Indonesian Journal of Rheumatology Vol 15 Issue 1 2023

Indonesian Journal of
Rheumatology
Journal Homepage: https://journalrheumatology.or.id/index.php/IJR

Indonesian Rheumatology Association (IRA) Recommendations for Diagnosis and

Management of Osteoarthritis (Knee, Hand, Hip)
Rakhma Yanti Hellmi1*, Najirman2, Ida Ayu Ratih Wulansari Manuaba3, Andri Reza Rahmadi4,
Pande Ketut Kurniari5, Malikul Chair6, Ika Vemilia Warlisti1, Eka Kurniawan2, Harry Isbagio7,
Handono Kalim8, Rudy Hidayat7, Laniyati Hamijoyo4, Cesarius Singgih Wahono8, Sumariyono7
1 Rheumatology Division, Department of Internal Medicine, Universitas Diponegoro, Semarang, Indonesia
2 Rheumatology Division, Department of Internal Medicine, Universitas Andalas, Padang, Indonesia
3 Manuaba General Hospital, Denpasar, Indonesia
4 Rheumatology Division, Department of Internal Medicine, Universitas Padjadjaran, Bandung, Indonesia
5 Rheumatology Division, Department of Internal Medicine, Universitas Udayana, Denpasar, Indonesia
6 Simeulue General Hospital, Sinabang, Indonesia
7 Rheumatology Division, Department of Internal Medicine, Universitas Indonesia, Jakarta, Indonesia
8 Rheumatology Division, Department of Internal Medicine, Universitas Brawijaya, Malang, Indonesia

ARTICLE INFO ABSTRACT

Keywords: Background: Osteoarthritis (OA) is the most common form arthritis in the
Hand world, and its prevalence is predicted to rise higher in the future due to
Hip increasing life expectancy and growing number of elderly population. With
Knee the emergence of new treatment options in the last several years, a better
understanding of OA diagnosis and management is required by every
Osteoarthritis
physician in Indonesia. Methods: A panel of eight selected rheumatologists
from the Indonesian Rheumatologist Association (IRA) developed
*Corresponding author: recommendations based on key questions formulated by a steering
Rakhma Yanti Hellmi committee from IRA. These recommendation materials were taken from
several online databases such as PubMed, Science Direct, and Google
Scholar. Level of evidence and grades of recommendation were then
E-mail address: assigned, and each member of the panelist team will assign a score to
express their level of agreement. Results: A total of 25 recommendations
hellmisppd77@gmail.com discussing the diagnosis, pharmacological and non-pharmacological
therapies, as well as monitoring for OA were formulated. Conclusion: These
All authors have reviewed and approved the recommendations can be used to help clinicians in accurately diagnosing OA
final version of the manuscript. and choosing the most suitable therapy for their patients. All
recommendation statements were tailored to the clinical setting, facility, and
drug availability in Indonesia.
https://doi.org/10.37275/IJR.v15i1.225

1. Introduction muscle weakness, strenuous physical activity, history

Osteoarthritis (OA) is the most prevalent form of
arthritis affecting nearly 302 million people worldwide,
and is one of the major causes of disability in the
elderly.1,2 OA may impair knee, hand, and hip joints,
damaging structures such as joint cartilage,
subchondral bone, ligament, capsule, synovial tissue,
and periarticular fibrous tissue.3 Risk factors of OA
include age, gender, ethnicity, genetics, diet, obesity,
of physical trauma, decreased proprioceptive function,
family history of OA, and mechanical factors.4 These
risk factors influence the progression of cartilage
destruction and abnormal bone formation in OA.4 The
degree of cartilage destruction corresponds to the pain
and movement impairment experienced by the
patients.4,5 Nowadays, although OA is no longer solely
attributed to degeneration or aging, age still remains

683
an important risk factor.4,6 Around 50% of patients from IRA. The panelist team consists of 51
aged 65 or older show radiographic signs of OA, yet rheumatologists from various branches of IRA and
only 10% of male and 13% of female elderlies show OA institutions in Indonesia, with at least five years of
clinical symptoms, and approximately 10% of them working experience as a rheumatologist. Each member
suffer from OA-related disabilities.7 of the panelist team gave an independent opinion
As life expectancy increases, demographic data regarding the level and strength of recommendations
from The USA Bureau of Census reported that the put forth by the recommendation team. No delegation
Indonesian elderly population has witnessed from the pharmacy industry was involved in the
significant growth, with a staggering 283.3% increase process of developing these recommendations.
between 1994 and 2020.8 The prevalence of A total of 10 key questions were formulated to
radiographic OA in Indonesia is 15.5% in men and determine the recommendations for diagnosing and
12.7% in women aged 40-60 years old. Data from the managing OA in Indonesia: 1) How can a patient be
rheumatology clinic at Hasan Sadikin Hospital in diagnosed with OA? 2) Is the classification or diagnosis
Bandung from 2007 to 2010 revealed that 73-74.48% criteria issued by ACR still used to diagnose OA? 3)
of rheumatology patients were diagnosed with OA, and What are the examinations required to diagnose OA?
69% of them were female, with knee OA (87%) being 4) How can comprehensive treatment be given to OA
the predominant type. These findings suggest that the patients? 5) What are the non-pharmacological
number of OA patients will continue to rise, making treatment choices available for OA patients? 6) What
OA a commonly encountered condition in daily clinical are the pharmacological treatment choices available
practice in the future. Therefore, it is necessary for for OA patients? 7) What educational information
physicians in Indonesia to have a better should be provided to OA patients? 8) What are the
understanding of OA diagnosis and treatment. difficulties and comorbidities that should be
OA therapy consists of pharmacological, non- considered in OA patients? 9) How can disease activity
pharmacological, and surgical interventions. However, be monitored and therapy results assessed in OA
this recommendation does not address surgical patients? 10) What are the indications to refer OA
therapy in OA. The aims of pharmacological and non- patients?
pharmacological therapy are to reduce pain, maintain Literature search was conducted through online
or improve joint movement function, reduce physical databases, including PubMed, Science Direct, Google
limitation, increase activity independence, and Scholar, and other databases, using these keywords:
increase the patient’s quality of life.9 Current osteoarthritis, diagnosis, NSAID, steroid,
pharmacological therapy is also expected to modify glucocorticoids, laboratory test, education, treatment,
disease progression or even prevent OA through the algorithm, DMOADs, monitoring, complication, and
use of disease-modifying osteoarthritis drugs prognosis. The search was limited to published
(DMOADs). Optimal outcomes in OA therapy can be English meta-analysis, systematic review, clinical
achieved by using a multidisciplinary approach and trial, randomized controlled trial (RCT), and
utilizing multimodal therapy.1,10 observational study, published within 2011 to 2021.
Initial literature search yielded 439 relevant articles.
2. Methods After a thorough reading, the team selected 114
The Indonesian Rheumatologist Association (IRA) articles to be included in the formulation of this
formed a recommendation team to formulate recommendation.
recommendation questions for diagnosis, therapy, and The development of this diagnostic and
monitoring of OA. There was also a team of supervisors management guideline is based on the Grading of
(steering committee) consisting of 6 core members Recommendations, Assessment, Development, and

