efficacy and safety of non-pharmacological, pharmacological ...an overview of the evidence on...

1Kroon FPB, et al. RMD Open 2018;4:e000734. doi:10.1136/rmdopen-2018-000734

Review

Efficacy and safety of non-pharmacological, pharmacological and surgical treatment for hand osteoarthritis: a systematic literature review informing the 2018 update of the EULAR recommendations for the management of hand osteoarthritis

Féline P B Kroon,1 Loreto Carmona,2 Jan W Schoones,3 Margreet Kloppenburg1,4

To cite: Kroon FPB, Carmona L, Schoones Jw, et al. efficacy and safety of non-pharmacological, pharmacological and surgical treatment for hand osteoarthritis: a systematic literature review informing the 2018 update of the eULAR recommendations for the management of hand osteoarthritis. RMD Open 2018;4:e000734. doi:10.1136/rmdopen-2018-000734

► Prepublication history for this paper is available online. To view these files, please visit the journal online (http:// dx. doi. org/ 10. 1136/ rmdopen- 2018- 000734).

Received 25 May 2018Revised 28 June 2018Accepted 11 July 2018

For numbered affiliations see end of article.

Correspondence toFéline P B Kroon; f. kroon. reum@ lumc. nl

Osteoarthritis

© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

AbstrActTo update the evidence on efficacy and safety of non-pharmacological, pharmacological and surgical interventions for hand osteoarthritis (OA), a systematic literature review was performed up to June 2017, including (randomised) controlled trials or Cochrane systematic reviews. Main efficacy outcomes were pain, function and hand strength. Risk of bias was assessed. Meta-analysis was performed when advisable. Of 7036 records, 127 references were included, of which 50 studies concerned non-pharmacological, 64 pharmacological and 12 surgical interventions. Many studies had high risk of bias, mainly due to inadequate randomisation or blinding. Beneficial non-pharmacological treatments included hand exercise and prolonged thumb base splinting, while single trials showed positive results for joint protection and using assistive devices. Topical and oral non-steroidal anti-inflammatory drugs (NSAiDs) proved equally effective, while topical NSAiDs led to less adverse events. Single trials demonstrated positive results for chondroitin sulfate and intra-articular glucocorticoid injections in interphalangeal joints. Pharmacological treatments for which no clear beneficial effect was shown include paracetamol, intra-articular thumb base injections of glucocorticoids or hyaluronic acid, low-dose oral glucocorticoids, hydroxychloroquine and anti-tumour necrosis factor. No trials compared surgery to sham or non-operative treatment. No surgical intervention for thumb base OA appeared more effective than another, although in general more complex procedures led to more complications. No interventions slowed radiographic progression. in conclusion, an overview of the evidence on efficacy and safety of treatment options for hand OA was presented and informed the task force for the updated european League Against Rheumatism management recommendations for hand OA.

InTroduCTIonIn 2007, the first European League Against Rheumatism (EULAR) recommendations for

the management of hand osteoarthritis (OA) were published, based on expert opinion and an overview of the literature.1 Many proposi-tions, however, were based mainly on expert opinion, as evidence was lacking.

Despite it being a prevalent disease, for years, options to treat patients with hand OA have been limited. In search of better alternatives for symptom relief, and in hopes of finding a disease-modifying anti-osteoarthritic drug, many clinical trials have been performed in the last decade, expanding the possible range of therapeutic options. At the same time, data have become available showing that some treat-ments which were believed to be beneficial do

Key messages

What is already known about this subject? ► The first european League Against Rheumatism (eULAR) recommendations for the management of hand osteoarthritis were published in 2007, based on expert opinion and available literature at that time.

What does this study add? ► Since 2007 many new trials were published in the hand osteoarthritis field.

► This systematic literature review provides an updat-ed overview of the current evidence on efficacy and safety of non-pharmacological, pharmacological and surgical treatment options for hand osteoarthritis.

How might this impact on clinical practice? ► This systematic literature review informed the task force for the 2018 update of the eULAR recommen-dations for the management of hand osteoarthritis. on June 15, 2021 by guest. P

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2 Kroon FPB, et al. RMD Open 2018;4:e000734. doi:10.1136/rmdopen-2018-000734

RMD OpenRMD OpenRMD Open

not appear to be efficacious after all. New evidence has emerged on various therapies, including but not limited to self-management, application of thumb base splints, topical non-steroidal anti-inflammatory drugs (NSAIDs), oral corticosteroids, various intra-articular therapies and treatment with conventional and biological disease-modi-fying anti-rheumatic drugs (cs/bDMARDs), for example, hydroxychloroquine and tumour necrosis factor (TNF) inhibitors.

In light of the newly accrued data, it was therefore time to update the 2007 management recommendations. This paper presents the systematic literature review (SLR) that accompanies the update of the recommendations. The aim of this SLR was to inform the task force on the current evidence for efficacy and safety of all non-pharmacological, pharmacological and surgical treatments for hand OA.

MeTHodssearch strategyA systematic search was conducted in PubMed/MEDLINE, Embase and the Cochrane CENTRAL databases up to 6 June 2017. Additionally, conference abstracts of the EULAR, American College of Rheuma-tology (ACR) and OsteoArthritis Research Society Inter-national (OARSI) annual conferences of the last two years, and reference lists of included studies and other relevant SLRs were screened. The search strategy can be found in the online supplementary file 1. Eligible study types were randomised controlled trials (RCTs) and clin-ical controlled trials (CCTs). Observational longitudinal studies were considered to assess safety, and to assess effi-cacy of surgical interventions, but only if a comparator group was available and the number of participants per group was at least 50. Cochrane systematic reviews were also included. The following hierarchy of study design was adopted to assess the evidence for each interven-tion: Cochrane systematic reviews, RCTs, CCTs and lastly observational studies.

Research questions were formulated according to the PICO format: Participants, Interventions, Compar-ators, Outcomes.2 Studies of any non-pharmacological, pharmacological or surgical intervention in adults diag-nosed with hand OA were included. Studies including participants with other diagnoses were only eligible for inclusion if the results were presented separately for participants with hand OA. The comparator could be placebo, care-as-usual, any other non-pharmacological, pharmacological or surgical intervention, or the same intervention in a different dose, formulation, regimen or treatment duration. Studies without a comparator were excluded. Other exclusion criteria were a total number of participants in non-surgical trials


OsteoarthritisOsteoarthritisOsteoarthritis

Figure 1 Flow chart of systematic literature review. ACR, American College of Rheumatology; EULAR, European League Against Rheumatism; OARSI, Osteoarthritis Research Society International.

