Abstract
Objective:
We aimed to describe the natural history leading to end-stage knee osteoarthritis (esKOA), focusing on knee symptoms, radiographic severity, and the presence of limited mobility or instability.
Methods:
We performed knee-based analyses of Osteoarthritis Initiative data from 7,691 knees (4,165 participants). We used a validated definition of esKOA that relied on meeting one of two criteria: 1) severe radiographic knee osteoarthritis (Kellgren-Lawrence [KL] grade=4) with moderate-to-intense pain (Likert WOMAC pain+function>11/88) or 2) KL grade<4 with intense or severe pain (WOMAC pain+function>22) and limited mobility (flexion contracture≥5°) or instability (based on a varus and valgus stress test). We also introduced an alternate definition of esKOA that relied on meeting one of two criteria that omitted physical exam findings: 1) severe radiographic knee osteoarthritis (KL grade=4) with at least moderate symptoms or 2) KL grade=2 or 3 with intense or severe symptoms and persistent knee pain (frequent knee pain during three or more months in the past year). We used descriptive statistics to explore the frequency of components of esKOA at the index visit when they had incident esKOA, at the annual visit before developing esKOA, and the interval change between those visits.
Results:
Our analytic sample was mostly female (58%), without radiographic knee osteoarthritis (KL grade=0 or 1; 60%), without stability or mobility concerns (91%), and without persistent knee pain (77%). At the visit before incident esKOA, most knees already had moderate-to-severe radiographic osteoarthritis using the original (62%) or alternate (50%) definition (versus <15% for either definition of no esKOA). Over 80% of knees that reached the criteria for esKOA achieved this based on increased knee symptom severity – typically without worsening radiographic severity (80%).
Conclusion:
Radiographic severity predisposed a knee to esKOA. However, worsening knee symptoms led to the development of incident esKOA. If investigators want to increase the chance of identifying incident esKOA as an outcome, they should enrich their study samples with people with moderate-to-severe radiographic osteoarthritis. Our findings also highlight the potential reversibility of esKOA (a knee that is classified with esKOA but later is not classified with esKOA). Reversibility is not a flaw of an outcome defining esKOA but rather a desirable clinical outcome to demonstrate a therapeutic intervention can help people with esKOA improve their knee symptoms and delay a knee replacement.
Keywords: pain, osteoarthritis, knee, patient-reported outcome measures
The United States Food and Drug Administration recognizes osteoarthritis as a serious disease1 since it is a leading cause of pain, disability, and arthroplasty2 with few effective treatments and none accepted to reduce its overall progression1,3. Barriers to developing effective therapies include an absence of structural endpoints that “reliably predict reduced pain, increased function, or prolonged time to end-stage disease”1. Specifically, we lack a structural endpoint or proxy indicator of severe knee osteoarthritis. Receipt of a knee replacement is often used as a patient-centered endpoint for knee osteoarthritis, but this has a highly variable relationship with biological measures of knee osteoarthritis severity and a strong dependence on many extraneous influences (e.g., expectations, mental and physical readiness for surgery)4. These aspects render knee replacements unreliable as a consistent disease severity endpoint5,6. Also, the low frequency of knee replacement as an outcome requires large sample sizes that are infeasible for most trials7,8.
To overcome these barriers, we developed a composite definition reflecting “end-stage knee osteoarthritis” (esKOA), which combines patient-reported outcomes with structural severity measures to eliminate the influence of extraneous factors in designating this disease status9. A consensus panel of experts adapted this definition from an appropriateness algorithm for knee arthroplasty10 that was further developed and validated for epidemiologic studies5. We defined esKOA as present in a knee that has 1) severe radiographic osteoarthritis (Kellgren-Lawrence [KL] grade = 4 out of 4) with moderate to intense pain or 2) KL grade < 4 with severe to intense pain and limited mobility or instability8,9.
We previously demonstrated that the incidence of esKOA was more than four times that of knee replacement (9.7% vs. 2.1%)9. People with incident esKOA had poorer health outcomes at baseline and greater declines in health outcomes9. Furthermore, people with prevalent or incident esKOA were more likely to receive a knee replacement (29% and 19%, respectively) than those who never had esKOA (1%)9. Our statistical models also indicated that using esKOA instead of knee replacement as the primary outcome in a trial would require a third of the sample size8.
A critical next step to encouraging adoption of this definition of esKOA is to determine how each component of esKOA and their proposed thresholds relate to disease progression towards esKOA. Furthermore, it would be informative to determine whether our current definition that relies on both biomarker and clinical outcome assessment components may be unnecessarily complicated and could be simplified. Hence, we aimed to determine how each component (knee symptoms, radiographic severity, presence of limited mobility or instability) related to disease progression towards esKOA. Furthermore, we sought to develop and validate an alternate definition of esKOA that would omit the need to assess the presence of limited mobility or instability, which can be challenging to acquire in large studies (e.g., multicenter studies).
