Complete the 2 tables using the article attached. See the example for guidance .
Contents lists available at ScienceDirect
Journal of Orthopaedics
journal homepage: www.elsevier.com/locate/jor
Review Article
Treating hand and foot osteoarthritis using a patient's own blood: A systematic review and meta-analysis of platelet-rich plasma
Adam Evansa,∗, Maryo Ibrahima, Rand Popeb, James Mwangia, Mina Botrosa, Shepard P. Johnsonc, Salam Al Kassisc
a Meharry Medical College, 1005 Dr DB Todd Jr Blvd, Nashville, TN, 37208, USA b Vanderbilt University School of Medicine, 1161 21st Ave South, Nashville, TN, 37232, USA c Vanderbilt University Medical Center Department of Plastic Surgery, D-4207 Medical Center North, 1211 Medical Center Drive, Nashville, TN, 37212, USA
A R T I C L E I N F O
Keywords: Platelet-rich plasma Osteoarthritis Cartilage Intra-articular injections Hand Foot Ankle
A B S T R A C T
Background: This study summarizes all literature investigating platelet-rich plasma (PRP) in the treatment of osteoarthritis of the hands and feet. Materials & methods: This is a PRISMA compliant systematic review of 7 databases and includes a meta-analysis of randomized controlled trial (RCT) data on pain and function. Results: Nine articles were included in the review. Meta-analysis of 4 RCTs shows PRP significantly improves pain and function versus control. More results are significant at longer duration follow-up. Conclusions: PRP improves pain and function of osteoarthritis. Heterogeneity and risk-of-bias limit current data, requiring more RCTs to determine any regenerative potential of PRP. Prospero Systematic Review Registration Number: 136582.
1. Introduction
Osteoarthritis is the most common form of degenerative joint dis- ease and the leading cause of disability in elderly populations. In 2012, approximately 52.5 million (22.7%) adults in the United States carried a diagnosis of osteoarthritis. As the elderly population grows, this in- cidence is expected to increase.1–3 In addition to the health implica- tions, osteoarthritis is the second most costly condition in the nation, with medical expenditures reaching an excess of $16.5 billion yearly.1–4
Healthcare costs and high incidence make this degenerative condition one of the most important chronic conditions in the world.
Osteoarthritis is the breakdown of joint cartilage and its underlying bone resulting in pain, stiffness, and a loss of joint function. Some joints experience osteoarthritis as a normal process of aging,5 while other joints such as the ankle predominately experience osteoarthritis sec- ondary to trauma that exposes subchondral bone.6 The size of the os- teochondral lesion not only correlates to pain, but predisposes to os- teoarthritis.7
On a molecular level, hyaline cartilage erosion and an imbalance of pro- and anti-inflammatory cytokines, such as interleukin-1β (IL-1β) and matrix metalloproteinases (MMPs), cause synovitis. Repetitive mechanical stress results in the remodeling of subarticular bone,
osteophyte formation, and capsular swelling which leads to the clinical sequelae of osteoarthritis with both the incidence and severity being affected by risk factors including genetics, traumatic injury, and obe- sity.8–12 As the disease progresses, the erosion of hyaline cartilage within the joint heals poorly due to minimal intrinsic circulation and ability for regrowth or regeneration.
There are no curative medications, however, in 2019 an exciting discovery was made that the potential for regrowth or regeneration of cartilage is the greatest in the most distal cartilage, such as of the hands and feet.13 Currently, physicians and patients pursue symptomatic management including thermal modalities, topical capsaicin, non-ster- oidal anti-inflammatory drugs, and steroid injections.14 Arthroplasty (e.g. hip replacement) is profoundly effective for large joint osteoar- thritis,15–17 but surgical interventions for small joint hand and foot osteoarthritis remain meager and come at the expense of functionality (e.g. joint fusion, denervation).18,19 Therefore, interest of patients and providers in intra-articular injection of autologous growth factors, platelet-rich plasma (PRP) in particular, is an exciting option that treats pain, and also carries a possibility for enhancing chondrocyte activity that is the most pronounced in the small joints of the hand and foot.20–22 While PRP treatments have been reviewed in the context of knee and large joint osteoarthritis,21–23 no such review has been
https://doi.org/10.1016/j.jor.2020.01.037 Received 22 January 2020; Accepted 25 January 2020
∗ Corresponding author. Washington University School of Medicine, Department of Surgery, Division of Plastic and Reconstructive Surgery, 660 S. Euclid Ave, St. Louis, MO, 63110, USA.
E-mail address: aevans17@email.mmc.edu (A. Evans).
Journal of Orthopaedics 18 (2020) 226–236
Available online 28 January 2020 0972-978X/ © 2020 Professor P K Surendran Memorial Education Foundation. Published by Elsevier B.V. All rights reserved.
performed on small, distal joint osteoarthritis.
