Total joint replacement surgery versus conservative care for knee osteoarthritis and other non-traumatic diseases

  • Protocol
  • Intervention

Authors


Abstract

This is the protocol for a review and there is no abstract. The objectives are as follows:

To assess the benefits and harms of total knee arthroplasty (TKA) compared to conservative treatment including continued medical therapy, other therapies such as physical therapy, acupuncture etc. or no treatment in patients with knee osteoarthritis and other non-traumatic diseases with refractory symptoms.

Background

Description of the condition

Total knee joint replacement surgery, also known as total knee arthroplasty (TKA), is an elective surgery performed in patients with severe end-stage arthritis of several types. The most common underlying diagnosis for TKA is osteoarthritis of the knee. Several other arthritic and non-arthritic conditions, including rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis and avascular necrosis, can also lead to TKA. TKA is associated with significant improvement in pain, function and quality of life of patients (Ethgen 2004; Jones 2003; Kane 2005; Wright 2004). It is not known whether TKA is more effective than continued conservative treatment (medical; other interventions such as physical therapy, and acupuncture) or no treatment in patients with symptomatic osteoarthritis, and if so what is the magnitude of this difference.

Arthritis is very common and is a major public health problem internationally. Significant healthcare resources are expended on the care of people with arthritis and rheumatic conditions. As an example, arthritis resulted in 992,100 annual hospitalizations (Helmick 2008) and 44 million annual outpatient visits in the US (AAOS). In 2003, the total cost of arthritis in the US was $128 billion, comprising $81 billion in direct medical costs and $47 billion in indirect costs (lost earnings) (CDC 2007). Osteoarthritis is the most common form of arthritis and affects hands, knees and hips most often. Osteoarthritis is associated with huge indirect costs, estimated at between $3.4 and $13.2 billion job-related costs each year (Buckwalter 2004; CDC 2010). Thus, arthritis is associated with significant socio-economic burden.

Description of the intervention

TKA includes replacement of both surfaces of a knee joint with metal or plastic components or both (AAOS 2011). These components are shaped similar to normal knee anatomy, and help to approximate the biomechanics of the knee to allow it to function normally. The implant can have a variety of designs and materials. In addition to the variation in metal versus polyethylene components (plastic) (metal on metal versus metal on polyethylene), variations included fixed platform or a rotating platform, the latter design hypothesized to allow more mobility and a greater bending of the knee.

Various treatment options are available to patients with knee osteoarthritis and other non-traumatic arthritic conditions. However, their limited efficacy and potential toxicity limits their use in many patients with refractory end-stage arthritis, which is associated with significant pain and activity limitations. Conservative non-surgical treatment options include oral medications (non-steroidal anti-inflammatory drugs (NSAIDs), narcotics, and analgesics such as acetaminophen), local applications (such as capsaicin and lidocaine), intra-articular joint injections, as well as non-medical therapies (such as acupuncture, Tai Chi, yoga, and physical therapy). Examples of narcotic medications are morphine and morphine-derived drugs such as oxycodone, codeine, and hydrocodone. In the elderly, the common side effects that limit the use of oral medications include gastrointestinal illness (acid reflux, peptic ulcer disease), renal failure and liver toxicity in patients using NSAIDs; sedation, confusion, constipation and falls in those taking narcotics; and liver toxicity in patients taking acetaminophen (Benyamin 2008; Chan 2006; Ge 2006; Singh 1998). Intra-articular therapies including corticosteroids and hyaluronic acid have short-term efficacy (Bellamy 2006a; Bellamy 2006b), and the local applications have limited efficacy and are used mostly as adjunctive therapies (Rains 1995). Non-pharmacological therapies including physical therapy, Tai Chi, and stretching are frequently used and are variably effective, but the beneficial effects may not last long, if the exercises are not continued regularly (Jamtvedt 2008). Recent guidelines from the American College of Rheumatology (Hochberg 2012) and the European League against Rheumatism (EULAR) (Zhang 2007; Zhang 2008) review the role of the above medications in the treatment of osteoarthritis, taking into account these challenges. The long natural history of arthritis and its slow progression means that most patients try more than one modality of these conservative treatments. When the conservative treatments fail satisfactorily to relieve pain and functional limitation, a surgical treatment such as TKA is considered.