MATERIALS AND METHODS
Study design
We performed knee-based analyses of Osteoarthritis Initiative (OAI) data to describe the natural history of esKOA. Specifically, we determined how each component of esKOA related to disease progression towards esKOA. Using the OAI offered an opportunity to study a well-characterized cohort to assess esKOA annually for the first four years of the OAI.
Participant selection
The OAI is a prospective cohort study of 4,796 men and women (9,592 knees) with or at risk for symptomatic knee osteoarthritis recruited at four clinical sites in the United States between February 2004 and May 2006. OAI data, documentation, and protocols are freely available online11. We excluded 977 knees missing component data at the baseline visit (including 671 knees without a baseline radiograph) and 924 knees with prevalent esKOA or a knee replacement at the OAI baseline. Hence, we analyzed data from 7,691 knees (4,165 participants) at risk for developing esKOA by the first annual follow-up visit.
Radiographic knee assessment
Weight-bearing, bilateral, fixed-flexion, posterior-anterior knee radiographs were obtained at the OAI baseline and each subsequent visit. Central readers read the images blinded to the order of follow-up images and scored the knees for KL grades (0 to 4)12. The agreement for these readings (read-reread) was good (weighted kappa (intra-rater reliability = 0.70 to 0.78). The KL grades are publicly available (File: kXR_SQ_BU; version 0.6, 1.6, 3.5, 5.5, 6.3)11.
Overall, 9.3% of knee-visits had a missing KL grade. We adopted a conservative strategy to replace the missing KL grades by carrying forward the KL grade from the previous visit.
Knee symptoms assessment
Knee symptoms were based on knee-specific WOMAC pain and WOMAC function (Likert scale), available at every annual visit. The data are publicly available (Files: allclinical; version 0.2.2, 1.2.1, 3.2.1, 5.2.1, 6.2.1)11. The proposed thresholds for interpreting knee symptoms were based on Riddle et al.5 that classified knee symptoms into four categories based on an aggregate score of WOMAC pain and function (aggregate score range=0 to 88): mild (≤ 11), moderate (12 to 22), severe (23 to 33), and intense (> 33) symptoms.
Assessments of knee mobility and instability
Knee range of motion, dichotomized based on the presence or absence of a flexion contracture (≥ 5 degrees)13, was only assessed at baseline. At the 24- and 36-month visits, clinic staff assessed knees for varus-valgus laxity based on a varus and valgus stress test with the knee flexed 20 degrees. We relied on baseline range of motion at every visit. We used varus-valgus laxity data from the most recent visit with data for the 48-month visit. If varus-valgus laxity was missing at the 36-month visit, then we used the results from the 24-month visit. If no varus-valgus data were available, we only used baseline range of motion for all visits. The data are publicly available (Files: allclinical (version 0.2.2, 1.2.1, 3.2.1, 5.2.1, 6.2.1)11.
At baseline and the 12-month visit, we categorized knee range of motion and instability based solely on the presence or absence of a flexion contracture (≥ 5 degrees) because varus-valgus laxity was not collected until the 24-month visit. At the 24-, 36-, and 48-month visits, we classified knees into two groups: limited mobility-instability (severe varus-valgus laxity or presence of baseline flexion contracture) or normal mobility-stability (no-mild varus-valgus laxity and no baseline flexion contracture).
End-stage knee osteoarthritis (esKOA)
We defined esKOA as 1) severe radiographic knee osteoarthritis (KL grade = 4) with moderate to intense pain (Likert WOMAC pain + function > 11) or 2) KL grade < 4 with intense or severe pain (WOMAC pain + function > 22) and limited mobility (flexion contracture ≥5°) or instability (based on a varus and valgus stress test)8,9.
An alternate end-stage knee osteoarthritis definition
Based on feedback from stakeholders, we recognized the need to address the challenges of relying on a physical examination to assess knee range of motion and instability at multiple centers. Thus, we describe our approach to developing and validating an alternate definition for esKOA in the Supplemental Material. In brief, we found that the number of months within the past year with knee symptoms on most days was a key patient-reported outcome statistically associated with limited mobility or instability. Among four candidate definitions, we identified the optimal alternate definition of esKOA: 1) severe radiographic knee osteoarthritis (KL grade = 4) with at least moderate symptoms OR 2) KL = 2 or 3 with intense or severe symptoms and persistent knee pain (we defined the latter as frequent knee pain during three or more months in the past year).
