use of imaging guidance
improves the accuracy of intra-articular injection in large joints including
the knee. Furthermore, the use of ultrasound guidance specifically at the knee
greatly increases the likelihood of correct needle placement. Ultrasound
guidance of knee injections resulted in better accuracy than anatomical
guidance (95.8% versus 77.8%, _P_ < 0.001), yielding an odds ratio of 6.4 (95%
confidence interval 2.9-14).9

Ong, et al. (2016) conducted a retrospective observational study design based
on the 5% sample of Part B Medicare data (carrier/physician claims) from 2005
to 2012. The 5% Part B Medicare data (2005-2012) were used to identify knee OA
patients who underwent knee arthroplasty (KA).The time from diagnosis of OA to
KA was compared between patients with HA injections and without (no HA) intra-
articular HA use. The "HA" cohort was associated with a longer time to KA of
8.7 months (95% confidence interval: 8.3 - 9.1 months; _P_ < 0.001) compared
with the "no HA" cohort. Their analysis of a large, elderly, knee OA
population showed a significantly longer time from diagnosis of OA to KA for
those who were treated with intra-articular HA. It is unclear if the extended
time may lead to less KA utilization or whether the delay could provide
additional time for patients to better address or control preexisting
conditions before KA, which could aid in reducing postoperative morbidity.12

Newberry, et al. (2015) conducted a systematic review of the effectiveness of
HA in the treatment of severe degenerative joint disease of the knee. The
Coverage and Analysis Group at the Centers for Medicare and Medicaid Services
(CMS) requested from The Technology Assessment Program (TAP) at the Agency for
Healthcare Research and Quality (AHRQ), a review of the evidence that intra-
articular injections of HA in individuals with degenerative joint disease (OA
[HA]) of the knee improve function and QoL and that they delay or prevent the
need for TKR, specifically for individuals age 65 and over. The results of the
study noted only 1 RCT reported on delay or avoidance of TKR as a pre-
specified outcome of interest and found a non-statistically significantly
longer delay of TKR compared with placebo; 2 RCTs reported TKR only as a
secondary outcome; and 13 published observational studies reported on TKR as
an outcome in HA-treated participants.

Eighteen RCTs that enrolled participants of average age 65 or older reported
on functional outcomes of intra-articular HA injection: pooled analysis of 10
sham-injection placebo-controlled, assessor-blinded trials showed a
standardized mean difference of -0.23 (95% CI -0.34, -0.02) significantly
favoring HA at 6 month follow-up. Durability of effect could not be assessed
because of the short duration of most studies. Too few head-to-head trials
were available to assess superiority of 1 product over another. Three RCTs
that compared changes in QoL/Health-Related QoL between HA- and placebo-
treated participants reported no differences between active treatment and
placebo. Two recent large, good quality systematic reviews that conducted
meta-analysis of the effects of HA on pain and function (pooling 71 and 52
RCTs for the outcome of pain, respectively) showed a significant and
clinically important effect of HA on both outcomes among adults of all ages,
but a subgroup analysis that included only the largest double-blind placebo-
controlled studies reduced the average effect of HA to less than the
prespecified minimum clinically important difference. Studies of intra-
articular HA reported few serious adverse events, with no statistically
significant difference in the rates of serious or non-serious adverse events
between HA- and placebo-treated groups.

They concluded that trials enrolling older participants show a small,
statistically significant effect of HA on function and relatively few serious
adverse events; however, no studies limited participation to those 65 years or
older. No conclusions can be drawn from the available literature on delay or
avoidance of TKR through the use of HA. Studies that can compare large numbers
of treated and untreated individuals, preferably with a randomized design, are
needed to answer this question.1

Kolasinski, et al. (2020) developed an evidence-based guideline for the
comprehensive management of OA as a collaboration between the American College
of Rheumatology (ACR) and the Arthritis Foundation, updating the 2012 ACR
recommendations for the management of hand, hip, and knee OA. Based on the
available evidence, either strong or conditional recommendations were made for
or against the approaches evaluated. This guideline provides direction for
clinicians and patients making treatment decisions for the management of OA.
Clinicians and patients should engage in shared decision-making that accounts
for patients' values, preferences, and comorbidities. These recommendations
should not be used to limit or deny access to therapies. In OA generally,
intra-articular glucocorticoid injection is conditionally recommended over
other forms of intra-articular injection, including HA preparations. Head-to-
head comparisons are few, but the evidence for efficacy of glucocorticoid
injections is of considerably higher quality than that for other agents.