The TKA procedure involves resection of the distal end of the femur and the proximal end of the tibia. The femoral implant is rounded and the tibial component is flat with a stem which is inserted into the tibia for further stability. Ligaments are balanced to provide stability and good range of motion. In some cases, the articular surface of the patella may also be removed and replaced with a polyethylene button. Cement may be used to stabilize the components.

TKA is usually considered as an option when conservative treatments have failed to provide adequate pain relief or the patient is developing significant activity limitation. Other surgical options included partial knee replacements (unicompartmental) in which only one compartment of the knee is replaced, and bone resection (high tibial osteotomy) (Brouwer 2007; Dettoni 2010). Though the traditional closing wedge osteotomy involves bone resection, opening wedge osteotomies (with no bone resection) are now commonly performed to correct alignment problems in younger, active patients with medial compartment knee arthritis. Both procedures have specific indications. Unicompartmental knee replacements are done less frequently compared to TKA, and other surgical procedures such as osteotomy are reserved for young patients only.

How the intervention might work

TKA involves the removal of pathologic joint tissue and cartilage and restoration of the joint anatomy by the use of metal or plastic components, and balance of ligaments in the knee joint. By removing the diseased and worn cartilage, synovial membrane and bone that may sometimes be inflamed in patients with osteoarthritis, TKA likely leads to reduction of pain. By restoration of joint articular surfaces with metal or plastic components, joint function and range of motion improve as well. TKA is associated with impressive improvements in multiple patient-reported outcomes (PROs) including pain, function and quality of life of patients (Ethgen 2004; Jones 2003; Kane 2005; Wright 2004). Very few patients have significant residual pain after TKA (Singh 2008).

Why it is important to do this review

TKA is the most common joint replacement surgery (Kurtz 2007; Singh 2010). The incidence of TKA is increasing rapidly due to the obesity epidemic and aging of the population. Approximately 500,000 procedures are performed annually in the US and the procedure volume is projected to increase six-fold by 2030 (Kurtz 2007). Although knee replacement surgery is an effective surgery, to our knowledge there are no systematic reviews of surgery compared with conservative treatment for knee osteoarthritis and other non-traumatic diseases. Other Cochrane reviews in this area have compared different approaches of surgery such as retention or sacrificing the posterior cruciate ligament (Jacobs 2004) or comparing a mobile platform compared to a fixed bearing knee implant (Jacobs 2005). Our review will compare TKA to alternative conservative treatments and will add significant knowledge in this field. A similar systematic review will be also done in patients with total hip replacement surgery (Singh 2013).

Objectives

To assess the benefits and harms of total knee arthroplasty (TKA) compared to conservative treatment including continued medical therapy, other therapies such as physical therapy, acupuncture etc. or no treatment in patients with knee osteoarthritis and other non-traumatic diseases with refractory symptoms.

Methods

Criteria for considering studies for this review

Types of studies

Randomized controlled trials (RCTs) or controlled clinical trials (CCTs).

Types of participants

Adults (aged 16 or over) with knee osteoarthritis and other non-traumatic knee diseases, who are candidates for total knee arthroplasty (TKA).

Types of interventions

TKA versus conservative treatment including continued medical treatment, other therapies such as physical therapy, acupuncture etc. or no treatment. We will include all types of primary TKA.

Types of outcome measures

Major outcomes
  1. Pain: as assessed by pain scales on a numeric rating scale (NRS) or Visual Analog Scale (VAS) or other similar scales.

  2. Function: as assessed by the Western Ontario McMaster Osteoarthritis Index (WOMAC), knee osteoarthritis and outcome score scale (KOOS), Oxford knee scale or other measures of knee function.

  3. Health-related Quality of Life (HRQoL), as assessed by Short form-36 (SF-36), SF-12 or other HRQoL instruments.

  4. Revision rate.

  5. Treatment failure: defined by the number of people who have undergone a non-routine secondary surgical intervention for any reason including refractory index arthroplasty pain, sub-optimal gain in function, fracture, infection, dislocation or other complications.

