Thursday, 6 May 2021

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].


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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  54. Bellamy N, Campbell J, Robinson V, Gee T, Bourne R, Wells G. Viscosupplementation for the treatment of osteoarthritis of the knee. Cochrane Database Syst Rev. 2006 Apr 19;(2):CD005321. doi: 10.1002/14651858.CD005321.pub2. PMID: 16625635.
  55. Rutjes AW, Jüni P, da Costa BR, Trelle S, Nüesch E, Reichenbach S. Viscosupplementation for osteoarthritis of the knee: a systematic review and meta-analysis. Ann Intern Med. 2012 Aug 7;157(3):180-91. doi: 10.7326/0003-4819-157-3-201208070-00473. PMID: 22868835.
  56. Richette P, Chevalier X, Ea HK, Eymard F, Henrotin Y, Ornetti P, Sellam J, Cucherat M, Marty M. Hyaluronan for knee osteoarthritis: an updated meta-analysis of trials with low risk of bias. RMD Open. 2015 May 14;1(1):e000071. doi: 10.1136/rmdopen-2015-000071. PMID: 26509069; PMCID: PMC4613148.
  57. Strand V, McIntyre LF, Beach WR, Miller LE, Block JE. Safety and efficacy of US-approved viscosupplements for knee osteoarthritis: a systematic review and meta-analysis of randomized, saline-controlled trials. J Pain Res. 2015 May 7;8:217-28. doi: 10.2147/JPR.S83076. PMID: 26005358; PMCID: PMC4428363.
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Friday, 2 April 2021

Osteoarthritis: Updates On Etiology And Treatment

      Osteoarthritis: Updates On Etiology And Treatment

                                            Dr. KS Dhillon


Osteoarthritis (OA) is a degenerative joint disease that usually affects the weight-bearing joints of the body and the hand[1]. 

According to the National Health Interview Survey (NHIS) in the USA between 2010 and 2012, 52.5 million adults have been diagnosed with osteoarthritis [2]. OA produces functional disability, pain, stiffness, and reduces mobility. In the USA the health care expenditure for OA is about $185.5 billion a year [3]. The productivity loss due to OA in the USA is between 0.25 and 0.50% of the Gross Domestic Product (GDP)[4].

Etiology of OA

Osteoarthritis (OA) has always been considered as a “wear and tear” disease where cartilage loss occurs. It was believed to be due to overload on weight-bearing joints, anatomical joint incongruency, and genetic fragility of the cartilage matrix. This was based on the observation that chondrocytes have low metabolic activity and no ability to repair cartilage. Furthermore, articular cartilage cannot respond by inflammatory activity once damaged, because it is avascular and not innervated.

The paradigm has made a major shift following progress in molecular biology in the 1990s.

Osteoarthritis is an inflammatory disease. Although initially OA was considered cartilage driven, now it is certain that OA is a much more complex disease with inflammatory mediators released by cartilage, bone, and synovium [5,6,7]. The source and type of mediators vary with OA phenotypes [8].

Many soluble mediators such as cytokines and prostaglandins can increase the production of matrix metalloproteinases (MMPs) by chondrocytes leading to an inflammatory process. It is now established that synovitis is a critical feature and driver of OA. Experimental data is now available which shows that subchondral bone may have a substantial role in the OA process. It acts as a mechanical damper, as well as a source of inflammatory mediators implicated in the OA pain process. It is also implicated in the degradation of the deep layer of cartilage[9]. 

How the synovium becomes inflamed remains controversial. 

One of the more widely accepted hypotheses is that cartilage flakes or fragments fall into the joint and they come in contact with the synovium. The synovial cell considers these fragments as foreign bodies and the synovial cells react by producing inflammatory mediators which are found in synovial fluid. These mediators activate superficial chondrocytes to synthesize metalloproteinases which then degrade cartilage.

Synovial angiogenesis is induced by the mediators and the mediators also increase the synthesis of inflammatory cytokines and matrix metalloproteinases by synovial cells. Hence, the synovitis perpetuates the cartilage degradation leading to OA [9].

Macrophages in the synovium are key players in OA pathology. They generate several MMPs in the synovium and also generate neoepitopes in the cartilage during an early phase of the disease. Macrophages therefore can contribute to cartilage damage[10].

Innate immunity can also trigger local inflammation in patients with OA. The innate(non-specific) immune system comprises of cells and mechanisms that defend the host against infection in a nonspecific manner. This immune system is triggered after the binding of pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) on pattern-recognition receptors (PRRs) [11,12]. 

The PRRs include membrane-associated PRRs (TLRs), cytoplasmic PRRs (nucleotide-binding oligomerization domains (NODs), and secreted PRRs PAMPs are recognized by TLRs as well as by other PRRs. 

The level of TLRs are increased in OA cartilage lesions[13]. TLR-2 and TLR-4 ligands such as low molecular-weight hyaluronic acid, alarmins, fibronectin, and tenascin-C have been found in OA synovial fluid[14,15,16]. These factors are known to induce catabolic responses in chondrocytes as well as inflammatory responses in synovial cells. 

Proteins such as S100A8 and S100A9 are known to produce synovial activation and cartilage destruction. High levels of these proteins may cause joint destruction in OA[17]. Proteins from OA synovial fluid can induce macrophage production of inflammatory cytokines via TLR-4 signaling[18]. 

There is some degree of low-grade systemic inflammation in OA. Inflammatory mediators produced locally are known to contribute to cartilage degradation and synovial cell activation. Inflammatory events occurring within the joint can be reflected outside the joint in plasma as well as in peripheral blood leukocytes (PBLs) in patients with OA. It is well known that the levels of several inflammatory mediators are higher in the serum of patients with OA than in healthy patients[17,19,20].

A study by Attur et al[21] assessed gene expression profiles in PBLs from

patients with OA and they found a subset of individuals with activated PBLs. Cluster analysis showed 2 distinct subgroups among the patients with OA. In one group there was an increased level of IL-1b and in the other group, there was normal expression. They found that in patients

with the inflammatory “IL-1b signature” the pain scores were higher and

there was decreased function and these individuals were at higher risk of radiographic progression of OA.

There is a two-fold increase in the risk of hand OA in obese patients[22].

Mechanical effect of overload cannot be the cause of this increased risk. What then is the cause of this increased risk? 

The increased risk is due to adipokines, which provides a metabolic link between obesity and osteoarthritis. Adipose tissue is now considered to be a real endocrine organ which releases several factors, including cytokines, such as interleukin 1 and tumour necrosis factor α. Adipose tissue also releases adipokines, such as leptin, resistin, visfatin, adiponectin, and so on. 