684
Evaluation (GRADE) approach, which requires
adaptation of scientific evidence summaries from
existing clinical practice guidelines, if available, or
generating de novo summaries of scientific evidence if
necessary. This process includes (1) identifying
prioritized research questions through PICO
(population-intervention-comparison-outcome)
framework, (2) extracting, assessing, and synthesizing
scientific evidence from existing clinical practice
guidelines, meta-analyses, and systematic reviews of
clinical trials or observational studies, (3) formulating
summaries of scientific evidence, (4) voting on critical
and important outcomes, (5) presenting scientific
evidence to the panelist team, (6) formulating final
recommendations, and (7) planning for dissemination,
implementation, and updating.
Recommendations were issued based on the 10 key
questions above. The recommendation team then
assigned the level of evidence (LoE) and grades of
recommendation (GoR) based on the criteria listed in
Table 1.11 These recommendations were then reviewed
by the steering committee. In the final step, the
Table 1. Level of evidence and grades of recommendations.
Level of evidence (LoE)
I High quality meta-analysis or
systematic review of RCTs, or
individual RCTs with low risk
of bias
II High quality systematic
review of observational
studies (case control or
cohort), or individual
observational studies
III Non-analytic studies (case
report or case series)
IV Non-analytic studies (case
report or case series)
3. Results
Based on the discussion, 25 recommendations
were agreed upon by the recommendation team,
panelist team members were asked to rate each
recommendation on a scale of 0 to 10 to determine the
level of agreement (LoA). A score of 0 indicated
complete disagreement and 10 indicated complete
agreement. The panelist member would be asked for
comments should a score below 8 was issued.
Recommendations with an average score below 8 were
then rediscussed by the recommendation team to be
revised and then reassessed by the panelist team to
determine the final LoA.
Levels of evidence is a hierarchical system for
classifying evidence based on the quality of the
methodological design, validity, and its applicability to
patient care. On the other hand, grades of
recommendation are based on levels of evidence,
considering the overall strength of evidence and the
judgment of recommendation makers. Grades of
recommendation are developed by considering cost,
value, preferences, feasibility, risk-benefit
assessment, along with the assessment of the quality
of available scientific evidence.
Grades of recommendation
(GoR)
A Strong recommendation:
referring to level I studies
B Moderate recommendation:
referring to level II studies or
extrapolation of level I studies
C Weak recommendation:
referring to level III studies or
extrapolation of level II
studies
D Consensus recommendation:
expert opinion or based on
limited evidence
steering committee, and panelist team. Summary of
these recommendations is provided in Table 2.
685
 Table 2. Summary of recommendations for diagnosis and management of osteoarthritis.
No Recommendation LoE GoR LoA
Diagnosis of OA can be established through anamnesis and complete
1 I A 9.36
physical examination
American College of Rheumatology (ACR) 1990 Classification Criteria for OA
2 I A 9.49
can be used to help diagnose OA
I
(hand & A 9.36
Plain radiographic examination can help establish OA diagnosis and rule out
3 knee)
other differential diagnosis
II-III
B-C 9.15
(hip)
In doubtful conditions, blood and synovial fluid examination can be
4 I A 9.30
performed to rule out inflammatory joint diseases
Education program including information about OA, risk factors,
5 examination and treatment plan, complication, and prognosis is I A 9.85
recommended in patients with hand, hip, and knee OA
Weight reduction is recommended in overweight or obese patients with knee
6 I A 9.85
and hip OA
Physical exercise, tai-chi, and yoga are recommended in patients with hand,
7 I A 9.12
hip, and knee OA
Walking aids (cane, tripod, and walker) are recommended in certain
8 I C 9.25
conditions for patients with knee and hip OA
9 Braces are recommended in certain conditions for patients with knee OA I B 9.22
Kinesio taping is recommended in early stages of knee and first
10 I B 8.52
carpometacarpal OA
11 Hand orthosis is recommended in patients with carpometacarpal OA I B 8.87
Acupuncture, thermotherapy, and TENS are recommended in certain
12 I B 8.91
conditions for patients with knee OA
Radiofrequency ablation is recommended as an alternative when total knee
13 I C 8.78
replacement is not possible for patients with knee OA
Low level laser therapy is recommended in certain conditions for patients with
14 I B 8.55
knee OA
Paracetamol is recommended in certain conditions for patients with hand,
15 I A 9.27
hip, and knee OA
Oral Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) are recommended in
16 I A 9.46
patients with hand, hip, and knee OA
Duloxetine is recommended in certain conditions for patients with hand, hip,
17 I B 8.91
and knee OA
Pregabalin is recommended to be combined with NSAIDs in hand and knee
18 II C 9.00
OA patients who also suffer from neuropathic pain
Tramadol is recommended in certain conditions for patients with hand, hip,
19 I B 9.06
and knee OA
20 Topical NSAIDs are recommended in patients with hand and knee OA I A 9.12
Hyaluronic acid injection is recommended in patients with Kellgren-Lawrence
21 I B 9.21
grade 1-3 knee OA who are not responsive to standard pain-relieving therapy
Corticosteroid injection is recommended in patients with knee OA undergoing
22 I B 9.38
acute or chronic inflammation and joint effusion
Monitoring of comorbidities and complications should be commenced since
23 I A 9.64
the beginning of OA therapy
Lequesne index and WOMAC are recommended as tools to evaluate the
24 I-II B 9.49
therapeutic effect in OA
25 OA patients should be considered for referral based on clinical indications I A 9.55

4. Discussion (gelling phenomenon).12 Patients may also suffer from

Recommendation 1: Diagnosis of OA can be morning stiffness or stiffness after resting. The joint
established through anamnesis and complete may also become swollen. Crepitation and limited
physical examination range of motion may be observed upon joint
The most common symptom of OA is joint pain movement. Inflammation is usually absent or
which worsens with activity and improves with rest minimal. OA can affect multiple joints, mainly the

686
knee, feet, hands, vertebrae, and hip joints.1 for OA can be used to help diagnose OA
Physical examination can be conducted using the Several diagnostic criteria were developed to assist
gait, arms, legs, spine (GALS) principle.13 The physician in diagnosing OA, including ACR 1990,
diagnosis of OA can be established clinically; no EULAR, and NICE criteria.14 We recommend using the
specific supporting examination is required. ACR 1990 criteria as they have high sensitivity and
specificity and have been clinically tested. The ACR
Recommendation 2: American College of 1990 criteria for hand, hip, and knee OA are provided
Rheumatology (ACR) 1990 classification criteria in Table 3-5.1,15–18

Table 3. ACR 1990 criteria for hand OA16,17

Based on clinical criteria:
(Sensitivity: 92%, specificity: 98%)
Pain, aching, or stiffness in the hand
and 3 of the following:
1. Hard tissue enlargement of 2 or more of the
following joints:
a. 2nd and 3rd distal interphalangeal,
b. 2nd and 3rd proximal interphalangeal,
c. 1st carpometacarpal joints of both hands
2. Hard tissue enlargement of 2 or more distal
interphalangeal joints
3. Less than 3 swollen MCP joints
4. Deformity of at least one of the joints listed in
the first criterion

Table 4. ACR 1990 criteria for knee OA19,20

Based on clinical criteria:
(Sensitivity 95%, specificity 69%)
Pain in the knee
and 3 of the following:
1. Over 50 years of age
2. Less than 30 minutes of morning stiffness
3. Crepitus on active motion
4. Bony tenderness
5. Bony enlargement
6. No palpable warmth of synovium
Based on clinical and laboratory criteria:
(Sensitivity: 92%, specificity: 75%)
1. Over 50 years of age
2. Less than 30 minutes of morning stiffness
3. Crepitus on active motion
4. Bony tenderness
5. Bony enlargement
6. No palpable warmth of synovium
7. ESR<40 mm/hour
8. Rheumatoid factor (RF) < 1:40
9. Synovial fluid shows signs of OA
Based on clinical and radiological criteria:
(Sensitivity: 91%, specificity: 86%)
Pain in the knee
and osteophytes
and one of the following:
1. Over 50 years of age
2. Less than 30 minutes of morning stiffness
3. Crepitus on active motion

687
 Table 5. ACR 1990 criteria for hip OA21,22
Based on clinical and laboratory criteria:
(Sensitivity: 89%, specificity: 91%)
Pain in the hip
and 1 of the following:
1. Internal hip rotation < 15o and ESR <= 45
mm/hour or hip flexion <= 115o if ESR
unavailable
2. Internal hip rotation >= 15o and pain
associated with internal hip and morning
stiffness of the hip <= 60 minutes and over 50
years of age
Based on clinical, laboratory, and radiological
criteria:
(Sensitivity: 89%, specificity: 91%)
Pain in the hip
and 2 of the following:
1. ESR < 20 mm/hour
2. Radiographic femoral and/or acetabular
osteophytes
3. Radiographic joint space narrowing (superior,
axial, and/or medial)

Recommendation 3: Plain radiographic Several meta-analyses have demonstrated that

examination can help establish OA diagnosis and plain radiography is highly reliable in assessing knee
rule out other differential diagnosis and hand OA severity based on joint space
Plain radiographic examination may show narrowing.25–27 However, the benefit of radiographic
structural changes in the joint of OA patients. examination in hip OA is still controversial, as the
Findings include joint space narrowing, osteophytes, radiographic findings often do not align with the
subchondral sclerosis, subchondral cyst, and joint patient’s clinical manifestation.27,28 Alternative
effusion.23 Kellgren-Lawrence classification can be imaging modalities such as ultrasonography (USG)
used to determine knee OA severity, ranging from and 1.5 T magnetic resonance imaging (MRI) may also
grade 0 to 4 (see Table 6). Plain knee radiographic be employed.29–31 However, these modalities are rarely
examination is done in anteroposterior projection indicated in OA patients, except for evaluating patients
while the patient is standing, with the knee flexed at a undergoing stem cell therapy.32
20o angle and the feet externally rotated at 15o.24

Table 6. Kellgren-Lawrence classification24

Grade Description
0 Normal
No significant osteophytes, doubtful clinical
1
signs
Definite osteophytes, no joint space
2
narrowing
Multiple osteophytes, definite joint space
3
narrowing, possible bone deformity
Multiple osteophytes, marked joint space
4 narrowing, severe sclerosis, subchondral
cyst, and bone deformity

