Antibiotic use in Hospitals

                                           Dr. KS Dhillon

Introduction

The last 60 plus years have witnessed the golden age of antibiotic discovery and their widespread use in hospitals. Many of the antibiotics available are regarded as very effective, safe, and relatively inexpensive. They have saved millions of lives. This availability of many antibiotics, however, has led to their misuse, leading to bacterial resistance.

There is a need to optimize antimicrobial use so as to slow the spread of resistant pathogens.

There is a dire need for hospitals to implement antimicrobial stewardship programs with the aim of improving antimicrobial use to optimize infection cure rates and minimize harm [1].

Most often efforts to evaluate antimicrobial stewardship programs’ effect on hospital antibiotic use focus on volume rather than prescribing quality [2,3,4]. It is, however, not known whether the volume of antimicrobial use correlates with the appropriateness of antibiotic use [5].

Prescribing decisions for patients in hospitals are associated with several factors, including allergies, comorbidities, adverse effects, and drug interactions.

Evaluating the appropriateness of hospital antimicrobial use is challenging. 

Evaluation of the appropriateness of antibiotic use is lacking in most hospitals. Hospital antimicrobial stewards usually perform intensive, small-scale antibiotic use evaluations to answer specific questions about the appropriateness of antibiotic use. Larger scale evaluations are usually more difficult to conduct.

Inappropriate antibiotic use in hospitals

Antibiotic use in hospitals is common and unfortunately frequently inappropriate. For several decades now it has been known that up to 50% of antimicrobial use is inappropriate [6].

Hecker et al [7] carried out a prospective observational study to evaluate the current pattern of misuse (unnecessary use) of antimicrobials in hospitalized patients. The study included all adult nonintensive care inpatients for whom new antimicrobials were prescribed during a 2-week period. They found that a total of 1941 antimicrobial days of therapy were prescribed for 129 patients. Thirty percent of the therapy was deemed unnecessary.

Administration of antimicrobials for longer than the recommended duration (192 days of therapy) was the most common reason for unnecessary therapy (33%). Other reasons included administration of antimicrobials for noninfectious or nonbacterial syndromes (32%) and treatment of colonizing or contaminating microorganisms (16%). The use of antianaerobic agents accounted for 35% of the unnecessary antimicrobial therapy, and these agents were frequently prescribed when equally efficacious alternative agents with minimal antianaerobic activity were available.

Magill et al [8] carried out a study to assess the appropriateness of antimicrobial use in US hospitals. Their aim was to evaluate the appropriateness of antimicrobial use for patients who were hospitalized for treatment of community-acquired pneumonia (CAP) or urinary tract infection (UTI) present at admission or for patients who had received fluoroquinolone or intravenous vancomycin treatment [8].

They found that overall, treatment was unsupported (inappropriate) for  55.9% of the patients. It was unsupported in 27.3% of the patients who received vancomycin, 46.6% in those who received fluoroquinolones, in 76.8% of those with a diagnosis of UTI, and in 79.5% in those with a diagnosis of CAP. The common reasons for unsupported treatment included excessive duration (59.2% patients with CAP) and lack of documented infection signs or symptoms (50.1% patients with UTI). 

The Australian Commission on Safety and Quality in Health Care in 2018 carried out a Hospital National Antimicrobial Prescribing Survey (NAPS) throughout Australia in both government and private hospitals. The survey showed that antimicrobials with the highest rates of inappropriate prescribing were: cefalexin, cefazolin, azithromycin, amoxicillin-clavulanic acid, and metronidazole. The survey also showed that the five most common indications for prescribing antimicrobials were surgical prophylaxis, community-acquired pneumonia, medical prophylaxis, cystitis, and cellulitis/erysipelas.  The highest proportions of prescriptions assessed as inappropriate were for chronic obstructive pulmonary disease (COPD), surgical prophylaxis, non-surgical wound infections, community-acquired pneumonia, and cystitis [9].

Trivedi et al [10] carried out a multicenter assessment of antibiotic appropriateness in 47 ICUs in the USA. The study included 667 patients in 47 ICUs. Three hundred and two patients (54%) were on antibiotics. The incidence of inappropriate antibiotic use was found to be 31%. The reasons for inappropriate antibiotic use included no infection or nonbacterial syndrome (22%), unnecessarily broad-spectrum (29%), and duration longer than necessary (21%). 

Generally, suboptimal or inappropriate antibiotic prescribing includes overly broad coverage, excessively long treatment, duplicate treatment, failure to de-escalate on the basis of microbiology test results, antimicrobial use when antimicrobials are not required and selection of antimicrobial where the dose, route, or duration is unlikely to treat the pathogen or the likely pathogen [9].

Rising threat of antimicrobial resistance

When antibiotics were first discovered they were called "miracle" drugs which saved millions of lives. Now we face a dramatic challenge as a result of two combined problems. First, bacteria are becoming extremely resistant to existing antibiotics, particularly, Gram-negative rods which are resistant to most of the currently available antibiotics in some settings. Second, there are no new antibiotics in the pipeline [11]. 

In the last few years several new powerful compounds active against Gram-positive cocci have become available, but this is not so for Gram-negative bacteria and there are almost no new antibiotic class active against multiresistant Gram-negative rods. None can be anticipated in the near future. Many doctors are likely to face a therapeutic dead-end in the treatment of certain types of severe bacterial infections. Such a situation will take us back to the pre-antibiotic era of the 1930s and early 1940s [12].

Over the last few years, several alarming facts regarding antimicrobial resistance (AMR) have become known [12]. These include:

• There has been an increase in global resistance rates in many bacterial species such as staphylococci, gonococci, enterococci,  enterobacteria (E. coli, Salmonella, and Shigella), Pseudomonas, Acinetobacter, and Mycobacterium tuberculosis.
• The burden of bacteremias due to E. coli (most common human pathogens) is increasing in Europe, partly due to resistant strains.
• New mechanisms of resistance have emerged and have disseminated. These include extended-spectrum beta-lactamases (ESBL) and carbapenemases. There now exist new resistance genes such as the New Delhi metallo-beta-lactamase 1 (NDM-1) and other carbapenemases in Enterobacteriacae. These "superbugs" are resistant to most available antibiotics and can disseminate around the world very rapidly. 
• Although there has been a rapid increase in the multi-resistance of Gram-negative rods, there has been a steady decrease in methicillin-resistant Staphylococcus aureus (MRSA) rates in many countries due to successful infection control programmes.  In other countries, resistance to both Gram-positive and Gram-negative bacteria is very high. There also other countries with vancomycin-resistant enterococci.
• There is a propensity to use last-line therapy (e.g., carbapenems) to treat infections. This is triggered by a fear of infections caused by ESBL-producing Enterobacteriaceae. These antibiotics should, in fact, be preserved as the last weapons for use against multiresistant Gram-negative bacterias.
• Due to the lack of alternative drugs, old drugs with poor safety and efficacy profiles and uncertain pharmacokinetic/pharmacodynamic characteristics (e.g., colistin) are used.
• Multiresistant bacteria in critically ill patients cause high morbidity and mortality. The European Centre for Disease Prevention and Control (ECDC) reported that in Europe 25,000 people die each year from antibiotic-resistant bacteria [13]. In the USA, there are 90,000 MRSA infections with an estimated 19,000 deaths annually [14].
• Serious financial consequences of bacterial resistance. The healthcare costs and productivity losses due to bacterial resistance is at least 1.5 billion euros each year in Europe [13]. The annual cost of AMR in hospitals in the USA is estimated at more than US$ 20 billion [15]. 

Morbidity, mortality, and the associated economic burden from AMR is very likely to increase dramatically during the next decade [16]. Due to financial crises in many countries in the world, massive cuts in healthcare expenditure and medical research can result in further spread of multiresistant bacteria in hospitals around the world.

The major cause of this frightening evolution is the massive overuse of antibiotics worldwide over the past decades. Excess antibiotics are used particularly for common colds and upper respiratory tract syndromes that are mostly of viral origin. Self-medication, an important driver of antibiotic overuse, is common in many developing countries where antibiotics can be bought over the counter in pharmacies. 

These resistant bacteria can be exchanged via travel activities and patient transfers leading to a rapidly growing "resistance globalization" [12].

At the same time, the antibiotic pipeline is drying up for the following reasons. Firstly it is difficult to find new antibiotics with novel mechanisms of action and secondly a high cost/benefit and risk/benefit ratio discourage pharmaceutical companies from investing in the research and development of new antibiotics. 

Improved diagnosis, education, and legislation can reduce antibiotic consumption. A sustained, multifaceted, community-level intervention can help reduce overall antibiotic use [17]. 

Patients can and should have a very active role in making healthcare safer. In many countries, national campaigns have been launched to educate patients and physicians about antimicrobial misuse and the threat of resistance.

Every hospital should have an antibiotic stewardship program. These programs are dedicated to improving antibiotic use and are commonly referred to as Antimicrobial Stewardship Programs (ASPs). They can both optimize the management of infections and reduce adverse events associated with antibiotic use.

It is important to implement antibiotic stewardship programs around the world. There should be a multidisciplinary approach aimed at the optimal selection, dosage, and duration of antimicrobial treatment that would result in the best clinical outcome for the treatment and prevention of infection with least toxicity to the patient, and least impact on subsequent bacterial resistance. 

Besides the diagnosis, the reason for the prescription and the planned duration of therapy should be indicated on every patient chart. 

An international programme should be able to markedly decrease the overall consumption of antibiotics in humans. There is a need for a strong and sustained cooperation between healthcare professionals and antibiotic users.  All antibiotic prescribers must work together to ensure the success of these programmes.

Strategies for correct antibiotic prophylaxis [18]

Antibiotics alone cannot prevent surgical site infections. Attention to infection and prevention control strategies including correct hand hygiene practices are important strategies to prevent surgical site infections. Other strategies include meticulous surgical techniques and minimization of tissue trauma, clean hospital and operating room environments, proper instrument sterilization processes, targeted glycemic control, and appropriate management of surgical wounds.

Prophylactic antibiotics should be used for operative procedures that have a high rate of postoperative surgical site infection, or when implants are inserted.

Prophylactic antibiotics should be effective against both aerobic and anaerobic bacteria most likely to contaminate the surgical site such as Gram-positive skin commensals or normal flora colonizing the mucosa that is to be incised.

Prophylactic antibiotics should be administered within 120 min prior to the incision. However, for most antibiotics, it is recommended that the first dose should be administered within 30–60 min before the surgical incision is made. This is to ensure an adequate serum and tissue concentration of antibiotics during the period of potential contamination. Obese patients will require higher doses of antibiotics.

A single dose of antibiotic is usually sufficient. Additional antibiotic doses need to be administered intraoperatively for procedures that last more than 2–4 hours and when there is significant blood loss (more than 1.5 L).

There is no evidence that postoperative antibiotic prophylaxis is of any value. Every institution should have guidelines for proper surgical prophylaxis.

Strategies for correct antibiotic therapy [18]

The source of infection should be identified and controlled as soon as possible. Empirical antibiotic therapy should be started after the infection is detected. Microbiological data (culture and sensitivity results) will only be available after 48–72 hours to guide the targeted therapy.

In patients who are critically ill, empiric broad-spectrum therapy which will cover all likely pathogens should be started as soon as possible once the infection is recognized. This empiric antimicrobial therapy should be narrowed once the culture and sensitivity results are available and there is adequate clinical improvement. 

Empirical therapy is chosen based on local epidemiology, clinical severity, individual patient risk factors for multidrug-resistant bacteria, and infection source.

Specimen, for culture and sensitivity, from the site of infection should always be taken for patients with hospital-acquired or with community-acquired infections at risk for resistant pathogens. This would be in patients with previous antimicrobial therapy, prior infection, or colonization with multidrug-resistant pathogens. 

Blood cultures should be taken before the administration of antibiotics in critically ill patients.

The dosages of antibiotics should be optimized to make sure that pharmacodynamic-pharmacokinetic targets are achieved.

The need for and appropriateness of the antibiotic treatment should be reassessed on a daily basis.

Once the source of infection has been controlled, short courses of antibiotic therapy are as effective as longer courses regardless of the fact that signs of inflammation are still present. 

For intra-abdominal infections, 4 days of antibiotics are as effective as 8 days in moderately ill patients [19]. For bloodstream infections, 5 to 7 days of antibiotics are as effective as 7 to 21 days for most patients [20]. For ventilator-associated pneumonia, 8 days of antibiotics are as effective as 15 days [21,22].

When there is failure of antibiotic therapy in patients having active infection a re-operation to clear the infection would be required.

Use of biomarkers such as procalcitonin may be useful to guide the duration and/or cessation of antibiotic therapy in critically ill patients.