These adipokines exhibit pleiotropic functions that are mediated through both central and peripheral systems, including lipid and glucose metabolism, reproductive functions, haemostasis, blood pressure regulation, angiogenesis, insulin sensitivity, and bone formation[23]. Recent studies show that osteoarthritis is a systemic disorder in which dysregulation of lipid homeostasis is one of the pathophysiological mechanisms leading to osteoarthritis[24].

There is a link between atherosclerosis and OA. There is an independent association between carotid intima media thickness with the prevalence of knee OA  and carotid plaque with distal interphalangeal OA[25]. One hypothesis for this link relies on the inflammatory theory of atherosclerosis.  Oxidized lipids are the most likely triggering factors for cytokine production.  Concentration of plasma adipokines is known to be associated with metabolic syndrome. There is an association between concentrations of serum adipokine  and severity of OA[26,27]. Systemic adipokines have been found to be associated with local synovial tissue inflammation[28]. 

The infrapatellar fat pad in the knee has been found to be a potential source of adipokines such as IL-653[29].

In patients with knee OA, massive weight loss by gastric surgery improves pain and function and decreases low-grade inflammation. There are changes in levels of joint biomarkers with weight loss and this suggests a structural effect on cartilage[30]. OA, hence, can be initiated and/or aggravated by the presence of a systemic low-grade inflammation. 

OA is a prototypic age-related disease. External mediators such as cytokines and proteases trigger inflammation. The inflammation leads to increased production of inflammatory mediators and also to a lack of elimination of oxidated proteins. These oxidated proteins increase the concentration of reactive oxygen species (ROS) in the cells, adding to the oxidative damage which triggers inflammation[31]. Oxidative stress can cause cell senescence including chondrocyte senescence[32].

Advanced glycation end products (AGEs) are produced by a non-enzymatic process in aging tissues. These end products weaken cartilage by modifying its mechanical properties. 

Treatment of Osteoarthritis

There are limited therapeutic approaches for OA because of its complex pathophysiology. A core set of evidence based-modalities of therapy has been established for management of OA. These modalities included non-pharmacological and pharmacological modalities. 

Non-pharmacological modalities include patient education and awareness, physical exercises and rehabilitation aids. 

Physical therapy in the form of mind–body exercises, strength training exercises and aerobic exercises has shown good outcome provided patients are consistently compliant with their therapy [33]. Nutritional supplements such as dimethyl sulphoxide and methylsulfonylmethane have been tried with some success [33].

The pharmacological modalities include prescription of acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors agents and some even give opioid prescription. 

NSAIDs are the most commonly prescribed agents for treatment of pain and stiffness in patients with OA. NSAIDS have both anti-inflammatory and analgesic effects. They inhibit biosynthesis of prostaglandins at the level of the cyclooxygenase enzyme. 

Different NSAIDs belong to different chemical class. They, however, all block production of prostaglandins (PGs). Prostaglandin blockage is accomplished by inhibition of the activity of the enzyme PGG/H synthase, which is also known as cyclooxygenase (COX). There are two COX  isoforms namely COX-1 and COX-2. These two COX differ in their tissue distribution and regulation.

The two isoforms serve different biological functions. COX-1 is expressed under basal conditions and it is involved in biosynthesis of PG serving homeostatic functions. COX-2 expression on the other hand is increased during inflammation and other pathologic situations [34]. The clinical effects of NSAIDs are evaluated in terms of effects on the different COX isoforms.  COX-2 inhibition by NSAIDs blocks PG production at sites of inflammation or other forms of tissue damage. Inhibition of COX-1 in certain other tissues such as platelets and the gastroduodenal mucosa can lead to common adverse effects of NSAIDs such as bleeding and gastrointestinal ulceration [35].

There are 3 common classes and 9 subclasses of NSAIDs [36]. 

Classification of common NSAIDs

Class                            Subclass                Drugs

Carboxylic acids     Salicylic acids      Acetylsalicylic acid (aspirin)

                                                                     Diflunisal (dolobid)

                                                                     Trisalicyliate (trilisate)

                                                                     Salsalate (disalcid, amigesic, salflex)

                                     Acetic acids       Diclofenac (voltaren, cataflam)

                                                                     Etodolac (lodine)

                                                                    Indomethacin (indocin)

                                                                   Sulindac (clinoril)

                                                                   Tolmetin (tolectin)

                                                                  Ketorolac (toradol)

                                 Propionic acids       Flurbiprofen (ansaid)

                                                                Ketoprofen (orudis, oruvail)

                                                                Oxaprozin (daypro)

                                                                Ibuprofen (motrin, advil, duexisc)

                                                                Naproxen (naprosyn, aleve)

                                                                Fenoprofen (nalfon)

                               Fenamic acids        Meclofenamate (meclomen)

Enolic acids       Pyrazolones        Phenylbutazone

                               Oxicams              Piroxicam (feldene)

                                                              Meloxicam (mobic)

                                                              Nabumetone (relafen)

Nonacidic                                   Nabumetone (relafen)

COX-2 selective   Sulfonamide       Celecoxib (celebrex)

                                  Sulfonylurea       Etoricoxib (arcoxia)

                                  Nonacid       Lumiracoxib (prexige)

Most traditional NSAIDs such as diclofenac inhibit both COX isoforms. There are, however, some differences in the relative potency for COX-1 and COX-2 inhibition. COX-2 selective NSAIDs such as celebrex lack inhibition of platelet function.

Traditional NSAIDs, such as diclofenac and meloxicam show some selectivity for inhibiting COX-2 over COX-1. NSAIDs such as celebrex, valdecoxib, rofecoxib, tend to enhance COX-2 selectivity. 

There is a common spectrum of clinical toxicities among the various NSAIDs. The frequency of particular side effects varies with the compound [36]. 