Statistical analysis
We used descriptive statistics to 1) describe our study sample, 2) explore the frequency of components of esKOA at the index visit when they had incident esKOA and the annual visit before developing esKOA, and 3) report the frequency of change in components of esKOA during the year before presenting with esKOA (visit before esKOA to the visit with incident esKOA). For knees that never developed esKOA during the first 48 months of the OAI, we defined their index visit as the 48-month visit, the last visit during our observational period. Finally, we replicated these descriptive summaries when we stratified by other components of the esKOA definition. For example, in strata of KL < 4 or KL = 4, we examined the frequency of flexion contractor or instability (yes/no) and pain/function (mild, moderate, severe, and intense) by esKOA status.
RESULTS
Our analytic sample included 7,691 knees. At the OAI baseline, on average (standard deviation), the cohort was 61 (9) years old, overweight (28.3 [4.7] kg/m2), with mild symptoms (WOMAC pain = 1.7 [2.5]; WOMAC function = 5.6 [8.2]). The cohort was also mostly white (82%), female (58%), without radiographic knee osteoarthritis (KL = 0 or 1; 60%), without stability or mobility concerns (91%), and without frequent knee pain during 3 or more months in the past year (77%).
Incidence of esKOA and knee replacements
Supplemental Table 1 demonstrates that the alternate definition of esKOA classified almost twice as many knees with incident esKOA than the original definition (10.2% vs. 5.6%) and had a moderate agreement (kappa = 0.50) with the original definition. Finally, 233 (3.0%) knees received a knee replacement during the first five years of the OAI.
Index visit with esKOA
Table 1 shows the frequency of each component of esKOA at the time when a knee meets the criteria for esKOA. Knees with esKOA were more likely than those without esKOA to have mobility/instability concerns (original definition: 70% vs. 10%), intense/severe knee symptoms (e.g., original definition: 75% vs. 9%), moderate-severe radiographic severity (KL= 3 or 4; e.g., original definition: 65% vs. 16%), and persistent knee pain (alternate definition: 96% vs. 19%).
Table 1.
At the Visit When a Knee First Meets the Criteria for End-Stage Knee Osteoarthritis (esKOA; Index Visit), it Commonly has Worse Components of esKOA than Those Knees without esKOA (at the 48-month visit).
| Original Definition | |||||
|---|---|---|---|---|---|
| Variable | Category | No esKOA n=7258 |
esKOA n=433 |
||
| Limited mobility or instability | Absent | 6501 (89.57) | 132 (30.48) | ||
| Present | 757 (10.43) | 301 (69.52) | |||
| Knee symptoms (WOMAC scores) | Mild (0-11) | 5785 (79.71) | 0 (0.00) | ||
| Moderate (12-22) | 837 (11.53) | 108 (24.94) | |||
| Intense (23-33) | 366 (5.04) | 221 (51.04) | |||
| Severe (>33) | 270 (3.72) | 104 (24.02) | |||
| Radiographic severity Kellgren-Lawrence [KL] grade) | 0 | 2917 (40.19) | 40 (9.24) | ||
| 1 | 1316 (18.13) | 34 (7.85) | |||
| 2 | 1888 (26.01) | 76 (17.55) | |||
| 3 | 1022 (14.08) | 90 (20.79) | |||
| 4 | 115 (1.58) | 193 (44.57) | |||
| Combinations of 3 componentsa | Instability | Symptoms | KL grade | ||
| Present | Low | 0/1 | 324 (4.46) | Not possibleb | |
| Present | Low | 2/3 | 393 (5.41) | Not possibleb | |
| Present | Low | 4 | 40 (0.55) | 40 (9.24) | |
| Present | High | 0/1 | Not possibleb | 74 (17.09) | |
| Present | High | 2/3 | Not possibleb | 166 (38.34) | |
| Present | High | 4 | Not possibleb | 21 (4.85) | |
| Absent | Low | 0/1 | 3585 (49.39) | Not possibleb | |
| Absent | Low | 2/3 | 2205 (30.38) | Not possibleb | |
| Absent | Low | 4 | 75 (1.03) | 68 (15.70) | |
| Absent | High | 0/1 | 324 (4.46) | Not possibleb | |
| Absent | High | 2/3 | 312 (4.30) | Not possibleb | |
| Absent | High | 4 | 0 (0.00) | 64 (14.78) | |
| Alternate Definition | |||||
| No esKOA n=6907 |
esKOA n=784 |
||||
| Persistent painc | Absent | 5600 (81.08) | 35 (4.46) | ||
| Present | 1307 (18.92) | 749 (95.54) | |||
| Knee symptoms (WOMAC scores) | Mild (0-11) | 5712 (82.70) | Not possibleb | ||
| Moderate (12-22) | 760 (11.00) | 96 (12.24) | |||
| Intense (23-33) | 259 (3.75) | 433 (55.23) | |||
| Severe (>33) | 176 (2.55) | 255 (32.53) | |||
