Effects of hyaluronic acid combined with anti-inflammatory drugs compared with hyaluronic acid alone, in clinical trials and experiments in osteoarthritis: a systematic review and meta-analysis

At present, researchers around the world have concluded that osteoarthritis (OA), or degenerative joint disease, a major common joint disease in humans and animals, cannot be cured [1‐5]. Although the cartilage cannot return to normal, some medications, such as corticosteroids (CS) and non-steroidal anti-inflammatory drugs (NSAIDs), are useful for relief of pain and inflammation in affected joints due to their inhibition of inflammatory cytokines [6, 7]. Intra-articular (IA) injection of CS (IA-CS) is allowed by the U.S. Food and Drug Administration (FDA) to reduce synovitis and effusion in OA [8], but NSAIDs are prohibited. Corticosteroids have potent anti-inflammatory effects by inhibiting phospholipase A₂, reducing pain and effusion to a comparatively greater extent than NSAIDs, but prolonged use of CS may result in negative effects and accelerate OA progression. In in vitro studies, triamcinolone acetonide (TA) reduced glycosaminoglycan (GAG) synthesis and increased GAG degradation [9], and dexamethasone (DEX) induced chondrocyte apoptosis through activation of caspases and suppression of the Akt-phosphatidylinositol 3′-kinase signaling pathway [10].

Hyaluronic acid (HA) is a symptomatic slow-acting drug for osteoarthritis (SYSADOA) which is modestly effective in the treatment of moderate knee OA pain [11]. Since 1997, intra-articular injection of HA (IA-HA) in various preparations has been approved by the FDA for knee OA [12]. Previous studies have conducted a meta-analysis of published reports on the use of IA-HA in OA. In nearly all of the papers, HA had a greater effect on pain relief than a placebo [13‐20]. Many recent reports have investigated the synergistic effects, drug interactions and decreased cytotoxicity of HA when combined with other drugs, in order to develop more effective OA treatments [21‐27].

Much research has been conducted on HA combined with anti-inflammatory drugs (IA-HA + AI), via clinical trials and in vivo and in vitro studies. Some experiments have focused on the synergistic or antagonistic effects of these drug combinations. However, there is a lack of strong evidence in the literature supporting the efficacy of IA-HA + AI. This has led to the objective of this study: to analyze the effects of IA-HA + AI in clinical trials and in vivo and in vitro studies, using a systematic review and meta-analysis, to gain new insights that may help clinicians treat OA with IA-HA + AI with more confidence.

For clinical trials, the results of five papers [30‐34] showed the same trend in pain relief. Intra-articular injection of NSAIDs (IA-NSAIDs) or IA-CS could act as rapid-onset pain relief – but not long (slow) acting as in the case of IA-HA – as observed from VAS or WOMAC pain scores within one year, especially at the earliest stage. High molecular weight HA (6000 kDa) was suggested for chronic knee OA pain because it relieved pain by week 12, while triamcinolone hexacetonide could relieve pain within 1 to 2 weeks [41]. Hence, using a combination of IA-HA + AI can be more effective for both short- and long-term pain reduction. This can be used either by pre-treating with anti-inflammatory drugs (IA-DEX or IA-TA) before a series of HA injections, or by administering in combination at the same time, e.g. IA-ketorolac (KE) combined with HA, or IA-TA combined with Hydros (modified HA polymer with a polyethylene glycol cross-linker), which can be entrapped by TA in its structure.

The reasons for collecting papers based on VAS and WOMAC pain scores, which were used as the main parameters for clinical trials, is because pain intensities were estimated by the patients themselves. The VAS, a unidimensional scale for measuring pain intensity, is the most frequently used pain rating scale [42] and is effective for determining average OA pain [43]; while the WOMAC pain subscale was included because it is widely used for measuring OA symptoms and physical disability status [44‐47]. Other parameters, such as joint function, stiffness, and joint swelling, are also important in estimating clinical OA, but were not included in this study because of the limited amount of available data for pooling. Moreover, these parameters have no standard scoring system and are more subjective than the WOMAC pain score, so they should not be used for comparison between studies.