Toxicities of NSAIDs

Organ system         Toxicity

Gastrointestinal Dyspepsia


                              Gastroduodenal ulcers

                              Ulcer complications (bleeding, perforation obstruction)

                              Small bowel erosions and strictures


Renal            Sodium retention

                           Weight gain and edema


                           Type IV renal tubular acidosis and hyperkalemia

                           Acute renal failure

                           Papillary necrosis

                           Acute interstitial nephritis

                           Accelerated chronic kidney disease

Cardiovascular   Heart failure

                           Myocardial infarction


                           Cardiovascular death

Hepatic          Elevated transaminases

Asthma/allergic  Aspirin-exacerbated respiratory diseases


Hematologic       Cytopenias

Nervous             Dizziness, confusion, drowsiness


                           Aseptic meningitis

Bone                   Delayed healing

Renal effects of NSAIDs

A vital role is played by prostaglandins in solute and renal vascular homeostasis. Sodium retention occurs in about 25% of patients who are treated with NSAID. This is particularly apparent in patients who have mild heart failure or liver disease [37]. Sodium retention can lead to weight gain and peripheral edema. It may also cause clinically important exacerbations of congestive heart failure.

NSAIDs can affect the blood pressure. Average increases in mean arterial pressure of between 5 and 10 mmHg has been seen in patients on NSAIDs. NSAIDs use increases the risk of initiating antihypertensive therapy in older patients. NSAIDs use increases the risk of incident hypertension in both males and females [38,39]. NSAIDs are also known to attenuate the effects of antihypertensive agents such as β-blockers, diuretics and angiotensin-converting enzyme inhibitors, thereby interfering with control of blood pressure.

NSAIDs can cause deleterious effects on kidney function. They affect solute homeostasis, maintenance of renal perfusion and glomerular filtration. NSAIDs produce qualitative changes in urinary prostaglandin excretion, glomerular filtration rate, sodium retention. Patients treated with NSAIDs can develop hyporeninemic hypoaldosteronism syndrome which is characterized by type IV renal tubular acidosis and hyperkalemia [37]. The degree of hyperkalemia is usually mild. Patients with renal insufficiency,  diabetes mellitus and those on angiotensin-converting enzyme inhibitors or potassium-sparing diuretics may be at greater risk.

NSAIDS are known to produce acute renal failure though it is uncommon. This failure is caused by vasoconstrictive effects of NSAIDs and is fortunately reversible. Renal failure is usually seen in patients who have a depleted intravascular volume such as in patients with congestive heart failure, cirrhosis, or renal insufficiency [37]. Excessive reduction in medullary blood flow can lead to papillary necrosis that can result from apoptosis of medullary interstitial cells . Inhibition of COX-2 may be a predisposing factor for renal failure [40].

Idiosyncratic reaction accompanied by massive proteinuria and acute interstitial nephritis is also known to occur with the use of NSAIDs. Fever, rash, and eosinophilia due to hypersensitivity can also occur. 

Aspirin and acetaminophen use has been associated with nephropathy leading to chronic renal failure [41]. 

Hepatic effects of NSAIDS

In about 15% of the patients taking NSAIDs small elevations of one or more liver tests can occur. Upto 3 times or more elevations of ALT or AST may be seen in about 1% of the patients. This elevation of levels usually produces no symptoms. Discontinuation or reduction in the dosage of NSAIDs usually results in normalization of the trans-aminase values. Rarely fatal outcome can be seen with all NSAIDs. Hepatic adverse events are more likely to be seen with diclofenac and sulindac [36].

Cardiovascular effects of NSAIDs

Risk of adverse cardiovascular events associated with NSAID use came into the limelight with the introduction of COX-2-selective NSAIDs into clinical practice. Rofecoxib (Viox), a potent COX-2 inhibitor was shown to have a substantially increased risk of stroke and myocardial infarction and because of that it was removed from the market [42,43].

The cardiovascular risk for all NSAIDs is related to the degree of COX-2 inhibition and an absence of complete inhibition of COX-1 [44]. The risk of myocardial infarction increases with treatment duration and the daily dose of NSAID [44]. 

COX-2 inhibition is not the only mechanism that contributes to cardiovascular complications. Other actions of NSAIDs which produces cardiovascular complications include their effects on blood pressure, nitric acid production, endothelial function, and other renal effects [42,45,46]. The risk of cardiovascular complications is significantly higher in patients with pre-existing coronary artery disease.

Ibuprofen and some other NSAIDs can interfere with the irreversible inhibition of platelet COX-1 by aspirin. This can increase the risk of  cardiovascular hazard in patients who are taking aspirin [44]. 

The incidence of myocardial infarction, stroke and cardiovascular death is low with use of NSAIDs.  All NSAIDS including COX-2-selective NSAIDs except naproxen carry an increased risk of myocardial infarction. Naproxen has the lowest risk for cardiovascular complication as compared to other NSAIDs [47]. Lower doses and once-daily regimens are associated with lower relative risks of cardiovascular complications.

The use of NSAIDs is associated with reduced sodium excretion, volume expansion, increased preload, as well as hypertension. Therefore, as a result of these properties, patients with pre-existing heart failure are at risk of decompensation. Older patients are at a higher risk for heart failure exacerbation.

Gastrointestinal effects of NSAIDs

Castellsague et al [48] carried out at systematic review and meta-analysis to examine the relative risk (RR) of upper GI complications including upper GI bleeding, perforation and peptic ulcers in patients on NSAIDs. They found an increased risk of upper GI complications across all 16 NSAIDs they studied. Their data showed that the risk was lowest for celecoxib and aceclofenac and highest for azapropazone and ketorolac. They also found that risk was dose dependent. Higher the dose higher the risk of GI complications.

Another meta-analysis [49] which examined the relationship between the use of NSAIDs and upper GI complications, such as bleeding, peptic ulcer perforations and obstructions found that there was an elevated risk of GI complications with use of all NSAIDs studied. Data was available for naproxen, ibuprofen, and diclofenac, as well as for the COX-2 inhibitors etoricoxib, rofecoxib, lumiracoxib and valdecoxib. The risk was higher for ibuprofen and naproxen as compared to diclofenac and COX-2 inhibitors.

Another study by Rahme et al [50] showed that patients on NSAIDs had a risk of developing GI adverse events that was 2.5 times higher than that in patients not taking NSAIDs.

Drug-drug interactions

Most NSAIDs are extensively bound to plasma proteins. They can displace other drugs from the binding sites or they may be displaced by other agents. Due to these interactions NSAIDs can increase the activity or toxicity of sulfonylurea, phenytoin, hypoglycemic agents, sulfonamides, oral anticoagulants and methotrexate [51]. 

The use of NSAIDs with methotrexate appears to be safe provided there is appropriate monitoring [52].

NSAIDs can blunt the antihypertensive effects of β-blockers, angiotensin-converting enzyme inhibitors, as well as thiazides, and lead to de-stabilization of blood pressure control [53].