| Radiographic severity (Kellgren-Lawrence [KL] grade) | 0 | 2955 (42.78) | Not possibleb | ||
| 1 | 1348 (19.52) | Not possibleb | |||
| 2 | 1662 (24.06) | 326 (41.58) | |||
| 3 | 828 (11.99) | 300 (38.27) | |||
| 4 | 114 (1.65) | 158 (20.15) | |||
| Combinations of 3 componentsa | Persistent pain | Symptoms | KL grade | ||
| Present | Low | 0/1 | 555 (8.04) | Not possibleb | |
| Present | Low | 2/3 | 468 (6.78) | Not possibleb | |
| Present | Low | 4 | 28 (0.41) | 71 (9.06) | |
| Present | High | 0/1 | 256 (3.71) | Not possibleb | |
| Present | High | 2/3 | Not possibleb | 626 (79.85) | |
| Present | High | 4 | Not possibleb | 52 (6.63) | |
| Absent | Low | 0/1 | 3383 (48.98) | Not possibleb | |
| Absent | Low | 2/3 | 1952 (28.26) | Not possibleb | |
| Absent | Low | 4 | 86 (1.25) | 25 (3.19) | |
| Absent | High | 0/1 | 109 (1.58) | Not possibleb | |
| Absent | High | 2/3 | 70 (1.01) | Not possibleb | |
| Absent | High | 4 | 0 (0.00) | 10 (1.28) | |
Notes:
Original definition: 1) severe radiographic knee osteoarthritis (KL grade = 4) with moderate to intense pain (Likert WOMAC pain + function > 11) OR 2) KL grade < 4 with intense or severe pain (WOMAC pain + function > 22) and [limited mobility (flexion contracture ≥5°) or instability (based on a varus and valgus stress test)].
Alternate definition: 1) severe radiographic knee osteoarthritis (KL grade = 4) with at least moderate symptoms OR 2) KL = 2 or 3 with intense or severe symptoms and persistent knee pain (frequent knee pain during three or more months in the past year).
We created a binary variable for symptoms (low: mild/moderate vs. high: intense/severe). Instability includes mobility and stability.
Not possible = a combination is not possible because it would have led to a knee to be classified in the other group at this visit.
Persistent pain = 3 or more months with pain more than half the days of the month during the past 12 months
These distinctions were common across strata (Supplemental Tables 2 and 3). However, the distinctions in mobility/instability concerns between knees with and without esKOA were less pronounced among knees with mild-moderate knee symptoms (37% vs. 11%) or KL grade = 4 (32% vs. 35%). The differences in the frequency of intense/severe knee symptoms between knees with and without esKOA were also less than our overall findings among knees without persistent knee pain (29% vs. 3%).
Change during the year before presenting with esKOA
Table 2 shows the frequency of change in each component of esKOA between the visit before a knee presents with esKOA and the index visit. While 70-80% of knees without esKOA remained stable in all components for the two definitions, over 80% of knees in the esKOA group experienced an increase in WOMAC category, regardless of definition, and often without an increase in radiographic severity. Among those who developed esKOA, almost one in five knees experienced worsening mobility or instability, 22 to 29% experienced radiographic worsening, and approximately half started to report persistent knee pain.
Table 2.
Change in Knee Symptoms Defines the Onset of End-Stage Knee Osteoarthritis (esKOA) During the Year Before Presenting with esKOA
| Original Definition | |||||
|---|---|---|---|---|---|
| Variable | Change from previous visita | No esKOA n=7252 |
esKOA n=433 |
||
| Limited mobility or instability | Developed limited mobility/instability (worsened) | 2 (0.03) | 81 (18.71) | ||
| No change | 7249 (99.96) | 350 (80.83) | |||
| Regained mobility/stability (improved) | 1 (0.01) | 2 (0.46) | |||
| Knee symptoms categoryb | Improved | 686 (9.46) | 26 (6.00) | ||
| No change | 5849 (80.65) | 53 (12.24) | |||
| Worsened | 717 (9.89) | 354 (81.76) | |||
| Radiographic severity (KL grade) | No change | 7074 (97.55) | 307 (70.90) | ||
| Worsened (KL increase) | 178 (2.45) | 126 (29.10) | |||
| Symptoms | Mobility/Instability | KL grade | |||
| Combinations of changes in 3 componentsc | Improved | Worsened | Improved | 0 (0.00) | 0 (0.00) |
| Improved | Worsened | No change | 0 (0.00) | 4 (0.92) | |
| Improved | Worsened | Worsened | 0 (0.00) | 1 (0.23) | |
| Improved | No change | Improved | 0 (0.00) | 0 (0.00) | |
| Improved | No change | No change | 660 (9.10) | 0 (0.00) | |
| Improved | No change | Worsened | 26 (0.36) | 21 (4.85) | |
