What are the best markers for disease progression in osteoarthritis (OA)?




To be able to prevent progression of osteoarthritis, the knowledge of prognostic factors of this progression is important. If certain prognostic factors are modifiable, they may enhance our ability to reduce osteoarthritis progression. Even if these prognostic factors are not modifiable, they can still be used to identify high-risk groups, which may have implications for patient information and the perspective of medical treatment. Prognostic factors of progression are reviewed here, mainly for hip and knee osteoarthritis as most data available concern these localisations. Areas of further research are highlighted.


Radiographic osteoarthritis (OA) is frequent and potentially debilitating. Due to an ageing population, the prevalence of OA is expected to increase in the next decades . In western countries, the increase in prevalence in the next 20 years is expected to be about 40%, making OA the fourth leading cause of disability .


Little is known, however, about the course of disability over time in patients with OA. To optimise the management of OA, it is important to increase our knowledge regarding the predictors of progression of OA. If certain prognostic factors are modifiable, they may enhance our ability to reduce OA progression. Even if they are not modifiable, it can still be used to identify high-risk groups, which may have implications for patient information and medical treatment . Knowledge about modifiable factors and high-risk groups is also relevant for clinical research, such as studies evaluating therapeutic interventions, including disease-modifying therapies.


Objective


The objective of this review is to summarise available data pertaining to prediction of OA progression.




Some necessary precisions


Localisation of OA


Although OA is frequent at several locations, that is, the lower limb joints (hip and knee), the spine and the fingers (hand OA), most data regarding prognostic factors of progression are available for hip and knee OA, for which this review concentrates mostly on.


How to define progression: symptoms versus X-rays


Progression of OA can be assessed through symptoms (i.e., pain and/or functional consequences) . Knowledge of functional consequences is essential for the development of optimal rehabilitation programmes in OA patients. Progression can also be defined through structural progression (generally assessed by radiologic progression on plain radiographs) . Scoring techniques used include the Kellgren and Lawrence grading , measurement of joint space width (JSW) in millimetres or use of the Osteoarthritis Research Society International (OARSI) atlas . Due to the contradictory association between radiologic OA and functioning , information about functional course cannot be derived from studies on radiologic progression. Another possible definition of progression is the requirement for total joint replacement, a surrogate marker of more severe spectrum of disease . In this review, we present the available data which relate mostly to predictors of radiographic progression.


Differences between data issued from trials and cohorts


One of the difficulties is that data available regarding prognostic factors of progression of OA are issued from two main different sources: clinical trials (e.g., the Evaluation of the Chondromodulating Effect of Diacerein in Osteoarthritis of the Hip trial, ECHODIAH , a French multicentre randomised controlled trial in hip OA) and epidemiologic cohorts, population based or not (e.g., Hawker et al. , a large prospective population cohort study of 2128 individuals studying factors on progression of hip and knee OA with a median follow-up of 6.1 years). As patients participating in clinical trials do not reflect the general population , epidemiologic cohort data may be more relevant for clinical practice. However, both types of data are reported here, since many elements have been reported mainly in trials.


For the purposes of this review, the current knowledge regarding prognostic factors of progression in OA will be divided into patient and disease characteristics.




Some necessary precisions


Localisation of OA


Although OA is frequent at several locations, that is, the lower limb joints (hip and knee), the spine and the fingers (hand OA), most data regarding prognostic factors of progression are available for hip and knee OA, for which this review concentrates mostly on.


How to define progression: symptoms versus X-rays


Progression of OA can be assessed through symptoms (i.e., pain and/or functional consequences) . Knowledge of functional consequences is essential for the development of optimal rehabilitation programmes in OA patients. Progression can also be defined through structural progression (generally assessed by radiologic progression on plain radiographs) . Scoring techniques used include the Kellgren and Lawrence grading , measurement of joint space width (JSW) in millimetres or use of the Osteoarthritis Research Society International (OARSI) atlas . Due to the contradictory association between radiologic OA and functioning , information about functional course cannot be derived from studies on radiologic progression. Another possible definition of progression is the requirement for total joint replacement, a surrogate marker of more severe spectrum of disease . In this review, we present the available data which relate mostly to predictors of radiographic progression.


Differences between data issued from trials and cohorts


One of the difficulties is that data available regarding prognostic factors of progression of OA are issued from two main different sources: clinical trials (e.g., the Evaluation of the Chondromodulating Effect of Diacerein in Osteoarthritis of the Hip trial, ECHODIAH , a French multicentre randomised controlled trial in hip OA) and epidemiologic cohorts, population based or not (e.g., Hawker et al. , a large prospective population cohort study of 2128 individuals studying factors on progression of hip and knee OA with a median follow-up of 6.1 years). As patients participating in clinical trials do not reflect the general population , epidemiologic cohort data may be more relevant for clinical practice. However, both types of data are reported here, since many elements have been reported mainly in trials.