Concurrent use of selective serotonin reuptake inhibitors (SSRI) and NSAID increases the risk of gastrointestinal complications such as bleeding. Care must be taken to avoid these negative outcomes by altering NSAID or SSRI therapy, or by using ulcer-protective drugs [54].

Drug reactions in older people

Physiology changes occur with age and these changes result in altered pharmacodynamics and pharmacokinetics. Drug clearance can be reduced due reductions in hepatic mass, blood flow, enzymatic activity, glomerular filtration rate, renal plasma flow and tubular function associated with aging. 

Adverse gastrointestinal and renal effects related to NSAIDs are more common in the older population. The cardiovascular risks are also more common in the elderly and there concerns of accelerated myocardial infarction and stroke. 

Concomitant use of NSAIDs and Aspirin lead to problems. Aspirin can increase the toxicity of NSAIDs. NSAIDs can also increase aspirin resistance. 

The use of proton pump inhibitors for gastric protection can interfere with the efficacy of antiplatelet agents such as clopidogrel [55].

Older individuals have more illnesses and therefore take more medications, increasing the possibility of drug-drug interactions. Hence the use of NSAIDs in older people must be closely monitored.

In patients with risk factors for NSAID toxicity, the lowest dose of a drug with a short half-life, only when it is needed, is probably the safest treatment option.

Other potential non-operative treatment methods for OA.

There are several other non-operative treatment methods used for the treatment of OA. These include the intra-articular injections of visco-supplements, corticosteroids, or blood-derived products and the use of glucosamines and chondroitin sulfate.

Controversy, however, exists about their efficacy and long-term safety in improving the patients' symptoms. 

Nutritional supplements such as dimethyl sulphoxide and methylsulfonylmethane have been tried with limited success. 

The American Academy Orthopaedic Surgeons (AAOS's) 2013 guidelines provided “Inconclusive” recommendations for both acetaminophen and intra-articular corticosteroids. For intra-articular steroids (IACS) there is a “lack of compelling evidence that has resulted in an unclear balance between benefits and potential harm” [56].

The OA Research Society International (OARSI) and American College of Rheumatology (ACR) 2012, guidelines, on the other hand, recommend both Acetaminophen (for those without relevant comorbidities) and IACS as appropriate for treatment of OA. They found that the potential benefits outweigh associated risks in certain clinical scenarios. 

The AAOS strongly recommends against the use of glucosamine and chondroitin. ACR conditionally recommended against the use of chondroitin and glucosamine [57]. The OARSI guidelines list chondroitin and glucosamine under the category of uncertain recommendation for symptom relief and non-appropriate recommendation for disease modification.

The AAOS recommends against the use of hyaluronic acid treatment, citing a lack of efficacy. The OARSI and ACR guidelines provide an “Uncertain” recommendation for intra-articular hyaluronic acid injections.


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Tuesday, 9 March 2021

Covid-19 vaccine

                     Covid-19 vaccine

                                             Dr. KS Dhillon

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the virus that causes coronavirus disease 2019 (COVID-19). It first emerged in December 2019 and the World Health Organization (WHO) declared the outbreak of coronavirus disease 2019 (COVID-19) to be a Public Health Emergency of International Concern on 30 January 2020.  WHO classified it as a pandemic on 11 March 2020. 

As of today, (7/3/21) authorities in 219 countries and territories around the world have reported about 116,822,839 Covid‑19 cases and 2,593,073 deaths [1]. The death rate amounts to 2.17 percent. 

The highest number of cases reported are from the USA where it stands at 27,895,979 cases of Covid-19 with 493,098 deaths. The 2nd highest numbers are from India with 10,963,394 cases and 156,111 deaths. In Malaysia, the figure stands at 274,875 cases with 1,030 deaths [1].

About 80% of COVID-19 patients have mild to moderate symptoms and 20% develop serious manifestations such as severe pneumonia, acute respiratory distress syndrome, sepsis, and even death [2].

The number of COVID-19 cases has increased rapidly around the world.  The causative virus of this ongoing pandemic belongs to the genus Betacoronavirus (β-CoV) of the family Coronaviridae. The other two betacoronavirus are the severe acute respiratory syndrome coronavirus (SARS-CoV) and the Middle Eastern respiratory syndrome-related coronavirus (MERS-CoV). All these three coronaviruses can produce life-threatening infections. When the SARS and MERS infection appeared there was no such fear and panic that we see today with the Covid-19 pandemic. 

This fear and panic of the Covi-19 pandemic has led to a rush to develop vaccines and not a vaccine to curb the epidemic.

Developing an effective and safe vaccine can take several years. It takes about 10 and 12 years and sometimes longer to develop a safe and effective vaccine. The search for an HIV vaccine has been going since the early 1980s with no success so far. 

There are more than 50 clinical trials worldwide testing potential vaccines, against COVID-19 [3]. To date, 11 vaccines have been approved for use around the world [4].

Usually, vaccines are extensively tested in animals before tests in humans are carried out. 

Due to the urgent need for a vaccine in a surging pandemic, Pfizer and Moderna were given approval to simultaneously test their vaccines on animals while they were conducting Phase 1 trials on humans. The vaccines were tested on mice and macaques.

The Oxford-Astrazeneca(ChAdOX) vaccine protected six monkeys from pneumonia, but the monkeys' noses harbored the same amount of virus as did the noses of unvaccinated monkeys [5]. The developers of the PiCoVacc, a purified inactivated SARS-CoV-2 virus vaccine, from China, reported similar caveats about their vaccine’s early animal tests which they reported in July 2020 [6].

Moderna first published their animal studies in July 2020. They found that viral replication was not detectable in bronchoalveolar-lavage (BAL) fluid by day 2, after challenge in seven of eight monkeys in the vaccinated groups. There was limited inflammation or detectable viral genome or antigen in the lungs of the vaccinated animals. Hence the vaccine did not completely protect the animals against Covid-19 infections [7]. 

There are at least 78 preclinical vaccines that are under active investigation in animals.

Multiple SARS-CoV-2 (Covid-19) vaccines are in development. These include DNA and RNA-based formulations, recombinant subunits which contain viral epitopes, adenovirus-based vectors, and purified inactivated virus [8,9,10]. Traditionally, purified inactivated viruses have been used for vaccine development as was the case with influenza virus and poliovirus. Such vaccines have been found to be safe and effective for the prevention of diseases [11,12]. 