| Improved | Improved | Improved | 0 (0.00) | 0 (0.00) | |
| Improved | Improved | No change | 0 (0.00) | 0 (0.00) | |
| Improved | Improved | Worsened | 0 (0.00) | 0 (0.00) | |
| No change | Worsened | Improved | 0 (0.00) | 0 (0.00) | |
| No change | Worsened | No change | 1 (0.01) | 21 (4.85) | |
| No change | Worsened | Worsened | 0 (0.00) | 3 (0.69) | |
| No change | No change | Improved | 0 (0.00) | 0 (0.00) | |
| No change | No change | No change | 5731 (79.03) | 0 (0.00) | |
| No change | No change | Worsened | 116 (1.60) | 29 (6.70) | |
| No change | Improved | Improved | 0 (0.00) | 0 (0.00) | |
| No change | Improved | No change | 1 (0.01) | 0 (0.00) | |
| No change | Improved | Worsened | 0 (0.00) | 0 (0.00) | |
| Worsened | Worsened | Improved | 0 (0.00) | 0 (0.00) | |
| Worsened | Worsened | No change | 0 (0.00) | 43 (9.93) | |
| Worsened | Worsened | Worsened | 1 (0.01) | 9 (2.08) | |
| Worsened | No change | Improved | 0 (0.00) | 0 (0.00) | |
| Worsened | No change | No change | 681 (9.39) | 238 (54.97) | |
| Worsened | No change | Worsened | 35 (0.48) | 62 (14.32) | |
| Worsened | Improved | Improved | 0 (0.00) | 0 (0.00) | |
| Worsened | Improved | No change | 0 (0.00) | 1 (0.23) | |
| Worsened | Improved | Worsened | 0 (0.00) | 1 (0.23) | |
| Symptoms | KL Grade | ||||
| Combinations, mobility/stability excludedd | Improved | Improved | 0 (0.00) | 0 (0.00) | |
| Improved | No change | 660 (9.10) | 4 (0.92) | ||
| Improved | Worsened | 26 (0.36) | 22 (5.08) | ||
| No change | Improved | 0 (0.00) | 0 (0.00) | ||
| No change | No change | 5733 (79.05) | 21 (4.85) | ||
| No change | Worsened | 116 (1.60) | 32 (7.39) | ||
| Worsened | Improved | 0 (0.00) | 0 (0.00) | ||
| Worsened | No change | 681 (9.39) | 282 (65.13) | ||
| Worsened | Worsened | 36 (0.50) | 72 (16.63) | ||
| Alternate Definition | |||||
| No esKOA n=6901 |
esKOA n=784 |
||||
| Persistent paind | Improved | 546 (7.91) | 7 (0.89) | ||
| Remained the same over time | 5747 (83.28) | 367 (46.81) | |||
| Developed persistent pain (more) | 608 (8.81) | 410 (52.3) | |||
| Knee symptoms categoryb | Improved (decrease) | 579 (8.39) | 25 (3.19) | ||
| Remained the same over time | 5715 (82.81) | 95 (12.12) | |||
| Worsened (increase) | 607 (8.80) | 664 (84.69) | |||
| Radiographic severity (KL grade) | Same | 6753 (97.86) | 608 (77.55) | ||
| Increased | 148 (2.14) | 176 (22.45) | |||
| Symptoms | Persistent pain | KL grade | |||
| Combinations of changes in 3 componentsc | Improved | Improved | Improved | 0 (0.00) | 0 (0.00) |
| Improved | Improved | No change | 127 (1.84) | 0 (0.00) | |
| Improved | Improved | Worsened | 7 (0.1) | 0 (0.00) | |
| Improved | No change | Improved | 0 (0.00) | 0 (0.00) | |
| Improved | No change | No change | 373 (5.41) | 0 (0.00) | |
| Improved | No change | Worsened | 13 (0.19) | 3 (0.38) | |
| Improved | Worsened | Improved | 0 (0.00) | 0 (0.00) | |
| Improved | Worsened | No change | 58 (0.84) | 13 (1.66) | |
| Improved | Worsened | Worsened | 1 (0.01) | 9 (1.15) | |
| No change | Improved | Improved | 0 (0.00) | 0 (0.00) | |
| No change | Improved | No change | 364 (5.27) | 0 (0.00) | |
| No change | Improved | Worsened | 8 (0.12) | 4 (0.51) | |
| No change | No change | Improved | 0 (0.00) | 0 (0.00) | |
| No change | No change | No change | 4883(70.76) | 0 (0.00) | |
| No change | No change | Worsened | 78 (1.13) | 25 (3.19) | |
| No change | Worsened | Improved | 0 (0.00) | 0 (0.00) | |
| No change | Worsened | No change | 359 (5.2) | 57 (7.27) | |
| No change | Worsened | Worsened | 23 (0.33) | 9 (1.15) | |
| Worsened | Improved | Improved | 0 (0.00) | 0 (0.00) | |
| Worsened | Improved | No change | 39 (0.57) | 3 (0.38) | |
| Worsened | Improved | Worsened | 1(0.01) | 0 (0.00) | |
| Worsened | No change | Improved | 0 (0.00) | 0 (0.00) | |
| Worsened | No change | No change | 389 (5.64) | 273 (34.82) | |
| Worsened | No change | Worsened | 11 (0.16) | 66 (8.42) | |
| Worsened | Worsened | Improved | 0 (0.00) | 0 (0.00) | |
| Worsened | Worsened | No change | 161 (2.33) | 262 (33.42) | |
| Worsened | Worsened | Worsened | 6 (0.09) | 60 (7.65) | |
| Worsened | Worsened | Worsened | 6 (0.09) | 60 (7.65) | |
Note:
Six knees in the no esKOA group had their last visit at the OAI baseline, which excluded them from this table.