The infection prevention and control (IPC) measures combined with ASPs should be implemented in clinical departments. These programs and interventions require regular, systematic monitoring to assess compliance and efficacy.

Antibiotic consumption should be monitored and feedback provided to all ASP team members on a regular basis (e.g. every 3 to 6 months). Data on resistance surveillance and outcome measures should also be provided.

Conclusion

We have overused and abused antibiotics not only in humans but also in animals with huge variations between countries [23]. Now regular and precise barometers to survey resistance levels and antibiotic consumption are available to us [24]. Bacterial resistance to antibiotics has reached levels that place the human race in real danger. There is a worldwide need for immediate, vigorous, and coordinated measures to be taken to save and protect the erosion of existing antibiotics and at the same time facilitate the discovery of new and potent antibiotics, active in particular against Gram-negative bacilli [25,26]. To achieve this there is a need for profound change in the way we diagnose and treat bacterial infections [27]. There is a dire and urgent need for educational programmes targeting both healthcare professionals and consumers, including children. The real key to success is strong cooperation and complicity between healthcare professionals (including researchers) and consumers. 

Reference

1. US Department of Health and Human Services, Centers for Disease Control and Prevention. Core elements of hospital antibiotic stewardship programs. Published 2019.  https://www.cdc.gov/antibioticuse/healthcare/pdfs/hospital-core-elements-H.pdf
2. US Centers for Disease Control and Prevention. Antimicrobial use and resistance module.  https://www.cdc.gov/nhsn/acute-care-hospital/aur/index.html
3. Baggs J, Fridkin SK, Pollack LA, Srinivasan A, Jernigan JA. Estimating national trends in inpatient antibiotic use among US hospitals from 2006 to 2012. JAMA Intern Med. 2016; 176(11): 1639-1648. doi:10.1001/jamainternmed. 2016.5651
4. Goodman KE, Cosgrove SE, Pineles L, et al. Significant regional differences in antibiotic use across 576 U.S. hospitals and 11,701,326 million adult admissions, 2016–2017. Clin Infect Dis. 2020;ciaa570. doi:10.1093/cid/ ciaa570.
5. Spivak ES, Cosgrove SE, Srinivasan A. Measuring appropriate antimicrobial use: attempts at opening the black box. Clin Infect Dis. 2016;63(12):1639-1644.
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7. Hecker MT, Aron DC, Patel NP, Lehmann MK, Donskey CJ. Unnecessary use of antimicrobials in hospitalized patients: current patterns of misuse with an emphasis on the antianaerobic spectrum of activity. Arch Intern Med. 2003 Apr 28;163(8):972-8. doi: 10.1001/archinte.163.8.972. PMID: 12719208.
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9. National Centre for Antimicrobial Stewardship and Australian Commission on Safety and Quality in Health Care. Antimicrobial prescribing practice in Australian hospitals: results of the 2018 Hospital National Antimicrobial Prescribing Survey. Published January 2020.  https://irp-cdn.multiscreensite.com/d820f98f/files/uploaded/Hospital%20NAPS%20Public%20Report%20-%202018.pdf.
10. Trivedi KK, Bartash R, Letourneau AR, et al; Partnership for Quality Care (PQC) Inpatient Antimicrobial Stewardship Working Group. Opportunities to improve antibiotic appropriateness in U.S. ICUs: a multicenter evaluation. Crit Care Med. 2020;48(7):968-976.
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14. Alliance for the Prudent Use of Antibiotics: The cost of antibiotic resistance to US families and the health care system. http://www.tufts.edu/med/apua/news/press_release_7-13-10.shtml http://www.tufts.edu/med/apua/consumers/personal_home_5_1451036133.pdf.
15. Roberts R, Hota B, Ahmad I, Scott RD, Foster SD, Abbasi F, Schabowski S, Kampe LM, Ciavarella GG, Supino M, Naples J, Cordell R, Levy SB, Weinstein RA. Hospital and societal costs of antimicrobial-resistant infections in a Chicago teaching hospital: implications for antibiotic stewardship. Clin Infect Dis. 2009;49:1175–1184. doi: 10.1086/605630.
16. De Kracker MEA, Davey PG, Grundmann H. on behalf of the BURDEN group. Mortality and hospital stay associated with resistant Staphylococcus aureus and Escherichia coli bacteremia: estimating the burden of antibiotic resistance in Europe. PLoS Med. 2011;8:e1001104. doi: 10.1371/journal.pmed.1001104.
17. Finkelstein JA, Huang SS, Kleinman K, Rifas-Shiman SL, Stille CJ, Daniel J, Schiff N, Steingard R, Soumerai SB, Ross-Degnan D, Goldmann D, Platt R. Impact of a 16-community trial to promote judicious antibiotic use in Massachusetts. Pediatrics. 2008 Jan;121(1):e15-23. doi: 10.1542/peds.2007-0819. PMID: 18166533.
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Risk of osteoarthritis after an ACL tear and ACL reconstruction

 Risk of osteoarthritis after an ACL tear and ACL reconstruction
                    

                                    Dr. KS Dhillon

Introduction

Osteoarthritis (OA) is the most common type of arthritis. OA is the leading cause of mobility-related disability. Post-traumatic osteoarthritis (PTOA), a subtype of  OA develops after an injury to the joint. The injuries include intra-articular fractures,  ligament injuries, and cartilage (articular or meniscus) injuries. PTOA  accounts for nearly 12% of all arthritis [1].

Unlike idiopathic OA which occurs in older people, PTOA represents a cause of functional disability in a younger population because joint injuries are more often sustained by younger individuals [2]. 

Risk factors for knee PTOA are anterior cruciate ligament (ACL) injury, meniscus tears, patellar dislocation, posterior cruciate ligament tears, and intra-articular fractures.

The incidence of ACL injury is high in adolescents playing sports that involve pivoting. The reported incidence of PTOA following ACL injury is particularly high.

ACL injury and PTOA

ACL rupture is a common and debilitating injury that occurs in athletes who are involved in pivoting sports such as basketball, American football, and soccer. The incidence of ACL tears has been estimated at 0.8 per 1,000 people in the general population. This number is likely to be much higher in younger, more athletic populations [11]. 

Gender is an important risk factor for ACL injuries. Younger women are roughly twice as likely to suffer ACL rupture than young men [4].

About 80,000 to 250,000 ACL ruptures occur annually, and the majority of them in individuals below the age of 30 [5,6,7].