For the purposes of this review, the current knowledge regarding prognostic factors of progression in OA will be divided into patient and disease characteristics.




Part I. Patient characteristics predictive of OA progression


The various patient characteristics studied in OA progression and the level of evidence are summarised in Table 1 .



Table 1

Patient characteristics and the strength of association in prediction of OA progression.
































































Risk factor Strength of association
Age Moderate
Gender Conflicting
Malalignment of the knee Strong
Adduction moment of the knee Limited
Quadriceps strength Limited
Sports and running No evidence
Nutrition Limited to moderate
Superolateral migration in hip OA Moderate
Atrophic bone response in hip Strong
Injury and knee OA No relationship
Meniscectomy and meniscal damage No evidence
Chondrocalcinosis No evidence
Obesity Conflicting
Smoking, anxiety and depression No relationship
Genetics Inconclusive
Hormones Inconclusive
Insulin Growth Factor 1 Conflicting
Hyaluronic acid Moderate
Bone mineral density Conflicting

Strong = majority of available studies showing positive association, Moderate = fewer studies but positive association is shown is majority of these studies, Limited = positive association is shown but there are limited studies, Conflicting = there are positive and negative studies, Inconclusive = there are studies but can neither conclude a positive or a negative association, No relationship = majority of studies show no relationship.




Age


There is moderate evidence that age is a risk factor for hip and knee OA progression


Age is a risk factor for occurrence of OA but may not be a risk factor for progression of OA . In a 12-year follow-up study of a general population of 239 patients, Schouten et al. found a significant association between age and progression of knee OA, measured by the change in joint space width (JSW). This was only for the comparison of the fourth quartile (higher age) versus the first quartile (lower age) with an odds ratio, OR, of 3.84 (95% confidence interval, CI: 1.10–13.4) in patients over 60 years old. On the other hand, a number of studies found no significant association .


In hip OA, there appears to be conflicting evidence that age is a risk factor for hip OA progression, although several studies have shown this association . Positive studies such as ECHODIAH analysed 507 patients with symptomatic hip OA. In patients over 65 years old at baseline, there was an OR of 1.9 (95% CI: 1.18–3.08) of having radiological progression of the hip at 12 months. By contrast, Conrozier et al. , in a prospective follow-up study of 1 year, found no association between age and OA hip progression measured radiographically (JSW).


Hawker et al. studied both hip and knee OA and showed that increased age had an increased hazard ratio (HR) ranging from 1.46 to 1.57 of undergoing total joint arthroplasty.




Gender


There is conflicting evidence that female sex is associated with progression of OA in the hip and there is no evidence for knee OA progression


There is no evidence supporting that female sex is a risk factor for progression of knee OA . There is conflicting evidence that female sex is associated with progression of OA in the hip with only one cohort study that reported a positive association. In the ECHODIAH trial , a greater proportion of women had more structural progression at 1 year and more women had undergone total hip arthroplasty at 5 years, with an HR of 1.4 (95% CI: 1.1–1.8) .




Malalignment of the knee


There is strong evidence of varus and valgus malalignment for OA progression of knee


Malalignment (either valgus or varus) concentrates loading on a focal area, to the level at which cartilage damage may occur, potentially leading to OA progression. The systematic review by Tanamas et al. found that knee malalignment is a strong independent risk factor for progression of knee OA. This was supported in both high-quality radiographic and magnetic resonance imaging (MRI) cohort studies .


Three studies reported a statistically significant association between varus alignment and progression of OA measured by a decrease in JSW. In the study by Miyazaki et al. , varus alignment and progression of knee OA had an OR of 3.10, (95% CI: 1.07–9.12) in the univariate analysis, but not multivariate analysis. Cerejo et al. and Miyazaki et al. found a statistically significant relationship with progression of OA when there was valgus malalignment (ORs 10.44 and 4.89, respectively). The third study reported association of OA progression with varus and valgus malalignment (ORs 2.98 and 3.42, respectively) .




Adduction moment of the knee


There is limited evidence that increase in adduction moment of the knee is a risk factor for progression of OA knee


Biomechanical factors such as the adduction moment of the knee have been considered to be an influential factor producing medial joint force in joints with varus deformity with the magnitude correlating with OA disease severity . The only study examining the risk of high adduction moment to OA progression in the knee investigated 106 patients with medial compartment OA followed up for 6 years . With a 1% increase in adduction moment, the risk of progression was increased by 6.5 times. However, gait analysis systems are not readily available for this risk factor to be useful in clinical practice.