  6. Serious adverse events (SAEs): including but not limited to cardiac and pulmonary adverse events that are associated with another hospitalization or the need for intravenous antibiotics or prolongation of the index hospitalization, or defined as SAEs in the study.

  7. Death.

The seven major outcomes will be reported in a 'Summary of findings' (SoF) table.

Minor outcomes
  1. Cardiac adverse events: myocardial infarction, cardiac arrest, arrhythmia, malignant hypertension, congestive heart failure and others.

  2. Pulmonary adverse events: pneumonia, pneumothorax, venous thromboembolism and others.

  3. Other complications.

  4. Cost.

  5. Patient satisfaction: measured on ordinal scales or on a VAS postoperatively

  6. Any (non-serious) adverse event (AE): related to interventions.

  7. Inpatient and outpatient healthcare utilization

  8. Withdrawals- overall and due to adverse events

We will assess all major and minor outcomes at the longest follow-up time after TKA. We anticipate that several adverse event outcomes may only be reported during the index hospitalization. In case outcomes are reported at multiple time-points (6-months and 2-years), we will use the data at 2-years and only include 6-month data as a separate analyses, if they are meaningful clinically (i.e. not cumulative for the longer outcome).

Search methods for identification of studies

Electronic searches

We will search the following databases for randomized or controlled clincial trials as detailed in the Appendices.

  1. The Cochrane Central Register of Controlled Trials (CENTRAL), via The Cochrane Library, Wiley InterScience (www.thecochranelibrary.com), to present (Appendix 1);

  2. MEDLINE (Ovid), 1966 to present (Appendix 2);

  3. EMBASE (Ovid) 1980 to present (Appendix 3);

  4. CINAHL (via EBSCOHost), 1982 to present (Appendix 4);

  5. ISI Web of Knowledge from inception to present (Appendix 5);

  6. World Health Organization International Clinical Trials Registry Platform from inception to present (Appendix 6);

There will be no language restrictions. Non-English articles will be translated. We will not include any abstracts in this review.

Searching other resources

We will search the reference lists of included studies for additional eligible articles. We will email experts to ask them for key trials in this topic area.

Data collection and analysis

Selection of studies

Two review authors (JS, MD/CB) will independently review studies for inclusion. Any disagreements between the two review authors will be resolved by consensus, and if needed, by referral to an arbiter (CB/MD).

Data extraction and management

Two review authors (JS, MD/CB) will independently extract data from the included trials using a standardized excel data abstraction sheet. The extracted data will include study population characteristics, intervention characteristics and pre-specified outcomes of interest.

Assessment of risk of bias in included studies

Two review authors (JS, MD/CB) will independently assess the risk of bias in each included study, using the Cochrane Collaboration's 'Risk of bias' tool. We will assess the following domains of included studies:

  1. selection bias: allocation concealment, random sequence generation;

  2. performance bias: blinding in the studies (of participants, caregivers);

  3. detection bias: blinding of outcome assessors;

  4. attrition bias: incomplete outcome data;

  5. reporting bias: selective outcome reporting; and

  6. other sources of bias not covered in the domains of bias above (Higgins 2011a) such as selective reporting of subgroups.

We will rate each criteria as "low risk of bias", "high risk of bias", or "unclear" (either lack of information or uncertainty over the potential for bias) for each included study.

Measures of treatment effect

We will calculate mean differences (MD) for continuous outcomes and risk ratios (RR) for dichotomous outcomes (including 95% confidence intervals) (Higgins 2011b). For rare events (i.e. less than 10%), we will calculate the Peto odds ratio. Standardized mean differences (SMD) will be used only in cases where different scales have been used to measure the same construct. Medians will be substituted for mean, where only medians have been provided. When the standard deviation is not presented for the outcomes we will use the baseline standard deviation or derive it from the interquartile range (IQR) We will calculate the standard deviation as recommended in the Cochrane Handbook (SD = IQR/1.35), provided the sample size is large.