ACL deficiency leads to suboptimal kinematics of the knee since effective transfer of loads relies on mechanical stability. ACL laxity causes deterioration of the physiologic roll-glide mechanism. This results in increased anterior tibial translation as well as increased tibial internal rotation [8]. ACL deficiency results in increased mean contact stress in the posterior parts of the medial and lateral compartments under anterior and rotational loads, respectively [9].

When there is muscle fatigue or poor neuromuscular control, patients with ACL deficiency experience combined anterior and rotatory instability as subluxation of the tibiofemoral joint occurs. In ACL deficient knees the failure of a primary restraint necessitates recruitment of secondary structures such as the menisci to resist external forces and to stabilize the joint. The higher loads borne by secondary structures can make them more susceptible to injury and degeneration [10]. 

ACL injury is usually associated with cartilage injury. Potter et al. [11] prospectively evaluated 40 knees with an acute isolated ACL injury and they found that all patients sustained a chondral injury at the time of ACL tear. They also found that there was an association between the initial size of bone marrow oedema pattern and subsequent degeneration of cartilage [11]. All of these changes may correlate with the eventual development of posttraumatic OA in the knee after an ACL injury. 

About 50% of ACL tears are accompanied by meniscal injury at the time of the acute injury. In the chronic ACL-deficient knee, meniscal tears have been seen in about 80% of the patient population [12,13]. 

Meniscectomy is an important risk factor for developing knee osteoarthritis after an ACL injury. The amount of meniscus resected is the most important surgical predictive factor for the development of OA. 

Lie et al [14] carried out an updated systematic review to assess the prevalence of knee OA at 10 years after an anterior cruciate ligament injury. They found that the prevalence of radiographic knee OA varied from 0% to 100%. They also found that the prevalence of symptomatic knee OA in the tibiofemoral joint was 35% and in the patellofemoral joint 15%.

Øiestad et al [15] carried out a systematic review to study the prevalence of osteoarthritis in the tibiofemoral joint more than 10 years after an anterior cruciate injury. Seven of the studies were prospective and 24 retrospective studies. They found that the prevalence of knee osteoarthritis for subjects with isolated anterior cruciate ligament injury was between 0% and 13% and for subjects with anterior cruciate ligament and additional meniscal injury, the prevalence varied between 21% and 48%. The study also found that the most frequently reported risk factor for the development of knee osteoarthritis was meniscal injury.

After ACL injury, grade III or IV radiologic changes in the knee are nearly 5 times more likely than in contralateral knees without a history of ACL injury. 

There are several risk factors for the development of OA after knee injuries. Meniscectomy is a consistent risk factor for radiographic OA. Meniscus injury often treated by meniscectomy occurs in approximately 75% of patients with ACL injury [14].

The menisci play an important role in providing stability to the tibiofemoral joint. It helps to distribute the load, absorb shock, lubricate the knee joint as well as protect the articular cartilage from excessive axial loading [16]. When the meniscus is damaged the axial loading on the articular cartilage increases and this predisposes and increases the risk of development of OA development [17]. There is a strong correlation between meniscal lesions, cartilage loss, and subchondral bone marrow lesions and these are important factors in the development of OA [18]. Meniscal injuries are common in patients with an acute ACL injury and meniscal injuries can also occur subsequent to ACL injuries. The incidence of OA is higher in patients with combined ACL and meniscus injuries as compared to patients with isolated ACL injuries [14].

Besides meniscectomy, the other risk factors for radiographic OA include gender (female) age, higher body mass index (BMI), obesity, physical activity level, smoking, low education level, subsequent surgery, the time interval between injury and surgery, and varus alignment of the uninjured knee, range of motion loss and articular cartilage damage. 

With older age, there is a disturbance of the balance between anabolic and catabolic processes. There is evidence that suggest that it is related to medial compartment joint space narrowing [19]. It is well known that BMI is associated with the onset and progression of knee OA in patients without ACL rupture. Multiple studies have found that patient BMI is correlated with joint space narrowing and OA following injury to the ACL [20]. Obesity also has a great influence on OA progress in several ways. One is increased joint loading and others include the catabolic effect of inflammatory substances released by adipose tissue, such as free fatty acids, reactive oxygen species cytokines, and adipokines, on joint tissues. 

Physical activity is also considered a risk factor for OA but there appears to be no consensus so far. Physical activity is usually recommended to improve function and promote health. A lack of mechanical loading is also known to contribute to thinning of articular cartilage. A low level of physical activity can lead to an increase in BMI, which is known to lead to the progression of OA.  Repetitive use of joints and joint overload can lead to matrix loss and chondrocyte apoptosis [21].

Some studies have report quadriceps weakness as a risk factor while there are others which state that quadriceps weakness is not a risk factor for radiographic OA [14].

Age has been identified as a risk factor for the development of PTOA. Chondrocyte senescence and preexisting joint degeneration seen in older people increases the possibility of developing OA. 

There have been several studies that have showed that chondral damage is a risk factor for OA [20]. Recurrent episodes of giving way of the knee after an ACL injury can also lead to chondral damage thereby increasing the risks of OA.

Chondral injuries are also known to produce a biochemical cascade, which increases the concentrations of chondrodestructive cytokines and decreases the concentration of chondroprotective cytokines as compared to the contralateral knee [20].

There is some evidence that a time delay between injury and surgery may be a risk factor for tibiofemoral OA. Studies have shown that early reconstruction of the ACL reduces the development of OA when compared with late reconstruction [20].

ACL reconstruction, however, cannot prevent the development of OA and OA can develop regardless of whether a patient undergoes ACL reconstruction or conservative treatment. There is a 57% incidence of knee OA 14 years following ACL reconstruction, as compared to an 18% incidence of knee OA in the contralateral knee [22]. 

A 2014 meta-analysis by Cinque et al [23] showed that the relative risk (RR) of developing radiographic moderate to severe osteoarthritis (grade III or IV) was 3.84. The incidence of moderate to severe OA was 20.3% in ACL-injured knees as compared to 4.9% in the uninjured contralateral knees at an average of 10 years following ACL reconstruction. 

The RR of developing OA in the ACL-injured knees not treated with surgery was significantly higher 4.98 as compared to an RR of 3.62 in knees that were treated with surgery [24]. A more recent meta-analysis showed that the prevalence of radiographic knee OA following ACL reconstruction at 5, 10, and 20 years was  11.3%, 20.6%, and 51.6% respectively [23].

