3.1

CS injection

Although OA is generally considered a degenerative joint disorder, there is evidence that a low-grade inflammation also occurs at some phases of the disease , which provides sound rationale for the use of drugs targeting local inflammation. CSs are potent anti-inflammatory agents that act by a variety of mechanisms on different cellular levels. IA CS has been used for knee OA for over 50 years and is available in both crystalline and non-crystalline forms. The crystalline triamcinolone and the non-crystalline prednisolone and methylprednisolone are used most frequently. Although the 2012 ACR and 2014 OARSI guidelines both recommend participation in exercise programs as well as weight loss (for overweight patients) as first-line treatments for all patients with symptomatic knee OA, the recommendations largely differ in the use of IA CS . ACR guidelines include a conditional, weak recommendation for the use of IA CS in patients unresponsive to basic treatment . Conversely, in OARSI guidelines, IA CS is considered an appropriate treatment, whatever the OA subtype and comorbidities . This recommendation is based on 2 systematic reviews, published before 2010, that supported clinically significant short-term decreases in pain . The quality of evidence was rated good. However, no effect size for pain was available .

The 2015 update of a 2006 Cochrane review included 14 new trials, for a total of 27 trials . Studies included were RCTs or quasi-RCTs, with a control group receiving sham or no intervention. The median prednisolone equivalent dose across all trials was 50 mg, and the median number of CS injections was one. Trials randomized a median of 76 participants (range 16–205). The meta-analysis found CS more effective for pain reduction than control interventions (standardized mean difference [SMD] −0.40, 95% CI −0.58 to −0.22), which corresponds to a difference in pain scores of 1.0 cm on a 10-cm visual analog scale (VAS) . When results were stratified by length of follow-up, benefits were moderate at 1–2 weeks (SMD −0.48, 95% CI −0.70 to −0.27), small to moderate at 4–6 weeks (SMD −0.41, 95% CI −0.61 to −0.21), and small at 13 weeks (SMD −0.22, 95% CI −0.44 to 0.00), with no effect found at 26 weeks (SMD −0.07, 95% CI −0.25 to 0.11) . In addition, CS injection was more effective for improving function than the control intervention (SMD −0.33, 95% CI −0.56 to −0.09) . Adverse events could not be accurately assessed. Little to no evidence was found for an association with CS dosage, ultrasound guidance, local anesthetic, crystalline preparation, or type of control intervention . However, the authors found a moderate to large degree of between-trial heterogeneity, and most of the identified trials were considered small, and the quality of evidence for the major outcomes was graded “low” . Interestingly, analysis of pain and function stratified by funding source, independent or not of industry, did not show any differences. No hierarchy could be clearly established between corticosteroids in terms of efficacy according to their half-life, onset of action or duration. Therefore, the choice of the corticoid mainly relies on the physician’s practice and the availability of the product.

Finally, a systematic review and network meta-analysis of pharmacological treatment for knee OA that included 129 trials (32,129 participants) found that for treating OA-related knee pain at 3 months, the effect size (ES) was superior for IA CS than IA placebo (ES = 0.32, 95% CI 0.16–0.47), oral placebo (ES = 0.61, 95% CI 0.32–0.89), oral acetaminophen (ES = 0.42, 95% CI 0.12–0.73) and all other oral treatments and was among the highest of all the pharmacological treatments assessed.

3.2

HA injection

The clinical benefit of IA HA on knee OA may rely on 2 mechanisms: mechanical viscosupplementation of the joint (allowing lubrication and shock absorption), and the re-establishment of joint homeostasis by inducing endogenous HA production, which continues long after the exogenous injection has left the joint. However, international guidelines are even more inconsistent for the use of IA HA than IA CS for knee OA. The 2014 OARSI guidelines recommended IA HA injection with a degree of uncertainty for knee-only OA and not appropriate for multiple-joint OA . This recommendation was based on a recent systematic review demonstrating a small but significant efficacy of IA HA for knee OA pain by week 4, with a peak at week 8 (reaching moderate clinical significance) and residual benefit until 24 weeks . Another review found moderate benefits of IA HA for pain and physical function in knee OA . A third review comparing IA HA and IA CS found that IA HA provided greater benefit at 12 and 26 weeks . Conversely, the 2012 ACR guidelines contain no recommendations regarding the use of IA HA as first-line treatment. IA HA injections for knee OA were conditionally recommended only for patients with inadequate response to initial therapy by the technical expert panel .