Unit of analysis issues

The unit of analysis will be the patient. When data are presented both at person-level and at joint-level, we will use person-level data. In cases where outcomes are only presented by events or joints, rather than by patients, we will use these data and will only combine the person-level data with the joint/event-level data where it is clinically sensible to do so. We prefer this option, rather than not using the data. We anticipate identifying few studies for inclusion, so it is important to pre-specify this consideration. The premise is that less than five per cent of TKAs are simultaneous bilateral surgeries, so this is unlikely to bias the results much. We anticipate that adverse event data may be patient-level data, while efficacy data may be presented in most studies at joint-level. If the patient- and event-level data can be combined in analyses, we will use these data and perform sensitivity analyses without combining the data and performing analyses only on person-level data.

Dealing with missing data

We will not impute missing data. We will use data based on intention-to-treat analysis, when possible. We will contact each study's corresponding author to obtain missing data. We will not impute missing data. In studies where the standard deviation is not presented at follow-up, we will use the baseline standard deviation, or standard deviation from a similar representative study. When the mean is not presented, we will use the median as mean. We will use the interquartile range (IQR) to calculate the standard deviation as recommended in the Cochrane Handbook (SD = IQR/1.35).

Assessment of heterogeneity

We will calculate the I2 statistic to quantify heterogeneity between trials and examine the forest plots for a qualitative assessment. We will use the cut-offs recommended in the Cochrane Handbook: 0% to 40% might not be important, 30% to 60% may represent moderate heterogeneity, 50% to 90% may represent substantial heterogeneity; and 75% to 100% considerable heterogeneity (Deeks 2011). In case the heterogeneity is in the overlapping areas, i.e., 30% or 60%, we will use 25%, 50% and 75% as low, moderate or high heterogeneity (Higgins 2003). If significant heterogeneity (I2 > 50%) is detected, we will examine the included studies for sources of heterogeneity, including differences in patient characteristics and other potential reasons for differences in effect size. We will repeat analyses by limiting the analyses to studies that seem homogeneous.

Assessment of reporting biases

If there are enough studies, we will examine the funnel plot to assess reporting bias. The funnel plot is a scatter plot of treatment effect on the x-axis and the study sample size on y-axis. The presence of considerable asymmetry in the funnel plot indicates reporting bias.

Data synthesis

We will report the risk ratio (RR) as a measure of the association for categorical outcomes. We will use the random-effects model to estimate pooled RRs as a more conservative approach to take into account heterogeneity between studies. For continuous outcomes, we will use the mean difference to calculate the absolute risk difference (benefit or harm). The inverse of the absolute risk difference will be used to calculate the number needed to treat to benefit (NNTB) or harm (NNTH), using the Cates calculator Visual Rx (available at www.nntonline.net) (Cates 2004). In some cases, the Peto odds ratio (Peto OR) will be used as an estimate of the RR because incident cases could be sufficiently rare. We will perform meta-analysis, if the study populations are not too heterogeneous (Deeks 2011) and heterogeneity is not too high as measured by I2. If they are clinically heterogeneous, we will present data narratively or in tabular form or both. For studies providing data at multiple time-points (e.g. 6-months, 2-years and 5-years), we will analyze the data both at short-term (up to 6-months) and long-term (> 6 months) using the longest time-point within each category.

Subgroup analysis and investigation of heterogeneity

The planned subgroup analyses are as follows, if data are available:

  1. Comparisons by severity of symptoms: moderate and severe symptoms

  2. Comparison by gender, race/ethnicity and socio-economic status

  3. Separate comparisons of TKA to conservative medical therapy, other non-medical conservative therapies and no treatment.

Sensitivity analysis

We will perform sensitivity analysis based on the risk of bias in the included studies by limiting analyses to studies with low risk of bias for allocation concealment, random sequence generation, blinding and missing data (loss of follow-up < 20%).