688
Recommendation 4: In doubtful conditions, blood
and synovial fluid examination can be performed
to rule out inflammatory joint diseases
Blood examinations are not routinely performed in
diagnosing OA patients. Erythrocyte sedimentation
rate (ESR) and C-reactive protein (CRP) can be
measured to rule out other inflammatory arthritis.
Rheumatoid factor (RF) and anti-citrullinated protein
antibody (ACPA) can also be measured to rule out
rheumatoid arthritis (RA).33 Serum uric acid levels can
be measured to rule out gout arthritis. Synovial fluid
analysis can be performed if there is joint effusion, to
rule out gout or other crystal arthropathies.34,35
Recommendation 5: Education program including
information about OA, risk factors, examination
and treatment plan, complication, and prognosis is
recommended in patients with hand, hip, and knee
OA
Education regarding patient’s disease condition,
treatment plan, complication, and prognosis is very
important. It can be done on an individual basis or in
a group-based session, either in-person or through
online session using any media. A meta-analysis
following up OA patients for 6 months showed that
effective education had significant effect in reducing
pain and improving physical function compared to
patients who did not receive education.36
Recommendation 6: Weight reduction is
recommended in overweight or obese patients with
knee and hip OA
Excessive body weight has been shown to
accelerate the progression of cartilage destruction.
Three meta-analyses have shown that weight
reduction is effective in reducing pain level and
improving joint function in patients with knee or hip
OA. For every 1% decrease in body weight, there was
a corresponding 2% decrease in WOMAC (The Western
Ontario and McMaster Universities Osteoarthritis
Index) score. To achieve optimal results, these studies
recommend weight reduction of up to 25% of the initial
body weight. Physical activities such as static cycling,
walking, and water sports can be done to help reduce
body weight. These physical activities modify the body
composition by reducing body fat mass to achieve
proportional body weight and may also strengthen
muscles and increase joint stability.37–39
Recommendation 7: Physical exercise, tai-chi, and
yoga are recommended in patients with hand, hip,
and knee OA
Suitable physical exercise has been proven to be
beneficial to joint health through chondroprotective
mechanism.40 Physical exercise can be done in OA
patients with mild to moderate pain. For those
experiencing severe and acute pain, it is recommended
to follow the PRICE protocol (Protection, Rest, Ice,
Compression, and Elevation). Three meta-analyses
have shown that physical exercise may reduce pain
and improve joint function in patients with hand, hip,
and knee OA. Land-based exercises are recommended
for patients with hip and knee OA, while isometric
exercises (such as gripping) for 3-6 months is effective
for patients with hand OA. The recommended exercise
duration is at least 60 minutes a week. Static cycling
is the most beneficial type of exercise for knee OA.
Quadriceps and lower leg muscle strengthening
exercises are also proven to relieve pain in knee OA.
Aquatic exercise can be an alternative for patients
unable to perform land-based exercise. The
recommended physical exercises are non-weight
bearing exercises, including swimming, static cycling,
and aerobic exercises.40–42
Tai-chi is a traditional Chinese exercise which
combines meditation with breathing exercises and
relaxation. Several studies have shown that tai-chi
significantly reduce pain levels, and improve physical
function in OA patients during 6 months of follow-up.
It is recommended to practice tai chi 2-3 times a week,
with 60 minutes duration.43–45
Another form of exercise that combines meditation
with physical exercise, relaxation, and breathing is
yoga, which originates from India. Studies have shown
that yoga is proven to be effective in relieving pain and
stiffness while also improving joint and physical
689
function. The recommended regimen is 60 minutes Recommendation 10: Kinesio taping is
duration for twice a week.43,46,47 recommended in early stages of knee and first
carpometacarpal OA
Recommendation 8: Walking aids (cane, tripod, In contrast to braces, kinesio taping still allows for
and walker) are recommended in certain joint movement, unlike braces which maintain joint
conditions for patients with knee and hip OA position.54 Three meta-analyses have demonstrated
Walking aids are recommended for OA patients that kinesio taping (with facilitation technique)
who are at high risk of falling, especially those with hip effectively reduces pain, improves physical function,
and knee OA. Walking aids may help these patients to and increases flexibility and muscle strength.54–56
increase joint stability, decrease pain, and halt the Optimal results are typically achieved after 6 weeks of
progression of cartilage destruction. Several RCTs usage. Kinesio taping is indicated in the early stages
(randomized controlled trials) have shown that walking of OA, provided that they do not have allergies, acute
aids were effective in decreasing pain, especially in OA infections, acute inflammation, or deep vein
patients with mild or moderate pain who can still thrombosis.57
walk.48,49
Cane is recommended for knee and hip OA patients Recommendation 11: Hand orthosis is
without stability impairment, with the recommended recommended in patients with carpometacarpal
type being the T cane, used in the contralateral side of OA
the affected hip or knee joint. Tripods, quadripods, or Several meta-analyses have shown that
walkers are recommended for knee and hip OA immobilizing carpometacarpal and
patients with stability impairment.50 metacarpophalangeal joints is effective in reducing
pain, improving function, and enhancing hand
Recommendation 9: Braces are recommended in strength in patients with hand OA.58–60 Long
certain conditions for patients with knee OA thermoplastic orthosis is the recommended choice for
Knee braces can be used as a part of occupational reducing pain, while short thermoplastic orthosis is
therapy to protect the joint. These braces include the recommended choice for improving function.58,60
tibiofemoral and patellofemoral braces. Tibiofemoral These effects can be observed after 2 weeks of hand
brace can be used in patients with knee joint orthosis usage.61
instability caused by quadriceps muscle weakness
without patellar instability. Whereas patellofemoral Recommendation 12: Acupuncture,
brace can be used in patients suffering patellar thermotherapy, and TENS are recommended in
instability.51,52 Several meta-analyses have shown that certain conditions for patients with knee OA
braces were effective in relieving pain and improving Thermotherapy is a form of therapy which utilizes
physical function.52,53 However, braces are temperature intervention, consisting of heat and cold
contraindicated in patients with severe venous modalities. Each modality is used depending on the
insufficiency or deep vein thrombosis. The patient’s condition. Heat thermotherapy was shown to
recommended duration of brace usage is 6 hours a be beneficial in reducing pain if used together with
day, 5 days a week, for at least 6 weeks, and should isokinetic exercise but did not give significant result in
be combined with muscle strengthening exercises to improving physical function. Thermotherapy can be
prevent muscle atrophy.53 considered as an additional therapy for obese patients
with knee OA, combined with physical exercise. The
recommended heat thermotherapy is pulse short-wave
therapy. 62,63

690
 The other form of thermotherapy is
thermotherapy, also known as cryotherapy, which
uses cryogens to freeze tissue under the skin or
mucosa. Limited evidence is available regarding the
use of cryotherapy for OA treatment, therefore
currently, cryotherapy is not included as a form of
non-pharmacological therapy in OA. 64
Acupuncture is a traditional therapy from China
which uses fine needles punctured in certain areas in
the body. Two meta-analyses have demonstrated that
acupuncture is effective in reducing pain
improving physical function. However, due to the lack
of standardization in the methods used
acupuncture therapy, it is considered as an adjuvant
therapy when classic analgesics do not give sufficient
results.65,66
Trans Electrical Nerve Stimulation (TENS) is a non-
invasive peripheral stimulation method which utilizes
low voltage electricity to reduce pain. Several meta-
analyses have shown that TENS is effective in reducing
pain, although it has not yielded significant result in
physical function improvement.67–69 Moreover, the
TENS procedure performed varies across studies in
terms of the number of sessions and duration. Thus,
TENS can be considered as an alternative or adjuvant
therapy to reduce chronic pain.
Recommendation 13: Radiofrequency ablation is
recommended as an alternative when total knee
replacement is not possible for patients with knee
OA
Knee radiofrequency ablation is a procedure that
utilizes heat or cold modalities to disrupt pain
signaling in the genicular nerve. This therapy is often
used in patients suffering from chronic pain. Two
meta-analyses have shown that radiofrequency
ablation is effective in reducing pain and improving
physical function.70,71 It can also be used for long-term
therapy without significant side effects, and it has the
potential to reduce the need for analgesics in knee OA
patients. Currently, radiofrequency ablation is only
recommended for grade IV knee OA patients, since
there is still no standardization in its utilization.70
cold Recommendation 14: Low level laser therapy is
recommended in certain conditions for patients
with knee OA
Low level laser therapy (LLLT) uses light-emitting
diodes to emit low-level laser onto body surface,
inducing changes in the cell biological activities to
reduce inflammation and pain. One meta-analysis has
shown a significant effect of LLLT in reducing pain
after 12 weeks of usage. However, another meta-
analysis reported no significant effect of LLLT in OA
and patients, probably due to high heterogeneity between
studies. In both studies, LLLT was used in grade II-IV
in knee OA patients experiencing persistent pain after 6
months. LLT is contraindicated in malignancy,
pregnancy, and photosensitive patients. 72–74
Recommendation 15: Paracetamol is
recommended in certain conditions for patients
with hand, hip, and knee OA
Paracetamol or acetaminophen is the chosen
analgesic for long-term use, especially in the elderly,
due to its good safety profile compared to NSAIDs.5,75–
77 Several meta-analyses have shown that paracetamol
provides minimal improvement in relieving pain,
without increasing the risk of side effects in OA
patients.78–80 The recommended dose is 1000 mg per
administration, with a maximum dose of 4000 mg per
day. Several guidelines also consistently recommend
paracetamol as the first-line analgesic for OA patients.
Monitoring of hepatotoxic effect is required in patients
receiving 3-4 grams of paracetamol a day. Paracetamol
is recommended for mild to moderate pain in grade I-
III OA patients. It can also be considered in OA
patients who are contraindicated to oral NSAIDs, or
elderly who need long-term analgesics.78
Recommendation 16: Oral Non-Steroidal Anti-
Inflammatory Drugs (NSAIDs) are recommended in
patients with hand, hip, and knee OA
NSAIDs have anti-inflammatory and analgetic
effects with good efficacy. They should be given in the
lowest dose that still gives therapeutic effect. Several
clinical conditions should be considered when
691
prescribing NSAIDs due to potential gastrointestinal,
cardiovascular, and renal side effects.1 A meta-
analysis have shown that NSAIDs have a significant
effect in relieving pain compared to placebo or
paracetamol in OA patients.79 The recommendation
regarding the selection of NSAIDs based on the
patient’s risk factors is provided in Table 7 and Figure
1, whereas the side effects of NSAIDs can be seen in
Table 8.