Although IA-AI and IA-HA have been widely used for treatment of OA joints, they could cause AE after injection. Overall RR results indicated that adding CS or NSAIDs in combination with IA-HA did not significantly increase AE compared with IA-HA alone. However, four of the studies included in this paper reported AE, such as severe pain and joint effusion [30, 32‐34]; in these studies, the overall percentage of AE was 10.64% in the IA-HA group (20 of 188 patients) and 13.02% in the IA-HA + AI group (22 of 169 patients). It is possible that both IA-HA and IA-HA + AI can cause AE. However, adding AI in the same injection with HA or injecting the drugs before injection of HA did not increase AE in knee OA patients. Along with certifying the safety of IA-HA and IA-AI, the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) has recommended using IA-HA or IA-CS in symptomatic OA patients [48]. However, the Osteoarthritis Research Society International (OARSI) remains uncertain about recommending the use of IA-HA (except possibly for knee OA, as determined by physician/patient interaction), and has designated it as not appropriate for use in multiple-joint OA [49]. For administration of HA alone, for US-approved HA products for knee OA there was no significant difference in safety outcome and serious AE risk between IA-HA and a saline control [17]. However, AE of IA-HA included: mild transient local reaction; severe post-inflammation reactions which could occur due to administration of highly cross-linked high molecular weight HA [50]; immunogenic response [51]; or possibly a crystal-like response to large particles of HA [52]. For administration of IA-CS, infection, post-injection flare, crystal-induced synovitis, cutaneous atrophy and steroid arthropathy were noted as complications [52]. Moreover, steroid-induced (Charcot-like) arthropathy may occur after multiple injections [52].

In this study, we collected papers on HA combined with various types of AI that had different actions of anti-inflammation and analgesia. In step 2 of advanced pharmacological OA management, IA CS could be injected if a patient still had symptomatic OA [53]. A study comparing the effects of IA CS reported that TH was more effective than MPA on pain reduction at week 3, but that MPA resulted in a greater decrease in VAS and Lequesne index scores at week 8 of treatment [54]. TH was found to have a longer duration of action than TA for improvement of weight-bearing joints [55], while DEX produced analgesia similar to morphine in chronic arthritis [56]. Along with IA NSAIDs, there are a few of the previous study when compared with IA CS. KE is a classical NSAID that could be safely used for IA administration in post-operative pain relief [57, 58]. Some NSAIDs also had beneficial effects in in vivo and in vitro studies, e.g. IA CLX could suppress IL-1β, TNF, and MMP-3, and improved pathological changes of cartilage, similar to IA HA in a rabbit OA model [59]. Likewise, carprofen could decrease the severity of OA cartilage lesions in conjunction with decreasing the width of osteophytes in dog OA model [60]. Based on this study, IA NSAIDs may be used for clinical treatment of OA.

Degradation of aggrecan and collagen in cartilage structure is a manifestation of OA [53, 54]. When considering drug combinations in experiments, this research revealed that adding IA-CS or IA-NSAIDs in combination with HA may reduce the anabolic effect of HA on cartilage by down-regulating anabolic gene (ACAN) expression when compared with IA-HA alone. Hence, those using IA-HA + AI should be aware that AI may reduce anabolic gene expression levels. But these combinations had no clear effect on the level of catabolic gene expression and of GAG protein remaining in cartilage, or on histological changes [61, 62]. This may be due to the use of various histological grading criteria, different drug dosages and study durations, and a limited number of research reports. Further research should be undertaken to confirm these points.

In this study, we analyzed various MW of exogenous HA preparations, including low (MW 500–730 kDa), intermediate (MW 800–2000 kDa) and high MW (average: 6000 kDa) [63] and newly modified structures of HA to entrap other drugs. The effect of each MW of IA-HA + AI on OA joints should be collected, but there were a low number of papers for pooling data. Although we included combinations of HA with several different drugs, the results showed significantly reduced pain for the combinations compared with HA alone.

Limitations of this study are a low number of related research reports and small pooled sample size because this research was conducted based on a literature database search [64]. Moreover, in clinical trials of OA, the comparison of IA-AI and IA-HA + AI is interesting to include, but no conclusions can be drawn because of the low number of experiments using anti-inflammatory drugs alone to treat OA for an extended period. However, the strengths of this paper are revealing data on the use of HA plus AI in the field of clinical, in vivo and in vitro. To update the new knowledge of HA + AI based on increased population of humans and animals, using statistical analysis.