There are three clinical trial phases for efficacy and safety in humans before a vaccine can be approved for use. The most significant difference in the three phases is the scale of testing:

  • Phase I, the vaccine is tested on a small group of patients.
  • Phase II, the vaccine is tested on larger groups of at least 100 patients and researchers can also test their vaccine in specific subgroups, including people with preexisting conditions, or patients with particular demographic characteristics, such as older age group.
  • Phase III, the vaccine is tested on at least 1,000 patients.

There are currently 71 vaccines that are being tested in clinical trials on humans, and 20 of them have reached the final stages of testing. There are 40 vaccines in phase 1 testing, 27 in phase 2, and 20 in phase 3 testing. Six vaccines have been authorized which are in early or limited use. Six have been approved for full use. Four vaccines have been abandoned after initial trials. 

The 6 approved vaccines include Pfizer-BioNTech (mRNA), Moderna (mRNA), Sinovac (inactivated), Cansino (ad5), Sinopharm (inactivated) and J&J (adenovirus) vaccines.

The Pfizer-BioNTech vaccine is Comirnaty (also known as tozinameran or BNT162b2). This vaccine has been approved in several countries. The safety and efficacy study for this vaccine was published in December 2020 [13]. 

In this study a total of 43,548 participants underwent randomization, 43,448 of them received injections: 21,728 with placebo and 21,720 with BNT162b2. There were 8 cases of Covid-19 with onset at least 7 days after the second dose among participants assigned to receive BNT162b2 and 162 cases among those assigned to placebo. This amounted to a 95% efficacy of the vaccine.

There were 10 cases of severe Covid-19 infections with onset after the first dose, 9 of these infections occurred in placebo recipients and 1 in a BNT162b2 recipient.

Four patients among those who received the vaccine had serious adverse events. These included shoulder injury related to vaccine administration, right axillary lymphadenopathy, paroxysmal ventricular arrhythmia, and right leg paresthesia. Two patients in the vaccine group and 4 in the placebo group died. The authors said that the deaths were not related to the vaccine, placebo, or covid-19 infection. The incidence of serious adverse events was similar in the vaccine and placebo groups. It is rather difficult to fathom that a saline injection into the deltoid muscle will produce similar serious adverse events as a vaccine.

In the vaccinated group, 0.036% developed infections and in the placebo group, 0.74% of the patients developed an infection. The number of unvaccinated people developing infections is very small. The number of vaccinated people developing severe infections was 1 and in the unvaccinated group, the number was 9. Vaccination, therefore, does not prevent infections and severe infections but reduces the chances of one developing infection.

All individuals in this study were not followed up with testing for the presence of Covid infection. The individuals were told to report for testing if they developed symptoms of the disease. Many in the vaccinated group may not have reported minor symptoms of the disease thinking that symptoms such as fever, fatigue, and headaches were adverse effects of the vaccine. This could make the final results inaccurate.

The study also did not report the incidence of asymptomatic Covid-19 disease. Hence it is not known if vaccination reduces the incidence of asymptomatic disease which is necessary to prevent the spread of the disease. It is also not known how long the effectiveness lasts. The patients in this study were followed up for 2 months only. It is not known if more vaccinated individuals developed infection after 2 months.

The study was supported by BioNTech and Pfizer and there were some conflicts of interest.

Moderna vaccine trial outcome was published on December 30, 2020 [14]. The trial enrolled 30,420 volunteers in the USA. There were 15,210 participants in the vaccinated group and 15,210 in the placebo group. 

Symptomatic Covid-19 illness was confirmed in 185 participants in the placebo group and in 11 participants in the mRNA-1273 group giving an efficacy of the vaccine of 94.1%.

Just as with the Pfizer-BioNTech trial, reactogenicity was more common in vaccine recipients in this trial and that makes it possible that they were less likely to believe that the minor symptoms they had were due to Covid-19 and therefore less likely to refer themselves for testing in the trial. That could have reduced the numbers in the vaccinated group.

Severe Covid-19 infections occurred in 30 individuals, with one fatality and all 30 were in the placebo group. Serious adverse events were rare, and the incidence of adverse events was similar in the two groups. Here again, it is difficult to fathom how a saline injection can produce similar adverse events as a vaccine.

This trial was sponsored and designed by Moderna. The authors had affiliations with Moderna creating conflicts of interest in this publication.

The outcome of the Sinovac vaccine trial was published in November 2020[15]. The primary immunogenic endpoint in this study was seroconversion of neutralizing antibodies to live SARS-CoV-2. The secondary immunogenic endpoints were geometric mean titers of neutralizing antibodies to live SARS-CoV-2, RBD-specific IgG, S-specific IgG, and IgM. 

Seven hundred and thirty-four individuals were eligible for the immunogenic evaluation at the end of 28 days. Seventy-nine percent of the participants seroconverted in the vaccinated group and none in the placebo group. The overall incidence of adverse reactions was 29%. The protective efficacy of Sinovac, however, remains to be determined. 

The outcome of the phase III study for the Sinovac vaccine has not yet been published.

Just as with the Sinovac vaccine, the Johnson and Johnson vaccine was tested for immunogenicity and safety. The study showed that their vaccine Ad26.COV2.S is safe and immunogenic in both younger and older adults. They have not published any phase III outcome study.

The Pfizer-BioNTech and Moderna vaccines were shown to have 94–95% efficacy in preventing symptomatic COVID-19. It does not mean that 95% of people are protected from disease with the vaccine. This is a general misconception of vaccine protection. These efficacy rates are obtained by the following calculations: 100 × (1 minus the attack rate with vaccine divided by the attack rate with placebo) [16].

Simply put, what it means is that in a population such as the one enrolled in the trials, if 1% of unvaccinated individuals developed symptomatic Covid-19 infection, roughly 0.05% of vaccinated individuals will develop symptomatic COVID-19 infection [16].

We are aware that risk reduction was achieved by these vaccines under trial conditions. What we do not know is how it could vary if the vaccines were used for populations with different exposures, transmission levels, and attack rates [16].

The efficacy of these vaccines in preventing severe disease and death is not really known. Protection against severe disease and death is difficult to assess in phase 3 clinical trials because the number of participants are simply too small. To assess efficacy against severe disease and death unfeasibly large numbers of participants are required. Future epidemiological studies may be able to provide such information.

Not all individuals who are exposed to SARS-CoV-2  become infected [17]  and there is heterogeneity in clinical outcomes [18].

The mechanisms, immunological or others, underlying protection or susceptibility to natural infection are not known.

Seroconversion with the presence of antibodies against SARS-CoV-2 is a marker of exposure to Covid-19, but it is not known whether the presence of neutralizing antibodies is sufficient to provide protection against subsequent infection or disease [19]. 