Type of migration in hip OA


There is moderate evidence of superolateral migration and progression of hip OA


In two out of the three highest-quality cohort studies reported in a systematic review , a more rapid progression of hip OA was found in patients with a superolateral migration of the femoral head . The third high-quality study reported a positive association with superior migration .




Atrophic bone response in hip


There is strong evidence that atrophic bone response is a risk for hip OA progression


From three cohort studies including two of high quality evaluating the association between atrophic bone response and progression of hip OA, all three reported a positive association .




Injury and knee OA


There is no association of knee injury and progression of knee OA


Cooper et al. studied the relationship between previous knee injury and progression of OA, while Schouten et al. studied the presence of knee injury including sporting injuries at follow-up. Both these studies reported no association.




Meniscectomy/meniscal damage and knee OA


There is evidence of the prognostic role of meniscal damage and meniscectomy for incident OA of the knee but not for progression of knee OA


Studies of meniscal damage on progression of OA have mainly used patients who have undergone meniscectomy. There has been a clear increase in risk of incident OA in patients who have undergone meniscectomy . On the other hand, the evidence for a relationship between meniscectomy and progression of OA is poor .




Chondrocalcinosis


There is no evidence for an association between chondrocalcinosis and progression of knee OA


A number of cross-sectional studies have found an association between the presence and severity of OA with chondrocalcinosis; however, evidence for radiographic progression on X-rays is lacking. A study evaluating two prospective cohorts on the progression of knee OA using longitudinal MRI assessments of cartilage loss failed to show a positive association . There is also a lack of association when measured by JSW .


However, some authors support an association between calcium pyrophosphate and OA progression .




Weight – body mass index (BMI)


There is conflicting evidence that obesity measured by BMI is a risk factor for knee and hip OA progression


Although obesity is a strong risk factor for incident (new-onset) tibiofemoral and hip OA , findings on the relationship between BMI and OA progression are inconsistent. The data from the Multicentre Osteoarthritis STudy (MOST), an epidemiologic study of knee OA, showed that obesity had no effect on progression in OA knees with varus alignment; however, it did increase the risk of progression in knees with neutral or valgus alignment . In that study, Niu et al. explained that the stress on varus knees might be sufficient by itself to produce progression, and that excess load conferred by obesity may not be necessary as an additional factor. Knees with valgus alignment do not necessarily produce comparable valgus stress.


The Rotterdam study, a large population cohort of 3585 patients, showed that a high body mass index (BMI) was associated with progression of knee OA (OR 3.2) but not with hip OA . In the study by Cooper et al. , a significant relationship with BMI was only found in the comparison of the highest tertile versus the lowest tertile in the group with baseline K/L grade 2 or higher. Other studies found no statistically significant association .


The relationship between change in BMI and progression of OA was also investigated, but no statistically significant association was found .




Quadriceps strength


There is no evidence that quadriceps strength is predictive of OA progression in the knee, except for perhaps the lateral compartment of the patellofemoral joint


Quadriceps strengthening has been widely recommended for treatment of knee OA, but the impact of quadriceps strength on the course of OA progression is not well understood. Several authors found no difference in baseline quadriceps strength between those with and without OA progression . Even when MRI was used as the outcome measure, there was no association between quadriceps strength and cartilage loss at the tibiofemoral joint . In that particular study, quadriceps strength was protective against cartilage loss only at the lateral compartment of the patellofemoral joint with an OR of 0.4 (95% CI: 0.2–0.9) when comparing the highest versus the lowest tertile of strength. Greater quadriceps strength may prevent lateral offset and tilt of the patella, thus protecting against cartilage loss at the lateral compartment of the patellofemoral joint. Despite these findings, maintaining strong quadriceps is of benefit to those with knee OA but more work is needed to determine the type and frequency of exercise regimen that would be beneficial.




Sports and running


There is no evidence that sports and running increases risk of OA progression, more studies are needed


Experimental studies in animals have indicated that running causes relatively little increased risk of OA progression, although it may stimulate osteophyte formation. The effect of sports activity on OA risk depends upon whether the activity was undertaken by a person with an already damaged joint or a normal joint. When protective mechanisms of damaged joints are impaired, it is vulnerable to the trans-articular loading that occurs with sports activity.


There are limited clinical studies on risk factors in OA progression. There is no significant association between running and progression of OA in three studies .

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Nov 11, 2017 | Posted by in RHEUMATOLOGY | Comments Off on What are the best markers for disease progression in osteoarthritis (OA)?
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