In a systematic review and network meta-analysis of pharmacological treatment for knee OA by Bannuru et al., the ES for IA CS (ES = 0.63, 95% CI 0.39–0.88) was the highest among all the pharmacological treatments assessed . In the most recently updated systematic review and meta-analysis, including only trials considered to have low risk of bias (adequate randomization and concealment, and double-blind design), 8 RCTs (2199 randomized patients) met the inclusion criteria . At 3 months, IA HA significantly reduced pain intensity (SMD −0.21, 95% CI −0.32 to −0.10) and improved function (SMD −0.12, 95% CI −0.22 to −0.02) as compared with placebo. The authors concluded that IA HA provided a moderate but real benefit for patients with knee OA . Experimental data suggest a differential action by HA molecular weight (MW). Consistently, some authors found that HA MW may affect its efficacy and safety, with the highest MW more efficient than low MW HA . However, the studies included were heterogeneous, publication bias was high and these conclusions were not supported by other studies. Another meta-analysis even suggested more frequent post-injection reactions with high rather than low MW HA . In clinical practice, HA LW is most commonly used. In trials with low risk of bias, the number of IA HA injections varied from 1 injection for 1 cycle to 5 injections for 4 cycles . However, trials directly comparing different regimens of injections are lacking, and till date, we lack evidence of an effect of number of joint injections. One can assume that increased number of injections might increase the risk for serious adverse events . Seven of the 8 trials included in this meta-analysis received industry funding, and the authors of the meta-analysis disclosed competing interests . However, stratified analysis by funding source has not been performed.

3.3

PRP injection

IA “biological therapies” have generated intense interest as possible modifiers of cartilage biology. PRP derived from autologous blood with a high concentration of activated platelets in a small volume of plasma, which can release a host of mediators and growth factors that act during the initial phase of tissue healing and regeneration. Several growth factors are released, such as insulin growth factor-1 (IGF-1), platelet-derived growth factor (PDGF), epidermal growth factor (EGF), vascular EGF (VEGF), transforming growth factor-β (TGF-β), and others . In vitro , PRP has been shown to have many and complex biological activities, including cellular proliferation, anti-apoptotic activity, cartilage regeneration, collagen synthesis, angiogenesis, and increased vascular permeability . PRP interacts with various tissues, including cartilage, synovial membrane, synovial fluid, and subchondral bone . In vivo , in 2 animal models of OA, treatment with IA PRP was associated with reduced chondrolysis .

The comparative efficacy and safety profile of IA PRP with other IA drugs for treating knee OA remains controversial. More than 20 open-label studies have been published and have suggested short- to mid-term efficacy in improving both pain and function . The many limitations of these studies included heterogeneity in selected patients and differences in PRP preparations and administration regimens . The most recent comprehensive systematic review of English language, original research RCTs for level I evidence identified only 6 eligible trials ; in 5 studies, IA PRP was compared to IA HA and in one study to IA saline . Because of the heterogeneity of outcome measures, a meta-analysis could not be performed, and a best-evidence synthesis was used instead . Authors of this systematic review concluded that all but one study showed significant differences in clinical outcomes between PRP and HA, or PRP and saline, in pain and function, with mean post-treatment Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores significantly better for PRP than HA at 3–6 months and 6–12 months . However, many limitations and biases were noted among the 6 studies included, with serious concerns about randomization and blinding procedures; only one of the RCTs used a double-blind approach , and in 2 studies, the randomization procedure was not reported . Furthermore, the PRP preparation and composition differed and were not standardized, so results were difficult to compare. In the absence of an appropriate blinding, a high placebo effect related to the novelty of the product could not be excluded. Finally, PRP is a blood product that should be submitted to specific regulation. Therefore, the long-term effects of IA PRP with this type of product on the joint ( i.e. , abnormal cell activation) should be cautiously assessed. Of note, the authors of this review disclosed potential conflicts of interest .

