Clinical, biochemical and imaging methods of assessing osteoarthritis and clinical trials with agents claiming ‘chondromodulating’ activity

doi:10.1016/S1063-4584(05)80002-0

Osteoarthritis and Cartilage

Volume 2, Issue 1, March 1994, Pages 1-23

https://doi.org/10.1016/S1063-4584(05)80002-0 Get rights and content

Summary

This paper reviews, in a first part, methods used for the clinical assessment of osteoarthritis (OA) with special reference, in a second part, to trials of drugs claimed to be chondromodulating agents. The agents examined include glycosaminoglycan-peptide complex (GP-C, Rumalon®) and glycosaminoglycan-polysulfate (GAGPS, Arteparon®), which both showed some beneficial clinical response. However, their effect on cartilage still remains controversial. The development of a functional hip and knee OA index in clinical assessment and the role of imaging methods and biochemical markers are discussed.

In future clinical trials only validated OA indices such as the Lequesne or WOMAC index and the newly established ILAR guidelines for classifying and testing drugs in OA will be accepted for registration purposes.

Imaging methods including magnetic resonance imaging (MRI) offer the capacity to provide more precise information concerning cartilage destruction in OA joints. In addition, the biochemical assessment of proteoglycan fragments, bone sialoprotein (BSP), cartilage oligometric matrix protein (COMP) and the balance between stromelysin and its inhibitor (TIMP) in synovial fluid would appear to offer potential applications for the determination of joint tissue damage in the early and later stages of OA. However, these biochemical markers have yet to be validated. It is clear that in the 1990s, for a drug to be designated as disease modifying in OA, it will require a more rigorous evaluation than was hitherto required.

