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Hyalgan

Hyaluronan (also called hyaluronic acid or hyaluronate) is a glycosaminoglycan distributed widely throughout connective, epithelial, and neural tissues. It is one of the chief components of the extracellular matrix, contributes significantly to cell proliferation and migration, and may also be involved in the progression of some malignant tumors. more...

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Functions

Until the late 1970s, hyaluronan was described as a "goo" molecule, a ubiquitous carbohydrate polymer that comprised the extracellular matrix. For example, hyaluronan is a major component of the extracellular matrix that constitutes synovial fluid. Along with lubricin, it is one of the fluid's main lubricating components. It helps protect joints by increasing the viscosity of the fluid and by making the cartilage between bones more elastic.

While it is found in large numbers in extracellular matrices, hyaluronan also contributes to tissue hydrodynamics, movement and proliferation of cells, and participates in a number of cell surface receptor interactions, notably those including its primary receptor in vivo, CD44. Upregulation of CD44 itself is widely accepted as a marker of cell activation in lymphocytes.

Hyaluronan's contribution to tumor growth may be due to its interaction with CD44. CD44, the chief in vivo hyaluronan receptor, participates in cell adhesion interactions required by tumor cells. Some of the enzymes that break down hyaluronan are known tumor suppressants; paradoxically, the gene for hyaluronidase-2 is an oncogene and promotes tumor growth.

Structure

The chemical structure of hyaluronan was determined in the 1950s in the laboratory of Karl Meyer. Hyaluronan is a polymer of disaccharides themselves composed of D-glucuronic acid and D-N-acetylglucosamine, linked together via alternating beta-1,4 and beta-1,3 glycosidic bonds. Polymers of hyaluronan can range in size from 10² to 10⁴ kDa in vivo.

Hyaluronan is energetically stable in part because of the stereochemistry of its component disaccharides. Bulky groups on each sugar molecule are in sterically favored positions while the smaller hydrogens assume the less favorable axial positions.

Synthesis

Hyaluronan is synthesized by a class of integral membrane proteins called hyaluronan synthases, of which vertebrates have three types: HAS1, HAS2, and HAS3. These enzymes lengthen hyaluronan by repeatedly adding glucuronic acid and N-acetylglucosamine to the nascent polysaccharide.

Degradation

Hyaluronan is degraded by a family of enzymes called hyaluronidases. In humans, there are at least seven types of hyaluronidase-like enzymes, several of which are tumor suppressors. The degradation products of hyaluronan, the oligosaccharides and very low molecular weight hyaluronan, exhibit pro-angiogenic properties.

Medical applications

Hyaluronan is naturally found in many tissues of the body such as skin, cartilage, and the vitreous humor. It is therefore well suited to biomedical applications targeting these tissues. The first hyaluronan biomedical product, Healon, was developed in the 1970s and 1980s and is approved for use in ophthalmic surgery (i.e. corneal transplantation, cataract surgery, glaucoma surgery and retinal attachment surgery). Other biomedical companies also produce brands of hyaluronan for ophthalmic surgery .

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Intra-articular corticosteroid for treating osteoarthritis of the knee
From American Family Physician, 10/1/05 by Steven E. Roskos

Clinical Scenario

A 60-year-old woman with osteoarthritis of her right knee has pain and swelling despite daily use of nonsteroidal anti-inflammatory drugs (NSAIDs).

Clinical Question

Would this patient benefit from an intraarticular injection of a corticosteroid?

Evidence-Based Answer

An injection of the knee joint with a corticosteroid may improve the patient's symptoms for up to three weeks after the injection (number needed to treat [NNT]= 3 to 4). There is no evidence that this intervention improves function, and there is little evidence of the benefits persisting beyond three weeks. Risk of dangerous adverse effects is minimal. Injection of hyaluronan and hylan products (Hyalgan, Orthovisc, Synvisc) may provide longer-lasting benefit.

Practice Pointers

This review (1) shows that intra-articular injection of a corticosteroid is useful in improving pain and the patient's global assessment of symptoms for up to three weeks in patients with osteoarthritis of the knee. The analysis was based on 26 trials with a total of 1,721 patients. However, most studies were small and brief, with fewer than 100 participants and a duration of less than 26 weeks. Only good-quality studies that used standardized rheumatologic outcome measures were included in the review. The authors made an adequate attempt to find all relevant articles and combined data using standard techniques.