'Summary of findings' table

We will present the seven key outcomes (listed above as major outcomes) in the 'Summary of findings' table, as recommended in the Cochrane Handbook (Schünemann 2011a). We will use GRADE software to grade the quality of the evidence using the GRADE approach (Atkins 2004a; Atkins 2004b; Schünemann 2011b). The relative risk difference between intervention and control groups, the absolute risk difference, and NNT will be presented in the 'Summary of findings' table. For certain outcomes that are only likely in the surgical group, such as infection, or hardware-related problems, we will not count it as zero for the conservative group, and will not calculate a risk ratio, but instead add a comment, indicating the rate in the group that underwent joint arthroplasty.

Acknowledgements

We thank Tamara Rader and Louise Falzon for performing the literature search.

Appendices

Appendix 1. CENTRAL search strategy

#1 MeSH descriptor Arthritis explode all trees

#2 ((rheumatoid or reumatoid or revmatoid or rheumatic or reumatic or revmatic or rheumat* or reumat* or revmarthrit*) near/3 (arthrit* or artrit* or diseas* or condition* or nodule*)):ti,ab

#3 MeSH descriptor Spondylitis, Ankylosing, this term only

#4 (ankylosing or spondyl*):ti,ab

#5 osteoarthr*:ti,ab

#6 (arthrit* or arthros*):ti,ab

#7 jia:ti,ab

#8 (avascular next necrosis):ti,ab

#9 (#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8)

#10 MeSH descriptor Arthroplasty explode all trees

#11 MeSH descriptor Joint Prosthesis, this term only

#12 MeSH descriptor Prostheses and Implants explode all trees

#13 MeSH descriptor Knee, this term only

#14 MeSH descriptor Knee Joint explode all trees

#15 (#10 OR #11 OR #12)

#16 (#13 OR #14)

#17 (#15 AND #16)

#18 MeSH descriptor Arthroplasty, Replacement, Knee, this term only

#19 MeSH descriptor Knee Prosthesis, this term only

#20 (tka or tkr):ti,ab

#21 (knee* next (replace* or arthroplast* or prosthe* or endoprosthe* or implant*)):ti,ab

#22 (#17 OR #18 OR #19 OR #20 OR #21)

#23 (#9 AND #22)

Appendix 2. MEDLINE search strategy

1. exp arthritis/

2. ((rheumatoid or reumatoid or revmatoid or rheumatic or reumatic or revmatic or rheumat$ or reumat$ or revmarthrit$) adj3 (arthrit$ or artrit$ or diseas$ or condition$ or nodule$)).tw.

3. Spondylitis, Ankylosing/

4. (ankylosing or spondyl$).tw.

5. osteoarthr$.tw.

6. (arthrit$ or arthros$).tw.

7. jia.tw.

8. avascular necrosis.tw.

9. or/1-8

10. Arthroplasty/

11. Joint Prosthesis/

12. "Prostheses and Implants"/

13. Knee/

14. exp Knee Joint/

15. or/10-12

16. 13 or 14

17. 15 and 16

18. Arthroplasty, Replacement, Knee/

19. Knee Prosthesis/

20. (tka or tkr).tw.

21. (knee$ adj (replace$ or arthroplast$ or prosthe$ or endoprosthe$ or implant$)).tw.

22. or/17-21

23. 9 and 22

24. randomized controlled trial.pt.

25. controlled clinical trial.pt.

26. randomized.ab.

27. placebo.ab.

28. drug therapy.fs.

29. randomly.ab.

30. trial.ab.

31. groups.ab.

32. or/24-31

33. (animals not (humans and animals)).sh.

34. 32 not 33

35. 23 and 34

35. (2005$ or 2006$ or 2007$ or 2008$ or 2009$ or 2010$).ed.

36. 34 and 36

Appendix 3. EMBASE search strategy

1. exp arthritis/

2. ((rheumatoid or reumatoid or revmatoid or rheumatic or reumatic or revmatic or rheumat$ or reumat$ or revmarthrit$) adj3 (arthrit$ or artrit$ or diseas$ or condition$ or nodule$)).tw.

3. ankylosing spondylitis/

4. (ankylosing or spondyl$).tw.

5. osteoarthr$.tw.

6. (arthrit$ or arthros$).tw.

7. jia.tw.

8. avascular necrosis.tw.