Many providers want the option of using HA injections when glucocorticoid
injections or other interventions fail to adequately control local joint
symptoms. In clinical practice, the choice to use HA injections in the knee OA
patient who has had an inadequate response to nonpharmacologic therapies,
topical and oral NSAIDs, and intra-articular steroids may be viewed more
favorably than offering no intervention, particularly given the impact of the
contextual effects of intra-articular HA injections. The conditional
recommendation against is consistent with the use of HA injections, in the
context of shared decision-making that recognizes the limited evidence of
benefit of this treatment, when other alternatives have been exhausted or
failed to provide satisfactory benefit.2

Trojian, et al. (2016) performed a network meta-analysis of the relevant
literature to determine if there is a benefit from HA as compared with intra-
articular corticosteroid and intra-articular placebo based on the evaluation
of treatment effect by examining the number of subjects within a treatment arm
that met the Outcome Measures in Rheumatoid Arthritis Clinical Trials-
Osteoarthritis Research Society International (OMERACT-OARSI) criteria, which
is different and more relevant than methods used in other reviews which
examined if the average change across the treatment groups was clinically
different. Our results demonstrate evidence of small but statistically
significant improvement for the group of subjects treated with HA injections
compared with those treated with intra-articular corticosteroid or intra-
articular placebo injections with regard to pain and function as assessed by
the relevant Western Ontario and McMaster University Arthritis Index (WOMAC)
subscales. The statistically significant results that we have identified for
HA versus intra-articular corticosteroid and intra-articular placebo also
represent a clinically relevant difference.

The American Medical Society for Sport Medicine (AMSSM) recommends the use of
HA for the appropriate patients with knee OA. "We RECOMMEND
viscosupplementation injections for K-L grade ll-lll knee OA in those patients
above the age of 60 years based on HIGH quality evidence demonstrating benefit
using OMERACT-OARSI Responder Rating." But the evidence should be downgraded
because of indirectness for those younger than 60 years. "We SUGGEST
viscosupplementation injections for knee OA for those under the age of 60
years based on MODERATE quality evidence due to response of treatment in those
over 60 years of age."14

Strand, et al. (2015) performed a meta-analysis for randomized, sham
controlled trials of intra-articular HA injection for treatment of knee OA.
All sham-controlled trials used saline injections as a control.
Viscosupplementation resulted in very large treatment effects between 4 and 26
weeks for knee pain and function compared to preinjection values, with
standardized mean difference values ranging from 1.07 to 1.37 (all _P_ <
0.001). Compared to controls, standardized mean difference with
viscosupplementation ranged from 0.38 to 0.43 for knee pain and 0.32 to 0.34
for knee function (all _P_ < 0.001). There were no statistically significant
differences between viscosupplementation and controls for any safety outcome.
They concluded that intra-articular injection of U.S.-approved
viscosupplements is safe and efficacious through 26 weeks in patients with
symptomatic knee OA. Limitations of this meta-analysis were significant
heterogeneity in efficacy outcomes among included studies and smaller
treatment effects in higher quality trials.15