Table 7. Risk factors to be considered when choosing NSAIDs based on patient’s risk factors81
Cardiovascular risk
1. Every patient who uses long-term NSAIDs should undergo
cardiovascular examination at least once a year.
2. NSAIDs usage is related to an increased risk of having acute
coronary syndrome or other cardiovascular atherothrombotic
events (stroke and other peripheral artery problems). The
increased cardiovascular risk also depends on the type of
NSAIDs used. Naproxen is considered one of the safest choices,
while rofecoxib, diclofenac, etodolac, and indomethacin are
associated with a higher cardiovascular risk.
3. Combination of anticoagulant (warfarin, coumarin derivatives,
etc.) and NSAIDs should be avoided. If truly necessary, coxibs
have the lowest risk.
4. The use of NSAIDs must be avoided in patients with acute
myocardial infarction, even for a short term, as it can increase
cardiovascular risk. Ibuprofen and naproxen can disrupt the
antiplatelet effect of low-dose aspirin. In patients who are
taking low-dose aspirin to prevent cardiovascular events,
coxibs can be considered as the safest long-term NSAIDs
choice.
Gastrointestinal risk
1. Gastrointestinal risk must be assessed in all patients taking
NSAIDs. Patients older than 60 years old or with history of
gastrointestinal ulcers have increased risk of having
gastrointestinal complications.
2. It is not advisable to combine two or more NSAIDs at the same
time.
3. Usage of H2 antagonist to prevent gastrointestinal
complication is not recommended. The use of proton pump
inhibitor (PPI) together with non-selective NSAIDs is the correct
strategy to prevent gastrointestinal complication. Coxibs are
more preferrable compared to combination of non-selective
NSAIDs and PPI.
4. NSAIDs are not recommended in patients with liver cirrhosis
and/or inflammatory bowel disease (IBD). If truly necessary,
coxibs can be chosen at the lowest effective dose and for the
shortest possible duration.
Renal risk
1. Renal function test must be conducted at least once a year in
patients who use long-term NSAIDs.
2. NSAIDs should not be used in patients with stage 3 chronic
kidney disease (CKD) with/without cardiovascular problems,
except in special situations, the usage of NSAIDs must be
tightly evaluated. NSAIDs are contraindicated in patients with
stage 4 and 5 CKD.
Other clinical conditions
1. Anemia or decrease of 2 g/dl of hemoglobin concentration is
common in patients who consume NSAIDs. Coxibs have lower
risk of inducing anemia.
2. Combination of paracetamol and NSAIDs is recommended for
short-term analgesics in post-operative patients.

692
 High cardiovascular Avoid NSAIDs if
risk and receiving possible, or low-dose
aspirin therapy celecoxib + PPI

Avoid NSAIDs if
High Low cardiovascular possible, or
gastrointestinal risk without aspirin naproxen + PPI, or
risk therapy low-dose celecoxib +
PPI

Low cardiovascular
risk Celecoxib  PPI

Patients in
need of NSAIDs

High cardiovascular
risk and receiving Low-dose celecoxib
aspirin therapy

Low Low cardiovascular

Naproxen or low-dose
gastrointestinal risk without aspirin
celecoxib
risk therapy

Low cardiovascular
Any type of NSAIDs
risk

Information:
• Low-dose celecoxib = 200 mg once daily
• Patients with history of peptic ulcer should be investigated for Helicobacter pylori infection

Figure 1. Algorithm in choosing NSAIDs in patients with gastrointestinal and cardiovascular risk82

693
 Table 8. Side Effects of non-selective NSAIDs and selective COX-2.
Non-
Selective
Side Effects Selective
COX-2
NSAIDs
Gastrointestinal
Dyspepsia + 
Gastric ulcer + 
Colitis + 
Bleeding + 
Renal
Hypertension + +
Fluid and salt
+ +
retention
Interstitial
+ +
nephritis
Papillary necrosis + +
Acute kidney
+ +
injury
Liver
Elevated serum
+ +
transaminase
Lung
Asthma attack + +
Skin
Sulfa allergy - + (celecoxib)
Cardiovascular
Thrombosis - +
Central nervous system
Vertigo + +
Cognitive
- +
Dysfunction
Note:
+ : side effect reported
 : minimal side effect
- : no side effect reported

Recommendation 17: Duloxetine is recommended can be used in OA patients with chronic pain, but it
in certain conditions for patients with hand, hip, should be used with caution, since it can increase
and knee OA suicide risk, and also bleeding risk when used in
Duloxetine is a serotonin and norepinephrine combination with warfarin, NSAIDs, or aspirin.85
reuptake inhibitor (SNRI) antidepressant drug, which
works by inhibiting the reuptake process of serotonin Recommendation 18: Pregabalin is recommended
and norepinephrine in the central nervous system. It to be combined with NSAIDs in hand and knee OA
is also used as an analgesic.84 patients who also suffer from neuropathic pain
Three meta-analyses have shown that duloxetine is Pregabalin (gabapentin) is a derivative form of
effective in relieving pain and improving joint function gamma-aminobutyric acid, which is a
of OA patients. Duloxetine is also proven to be effective neurotransmitter that inhibits the calcium ion
in improving mood and patient’s quality of life with channel. It is usually used to treat epilepsy and
minimal side effect.84–86 Duloxetine can be used in OA neuropathic pain. Pregabalin is thought to relieve pain
patients if other analgesics give inadequate effect. The in OA patients through inhibition of pain sensitization.
starting dose for duloxetine is 30-40 mg/day for 1-2 Three RCTs have demonstrated that pregabalin
weeks, which can be increased to 60 mg/day and significantly reduces pain and improves joint function
combined with NSAIDs or paracetamol.85 Duloxetine in patients with hand and knee OA.87–89 The

694
effectiveness increases when used in combination with and easier to control compared to systemic NSAIDs.
NSAIDs.88,89 The therapeutic dose is 150 mg/day for 3 Most used patches include diclofenac and proven
months. The contraindication for pregabalin includes group.92,93
history of depression, concomitant use of Meta-analysis studies have shown that topical
antidepressant, glomerular filtration rate <60 ml/min, NSAIDs are beneficial in decreasing pain in OA
liver impairment (increase of ALT >2.5 times of upper patients, with lower gastrointestinal toxicity and no
normal limit), and alcoholism.87 serious side effects.94–96 Diclofenac patch was shown
to be the most effective topical NSAIDs in relieving
Recommendation 19: Tramadol is recommended in pain.96 Another study also showed that ketoprofen
certain conditions for patients with hand, hip, and patch has similar effectiveness to diclofenac patch.93
knee OA
Tramadol is an opioid agonist which is used as an Recommendation 21: Hyaluronic acid injection is
analgesic for treating moderate to severe pain with a recommended in patients with Kellgren-Lawrence
rapid onset.90 A meta-analysis study has shown that grade 1-3 knee OA who are not responsive to
tramadol significantly decreases pain.91 However, standard pain-relieving therapy
another meta-analysis reported that compared to Intraarticular or periarticular injection is not the
placebo, tramadol alone or in combination with main choice in treating OA, and its usage should also
acetaminophen did not give significant pain relief or be done with caution and selectivity, considering the
joint function improvement in OA patients.90 The local and systemic side effects that may arise. The
recommended dose for tramadol ranges between 37.5 procedure should also be done by rheumatologists,
and 400 mg per day.90 Tramadol can be considered in internists, or other competent specialists.
patients who are contraindicated to NSAIDs, Intraarticular injection can be considered in Kellgren-
unresponsive to other analgesics, or in patients who Lawrence grade 1-3 patients, in whom standard
are ineligible for surgery.1 The possible side effects therapy fails.97 The contraindications for intraarticular
include nausea, vomiting, dizziness, constipation, injection include joint infection, skin infection in the
fatigue, headache, addiction, and respiratory site of injection, thrombocytopenia, coagulopathy, and
depression.1,90 allergy to the injected agent.98
Hyaluronic acid has anti-inflammatory, mechanic,
Recommendation 20: Topical NSAIDs are analgetic effects, and positive affects proteoglycan and
recommended in patients with hand and knee OA glycosaminoglycan synthesis. There are two types of
Topical NSAIDs relieve pain by locally inhibiting hyaluronic acid available in Indonesia, which are high
inflammatory mediators. They are available in the form molecular weight and low molecular weight, and the
of gel, cream, or patch. Topical NSAIDs are mainly mixed type. A study has shown that intraarticular
used for patients who are contraindicated to systemic hyaluronic acid has chondroprotective, anti-
therapy. inflammatory, analgetic, joint lubricant, and shock-
Patch is proven to be effective in relieving pain, with absorbing effects.99 The recommended dose is 20 mg a
the advantages of having adhesive agent, retaining week for 5 weeks, 30 mg a week for 3 weeks, or 60 mg
layer, and a membrane which controls the releasing single dose.97
rate of active agents. The active agents enter through Hyaluronic acid injection is recommended in
subcutaneous tissue to intraarticular tissue with Kellgren-Lawrence grade 1-3 patients, who are
higher concentration compared to plasma. The unresponsive to standard therapy and/or
concentration of the active agents also drops faster contraindicated to other therapy. Meta-analysis
when the patch is removed, which makes patch safer studies have shown that corticosteroid injection is