1.1. PRP preparation and mechanism
PRP is an autologous product of whole blood centrifugation which separates blood by density into cellular layers and a supernatant layer. The supernatant is further divided, often by pipetting or by a second centrifugation step, into a platelet-rich segment called platelet-rich plasma (PRP) and a platelet-poor segment termed platelet-poor plasma (PPP). PRP contains a platelet concentration 2–5 times higher than that of normal blood. Many protocols for preparing PRP exist. One re- searched variant is whether to include the leukocyte-containing buffy coat; the inclusion of this layer provides the designation leukocyte-rich (LR) PRP while the absence of leukocytes is termed leukocyte-poor (LP) PRP.24 LP-PRP is the standard preparation for osteoarthritis due to in- vitro and animal studies demonstrating that LR PRP induces more IL-1β and less chondrocyte proliferation than LP PRP.25–28 Furthermore, In- travia et al. tested LR versus LP PRP and both significantly inhibited bacterial growth when compared to normal blood culture, and had no significant difference between each other.29
The biomolecular mechanisms by which PRP functions is a topic heavily under study. The current understanding is that local stimuli induce platelet release of a subset of their cytokine and growth factor containing α-granules. In the instance of osteoarthritis, these molecules act predominately via anti-inflammatory cascades to reduce the pain of osteoarthritis.23,30 The anti-inflammatory effect of PRP includes sup- pressing the actions of the inflammatory and catabolic cytokines tumor necrosis factor α (TNF-α) and interferon-γ in endothelial cells.31 Sur- prisingly, PRP also induces molecules associated with sterile in- flammation, such as interleukin-1β (IL-1β), for which the net effect on osteoarthritis chondrocytes is a production of molecules that would ordinarily not be produced in the presence of IL-1β, such as the re- generative building blocks type II collagen and aggrecan, while still resulting in increased production of the chondroprotective hyaluronan by synoviocyte in response to IL-1β.32–34 Another growth factor, transforming growth factor β1 (TGF-β1), has an antagonistic effect to IL-1β while also increasing differentiation of mesenchymal stem cells into chondrocytes.35,36 PRP is thought to protect cartilage largely due to IGF-1 and TGF-β1, which promote cell survival and deposition of extracellular matrix.37 Vascular endothelial growth factor (VEGF) is an important influencer of angiogenesis that is found in PRP, however, its antagonist, thrombospondin (TSP1), is interestingly found in the highest physiologic concentration in platelet α-granules. The net effect of these pro- and anti-angiogenesis proteins may correct the pathologic angiogenesis found in osteoarthritis.37–40
These findings promote that PRP may mediate cartilage regenera- tion in addition to reducing pain. Therefore, this systematic review and meta-analysis aims to summarize all literature on PRP applied for the treatment of small, distal joint osteoarthritis of the hands and feet in order to investigate the therapeutic efficacy and regenerative potential of PRP.
2. Methods
This study was done in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines with the protocol ID 136582 being established prior to the conduct of the review.41
2.1. Search strategy
Independent literature searches were performed by two authors (M.I. and J.M.) of all published articles up to June 2019 utilizing: Cochrane Library, Ovid Medline, Ovid Embase, Web of Science, clinicaltrials.gov, World Health Organization Clinical Trials Registry, and EBSCO. The search was conducted in June of 2019 using the search
terms: “platelet-rich plasma” OR “platelet rich fibrin” OR “platelet-rich fibrin” OR “platelet gel” OR “autologous conditioned plasma” OR “pure platelet-rich-plasma” OR “platelets” OR platelet concentrate” OR “prp” OR “prgf” OR “acp” AND “arthritis” OR “osteoarthritis” OR “OA.” The search strategy was designed and altered as necessary and appropriate to the different databases (Appendix). Bibliographies of included stu- dies were also searched. An additional reviewer (A.E.) assisted in the discussion of study selection in any instance of disagreement between the two reviewers. To capture all published clinical trials, both rando- mized controlled trials (RCTs) and non-randomized studies of inter- ventions (NRSI) were included. The largest cohort was included in the study if multiple publications described the same cohort. Data extrac- tion was performed by one reviewer (M.I.) using a piloted form excel spreadsheet method, with a second reviewer (A.E.) checking over 90% of the extracted data. Experts in the field of plastic & reconstructive surgery and in the application of PRP were consulted and included in the study.
2.2. Inclusion and exclusion criteria
Included studies: 1) treated patients over the age of 18, 2) used intra-articular injections of PRP, 3) treated osteoarthritis and os- teochondral lesions affecting a joint of the hand and foot, 4) had a minimum follow-up of at least 3 months, 5) were published in English.
Excluded studies: 1) were duplicates of studies or cohorts, 2) treated conditions different than osteoarthritis or osteochondral lesions, e.g. (rheumatoid arthritis, epicondylitis, carpal tunnel, plantar fasciitis), 3) treated joints other than the hand, wrist, foot, or ankle, e.g. (knee os- teoarthritis, hip osteoarthritis), 4) pending trials, 5) studies with absent baseline functional/pain data, 6) animal studies, case reports, review articles, or retrospective studies, 7) non peer-reviewed “grey” literature.
2.3. Risk of bias
Risk of Bias assessment was performed at a study and outcome level through use of the Cochrane risk-of-bias tool for randomized controlled trials. Study sources of funding and reported conflicts of interest were recorded.
2.4. Outcomes
The primary outcome compared between studies was an assessment of the efficacy of PRP in treating pain using a visual analog scale (VAS) for pain.26,42–49 Secondary outcomes included adverse reactions, radiographic imaging of the joint space, patient satisfaction,42,48,49 and measures of joint function using: Foot and Ankle Disability Index,42
Japanese Society for Surgery of the Foot (JSSF) ankle/hindfoot scale, the Self-Administered Foot Evaluation Questionnaire (SAFE-Q),43
American Orthopaedic Foot & Ankle Society scale (AOFAS),44,45 Visual Analog Scale (VAS) for function,49 Mayo Wrist Score,26 Disabilities of the Arm, and Shoulder and Hand (DASH).26,47
2.5. Statistical data analysis and synthesis
RevMan 5.3.5 (Cochrane Collaboration) software package was uti- lized for all statistical analysis in this study. Only RCTs were included in the meta-analysis. Dichotomous variables were presented as odds ratios with a 95% CI. To incorporate the heterogeneity between studies, the authors calculated I2 and I2 > 50% was considered to be high hetero- geneity and warranted investigation of study details contributing to heterogeneity. Random-effects model was chosen. Data on pain and function were grouped as either short-term, defined as patient follow- up visits taking place less than 6 months after final treatment, and long- term, defined as patient follow-up visits taking place at 6 months or more after final treatment. In the instance that no significant difference was found between treatment and control, an analysis was performed
A. Evans, et al. Journal of Orthopaedics 18 (2020) 226–236
227
comparing treatment to the baseline measurements of the treatment group.
3. Results
3.1. Literature search
Six thousand two hundred and thirty-six results were identified by our search strategy. After removal of duplicates, there were 3869 un- ique records screened by title and abstract. 12 articles underwent full- text review and of which 2 were excluded for being pending studies, and 1 was excluded being a duplicate cohort. Therefore, 9 studies were included in the systematic review, 4 of which were included in the meta-analysis.26,42–49 A PRISMA flow-chart is included in Fig. 1.