Pharmacological interventions were investigated in 64 studies, including one observational study. Surgical inter-ventions were assessed in 11 trials, all summarised in one Cochrane review.

non-pharmacological interventionsTable 1 presents an overview of the characteristics and RoB of the 28 studies of the most relevant non-pharma-cological interventions to inform the 2018 update of the EULAR management recommendations for hand OA. The remaining trials studied thermal modalities (n=3), manual therapy (n=3), balneotherapy (n=6), low-level laser therapy (n=4), yoga (n=1), nuclear magnetic reso-nance (n=1), magnetotherapy (n=1), leeches (n=1) and alkalinisation of diet (n=1), and are described in online supplementary tables (3.1.5, 3.1.7, 3.1.9, 3.1.11).

The studies were heterogeneous, especially with respect to type of intervention, study duration (range: 1 week to 1 year, most up to 8 weeks) and assessed outcomes. Most were RCTs (n=19), and a minority CCTs (n=3) or cross-over trials (n=6). Many studies were small: 15 trials (54%) included 60 participants or less. All studies were judged to be at high or unclear RoB, most often due to

lack of blinding. A detailed RoB assessment is presented in online supplementary tables 3.1.1-3.1.12

Table 2 presents an overview of the main results of the most relevant non-pharmacological trials for which the outcomes pain, function, fulfilment of OARSI-OMERACT criteria4 or grip strength could be assessed. Safety outcomes are presented in online supplemen-tary table 4.1. If studies were pooled, results are also presented in forest plots (online supplementary figures S1-S8).

In summary, exercise leads to beneficial effects on hand pain, function, joint stiffness and grip strength, although effect sizes are small. Few (non-severe) AEs were reported, showing a signal for increased number of AEs in participants undergoing exercise therapy, in particular increased joint inflammation and hand pain (RR 4.6 (95% CI 0.5 to 39.3); online supplementary table 4.1).6

Joint protection led to a higher proportion of partic-ipants being classified as responder to treatment according to OARSI-OMERACT criteria after 6 months, though mean AUSCAN pain and function subscales did not differ between groups.7

on June 15, 2021 by guest. Protected by copyright.

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pen: first published as 10.1136/rmdopen-2018-000734 on 11 O

ctober 2018. Dow

nloaded from

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Tab

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C

hara

cter

istic

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stu

die

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mai

n no

n-p

harm

acol

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terv

entio

ns (n

=28

stu

die

s)

Ro

BS

tud

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esig

nIn

terv

enti

on

Freq

uenc

y, d

urat

ion

(inst

ruct

ions

)N

OA

loca

tio

n, d

efini

tio

nW

om

en (%

)A

ge

(yea

rs)

Pri

mar

y o

utco

me

Exe

rcis

e

Øst

eras

et

al 2

0176

SLR

(6 R

CT,

1 C

O)

Han

d e

xerc

ise

vs n

o ex

erci

se (N

=6)

; diff

eren

t C

MC

ex

erci

se p

rogr

amm

e (N

=1)

6–12

mon

ths

534

Han

d (6

) or

CM

C (1

), A

CR

or

clin

ical

dia

gnos

isM

edia

n 90

Mea

n 60

–81

–

Join

t p

rote

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n Dzi

edzi

c et

al 2

0157

Fact

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l RC

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roup

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int

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pro

gram

me

(incl

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g sp

lints

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Ex–

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sess

ions

in 4

wee

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AC

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exe

rcis

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6364

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n p

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duc

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n,

join

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n (in

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exer

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6571

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6562

67.2

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16C

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E-L

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50.2

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No

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rven

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988

52.3

(6.4

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Ban

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al 2

0131

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CM

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54.9

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4 w

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1173

58.6

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201

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an

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ical

dia

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62.8

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AS

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(pre

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6175

63.3

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TS

plin

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hou

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CM

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9359

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an

d E

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tage

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VAS

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rven

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2090

65.1

(10.

1)

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uenc

y, d

urat

ion

(inst

ruct

ions

)N

OA

loca

tio

n, d

efini

tio

nW

om

en (%

)A

ge

(yea

rs)

Pri

mar

y o

utco

me

Stu

kste

tte

et a

l 201

427 (

A)

RC

TG

roup

-bas

ed b

oost

er s

essi

on a

fter

com

bin

atio

n p

rogr

amm

e26

Sin

gle

sess

ion,

1 y

ear

147

AC

R84

59 (8

)A

US

CA

N fu

nctio

n,

OA

RS

I-O

ME

RA

CT

resp

ond

erN

o b

oost

er s

essi

on a

fter

com

bin

atio

n p

rogr

amm

e26

1 ye

ar

Vill

afan

e 20

1328

RC

TIn

div

idua

l com

bin

atio

n p

rogr

amm

e: m

anua

l the

rap

y,

exer

cise

12 s

essi

ons

in 4

wee

ks30

CM

C, c

linic

al d

iagn

osis

an

d R

x d

amag

e90

82 (2

)VA

S p

ain

Sha

m in

terv

entio

n (n

on-t

hera

peu

tic u

ltras

ound

of t

he

thum

b r

egio

n)30

8083

(1)

Waj

on 2

0051

5R

CT

Sp

lint

(cus

tom

-mad

e, t

herm

opla

st, C

MC

)+ab

duc

tion

exer

cise

reg

imen

2 w

eeks

sp

lint

only

, 4 w

eeks

sp

lint+

exce

rcis

e; u

se fu

ll-tim

e19

CM

C, c

linic

al d

iagn

osis

an

d E

-L s

tage

I–III

7459

.7 (9

.0)

NR

Sp

lint

(cus

tom

-mad

e, t

herm

opla

st, C

MC

/M

CP

)+p

inch

exe

rcis

e re

gim

en21

8161

.2 (1

2.5)

Valu

es a

re m

ean

(SD

) or

med

ian

(min

–max

). C

olou

rs d

enot

e R

oB (g

reen

: low

, yel

low

: unc

lear

, red

: hig

h). (

A) i

ndic

ates

con

fere

nce

abst

ract

.A

CR

, Am

eric

an C

olle

ge o

f Rhe

umat

olog

y; A

DLs

, act

iviti

es o

f dai

ly li

ving

; AU

SC

AN

, Aus

tral

ian/

Can

adia

n H

and

Ost

eoar

thrit

is In

dex

; CM

C, fi

rst

carp

omet

acar

pal

join

t; C

O, c

ross

-ove

r tr

ial;

CO

PM

, Can

adia

n O

ccup

atio

nal P

erfo

rman

ce M

easu

re; D

AS

H, D

isab

ilitie

s of

the

Arm

, Sho

uld

er a

nd H

and

; DIP

, dis

tal i

nter

pha

lang

eal

join

t; E

-L, E

aton

-Litt

er; F

IHO

A, F

unct

iona

l Ind

ex fo

r H

and

Ost

eoA

rthr

itis;

IP, i

nter

pha

lang

eal j

oint

; MC

P,m

etac

arp

opha

lang

eal;

N, n

umb

er; N

R, n

ot r

epor

ted

; NR

S, n

umer

ical

rat

ing

scal

e; O

A, o

steo

arth

ritis

; RC

T, r

and

omis

ed c

ontr

olle

d t

rial;

RoB

, ris

k of

bia

s; R

x, r

adio

grap

hy; S

LR, s

yste

mat

ic li

tera

ture

rev

iew

; VA

S, v

isua

l an

alog

ue s

cale

; WA

, was

h-ou

t p

erio

d.