One study showed that a prior history of SARS-CoV-2 infection was associated with an 83% lower risk of reinfection, i.e 17% chance of catching it a second time, with the median protective effect observed five months following primary infection. Sixty-six percent of the 17% who were reinfected were asymptomatic, [20].

In conclusion, vaccination with the Covid-19 vaccine reduces the chance of contracting the disease but it does not prevent a person from contracting the disease. The efficacy of the vaccine in preventing severe disease and death is not known. The incidence of asymptomatic infection after vaccination is also not known. A vaccinated person who contracts the disease can still spread the infection. 

Between 75 and 90% of the population has to be vaccinated to obtain herd immunity. It is unlikely that the vaccines will provide herd immunity in the near future. The need for social distancing rules will continue till the disease disappears with time as did SARS and MERS-CoV. 

Covid-19 vaccines are believed to be generally safe. There have been sporadic reports of death following vaccination but most of the time there is denial that the deaths are due to the vaccine. The latest news report is that

Austria has suspended the AstraZeneca COVID-19 vaccination after the death of one person and illness of another after the shots. The Austrian Federal Office for Safety in Health Care said that currently there is no evidence of a causal relationship between the vaccination and the death and illness [21]. 


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  5. van Doremalen N, Lambe T, Spencer A, Belij-Rammerstorfer S, Purushotham JN, Port JR, Avanzato VA, Bushmaker T, Flaxman A, Ulaszewska M, Feldmann F, Allen ER, Sharpe H, Schulz J, Holbrook M, Okumura A, Meade-White K, Pérez-Pérez L, Edwards NJ, Wright D, Bissett C, Gilbride C, Williamson BN, Rosenke R, Long D, Ishwarbhai A, Kailath R, Rose L, Morris S, Powers C, Lovaglio J, Hanley PW, Scott D, Saturday G, de Wit E, Gilbert SC, Munster VJ. ChAdOx1 nCoV-19 vaccine prevents SARS-CoV-2 pneumonia in rhesus macaques. Nature. 2020 Oct;586(7830):578-582. doi: 10.1038/s41586-020-2608-y. Epub 2020 Jul 30. Erratum in: Nature. 2021 Feb;590(7844):E24. PMID: 32731258. 
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  7. Corbett KS, Flynn B, Foulds KE, et al. Evaluation of the mRNA-1273 Vaccine against SARS-CoV-2 in Nonhuman Primates. N Engl J Med. 2020;383(16):1544-1555. doi:10.1056/NEJMoa2024671.
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  14. Baden LR, El Sahly HM, Essink B, Kotloff K, Frey S, Novak R, Diemert D, Spector SA, Rouphael N, Creech CB, McGettigan J, Khetan S, Segall N, Solis J, Brosz A, Fierro C, Schwartz H, Neuzil K, Corey L, Gilbert P, Janes H, Follmann D, Marovich M, Mascola J, Polakowski L, Ledgerwood J, Graham BS, Bennett H, Pajon R, Knightly C, Leav B, Deng W, Zhou H, Han S, Ivarsson M, Miller J, Zaks T; COVE Study Group. Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine. N Engl J Med. 2021 Feb 4;384(5):403-416. doi: 10.1056/NEJMoa2035389. Epub 2020 Dec 30. PMID: 33378609; PMCID: PMC7787219.
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Sunday, 7 February 2021

Diagnosis and Management of Superior Labral (SLAP) Tears of the Shoulder

 Diagnosis and Management of Superior Labral (SLAP) Tears of the Shoulder

                                                       Dr. KS Dhillon

Anatomy of the labrum and its normal variants

The labrum is a fibrous structure that is attached around the edge of the glenoid and it serves to increase the contact surface area between the glenoid and the humeral head at the shoulder joint. It consists mainly of fibrous cartilage, although some studies have shown that it is composed of dense fibrous collagen tissue [1].

The superior and anterosuperior portions of the labrum are loosely attached to the glenoid. The macro-anatomy of these portions of the labrum is similar to that of the meniscus of the knee. The inferior labrum is more rounded and is more tightly attached to the glenoid rim.

The inferior portion of the labrum is fixed firmly by inelastic fibrous tissue to the glenoid rim and the superior portion is attached by loose connective fibers [1]. 

The labrum serves as the attachment site for the long head of the biceps tendon, and the superior, middle, and inferior glenohumeral ligaments are continuous with the labrum [2].

The blood supply for the labrum comes from a network of vessels originating from the suprascapular artery, the circumflex scapular branch of the subscapular artery, and the posterior circumflex humeral artery. The vascular penetration of the labrum is more at the periphery close to the capsular attachment [1]. The vascular penetration is less in the central zone. The anterosuperior portion of the labrum is less vascular than the rest of the labrum. The vascularity diminishes with age [3].

Free nerve endings are present in the fibrocartilaginous tissue of the labrum [4]. 

The cross‐sectional shape of the superior labrum is normally triangular with a sharp edge pointing towards the center of the joint and its appearance is similar to the knee meniscus [1]. In some individuals, the free edge of the labrum is more prominent and may extend into the center of the joint. This type of labrum is termed as “meniscoid‐type” superior labrum and it must not be considered pathological. 

In some individuals, there is a minimal recess or anterior sublabral hole that is normal and it must not be confused with a SLAP lesion [5]. 

A third normal anatomical variation of the glenoid labrum is known as the Buford complex. It is a cord‐like middle glenohumeral ligament that blends with the anterior superior labrum with the absence of part of the anterior superior labrum on the glenoid [6].


Pathogenesis of SLAP Lesions

Several injury mechanisms are responsible for SLAP lesions. These lesions can result from a single traumatic event or be due to repetitive micro traumatic injuries. Traumatic events include falling on an outstretched arm, falling onto the shoulder, bracing oneself during a motor vehicle accident, direct blows, and forceful traction injuries of the upper extremity [7].

Repetitive overhead activity, such as that seen in throwing a baseball, is another common mechanism of injury that produces SLAP lesions [8].

There is a strong correlation between SLAP lesions and glenohumeral instability [9].