3.2. Study characteristics and findings
Study characteristics and findings are summarized in Table 1. Of the 9 included studies, 4 were RCTs,44–46,49 and 5 were case series.26,42,43,47,48 All included studies were published between 2014 and 2019.4 studies were conducted in Europe,26,42,46,47 4 in Asia,43–45,49 and 1 in North America.48
Results included the efficacy of intra-articular PRP injections for osteoarthritis of the hand,26,46,47 ankle,42,43 and for talar osteochondral lesions,44,45,49 and Sampson et al. examined the effects of PRP on multiple joints including the ankle.48 Controls included intra-articular hyaluronic acid (HA),44,49 saline,44 and corticosteroids.46 One study utilized a control of surgery without injections in their examination of PRP as an adjunct to surgery.44 Diagnosis and grading of osteoarthritis was established using joint-appropriate radiographic criteria and
clinical presentation (Table 1). Table 2 summarizes the alternative methods for PRP preparation and administration between studies. 7 studies reported using LP-PRP, and 2 studies did not report on the leukocyte status of the PRP.44,45 2 studies activated PRP with calcium chloride,43,49 and the mean number of treatments was 2 (range: 1–4) separated by 1–2 weeks.
3.3. Risk of Bias Assessment
Cochrane risk of bias analysis (Fig. 2) of the RCTs demonstrated that 3 studies had a high risk of bias,45,46,49 and 1 study had a low risk of bias.44 All studies reported on conflicts of interest or sources of funding, and only 1 study reported having an author who is an industry-related expert advisor.26
3.4. Meta-analysis
Our meta-analysis includes 4 RCTs and shows that PRP effectively improves pain and function when measured at both short-term follow- up defined as fewer than 6 months post-treatment, and at long-term follow-up, defined as 6 months or longer since treatment. For im- proving function, when compared to control, the results show that PRP is superior to control in improving function at long-term follow-up (Fig. 3 p = 0.0004) and short-term follow-up (Fig. 4 p < 0.02). For improving pain, when compared to control, PRP is superior to control at long-term follow-up (Fig. 5 p < 0.01). Although the improvement of pain from PRP treatment was not significantly different from control at short-term follow-up (Fig. 6 p < 0.51), there was still a significant improvement following treatment with PRP compared to the baseline values at the time of treatment (Fig. 7 p < 0.00001). Significant
Fig. 1. PRISMA Flow Chart of the Literature Search. This figure details the literature search of 7 databases from the inception of the database until through May 31, 2019. 6236 records were screened, including 3869 unique records, 9 of which were included in the systematic review, and 4 were included in the meta-analysis.
A. Evans, et al. Journal of Orthopaedics 18 (2020) 226–236
228
T ab
le 1
St u d y d et ai ls
an d fi n d in gs .
A u th or , Y ea r
St u d y T yp
e, C oh
or t Si ze
C on
tr ol
O st eo
ar th ri ti s
C la ss ifi ca ti on
O u tc om
es Im
p ro ve
m en
ts at
Fo ll ow
-u p
M al ah
ia s et
al .4 6 2 0 1 8
R C T , n =
3 3
M et h yl p re d n is ol on
e w it h li d oc
ai n e (1 7
p at ie n ts )
G ra d e IV
E at on
an d Li tt le r
V A S p ai n : Im
p ro ve
d (p
< 0 .0 5 )
Q D A SH
: Im
p ro ve
d (p
< 0 .0 5 )
P at ie n t Sa
ti sf ac ti on
: Im
p ro ve
d (p
< 0 .0 5 )
A d ve
rs e E ff ec ts : N on
e oc
cu rr ed
C om
p ar ed
to co
n tr ol : N o ch
an ge
at 3 m on
th s, si gn
ifi ca n tl y
im p ro ve
d at
1 2 m on
th s
M ay
ol y et
al .4 7 2 0 1 9
C as e- se ri es , n =
3 –
G ra d e IV
K el lg re n La
w re n ce
V A S p ai n : Im
p ro ve
d D A SH
: Im
p ro ve
d P R W E : Im
p ro ve
d P at ie n t Sa
ti sf ac ti on
: Sa
ti sfi
ed or
V er y Sa
ti sfi
ed
Im p ro ve
d at
3 , 6 , an
d 1 2 m on
th s
Lo ib l et
