Introduction

Knee osteoarthritis (KOA) is a chronic slowly progressive and debilitating condition, which is characterized by pain, limitation of physical activity. It is a leading cause of disability, impaired quality of life and activities of daily living [1].

Traditionally, knee osteoarthritis is considered as a degenerative disease because of cartilage degeneration, loss of joint space and osteophyte formation in radiography, but recent observations indicate existence of an inflammatory process which involves the whole tissues of the joint, and contributes to the development of symptoms and progression of structural changes [2, 3].

Mechanical and biochemical factors are also responsible for the development of synovitis, cartilage breakdown, osteophytes formation, subchondral bone sclerosis and alterations in the joint capsule [3]. Synovial membrane inflammation is important, because it is linked with symptoms such as joint pain, effusion, joint dysfunction, and progression of structural changes and cytokines abnormalities [4–7].

Reduction of osteoarthritic pain by anti-inflammatory drugs supports an association between inflammatory process and pain. However, response to anti-inflammatory drugs in KOA is complex. It is partly dependent on the patterns of clinical symptoms, type of involved joints and responsible factors of pain [8, 9]. Existing data suggest that targeting synovial inflammation at early stage of KOA may provide a possible beneficial effect in delaying cartilage damage or osteophytes formation [4, 5, 10].

Several treatment guidelines have been established to relieve pain, improve function and prevent clinical exacerbation in knee osteoarthritis [11]. Multiple medications including systemic and local non-steroidal anti-inflammatory drugs (NSAIDs), acetaminophen, opioids which have been considered for treatment of KOA are effective only in a proportion of patients.

In non-responders to standard therapy, particularly in patients with joint effusion, many drugs are administrated through intra-articular injection to attain a rapid benefit through direct effect on synovial inflammation [11, 12].

About 50% of patients with KOA have synovitis and joint effusion at the time of arthroscopy. Severity of synovitis correlates positively with pain, and shrinkage of synovial tissue volume correlates with treatment response [13, 14]. Hence, suppression of synovial inflammation has been considered as the main target of treatment for pain relief [10].

Unlike most osteoarthritis drugs, intra-articular corticosteroids (IACS) are safe, inexpensive and well tolerated by patients. Because of their moderate analgesic effect, they can be considered for pain relief in patients who are not responsive to conventional medications [15].

The beneficial effect of intra-articular corticosteroid in KOA is assumed to be mediated through its anti-inflammatory effect against synovial inflammation which is an integral part of osteoarthritis (OA) process. However, efficacy of intra-articular corticosteroids in KOA depends upon the presence, extent and severity of synovitis and its association with pain [14, 16]. However, the prevalence of synovitis varies across different study populations and is dependent to its definition and diagnostic methods [17, 18].

At present, it is not possible to determine which patients gain the most therapeutic benefits from IACS treatment. Based on anti-inflammatory characteristics of IACS, it is hypothesized that, patients with knee joint synovitis and effusion, or KOA patients with clinical exacerbations will attain greater benefit from IACS therapy.

In particular, individuals with minimal cartilage destruction are expected to attain most improvement in knee function [10, 11]. However, the results of many meta-analyses and RCTs which addressed efficacy of IACS in KOA are conflicting, and the outcomes of treatment vary from no efficacy or little short duration of improvement in pain and/or joint function to a few or several weeks of pain relief [14, 16, 19–21].

Inconsistent results can be attributed to variations in study design, outcome measures, patients selection, treatment strategy, duration of follow-up period. Other factors such as presence or absence of synovitis, joint effusion, severity of structural lesions, severity of synovial inflammation, sources of pain, accuracy of intra-articular injection can also affect treatment responses [8, 22].

Even intra-articular injection of normal saline, or joint fluid aspiration itself can provide pain relief [7, 16]. A meta-analysis of 32 studies involving 1705 patients revealed a significant long-term pain reduction by intra-articular injection of normal saline in patients with knee osteoarthritis [23].