695
more effective compared to hyaluronic acid in relieving anticoagulant, comorbidities, use of more than one
pain in the short-term (up to one month), but NSAIDs, smoking, and alcoholism.82
hyaluronic acid is more effective for long-term pain- Regarding cardiovascular and renal safety, several
relief (up to 6 months).97,100,101 problems need to be considered, including
hypertension, congestive heart failure, kidney failure,
Recommendation 22: Corticosteroid injection is and hyperkalemia. Long-term use of NSAIDs may
recommended in patients with knee OA undergoing cause a decrease in glomerular filtration rate.109,110
acute or chronic inflammation and joint effusion
Corticosteroid intraarticular injection can relieve Recommendation 24: Lequesne index and WOMAC
pain in knee OA by inhibiting inflammation and are recommended as tools to evaluate the
decreasing prostaglandin synthesis.102 Corticosteroid therapeutic effect in OA
injection is recommended in OA patients with acute or Lequesne index is used to objectively assess the
chronic inflammation and joint effusion.103 Three severity of knee and hip OA based on clinical aspects.
meta-analyses have shown that corticosteroid This severity categorization can help guide treatment
injection is more effective compared to hyaluronic acid modality selection in OA patients.111
in relieving pain for short-term duration (up to one WOMAC index can also be used to assess
month).97,100,101 functional impairment and pain in OA patients. It is a
valid and reliable index which assess 17 functional
Recommendation 23: Monitoring of comorbidities activities, 5 painful activities, and 2 stiffness
and complications should be commenced since the problems.112,113
beginning of OA therapy
Comprehensive assessment regarding OA patient’s Recommendation 25: OA patients should be
quality of life should be done in the beginning of considered for referral based on clinical indications
therapy. The decision to treat OA should be OA patients should be referred to internists or
individualized and take into account other medical rheumatologists for further examination and
conditions such as hypertension, cardiovascular appropriate therapy.114 The indications for referral
disease, gastrointestinal bleeding risk, renal disease, include: 1) Patients with doubtful diagnosis or
etc. Liver and renal function should be monitored to suspicion of other joint diseases. 2) Patients with
minimize risk of drug side effects. Hepatotoxic drugs comorbidities and multiple pathologies. 3) Patients
such as paracetamol must be avoided in patients with who fail to respond to standard therapy. 4) Patients
impaired liver function, while drugs that are who need non-surgical intervention.
eliminated by urine excretion must be avoided in Surgical therapy should be considered in OA patients
patients with impaired kidney function. Local therapy, with these conditions: 1) OA patients with severe joint
if possible, is more recommended than systemic symptoms (pain, stiffness, functional impairment) that
therapy to minimize risk of side effects. NSAIDs should severely impact patients’ quality of life. 2) Patients with
be used for the shortest duration at the lowest refractory joint symptoms despite adequate non-
therapeutic dose.107,108 surgical therapy. 3) Patients with severe pain can be
Gastrointestinal problems that may arise during considered to be referred for surgical therapy before
OA therapy include heartburn sensation, abdominal prolonged functional limitation occurs. If joint
discomfort, peptic ulcer, hematemesis, and melena. damage/deformity meets the indication as stated in
Risk factors that may increase gastrointestinal side number 1, then it falls under the indication for
effects include history of peptic ulcer, dyspepsia, GI surgery.
bleeding, previous intolerance to NSAIDs, steroids use,

696
 Table 9. Summary of therapy recommendation in osteoarthritis.
Hand OA Knee OA Hip OA
Intervention
Level of Recommendation

Education program +++ +++ +++

Decreasing body weight +++ +++

Physical exercise +++ +++ +++

Tai Chi +++ +++ +++

Yoga +++ +++ +++

Cane ++ ++

Tripod ++ ++

Quadripod ++ ++

Walker ++ ++

Knee brace ++

Kinesiotaping ++ ++

Hand orthosis ++

Thermotherapy, acupuncture, TENS ++

Radiofrequency ablation ++

Low level laser therapy ++

Paracetamol ++ ++ ++

Oral NSAIDs +++ +++ +++

Duloxetine ++ ++ ++

Pregabalin ++ ++

Tramadol ++ ++ ++

Topical NSAIDs +++ +++

Hyaluronic acid injection ++

Corticosteroids injection ++

Note:

Recommended (+++) when supported by high-quality scientific evidence which indicates that the benefits outweigh
the harms in the target population.
Recommended in specific conditions (++) when supported by scientific evidence of good quality in specific
conditions and related to cost, equity, and implementation issues.
Considered in specific conditions (+) when the existing scientific evidence is not strong enough or when there are
differences in outcomes and related to cost, equity, and implementation issues.

697
 Patients suspected of osteoarthritis

Clinical Approach Diagnosis Documentation of

Supporting Examination

Clinical history - The date when

Standard radiography radiography
Excluded factors: examination was
Trauma OA diagnosis performed
Soft tissue condition based on ACR - Base of diagnosis: ACR
Pain radiation syndrome criteria classification criteria
Septic/crystal-based for OA
arthritis - Differential diagnosis
Hemarthrosis

Evaluation of the joint:

- Pain, edema - The most recent grade
- Function, mobility of OA
impairment - If the patient
- Emotional & other consumes NSAIDs,
disability Perform perform blood
Comorbidities: comprehensiv pressure examination
- Nutritional assessment e assessment and renal function test
(BMI) - Previous therapeutic
- Fall Risk response
- Previous chronic
NSAIDs risk factor: comorbidities
- Age, hypertension, GI
problems, cardiovascular,
renal, or liver diseases

Treatment risk:
- Polypharmacy
- Drug / aspirin allergy
- Diuretics / ACE-I usage
- Anticoagulant usage

Education & socioeconomic

status

Non-pharmacological and pharmacological treatment

Figure 2. Diagnostic approach diagram in osteoarthritis.

698
5. Conclusion Epidemiology of Aging. 2012; 26(3): 523–36.
These recommendations aim to provide guidance 8. BAPPENAS. Indonesian population projection
on the diagnosis and management of osteoarthritis in 2000-2025. Jakarta: Pusat Penelitian dan
Indonesia. The diagnostic, therapy, and monitoring Pengembangan Kementerian Kesehatan
algorithms in this recommendation are all tailored to Republik Indonesia; 2005.
suit Indonesia’s clinical setting, facility, and drug 9. Grässel S, Muschter D. Recent advances in the
availability. A summary of the diagnostic approach in treatment of osteoarthritis [ version 1; peer
OA is presented in Figure 2. We hope that this review: 3 approved]. F1000Res. 2020; 9(325): 1–
recommendation can serve as a guideline for 17.
physicians in Indonesia when managing OA patients. 10.Karsdal MA, Michaelis M, Ladel C, Siebuhr AS,
Bihlet AR, Andersen JR, et al. Disease-
6. References modifying treatments for osteoarthritis
1. Kolasinski SL, Neogi T, Hochberg MC, Oatis C, (DMOADs) of the knee and hip: lessons learned
Guyatt G, Block J, et al. 2019 American College from failures and opportunities for the future.
of rheumatology/arthritis foundation guideline Osteoarthritis Cartilage. 2016; 24(12): 2013–21.
for the management of osteoarthritis of the 11.Hancock JL. A new system for grading
hand, hip, and knee. Arthritis Care Res recommendations in evidence based guidelines.
(Hoboken). 2020; 72(2): 149–62. Br Med J. 2001; 323(3): 334–6.
2. Murray CJL, Vos T, Lozano R, Naghavi M, 12.Sinusas K. Osteoarthritis:Diagnosis and
Flaxman AD, Michaud C, et al. Disability- treatment. Am Fam Physician. 2012; 85(1): 49–
adjusted life years (DALYs) for 291 diseases and 56.
injuries in 21 regions, 1990-2010: A systematic 13.Beattie KA, Bobba R, Bayoumi I, Chan D,
analysis for the Global Burden of Disease Study Schabort I, Boulos P, et al. Validation of the
2010. The Lancet. 2012; 380(9859): 2197–223. GALS musculoskeletal screening exam for use
3. Bannuru RR, Osani MC, Vaysbrot EE, Arden in primary care: A pilot study. BMC
NK, Bennell K, Bierma-Zeinstra SMA, et al. Musculoskelet Disord. 2008; 9(5): 115–22.
OARSI guidelines for the non-surgical 14.Skou ST, Koes BW, Grønne DT, Young J, Roos
management of knee, hip, and polyarticular EM. Comparison of three sets of clinical
osteoarthritis. Osteoarthritis Cartilage. 2019; classification criteria for knee osteoarthritis: a
27(11): 1578–89. cross-sectional study of 13,459 patients treated
4. Palazzo C, Nguyen C, Lefevre-Colau MM, in primary care. Osteoarthritis Cartilage. 2020;
Rannou F, Poiraudeau S. Risk factors and 28(2): 167–72.
burden of osteoarthritis. Ann Phys Rehabil Med. 15.Martel-Pelletier J, Maheu E, Pelletier JP,
2016; 59(3): 134–8. Alekseeva L, Mkinsi O, Branco J, et al. A new
5. Rillo O, Riera H, Acosta C, Liendo V, Bolaños J, decision tree for diagnosis of osteoarthritis in
Monterola L, et al. PANLAR consensus primary care: international consensus of
recommendations for the management in experts. Aging Clin Exp Res. 2019; 31(1): 19–30.
osteoarthritis of hand, hip, and knee. Journal of 16.Haugen IK, Felson DT, Abhishek A, Berenbaum
Clinical Rheumatology. 2016;22(7):345–54. F, Bierma-Zeinstra S, Borgen T, et al.
6. Anderson AS, Loeser RF. Why is OA an age- Development of classification criteria for hand
related disease. Best Pract Res Clin Rheumatol. osteoarthritis: Comparative analyses of persons
2010; 24(1): 1–18. with and without hand osteoarthritis. RMD
7. Kwoh CK. Epidemiology of osteoarthritis. The Open. 2020; 6(2): 1–8.