al .2 6 2 0 1 6
C as e- se ri es , n =
1 0
– G ra d e II /I II /I V E at on
an d
Li tt le r
V A S p ai n : Im
p ro ve
d (p
< 0 .0 5 )
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o W ri st
Sc or e:
Im p ro ve
d (p
< 0 .0 5 )
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N o ch
an ge
D A SH
: N o ch
an ge
A d ve
rs e E ff ec ts : 1 au
to -r es ol vi n g w ri st
ga n gl io n
Si gn
ifi ca n tl y im
p ro ve
d at
3 an
d 6 m on
th s
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al .4 8 2 0 1 6
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1 2 5
(a n kl e n =
6 )
– G ra d e II I or
IV K el lg re n
La w re n ce
V A S p ai n : Im
p ro ve
d P at ie n t Sa
ti sf ac ti on
: m ed
ia n 9 .0 /1
0 .0
A d ve
rs e E ff ec ts : N on
e oc
cu rr ed
Fo ll ow
-u p m ea n 1 4 8 d ay
, m in im
u m
5 6 d ay
M ei -D
an et
al .4 9 2 0 1 2
R C T , n =
3 0
H ya
lu ro n ic
A ci d (1 5 p at ie n ts )
G ra d e 1 /2
a/ 2 b/
3 Fe
rk el
V A S p ai n : Im
p ro ve
d V A S st iff n es s:
Im p ro ve
d (p
< 0 .0 5 )
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p ro ve
d (p
< 0 .0 5 )
A H FS
: Im
p ro ve
d (p
< 0 .0 5 )
A d ve
rs e E ff ec ts : 1 p at ie n t re p or te d m il d p ai n
re so lv in g sp on
ta n eo
u sl y by
w ee k 3
Si gn
ifi ca n tl y im
p ro ve
d as
co m p ar ed
to co
n tr ol
at 4 ,1
2 ,a
n d
2 8 w ee ks
G ör m el i et
al .4 4 2 0 1 5
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4 0
H ya
lu ro n ic
ac id
(1 4 p at ie n ts ), Sa
li n e (1 3
p at ie n ts )
G ra d e II /I II /I V H ep
p le
V A S p ai n : Im
p ro ve
d (p
< 0 .0 5 )
A O FA
S: Im
p ro ve
d (p
< 0 .0 5 )
P at ie n t Sa
ti sf ac ti on
: 6 1 .5 %
sa ti sfi
ed A d ve
rs e E ve
n ts : N on
e re p or te d
Si gn
ifi ca n tl y im
p ro ve
d at
p os to p ti m e as
co m p ar ed
to co
n tr ol , im
p ro ve
d p at ie n t sa ti sf ac ti on
at 1 ye
ar
G u n ey
et al .4 5 2 0 1 6
R C T , n =
5 4
M ic ro fr ac tu re
(1 9 p at ie n ts ), M os ai cp
la st y
(1 3 p at ie n ts )
G ra d e II /I II /I V H ep
p le
V A S P ai n : Im
p ro ve
d (p
< 0 .0 5 )
A O FA
S: Im
p ro ve
d (p
< 0 .0 5 )
FA A M : A bs en
t ba
se li n e d at a;
n o in te rg ro u p
d iff er en
ce s at
en d p oi n t
N o d iff er en
ce s be
tw ee n gr ou
p s at
la st
fo ll ow
-u p m ed
ia n 4 2
m on
th s (r an
ge : 1 2 –8
4 )
Fu ka
w a et
al .4 3 2 0 1 7
C as e- se ri es , n =
2 0
– St ag
e 2 /3
a/ 3 b/
4 T an
ak a-
T ak
ak u ra
V A S p ai n : Im
p ro ve
d (p
< 0 .0 5 )
JS SF
A n kl e/ H in d fo ot
Sc al e:
Im p ro ve
d (p
< 0 .0 5 )
SA FE
-Q : Im
p ro ve
d (p
< 0 .0 5 )
A d ve
rs e E ve
n ts : 1 p at ie n t h ad
m il d p ai n an
d sw
el li n g re so lv ed
w it h in
2 d ay
s
Si gn
ifi ca n tl y im
p ro ve
d V A S an
d JS
SF sc or es
at 4 , 1 2 , an
d 2 4 w ee ks .
Si gn
ifi ca n tl y im
p ro ve
d SA
FE -Q
at 1 2 w ee ks .
R ep
et to
et al .4 2 2 0 1 7
C as e- Se
ri es , n =
2 0
– St ag
e 3 /4
K el lg re n
La w re n ce
V A S p ai n : Im
p ro ve
d (p
< 0 .0 5 )
FA D I: Im
p ro ve
d (p
< 0 .0 5 )
P at ie n t Sa
ti sf ac ti on
: 8 0 %
sa ti sfi
ed A d ve
rs e E ve
n ts : N on
e re p or te d
Si gn
ifi ca n tl y im
p ro ve
d V A S an
d FA
D I at
m ea n 1 8 m on
th fo ll ow
-u p (r an
ge : 1 2 –3
0 )
R C T : R an
d om
iz ed
C on
tr ol le d C li n ic al
T ri al . V A S:
V is u al
A n al og
Sc al e.
D A SH
: D is ab
il it ie s of
A rm
an d Sh
ou ld er . A H FS
: A n kl e- H in d fo ot
Sc al e.
FA A M : Fo
ot an
d A n kl e A bi li ty
M ea su re . A O FA
S: A m er ic an
O rt h op
ae d ic
Fo ot
an d A n kl e So
ci et y sc or in g sy st em
. JS
SF : Ja p an
es e So
ci et y fo r Su
rg er y of
th e Fo
ot . SA
FE -Q
: Se
lf -A d m in is te re d Fo
ot E va
lu at io n Q u es ti on
n ai re . FA
D I: Fo
ot an
d A n kl e D is ab
il it y In d ex .
A. Evans, et al. Journal of Orthopaedics 18 (2020) 226–236
229
T ab
le 2
P R P p re p ar at io n an
d ad
m in is tr at io n .