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2014, Osteoarthritis and Cartilage
Citation Excerpt :
Recent exciting approaches that combine complementary biomarkers, often termed as ‘multicontrast’ or ‘multiparametric’ methods, show increased sensitivity and specificity for cartilage function and OA. Interestingly, the use of multiple independent assessment of disease severity is not unlike the development of WOMAC and related scoring systems18,19,22,49. In one study, authors combined dualMRI, relaxivity measures (e.g., T1ρ, T1 and T2; Fig. 3), and standard MRI (e.g., thickness) in a statistical model to quantify the ability to detect OA severity in human cartilage explants from patients undergoing total knee replacement surgery151.
Functional imaging refers broadly to the visualization of organ or tissue physiology using medical image modalities. In load-bearing tissues of the body, including articular cartilage lining the bony ends of joints, changes in strain, stress, and material properties occur in osteoarthritis (OA), providing an opportunity to probe tissue function through the progression of the disease. Here, biomechanical measures in cartilage and related joint tissues are discussed as key imaging biomarkers in the evaluation of OA. Emphasis will be placed on the (1) potential of radiography, ultrasound, and magnetic resonance imaging to assess early tissue pathomechanics in OA, (2) relative utility of kinematic, structural, morphological, and biomechanical measures as functional imaging biomarkers, and (3) improved diagnostic specificity through the combination of multiple imaging biomarkers with unique contrasts, including elastography and quantitative assessments of tissue biochemistry. In comparison to other modalities, magnetic resonance imaging provides an extensive range of functional measures at the tissue level, with conventional and emerging techniques available to potentially to assess the spectrum of preclinical to advance OA.
Serum protein signatures detect early radiographic osteoarthritis
2009, Osteoarthritis and Cartilage
Citation Excerpt :
Additional evidence is mounting to suggest that clusters of markers7–9 may comprise “signatures” predictive of OA development, activity or progression. Reliable and valid biomarkers may identify individuals at high risk of OA9–11 who may be ideal participants for clinical trials testing interventions of disease modification12,13. One promising approach to identify biomarkers that can reveal the early stages of OA development is to apply high sensitivity technology to characterize the profile of candidate circulating proteins in subjects who have been radiographically characterized at multiple points in time over many years.
To test the hypothesis that early knee and hand osteoarthritis (OA) development is characterized by detectable changes in serum proteins relevant to inflammation, cell growth, activation, and metabolism several years before OA becomes radiographically evident.
Using microarray platforms that simultaneously test 169 proteins relevant to inflammation, cell growth, activation and metabolism, we conducted a case–control study nested within the Baltimore Longitudinal Study of Aging (BLSA). Subjects included 22 incident cases of OA and 66 age-, sex- and body mass index (BMI)-matched controls. Serum samples tested were obtained at the time of radiographic classification as either case or control, and up to 10 years earlier at a time when all participants were free of radiographic OA. Proteins with mean signal intensities fourfold higher than background were compared between cases and controls using multivariate techniques.
Sixteen proteins were different between OA cases compared to controls. Four of these proteins [matrix metalloproteinase (MMP)-7, interleukin (IL)-15, plasminogen activator inhibitor (PAI)-1 and soluble vascular adhesion protein (sVAP)-1] were already different in samples obtained 10 years before radiographic classification and remained different at the time of diagnosis. Six additional proteins were only associated with subsequent OA development and not with established OA.
Changes in serum proteins implicated in matrix degradation, cell activation, inflammation and bone collagen degradation products accompany early OA development and can precede radiographic detection by several years.
Effects of pentosan polysulfate in osteoarthritis of the knee: A randomized, double-blind, placebo-controlled pilot study
2005, Current Therapeutic Research - Clinical and Experimental
Recent recommendations from the Group for the Respect of Excellence and Ethics in Science for the clinical assessment of the effects of disease-modifying osteoarthritis (OA) drugs suggest that improvement in joint space narrowing, pain, and function relative to a control group should be the primary end points.
The aim of this study was to assess the ability of sodium pentosan polysulfate (NaPPS) to improve pain and function in patients with OA of the knee.
This randomized, double-blind, placebo-controlled pilot study was performed at the Queen Elizabeth II Medical Centre, Perth, Australia. Patients aged ≥18 years with OA of the knee were randomly assigned to receive NaPPS 3 mg/kg or Ringer's solution (control), IM QW for 4 weeks. Efficacy was assessed at enrollment and weekly during the 4 weeks of treatment and at weeks 8, 12, 16, and 24. Seven direct clinical assessments were made, including intensity of early morning joint stiffness, pain at rest, and pain on walking. A 10-cm visual analog scale (VAS) was used to assess pain at rest and on walking and early morning joint stiffness. Response was defined as a change from baseline in VAS score ≥2 cm. Function was assessed using the 10-cm VAS to rate 13 activities of daily living (ADLs), including stair climbing and domestic chores. Patient global assessment of the overall effectiveness of the study drug comprised a 4-point Likert scale (0 = not effective to 3 = maximally effective). An aggregate score for all ADL functions was calculated as the mean change from baseline score of all of the ADLs as determined at 4, 8, 12, 16, and 24 weeks after commencement of the study. For tolerability monitoring, hematology and biochemistry were used, and patients were questioned about adverse events at each visit.