Tab

le 1

C

ontin

ued

On the short term, thumb base splinting did not lead to pain relief or functional improvement,8–12 though studies assessing long-term use showed that this was associated with more pain relief and improved function (online supplementary figures S1-S4).10 12 Studies assessed many different types of splints (eg, short or long, custom-made or prefabricated, neoprene or thermoplast or other material) and instructions for use (eg, during activities of daily living, at night, constantly). Only short versus long thumb base splints (ie, including only CMC joint vs both CMC and MCP joint) could formally be compared and were not associated with different clinical outcomes (online supplementary figures S5-S6).13–15 For other splint types or instructions, no consistent benefit of one over another could be identified in RCTs/CCTs or cross-over studies.16–20 A single study assessed night-time DIP splinting specifically, but did not show improvements in pain, function or pinch strength after 3 months.21

Use of assistive devices led to small improvements in function, as measured with the patient-specific Canadian Occupational Performance Measure (COPM) and the AUSCAN function subscale, but not in pain.22

Several studies assessed different combination programmes of multiple non-pharmacological inter-ventions.7 15 23–28 Three trials compared a programme including education, joint protection and hand exercises to education alone, and though no formal meta-anal-ysis could be performed, no between-group differences in pain, function or grip strength could be confirmed (online supplementary figures S7-S8).7 25 26 The other studies of combination programme were more hetero-geneous, especially in the type of intervention studied. Some reported positive effects of the combination versus non-combination interventions, especially on subjec-tive measures like pain,23 28 and not on more objective measures like hand strength,24 28 though others reported no between-group differences.15 27

Furthermore, application of heat was assessed in three heterogeneous trials, both in design and type of interven-tion (high RoB). Two studies reported improvements in, for example, pain and grip strength in the intervention group compared with control,29 30 and one cross-over trial reported no between-group differences.31 Three studies (high RoB) focused on different forms of manual therapy in elderly, severe CMC patients with OA (mean age 81.4 years) and showed positive effects on pain sensitivity and hand strength in the intervention group compared with control, both in the treated, symptomatic hand, and in the contralateral non-treated non-symptomatic hand.32–37 Finally, six studies (five high RoB, one unclear RoB) assessed different forms of balneotherapy to another active intervention,38–40 sham intervention41 42 or usual care.43 The studies comparing balneotherapy to another active intervention or to usual care all report positive effects of balneotherapy on pain, function and hand strength compared with the chosen control group.38–40 43 However, balneotherapy (mud application or mineral thermal bath) was not convincingly better than a sham intervention.41 42


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Tab

le 2

E

ffica

cy o

f mai

n no

n-p

harm

acol

ogic

al in

terv

entio

ns fo

r ha

nd o

steo

arth

ritis

from

ran

dom

ised

con

trol

led

tria

ls/c

linic

al c

ontr

olle

d t

rials

Inte

rven

tio

nC

ont

rol

Out

com

eP

arti

cip

ants

(s

tud

ies)

, nD

urat

ion

Qua

lity

of

evid

ence

Eff

ect

esti

mat

e (9

5%C

I)R

efer

ence

s; c

om

men

ts

Exe

rcis

e

Han

d e

xerc

ise

No

exer

cise

P

ain

381

(5)

12 w

eeks

GR

AD

E: l

owS

MD

−0.

27 (−

0.47

to

−0.

07)*

6; C

ochr

ane

revi

ew

Func

tion

369

(4)

12 w

eeks

GR

AD

E: l

owS

MD

−0.

28 (−

0.58

to

0.02

)*Id

em

OA

RS

I-O

ME

RA

CT

resp

ond

er30

5 (3

)12

wee

ksN

ot r

epor

ted

RR

2.8

(1.4

to

5.6)

*Id

em

Grip

str

engt

h36

2 (5

)12

wee

ksN

ot r

epor

ted

SM

D 0

.34

(−0.

01 t

o 0.

69)*

Idem

Join

t p

rote

ctio

n

Join

t p

rote

ctio

n N

o jo

int

pro

tect

ion

Pai

n25

7 (1

)26

wee

ksR

oB: h

igh

MD

−0.

79 (−

1.7

to 0

.12)

on

AU

SC

AN

p

ain

scal

e (r

ange

0–2

0)*

7; a

dju

sted

for

age,

gen

der

, soc

ial

clas

s,ce

ntre

, dis

ease

dur

atio

n

Func

tion

257

(1)

26 w

eeks

RoB

: hig

hM

D −

0.6

(−1.

9 to

1.1

) on

AU

SC

AN

fu

nctio

n sc

ale

(ran

ge 0

–36)

*Id

em

OA

RS

I-O

ME

RA

CT

resp

ond

er25

7 (1

)26

wee

ksR

oB: h

igh

OR

2.1

(1.1

to

4.0)

*Id

em

Grip

str

engt

h25

7 (1

)26

wee

ksR

oB: h

igh

MD

−0.

47 (−

1.9

to 0

.94)

kg†

Idem

Sp

lints

Thum

b s

plin

t U

sual

car

e or

no

inte

rven

tion

Pai

n22

1 (4

)4–

8 w

eeks

RoB

: hig

hM

D −

2.9

(−12

.2 t

o 6.

5) o

n 10

0 m

m V

AS

*9–

12

Pai

n13

7 (2

)13

–52

wee

ksR

oB: h

igh

MD

−17

.4 (−

25.6

to

−9.

2) o

n 10

0 m

m

VAS

*10

12

Func

tion

144

(3)

4 w

eeks

RoB

: hig

hS

MD

0.2

4 (−

0.11

to

0.60

)†8

9 12

; effe

ct e

stim

ate

bas

ed o

n tw

o tr

ials

(n=

126)

9 12

Func

tion

112

(1)

52 w

eeks

RoB

: hig

hM

D −

6.3

(−10

.9 t

o −

1.7)

on

Coc

hin

hand

fu

nctio

n sc

ale

(ran

ge 0

–90)

*12

Grip

str

engt

h95

(2)

6–8

wee

ksR

oB: h

igh

SM

D 0

.39

(−0.