Yet, it is difficult to predict the therapeutic effect of IACS, and to discriminate patients who are responders or non-responders. Hence this narrative review aims to elucidate the effect of IACS in KOA and to recognize the factors that predict treatment response by review of the existing data. Treatment response was defined as pain relief or significant pain reduction with or without functional improvement for one week or longer duration after IACS therapy or prevention of structural progression in long-term studies.

For these purposes, English language databases were searched as recommended to identify potential studies which have been published in Medline/PubMed, Scopus and Google Scholar since 2000 by using keywords such as knee osteoarthritis, synovitis, effusion, intra-articular corticosteroid, efficacy, treatment, pain relief, functional improvement, predictors. In addition the references of the selected papers were searched to find eligible studies.

Studies in which pain relief with or without functional improvement or changes in pain was considered as an outcome and was evaluated by either Visual Analogue Scale (VAS) or Western Ontario and McMaster Universities OA Index (WOMAC), or other valid measures were selected. Studies without pain assessment were excluded.

A total of 345 studies were found which 219 papers were irrelevant based on the titles and so were excluded. Among 126 remaining full-text 93 studies were not eligible due to lack of interested data and removed. A total of 33 full-texts which have been found to be interest were selected for analysis (Fig. 1).

Fig. 1

Flow diagram of selected studies.

All relevant sources were critically analyzed to ensure diversity in the sources and to avoid bias [24]. The selected studies were categorized according to study designs and the results were presented under subheadings in relation to the diagnosis and prevalence of synovitis, synovitis and pain, efficacy of IACS and predictors of treatment response.

Diagnosis of synovitis

The diagnosis of knee synovitis is important for identification of patients who are likely to benefit from IACS therapy. Fluctuations in synovial inflammation and joint effusion can be a sign of KOA flare or treatment response. Arthrocentesis is the best method for the diagnosis and quantification of joint effusion, but this measure is invasive and painful. Accurate estimation of total effusion by joint aspiration is often impossible [25].

A clinical diagnosis of synovitis is suspected in the presence of a swollen joint with effusion, redness, warmness, and pain. However, clinical detection of synovitis at early stage of KOA is difficult because of low specificity as well as low intraobserver and interobserver reliability of clinical examination [26].

Existence and extent of synovial inflammation can be also confirmed by ultrasonography and MRI, even in subjects with few symptoms or without clinical synovitis who have limited cartilage or subchondral bone lesions.

Moreover, synovitis can be detected as changes in thickening of synovium or localized proliferative changes by arthroscopic examination of the knee joint [4].

Prevalence of synovitis in knee osteoarthritis

Synovial abnormalities have been shown in different stages of osteoarthritis and existing data indicate an important role for synovial abnormalities in the pathogenesis of osteoarthritis [27].

About 50% of patients with KOA have synovial inflammatory changes such as thickening of synovium or localized proliferative changes [4]. Application of sensitive imaging technics and tissue examination indicated a high prevalence of synovial inflammation in all stage of osteoarthritis [1].

Nonetheless, the prevalence of synovitis in KOA varies across different studies according to diagnostic measures. In one large study of patients with symptomatic KOA, 46% of patients had synovial inflammation or joint effusion on sonographic examination [17]. By using contrast-enhanced as well as non-enhance magnetic resonance imaging (MRI), synovitis was detected in 70% of patients without joint effusion and in more than 95% of patients with knee joint effusion [18].

A meta-analysis of 24 observational studies revealed a pooled prevalence of ultrasound detected synovial effusion, synovial hypertrophy, and Doppler signal in 51.5%, 41.5%, and 23.5% of people with KOA and pain respectively [28].

Association between synovitis and pain in knee osteoarthritis

In patients with KOA several parameters including synovitis, joint effusion, meniscal tears and bone marrow lesions are associated with pain [29].

Wang et al. [27] found an independent association between MRI-detected synovitis and pain in a large cross-sectional and longitudinal study of patients with knee osteoarthritis [30].