A total of 114 patients were enrolled (83 women, 31 men; mean [SD] age, 63.3 [1.5] years; NaPPS group, 54 patients; control group, 60 patients). Significant differences in scores of 3 of the 7 direct clinical assessments were found between the 2 groups (duration of joint stiffness at 4, 8, 12, and 16 weeks [all, P:5 0.015]; pain at rest at 8, 12, 16, and 24 weeks [all, P ≤ 0.017]; and patient global assessment at 4, 8, 12, 16, and 24 weeks [all, P <- 0.006]). The rates of trial continuation were higher in the NaPPS group compared with those in the control group at 8, 12, and 24 weeks (all, P < 0.05). Mean scores for 3 of 13 ADLs were significantly higher in the NaPPS group compared with those in the control group at weeks 8 and 12 (all, P ≤ 0.03). On combining all of the ADL scores, functional improvement from baseline was found at weeks 8 and 12 in the NaPPS group (both, P = 0.02). Mild bruising at the injection site occurred in <1% of patients in both treatment groups.
In this pilot study, 4 weekly injections of NaPPS were associated with significantly improved duration of joint stiffness and pain at rest compared with controls for 20 weeks after the cessation of treatment, and significantly improved pain on walking and overall function for 8 weeks after the cessation of treatment in these patients with OA of the knee.
Structure modification in knee osteoarthritis: Methodology and outcome parameters
2001, Osteoarthritis and Cartilage
Managing osteoarthritis (OA) with structure-modifying agents (SMAs) is an important emerging topic receiving increased attention from both lay individuals and health care professionals as a promising alternative in the management of OA.
Objective To review the methodology and outcome parameters purported to be used in the assessment of the structure-modifying potential of various interventions.
Design A Medline search was performed to select the relevant published articles. This review does not go into detail about various aspects of the design and conduct of structure-modifying studies; however, a vast number of relevant references are provided and may be accessed by interested readers.
Results Enhancing the feasibility of SMAs trials aimed at documenting efficacy can be accomplished by carefully selecting: (1) the outcome parameters, (2) the imaging methodology, and (3) the patient population. Most of the relevant issues that need to be considered by investigators before embarking on a study of this nature have been addressed in this article.
Conclusion Most of the evidence to date focuses on the superiority of the radiographic-based techniques in measuring joint space narrowing among a homogeneous population of OA patients. More research is warranted before other techniques such as ultrasound, chondroscopy, and magnetic resonance imaging, can be proven to be reliable.
Superior responsiveness of the pain and function sections of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) as compared to the Lequesne-algofunctional Index in patients with osteoarthritis of the lower extremities
1999, Osteoarthritis and Cartilage
Objective To compare the responsiveness of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and a questionnaire format of the Lequesne-Algofunctional Index in patients with OA of the lower extremities.
Methods Longitudinal analysis of the instruments' responsiveness [standardized response mean (SRM), effect size (ES)] in ambulatory patients undergoing hip or knee arthroplasty.
Results At six months 36, and at one year 40 out of 43 patients undergoing hip (N=30) or knee arthroplasty (N=13) could be examined. Both responsiveness statistics revealed the same order of responsiveness. For both indices and for both locations, the pain sections were more responsive than the function sections. However, the WOMAC scales and the WOMAC global index (hip at 12 months: SRM=2.4; knee at 12 months: SRM=2.0 ) were more responsive than the comparable Lequesne sections and Lequesne index (hip at 12 months: SRM=2.1; knee at 12 months: SRM=1.5).
Conclusions Although our results are based on a German version using a self-report format, the WOMAC scales appear to be more responsive than the Lequesne index in patients with OA of the lower extremities.{copy}
Comparison of the WOMAC (Western Ontario and McMaster Universities) osteoarthritis index and a self-report format of the self-administered Lequesne-Algofunctional index in patients with knee and hip osteoarthritis
1998, Osteoarthritis and Cartilage
Objective: To compare the metric properties and validity of German versions of the WOMAC (Western Ontario and McMaster Universities) and a self-administered questionnaire-format of the Lequesne–Algofunctional–Index in patients with osteoarthritis (OA) of the lower extremities.
Design: Cross-sectional analysis of the instruments' internal consistency (Cronbach's coefficient alpha) and construct validity (correlation with radiological OA-severity and limitation in range-of-motion) in ambulatory patients and patients before hip arthroplasty. Test–retest reliability was assessed on a subsample after 10 days.
Results: Data from 51 patients out of 91 contacted could be analyzed. Twenty-nine patients had knee and 22 patients had hip OA. Both the WOMAC and Lequesne OA-indices and their scales or sections had a satisfactory test–retest reliability (Intraclass correlation coefficient 0.43–0.96). All scales of the WOMAC were internally consistent (Cronbach's coefficient alpha 0.81–0.96) and associated with radiological OA-severity and joint range of motion. However, only the function but not the symptom sections (Cronbach's coefficient alpha knee: 0.55; hip: 0.63) of the self-administered Lequesne OA index were internally consistent for both, patients with knee and hip OA. Also, the symptom components were not or only weakly associated with radiological OA-severity and joint range of motion.
Conclusions: Although our results are based on a German version using a self-report format we may caution using the self-administered Lequesne OA index without prior testing of its metric properties and validity.