35 t

o 1.

1)*

10 1

1

Grip

str

engt

h40

(1)

13 w

eeks

RoB

: hig

hM

D 0

.8 (−

3.1

to 4

.7) k

g*10

Long

thu

mb

sp

lint

(MC

P+

CM

C jo

int)

Sho

rt t

hum

b

splin

t (o

nly

CM

C

join

t)

Pai

n18

5 (3

)2–

12 w

eeks

RoB

: hig

hM

D −

0.85

(−5.

1 to

3.4

) on

100

mm

VA

S*

13–1

5; W

ajon

: res

ults

aft

er s

plin

t p

erio

d u

sed

for

poo

ling

Func

tion

146

(2)

9–12

wee

ksR

oB: h

igh

MD

1.7

(−0.

94 t

o 4.

3)†

13 1

4

DIP

sp

lint

No

inte

rven

tion

Pai

n26

(1)

12 w

eeks

RoB

: hig

hM

edia

n d

iffer

ence

0.5

(ran

ge−

7 to

3.5

, p=

0.53

) on

10 c

m V

AS

*21

; out

com

e: a

vera

ge p

ain

Func

tion

26 (1

)12

wee

ksR

oB: h

igh

No

bet

wee

n-gr

oup

diff

eren

ce21

; no

raw

dat

a p

rese

nted

Ass

isti

ve d

evic

es

Ass

istiv

e d

evic

e In

form

atio

n p

rovi

sion

P

ain

70 (1

)12

wee

ksR

oB: h

igh

MD

0.4

(−9.

8 to

10.

6) o

n 10

0 m

m V

AS

†22

; ad

just

ed fo

r b

asel

ine

Func

tion

70 (1

)12

wee

ksR

oB: h

igh

MD

−0.

3 (−

0.6

to 0

.01)

on

AU

SC

AN

fu

nctio

n sc

ale

(ran

ge 1

–5)*

22; a

dju

sted

for

bas

elin

e, C

OP

M

scor

es (p

rimar

y ou

tcom

e) a

lso

sign

ifica

nt im

pro

vem

ents

*

Co

mb

inat

ion

pro

gra

mm

e

Con

tinue

d


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Inte

rven

tio

nC

ont

rol

Out

com

eP

arti

cip

ants

(s

tud

ies)

, nD

urat

ion

Qua

lity

of

evid

ence

Eff

ect

esti

mat

e (9

5%C

I)R

efer

ence

s; c

om

men

ts

Com

bin

atio

n p

rogr

amm

e: e

duc

atio

n,

join

t p

rote

ctio

n,

exer

cise

Ed

ucat

ion

alon

e P

ain

321

(3)

12 w

eeks

RoB

: hig

hM

D 0

.40

(−0.

50 t

o 1.

3) o

n A

US

CA

N p

ain

scal

e (r

ange

0–2

0)†

7 25

26;

effe

ct e

stim

ate

bas

ed o

n on

e tr

ial (

n=15

1),2

6ad

just

ed fo

r b

asel

ine

Func

tion

321

(3)

12 w

eeks

RoB

: hig

hM

D 0

.49

(−1.

0 to

2.0

) on

AU

SC

AN

fu

nctio

n sc

ale

(ran

ge 0

–36)

*7

25 2

6; e

ffect

est

imat

e b

ased

on

one

tria

l (n=

151)

,26a

dju

sted

for

bas

elin

e

OA

RS

I-O

ME

RA

CT

resp

ond

er28

1 (2

)12

wee

ksR

oB: h

igh

OR

0.8

2 (0

.42

to 1

.6)†

7 26

; effe

ct e

stim

ate

bas

ed o

n on

e tr

ial (

n=15

1)26

Grip

str

engt

h32

1 (3

)12

wee

ksR

oB: h

igh

SM

D −

0.21

(−0.

49 t

o 0.

08)†

7 25

26;

effe

ct e

stim

ate

bas

ed o

n tw

o tr

ials

(n=

186)

25 2

6

Qua

lity

of

evid

ence

:G

RA

DE

: ver

y lo

w/lo

wR

oB: h

igh

GR

AD

E: m

oder

ate

RoB

: unc

lear

GR

AD

E: h

igh

RoB

: low

Effe

ct e

stim

ate:

No

effe

ctB

etw

een-

grou

p d

iffer

ence

*In

favo

ur o

f the

inte

rven

tion

grou

p.

†In

favo

ur o

f the

con

trol

gro

up.

AU

SC

AN

, Aus

tral

ian/

Can

adia

n H

and

Ost

eoar

thrit

is In

dex

; CM

C, fi

rst

carp

omet

acar

pal

; CO

PM

, Can

adia

n O

ccup

atio

nal P

erfo

rman

ce M

easu

re; D

IP, d

ista

l int

erp

hala

ngea

l joi

nt; i

dem

, sam

e as

ab

ove;

M

CP,

met

acar

pop

hala

ngea

l joi

nt; M

D, m

ean

diff

eren

ce; O

A, o

steo

arth

ritis

; RoB

, ris

k of

bia

s; R

R, r

isk

ratio

; SM

D, s

tand

ard

ised

mea

n d

iffer

ence

; VA

S, v

isua

l ana

logu

e sc

ale.

Tab

le 2

C

ontin

ued

Pharmacological interventionsTable 3 presents an overview of the characteristics and RoB of the 33 trials of the most relevant pharmacological interventions to inform the 2018 update of the EULAR management recommendations for hand OA. Trials not listed in table 3 studied topical capsaicin (n=1), topical salicylates (n=2), paracetamol (n=4), glucosamine (n=1), diacerhein (n=1), different herbal formulations (n=3), anti-interleukin-1 (n=1), clodronate (n=1), several types of periarticular injections (n=3), intra-articular hyalu-ronic acid (n=9), other intra-articular therapies (n=2), folate/cobalamin supplementation (n=1), apremilast (n=1), galactosaminoglycuronglycan sulfate (n=1), and pregabalin and duloxetine (n=1). A description can be found in online supplementary tables (3.2.2, 3.2.4, 3.2.6, 3.2.10, 3.2.12, 3.2.15, 3.2.17, 3.2.22).