Another longitudinal study found a relationship between fluctuations of synovitis and change in pain and cartilage volume in knee osteoarthritis. In this study changes in pain and synovial inflammation were assessed by VAS and MRI at baseline, 15 months and 30 months later. The strongest correlation was observed between pain and infrapatellar synovitis [31].

In one study, 80% of patients with moderate pain had synovitis, and there was a strong correlation between severity of pain and synovitis detected with dynamic contrast-enhanced MRI (DCE-MR). In patients with synovitis pain was 9.2 times greater than those without synovitis [32]. However, knee pain can occur in the absence of synovitis or effusion due to bone marrow lesions or intra-articular pathology [33].

Efficacy of intra-articular corticosteroids in knee osteoarthritis

Predictors of treatment response

Identification of a clinical or imaging findings to predict response to IACS therapy in KOA was the topic of many RCTs and meta-analyses as well as a number of uncontrolled clinical studies. A few clinical or imaging parameters have been found to yield predictive ability (Table III and Table IV).

A relationship between synovitis with pain, swelling, effusion, and cartilage destruction [4, 10, 16, 34, 47, 48] suggests synovitis as a target for treatment as well as a parameter in predicting treatment response. Predictive accuracy of other parameters such as the presence of joint effusion, severity of symptoms at baseline, even predictive performance of just joint fluid aspiration alone, has been also investigated in a few studies [16, 49].

In 3 clinical trials, the presence of synovitis was a predictor of treatment response, and improvement of synovitis as detected by either ultrasound or MRI was significantly associated with reduction of knee pain [10, 34, 49].

In a recent 1-year prospective study of 132 patients with KOA the presence of pain or ultrasound-detected joint effusion one month after initiation of IACS treatment was predictor of treatment response at one year [41].

In contrast in an uncontrolled study neither synovitis nor effusion was predictor of treatment response, but higher scores of pain and the presence of patellar tendinopathy at baseline were predictors of significant improvement. In this study 68% of patients had synovitis and 46% had joint effusion in clinical examination, and musculoskeletal ultrasound detected synovitis and effusion were found in 79 % and 62% of patients respectively [42].

Similarly, in another prospective study by Bevers et al. [50] ultrasound-detected synovitis was not predictor of pain relief. This issue may indicate the existence of synovitis could not be detected by using current diagnostic methods or pain reduction in KOA is not related to suppression of synovitis alone. Higher number of synovial fluid white blood cells (SF-WBC) was predictor of treatment response in one study of patients with symptomatic knee osteoarthritis. In this study a single 80 mg IAMP injection in subjects with higher total SF-WBC count was associated with greater pain reduction [51].

In some studies lower structural damages, age, local tenderness were predictors of treatment response [46, 52, 53]. In many studies no predictors were detected and even, the presence of synovitis was not predictor of treatment response [14, 46, 52–54]. In a meta-analysis of 21 studies by Hirsch et al. [55] none of clinical, sonographic or radiographic features of KOA were predictor of treatment response.

Nonetheless, Maricar et al. [49] in a meta-analysis of 11 studies found an association of treatment response with several parameters such as, joint effusion, joint fluid withdrawal, severity of disease, absence of synovitis, baseline severity, accuracy of intra-articular injection of corticosteroid. In this study identification of a specific predictor was impossible.

Safety of intra-articular corticosteroids in knee osteoarthritis

Long-term safety of IACS therapy in symptomatic KOA has been shown in 2 meta-analyses [20, 39]. In these studies adverse effects in the treatment and placebo groups were similar. In one meta-analysis local adverse effect in IACS group was lower than in IAHA group [39]. The safety of IACS has been also addressed in 2 RCTs [19, 36].

Raynauld et al. [36] found no deleterious anatomical structures changes despite of clinical improvement in patients taking repeated IACS every 3 months over 2 years of the study period.

By contrast, McAlindon et al. [19] in another RCT, found that repeated IACS every 3 months was associated with greater cartilage volume loss without any beneficial effect. Two observational studies [56, 57] found and association between IACS and progression of knee osteoarthritis.