699
17.Brown C, Cooke TD, Daniel W, Greenwald RGR, change and reliability of measurement of
Hochberg M, Howell D, et al. Arthritis & radiographic joint space width in osteoarthritis
rheumatism the American College of of the knee: A systematic review. Osteoarthritis
rheumatology reporting of osteoarthritis of the Cartilage. 2011; 19(5): 550–6.
hand. Arthritis Rheum. 1990; 33(6): 1601–10. 26.van der Oest MJW, Duraku LS, Andrinopoulou
18.Altman RD, Manjoo A, Fierlinger A, Niazi F, ER, Wouters RM, Bierma-Zeinstra SMA, Selles
Nicholls M. The mechanism of action for RW, et al. The prevalence of radiographic thumb
hyaluronic acid treatment in the osteoarthritic base osteoarthritis: a meta-analysis.
knee: A systematic review. BMC Musculoskelet Osteoarthritis Cartilage. 2021; 29(6): 785–92.
Disord. 2015; 16(1): 1–10. 27.Perrotta FM, Scriffignano S, de Socio A, Lubrano
19.Altman R, Asch E, Bloch D, Bole G, Borenstein E. An Assessment of Hand Erosive
D, Brandt K, et al. Development of criteria for Osteoarthritis: Correlation of Radiographic
the classification and reporting of osteoarthritis: Severity with Clinical, Functional and
Classification of osteoarthritis of the knee. Laboratory Findings. Rheumatol Ther. 2019;
Arthritis Rheum. 1986; 29(8): 1039–49. 6(1): 125–33.
20.Zhang W, Doherty M, Peat G, Bierma-Zeinstra 28.Kim C, Nevitt MC, Niu J, Clancy MM, Lane NE,
SMA, Arden NK, Bresnihan B, et al. EULAR Link TM, et al. Association of hip pain with
evidence-based recommendations for the radiographic evidence of hip osteoarthritis:
diagnosis of knee osteoarthritis. Ann Rheum Diagnostic test study. BMJ (Online). 2015; 351.
Dis. 2010; 69(3): 483–9. 29.Oo WM, Linklater JM, Daniel M, Saarakkala S,
21.Brown C, Cooke TD, Daniel W, Greenwald RGR, Samuels J, Conaghan PG, et al. Clinimetrics of
Hochberg M, Howell D, et al. The American ultrasound pathologies in osteoarthritis:
College of rheumatology reporting of systematic literature review and meta-analysis.
osteoarthritis of the hip. Arthritis Rheum. 1990; Osteoarthritis Cartilage. 2018; 26(5): 601–11.
33(6): 1601–10. 30.Hart HF, Stefanik JJ, Wyndow N, Machotka Z,
22.Runhaar J, Özbulut Ö, Kloppenburg M, Boers Crossley KM. The prevalence of radiographic
M, Bijlsma JWJ, Bierma-Zeinstra SMA. and MRI-defined patellofemoral osteoarthritis
Diagnostic criteria for early hip osteoarthritis: and structural pathology: A systematic review
first steps, based on the CHECK study. and meta-analysis. Br J Sports Med. 2017;
Rheumatology. 2021; 1(1): 1–7. 51(16): 1195–208.
23.Nieminen MT, Casula V, Nevalainen MT, 31.MacKay JW, Low SBL, Smith TO, Toms AP,
Saarakkala S. Osteoarthritis year in review McCaskie AW, Gilbert FJ. Systematic review
2018: imaging. Osteoarthritis Cartilage. 2019; and meta-analysis of the reliability and
27(3): 401–11. discriminative validity of cartilage
24.Culvenor AG, Engen CN, Øiestad BE, compositional MRI in knee osteoarthritis.
Engebretsen L, Risberg MA. Defining the Osteoarthritis Cartilage. 2018; 26(9): 1140–52.
presence of radiographic knee osteoarthritis: a 32.Zhao X, Ruan J, Tang H, Li J, Shi Y, Li M, et al.
comparison between the Kellgren and Lawrence Multi-compositional MRI evaluation of repair
system and OARSI atlas criteria. Knee Surgery, cartilage in knee osteoarthritis with treatment
Sports Traumatology, Arthroscopy. 2015; of allogeneic human adipose-derived
23(12): 3532–9. mesenchymal progenitor cells. Stem Cell Res
25.Reichmann WM, Maillefert JF, Hunter DJ, Katz Ther. 2019; 10(1): 1–15.
JN, Conaghan PG, Losina E. Responsiveness to