9. or/1-8

10. exp Arthroplasty/

11. exp Joint Prosthesis/

12. exp "Prostheses and Implants"/

13. exp KNEE/

14. exp Knee Joint/

15. or/10-12

16. 13 or 14

17. 15 and 16

18. exp Arthroplasty, Replacement, Knee/

19. exp Knee Prosthesis/

20. tka.tw.

21. (knee$ and (replace$ or arthroplast$ or prosthe$)).tw.

22. or/17-21

23. 9 and 22

24. (random$ or placebo$).ti,ab.

25. ((single$ or double$ or triple$ or treble$) and (blind$ or mask$)).ti,ab.

26. controlled clinical trial$.ti,ab.

27. RETRACTED ARTICLE/

28. or/24-27

29. (animal$ not human$).sh,hw.

30. 28 not 29

31. 23 and 30

32. (2010$ or 2011$).em.

33. 31 and 32

34. 2010$.em

35. 33 and 34

Appendix 4. CINAHL search strategy

S46 S16 and S32 and S45

S45 S33 or S34 or S35 or S36 or S37 or S38 or S39 or S40 or S41 or S42 or S43 or S44

S44 TI Allocat* random* or AB Allocat* random*

S43 (MH "Quantitative Studies")

S42 (MH "Placebos")

S41 TI Placebo* or AB Placebo*

S40 TI Random* allocat* or AB Random* allocat*

S39 (MH "Random Assignment")

S38 TI Randomi?ed control* trial* or AB Randomi?ed control* trial*

S37 AB singl* blind* or AB singl* mask* or AB doub* blind* or AB doubl* mask* or AB trebl* blind* or AB trebl* mask* or AB tripl* blind* or AB tripl* mask*

S36 TI singl* blind* or TI singl* mask* or TI doub* blind* or TI doubl* mask* or TI trebl* blind* or TI trebl* mask* or TI tripl* blind* or TI tripl* mask*

S35 TI clinical* trial* or AB clinical* trial*

S34 PT clinical trial

S33 (MH "Clinical Trials+")

S32 S24 or S25 or S26 or S27 or S28 or S29 or S30 or S31

S31 TI knee* implant* OR AB knee* implant*

S30 TI knee* endoprosthe* OR AB knee* endoprosthe*

S29 TI knee* prosthe* OR AB knee* prosthe*

S28 TI knee* arthroplast* OR AB knee* arthroplast*

S27 TI knee* replace* OR AB knee* replace*

S26 TI tkr OR AB tkr OR TI tka OR AB tka

S25 (MH "Arthroplasty, Replacement, Knee")

S24 S22 and S23

S23 S20 or S21

S22 S17 or S18 or S19

S21 (MH "Knee Joint+")

S20 (MH "Knee")

S19 (MH "Prostheses and Implants")

S18 (MH "Joint Prosthesis")

S17 (MH "Arthroplasty")

S16 S1 or S2 or S3 or S4 or S5 or S6 or S7 or S8 or S9 or S10 or S11 or S12 or S13 or S14 or S15

S15 TI avascular necrosis OR AB avascular necrosis

S14 TI jia OR AB jia

S13 TI arthrit* OR TI arthros* OR AB arthrit* OR AB arthros*

S12 TI osteoarthr* OR AB osteoarthr*

S11 TI ankylosing OR TI spondyl* OR AB ankylosing or AB spondyl*

S10 (MH "Spondylitis, Ankylosing")

S9 TI reumat* N3 arthrit* or AB reumat* N3 arthrit* or TI reumat* N3 artrit* or AB reumat* N3 artrit* or TI reumat* N3 diseas* or AB reumat* N3 diseas* or TI reumat* N3 condition* or AB reumat* N3 condition* or TI reumat* N3 nodule* or AB reumat* N3 nodule*

S8 TI revmarthrit* N3 arthrit* or AB revmarthrit* N3 arthrit* or TI revmarthrit* N3 artrit* or AB revmarthrit* N3 artrit* or TI revmarthrit* N3 diseas* or AB revmarthrit* N3 diseas* or TI revmarthrit* N3 condition* or AB revmarthrit* N3 condition* or TI revmarthrit* N3 nodule* or AB revmarthrit* N3