ACL reconstruction does not prevent OA, but ACL reconstruction can delay its onset [25]. 

This is in sharp contrast to other studies that have found no statistical difference in knee osteoarthritis between operative versus nonoperative treatment groups [26,27]. 

A study by Daniel et al [28] concluded that patients who had undergone ACL reconstruction had a higher level of arthrosis by radiograph and bone scan evaluation. Overall, a comparison of bone scan scores for patients who ACL reconstruction as compared to those who did not have surgery revealed a greater incidence of arthrosis in patients who had reconstructed knees.

Risk of arthroplasty after ACL injury

Studies evaluating the risk of knee replacement after ACL injuries is lacking probably because the incidence is very low. Leroux et al (22) did a population-based matched cohort study to evaluate the risk of arthroplasty following ACL reconstruction. They obtained administrative databases of patients who had ACL reconstruction in Ontario, Canada, from 1993 to 2008. They identified 30,301 patients who had ACL reconstruction and 151,362 individuals from the general population with similar demographic variables. They found that 209 patients with ACL reconstruction and 125 patients from the general population had knee arthroplasty. The cumulative incidence of knee arthroplasty following ACL reconstruction after 15 years was low at 1.4% and in the general population, it was 0.2%. Age of 50 years or more, female sex, comorbidity, surgeon annual volume of ACL reconstruction of 12 or less per year, and reconstruction of the ACL done at a university-affiliated hospital, increased the odds of knee arthroplasty. Male sex and an age of 20 years or less were protective indicators. Meniscal tears, however, were not associated with an increased risk of knee arthroplasty.

The limitations of this level 3 study was that it is not known how many of these patients had OA at the time of ACL reconstruction and neither was information about concomitant PCL injury and revision reconstructions available.

Conclusion

Post-traumatic osteoarthritis (PTOA) develops after injury to the joint. The injuries include intra-articular fractures, ligament injuries, and cartilage (articular or meniscus) injuries. PTOA  accounts for nearly 12% of all arthritis.

Unlike idiopathic OA which occurs in older people, PTOA represents a cause of functional disability in a younger population because joint injuries are more often

sustained by younger individuals. 

Risk factors for knee PTOA are anterior cruciate ligament (ACL) injury, meniscus tears, patellar dislocation, posterior cruciate ligament tears, and intra-articular fractures.

ACL injuries are a common cause of PTOA of the knee. The incidence of ACL tears has been estimated at 0.8 per 1,000 people in the general population. About 50% of ACL tears are accompanied by meniscal injury at the time of the acute injury. In the chronic ACL-deficient knee, meniscal tears have been seen in about 80% of the patient population. The incidence of knee OA is higher when there is an ACL tear with a meniscal tear.

The prevalence of radiographic knee OA at 10 years after an anterior cruciate ligament injury varies from 0% to 100%. The prevalence of symptomatic knee OA in the tibiofemoral joint is 35% and in the patellofemoral joint 15%, following an ACL injury.

ACL reconstruction does not prevent OA. Some studies suggest that the incidence of OA is lower after ACL reconstruction as compared to no surgery, others say that the incidence is the same and there is also evidence to show that the incidence is higher after ACL reconstruction.

The cumulative incidence of knee arthroplasty following ACL reconstruction after 15 years is low at 1.4% and in the general population, it is 0.2%. Meniscal tears, however, are not associated with an increased risk of knee arthroplasty.

 

References

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2. Riordan EA, Little C, Hunter D. Pathogenesis of post-traumatic OA with a view to intervention. Best Pract Res Clin Rheumatol. 2014 Feb;28(1):17-30. doi: 10.1016/j.berh.2014.02.001. PMID: 24792943.
3. Frobell RB, Lohmander LS, Roos HP. 2007. Acute rotational trauma to the knee: poor agreement between clinical assessment and magnetic resonance imaging findings. Scand J Med Sci Sports 17: 109– 114.
4. Bell NS, Mangione TW, Hemenway D, et al. 2000. High injury rates among female army trainees a function of gender? Am J Prev Med 18: 141– 146.
5. Majewski M, Susanne H, Klaus S. 2006. Epidemiology of athletic knee injuries: a 10‐year study. Knee 13: 184– 188.
6. Griffin LY. 2006. Understanding and preventing noncontact anterior cruciate ligament injuries: a review of the hunt valley II meeting, january 2005 [Internet]. Am J Sports Med 34: 1512– 1532. Available from: http://journal.ajsm.org/cgi/doi/10.1177/0363546506286866
7. Hewett TE, Stasi SL, Di Myer GD. 2013. Current concepts for injury prevention in athletes after anterior cruciate ligament reconstruction. Am J Sports Med 41: 216– 224.
8. J. Dargel, M. Gotter, K. Mader, D. Pennig, J. Koebke, and R. Schmidt-Wiethoff, “Biomechanics of the anterior cruciate ligament and implications for surgical reconstruction,” Strategies in Trauma and Limb Reconstruction, vol. 2, no. 1, pp. 1–12, 2007.
9. C. Imhauser, C. Mauro, D. Choi et al., “Abnormal tibiofemoral contact stress and its association with altered kinematics after center-center anterior cruciate ligament reconstruction: an in vitro study,” The American Journal of Sports Medicine, vol. 41, no. 4, pp. 815–825, 2013.
10. David Simon, Randy Mascarenhas, Bryan M. Saltzman, Meaghan Rollins, Bernard R. Bach, Peter MacDonald, "The Relationship between Anterior Cruciate Ligament Injury and Osteoarthritis of the Knee", Advances in Orthopedics, vol. 2015, Article ID 928301, 11 pages, 2015. https://doi.org/10.1155/2015/928301.
11. H. G. Potter, S. K. Jain, Y. Ma, B. R. Black, S. Fung, and S. Lyman, “Cartilage injury after acute, isolated anterior cruciate ligament tear: immediate and longitudinal effect with clinical/MRI follow-up,” The American Journal of Sports Medicine, vol. 40, no. 2, pp. 276–285, 2012.
12. P. Neuman, M. Englund, I. Kostogiannis, T. Fridén, H. Roos, and L. E. Dahlberg, “Prevalence of tibiofemoral osteoarthritis 15 years after nonoperative treatment of anterior cruciate ligament injury: a prospective cohort study,” The American Journal of Sports Medicine, vol. 36, no. 9, pp. 1717–1725, 2008.
13. H. Louboutin, R. Debarge, J. Richou, et al., “Osteoarthritis in patients with anterior cruciate ligament rupture: a review of risk factors,” Knee, vol. 16, no. 4, pp. 239–244, 2009.
14. Lie MM, Risberg MA, Storheim K, et al. What’s the rate of knee osteoarthritis 10 years after anterior cruciate ligament injury? An updated systematic review. British Journal of Sports Medicine 2019;53:1162-1167.
15. Øiestad BE, Engebretsen L, Storheim K, Risberg MA. Knee osteoarthritis after anterior cruciate ligament injury: a systematic review. Am J Sports Med. 2009 Jul;37(7):1434-43. doi: 10.1177/0363546509338827. PMID: 19567666.
16. Fox AJ , Bedi A , Rodeo SA . The basic science of human knee menisci: structure, composition, and function. Sports Health 2012;4:340–51.doi:10.1177/1941738111429419.
17. Bedi A , Kelly NH, Baad M, et al. Dynamic contact mechanics of the medial meniscus as a function of radial tear, repair, and partial meniscectomy. J Bone Joint Surg Am 2010;92:1398–408. doi:10.2106/JBJS.I.00539.
18. Englund M , Guermazi A , Lohmander SL . The role of the meniscus in knee osteoarthritis: a cause or consequence? Radiol Clin North Am 2009;47:703–12. doi:10.1016/j.rcl.2009.03.003.
19. Jones MH, Spindler KP. Risk factors for radiographic joint space narrowing and patient reported outcomes of post-traumatic osteoarthritis after ACL reconstruction: data from the MOON cohort. J Orthop Res. 2017; 35:1366–74.
20. Friel NA, Chu CR. The role of ACL injury in the development of posttraumatic knee osteoarthritis. Clin Sports Med. 2013;32(1):1-12. doi:10.1016/j.csm.2012.08.017.
21. Thomas AC, Hubbard-Turner T, Wikstrom EA, Palmieri-Smith RM. Epidemiology of posttraumatic osteoarthritis. J Athl Train. 2017;52:491–6.
22. Mihelic R, Jurdana H, Jotanovic Z, Madjarevic T, Tudor A. Long-term results of anterior cruciate ligament reconstruction: a comparison with non-operative treatment with a follow-up of 17-20 years. Int Orthop. 2011;35(7):1093–1097.
23. Cinque ME, Dornan GJ, Chahla J, Moatshe G, LaPrade RF. High Rates of Osteoarthritis Develop After Anterior Cruciate Ligament Surgery: An Analysis of 4108 Patients. Am J Sports Med. 2018 Jul;46(8):2011-2019. doi: 10.1177/0363546517730072. Epub 2017 Oct 6. PMID: 28982255.
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Hyaluronic Acid in the Treatment of Osteoarthritis