Original definition: 1) severe radiographic knee osteoarthritis (KL grade = 4) with moderate to intense pain (Likert WOMAC pain + function > 11) or 2) KL grade < 4 with intense or severe pain (WOMAC pain + function > 22) and limited mobility (flexion contracture ≥5°) or instability (based on a varus and valgus stress test).
Alternate definition: 1) severe radiographic knee osteoarthritis (KL grade = 4) with at least moderate symptoms or 2) KL = 2 or 3 with intense or severe symptoms and persistent knee pain (frequent knee pain during three or more months in the past year).
Gray font = A row had 0 participants in both esKOA and no esKOA columns.
For knees with No esKOA, we focused on change during the last year of the observation period (36- to 48-month visits).
Change in knee symptoms was based on change among the 4 ordinal categories.
By definition, KL decrease is not possible but is included above to include all possible combinations. Stable status includes mobility and stability.
Persistent pain = 3 or more months with pain more than half the days of the month during the past 12 months
Stratified results revealed some contrasts to the overall findings described above (Supplemental Tables 3 and 4). An increase in WOMAC category occurred in less than 80% of knees in the esKOA group if they had normal mobility or stability (original definition: 67%), KL grade = 4 (original definition: 72%), or no persistent pain (alternate definition: 71%). Furthermore, worsening mobility or stability rarely occurred in knees that developed esKOA (original definition) if they started with mild to moderate knee symptoms (4%) or KL grade = 4 (7%). Worsening radiographic severity among knees that developed esKOA was less common in those with limited mobility or instability (original definition: 13%). However, worsening radiographic severity was more common among knees that developed esKOA if they started with normal mobility and stability (66%), mild to moderate symptoms (original definition: 46%, alternate definition: 42%), and no persistent pain (alternate definition: 43%). Fewer knees that developed esKOA began to report persistent knee pain if they originally had mild to moderate knee symptoms (34%) or KL grade = 4 (35%). In brief, initial knee symptom severity, radiographic severity, persistent knee pain, and mobility or stability may be important factors that influence how each component contributes to the onset of esKOA.
The visit before esKOA
Table 3 shows the frequency of each component of esKOA at the visit before a knee presents with esKOA. For the original definition, at that visit before incident esKOA, the most discordant findings between those who would develop esKOA versus those who would not were the higher prevalence of limited mobility or instability (51% vs. 10%), moderate-to-severe radiographic osteoarthritis (KL 3 or 4; 62% vs. 14%), and moderate-to-severe knee symptoms (52% vs. 20%). Similarly, for the alternate definition, the most discordant findings between groups were the higher prevalence of persistent knee pain (44% vs. 18%), moderate-to-severe radiographic osteoarthritis (50% vs. 13%), and moderate-to-severe knee symptoms (59% vs. 17%) among those who would develop esKOA. These distinctions were common across strata (Supplemental Tables 6 and 7).
Table 3.