The longest trial lasted up to 3 years, though most trials had a duration of 3 weeks. Most studies focused on clinical outcomes, while structure modification was the primary outcome of two trials.44 45 The majority were RCTs (n=30), and few were set-up as CCTs (n=1) or cross-over trials (n=2). Seven trials specifically included partic-ipants with signs of 'inflammatory OA', all investigating anti-inflammatory agents (ie, NSAIDs, glucocorticoids and anti-TNF).45–51 Compared with non-pharmacolog-ical interventions, less studies were small (n≤60; 15 trials, 45%). Twelve studies (36%) were at low RoB. Reason to judge studies to be at high or unclear RoB was most often due to problems with randomisation or blinding, and for six studies only a conference abstract was available thus RoB remained unclear. The detailed RoB assessment is presented in online supplementary (3.2.1–3.2.23).

Table 4 presents an overview of the main results of the most relevant pharmacological trials for which the outcomes pain, function, fulfilment of OARSI-OMERACT criteria4 or grip strength could be assessed. Safety outcomes are presented in online supplementary table 4.2. Forest plots of pooled results are presented in online supplementary figures S9-S20.

Topical pharmacological interventionsTopical diclofenac gel was shown to be superior to placebo in a large RCT (low RoB), leading to small improvements in pain and function, and not more AEs, after 8 weeks.52 Topical NSAIDs led to similar pain relief as oral NSAIDs,50 51 yet lower risk of any AE (RR 0.40 (95% CI 0.09 to 1.74)),50 51 gastrointestinal AEs (RR 0.64 (0.35 to 1.20)),51 severe AEs (RR 0.54 (0.17 to 1.71)),51 and withdrawals due to AEs (RR 0.15 (0.03 to 0.63)) (online supplementary table 5.2, figures S9-S11).51 Pooled safety data from two RCTs comparing topical diclofenac gel to placebo in patients with hand OA showed similar and low rates of AEs in subgroups at low versus high risk of NSAID-related AEs (ie, age ≥65 years, and with comorbid hypertension, type 2 diabetes or cere-brovascular or cardiovascular disease).53 A trial (low RoB) comparing topical ibuprofen cream to arnica cream found no between-group differences.54 Two studies (one high RoB, one unclear RoB) comparing topical NSAIDs with a


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Tab

le 3

C

hara

cter

istic

s of

stu

die

s of

mai

n p

harm

acol

ogic

al in

terv

entio

ns (n

=33

stu

die

s)

Ro

BS

tud

yD

esig

nIn

terv

enti

on

Freq

uenc

y, d

urat

ion

NO

A lo

cati

on,

defi

niti

on

Wo

men

(%)

Ag

e (y

ears

)P

rim

ary

out

com

e

Top

ical

NS

AID

s

Altm

an e

t al

200

952

RC

TTo

pic

al d

iclo

fena

c ge

l 1%

4 p

er d

ay, 8

wee

ks19

8A

CR

, Rx

KL1

–377

63.6

(10.

3)VA

S p

ain,

AU

SC

AN

, VA

S

pat

ient

glo

bal

Top

ical

pla

ceb

o cr

eam

187

7764

.7 (9

.6)

Gra

ber

et

al 1

9973

9R

CT

Top

ical

ibup

rofe

n cr

eam

3 p

er d

ay, 2

wee

ks57

AC

R o

r cl

inic

al d

iagn

osis

is

olat

ed C

MC

OA

9165

.8 (8

.6)

FIH

OA

Ber

thol

let

trea

tmen

t (lo

cal s

team

bat

h an

d

finge

r sh

ower

)D

aily

, 3 w

eeks

5986

63.2

(10.

0)

Mic

hals

en e

t al

200

892

RC

TD

iclo

fena

c ge

l 10

mg/

g2

per

day

, 4 w

eeks

16C

MC

, clin

ical

dia

gnos

is a

nd

Rx

dam

age

100

64.3

(9.1

)VA

S p

ain

Med

icin

al le

eche

sO

nce

in 4

wee

ks16

64.1

(6.4

)

Rom

ero

et a

l 201

355

RC

TTo

pic

al d

iclo

fena

c ge

l 2%

3 p

er d

ay, 4

wee

ks65

AC

R86

62 (1

0.2)

NR

Top

ical

her

bal

cre

am65

95

Talk

e et

al 1

9855

0R

CT

Top

ical

eto

fena

mat

e 10

0 m

g/g

3 p

er d

ay, 3

wee

ks30

IP, c

linic

al d

iagn

osis

, 'a

ctiv

ated

'83

64.3

(13.

5)N

R

Ora

l ind

omet

haci

n 15

0 m

g/d

ay3

wee

ks30

9063

.3 (1

1.0)

Wid

rig e

t al

200

754

RC

TTo

pic

al ib

upro

fen

crea

m 5

%3

per

day

, 3 w

eeks

99A

CR

6164

(11.

4)VA

S p

ain,

FIH

OA

Top

ical

arn

ica

crea

m 5

0%10

567

64 (1

2.0)

Zac

her

et a

l 200

151

RC

TTo

pic

al d

iclo

fena

c ge

l 1%

4 p

er d

ay, 3

wee

ks16

5IP

, clin

ical

dia

gnos

is,

'act

ivat

ed'

8660

.7 (9

.4)

VAS

pai

n im

pro

ve≥4

0%

Ora

l ib

upro

fen

1200

mg/

day

3 w

eeks

156

9063

.2 (9

.4)

Ora

l NS

AID

s

Dre

iser

et

al 1

9936

2R

CT

Ibup

rofe

n 80

0 m

g/d

ay2

wee

ks30

Rx

dam

age,

pai

n ex

acer

bat

ion

8058

.5 (1

.7)

NR

Pla

ceb

o30

9060

.3 (2

.0)

Grif

ka e

t al

200

463

RC

TLu

mira

coxi

b 2

00 m

g/d

ay4

wee

ks20

5A

CR

8262

.0 (1

2.1)

VAS

pai

n

Lum

iraco

xib

400

mg/

day

193

8361

.0 (1

2.4)

Pla

ceb

o19

683

62.7

(11.