Altman, et al. (2018) stated the evidence suggests HA has significant short-
term efficacy (less than or equal to 6 months) for treating knee OA pain.
While a single series of intra-articular HA has been well studied, the
efficacy and safety of repeated courses of intra-articular HA injection
therapy in knee OA patients have not been evaluated as frequently. They
conducted a literature search using MEDLINE, EMBASE and PubMed databases. A
total of 17 articles (RCTs and 10 cohort studies) met the pre-defined
inclusion criteria. The inclusion criteria were (1) RCTs, (2) cohort studies
with intra-articular HA as the primary treatment, (3) studies that provide at
least 1 repeat course of intra-articular HA, (4) studies that measured knee
pain as an outcome and (5) articles published in English. Studies ranged from
investigating a single reinjection cycle to 4 repeat injection cycles. All
studies reported pain reduction from baseline in the intra-articular HA
treatment group throughout the initial treatment cycle, and either sustained
or further reduced pain throughout the repeated courses of treatment. The
study with the longest follow-up repeated intra-articular HA injection every 6
months for 25 months. Pain decreased after the first course and continued to
decrease until the end of the study, with an approximate 55% reduction in pain
compared to baseline. The authors concluded that repeated courses of intra-
articular HA injections are an effective and safe treatment for knee OA.
Repeat courses were demonstrated to maintain or further improve pain reduction
while introducing no increased safety risk.16

The 2020 Department of Veteran Affairs/Department of Defense (VA/DoD) OA
Clinical Practice Guidelines (CPG) Work Group decided upon a "Weak for"
recommendation and suggest offering intra-articular viscosupplementation
injection(s) for patients with persistent pain due to OA of the knee
inadequately relieved by other interventions. Recent evidence comparing
viscosupplementation injections to corticosteroid injections found that
corticosteroid injections improved the short-term (1 month) visual analog
scale (VAS) pain scores better than viscosupplementation injections, but that
they are equivalent at 3 months, and viscosupplementation injections provided
statistically significant improvement in VAS pain scores compared to
corticosteroid injections at 6, 9, and 12 months. Further, they shared similar
functional improvements in range of motion at 3 and 6 months and similar risk
profiles.18

The analysis of evidence reviewed for the use of HA injections for knee OA
included a literature review from RCTs and meta-analyses, retrospective
observational study design, and evidence based clinical practice guidelines
from the AAOS and the ACR and the Arthritis Foundation and the VA/DoD OA CPG
Work Group. The results of an analysis of literature reviewed to determine the
strength of evidence in support of the efficacy and safety of intra-articular
HA showed that intra-articular HA provides a moderate symptomatic benefit in
knee OA patients and without safety concerns.3

The Evidence-Based Clinical Practice Guidelines from the AAOS concluded that
viscosupplementation can represent a viable option for some patients that
failed other treatments when appropriately indicated. HA intra-articular
injection(s) is not recommended for routine use in the treatment of
symptomatic OA of the knee.4 The HA recommendation was downgraded to Moderate
Strength of recommendation due to lack of generalized results.4

Literature evaluating pain control and function concluded that intra-articular
HA results in improvements in knee pain and function that can persist for up
to 26 weeks in comparison with other treatment modalities.6,8

The systematic review by the TAP concluded that trials enrolling older
participants showed a small, statistically significant effect of HA on
function and relatively few serious adverse events.1

The Evidence Based Guideline from the ACR and the Arthritis Foundation stated
"a conditional recommendation against is consistent with the use of HA
injections, in the context of shared decision making that recognizes the
limited evidence of benefit of this treatment, when other alternatives have
been exhausted or failed to provide satisfactory benefit."2

Literature evaluating the efficacy and safety of repeated courses of intra-
articular HA injection therapy in knee OA patients concluded that repeated
courses of intra-articular HA injections are an effective and safe treatment
for knee OA.16

The AMSSM recommends the use of HA for the appropriate patients with knee OA.
"We RECOMMEND viscosupplementation injections for K-L grade ll-lll knee OA in
those patients above the age of 60 years based on HIGH quality evidence
demonstrating benefit using OMERACT-OARSI Responder Rating." But the evidence
should be downgraded because of indirectness for those younger than 60 years.
"We SUGGEST viscosupplementation injections for knee OA for those under the
age of 60 years based on MODERATE quality evidence due to response of
treatment in those over 60 years of age."14

The VA/DoD OA CPG Work Group decided upon a "Weak for" recommendation and
suggest offering intra-articular viscosupplementation injection(s) for
patients with persistent pain due to OA of the knee inadequately relieved by
other interventions.18