However, the results of latter studies in assigning radiographic progression to IACS alone are limited because, several factors such as retrospective study design, patients selection, self-reported data regarding the type, time and number of IACS could confound the results.

Furthermore, patients with and without progressions have not been matched regarding baseline severity of osteoarthritis, as well as many associated factors of osteoarthritis progression. In addition, the safety outcome was not the primary objective of these studies.

The results of a meta-analysis of 40 studies which reviewed current literature on the effect of IACS on articular cartilage, supported the beneficial effects of IACS administration in knee osteoarthritis. In this study the impact of IACS on articular cartilage was time-and-dose dependent.

The beneficial effects were observed in studies with low doses of steroids and short duration of treatment, whereas high doses and long-term IACS therapy were associated with detrimental effects [58].

Overall, using intra-articular corticosteroids in KOA is relatively safe for short-term period, but its long-term effects on articular cartilage and other joint structures are unknown and remain to be determined [59].

Limitations

This study has several limitations, because, the studies included in this review were different in respect to study design, study population, patients characteristics, severity of structural damages, dosage of IACS, number of injections, duration of follow-up, treatment outcome and measures applied for assessment of treatment efficacy. In particular, the presence or absence of synovial inflammation and the method of diagnosis of synovitis is important. These factors can differently affect the results of treatment across studies.

Osteoarthritis is a multifactorial disease with heterogeneous phenotypes in terms of clinical manifestations and etiologies. Hence, knee osteoarthritis patients are classified to subgroups according to structural, etiological and epidemiological phenotypes. This classification system is helpful to identify a specific subgroup of patients who display inflammatory characteristics and thus may gain more benefit from anti-inflammatory treatment [60].

Therefore, in each study population response to treatment is expected to vary according to the etiology and structural changes, the presence or absence of risk factors. Clinical trials which were included in meta-analyses also differed in respect to study design, sample size, duration of study, statistic power and outcomes measures.

A number of clinical trial may lack important covariates or data which are necessary for detection of a significant differences in meta-analysis. These factors and many unknown confounding variables should be considered in confronting with controversies across different studies.

The main purpose of treatment in KOA is improvement of pain and function through suppression of synovial inflammation, and IACS is expected to affect only on anti-inflammatory component of pain [8].

As a results in subjects with advanced radiological KOA or in patients with coexistent associated factors of KOA progression efficacy of IACS is lower as compared with those who had mild disease without risk factors.

Conclusions

Existing data indicate that intra-articular corticosteroids in knee osteoarthritis provides a short-term pain relief and functional improvement which may last from one to several weeks.

At present, synovitis is the most important predictor of treatment response, and also a target for anti-inflammatory treatment for intra-articular corticosteroids. Hence, subgroup of patients with inflammatory phenotype with clinical features of pain, stiffness joint swelling and effusion are expected to be more responsive than other phenotypes who do not display clinical manifestations of inflammation.

Nonetheless, identification of responder from non-responder patients is challenging because, inflammatory presentation of KOA is temporal and is not present at all stages of the KOA process.

At present, patients with significant disability or advanced KOA who are non-responsive to standard therapy are considered for treatment with intra-articular corticosteroids.

Inefficiency of intra-articular corticosteroids in these patients is predictable, because in these subgroups, synovitis alone is not the cause of pain, but structural changes, mechanical and anatomical factors, and even extraarticular factors are also responsible, thus suppression of synovial inflammation by using IACS is likely to provide a short-term pain relief or no therapeutic benefit.

This issue is important, in particular patients who are expected to be respondent to IACS needs to be selected among population of KOA who have synovial inflammation with minimal or moderate anatomical abnormalities. Suppression of inflammatory process at early stages of KOA in addition to pain relief and functional improvement may prevent progression of structural changes.

Given an anti-inflammatory and chondroprotective properties of corticosteroids, the goals of future clinical trials should not be limited to short-term pain relief, but also prevention of osteoarthritis progression by identification of patients who not only have synovitis but they are also at higher risk of disease progression.