7)

Mur

ator

e et

al 2

0046

5

(A)

RC

TK

etop

rofe

n ly

sine

sal

t 16

0 m

g/d

ay+

gluc

osam

ine+

chon

dro

itin

sulfa

te20

day

s30

Han

d, N

R10

0N

RN

R

Glu

cosa

min

e+ch

ond

roiti

n su

lfate

28

Rov

etta

et

al,2

001-

B49

CC

TD

exke

top

rofe

n-tr

omet

amol

50

mg/

day

3 w

eeks

35A

CR

, 'ac

tive

OA

'86

57.7

(3.4

)M

orni

ng s

tiffn

ess

(WO

MA

C)

No

inte

rven

tion

1963

Rov

etta

et

al, 2

001-

A48

CO

(WA

-)D

exke

top

rofe

n-tr

omet

amol

50

mg/

day

13 d

ays

36A

CR

, 'ac

tive

OA

'N

RN

RM

orni

ng s

tiffn

ess

and

p

ain

(WO

MA

C)

Par

acet

amol

100

0 m

g/d

ay

Sei

ler

1983

64R

CT

Mec

lofe

nam

ate

sod

ium

300

mg/

day

4 w

eeks

22C

linic

al d

iagn

osis

,≥1

infla

med

D

IP a

nd R

x d

amag

e95

62.5

(34–

77)

NR

Pla

ceb

o19

8465

.0 (4

9–80

)

Talk

e 19

8550

RC

TO

ral i

ndom

etha

cin

150

mg/

day

3 w

eeks

30IP

, clin

ical

dia

gnos

is,

'act

ivat

ed'

8364

.3 (1

3.5)

NR

Top

ical

eto

fena

mat

e 10

0 m

g/g

3 p

er d

ay, 3

wee

ks30

9063

.3 (1

1.0)

Zac

her

et a

l 200

151

RC

TO

ral i

bup

rofe

n 12

00 m

g/d

ay3

wee

ks15

6IP

, clin

ical

d

iagn

osis

,'act

ivat

ed'

9063

.2 (9

.4)

VAS

pai

n im

pro

ve≥4

0%

Top

ical

dic

lofe

nac

gel 1

%4

per

day

, 3 w

eeks

165

8660

.7 (9

.4)

Cho

ndro

itin

sul

fate

Con

tinue

d


http://rmdopen.bm

j.com/

RM

D O


ctober 2018. Dow

nloaded from




Ro

BS

tud

yD

esig

nIn

terv

enti

on

Freq

uenc

y, d

urat

ion

NO

A lo

cati

on,

defi

niti

on

Wo

men

(%)

Ag

e (y

ears

)P

rim

ary

out

com

e

Gab

ay e

t al

201

166

RC

TC

hond

roiti

n su

lfate

800

mg/

day

6 m

onth

s80

AC

R73

63.9

(8.5

)VA

S p

ain,

FIH

OA

Pla

ceb

o82

7663

.0 (7

.2)

Verb

rugg

en 2

0024

4R

CT

Cho

ndro

itin

pol

ysul

pha

te 5

0 m

g/d

ay

intr

amus

cula

rly3

year

s66

IP, c

linic

al d

iagn

osis

and

Rx

dam

age

9155

.2 (6

.7)

Rx

pro

gres

sion

Pla

ceb

o in

tram

uscu

larly

6497

56.1

(9.2

)

RC

TC

hond

roiti

n su

lfate

120

0 m

g/d

ay3

year

s44

IP, c

linic

al d

iagn

osis

and

Rx

dam

age

9157

.6 (7

.1)

Rx

pro

gres

sion

Pla

ceb

o48

8855

.9 (8

.9)

Intr

a-ar

ticu

lar

glu

coco

rtic

oid

s

Bah

adire

t al

200

973

RC

TG

luco

cort

icoi

d i.

a. 2

0 m

g/0.

5 m

LO

nce

20C

MC

, Rx

E-L

sta

ge II

–III

100

62.9

(9.1

)N

R

Hya

luro

nic

acid

i.a.

5 m

g/0.

5 m

L1

per

wee

k, 3

wee

ks20

60.8

(7.3

)

Fuch

s et

al 2

0067

4R

CT

Glu

coco

rtic

oid

i.a.

10

mg/

1 m

L1

per

wee

k, 3

wee

ks28

CM

C, c

linic

al d

iagn

osis

and

R

x K

L>0

80M

edia

n 61

.0N

R

Hya

luro

nic

acid

i.a.

10

mg/

1 m

L28

Med

ian

59.5

Hey

wor

th e

t al

200

868

RC

TG

luco

cort

icoi

ds

i.a.1

mL

Onc

e+1

i.a. p

lace

bo,

2

wee

ks22

CM

C, R

x E

-L s

tage

I–IV

9060

(9.4

)N

R

Hya

luro

nic

acid

i.a.

8 m

g/1

mL

1 p

er w

eek,

2 w

eeks

2880

65 (1

0.6)

Pla

ceb

o i.a

. (1

mL,

sal

ine)

1 p

er w

eek,

2 w

eeks

1889

64 (8

.5)

Jaha

ngiri

201

493

RC

TG

luoc

ortic

oid

i.a.

40

mg/

0.5

mL+

0.5

mL

lidoc

aine

Onc

e+2

i.a. p

lace

bo,

3

wee

ks30

CM

C, c

linic

al d

iagn

osis

and

R

x E

-L s

tage

>I

7063

.3 (1

0.1)

VAS

pai

n

Dex

tros

e i.a

. 100

mg/

0.5

mL+

0.5

mL

lidoc

aine

1 p

er w

eek,

3 w

eeks

3077

63.9

(9.4

)

Man

dl,e

t al

2012

69(A

)R

CT

Glu

coco

rtic

oid

i.a.

40

mg/

1 m

LO

nce+

1 i.a

. pla

ceb

o,2

wee

ks65

CM

C, c

linic

al d

iagn

osis

and

R

x K

L>0

6866

.5 (4

5–89

)N

R

Hya

luro

nic

acid

i.a.

8 m

g/1

mL

1 p

er w

eek,

2 w

eeks

62

Pla

ceb

o i.a

. (1

mL,

bup

ivac

aine

)1

per

wee

k, 2

wee

ks61

Mee

nagh

et

al 2

0047

0R

CT

Glu

coco

rtic

oid

i.a.

5 m

g/0.

25 m

LO

nce

20C

MC

, NR

9560

.6 (4

1–71

)VA

S p

ain

imp

rove

≥20%

Pla

ceb

o i.a

. (0.

25 m

L, s

alin

e)20

8559

.3 (4

6–69

)

Mon

fort

et

al 2

0147

5R

CT

Glu

coco

rtic

oid

i.a.

3 m

g/0.

5 m

L1

per

wee

k, 3

wee

ks40

CM

C, c

linic

al d

iagn

osis

and

R

x K

L1–3

8862

.8 (8

.7)

FIH

OA

Hya

luro

nic

acid

i.a.

5 m

g/0.

5 m

L48

Sp

olid

oro,

et a

l20

1571

RC

TG

luco

cort

icoi

d i.

a.4

mg/

0.2

mL

(DIP

) or

6 m

g/0.

3 m

L(P

IP)+

0.1

mL

lidoc

aine

Onc

e30

IP, c

linic

al d

iagn

osis

and

Rx

oste

ophy

te10

060

.7 (9

.1)

VAS

pai

n, V

AS

join

t sw

ellin

g

Pla

ceb

o i.a

. (0.