A u th or , Y ea r
A p p li ca ti on
Si te
P la te le t C on
ce n tr at io n vs
B as el in e
Le u ko
cy te
St at u s
N u m be
r of
T re at m en
ts In je ct io n In te rv al
(d ay
s) A p p li ca ti on
M et h od
P la te le t
A ct iv at io n
C en
tr if u ga
ti on
P ro ce d u re
M al ah
ia s et
al .4 6 2 0 1 8
C M C jo in t
2 .6
Le u ko
cy te -p oo
r 2
1 5
U lt ra so u n d gu
id ed
– 1 st
ce n tr if u ga
ti on
: 3 1 0 0 rp m
2 n d ce n tr if u ga
ti on
: 3 1 0 0 rp m
T ot al
ti m e ce n tr if u ge
d : 1 0 m in
M ay
ol y et
al .4 7 2 0 1 9
R ad
io ca rp al
jo in t
2 0 .0 4 %
( ±
0 .0 4 % )
Le u ko
cy te s
1 –
X -r ay
gu id ed
P R P in je ct ed
im m ed
ia te ly
af te r m ic ro -f at
in je ct io n
– 3 2 0 0 rp m
fo r 1 0 m in
Lo ib l et
al .2 6 2 0 1 6
T M C jo in t
2 .4
Le u ko
cy te -r ed
u ce d
2 1 4
Fl u or os co
p ic
gu id an
ce –
1 5 0 0 rp m
fo r 4 m in
Sa m p so n et
al .4 8 2 0 1 6
A n kl e,
kn ee , h ip , ce rv ic al
sp in e,
sh ou
ld er
4 .2
Lo w
le u ko
cy te
1 –
B on
e m ar ro w
co n ce n tr at e w as
in je ct ed
in tr a-
ar ti cu
la r 8 w ee ks
be fo re
P R P
– 1 st
ce n tr if u ga
ti on
: 2 8 0 0 rp m
fo r
1 0 m in
2 n d ce n tr if u ga
ti on
: 3 4 0 0 rp m
fo r
6 m in
M ei -D
an et
al .4 9 2 0 1 2
T al u s
2 –3
N o Le
u ko
cy te s
3 1 4
– C al ci u m
C h lo ri d e
6 4 0 g fo r 8 m in
G ör m el i et
al .4 4 2 0 1 5
T al u s
5 .2
N ot
R ep
or te d
1 –
P R P in je ct ed
2 4 –3
6 h p os t- m ic ro fr ac tu re
at ti m e of
H em
ov ac
d ra in
re m ov
al –
–
G u n ey
et al .4 5 2 0 1 6
T al u s
5 .4
N ot
R ep
or te d
1 –
P R P in je ct ed
6 –2
4 h p os t- m ic ro fr ac tu re
at ti m e
of H em
ov ac
d ra in
re m ov
al –
–
Fu ka
w a et
al .4 3 2 0 1 7
A n kl e
5 .1
Le u ko
cy te
P oo
r 3
1 4
U lt ra so u n d gu
id ed
C al ci u m
ch lo ri d e
1 st ce n tr if u ga
ti on
:8 0 0 g fo r 5 m in
2 n d ce n tr if u ga
ti on
: 1 5 0 0 g fo r
8 m in
R ep
et to
et al .4 2 2 0 1 7
A n kl e
2 –3
Lo w
(< 1 0 0 0 le u ko
cy te s/ μL
) 4
7 –
1 st
ce n tr if u ga
ti on
: 3 5 5 0 rp m
fo r
1 2 m in
2 n d ce n tr if u ga
ti on
: 1 1 0 0 rp m
fo r
1 0 m in
3 rd
ce n tr if u ga
ti on
: 2 6 0 0 rp m
fo r
2 0 m in
C M C =
C ar p om
et ac ar p al . T M C =
T ra p ez io m et ac ar p al .
A. Evans, et al. Journal of Orthopaedics 18 (2020) 226–236
230
heterogeneity was present in the meta-analysis of pain due to the in- clusion of Malahias et al., who reported values with interquartile range, thereby the conversion to standard deviation provided an acknowl- edged source of heterogeneity.
4. Discussion
4.1. Osteoarthritis of the hand and wrist
Pain and a decline of function are the most common manifestations of osteoarthritis in the small joints of the hands and wrists. As in- flammation and degeneration progresses, patients develop joint defor- mity and debilitating stiffness. Symptomatic control with NSAIDs and intra-articular corticosteroid injections has been the mainstay of treat- ment, but it fails to halt disease progression and many physicians and patients desire a method of restoring the joint integrity and function.
Focusing on potential curative or restorative therapies, Loibl et al. in a 2016 small pilot study of ten patients used two injections of PRP into the trapeziometacarpal (TMC) joint over four weeks to treat patients with osteoarthritis. They found a significant (p < 0.05) improvement
in both VAS pain and MAYO wrist scores, however, no improvement in functional DASH scores at six months of follow-up.26 These results are supported by a small 2019 study by Mayoly et al. showing that in three patients with severe osteoarthritis (Kellgren-Lawrence stage four), one PRP and mixed micro-fat preparation injection into the wrist reached a Minimally Clinically Important Difference (MCID) for DASH score in all three patients, and a MCID in VAS pain for two out of three patients when followed up at one year.47 Both of these studies are limited by the small sample size and a lack of control groups.50
Malahias et al. conducted a 2018 RCT with thirty-three patients with grade I-III Eaton and Littler osteoarthritis of the TMC joint, com- paring outcomes at three and twelve months between patients who received two intra-articular PRP injection two weeks apart and control patients who received two intra-articular methylprednisolone and li- docaine injections two weeks apart. While patients in the corticosteroid and anesthetic group had good relief of pain in the first weeks, at twelve month follow-up, the group that received PRP had significantly im- proved VAS, Q-DASH and subjective satisfaction with the procedure when compared to controls (p < 0.025).46
The majority of guidelines for recommended treatments at this time are supportive and conservative. Steroid injections have shown some benefit, and therefore many physicians use them as a cornerstone of their practice.51 However, while they provide symptomatic relief, there are drawbacks including a short-lasting effect and several relative contraindications including diabetes mellitus and immunosuppres- sion.52
4.2. Osteoarthritis of the foot and ankle
While estimates of the rates of osteoarthritis of the feet and ankles vary widely, a review of the literature by Murray et al. demonstrated that around 5% of adults over the age of 50 had osteoarthritis in their ankles.53 As weight bearing becomes painful, the quality of life for these patients is greatly affected. Fukawa et al., in a case series of 20 patients, demonstrated the efficacy of three PRP injections into the ankles se- parated by two-week intervals. The patients had significantly improved pain and function scores by JSSF, VAS and SAFE-Q (P = 0.04) at 24 weeks post treatment, although pain reduction peaked at 12 weeks.43
When comparing PRP versus HA injections, a 2012 RCT found that PRP was significantly better than HA for treatment of osteochondral lesions of the talus, with superior improvement in pain and function at 6 months.49 A 2017 retrospective study by Repetto et al. found that at 17 months, patients who received four intra-articular PRP injections over the course of four weeks, had a significant reduction in VAS with a positive effect on function (p < 0.001), and 80% of patients were satisfied or very satisfied.42
The effects of PRP have also been evaluated in patients who have had surgery. Two studies published examined the effects of PRP in patients who received microfracture surgery of the talus. In 2015, Guney et al. published a RCT containing 35 patients that showed intra- articular PRP provided improvement in functional status (p = 0.001) and VAS pain (p = 0.001) at 16 months, despite having controls who had significantly less pain at baseline (p = 0.014).54 Görmeli et al., in
Fig. 2. Cochrane Risk of Bias Assessment of Randomized Controlled Trials. Four studies assessed for bias included 3 studies with high risk of bias, and 1 study with low risk of bias.