700
33.Ingegnoli F, Castelli R, Gualtierotti
Rheumatoid factors: Clinical applications. Dis
Markers. 2013; 35(6): 727–34.
34.Qaseem A, McLean RM, Starkey M, Forciea MA,
Denberg TD, Barry MJ, et al. Diagnosis of acute
gout: A clinical practice guideline from the
American College of Physicians. Ann Intern
Med. 2017; 166(1): 52–7.
35.Saraiva AMCF, Pereira JP. Calcium
Pyrophosphate Dihydrate Deposition
Pseudarthrosis. Journal of
Rheumatology. 2017; 23(3): 176–8.
36.Fpb K, Lra VDB, Buchbinder R, Rh O, Rv J, Pitt
V. Self-management education programmes for
osteoarthritis (Review). Cochrane Database Syst
Rev. 2014; (1).
37.Hall M, Castelein B, Wittoek R, Calders P, van
Ginckel A. Diet-induced weight loss alone or
combined with exercise in overweight or obese
people with knee osteoarthritis: A systematic
review and meta-analysis. Semin Arthritis
Rheum. 2019; 48(5): 765–77.
38.Robson EK, Hodder RK, Kamper SJ, O’Brien
KM, Williams A, Lee H, et al. Effectiveness of
weight-loss interventions for reducing pain and
disability in people with common
musculoskeletal disorders: A systematic review
with meta-analysis. Journal of Orthopaedic and
Sports Physical Therapy. 2020; 50(6): 319–33.
39.Panunzi S, Maltese S, de Gaetano A, Capristo E,
Bornstein SR, Mingrone G. Comparative efficacy
of different weight loss treatments on knee
osteoarthritis: A network meta-analysis.
Obesity Reviews. 2021; 22(8): 1–11.
40.Yamato TP, Deveza LA, Maher CG. Exercise for
osteoarthritis of the knee. Cochrane Database
Syst Rev. 2016; 50(16): 1–146.
41.Østerås N, Kjeken I, Smedslund G, Rh M, Uhlig
T, Kb H. Exercise for hand osteoarthritis
(Review). Cochrane Database Syst
2017;(1):1–70.
42.Fransen M, Mcconnell S, Hernandez-Molina G,
Reichenbach S. Exercise for osteoarthritis of the
R. hip. Cochrane Database of Systematic Reviews.
2014; 2014(4): 1–52.
43.You Y, Liu J, Tang M, Wang D, Ma X. Effects of
Tai Chi exercise on improving walking function
and posture control in elderly patients with
knee osteoarthritis: A systematic review and
meta-analysis. Medicine. 2021; 100(16): 1–7.
44.Yan JH, Gu WJ, Sun J, Zhang WX, Li BW, Pan
L. Efficacy of Tai Chi on Pain, Stiffness and
in a Function in Patients with Osteoarthritis: A
Clinical Meta-Analysis. PLoS One. 2013; 8(4): 1–9.
45.Hu L, Wang Y, Liu X, Ji X, Ma Y, Man S, et al.
Tai Chi exercise can ameliorate physical and
mental health of patients with knee
osteoarthritis: systematic review and meta-
analysis. Clin Rehabil. 2021; 35(1): 64–79.
46.Lauche R, Hunter DJ, Adams J, Cramer H. Yoga
for osteoarthritis: a systematic review and meta-
analysis. Curr Rheumatol Rep. 2019; 21(9).
47.Wang Y, Lu S, Wang R, Jiang P, Rao F, Wang B,
et al. Integrative effect of yoga practice in
patients with knee arthritis A PRISMA-
compliant meta-analysis. Medicine (United
States). 2018; 97(31): 1–8.
48.van Ginckel A, Hinman RS, Wrigley VT, Hunter
DJ, Marshall CJ, Duryea J, et al. Effect of cane
use on bone marrow lesion volume in people
with medial tibiofemoral knee osteoarthritis:
randomized clinical trial. Osteoarthritis
Cartilage. 2019; 27(9): 1324–38.
49.Jones A, Silva PG, Silva AC, Colucci M, Tuffanin
A, Jardim JR, et al. Impact of cane use on pain,
function, general health and energy expenditure
during gait in patients with knee osteoarthritis:
A randomised controlled trial. Ann Rheum Dis.
2012; 71(2): 172–9.
50.Carbone LD, Satterfield S, Liu C, Kwoh KC,
Neogi T, Tolley E, et al. Assistive walking device
Rev. use and knee osteoarthritis: Results from the
health, aging and body composition study
(Health ABC Study). Arch Phys Med Rehabil.
2013; 94(2): 332–9.
701
51.Rebbeca FM, Trevor B B, Dianne M B. Valgus review and meta-analysis. Disabil Rehabil.
Bracing for Knee Osteoarthritis: A Meta- 2015; 37(22): 2025–43.
analysis of Randomized Trials. Arthritis Care 59.Bobos P, Nazari G, Szekeres M, Lalone EA,
Res (Hoboken). 2014; 1(1): 1–32. Ferreira L, MacDermid JC. The effectiveness of
52.Cudejko T, van der Esch M, van der Leeden M, joint-protection programs on pain, hand
Roorda LD, Pallari J, Bennell KL, et al. Effect of function, and grip strength levels in patients
soft braces on pain and physical function in with hand arthritis: A systematic review and
patients with knee osteoarthritis: systematic meta-analysis. Journal of Hand Therapy. 2019;
review with meta-analyses. Arch Phys Med 32(2): 194–211.
Rehabil. 2018; 99(1): 153–63. 60.Marotta N, Demeco A, Marinaro C, Moggio L,
53.Gueugnon M, Fournel I, Soilly AL, Diaz A, Pino I, Barletta M, et al. Comparative
Baulot E, Bussière C, et al. Effectiveness, safety, Effectiveness of Orthoses for Thumb
and cost–utility of a knee brace in medial knee Osteoarthritis: A Systematic Review and
osteoarthritis: the ERGONOMIE randomized Network Meta-analysis. Arch Phys Med Rehabil.
controlled trial. Osteoarthritis Cartilage. 2021; 2021; 102(3): 502–9.
29(4): 491–501. 61.de Almeida PHTQ, MacDermid J, Pontes TB, dos
54.Lu Z, Li X, Chen R, Guo C. Kinesio taping Santos-Couto-Paz CC, Matheus JPC.
improves pain and function in patients with Differences in orthotic design for thumb
knee osteoarthritis: A meta-analysis of osteoarthritis and its impact on functional
randomized controlled trials. International outcomes: A scoping review. Prosthet Orthot
Journal of Surgery. 2018; 59(September): 27– Int. 2017; 41(4): 323–35.
35. 62.Wang H, Zhang C, Gao C, Zhu S, Yang L, Wei Q,
55.Ye W, Jia C, Jiang J, Liang Q, He C. et al. Effects of short-wave therapy in patients
Effectiveness of elastic taping in patients with with knee osteoarthritis: A systematic review
knee osteoarthritis: A systematic review and and meta-analysis. Clin Rehabil. 2017; 31(5):
meta-analysis. Am J Phys Med Rehabil. 2020; 660–71.
99(6): 495–503. 63.Laufer Y, Dar G. Effectiveness of thermal and
56.Lin CH, Lee M, Lu KY, Chang CH, Huang SS, athermal short-wave diathermy for the
Chen CM. Comparative effects of combined management of knee osteoarthritis: A
physical therapy with Kinesio taping and systematic review and meta-analysis.
physical therapy in patients with knee Osteoarthritis Cartilage. 2012; 20(9): 957–66.
osteoarthritis: a systematic review and meta- 64.Dantas LO, Breda CC, Mendes Silva Serrao PR,
analysis. Clin Rehabil. 2020; 34(8): 1014–27. Serafim Jorge AH, Salvini TF. Cryotherapy
57.Weleslassie GG, Temesgen MH, Alamer A, short-term use relieves pain, improves function
Tsegay GS, Hailemariam TT, Melese H. and quality of life in individuals with knee
Effectiveness of Mobilization with Movement on osteoarthritis – randomized controlled trial.
the Management of Knee Osteoarthritis: A Osteoarthritis Cartilage. 2017; 25.
Systematic Review of Randomized Controlled 65.Taru M, Maria F, Ryan Z. Pain management
Trials. Pain Res Manag. 2021; 2021: 1267–76. with acupuncture in osteoarthritis: a systematic
58.Bertozzi L, Valdes K, Vanti C, Negrini S, review and meta-analysis. BMC Musculoskelet
Pillastrini P, Villafañe JH. Investigation of the Disord. 2014; 14(312): 1–9.
effect of conservative interventions in thumb 66.Corbett MS, Rice SJC, Madurasinghe V, Slack
carpometacarpal osteoarthritis: Systematic R, Fayter DA, Harden M, et al. Acupuncture and

702
 other physical treatments for the relief of pain Chou LW. Efficacy of acupoints dual-frequency
due to osteoarthritis of the knee: Network meta- low-level laser therapy on knee osteoarthritis.
analysis. Osteoarthritis Cartilage. 2013; 21(9): Evidence-based Complementary and
1290–8. Alternative Medicine. 2020; 1–7.
67.Shi X, Yu W, Zhang W, Wang T, Battulga O, 75.Marks JL, van der Heijde DM, Colebatch AN,
Wang L, et al. A comparison of the effects of Buchbinder R, Edwards CJ. Pain
electroacupuncture versus transcutaneous pharmacotherapy in patients with inflammatory
electrical nerve stimulation for pain control in arthritis and concurrent cardiovascular or renal
knee osteoarthritis: a Bayesian network meta- disease: A Cochrane systematic review. Journal
analysis of randomized controlled trials. of Rheumatology. 2012; 39(SUPPL. 90): 81–4.
Acupuncture in Medicine. 2021; 39(3): 163–74. 76.Kloppenburg M, Kroon FPB, Blanco FJ, Doherty
68.Chen LX, Zhou ZR, Li YL, Ning GZ, Li Y, Wang M, Dziedzic KS, Greibrokk E, et al. 2018 update
XB, et al. Transcutaneous electrical nerve of the EULAR recommendations for the
stimulation in patients with knee osteoarthritis: management of hand osteoarthritis. Ann
Evidence from randomized-controlled trials. Rheum Dis. 2019; 78(1): 16–24.
Clinical Journal of Pain. 2016; 32(2): 146–54. 77.Verkleij SPJ, Luijsterburg PAJ, Bohnen AM,
69.Zeng C, li H, Yang T, Deng ZH, Yang Y, Zhang Koes BW, Bierma-Zeinstra SMA. NSAIDs vs
Y, et al. Electrical stimulation for pain relief in acetaminophen in knee and hip osteoarthritis:
knee osteoarthritis: Systematic review and A systematic review regarding heterogeneity
network meta-analysis. Osteoarthritis influencing the outcomes. Osteoarthritis
Cartilage. 2015; 23(2): 189–202. Cartilage. 2011; 19(8): 921–9.
70.Hong T, Wang H, Li G, Yao P, Ding Y. Systematic 78.Leopoldino AO, Gc M, Ph F, Mb P, Aj M, Dj H, et
review and meta-analysis of 12 randomized al. Paracetamol versus placebo for knee and hip
controlled trials evaluating the efficacy of osteoarthritis (Review). Cochrane Database of
invasive radiofrequency treatment for knee pain Systematic Reviews. 2019; (2): 1–51.
and function. Biomed Res Int. 2019;1–15. 79.Bannuru RR, Schmid CH, Kent DM, Vaysbrot
71.Li G, Zhang Y, Tian L, Pan J. Radiofrequency EE, Wong JB, McAlindon TE. Comparative
ablation reduces pain for knee osteoarthritis: A effectiveness of pharmacologic interventions for
meta-analysis of randomized controlled trials. knee osteoarthritis: A systematic review and
International Journal of Surgery. 2021; 91: 1– network meta-analysis. Ann Intern Med. 2015;
32. 162(1): 46–54.
72.Stausholm MB, Naterstad IF, Joensen J, Lopes- 80.Gustavo M. Efficacy and safety of paracetamol
Martins RÁB, Sæbø H, Lund H, et al. Efficacy of for spinal pain and osteoarthritis: systematic
low-level laser therapy on pain and disability in review and meta-analysis of randomised
knee osteoarthritis: Systematic review and placebo controlled trials. BMJ Clin Evid. 2015;
meta-analysis of randomised placebo-controlled 23(2): 1–13.
trials. BMJ Open. 2019; 9(10): 1–13. 81.Lanas A, Benito P, Alonso J, Hernández-Cruz B,
73.Huang Z, Chen J, Ma J, Shen B, Pei F, Kraus Barón-Esquivias G, Perez-Aísa Á, et al. Safe
VB. Effectiveness of low-level laser therapy in Prescription Recommendations for Non
patients with knee osteoarthritis: A systematic Steroidal Anti-inflammatory Drugs: Consensus
review and meta-analysis. Osteoarthritis Document Elaborated by Nominated Experts of
Cartilage. 2015; 23(9): 1437–44. Three Scientific Associations (SER-SEC-AEG).
74.Liao FY, Lin CL, Lo SF, Chang CC, Liao WY, Reumatología Clínica (English Edition). 2014;