At the Visit Before Presenting with End-Stage Knee Osteoarthritis (esKOA), Moderate-Severe Radiographic Osteoarthritis and Limited Mobility or Instability but Not Intense-Severe Knee Symptoms are Common Among Knees that Will Develop esKOA
| Variable | Category | Original Definition | |||
|---|---|---|---|---|---|
| No esKOA n=7252 |
esKOA n=433 |
||||
| Limited mobility or instability | Absent | 6498 (89.60) | 211 (48.73) | ||
| Present | 754 (10.40) | 222 (51.27) | |||
| Knee symptoms (WOMAC scores) | Mild (0-11) | 5792 (79.87) | 210 (48.50) | ||
| Moderate (12-22) | 872 (12.02) | 154 (35.57) | |||
| Intense (23-33) | 325 (4.48) | 26 (6.00) | |||
| Severe (>33) | 263 (3.63) | 43 (9.93) | |||
| Radiographic severity (Kellgren-Lawrence [KL] grade) | 0 | 2952 (40.71) | 43 (9.93) | ||
| 1 | 1333 (18.38) | 37 (8.55) | |||
| 2 | 1924 (26.53) | 85 (19.63) | |||
| 3 | 961 (13.25) | 189 (43.65) | |||
| 4 | 82 (1.13) | 79 (18.24) | |||
| Instability | Symptoms | KL grade | |||
| Combinations of 3 componentsa | Present | Low | 0/1 | 327 (4.51) | 45 (10.39) |
| Present | Low | 2/3 | 393 (5.42) | 146 (33.72) | |
| Present | Low | 4 | 34 (0.47) | 31 (7.16) | |
| Present | High | 0/1 | Not possibleb | Not possibleb | |
| Present | High | 2/3 | Not possibleb | Not possibleb | |
| Present | High | 4 | Not possibleb | Not possibleb | |
| Absent | Low | 0/1 | 3660 (50.47) | 15 (3.46) | |
| Absent | Low | 2/3 | 2202 (30.36) | 79 (18.24) | |
| Absent | Low | 4 | 48 (0.66) | 48 (11.09) | |
| Absent | High | 0/1 | 298 (4.11) | 20 (4.62) | |
| Absent | High | 2/3 | 290 (4.00) | 49 (11.32) | |
| Absent | High | 4 | 0 (0.00) | 0 (0.00) | |
| Alternate Definition | |||||
| No esKOA n=6901 |
esKOA n=784 |
||||
| Persistent painc | Absent | 5658 (81.99) | 438 (55.87) | ||
| Present | 1243 (18.01) | 346 (44.13) | |||
| Knee symptoms (WOMAC scores) | Mild (0-11) | 5721 (82.9) | 325 (41.45) | ||
| Moderate (12-22) | 786 (11.39) | 326 (41.58) | |||
| Intense (23-33) | 221 (3.20) | 69 (8.80) | |||
| Severe (>33) | 173 (2.51) | 64 (8.16) | |||
| Radiographic Severity (KL grade) | 0 | 2987 (43.28) | 19 (2.42) | ||
| 1 | 1361 (19.72) | 38 (4.85) | |||
| 2 | 1679 (24.33) | 333 (42.47) | |||
| 3 | 792 (11.48) | 318 (40.56) | |||
| 4 | 82 (1.19) | 76 (9.69) | |||
| Persistent pain | Symptoms | KL grade | |||
| Combinations of 3 componentsa | Present | Low | 0/1 | 567 (8.22) | 13 (1.66) |
| Present | Low | 2/3 | 444 (6.43) | 283 (36.1) | |
| Present | Low | 4 | 16 (0.23) | 32 (4.08) | |
| Present | High | 0/1 | 216 (3.13) | 18 (2.30) | |
| Present | High | 2/3 | Not possibleb | Not possibleb | |
| Present | High | 4 | Not possibleb | Not possibleb | |
| Absent | Low | 0/1 | 3450 (49.99) | 18 (2.30) | |
| Absent | Low | 2/3 | 1964 (28.46) | 261 (33.29) | |
| Absent | Low | 4 | 66 (0.96) | 44 (5.61) | |
| Absent | High | 0/1 | 115 (1.67) | 8 (1.02) | |
| Absent | High | 2/3 | 63 (0.91) | 107 (13.65) | |
| Absent | High | 4 | 0 (0.00) | 0 (0.00) | |
Notes:
For knees with No esKOA, we focused on the 36-month visit, which was the visit before the last observation (48 months).
Six knees in the no esKOA group had their last visit at the OAI baseline, which excluded them from this table.
Original definition: 1) severe radiographic knee osteoarthritis (KL grade = 4) with moderate to intense pain (Likert WOMAC pain + function > 11) or 2) KL grade < 4 with intense or severe pain (WOMAC pain + function > 22) and limited mobility (flexion contracture ≥5°) or instability (based on a varus and valgus stress test).
Alternate definition: 1) severe radiographic knee osteoarthritis (KL grade = 4) with at least moderate symptoms or 2) KL = 2 or 3 with intense or severe symptoms and persistent knee pain (frequent knee pain during three or more months in the past year).
We created a binary variable for symptoms (low: mild/moderate vs. high: intense/severe). Instability includes mobility and stability.
Not possible = a combination is not possible because it would have led to a knee to be classified as esKOA at this visit (e.g., KL=4 with intense knee symptoms)
Persistent pain = 3 or more months with pain more than half the days of the month during the past 12 months
DISCUSSION
A fundamental requirement of a definition of esKOA is that it reflects the complex natural history of osteoarthritis both as a disease (defined by structural changes) and an illness (characterized by patient-reported outcomes). We found that progression to esKOA was frequently preceded by moderate-to-severe radiographic osteoarthritis or limited mobility or instability. Furthermore, over 80% of knees that reached the criteria for esKOA achieved this based on increased knee symptom severity – typically without worsening radiographic severity. Hence, radiographic severity predisposed a knee to esKOA, but worsening knee symptoms defined the onset of esKOA. We also observed that initial knee symptom severity, radiographic severity, persistent knee pain, and mobility or instability might be important factors that influence how each component contributes to the onset of esKOA. Hence, each component that defined esKOA may be clinically significant.
