CORR Insights®: No Benefit to Platelet-rich Plasma Over Placebo Injections in Terms of Pain or Function in Patients With Hemophilic Knee Arthritis: A Randomized Trial : Clinical Orthopaedics and Related Research®

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CORR Insights®: No Benefit to Platelet-rich Plasma Over Placebo Injections in Terms of Pain or Function in Patients With Hemophilic Knee Arthritis: A Randomized Trial

Piuzzi, Nicolas S. MD1

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Clinical Orthopaedics and Related Research: December 2022 - Volume 480 - Issue 12 - p 2371-2373
doi: 10.1097/CORR.0000000000002302

Where Are We Now?

Hemophilic arthropathy is a particular type of secondary osteoarthritis (OA) that occurs because of recurrent hemarthrosis in patients with hemophilia Types A or B, which are rare X-linked inherited bleeding disorders caused by a complete or partial deficiency in or the absence of coagulation factors VIII and IX [9]. Recent epidemiologic work suggested that hemophilia, although not common, is more prevalent than once believed, and it appears to infect more than 30,000 men in the United States alone [3].

Despite advances in the clinical treatment of hemophilia, hemophilic OA remains a major problem [10, 18]. Once hemophilic arthropathy is established, evidence supporting the use of intra-articular injections of various drugs (such as hyaluronic acid, corticosteroids, platelet-rich-plasma [PRP], and cell-based therapies) remains very low [2]. Therefore, we need clinical studies to assess the efficacy of clinically available treatments to improve the pain and function of patients suffering from this condition.

In this issue of Clinical Orthopaedics and Related Research®, Duan al. [7] compared the effect of PRP with that of placebo in patients with hemophilic knee arthritis at 2 years of follow-up. This randomized controlled study did not find any evidence that PRP reduces pain or improves clinical function in patients with hemophilic arthritis; therefore, the authors recommended against using these injections. I agree.

Where Do We Need To Go?

Orthobiologic approaches (such as PRP or bone marrow aspirate concentrate) to treating various musculoskeletal conditions continue to attract interest [5, 13, 16]. Despite advances, further basic and translational research is required, as well as well-designed randomized controlled trials to better determine the best indications for and efficacy of orthobiologics.

Because there is a continued need for evidence-based orthopaedic practice to better inform patient care, studies with both positive and no-difference (or negative) findings are important [8]. Overall, many studies have had conflicting clinical findings regarding the use of PRP for knee OA. Despite limitations and methodologic flaws in previous studies [6, 11, 15, 20], PRP to treat knee OA may be as or more effective than other available nonsurgical treatments in terms of pain, function, and adverse events. However, in primary OA, when considering direct and unpaid indirect costs, PRP injections have been deemed to be not cost-effective compared with TKA, mainly because there is little established evidence supporting its clinical efficacy in relieving pain, improving function, and delaying TKA [17]. However, PRP may have value for higher-risk patients who have greater perioperative complication rates, TKA revision rates, or poorer postoperative outcomes [17]. Identifying these potential indications remains of paramount importance.

Additionally, not all PRP preparations are the same [19]. The reporting of PRP preparation protocols in clinical studies has been highly inconsistent [4], and most studies do not provide sufficient information to allow the protocol to be reproduced. This heterogeneity in the reporting of PRP preparation and composition also hinders comparison among PRP products and PRP studies [4]. Future studies will need to expand on PRP formulations that appear to decrease pain or improve function more effectively than others.

Furthermore, there are still gaps regarding our understanding of disease pathogenesis for symptomatic primary OA and secondary arthritis, and the mechanism of disease needs to be better understood in order to allow a better understanding of treatment for these conditions.

Similar to primary OA, in hemophilic arthritis, there is a need for not only new treatments but also biomarkers that can help with early screening for joint disease for more rapid diagnosis and to help monitor progression so that timely interventions might be administered [10, 11, 14].

How Do We Get There?

The presence of different OA phenotypes and patient subgroups raises the opportunity for more-targeted, patient-specific approaches to prevention and treatment [12]. For example, degradomics (genomic and proteomic approaches devoted to identifying protease and protease-substrate repertoires, or “degradomes”) of OA cartilage (such as HtrA1) may explain OA proteolytic pathways and provide new biomarkers [1]. An enhanced understanding of disease mechanisms and pathogenesis will then shed light on new treatment targets.

A difference is only important if it makes a difference. Effect size should be the focus of our clinical research, and we should take care to report clinical thresholds such as the minimum clinically important difference, substantial clinical benefit, and the patient-acceptable symptom state to determine the clinical effect of new treatments [14]. These thresholds relate to clinical significance to help determine whether the results or outcomes used to assess the effectiveness or efficacy of a treatment modality will have genuine and quantifiable clinical effects. When interpreting a clinical study, statistically significant results may not be of clinical importance; on the other hand, results that are of clinical importance may not be statistically significant.

As PRP research continues, further basic and translational research is still required to elucidate which factors in PRP affect patients who are responders. Different PRP formulations may be needed for different tissues and pathologies, and an improved understanding of the underlying structural and compositional deficiencies of the diseased tissue will help to identify the biologic needs that can be targeted with PRP. This will allow the field to progress to more sophisticated PRP preparations. Finally, well-design randomized control trials and prospective studies will be required to determine the efficacy of and best indications for orthobiologics. Overall, studies with negative findings such as the one by Duan et al. [7] may seem disappointing; however, they provide an essential step in our search to advance patient care.


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2. Buccheri E, Avola M, Vitale N, Pavone P, Vecchio M. Haemophilic arthropathy: a narrative review on the use of intra-articular drugs for arthritis. Haemophilia. 2019;25:919-927.
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