Fig. 3. Random effects forrest plot comparing PRP and control for function at long-term follow-up.
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2015, in a RCT of 40 patients, also examined PRP after microfracture repair of talar osteochondral lesions, where they compared adjunct PRP versus HA versus saline intra-articular injections and found that PRP resulted in the greatest subjective improvement in functional status in addition to the greatest reduction in VAS pain (p < 0.005) at average 15-month follow-up.44
Other attempts at using PRP in conjunction with biologic molecules include a 2016 study by Sampson et al. who showed that in 125 pa- tients, eight weeks after initial injection of autologous bone marrow aspirate, PRP injection resulted in a significant decrease in VAS pain scores at twenty weeks follow-up. However, the effect was less pro- nounced in non-weight bearing joints than in weight-bearing joints.48
4.3. Cartilage regeneration
Chondrocyte expression of ribonucleic acid (RNA) and proteins varies both by the presence of osteoarthritis pathology as well as by the region of the body.13 The reparative and regenerative potential of a cartilaginous joint is position-dependent, with the small joints of the hands and feet having the most potential.13 Although many studies included pre-treatment diagnostic imaging such as ultrasound, X-ray, CT scan, and MRI, there were no studies utilizing a post-treatment imaging. As such, further clinical trials are needed to examine whether PRP produces a measurable regeneration of cartilage or a cessation to cartilage degeneration.
The current evidence provided by our meta-analysis, whereby comparison of PRP to control was superior in reducing pain only in long-term follow-ups, lends to provide support to the idea that the components of PRP may stimulate chondrocyte activity to provide a regenerative effect on the pathology of the joint.
Future studies investigating a regenerative potential of PRP on cartilage should bear in mind that multiple treatments appear to be preferred for providing additive benefits when treating small joint os- teoarthritis.26,42,43,46,49 When PRP is utilized in different applications, such as facial skin rejuvenation, skin thickness increases ranged from 10 to 290 μm as measured on ultrasound,55,56 optical coherence tomo- graphy,57 and biopsy.58,59 Therefore, when examining the effect on cartilage, high resolution imaging systems will likely be needed to de- termine whether PRP produces a measurable effect on cartilage re- generation. Studies show benefits at 1 and 2 months after the final treatment, and the effects may continue to increase months after treatment.55,57 Therefore, long-term follow-up of the patients in future
trials is needed.
4.4. Protocols for PRP preparation and injection
Across the fields of PRP application, PRP has shown efficacy despite significant variability in centrifugation methods. Small joint osteoar- thritis treatments have maintained statistical and clinical significance whether the PRP protocol calls for 1–3 centrifugations for times ranging from 4 to 42 min. Loibl et al. had the least intensive centrifugation protocol consisting of a single 4-min centrifugation at 1500 rpm, however, they disabled the brake on their centrifuge in an effort to enhance their leukocyte reduction for LP PRP.26 Of the 7 studies that reported on leukocyte counts, 100% prepared LP PRP which is con- sistent with other reviews on PRP used to treat large joint or knee os- teoarthritis.21,23
Due to the heterogeneity of PRP preparations protocols, there is an incompletely defined range at which PRP remains effective in reducing pain and increasing joint function. Most studies have platelet con- centrations of two to five times greater than baseline which has been shown to have optimal effects as excessive platelet concentration can inhibit cell function.24,60,61 Additionally, although many studies use multiple PRP injections, there is debate for whether multiple PRP in- jections result in better outcomes compared to a single injection.62 Due to the short half-lives of many beneficial growth factors in PRP, it is theorized that multiple injections are needed.37,63,64 In a 2017 RCT with 162 patients, Görmeli et al. demonstrated that multiple PRP in- jections significantly improved (p < 0.05) functional and pain scores at 6-month follow-up compared with a single PRP injection or HA for early knee osteoarthritis only.65 Alternatively, a 2013 RCT of 78 pa- tients by Patel et al. did not find a difference between one injection of PRP and two injections, however, this study used a concentration three times greater than is standard which may have confounded the re- sults.66 The use of single versus multiple PRP injections for the treat- ment of osteoarthritis lacks consensus on determining an optimal PRP dosage and concentration.
4.5. Confounding effects of severity
While many studies have demonstrated that PRP is more effective in early stages compared to late stages of osteoarthritis,43,65,66 other stu- dies looked exclusively at the effects of PRP on early osteoarthritis, limiting the amount of evidence for a comparison.46,67 Although PRP is
Fig. 4. Random effects forrest plot comparing PRP and control for function at short-term follow-up.
Fig. 5. Random effects forrest plot comparing PRP and control for pain at long-term follow-up.
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demonstrably effective at treating symptoms of both early and late osteoarthritis via anti-inflammatory mechanisms, it has been proposed that patients with a lower degree of cartilage injury have improved clinical outcomes due to the higher prevalence of chondrocytes and other living cells that are able to respond to growth factors in PRP.65
4.6. Study limitations
This study is limited by a low number of RCTs published in litera- ture on treatment of small joint osteoarthritis, small study sample sizes, variable pathologies and grades of pathologies, heterogeneous PRP protocols and treatment evaluation methods, and non-blinded RCT study designs. Additionally, our meta-analysis of pain is limited by significant heterogeneity between the included studies. An additional limitation exists due to reporting bias of published studies.
5. Conclusion
The past decade has seen an expanding interest in applying PRP for the treatment of various musculoskeletal disorders due to its re- generative potential and bioactive factors which promote resolution of pain and tissue healing. The growing body of evidence demonstrates the utility of PRP in healing cartilage defects, promoting stem cell proliferation, and preventing chondrocyte and ECM degradation in the treatment of osteoarthritis. Our meta-analysis of RCTs shows that PRP effectively improves both pain and function in patients with small joint osteoarthritis. The data suggests that PRP may be superior to other intra-articular injections, and that the superiority of PRP in improving pain and function is magnified as the duration of follow-up increases. Evidence from a limited number of case series suggests beneficial use of
PRP for the treatment of osteoarthritis pain in low grade osteoarthritis, and the RCTs reviewed indicate the benefit of PRP after surgical repair of the ankle. Larger RCTs with less heterogeneity and less risk of bias are needed to elucidate the effectiveness of intra-articular PRP injec- tions, to make PRP a more convincing treatment option, and to de- lineate appropriate indications and standardized protocols.