1 m

L, li

doc

aine

)30

9360

.7 (7

.3)

Sta

hl e

t al

200

576

RC

TG

luco

cort

icoi

d i.

a. 4

0 m

g/1

mL

Onc

e25

CM

C, R

x E

-L s

tage

II84

62 (5

0–91

)N

R

Hya

luro

nic

acid

i.a.

15

mg/

1 m

L27

92.5

62 (3

7–80

)

Ora

l glu

coco

rtic

oid

s

Kvi

en e

t al

200

881

RC

TP

red

niso

ne 3

mg/

day

+d

ipyr

idam

ole

200

mg/

day

6 w

eeks

42A

CR

, Rx

KL>

193

61.1

(5.0

)A

US

CA

N p

ain

Pla

ceb

o41

9359

.6 (5

.3)

Wen

ham

et

al 2

0128

2R

CT

Pre

dni

sone

5 m

g/d

ay4

wee

ks35

AC

R, R

x K

L>0

7461

.9 (6

.6)

VAS

pai

n

Pla

ceb

o35

8961

.1 (9

.0)

Tab

le 3

C

ontin

ued

Con

tinue

d


http://rmdopen.bm

j.com/

RM

D O


ctober 2018. Dow

nloaded from




Ro

BS

tud

yD

esig

nIn

terv

enti

on

Freq

uenc

y, d

urat

ion

NO

A lo

cati

on,

defi

niti

on

Wo

men

(%)

Ag

e (y

ears

)P

rim

ary

out

com

e

Hyd

roxy

chlo

roq

uine

Bas

oski

et

al 2

0158

3 (A

)R

CT

Hyd

roxy

chlo

roq

uine

400

mg/

day

24 w

eeks

98A

CR

8657

VAS

pai

n

Pla

ceb

o98

Kin

gsb

ury,

et a

l 201

684 (

A)

RC

TH

ydro

xych

loro

qui

ne 2

00–4

00 m

g/d

ay1

year

124

AC

RN

RN

RN

RS

pai

n

Pla

ceb

o12

4

McK

end

ry e

t al

200

159 (

A)

RC

TH

ydro

xych

loro

qui

ne 4

00 m

g/d

ay24

wee

ks29

Han

d, N

RN

RN

RN

R

Par

acet

amol

390

0 m

g/d

ay29

Pla

ceb

o30

TN

F in

hib

ito

rs

Aitk

en e

t al

201

746 (

A)

CO

(WA

+)

Ad

alim

umab

40

mg

sub

cuta

neou

sly

2 su

bcu

tane

ousl

y p

er

2 w

eeks

,12

wee

ks43

AC

R, e

rosi

ve (R

x er

osio

n),

MR

I syn

oviti

s77

61 (8

.4)

AU

SC

AN

pai

n

Pla

ceb

o su

bcu

tane

ousl

y

Che

valie

r et

al 2

0158

5R

CT

Ad

alim

umab

40

mg

sub

cuta

neou

sly

Onc

e 2

sub

cuta

neou

sly,

2 w

eeks

42A

CR

, Rx

dam

age

IPs

8762

.8 (6

.9)

VAS

pai

n im

pro

ve≥5

0%

Pla

ceb

o su

bcu

tane

ousl

y43

8362

.2 (7

.0)

Klo

pp

enb

urg

et a

l 201

647

86 8

7

(A)

RC

TE

tane

rcep

t 25

–50

mg

sub

cuta

neou

sly

1 su

bcu

tane

ousl

y p

er

wee

k, 1

yea

r45

IP, A

CR

, ero

sive

(Rx

eros

ion

IP)

8259

.4 (6

.5)

VAS

pai

n

Pla

ceb

o su

bcu

tane

ousl

y45

8060

.1 (8

.7)

Verb

rugg

en e

t al

201

245

RC

TA

dal

imum

ab 4

0 m

g su

bcu

tane

ousl

y1

sub

cuta

neou

sly

per

2

wee

ks,

1 ye

ar

30IP

, AC

R, e

rosi

ve (R

x er

osio

n IP

)87

61.9

(6.1

)R

x p

rogr

essi

on

Pla

ceb

o su

bcu

tane

ousl

y30

8360

.7 (6

.9)

Valu

es a

re m

ean

(SD

) or

med

ian

(min

-max

). C

olou

rs d

enot

e R

oB (g

reen

:low

, yel

low

: unc

lear

, red

: hig

h). (

A) i

ndic

ates

con

fere

nce

abst

ract

.A

CR

,Am

eric

an C

olle

ge o

f Rhe

umat

olog

y; A

US

CA

N, A

ustr

alia

n/C

anad

ian

Han

d O

steo

arth

ritis

Ind

ex; C

CT,

clin

ical

con

trol

led

tria

ls; C

MC

, firs

t ca

rpom

etac

arp

al; C

O, c

ross

-ove

r tr

ial;

FIH

OA

, Fun

ctio

nal I

ndex

for

Han

d O

steo

Art

hriti

s; i.

a., i

ntra

-ar

ticul

ar; I

P, in

terp

hala

ngea

l joi

nt; N

R, n

ot r

epor

ted

; NR

S, n

umer

ical

rat

ing

scal

e; N

SA

ID, n

on-s

tero

idal

ant

i-in

flam

mat

ory

dru

gs; O

A, o

steo

arth

ritis

; RC

T, r

and

omis

ed c

ontr

olle

d t

rial;

TNF,

tum

our

necr

osis

fact

or; V

AS

, vis

ual a

nalo

gue

scal

e; W

A,

was

h-ou

t p

erio

d; W

OM

AC

, Wes

tern

Ont

ario

and

McM

aste

r U

nive

rsiti

es O

steo

arth

ritis

Ind

ex.

Tab

le 3

C

ontin

ued


http://rmdopen.bm

j.com/

RM

D O


ctober 2018. Dow

nloaded from




Tab

le 4

E

ffica

cy o

f mai

n p

harm

acol

ogic

al in

terv

entio

ns fo

r ha

nd o

steo

arth

ritis

from

ran

dom

ised

con

trol

led

tria

ls/c

linic

al c

ontr

olle

d t

rials

Inte

rven

tio

nC

ont

rol

Out

com

eP

arti

cip

ants

(s

tud

ies)

, nD

urat

ion

Sp

ecifi

c O

A

loca

tio

n o

r ty

pe

Qua

lity

of

evid

ence

Eff

ect

esti

mat

e (9

5%C

I)R

efer

ence

s; c

om

men

ts

Top

ical

NS

AID

s

Top

ical

NS

AID

To

pic

al

pla

ceb

o P

ain

385

(1)

8 w

eeks

–R

oB: l

owM

D −

5.9

(−11

.7 t

o −

0.06

) on

100

mm

VA

S*

52

Func

tion

385

(1)

8 w

eeks

–R

oB: l

owM

D −

7.3

(−12

.9 t

o −

1.7)

on

AU

SC

AN

func

tion

scal

e (r

ange

0–3

6)*

52

OA

RS

I-O

ME

RA

CT

resp

onse

385

(1)

8 w

eeks

–R

oB: l

owR

R 1

.2 (0

.99

to 1

.4)*

52

Top

ical

NS

AID

O

ral N

SA

ID

Pai

n38

1 (2

)3

wee

ks'A

ctiv

ated

' IP

O

AR

oB: l

owS

MD

−0.