After February 2015, 3 supplementary RCTs were published: 2 RCTs comparing IA PRP to IA HA and 1 RCT comparing, for the first time, IA PRP to IA CS . The first study randomized 162 patients with different stages of knee OA into 4 groups receiving 3 doses of IA PRP, 1 dose of IA PRP, 1 dose of IA HA or 1 dose of IA saline (control group). Patients were assessed at 6 months. All groups showed improvement on the EuroQol VAS and International Knee Documentation Committee scores as compared with controls. Patients injected with 1 dose of IA PRP or IA HA did not differ in outcome. In the early OA subgroups (Kellgren–Lawrence score I–II), patients who received 3 IA PRP doses showed better clinical results. Patients with advanced OA (Kellgren–Lawrence score III–IV) showed no difference among treatments . The second study randomized 192 knee OA patients (Kellgren–Lawrence score 0–III) to 2 groups: 3 weekly IA PRP or IA HA. Patients were assessed at 2, 6, and 12 months. Post-injection swelling and pain were more frequent with PRP than HA. Both treatments were effective in improving knee functional status and reducing symptoms by the International Knee Documentation Committee (IKDC) subjective score. The 2 groups did not differ at any follow-up time . Finally, in a double-blind RCT, Forogh et al. compared, for the first time, a single IA PRP injection to IA CS in 41 participants with knee OA (Kellgren–Lawrence score II–III), at 2 and 6 months. As compared with IA CS, IA PRP decreased joint pain more and for longer than IA CS and improved activities of daily living and quality of life in the short-term .

3.4

BTA injection

BTA is a potent neurotoxin produced by the bacterium Clostridium botulinum . BTA inhibits acetylcholine release into the synaptic cleft in cholinergic nerve terminals causing muscle paralysis . In humans, BTA was originally used for its muscle paralyzing effects in neuromuscular disorders, such as spasticity, cervical dystonia and blepharospasm . However, growing evidence from RCTs also supports a potent role of IA BTA as a pain modulator in various types of musculoskeletal conditions . Consistently, preclinical experimental studies of dogs (OA), horses (synovitis) or mice with painful joint conditions confirmed an antinociceptive efficacy of IA BTA. The exact mechanisms of pain modulation by BTA in OA remain unclear. Pain in OA involves both nociceptive and neuropathic complex mechanisms and abnormal excitability in peripheral and central pain pathways . BTA was suggested to suppress the secretion of neurotransmitters, thus directly decreasing peripheral sensitization and indirectly decreasing central sensitization . Recent studies also suggest an inhibitory role of BTA on the release of mediators involved in nociception, such as substance P, calcitonin gene-related peptide and glutamate .

Non-randomized trials and RCTs of BTA in various osteoarticular conditions, including OA, were comprehensively reviewed in 2013 . The author of the review declared no financial competing interests directly related to the study . In the Boon et al. study, 60 patients (61–64 years old) with chronic knee pain (symptom duration 6–10 years) were randomized to 3 groups: IA BTA 100 U ( n = 20), IA BTA 200 U ( n = 20), and IA CS ( n = 20). At week 8, the 3 groups showed reduced pain and improved function as assessed by the WOMAC, with no differences between the 3 groups. Quality of life assessed by the Medical Outcomes Survey 36-Item Short Form was improved only in the IA BTA group for the pain index . In the Mahowald et al. study, 42 patients with refractory chronic painful knees (pain duration not provided) were randomly assigned to IA BTA 100 U ( n = 21) or IA saline ( n = 21). At 1 month, the 2 groups were comparable for pain reduction. At 3 months, pain reduction compared to baseline was significant only for the IA BTA group . In these 2 studies, whether knee pain was related to knee OA or to another knee condition was not detailed.