703
 10(2): 68–84. Systematic Reviews. 2019; (5): 1–102.
82.Scarpignato C, Lanas A, Blandizzi C, Lems WF, 91.Jung SY, Jang EJ, Nam SW, Kwon HH, Im SG,
Hermann M, Hunt RH. Safe prescribing of non- Kim D, et al. Comparative effectiveness of oral
steroidal anti-inflammatory drugs in patients pharmacologic interventions for knee
with osteoarthritis - an expert consensus osteoarthritis: A network meta-analysis. Mod
addressing benefits as well as gastrointestinal Rheumatol. 2018; 28(6): 1021–8.
and cardiovascular risks. BMC Med. 2015; 92.Yataba I, Otsuka N, Matsushita I, Matsumoto H,
13(1). Hoshino Y. Efficacy of S-flurbiprofen plaster in
83.Use of non-steroidal anti-inflammatory drugs. knee osteoarthritis treatment: Results from a
Jakarta: Perhimpunan Reumatologi Indonesia; phase III, randomized, active-controlled,
2014; 8. adequate, and well-controlled trial. Mod
84.Chen L, Gong M, Liu G, Xing F, Liu J, Xiang Z. Rheumatol. 2017; 27(1): 130–6.
Efficacy and tolerability of duloxetine in 93.Yakushin S, Polyakova S, Shvarts Y,
patients with knee osteoarthritis: a meta- Kastanayan A, Krechikova D, Ershova O, et al.
analysis of randomised controlled trials. Intern Comparison of the efficacy and safety of
Med J. 2019; 49(12): 1514–23. ketoprofen plaster and diclofenac plaster for
85.Weng C, Xu J, Wang Q, Lu W, Liu Z. Efficacy osteoarthritis-related knee pain: A multicenter,
and safety of duloxetine in osteoarthritis or randomized, active-controlled, open-label,
chronic low back pain: a Systematic review and parallel-group, phase III clinical trial. Clin Ther.
meta-analysis. Osteoarthritis Cartilage. 2020; 2021; 43(10): 1720–34.
28(6): 721–34. 94.Honvo G. Safety of topical non steroidal anti
86.Gao SH, Huo BJ, Pan QM, Li XW, Chen HY, inflammatory drugs in osteoarthritis: Outcomes
Huang JH. The short-term effect and safety of of a systematic review and meta analysis. Drugs
duloxetine in osteoarthritis: A systematic review Aging. 2019; 36(1): 45–64.
and meta-analysis. Medicine (United States). 95.Persson MSM, Stocks J, Walsh DA, Doherty M,
2019; 98(44): 1–81. Zhang W. The relative efficacy of topical non-
87.Sofat N, Harrison A, Russell MD, Ayis S, Kiely steroidal anti-inflammatory drugs and
PD, Baker EH, et al. The effect of pregabalin or capsaicin in osteoarthritis: a network meta-
duloxetine on arthritis pain: A clinical and analysis of randomised controlled trials.
mechanistic study in people with hand Osteoarthritis Cartilage. 2018; 26(12): 1575–82.
osteoarthritis. J Pain Res. 2017; 10: 2437–49. 96.Zeng C, Wei J, Persson MSM, Sarmanova A,
88.Filatova E, Turovskaya E, Alekseeva L. Doherty M, Xie D, et al. Relative efficacy and
Pregabalin efficacy in treatment of chronic pain safety of topical non-steroidal anti-
in patients with knee osteoarthritis. Annal of the inflammatory drugs for osteoarthritis: A
Rheumatic Disease. 2018; 793–4. systematic review and network meta-analysis of
89.Ohtori S, Inoue G, Orita S, Takaso M, Eguchi Y, randomised controlled trials and observational
Ochiai N, et al. Efficacy of combination of studies. Br J Sports Med. 2018; 52(10): 642–50.
meloxicam and pregabalin for pain in knee 97.Ma X long, Kuang M jie, Zhao J, Sun L, Lu B,
osteoarthritis. Yonsei Med J. 2013; 54(5): 1253– Wang Y, et al. Efficacy and safety of
8. intraarticular hyaluronic acid and
90.April KT, Bisaillon J, Welch V, Maxwell LJ, Jüni corticosteroid for knee osteoarthritis: A meta-
P, Rutjes AWS, et al. Tramadol for analysis. International Journal of Surgery.
osteoarthritis. Cochrane Database of 2017; 39: 95–103.

704
98.Tan J, Chen H, Zhao L, Huang W. Platelet-Rich analysis. Arch Orthop Trauma Surg. 2021;
plasma versus hyaluronic acid in the treatment 141(9): 1473–90.
of knee osteoarthritis: A meta-analysis of 26 105. McLarnon M, Heron N. Intra-articular platelet-
randomized controlled trials. Arthroscopy - rich plasma injections versus intra-articular
Journal of Arthroscopic and Related Surgery. corticosteroid injections for symptomatic
2021; 37(1): 309–25. management of knee osteoarthritis:
99.Bahrami MH, Raeissadat SA, Cheraghi M, systematic review and meta-analysis. BMC
Rahimi-Dehgolan S, Ebrahimpour A. Efficacy of Musculoskelet Disord. 2021; 22(1): 1–13.
single high-molecular-weight versus triple low- 106. Han Y, Huang H, Pan J, Lin J, Zeng L, Liang
molecular-weight hyaluronic acid intra- G, et al. Meta-analysis Comparing Platelet-
articular injection among knee osteoarthritis Rich Plasma vs Hyaluronic Acid Injection in
patients. BMC Musculoskelet Disord. 2020; Patients with Knee Osteoarthritis. Pain
21(1): 1–8. Medicine (United States). 2019;20(7):1418–29.
100. Ran J, Yang X, Ren Z, Wang J, Dong H. 107. Fernandes L, Hagen KB, Bijlsma JWJ,
Comparison of intra-articular hyaluronic acid Andreassen O, Christensen P, Conaghan PG,
and methylprednisolone for pain management et al. EULAR recommendations for the non-
in knee osteoarthritis: A meta-analysis of pharmacological core management of hip and
randomized controlled trials. International knee osteoarthritis. Ann Rheum Dis. 2013;
Journal of Surgery. 2018;53:103–10. 72(7): 1125–35.
101. Han SB, Seo IW, Shin YS. Intra-articular 108. Oo WM, Liu X, Hunter DJ.
injections of hyaluronic acid or steroids Pharmacodynamics, efficacy, safety and
associated with better outcomes than platelet- administration of intra-articular therapies for
rich plasma, adipose mesenchymal stromal knee osteoarthritis. Expert Opin Drug Metab
cells, or placebo in knee osteoarthritis: A Toxicol. 2019; 15(12): 1021–32.
network meta-analysis. arthroscopy - Journal 109. Varga Z, Sabzwari S rafay ali, Vargova V.
of Arthroscopic and Related Surgery. 2021; Cardiovascular Risk of Nonsteroidal Anti-
37(1): 292–306. Inflammatory Drugs: An Under-Recognized
102. Zeng C, Lane NE, Hunter DJ, Wei J, Choi HK, Public Health Issue. Cureus. 2017; 9(4): 1–12.
McAlindon TE, et al. Intra-articular 110. Nelson DA, Marks ES, Deuster PA, O’Connor
corticosteroids and the risk of knee FG, Kurina LM. Association of Nonsteroidal
osteoarthritis progression: results from the Anti-inflammatory Drug Prescriptions with
Osteoarthritis Initiative. Osteoarthritis Kidney Disease among Active Young and
Cartilage. 2019; 27(6): 855–62. Middle-aged Adults. JAMA Netw Open. 2019;
103. Ayhan E, Kesmezacar H, Akgun I. 2(2): 1–12.
Intraarticular injections (corticosteroid, 111. Dawson J, Linsell L, Doll H, Zondervan K,
hyaluronic acid, platelet rich plasma) for the Rose P, Carr A, et al. Assessment of the
knee osteoarthritis. World J Orthop. 2014; Lequesne index of severity for osteoarthritis of
5(3): 351–61. the hip in an elderly population. Osteoarthritis
104. Migliorini F, Driessen A, Quack V, Sippel N, Cartilage. 2005; 13(10): 854–60.
Cooper B, Mansy EY, et al. Comparison 112. Salaffi F, Leardini G, Canesi B, Mannoni A,
between intra-articular infiltrations of Fioravanti A, Caporali R, et al. Reliability and
placebo, steroids, hyaluronic and PRP for knee validity of the Western Ontario and McMaster
osteoarthritis: a Bayesian network meta- Universities (WOMAC) Osteoarthritis Index in

705
 Italian patients with osteoarthritis of the knee.
Osteoarthritis Cartilage. 2003; 11(8): 551–60.
113. Ebrahimzadeh MH, Makhmalbaf H,
Birjandinejad A, Keshtan FG, Hoseini HA,
Mazloumi SM. The Western Ontario and
McMaster Universities Osteoarthritis Index
(WOMAC) in Persian speaking patients with
knee osteoarthritis. Archives of Bone and
Joint Surgery. 2014; 2(1): 57–62.
114. Musila N, Underwood M, McCaskie AW, Black
N, Clarke A, van der Meulen JH. Referral
recommendations for osteoarthritis of the
knee incorporating patients’ preferences. Fam
Pract. 2011; 28(1): 68–74.

706