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Clinical, biochemical and imaging methods of assessing osteoarthritis and clinical trials with agents claiming ‘chondromodulating’ activity

Summary

Semin Arthritis Rheum

Rheum Dis Clin North Am

Lancet

Lancet

Baillieres Clin Rheumatol

Pain

Arthritis Rheum

Semin Arthritis Rheum

Radiol Clin North Am

Curr Ther Res

Am J Med

The pathology and aetiology of arthritis deformans

JAMA

Ueber die Arthritis deformans

Virchows Arch [A]

Changes in the knee joint at various ages, with particular reference to the nature and development of degenerative joint disease

Osteoarthrosis in the U.S.

Die Rheumamorbidität

Epidemiology of osteoarthritis: Zoetermeer survey. Comparison of radiological osteoarthritis in a Dutch population with that in 10 other populations

Ann Rheum Dis

Development of criteria for the classification and reporting of osteoarthritis: classification of osteoarthritis of the knee

Arthritis Rheum

Development of clinical criteria for osteoarthritis

J Rheumatol

The American College of Rheumatology Criteria for The Classification and Reporting of OA of the Hand

Arthritis Rheum

Osteoarthritis: A review

J R Coll Physicians Lond

Design and conduct of clinical trials in OA

Scand J Rheumatol

Die Arthrose aus klinischer Sicht

Ther Umsch

Osteoarthritis—an evaluative index for clinical trials

Clinical evaluation in rheumatic diseases

Outcome measurement in osteoarthritis clinical trials: the case for standardisation

Clin Rheumatol

Comment évaluer l'evolution de l'arthrose à long-temps

Rev Rhum

Studies with pain rating scales

Ann Rheum Dis

Analogue chromatic continuous scale: a new method for pain assessment

Clin Exp Rheumatol

A comparison of three ways of measuring pain

Rheumatol Rehab

Measuring the pain of arthritis—validation of a new scale

Assessment of construct and criterion validity of the children's faces pain scale

Signal measurement strategies: Are they feasible and do they offer any advantage in outcome measurement in OA?

Arthritis Rheum

Measurement of proximal interphalangeal joint circumference in rheumatoid arthritis; a prospective, comparative study with thermography

Ann Rheum Dis

Indexes of severity for OA of the hip and knee

Scand J Rheumatol

Assessment of function after arthroplasty of the hip

J Bone and Joint Surg

A preliminary evaluation of the dimensionality and clinical importance of pain and disability in osteoarthritis of the hip and knee

Clin Rheumatol

Validation study of WOMAC: a health status instrument for measuring clinically important patient relevant outcomes to antirheumatic drug therapy in patients with osteoarthritis of the hip or knee

J Rheumatol

Double-blind, randomized controlled trial of isoxicam vs. piroxicam in elderly patients with osteoarthritis of the hip and knee

Br J Clin Pharmacol

Measurement of patient outcome in arthritis

Arthritis Rheum

Assessment of disability caused by rheumatic diseases in general practice

Ann Rheum Dis

Measuring health status in arthritis. The arthritis impact measurement scale

Arthritis Rheum

Outcome assessment in clinical trials. Evidence for the sensitivity of a health status measure

Arthritis Rheum

Validation study of AIMS 2

Report of a three year study on the systemic and articular indexes in rheumatoid arthritis—theoretic and clinical considerations

Arthritis Rheum

Articular indices of joint inflammation in rheumatoid arthritis. Correlation with the acute-phase response

Arthritis Rheum

An experiment in reducing interobserver variability of the examination of joint tenderness in patients

J Rheumatol

An articular index for the assessment of osteoarthritis

Ann Rheum Dis