Classification of SLAP Lesions

Snyder et al [10] in 1990 described four types of SLAP lesions based on a retrospective review of 700 shoulder arthroscopies. The 4 types of SLAP lesions include:

Type                                  Description                                               %

   I                  Labral and biceps fraying, anchor intact                  11%

   II           Labral fraying with detached biceps tendon anchor          41%

III  Bucket handle tear with intact biceps tendon anchor where             33%

      the biceps separates from bucket handle tear

IV  Bucket handle tear with detached biceps tendon anchor which        15%

     remains attached to bucket handle tear

Over the years, this classification has been expanded to include six more types. These include: 

Type                                    Description


V        Type II + anteroinferior labral extension (Bankart lesion)

VI        Type II + unstable flap

VII        Type II + middle glenohumeral ligament injury

VIII     Type II + posterior extension


IX     Circumferential


 X     Type II + posteroinferior extension (reverse Bankart)

The Snyder classification is still the most recognized and widely used classification.

Clinical diagnosis

Making a clinical diagnosis of a SLAP lesion can be difficult due to several reasons. The history and physical findings can often be ambiguous. There are several pathologies in the shoulder that can coexist with SLAP lesions making the diagnosis more difficult. 


Symptoms from SLAP lesions can be acute or insidious depending on the mechanism of injury. Individuals involved in overhead throwing are most likely to present with an insidious history. They complain of reduced ability to throw and to carry out overhead movements. Acute symptoms result from acute trauma following a fall on an outstretched limb and injury due to traction.

The most common complaint in patients with a SLAP lesion is pain [11]. The patient can present with pain deep in the shoulder or with discomfort radiating to the front of the shoulder.

The nature of the pain is usually exacerbated by activities such as pushing, lifting heavy objects, and carrying out overhead activities. Patients with Type III or IV SLAP lesions complain of mechanical symptoms including sensation of giving way especially when they perform overhead activities. They can also complain of weakness of the limb.


Clinical examination of patients with SLAP lesions is usually unequivocal and clinical diagnosis is extremely challenging. There are several provocative tests to diagnose SLAP lesions but these tests lack sensitivity or specificity. These include: 

  • Active compression test (O'Brien's test)
  • Speed test 
  • Anterior slide test 
  • Crank test 
  • Yergason test

Hegedus et al. [12] and Parentis et al. [13] showed that no single test had sufficient sensitivity and specificity to make a consistent diagnosis of SLAP lesion. The active compression test had the highest sensitivity (67%) but the specificity was only 37% [14]. The Yergason test had the highest specificity (95) but the sensitivity was low at 12% [12].

Co-existing shoulder pathology further clouds the clinical picture in patients with SLAP lesions. A study by Kim et al [13] found that 88% of patients with SLAP lesions had coexisting shoulder pathology. 

In patients with SLAP lesions, the active range of motions of the shoulder joint is usually normal but pain may be elicited in the position of internal impingement i.e on external rotation of the abducted and externally rotated shoulder [16]. The O’Brien test is probably the most commonly utilized test for the diagnosis of SLAP lesions [17]. To perform this test, the shoulder is flexed to 90°, adducted 15°, fully internal rotated, and the forearm is pronated. The patient is asked to flex the shoulder against resistance. The test is positive if the patient experiences deep or anterior shoulder pain.

Arnander & Tennant [17] suggested that a combination of O’Brien’s test and Kim’s biceps load test II gave the best likelihood of making a diagnosis of a SLAP lesion. 

The biceps load test II is carried out by placing the shoulder in 120 degrees of abduction, maximal external rotation with the forearm in supination. The patient is then instructed to perform a biceps contraction against resistance. Deep pain in the shoulder during this contraction is indicative of a SLAP lesion. 

Mayo Shear test which is also known as the modified O’Driscoll test or the modified dynamic labral shear test is useful to detect a labral click that is indicative of an unstable SLAP lesion. This test is carried out with the patient standing with his elbow flexed 90 degrees and shoulder abducted above 120 degrees. The examiner then applies further external rotation until resistance is felt. The examiner then applies a shear force through the shoulder joint by maintaining external rotation and horizontal abduction and lowering the arm from 120 to 60 degrees abduction. Reproduction of pain and/or a painful click or catch in the joint along the posterior joint line between 120 and 90 degrees of abduction denotes a positive test [18].

Diagnostic imaging

MRI-arthrography has been reported to have a 96% sensitivity and 85% specificity in the diagnosis of SLAP lesions [19-21]. Unfortunately, these imaging studies are poor in differentiating normal age-related abnormalities from truly unstable symptomatic labral lesions. MRI findings cannot be taken in isolation when determining indications for surgery.

The anatomic variability of the superior labrum makes it difficult to determine whether the anatomic abnormality is truly symptomatic. Hence, the radiological report must be carefully correlated with the patient’s history and physical examination. Even diagnostic arthroscopy among experienced shoulder surgeons gives mixed results in terms of inter-observer and intra-observer reliability with substantial interobserver and intraobserver variability [22-24].

Treatment options

Conservative treatment

The conservative management of SLAP lesions involves 3 basic principles [2]: 

1. Reducing inflammation with the use of NSAIDs, cryotherapy, and/or steroid injections. 

2. Postural correction through scapular retraction exercises, posture bracing and taping, and biofeedback exercises. 

3. Rotator cuff rehabilitation and proprioceptive neuromuscular rehabilitation exercises to return to normal function while monitoring the scapular position.

Fedoriw et al. [25] in a retrospective review of 119 consecutive baseball players showed that about two-thirds of SLAP patients responded to rehabilitation focused on postural correction and balancing exercises.  

Hip range of motion, abductor strength, and core exercises are emphasized and corrected in throwing athletes [2]. 

Edwards et al [26] showed that 10 of 15 overhead throwers with a SLAP lesion treated conservatively were able to return to play at the same level or better.

There are, however, some patients who do not get better with conservative management. These patients would then require surgery.

Surgical treatment

The role of surgery in the treatment of SLAP tears remains shrouded in controversy. There are no clear guidelines and no randomized control studies for surgical treatment of SLAP lesions. It is important to note that not all SLAP lesions seen during arthroscopy require repair/surgery. Meticulous patient selection becomes very important. Factors to take into consideration before embarking on surgery include the patient's age, occupation, levels of activity, expectations, workers’ compensation status, and co-existing shoulder pathology. 

Type I

Type I SLAP lesion is usually an incidental finding at arthroscopy of the shoulder. Such lesions are usually asymptomatic.  They are due to age-related degeneration which results in fraying of the superior labrum. Such lesions need no specific treatment. These lesions are usually not seen on MRI of the shoulder.

The shoulder pain in patients with type I lesions is usually due to coexisting pathology such as subacromial impingement or rotator cuff pathology.