There are many effective treatments available for mild symptomatic osteoarthritis, including patient education, physical and occupational therapy, oral and topical analgesics, and NSAIDs. (2-4) Nonetheless, many patients still suffer from pain and reduced function despite treatment efforts. Since the 1950s, patients have been given intra-articular corticosteroid injections when other nonsurgical therapies are inadequate. This review did not find strong evidence to support the use of one particular corticosteroid preparation, dose, injection technique, or frequency of injection, but triamcinolone hexacetonide (Aristospan) was superior to betamethasone (Celestone) in the number of patients reporting pain relief at four weeks. The reviewers also found no particular indication (e.g., joint effusion) that would help select patients who are more likely to benefit.

The same authors published a separate review (5) of injection with hyaluronan and hylan derivatives for osteoarthritis of the knee, in which they found this treatment to be effective. The Cochrane Collaboration has elsewhere reviewed corticosteroid injections for shoulder pain, (6) finding weak evidence for a small and short-lived benefit in rotator cuff disease and adhesive capsulitis. The collaboration also has reviewed local injection of corticosteroid for carpal tunnel syndrome (7) and found benefit lasting up to one month. Some evidence-based clinical guidelines (2,4) recommend intra-articular corticosteroid injection for treatment of osteoarthritis of the knee when other, more conservative, treatments are not effective. Several authors have described injection techniques in detail. (8-10) This Cochrane review covers the best and most recent evidence available and supports the use of intra-articular corticosteroids for osteoarthritis of the knee.

The Cochrane Abstract below is a summary of a review from the Cochrane Library. It is accompanied by an interpretation that will help clinicians put evidence into practice. Steven E. Roskos, M.D., presents a clinical scenario and question based on the Cochrane Abstract, followed by an evidence-based answer and a full critique of the review.

EB CME

This clinical content conforms to AAFP criteria for evidence-based continuing medical education (EB CME). EB CME is clinical content presented with practice recommendations supported by evidence that has been reviewed systematically by an AAFP-approved source. The practice recommendations in this activity are available online at http://www.cochrane. org/cochrane/revabstr/ AB005328.htm.

REFERENCES

(1.) Bellamy N, Campbell J, Robinson V, Gee T, Bourne R, Wells G. Intraarticular corticosteroid for treatment of osteoarthritis of the knee. Cochrane Database Syst Rev 2005;(2):CD005328.

(2.) Recommendations for the medical management of osteoarthritis of the hip and knee: 2000 update. American College of Rheumatology Subcommittee on osteoarthritis Guidelines. Arthritis Rheum 2000;43:1905-15.

(3.) Health care guideline: diagnosis and treatment of adult degenerative joint disease (DJD) of the knee. Bloomington, Minn.: Institute for Clinical Systems Improvement, 2004. Accessed online July 13, 2005, at: http://www.icsi.org/knowledge/detail.asp?catID=29&itemID=165.

(4.) Simon LS, Lipman AG, Jacox Ak, Caudill-Slosberg M, Gill LH, Keefe FJ, et al. Pain in osteoarthritis, rheumatoid arthritis, and juvenile chronic arthritis. 2d ed. Glenview, Ill.: American Pain Society, 2002. Summary accessed online July 13, 2005, at: http://www.guideline.gov/summary/ summary.aspx?ss=15&doc_id=3691.

(5.) 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 2005;(2):CD005321.

(6.) Buchbinder R, Green S, Youd JM. Corticosteroid injections for shoulder pain. Cochrane Database Syst Rev 2003;(1):CD004016.

(7.) Marshall S, Tardif G, Ashworth N. Local corticosteroid injection for carpal tunnel syndrome. Cochrane Database Syst Rev 2002;(4): CD001554.

(8.) Cardone DA, Tallia AF. Diagnostic and therapeutic injection of the hip and knee. Am Fam Physician 2003;67:2147-52.

(9.) Greene WB, ed. essentials of musculoskeletal care. 2d ed. Rosemont, Ill.: American Academy of orthopaedic Surgeons, 2001:20-3,371-2.

(10.) Pfenninger JL. Joint and soft tissue aspiration and injection (arthrocentesis). In: Pfenninger JL, Fowler GC, eds. Pfenninger and Fowler's Procedures for primary care. 2d ed. St. Louis: Mosby, 2003:1479-500.

STEVEN E. ROSKOS, M.D., is assistant professor of family medicine at the University of Tennessee, Graduate School of Medicine, Knoxville. He received his medical degree from temple University School of Medicine, Philadelphia, and completed a residency in family medicine at Lancaster General Hospital, Lancaster, Pa.

Address correspondence to Steven E. Roskos, M.D., Department of Family Medicine, University of Tennessee, Graduate School of Medicine, 1924 Alcoa Highway, U-67, Knoxville, TN 37920 (e-mail: sroskos@mc.utmck.edu). Reprints are not available from the author.

STEVEN E. ROSKOS, M.D., University of Tennessee, Graduate School of Medicine, Knoxville, Tennessee

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