Reliable predictive determinants that can distinguish patients who could best benefit from intra-articular hyaluronic acid (IAHA) treatment include severe knee pain, younger age, and less severe structural damage. These could be implemented in clinical practice as a useful guide for physicians to plan the treatment. 

Knee osteoarthritis (OA) is a chronic inflammatory disorder. Various types of treatments are recommended nowadays that primarily focus on two strategies: 1) achieving relief from the symptoms and 2) significant improvement in the body functions. The number of drugs in a different dosage form such as oral, topical, and intra-articular therapies including acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs) are used as first-line treatment for OA.

Previous studies have reported that IAHA injections are the most commonly prescribed intra articular drugs for the treatment of OA. However, unanimity concerning the usefulness of IAHA injections for the symptomatic treatment of knee OA is not yet established. This may be attributed to the fact that the current literature provides inconsistent results and conclusions about this treatment.

The present study aimed to identify the determinants that best correlate with the level of response to IAHA in patients with symptomatic knee OA

Rationale behind the research:

To overcome the controversy behind the inconsistent results and conclusion about the use of IAHA for the knee OA treatment.

Objective:

To identify the determinants that best correlate with the level of response to IAHA in patients with symptomatic knee OA. 

Study outcomes measures:

• Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score: The WOMAC questionnaire is self-administered and scores are built upon three domains (pain: 0–20, stiffness: 0–8, and function: 0–68), and their summation yields a total score (0–96)
• Imaging characteristics at T0 as predictors of disease response: The Kellgren–Lawrence (KL) score and the joint space width (JSW) data was obtained from the Osteoarthritis Initiative (OAI)  database (central reading). The magnetic resonance (MR) images were acquired using a double-echo steady-state imaging protocol from 3.0 T apparatus (Magnetom Trio, Siemens) at the four OAI clinical centers.

Time period: T0 and T1 (6 months).

Study Outcomes:

• WOMAC Score:

A significant increase in the average WOMAC pain at from the low pain group to the hgh pain group T0 was reported. This result showed that the level of pain had slightly increased over time. On the other hand, when it was analyzed by the group, the low and moderate group showed an increase in WOMAC score while the hight pain group showed a reduction in the score. There were significant differences between the low and high pain groups, and between the moderate and high pain groups.

The proportion of participants with a decrease in pain level ≥ 20% was highest in the high pain group and that this group also had a significantly smaller percentage of participants with an increase in pain. The number of participants taking glucosamine and chondroitin sulfate was markedly lower in the High pain group than in the other two groups; however, the number receiving steroid injections was significantly higher than in the low pain group. No differences were observed for non-steroidal anti-nflammatory drugs (NSAIDs) with or without analgesics or bone anti-remodeling agents.

• Responders and nonresponders:

The participants with high WOMAC pain score were identified as most critical patients for at least two reasons: 1) the level of pain is clinically meaningful, and 2) the highest improvement was seen with IAHA treatment in this group of participants. These participants’ data was further divided into responders and nonresponders. Based on the level of change in the WOMAC score following treatment: responders had a WOMAC pain score decrease ≥ 20%, and nonresponders had a stable or increased WOMAC pain score.

Also, the participant characteristics at T0 were not significantly different between responders and nonresponders when adjusted for age, sex, and body mass index (BMI). About the change in WOMAC score, the differences between responders and nonresponders were highly significant. In responders,  about 50% participants showed the reduction in WOMAC pain score. The reductions in WOMAC function, stiffness, and total scores were less pronounced than the WOMAC pain, with a similar proportion experiencing a reduction > 40%. The changes in the WOMAC scores in the nonresponder group were positive, indicating, as expected, a worsening of symptoms. Overall, there were no significant differences in the use of concomitant arthritis medication between the low, moderate, and high pain groups and no significant differences in such use were observed between responders and nonresponders.

The finding of the currents study revealed that IAHA injections could be useful not only for the symptomatic treatment of knee OA, but also to improve the joint functions. Data suggested that IAHA injections could be effective for a subset of OA patients. To our knowledge, this is the first time that a longitudinal study of predictive variables showed an excellent response to IAHA injection therapy.

Another key finding was the need to select the responders to IAHA therapy using a cutoff point of at least 20% improvement in WOMAC pain in a population that had a pain score of at least 8 out of 20. T0 pain score ≥ 8 was chosen as it corresponds to a level of symptoms that is perceived as clinically meaningful for patients and, accordingly, was a part of the inclusion criteria for many previous clinical trials. Here, such participants demonstrated clinically significant results of identifying predictors of response and optimizing patient stratification based on a relatively small population. Although the pain improvement cutoff point of 20% might seem somewhat arbitrary, it is well explained by the OMERACT group definition of what minimal pain improvement should be in a responder. Interestingly, this subgroup representing 41% of the responders had > 40% pain improvement, a particular landmark that yielded even more clinical importance. This subgroup, however, was too small to further identify predictors of such excellent response to IAHA therapy.

These results may help physicians in treating patients with IAHA. Some guidelines based on systematic review of the randomized controlled trials data on IAHA concluded that, despite mixed results, the overall data support the efficacy of IAHA injections and recommend such therapy.

This study supports the usefulness of IAHA therapy, especially for the knee OA patients with high levels of knee pain, younger age, higher BMI, and less severe structural damage.