Disclosures
The authors report no proprietary or commercial interest in any product mentioned or concept discussed in this article.
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
CRediT authorship contribution statement
Adam Evans: Methodology, Validation, Formal analysis, Investigation, Writing - original draft, Writing - review & editing, Visualization, Project administration. Maryo Ibrahim: Formal analysis, Investigation, Resources, Writing - original draft, Visualization. Rand Pope: Validation, Writing - review & editing. James Mwangi: Investigation. Mina Botros: Formal analysis, Resources, Writing - ori- ginal draft, Writing - review & editing. Shepard P. Johnson: Writing - review & editing. Salam Al Kassis: Conceptualization, Methodology, Supervision, Project administration.
Declaration of competing interest
None.
Appendix. Search Strategy
Cochrane Database Search Search Num-
ber Search Terms Results
22 #20 AND #21 1463 21 (OR #1-#16) 131214 20 (OR #17-#19) 1130 19 ((platelet-rich plasma) OR (platelet rich fibrin) OR (platelet-rich fibrin) OR (platelet gel) OR (autologous conditioned plasma) OR (prp) OR (prf) OR
(prgf) OR (acp) OR (pure platelet-rich-plasma) OR (platelets)) (Word variations have been searched) 28207
18 MeSH descriptor: [Platelet-Rich Fibrin] explode all trees 42 17 MeSH descriptor: [Platelet-Rich Plasma] explode all trees 374
Fig. 6. Random effects forrest plot comparing PRP and control for pain at short-term follow-up.
Fig. 7. Random effects forrest plot comparing PRP and baseline values of the PRP group for pain at short-term follow-up.
A. Evans, et al. Journal of Orthopaedics 18 (2020) 226–236
233
16 MeSH descriptor: [Foot Bones] explode all trees 254 15 MeSH descriptor: [Foot] explode all trees 1559 14 MeSH descriptor: [Visual Analog Scale] explode all trees 659 13 MeSH descriptor: [Hand Bones] explode all trees 141 12 MeSH descriptor: [Forefoot, Human] explode all trees 191 11 MeSH descriptor: [Joints] explode all trees 7656 10 MeSH descriptor: [Thumb] explode all trees 170 9 MeSH descriptor: [Hand] explode all trees 2525 8 MeSH descriptor: [Carpometacarpal Joints] explode all trees 38 7 MeSH descriptor: [Injections, Intra-Articular] explode all trees 1195 6 MeSH descriptor: [Arthritis] explode all trees 13494 5 MeSH descriptor: [Chondrogenesis] explode all trees 6 4 MeSH descriptor: [Cartilage, Articular] explode all trees 266 3 MeSH descriptor: [Joint Capsule] explode all trees 287 2 MeSH descriptor: [Osteoarthritis] explode all trees 6385 1 (Osteoarthritis) OR (synovium) OR (articular cartilage) OR (synovial joint) OR (cartilage) OR (chondrocyte) OR (chondrogenesis) OR (arthritis) OR
(joint capsule) OR (intra-articular) OR (CMC) OR (MCP) OR (carpal) OR (hand) OR (wrist) OR (thumb) OR (pollex) OR (pollicis) OR (finger) OR (finger*) OR (carpometacarpal) OR (metacarpophalangeal) OR (phalange) OR (phalanx) OR (phalan*) OR (metacarp*) OR (metacarpus) OR (knuckle) OR (digit) OR (digital) OR (basal joint) OR (basal-joint) OR (carpo*) OR (trapeziometacarpal) OR (synovitis) OR (interphalangeal) OR (metatarsus) OR (hallux) OR (hallucis) OR (toe) OR (toes) OR (tarsal) OR (PIP) OR (DIP) OR (tarsometatarsal) OR (radiocarpal) OR (radius) OR (ulna) OR (ankle) OR (tarsus) OR (Rhizarthrosis) OR (VAS) OR (Eaton-Littler) OR (Michigan hand) OR (MHQ) OR (Mayo wrist) OR (distal metacarp*) OR (metatars*) OR (distal metacarp*) OR (scaphoid) OR (lunate) OR (pisiform) OR (trapezium) OR (trapezoid) OR (capitate) OR (hamate) OR (Ankle OA scale) OR (degenerative) OR (Disabilities of the Arm, Shoulder) OR (Kellegren Lawrence) OR (enthesitis) OR (enthesis) OR (enthesopathy)
126631
Ovid Medline Database Search
Search Num- ber
Search Terms Results
25 10 and 23 and 24 1178 24 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 or 22 or 1 or 2 or 3 or 4 or 5 1296025 23 1 or 2 or 3 or 4 or 5 or 11 or 12 or 13 415279 22 exp Carpometacarpal Joints/ 708 21 exp Hand Bones/ 11400 20 exp Hand/ 82786 19 exp Thumb/ 8748 18 exp Forefoot, Human/ 14721 17 exp visual analog scale/ 2467 16 exp Foot/ 48868 15 exp Foot Bones/ 16920 14 (CMC or MCP or carpal or hand or wrist or thumb or pollex or pollicis or finger or finger* or carpometacarpal or metacarpophalangeal or phalange or
phalanx or phalan* or metacarp* or metacarpus or knuckle or digit or basal joint or basal-joint or carpo* or trapeziometacarpal or interphalangeal or metatarsus or hallux or hallucis or toe or toes or tarsal or tarsus or Rhizarthrosis or visual analog or VAS or Eaton-Littler or Michigan hand or MHQ or Mayo wrist or distal metacarp* or metatars* or distal metacarp* or unl* or scaphoid or lunate or pisiform or trapezium or trapezoid or capitate or hamate or Ankle OA scale or degenerative or Disabilities of the Arm, Shoulder or Kellegren Lawrence or enthesitis or enthesis or enthesopathy).mp.