            Hyaluronic Acid in the Treatment of Osteoarthritis

                                       DR KS Dhillon

What is hyaluronic acid?

Hyaluronate is a high molecular weight molecule that is naturally present within the cartilage as well as the synovial fluid. It is made of alternating d-glucuronic acid and N-acetyl-d-glucosamine residues attached by β(1–4) and β(1–3) bonds. Its molecular mass ranges from 6500 to 10,900 kDa [1]. 

Its main function in the synovial fluid is to serve as a lubricant, scavenger for free radicals as well as for the regulation of cellular activities such as binding of proteins [1]. Its function in the joint is to lubricate the joint, serve as a space filler to allow the joint to stay open. 

During osteoarthritis (OA) progression the endogenous hyaluronic acid (HA) in the joint is depolymerized from high molecular weight (6500–10,900 kDa) to lower molecular weight (2700–4500 kDa). This depolymerization diminishes the mechanical and viscoelastic properties of the synovial fluid in the affected joint [1,2].

Hence, exogenous HA injections are used to mitigate the macerated functions of the depolymerized endogenous HA in patients with OA [2]. 

The exogenous HA does not replace and restore the full properties and activities of the depolymerized endogenous HA of the synovial fluid. It may, however, induce pain relief via several mechanisms [2]. These mechanisms include the synthesis of glycosaminoglycan and/or proteoglycan, anti-inflammatory effect, and maintenance of viscoelasticity [2]. There is, however, heterogeneity in the therapeutic trajectory for OA patients following HA injections, since some studies report an overall beneficial effect while others report that there is only a small benefit [3].

One of the reasons for the variable effect of HA in the treatment of OA patients is the variable levels of hyaluronidases in a patient’s synovial fluid. Hyaluronidases are enzymes that degrade hyaluronic acid through cleaving the β(1–4) linkages of HA and thereby fracturing the large molecule into smaller pieces before degrading it [4].

Hyaluronic acid preparations for treatment of OA

Two forms of HA are available. One is oral form and the other is the injection form. The injectable form includes several preparations. These include Orthovisc, Euflexxa, Monovisc Gel-Syn, Synvisc, Synvisc-One, Gel-One, Hyalgan, and Supartz FX [5]. 

Each product has several varying characteristics, including the source (animal versus bacterial bio-fermentation), average molecular weight ranging from 500 to 6000 kDa, molecular structure (linear, cross-linked, or both), concentration (0.8–30 mg/mL), the volume of injection (0.5–6.0 mL), as well as dosing [6]. 

Animal source of HA obtained from rooster combs was traditionally used for many years. Now many source HA from bio-fermentation using genetically modified organisms. This modified bacterial source is cheaper and has fewer side effects [7,8].

There is no significant difference in the long-term outcome regardless of the preparation used for injection [9]. There are a variety of different mechanisms for relief of symptoms after injection of HA into the joint [10]. 

These include maintaining cartilage thickness, area, and surface smoothness, reducing the motility of lymphocytes, enhancing the synthesis of extracellular matrix proteins, altering inflammatory mediators in order to shift away from degradation [11].

When oral HA is taken the body absorbs the high molecular weight polymer in the form of decomposed 2–6 membered polysaccharide. The ingested HA binds to Toll-like receptor-4 and thereby promotes the expressions of interleukin-10 and cytokine signaling, both of which lead to reduction of inflammation in the arthritic joint [12]. 

Both the oral HA and the injection HA appear to be effective in combating OA symptoms. Oral HA appears to extend the benefits of injection HA when the two treatments are combined [13].

Mechanism of action of hyaluronic acid (HA)

The predominant mechanism of action of HA for the treatment of pain associated with knee osteoarthritis (OA) remains unknown. 

Studies demonstrate various physiological effects of HA [14]. 