During arthroscopy, if the labrum is found to be extensively frayed

debridement back to healthy labral tissue is recommended [27,28].

Type II

This is the most common and clinically important subtype of SLAP lesion. In patients with shoulder symptoms in whom the clinical examination is suggestive of SLAP lesion and arthroscopy of the shoulder reveals no other pathology, treatment of the SLAB lesion is recommended.

There are several techniques to treat type II lesions and these are also a source of much controversy.

The most common method of repairing these lesions is suture anchors. Some surgeons use biodegradable tacks. 

The number of anchors and suturing techniques i.e simple, dual simple, or horizontal mattress, is again controversial and a subject of debate [29]. 

There have been several studies which showed good outcome following primary repair for SLAP II lesions [28,30,31].

Although there are several studies which show good outcome with primary repair there are other studies which show poorer outcome with increasing age. 

Denard et al [32], carried out a study to evaluate the outcome of surgical treatment of SLAB II lesions and they found a trend of poor outcomes with increasing age. 

Provencher et al [33] carried out a large prospective study of patients with SLAP II lesions who were treated with a repair. They also found an increased rate of failure of SLAP repairs in patients above the age of 36 years. 

Boileau et al [34]  were the first to study the differences in clinical outcome between primary repairs versus biceps tenodesis for SLAP lesions. They found that 60% of patients who had a repair were not satisfied or were disappointed with the outcome while 87% of patients who had a tenodesis were satisfied with the outcome and had a higher rate of return to sports. Forty percent of the patients who had a repair required revision surgery due to persistent pain and inability to participate in sports [34]. In this study average age in the two groups differed. The average age in the repair group was 37 years and in the tenodesis group, the average age was 52 years.

There is now a tendency to treat patients with isolated type II lesions who are above the age of 36 years with low sporting demand and poor tissue quality by biceps tenodesis. In patients below the age of 36 years who are active in sports and have good tissue quality repair of the lesion is recommended. After the repair, if symptoms persist biceps tenodesis can still be performed with good and predictable outcomes [29].

There still exists controversy regarding surgical strategies in the treatment of patients with type II lesions. 

A recent study by Schroder et al. [35] showed that SLAP repair or biceps tenodesis had no significant clinical benefit over sham surgery. They carried out a double-blind, sham-controlled trial in 118 patients with an average age of 40 years. They randomly assigned patients to either labral

repair (n=40), biceps tenodesis (n=39), or sham surgery (n=39), if at arthroscopy they found an isolated SLAP II lesion. They found that there were no significant differences in the clinical outcome between the 3 groups at 2 years follow up. The authors were of the opinion that there is a possibility of overtreatment of SLAP lesions and that there is a need to narrow indications for surgery in the treatment of SLAP lesions.

Type III

Type III SLAP lesions are treated by resection of the unstable bucket handle lesion and debridement back to stable rim just like for bucket handle meniscus tears in the knee. During the resection, it is very important to make sure that the middle glenohumeral ligament (MGHL) is not destabilized because damage to the MGHL can cause significant anterior instability of the joint [29]. 

Type III lesions involving the Buford complex, however, are treated as type II SLAP lesions [7]. 

Type IV

Treatment of type IV lesions depends on several factors including the age of the patient, quality of labral tissue, and extent of bicep tendon involvement. In patients with less than 30% of biceps tendon involvement, the labrum and the pathological biceps tendon is debrided and resected. In young patients with more than 30% of biceps tendon involvement, biceps tenodesis and labral repair are carried out. In older patients and in patients with poor quality labral tissue labral debridement is carried out with either biceps tenotomy or tenodesis [29].

Type V to X

There is a more significant injury to the labrum in patients with type V to X SLAP lesions. The labral injury is often associated with shoulder instability. Treatment of these lesions includes the treatment of labral-tendon complex injury, MGHL injury, and injury to other parts of the labrum [29].

SLAP and co-existing pathology

Isolated SLAP lesions with no co-existing pathology are uncommon. Co-existing intra-articular and extra-articular pathology is common in patients with SLAP lesions. A study by Kim et al [15] showed that 88% of patients with SLAP lesions have co-existing pathology. Hence, there is a need for the surgeons to be aware that for resolution of the patient’s symptoms the co-existing pathology has to be adequately managed [29].

SLAP tear with rotator cuff pathology

In patients with rotator cuff pathology and concomitant SLAP lesions, it can be difficult to clinically determine which pathology is causing the symptoms. If both structures are the cause of symptoms then repair of both can be carried out with good clinical outcome, restoration of motion, and a high degree of patient satisfaction [36].

A randomized controlled clinical trial by Franceschi et al [37] showed that in patients over the age of 50 years with rotator cuff pathology and SLAP II lesions there is no advantage in repairing the SLAP lesion because a rotator cuff repair and a biceps tenotomy produced significantly better outcome compared to a SLAP and rotator cuff repair.

Another study by Abbot et al [38] showed that in patients above the age of 45 years with SLAP II lesion and rotator cuff tear, rotator cuff repair with debridement of the SLAP lesion provided greater patient satisfaction and better functional outcome in terms of pain relief and range of motion as compared to rotator cuff and type II SLAP repair. 

Complications of surgical treatment

There are several complications that have been reported following SLAP lesion surgery. These include residual pain, shoulder stiffness, nerve injury, persistent symptoms, failure of repair, adhesive capsulitis, chondral injury, infection, post-infection arthrosis, chondrolysis, and non-return to previous activity level [34,39,40,41]. The risk factors for these unsatisfactory results remain unknown.

Complications occur in about 21% of the patients [42]. The most common is the presence of residual pain, followed by adhesive capsulitis [42]. 

Overdrilling the glenoid can cause injury to the suprascapular nerve.


SlAP lesion diagnosis and management remains controversial. A proper detailed history and a good physical examination are more valuable than imaging in the diagnosis of these lesions. 

Conservative non-operative management which focuses on scapular rebalancing is usually effective in managing these patients. 

Surgery to repair SLAP lesions is needed if the history and physical examination show instability. If there is no instability a tenotomy or tenodesis should be sufficient. Sometimes both procedures may be needed.

In patients with an unstable bucket-handle lesion, the bucket handle is resected and debridement is carried out to stable rim. 

In patients with SLAP lesions coexisting pathology is common and this has to be dealt with to achieve resolution of symptoms.

In overhead throwing athletes, such as baseball players, aggressive rehabilitation is required. Surgery, if performed, in these athletes, should be as minimal as possible to improve their chances of both returning to sport and preinjury activity level [2].


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