While radiographic severity and limited mobility or instability predisposed a knee to esKOA, worsening symptoms defined the incidence of esKOA. Ceiling effects partially explain this. For example, 62% of knees that developed esKOA already had moderate-to-severe radiographic osteoarthritis (KL grade = 3 or 4) at the prior visit compared to only 16% that had intense or severe knee symptoms at the prior visit. Interestingly, Supplemental Tables 3 and 4 failed to show that knees with KL grade = 4 were more likely to report increased knee symptoms than KL grade < 4. The discordance may suggest that KL grade = 3 was highly relevant in determining the risk of increased knee symptoms. However, we did not explore this stratum because we decided a priori to focus on KL = 4 and KL < 4 to define esKOA. These observations suggest that recruiting participants with a knee with moderate-to-severe radiographic osteoarthritis and mild-to-moderate knee symptoms should enrich a study sample for a greater incidence of esKOA.
The natural history of esKOA also highlights that the reversibility of esKOA (a knee that is classified with esKOA but later is not classified with esKOA) is not a flaw of an outcome defining esKOA but rather a desirable clinical outcome. It may be beneficial to demonstrate that a therapeutic intervention can help people with esKOA improve their knee symptoms and delay, or completely avoid a knee replacement.
In this manuscript, we have also described an alternate definition of esKOA that omits limited mobility or instability assessments because they are based on physical examinations, which can be challenging to perform reliably in multicenter studies. However, half of those who developed esKOA had limited mobility or instability at the visit before esKOA onset, and 1 in 5 knees developed limited mobility or instability. These results likely underestimate the critical role of assessing limited mobility or instability because the Osteoarthritis Initiative lacked annual assessments, and we often carried data forward for these assessments. While the alternate definition has good face and construct validity, there is merit in adopting the original definition when feasible.
While this study helped clarify the natural history of esKOA, there are some limitations. First, we had limited longitudinal data on assessments of mobility or instability, which may have caused us to underestimate the value of these exams. Despite this, we found compelling evidence that these may be important factors to consider when defining esKOA. The Osteoarthritis Initiative also lacked radiographic assessments of the patellofemoral joint, causing us to underestimate the number of knees with moderate-to-severe radiographic patellofemoral osteoarthritis. Despite this, we believe these analyses suggest that knees with moderate-to-severe radiographic osteoarthritis (KL grade = 3 or 4) are likely to develop esKOA because of increased knee symptoms. Finally, exploring the natural history of esKOA and further validating these definitions among various subsets of osteoarthritis and other prospective cohorts or in clinical trials would be valuable.
In conclusion, esKOA often develops in knees with moderate-to-severe radiographic osteoarthritis or limited mobility or instability. If investigators want to increase the chance of identifying incident esKOA as an outcome, they should enrich their study samples with people with moderate-to-severe radiographic osteoarthritis. We also observed that the incidence of esKOA is predominantly defined by worsening knee symptoms and secondarily by worsening radiographic severity or instability/mobility concerns. Hence, it should not be surprising that esKOA could be reversed and that this should be perceived as analogous to someone reporting that they want to delay or completely avoid a knee replacement.
Supplementary Material
Acknowledgments
These analyses were financially supported by a grant funded by the U.S. Food and Drug Administration (U01 FD007471). The Osteoarthritis Initiative is funded by a public-private partnership comprised of five contracts (N01-AR-2-2258; N01-AR-2-2259; N01-AR-2-2260; N01-AR-2-2261; N01-AR-2-2262) funded by the National Institutes of Health, a branch of the Department of Health and Human Services, and conducted by the OAI Study Investigators. Private funding partners include Merck Research Laboratories; Novartis Pharmaceuticals Corporation, GlaxoSmithKline; and Pfizer, Inc. Private sector funding for the OAI is managed by the Foundation for the National Institutes of Health. This manuscript was prepared using an OAI public use data set and does not necessarily reflect the opinions or views of the OAI investigators, the NIH, or the private funding partners. The project described was supported by the National Center for Advancing Translational Sciences, National Institutes of Health, Award Number UL1TR002544. This work was also supported in part by the Center for Innovations in Quality, Effectiveness and Safety (#CIN 13-413), Michael E. DeBakey VA Medical Center, Houston, Texas. The views expressed in this article are those of the author(s) and do not necessarily represent the views of the National Institutes of Health or the Department of Veterans Affairs.
Footnotes
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CONFLICT OF INTEREST: JBD and TEM served on an advisory board for Novartis. The authors have no other conflicts of interest with regard to this work.
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