• Reduction of nerve impulses and nerve sensitivity leading to reduction of pain.
• Glycosaminoglycan has protective effects on cartilage. This is mediated by its molecular and cellular effects. 
• Exogenous HA increases the chondrocyte HA and enhances proteoglycan synthesis. It reduces the production and activity of pro-inflammatory mediators and matrix metalloproteinases. It also alters the behavior of immune cells.

Most of the physiological effects of exogenous HA are a function of its molecular weight. 

Role of hyaluronan in the synovial fluid

The viscoelastic quality of synovial fluid that acts as a lubricant and shock absorber is due to HA in the synovial fluid [15]. The concentration of HA in synovial fluid of the knee joint is 2-3mg/ml. The Ha coats the surface of the articular cartilage and also shares space deeper in the cartilage among the collagen fibrils and sulfated PGs [15]. 

The HA probably protects the articular cartilage and blocks the loss of PGs from the cartilage matrix into the synovial space, thereby maintaining the normal cartilage matrix [15]. The HA may also help prevent penetration of inflammatory cells into the joint space.

In patients with joint inflammation, the size of HA molecules decreases, and the number of cells in the joint space increases [15]. The concentrations of HA, glycosaminoglycans and keratan sulfate in the synovial fluid from patients with OA are lower than in synovial fluid from normal knee joints [16]. 

Experiments in rabbits showed that the pro-inflammatory cytokines IL-1 and TNF-α stimulate the expression of HA synthetase [17], which contributes to the fragmentation of HA when there is inflammation in the joint.

Exogenous hyaluronic acid may facilitate the production of newly synthesized HA. Smith and Ghosh [18] cultured synovial fibroblasts obtained from patients with knee OA with HA formulations of various MWs. They found that the amount of newly synthesized HA in response to the exogenous HA was both concentration and MW-dependent. Higher MW agents stimulated the synthesis of more HA than lower MW formulations. and an optimal concentration was noted for each MW [18].

Synovial fluid HA binds to chondrocytes via the CD44 receptor, thereby playing a supporting role in healthy cartilage. 

The CD44 HA receptor helps in the retention and anchoring of PG aggregates to chondrocytes. Adhesion of CD44 to HA also mediates chondrocyte proliferation and function [19].

Hyaluronan and pain relief

HA has an effect on nerve sensitivity and nerve impulses and this is possibly the mechanism of pain relief in patients with knee OA.

Inflammation of the knee joint is known to influence excitability of nociceptors of nerves in the joint [20]. In cats with experimental OA, there was hyperalgesia in intraarticular nerves with spontaneous discharge, and the nerves were sensitive to normal joint movements [20]. Ongoing nerve activity and movement-evoked nerve activity is decreased with HA administration to isolated medial articular nerves in an experimental model of OA [20]. 

HA improved the abnormal gait in rats in whom OA was induced in the laboratory. This reflects the antinociceptive effect of HA [21]. 

HA may also have a direct or indirect effect on substance P, which is involved in pain generation [22]. HA can inhibit an increased vascular permeability induced by substance P [22].

Effects of hyaluronan on the extracellular matrix

In vitro laboratory, experiments show that HA administration can enhance the synthesis of extracellular matrix proteins such as keratin sulphate and chondroitin as well as PGs. Experiments in rabbits show that HA increased the synthesis glycosaminoglycan in rabbit chondrocytes cultured on collagen gels [23]. Release of keratan sulfate into synovial fluid is also suppressed by HA in an ovine model [24].

A clinical study by Creamer et al [25] showed that in patients treated with HA the levels of keratin sulfate in the synovial fluid were lower in more knees as compared to those treated with saline. The difference, however, did not reach clinical significance.

HA has been shown to increase PG synthesis in equine articular cartilage [26], rabbit chondrocytes [27], and bovine articular cartilage [28].

Experiments in rabbits also show that intra-articular administration of higher molecular weight HA is more effective than lower molecular weight HA in inhibiting cartilage degeneration in early OA [27].

In human osteoarthritic chondrocytes, HA alone decreased PG production. HA, however, countered the reduction of PG production induced by IL-1αb  [29]. 

HA suppresses the release of PGs from rabbit chondrocytes [30] and bovine articular cartilage [31] in the absence as well as in the presence of IL-1. 

Experiments show that Hylan inhibits the resorption of PGs from cartilage. High viscosity Hylan is more effective than a low-viscosity Hylan [32]. HA can also suppress the reduction in collagen gene expression induced by IL-1β in rabbit articular chondrocytes [33]. The amount of glycosaminoglycan released was reduced in hyaluronate-treated canine OA joints and there was an increased release in untreated joints [34].

Fragments of fibronectin can bind and penetrate articular cartilage and increase levels of MMPs and suppress PG synthesis [35]. HA can block PG depletion induced by fibronectin fragments [36]. 

Effects of hyaluronan on inflammatory mediators

HA has significant effects on inflammatory mediators such as prostaglandins, cytokines, and proteases. HA alters the profile of inflammatory mediators, resulting in a shift away from cartilage degradation, by altering the balance between cell-matrix synthesis and degradation. 

HA has a chondrostabilizing influence on articular cartilage by down-regulating TNF-alpha. HA exerts its inhibitory influence on TNF-alpha, as well as stromelysin and TNF receptors [37]. 

The cytokine TNF-α and its receptor were not present in canine atrophied articular cartilage treated with HA but were seen in untreated cartilage [37]. 

HA also reduced the expression of IL-1β and stromelysin (MMP-3) in the synovium of rabbits with early OA [38]. These two mediators are known to play a role in cartilage degradation. 

High-MW HA stimulates the production of TIMP-1 in bovine articular chondrocytes. TIMP-1 inhibits MMP [39]. High-MW HA reduced the stromelysin/TIMP-1 ratio leading to a cartilage protective effect [39]. 

HA can also reduce the secreted antigen and activity urokinase plasminogen activator and its receptor in synovial fibroblast in OA and RA patients [40].

Intra-articular administration of HA decreases the urokinase plasminogen activator activity in the synovial fluid of patients who showed improvement in clinical parameters. Hence, a decrease of fibrinolytic activity in synovial fluid is associated with improvement of clinical parameters in patients with OA who are treated with HA [41].

Prostaglandins and other metabolites of arachidonic acid mediate inflammatory responses. HA can reduce arachidonic acid release [42] and IL-1α-induced PGE2 production [43]. These actions of HA are dose and MW-dependent. The higher the MW and concentration, the more potent is the inhibition. 