05 (−

0.27

to

0.17

)*50

51;

effe

ct e

stim

ate

bas

ed

on o

ne t

rial (

n=32

1)51

; sam

e st

udie

s as

pre

viou

s S

LR1

Grip

str

engt

h38

1 (2

)3

wee

ks'A

ctiv

ated

' IP

O

AR

oB: l

owM

D −

0.01

(−0.

03 t

o 0.

01)

bar

*50

51;

effe

ct e

stim

ate

bas

ed o

n on

e tr

ial (

n=32

1)51

Ora

l NS

AID

s

Ora

l NS

AID

P

lace

bo

Pai

n69

5 (3

)2–

4 w

eeks

–R

oB: l

owS

MD

0.4

0 (0

.20

to 0

.60)

*62

–64;

effe

ct e

stim

ate

bas

ed

on t

wo

tria

ls w

ith ib

upro

fen

800

mg

and

lum

iraco

xib

200

–400

m

g (n

=65

4)62

63;

sam

e st

udie

s as

pre

viou

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a-ar

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a-ar

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pla

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CR

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rial (

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o 0.

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5 86

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stim

ate

bas

ed

on t

wo

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85

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0 (2

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to

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6; e

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ased

on

one

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60)4

5

Qua

lity

of

evid

ence

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RA

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: ver

y lo

w/lo

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AD

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mod

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: low

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ct

estim

ate:

No

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etw

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p d

iffer

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favo

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f the

inte

rven

tion

grou

p. †

In fa

vour

of t

he c

ontr

ol g

roup

.A

US

CA

N, A

ustr

alia

n/C

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ian

hand

ost

eoar

thrit

is in

dex

; CM

C, fi

rst

carp

omet

acar

pal

join

t; D

AS

H, D

isab

ilitie

s of

the

Arm

, Sho

uld

er a

nd H

and

; DIP

, dis

tal i

nter

pha

lang

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oint

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em, s

ame

as

abov

e; IP

, int

erp

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ngea

l joi

nt; M

D, m

ean

diff

eren

ce; N

SA

ID, n

on-s

tero

idal

ant

i-in

flam

mat

ory

dru

g; O

A, o

steo

arth

ritis

; RoB

, ris

k of

bia

s; R

R, r

isk

ratio

; SLR

, sys

tem

atic

lite

ratu

re r

evie

w; S

MD

, st

and

ard

ised

mea

n d

iffer

ence

; TN

F, t

umou

r ne

cros

is fa

ctor

; VA

S, v

isua

l ana

logu

e sc

ale.

Tab

le 4

C

ontin

ued


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non-pharmacological treatment reported superiority of the comparator.39 55 Topical capsaicin was assessed in one RCT (unclear RoB), reporting better pain relief than placebo at the cost of increased risk of local AEs (burning and stinging sensation, RR 3.1 (95% CI 1.1 to 8.5)), which likely also compromised the trial’s success of blinding.56 A single application of topical salicylates was reported in two trials (high RoB) to lead to improvements in pain and stiffness, but also numerically more local AEs.57 58

Oral analgesicsParacetamol was included as a treatment arm in three conference abstracts (unclear RoB) and one cross-over trial (high RoB), in various dosages and for different duration.48 59–61 Three trials intended paracetamol to be the control group. One trial (unclear RoB) included a placebo arm, and reports no between-group difference in pain or morning stiffness.59 Paracetamol was not supe-rior to any of the active comparators.48 60 61

Oral NSAIDs lead to moderate improvements in pain and function compared with no intervention,49 placebo62–64 and other active interventions (glucos-amine/chondroitin sulfate,65 paracetamol48).

NutraceuticalsThe effectiveness of chondroitin sulfate was studied in two papers. One trial (low RoB) focused on clinical outcomes after 6 months, reporting beneficial effects on pain and function compared with placebo.66 The other study (high RoB) assessed structural outcomes in two long-term trials (published in one paper), assessing chondroitin sulfate and chondroitin polysulphate.44 Only for chondroitin polysulphate, a preparation not commercially available, less erosive damage after 3 years was reported and not for chondroitin sulfate. The trials did not report higher risk of sAEs in the intervention groups.

Glucosamine is reported to have beneficial effects on pain and function after 6 weeks in an RCT (unclear RoB) published as conference abstract (no raw data provided).61

Diacerhein was not better than placebo for pain relief or any of the other secondary outcomes in a study (unclear RoB) of Korean patients with hand OA, while more (mild) AEs were reported in the intervention group, especially discoloration of urine (88% vs 20%) and abdominal pain (31% vs 14%), but remarkably not diarrhoea (21% vs 20%).67

intra-articular treatmentsSeveral intra-articular therapies were assessed, of which glucocorticoids and hyaluronic acid are the most commonly used. Intra-articular injection of glucocorti-coids in the thumb base was not more beneficial than placebo with respect to pain and function (online supple-mentary figures S12-13),68–70 while in one study (low RoB) participants reported less pain during movement and soft swelling after intra-articular glucocorticoid injec-tion in IP joints.71 However, the latter study did not find beneficial effects on pain in rest or function.

Intra-articular injection of hyaluronic acid in the thumb base did not lead to improvements in pain or function compared with placebo (online supplementary figure S14).68 69 72 Six trials (four high RoB, two unclear RoB) compared intra-articular thumb base injection of glucocorticoids to hyaluronic acid, but no consistent beneficial effect of one treatment over the other could be shown.68 69 73–76 Single studies (two high RoB, two unclear RoB) assessed alternative dosages (ie, one, two or three hyaluronic acid injections,77 low vs high molecular weight hyaluronic acid78) and therapies (ie, intra-articular inflix-imab,79 dextrose80) and are not described in depth.

Glucocorticoids and conventional or biological DMARDsShort-term treatment with low-dose oral glucocorti-coids were evaluated in two RCTs (low RoB). Six-week treatment with prednisolone/dipyridamole led to more improvement in pain (MD 12.3 (95% CI 3.0 to 21.5) on 100 mm VAS), at the cost of more withdrawals due to AEs (38% vs 15%), mostly due to headache.81 In a tri

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