1141084
13 exp Arthritis/ 246941 12 exp Osteoarthritis/ 58777 11 (Osteoarthritis or arthritis or chondrogenesis or synovitis).mp. 286379 10 6 or 7 or 8 or 9 157815 9 exp Platelet Activation/ 47198 8 exp Platelet-Rich Plasma/ 3557 7 exp Platelet-Rich Fibrin/ 197 6 (platelet-rich plasma or platelet rich fibrin or platelet-rich fibrin or platelet gel or autologous conditioned plasma or prp or prf or prgf or acp or pure
platelet-rich-plasma or platelets or platelet concentrate).mp. 140322
5 exp Joint Capsule/ 27673 4 exp Chondrogenesis/ 4734 3 exp Cartilage, Articular/ 27883 2 exp Injections, Intra-Articular/ 7442 1 (synovium or articular cartilage or synovial joint or cartilage or joint capsule or intra-articular).mp.
[mp = title, abstract, original title, name of substance word, subject heading word, floating sub-heading word, keyword heading word, organism supplementary concept word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms]
Ovid Embase Database Search
Search Num- ber
Search Terms Results
25 10 and 23 and 24 1839 24 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 or 22 or 1 or 2 or 3 or 4 or 5 1602385 23 1 or 2 or 3 or 4 or 5 or 11 or 12 or 13 593085 22 exp Carpometacarpal Joints/ 1802 21 exp Hand Bones/ 13233 20 exp Hand/ 73177 19 exp Thumb/ 8712 18 exp Forefoot, Human/ 4311 17 exp visual analog scale/ 77170 16 exp Foot/ 53488 15 exp Foot Bones/ 19027
A. Evans, et al. Journal of Orthopaedics 18 (2020) 226–236
234
14 (CMC or MCP or carpal or hand or wrist or thumb or pollex or pollicis or finger or finger* or carpometacarpal or metacarpophalangeal or phalange or phalanx or phalan* or metacarp* or metacarpus or knuckle or digit or basal joint or basal-joint or carpo* or trapeziometacarpal or interphalangeal or metatarsus or hallux or hallucis or toe or toes or tarsal or tarsus or Rhizarthrosis or visual analog or VAS or Eaton-Littler or Michigan hand or MHQ or Mayo wrist or distal metacarp* or metatars* or distal metacarp* or unl* or scaphoid or lunate or pisiform or trapezium or trapezoid or capitate or hamate or Ankle OA scale or degenerative or Disabilities of the Arm, Shoulder or Kellegren Lawrence or enthesitis or enthesis or enthesopathy).mp.
1422375
13 exp Arthritis/ 434746 12 exp Osteoarthritis/ 119919 11 (Osteoarthritis or arthritis or chondrogenesis or synovitis).mp. 432615 10 6 or 7 or 8 or 9 158655 9 exp Platelet Activation/ 26727 8 exp Platelet-Rich Plasma/ 10937 7 exp Platelet-Rich Fibrin/ 502 6 (platelet-rich plasma or platelet rich fibrin or platelet-rich fibrin or platelet gel or autologous conditioned plasma or prp or prf or prgf or acp or pure
platelet-rich-plasma or platelets or platelet concentrate).mp. 146829
5 exp Joint Capsule/ 3370 4 exp Chondrogenesis/ 9898 3 exp Cartilage, Articular/ 26990 2 exp Injections, Intra-Articular/ 6194 1 (synovium or articular cartilage or synovial joint or cartilage or joint capsule or intra-articular).mp.
[mp = title, abstract, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword, floating subheading word, candidate term word]
164182
Clincialtrials.gov Database
Total Results: 507
Condition or disease: Platelet rich plasma OR platelet rich fibrin OR platelet gel OR autologous conditioned plasma OR prp OR prf OR prgf OR acp OR platelet concentrate OR platelet rich growth factor or platelet activation OR thrombocyte rich plasma
Other terms: osteoarthritis OR thumb OR first carpometacarpal joint OR rhizarthrosis OR basal joint OR carpometacarpal OR hand osteoarthritis OR Osteoarthritis Both Hands OR Osteoarthritis Hand OR CMC OR Basal joint OR Carpometacarpal OR platelet OR Visual Analog Pain Scale OR Eaton-Littler OR Michigan hand OR MHQ OR Mayo wrist OR distal metacarp* OR metatars* OR distal metacarp* OR unl* OR scaphoid OR lunate OR pisiform OR trapezium OR trapezoid Or capitate OR hamate OR Ankle OA scale OR degenerative OR Disabilities of the Arm, Shoulder OR Kellegren Lawrence OR enthesitis OR enthesis OR enthesopathy
Web of Science Database
Total Results: 1455
Search Num- ber
Search Terms Results
9 #8 AND #7 AND #2 1249 8 #6 OR #1 2162127 7 #3 OR #1 495870 6 #4 OR #5 2039214 5 ALL = (Visual Analog Pain Scale OR Eaton-Littler OR Michigan hand OR Mayo wrist OR distal metacarp* OR metatars* OR unl* OR scaphoid OR lunate
OR pisiform OR trapezium OR trapezoid OR hamate OR Ankle OA scale OR Kellegren Lawrence OR enthesitis OR enthesis OR enthesopathy) 564300
4 ALL = (CMC or MCP or carpal or hand or wrist or thumb or pollex or pollicis or finger or finger* or carpometacarpal or metacarpophalangeal or phalan* or metacarp* or metacarpus or knuckle or digit or basal or carpo* or trapeziometacarpal or metatarsus or hallux or hallucis or toe or toes or tarsal or tarsus or rhizarthrosis)
1521843
3 ALL = (Osteoarthritis or arthritis or chondrogenesis or synovitis) 419073 2 ALL = (platelet-rich plasma or platelet rich fibrin or platelet-rich fibrin or platelet gel or autologous conditioned plasma or prp or prf or prgf or acp or
pure platelet-rich-plasma or platelet concentrate) 62428
1 ALL = (synovium or articular cartilage or synovial joint or cartilage or joint capsule or intra-articular) 136904
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