S7 TI rheumat* N3 arthrit* or AB rheumat* N3 arthrit* or TI rheumat* N3 artrit* or AB rheumat* N3 artrit* or TI rheumat* N3 diseas* or AB rheumat* N3 diseas* or TI rheumat* N3 condition* or AB rheumat* N3 condition* or TI rheumat* N3 nodule* or AB rheumat* N3 nodule*

S6 TI revmatic N3 arthrit* or AB revmatic N3 arthrit* or TI revmaticN3 artrit* or AB revmatic N3 artrit* or TI revmatic N3 diseas* or AB revmatic N3 diseas* or TI revmatic N3 condition* or AB revmatic N3 condition* or TI revmatic N3 nodule* or AB revmatic N3 nodule*

S5 TI rheumatic N3 arthrit* or AB rheumatic N3 arthrit* or TI rheumatic N3 artrit* or AB rheumatic N3 artrit* or TI rheumatic N3 diseas* or AB rheumatic N3 diseas* or TI rheumatic N3 condition* or AB rheumatic N3 condition* or TI rheumatic N3 nodule* or AB rheumatic N3 nodule*

S4 TI revmatoid N3 arthrit* or AB revmatoid N3 arthrit* or TI revmatoid N3 artrit* or AB revmatoid N3 artrit* or TI revmatoid N3 diseas* or AB revmatoid N3 diseas* or TI revmatoid N3 condition* or AB revmatoid N3 condition* or TI revmatoid N3 nodule* or AB revmatoid N3 nodule*

S3 TI reumatoid N3 arthrit* or AB reumatoid N3 arthrit* or TI reumatoid N3 artrit* or AB reumatoid N3 artrit* or TI reumatoid N3 diseas* or AB reumatoid N3 diseas* or TI reumatoid N3 condition* or AB reumatoid N3 condition* or TI reumatoid N3 nodule* or AB reumatoid N3 nodule*

S2 TI rheumatoid N3 arthrit* or AB rheumatoid N3 arthrit* or TI rheumatoid N3 artrit* or AB rheumatoid N3 artrit* or TI rheumatoid N3 diseas* or AB rheumatoid N3 diseas* or TI rheumatoid N3 condition* or AB rheumatoid N3 condition* or TI rheumatoid N3 nodule* or AB rheumatoid N3 nodule*

S1 (MH "Arthritis+")

Appendix 5. ISI Web of knowledge search strategy

# 5 #3 AND #2 AND #1  Refined by: Document Type=( ABSTRACT OR MEETING OR CLINICAL TRIAL )

# 4 #3 AND #2 AND #1

#3 Topic=((trial* or random* or placebo* or control* or double or treble or triple or blind* or mask* or allocat* or prospective* or volunteer*or comparative or evaluation or follow-up or followup))

#2 Topic=((knee* and (replace* or arthroplast* or prosthe* or endoprosthe* or implant*)))

#1 Topic=(((rheumatoid or reumatoid or revmatoid or rheumatic or reumatic or revmatic or rheumat* or reumat* or revmarthrit*) and (arthrit* or artrit* or diseas* or condition* or nodule*))) OR Topic=(ankylosing or spondyl* or osteoarthr* or arthrit* or arthros* or jia or avascular necrosis)

Appendix 6. WHO International Clinical Trials Registry Platform search strategy

Rheumatoid OR ankylosing OR spondyl* OR osteoarthr* OR arthrit* OR arthros* OR jia OR avascular necrosis In Intervention

AND

Total knee In Condition

Contributions of authors

JAS: protocol development and editing

JAS, MD, CB: approval of the protocol

Declarations of interest

JAS: JAS has received research grants from Takeda, and Savient, and consultant fees from Regeneron, Allergan, Takeda and Savient; he is a member of the executive of OMERACT, an organization that develops outcome measures in rheumatology and receives arms-length funding from 36 companies.

CB: none known

MD: none known

Sources of support

Internal sources

  • Birmingham Veterans Affairs Medical Center, Alabama, USA.

    Facilities and Resources

External sources

  • No sources of support supplied

Ancillary