HA injections reduced levels of prostaglandin F2α, 6-keto-prostaglandin F1α, and leukotriene C4 [44] and also reduced PGE2 levels and stimulated cAMP, thereby producing its anti-inflammatory effect [45,46]. 

HA also has antioxidant effects which were both MW- and dose-dependent [47].

High-MW HA protects against damage to articular chondrocytes by oxygen-derived free radicals, which play a role in the pathogenesis of arthritic disorders [48]. 

Nitric acid (NO) is well known for its role in inflammation. Production of NO is significantly reduced by HA in some tissues [49].

Cartilage effects of HA

There is no strong clinical trial data on the effects of HA and hylans on cartilage histology, although there is well-documented data in experimental animal studies. The protective effect of HA on cartilage has been shown in several animal models of experimental OA. HA has been shown to reduce the severity of OA and also to maintain cartilage thickness and surface smoothness [4]. 

Beneficial effects of HA on cartilage has been shown in rabbits with experimental OA of the knee induced after anterior cruciate ligament transection. The grade of cartilage damage 9 weeks after treatment with HA was less severe in animals treated with HA as compared to those who were not treated with HA [50]. Surface roughness was also significantly less in HA-treated animals when compared to non-HA treated rabbits [50].

Beneficial effects have been seen after 21 weeks [50] and after 6 months [51].

Another study in dogs showed that HA treatment significantly reduced OA progression [52]. 

Clinical studies involving hyaluronic acid use in humans

Over the last several decades there have been clinical trials that investigated the efficacy and safety of HA in the treatment of OA. 

Dan Xing et al [53] carried out a systematic review of overlapping meta-analysis that compared HA and placebo for knee OA. They found that HA is an effective intervention in treating knee OA without an increased risk of adverse events. The authors, however, admitted that there were limitations in their study. There could be variances in study design, publication bias, and clinical heterogeneity in the articles reviewed.

There are, however, a larger number of meta-analyses on this topic that have published conflicting results.

Bellamy et al [54] conducted a Cochrane meta-analysis on the effectiveness of viscosupplementation in the treatment of OA of the knee. They reported that HA was an effective treatment for knee OA at different post-injection periods. They found few adverse events with the use of HA.   A critical review of the study reveals that there was ‘considerable between-product, between-variable and time-dependent variability in the clinical response’ [53]. Doubts have been raised regarding the effectiveness of HA in the treatment of knee OA [53]. 

Rutjes et al [55] carried out a high-quality systematic review and meta-analysis on the use of viscosupplementation in OA of the knee. Their study used effect size statistics and they demonstrated that HA use was associated with a small and clinically irrelevant benefit. There was also an increased risk for serious adverse events.   

Richette et al [56] performed a systematic review and meta-analysis by only including low bias and high-quality RCTs. They showed that HA provided a moderate but real benefit for patients with knee OA. 

Strand et al [57] conducted a systematic review and meta-analysis to investigate the safety and efficacy of HA for knee OA. They found that  US-approved HA is safe and efficacious through 26 weeks in treating knee OA.

The American Academy of Orthopaedic Surgeons (AAOS) evidence-based clinical practice guidelines for the treatment of OA of the knee (2013) do not recommend the use of hyaluronic acid for patients with symptomatic osteoarthritis of the knee [58]. The strength of recommendation is strong, which means the quality of the supporting evidence is high.

Orthopedic surgeons are urged to follow a strong recommendation unless there is a clear and compelling rationale for an alternative approach.

The authors of the guideline evaluated 14 studies (three high-strength studies and 11 moderate-strength studies) to assess intraarticular hyaluronic acid (HA) injections. 

Analysis of the studies showed that there was a low likelihood that an appreciable number of patients achieved clinically important benefits in the outcomes from the use of HA. 

Although the studies showed statistically significant treatment effects as far as the WOMAC pain, function, and stiffness subscales scores were concerned, none of the improvements met the minimum clinically important improvement thresholds. 

The authors of the guidelines concluded that there was a lack of efficacy of HA in the treatment of OA of the knee and therefore they strongly recommend against the use of HA for OA of the knee.

Intraarticular hyaluronic acid injections are conditionally recommended against in patients with knee OA by the 2019 American College of Rheumatology/Arthritis Foundation Guideline for the management of osteoarthritis of the hand, hip, and knee [59].

The Osteoarthritis Research Society International (OARSI) guidelines

conditionally recommended HA (with degree of uncertainty) in individuals with knee OA [60]. They believe that HA may have benefits in the treatment of knee OA and there is a degree of uncertainty.

Generally, the current clinical guidelines on the use of HA makes mention of poor study quality, publication bias, conflicting results, industry sponsorship, as well as unclear clinical significance for their inconclusive recommendations [61].

Conclusion

There is more data now on how HA works when injected into joints. There is no strong clinical trial data on the effects of HA and hylans on cartilage histology, although there is well-documented data in experimental animal studies. The protective effect of HA on cartilage has been shown in several animal models of experimental OA. HA has been shown to reduce the severity of OA and also to maintain cartilage thickness and surface smoothness.

Over the last several decades there have been clinical trials that investigated the efficacy and safety of HA in the treatment of OA in humans. 

Although HA is widely used in clinical practice, there are reservations about its use and effectiveness. The American Academy of Orthopaedic Surgeons (AAOS) evidence-based clinical practice guidelines for the treatment of OA of the knee (2013) do not recommend the use of hyaluronic acid for patients with symptomatic osteoarthritis of the knee. The strength of recommendation is strong, which means the quality of the supporting evidence is high.

The American College of Rheumatology has conditionally recommended against the use of intraarticular hyaluronic acid injections. The Osteoarthritis Research Society International (OARSI) guidelines

conditionally recommended HA in individuals with knee OA. They found that patients may benefit from the use of HA and that there is uncertainty about the benefits in the literature.

Generally, the current clinical guidelines on the use of HA makes mention of poor quality of clinical studies, publication bias, conflicting results, industry sponsorship, as well as unclear clinical significance for their inconclusive recommendations. 

The treatment with HA also does not provide immediate relief to most patients, as studies have shown that it takes about 5 weeks before patients feel the full effect of the treatment.

There are some side effects associated with the use of HA including local pain and swelling of the joint with frequent injections. More randomized controlled trials with a large sample are required to test the efficacy of HA versus the other established therapies of OA.

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